GTG From 2010 To 2015

GREEN TOP
GUIDELINES
(GTG)
20102015
Tocolysis for Women in

Preterm Labour
Greentop Guideline No. 1b
February 2011
Tocolysis for Women in Preterm Labour

This is the second edition of this guideline, which was first published in October 2002 under the
same title.
1.
Background
Preterm birth, defined as birth at less than 37+0 weeks of gestation, is the most important single determinant
of adverse infant outcome in terms of both survival and quality of life.1 In the UK, infant mortality among
preterm births was 42/1000 live births in 2005, compared with 5/1000 live births overall.2 For very preterm
births (at less than 32+0 weeks of gestation), mortality in the first year was 144/1000 live births, compared
with 1.8/1000 live births for babies born at term (38+0 to 41+6 weeks).2 Very preterm birth accounts for
1.4% of UK births but 51% of infant deaths. Although birth at 32+0 to 37+0 weeks of gestation is associated
with less risk than very preterm birth, there is growing recognition that even this moderately preterm
birth is associated with increased risk of infant death.2,3 Risk of death or neurosensory disability increases
with decreasing gestational age.1 Preterm birth may have huge psychosocial and emotional effects on the
family, as well as being costly for health services.
Prevention and treatment of preterm birth is important, not as an end in itself but as a means of improving
outcome for the child. Cervical cerclage is one strategy for prevention of preterm birth and this topic is
covered in a separate Green-top Guideline.4 For many women in preterm labour, it may not be appropriate
to consider attempting tocolysis. Labour may be too advanced, for example, or prolonging the pregnancy
may be hazardous for the woman or her baby because of intrauterine infection or placental abruption.As
it is the woman who receives the intervention, there is also a responsibility to ensure that she is not harmed
by any treatment.
A wide variety of agents have been advocated as suppressing uterine contractions. Those in current use
include beta-agonists, calcium channel blockers, oxytocin receptor antagonists, prostaglandin synthetase
inhibitors, nitric oxide donors and magnesium sulphate. There is little reliable information about current
clinical practice but it is likely that use of the beta-agonist ritodrine hydrochloride, which was widespread
in the past, has declined. Magnesium sulphate is popular for tocolysis in the USA and some other parts of
the world but has rarely been used for this indication in the UK.
2.
Purpose and scope
This guideline summarises evidence about the effectiveness and safety of tocolytic drugs for treatment of
preterm labour and provides guidance on incorporating this evidence into clinical practice.
Tocolysis has been advocated for the management of intrapartum fetal distress and impaired fetal growth
and to facilitate external cephalic version at term. These uses will not be considered further here. Also
outside the scope of this guideline are interventions aimed at preventing the onset of preterm labour, for
women at risk of preterm birth, and interventions to improve outcome for children at risk of being born
preterm, such as use of antenatal corticosteroids and of magnesium sulphate for neuroprotection.
3.
Identification and assessment of evidence
This RCOG guideline was developed in accordance with the standard methodology for producing RCOG
Green-top Guidelines. The Cochrane library (including the Database of Systematic Reviews and the
Cochrane Control Register of Controlled Trials), the Database of Abstracts of Reviews and Effects, Embase,
ACP Journal Club and Medline, including in-process and other non-indexed citations, were searched from
RCOG Green-top Guideline No. 1b
2 of 13
Royal College of Obstetricians and Gynaecologists
2000 to September 2010 to identify all relevant randomised controlled trials (RCTs), systematic reviews
and meta-analyses published since the previous edition of the guideline. The databases were searched
using the relevant MeSH terms including all sub-headings. Search terms included were:preterm labour,
preterm birth,tocolysis,tocolytic,beta-agonist,calcium channel blocker,magnesium sulphate,nitric
oxide donor, oxytocin receptor antagonist, prostaglandin synthetase inhibitor, magnesium sulphate
and uterine contraction + suppression.The search was limited to humans and the English language.The
National Library for Health and the National Guidelines Clearing House were also searched for relevant
guidelines and reviews.
4.
Uses of tocolysis for women in preterm labour.
4.1 Does tocolysis prevent preterm birth?

Use of a tocolytic drug is associated with a prolongation of pregnancy for up to 7 days but with no
significant effect on preterm birth and no clear effect on perinatal or neonatal morbidity.
There is no clear evidence that tocolytic drugs improve outcome and therefore it is reasonable not to use
them. However, tocolysis should be considered if the few days gained would be put to good use, such as
completing a course of corticosteroids or in utero transfer.
A systematic review identified 17 trials (2800 women) comparing tocolysis with no treatment
or placebo.5 Many trials included maintenance treatment if and after contractions stopped. Some
trials excluded women with ruptured membranes but they were included in others. The most
frequently evaluated agent was ritodrine. Ritodrine has predominantly beta 2-receptor effects,
relaxing muscles in the uterus, arterioles and bronchi. Other tocolytic drugs evaluated in these
trials included isoxuprine, terbutaline, magnesium sulphate, indomethacin and atosiban. Overall,
tocolytics were associated with a reduction in the odds of birth within 24 hours (odds ratio
[OR] 0.47; 95% confidence interval [CI] 0.290.77), 48 hours (OR 0.57; 95% CI 0.380.83) and
7 days (OR 0.60; 95% CI 0.380.95). For the beta-agonists indomethacin and atosiban these
effects were statistically significant, but not for magnesium sulphate. However, use of any
tocolytic drug was not associated with a statistically significant reduction in births before 30
weeks of gestation (OR 1.33; 95% CI 0.533.33), before 32 weeks of gestation (OR 0.81; 95% CI
0.611.07) or before 37 weeks of gestation (OR 0.17; 95% CI 0.021.62).
Evidence
level 1+
Since this review, three further placebo-controlled trials have been reported. The largest
compared atosiban with placebo (531 women).6 Data from this study are consistent with the
results of the systematic review above as, although time to delivery was not reported for all
women (it was reported only for the subset of women who did not have an alternative tocolytic
drug), there was no clear effect on birth before 37 weeks of gestation (relative risk [RR] 1.17;
95% CI 0.991.37) or before 28 weeks of gestation (RR 2.25; 95% CI 0.806.35).6,7 The second
study recruited 158 women and compared glyceryl trinitrate skin patches with placebo
patches.8 There was no clear difference in birth within 48 hours (RR 0.92, 95% CI 0.531.58)
or before 37 weeks of gestation (RR 1.01; 95% CI 0.731.40).The third study compared glyceryl
trinitrate with placebo (33 women) but was too small for any firm conclusions about the
possible benefits or hazards of glyceryl trinitrate to be drawn.9
Evidence
level 1+
A more recent review included ten trials (904 women) comparing tocolysis with placebo.10
This review restricted inclusion to studies in which the mean gestation at randomisation was
between 28 weeks and 32 weeks of gestation but the methodology used did not allow
calculation of an overall event rate. Nevertheless, it was concluded that use of a tocolytic drug,
rather than placebo or no tocolytic drug, increased delay to delivery at 48 hours and at 7 days.
Evidence
level 1+
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Taken together, these studies show that tocolytic drugs reduce the proportion of births occurring up to 7
days after beginning treatment. Most women in these studies had singleton pregnancies.
4.2 Does the use of any tocolytic drug prevent perinatal or neonatal death and neonatal morbidity?
Use of a tocolytic drug is not associated with a clear reduction in perinatal or neonatal mortality, or
neonatal morbidity.
Tocolysis was not associated with a clear reduction in perinatal mortality (OR 1.22; 95%
CI 0.84 1.78) nor in neonatal morbidity was it related to being born too early, such as
respiratory distress syndrome (OR 0.82; 95% CI 0.641.07) or intraventricular haemorrhage (OR
0.73; 95% CI 0.461.15).5
Evidence
level 1+
Of the three studies published after this review, in the trial comparing atosiban with placebo
there was no clear difference between the groups in perinatal mortality (RR 2.25; 95% CI 0.79
6.40).6 Follow-up to 1 year was subsequently reported and, although the confidence remained
wide, this showed an increase in deaths in the first year of life associated with atosiban rather
than placebo (RR 6.15; 95% CI 1.3927.22).7 Possible explanations for this increase are an
imbalance in allocation with more women at very early gestation (under 26 weeks) allocated
to atosiban or fetal vasopressin receptor blockade by atosiban, which could lead to changes in
amniotic fluid volume, with resultant alterations to fetal renal development and fetal lung
development.7 Although atosiban is licensed in the UK for the treatment of threatened preterm
labour, there are insufficient data on long-term outcome for children exposed to atosiban in
utero.
Evidence
level 1+
The trial comparing glycerol trinitrate patches with placebo reported few perinatal deaths (0/74
with glycerol trinitrate compared with 3/79 with placebo).The primary outcome in this study
was a composite outcome (occurrence of one or more of chronic lung disease, necrotising
enterocolitis, significant intraventricular haemorrhage, periventricular leucomalacia or perinatal
death). There was a reduction in this outcome associated with glycerol trinitrate which was
borderline for statistical significance (RR 0.29; 95% CI 0.091.00).
Evidence
level 1+
Although tocolytic drugs reduce the proportion of births occurring within 7 days, this is not reflected in
clear evidence for any overall effect on perinatal mortality or serious neonatal morbidity; moderate
increases or decreases in these outcomes remain possible.The increase in mortality at age 1 year associated
with use of atosiban rather than placebo is also a concern.To demonstrate reliably small to moderate shortterm effects requires large randomised trials, with follow-up of the children for several years to assess the
potential effects on subsequent mortality and neurodevelopment. Follow-up data are not available for
other tocolytic drugs.
There are four plausible explanations for the lack of a major effect of tocolytic drugs on substantive
perinatal outcomes. First, the trials may have included too many women who were so advanced in gestation
that any further prolongation of pregnancy would have little potential to benefit the baby. Second, the
trials may have included too many women who were not genuinely in preterm labour or at risk of preterm
birth. Third, the time gained by tocolytic treatment may not have been used to implement potentially
beneficial measures, such as corticosteroids or transfer to a unit with better neonatal health services.
Fourth, there may be direct or indirect adverse effects of tocolytic drugs (including prolongation of
pregnancy when this is detrimental to the baby), which counteract their potential gain.
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5.
When should tocolytic drugs be used?
Tocolysis may be considered for women with suspected preterm labour who have had an otherwise
uncomplicated pregnancy. It is reasonable not to use any tocolytic drug. B
Women most likely to benefit from use of a tocolytic drug are those who are in very preterm labour, those
needing transfer to a hospital which can provide neonatal intensive care and those who have not yet
completed a full course of corticosteroids.
Tocolysis should not be used where there is a contraindication to prolonging pregnancy.
In the absence of clear evidence that tocolytic drugs improve outcome following preterm labour,
it is reasonable not to use them.11 The women most likely to benefit from use of a tocolytic drug
are those who are in very preterm labour, those needing transfer to a hospital that can provide
neonatal intensive care and those who have not yet completed a full course of corticosteroids.
For these women, tocolytic drugs should be considered, provided that there is no contraindication to prolonging the pregnancy.
Evidence
level 1+
Tocolysis may be considered for women with suspected preterm labour who have had an otherwise
uncomplicated pregnancy.Any contraindication to prolonging pregnancy is a contraindication to tocolytic
therapy; for example,known lethal congenital or chromosomal malformation, intrauterine infection, severe
pre-eclampsia, placental abruption, advanced cervical dilatation and evidence of fetal compromise or
placental insufficiency. Relative contraindications include mild haemorrhage due to placenta praevia, nonreassuring cardiotocograph, fetal growth restriction and multiple pregnancy.
In view of the current lack of evidence for any substantive short-term benefit to the baby from tocolysis,
the possibility of hazard for the mother and the lack of reliable information about long-term outcome, the
available evidence should be discussed with the woman and her partner and their preferences taken into
account in determining her care.A senior obstetrician should be involved in the decision to offer tocolysis.
6. Is one tocolytic drug more effective in preventing preterm birth than another?
Nifedipine and atosiban have comparable effectiveness in delaying birth for up to seven days.
Compared with beta-agonists, nifedipine is associated with improvement in neonatal outcome, although
there are no long-term data.
Ritodrine and atosiban are licensed in the UK for the treatment of threatened preterm labour.Although the
use of nifedipine for preterm labour is an unlicensed indication,12 it has the advantages of oral administration and a low purchase price.
The comparative effects of alternative tocolytic drugs have been evaluated in a range of trials.
Beta-agonists reduce the risk of giving birth within 48 hours (11 trials, 1320 women; RR 0.63;
95% CI 0.530.75) compared with placebo,13 but there is no clear evidence that they are any
more effective at preventing preterm birth than other tocolytic drugs.14,15
Evidence
level 1+
A Cochrane review comparing calcium channel blockers with other tocolytic drugs included
12 trials with 1029 women.14 In ten of these trials, oral nifedipine was the calcium channel
blocker and in eight the comparator was intravenous ritodrine. The use of calcium channel
blockers, rather than other tocolytic drugs, was associated with a reduction in the number of
women giving birth within 7 days of receiving treatment (RR 0.76; 95% CI 0.600.97) and before
34 weeks of gestation (RR 0.83; 95% CI 0.690.99) compared with other tocolytic drugs.
Evidence
level 1+
5 of 13
The oxytocin receptor agonist atosiban has been compared with beta-agonists in four trials
with 1044 women.7 There was no clear difference between the groups either in birth within 48
hours (RR 0.98; 95% CI 0.681.41) or birth within 7 days (RR0.91; 95% CI 0.691.20). Atosiban
has not been compared with calcium channel blockers in randomised trials.A systematic review
using adjusted indirect comparison between nifedipine and atosiban concluded that nifedipine
was associated with a non-significant trend towards increased delay in delivery by 48 hours.16
Evidence
level 1+
Cyclo-oxygenase (COX) enzymes contribute to production of prostaglandins, which are

important in the onset and maintenance of labour. It has been hypothesised that inhibitors of
the inducible COX-2 enzyme might be effective tocolytics with fewer fetal side effects.
Indomethacin is the COX inhibitor most commonly used for tocolysis. The Cochrane review
identified eight trials with 557 women comparing COX inhibitors with other tocolytic drugs
(beta-agonists or magnesium sulphate).17 COX inhibition reduced birth before 37 weeks of
gestation (3 trials, 168 women; RR 0.53; 95% CI 0.310.94). Short-term use of NSAIDs in the
third trimester of pregnancy is associated with a significant increase in the risk of premature
ductal closure.18 There have been two RCTs comparing COX-2 inhibitors with magnesium
sulphate for acute tocolysis,19,20 each of which showed no difference between oral COX-2
inhibitor and intravenous magnesium sulphate in delaying preterm labour. However, there is a
lack of evidence that magnesium sulphate itself reduces the risk of preterm birth. The COX-2
inhibitor rofecoxib has been compared with placebo for prophylaxis in one RCT,21 which
showed that it has a significant but reversible effect on fetal renal function and the ductus
arteriosus but does not decrease the risk of preterm labour before 32 weeks of gestation and
increases the risk after treatment is withdrawn at 32 weeks of gestation. There is therefore no
good evidence that COX-2 inhibitors reduce the risk of preterm birth.
Evidence
level 1+
The nitric oxide donor nitroglycerine has been compared with ritodrine, albuterol and
magnesium sulphate.22 Although there was a reduction in births before 37 weeks of gestation
(three trials, 391 women; OR 0.53; 95% CI 0.350.81), there was no clear impact on birth before
3234 weeks of gestation.
Evidence
level 1+
Magnesium sulphate for prevention of preterm birth has been evaluated in 23 trials with 2036
women.15 There is no clear evidence that magnesium sulphate reduces the risk of preterm birth.
However, administration of magnesium sulphate to women considered at risk of preterm birth
reduces the risk of cerebral palsy (RR 0.68; 95% CI 0.540.87; five trials; 6145 infants).23 If a
woman is at risk of preterm birth, she should receive magnesium sulphate for 24 hours to reduce
the risk of cerebral palsy.
Evidence
level 1+
7.
What are the comparative adverse effects for the woman of alternative tocolytic drugs for
preterm labour?
Beta-agonists have a high frequency of adverse effects. Nifedipine, atosiban and the COX inhibitors have
fewer types of adverse effects, and they occur less frequently than for beta-agonists but how they compare
with each other is unclear.
Using multiple tocolytic drugs appears to be associated with a higher risk of adverse effects and so should
be avoided.
Once a decision is made to use a tocolytic drug, the best choice of drug would be the most effective with
the fewest adverse effects, both immediate and long-term. Ritodrine was widely used in the past in the UK
and is still in common use in some parts of the world. It has been the most thoroughly evaluated in trials
but, like all beta-agonists, it has a high frequency of unpleasant and sometimes severe or potentially lifethreatening adverse effects for the woman.13,24 In recent years there has therefore been considerable
interest in identifying a safer alternative.
6 of 13
Common adverse effects when beta-agonists are compared with placebo include palpitations
(38% for beta-agonists compared with 4% for placebo), tremor (39% compared with 4%), nausea
or vomiting (21% compared with 12%), headache (19% compared with 5%), chest pain (10%
compared with 1%) and dyspnoea (14% compared with 3%).13 Women allocated beta-agonists
were far more likely to stop treatment because of adverse effects than those allocated placebo
(five trials, 1081 women; RR 11.38; 95% CI 5.2124.86).13 Rare but serious and potentially lifethreatening adverse effects have been reported following beta-agonist use and there are case
reports of a small number of maternal deaths associated with use of these drugs. Pulmonary
oedema is a well-documented complication, usually associated with aggressive intravenous
hydration. A systematic review reported one case of pulmonary oedema among 852 women
(1/425 beta-agonists compared with 0/427 placebo).13
Evidence
level 1+
Fewer types of adverse effects are reported for the other tocolytic drugs and they occur less
frequently. No trials have compared calcium channel blockers with placebo for treatment of
preterm labour.14 When compared with other tocolytic drugs (ritodrine in most of the trials),
calcium channel blockers are associated with fewer adverse effects (RR 0.32; 95% CI 0.240.41)
and less need to stop treatment because of adverse effects (RR 0.14; 95% CI 0.050.36).14
Reported adverse effects for nifedipine, the most widely used calcium antagonist, include
flushing, palpitations, nausea and vomiting and hypotension.25,26 Nifedipine is contraindicated
if the woman has cardiac disease and should be used with caution if she has diabetes or multiple
pregnancy, owing to the risk of pulmonary oedema.12
Evidence
level 1+
With atosiban, reported adverse effects are nausea (11% for atosiban compared with 5% for
placebo), vomiting (3% compared with 4%), headache (5% compared with 7%), chest pain (1%
compared with 4%) and dyspnoea (0.4% compared with 3%).5 Only nausea was statistically
significantly increased (OR 2.28, 95% CI 1.264.13).5 Women allocated atosiban were also more
likely to stop treatment because of adverse effects than those allocated placebo (two trials, 613
women; RR 4.02; 95% CI 2.057.85).7 A common reason for stopping treatment was injectionsite reactions.6 Compared with beta-agonists, however, fewer women allocated atosiban stop
treatment because of adverse effects (RR 0.04; 95% CI 0.020.11; number needed to treat 6;
95% CI 57). Atosiban has not been compared with calcium antagonists in randomised trials.
Diabetes and cardiac disease are not contraindications to atosiban.
Evidence
level 1+
COX inhibitors are well tolerated by the women and, when compared with placebo, there is no
clear effect on the need to discontinue treatment (three trials, 101 women; RR 1.58; 95% CI
0.663.78).17 When compared with other tocolytic drugs, COX inhibitors were associated with
fewer women needing to stop treatment because of adverse effects (five trials, 355 women; RR
0.07; 95% CI 0.020.29).17
Evidence
level 1+
Adverse effects (other than headache) were reduced in women who received the nitroglycerine, a nitric
oxide donor, rather than ritodrine, albuterol or magnesium sulphate but headache was increased.22
Magnesium sulphate is associated with adverse effects for the woman but, as it is ineffective in delaying
preterm birth, it should not be used.15
Using more than one type of tocolytic in combination with another appears to increase the risk
of adverse effects and so should be avoided.24
7 of 13
Evidence
level 2++
8.
What are the comparative effects for the baby of alternative tocolytic drugs for preterm
labour?
The comparative effects for the baby of alternative drugs are unclear. Most drugs have been compared
with beta-agonists. There are insufficient data on long-term follow-up for reliable conclusions about the
effects on the baby for any of these tocolytic drugs.
Calcium channel blockers were associated with less neonatal respiratory distress syndrome
(RR 0.63; 95% CI 0.460.88), less necrotising enterocolitis (RR 0.21; 95% CI 0.050.96) and less
intraventricular haemorrhage (RR 0.59; 95% CI 0.360.98) than other tocolytic drugs.14 There
was no clear difference between the treatment groups either in stillbirths (RR 3.00; 95%
CI 0.1371.07) or in neonatal deaths (RR 1.40; 95% CI 0.633.12).14
Evidence
level 1+
Nifedipine, the most commonly used calcium channel blocker, crosses the placenta,but whether
it has any long-term effect on the child is uncertain. Animal studies with very high doses have
reported abnormalities of fetal and placental blood flow and abnormal digital development.14
No specific congenital defects have been associated with its use in humans.
Evidence
level 2+
The oxytocin receptor agonist atosiban has been compared with beta-agonists in four trials
with 1044 women.7 There was no clear difference between the groups in neonatal deaths (RR
0.70; 95% CI 0.271.81) or neonatal morbidity. The only difference was that atosiban was
associated with an increase in birth weight under 1500 g (RR 1.96; 95% CI 1.153.35).7 Oxytocin
receptor agonists have not been compared with calcium channel blockers in randomised trials.
A systematic review using adjusted indirect comparison between nifedipine and atosiban
concluded that nifedipine was associated with a reduction in respiratory distress syndrome but
there were insufficient data for reliable conclusions about other measures of morbidity and
mortality.16
Evidence
level 1
COX inhibitors cross the placenta and potential adverse effects for the baby include premature closure of
the ductus arteriosus with consequent pulmonary hypertension, persistent patent ductus arteriosus,
necrotising enterocolitis and intraventricular haemorrhage. The trials conducted to date are too small to
provide reliable information about the potential effects on the baby.17,27
Magnesium sulphate for prevention of preterm birth has been evaluated in 23 trials with 2036
women.15 In these trials, exposure to magnesium sulphate was associated with an increased
risk of fetal, neonatal or infant death (seven trials, 727 infants; RR 2.82; 95% CI 1.206.62).
9.
Evidence
level 1+
What are the recommended dose regimens for nifedipine and atosiban?
The suggested dose of nifedipine is an initial oral dose of 20 mg followed by 1020 mg three to four times
daily, adjusted according to uterine activity for up to 48 hours. A total dose above 60 mg appears to be
associated with a three- to four-fold increase in adverse events.
A suggested dose of atosiban of an initial bolus dose of 6.75 mg over 1 minute, followed by an infusion of
18 mg/hour for 3 hours, then 6 mg/hour for up to 45 hours (to a maximum of 330 mg).
There is no clear consensus on the ideal dose regimen for nifedipine when used for tocolysis. A sensible
recommendation is for an initial oral dose of 20 mg followed by 1020 mg three to four times daily adjusted
according to uterine activity.12 Total dose above 60 mg appears to be associated with a three- to four-fold
increase in adverse events such as headache and hypotension.26
8 of 13
For atosiban, the recommended regimen is a three-step procedure: an initial bolus dose of 6.75 mg over 1
minute, followed by an infusion of 18 mg/hour for 3 hours, then 6 mg/hour for up to 45 hours (to a
maximum of 330 mg).12 For both, duration of treatment is 48 hours.
10. What is the cost effectiveness of tocolysis for preterm labour?

Cost effectiveness has not been reported but the purchase price of atosiban is nearly ten times that of nifedipine.
The purchase price of atosiban is substantially higher than nifedipine or other tocolytic agents such as COX
inhibitors and beta-agonists. The purchase price of the drug for a standard 48 hours of treatment with
atosiban is 494,12 compared with 1 for nifedipine12 and 50 for ritodrine.18 Cost effectiveness analysis
has not been reported but this should also take into account the cost of administering each drug and any
benefits or adverse effects.
A cost decision analysis in the USA comparing terbutaline, magnesium sulphate, indomethacin and
nifedipine concluded that indomethacin and nifedipine were the least expensive options.28 A similar
analysis in Germany compared atosiban with beta-agonists and concluded atosiban was the cheaper
option.29 The relevant comparison for the UK would be of atosiban with nifedipine.
11.
Should tocolysis by used in multiple pregnancy?
There is insufficient evidence for any firm conclusions about whether or not tocolysis leads to any benefit
in preterm labour in multiple pregnancy.
There is no specific evidence for a beneficial role for tocolytic drugs in preterm labour in multiple
pregnancy, although both nifedipine and atosiban have been widely used in this context. A series of case
reports has suggested an association between nifedipine use in multiple pregnancy and pulmonary
oedema,30 suggesting that atosiban may be preferable to nifedipine in this context, although this association
was not confirmed in a prospective cohort study.24
12. Is maintenance tocolytic therapy worthwhile?

There is insufficient evidence for any firm conclusions about whether or not maintenance tocolytic therapy
following threatened preterm labour is worthwhile. Thus, maintenance therapy is not recommended.
A systematic review of any maintenance tocolytic therapy compared with placebo or no

treatment after threatened preterm labour found no clear evidence of an effect on preterm
birth or its consequences (12 trials, 1590 women).31 A Cochrane review of oral beta-agonists for
maintenance therapy following threatened preterm labour compared with placebo or no
treatment identified eight trials with 994 women.32 There was no clear difference in preterm
birth (before 37 weeks of gestation) (four trials, 384 women; RR 1.08; 95% CI 0.881.32), nor in
any other measure of perinatal morbidity or mortality. One trial with 513 women has compared
maintenance therapy with oxytocin receptor antagonists (in this trial subcutaneous atosiban)
with placebo (513 women).33 There was no clear difference between the groups in preterm
birth (RR 0.89; 95% CI 0.711.12) or in any other substantive outcome. Only one trial with 74
women has evaluated calcium channel blockers for maintenance therapy, which provides
insufficient evidence for any reliable conclusions.34 Similarly, the one trial (100 women)
evaluating magnesium sulphate for maintenance therapy is too small for any reliable
conclusions.35
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Evidence
level 1+
13. Summary
Use of a tocolytic drug is not associated with a clear reduction in perinatal or neonatal mortality or neonatal
morbidity. The main effect of tocolytic drugs when used for women in preterm labour is to reduce the
numbers who deliver within 48 hours or within 7 days of commencing the drug. Data on long-term
outcome are sparse. It remains plausible that, for selected women, such as those who require transfer for
neonatal care or time to complete a course of corticosteroids, there may be benefit associated with
tocolysis. However, this benefit has not been formally evaluated in randomised trials.
If reliable prediction of which women in suspected preterm labour are likely to have a preterm birth were
possible, the use of tocolysis could be reserved for these women. Unfortunately, few tests offer useful
predictive value.36 Fetal fibronectin has been advocated as a promising predictive test36 but it may have
limited accuracy in predicting preterm birth within 7 days for women with symptoms of preterm labour.37
Ultrasound assessment of cervical length is also a promising predictive test for symptomatic women.36 It
remains unclear whether any predictive test, or combination of tests, is sufficiently accurate to be cost
effective.36,38
If the decision is made to use a tocolytic drug, nifedipine and atosiban appear to have comparable
effectiveness in delaying delivery, with fewer maternal adverse effects and less risk of rare serious adverse
events than alternatives such as ritodrine or indomethacin.There is limited evidence that use of nifedipine,
rather than a beta-agonist, is associated with improved short-term neonatal outcome. There is little
information about the long-term growth and development of the child for any of the drugs.
Ritodrine and atosiban are licensed in the UK for the treatment of threatened preterm labour.Although the
use of nifedipine for preterm labour is an unlicensed indication,12 it has the advantages of oral administration and a low purchase price.
The available evidence should be discussed with the woman and her partner and their preferences taken
into account in determining her care.
14. Auditable standards
Number of women who received a tocolytic drug for suspected preterm birth.
Documented involvement of a consultant obstetrician in the decision to commence a tocolytic drug.
Choice and duration of tocolytic drug.
Proportion of women on local first-line tocolytic drug and on multiple drugs.
Number of women receiving a course of antenatal corticosteroids births before 34 weeks of
gestation.
Proportion of women and babies with adverse effects associated with tocolytic drugs.
Number of babies born without exposure to antenatal corticosteroids.
Use of a guideline on tocolysis.
10 of 13
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infant mortality. JAMA 2000;284:8439.
Royal College of Obstetricians and Gynaecologists. Cervical
Cerclage. Green-top Guideline No. 60. London: RCOG; 2011.
Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A.Tocolytics for
preterm labor: a systematic review. Obstet Gynecol
1999;94:86977.
Romero R, Sibai BM, Sanchez-Ramos L, Valenzuela GJ, Veille
JC,Tabor B, et al. An oxytocin receptor antagonist (atosiban)
in the treatment of preterm labor: a randomized, doubleblind, placebo-controlled trial with tocolytic rescue. Am J
Obstet Gynecol 2000;182:117383.
Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor
antagonists for inhibiting preterm labour. Cochrane
Database Syst Rev 2005;(3): CD004452.
Smith GN, Walker MC, Ohlsson A, OBrien K, Windrim R.
Randomized double-blind placebo-controlled trial of
transdermal nitroglycerin for preterm labor. Am J Obstet
Gynecol 2007;196:37.e18.
Smith GN, Walker MC, McGrath MJ. Randomised, doubleblind, placebo controlled pilot study assessing nitroglycerin
as a tocolytic. Br J Obstet Gynaecol 1999;106:7369.
Haas DM, Imperiale TF, Kirkpatrick PR, Klein RW, Zollinger
TW, Golichowski AM.Tocolytic therapy: a meta-analysis and
decision analysis. Obstet Gynecol 2009;113:58594.
Hannah ME. Search for best tocolytic for preterm labour.
Lancet 2000;356:699700.
British National Formulary [http://bnf.org].
Anotayanonth S, Subhedar NV, Neilson JP, Harigopal S.
Betamimetics for inhibiting preterm labour. Cochrane
Database Syst Rev 2004;(4):CD004352.
King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B.
Calcium channel blockers for inhibiting preterm labour.
Cochrane Database Syst Rev 2003;(1):CD002255.
Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for
preventing preterm birth in threatened preterm labour.
Coomarasamy A, Knox EM, Gee H, Song F, Khan KS.
Effectiveness of nifedipine versus atosiban for tocolysis in
preterm labour: a meta-analysis with an indirect comparison
of randomised trials. BJOG 2003;110:10459.
King J, Flenady V, Cole S,Thornton S. Cyclo-oxygenase (COX)
inhibitors for treating preterm labour. Cochrane Database
Syst Rev 2005;(2):CD001992.
Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME.
Nonsteroidal antiinflammatory drugs during third trimester
and the risk of premature closure of the ductus arteriosus: a
meta-analysis. Ann Pharmacother 2006;40:8249.
Borna S, Saeidi FM. Celecoxib versus magnesium sulfate to
arrest preterm labor: randomized trial. J Obstet Gynaecol Res
2007;33:6314.
McWhorter J, Carlan SJ, OLeary TD, Richichi K, Obrien WF.
Rofecoxib versus magnesium sulfate to arrest preterm labor:
a randomized trial. Obstet Gynecol 2004;103:92330.
Groom KM, Shennan AH, Jones BA, Seed P, Bennett PR.
TOCOX: a randomised, double-blind, placebo-controlled trial
of rofecoxib (a COX-2-specific prostaglandin inhibitor) for
the prevention of preterm delivery in women at high risk.
BJOG 2005;112:72530.
22. Duckitt K,Thornton S. Nitric oxide donors for the treatment
of preterm labour. Cochrane Database Syst Rev
2002;(3):CD002860.
23. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D.
Magnesium sulphate for women at risk of preterm birth for
neuroprotection of the fetus. Cochrane Database Syst Rev
2009;(1):CD004661.
24. de Heus R, Mol BW, Erwich JJ, van Geijn HP, Gyselaers WJ,
Hanssens M, et al. Adverse drug reactions to tocolytic
treatment for preterm labour: prospective cohort study. BMJ
2009;338:b744.
25. Al-Qattan F, Omu A, Labeeb N. A prospective randomized
study comparing nifedipine versus ritodrine for suppression
of preterm labour. Med Princ Pract 2000;9:164173.
26. Khan K, Zamora J, Lamont RF, Van Geijn Hp H, Svare J, SantosJorge C, et al. Safety concerns for the use of calcium channel
blockers in pregnancy for the treatment of spontaneous
preterm labour and hypertension: a systematic review and
meta-regression analysis. J Matern Fetal Neonatal
Med.2010;23:10308.
27. Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal
safety of indomethacin tocolysis: a systematic review with
meta-analysis. Obstet Gynecol 2005;106:1739.
28. Hayes E, Moroz L, Pizzi L, Baxter J. A cost decision analysis of
4 tocolytic drugs. Am J Obstet Gynecol 2007;197:383.e16.
29. Wex J, Connolly M, Rath W. Atosiban versus betamimetics in
the treatment of preterm labour in Germany: an economic
evaluation. BMC Pregnancy Childbirth 2009;9:23.
30. Oei S. Calcium channel blockers for tocolysis: a review of
their role and safety following reports of serious adverse
events. Eur J Obstet Gynecol Reprod Biol 2006;126:13745.
31. Sanchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of
maintenance therapy after acute tocolysis: a meta-analysis.
Am J Obstet Gynecol 1999;181:48490.
32. Dodd JM, Crowther CA, Dare MR, Middleton P. Oral
betamimetics for maintenance therapy after threatened
preterm labour. Cochrane Database Syst Rev
2006;(1):CD003927.
33. Papatsonis D, Flenady V, Liley H. Maintenance therapy with
oxytocin antagonists for inhibiting preterm birth after
threatened preterm labour. Cochrane Database Syst Rev
2009;(1):CD005938.
34. Gaunekar NN, Crowther CA. Maintenance therapy with
calcium channel blockers for preventing preterm birth after
threatened preterm labour. Cochrane Database Syst Rev
2004;(3):CD004071.
35. Han S, Crowther CA, Moore V. Magnesium maintenance
therapy for preventing preterm birth after threatened
preterm labour. Cochrane Database Syst Rev
2000;(7):CD000940.
36. Honest H, Forbes CA, Dure KH, Norman G, Duffy SB,
Tsourapas A, et al. Screening to prevent spontaneous
preterm birth: systematic reviews of accuracy and
effectiveness literature with economic modelling. Health
Technol Assess 2009;13:1627.
37. Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. Fetal
fibronectin as a short-term predictor of preterm birth in
symptomatic patients: a meta-analysis. Obstet Gynecol
2009;114:63140.
38. Vis JY, Wilms FF, Oudijk MA, Porath MM, Scheepers HC,
Bloemenkamp KW, et al. Cost-effectiveness of fibronectin
testing in a triage in women with threatened preterm labor:
alleviation of pregnancy outcome by suspending tocolysis in
early labor (APOSTEL-I trial). BMC Pregnancy Childbirth
2009;9:38.
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Appendix 1
Classification of evidence levels
1++ High-quality meta-analyses, systematic
reviews of randomised controlled trials
or randomised controlled trials with a
very low risk of bias
1+
Well-conducted meta-analyses, systematic

low risk of bias
Meta-analyses, systematic reviews of

randomised controlled trials or
randomised controlled trials with a high
risk of bias
2++ High-quality systematic reviews of case

control or cohort studies or high-quality
casecontrol or cohort studies with a
very low risk of confounding, bias or
chance and a high probability that the
relationship is causal
2+
2-
Well-conducted casecontrol or cohort

studies with a low risk of confounding,
bias or chance and a moderate
probability that the relationship is causal
Casecontrol or cohort studies with a
high risk of confounding, bias or chance
and a significant risk that the relationship
is not causal
Non-analytical studies, e.g. case reports,

case series
Expert opinion
Grades of recommendations
At least one meta-analysis, systematic review or

randomised controlled trial rated as 1++ and
directly applicable to the target population; or
A systematic review of randomised controlled
trials or a body of evidence consisting
principally of studies rated as 1+ directly
applicable to the target population and
demonstrating overall consistency of results
A body of evidence including studies rated as

2++ directly applicable to the target
population, and demonstrating overall
consistency of results; or
Extrapolated evidence from studies rated as
1++ or 1+

2+ directly applicable to the target population
and demonstrating overall consistency of
results; or
2++
Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
Good practice point
12 of 13
Recommended best practice based on the

clinical experience of the guideline
development group
This guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and
Gynaecologists by:
Miss L Duley, FRCOG, Leeds, and Professor P Bennett, FRCOG, London.
It was peer reviewed by: BLISS (Babies Born too Soon, too Small, too Sick); Ferring Pharmaceuticals Ltd (UK); RCOG
Consumers Forum; Royal College of Midwives; Professor Z Alfirevic FRCOG, Liverpool; Professor KS Khan MRCOG,
Birmingham; Mrs G Kumar MRCOG, Wrexham, North Wales; Mr KT Moriarty MRCOG, Warwickshire; Professor JE
Norman FRCOG, Edinburgh, Scotland; Dr D Siassakos MRCOG, Bristol; Professor S Thornton FRCOG, Warwick;
Mr DJ Tuffnell FRCOG, Bradford.
The Guidelines Committee lead peer reviewers were: Dr TJA Shillito MRCOG, Leeds, Dr SK Surendran FRCOG, London,
Dr JM Thomas MRCOG, London and Professor FM McAuliffe MRCOG, Dublin, Ireland.
The final version is the responsibility of the Guidelines Committee of the RCOG.
The guideline review process will commence in 2014 unless evidence requires earlier review.
DISCLAIMER
The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice.
They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by
obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular
clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented
by the patient and the diagnostic and treatment options available.
This means that RCOG guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be
prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or
guidelines should be fully documented in the patients case notes at the time the relevant decision is taken.
13 of 13
Antenatal Corticosteroids to Reduce

Neonatal Morbidity and Mortality
Greentop Guideline No. 7
October 2010
Antenatal Corticosteroids to Reduce Neonatal Morbidity and

Mortality
This is the fourth edition of this guideline, which was previously published in April 1996, December 1999 and
February 2004.The previous guideline was entitled Antenatal Corticosteroids to Prevent Respiratory Distress
Syndrome.
1.
Purpose and scope
The aim of this guideline is to provide up-to-date information on the appropriate use of antenatal corticosteroid therapy in women whose babies are at risk of complications owing to either preterm birth or elective
caesarean section at term.
This guideline does not assess the effectiveness of tests in the prediction of preterm delivery (e.g. ultrasound
scanning for cervical length, cervical fibronectin measurement) or other interventions that may prevent
preterm labour (e.g. tocolysis).
2.
Background
There is evidence to suggest that antenatal corticosteroids are effective not only in reducing respiratory
distress syndrome (RDS) but also in reducing other complications of prematurity such as intraventricular
haemorrhage (IVH). The title of this guideline has been changed to Antenatal Corticosteroids to Prevent
Neonatal Morbidity and Mortality to include all groups of women and all outcomes.
3.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines. The Cochrane Library (including the Cochrane Database of Systematic Reviews), DARE,
Embase, TRIP, Medline and PubMed (electronic databases) were searched for relevant randomised controlled
trials, systematic reviews and meta-analyses and cohort studies.The search was restricted to articles published
between 2002 to July 2008. The databases were searched using the relevant MeSH terms, including all
subheadings, and this was combined with a keyword search. Search words included steroids, premature
labour, premature fetus and membrane rupture, and the search was limited to humans and to the English
language.The National Library for Health and the National Guidelines Clearing House were also searched for
relevant guidelines and reviews.
4.
What are the benefits of antenatal corticosteroids?
Antenatal steroids are associated with a significant reduction in rates of neonatal death, RDS and
intraventricular haemorrhage and are safe for the mother.
Antenatal corticosteroids have no known benefits for the mother.
A Cochrane review of 21 studies (3885 women and 4269 infants) showed that treatment of women
at risk of preterm birth with a single course of antenatal corticosteroids reduced the risk of
neonatal death by 31% (95% CI 1942%), RDS by 44% (95% CI 3157%) and intraventricular
haemorrhage by 46% (95% CI 31%67%).1 Antenatal corticosteroid use is also associated with a
reduction in necrotising enterocolitis, respiratory support, intensive care admissions and systemic
infections in the first 48 hours of life compared with no treatment or treatment with placebo.1
RCOG Green-top Guideline No. 7
2 of 13
Evidence
level 1++
5.
At what gestation should antenatal steroids be used?
Clinicians should offer a single course of antenatal corticosteroids to women between 24+0 and 34+6
weeks of gestation who are at risk of preterm birth.
Antenatal corticosteroids can be considered for women between 23+0 and 23+6 weeks of gestation who
are at risk of preterm birth.
The decision to administer corticosteroids at gestations less than 24+0 weeks should be made at a senior
level taking all clinical aspects into consideration.
The data are strongest for gestations between 26+0 and 34+6 weeks.The data for pregnancies between
24+0 and 26+0 weeks of gestation are scarce, with only one trial (49 infants) contributing data to the
Cochrane review.1
Evidence
level 1++
The conclusion of the authors of the Cochrane review1 and the American Congress of Obstetricians
and Gynecologists (ACOG) Committee opinion (2008)2 is that, despite the paucity of data at earlier
gestations, the reduction in outcomes other than RDS at 26+0 weeks of gestation would suggest that
there is some benefit in corticosteroid prophylaxis at earlier gestations between 24+0 and 26+0 weeks.
Evidence
level 4
In a prospective cohort of 4446 infants between 22+0 and 25+0 weeks of gestation, multivariable
analyses showed that those who received intensive care, were exposed to antenatal corticosteroids,
were of female sex, were from singleton pregnancies, and of higher birth weight (per each 100g
increment) had a reduced risk of death. Among survivors, the risk of death, or profound or any
neurodevelopmental impairment at 1822 months corrected age, was reduced.3 These reductions
were similar to those associated with a 1-week increase in gestational age.
Evidence
level 2+
A retrospective cohort study on 181 infants born at 23 weeks of gestation revealed that those
exposed to antenatal corticosteroids had decreased odds of death (OR 0.32, 95% CI 0.120.84),
with no significant differences in the occurrence of necrotising enterocolitis among survivors
(15.4% compared with 28.6%, P=0.59) or severe intraventricular hemorrhage (23.1% compared
with 57.1%, P=0.17). Only a complete course of corticosteroids was associated with a decreased
odds of death (OR 0.18, 95% CI 0.060.54).4 The study concluded that neonates at 23 weeks of
gestation whose mothers completed a course of antenatal corticosteroids had an associated 82%
reduction in odds of death.
Evidence
level 2-
Evidence from the EPICure study, a prospective cohort study, showed that of 283 babies born at
less than 26+0 weeks of gestation assessed at 2.5 years and 241 assessed at 6 years, antenatal
corticosteroids was associated with an increased mental development index.5
Evidence
level 2+
Trial data are scanty for pregnancies at the extreme of prematurity. Obstetricians currently have the discretion
to administer steroids before the 24th week of pregnancy, but the whole clinical picture needs to be taken
into account with respect to intact survival data as well as the chance of any survival based on antenatal
assessment of viability at these extremes (e.g. by estimation of fetal weight). In this context, we have advised
caution and discussion at senior level prior to considering antenatal corticosteroid administration at 23+0 to
23+6 weeks of gestation.
6.
How long after administration is a course of antenatal corticosteroids most effective?
Antenatal corticosteroids are most effective in reducing RDS in pregnancies that deliver 24 hours after
and up to 7 days after administration of the second dose of antenatal corticosteroids.
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Antenatal corticosteroid use reduces neonatal death within the first 24 hours and therefore should still
be given even if delivery is expected within this time. A.
Reduction in RDS is seen in infants born up to 7 days after the first dose (RR 0.46, 95% CI 0.350.60,
nine studies, 1110 infants).1 No reduction in neonatal death, RDS or cerebro-ventricular haemorrhage
is seen in infants delivered more than 7 days after treatment with antenatal corticosteroids.1
Evidence
level 1+
Antenatal corticosteroid use reduces neonatal death even when infants are born less than 24 hours
after the first dose has been given (RR 0.53, 95% CI 0.290.96, four studies, 295 infants).1
However, caution should be exercised in the interpretation of the data.The question as to whether the effects
of antenatal corticosteroids change with time to delivery cannot be answered by existing analyses, the main
reason being that the time periods chosen for subgroup analysis were arbitrary. All the babies born at term
were in one subgroup. Analyses based on subgroups defined by outcomes not known at randomisation are
subject to considerable bias. This question would require re-analysis of individual patient data to clarify
whether the association is real.6
7.
How safe is the use of antenatal corticosteroids?
Women may be advised that the use of a single course of antenatal corticosteroids does not appear to
be associated with any significant short-term maternal or fetal adverse effects.
Evidence on the longer-term benefits and risks of a single course of antenatal corticosteroids shows no
clear difference in adverse neurological or cognitive effects. There is still insufficient evidence on the
longer-term benefits and risks of multiple courses of antenatal corticosteroids.
Studies in the sheep model have shown that injections with glucocorticoids enhance fetal lung maturation but
are associated with developmental and other functional alterations that are of concern. Weekly doses to the
sheep mother are associated with restricted fetal growth, delayed myelination of the central nervous system,
altered blood pressure soon after birth and increased insulin response to glucose challenge in early adulthood.
There have therefore been concerns about whether steroid administration may have adverse effects on the
long-term outcomes of children exposed in the antenatal period. Multivariate analyses in humans have shown
that increasing the number of glucocorticoid exposures, for the purpose of enhancing lung maturation prior
to preterm birth, is associated with reduced birth weight and behavioural disorders at 3 years of age.7
The Cochrane review and other studies have shown that a single course of corticosteroid therapy for preterm
birth results in benefit without causing significant adverse effects such as neonatal or maternal sepsis.1,8,9 The
Cochrane review revealed that no statistically significant differences were seen for chorioamnionitis (RR 0.91,
95% CI 0.701.18, 12 studies, 2485 women) or puerperal sepsis (RR 1.35, 95% CI 0.931.95, eight studies,
1003 women). There were no maternal deaths, but the randomised controlled trials were underpowered to
detect such a difference (RR 0.98, 95% CI 0.0615.50, three studies, 365 women).1
Long-term follow-up of survivors from randomised trials of antenatal corticosteroid therapy
through childhood to adulthood (up to 20 years of age) shows no clear adverse neurological or
cognitive effects.10,11
Evidence
level 1-
A randomised controlled trial showed that children who had been exposed to repeat as compared
with single courses of antenatal corticosteroids did not differ significantly in physical or neurocognitive measures. However, there was a nonsignificant higher risk of cerebral palsy among
children who had been exposed to repeat doses of corticosteroids (RR 5.7, 95% CI 0.746.7,
P=0.12). The number of children with cerebral palsy was small. This was, however, felt to be of
concern and warranting further study.12
Evidence
level 1++
4 of 13
Furthermore, studies on long-term cardiovascular risks, cognitive functioning, working memory and
attention, psychiatric morbidity, handedness or health-related quality of life on the survivors of the
first and largest double-blind, placebo-controlled, randomised trial of a single course of antenatal
betamethasone for the prevention of neonatal RDS at age 31 found no differences between groups
exposed to betamethasone and placebo.13,14
8.
Evidence
level 1+
Are there any contraindications to the use of antenatal corticosteroids?
Caution should be exercised when giving corticosteroid therapy to women with systemic infection
including tuberculosis or sepsis.
Corticosteroids suppress the immune system, so there is a risk that their use may activate latent infections or
exacerbate fungal infections. In a woman with systemic infection, it may theoretically suppress the immune
response to infection. There is no evidence to suggest that a single course of corticosteroids would have a
profound effect in women with systemic infection, but caution should be exercised in its use.
Senior opinion should be sought when contemplating delaying delivery for steroid prophylaxis in cases
of overt chorioamnionitis.
A large meta-analysis of observational studies reports that clinical chorioamnionitis is significantly associated
with both cystic periventricular leucomalacia (RR 2.6, 95% CI 1.73.9) and cerebral palsy (RR, 1.9, 95% CI
1.52.5).15,16 This would suggest that with chorioamnionitis, a course of antenatal corticosteroids may be
started, but should not delay delivery if indicated by maternal or fetal condition.
9.
Who should receive antenatal corticosteroids?
Antenatal corticosteroids should be given to all women at risk of iatrogenic or spontaneous preterm
birth up to 34+6 weeks of gestation.
Antenatal corticosteroids should be given to all women for whom an elective caesarean section is
planned prior to 38+6 weeks of gestation.
There is no evidence to support a practice of prophylactic steroids in women with a previous history of preterm
delivery or multiple pregnancy who show no signs of being at risk of iatrogenic or spontaneous preterm birth.
There is evidence of benefit in all major subgroups of preterm babies, such as women with
premature rupture of membranes and pregnancy-related hypertension syndromes as well as the
subgroups discussed below.1 This benefit is irrespective of race or gender. A single course of
antenatal corticosteroids should be considered routine for preterm delivery with few exceptions.
Evidence
level 1++
9.1 In multifetal pregnancy

Clinicians should continue to offer a single course of antenatal corticosteroid treatment to women with
multiple pregnancy at risk of imminent iatrogenic or spontaneous preterm delivery between 24+0 and
34+6 weeks of gestation.
In the Cochrane review, no statistically significant differences in women with multiple pregnancies were seen
for chorioamnionitis (RR 0.48, 95% CI 0.044.49, one study, 74 women), fetal death (RR 0.53, 95% CI 0.201.40,
two studies, 252 infants), neonatal death (RR 0.79, 95% CI 0.390.61, two studies, 236 infants), RDS (RR 0.85,
95% CI 0.601.20, four studies, 320 infants), cerebro-ventricular haemorrhage (RR 0.39, 95% CI 0.072.06, one
study, 137 infants) or birth weight (fixed weighted mean difference 82.36 g, 95% CI 146.23 to 310.95 g, one
study, 150 infants). However, only two studies contributed data for multiple pregnancy (252 infants).1
5 of 13
The optimal dose and pharmacokinetics in multiple pregnancies is not clearly understood.
Evidence suggests that multiple pregnancy attenuates the beneficial effect of antenatal steroids.17
Although there are limited data to support the use of antenatal corticosteroids in multiple
pregnancy, the overall improvement in outcomes in singleton fetuses would suggest that steroids
could be beneficial in multiple pregnancy.
Evidence
level 4
A retrospective cohort study of 1038 twin babies delivered between 1990 and 1996 demonstrated
that a prophylactic approach of administering antenatal corticosteroids every two weeks from 24
to 32 weeks of gestation was not associated with a significant reduction in RDS (adjusted OR 0.7,
95% CI 0.22.0).18 Mean birth weight was reduced in term babies by 129 g (95% CI 218 to 33,
P=0.008).
Evidence
level 2-
9.2 In women with diabetes mellitus

Diabetes mellitus is not a contraindication to antenatal corticosteroid treatment for fetal lung maturation.
Women with impaired glucose tolerance or diabetes who are receiving fetal steroids should have
additional insulin according to an agreed protocol and be closely monitored.
Women with either insulin-dependent diabetes or gestational diabetes were not entered into
randomised controlled trials of antenatal corticosteroid therapy. There is therefore no evidence
from randomised controlled trials that antenatal corticosteroid therapy is either safe or effective in
these circumstances. Maternal hyperglycaemia can adversely affect fetal lung maturity. It is possible
that any benefit of corticosteroids could be offset by corticosteroid-induced hyperglycaemia.19
However, the National Institute of Health and Clinical Excellence (NICE) has published a clinical
guideline for diabetes in pregnancy that states that diabetes should not be considered a contraindication to antenatal corticosteroids.20 The NICE guideline recommends that diabetic women
receiving steroids should have additional insulin according to an agreed protocol.20
Evidence
level 4
9.3 In women undergoing elective caesarean section

Elective lower segment caesarean section should normally be performed at or after 39+0 weeks of
gestation to reduce respiratory morbidity.
Corticosteroids should be given to reduce the risk of respiratory morbidity in all babies delivered by
elective caesarean section prior to 38+6 weeks of gestation.
Studies have shown that delivery by elective caesarean section at less than 39+0 weeks of gestation
can lead to respiratory morbidity in neonates, requiring admission to the neonatal intensive care
unit (NICU).2124 A recent retrospective cohort study showed that, compared with elective caesarean
section births at 39+0 weeks of gestation, births at 37+0 weeks of gestation and at 38+0 weeks of
gestation were associated with an increased risk of a composite outcome of neonatal death and/or
respiratory complications, treated hypoglycaemia, newborn sepsis and admission to the NICU
(adjusted OR for births at 37 weeks of gestation 2.1, 95% CI 1.72.5; adjusted OR for births at 38
weeks of gestation 1.5; 95% CI 1.31.7; P for trend <0.001).21 The rates of adverse respiratory
outcomes, mechanical ventilation, newborn sepsis, hypoglycaemia, admission to the NICU and
hospitalisation for 5 days or more were increased by a factor of 1.84.2 for births at 37 weeks of
gestation and 1.32.1 for births at 38 weeks of gestation. A further study in Denmark23 showed the
risk of respiratory morbidity for infants delivered by elective caesarean section decreased by
gestation compared with vaginal birth (37 weeks of gestation OR 3.9, 95% CI 2.46.5; 38 weeks of
gestation OR 3.0, 95% CI 2.14.3; and 39 weeks of gestation OR 1.9, 95% CI 1.23.0).
6 of 13
Evidence
level 2-
Treatment with antenatal corticosteroids prior to delivery by elective caesarean section has been
shown to reduce the need for admission to the NICU up to 38+6 weeks of gestation compared with
controls. A randomised controlled trial showed that the relative risk of admission with RDS in
babies treated with antenatal corticosteroids prior to elective caesarean section at term was 0.46
(95% CI 0.230.93, P=0.02).The relative risk of transient tachypnoea of the newborn was 0.040 in
the control group and 0.021 in the treatment group (RR 0.54, 95% CI 0.261.12). The relative risk
of RDS was 0.011 in the control group and 0.002 in the treatment group (RR 0.21, 95% CI
0.031.32). The predicted probability of admission to NICU at 37 weeks of gestation was 11.4% in
the control group and 5.2% in the treatment group, at 38 weeks it was 6.2% and 2.8%, respectively,
and at 39 weeks it was 1.5% and 0.6%, respectively.25
Evidence
level 1+
There is an absence of evidence available for the safety of antenatal corticosteroids in babies born after 36+0
weeks of gestation. Elective lower segment caesarean section should not normally be performed until 39+0
weeks of gestation, rather than the administration of antenatal corticosteroids.
9.4 In pregnancies with fetal growth restriction

Pregnancies affected by fetal growth restriction between 24+0 and 35+6 weeks of gestation at risk of
delivery should receive a single course of antenatal corticosteroids.
There is evidence to suggest that antenatal corticosteroids have an effect on cerebral blood flow in growthrestricted fetuses that is different from that in normally grown fetuses.26,27 This has led to speculation as to
whether corticosteroids should be used in such pregnancies.
In a well-designed casecontrol study of 124 preterm infants between 26 and 32 weeks of gestation
with growth restriction secondary to placental insufficiency,28 survival without disability or
handicap at 2 years of age was better in the corticosteroid group than in the matched group of
growth-restricted babies who did not receive corticosteroids. Although there were more children
with physical growth problems in the corticosteroid group, there was no difference detected in
behaviour. The benefits from antenatal corticosteroids for early preterm growth-restricted infants
appear to outweigh the possible adverse effects.
Evidence
level 2+
10. What is the best dose and route of administration for a course of antenatal corticosteroids?
Betamethasone 12 mg given intramuscularly in two doses or dexamethasone 6 mg given
intramuscularly in four doses are the steroids of choice to enhance lung maturation.
The most extensively studied regimens of corticosteroid treatment for the prevention of RDS are two doses
of betamethasone 12 mg given intramuscularly 24 hours apart or four doses of dexamethasone 6 mg given
intramuscularly 12 hours apart. Evidence for other dosing regimens such as the commonly used two doses of
betamethasone 12 mg given 12 hours apart is sparse (two trials, 92 women),29,30 but it would seem reasonable
that as long as 24 mg of either drug is given within a 2448-hour period, any dosing regimen can be used.
A large nonrandomised retrospective study has suggested that infants exposed to antenatal
betamethasone have less neonatal cystic periventricular leukomalacia than infants exposed to
antenatal dexamethasone.31 Another historical cohort study used multivariate logistic regression
analysis to compare the two steroid-treated groups with each other. It showed the risk of neonatal
death was lower with betamethasone than with dexamethasone (OR 0.44 for betamethasone
versus 0.73 with dexamethasone, P<0.05).32
Evidence
level 2-
The Cochrane review on antenatal corticosteroids for accelerating fetal lung maturation for women
at risk of preterm birth suggests that betamethasone treatment causes a larger reduction in RDS
Evidence
level 1++
7 of 13
than dexamethasone.1 Since then, in a Cochrane review on different corticosteroid regimes (ten
trials, 1089 women and 1161 infants), dexamethasone decreased the incidence of intraventricular
haemorrhage compared with betamethasone (RR 0.44, 95% CI 0.210.92, four trials, 549 infants).33
This review advised caution in suggesting benefit of dexamethasone over betamethasone. A
randomised controlled trial looking at long-term outcomes in children treated with dexamethasone
would be required as this form of corticosteroid has not been studied in the long term. For current
practice, the use of either corticosteroid is acceptable.
Evidence
level 1++
Comparison of oral versus intramuscular administration of dexamethasone (one trial, 183 infants)
suggests that oral administration increased the incidence of neonatal sepsis (RR 8.48, 95% CI 1.11
64.93) in one trial of 183 infants. No statistically significant differences were seen for other
outcomes reported. The authors suggest that very few conclusions about the optimum regimens
can be made.34
11.
When should an antenatal course of corticosteroids be repeated?
Weekly repeat courses of antenatal corticosteroids reduce the occurrence and severity of neonatal
respiratory disease, but the short-term benefits are associated with a reduction in weight and head
circumference. Weekly repeat courses are not recommended.
A single rescue course may be considered with caution in pregnancies where the initial course was given
at less than 26+0 weeks of gestation. Senior opinion should be sought if a rescue course is to be
considered.
Animal studies and observational studies in humans have suggested that multiple courses of
steroids may lead to possible harmful effects including growth delay, brain developmental delay,
lung development problems, necrotising enterocolitis, maternal and neonatal sepsis, adrenal gland
insufficiency and placental infarction.3541 A systematic review of 19 randomised controlled trials of
repeat doses of antenatal corticosteroids in animals concluded that there might be beneficial
effects in terms of lung function but adverse effects on brain function and fetal growth.40
Evidence
level 1+
The effect of repeat courses of antenatal corticosteroids in humans is the subject of a Cochrane
review by Crowther et al.42 The review suggests that although repeat courses reduce the
occurrence and severity of neonatal lung disease (RR 0.60, 95% CI 0.480.75, three trials, 2139
infants) and the risk of serious health problems in the first few weeks of life (RR 0.79, 95% CI
0.670.93, four trials, 2157 infants), they are associated with a reduction in some measures of
weight (Z-score [weighted mean difference] 0.13, 95% CI 26 to 0.00, one trial, 1144 infants) and
with being small for gestational age at birth (RR 1.63, 95% CI 1.122.37, two trials, 602 infants).
There is still insufficient evidence on the longer-term benefits and risks to be able to recommend
the routine use of repeat courses.
Evidence
level 1++
The Cochrane review did not include the results of several continuing trials, two of which have
been completed since its publication.43,44 The results of TEAMS (Trial of early and multiple steroids)
are awaited.43 In the MACS (Multiple Courses of Antenatal Corticosteroids for Preterm Birth) trial of
1858 women at 2532 weeks of gestation, multiple courses of antenatal corticosteroids (n=937) or
placebo (n=921) every 14 days until week 33 or delivery (whichever came first) found that
although infants exposed to multiple courses of antenatal corticosteroids had similar morbidity and
mortality to those exposed to placebo (12.9% versus 12.5%), those receiving multiple doses of
corticosteroids weighed less at birth (2216 g versus 2330 g, P=0.0026), were shorter (44.5 cm
versus 45.4 cm, P<0.001), and had a smaller head circumference (31.1 cm versus 31.7 cm,
P<0.001). A regime of repeat doses should not be recommended.44
Evidence
level 1+
8 of 13
In 2000, a National Institutes of Health consensus statement concluded that repeat courses of
corticosteroids should not be used routinely and should be reserved for women enrolled in
randomised controlled trials.45 A recent randomised controlled trial recruited 437 patients with
singleton or twin pregnancies at less than 33+0 weeks of gestation who had completed a single
course of corticosteroids before 30+0 weeks of gestation and randomised them to a single rescue
course of betamethasone (two 12 mg doses 24 hours apart) or placebo. There was a significant
reduction in the primary outcome of composite neonatal morbidity at less than 34 weeks of
gestation in the rescue steroid group than in the placebo group (43.9% versus 63.6%, OR 0.45, 95%
CI 0.270.75, P=0.002) and significantly decreased RDS, ventilator support and surfactant use.
Perinatal mortality and other morbidities were similar in each group. No long-term outcomes were
reported for this study.46
Evidence
level 1+
Peltoniemi et al. looked at whether a single additional dose of 12 mg betamethasone given when
preterm birth is imminent before 34+0 weeks of gestation and at least a week after the full treatment
course would lower the risk of RDS and severe (grade 3 or 4) intraventricular haemorrhage
compared with placebo. This study showed that more infants in the steroid group required
surfactant therapy. Post hoc analysis of data on 206 infants who were delivered within 1 to 24 hours
indicated that the additional steroid dose tended to increase the risk of RDS and reduce the rate of
intact survival. No differences were found between the steroid and placebo groups in mortality
rates or rates of severe intraventricular haemorrhage. The results of this study would suggest that
rescue doses may alter respiratory adaptation.47 A subanalysis within the MACS study also showed
no benefit from a rescue dose.44
Evidence
level 1and
level 1+
A rescue course of two doses of 12 mg betamethasone or four doses of 6 mg dexamethasone should only
be considered with caution in those pregnancies where the first course was given at less than 26+0
weeks of gestation and another obstetric indication arises later in pregnancy.
In the absence of evidence, a rescue course of two doses of 12 mg betamethasone or four doses of 6 mg
dexamethasone should only be considered with caution in those pregnancies where the first course was
given at less than 26+0 weeks of gestation and another obstetric indication arises later in pregnancy.This would
be justified by the paucity of data on the efficacy of the current dosing regimens on babies less than 26+0
weeks of gestation.
The proportion of babies delivered before 36+0 weeks of gestation and exposed to antenatal corticosteroids
(i.e. did all babies who could have received corticosteroids receive them?).
The proportion of all babies delivered before 36+0 weeks of gestation exposed to more than one course of
antenatal corticosteroids.
The proportion of babies delivered after 36+0 weeks of gestation exposed to steroids at any time during the
pregnancy (false positive for preterm delivery).
The proportion of babies delivered by elective caesarean section at less than 39+0 weeks of gestation exposed
to antenatal corticosteroids.
The proportion of babies with intrauterine growth restriction requiring preterm delivery exposed to
antenatal corticosteroids.
The proportion of babies born who were exposed to less than 24 hours of antenatal steroids as a function of
when a diagnosis of risk of preterm labour was made.
The diabetic management of women with diabetes who are given antenatal corticosteroids.
9 of 13
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fetal lung maturation for women at risk of preterm birth.
DOI:0.1002/14651858.CD004454.pub2.
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Committee on Obstetric Practice. ACOG Committee Opinion
No. 402: Antenatal corticosteroid therapy for fetal maturation.
Tyson JE, Parikh NA, Langer J, Green C, Higgins RD; National
Institute of Child Health and Human Development Neonatal
Research Network. Intensive care for extreme prematurity
moving beyond gestational age. N Engl J Med
2008;358:167281.
Hayes EJ, Paul DA, Stahl GE, Seibel-Seamon J, Dysart K, Leiby BE,
et al. Effect of antenatal corticosteroids on survival for
neonates born at 23 weeks of gestation. Obstet Gynecol
2008;111:9216.
Costeloe K; EPICure Study Group. EPICure: facts and figures:
why preterm labour should be treated. BJOG 2006;113 Suppl
3:102.
Gates S, Brocklehurst P. Decline in effectiveness of antenatal
corticosteroids with time to birth: real or artefact? BMJ
2007;335:779.
Newnham JP. Is prenatal glucocorticoid administration another
origin of adult disease? Clin Exp Pharmacol Physiol
2001;28:95761.
Goldenberg RL, Andrews WW, Faye-Petersen OM, Cliver SP,
Goepfert AR, Hauth JC.The Alabama preterm birth study:
corticosteroids and neonatal outcomes in 23- to 32-week
newborns with various markers of intrauterine infection. Am J
Smrcek JM, Schwartau N, Kohl M, Berg C, Geipel A, Krapp M, et
al. Antenatal corticosteroid therapy in premature infants. Arch
Gynecol Obstet 2005;271:2632.
Smolders-de Haas H, Neuvel J, Schmand B,Treffers PE, Koppe
JG, Hoeks J. Physical development and medical history of
children who were treated antenatally with corticosteroids to
prevent respiratory distress syndrome: a 10- to 12-year followup. Pediatrics 1990;86:6570.
Dessens AB, Haas HS, Koppe JG.Twenty-year follow-up of
antenatal corticosteroid treatment. Pediatrics 2000;105:E77.
Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY,
et al. Long-term outcomes after repeat doses of antenatal
corticosteroids. N Engl J Med 2007;357:11908.
Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A, et
al. Cardiovascular risk factors after antenatal exposure to
betamethasone: 30-year follow-up of a randomised controlled
trial. Lancet 2005;365:185662.
Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A,
et al. Antenatal exposure to betamethasone: psychological
functioning and health related quality of life 31 years after
inclusion in randomised controlled trial. BMJ 2005;331:665.
Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for
cerebral palsy: A meta-analysis. JAMA 2000;284:141724.
Wu YW. Systematic review of chorioamnionitis and cerebral
palsy. Ment Retard Dev Disabil Res Rev 2002;8:259.
Quist-Therson EC, Myhr TL, Ohlsson A. Antenatal steroids to
prevent respiratory distress syndrome: multiple gestation as an
effect modifier. Acta Obstet Gynecol Scand 1999;78:38892.
Murphy DJ, Caukwell S, Joels LA, Wardle P. Cohort study of the
neonatal outcome of twin pregnancies that were treated with
prophylactic or rescue antenatal corticosteroids. Am J Obstet
Gynecol 2002;187:4838.
Carlson KS, Smith BT, Post M. Insulin acts on the fibroblast to
inhibit glucocorticoid stimulation of lung maturation. J Appl
Physiol 1984;57:15779.
National Institute for Health and Clinical Excellence. NICE
Clinical Guideline 63: Diabetes in pregnancy. Management of
diabetes and its complications from pre-conception to the
postnatal period. London: NICE; 2008.
21. Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW, et
al.; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine
Units Network.Timing of elective repeat cesarean delivery at
term and neonatal outcomes. N Engl J Med 2009;360:11120.
22. Yee W, Amin H, Wood S. Elective cesarean delivery, neonatal
intensive care unit admission, and neonatal respiratory distress.
23. Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB. Risk of
respiratory morbidity in term infants delivered by elective
caesarean section: cohort study. BMJ 2008;336:857.
24. Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory morbidity and mode of delivery at term: influence of timing of elective
caesarean section. Br J Obstet Gynecol 1995;102:1016.
25. Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term
Elective Caesarean Section (ASTECS) Research Team. Antenatal
betamethasone and incidence of neonatal respiratory distress
after elective caesarean section: pragmatic randomised trial.
BMJ 2005;331:662.
26. Miller SL, Chai M, Loose J, Castillo-Melndez M, Walker DW,
Jenkin G, et al.The effects of maternal betamethasone
administration on the intrauterine growth-restricted fetus.
Endocrinology 2007;148:128895.
27. Simchen MJ, Alkazaleh F, Adamson SL, Windrim R,Telford J,
Beyene J, et al.The fetal cardiovascular response to antenatal
steroids in severe early-onset intrauterine growth restriction.
28. Schaap AH, Wolf H, Bruinse HW, Smolders-De Haas H, Van
Ertbruggen I,Treffers PE. Effects of antenatal corticosteroid
administration on mortality and long-term morbidity in early
preterm, growth-restricted infants. Obstet Gynecol
2001;97:95460.
29. Magee LA, Dawes GS, Moulden M, Redman CW. A randomised
controlled comparison of betamethasone with
dexamethasone: effects on the antenatal fetal heart rate. Br J
Obstet Gynaecol 1997;104:12338.
30. Mushkat Y, Ascher-Landsberg J, Keidar R, Carmon E, Pauzner D,
David MP.The effects of betamethasone versus dexamethasone
on fetal biophysical parameters. Eur J Obstet Gynecol Reprod
Biol 2001;97:502.
31. Baud O, Foix-LHelias L, Kaminski M, Audibert F, Jarreau PH,
Papiernik E, et al. Antenatal glucocorticoid treatment and cystic
periventricular leukomalacia in very premature infants. N Engl
J Med 1999;341:11906.
32. Lee BH, Stoll BJ, McDonald SA, Higgins RD; National Institute of
Child Health and Human Development Neonatal Research
Network. Adverse neonatal outcomes associated with antenatal
dexamethasone versus antenatal betamethasone. Obstet
Gynecol Surv 2006;61:56869.
33. Brownfoot FC, Crowther CA, Middleton P. Different
corticosteroids and regimens for accelerating fetal lung
maturation for women at risk of preterm birth. Cochrane
Database Syst Rev 2008;(4):CD006764. DOI:
10.1002/14651858.CD006764.pub2.
34. Egerman RS, Mercer BM, Doss JL, Sibai BM. A randomized,
controlled trial of oral and intramuscular dexamethasone in
the prevention of neonatal respiratory distress syndrome. Am J
35. Jobe AH, Wada N, Berry LM, Ikegami M, Ervin MG. Single and
repetitive maternal glucocorticoid exposures reduce fetal
growth in sheep. Am J Obstet Gynecol 1998;178:8805.
36. Walfisch A, Hallak M, Mazor M. Multiple courses of antenatal
steroids: risks and benefits. Obstet Gynecol 2001;98:4917.
37. Kay HH, Bird IM, Coe CL, Dudley DJ. Antenatal steroid
treatment and adverse fetal effects: what is the evidence? J Soc
Gynecol Investig 2000;7:6978.
38. Goldenberg RL, Wright LL. Repeated courses of antenatal
corticosteroids. Obstet Gynecol 2001;97:3167.
39. Vermillion ST, Soper DE, Newman RB. Neonatal sepsis and
death after multiple courses of antenatal betamethasone
therapy. Am J Obstet Gynecol 2000;183:8104.
10 of 13
40. Aghajafari F, Murphy K, Matthews S, Ohlsson A, Amankwah K,

Hannah M. Repeated doses of antenatal corticosteroids in
animals: a systematic review. Am J Obstet Gynecol
2002;186:8439.
41. Aghajafari F, Murphy K, Willan A, Ohlsson A, Amankwah K,
Matthews S, et al. Multiple courses of antenatal corticosteroids:
a systematic review and meta-analysis. Am J Obstet Gynecol
2001;185:107380.
42. Crowther CA, Harding JE. Repeat doses of prenatal
corticosteroids for women at risk of preterm birth for
preventing neonatal respiratory disease. Cochrane Database
Syst Rev 2007;(3):CD003935. DOI:
10.1002/14651858.CD003935.pub2.
43. TEAMS Trial of early and multiple steroids.
44. Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A,
Kelly EN, et al.; MACS Collaborative Group. Multiple courses of
antenatal corticosteroids for preterm birth (MACS): a
randomised controlled trial. Lancet 2008;372:214351.
45. National Institutes of Health Consensus Development Panel.

Antenatal corticosteroids revisited: repeat courses National
Institutes of Health Consensus Development Conference
Statement, August 1718, 2000. Obstet Gynecol
2001;98:14450.
46. Garite TJ, Kurtzman J, Maurel K, Clark R; Obstetrix Collaborative
Research Network. Impact of a rescue course of antenatal
corticosteroids: a multicenter randomized placebo-controlled
trial. Am J Obstet Gynecol 2009;200:248.e19.
47. Peltoniemi OM, Kari M,Tammela O, Lehtonen L, Marttila R,
Halmesmki E, et al.;The Repeat Antenatal Betamethasone
Study Group. Randomized trial of a single repeat dose of
prenatal betamethasone treatment in imminent preterm birth.
Obstet Gynecol Surv 2007;62:36870.
11 of 13
APPENDIX
Clinical guidelines are: systematically developed statements which assist clinicians and patients in
making decisions about appropriate treatment for specific conditions. Each guideline is systematically
developed using a standardised methodology. Exact details of this process can be found in Clinical
Governance Advice No. 1: Development of RCOG Green-top Guidelines (available on the RCOG website
at http://www.rcog.org.uk/womens-health/clinical-guidance/development-rcog-green-top-guide
lines-policies-and-processes). These recommendations are not intended to dictate an exclusive course
of management or treatment.They must be evaluated with reference to individual patient needs, resources
and limitations unique to the institution and variations in local populations. It is hoped that this process of
local ownership will help to incorporate these guidelines into routine practice.Attention is drawn to areas
of clinical uncertainty where further research may be indicated. The evidence used in this guideline was
graded using the scheme below and the recommendations formulated in a similar fashion with a
standardised grading scheme.

1+

low risk of bias

risk of bias
2++ High-quality systematic reviews of

casecontrol or cohort studies or highquality casecontrol or cohort studies
with a very low risk of confounding, bias
or chance and a high probability that the
2+
3
4

bias or chance and a moderate probability that the relationship is causal
and a significant risk that the
relationship is not causal
case series

1++ or 1+
results; or
2++
2+
Good practice point
Expert opinion
At least one meta-analysis, systematic review

or randomised controlled trial rated as 1++,
and directly applicable to the target
population; or
principally of studies rated as 1+, directly
12 of 13

development group
This Guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists
by Dr D Roberts MRCOG, Liverpool.
It was peer-reviewed by the British Association of Perinatal Medicine; British Maternal and Fetal Medicine Society;
RCOG Consumers Forum; Royal College of Midwives; Professor P Brocklehurst FRCOG, Oxford; Professor LMM Duley
FRCOG, Leeds; Mr KW Murphy FRCOG, London; Dr SR Sheehan MRCOG, Ireland.
The Guidelines Committee Lead reviewer was Mrs C Overton FRCOG.
The Guidelines review process will commence in 2013 unless evidence requires earlier review.
DISCLAIMER
The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical
practice. They present recognised methods and techniques of clinical practice, based on published evidence, for
consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement
regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light
of clinical data presented by the patient and the diagnostic and treatment options available.
This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to
be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or
13 of 13
Amniocentesis and
Chorionic Villus Sampling
June 2010
Amniocentesis and Chorionic Villus Sampling

This is the fourth edition of this guideline, which was previously published in October 1996, February 2000
and January 2005.
1.
Aim
It is estimated that around 5% of the pregnant population (approximately 30 000 women per annum in the
UK) are offered a choice of invasive prenatal diagnostic tests (most commonly amniocentesis or chorionic
villus sampling). The type of diagnostic test available and offered is likely to vary depending upon the timing
of any initial screening test that is performed. The aim of this guideline is to set a series of evidence-based
standards to ensure a high level and consistency of practice in the provision and performance of
amniocentesis and chorionic villus sampling.
2.
Background and introduction
Amniocentesis is the most common invasive prenatal diagnostic procedure undertaken in the UK. Most
amniocenteses are performed to obtain amniotic fluid for karyotyping from 15 weeks (15+0 ) onwards.
Amniocentesis performed before 15 completed weeks of gestation is referred to as early amniocentesis.
Chorionic villus sampling (CVS) is usually performed between 11 (11+0 ) and 13 (13+6 ) weeks of gestation and
involves aspiration or biopsy of placental villi. CVS can be performed using either a transabdominal or a
transcervical approach.
3.
EMBASE, TRIP, Medline and PubMed electronic databases were searched for relevant randomised controlled
trials, systematic reviews, meta-analyses and cohort studies. The search was restricted to articles published
from 2000 to July 2008. The databases were searched using the relevant MeSH terms, including all
subheadings, and this was combined with a keyword search. Search words included amniocentesis,
chorionic villus sampling, standards, adverse effects and audit and the search was limited to humans and
the English language. The National Library for Health and the National Guidelines Clearing House were also
searched for relevant guidelines and reviews.
4.
Rates of miscarriage
Women should be informed that the additional risk of miscarriage following amniocentesis is around 1%.
Women should be informed that the additional risk of miscarriage following CVS may be slightly higher
than that of amniocentesis carried out after 15 weeks gestation.
The best estimate of miscarriage risk associated with amniocentesis comes from a randomised trial
from Denmark reported in 1986.1 This study randomised 4606 women at low risk of miscarriage
aged 2435 years to have (or not to have) an amniocentesis carried out using a 20-gauge needle
under continuous real-time ultrasound guidance. Most procedures were performed between 16 and
18 weeks of gestation.The amniocentesis group had a loss rate which exceeded the control group
by 1%. More than 50% of the amniocenteses were performed by one operator and the remainder
by four other operators who were less experienced. The placenta was avoided whenever possible
but a transplacental approach was recorded in 15% of cases. Bloodstained amniotic fluid was
obtained in 0.5% of cases overall.
2 of 13
Evidence
level 1+
More recently, several large cohort studies have suggested significantly lower procedure-related loss
rates after amniocentesis.2,3 There is a debate, however, on what should constitute an appropriate
control group and what constitutes a true procedure-related loss, particularly in relation to the time
interval after the procedure. A recent systematic review estimated total post-amniocentesis
pregnancy loss (background and procedure related loss combined) to be 1.9% (95% CI 1.42.5).4
Practitioners should be aware of these issues and, if quoting procedure-related loss rates lower than
1%, they should carefully evaluate the adequacy of their own follow-up data.There is also increasing
evidence that operators who perform procedures frequently have lower miscarriage rates.5
Evidence
level 1+
There are no published studies comparing CVS with no testing. Meta-analyses of all randomised
trials comparing CVS by any route with second-trimester amniocentesis showed an excess
pregnancy loss following CVS.6 However, there was only one direct randomised comparison of
transabdominal CVS with second-trimester amniocentesis reporting similar total pregnancy loss in
the two groups (6.3% compared with 7%).7
As previously mentioned, recent uncontrolled cohort series report significantly lower pregnancy
losses after CVS as well as after amniocentesis.8 However, the potential for bias is considerable in
all of these studies and these data may have limited utility in counselling.
Several randomised trials show almost identical miscarriage rates after transcervical CVS compared
with the transabdominal approach.9,10 Only one trial demonstrated the transabdominal approach to
be significantly safer; however, it should be noted that operator experience in the two techniques
in this study differed.7 Interestingly, meta-analysis comparing transcervical CVS with secondtrimester amniocentesis showed amniocentesis to be significantly safer.6 Women should be
informed that the additional risk of miscarriage following CVS may be higher than that of
amniocentesis carried out after 15 weeks of gestation.
5.
Evidence
level 2-
Evidence
level 1+
At what gestation should amniocentesis and CVS be carried out?
Amniocentesis should be performed after 15 (15+0) weeks of gestation.

Amniocentesis before 14 (14+0) weeks of gestation (early amniocentesis) has a higher fetal loss rate and
increased incidence of fetal talipes and respiratory morbidity compared with other procedures.
CVS should not be performed before 10 (10+0) completed weeks of gestation.
A
A
D
Early amniocentesis is not a safe alternative to second-trimester amniocentesis because of increased

pregnancy loss (7.6% compared with 5.9%; RR 1.29; 95% CI 1.031.61). Early amniocentesis has a
higher incidence of talipes when compared with CVS (RR 4.61; 95% CI 1.8211.66).6 Early
amniocentesis is not recommended.
Evidence
level 1+
The association between CVS, oromandibular limb hypoplasia and isolated limb disruption defects
has been debated since the issue was first raised in 1991 when a cluster of five babies with limb
reduction defects was reported among a series of 289 women undergoing transabdominal CVS
between 8 and 9 (9+3) weeks.11 A subsequent analysis showed no difference in the rate of this
abnormality compared with the population incidence, although the vast majority of procedures
were performed after 10 weeks of gestation.12 Although a few publications subsequently appeared
to support this association, most found few, if any, cases of oromandibular limb hypogenesis
syndrome and an incidence of limb reduction defects no higher than the background incidence.
Despite reassuring reports, most units stopped performing CVS before 10 weeks of gestation and
thus most subsequent analyses include later procedures only. Furthermore, CVS before 11 (11+0)
weeks can be technically difficult to perform, owing to a smaller uterus and thinner placenta.
Evidence
level 3
3 of 13
6.
What consent is required prior to performing amniocentesis or CVS?
Written consent should be obtained prior to performing amniocentesis or CVS.
It is good clinical practice to obtain formal written consent for amniocentesis or CVS before the procedure.
Practice should conform to recommendations on consent from the General Medical Council and the RCOG.
Use of the Department of Health Consent Form 3 is recommended.Written or oral information should include
the reason for offering the invasive procedure, the explanation of the type of cytogenetic results which will
become available, processes for any long-term sample storage and quality control. Information should also be
provided in relation to:
national and locally estimated risks of procedure related pregnancy loss
accuracy and limitations of the particular laboratory test(s) being performed, with information noted on
culture failure rates and reporting times

method of communication of results
indications for seeking medical advice following the test
the need for anti-D post procedure if the woman is RhD negative.
A record of the counselling process, including consent, should be clearly recorded in the patient notes.
7.
What technique should be used to perform amniocentesis or CVS?
Needle insertion during amniocentesis and transabdominal CVS should be carried out under
simultaneous ultrasound visualisation by the practitioner performing the ultrasound guidance.
Transplacental passage of the amniocentesis needle should be avoided unless it provides the only safe
access to an adequate pool of liquor.
Maximum outer needle gauge size of 0.9 mm (20-gauge) should be used to perform amniocentesis.
Clinicians should use the CVS technique with which they are competent, using local anaesthesia for
transabdominal CVS.
Methods of amniocentesis have been variously described in the literature. A blind procedure
involving palpating the outline of the uterus and inserting a needle into a selected spot is no longer
an acceptable technique. With ultrasound guidance, the contents of the uterus, particularly the
position of the placenta and the umbilical cord insertion, are visualised prior to amniocentesis and
a suitable entry point on the mothers abdomen noted. The use of real-time ultrasound allows the
insertion of the needle under continuous ultrasound control and is the technique of choice.
Evidence
level 2+
Continuous visualisation of the needle with ultrasound reduces bloodstaining from 2.4% to 0.8%.13 Similar
evidence for adopting continuous ultrasound guidance is drawn from other studies14,15 and, although most
studies used historical controls, the trend of improved outcome, reduced bloodstaining of the amniotic fluid
and greater success in obtaining amniotic fluid is apparent.
There are case reports documenting serious fetal trauma caused by an amniocentesis needle, although
continuous ultrasound guidance minimises the risk.16 Continuous guidance is more likely to avoid maternal
bowel injury at needle insertion.The current recommendation for continuous ultrasound control rests on the
need to avoid dry and bloody taps principally because the presence of blood may interfere with amniocyte
culture.
Traditionally, amniocentesis techniques aimed at avoiding the placenta have been adopted;Tabor et
al. suggested an increased miscarriage rate following placental puncture.1 However, recent
evidence suggests that penetration of the placenta may not be associated with increased
complications where continuous ultrasound guidance is used. Three large studies involving over
2000 cases have not demonstrated increased miscarriage rates where the transplacental approach
4 of 13
Evidence
level 2+
was used.1719 Unfortunately, needle size is only mentioned in one of the studies.17 In fact, if a clear
pool of amniotic fluid can be reached only by passage through the placenta then this is the
approach of choice. Under these circumstances, placing the needle through the thinnest available
part of the placenta is recommended. It is also important to ensure that the placental cord insertion
is avoided.
Needle diameter is likely to be important but there are few clinical data upon which to base choice.
The study of Tabor et al. used a 20-gauge needle (note that in the original report the size of the
needle was reported as 18-gauge by mistake).1 One experimental model comparing 18-, 20- and 22gauge needles suggested that there was less amniotic fluid flow from the puncture site with smaller
gauge needles.20
Evidence
level 2+
Some experts recommend particular angles at which the needle should enter the uterus but the
data are not robust enough to guide practice.21
Amniocentesis generates considerable parental anxiety but most women rate the discomfort as
equivalent to that of venepuncture.22 A randomised trial by van Schonbrock et al. showed that
injection of local anesthetic did not reduce pain scores reported by women undergoing
amniocentesis.22
Evidence
level 1+
A recent survey of practice revealed that only 4% of the specialists in the UK use local anesthesia
for amniocentesis compared with 98% when transabdominal CVS is performed.23
Evidence
level 3
There is a consensus that CVS, both transabdominal and transcervical, must be performed under
continuous ultrasound control. Techniques for transabdominal CVS vary significantly both in the
size of the needle used (18-gauge, 20-gauge, double needle 17/19-gauge, double needle 18/21gauge) and method of aspiration (negative pressure by syringe, negative pressure by vacuum
aspirator, biopsy forceps). As there are no published studies comparing clinical outcomes using
different techniques, clinicians are advised to use the technique with which they are familiar. The
same applies to transcervical CVS; although there is some evidence to support use of small forceps
as opposed to aspiration cannulae, the evidence is not strong enough to support change in practice
for clinicians familiar with aspiration cannulae.24
Evidence
level 1-
8.
What is required for training and maintaining good practice in amniocentesis or CVS?
Operators carrying out unsupervised amniocentesis and CVS should be trained to the competencies
expected of subspecialty training in maternal and fetal medicine, the RCOG Fetal Medicine Advanced
Training Skills Module (ATSM) or other international equivalent.
Clinical skills models, assessment of interaction with patients and supervised procedures should be an
integral part of training.
Competency should be maintained by carrying out at least 30 ultrasound guided invasive procedures
per annum.
Units and operators should carry out continuous audit of frequencies of multiple insertions, failures,
bloody taps and post procedure losses.
Very experienced operators (more than 100 per annum) may have a higher success rate and a lower
procedure-related loss rate. Occasional operators who perform a low number of procedures per annum
may have increased rates of procedure-related loss.
Further opinion should be sought from a more experienced operator if difficulties are anticipated or
encountered.
5 of 13
Expert opinion suggests that an operators competence should be reviewed where loss rates appear high
and audit should certainly occur where they exceed 4/100 consecutive amniocenteses or 8/100 CVS.
Operator experience, as well as technique, may be important. Results from a study in which the
majority of amniocenteses were undertaken by a single operator were compared with those of an
occasional operator.With the former, success at the first attempt occurred in 94% of amniocenteses,
with 3% of bloody taps, compared with 69% and 16%, respectively, for the latter.25 Maternal
contamination rates are lower when practitioners perform greater numbers of amniocentesis.26
Studies comparing very experienced practitioners (more than 100 procedures per annum) with
less experienced practitioners have shown substantial differences in outcome, with a six- to eightfold increase in loss rates associated with less experience.27,28
Evidence
level 2+
A Medical Research Council (MRC) trial found no clear evidence that over the course of the trial (4 years)
increased operator experience improved safety of CVS.29 However, each operator was required to perform at
least 30 procedures before participation.
Adequate training and maintenance of skills are important. Ultrasound skills for performing invasive prenatal
procedures are greater than those required for the completion of the RCOG specialist training logbook.
Specific training in invasive diagnostic procedures will include ultrasound training beyond this level. Best
practice requires ultrasound training to the level of the current RCOG subspecialty training in maternal and
fetal medicine, ATSM in fetal medicine or equivalent.
Before undertaking procedures on women, consideration should be given to initial training using a
clinical skills model. Several suitable models have been constructed and some of these validated.30
Pittini et al. used a well-validated educational approach that included examination of patient
interactive skills.31 They demonstrated improved performance among all levels of trainees but
particularly those with the least experience before the training, suggesting an ability to shorten the
learning curve. Nizard et al. suggest that between 50 and 100 procedures are required to be
undertaken before there is no further improvement.32
Evidence
level 2+
Postgraduate training is moving to competence-based assessments rather than adherence to a particular

numerical goal and no concrete data exist on the number of supervised prenatal invasive procedures
necessary before competence is gained. Amniocentesis and CVS procedures are practical skills and trainees
will achieve competence at different rates. Individual centres should agree to a training and assessment
process that is open and transparent, and with a clearly responsible trainer. Local deaneries and NHS trust
clinical governance systems should have a role in ensuring quality training.
Although it is not currently possible to make evidence-based recommendations on the annual number of
procedures required to maintain competency, an arbitrary number of at least 30 ultrasound-guided invasive
procedures per annum is reasonable. This number should be feasible in most clinical settings in the UK.
Operators performing less than this number should ensure that they have audit processes in place to provide
robust evidence of safety.
Competence is best assessed through continuous audit of complications such as need for second insertion
and miscarriage rate.The 95% confidence intervals for complications from experienced operators1,33 indicate
that second insertion may be acceptable in, at most, 7/100 consecutive amniocentesis cases. Pregnancy loss
should not exceed 4/100 amniocenteses. Higher numbers of complications may be an unfortunate cluster or
consequence of high background risk of miscarriage. Nevertheless, where loss rates exceed these limits, an
independent review of the operators skills should be carried out.
Comparable numbers for CVS are different because of the higher background risk of miscarriage. Also, CVS is
often performed in the presence of increased nuchal translucency, cystic hygroma, fetal anomalies or genetic
6 of 13
conditions, most of which are associated with a higher spontaneous miscarriage rate. The Cochrane Review
quotes CVS sampling failure between 2.5% and 4.8% and spontaneous miscarriage rate of 3% after transabdominal CVS in the Danish trial and 7.9% in the MRC trial.24 If one accepts a 3% sampling failure rate and a
3% pregnancy loss as the gold standard, an audit of practice should be carried out when either five sampling
failures or eight miscarriages occur in 100 consecutive cases.6
Obviously, any such audit should take into account the background risk of miscarriage, which is likely to be
significantly higher in the presence of fetal anomaly or subsequently diagnosed abnormal karyotype. All
organisations where prenatal invasive procedures are carried out should have robust mechanisms for
collecting and monitoring these data.The mechanisms of review should be agreed locally, though national or
regional guidance should be developed.
For either procedure, a more experienced operator should be consulted if two attempts at uterine insertion
have failed to produce an adequate sample for analysis.
9.
What are the clinical considerations when performing amniocentesis or CVS for multiple
pregnancy?
It is recommended that, in the case of multiple pregnancies, a CVS or amniocentesis is performed by a

specialist who has the expertise to subsequently perform a selective termination of pregnancy if
required.
A high level of expertise in ultrasound scanning is essential for operators undertaking amniocentesis or CVS
in multiple, dichorionic pregnancies, because uterine contents have to be mapped with great care. This is
essential to ensure that separate samples are taken for each fetus and clearly labelled as such.
Labelling is greatly assisted by the presence of obvious fetal abnormality (such as hydrocephalus or heart
defect) or discordant fetal gender. However, to minimise the risk of chromosomal abnormality being assigned
to the wrong twin, invasive procedures in multiple pregnancy should only be performed by a specialist who
is able to proceed to selective termination of pregnancy. It is very unlikely that a specialist would be prepared
to carry out a selective termination of pregnancy relying on information provided by a referring doctor,
particularly in the absence of clearly identifiable ultrasound appearances.
Most clinicians will use two separate puncture sites when performing amniocentesis or CVS in multiple
pregnancies, although there are series using single-entry techniques with low rates of complications.34 Either
way, the miscarriage rate is likely to be higher than in singleton pregnancies.35 A recent single-centre study of
311 twin, mid-trimester amniocenteses estimated the attributable pregnancy loss rate at 1/56 (1.8%).36
The role of CVS in dichorionic placentas remains controversial because of a relatively high risk of crosscontamination of chorionic tissue, which may lead to false positive or false negative results. This risk may be
minimised if two separate needles are used. Such procedures should be performed only after detailed
counselling.
10. What information should women be given about third-trimester amniocentesis?

Women should be informed that third-trimester amniocentesis does not appear to be associated with a
significant risk of emergency delivery.
Women should be informed that, compared with mid-trimester procedures, complications including
multiple attempts and bloodstained fluid are more common in third-trimester procedures.
Amniocentesis in the third trimester is carried out for a number of indications, most commonly, for late
karyotyping and detection of suspected fetal infection in prelabour preterm rupture of the membranes
7 of 13
Evidence
level 2+
(PPROM). Much of the literature on the risks of late amniocentesis predates the use of continuous
ultrasound-guided amniocentesis. More recent series report more than one attempt in over 5% of
samplings and bloodstained fluid in 510% of cases.37,38 When amniocentesis is carried out in the
presence of PPROM, failure rates are higher.39 Serious complications are rare.Two series with 194 and
562 procedures did not describe any emergency deliveries as a result of amniocentesis, while Stark et
al. suggested a rate of 0.7% for procedure-related delivery.37,38,40 A casecontrol study of 167 matched
pairs reported a composite poor outcome (urgent birth, abruption, premature rupture of the
membranes and 5-minute Apgar score less than 7) among women undergoing amniocentesis after 32
weeks for lung maturity studies; late amniocentesis resulted in no adverse outcomes compared with
one adverse outcome in controls.41 There is a suggestion that culture failure rates may be higher
following third-trimester amniocentesis with a rate of 9.7% reported in the series of ODonoghue et al.42
11.
Evidence
level 2+
What are the risks of transmission of infection?
The ultrasound probe should be enclosed in a sterile bag during any invasive prenatal procedure unless
suitably audited processes for probe decontamination and gel microbiological surveillance are in place.
Separate sterile gel should be used.
P
P
Invasive prenatal procedures should not be carried out without reviewing available bloodborne virus
screening tests.
Where women decline screening for bloodborne viruses and are being counselled for prenatal
diagnostic procedures, inform and document the potential risk of vertical transmission of infection to
the fetus.
Review viral load and treatment regimens prior to invasive prenatal testing in women with HIV and
consider delaying the procedure until there is no detectable viral load if the woman is already on
treatment.
Consider antiretroviral therapy prior to prenatal invasive procedures in women not yet on treatment for
HIV.
Invasive prenatal testing in the first or second trimester can be carried out in women who carry hepatitis
B or C. The limitations of the available data should be explained.
Severe sepsis, including maternal death, has been reported following invasive prenatal procedures. The level
of risk cannot be quantified as case report literature does not provide denominator information but the risk
of severe sepsis is likely to be less than 1/1000 procedures. Infection can be caused by inadvertent puncture
of the bowel, skin contaminants or organisms present on the ultrasound probe or gel. The first two sources
should be avoidable by standard practices. Decontamination of ultrasound probes between patients is variable
and there are practical difficulties in balancing the need for cleaning with prevention of degradation of the
probe.43 Ultrasound gel may contain organisms and many departments have mechanisms to minimise the risks
including the use of sterile ultrasound gel when performing invasive procedures. Standards for control of
infection should conform to those for any invasive diagnostic radiological procedure and are commented on
by the Health Care Commission.
Bloodborne viruses constitute both an infection-control risk and a possible risk factor for
maternalfetal transmission. For hepatitis B, individual studies are small but show no evidence of a
transmission risk.44 Davies et al. concluded that the risk of transmission of hepatitis B was very
low.45 It has been suggested that e antigen status may be important and recent evidence shows that
maternal viral load is more important for determining the risk of transmission.45 There are fewer
data on transmission of hepatitis C but, to date, there is currently no evidence that transmission is
increased following amniocentesis.41,46
8 of 13
Evidence
level 2+
Most studies examining HIV suggest that invasive testing may be a risk factor in transmission to the
fetus and recommend avoidance, although most studies predate the use of antiretroviral drugs.47,48
The data are most robust for third-trimester procedures where the relative risk is 4.48 Others have
suggested that testing earlier in pregnancy is safe provided that retroviral therapy is being used and
the maternal viral load is low.49 Specialists need to be aware and inform women that the vast
majority of evidence is based on amniocentesis and that data on CVS are very limited. Where
antiretroviral therapy is used, an Italian study demonstrated no difference in transmission rates
between HIV positive women undergoing amniocentesis and those who did not.50 A small French
study involving women where triple retroviral therapy was instituted did not show an increase in
transmissions following amniocentesis.51 Of 166 procedures in the 81 women receiving highly
active antiretroviral therapy, there were no cases of transmission; however, there were significant
rates of transmission where no treatment was in place (25%) and where mono or double therapy
was used (6.1%).52 Whenever possible, procedures should be delayed until treatment has optimised
the maternal viral load.
Evidence
level 2+
Where the results of screening for maternal infection are not yet known or the woman has declined such
testing then informed consent should include discussion of the risks of vertical transmission of infection. If
no HIV test result is available, advise delaying the invasive test and perform a rapid HIV test. If results indicate
maternal infection then the risk of transmission should be discussed and consideration given to starting
antiretroviral therapy to reduce the viral load prior to the procedure.
11.1 Rhesus status

Maternal RhD status should be available or obtained in every case. Prophylaxis with anti-D immunoglobulin must be offered following each procedure in line with national recommendations.53
Evidence
level 1+
12. How should care be organised in providing amniocentesis and CVS?

The scope of this guideline is confined to technical aspects of the two procedures. For the woman and her
family, good care in these circumstances encompasses more than the simple performance of a technique.
Women facing either procedure are usually anxious and clinicians should bear this in mind.
Hospital trusts and organisations should ensure that the equipment, environment, staff training, arrangements
for follow-up and links with related services carrying out pregnancy termination or support for women with
diagnosed chromosomal or genetic disease are of sufficient standard. The National Screening Committee
provides advice and direction on service organisation for prenatal diagnosis.
Rate of pregnancy loss at any gestation after a procedure.

Rate of pregnancy loss less than 24+0 weeks after a procedure.
Rate of pregnancy loss within 14 days of procedure.
Local cytogenetic laboratory culture failure rates for amniocentesis and CVS.
Proportion of procedures requiring more than one needle insertion.
Proportion of procedures with failure to obtain an adequate sample.
Complication rates (bloody tap, amniotic fluid leakage).
Maintenance of a register of invasive diagnostic procedures to facilitate audit. Audit should be performed
annually and the results made accessible to patients.
Rate of antiD prophylaxis for women who are RhD-negative undergoing amniocentesis or CVS.
14. Areas for further research
Comparison of safety of different techniques for transabdominal CVS.

Transmission rates of bloodborne virus following invasive prenatal testing.
9 of 13
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Giorlandino C, Mobili L, Bilancioni E, DAlessio P, Carcioppolo
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Marthin T, Liedgren S, Hammar M.Transplacental needle
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Bombard AT, Powers JF, Carter S, Schwartz A, Nitowsky HM.
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Gratacos E, Devleiger R, Decaluwe H, Wu J, Nicolini U, Deprest
JA. Is the angle of needle insertion influencing the created
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between specialists opinions and ex vivo observations. Am J
22. van Schonbrock D,Verhaeghe J. Does local anaesthesia at midtrimester amniocentesis decrease pain experience? A
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23. Carlin AJ, Alfirevic Z.Techniques for chorionic villus sampling
and amniocentesis: a survey of practice in specialist UK
centres. Prenat Diagn 2008;28:91419.
24. Alfirevic Z, von Dadelszen P. Instruments for chorionic villus
sampling for prenatal diagnosis. Cochrane Database Syst Rev
2003;CD000114.
25. Wiener JJ, Farrow A, Farrrow SC. Audit of amniocentesis from a
district general hospital: is it worth it? BMJ 1990;300:12435.
26. Welch RA, Salem-Elgharb S, Wiktor AE, Van Dyke DL, Blessed
WB. Operator experience and sample quality in genetic
amniocetesis. Am J Obstet Gynecol 2006;194:18991.
27. Blessed WB, Lacoste H, Welch RA. Obstetrician-gynecologists
performing genetic amniocentesis may be misleading
themselves and their patients. Am J Obstet Gynecol
2001;1784:13402.
28. Anandakumar C, Wong YC, Annapoorna V, Arulkumaran S, Chia
D, Bongso A, et al. Amniocentesis and its complications. Aust N
Z J Obstet Gynaecol 1992;32:979.
29. MRC Working Party On The Evaluation Of Chorionic Villus
Sampling. Medical Research Council European trial of
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30. Maher JE, Kleinman GE, Lile W,Tolaymat L, Steele D, Bernard J.
The construction and utility of an amniocentesis trainer. Am J
31. Pittini R, Oepkes D, Macrury K, Reznick R, Beyene J, Windrim R.
Teaching invasive perinatal procedures:assessment of a high
fidelity simulator-based curriculum. Ultrasound Obstet
Gynecol 2002;19:47883.
32. Nizard J, Duyme M, Ville Y.Teaching ultrasound-guided invasive
procedures in fetal medicine: learning curves with and without
an electronic guidance system. Ultrasound Obstet Gynecol
2002;19:2747.
33. Horger EO, Finch H, Vincent VA. Single physicians experience
with four thousand six hundred genetic amniocentes. Am J
34. Antsaklis A, Souka AP, Daskalakis G, Kavalakis Y, Michalas S.
Second-trimester amniocentesis vs. chorionic villus sampling
for prenatal diagnosis in multiple gestations. Ultrasound Obstet
Gynecol 2002;20:47681.
35. Yukobowich E, Anteby EY, Cohen SM, Lavy Y, Granat M,Yagel S.
Risk of fetal loss in twin pregnancies undergoing second
trimester amniocentesis. Obstet Gynecol 2001;98:2314.
36. Cahill AG, Macones GA, Stamilio DM, Dicke JM, Crane JP, Odibo
AO. Pregnancy loss rate after mid-trimester amniocentesis in
twin pregnancies. Am J Obstet Gynecol 2009;200:257.
37. Gordon MC, Narula K, OShaughnessy R, Barth WH Jr.
Complications of third-trimester amniocentesis using
continuous ultrasound guidance. Obstet Gynecol
2002;99:2559.
38. Stark CM, Smith RS, Lagrandeur RM, Batton DG, Lorenz RP.
Need for urgent delivery after third-trimester amniocentesis.
39. Blackwell SC, Berry SM. Role of amniocentesis for the diagnosis
of subclinical intra-amniotic infection in preterm premature
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40. Hausler MC, Konstantinuik P, Dorfer M, Weiss PA. Amniotic fluid
insulin testing in gestational diabetes: safety and acceptance of
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41. Hodor JG, Poggi SH, Spong CY, Goodwin KM, Vink JS, Pezzulio
JC, et al. Risk of third trimester amniocetesis:a casecontrol
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43. Backhouse S. Establishing a protocol for the cleaning and

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44. Alexander JM, Ramus R, Jackson G, Sercely B, Wendel GD Jr.
Risk of hepatitis B transmission after amniocentesis in chronic
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45. Davies G, Wilson RD, Desilets V, Reid GJ, Shaw D, Summers A, et
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46. Delamare C, Carbonne B, Heim N, Berkane N, Petit JC, Uzan S,
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47. Mandelbrot L, Mayaux MJ, Bongain A, Berrebi A, MoudoubJeanpetit Y, Bnifla JL, et al. Obstetric factors and mother-tochild transmission of human immunodeficiency virus type 1:
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51. Ekouko D, Khoung-Josses MA, Ghibaudo N, Mechali D, Rotten
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52. Mandelbrot L, Jasseron C, Ekoukou D, Batallan A, Bongain A,
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APPENDIX
at www.rcog.org.uk/womens-health/clinical-guidance/development-rcog-green-top-guidelinespolicies-and-processes). These recommendations are not intended to dictate an exclusive course of
management or treatment. They must be evaluated with reference to individual patient needs, resources
of clinical uncertainty where further research may be indicated within the appropriate health services.
The evidence used in this guideline was graded using the scheme below and the recommendations
formulated in a similar fashion with a standardised grading scheme. Once adapted for local use, these
guidelines are no longer representative of the RCOG.

reviews of randomised controlled trials or
randomised controlled trials with a very low
risk of bias
1+

low risk of bias

risk of bias

2+
3
4

Non-analytical studies; e.g. case reports,
case series

population and demonstrating overall
1++ or 1+
results; or
2++
2+
Good practice point
Expert opinion
At least one meta-analysis, systematic reviews

or randomised controlled trial rated as 1++
population; or
12 of 13

development group
The first two versions of this guideline were produced by Professor MJ Whittle FRCOG. This guideline was produced
on behalf of the Guidelines Committee of the Royal College of Obstetricians and Gynaecologists by
Professor Z Alfirevic FRCOG, Liverpool; Mr SA Walkinshaw FRCOG, Liverpool; and Professor MD Kilby
FRCOG, Birmingham.
It was peer reviewed by the British Medical Ultrasound Society; British Maternal and Fetal Medicine Society; NHS
Infectious Diseases in Pregnancy Screening Programme; Antenatal Results and Choices; Mr DT Liu FRCOG,
Nottingham; RCOG Consumers Forum; Genetic Interest Group; Antenatal Screening Wales; Professor CH Rodeck
FRCOG, London; Professor AD Cameron FRCOG, Glasgow.
The Guidelines Committee lead reviewers were Dr P Owen MRCOG and Dr SK Surendran FRCOG.
The guideline review process will commence in 2013
unless otherwise indicated
DISCLAIMER
of clinical data presented by the patient and the diagnostic and treatment options available within the appropriate
health services.
13 of 13
Pregnancy and Breast Cancer

March 2011
Pregnancy and Breast Cancer

This title was first published as RCOG advice in 1997 and subsequently as a Green-top Guideline in January
2004.This document is the second edition of the guideline and updates the previous 2004 edition.
1.
Purpose and scope
This document aims to provide clinical guidance to health professionals caring for women of childbearing
age with a diagnosis or history of breast cancer.The management of pregnancy in relation to breast cancer
is multidisciplinary.The guideline will be of value to obstetricians and gynaecologists, fertility specialists
and midwives as well as oncologists and breast care nurses.
2.
Background
Breast cancer is the most common cancer in females, with a lifetime risk of one in nine in the UK, and is
the leading cause of death in women aged 3554 years. Fifteen percent of cases are diagnosed before the
age of 45 years, thus breast cancer affects almost 5000 women of reproductive age in the UK annually.
Between 1991 and 1997 there were 1.32.4 cases of breast cancer in women per 10 000 live births,1,2
although when breast cancer is diagnosed in women aged 30 years or less, 1020% of cases may be
associated with pregnancy or occur within 1 year postpartum.
The prognosis of breast cancer is improving, with 5-year survival around 80% for the under 50s age group;
however, the survival rate may be lower in very young women.3 Treatment of pregnancy-associated cancer
should be in a multidisciplinary team according to standard UK guidelines4 with inclusion of the obstetric
team as core members.
Fewer than 10% of women diagnosed with breast cancer subsequently become pregnant,5,6 but increasing
numbers of women are seeking pregnancy following treatment.Young women presenting with breast
cancer often have fertility-related concerns79 and need well-informed discussions on fertility, pregnancy
and lactation after breast cancer and the availability of fertility preservation procedures.
3.
This guideline was developed in accordance with standard methodology for producing RCOG Green-top
Guidelines.Medline,Pubmed,all EBM reviews (Cochrane CRCT, Cochrane Database of Systematic Reviews,
Methodology register, ACP journal club, DARE, HTA, Maternity and Infant Care), EMBASE and TRIP were
searched for relevant randomised controlled trials,systematic reviews and meta-analyses,cohort studies and
case studies.The search was restricted to articles published between 2002 and December 2009, updated
from the original search for the previous edition.The search terms included were:breast neoplasms,
breast cancer,pregnancy,pregnancy complications,breast cancer and fertility,mastectomy,breastfeeding,lactation,contraception,fertilityandinfertility.Abstracts were used to identify key articles.The
National Library for Health and the National Guidelines Clearing House were searched for relevant
guidelines.
In contrast to the extensive literature on treatment of breast cancer, there is no level 1 evidence on
pregnancy and breast cancer.There are some well-designed observational studies.Thus, recommendations
for practice are limited to grade C/D but, where possible, recommendations are based on, and explicitly
linked to, the evidence that supports them.Areas lacking evidence are highlighted and annotated as good
practice points.
2 of 15
4.
What is the optimal management of breast cancer diagnosed during pregnancy?
4.1 Prognosis
Pregnancy itself does not appear to worsen the prognosis for women diagnosed in pregnancy
compared with non-pregnant controls matched for age and stage10 (provided that standard
treatment guidelines for the breast cancer are adhered to).
Evidence
level 2
However, as pregnancy-associated breast cancer occurs in a younger population who may have
features that carry a higher risk of metastases such as high-grade tumours and estrogen receptor
negative tumours, these younger women may be expected to have an inferior prognosis.11,12
Evidence
level 2+/3
4.2 Diagnosis
Women presenting with a breast lump during pregnancy should be referred to a
breast specialist team and any imaging or further tests should be conducted in
conjunction with the multidisciplinary team.
Diagnosis may be difficult in women who are pregnant or lactating.Women presenting with a breast lump
during pregnancy should be referred to a breast specialist team and any imaging or further tests should
be conducted within the breast multidisciplinary team. Women should have a designated key worker,
usually a breast care nurse. Ultrasound is used first to assess a discrete lump, but if cancer is confirmed,
mammography is necessary (with fetal shielding) to assess the extent of disease and the contralateral
breast.Tissue diagnosis is with ultrasound-guided biopsy for histology rather than cytology, as proliferative
change during pregnancy renders cytology inconclusive in many women.Histology is similar to that in agematched non-pregnant counterparts: histological grade, receptor status and human epidermal growth
factor receptor 2 (HER2) inform treatment planning. Staging for metastases is conducted only if there is
high clinical suspicion and should comprise chest X-ray and liver ultrasound if possible. Gadoliniumenhanced magnetic resonance imaging is not recommended unless there is a specific need for it to
investigate a clinical problem; there are limited data for the use of this imaging method in pregnancy,
although no adverse effects of gadolinium on the fetus have been reported.13 Tumour markers such as
CA15-3, CEA and CA125 are not used in early breast cancer and may be misleading in pregnancy, and are
not recommended.
Bone scanning and pelvic X-ray computed tomography are not recommended
because of the possible effect of irradiation on the fetus.
In women who are not pregnant, X-ray computed tomography (CT) and isotope bone scan are the
preferred methods of investigation to establish or exclude metastases.These methods are not appropriate
in women who are pregnant, in whom chest X-ray and liver ultrasound are preferred. If there is concern
about bone involvement, a plain film of the relevant area and/or magnetic resonance imaging to minimise
radiation exposure to the fetus is suggested.
4.3 Consideration of termination of pregnancy

The decision to continue the pregnancy should be based on careful discussion of the
cancer prognosis, treatment and future fertility with the woman and her partner and
multidisciplinary team.
4.4 Treatment during pregnancy

The multidisciplinary team review outcome should be forwarded to the obstetric team
and family doctor.
3 of 15
Surgical treatment including loco-regional clearance can be undertaken in all trimesters. Breastconserving surgery or mastectomy can be considered, based on tumour characteristics and
breast size, following multidisciplinary team discussion. Reconstruction should be delayed to
avoid prolonged anaesthesia and to allow optimal symmetrisation of the breasts after delivery.
Sentinel node assessment using radioisotope scintigraphy does not cause significant uterine
radiation,14 but blue dye is not recommended as the effect upon the fetus is unknown. Sentinel
node biopsy is indicated in women who have a negative result from a preoperative axillary
ultrasound and needle biopsy. If the axilla is positive, axillary clearance is indicated.
Evidence
level 4
Radiotherapy is contraindicated until delivery unless it is life saving or to preserve organ function (e.g.
spinal cord compression). If necessary, radiotherapy can be considered with fetal shielding or, depending
on gestational age, early elective delivery could be discussed. Routine breast/chest wall radiotherapy can
be deferred until after delivery.
Systemic chemotherapy is contraindicated in the first trimester because of a high rate of fetal
abnormality, but is safe from the second trimester and should be offered according to protocols
defined by the risk of breast cancer relapse and mortality.Anthracyline regimens are safe; there
are fewer data on taxanes, which should be reserved for high-risk (node-positive) or metastatic
disease.1517 Standard antiemetics including 5HT3 serotonin antagonists and dexamethasone
should be used.There are no data on a neurokinin recptor antagonist with very high efficacy in
chemotherapy-induced emesis.There is no evidence for an increased rate of second-trimester
miscarriage or fetal growth restriction, organ dysfunction or long-term adverse outcome with
the use of chemotherapy.17,18
Evidence
level 3
For women in whom tumour characteristics,defined by imaging and core biopsy,mean that chemotherapy
is indicated, a decision may be made to offer neoadjuvant chemotherapy before surgery to allow tumour
downstaging and to facilitate surgery. Occasionally, with a low-risk tumour in which chemotherapy is not
indicated, there may be an indication for mastectomy. In this situation radiotherapy would be deferred.
Tamoxifen and trastuzumab are contraindicated in pregnancy and should not be
used.
Tamoxifen is not used until after delivery.Trastuzumab, a monoclonal antibody targeted against
the HER2/neu receptor, is contraindicated during pregnancy because of reported adverse fetal
outcome.19,20 There are no data on other targeted therapies such as vascular endothelial growth
factor antagonists, including bevacizumab. However, there are no compelling oncological
reasons for use of targeted therapies including monoclonal antibodies or small-molecule tyrosine
kinase inhibitors during pregnancy as conventional chemotherapy can be used, allowing these
drugs to be reserved for postpartum. Haemopoietic growth factors (granulocyte colonystimulating factor) may be employed to ameliorate chemotherapy-induced neutropenia and
have been used extensively in haematological malignancy; their use is recommended to
minimise potential maternal and fetal problems associated with neutropenia.21 Use of these and
other drugs should be discussed with the obstetrician.
Evidence
level 3
4.5 Timing of delivery of the baby

The birth of the baby should be timed after discussion with the woman and the
multidisciplinary team.
Most women can go to full term of pregnancy and have a normal or induced delivery. If early delivery of
the baby is necessary, consideration of corticosteroids for fetal lung maturation is appropriate. However,
birth should be more than 23 weeks after the last chemotherapy session to allow maternal bone marrow
recovery and to minimise problems with neutropenia.
4 of 15
4.6 Lactation
Women should not breastfeed when taking trastuzumab (Herceptin, Roche) or

tamoxifen, as it is unknown whether these drugs are transmitted in breast milk.
The ability to breastfeed may depend on surgery and whether major ducts have been excised.
Breastfeeding while on chemotherapy is not advised,as the drugs cross into breast milk and may
cause neonatal leucopenia with a risk of infection.There should be a time interval of 14 days or
more from the last chemotherapy session to start of breastfeeding to allow drug clearance from
breast milk.22
Evidence
level 3
If chemotherapy is restarted, breastfeeding must cease. A short period of lactation may be

psychologically beneficial after a stressful pregnancy and be beneficial to the baby.23 Women
taking tamoxifen should not breastfeed.
Evidence
level 4
Women should not breastfeed when taking trastuzumab as it is unknown whether this drug is transmitted
in breast milk.
5.
What are the contraceptive choices for women wishing to avoid pregnancy after
treatment of breast cancer?
Non-hormonal contraceptive methods are recommended.

Women with a history of breast cancer should seek specialist contraceptive advice. Hormonal
contraception is contraindicated in women with current or recent breast cancer (World Health
Organization/UK medical eligibility category 4).24 This advice does not differentiate between
hormone-sensitive and hormone-insensitive tumours. Although hormonal contraception may
be considered after at least 5 years free of recurrence (World Health Organization/UK category
3)24 and current evidence allays concerns that long-term oral contraceptive use affects breast
cancer risk,25,26 there is insufficient evidence to support the use of combined or progestogenonly hormonal contraceptives when alternative non-hormonal methods are suitable and
acceptable.
Evidence
level 4
The levonorgestrel intrauterine system (LNG-IUS: Mirena, Bayer Healthcare Pharmaceuticals)

may reduce the risk of endometrial abnormalities during tamoxifen therapy,27 but further
evidence is required on its safety in breast cancer survivors. No overall increase in recurrence
risk was found in a retrospective controlled cohort study of LNG-IUS users compared with nonusers (adjusted hazard ratio 1.86, 95% CI 0.864.00),28 although subgroup analysis suggested a
higher recurrence risk, which was of borderline significance, in women who developed breast
cancer while using LNG-IUS and continued its use (adjusted hazard ratio 3.39, 95% CI 1.01
11.35).28
Evidence
level 2+
6.
What advice should be given to women planning pregnancy following breast cancer?
Women planning a pregnancy after treatment for breast cancer should consult their
clinical oncologist, breast surgeon and obstetrician.
Women on tamoxifen are advised to stop this treatment 3 months before trying to conceive because of
the long half-life of the drug, and to have any routine imaging before trying to conceive to avoid the need
for imaging during pregnancy. Women with metastatic disease should be advised against a further
pregnancy as life expectancy is limited and treatment of metastatic disease would be compromised.The
remainder of this section concerns women treated for early-stage disease.
5 of 15
6.1 Impact of pregnancy on risk of recurrence

Women can be reassured that long-term survival after breast cancer is not adversely
affected by pregnancy.
Since many breast cancers are estrogen receptor positive and endocrine responsive, women used to be
advised against pregnancy because of concerns that it would worsen prognosis. However, the evidence
from the published studies is reassuring, showing either no impact on survival or improved survival.
Despite the limitations of the studies, which are mainly retrospective casecontrol series with limited
numbers,they at least demonstrate that outcome after treatment for breast cancer is not adversely affected
by pregnancy.29,30
The prognosis is good for women with a subsequent pregnancy after early-stage breast cancer.3133
The published series reflect an improvement in treatment over recent decades. A recent
population-based study in Western Australia from 1982 to 2003 reported survival rates of 92%
at 5 years and 86% at 10 years.6
Evidence
level 2+
Several studies show better survival outcome in women who conceive after treatment for breast
cancer.5,6,32,34,35 In the largest series, women who had a full-term pregnancy (n = 199) had a
relative risk of death of 0.73 (95% CI 0.540.99).5 These findings may be explained by selection
bias and the healthy mother effect described by Sankila:36 healthy women are more likely to
conceive, and women with poor prognosis or early relapse do not embark upon pregnancy.
Evidence
level 2+
However, some authors postulate an actual protective effect of pregnancy.6,37

The impact of pregnancy does not seem to be modified by tumour characteristics (e.g. size,
hormone receptor status),5 but there are insufficient data to draw firm conclusions. In women
with BRCA gene mutations, the risks associated with subsequent pregnancy are uncertain.38
Evidence
level 2+
6.2 Time interval before pregnancy

Advice on postponement of pregnancy should be individualised and based on
treatment needs and prognosis over time. Most women should wait at least 2 years
after treatment, which is when the risk of cancer recurrence is highest.
Women are generally advised to wait for at least 2 years after treatment for breast cancer before
conception37,3941 because of the risk of early relapse.The rate of disease recurrence is highest
in the first 3 years after diagnosis and then declines,42 although late relapses do occur up to 10
years and more from diagnosis.3
Evidence
level 3
Women with estrogen receptor positive disease should be advised that the recommended duration of
tamoxifen treatment is 5 years.
This advice has been challenged because of the lack of published data showing that postponing
pregnancy has an impact on outcome;6 the literature on recurrent disease also needs to be
reviewed in the light of changing treatment regimens and improved understanding of cancer
subtypes. It has been suggested that women with a good prognosis need not wait 2 years to
become pregnant.6
6 of 15
Evidence
level 2+
An understanding of the prognostic factors affecting the individual woman tumour size,grade,
nodal status,estrogen and progesterone receptor and HER2 status should enable the oncologist
to give appropriate advice.43,44 This is of great importance to the woman desiring pregnancy,who
may need to weigh up the benefit of postponing conception, for example to complete
prolonged adjuvant therapy with tamoxifen, against the risk of infertility as a result of delay.
Evidence
level 4
6.3 Outcome of pregnancy

The majority of pregnancies after breast cancer proceed to live birth.There may be an increased
miscarriage rate following breast cancer,45 but the published series are small and not all report
maternal age (a major risk factor for miscarriage) or distinguish between spontaneous
miscarriage and induced termination.31,46,47 A recently reported series of 465 pregnant women
who were breast cancer survivors resulted in 236 full-term births (51%),36 spontaneous miscarriages (8%) and 193 induced terminations (41%).5 Women are more likely to terminate a
pregnancy when it occurs soon after treatment or during adjuvant therapy.5,6
Evidence
level 3
Women can be reassured concerning the risk of malformation in children conceived

after treatment for breast cancer.
Most of the available data do not show any increase in congenital malformations or stillbirth
among the offspring of women who have completed treatment for breast cancer.6,48,49 A large
study derived from the Danish registries identified 216 births to women with a prior diagnosis
of breast cancer and found no stillbirths, no increase in congenital anomalies no increase in low
birth weight and no substantial risk of preterm birth (OR 1.3, 95% CI 0.72.2).49 The Swedish
data on 331 births, however, showed a tendency towards an increased risk of malformations
(OR 2.1, 95% CI 1.23.7), birth before 32 weeks of gestation (OR 3.2, 95% CI 1.76.0) and birth
weight below 1500 g (OR 2.9,95% CI 1.45.8);50 nevertheless,adverse outcomes are uncommon.
Evidence
level 2+/3
The heritability of breast cancer is a source of anxiety but does not affect childhood health.Women who
are known to be breast cancer gene (BRCA) carriers may wish to consider preimplantation genetic
diagnosis, which is now available in the UK. However, some young women with a family history indicative
of genetic risk may not wish to undergo testing so as not to compromise their decisions regarding having
a family.
7.
What is the optimal management of pregnancy following treatment for breast cancer?
Pregnancy following breast cancer should be jointly supervised by the obstetrician,

oncologist and breast surgeon.
Echocardiography should be performed during pregnancy in women at risk to detect
cardiomyopathy through resting left ventricular ejection fraction or echocardiographic fractional shortening.

D
During pregnancy, a breast treated by surgery/radiotherapy may not undergo hormonal change and the
woman may require a temporary prosthesis. If breast imaging is needed, ultrasound (performed through
the breast multidisciplinary team) is preferred. Metastatic relapse may be harder to detect and common
complaints in pregnancy such as backache can be difficult to assess.
These women may have received adjuvant chemotherapy with anthracyclines (doxorubicin, epirubicin),
which can cause cumulative dose-dependent left ventricular dysfunction and, rarely, cardiomyopathy.51,52
Although cardiac complications during pregnancy are rare in cancer survivors,53 echocardiography should
be performed during pregnancy in women at risk to detect cardiomyopathy through resting left ventricular
ejection fraction or echocardiographic fractional shortening.
7 of 15
A slightly increased risk of delivery complications (OR 1.5, 95% CI 1.21.9) and caesarean
section (OR 1.3, 95% CI 1.01.7) has been reported in breast cancer survivors.50
Evidence
level 2+
The supervision of pregnancy after breast cancer should be consultant led,but midwifery involvement will
help to normalise care.
8.
What advice should be given to women wishing to breastfeed following treatment for
breast cancer?
Women can be reassured that they can breastfeed from the unaffected breast.
There is no evidence that breastfeeding increases the risk of recurrence in women who have
completed treatment for breast cancer. Only one study has reported on survival in relation to
lactation,32 and suggested that breastfeeding was associated with better survival than bottlefeeding.
Evidence
level 2+
Breast-conserving surgery may not inhibit lactation in the affected breast, but radiotherapy
causes fibrosis, making lactation unlikely.5457 There is no evidence that previous chemotherapy
affects the safety of breastfeeding.
Evidence
level 3
In view of the well-recognised benefits of breastfeeding to the baby,23 women who wish to breastfeed
should be encouraged to do so.39,58 Midwifery support helps to establish successful lactation.59
9.
What is the effect of breast cancer treatment on the womans fertility?
The effect of treatment on fertility should be discussed with all women of reproductive age diagnosed with breast cancer, and written information should be
provided. Referral to a fertility specialist should be available. Specialist counselling
should be available.
Infertility after treatment is a major concern for young women with breast cancer.6063 In an
American survey of 657 women diagnosed with breast cancer under the age of 40 years, 57%
reported substantial concern about becoming infertile and 29% stated that it influenced their
treatment decisions.63 In this sample, only 51% felt that their concerns had been adequately
addressed, and several other authors have noted womens frustration with the paucity of
information available.6466 Womens preferred source of information on fertility is consultation
with a fertility specialist backed up by an information booklet.64,67
Evidence
level 3
A recent joint working party of the Royal Colleges of Physicians, Radiologists and Obstetricians
and Gynaecologists in the UK recommended that people with cancer should be fully informed
of potential gonadotoxicity before treatment, and that specialist psychological support and
counselling should be available.68
Evidence
level 4
9.1 What is the effect of adjuvant chemotherapy on fertility?

Chemotherapy-induced gonadotoxicity may cause permanent amenorrhoea with complete loss
of germ cells,transient amenorrhoea,menstrual irregularity and subfertility.The degree of gonadotoxicity is dependent on the specific agents used, the cumulative dose administered and the
womans age.Amenorrhoea is reported in 2070% of premenopausal women with breast cancer,69
but the rate ranges from less than 5% in women under 30 years of age to 50% in women aged
3640 years.70 Alkylating agents such as cyclophosphamide have well-recognised gonadotoxicity,
8 of 15
Evidence
level 3
and the classic CMF regimen (cyclophosphamide, methotrexate, 5-fluorouracil) causes a higher
incidence of amenorrhoea than anthracycline-based regimens such as FEC (5-fluorouracil,
epirubicin, cyclophosphamide).71 The newer taxanes appear to be less gonadotoxic.72
Evidence
level 3
9.2 What is the effect of adjuvant hormonal therapy on fertility?

The agents used for adjuvant hormonal therapy do not in themselves cause long-term effects on fertility.
Tamoxifen (a selective estrogen receptor modulator) often causes menstrual irregularity and there is an
increased risk of endometrial pathology; conception during tamoxifen therapy should be avoided because
of potential teratogenicity, and a washout period of 23 months is advised. Gonadotrophin-releasing
hormone (GnRH) analogues cause amenorrhoea and profound estrogen deficiency; women may find the
menopausal symptoms worrying,but the effect is entirely reversible.Trastuzumab is a monoclonal antibody
that binds selectively to the HER2 protein expressed by some breast cancers; there is no evidence that it
impairs fertility, but pregnancy is not advised during treatment.
9.3 What advice should be given to the woman about postponement of pregnancy before embarking on further
pregnancy?
Women are generally advised to postpone pregnancy for at least 2 years after treatment and may be advised
to continue tamoxifen for 5 years. However, age is a major determinant of fertility and delay with already
poor ovarian function owing to chemotherapy is likely to lead to infertility.Women in their 30s desiring
pregnancy may wish to discuss the value of prolonged treatment with tamoxifen and consider discontinuation after 23 years. Resuming treatment with tamoxifen after childbearing has not been studied, but it
is a reasonable strategy.
9.4 Can fertility be preserved before treatment?

There is a rapidly growing literature on preservation of fertility potential before chemotherapy.At present,
only a minority of women of reproductive age undertake fertility-preservation procedures and there are
scarcely any data on long-term outcome.
9.4.1 GnRH analogues
There are insufficient level 1 data to support the routine use of GnRH analogues for
ovarian protection in estrogen receptor positive breast cancer.
GnRH analogues have therapeutic use in hormone-sensitive breast cancer, as they induce
profound ovarian suppression and create a low-estrogen state.Trials are in progress to examine
the effect on fertility potential, although there are concerns that concomitant GnRH analogues
may lessen tumour response to chemotherapy in estrogen receptor positive breast cancer.There
are several observational and phase II studies of the use of GnRH analogues during chemotherapy with the intention of protecting the oocyte pool from depletion.73 Non-randomised
studies in women with breast cancer (total n = 222) are suggestive of benefit.7476
Evidence
level 3
A recently reported randomised controlled trial in premenopausal women with breast cancer
found that co-treatment with GnRH analogues during chemotherapy lessened the risk of ovarian
damage (35/39 resumed menses versus 13/39, P < 0.001).77 The uncertainties can be discussed
with the woman by the treating oncologist.
Evidence
level 1+
9.4.2 Cryopreservation
Ovarian stimulation for egg or embryo freezing requires careful discussion in light of
unknown long-term risks. Modified stimulation regimes should be considered for
women with estrogen-sensitive breast cancer.
9 of 15
Embryo cryopreservation is a well established technique with success rates of at least 20% per
cycle,78 although it is possible that success rates may be lower when oocytes are retrieved from
women with cancer.The time required for ovarian stimulation and egg harvest may postpone
chemotherapy, and there is a small risk of procedural complications such as ovarian hyperstimulation. There is concern that elevated estrogen levels may be deleterious in estrogen receptor
positive breast cancer; to minimise this risk, stimulation regimens with tamoxifen or letrozole,
usually combined with gonadotrophins, are proposed.79,80
Evidence
level 2+
Oocyte storage may be offered to women without a partner.Freezethaw techniques are rapidly
improving,but there have been only a few hundred births worldwide after use of this technique
and there are no long-term safety data. Harvesting immature oocytes without requiring a
hormone-stimulated cycle is an attractive proposition, but is not an established technique.81
Evidence
level 3
There are insufficient data to support ovarian tissue storage for fertility preservation
in women with breast cancer; this should be offered only in the context of a research
trial.
Cryopreservation of ovarian cortex or the whole ovary has resulted in a small number of
pregnancies after regrafting.82 This remains an experimental technique and tissue storage
regulations in the UK have restricted its use.The need for a surgical procedure is a disadvantage,
but this technique does not delay chemotherapy.
Every breast oncology service should have a designated pathway for prompt referral
to a fertility specialist able to offer assisted conception; service provision should not
be dependent on local in vitro fertilistion funding arrangements.
Evidence
level 3
The organisational aspects of the expanding breast oncology service need to be addressed.Prompt referral
is essential; preparations for egg retrieval can be instigated during breast cancer diagnostic procedures
and surgery to minimise delays in starting systemic treatment.The National Institute for Health and Clinical
Excellence83 recommended universal access to sperm, egg and embryo storage for people undergoing
gonadotoxic treatment. However, NHS funding is not available in all areas, and is dependent upon the
primary care trust and the local infertility budget.The oncology referral pathway in the cancer network
does not necessarily coincide with local in vitro fertilisation arrangements.The joint Royal Colleges working
party recommended that adequate funding should be made available.68
9.5 Assisted reproduction after treatment for breast cancer

Fertility treatment after chemotherapy is limited by loss of ovarian reserve.84,85 The stimulation aspect of
in vitro fertilisation carries a theoretical risk as it is a hyperestrogenic state, although of shorter duration
than pregnancy.Women who have chemotherapy-induced menopause can become pregnant with donated
eggs; this requires short-term hormone replacement therapy, which again carries a theoretical risk.
Replacement of cryopreserved embryos is also performed in a medicated hormone replacement therapy
cycle.Women for whom pregnancy is contraindicated may wish to consider surrogacy.
10 of 15
10. Suggested audit topics

Relatively few women present with pregnancy during or after treatment for breast cancer.
Oncologists may wish to audit:
what percentage of young women treated for breast cancer have been given information on
contraception and future pregnancy
outcome of referrals to a fertility specialist.
Gynaecologists may wish to audit:
outcome of referrals for fertility preservation.
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27. Chan SS,Tam WH,Yeo W,Yu MM, Ng DP,Wong AW, et al.A
randomised controlled trial of prophylactic levonorgestrel
intrauterine system in tamoxifen-treated women. BJOG
2007;114:15105.
28. Trinh XB,Tjalma WA, Makar AP, Buytaert G,Weyler J, van
Dam PA. Use of the levonorgestrel-releasing intrauterine
system in breast cancer patients. Fertil Steril 2008;90:
1722.
29. Calhoun K, Hansen N.The effect of pregnancy on survival
in women with a history of breast cancer. Breast Dis
2005;23:816.
11 of 15
30. Barthelmes L, Davidson LA, Gaffney C, Gateley CA.

Pregnancy and breast cancer. BMJ 2005;330:13758.
31. Velentgas P, Daling JR, Malone KE,Weiss NS,Williams MA,
Self SG, et al. Pregnancy after breast carcinoma: outcomes
and influence on mortality. Cancer 1999;85:242432.
32. Gelber S, Coates AS, Goldhirsch A, Castiglione-Gertsch M,
Marini G, Lindtner J; International Breast Cancer Study
Group. Effect of pregnancy on overall survival after the
diagnosis of early-stage breast cancer. J Clin Oncol
2001;19:16715.
33. von Schoultz E, Johansson H,Wilking N, Rutqvist LE.
Influence of prior and subsequent pregnancy on breast
cancer prognosis. J Clin Oncol 1995;13:4304.
34. Blakely LJ, Buzdar AU, Lozada JA, Shullaih SA, Hoy E, Smith
TL, et al. Effects of pregnancy after treatment for breast
carcinoma on survival and risk of recurrence. Cancer
2004;100:4659.
35. Mueller BA, Simon MS, Deapen D, Kamineni A, Malone KE,
Daling JR. Childbearing and survival after breast
carcinoma in young women. Cancer 2003;98:113140.
36. Sankila R, Heinvaara S, Hakulinen T. Survival of breast
cancer patients after subsequent term pregnancy:healthy
mother effect. Am J Obstet Gynecol 1994;170:81823.
37. Petrek J, Seltzer V. Breast cancer in pregnant and
postpartum women. J Obstet Gynaecol Can 2003;25:
94450.
38. Andrieu N, Goldgar DE, Easton DF, Rookus M, Brohet R,
Antoniou AC, et al; EMBRACE; GENEPSO; IBCCS
Collaborators Group. Pregnancies, breast-feeding,
and breast cancer risk in the International BRCA1/2
Carrier Cohort Study (IBCCS). J Natl Cancer Inst
2006;98:53544.
39. Society of Obstetricians and Gynaecologists of Canada.
Clinical practice Guideline No. 111: Breast cancer,
pregnancy, and breastfeeding. Ottawa: SOGC; 2002
[http://www.sogc.org/guidelines/public/111E-CPGFebruary2002.pdf].
40. Isaacs JH. Cancer of the breast in pregnancy. Surg Clin
North Am 1995;75:4751.
41. Gwyn K,Theriault R. Breast cancer during pregnancy.
Oncology (Williston Park) 2001;15:3946; discussion 46,
4951.
42. Saphner T,Tormey DC, Gray R.Annual hazard rates of
recurrence for breast cancer after primary therapy.
J Clin Oncol 1996;14:273846.
43. Averette HE, Mirhashemi R, Moffat FL. Pregnancy after
breast carcinoma: the ultimate medical challenge. Cancer
1999;85:23014.
44. Hickey M, Peate M, Saunders CM, Friedlander M. Breast
cancer in young women and its impact on reproductive
function. Hum Reprod Update 2009;15:32339.
45. Del Mastro L, Catzeddu T,Venturini M. Infertility and
pregnancy after breast cancer: current knowledge and
future perspectives. Cancer Treat Rev 2006;32:41722.
46. Blakely LJ, Buzdar AU, Lozada JA, Shullaih SA, Hoy E, Smith
TL, et al. Effects of pregnancy after treatment for breast
carcinoma on survival and risk of recurrence. Cancer
2004;100:4659.
47. Mulvihill JJ, McKeen EA, Rosner F, Zarrabi MH. Pregnancy
outcome in cancer patients. Experience in a large
cooperative group. Cancer 1987;60:114350.
48. Sutton R, Buzdar AU, Hortobagyi GN. Pregnancy and
offspring after adjuvant chemotherapy in breast cancer
patients. Cancer 1990;65:84750.
49. Langagergaard V, Gislum M, Skriver MV, Nrgrd B, Lash TL,
Rothman KJ, et al. Birth outcome in women with breast
cancer. Br J Cancer 2006;94:1426.
50. Dalberg K, Eriksson J, Holmberg L. Birth outcome in
women with previously treated breast cancer a
population-based cohort study from Sweden. PLoS Med
2006;9:e336.
51. Hershman DL, Shao T.Anthracycline cardiotoxicity after
breast cancer treatment. Oncology (Williston Park)
2009;23:22734.
52. Shan K, Lincoff AM,Young JB.Anthracycline-induced
cardiotoxicity. Ann Intern Med 1996;125:4758.
53. van Dalen EC, van der Pal HJ, van den Bos C, Kok WE,
Caron HN, Kremer LC. Clinical heart failure during
pregnancy and delivery in a cohort of female childhood
cancer survivors treated with anthracyclines. Eur J
Cancer 2006;42:254953.
54. Higgins S, Haffty BG. Pregnancy and lactation after breastconserving therapy for early stage breast cancer. Cancer
1994;73:217580.
55. Tralins AH. Lactation after conservative breast surgery
combined with radiation therapy. Am J Clin Oncol
1995;18:403.
56. Moran MS, Colasanto JM, Haffty BG,Wilson LD, Lund MW,
Higgins SA. Effects of breast-conserving therapy on
lactation after pregnancy. Cancer J 2005;11:399403.
57. Varsos G,Yahalom J. Lactation following conservation
surgery and radiotherapy for breast cancer. J Surg Oncol
1991;46:1414.
58. Azim HA Jr, Bellettini G, Gelber S, Peccatori FA. Breastfeeding after breast cancer: if you wish, madam. Breast
59. Camune B, Gabzdyl E. Breast-feeding after breast cancer in
childbearing women. J Perinat Neonatal Nurs
2007;21:22533.
60. Partridge AH, Gelber S, Peppercorn J, Sampson E, Knudsen
K, Laufer, M, et al.Web-based survey of fertility issues in
young women with breast cancer. J Clin Oncol
2004;22:417483.
61. Braun M, Hasson-Ohayon I, Perry S, Kaufman B, Uziely B.
Motivation for giving birth after breast cancer.
62. Connell S, Patterson C, Newman B.A qualitative analysis of
reproductive issues raised by young Australian women
with breast cancer. Health Care Women Int 2006;
27:94110.
63. Peate M, Meiser B, Hickey M, Friedlander M.The fertilityrelated concerns, needs and preferences of younger
women with breast cancer: a systematic review. Breast
64. Thewes B, Meiser B, Rickard J, Friedlander M.The fertilityand menopause-related information needs of younger
women with a diagnosis of breast cancer: a qualitative
study. Psychooncology 2003;12:50011.
65. Knobf MT.The menopausal symptom experience in young
mid-life women with breast cancer. Cancer Nurs
2001;24:20110.
66. Dunn J, Steginga SK.Young womens experience of breast
cancer: defining young and identifying concerns.
67. Thewes BM. Fertility- and menopause-related information
needs of younger women with a diagnosis of early breast
cancer. J Clin Oncol 2005;23:515565.
68. Royal College of Physicians,The Royal College of
Radiologists, Royal College of Obstetricians and
Gynaecologists.The effects of cancer treatment on
reproductive functions. Guidance on management.
Report of a Working Party. London: RCP; 2007
[http://bookshop.rcplondon.ac.uk/contents/
pub238-5e88e6e4-d9d0-4e99-a2f9-b1bea2daf562.pdf].
69. Minton SE, Munster PN. Chemotherapy-induced
amenorrhea and fertility in women undergoing adjuvant
treatment for breast cancer. Cancer Control 2002;9:
46672.
70. Bines J, Oleske DM, Cobleigh MA. Ovarian function in
premenopausal women treated with adjuvant
chemotherapy for breast cancer. J Clin Oncol
1996;14:171829.
71. Zekri JM, El-Helw LM, Purohit OP, Hatton MQ, Coleman RE.
Epirubicin/vinorelbine adjuvant chemotherapy in young
women with breast cancer is associated with preservation
of menstrual function. Clin Oncol (R Coll Radiol)
2008;20:5136.
72. Minisini AM, Menis J,Valent F,Andreetta C,Alessi B,
Pascoletti G, et al. Determinants of recovery from
amenorrhea in premenopausal breast cancer patients
receiving adjuvant chemotherapy in the taxane era.
Anticancer Drugs 2009;20:5037.
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73. Blumenfeld Z. How to preserve fertility in young women

exposed to chemotherapy? The role of GnRH agonist
cotreatment in addition to cryopreservation of embrya,
oocytes, or ovaries. Oncologist 2007;12:104454.
74. Maltaris T,Weigel M, Mueller A, Schmidt M, Seufert R, Fischl
F, et al. Cancer and fertility preservation: fertility
preservation in breast cancer patients. Breast Cancer Res
2008;10:206.
75. Recchia F, Saggio G,Amiconi G, Di Blasio A, Cesta A,
Candeloro G, et al. Gonadotropin-releasing hormone
analogues added to adjuvant chemotherapy protect
ovarian function and improve clinical outcomes in young
women with early breast carcinoma. Cancer
2006;106:51423.
76. Maisano R, Caristi N, Mare M, Bottari M,Adamo V, Mafodda
A, et al. Protective effect of leuprolide on ovarian function
in young women treated with adjuvant chemotherapy for
early breast cancer: a multicenter phase II study.
J Chemother 2008;20:7403.
77. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropinreleasing hormone agonists for prevention of
chemotherapy-induced ovarian damage: prospective
randomized study. Fertil Steril 2009;91:6947.
78. Human Fertilisation & Embryology Authority. Code of
Practice. London: HFEA; 2009 [http://www.hfea.gov.uk/
code.html].
79. Oktay K, Buyuk E, Libertella N,Akar M, Rosenwaks Z.
Fertility preservation in breast cancer patients: a
prospective controlled comparison of ovarian stimulation
with tamoxifen and letrozole for embryo
cryopreservation. J Clin Oncol 2005;23:434753.
80. Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, et al.

Letrozole reduces estrogen and gonadotropin exposure in
women with breast cancer undergoing ovarian
stimulation before chemotherapy. J Clin Endocrinol
Metab 2006;91:388590.
81. Demirtas E, Elizur SE, Holzer H, Gidoni Y, Son WY, Chian
RC, et al. Immature oocyte retrieval in the luteal phase to
preserve fertility in cancer patients. Reprod Biomed
Online 2008;17:5203.
82. Donnez J, Martinez-Madrid B, Jadoul P,Van Langendonckt A,
Demylle D, Dolmans MM. Ovarian tissue cryopreservation
and transplantation: a review. Hum Reprod Update
2006;12:51935.
83. National Institute for Health and Clinical Excellence.
Assessment and treatment for people with fertility
problems. London: NICE; 2004 [http://www.
nice.org.uk/nicemedia/pdf/CG011publicinfoenglish.pdf].
84. Lutchman Singh K, Muttukrishna S, Stein RC, McGarrigle
HH, Patel A, Parikh B, et al. Predictors of ovarian reserve in
young women with breast cancer. Br J Cancer
2007;96:180816.
85. Anderson RA,Themmen AP,Al-Qahtani A, Groome NP,
Cameron DA.The effects of chemotherapy and long-term
gonadotrophin suppression on the ovarian reserve in
premenopausal women with breast cancer. Hum Reprod
2006;21:258392.
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Appendix
1+

low risk of bias

risk of bias

2+
2-

is not causal

case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
14 of 15

development group
Gynaecologists by:
Ms MC Davies FRCOG, London and Dr AL Jones, UCLH Foundation Trust, Cancer Management, London
and peer reviewed by:Association of Breast Surgery; British Maternal and Fetal Medicine Society; Breast Cancer Care;
RCOG Consumers Forum; Professor JM Dixon, Professor of Surgery and Consultant Surgeon,Western General Hospital,
Edinburgh, Scotland; Dr AHD Diyaf MRCOG, Birmingham; Dr A Francis, Consultant Breast Surgeon, University Hospital
Birmingham; Professor AB MacLean FRCOG, London; Professor J Lansac FRCOG, France; Professor P Sauven, Professor
of Surgical Oncology, Broomfield Hospital, Chelmsford, UK.
Committee lead peer reviewers were: Dr K Harding FRCOG, London and Dr NA Siddiqui FRCOG, Glasgow, Scotland.
Conflicts of interest: none declared
The guidelines review process will commence in 2014, unless evidence requires earlier review
DISCLAIMER
obstetricians and gynaecologists and other relevant health professionals.The ultimate judgement regarding a particular
by the patient and the diagnostic and treatment options available.This means that RCOG guidelines are unlike protocols
or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of
management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patients
case notes at the time the relevant decision is taken.
15 of 15
Chickenpox in Pregnancy
Green-top Guideline No. 13

January 2015
Chickenpox in Pregnancy
This is the fourth edition of this guideline, originally published in 1997 and reviewed in 2001 and 2007
under the same title.
Executive summary of recommendations
Varicella prevention
Can the non-immune woman be immunised prior to pregnancy or postnatally?
Varicella vaccination prepregnancy or postpartum is an option that should be considered for
women who are found to be seronegative for varicella-zoster virus immunoglobulin G (VZV IgG).
While universal serological antenatal testing is not recommended in the UK (see below),
seronegative women identified in pregnancy could be offered postpartum immunisation.
Women who are vaccinated postpartum can be reassured that it is safe to breastfeed.
Can varicella be prevented in the pregnant woman at her initial antenatal visit?
Women booking for antenatal care should be asked about previous chickenpox/shingles infection.
Women who have not had chickenpox, or are known to be seronegative for chickenpox, should be
advised to avoid contact with chickenpox and shingles during pregnancy and to inform healthcare
workers of a potential exposure without delay.
Can varicella infection be prevented in the pregnant woman who gives a history of contact with
chickenpox or shingles?
When contact occurs with chickenpox or shingles, a careful history must be taken to confirm the
significance of the contact and the susceptibility of the patient.
Pregnant women with an uncertain or no previous history of chickenpox, or who come from tropical
or subtropical countries, who have been exposed to infection should have a blood test to determine
VZV immunity or non-immunity.
P
P
If the pregnant woman is not immune to VZV and she has had a significant exposure, she should be
offered varicella-zoster immunoglobulin (VZIG) as soon as possible. VZIG is effective when given
up to 10 days after contact (in the case of continuous exposures, this is defined as 10 days from the
appearance of the rash in the index case).
Non-immune pregnant women who have been exposed to chickenpox should be managed as
potentially infectious from 828 days after exposure if they receive VZIG and from 821 days after
exposure if they do not receive VZIG.
When supplies are limited, issues to pregnant women may be restricted and clinicians are advised
to establish the availability of VZIG before offering it to pregnant women.
Women who have had exposure to chickenpox or shingles (regardless of whether or not they have
received VZIG) should be asked to notify their doctor or midwife early if a rash develops.
A pregnant woman who develops a chickenpox rash should be isolated from other pregnant women
when she attends a general practice surgery or a hospital for assessment.
2 of 17
A second dose of VZIG may be required if a further exposure is reported and 3 weeks have elapsed
since the last dose.
The pregnant woman who develops chickenpox

What are the maternal risks of varicella in pregnancy?
Clinicians should be aware of the increased morbidity associated with varicella infection in adults,
including pneumonia, hepatitis and encephalitis. Rarely, it may result in death.
How should the pregnant woman who develops chickenpox be cared for?
Pregnant women who develop a chickenpox rash should immediately contact their general
practitioner.
Women should avoid contact with potentially susceptible individuals, e.g. other pregnant women
and neonates, until the lesions have crusted over. This is usually about 5 days after the onset of
the rash.
Symptomatic treatment and hygiene is advised to prevent secondary bacterial infection of the
lesions.
Oral aciclovir should be prescribed for pregnant women with chickenpox if they present within 24
hours of the onset of the rash and if they are 20+0 weeks of gestation or beyond. Use of aciclovir
before 20+0 weeks should also be considered.
Aciclovir is not licensed for use in pregnancy and the risks and benefits of its use should be
discussed with the woman.
P
P
P
C
Intravenous aciclovir should be given to all pregnant women with severe chickenpox.
VZIG has no therapeutic benefit once chickenpox has developed and should therefore not be used
in pregnant women who have developed a chickenpox rash.
Should women be referred to hospital?

The pregnant woman with chickenpox should be asked to contact her doctor immediately if she
develops respiratory symptoms or any other deterioration in her condition. Women who develop
the symptoms or signs of severe chickenpox should be referred immediately to hospital.
A hospital assessment should be considered in a woman at high risk of severe or complicated
chickenpox even in the absence of concerning symptoms or signs. This assessment needs to take
place in an area where she will not come into contact with other pregnant women. Appropriate
treatment should be decided in consultation with a multidisciplinary team that includes an
obstetrician or fetal medicine specialist, a virologist and a neonatologist.
Women hospitalised with varicella should be nursed in isolation from babies, potentially
susceptible pregnant women or non-immune staff.
When and how should the woman with chickenpox be delivered?

The timing and mode of delivery of the pregnant woman with chickenpox must be individualised.
When epidural or spinal anaesthesia is undertaken in women with chickenpox, a site free of
cutaneous lesions should be chosen for needle placement.
3 of 17
Risks of maternal varicella infection to the fetus or baby

What are the risks to the fetus of varicella infection in pregnancy and can they be prevented or ameliorated?
Women should be advised that the risk of spontaneous miscarriage does not appear to be increased
if chickenpox occurs in the first trimester.
If the pregnant woman develops varicella or shows serological conversion in the first 28 weeks of
pregnancy, she has a small risk of fetal varicella syndrome (FVS) and she should be informed of
the implications.
Can varicella infection of the fetus be diagnosed prenatally?

Women who develop chickenpox in pregnancy should be referred to a fetal medicine specialist, at
1620 weeks or 5 weeks after infection, for discussion and detailed ultrasound examination.
Given that amniocentesis has a strong negative predictive value but a poor positive predictive
value in detecting fetal damage that cannot be detected by non-invasive methods, women who
develop varicella infection during pregnancy should be counselled about the risks versus benefits
of amniocentesis to detect varicella DNA by polymerase chain reaction (PCR).
Amniocentesis should not be performed before the skin lesions have completely healed.
P
P
What are the neonatal risks of varicella infection in pregnancy and can they be prevented or ameliorated?
If maternal infection occurs in the last 4 weeks of a womans pregnancy, there is a significant risk
of varicella infection of the newborn. A planned delivery should normally be avoided for at least
7 days after the onset of the maternal rash to allow for the passive transfer of antibodies from
mother to child, provided that continuing the pregnancy does not pose any additional risks to the
mother or baby.
A neonatologist should be informed of the birth of all babies born to women who have developed
chickenpox at any gestation during pregnancy.
Women with chickenpox should breastfeed if they wish to and are well enough to do so.
1.
P
P
Purpose and scope
Varicella, the primary infection with varicella-zoster virus (VZV; human herpesvirus 3), in pregnancy may
cause maternal mortality or serious morbidity. It may also cause fetal varicella syndrome (FVS) and varicella
infection of the newborn, which includes congenital varicella syndrome (CVS) and neonatal varicella.
This guideline addresses the role of varicella vaccination in susceptible women of reproductive age. The
guideline also assesses the evidence regarding the maternal and fetal risks of VZV infection in pregnancy
and whether or not these complications can be prevented or modified beneficially by the administration
of varicella-zoster immunoglobulin (VZIG) or by treatment of infected individuals with aciclovir. This
information should guide the prudent use of VZIG, which is manufactured from the plasma of human
blood donors and hence is a limited and expensive resource. The management of neonates is outside the
scope of this guideline. Guidance on neonatal exposure and disease is available from other sources.1,2
2.
Introduction and background epidemiology
VZV is a DNA virus of the herpes family that is highly contagious and transmitted by respiratory droplets
and by direct personal contact with vesicle fluid or indirectly via fomites (e.g. skin cells, hair, clothing
and bedding). The primary infection is characterised by fever, malaise and a pruritic rash that develops
into crops of maculopapules, which become vesicular and crust over before healing. The incubation
4 of 17
period is between 1 and 3 weeks and the disease is infectious 48 hours before the rash appears and
continues to be infectious until the vesicles crust over. The vesicles usually crust over within 5 days.
Chickenpox (or primary VZV infection) is a common childhood disease that usually causes a mild
infection. Over 90% of individuals over 15 years of age in England and Wales are seropositive for VZV
immunoglobulin G (IgG) antibody.3 Studies of pregnant women in Spain and France found that 96.1%
and 98.8% respectively were immune to varicella.4,5 For this reason, although contact with chickenpox is
common in pregnancy, especially in women with young children, primary VZV infection in pregnancy
is uncommon; it is estimated to complicate 3 in every 1000 pregnancies.6 Women from tropical and
subtropical areas are more likely to be seronegative for VZV IgG and are therefore more susceptible to
the development of chickenpox in pregnancy.7
Following the primary infection, the virus remains dormant in sensory nerve root ganglia but can be
reactivated to cause a vesicular erythematous skin rash in a dermatomal distribution known as herpes
zoster, also called zoster or shingles. The risk of acquiring infection from an immunocompetent
individual with herpes zoster in non-exposed sites (e.g. thoracolumbar) is remote but can occur.8
However, disseminated zoster or exposed zoster (e.g. ophthalmic) in any individual or localised zoster in
an immunosuppressed patient should be considered to be infectious as the viral shedding may be greater.1
3.
The Cochrane Library, including the Cochrane Central Register of Controlled Trials, was searched for
relevant randomised controlled trials, systematic reviews and meta-analyses. A search of MEDLINE and
PubMed (electronic databases) from 1966 to January 2013 was also carried out. The databases were
searched using the relevant Medical Subject Headings (MeSH) terms, including all subheadings, and this
was combined with a keyword search using the terms chickenpox, varicella zoster and pregnancy.
The definitions of the types of evidence used in this guideline originate from the Scottish Intercollegiate
Guidelines Network (SIGN) Grading Review Group.9 Where possible, recommendations are based
on and explicitly linked to the evidence that supports them. Recommendations lacking evidence are
highlighted and annotated as Good Practice Points.
4.
Varicella prevention
4.1 Can the non-immune woman be immunised prior to pregnancy or postnatally?

Varicella vaccination prepregnancy or postpartum is an option that should be considered for
women who are found to be seronegative for VZV IgG.
While universal serological antenatal testing is not recommended in the UK (see below),
seronegative women identified in pregnancy could be offered postpartum immunisation.
Women who are vaccinated postpartum can be reassured that it is safe to breastfeed.
Varicella vaccine contains live attenuated virus derived from the Oka strain of VZV and has
been licensed for use in the USA since March 1995. Following its introduction, the incidence
of primary infection (chickenpox) in the general population has fallen by over 80% and the
mortality related to the condition has decreased by two-thirds.10 Immunity from the vaccine Evidence
persists for up to 20 years.11,12 Two varicella vaccines are licensed for use in the UK for the level 2+
prevention of chickenpox: Varivax (Oka/Merck; Sanofi Pasteur MSD Limited, Maidenhead,
Berkshire, UK) and Varilrix (OkaRIT; GlaxoSmithKline UK, Uxbridge, Middlesex, UK).
Both are live attenuated vaccines administered in two separate doses 48 weeks apart.
5 of 17
The varicella immune status of women planning a pregnancy or receiving treatment for
infertility can be determined by obtaining a past history of chickenpox and by testing
the serum for varicella antibodies in those who have no history or an uncertain history of
previous infection. In 2009, the UK National Screening Committee reviewed the evidence for
antenatal screening for susceptibility to varicella-zoster infection. The committee concluded
that there was insufficient evidence to support antenatal screening because of a lack of
reliable information on the true incidence of VZV infection in pregnancy and on the outcomes Evidence
level 4
following treatment.13
An economic model of postpartum vaccination of women who are seronegative for chickenpox
indicates that it is cost-effective.15 However, this is currently not listed as an indication for
varicella immunisation in the National Health Service and women in this category may have
to discuss the provision of free vaccination with their general practitioners.1
If a woman of reproductive age is vaccinated, she should be advised to avoid pregnancy for
4 weeks after completing the two-dose vaccine schedule and to avoid contact with susceptible
pregnant women should a post-vaccination rash occur. Transmission of vaccine virus is rare, Evidence
despite it being a live attenuated virus. Inadvertent exposures to the vaccine in pregnancy level 2
have been reported to a register. There have been no cases of FVS and no increase in the risk
of fetal abnormality above the background risk.14
Small studies have not detected the varicella vaccine in the breast milk of women who have Evidence
level 3
been vaccinated postpartum.16,17
4.2 Can varicella be prevented in the pregnant woman at her initial antenatal visit?
Women booking for antenatal care should be asked about previous chickenpox/shingles infection.
Women who have not had chickenpox, or are known to be seronegative for chickenpox, should be
advised to avoid contact with chickenpox and shingles during pregnancy and to inform healthcare
workers of a potential exposure without delay.
A previous history of chickenpox infection had a 97.999.7% positive predictive value for the
presence of serum varicella antibodies in women booking for antenatal care in the USA.18 In a
study of British healthcare workers, 95% of those who reported previous chickenpox infection
had antibodies.19 Individuals born and raised in tropical climates are less likely to be immune Evidence
level 3
to varicella7,20 and a history of chickenpox can be a less reliable predictor of immunity in this
population.19 It may be appropriate to undertake serum screening routinely in this group of
women. If seronegativity is identified, postpartum vaccination could be considered.
4.3 Can varicella infection be prevented in the pregnant woman who gives a history of
contact with chickenpox or shingles?
When contact occurs with chickenpox or shingles, a careful history must be taken to confirm the
significance of the contact and the susceptibility of the patient.
Pregnant women with an uncertain or no previous history of chickenpox, or who come from tropical
or subtropical countries, who have been exposed to infection should have a blood test to determine
VZV immunity or non-immunity.
If the pregnant woman is not immune to VZV and she has had a significant exposure, she should
be offered VZIG as soon as possible. VZIG is effective when given up to 10 days after contact
(in the case of continuous exposures, this is defined as 10 days from the appearance of the rash in
the index case).
6 of 17
P
P
D
Non-immune pregnant women who have been exposed to chickenpox should be managed as
potentially infectious from 828 days after exposure if they receive VZIG and from 821 days after
exposure if they do not receive VZIG.
When supplies are limited, issues to pregnant women may be restricted and clinicians are advised
to establish the availability of VZIG before offering it to pregnant women.
Women who have had exposure to chickenpox or shingles (regardless of whether or not they have
received VZIG) should be asked to notify their doctor or midwife early if a rash develops.
A pregnant woman who develops a chickenpox rash should be isolated from other pregnant women
when she attends a general practice surgery or a hospital for assessment.
A second dose of VZIG may be required if a further exposure is reported and 3 weeks have elapsed
since the last dose.
The history must be confirmed with particular respect to:

l the type of VZV infection
l the timing of the exposure
l the closeness and duration of contact.
Chickenpox is infectious for 2 days before the appearance of the rash and for the duration of
the illness while the skin lesions are active. It ceases to be infectious when the lesions have
crusted over. Herpes zoster (shingles) also poses a risk if it is disseminated or it occurs in an Evidence
exposed area of the body (e.g. ophthalmic shingles) or in an immunocompromised individual level 4
where viral shedding may be greater. The risk of infection following contact with herpes
zoster that is not in an exposed area (e.g. thoracolumbar shingles) is remote but can occur.8
Significant contact is defined as contact in the same room for 15 minutes or more, face-to-face
contact or contact in the setting of a large open ward.1 The susceptibility of the woman should
then be determined by eliciting a past history of chickenpox or shingles. If there is a definite
past history of chickenpox, it is reasonable to assume that she is immune to varicella infection.
If the womans immunity to chickenpox is unknown and if there is any doubt about previous
infection, or if there is no previous history of chickenpox or shingles, serum should be tested
for VZV IgG. This can usually be performed within 2448 hours and often within a few hours
if the laboratory can access serum stored from an antenatal booking blood sample. At least
80% of women tested will have VZV IgG and can be reassured.21
If the pregnant woman is not immune to VZV and she has had a significant exposure to
chickenpox or shingles, she should be offered VZIG as soon as possible or at the very latest
within 10 days of the exposure (in the case of continuous household exposures, within 10 days Evidence
level 3
of appearance of the rash in the index case).22 VZIG is indicated after significant exposure to
VZV at any stage of pregnancy, and postnatally if birth occurs within 10 days of exposure.22 If
the immune status of the woman is unknown, the administration of VZIG can be delayed until
serology results are available (if the laboratory turnaround time is 2448 hours). The rationale
for administration of VZIG is that it may prevent or attenuate chickenpox in non-immune
individuals1 and it may reduce the risk of development of FVS.23 In an observational study of
212 seronegative women who received an appropriate dose of VZIG, either intramuscular
or intravenous, within 10 days of significant exposure to chickenpox, half of the women
developed either a normal or an attenuated form of chickenpox and a further 5% had a
subclinical infection.24 A recent meta-analysis of three case series has shown that 0/142 babies
of women who developed varicella during pregnancy despite receiving VZIG suffered from
FVS, compared with 14/498 (2.8%) among those who did not receive VZIG.23 However, a case
7 of 17
series of 106 women who developed chickenpox in the first 20 weeks of pregnancy included
five women who had been treated with VZIG, one of whom delivered a baby with congenital Evidence
varicella syndrome.25 This evidence supports the use of VZIG to prevent FVS but is based on level 3
observational data and may be subject to reporting bias.
VZIG is a human immunoglobulin product manufactured from the plasma of non-UK donors
with high VZV antibody titres. Issues to pregnant women may be restricted when supplies are Evidence
limited and hence clinicians are advised to establish the availability of VZIG before offering it level 4
to pregnant women.1
Adverse effects of VZIG include pain and erythema at the injection site. The risk of anaphylaxis
is cited as less than 0.1% by the US Centers for Disease Control and Prevention26 and very rare
by Public Health England.1 Patients with hypogammaglobinaemia with immunoglobulin A Evidence
antibodies who are already receiving replacement therapy with immunoglobulin do not level 3
require VZIG and are at increased risk of anaphylactic reactions. No case of blood-borne
infection has been reported with the use of VZIG.1
Susceptible women who have had contact with chickenpox or shingles (regardless of whether or not
they have received VZIG) should be asked to notify their doctor or midwife early if a rash develops.
Despite the benefits of VZIG in preventing or attenuating the disease, pregnant women may still become
seriously ill.
5.
The pregnant woman who develops chickenpox
5.1 What are the maternal risks of varicella in pregnancy?

Clinicians should be aware of the increased morbidity associated with varicella infection in adults,
including pneumonia, hepatitis and encephalitis. Rarely, it may result in death.
Although varicella infection is much less common in adults than in children, it is associated
with a greater morbidity, namely pneumonia, hepatitis and encephalitis. As recently as the
1990s, chickenpox resulted in the deaths of 25 people per year in England and Wales; 80% of
these deaths occurred in adults.27
The incidence of pneumonia complicating varicella in pregnancy has been quoted at 10
14%,28 but these rates are based on small case series. In a series of 347 cases of varicella
infection in pregnancy, prospectively documented, 5% of women developed pneumonia.29
The overall mortality rate in case series of varicella pneumonia in pregnancy published in Evidence
level 2+
the English language literature in the pre-antiviral era was 10/28 (36%), which may reflect
publication bias.30 More recent case series report mortality rates of 014%, with improvements
attributed to antiviral therapy and improved intensive care.29,31,32 Between 1985 and 1999 there
were nine indirect maternal deaths and one late maternal death reported in the UK from
complications of maternal varicella infection,3337 suggesting a low case fatality rate. There has
been no maternal death from varicella reported in the subsequent confidential enquiries.3840
Pneumonia may be more severe at later gestational ages due to the effects of the gravid uterus
on respiratory function.28
5.2 How should the pregnant woman who develops chickenpox be cared for?
Pregnant women who develop a chickenpox rash should immediately contact their general
practitioner.
8 of 17
Women should avoid contact with potentially susceptible individuals, e.g. other pregnant women
and neonates, until the lesions have crusted over. This is usually about 5 days after the onset of
the rash.
Symptomatic treatment and hygiene is advised to prevent secondary bacterial infection of the
lesions.
Oral aciclovir should be prescribed for pregnant women with chickenpox if they present within 24
hours of the onset of the rash and if they are 20+0 weeks of gestation or beyond. Use of aciclovir
before 20+0 weeks should also be considered.
Aciclovir is not licensed for use in pregnancy and the risks and benefits of its use should be
discussed with the woman.
P
P
C
Intravenous aciclovir should be given to all pregnant women with severe chickenpox.
VZIG has no therapeutic benefit once chickenpox has developed and should therefore not be used
in pregnant women who have developed a chickenpox rash.
Aciclovir is a synthetic nucleoside analogue that inhibits replication of the varicella-zoster

virus. A randomised controlled trial has shown that aciclovir administered orally (800 mg
five times a day for 7 days) reduces the duration of fever and symptomatology of varicella Evidence
infection in immunocompetent adults if commenced within 24 hours of developing the rash level 1
when compared to placebo. This randomised controlled trial did not have sufficient power to
comment on the impact of early oral aciclovir on the serious complications of chickenpox.41
Data are accumulating to suggest that there is no increase in the risk of major fetal malformation
with aciclovir exposure in pregnancy.4244 A Danish registry-based cohort study of 837795 live
births between 1996 and 200843 reported the pregnancy outcome in 1804 pregnancies exposed
to aciclovir, valciclovir or famciclovir in the first trimester. The rate of major birth defects in
the exposed group was 2.2% compared to 2.4% in the unexposed (adjusted prevalence odds Evidence
ratio 0.89, 95% CI 0.651.22). The most common antiviral drug used was aciclovir. Among level 2
1561 pregnancies exposed to aciclovir, 32 babies (2.0%) had a major anomaly compared with
2.4% of controls. The study is limited in that it is based on records of prescriptions that were
filled and this is indirect evidence of exposure. In addition, the study did not have the power
to exclude an increased risk of any individual defect.44
While some multidisciplinary publications4547 recommend the use of antiviral agents in all
pregnant women with chickenpox, the Swiss and Canadian national guidelines dissent.48,49
The UK Advisory Group on Chickenpox recommends oral aciclovir for pregnant women with
chickenpox if they present within 24 hours of the onset of the rash and if they are more than 20
weeks of gestation.50 Use of aciclovir before 20 weeks should also be considered.51 Guidelines
are unanimous, however, in recommending that intravenous aciclovir be administered in Evidence
level 4
cases of severe maternal infection.4550
VZIG is recommended for post-exposure prophylaxis and is not appropriate treatment for
patients with clinical chickenpox.1 This recommendation is based on the opinion of experts
and reflects the accepted understanding of how VZIG works.
5.3 Should women be referred to hospital?

The pregnant woman with chickenpox should be asked to contact her doctor immediately if she
develops respiratory symptoms or any other deterioration in her condition. Women who develop
the symptoms or signs of severe chickenpox should be referred immediately to hospital.
9 of 17
A hospital assessment should be considered in a woman at high risk of severe or complicated

chickenpox even in the absence of concerning symptoms or signs. This assessment needs to take
place in an area where she will not come into contact with other pregnant women. Appropriate
treatment should be decided in consultation with a multidisciplinary team that includes an
obstetrician or fetal medicine specialist, a virologist and a neonatologist.
Women hospitalised with varicella should be nursed in isolation from babies, potentially
susceptible pregnant women or non-immune staff.
Respiratory symptoms, neurological symptoms such as photophobia, seizures or drowsiness, a

haemorrhagic rash or bleeding, or a dense rash with or without mucosal lesions are indicative
of potentially life-threatening chickenpox and are indications for referral to a hospital
with intensive care access. If the woman smokes cigarettes, has chronic lung disease, is Evidence
level 4
immunosuppressed (including those who have taken systemic corticosteroids in the preceding
3 months) or is in the second half of pregnancy, a hospital assessment should be considered
even in the absence of complications.50
5.4 When and how should the woman with chickenpox be delivered?
The timing and mode of delivery of the pregnant woman with chickenpox must be individualised.
When epidural or spinal anaesthesia is undertaken in women with chickenpox, a site free of
cutaneous lesions should be chosen for needle placement.
Depending on the severity of the maternal condition, a respiratory physician and intensive
care specialist may be involved in peripartum care. Delivery during the viraemic period, while
the chickenpox vesicles are active, may be extremely hazardous. Delivery may precipitate
maternal haemorrhage and/or coagulopathy due to thrombocytopenia or hepatitis. There is
also a high risk of varicella infection of the newborn with significant morbidity and mortality.52,53
Supportive treatment and intravenous aciclovir are therefore desirable, allowing resolution of
the rash, immune recovery and transfer of protective antibodies from the mother to the fetus.
Ideally, a minimum of 7 days should elapse between onset of the rash and delivery. However,
delivery may be required to facilitate assisted ventilation in cases where varicella pneumonia
Evidence
is complicated by respiratory failure.
level 3
There is no evidence available to inform decisions about the optimum method of anaesthesia
for women requiring delivery by caesarean section. General anaesthesia may exacerbate the
respiratory compromise associated with varicella pneumonia. There is a theoretical risk of
transmitting the varicella-zoster virus from skin lesions to the central nervous system via
spinal anaesthesia. As the dura is not penetrated, epidural anaesthesia may be safer than
spinal anaesthesia, however the larger needle required for epidural anaesthesia carries the
theoretical risk of transferring a greater viral load from the skin to the epidural space. A site
free of cutaneous lesions should be chosen for needle placement.54
6.
Risks of maternal varicella infection to the fetus or baby
6.1 What are the risks to the fetus of varicella infection in pregnancy and can they be
prevented or ameliorated?
Women should be advised that the risk of spontaneous miscarriage does not appear to be increased
if chickenpox occurs in the first trimester.
If the pregnant woman develops varicella or shows serological conversion in the first 28 weeks of
pregnancy, she has a small risk of FVS and she should be informed of the implications.
10 of 17
Spontaneous miscarriage does not appear to be increased if chickenpox occurs in the first Evidence
level 2
trimester.25
FVS is characterised by one or more of the following: skin scarring in a dermatomal distribution;
eye defects (microphthalmia, chorioretinitis or cataracts); hypoplasia of the limbs; and
neurological abnormalities (microcephaly, cortical atrophy, mental retardation or dysfunction Evidence
of bowel and bladder sphincters).25,55 It does not occur at the time of initial fetal infection but level 2+
results from a subsequent herpes zoster reactivation in utero and only occurs in a minority of
infected fetuses.
FVS has been reported to complicate maternal chickenpox occurring as early as 3 weeks55 and
as late as 28 weeks56 of gestation. Pooled data from nine cohort studies detected 13 cases of
FVS following 1423 cases of maternal chickenpox occurring before 20 weeks of gestation: an
incidence of 0.91%.28 The risk appears to be lower in the first trimester (0.55%).28 These cohort
studies identified one case of FVS occurring among approximately 180 women who developed
chickenpox between 20 and 28 weeks of gestation.28 In addition, this review identified seven Evidence
case reports of FVS following maternal infection from 2028 weeks and one where maternal level 2
infection occurred at 28 weeks.28,56 These case reports provide no denominators, so an
incidence rate for FVS following late second trimester infection cannot be quoted, but they
make the point that FVS is not confined to cases of maternal infection before 20 weeks. The
observational evidence presented in section 4.3 suggests that post-exposure prophylaxis in
susceptible pregnant women reduces the risk of developing FVS.
6.2 Can varicella infection of the fetus be diagnosed prenatally?

Women who develop chickenpox in pregnancy should be referred to a fetal medicine specialist, at
1620 weeks or 5 weeks after infection, for discussion and detailed ultrasound examination.
Given that amniocentesis has a strong negative predictive value but a poor positive predictive
value in detecting fetal damage that cannot be detected by non-invasive methods, women who
develop varicella infection during pregnancy should be counselled about the risks versus benefits
of amniocentesis to detect varicella DNA by polymerase chain reaction (PCR).
Amniocentesis should not be performed before the skin lesions have completely healed.
P
P
Prenatal diagnosis of FVS is possible by ultrasound when findings such as limb deformity,
microcephaly, hydrocephalus, soft tissue calcification and fetal growth restriction can be
detected. A time lag of at least 5 weeks after the primary maternal infection is advised because Evidence
ultrasound performed at 4 weeks has failed to detect the abnormalities.57 Fetal magnetic level 4
resonance imaging (MRI) may provide additional information in cases where ultrasound has
identified morphological abnormalities.58
VZV DNA can be detected in amniotic fluid by PCR. The presence of VZV DNA has a high
sensitivity but a low specificity for the development of FVS. In one observational study,59 nine
(8.4%) out of 107 women who developed chickenpox before 24 weeks of gestation had VZV
DNA detected in the amniotic fluid. Amniotic fluid PCR for VZV DNA correctly identified the
two cases of FVS that occurred in this series, but was positive in seven other cases, five of
which ended in the birth of a normal baby, one in a termination where there was no evidence Evidence
level 3
of FVS in the fetus and one where intrauterine death occurred in a baby with triploidy and no
evidence of FVS.
Ultrasound was abnormal in two of the nine cases with positive VZV PCR: a case where
FVS was confirmed following termination of pregnancy and a case where ultrasound showed
11 of 17
microcalcifications of the liver but no evidence of FVS at delivery. One of the two cases of FVS,
a baby born at term with bilateral micropthalmia, was not detected by ultrasound. No case
of FVS occurred when amniocentesis was negative for VZV DNA.59 The negative predictive Evidence
level 3
value of this combination of amniotic fluid PCR testing and ultrasound is good but the positive
predictive value is poor.
6.3. What are the neonatal risks of varicella infection in pregnancy and can they be prevented
or ameliorated?
If maternal infection occurs in the last 4 weeks of a womans pregnancy, there is a significant risk
of varicella infection of the newborn. A planned delivery should normally be avoided for at least
7 days after the onset of the maternal rash to allow for the passive transfer of antibodies from
mother to child, provided that continuing the pregnancy does not pose any additional risks to the
mother or baby.
A neonatologist should be informed of the birth of all babies born to women who have developed
chickenpox at any gestation during pregnancy.
Women with chickenpox should breastfeed if they wish to and are well enough to do so.
P
P
Varicella infection of the newborn (previously called congenital varicella) refers to VZV
infection in early neonatal life resulting from maternal infection near the time of delivery or
immediately postpartum, or from contact with a person other than the mother with chickenpox
or shingles during this time. The route of infection could be transplacental, ascending vaginal
or result from direct contact with lesions during or after delivery. If maternal infection occurs
14 weeks before delivery, up to 50% of babies are infected and approximately 23% develop Evidence
clinical varicella, despite high titres of passively acquired maternal antibody. Severe chickenpox level 3
is most likely to occur if the infant is born within 7 days of onset of the mothers rash or if the
mother develops the rash up to 7 days after delivery.52 For babies born to mothers who have
had chickenpox within the period 7 days before to 7 days after delivery, it is therefore vital
that the neonate receives prophylaxis as soon as possible with VZIG with or without aciclovir;
there is no need to test in these circumstances.1,2
Women with chickenpox should breastfeed if they wish to and are well enough to do so. If
there are active chickenpox lesions close to the nipple, they should express breast milk from Evidence
the affected breast until the lesions have crusted over. The expressed breast milk may be fed level 4
to the baby who is receiving treatment with VZIG and/or aciclovir.22
7.
Recommendations for future research
l A randomised controlled trial should be performed in a population of women who were not born
in the UK, comparing a policy of serological screening at the antenatal booking visit with the
current practice of testing only if a varicella contact occurs. Measurable outcomes would be use of
VZIG, rates of postnatal vaccination and cost.
l Given the apparent equipoise in the literature regarding the benefit or otherwise of aciclovir,
women with mild cases of chickenpox in pregnancy could be recruited to a randomised controlled
trial of oral aciclovir versus placebo.
8.
Auditable topics
l The proportion of pregnant women who are not immune to VZV who are offered VZIG following a
significant exposure (100%).
12 of 17
l The proportion of women who develop chickenpox in pregnancy who are referred to a fetal
medicine specialist at 1620 weeks of gestation or 5 weeks after infection (100%).

l The proportion of pregnant women with severe chickenpox who are given intravenous aciclovir
(100%).
l The proportion of cases where a neonatologist has been informed of the birth of a baby born to a
woman who developed chickenpox during pregnancy (100%).
9.
Useful links and support groups
l NHS Choices. What are the risks of chickenpox during pregnancy?
[http://www.nhs.uk/chq/pages/1109.aspx?categoryid=54&subcategoryid=137]
l RCOG patient information leaflet. Chickenpox in pregnancy: what you need to know
[https://www.rcog.org.uk/en/patients/patient-leaflets/chickenpox-in-pregnancy/]
l Royal College of Physicians, Faculty of Occupational Medicine, NHS Plus. Varicella zoster virus:
occupational aspects of management. A national guideline. London: RCP; 2010

[https://www.rcplondon.ac.uk/sites/default/files/varicella-zoster-guidelines-web-navigable.pdf].
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behalf of the British Society for the Study of Infection. J
Infect 1998;36 Suppl 1:5971.
51. Tunbridge AJ, Breuer J, Jeffery KJ; British Infection
Society. Chickenpox in adults clinical management. J
Infect 2008;57:95102.
52. Miller E, Cradock-Watson JE, Ridehalgh MK. Outcome in
newborn babies given anti-varicella-zoster immunoglobulin
after perinatal maternal infection with varicella-zoster
virus. Lancet 1989;2:3713.
53. Meyers JD. Congenital varicella in term infants: risks
reconsidered. J Infect Dis 1974;129:2157.
54. Brown NW, Parsons AP, Kam PC. Anaesthetic considerations
in a parturient with varicella presenting for Caesarean
section. Anaesthesia 2003;58:10925.
55. Enders G, Miller E, Cradock-Watson J, Bolley I, Ridehalgh M.
Consequences of varicella and herpes zoster in pregnancy:
prospective study of 1739 cases. Lancet 1994;343:154851.
56. Bai PV, John TJ. Congenital skin ulcers following varicella
in late pregnancy. J Pediatr 1979;94:657.
57. Pretorius DH, Hayward I, Jones KL, Stamm E. Sonographic
evaluation of pregnancies with maternal varicella infection.
J Ultrasound Med 1992;11:45963.
58. Verstraelen H, Vanzieleghem B, Defoort P, Vanhaesebrouck
P, Temmerman M. Prenatal ultrasound and magnetic
resonance imaging in fetal varicella syndrome: correlation
with pathology findings. Prenat Diag 2003;23:7059.
59. Mouly F, Mirlesse V, Mritet JF, Rozenberg F, Poissonier
MH, Lebon P, et al. Prenatal diagnosis of fetal varicellazoster virus infection with polymerase chain reaction
of amniotic fluid in 107 cases. Am J Obstet Gynecol
1997;177:8948.
14 of 17
Appendix I: Algorithm for the management of varicella-zoster contact in pregnancy
Varicella-zoster contact
clarify significance of the contact
Past history of
chickenpox
Uncertain or no past history of

chickenpox, or woman from a
tropical or subtropical country
Presents with chickenpox

initial contact should be
with the womans GP
Check blood
(booking sample if available)
for VZV IgG
No action needed.
Reassure and return to
normal antenatal care
VZV IgG
present
Give VZIG if less than 10 days since contact or, for

continuous exposure, less than 10 days since the
appearance of the rash in the index case
VZV IgG not

present
Woman
develops
chickenpox
despite VZIG
Advise the woman that she is potentially infectious

from 828 days after contact
Symptomatic treatment and

hygiene should be advised
Discuss postpartum varicella immunisation
If the woman presents < 24 hours

of the appearance of the rash
and she is 20 +0 weeks of
gestation, prescribe aciclovir
If the woman presents < 24 hours
of the appearance of the rash
and she is < 20 +0 weeks of
gestation, consider aciclovir
Severe
infection
Women who develop severe infection and women

at high risk of complicated chickenpox should be
referred to hospital
Avoid delivery of the baby

until at least 7 days since the
rash appeared
Intravenous aciclovir should be given
Inform women that infection at < 28 +0 weeks is

associated with a small (~1%) risk of FVS
Refer to a fetal medicine specialist at 1620 weeks
or 5 weeks after infection
Avoid contact with potentially

susceptible individuals
(e.g. neonates and other
pregnant women)
Infection at
less than
28 weeks
of gestation
Amniocentesis to detect varicella DNA may be

considered
Abbreviations: F VS fetal varicella syndrome; GP general practitioner; IgG immunoglobulin G;

VZIG varicella-zoster immunoglobulin; VZV varicella-zoster virus
15 of 17
Appendix II: Explanation of guidelines and evidence levels

Governance Advice No. 1 Development of RCOG Green-top Guidelines (available on the RCOG website
at http://www.rcog.org.uk/green-top-development). These recommendations are not intended to dictate
an exclusive course of management or treatment. They must be evaluated with reference to individual
patient needs, resources and limitations unique to the institution and variations in local populations.
It is hoped that this process of local ownership will help to incorporate these guidelines into routine
practice. Attention is drawn to areas of clinical uncertainty where further research may be indicated.
formulated in a similar fashion with a standardised grading scheme.

randomised controlled trials with a very
low risk of bias

1+ Well-conducted meta-analyses, systematic

low risk of bias
1 Meta-analyses, systematic reviews of
risk of bias
A body of evidence including studies rated

as 2++ directly applicable to the target
1++ or 1+

2+ directly applicable to the target population,
results; or
2++
2+ Well-conducted casecontrol or cohort

2 Casecontrol or cohort studies with a
3 Non-analytical studies, e.g. case reports,
case series
4
Good practice point
Expert opinion

or randomised controlled trial rated as 1++, and
16 of 17

development group
This guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Dr BMP Byrne FRCOG, Dublin; Dr PA Crowley FRCOG, Dublin; and Dr C Aitken FRCPath, Glasgow
and peer reviewed by:
Dr HM Cameron FRCOG, Sunderland; Mrs AHD Diyaf MRCOG, Barnstaple; Dr PP Fogarty FRCOG, County Down;
Professor P Heath, Paediatric Infectious Diseases Research Group, St Georges, University of London;
Dr M Khare FRCOG, Leicester; Mr S Maiti FRCOG, Manchester; Professor E Miller OBE FMedSci, Immunisation
Hepatitis and Blood Safety Department, Public Health England; Dr H Narayan FRCOG, Swindon;
Dr C OSullivan, Paediatric Infectious Diseases Research Group, St Georges, University of London; RCOG Womens
Network; Royal College of Paediatrics and Child Health; Royal College of Pathologists; Dr S Sabir MRCOG, Bradford;
Dr P Sarkar FRCOG, Slough; Dr JB Wright FRCOG, Bradford; Dr GL Young MA FRCGP, Penrith.
Committee lead reviewers were:
Dr S Ismail MRCOG, Brighton; Dr P Owen FRCOG, Glasgow; and Dr AJ Thomson MRCOG, Paisley.
Conflicts of interest: none declared.
The review process will commence in 2018, unless otherwise indicated.
DISCLAIMER
be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols
or guidelines should be fully documented in the patients case notes at the time the relevant decision is taken.
17 of 17
The Investigation and Treatment

of Couples with Recurrent Firsttrimester and Second-trimester
Miscarriage
April 2011
The Investigation and Treatment of Couples with Recurrent

First-trimester and Second-trimester Miscarriage
This is the third edition of this guideline, which was first published in 1998 and then in 2003 under the
title The Investigation and Treatment of Couples with Recurrent Miscarriage.
1.
Purpose and scope
The purpose of this guideline is to provide guidance on the investigation and treatment of couples with
three or more first-trimester miscarriages, or one or more second-trimester miscarriages.
2.
Miscarriage is defined as the spontaneous loss of pregnancy before the fetus reaches viability.The term
therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation. It should
be noted that advances in neonatal care have resulted in a small number of babies surviving birth before
Recurrent miscarriage, defined as the loss of three or more consecutive pregnancies, affects 1% of couples
trying to conceive.1 It has been estimated that 12% of second-trimester pregnancies miscarry before 24
weeks of gestation.2
3.
The Cochrane Library and Cochrane Register of Controlled Trials were searched for relevant randomised
controlled trials, systematic reviews and meta-analyses.A search of Medline from 1966 to 2010 was also
carried out.The date of the last search was November 2010. In addition, relevant conference proceedings
and abstracts were searched.
The databases were searched using the relevant MeSH terms including all sub-headings.This was combined
with a keyword search using human,female,pregnancy,abortion,miscarriage,habitual,recurrent,
randomised controlled trials and meta-analysis.
Guidelines Network (SIGN) grading scheme.Where possible,recommendations are based on,and explicitly
linked to, the evidence that supports them.Areas lacking evidence are highlighted and annotated as good
practice points.
4.
Risk factors for recurrent miscarriage
What are the causes of recurrent first trimester miscarriage and second trimester miscarriage?
4.1 Epidemiological factors

Maternal age and number of previous miscarriages are two independent risk factors for a further
miscarriage.3,4 Advancing maternal age is associated with a decline in both the number and quality of the
remaining oocytes.A large prospective register linkage study3 reported the age-related risk of miscarriage
in recognised pregnancies to be: 1219 years, 13%; 2024 years, 11%; 2529 years, 12%; 3034 years, 15%;
3539 years, 25%; 4044 years, 51%; and 45 years, 93%.Advanced paternal age has also been identified as
a risk factor for miscarriage.The risk of miscarriage is highest among couples where the woman is 35
years of age and the man 40 years of age.5
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Previous reproductive history is an independent predictor of future pregnancy outcome.The risk of a

further miscarriage increases after each successive pregnancy loss,reaching approximately 40% after three
consecutive pregnancy losses, and the prognosis worsens with increasing maternal age.3,4 A previous live
birth does not preclude a woman developing recurrent miscarriage.6
The evidence on the effect of environmental risk factors is based mainly on data studying women with
sporadic rather than recurrent miscarriage. The results are conflicting and biased by difficulties in
controlling for confounding factors and the inaccuracy of data on exposure and the measurement of toxin
dose. Maternal cigarette smoking and caffeine consumption have been associated with an increased risk
of spontaneous miscarriage in a dose-dependent manner. However, current evidence is insufficient to
confirm this association.79 Heavy alcohol consumption is toxic to the embryo and the fetus.Even moderate
consumption of five or more units per week may increase the risk of sporadic miscarriage.10 Working with
or using video display terminals does not increase the risk of miscarriage.11 The evidence on the effect of
anaesthetic gases for theatre workers is conflicting.12,13
Recent retrospective studies have reported that obesity increases the risk of both sporadic and recurrent
miscarriage.1416
4.2 Antiphospholipid syndrome

Antiphospholipid syndrome is the most important treatable cause of recurrent miscarriage. Antiphospholipid syndrome refers to the association between antiphospholipid antibodies lupus anticoagulant,
anticardiolipin antibodies and anti-B2 glycoprotein-I antibodies and adverse pregnancy outcome or
vascular thrombosis.17,18
Adverse pregnancy outcomes include:
three or more consecutive miscarriages before 10 weeks of gestation

one or more morphologically normal fetal losses after the 10th week of gestation
one or more preterm births before the 34th week of gestation owing to placental disease.
The mechanisms by which antiphospholipid antibodies cause pregnancy morbidity include inhibition of
trophoblastic function and differentiation,1923 activation of complement pathways at the maternalfetal
interface resulting in a local inflammatory response24 and, in later pregnancy, thrombosis of the uteroplacental vasculature.2527 In vitro studies have shown that the effect of antiphospholipid antibodies on
trophoblast function28,29 and complement activation30 is reversed by heparin.
Antiphospholipid antibodies are present in 15% of women with recurrent miscarriage.31 By comparison,
the prevalence of antiphospholipid antibodies in women with a low-risk obstetric history is less than
2%.32,33 In women with recurrent miscarriage associated with antiphospholipid antibodies, the live birth
rate in pregnancies with no pharmacological intervention has been reported to be as low as 10%.34
4.3 Genetic factors

4.3.1 Parental chromosomal rearrangements
In approximately 25% of couples with recurrent miscarriage, one of the partners carries a balanced
structural chromosomal anomaly: most commonly a balanced reciprocal or Robertsonian translocation.3538
Although carriers of a balanced translocation are usually phenotypically normal, their pregnancies are at
increased risk of miscarriage and may result in a live birth with multiple congenital malformation and/or
mental disability secondary to an unbalanced chromosomal arrangement. The risk of miscarriage is
influenced by the size and the genetic content of the rearranged chromosomal segments.
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4.3.2 Embryonic chromosomal abnormalities

In couples with recurrent miscarriage, chromosomal abnormalities of the embryo account for 3057% of
further miscarriages.39,40 The risk of miscarriage resulting from chromosomal abnormalities of the embryo
increases with advancing maternal age.However, it is important to note that as the number of miscarriages
increases, the risk of euploid pregnancy loss increases.40,41
4.4 Anatomical factors

4.4.1 Congenital uterine malformations
The exact contribution that congenital uterine anomalies make to recurrent miscarriage remains unclear
since the prevalence and reproductive implications of uterine anomalies in the general population are
unknown. The reported prevalence of uterine anomalies in recurrent miscarriage populations ranges
between 1.8% and 37.6%.42,43 This variability reflects the differences in the criteria and techniques used for
diagnosis and the fact that available studies have included women with two, three or more miscarriages
in both the first and second trimester of pregnancy.The prevalence of uterine malformations appears to
be higher in women with second-trimester miscarriages compared with women who suffer first-trimester
miscarriages, but this may be related to the cervical weakness that is frequently associated with uterine
malformation.44 It has been reported that women with arcuate uteri tend to miscarry more in the second
trimester while women with septate uteri are more likely to miscarry in the first trimester.45
A retrospective review of reproductive performance in women with untreated uterine anomalies has
suggested that these women experience high rates of miscarriage and preterm delivery, with a term
delivery rate of only 50%.42 However, retrospective studies are biased by patient selection and, until well
controlled prospective data become available, the role of uterine anomalies in recurrent miscarriage will
remain debatable.
4.4.2 Cervical weakness
Cervical weakness is a recognised cause of second-trimester miscarriage, but the true incidence is
unknown, since the diagnosis is essentially a clinical one.There is currently no satisfactory objective test
that can identify women with cervical weakness in the non-pregnant state.The diagnosis is usually based
on a history of second-trimester miscarriage preceded by spontaneous rupture of membranes or painless
cervical dilatation.
4.5 Endocrine factors

Systemic maternal endocrine disorders such as diabetes mellitus and thyroid disease have been associated
with miscarriage.Women with diabetes who have high haemoglobin A1c levels in the first trimester are
at risk of miscarriage and fetal malformation.46 However, well-controlled diabetes mellitus is not a risk
factor for recurrent miscarriage, nor is treated thyroid dysfunction.47,48 The prevalence of diabetes mellitus
and thyroid dysfunction in women who suffer recurrent miscarriage is similar to that reported in the
general population.49,50
Anti-thyroid antibodies have been linked to recurrent miscarriage. However, one casecontrol
study51 from 1998 has reported that women with recurrent miscarriages are no more likely than
women without recurrent miscarriage to have circulating thyroid antibodies. A single
prospective study52 has shown that the presence of thyroid antibodies in euthyroid women
with a history of recurrent miscarriage does not affect future pregnancy outcome.
Evidence
level 3
Polycystic ovary syndrome (PCOS) has been linked to an increased risk of miscarriage but the exact
mechanism remains unclear. Polycystic ovarian morphology, elevated serum luteinising hormone levels or
elevated serum testosterone levels, although markers of PCOS, do not predict an increased risk of future
4 of 18
pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously.53 The increased risk of miscarriage in women with PCOS has been recently attributed to insulin
resistance,hyperinsulinaemia and hyperandrogenaemia.The prevalence of insulin resistance is increased in
women with recurrent miscarriage compared with matched fertile controls.54 An elevated free androgen
index appears to be a prognostic factor for a subsequent miscarriage in women with recurrent miscarriage.55
4.6 Immune factors

There is no clear evidence to support the hypothesis of human leucocyte antigen incompatibility between
couples,the absence of maternal leucocytotoxic antibodies or the absence of maternal blocking antibodies.
Hence, they should not be offered routinely in the investigation of couples with recurrent miscarriage.
Natural killer (NK) cells are found in peripheral blood and the uterine mucosa. Peripheral blood NK cells
are phenotypically and functionally different from uterine NK (uNK) cells.56 There is no clear evidence that
altered peripheral blood NK cells are related to recurrent miscarriage.57,58 Therefore, testing for peripheral
blood NK cells as a surrogate marker of the events at the maternalfetal interface is inappropriate and
should not be offered routinely in the investigation of couples with recurrent miscarriage.
It has been suggested that uNK cells may play a role in trophoblastic invasion and angiogenesis in addition
to being an important component of the local maternal immune response to pathogens.59 It should be
noted that the largest study60 examining the relationship between uNK cell numbers and future pregnancy
outcome reported that raised uNK cell numbers in women with recurrent miscarriage was not associated
with an increased risk of miscarriage.This remains a research field and testing for uNK cells should not be
offered routinely in the investigation of recurrent miscarriage.
Cytokines are immune molecules that control both immune and other cells. Cytokine responses are
generally characterised either asT-helper-1 (Th-1) type,with production of the pro-inflammatory cytokines
interleukin 2, interferon and tumour necrosis factor alpha (TNF ), or as T-helper-2 (Th-2) type, with
production of the anti-inflammatory cytokines interleukins 4, 6 and 10. It has been suggested that normal
pregnancy might be the result of a predominantly Th-2 cytokine response, whereas women with recurrent
miscarriage have a bias towards mounting a Th-1 cytokine response.
A meta-analysis61 concluded that the available data are not consistent with more than modest
associations between cytokine polymorphisms and recurrent miscarriage. Further research is
required to assess the contribution that disordered cytokines make to recurrent miscarriage
before routine cytokine tests can be introduced to clinical practice.
Evidence
level 2++
4.7 Infective agents

Any severe infection that leads to bacteraemia or viraemia can cause sporadic miscarriage.The
role of infection in recurrent miscarriage is unclear. For an infective agent to be implicated in
the aetiology of repeated pregnancy loss, it must be capable of persisting in the genital tract and
avoiding detection, or must cause insufficient symptoms to disturb the woman.Toxoplasmosis,
rubella, cytomegalovirus, herpes and listeria infections do not fulfil these criteria and routine
TORCH screening should be abandoned.62
Evidence
level 3
The presence of bacterial vaginosis in the first trimester of pregnancy has been reported as a risk factor
for second-trimester miscarriage and preterm delivery,63,64 but the evidence for an association with firsttrimester miscarriage is inconsistent.65,66 A randomised placebo-controlled trial67 reported that treatment
of bacterial vaginosis early in the second trimester with oral clindamycin significantly reduces the
incidence of second-trimester miscarriage and preterm birth in the general population. There are no
published data to assess the role of antibiotic therapy in women with a previous second-trimester
miscarriage.
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4.8 Inherited thrombophilic defects

Both inherited and acquired thrombophilias, including activated protein C resistance (most commonly
due to factor V Leiden mutation),deficiencies of protein C/S and antithrombin III,hyperhomocysteinaemia
and prothrombin gene mutation, are established causes of systemic thrombosis. In addition, inherited
thrombophilias have been implicated as a possible cause in recurrent miscarriage and late pregnancy
complications with the presumed mechanism being thrombosis of the uteroplacental circulation.
A meta-analysis68 of pooled data from 31 retrospective studies suggested that the magnitude of
the association between inherited thrombophilias and fetal loss varies according to type of fetal
loss and type of thrombophilia.The association between thrombophilia and late pregnancy loss
has been consistently stronger than for early pregnancy loss.In this meta-analysis,factor V Leiden
was associated with recurrent first-trimester fetal loss (OR 2.01, 95% CI 1.133.58), recurrent
fetal loss after 22 weeks (OR 7.83, 95% CI 2.8321.67) and non-recurrent fetal loss after 19
weeks (OR 3.26,95% CI 1.825.83).Activated protein C resistance was associated with recurrent
first-trimester fetal loss (OR 3.48,95% CI 1.587.69).Prothrombin gene mutation was associated
with recurrent first-trimester fetal loss (OR 2.32, 95% CI 1.124.79), recurrent fetal loss before
25 weeks (OR 2.56, 95% CI 1.046.29) and late non-recurrent fetal loss (OR 2.3, 95% CI 1.09
4.87).Protein S deficiency was associated with recurrent fetal loss (OR 14,95% CI 0.99218) and
non-recurrent fetal loss after 22 weeks (OR 7.39,95% CI 1.2842.83).Methylenetetrahydrofolate
mutation and protein C and antithrombin deficiencies were not associated with fetal loss.
However, since protein C and antithrombin III deficiencies are rare, the number of women
included in the study was too small to show any difference in pregnancy outcome.
Evidence
level 2++
Similarly, another meta-analysis69 of 16 casecontrol studies reported that carriers of factor V

Leiden or prothrombin gene mutation have double the risk of experiencing recurrent
miscarriage compared with women without these thrombophilic mutations.
Evidence
level 2++
Prospective data on the outcome of untreated pregnancies in women with hereditary

thrombophilias are scarce. One small study70 of six hereditary thrombophilias reported no
adverse effects on the live birth rate of women with recurrent miscarriage. By contrast, two
small prospective studies71,72 reported an increased risk of miscarriage in untreated pregnancies
for women with recurrent miscarriage who carry the factor V Leiden mutation compared with
those with a normal factor V genotype.
Evidence
level 2+
5.
What are the recommended investigations of couples with recurrent first-trimester

miscarriage and second-trimester miscarriage?
Women with recurrent first-trimester and second-trimester miscarriage should be

looked after by a health professional with the necessary skills and expertise. Where
available, this might be within a recurrent miscarriage clinic.
The loss of pregnancy at any stage can be a devastating experience and particular sensitivity is required
in assessing and counselling couples with recurrent miscarriage.Ideally,the couple should be seen together
at a dedicated recurrent miscarriage clinic and given accurate information to facilitate decision making
about future pregnancies.Clearly written patient leaflets are recommended to provide written information
that the couple can take home.
5.1 Antiphospholipid antibodies

All women with recurrent first-trimester miscarriage and all women with one or
more second-trimester miscarriage should be screened before pregnancy for
antiphospholipid antibodies.
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To diagnose antiphospholipid syndrome it is mandatory that the woman has two positive tests at least 12
weeks apart for either lupus anticoagulant or anticardiolipin antibodies of immunoglobulin G and/or
immunoglobulin M class present in a medium or high titre over 40 g/l or ml/l,or above the 99th percentile).
In the detection of lupus anticoagulant, the dilute Russells viper venom time test together with a platelet
neutralisation procedure is more sensitive and specific than either the activated partial thromboplastin time
test or the kaolin clotting time test.31 Anticardiolipin antibodies are detected using a standardised enzymelinked immunosorbent assay.
The detection of antiphospholipid antibodies is subject to considerable inter-laboratory variation.73 This
is a result of temporal fluctuation of antiphospholipid antibody titres in individual women, transient
positivity secondary to infections, suboptimal sample collection and preparation and lack of standardisation of laboratory tests for their detection.
5.2 Karyotyping
Cytogenetic analysis should be performed on products of conception of the third and
subsequent consecutive miscarriage(s).
Parental peripheral blood karyotyping of both partners should be performed in

couples with recurrent miscarriage where testing of products of conception reports
an unbalanced structural chromosomal abnormality.
Knowledge of the karyotype of the products of conception allows an informed prognosis for a
future pregnancy outcome to be given.While a sporadic fetal chromosome abnormality is the
most common cause of any single miscarriage, the risk of miscarriage as a result of fetal
aneuploidy decreases with an increasing number of pregnancy losses.41 If the karyotype of the
miscarried pregnancy is abnormal, there is a better prognosis for the next pregnancy.39
Evidence
level 4
A Dutch study38 reported that couples with balanced translocations have a low risk (0.8%) of
pregnancies with an unbalanced karyotype surviving into the second trimester and that their
chance of having a healthy child is 83%.A recent retrospective UK audit74 of four UK centres over
periods of 530 years reported that balanced translocations were found in 1.9% (406 of 20 432)
of parents with recurrent miscarriage, but only four unbalanced translocations were found after
referral for prenatal diagnosis because of balanced parental translocation ascertained for
recurrent miscarriage.At an estimated cost of 34 million (the total cost of karyotyping 20 432
individuals calculated at 160200 per karyotype), the data suggest that routine karyotyping of
couples with recurrent miscarriage cannot be justified. Selective parental karyotyping may be
more appropriate when an unbalanced chromosome abnormality is identified in the products
of conception.
Evidence
level 3

All women with recurrent first-trimester miscarriage and all women with one or
more second-trimester miscarriages should have a pelvic ultrasound to assess uterine
anatomy.
Suspected uterine anomalies may require further investigations to confirm the
diagnosis, using hysteroscopy, laparoscopy or three-dimensional pelvic ultrasound.
7 of 18

A review75 of studies comparing the diagnostic accuracy of various imaging modalities has
reported that two-dimensional ultrasound scanning and/or hysterosalpingography can be used
as an initial screening test. Combined hysteroscopy and laparoscopy and possibly threedimensional ultrasound scanning should be used for definitive diagnosis.The value of magnetic
resonance imaging scanning remains undetermined.
Evidence
level 3
5.4 Thrombophilias
Women with second-trimester miscarriage should be screened for inherited
thrombophilias including factor V Leiden, factor II (prothrombin) gene mutation and
protein S.
A meta-analysis68 of retrospective studies has reported a strong association between secondtrimester miscarriage and inherited thrombophilias: factor V Leiden, factor II (prothrombin)
gene mutation and protein S deficiency.
6.
Evidence
level 2++
Treatment options for recurrent miscarriage
6.1 What are the treatment options for recurrent first trimester and second trimester miscarriage?
Women with recurrent miscarriage should be offered referral to a specialist clinic.
6.2 Antiphospholipid syndrome

Pregnant women with antiphospholipid syndrome should be considered for
treatment with low-dose aspirin plus heparin to prevent further miscarriage.
A meta-analysis76 of randomised controlled trials examined the outcomes of various treatments

including aspirin, steroids, intravenous globulin and heparin given to improve pregnancy
outcome of women with recurrent miscarriage associated with antiphospholipid antibodies.
This meta-analysis reported that the only treatment or treatment combination that leads to a
significant increase in the live birth rate among women with antiphospholipid syndrome is
aspirin plus unfractionated heparin. This treatment combination significantly reduces the
miscarriage rate by 54% (aspirin plus unfractionated heparin compared with aspirin alone: RR
0.46, 95% CI 0.290.71).
Evidence
level 1+
Two small prospective studies77,78 reported no difference in efficacy and safety between unfractionated heparin and low-molecular-weight heparin when combined with aspirin in the
treatment of women with recurrent miscarriage associated with antiphospholipid antibodies.
Evidence
level 1+
The value of heparin has been questioned in two studies.79,80 However, there were methodological
weaknesses in both demographic and laboratory entry criteria and time of randomisation.
There are no adverse fetal outcomes reported in the meta-analysis of randomised controlled
trials of low-dose aspirin for the prevention of pre-eclampsia in pregnancy.81 Heparin does not
cross the placenta and hence there is no potential to cause fetal haemorrhage or teratogenicity.
Heparin can,however, be associated with maternal complications including bleeding,hypersensitivity reactions,heparin-induced thrombocytopenia and,when used long term,osteopenia and
vertebral fractures.Two prospective studies82,83 have shown that the loss of bone mineral density
at the lumbar spine associated with low-dose long-term heparin therapy is similar to that which
occurs physiologically during normal pregnancy.
8 of 18
Evidence
level 2+
Low-molecular-weight heparin is as safe as unfractionated heparin and has potential advantages during
pregnancy, since it causes less heparin-induced thrombocytopenia, can be administered once daily and is
associated with a lower risk of heparin-induced osteoporosis.84
Pregnancies associated with antiphospholipid antibodies treated with aspirin and heparin
remain at high risk of complications during all three trimesters.Although aspirin plus heparin
treatment substantially improves the live birth rate of women with recurrent miscarriage
associated with antiphospholipid antibodies, these pregnancies remain at high risk of complications during all three trimesters, including repeated miscarriage, pre-eclampsia, fetal growth
restriction and preterm birth;85,86 this necessitates careful antenatal surveillance.
Neither corticosteroids nor intravenous immunoglobulin therapy improve the live
birth rate of women with recurrent miscarriage associated with antiphospholipid
antibodies compared with other treatment modalities; their use may provoke
significant maternal and fetal morbidity.
Evidence
level 2+
A meta-analysis76 of randomised controlled trials reported that treating women who suffer
recurrent miscarriage associated with antiphospholipid antibodies with corticosteroids during
pregnancy does not improve the live birth rate compared with aspirin or aspirin plus heparin
(prednisone and aspirin compared with placebo or aspirin alone:RR 0.85,95% CI 0.531.36;and
compared with heparin and aspirin: RR 1.17, 95% CI 0.472.93). Steroid therapy is associated
with significant maternal and fetal morbidity.
Evidence
level 1+
A randomised controlled trial87 reported that women with recurrent miscarriage associated
with antiphospholipid antibodies treated with low-molecular-weight heparin plus aspirin had
a higher rate of live births than those treated with intravenous immunoglobulin (RR 2.28, 95%
CI 0.816.4).Similarly,another randomised controlled trial88 reported that low-molecular-weight
heparin plus aspirin resulted in a higher live birth rate than intravenous immunoglobulin in the
treatment of women with recurrent miscarriage associated with antiphospholipid antibodies
(OR 1.80, 95% CI 1.142.84).
Evidence
level 1+
6.2 Genetic factors

The finding of an abnormal parental karyotype should prompt referral to a clinical
geneticist.
Genetic counselling offers the couple a prognosis for the risk of future pregnancies with an unbalanced
chromosome complement and the opportunity for familial chromosome studies.
Reproductive options in couples with chromosomal rearrangements include proceeding to a further
natural pregnancy with or without a prenatal diagnosis test, gamete donation and adoption.
Preimplantation genetic diagnosis has been proposed as a treatment option for translocation
carriers.89,90 Since preimplantation genetic diagnosis necessitates that the couple undergo in
vitro fertilisation to produce embryos, couples with proven fertility need to be aware of the
financial cost as well as implantation and live birth rates per cycle following in vitro fertilisation/preimplantation genetic diagnosis. Furthermore, they should be informed that they have
a higher (5070%) chance of a healthy live birth in future untreated pregnancies following
natural conception37,38,91 than is currently achieved after preimplantation genetic diagnosis/in
vitro fertilisation (approximately 30%).92
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Evidence
level 4
Preimplantation genetic screening with in vitro fertilisation treatment in women with

unexplained recurrent miscarriage does not improve live birth rates.
Preimplantation genetic screening in conjunction with in vitro fertilisation has been advocated
as a treatment option for women with recurrent miscarriage, the rationale being that the identification and transfer of what are thought to be genetically normal embryos will lead to a live
birth. The live birth rate of women with unexplained recurrent miscarriage who conceive
naturally is significantly higher than currently achieved after preimplantation genetic
screening/in vitro fertilisation (2030%).9295
Evidence
level 2+

6.3.1 Congenital uterine malformations
There is insufficient evidence to assess the effect of uterine septum resection in
women with recurrent miscarriage and uterine septum to prevent further miscarriage.
There are no published randomised trials assessing the benefits of surgical correction of uterine
abnormalities on pregnancy outcome. Open uterine surgery has never been assessed in prospective trials
but is associated with postoperative infertility and carries a significant risk of uterine scar rupture during
pregnancy.96 These complications are less likely to occur after transcervical hysteroscopic resection of
uterine septae; experience from case series appears promising.97 However, before a clear judgement can
be made, this procedure must be evaluated in a prospective controlled trial.
6.3.2 Cervical weakness and cervical cerclage
Cervical cerclage is associated with potential hazards related to the surgery and the
risk of stimulating uterine contractions and hence should be considered only in
women who are likely to benefit.
Women with a history of second-trimester miscarriage and suspected cervical
weakness who have not undergone a history-indicated cerclage may be offered serial
cervical sonographic surveillance.
In women with a singleton pregnancy and a history of one second-trimester
miscarriage attributable to cervical factors, an ultrasound-indicated cerclage should
be offered if a cervical length of 25 mm or less is detected by transvaginal scan before
The role of cervical cerclage in the prevention of preterm birth has been examined in a recently published
RCOG Green-top Guideline.98 A Cochrane review99 of four randomised controlled trials found no conclusive
evidence that prophylactic cerclage reduces the risk of pregnancy loss and preterm delivery in women at
risk of preterm birth or mid-trimester loss owing to cervical factors. Furthermore, the procedure was
associated with a high risk of minor morbidity but no serious morbidity.A small reduction in deliveries
before 33 weeks of gestation was noted in the largest trial.100 The benefit was most marked in women
with three or more second-trimester miscarriages or preterm births. However, there was no significant
improvement in perinatal survival.
A short cervical length on transvaginal ultrasound during pregnancy may be useful in predicting
preterm birth in some cases of suspected cervical weakness. A meta-analysis101 of individual
patient-level data from four randomised controlled trials reported that in a subgroup analysis of
women with singleton pregnancies, a short cervix (less than 25 mm) and previous secondtrimester miscarriage, cerclage may reduce the incidence of preterm birth before 35 weeks of
gestation (RR 0.57, 95% CI 0.3399).
10 of 18
Evidence
level 1+
Transabdominal cerclage has been advocated as a treatment for second-trimester miscarriage and the
prevention of early preterm labour in selected women with a previous failed transvaginal cerclage and/or
a very short and scarred cervix.102104 In the absence of any control groups, the reported improvement in
pregnancy outcome is difficult to assess.A systematic review105 compared abdominal with vaginal cerclage
in women with failed vaginal cerclage in a previous pregnancy.This review concluded that abdominal
cerclage may be associated with a lower risk of perinatal death or delivery before 24 weeks of gestation
and a higher risk of serious operative complications.Whether to perform transabdominal cerclage before
pregnancy or during pregnancy remains uncertain.106
6.4 Endocrine factors

There is insufficient evidence to evaluate the effect of progesterone supplementation
in pregnancy to prevent a miscarriage in women with recurrent miscarriage.
Progesterone is necessary for successful implantation and the maintenance of pregnancy.This
benefit of progesterone could be explained by its immmunomodulatory actions in inducing a
pregnancy-protective shift from pro-inflammatoryTh-1 cytokine responses to a more favourable
anti-inflammatory Th-2 cytokine response.107 A meta-analysis108 to assess progesterone support
for pregnancy showed that it did not reduce the sporadic miscarriage rate. However, in a
subgroup analysis of trials involving women with recurrent miscarriage,progesterone treatment
offered a statistically significant decrease in miscarriage rate compared with placebo or no
treatment (OR 0.38, 95% CI 0.20.7). However, this meta-analysis was based on three small
controlled studies, none of which detected a significant improvement in pregnancy outcome.
A large multicentre study (PROMISE,http://www.medscinet.net/promise) is currently under
way to assess the benefit of progesterone supplementation in women with unexplained
recurrent miscarriage.
There is insufficient evidence to evaluate the effect of human chorionic gonadotrophin supplementation in pregnancy to prevent a miscarriage in women with
recurrent miscarriage.
A multicentre placebo-controlled study of human chorionic gonadotrophin supplementation
in early pregnancy failed to show any benefit in pregnancy outcome.109 However, another small
placebo-controlled study stated that the benefit of human chorionic gonadotrophin is confined
to a small subgroup (n = 23) of women with recurrent miscarriage and oligomenorrhoea.110
Human chorionic gonadotrophin supplementation in early pregnancy should be used only in
the context of randomised controlled trials.
Suppression of high luteinising hormone levels among ovulatory women with
recurrent miscarriage and polycystic ovaries does not improve the live birth rate.
Luteinising hormone hypersecretion, a frequent feature of PCOS, has been reported as a risk
factor for early pregnancy loss.A randomised controlled trial111 has shown that prepregnancy
pituitary suppression of luteinising hormone among ovulatory women with recurrent
miscarriage and polycystic ovaries who hypersecrete luteinising hormone does not improve
the live birth rate. Furthermore, the outcome of pregnancy without pituitary suppression is
similar to that of women without raised luteinising hormone.
There is insufficient evidence to evaluate the effect of metformin supplementation in
pregnancy to prevent a miscarriage in women with recurrent miscarriage.
11 of 18
Evidence
level 1+
Evidence
level 1+
Evidence
level 1+
The increased risk of miscarriage in women with PCOS has been attributed to insulin resistance
and hyperinsulinaemia. However, a meta-analysis112 of 17 randomised controlled trials of
metformin, an insulin-sensitising agent, in women with PCOS and infertility showed that
metformin has no effect on the sporadic miscarriage risk when administered prepregnancy.
Evidence
level 1++
Uncontrolled small studies113 have shown that use of metformin during pregnancy is associated with a
reduction in the miscarriage rate in women with recurrent miscarriage and PCOS. However, there are no
randomised controlled trials to assess the role of metformin in women with recurrent miscarriage.
6.5 Immunotherapy
Paternal cell immunisation, third-party donor leucocytes, trophoblast membranes
and intravenous immunoglobulin in women with previous unexplained recurrent
miscarriage does not improve the live birth rate.
A Cochrane systematic review114 has shown that the use of various forms of immunotherapy,
including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes and
intravenous immunoglobulin, in women with unexplained recurrent miscarriage provides no
significant beneficial effect over placebo in preventing further miscarriage. A 2010 metaanalysis115 confirmed this conclusion with respect to intravenous immunoglobulin. Moreover,
immunotherapy is expensive and has potentially serious adverse effects including transfusion
reaction, anaphylactic shock and hepatitis.The use of immunotherapy should no longer be
offered to women with unexplained recurrent miscarriage.
Evidence
level 1++
There are no published data on the use of anti-TNF agents to improve pregnancy outcome in women with
recurrent miscarriage. Furthermore, anti-TNF agents could potentially cause serious morbidity including
lymphoma,granulomatous disease such as tuberculosis, demyelinating disease,congestive heart failure and
syndromes similar to systemic lupus erythematosus.
Immune treatments should not be offered routinely to women with recurrent miscarriage outside formal
research studies.
6.6 Inherited thrombophilias

There is insufficient evidence to evaluate the effect of heparin in pregnancy to
prevent a miscarriage in women with recurrent first-trimester miscarriage associated
with inherited thrombophilia.
Heparin therapy during pregnancy may improve the live birth rate of women with
second-trimester miscarriage associated with inherited thrombophilias.
Women with known heritable thrombophilia are at an increased risk of venous thromboembolism. See
RCOG Green-top Guideline No. 37a: Reducing the risk of thrombosis and embolism during pregnancy
and the puerperium.116
The efficacy of thromboprophylaxis during pregnancy in women with recurrent first-trimester
miscarriage who have inherited thrombophilias, but who are otherwise asymptomatic, has not
been assessed in prospective randomised controlled trials. Cohort studies117119 have suggested
that heparin therapy may improve the live birth rate for these women.
12 of 18
Evidence
level 3
One prospective randomised trial120 demonstrated the efficacy of the low-molecular-weight

heparin enoxaparin for the treatment of women with a history of a single late miscarriage after
10 weeks of gestation who carry the factor V Leiden or prothrombin gene mutation or have
protein S deficiency.The live birth rate of women treated with enoxaparin was 86% compared
with 29% in women taking low-dose aspirin alone (OR 15.5, 95% CI 734).
Evidence
level 1+
6.7 Unexplained recurrent miscarriage

Women with unexplained recurrent miscarriage have an excellent prognosis for
future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit.
A significant proportion of cases of recurrent miscarriage remain unexplained despite detailed

investigation. These women can be reassured that the prognosis for a successful future
pregnancy with supportive care alone is in the region of 75%.6,121 However, the prognosis
worsens with increasing maternal age and the number of previous miscarriages.The value of
psychological support in improving pregnancy outcome has not been tested in the form of a
randomised controlled trial. However, data from several non-randomised studies6,121,122 have
suggested that attendance at a dedicated early pregnancy clinic has a beneficial effect, although
the mechanism is unclear.
Evidence
level 2+
Aspirin alone or in combination with heparin is being prescribed for women with unexplained
recurrent miscarriage, with the aim of improving pregnancy outcome.Two recent randomised
controlled trials reported that neither of these interventions improves the live birth rate among
women with unexplained recurrent miscarriage.123,124 However, it should be noted that both
studies included a significant number of women with only two previous miscarriages (40% and
57% of the study population, respectively).
Evidence
level 1+
These data suggest that the use of empirical treatment in women with unexplained recurrent miscarriage
is unnecessary and should be resisted. Furthermore, clinical evaluation of future treatments for recurrent
miscarriage should be performed only in the context of randomised trials of sufficient power to determine
efficacy.
7.
8.
Suggested audit topics

Correct assessment and investigations of couples with recurrent miscarriage.
Pregnancy outcome of women with recurrent miscarriage.
Future research
The role of uterine NK cells and cytokines in recurrent miscarriage.
The role of uterine septum resection in women with recurrent miscarriage and septate uterus.
Thromboprophylaxis in women with thrombophilia and recurrent first-trimester miscarriage.
Progesterone treatment in women with unexplained recurrent miscarriage.
Metformin treatment in women with recurrent miscarriage and insulin resistance.
13 of 18
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94. Munn S, Chen S, Fischer J, Colls P, Zheng X, Stevens J, et al.
Preimplantation genetic diagnosis reduces pregnancy loss in
women aged 35 years and older with a history of recurrent
95. Garrisi JG, Colls P, Ferry KM, Zheng X, Garrisi MG, Munn S.
Effect of infertility, maternal age, and number of previous
miscarriages on the outcome of preimplantation genetic
diagnosis for idiopathic recurrent pregnancy loss. Fertil
Steril 2009;92:28895.
96. Jacobsen LJ, DeCherney A. Results of conventional and
hysteroscopic surgery. Hum Reprod 1997;12:137681.
97. Homer HA, Li TC, Cooke ID.The septate uterus: a review of
management and reproductive outcome. Fertil Steril
2000;73:114.
98. Royal College of Obstetricians and Gynaecologists. Cervical
cerclage. Green-top Guideline No. 60. London: RCOG; 2011.
99. Drakeley AJ, Roberts D,Alfirevic Z. Cervical cerclage for
prevention of preterm delivery: meta-analysis of randomized
trials. Obstet Gynecol 2003;102:6217. Erratum in: Obstet
Gynecol 2004;103:201.
100. Final report of the Medical Research Council/Royal College
of Obstetricians and Gynaecologists multicentre randomised
trial of cervical cerclage. MRC/RCOG Working Party on
Cervical Cerclage. Br J Obstet Gynaecol 1993;100:51623.
101. Berghella V, Odibo AO,To MS, Rust OA,Althuisius SM.
Cerclage for short cervix on ultrasonography: meta-analysis
of trials using individual patient-level data. Obstet Gynecol
2005;106:1819.
102. Gibb DM, Salaria DA.Transabdominal cervicoisthmic cerclage
in the management of recurrent second trimester
miscarriage and preterm delivery. Br J Obstet Gynaecol
1995;102:8026.
103. Anthony GS,Walker RG, Cameron AD, Price JL,Walker JJ,

Calder AA.Transabdominal cervico-isthmic cerclage in the
management of cervical incompetence. Eur J Obstet
Gynecol Reprod Biol 1997;72:12730.
104. Debbs RH, DeLa Vega GA, Pearson S, Sehdev H, Marchiano D,
Ludmir J.Transabdominal cerclage after comprehensive
evaluation of women with previous unsuccessful
transvaginal cerclage. Am J Obstet Gynecol
2007;197:317.e14.
105. Zaveri V,Aghajafari F,Amankwah K, Hannah M.Abdominal
versus vaginal cerclage after a failed transvaginal cerclage: a
systematic review. Am J Obstet Gynecol 2002;187:86872.
106. Thuesen LL, Diness BR, Langhoff-Roos J. Pre-pregnancy
transabdominal cerclage. Acta Obstet Gynecol Scand
2009;88:4836.
107. Raghupathy R,Al-Mutawa E,Al-Azemi M, Makhseed M,Azizieh
F, Szekeres-Bartho J. Progesterone-induced blocking factor
(PIBF) modulates cytokine production by lymphocytes from
women with recurrent miscarriage or preterm delivery. J
Reprod Immunol 2009;80:919.
108. Haas DM, Ramsey PS. Progestogen for preventing
miscarriage. Cochrane Database Syst Rev
2008;(2):CD003511.
109. Harrison RF. Human chorionic gonadotrophin (hCG) in the
management of recurrent abortion; results of a multi-centre
placebo-controlled study. Eur J Obstet Gynecol Reprod Biol
1992;47:1759.
110. Quenby S, Farquharson RG. Human chorionic gonadotropin
supplementation in recurring pregnancy loss: a controlled
trial. Fertil Steril 1994;62:70810.
111. Clifford K, Rai R,Watson H, Franks S, Regan L. Does
suppressing luteinising hormone secretion reduce the
miscarriage rate? Results of a randomised controlled trial.
BMJ 1996;312:150811.
112. Palomba S, Falbo A, Orio F Jr, Zullo F. Effect of
preconceptional metformin on abortion risk in polycystic
ovary syndrome: a systematic review and meta-analysis of
randomized controlled trials. Fertil Steril 2009;92:164658.
113. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler
JE. Effects of metformin on early pregnancy loss in the
polycystic ovary syndrome. J Clin Endocrinol Metab
2002;87:5249.
114. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for
recurrent miscarriage. Cochrane Database Syst Rev
2006;(2):CD000112.
115. Stephenson MD, Kutteh WH, Purkiss S, Librach C, Schultz P,
Houlihan E, et al. Intravenous immunoglobulin and
idiopathic secondary recurrent miscarriage: a multicentered
randomized placebo-controlled trial. Hum Reprod
2010;25:22039.
116. Royal College of Obstetricians and Gynaecologists. Reducing
the risk of thrombosis and embolism during pregnancy
and the puerperium. Green-top Guideline No. 37a. London:
RCOG; 2009
[http://www.rcog.org.uk/womens-health/clinical-guidance/r
educing-risk-of-thrombosis-greentop37a].
117. Carp H, Dolitzky M, Inbal A.Thromboprophylaxis improves
the live birth rate in women with consecutive recurrent
miscarriages and hereditary thrombophilia. J Thromb
Haemost 2003;1:4338.
118. Brenner B, Hoffman R, Carp H, Dulitsky M,Younis J;
LIVE-ENOX Investigators. Efficacy and safety of two doses of
enoxaparin in women with thrombophilia and recurrent
pregnancy loss: the LIVE-ENOX study. J Thromb Haemost
2005;3:2279.
119. Ogueh O, Chen MF, Spurll G, Benjamin A. Outcome of
pregnancy in women with hereditary thrombophilia. Int J
Gynaecol Obstet 2001;74:24753.
120. Gris JC, Mercier E, Qur I, Lavigne-Lissalde G,
Cochery-Nouvellon E, Hoffet M, et al. Low-molecular weight
heparin versus low-dose aspirin in women with one fetal
loss and constitutional thrombophilic disorder. Blood
2004;103:36959.
121. Brigham SA, Conlon C, Farquharson RG.A longitudinal study
of pregnancy outcome following idiopathic recurrent
miscarriage. Hum Reprod 1999;14:286871.
16 of 18
122. Liddell HS, Pattison NS, Zanderigo A. Recurrent miscarriage

outcome after supportive care in early pregnancy. Aust N Z J
123. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA,
Verhoeve HR, Hamulyk K, et al.Aspirin plus heparin or
aspirin alone in women with recurrent miscarriage. N Engl J
Med 2010;362:158696.
124. Clark P,Walker ID, Langhorne P, Crichton L,Thomson A,

Greaves M, et al.; Scottish Pregnancy Intervention Study
(SPIN) collaborators. SPIN (Scottish Pregnancy Intervention)
study: a multicenter, randomized controlled trial of
low-molecular-weight heparin and low-dose aspirin in
women with recurrent miscarriage. Blood 2010;115:41627.
Appendix

1+

low risk of bias

risk of bias

2+
2-

is not causal

case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
17 of 18

development group
Professor L Regan FRCOG, Miss M Backos MRCOG, and Dr R Rai MRCOG, London
and peer-reviewed by: RCOG Consumers Forum;The Miscarriage Association; Royal College of Midwives; Dr A Eapen,
Research Registrar in Gynaecology, Keele University, Stoke on Trent; Mr RG Farquharson FRCOG, Liverpool; Mr DI Fraser
MRCOG, Norwich; Professor M Greaves MBChB, MD, FRCPath, FRCP, University of Aberdeen,Aberdeen, Scotland; Mr D
Jurkovic FRCOG, London; Professsor T Li FRCOG, Sheffield; Professor SM Quenby FRCOG,Warwick; Ms MS To MRCOG,
London.
Guideline Committee lead reviewers were Dr J Shillito MRCOG, Leeds and Dr SK Surendran FRCOG, London.
DISCLAIMER
The British Society of Gynaecological Endoscopists produces guidelines as an educational aid to good clinical practice.
gynaecologists and other relevant health professionals.The ultimate judgement regarding a particular clinical procedure
or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient
and the diagnostic and treatment options available.This means that BSGE guidelines are unlike protocols or guidelines
issued by employers,not being intended to be prescriptive directions defining a single course of management.Departure
from the local prescriptive protocols or guidelines should be fully documented in the patients case notes at the time the
relevant decision is taken.
18 of 18
GREEN TOP GUIDELINE No. 19
Faculty of Sexual & Reproductive Healthcare

Statement
Venous Thromboembolism (VTE) and Hormonal Contraception
November 2014
Background
This statement updates and replaces the Royal College of Obstetricians and
Gynaecologists (RCOG) Green-top Guideline No. 40 on the same topic. It
summarises Faculty of Sexual and Reproductive Healthcare (FSRH)
recommendations and relevant information found within FSRH clinical
guidance.1-5
Hormonal contraceptives contain either a combination of estrogen and
progestogen (combined hormonal contraceptives (CHC)), or progestogen
alone (progestogen-only contraceptives). In the UK, the majority of combined
hormonal contraceptives contain the synthetic estrogen, ethinylestradiol. A
combined oral contraceptive (COC) product containing mestranol is also
available, with 50g of mestranol roughly equating to 35g of ethinylestradiol.
More recently, COC products have been introduced onto the market that
contain the naturally occurring human hormone, estradiol, either as estradiol
valerate or as estradiol hemihydrate.
Progestogens are often grouped according to the time they were first marketed
as constituents of COCs and may be referred to by generation.
Examples of progestogens according to their classified generation
Generation of progestogen
Examples of Progestogen
First generation
Norethisterone, norethisterone acetate
Second generation
Levonorgestrel
Third generation
Desogestrel, gestodene, norgestimate
Fourth generation
Drospirenone, dienogest, nomegestrol acetate
VTE and Hormonal Contraception November 2014

This summary document examines the VTE risk associated with hormonal
contraception and the relevant risk factors to consider when choosing a
combined hormonal contraceptive.
Risk of venous thromboembolism

The term venous thromboembolism (VTE) includes deep vein thrombosis (DVT),
pulmonary embolism, and cerebral venous sinus thrombosis. Most studies of
venous thrombosis and hormonal contraceptive use relate to DVT and
pulmonary embolism. The true background incidence of VTE in women of
reproductive age is difficult to quantify but recently published figures suggest it is
in the range of 2 per 10,000 women in 1 year.6
Concerns about the role of hormonal contraceptives in mediating thrombosis risk
are not new and have been ongoing since the introduction of hormonal
contraceptives in the 1960s. Non-randomized studies have consistently reported
an increased risk of VTE associated with combined hormonal contraceptive
use,7-19 suggesting that this effect is real.
What is the venous thromboembolism risk associated with different

combined hormonal contraceptives (pill, patch and vaginal ring)?
Combined oral contraception
Data10;18 suggest that COCs containing the third generation progestogens
gestodene or desogestrel are associated with an increased risk of venous
thromboemolism (VTE) when compared with those containing the second
generation progestogens levonorgestrel or norethisterone. The first publications
to show differences in VTE risk led to the UK pill scare in 1995 and a reduction in
oral contraceptive use with a corresponding increase in unintended
pregnancies.20;21
Since the publications in the 1990s, debate has continued about the effect of
newly introduced progestogens on VTE risk. Some studies have reported no
increased risk for fourth generation drospirenone-containing COCS;14,15;22 others
have demonstrated an increased risk along with other newer progestogens.12;13;23
The biological mechanism is not fully understood but different progestogens
appear to modify the thrombogenic effects of estrogen to different extents, for
example, acquired resistance to activated protein C is more pronounced during
use of COCs containing desogestrel than levonorgestrel.24 Although bias and
confounding cannot be excluded, the consistency of recent studies coupled
with evidence supporting biological plausibility suggests that this is a true effect.
In 2013 the European Medicines Agency (EMA) initiated a review of the risk of
VTE associated with use of CHC. This review concluded that there was good
evidence to suggest that the risk of VTE associated with different COCs was
influenced by progestogen type, with those containing levonorgestrel,

norethisterone or norgestimate having the lowest risk (5-7 per 10,000 women) and
those containing drospirenone, desogestrel or gestodene having the highest risk
(9-12 per 10,000 women).6 The risk of VTE with use of CHC was therefore reported
to range from 5-12 per 10,000 women years, compared with 2 per 10,000 nonusers. However the EMA noted that the benefits of CHC use generally
outweighed the risk of venous thrombosis, which is low overall and is lower than
the VTE risk associated with pregnancy and the postpartum period (29 per 10,
000 woman-years and 300400 per 10,000 woman-years, respectively).25 Despite
evidence of more favourable effects on lipid profiles and carbohydrate
metabolism, there is no evidence to suggest that the newer, less androgenic
progestogens are any safer in terms of arterial thrombosis risk than older
progestogens.26
A Cochrane review27 examined the findings of 26 studies and concluded that
the risk of VTE with use of 30-35g ethinylestradiol oral contraceptives was similar,
regardless of whether they contained gestodene, desogestrel, cyproterone
acetate or drospirenone, but that these oral contraceptives were associated
with a 50-80% increased risk than 30-35g ethinylestradiol oral contraceptives
containing levonorgestrel.
Newer synthetic hormones such as estradiol valerate, estradiol hemihydrate,
dienogest, and nomegestrol acetate are being incorporated into COC
products. Long-term safety data for these new formulations are not yet
available. Therefore, the risks and benefits of use must be assumed to be as for
other CHCs.28;29
Combined transdermal patch and vaginal ring
Long-term data on VTE risk with the combined ethinylestradiol and
norelgestromin transdermal patch are limited. Those studies comparing the risk
associated with transdermal patch use to oral contraceptives containing second
generation progestogens have reported mixed results. Some observational
studies of the transdermal patch have reported a similar level of venous
thromboembolism (VTE) risk30-32 to COCs containing second generation
progestogens, whereas other studies have suggested an increased risk.33-35
There is less available data for the vaginal ring which contains ethinylestradiol
and etonogestrel. A national registry-based study35, which sought to assess the
risk of VTE in users of non-oral contraceptives, reported that compared to nonusers use of the ring conferred a relative risk of 6.5 (95% CI 4.7-8.9) with a
corresponding incidence rate of 7.8 per 10,000 exposure years. A prospective
cohort study that examined the short and long-term cardiovascular risks
associated with use of the combined vaginal ring, and COC in new users from
the United States and five European countries, reported an incidence rate for
the vaginal ring of 8.3 per 10,000 woman-years.36
In 2014 the Medicines and Healthcare Regulatory Authority (MHRA) produced
updated advice for UK prescribers based on the EMAs estimates of VTE risk for

different products (see table 2).6 The advice suggested a risk of 6-12 per 10,000
women over a year for CHCs containing norelgestromin or etonogestrel.6
Table 2: Risk of venous thromboembolism (VTE) associated with non-use,
combined hormonal contraception (CHC) use over the course of 1 year
(adapted from
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/11
/news_detail_001969.jsp&mid=WC0b01ac058004d5c1)
Risk of VTE per 10,000 healthy women

over one year
Non contraceptive users and not
pregnant
CHC containing ethinylestradiol plus
levonorgestrel, norgestimate or
norethisterone
CHC containing etonogestrel (ring) or
norelgestromin (patch)
gestodene, desogestrel or
drospirenone
2
5-7
6-12
9-12
Cyproterone-containing combined oral contraceptives

Co-cyprindiol (brands in the UK include Dianette, Clairette, Cicafem and
Acnocin) is a product containing the anti-androgen cyproterone acetate 2mg
in combination with ethinylestradiol 35 micrograms. It is licensed for the
treatment of acne that has not responded to antibiotics and while it can be
used as a contraceptive, it should not be used solely for this purpose.
Observational studies have suggested that cyproterone containing COCs may
be associated with an increased risk of VTE compared with levonorgestrel
COCs.12;13;37 The VTE risk initially appeared to be four-fold higher than
levonorgestrel COCs38, which conferred the highest VTE risk of all COCs available
in the UK at that time. The Committee on Safety of Medicines (CSM) previously
advised that co-cyprindiol should be discontinued 3-4 months after the
complete resolution of symptoms.39
In 2008 the Medicines and Healthcare Products Regulatory Agency (MHRA) and
the Commission on Human Medicines (CHM formerly the CSM) endorsed this
advice but acknowledged that in women with severe hyperandrogenism
symptoms usually recur when treatment is stopped.40 The MHRA advised that for
these women co-cyprindiol could be continued until symptoms are judged
unlikely to recur and that in all women co-cyprindiol could be re-started at any
time if acne or hirsutism recurs on stopping treatment.40

Following reported deaths from VTE in women prescribed co-cyprindiol in France,
the EMAs Pharmacovigilance Risk Assessment Committee (PRAC) conducted an
evaluation of the risk of venous and arterial thromboembolism (VTE and ATE)
associated with use of cyproterone-containing products.41 A review of postmarketing data suggested that in some of the reported cases of death, women
had been using Dianette as well as CHCs. In 2013 the PRAC42 report concluded
that the incidence of VTE is 1.5 to 2 times higher in users of co-cyprindiol than in
users of levonorgestrel-containing COCs and that there may be similar risk to that
associated with desogestrel / gestodene / drospirenone-containing COCs41.
In response to the PRAC report, the MHRA issued updated advice for health
professionals in the UK42:
The benefits of co-cyprindiol outweigh the risks in women of reproductive

age for the treatment of:
o Skin conditions related to androgen sensitivity (for example, severe
acne with or without seborrhoea)
o Hirsutism
Co-cyprindiol provides effective contraception in these women. An
additional hormonal contraceptive should not be used in combination
with co-cyprindiol.
The need to continue treatment should be evaluated periodically by the
treating physician.
The risk of VTE is rare but this remains an important side effect, and
healthcare professionals should themselves be vigilant for signs and
counsel patients to remain vigilant for signs and symptoms.
Duration of use
The risk of VTE is highest in the four months following initiation of CHC43 or when
restarting after a break of at least one month. The risk then reduces over the next
year and remains stable thereafter.14;19;44-46 Although the risk is high in the first few
months of CHC use and then falls, it remains higher than in non-users.
B
Health professionals should be aware that compared to non-users, the risk

of VTE with use of CHC is approximately doubled but that the absolute risk
remains very low.
Health professionals prescribing CHCs should be guided by a womans

own personal preference, risk of VTE, any contraindications, possible noncontraceptive benefits, and experience with other contraceptive
formulations.
A personal history of VTE or having a known thrombogenic mutation

represents an unacceptable health risk to CHC use.
For women with a family history of VTE, a negative thrombophillia screen

does not necessarily exclude all thrombogenic mutations

C
A thrombophillia screen is not recommended routinely before prescribing

CHC
Do progestogen-only methods of contraception (pill, injectable, implant

and intrauterine system) increase the risk of VTE?
There are fewer data on VTE risk with progestogen-only methods of
contraception and, although a lack of evidence does not necessarily suggest an
absence of effect, data12;47 do not generally support an increased risk.
Data from a WHO study suggested that there was little or no increased risk of VTE
associated with use of oral or injectable progestogen-only methods.47 The odds
ratio for progestogen-only pill (POP) users was 1.74 (95% CI 0.76-3.99) and for
progestogen-only injectable users 2.19 (95% CI 0.66-7.26).47 More recently a casecontrol study48 reported a 3.6-fold (95% CI, 1.8- to 7.1-fold) increased risk of
venous thrombosis associated with use of the injectable compared with nonusers
of hormonal contraceptives. A meta-analysis of eight observational studies,
designed to investigate the risk of VTE associated with progestogen-only
methods, noted that from the small amount of available data the relative risk of
a VTE event for users of the progestogen-only injectable was increased
compared with non-users (2.67 (95% CI, 1.29 to 5.53).49 However, the studies
included in the analysis had small sample sizes and bias and confounding
cannot be excluded.
Norethisterone and norethisterone acetate have been shown to be partly
metabolised to ethinylestradiol.50;51 At an oral dose of 5mg a conversion ratio of
about 0.4+/-0.4 was found. This approximated to equate to an oral dose
equivalent of 4g of ethinylestradiol per 1mg of norethisterone, although the
authors noted that they could not rule out individual variations.51 While
therapeutic doses of norethisterone used for gynaecological treatment should
perhaps be prescribed with care in women with risk factors or contraindications
to estrogen, POPs in the UK only contain 350g of norethisterone, and therefore
this conversion is not likely to be clinically significant.
The progestogen-only injectable Noristerat contains norethisterone enanthate
(NET-EN). The degree of conversion to ethinylestradiol after intramuscular
injection (IM) of NET-EN is unknown. However, if the conversion rate is assumed to
be the same as for oral administration then levels similar to a combined oral
product would be expected during the first 4 weeks of use (personal
communication with Bayer Healthcare Pharmaceuticals). An open label oneway crossover pharmacokinetic study designed to assess the in vivo formation of
EE following administration of IM NET-EN is currently ongoing.
No statistically significant increased risk has been observed for the levonorgestrel
intrauterine system35;48 or the progestogen-only implant.35

There is no evidence to suggest that use of progestogen-only emergency
contraception is associated with an increased risk of VTE.
Progestogen-only methods of contraception do not appear to be

associated with an increased risk of venous thromboembolism.
What conditions increase the risk of VTE in women considering

hormonal contraception?
There is synergism between acquired risk factors associated with venous
thrombosis, such as, CHC use, antiphospholipid syndrome, pregnancy, surgery,
trauma, immobilisation, malignancy52 and high altitude53, and genetic factors,
such as, factor V Leiden mutation, prothombin 20210A, protein C or protein S
deficiency, and antithrombim III deficiency. The use of hormonal contraceptives,
in particular CHC, in women with such conditions may negatively affect the
balance of risk and therefore contraindicate the use of such methods.
The UK Medical Eligibility Criteria for Contraceptive Use (UKMEC) provides
consensus-based recommendations to allow health professionals and individuals
to select the most appropriate method of contraception, without imposing
unnecessary restrictions. On the balance of the available evidence and
consensus opinion of experts, conditions are assigned one of four categories for
each category of contraceptive method (see table 3).
Table 3: Definitions of UK Medical Eligibility Criteria categories for contraceptive
use54
UKMEC Category
Definition
1
2
3
A condition for which there is no restriction for the use of

the contraceptive method
A condition for which the advantages of using the
method generally outweigh the theoretical or proven
risks
A condition where the theoretical or proven risks usually
outweigh the advantages of using the method. The
provision of a method requires expert clinical judgement
and/or referral to a specialist contraceptive provider,
since use of the method is not usually recommended
unless other more appropriate methods are not
available or not acceptable.
A condition which represents an unacceptable health
risk if the method is used.

A clinical history should identify any conditions which fall within the categories 3
or 4 for use of hormonal contraception. Since progestogen-only methods do not
increase the risk of VTE most of the risk assessment relates to CHC use. UKMEC is
updated following each update of the World Health Organisation Medical
Eligibility Criteria (WHOMEC). Health professionals should refer to the current
version of UKMEC, available via the FSRH website www.fsrh.org
Summary of UKMEC categories relevant to VTE risk
CHC
POP
DMPA/NETEN
History of VTE
4
2
2
PO
Implant
2
LNG-IUS
Cu-IUD
Current VTE (on

anticoagulants)
Family history of
VTE in a first
degree relative
aged under 45
Family history of
VTE in a first
degree relative
aged 45 or over
Major surgery
with prolonged
immobilisation
Major surgery
without
prolonged
immobilisation
Minor surgery
without
immobilisation
Immobility
unrelated to
surgery (e.g.
wheelchair use,
debilitating
illness)
Known

thrombogenic
mutation
(Factor
V
Leiden,
Prothrombin
mutation,
Protein
S,
Protein C, and
Antithrombin
deficiencies)
BMI 3034kg/m2
BMI 35kg/m2
Smoking aged
< 35 years
3
2
1
1
1
1
1
1
1
1
1
1
Smoking less
than 15
cigarettes/day
aged >35years
Smoking > 15
cigarettes/day
aged >35years
Aged > 35 and

stopped
smoking < 1
year ago
Aged >35 and

stopped
smoking a year
or more ago
Postpartum
(non
breastfeeding)1
<21 days
21 days
WHOMEC55 and USMEC56 are more restrictive than UKMEC depending on whether there
are other risk factors
1

While the advantages of using the progestogen-only implant, injectable and
intrauterine methods generally outweigh the theoretical or proven risks in women
who are anticoagulated, the CEU would advise ensuring that coagulation has
been monitored recently. FSRH guidance57 advises that there is generally no
need to alter anticoagulant therapy if the woman is anticoagulated within the
target therapeutic range. A community setting for fitting implants and
intrauterine contraceptives is generally appropriate providing there are no other
risks, for example, severe vasovagal reaction. However, it is recommended that
an experienced clinician performs the procedure with careful attention to
haemostasis, and application of a pressure bandage following implant
procedures. Subcutaneous administration of the progestogen-only injectable
(Sayana-Press) can be considered as an alternative to IM injection, although
any advantage in terms of bleeding is currently unproven.
While women with reduced levels of naturally occurring anticoagulants (antithrombin III, Protein C or Protein S) factor V Leiden, or prothrombin gene
mutations (G20210A) are predisposed to VTE58 FSRH guidance1 does not
recommend the need for routine thrombophillia screening prior to use of CHC,
as a negative screen may not exclude all types of thrombophilia.
The United Kingdom Medical Eligibility Criteria for Contraceptive Use

provides
consensus-based
recommendations
for
the
use
of
contraception. A clinical history should be taken to identify any relevant
medical conditions which may influence contraceptive choice.
A thrombophillia screen is not recommended routinely before use of CHC
Summary
Although the relative risk of VTE does increase with CHC use, the absolute risk in
women of reproductive age is very low. Other hormonal contraceptives do not
appear to be associated with an increased risk of VTE, although more evidence
is required, particularly for high risk groups. Clinicians advising women on
hormonal contraceptive use should be able to convey the risk of VTE and
provide information on overall risks and benefits to help women judge the level
of risk that is acceptable to them.
10

References
(1) Faculty of Sexual and Reproductive Healthcare. Combined Hormonal
Contraception. 2011. Avaialble at:
http://www.fsrh.org/pdfs/CEUGuidanceCombinedHormonalContraceptio
n.pdf.2(Accessed:30/10/14).
(2) Faculty of Sexual and Reproductive Health Care. Progestogen-only
injectables. 2008. Available at:
http://www.fsrh.org/admin/uploads/CEUGuidanceProgestogenOnlyInject
ables09.pdf. (Accessed: 30/10/14).
(3) Faculty of Sexual and Reproductive Health Care. Progestogen-only pills.
2008. Available at:
http://www.fsrh.org/admin/uploads/CEUGuidanceProgestogenOnlyPill09.
pdf. (Accessed: 30/10/14).
(4) Faculty of Sexual & Reproductive Healthcare. Progestogen-only implants.
2014. Available at:
http://www.fsrh.org/pdfs/CEUGuidanceProgestogenOnlyImplants.pdf.
(Accessed: 30/10/14).
(5) Faculty of Sexual and Reproductive Health Care. Intrauterine
Contraception. 2007. Available at:
http://www.fsrh.org/admin/uploads/CEUGuidanceIntrauterineContracept
ionNov07.pdf. (Accessed: 30/10/14).
(6) European Medicines Agency. Benefits of combined hormonal
contraceptives (CHCs) continue to outweigh risks. Product information
updated to help women make informed decisions about their choice of
contraception. London, UK: EMA, 2014. Available at: .
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/huma
n/referrals/Combined_hormonal_contraceptives/human_referral_prac_00
0016.jsp&mid=WC0b01ac05805c516f. (Accessed: 30/10/14)
(7) WHO. WHO Collaborative study of cardiovascular disease and steroid
hormone contraception. Effect of different progestogens in low oestrogen
containing oral contraceptives on venous thromboembolism. Lancet
1995; 346:1575-1582.
(8) Committee on Safety of Medicines. Combined oral contraceptives:
Venous thromboembolism. Current Problems in Pharmacovigilance 2004;
30:7.
(9) Heinemann, L. A. J., Dinger, J. C., Assmann, A., and Minh, T. D. Use of oral
contraceptives containing gestodene and risk of venous
thromboembolism: outlook 10 years after the third generation "pill scare".
Contraception 2010; 81:401-407.
11

(10) World Health Organisation. World Health Organisation Collaborative Study
of Cardiovascular Disease and Steroid Hormone Contraception. Venous
thromboembolic disease and and combined contraceptives: results of
international multicentre case-control study. Lancet 1995; 346:1575-1582.
(11) Jick S.S., Kaye, J. A., Russmann S., and Jick, H. Risk of nonfatal venous
thromboembolism with oral contraceptives containing norgestimate or
desogestrel compared with oral contraceptives containing levonorgestrel.
(12) Lidegaard, O., Lokkegaard, E., Svendsen, A. L., and Agger, C. Hormonal
contraception and risk of venous thromboembolism:national follow-up
study. British Medical Journal 2009; 339:b2890.
(13) van Hylckama Vlieg, A., Helmerhorst, F. M., Vandenbroucke, J. P.,
Doggen, C. J. M., and Rosendaal, F. R. The venous thrombotic risk of oral
contraceptives, effects of oestrogen dose and progestogen type: results
of the MEGA case-control study. British Medical Journal 2009; 339:b2921.
(14) Dinger, J. C., Heinemann, L. A. J., and Kuhl-Habichl, D. The safety of
drospirenone-containing oral contraceptive: final results from the
European Active Surveillance study on Oral Contraceptives based on
142,475 women-years of observation. Contraception 2007; 75:344-354.
(15) Dinger, J., Assmann, A., Mohner, S., and Minh, T. D. Risk of venous
thromboembolism and the use of dienogest- and drospirenonecontaining oral contraceptives: results from a German case-control study.
Journal of Family Planning and Reproductive Health Care 2010; 36(3):123129.
(16) Parkin, L., Sharples, K., Hernandex RK, and Jick S. Risk of venous
thromboembolism in users of oral contraceptives containing drospirenone
or levonorgestrel: nested case-control study based on UK general
practice research database. BMJ 2011; 342: 1-7.
(17) Jick, H., Kaye, J. A., Vasilakis-Scaramozza, C., and Jick, S. S. Risk of venous
thromboembolism among users of third generation oral contraceptives
compared with users of oral contraceptives with levonorgestrel before
and after 1995: cohort and case-control analysis. British Medical Journal
2000; 321:1190-1195.
(18) Jick, H., Jick, S. S., Gwewich, K., and et al. Risk of idiopathic cardiovascular
death and non fatal venous thromboembolism in women using oral
contraceptives with differing progestogen components. Lancet 1995;
346:1589-1593.
(19) Bloemenkamp, K. W. M., Rosendaal, F. R., Helmerhorst, F. M., and et al.
Enhancement by Factor V Leiden mutation of risk of deep venous
12

thrombosis associated with oral contraceptives containing a third
generation progestogen. Lancet 1995; 346:1593-1596.
(20) Szarewski, A. and Mansour, D. The 'pill scare': the responses of authorities,
doctors and patients using oral contraception. [Review] [57 refs]. Human
Reproduction Update 1999; 5(6):627-632.
(21) Furedi, A. The public health implications of the 1995 'pill scare'.
Hum.Reprod.Update. 1999; 5(6):621-626.
(22) Dinger, J., Bardenheuer, K., and Heinemann, K. Cardiovascular and
general safety of a 24-day regimen of drospirenone-containing combined
oral contraceptives: Final results from the International Active Surveillance
Study of Women Taking Oral Contraceptives. Contraception 2014;
89(4):April.
(23) Stegeman, B. H., de, Bastos M., Rosendaal, F. R., van, Hylckama, V,
Helmerhorst, F. M., Stijnen, T., and Dekkers, O. M. Different combined oral
contraceptives and the risk of venous thrombosis: systematic review and
network meta-analysis. BMJ 2013; 347:f5298.
(24) Odlind, V., Milsom, I., Persson, I., and Victor, A. Can changes in sex
hormone binding globulin predict the risk of venous thromboembolism
with combined oral contraceptive pills? Acta Obstet Gynecol Scand
2002; 81(6):482-490.
(25) Reid, R. L., Westhoff, C., Mansour, D., de Vries, C., Verhaeghe, J.,
Boschitsch, E., Gompel, A., Birkhauser, M., Krepelka, P., Dulicek, P.,
Iversen.O-E., Khamoshina, M., Dezman, L. V., Fruzzetti, F., Szarewski, A.,
Wilken-Jensen, C., Seidman, D., Kaaja, R., and Shapiro, S. Oral
contraceptives and venous thromboembolism: Consensus opinion from
an international workshop. Journal of Family Planning and Reproductive
Healthcare 2010; 36(3):117-122.
(26) Lidegaard, O., Lokkegaard, E., Jensen, A., Skovlund, C. W., and Keiding, N.
Thrombotic stroke and myocardial infarction with hormonal
contraception. New England Journal of Medicine 2012; 366(24):2257-2266.
(27) de Bastos M., Stegeman BH, Rosendaal FR, Van Hylckama Vlieg,
Helmerhorst FM, and Stijnen T. Combined oral contraceptives: venous
thrombosis. Cochrane Database of Systematic Review 2014;(3):Art. No.:
CD010813. DOI: 10.1002/14651858.CD010813.pub2.
(28) Faculty of Sexual and Reproductive Health Care. The estradiol valerate /
dienogest combined pill, Qlaira. 2009. Available at:
http://www.fsrh.org/admin/uploads/CEU_Qlaira.pdf. (Accessed:
30/10/14).
13

(29) Faculty of Sexual and Reproductive Healthcare. Estradiol/Nomegestrol
Combined Pill, Zoely. 2013. Available at:
http://www.fsrh.org/pdfs/CEUstatementZoely.pdf. (Accessed: 30/10/14).
(30) Jick S.S, Kaye J.A, Russmann S, and Jick, H. Risk of nonfatal venous
thromboembolism in women using a contraceptive transdermal patch
and oral contraceptives containing norgestimate and 35ug of ethinyl
estradiol. Contraception 2006; 73:223-228.
(31) Jick, S. S., Hagberg, K. W., Hernandez, R. K., and Kaye, J. A. Postmarketing
study of ORTHO EVRA and levonorgestrel oral contraceptive containing
hormonal contraceptives with 30mcg of ethinylestradiol in relation to
nonfatal venous thromoembolism. Contraception 2010; 81:16-21.
(32) Jick, S., Kaye, J. A., Li, L., and Jick, H. Further results on the risk of nonfatal
venous thromboemolism in users of the contraceptive transdermal patch
compared to users of oral contraceptive containing norgestimate and
35ug of ethinyl estradiol. Contraception 2007; 76:4-7.
(33) Cole, J. A., Norman, H., Doherty, M., and Walker, A. M. Venous
Thromboembolism, Myocardial Infaction, and Stroke Among Transdermal
Contraceptive System Users. American Journal of Obstetrics and
Gynecology 2007; 109(2):339-346.
(34) Dore, D. D., Norman H., Loughlin, J., and Seeger, J. D. Extended casecontrol study results on thromboembolic outcomes among transdermal
contraceptive users. Contraception 2010; 81:408-413.
(35) Lidegaard O, Nielson L, Skovlund CW, and Lokkegaard E. Venous
thrombosis in users of non-oral hormonal contraception: follow-up study,
Denmark 2001-10. BMJ 2012; 344:e2990.
(36) Dinger, Jurgen MD, Mohner, Sabine PhD, and Heinemann, Klaas MD.
Cardiovascular Risk Associated With the Use of an EtonogestrelContaining Vaginal Ring. [Article]. Obstetrics & Gynecology 2013;
122(4):800-808.
(37) Vasilakis-Scaramozza, C. and Jick, H. Risk of venous thromboembolism
with cyproterone or levonorgestrel contraceptives. Lancet 2001;
358(9291):1427-1429.
with cyproterone or levonorgestrel contraceptives. Lancet 27-10-2001;
358(9291):1427-1429.
(39) Medicines Control Agency Committee on Safety of Medicines.
Cyproterone acetate (Dianette): risk of venous thromboembolism (VTE).
Current Problems in Pharmacovigilance 2002; 28(October):9-10.
14

(40) Medicines Control Agency Committee on Safety of Medicines. Combined
hormonal contraceptives: venous thromboembolism - update. Drug
Safety Update 2008; 1(9):3-4.
(41) European Medicines Agency Pharmacovigillance Risk Assessment
Committee. Cyproterone and ethinylestradiol containing medicinal
products. 2013. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_doc
ument/cyproterone_ethinylestradiol_107i/Position_provided_by_CMDh/W
C500143778.pdf. (Accessed: 30/10/14).
Cyproterone acetate with ethinyloestradiol (co-cyprindiol) balance of
benefits and risks remains positive. Drug Safety Update 2013; 6(11):A3.
(43) Farley, T. M., Meirik, O., Chang, C. L., Marmot, M. G., and Poulter, N. R.
Effect of different progestagens in low oestrogen oral contraceptives on
venous thromboembolic disease. World Health Organization
Collaborative Study of Cardiovascular Disease and Steroid Hormone
Contraception. Lancet 1995; 346(8990):1582-1588.
(44) Farmer, R. D. T., Lawrenson, R. A., Todd, J. C., Williams, T. J., MacRae, K. D.,
Tyrer, F., and Leydon, G. M. A comparison of the risks of venous
thromboembolic disease in association with different combined oral
contraceptives. British Journal of Cinical Pharmacology 2000; 49:580-590.
(45) Suissa, S, Blais, L, Spitzer, W. O., Cusson, J, Lewis, M, and Heinemann, L. FirstTime Use of Newer Oral Contraceptives and the Risk of Venous
Thromboembolism. Contraception 1997; 56:141-146.
(46) Lidegaard, O., Edstrom, B., and Kreiner, S. Oral contraceptives and venous
thromboembolism: a five year national case-control study. Contraception
2002; 65(3):187-196.
(47) World Health Organization Collaborative Study of Cardiovascular Disease
and Steroid Hormone Contraception. Cardiovascular disease and use of
oral and injectable progestogen-only contraceptives and combined
injectable contraceptives. Contraception 1998; 57:315-324.
(48) van, Hylckama, V, Helmerhorst, F. M., and Rosendaal, F. R. The risk of deep
venous thrombosis associated with injectable depotmedroxyprogesterone acetate contraceptives or a levonorgestrel
intrauterine device. Arteriosclerosis, Thrombosis & Vascular Biology 2010;
30(11):2297-2300.
(49) Mantha, S., Karp, R., Raghavan, V., Terrin, N., Bauer, K. A., and Zwicker, J. I.
Assessing the risk of venous thromboembolic events in women taking
progestin-only contraception: a meta-analysis. [Review]. BMJ 2012;
345:e4944.
15

(50) Chu, M. C., Zhang, X., Gentzschein, E., Stanczyk, F. Z., and Lobo, R. A.
Formation of ethinyl estradiol in women during treatment with
norethindrone acetate. J Clin Endocrinol Metab 2007; 92(6):2205-2207.
(51) Kuhnz, W., Heuner, A., Humpel, M., Seifert, W., and Michaelis, K. In vivo
conversion of norethisterone and norethisterone acetate to ethinyl
etradiol in postmenopausal women. Contraception 1997; 56(6):379-385.
(52) Rosendaal, F. R. Venous thrombosis: a multicausal disease. Lancet 1993;
353:1167-1173.
(53) Hillebrandt D, Meijer H. Contraception and Period Control at Altitude:
Consensus Statement of the UIAA Medical Commission. Standard No 14.
2009.
(54) Faculty of Sexual and Reproductive Health Care. UK Medical Eligibility
Criteria for Contraceptive Use. (UKMEC 2009). Available at:
http://www.fsrh.org/admin/uploads/UKMEC2009.pdf. (Accessed:
30/10/14).
(55) World Health Organization. Medical Eligibility Criteria for Contraceptive
Use 4th Edition 2009. [4th Edition]. Geneva, Switzerland: WHO, 2009.
Available at:
http://www.who.int/reproductivehealth/publications/family_planning/978
9241563888/en/index.html. (Accessed: 30/10/14).
(56) Centre for Disease Control and Prevention. U.S. Medical Eligibility Criteria
for Contraceptive Use 2010. MMWR 2010; 59(RR4):1-85.
(57) Faculty of Sexual and Reproductive Healthcare. Contraceptive Choices
for Women with Cardiac Disease. 2014. Available at:
http://www.fsrh.org/pdfs/CEUGuidanceContraceptiveChoicesWomenCar
diacDisease.pdf. (Accessed: 30/10/14).
(58) Vandenbroucke, J. P., van der Meer, Felix, Helmerhorst, F M, and
Rosendaal, F R. Family history and risks of venous thromboembolism with
oral contraception. British Medical Journal 2001; 323:752.
COMMENTS AND FEEDBACK ON PUBLISHED GUIDANCE
All comments on published statements can be sent directly to the Faculty of
Sexual and Reproductive Healthcare (FSRH) at: [email protected]
FSRH are unable to respond individually to all feedback. However, FSRH will
review all comments and provide an anonymised summary of comments and
responses, which are reviewed by the Clinical Effectiveness Committee and any
necessary amendments made.
16
Guideline No. 20a

December 2006
Reviewed 2010
EXTERNAL CEPHALIC VERSION AND REDUCING THE INCIDENCE OF

BREECH PRESENTATION
This is the first edition of this guideline. Methods of delivery for women with breech presentation is covered in
RCOG Green-top Guideline No. 20b, The Management of Breech Presentation, published in December 2006.
1.
Purpose and scope
External cephalic version (ECV) is the manipulation of the fetus, through the maternal abdomen, to a cephalic
presentation. This guideline summarises the evidence regarding the routine use of ECV for breech
presentation. The rationale behind ECV is to reduce the incidence of breech presentation at term and
therefore the associated risks, particularly of avoidable caesarean section.The evidence concerning mode and
technique of delivery of the persistent breech presentation is summarised in Green-top Guideline No. 20b,
The Management of Breech Presentation.
2.
Background
Breech presentation complicates 34% of all term deliveries and a higher proportion of preterm deliveries. It
is more common where there has been a previous breech presentation. The incidence of caesarean section
for breech presentation has increased markedly in the last 20 years and further1 with the publication of the
term breech trial.2 This trial concluded that, at least for mortality and markers of intermediate term morbidity,
elective caesarean section was safer for the fetus and of similar safety to the mother when compared with
intention to deliver vaginally.3 This means that measures to reduce the incidence of breech presentation have
become more important and that the effect of any such measure on the incidence of caesarean section will
be more marked.
3.
Evidence-based medicine reviews, including the Cochrane Register of Controlled Trials, were searched,
together with the TRIP database for relevant randomised controlled trials, systematic reviews and metaanalyses. A search of Medline and PubMed (electronic databases) from 1966 to 2005 was also carried out.
Search words included breech, external cephalic version, fetal, tocolysis and tocolytic agents and the
search was limited to humans and English language.
4.
External cephalic version
4.1 What is the impact of ECV on the incidence of breech presentation at delivery?
Women should be counselled that ECV reduces the chance of breech presentation at delivery.
1 of 8
A
RCOG Guideline No. 20a
ECV at term reduces the incidence of noncephalic presentation at delivery (RR 0.38, 95% CI
0.180.80, risk difference 52%, NNT 2).4 Spontaneous version rates for nulliparous women are
approximately 8% after 36 weeks5 but less than 5% after unsuccessful ECV;6 success rates of ECV are
3080%. Spontaneous reversion to breech presentation after successful ECV occurs in less than 5%.7,8
Evidence
level Ia
4.2 What is the effect of ECV on the caesarean section rate?

Women with a breech baby should be informed that attempting ECV lowers their chances of having a
caesarean section.
Labour with a cephalic presentation following ECV is associated with a higher rate of obstetric
intervention than when ECV has not been required.
ECV reduces the caesarean section rate by lowering the incidence of breech presentation (RR 0.55,
95% CI 0.330.91, risk difference 17%, NNT 6).4 Provision of an ECV service also reduces the
caesarean section rates for breech presentation.9 This reduction was not necessarily seen when and
where unidentified breeches were more likely to be delivered vaginally.10 In current practice,
breech babies are increasingly delivered by caesarean section, so the effect is likely to be more
marked than the randomised trials.11,12
Evidence
level Ia
This reduction is in spite of a two-fold increase in intrapartum caesarean sections for successfully
turned babies,13,14 when compared with babies that were not breech at term. This is independent
of an increased induction rate: both fetal and maternal indications for intervention are implicated.15
A small increase in instrumental delivery is also seen.
Evidence
level III
4.3 What is the success rate of ECV and what influences it?
Women should be counselled that, with a trained operator, about 50% of ECV attempts will be
successful but this rate can be individualised for them.
Results vary from 30% up to 80% in different series.7,16,17,18 Race, parity, uterine tone, liquor volume,
engagement of the breech and whether the head is palpable, and the use of tocolysis, all affect the
success rate.18,19 Published individual success rates may vary because of case selection as well as
these factors.The highest success rates are seen with multiparous, non-white women with a relaxed
uterus, where the breech is not engaged and the head is easily palpable.18 Success rates are also
higher with increasing liquor volume16,20 but, in practice, very high liquor volume may be associated
with spontaneous reversion. Maternal weight, placental position, gestation, fetal size and position
of the legs make less difference and are probably not independent of other factors.18 An overall
success rate of 40% for nulliparous, and 60% for multiparous women can usually be achieved.
Evidence
level III
4.4 Does the use of tocolysis improve the success rate of ECV?
The use of tocolysis with beta-sympathomimetics may be offered to women undergoing ECV as it has
been shown to increase the success rate.
The use of tocolysis should be considered where an initial attempt at ECV without tocolysis has failed.
The success rate of ECV is increased by the use of tocolysis. This has been proven with ritodrine,
salbutamol and terbutaline but not with glyceryl trinitrate (GTN) as a patch or sublingually,21 or
with nifedipine. Intravenous and subcutaneous routes can be used. Data on those women who
benefit most are contradictory. Tocolysis is also beneficial where an initial attempt without it has
failed22 and can be attempted immediately. However, this policy has not been compared to tocolysis
2 of 8
Evidence
level Ia
for all. A simple protocol is to offer a slow intravenous or subcutaneous bolus of salbutamol or
terbutaline either routinely or if an initial ECV attempt has failed. Women should be advised of the
adverse effects of tocolysis with beta-2 agonists.
Evidence
level Ia
4.5 What other methods can be used to increase the success rate of ECV?
Where ECV fails the possibility of a further attempt should be discussed.
A later, second attempt, particularly with a second operator or where the back has been in the midline, may
lead to a small increase in overall success rates but tocolysis markedly increases the success rate at a second
attempt if it has not been used first.22 Other methods employed to increase success rates include the
application of noise to the abdomen (fetal acoustic stimulation) where the back is in the midline,23 and
regional analgesia, including after a failed initial attempt. For the latter, an increase in success rate is evident
with epidural but not spinal analgesia.24 As maternal pain might indicate a complication, concerns regarding
safety remain.
4.6 When should ECV be offered?

ECV should be offered from 36 weeks in nulliparous women and from 37 weeks in multiparous women.
ECV before 36 weeks of gestation is not associated with a significant reduction in noncephalic
births or caesarean section.25 However, one controlled trial26 randomised women, where low
spontaneous version rates were anticipated, to ECV at 3436 or at 3738 weeks of gestation. This
demonstrated a non-significant reduction in noncephalic births and caesarean section in the early
ECV group, although fewer women in the delayed ECV group underwent an ECV and a larger trial
investigating this is continuing. Importantly, the trial did not show an increased preterm labour rate
and confirmed the safety of early ECV and the low spontaneous reversion rate in this group. With
a spontaneous version rate of 8% in nulliparous breeches after 36 weeks of gestation5 and the very
low complication rate, ECV from 36 weeks of gestation in nulliparous women therefore seems a
reasonable compromise.
Evidence
level IIb
There is no upper time limit on the appropriate gestation for ECV. Successes has been reported at 42 weeks
of gestation7 and can be performed in early labour27 provided that the membranes are intact.
4.7 Is ECV safe?

Women should be counselled that ECV has a very low complication rate.
Women should be alerted to potential complications of ECV.
ECV is rarely associated with complications. Nevertheless, a few case reports exist of complications
such as placental abruption, uterine rupture and fetomaternal haemorrhage. Randomised
controlled trials4 have reported no evidence of an increase in neonatal morbidity and mortality (RR
0.44, 95% CI 0.072.92) but are underpowered for these rare outcomes. Systematic reviews report
a very low complication rate6,28 but are subject to the limitations of reporting bias.These, and large
consecutive series,7,29 however, suggest a 0.5% immediate emergency caesarean section rate and no
excess perinatal morbidity and perinatal mortality.
Evidence
level III
ECV does not appear to promote labour7 but is associated with alterations in fetal parameters. These include
a fetal bradycardia and a nonreactive cardiotocograph30 that are almost invariably transient, alterations in
umbilical artery and middle cerebral artery waveforms31 and an increase in amniotic fluid volume.32 The
significance of these is unknown.
3 of 8
ECV should be performed where facilities for monitoring and immediate delivery are available.
The standard preoperative preparations for caesarean section are not necessary for women undergoing ECV.
ECV should be performed where ultrasound to enable fetal heart rate visualisation, cardiotocography and
theatre facilities are available. Cardiotocography should be performed after the procedure. Kleihauer testing
is unnecessary33 but anti-D immunoglobulin is normally offered to rhesus-negative women. Given the low
complication rate, particularly when compared with labour, starvation, anaesthetic premedication and
intravenous access are all unnecessary.
4.8 Is ECV painful?

Women should be advised that ECV can be painful and the procedure will be stopped if they wish.
ECV can be painful, with few women experiencing no discomfort and around 5% reporting high pain
scores.22,33 The procedure may need to be stopped because of this. Reported experience of pain is greater
where the procedure fails. Data on analgesia for ECV are lacking.
4.9 What are contraindications to ECV?

There are few absolute contraindications to ECV.
Absolute contraindications for ECV that are likely to be associated with increased mortality or morbidity:
where caesarean delivery is required

antepartum haemorrhage within the last 7 days
abnormal cardiotocography
major uterine anomaly
ruptured membranes
multiple pregnancy (except delivery of second twin).
Relative contraindications where ECV might be more complicated:
small-for-gestational-age fetus with abnormal Doppler parameters

proteinuric pre-eclampsia
oligohydramnios
major fetal anomalies
scarred uterus
unstable lie.
In one UK report without any adverse events, ECV was considered contraindicated in only 4% of
women with a breech presentation at term.22 With an unstable lie, ECV is only logical in the context
of a stabilising induction. There are few available data on this procedure, which should only be
performed for a valid indication and may be associated with a significant intrapartum complication
rate. The available data on ECV after one caesarean section are reassuring35,36 but are insufficient to
confidently conclude that the risk is not increased.
5.
Evidence
level III
Increasing the uptake of ECV
Local policies should be implemented to actively increase the number of women offered and undergoing ECV.
Obstetricians and midwives should be able to discuss the benefits and risks of ECV accurately.
4 of 8
ECV may not be performed because breech is not diagnosed in about 25%37 because the procedure
is not offered or available, because it was refused or because it was not recommended.38 Detection
rates can be increased through reminders to women and staff;39 ECV uptake rates can be increased
by education of staff40 and are likely to be improved by accurate dissemination of the benefits
and risks.
6.
Evidence
level III
Alternatives to ECV
There is insufficient evidence to support the use of postural management as a method of promoting
spontaneous version over ECV.
Moxibustion should not be recommended as a method of promoting spontaneous version over ECV.
There is no evidence to support the use of postural management in the management of the breech
presentation.41 Moxibustion, burnt at the tip of the fifth toe (acupuncture point BL67) has been
used to promote spontaneous version of the breech, with some success, and appears to be safe.42
However, pooled43 and recent data44 conclude that there is insufficient evidence to support its use,
highlighting the need for good quality studies.
Evidence
level Ia
7. Developing an ECV service

An ECV service, provided by appropriately trained clinicians, should be available to all women with a
breech presentation at term.
All women undergoing ECV should be offered detailed information (preferably written) concerning the
risks and benefits of the procedure. Consent may also be appropriate.
ECV is best performed at a weekly session with access to ultrasound, cardiotocography and theatre facilities.
ECV is not difficult and skills should be developed, if necessary, by visiting other hospitals. ECV can be
performed by suitably trained midwives; experience with ultrasound is essential. Vigilance for breech
presentation after 34 weeks is important. A proper understanding of the risks is essential for the obstetrician
and midwife to allow accurate counselling. Local audit should be used to aid this.
1.
2.
3.
4.
5.
Antenatal detection of breech presentation.

Proportion of women with a breech presentation offered ECV.
Success rates of ECV.
Complications of/after ECV.
Maternal perceptions of ECV.
References
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2.
3.
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Term Breech Trial on medical intervention behaviour and
neonatal outcome in The Netherlands: an analysis of 35,453
term breech infants. BJOG 2005;112:2059.
Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S,
Willan AR. Planned caesarean section versus planned vaginal
birth for breech presentation at term: a randomised multicentre
trial. Term Breech Trial Collaborative Group. Lancet
2000;356:137583.
Hofmeyr GJ, Hannah ME. Planned caesarean section for term
breech delivery. Cochrane Database Syst Rev 2003;(3):
CD000166.
4.
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Hofmeyr GJ, Kulier R. External cephalic version for breech

presentation at term. Cochrane Database Syst Rev 2000;(2):
CD000083.
Westgren M, Edvall H, Nordstrom L, Svalenius E, Ranstam J.
Spontaneous cephalic version of breech presentation in the
last trimester. Br J Obstet Gynaecol 1985;92:1922.
Collaris RJ, Oei SG. External cephalic version: a safe procedure?
A systematic review of version-related risks. Acta Obstet
Gynecol Scand 2004;83:51118.
Impey L, Lissoni D. Outcome of external cephalic version after
36 weeks gestation without tocolysis. J Matern Fetal Med
1999;8:2037.
8.
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23.
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25.
26.
Wallace RL, VanDorsten JP, Eglinton GS, Meuller E, McCart D,

Schifrin BS. External cephalic version with tocolysis.
Observations and continuing experience at the Los Angeles
County/University of Southern California Medical Center. J
Reprod Med 1984;29:7458.
Coltart T, Edmonds DK, al-Mufti R. External cephalic version at
term: a survey of consultant obstetric practice in the United
Kingdom and Republic of Ireland. Br J Obstet Gynaecol
1997;104:5447.
Nwosu EC, Walkinshaw S, Chia P, Manasse PR, Atlay RD.
Undiagnosed breech. Br J Obstet Gynaecol 1993;100:5315.
Vandenbussche FP, Oepkes D. The effect of the Term Breech
Trial on medical intervention behaviour and neonatal outcome
in The Netherlands: an analysis of 35,453 term breech infants.
BJOG 2005;112:1163.
Royal College of Obstetricians and Gynaecologists Clinical
Effectiveness Support Unit. National Sentinel Caesarean
Section Audit Report. London: RCOG Press; 2001.
Chan LY,Tang JL,Tsoi KF, Fok WY, Chan LW, Lau TK. Intrapartum
cesarean delivery after successful external cephalic version: a
meta-analysis. Obstet Gynecol 2004;104:15560.
Vezina Y, Bujold E, Varin J, Marquette GP, Boucher M. Cesarean
delivery after successful external cephalic version of breech
presentation at term: a comparative study. Am J Obstet Gynecol
2004;190:7638.
Chan LY-S, Leung TK, Fok WY, Chan LW, Lau TK. High incidence
of obstetric interventions after successful external cephalic
version. BJOG 2002;109:62731.
Boucher M, Bujold E, Marquette GP, Vezina Y. The relationship
between amniotic fluid index and successful external cephalic
version: a 14-year experience. Am J Obstet Gynecol 2003;
189:7514.
Nor Azlin MI, Haliza H, Mahdy ZA,Anson I, Fahya MN, Jamil MA.
Tocolysis in term breech external cephalic version. Int J
Lau TK, Lo KWK, Wan D, Rogers M. Predictors of successful
external cephalic version at term: a prospective study. Br J
Hofmeyr GJ, Sadan O, Myer IG, Galal KC, Simko G. External
cephalic version and spontaneous version rates: ethnic and
other determinants. Br J Obstet Gynaecol 1986;93:1316.
Haas DM, Magann EF. External cephalic version with an
amniotic fluid index < or = 10: a systematic review. J Matern
Fetal Neonatal Med 2005;18:24952.
Hofmeyr GJ. Interventions to help external cephalic version for
breech presentation at term. Cochrane Database Syst Rev
2004;(1):CD000184.
Impey L, Pandit M. Tocolysis for repeat external cephalic
version after a failed version for breech presentation at term: a
randomised double-blind placebo controlled trial. BJOG
2005;112:62731.
Johnson RL, Elliott JP. Fetal acoustic stimulation, an adjunct to
external cephalic version: a blinded, randomized crossover
study. Am J Obstet Gynecol 1995;173:136972.
Macarthur AJ, Gagnon S, Tureanu LM, Downey KN. Anesthesia
facilitation of external cephalic version: a meta-analysis. Am J
Hutton EK, Hofmeyr GJ. External cephalic version for breech
presentation before term. Cochrane Database Syst Rev 2006;
(1):CD000084.
Hutton EK, Kaufman K, Hodnett E, Amankwah K, Hewson SA,
McKay D, Szalai JP, Hannah ME. External cephalic version
beginning at 34 weeks gestation versus 37 weeks gestation: a
randomized multicenter trial. Am J Obstet Gynecol 2003;
189:24554.
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27. Ferguson JE 2nd, Dyson DC. Intrapartum external cephalic

version. Am J Obstet Gynecol 1985;152:2978.
28. Nassar N, Roberts CL, Barratt A, Bell JC, Olive EC, Peat B.
Systematic review of adverse outcomes of external cephalic
version and persisting breech presentation at term. Paediatr
Perinat Epidemiol 2006;20:16371.
29. Ben-Arie A, Kogan S, Schachter M, Hagay ZJ, Insler V.The impact
of external cephalic version on the rate of vaginal and
caesarean breech deliveries: a 3-year cumulative experience.
30. Hofmeyr GJ, Sonnendecker EW. Cardiotocographic changes
after external cephalic version. Br J Obstet Gynaecol 1983;
90:91418.
31. Leung TY, Sahota DS, Fok WY, Chan LW, Lau TK. External
cephalic version induced fetal cerebral and umbilical blood
flow changes are related to the amount of pressure exerted.
BJOG 2004;111:4305.
32. Brost BC, Scardo JA, Newman RB, Van Dorsten JP. Effect of fetal
presentation on the amniotic fluid index. Am J Obstet Gynecol
1999;181:12224.
33. Karantanis E, Alcock D, Phelan LK, Homer CS, Davis GK.
Introducing external cephalic version to clinical practice. Aust
N Z J Obstet Gynaecol 2001;41:3957.
34. Fok WY, Chan LW, Leung TY, Lau TK. Maternal experience of
pain during external cephalic version at term. Acta Obstet
35. Flamm BL, Fried MW, Lonky NM, Giles WS. External cephalic
version after previous caesarean section. Am J Obstet Gynecol
1991;165:3702.
36. de Meeus JB, Ellia F, Magnin G. External cephalic version after
previous cesarean section: a series of 38 cases. Eur J Obstet
37. Leung WC, Pun TC,Wong WM. Undiagnosed breech revisited. Br
J Obstet Gynaecol 1999;106:63841.
38. Caukwell S, Joels LA, Kyle PM, Mills MS. Womens attitudes
towards management of breech presentation at term. J Obstet
Gynaecol 2002;22:4868.
39. Roberts CL, Cameron CA, Nassar N, Raynes-Greenow CH. A
simple patient-initiated intervention to increase antenatal
detection of breech presentation at term. Paediatr Perinat
Epidemiol 2004;18:3716.
40. Burr R, Johanson R,Wyatt J,Watt I, Jones P.A randomised trial of
an intervention package designed to promote external
cephalic version at term. Eur J Obstet Gynecol Reprod Biol
2001;100:3640.
41. Hofmeyr GJ, Kulier R. Cephalic version by postural
management for breech presentation. Cochrane Database Syst
Rev 2000;(3):CD000051.
42. Cardini F, Weixin H. Moxibustion for correction of breech
presentation: a randomised controlled trial. JAMA 1998;
280:15804.
43. Coyle ME, Smith CA, Peat B. Cephalic version by moxibustion
for breech presentation. Cochrane Database Syst Rev
2005;(2):CD003928.
44. Cardini F, Lombardo P, Regalia AL, Regaldo G, Zanini A, Negri MG,
et al. A randomised controlled trial of moxibustion for breech
presentation. BJOG 2005;112:7437.
APPENDIX
Governance Advice No. 1: Guidance for the Development of RCOG Green-top Guidelines (available on
the RCOG website at www.rcog.org.uk/clingov1). These recommendations are not intended to dictate
patient needs, resources and limitations unique to the institution and variations in local populations. It is
hoped that this process of local ownership will help to incorporate these guidelines into routine

Ia
Evidence obtained from meta-analysis of

randomised controlled trials.
Ib
Evidence obtained from at least one

randomised controlled trial.
IIa

well-designed controlled study without
randomisation.
IIb

other type of well-designed quasiexperimental study.
III
Evidence obtained from well-designed

non-experimental descriptive studies,
such as comparative studies, correlation
studies and case studies.
IV
Evidence obtained from expert

committee reports or opinions and/or
clinical experience of respected
authorities.
Requires at least one randomised

controlled trial as part of a body of
literature of overall good quality and
consistency addressing the specific
recommendation. (Evidence levels Ia, Ib)
Requires the availability of well controlled

clinical studies but no randomised clinical
trials on the topic of recommendations.
(Evidence levels IIa, IIb, III)
Requires evidence obtained from expert

clinical experiences of respected
authorities. Indicates an absence of directly
applicable clinical studies of good quality.
(Evidence level IV)
Good practice point
7 of 8

development group.
This guideline was produced on behalf of the Guidelines and Audit Committee of the Royal College of Obstetricians
and Gynaecologists by:
Mr LWM Impey MRCOG, Oxford and Professor GJ Hofmeyr FRCOG, East London, South Africa
Mr Alok K Ash FRCOG, Consultant Obstetrician, Guys and St Thomas Hospital; British Association of Perinatal Medicine;
British Maternal and Fetal Medicine Society; Dr AN Griffiths MRCOG; Cardiff; Professor M Hannah, Sunnybrook and
Womens Hospitals, Ontario; Dr B Kumar MRCOG, Wrexham; Obstetric Anaesthetists Association; RCOG Consumers
Forum; Royal College of Midwives; Dr DM Siassakos, Specialist Registrar, Southmead Hospital, Bristol; Mr PJ Thompson
FRCOG, Birmingham; Dr Evelyn Verheijen, Specialist Registrar, Royal Blackburn Hospital.
The Guidelines and Audit Committee lead peer reviewers were:
Mr SA Walkinshaw FRCOG, Liverpool and Dr RG Hughes FRCOG, Edinburgh.
The final version is the responsibility of the Guidelines and Audit Committee of the RCOG.unless otherwise indicated.
DISCLAIMER
This guideline was reviewed in 2010. A literature review indicated there was no new evidence available which would alter
the recommendations and therefore the guideline review date has been extended until 2012, unless evidence requires
earlier review.
8 of 8
Guideline No. 21
May 2004
Reviewed 2010
THE MANAGEMENT OF TUBAL PREGNANCY
This guideline replaces The management of tubal pregnancies, produced in October 1999.
1.
Purpose and scope
There were 13 maternal deaths resulting from ectopic pregnancy in the UK during the period 199799.
The incidence of ectopic pregnancy has remained static in recent years (11.1/1000 pregnancies) and nearly
32000 ectopic pregnancies are diagnosed in the UK within a three year period.1
Tubal pregnancy can be managed by laparotomy, operative laparoscopy, medically and occasionally by
observation alone. Management must be tailored to the clinical condition and future fertility requirements of
the woman.
One concern raised in the Confidential Enquiry into Maternal Deaths was the difficulty encountered in
diagnosing ectopic pregnancy.1 The remit of this guideline is not to discuss the methods available for the
diagnosis of ectopic pregnancy but to discuss the methods and techniques that may be used once a diagnosis
has been made. However, it is acknowledged that, when discussing the expectant and medical management
of tubal pregnancy, in some women the site of pregnancy implantation will be uncertain.
2.
Previous guidelines within this subject area were sought using the sites and gateways laid out in the RCOG
clinical governance advice document Searching for evidence.2 The Cochrane Library (including the
Database of Systematic Reviews, DARE and the trials registry) and Medline were searched using a
combination of MeSH terms and keywords. The keywords used were ectopic pregnancy, tubal pregnancy,
laparoscopy,laparoscopic,salpingectomy,salpingotomy,methotrexate,persistent trophoblast and beta
human chorionic gonadotrophin (hCG). Reference lists of the articles identified were hand searched for
additional articles, and some experts within the field were contacted.
The levels of evidence and the grades of recommendations used in this guideline for effectiveness originate
from the US Agency for Healthcare Research and Quality.Where possible, recommendations are based on, and
explicitly linked to, the evidence that supports them. Areas lacking evidence are highlighted and annotated
as good practice points.
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RCOG Guideline No. 21
3.
Surgical management of tubal pregnancy
A laparoscopic approach to the surgical management of tubal pregnancy, in the haemodynamically

stable patient, is preferable to an open approach.
Laparoscopic surgery has been compared with open surgery in 228 women in three randomised
controlled trials (RCTs). Laparoscopic procedures were associated with shorter operation times,
less intraoperative blood loss, shorter hospital stays and lower analgesic requirements.37 There was
no difference in overall tubal patency rates (RR 0.89, 95% CI 0.741.1) between the two
approaches. In women who desired future fertility (n = 145), the subsequent intrauterine
pregnancy rates were similar (RR 1.2, 95% CI 0.881.15) and there was a trend toward lower repeat
ectopic pregnancy rates if a laparoscopic approach was used (RR 0.43, 95% CI 0.151.2). However,
laparoscopic salpingotomy was less successful than an open approach in elimination of the tubal
pregnancy (RR 0.90, 95% CI 0.830.97), reflected in a trend towards higher rates of persistent
trophoblast (RR 3.6, 95% CI 0.6321.0).
Evidence
level Ia
It is important to note that these three trials only include 228 women, which is insufficient to look
at small differences between the two interventions with respect to many of the outcomes
examined.
Management of tubal pregnancy in the presence of haemodynamic instability should be by the most
expedient method. In most cases this will be laparotomy.
There is no role for medical management in the treatment of tubal pregnancy or suspected tubal
pregnancy when a patient shows signs of hypovolaemic shock. Transvaginal ultrasonography can
rapidly confirm the presence of haemoperitoneum if there is any diagnostic uncertainty8 but
expedient resuscitation and surgery should be undertaken. Experienced operators may be able to
manage laparoscopically women with even a large haemoperitoneum safely9 but the surgical
procedure which prevents further blood loss most quickly should be used. In most centres this will
be laparotomy.
In the presence of a healthy contralateral tube there is no clear evidence that salpingotomy should be
used in preference to salpingectomy.
A number of systematic reviews have examined reproductive outcomes following the management
of tubal pregnancy with either salpingotomy or salpingectomy. However, there are no RCTs that
specifically compare laparoscopic (or open) salpingectomy and salpingotomy. The reviews
published on this subject include data from observational studies, often a mixture of both cohort
studies and case series, as well as a mixture of open and laparoscopic comparisons.These reviews
show that there is not an increased chance of subsequent intrauterine pregnancy after
salpingotomy compared with salpingectomy. However, these data must be interpreted with
caution. Included studies are subject to a wide range of biases relating to patient selection, surgical
procedures used, length of follow-up and the proportion of patients lost to follow-up.1016
There are four recent cohort studies that specifically compare laparoscopic conservative and
radical treatments of ectopic pregnancy1720 Silva et al.17 examined reproductive outcomes
prospectively in 143 women undergoing laparoscopic salpingectomy (55.9%) or laparoscopic
salpingotomy (36.4%). The intrauterine pregnancy rates were similar when comparing the two
groups but there was a trend towards higher subsequent ectopic pregnancy in the salpingotomy
arm (intrauterine pregnancy 60% versus 54%, RR 1.11, 95% CI 0.741.68; recurrent ectopic
pregnancy 18% versus 8%, RR 2.38, 95% CI 0.5710.01).17
2 of 10
Evidence
level IV
Evidence
level IIa
Job-Spira et al.,18 in a study of 155 women, performed a multivariate analysis on reproductive

outcomes following ectopic pregnancy. They demonstrated a trend towards improved subsequent
intrauterine pregnancy rates with conservative surgery (hazard ratio 1.22, 95% CI 0.682.20). The
cumulative pregnancy rates at one year were 72.4% after conservative and 56.3% after radical surgery.18
In study by Mol et al.19 of a cohort of 135 women, the fecundity rate ratio (FRR) when comparing
laparoscopic salpingotomy to salpingectomy during the 18-month follow-up period was 1.4 (95%
CI 0.682.7) for women with a healthy contralateral tube and 3.1 (95% CI 0.7612.0) for women
with contralateral tubal disease. The three-year cumulative pregnancy rate was 62% after
salpingotomy and 38% after salpingectomy.19
In a study by Bangsgaard et al.20 reviewing a cohort of 276 women undergoing salpingotomy or
salpingectomy, the subsequent cumulative pregnancy rate at seven years was 89% following
salpingotomy and 66% following salpingectomy (log rank P<0.05).The hazard ratio for intrauterine
pregnancy following salpingectomy was 0.630 (95% CI 0.4210.940) when compared with
salpingotomy.20
Evidence
level IIa
These results suggest that there may be a higher subsequent intrauterine pregnancy rate associated
with salpingotomy but the magnitude of this benefit may be small. Data from future RCTs
examining this question are needed. The use of conservative surgical techniques exposes women
to a small risk of tubal bleeding in the immediate postoperative period and the potential need for
further treatment for persistent trophoblast. Both these risks and the possibility of further ectopic
pregnancies in the conserved tube should be discussed if salpingotomy is being considered by the
surgeon or requested by the patient.
Laparoscopic salpingotomy should be considered as the primary treatment when managing tubal
pregnancy in the presence of contralateral tubal disease and the desire for future fertility.
Four cohort studies have examined reproductive outcomes in women with contralateral tubal
disease and show a trend toward a greater subsequent intrauterine pregnancy following
laparoscopic salpingotomy compared with laparoscopic salpingectomy (Silva et al.,17 intrauterine
pregnancy rate 49% versus 27%; Mol et al.,19 FRR 3.1, 95% CI 0.7612; Job-Spira et al.,18 OR 4.0, 95%
CI 0.9616.7); Bangsgaard et al.,20 hazard ratio 0.463 (95% CI 0.2620.820).
In women with a damaged or absent contralateral tube in vitro fertilisation is likely to be required
if salpingectomy is performed. Because of the requirement for postoperative follow-up and the
treatment of persistent trophoblast, the short-term costs of salpingotomy are greater than
salpingectomy.21 However, if the subsequent need for assisted conception is taken into account, an
increase in intrauterine pregnancy rate of only 3% would make salpingotomy more cost effective
than salpingectomy.19 In the presence of contralateral tubal disease the use of more conservative
surgery is appropriate. Women must be made aware of the risk of a further ectopic pregnancy.
4.
Evidence
level IIa
Medical management of tubal pregnancy
Medical therapy should be offered to suitable women, and units should have treatment and follow-up
protocols for the use of methotrexate in the treatment of ectopic pregnancy.
Many ectopic pregnancies will follow a relatively chronic course and transvaginal ultrasonography
combined with serum hCG measurement permits the confident diagnosis of ectopic pregnancy in
many women without resort to laparoscopy.2224 The use of laparoscopy for the diagnosis of ectopic
pregnancy is often the main reason for the use of surgical interventions.
3 of 10
Evidence
level IIa
A review of uncontrolled and controlled studies has shown that in stable patients a variety of
medical treatments are as effective as surgery.25 The most widely used medical treatment at present
is intramuscular methotrexate given as a single dose calculated from patient body surface area
(50 mg/m2). For most women this will be between 75 mg and 90 mg. Serum hCG levels are
checked on days four and seven and a further dose is given if hCG levels have failed to fall by more
than 15% between day four and day seven.16,27,28 Large uncontrolled studies have reported that
about 14% of women will require more than one dose of methotrexate and less than 10% of
women treated with this regimen will require surgical intervention.25,26 This has also been reported
in randomised trials comparing methotrexate with laparoscopic surgery.27,28
If medical therapy is offered, women should be given clear information (preferably written) about the
possible need for further treatment and adverse effects following treatment. Women should be able to
return easily for assessment at any time during follow-up.
Pooled data from uncontrolled studies suggests that at least 15% of medically treated women will
require more than one dose of methotrexate and 7% will experience tubal rupture during followup.15,16 Nearly 75% will experience abdominal pain following treatment. Occasional women will
also experience conjunctivitis, stomatitis and gastrointestinal upset. Differentiating so-called
separation pain due to a tubal abortion from pain due to tubal rupture can be difficult and a
proportion of women will need to be admitted for observation and assessment by transvaginal
ultrasound following methotrexate therapy.25,29 Women should also be advised to avoid sexual
intercourse during treatment, to maintain ample fluid intake and to use reliable contraception for
three months after methotrexate has been given, because of a possible teratogenic risk.
Women most suitable for methotrexate therapy are those with a serum hCG below 3000 iu/l, and
minimal symptoms.
Evidence
level IIa
Evidence
level IIa
Large uncontrolled studies have used methotrexate in women presenting at a wide range of serum
hCG concentrations, although the great majority of women in these studies have had serum hCG
concentrations below 5000 iu/l.15,16 Duration of follow up, the need for further doses of methotrexate and the likelihood of surgical intervention all increase with serum hCG concentration at
presentation.26
Although medical therapy can be successful at serum hCG concentrations considerably higher
than 3000 iu/l, quality-of-life data suggest that methotrexate is only an attractive option for women
with an hCG below 3000 iu/l.30,31
Evidence
level IIa
Data concerning the effect of ectopic pregnancy size on outcome are less clear but women with
large adnexal masses are more likely to have already ruptured.26
The presence of cardiac activity in an ectopic pregnancy is associated with a reduced chance of
success following medical therapy and should be considered a contraindication to medical
therapy.15,16
Outpatient medical therapy with single-dose methotrexate is associated with a saving in treatment
costs.
One important advantage of medical therapy is the potential for considerable savings in treatment
costs. Economic evaluations undertaken alongside randomised trials comparing methotrexate and
laparoscopic surgery have shown direct costs for medical therapy to be less than half of those
associated with laparoscopy. Indirect costs are also less with women and their carers losing less
4 of 10
Evidence
level Ib
time from work.30,31 However, in both these randomised trials no cost saving was seen at serum hCG
levels above 1500 iu/l due to the increased need for further treatment and prolonged follow-up.
5.
Evidence
level Ib
Expectant management of pregnancy of unknown location
Expectant management is an option for clinically stable women with minimal symptoms and a
pregnancy of unknown location.
In the management of suspected ectopic pregnancy there is a serum hCG level at which it is
assumed that all viable intrauterine pregnancies will be visualised by transvaginal ultrasound. This
is referred to as the discriminatory zone.32 When serum hCG levels are below the discriminatory
zone (<1000 iu) and there is no pregnancy (intra- or extrauterine) visible on transvaginal
ultrasound scan, the pregnancy can be described as being of unknown location.33
The concept of a discriminatory zone has limitations. Levels of hCG of 1000 iu/l, 1500 iu/l and
2000 iu/l have been used as discriminatory levels.23,24,33 These levels are dependent upon the
quality of the ultrasound equipment, the experience of the sonographer, prior knowledge of the
womans risks and symptoms and the presence of physical factors such as uterine fibroids and
multiple pregnancy. For specialised units performing high resolution vaginal ultrasound with prior
knowledge of the womans symptoms and serum hCG, a discriminatory zone of 1000 iu/l can be
used. In other units offering a diagnostic transvaginal scan without prior clinical or biochemical
knowledge a discriminatory zone of 1500 iu/l or 2000 iu/l is acceptable.
Five observational studies have shown that 4469% of pregnancies of unknown location resolve
spontaneously with expectant management.3438 It is probable that a number of the spontaneously
resolving pregnancies or trophoblast in regression35 in these studies were small ectopic
pregnancies which were spontaneously absorbed or resolved by tubal abortion. The remainder
were early intrauterine pregnancies that miscarried. Ectopic pregnancy was subsequently
diagnosed in 1428% of cases of pregnancy of unknown location.36,38
Evidence
level III
Using an initial upper level of serum hCG of 10001500 iu/l to diagnose pregnancy of unknown
location, women with minimal or no symptoms at risk of ectopic pregnancy should be managed
expectantly with 4872 hours of follow-up and should be considered for active intervention
if symptoms of ectopic pregnancy occur, serum hCG levels rise above the discriminatory level
(1000 iu/l) or levels start to plateau.36,38
Intervention has been shown to be required in 2329% of cases34,36 but with more experience
lower intervention levels are achievable.37 If women are managed expectantly, serial serum hCG
measurements should be performed until hCG levels are less than 20 iu/l. In addition, women
selected for expectant management of pregnancy of unknown location should be given clear
information (preferably written) about the importance of compliance with follow-up and should
be within easy access to the hospital treating them.
Expectant management is an option for clinically stable asymptomatic women with an ultrasound
diagnosis of ectopic pregnancy and a decreasing serum hCG, initially less than serum 1000 iu/l.
Studies examining the role of expectant management of ectopic pregnancy vary in their methods
of diagnosis. Laparoscopic identification of ectopic pregnancy prior to expectant management is
used in some.39,40 In others there is no surgical proof that ectopic pregnancies managed expectantly
were in fact of ectopic location. In this guideline, only studies with clear ultrasound identification
of an ectopic gestation sac or predominantly solid extraovarian adnexal mass or absence of villi
5 of 10
Evidence
level III
with endometrial sampling were considered. All reviewed studies required the patient to be
clinically stable, with minimal symptoms. Most studies required an adnexal mass of less than
4 cm41,42 or less than 5 cm43 and less than 50 ml43 or 100 ml42 of free fluid. A fall in initial hCG of
greater than 15% in 24 hours was required for entry into one study.43
Seven observational studies were reviewed and a total of 478 women were treated expectantly.3945
Expectant management was successful in 318 (67%) women. Lower initial hCG levels were a
significant predictor of spontaneous resolution.44 Expectant management was more successful
(88%) when the initial hCG level was less than 1000 iu/l,42 a finding confirmed in a review by
Cohen et al.46 In addition, a rapidly decreasing hCG level appears to predict a favourable
outcome.42,45 The lack of an identifiable extrauterine gestational sac on transvaginal ultrasound
increased the odds of a spontaneous resolution by 5.6 times.44 However, it is uncertain whether the
initial size of an ectopic pregnancy is a predictor of the eventual outcome, with one study showing
no effect.44 What does appear to be significant to successful resolution is a reduction in the average
diameter of the adnexal mass by day seven.43
Evidence
level III
Expectant management is a useful form of treatment management for ectopic pregnancy in

selected cases. It is however only acceptable if it involves minimal risks to the woman. Expectant
management should only be used for asymptomatic women with an ultrasound diagnosis of
ectopic pregnancy, with no evidence of blood in the pouch of Douglas and decreasing hCG levels
that are less than hCG 1000 iu/l at initial presentation and less than 100 ml fluid in the pouch of
Douglas. Women managed expectantly should be followed twice weekly with serial hCG
measurements and weekly by transvaginal examinations to ensure a rapidly decreasing hCG level
(ideally less than 50% of its initial level within seven days) and a reduction in the size of adnexal
mass by seven days. Thereafter, weekly hCG and transvaginal ultrasound examinations are advised
until serum hCG levels are less than 20 iu/l as there are case reports of tubal rupture at low levels
of hCG.47 In addition, women selected for expectant management of pregnancy of unknown
origin should be counselled about the importance of compliance with follow-up and should be
within easy access to the hospital in question.
6.
Persistent trophoblast
When salpingotomy is used for the management of tubal pregnancy, protocols should be in place for
the identification and treatment of women with persistent trophoblast.
Persistent trophoblast is detected by the failure of serum hCG levels to fall as expected after initial
treatment. It is primarily a problem occurring after salpingotomy rather than following
salpingectomy. Although, even in the presence of persistent trophoblast, hCG levels may return
uneventfully to normal, cases of delayed haemorrhage due to persistent trophoblast have been
described48 and this provides the rationale for following women with serial hCG measurements
after treatment and administering methotrexate if levels fail to fall as expected.
In reviews of controlled and uncontrolled studies, rates of persistent trophoblast from pooled data
have been 8.18.3% after laparoscopic salpingotomy and 3.94.1% after open salpingotomy.15,16,49
Factors that have been suggested as increasing the risk of developing persistent trophoblast
include higher preoperative serum hCG levels (>3000 iu/l),50 a rapid preoperative rise in serum
hCG51 and the presence of active tubal bleeding.50
Following the elimination of all trophoblastic tissue, serum hCG levels will fall a predictable
clearance curve49 but the proportion of women treated for persistent trophoblast will in part
depend upon the frequency of postoperative measurement and the cut off used for its definition.
6 of 10
Evidence
level IV
In one study the treatment of persistent trophoblast was initiated if the serum hCG was greater
than 10% of the preoperative level ten days after surgery.52 Another study has suggested initiating
treatment if hCG levels are above 65% of their initial level at 48 hours after surgery.53 The definition
used to define persistent trophoblast within a unit will affect both the reporting of its incidence
and the effectiveness of its treatment. Currently, there are insufficient data to recommend one
method of diagnosing and treating persistent trophoblast over another but protocols for its early
identification and treatment should be used.
Evidence
level IV
Methotrexate at a dose of 50 mg/m2 has been widely used as a single dose instead of a repeat
surgical procedure, although no formal comparative studies have been performed. The use of
prophylactic methotrexate at the time of laparoscopic salpingotomy has also been reported and in
one randomised trial and when compared with simple salpingotomy alone there was a significant
reduction in the rate of persistent trophoblast (1.9% versus 14%, RR 0.12, 95% CI 0.020.97).54
7.
Service provision and training
All NHS trusts should provide an early pregnancy assessment unit with direct access for general
practitioners and accident and emergency departments. Available facilities for the management of
suspected ectopic pregnancy should include:
diagnostic and therapeutic algorithms

transvaginal ultrasound
serum hCG estimations.
In line with previous recommendations from guidelines on the management of early pregnancy
complications and RCOG study groups, women with suspected ectopic pregnancy should be
managed in dedicated early pregnancy clinics.55,56
Evidence
level IV
Ideally, these clinics should be sited in a dedicated area with appropriate staffing, and should be
available on a daily basis, at least during the working week.
Clinicians undertaking the surgical management of ectopic pregnancy must have received appropriate
training. Laparoscopic surgery requires appropriate equipment and trained theatre staff.
Clinical staff should be trained to undertake both the open and laparoscopic management of ectopic
pregnancy. This should include the safe use of monopolar and bipolar diathermy. They should have
attended an appropriate RCOG-approved course in basic or intermediate laparoscopic skills. They
should also be supported with sufficient efficient modern equipment to facilitate safe surgery.
Evidence
level IV
Retrospective studies of the laparoscopic management of ectopic pregnancy report a low rate of
intraoperative and postoperative complications and demonstrate that surgery can safely be
undertaken by appropriately trained registrars.57,58
8.
Anti-D immunoglobulin
Nonsensitised women who are rhesus negative with a confirmed or suspected ectopic pregnancy
should receive anti-D immunoglobulin.
In accordance with RCOG Guideline No. 22 it is recommended that anti-D immunoglobulin at a

dose of 250 iu (50 microgrammes) be given to all nonsensitised women who are rhesus negative
and who have an ectopic pregnancy.59
7 of 10
P
Evidence
level IV
9.
Patient involvement
Women should be carefully advised, whenever possible, of the advantages and disadvantages
associated with each approach used for the treatment of ectopic pregnancy. They should participate
fully in the selection of the most appropriate treatment.
The psychological impact of early pregnancy loss may seriously affect a significant proportion of
women, their partners and families.55 Plans for follow-up should be clearly recorded in the
discharge letter from the early pregnancy clinic. Women should be provided with written
information concerning their treatment options, follow-up and the availability of local and national
support services.
Evidence
level IV
Evidence has shown that there may be little difference in psychological outcomes when
comparing surgical and medical methods of managing ectopic pregnancy.28,60
10. Audit topics
The proportion of women who are haemodynamically stable with ectopic pregnancy treated laparoscopically.
The proportion of women managed expectantly with pregnancy of unknown location who required surgical
intervention.
The proportion of women with persistent trophoblast after salpingotomy.
References
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Murphy AA, Nager CW, Wujek JJ, Kettel LM, Torp VA, Chin
HG. Operative laparoscopy versus laparotomy for the
management of ectopic pregnancy. Fertil Steril
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Vermesh M, Silva P, Rosen G, Stein AL, Fossum GT, Sauer MV.
Management of unruptured ectopic gestation by linear
salpingostomy: a prospective, randomized clinical trial of
laparoscopy versus laparotomy. Obstet Gynecol
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Lundorff P, Thorburn J, Hahlin M, Kallfelt B, Lindblom B.
Laparoscopic surgery in ectopic pregnancy: a randomized
trial versus laparoscopy. Acta Obstet Gynecol Scand
1991;70:3438.
Lundorff P,Thorburn J, Lindblom B. Fertility outcome after
conservative surgical treatment of ectopic pregnancy
evaluated in a randomized trial. Fertil Steril 1992;
57:9981002.
Gray D, Thorburn J, Lundorff P, Strandell A, Lindblom B. A
cost-effectiveness study of a randomised trial of
laparoscopy versus laparotomy for ectopic pregnancy.
Lancet 1995;345:113943.
Popat R, Adams C. Diagnosis of ruptured ectopic
pregnancy by bedside ultrasonography. J Emerg Med
2002;22:40910.
Li Z, Leng J, Lang J, Liu Z, Sun D, Zhu L. Laparoscopic
surgery in patients with hypovolemic shock due to
ectopic pregnancy. Zhonghua Fu Chan Ke Za Zhi
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10. Thornton K, Diamond M, DeCerney A. Linear

salpingostomy for ectopic pregnancy. Obstet Gynecol Clin
North Am 1991;18:95109.
11. Clausen I. Conservative versus radical surgery for tubal
pregnancy. Acta Obstet Gynecol Scand 1996;75:812.
12. Mol BW, Hajenius PJ, Engelsbel S, Ankum WM, Hemrika DJ,
van der Veen F, et al. Is conservative surgery for tubal
pregnancy preferable to salpingectomy? An economic
analysis. Br J Obstet Gynaecol 1997;104:8349.
13. Parker J, Bisits A. Laparoscopic surgical treatment of
ectopic pregnancy: salpingectomy or salpingostomy? Aust
N Z J Obstet Gynaecol 1997;37:1157.
14. Tulandi T, Saleh A. Surgical management of ectopic
pregnancy. Clin Obstet Gynecol 1999;42:318.
15. Yao M,Tulandi T. Current status of surgical and nonsurgical
management of ectopic pregnancy. Fertil Steril 1997;67:
42133.
16. Sowter M, Frappell J. The role of laparoscopy in the
management of ectopic pregnancy. Rev Gynaecol Practice
2002;2:7382.
17. Silva P, Schaper A, Rooney B. Reproductive outcome after
143 laparoscopic procedures for ectopic pregnancy. Fertil
Steril 1993;81:7105.
18. Job-Spira N, Bouyer J, Pouly J, Germain E, Coste J, AubletCuvelier B, et al. Fertility after ectopic pregnancy: first
results of a population-based cohort study in France. Hum
Reprod 1996;11:99104.
19. Mol B, Matthijsse H,Tinga D, Huynh T, Hajenius P,Ankum W,
et al. Fertility after conservative and radical surgery for
tubal pregnancy. Hum Reprod 1998;13:18049.
20. Bangsgaard N, Lund C, Ottesen B, Nilas L. Improved fertility
following conservative surgical treatment of ectopic
pregnancy. Br J Obstet Gynaecol 2003;110:76570.
21. Rulin M. Is salpingostomy the surgical treatment of choice
for unruptured tubal pregnancy? Obstet Gynecol 1995;
86:10103.
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22. Ankum W. Laparoscopy in the diagnosis of ectopic

pregnancy. In: Grudzinskas JG, OBrien PMS, editors.
Problems in Early Pregnancy: Advances in Diagnosis and
Treatment. London: RCOG Press; 1997. p. 1549.
23. Mol B,Van der Veen F. Role of transvaginal ultrasonography
in the diagnosis of ectopic pregnancy. Fertil Steril
1998;70:5945.
24. Ankum W, Hajenius P, Schrevel L, Van der Veen F.
Management of suspected ectopic pregnancy: impact of
new diagnostic tools in 686 consecutive cases. J Reprod
Med 1996;41:7248.
25. Lipscomb G, Bran D, McCord M, Portera J, Ling F. Analysis
of three hundred fifteen ectopic pregnancies treated
with single-dose methotrexate. Am J Obstet Gynecol 1998;
178:13548.
26. Lipscomb G, McCord M, Stovall T, Huff G, Portera S, Ling F.
Predictors of success of methotrexate treatment in
women with tubal ectopic pregnancies. N Engl J Med
1999;341:19748.
27. Saraj A, Wilcox J, Najmabadi S, Stein S, Johnson M, Paulson
R. Resolution of hormonal markers of ectopic gestation: a
randomized trial comparing single-dose intramuscular
methotrexate with salpingostomy. Obstet Gynecol 1998;
92:98994.
28. Sowter M, Farquhar C, Petrie K, Gudex G. A randomised
trial comparing single dose systemic methotrexate and
laparoscopic surgery for the treatment of unruptured
tubal pregnancy. Br J Obstet Gynaecol 2001;108:192203.
29. Lipscomb G, Puckett K, Bran D, Ling F. Management of
separation pain after single-dose methotrexate therapy for
ectopic pregnancy. Obstet Gynecol 1999;93:5903.
30. Sowter M, Farquhar C, Gudex G. An economic evaluation
of single dose systemic methotrexate and laparoscopic
surgery for the treatment of unruptured ectopic
31. Mol B, Hajenius P, Engelsbel S,Ankum W, Hemrika D,Van der
Veen F, et al. Treatment of tubal pregnancy in the
Netherlands: an economic comparison of systemic methotrexate administration and laparoscopic salpingostomy.
32. Kadar N, DeVore G, Romero R. Discriminatory hCG zone
use in the sonographic evaluation for ectopic pregnancy.
33. Cacciatore B, Stenman U,Ylstolalo P. Diagnosis of ectopic
pregnancy by vaginal ultrasonography in combination
with a discriminatory serum hCG level of 1000 iu/l (IRP).
Br J Obstet Gynaecol 1990;97:9048.
34. Hahlin M, Thorburn J, Bryman I. The expectant
management of early pregnancies of uncertain site. Hum
Reprod 1995;10:12237.
35. Ankum W, Van der Veen F, Hamerlynck J, Lammes F.
Suspected ectopic pregnancy. What to do when human
chorionic gonadotropin levels are below the
discriminatory zone. J Reprod Med 1995;40:5258.
36. Banerjee S, Aslam N, Zosmer N, Woelfer B, Jurkovic D. The
expectant management of women with early pregnancy
of unknown location. Ultrasound Obstet Gynecol 1999;
14:2316.
37. Banerjee S,Aslam N,Woelfer B, Lawrence A, Elson J, Jurkovic
D. Expectant management of early pregnancies of
unknown location: a prospective evaluation of methods to
predict spontaneous resolution of pregnancy. BJOG
2001;108:15863.
38. Hajenius P, Mol B, Ankum W, Van der Veen F, Bossuyt P,
Lammes F. Suspected ectopic pregnancy: expectant
management in patients with negative sonographic
findings and low serum -hCG concentrations. Early
Pregnancy 1995;1:25862.
39. Mkinen J, Kivijrvi A, Irjala K. Success of non-surgical
management of ectopic pregnancy. Lancet 1990;335:1099.
40. Shalev E, Peleg D, Tsabari A, Romano S, Bustan M.

Spontaneous resolution of ectopic tubal pregnancy:
natural history. Fertil Steril 1995;63:159.
41. Ylstalo P, Cacciatore B, Korhonen J, Kriinen M, Mkel
P, Sjberg J, et al. Expectant management of ectopic
pregnancy. Eur J Obstet Gynecol Reprod Biol 1993;49:834.
42. Trio D, Strobelt N, Picciolo C, Lapinski R, Ghidini A.
Prognostic factors for successful expectant management
of ectopic pregnancy. Fertil Steril 1995;63:46972.
43. Cacciatore B, Korhonen J., Stenman U, Ylostalo P.
Transvaginal sonography and serum hCG in monitoring of
presumed ectopic pregnancies selected for expectant
management . Ultrasound Obstet Gynecol 1995;5:297300.
44. Atri M, Chow C, Kintzen G, Gillett P, Aldis A, Thibodeau M.
Expectant management of ectopic pregnancies: clinical and
sonographic predictors. Am J Roentgenol 2001;176:1237.
45. Korhonen J, Stenman U,Ylstalo P. Serum human chorionic
gonadotrophin dynamics during spontaneous resolution
of ectopic pregnancy. Fertil Steril 1994;61:6326.
46. Cohen M,Sauer M. Expectant management of ectopic
pregnancy. Clin Obstet Gynecol 1999;42:4854.
47. Tulandi T, Hemmings R, Khalifa F. Rupture of ectopic
pregnancy in women with low and declining serum
-human chorionic gonadotrophin concentrations. Fertil
Steril 1991;56:7867.
48. Kelley R, Martin S, Strickler R. Delayed hemorrhage in
conservative surgery for ectopic pregnancy. Am J Obstet
Gynecol 1979;133:2256.
49. Hajenius P, Mol B, Ankum W, van der Veen F, Bossuyt P,
Lammes F. Clearance curves of serum human chorionic
gonadotrophin for the diagnosis of persistent trophoblast.
Hum Reprod 1995;10:6837.
50. Lundorff P, Hahlin M, Sjblom P, Lindblom B. Persistent
trophoblast after conservative treatment of ectopic
pregnancy: prediction and detection. Obstet Gynecol
1991;77:12933.
51. Kemmann E, Trout S, Garcia A. Can we predict patients at
risk for persistent ectopic pregnancy after laparoscopic
salpingotomy? J Am Assoc Gynecol Laparosc 1994;1:1226.
52. Sauer M, Vidali A, James W. Treating persistent ectopic
pregnancy by methotrexate using a sliding scale:
preliminary experience. J Gynecol Surg 1997;13:136.
53. Pouly J, Chapron C, Mage G, Mahnes H,Wattiez A.The drop
in the level of HCG after conservative laparoscopic
treatment of ectopic pregnancy. J Gynecol Surg 1991;
7:2117.
54. Graczykowski J, Mishell D. Methotrexate prophylaxis for
persistent ectopic pregnancy. Obstet Gynecol 1997;89:
11822.
55. Recommendations arising from the 33rd RCOG Study
Group: Problems in Early pregnancy advances in diagnosis
and management. In: Grudzinskas JG, OBrien PMS, editors.
Problems in Early Pregnancy: Advances in Diagnosis and
Treatment. London: RCOG Press; 1997. p. 32731.
56. Royal College of Obstetricians and Gynaecologists. The
management of early pregnancy loss. Clinical Guideline
No. 25. London: RCOG Press; 2000.
57. Cooray H, Harilall M, Farquahar C. A six year audit of the
management of ectopic pregnancy. Aust N Z J Obstet
Gynaecol 2002;42:53842.
58. Mohamed H, Maiti S, Phillips G. Laparoscopic management
of ectopic pregnancy: a 5-year experience. J Obstet Gynecol
2002;22:4114.
59. Royal College of Obstetricians and Gynaecologists. The use
of anti-D immunoglobulin for rhesus prophylaxis.
Guideline No. 22. London: RCOG Press; 2002.
60. Nieuwkerk P, Hajenius P, Van der Veen F, Ankum W, Wijker
W, Bossuyt P. Systemic methotrexate therapy versus
laparoscopic salpingostomy in tubal pregnancy. Part II.
Patient preferences for systemic methotrexate. Fertil Steril
1998;70:51822.
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APPENDIX
Clinical guidelines are: systematically developed statements which assist clinicians and patients in making
decisions about appropriate treatment for specific conditions. Each guideline is systematically developed
using a standardised methodology. Exact details of this process can be found in Clinical Governance Advice
No. 1: Guidance for the Development of RCOG Green-top Guidelines (available on the RCOG website at
www.rcog.org.uk/clingov1). These recommendations are not intended to dictate an exclusive course of
management or treatment.They must be evaluated with reference to individual patient needs, resources and
limitations unique to the institution and variations in local populations. It is hoped that this process of local
ownership will help to incorporate these guidelines into routine practice. Attention is drawn to areas of
clinical uncertainty where further research may be indicated.

Ia

Ib

IIa
Evidence obtained from at least one welldesigned controlled study without

randomisation.
IIb
Evidence obtained from at least one other

type of well-designed quasi-experimental
study.
III
IV
Evidence obtained from well-designed nonexperimental descriptive studies, such as

comparative studies, correlation studies
and case studies.
Evidence obtained from expert committee
reports or opinions and/or clinical
experience of respected authorities.
Requires at least one randomised controlled trial

as part of a body of literature of overall good
quality and consistency addressing the specific
Requires the availability of well controlled clinical
studies but no randomised clinical trials on the
topic of recommendations. (Evidence levels IIa,
IIb, III)
committee reports or opinions and/or clinical
experiences of respected authorities. Indicates an
absence of directly applicable clinical studies of
good quality. (Evidence level IV)
Good practice point
Recommended best practice based on the clinical

experience of the guideline development group.
This Guideline was produced on behalf of the Guidelines and Audit Committee of the Royal College of Obstetricians and Gynaecologists by:
Mr AJ Kelly MRCOG, Bristol, Dr MC Sowter MRCOG, Auckland, New Zealand, and Dr J Trinder MRCOG, Bristol
Dr WM Ankum, Academic Medical Centre, University of Amsterdam, Netherlands; Ms R Bender Atik, The Miscarriage Association,
Wakefield; Dr MR Gazvani MRCOG, Liverpool; Professor R Garry FRCOG, Perth, Australia; Dr D Jurkovic MRCOG, London;
Ms M Manion, EPAU Matron, Birmingham Womens Healthcare NHS Trust, Birmingham; Dr BW Mol, Maxima Medical Centre, Veldhoven,
The Netherlands; RCOG Consumers Forum; Professor T Tulandi, Department of Obstetrics and Gynaecology, Royal Victoria Hospital,
Montreal, Canada.
The final version is the responsibility of the Guidelines and Audit Committee of the RCOG.
The previous version of this guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Professor Garry and Mr Kelly.
This guideline was reviewed in 2010. A literature review indicated there was no new evidence available
which would alter the recommendations and therefore the guideline review date has been extended
until 2012, unless evidence requires earlier review.
10 of 10
Operative Vaginal Delivery

January 2011
Operative Vaginal Delivery

This is the third edition of this guideline, which was published under the same title in October 2005 and
formerly as Instrumental vaginal delivery, which was published in October 2000.
1.
Purpose and scope
The aim of this guideline is to provide up-to-date information on the use of forceps and vacuum extractor for
both rotational and non-rotational operative vaginal deliveries. Obstetricians should be confident and
competent in the use of both instruments for non-rotational delivery and in the use of a minimum of one
technique for rotational delivery. An understanding of the anatomy of the birth canal and the fetal head is a
prerequisite to becoming skilled in the safe use of forceps or vacuum extractor. It is strongly recommended
that obstetricians achieve experience in spontaneous vaginal delivery prior to commencing training in
operative vaginal delivery. The goal of operative vaginal delivery is to mimic spontaneous vaginal birth,
thereby expediting delivery with a minimum of maternal or neonatal morbidity. The scope of this guideline
will include indications for operative vaginal delivery, choice of instrument, aspects of safe clinical practice,
risk of physical and psychological complications and a review of special circumstances. Concern was raised
following publication of the second edition of the guideline that there had been insufficient attention paid to
the safety of the instruments used and particularly the potential for neonatal morbidity following failed
operative deliveries. These issues have been addressed in this edition.
2.
Background
Operative vaginal delivery rates have remained stable at between 10% and 13% in the UK, yielding safe and
satisfactory outcomes for the majority of mothers and babies.1,2 There has been an increasing awareness of the
potential for morbidity for both the mother and the baby.The increased risk of neonatal morbidity in relation
to operative vaginal delivery is long established although with careful practice overall rates of morbidity are
low.3
In 1998, the US Food and Drug Administration issued a warning about the potential dangers of delivery with
vacuum extractor.4 This followed several reports of infant fatality secondary to intracranial haemorrhage. In
addition, there has been a growing awareness of the short-term and long-term morbidity of pelvic floor injury
as well as neurodevelopmental outcomes for children following operative vaginal delivery.511 Caesarean
section in the second stage of labour is an alternative approach but also carries significant morbidity and
implications for future births. The goal should be to minimise the risk of morbidity and, where morbidity
occurs, to minimise the likelihood of serious harm while maximising maternal choice.
3.
Identification and assessment of the evidence
A search of Medline and Embase from 2004 to 2009 and of the Cochrane Library Issue 2, 2009 was undertaken
for relevant systematic reviews, meta-analyses, randomised controlled trials and other clinical trials. The date
of the last search was May 2009. The main keywords used were extraction, obstetrical, vacuum extraction,
obstetrical, vacuum extraction, instrumental delivery, obstetrical forceps, forceps delivery, forceps,
ventouse, labour, obstetric, delivery, obstetric and parturition.
4.
Preparation for operative vaginal delivery
4.1 Can operative vaginal delivery be avoided?

All women should be encouraged to have continuous support during labour as this can reduce the need
for operative vaginal delivery.
2 of 19
Use of upright or lateral positions and avoiding epidural analgesia can reduce the need for operative
vaginal delivery.
Delayed pushing in primiparous women with an epidural can reduce the need for rotational and
midcavity deliveries.
As operative vaginal delivery can be associated with maternal and neonatal morbidity, strategies
that reduce the need for operative vaginal delivery should be used. Continuous support for women
during childbirth can reduce the incidence of operative vaginal delivery (15 trials; n=13 357; RR
0.82; 95% CI 0.820.96), particularly when the carer was not a member of staff.12 Use of any upright
or lateral position in the second stage of labour compared with supine or lithotomy positions
was associated with a reduction in the number of assisted deliveries (20 trials; n=6135; RR 0.80;
95% CI 0.690.92).13 Epidural analgesia compared with non-epidural methods is associated with an
increased incidence of operative vaginal deliveries (17 trials; n=6162; OR 1.38; 95% CI 1.241.53),
but provides better pain relief than non-epidural analgesia (one trial; n=105; weighted mean
difference 2.60; 95% CI 3.82 to 1.3.14
Evidence
level 1++
A recent Cochrane review concluded that using a partogram does not lead to a reduction in the
incidence of operative births (RR 1.00; 95% CI 0.851.17).15 One study showed that in primiparous
women with an epidural, starting oxytocin in the second stage of labour can reduce the need for
non-rotational forceps delivery.16 The National Institute for Health and Clinical Excellence Clinical
Guideline 55: Intrapartum care cites this study and concludes that oxytocin should not be used as
a matter of routine in the second stage of labour, on the basis of one study.17 In particular, oxytocin
should be used with extreme caution in the second stage of labour in multiparous women.
Therefore, we recommend that each woman should be assessed individually for the management
of the second stage of labour.
Evidence
level 1+
A meta-analysis demonstrated that primiparous women who received epidurals were likely to have
fewer rotational or mid-cavity operative interventions when pushing was delayed for 1 to 2 hours
or until they had a strong urge to push.18
There is insufficient evidence to support the hypothesis that discontinuing epidural analgesia
reduces the incidence of operative vaginal delivery (23% versus 28%; RR 0.84; 95% CI 0.611.15),
but there is evidence that it increases the womans pain (22% versus 6%; RR 3.68; 95% CI
1.996.80).19
Evidence
level 1++
There is no difference between the rates of operative vaginal delivery for combined spinalepidural
and standard epidural techniques (19 trials; n=2658; OR 0.82; 95% CI 0.671.00)20 or patientcontrolled epidural analgesia and standard epidural technique. A meta-analysis of nine studies,
including 641 women, comparing patient-controlled epidural analgesia with continuous infusion
showed that obstetric outcome was comparable in all included studies.21 A randomised controlled
trial of 126 women comparing patient-controlled epidural analgesia with continuous epidural
infusion reported similar rates of normal delivery with a P value of 0.56.22
4.2 How should operative vaginal delivery be classified?

A standard classification of operative vaginal delivery should be used.
To enable bench marking, audit and comparison between studies, a standard definition of the types
of operative delivery should be used. The American College of Obstetricians and Gynecologists
criteria are adapted in Table 1 and define the delivery by station and position.23
3 of 19
Evidence
level 4
Table 1. Classification for operative vaginal delivery

Outlet
Fetal scalp visible without separating the labia

Fetal skull has reached the pelvic floor
Sagittal suture is in the anterio-posterior diameter or right or left occiput anterior or posterior position (rotation does not exceed 45)
Fetal head is at or on the perineum
Low
Leading point of the skull (not caput) is at station plus 2 cm or more and not on the pelvic floor
Two subdivisions:
rotation of 45 or less from the occipito-anterior position
rotation of more than 45 including the occipito-posterior position
Mid
Fetal head is no more than 1/5th palpable per abdomen

Leading point of the skull is above station plus 2 cm but not above the ischial spines
Two subdivisions:
rotation of 45 or less from the occipito-anterior position
rotation of more than 45 including the occipito-posterior position
High
Not included in the classification as operative vaginal delivery is not recommended in this situation where the head is 2/5th or more
palpable abdominally and the presenting part is above the level of the ischial spines
Adapted from the American College of Obstetrics and Gynecology, 200023
4.3 When should operative vaginal delivery be offered?

Operators should be aware that no indication is absolute and should be able to distinguish standard
from special indications.
A vacuum extractor should not be used at gestations of less than 34 weeks +0 days. The safety of
vacuum extraction at between 34 weeks +0 days and 36 weeks +0 days of gestation is uncertain and
should therefore be used with caution.
Operative intervention is used to shorten the second stage of labour. It may be indicated for
conditions of the fetus or of the mother (Table 2).24 A retrospective cohort study of 15 759 nulliparous
women demonstrated that maternal morbidity increased significantly after 3 hours of the second
stage and further increased after 4 hours.The benefits of a shortened second stage for certain medical
conditions should be discussed where possible in the antenatal period. There was no evidence of
neonatal morbidity increasing in this retrospective study, where fetal surveillance and timely obstetric
intervention were used.25 The time constraints listed in Table 2 are therefore for guidance. The
question of when to intervene should involve balancing the risks and benefits of continuing pushing
versus an operative delivery. There is no evidence that elective operative delivery for inadvertent
dural puncture is of benefit, unless the woman has a headache that worsens with pushing.26
Evidence
level 2-
Fetal bleeding disorders (e.g. alloimmune thrombocytopenia) or a predisposition to fracture (e.g.

osteogenesis imperfecta) are relative contraindications to operative vaginal delivery. However, there
Evidence
level 4
Table 2. Indications for operative vaginal delivery24

Type
Indication
Fetal
Presumed fetal compromise (see text)
Maternal
To shorten and reduce the effects of the second stage of labour on medical conditions (e.g. cardiac disease
Class III or IV*, hypertensive crises, myasthenia gravis, spinal cord injury patients at risk of autonomic dysreflexia,
proliferative retinopathy)
Inadequate progress
Nulliparous women lack of continuing progress for 3 hours (total of active and passive second-stage labour)17
with regional anaesthesia, or 2 hours without regional anaesthesia
Multiparous women lack of continuing progress for 2 hours (total of active and passive second-stage labour)17
with regional anaesthesia, or 1 hour without regional anaesthesia
Maternal fatigue/exhaustion
* New York Heart Association classification

No indication is absolute and each case should be considered individually
4 of 19
may be considerable fetal risk if the head has to be delivered abdominally from deep in the pelvis.27,28
Blood-borne viral infections of the mother are not a contraindication to operative vaginal delivery.
However, it is sensible to avoid difficult operative delivery where there is an increased chance of fetal
abrasion or scalp trauma and to avoid fetal scalp clips or blood sampling during labour.29
Vacuum extractors are contraindicated with a face presentation. It has been suggested that vacuum
extractors should not be used at gestations of less than 36 weeks because of the risk of subgaleal
and intracranial haemorrhage.30,31 One casecontrol study suggests that this restriction may be
unnecessary, but this study was small and undertaken outside the UK.32 Below 34 weeks +0 days of
gestation, the use of vacuum extraction is not recommended because of the susceptibility of the
preterm infant to cephalohaematoma, intracranial haemorrhage, subgaleal haemorrhage and
neonatal jaundice. There is insufficient evidence to establish the safety of vacuum extractors at
gestations between 34 weeks +0 days and 36 weeks +0 days.
Evidence
level 4
Two case studies reported a minimal risk of fetal haemorrhage if the extractor is applied following
fetal blood sampling or application of a spiral scalp electrode.33,34 However, no bleeding was
reported in two randomised trials comparing forceps and vacuum extraction.3537
Evidence
level 2+
Forceps and vacuum extractor deliveries before full dilatation of the cervix are contraindicated.
Forceps can be used for the after-coming head of the breech and in situations where maternal effort
is impossible or contraindicated.
Evidence
level 4
4.4 What are the essential conditions for safe operative vaginal delivery?
Safe operative vaginal delivery requires a careful assessment of the clinical situation, clear
communication with the mother and healthcare personnel and expertise in the chosen procedure.
The role of ultrasound to assess fetal head position in the second stage of labour and prior to conducting an
operative vaginal delivery has been investigated.3840 However, at present there is insufficient evidence to
recommend routine use of ultrasound to determine fetal head position as part of assessment for operative
vaginal delivery.
Table 3. Prerequisites for operative vaginal delivery
Full abdominal and
vaginal examination
Head is 1/5th palpable per abdomen

Vertex presentation.
Cervix is fully dilated and the membranes ruptured.
Exact position of the head can be determined so proper placement of the instrument can be achieved.
Assessment of caput and moulding.
Pelvis is deemed adequate. Irreducible moulding may indicate cephalopelvic disproportion.
Preparation of mother
Clear explanation should be given and informed consent obtained.

Appropriate analgesia is in place for mid-cavity rotational deliveries. This will usually be a regional block.
A pudendal block may be appropriate, particularly in the context of urgent delivery.
Maternal bladder has been emptied recently. In-dwelling catheter should be removed or balloon deflated.
Aseptic technique.
Preparation of staff
Operator must have the knowledge, experience and skill necessary.

Adequate facilities are available (appropriate equipment, bed, lighting).
Back-up plan in place in case of failure to deliver. When conducting mid-cavity deliveries, theatre staff should
be immediately available to allow a caesarean section to be performed without delay (less than 30 minutes).
A senior obstetrician competent in performing mid-cavity deliveries should be present if a junior trainee is
performing the delivery.
Anticipation of complications that may arise (e.g. shoulder dystocia, postpartum haemorrhage)
Personnel present that are trained in neonatal resuscitation
* Adapted from the Society of Obstetricians and Gynaecologists of Canada 200441 and the Royal Australian and New Zealand College of
Obstetricians and Gynaecologists 200927,28
5 of 19
Table 3 lists prerequisites for operative vaginal delivery. Like any operative intervention, adequate preparation
and planning is important. Be cautious in the urgent situation and at handover periods when time pressures
can limit the information given.
4.5 What type of consent is required?

Women should be informed in the antenatal period about operative vaginal delivery, especially during
their first pregnancy.
For deliveries in the delivery room, verbal consent should be obtained before an operative vaginal
delivery and the discussion documented in the notes. If circumstances allow, written consent may also
be obtained.
Written consent should be obtained for trial of operative vaginal delivery in theatre.
Women should be informed about operative vaginal delivery as part of routine antenatal education,
particularly women having their first baby when the risk of requiring a forceps or ventouse delivery is higher.
This information should include the strategies known to be effective in reducing the need for operative
vaginal birth.
The birth plan of the mother, including any preferences for or objections to a particular instrument, should
be taken into account and discussed.17
By the very nature of the procedure, consent will need to be obtained at the end of labour in an emergency
setting. Care needs to be taken as women may be exhausted, in pain or affected by narcotic drugs or Entonox.
The principles of obtaining valid consent during labour should be followed.41 Where possible, information
should be given to women in labour between contractions.
Obstetricians must document the decision, the reasons for proceeding to an operative birth and consent.The
RCOG provides consent advice on operative delivery.42
An accurate record of the operative vaginal delivery must be completed. This is aided by standardised
documentation, an example of which can be found in Appendix 1.
5.
Performing operative vaginal delivery
5.1 Who should perform operative vaginal delivery?

An operative vaginal delivery should be performed by an operator who has the knowledge, experience
and skills necessary to assess and to use the instruments and manage complications that may arise.
Obstetricians should achieve experience in spontaneous vertex delivery before commencing training in
operative vaginal delivery.
Obstetric trainees should receive appropriate training in operative vaginal delivery. Competency should
be achieved before conducting unsupervised deliveries and should be monitored regularly thereafter.
An experienced operator, competent at mid-cavity deliveries, should be present from the outset for all
attempts at rotational or mid-cavity operative vaginal delivery.
The goal of operative vaginal delivery is to mimic spontaneous vaginal birth, thereby expediting
delivery with a minimum of maternal or neonatal morbidity. The complexity of the delivery is
6 of 19
Evidence
level 4
related to the type of delivery as classified in Table 1. Mid-cavity and rotational deliveries,
independent of the type of instrument used, demand a high level of clinical and technical skill and
the operator must have received adequate training.41
Evidence
level 4
System analysis often reveals inadequate training as a key contributor to adverse outcomes, and
training is central to patient safety initiatives.43 Neonatal trauma is associated with initial
unsuccessful attempts at operative vaginal delivery by inexperienced operators.44
Evidence
level 2+
Dedicated consultant sessions on the labour ward should facilitate better training and supervision
of trainees and a higher proportion of operative deliveries being performed by experienced
obstetricians. Assessment of clinical competence is a key element of core training. Ideally,
competence should be assessed using the Objective Structured Assessment of Technical Skills
(OSATS) form designed for operative vaginal delivery by the RCOG.45 For a trial of instrumental
delivery in theatre, the consultant should attend in person or should be immediately available if the
trainee on duty has not been assessed and signed off by OSATS as competent.46 No data exist on
the number of supervised procedures necessary before competence is gained. Individual centres
should have a specified trainer responsible for coordinating training and assessment of the trainees.
Local and specialist courses in labour ward management can contribute to the development and
maintenance of operative delivery expertise. The operator should be aware of the peculiarities of
different vacuum devices.Where available, the operator should also be aware of the manufacturer's
recommendations for the chosen instrument.
Evidence
level 4
Further work should be done to evaluate the merits of different methods of training in operative
vaginal delivery. Once trained, practitioners will need to audit their performance. One study has
demonstrated the potential for monitoring obstetricians performance on vacuum extraction by the
use of statistical process control charts.47 Another study has looked at the position of chignon as a
monitoring tool for cup application.48 The RCOG report of a Working Party on Recertification in
Obstetrics and Gynaecology identified third- and fourth-degree tears as a potential monitoring
measure.49 Further work needs to be done to develop the data collection tools with consideration of
case complexity and how the results can be fed back to individuals in a sensitive and constructive way.
5.2 Where should operative vaginal delivery take place?

Operative vaginal births that have a higher risk of failure should be considered a trial and conducted in
a place where immediate recourse to caesarean section can be undertaken.
Higher rates of failure are associated with:

maternal body mass index over 30
estimated fetal weight over 4000 g or clinically big baby
occipito-posterior position
mid-cavity delivery or when 1/5th of the head palpable per abdomen.

At mid-cavity the biparietal diameter is still above the level of the ischial spines. Failure rates are higher at this
station. High maternal body mass index (over 30), neonatal birth weight over 4000 g and occipito-posterior
positions are also indicators of increased failure.50 Fetal injuries have been attributed to delay between a failed
operative vaginal delivery and a caesarean section.51 Therefore, operative deliveries that are anticipated to have
a higher rate of failure should be considered a trial and conducted in a place where immediate recourse to
caesarean section can be undertaken. There is little evidence of increased maternal or neonatal morbidity
following failed operative vaginal delivery compared with immediate caesarean section where immediate
recourse to caesarean section is available.52
The alternative view is that when an operative vaginal delivery is conducted in an operating
theatre, there may be a delay associated with transfer that may have a negative impact on the
7 of 19
Evidence
levels
2- to 4
neonatal outcome. Two retrospective studies comparing operative vaginal delivery in the labour
room with deliveries in an operating theatre reported a doubling in the decision-to-delivery interval
when deliveries were carried out in theatre.53,54 A study of 229 operative deliveries had a decisionto-delivery interval of 20 minutes for deliveries in the labour room and 59 minutes for deliveries in
theatre.53 Operative vaginal deliveries for all indications were included in the analysis. A study of
1021 singleton term operative deliveries for fetal distress showed that a decision-to-delivery interval
of 15 minutes was an achievable target in the labour room whereas 30 minutes was the average
decision-to-delivery interval in theatre.54 There were no statistically significant differences in the
neonatal outcomes in either study. Therefore, the risks of failed operative vaginal delivery in the
labour room should be balanced with the risks associated with the transfer time when the delivery
is conducted in an operating theatre.
Evidence
levels
2- to 4
There has been one small study reviewing the use of midwifery ventouse practitioners in standalone units and consultant units. This showed a very low rate of obstetric intervention and
prevented ambulance transfers. However, the study was small and retrospective.55 There is
insufficient evidence to assess the benefits and risks of conducting operative vaginal birth in
midwifery-led units. There is a need for further studies in this area.
Evidence
level 3
5.3 What instruments should be used for operative vaginal delivery?

The operator should choose the instrument most appropriate to the clinical circumstances and their
level of skill. Forceps and vacuum extraction are associated with different benefits and risks. Failed
delivery with selected instrument is more likely with vacuum extraction.
The options available for rotational delivery include Kielland forceps, manual rotation followed by
direct traction forceps or rotational vacuum extraction. Rotational deliveries should be performed by
experienced operators, with the choice depending on the expertise of the individual operator.
There are over 700 different models of forceps. There have been no randomised controlled trials
comparing different forceps types and it is recognised that the choice is often subjective. Rotational
delivery with the Kielland forceps carries additional risks and requires specific expertise and
training.Alternatives to Kielland forceps include manual rotation followed by direct traction forceps
or rotational vacuum extractor.41 There have been no randomised controlled trials comparing these
approaches and the operator should choose an appropriate approach within their expertise.
Maintenance of skills in this area may reduce the need for second-stage caesarean section and
training should be encouraged for trainees, particularly those embarking on the advanced labour
ward and labour ward leadership Advanced Training Skills Modules.
Evidence
level 4
A Cochrane systematic review of nine randomised controlled studies involving 1368 primiparous
and multiparous women showed that soft vacuum extractor cups compared with rigid cups were
associated with a significant increase in the rate of failure (OR 1.6; 95% CI 1.22.3) but a significant
reduction in puerperal scalp trauma (OR 0.4; 95% CI 0.30.6).56
Evidence
level 1++
There are several types of disposable vacuum extractor now available. The Kiwi OmniCup
(Clinical Innovations Europe Ltd, Abingdon, UK) is a vacuum device that has been reported to be
both safe and effective for rotational and non-rotational operative vaginal delivery in non-trial
settings.57,58 However, two UK-based randomised controlled trials comparing the use of the Kiwi
OmniCup with the conventional cup (soft and metal) concluded that the Kiwi OmniCup was less
successful in achieving a vaginal delivery. In one trial including 194 women who underwent
vacuum delivery, the failure rate with Kiwi OmniCup was 34% compared with 21% with the
standard cup (adjusted OR 2.3; 95% CI 1.015.0), thereby increasing the sequential use of
instruments (vacuum and forceps) (22% versus 10%; adjusted OR 2.7; 95% CI 1.16.4).59 In the
Evidence
level 1+
8 of 19
second trial including 404 women, the failure rate for occipito-anterior deliveries was 25.9%
compared with 16.8% with the conventional cup (RR 1.55; 95% CI 1.002.40). Neither study
reported any differences in morbidity.60 A recent prospective observational study of 1000 vacuumassisted deliveries with the Kiwi OmniCup reported a failure rate of 12.9%.61
Evidence
level 1+
The relative merits of vacuum extraction and forceps have been evaluated in a Cochrane systematic
review of ten randomised controlled trials, involving 2923 primiparous and multiparous women.37
Evidence
level 1++
Vacuum extraction compared with forceps is:

more likely to fail delivery with the selected instrument (OR 1.7; 95% CI 1.32.2)
more likely to be associated with cephalhaematoma (OR 2.4; 95% CI 1.73.4)
more likely to be associated with retinal haemorrhage (OR 2.0; 95% CI 1.33.0)
more likely to be associated with maternal worries about baby (OR 2.2; 95% CI 1.23.9)
less likely to be associated with significant maternal perineal and vaginal trauma (OR 0.4; 95% CI 0.30.5)
no more likely to be associated with delivery by caesarean section (OR 0.6; 95% CI 0.31.0)
no more likely to be associated with low 5-minute Apgar scores (OR 1.7; 95% CI 1.02.8)
no more likely to be associated with the need for phototherapy (OR 1.1; 95% CI 0.71.8).
In view of the reduction of maternal pelvic floor injuries, the vacuum was advocated as the instrument of first
choice in 1989.62 The downside of this approach has been the increased risk of failed operative delivery and
of sequential use of instruments (vacuum followed by forceps) with inherent additional risks to the mother
and infant. Therefore, a careful, well-trained operator will select the instrument best suited to the individual
circumstances.
A randomised controlled trial has reported that symptoms of altered faecal continence are significantly more common following forceps delivery compared with vacuum extraction.9 However, a 5year follow-up of women enrolled in one of the randomised controlled trials above did not show
any significant differences in long-term outcome between the two instruments for either the mother
or the child.63 The data available from the published controlled trials cannot be analysed separately
to compare vacuum and forceps in their use for rotational deliveries.
There is insufficient evidence to favour either a rapid (over 2 minutes) or a stepwise increment in
negative pressure with vacuum extraction.
A recent Cochrane review including one small randomised controlled trial of 94 women found no
significant difference in detachment rate, degree of perineal tear, Apgar score, umbilical artery pH
less than 7.2, scalp laceration greater than one-quarter of the scalp surface involved, cephalhaematoma and number of tractions comparing rapid with stepwise (02 kg/2 minutes until 08 kg)
increments in pressure using a Malmstrom metal 50 mm cup.64
Evidence
level 1+
Evidence
level 1-
The size of the trial was small. Further research is needed to establish the relative advantages and disadvantages
of either policy.
5.4 When should operative vaginal delivery be abandoned?

Operative vaginal delivery should not be attempted unless the criteria for safe delivery have been met (see Table 3).
Operative vaginal delivery should be abandoned where there is no evidence of progressive descent with
moderate traction during each contraction or where delivery is not imminent following three
contractions of a correctly applied instrument by an experienced operator.
Adverse outcomes, including unsuccessful forceps or vacuum delivery, should trigger an incident report
as part of effective risk management processes.
9 of 19
Paired cord blood samples should be processed and recorded following all attempts at operative
vaginal delivery.
Vacuum and forceps delivery can be associated with significant complications, both maternal and
fetal.Two maternal deaths have been described in association with tearing of the cervix at vacuum
delivery and a further maternal death has been described following uterine rupture in association
with forceps delivery.65,66 Neonatal intracranial and subgaleal haemorrhage are life-threatening
complications of particular concern.67,68 In a review of 583 340 liveborn singleton infants born to
nulliparous women, the rate of subdural or cerebral haemorrhage in vacuum deliveries (one in 860)
did not differ significantly from that associated with forceps use (one in 664) or caesarean section
during labour (one in 954). However, risks increased significantly among babies exposed to
attempts at both vacuum and forceps delivery (one in 256).68
Evidence
level 2++
A prospective cohort study of 393 women experiencing operative delivery in the second stage of
labour reported an increased risk of neonatal trauma and admission to the special care baby unit
following excessive pulls (more than three) and sequential use of instruments.The risk was further
increased where delivery was completed by caesarean section following a protracted attempt at
operative vaginal delivery.44 At 5 years of follow-up, there was no difference in neurodevelopmental
outcomes of babies born by operative vaginal delivery compared with babies born by caesarean
section. The two cases of cerebral palsy did not have a causal relationship to the mode of delivery
and were delivered by caesarean section.11
Evidence
level 2+
The bulk of malpractice litigation results from failure to abandon the procedure at the appropriate time,
particularly the failure to eschew prolonged, repeated or excessive traction efforts in the presence of poor
progress. Adverse events, including unsuccessful forceps or vacuum, birth trauma, term baby admitted to the
neonatal unit, low Apgar scores (Apgar less than 7 at 5 minutes) and cord arterial pH under 7.1, should trigger
an incident report and review if necessary as part of effective risk management processes.69
5.5 Is there a place for sequential use of instruments?

The use of sequential instruments is associated with an increased risk of trauma to the infant; however,
the operator must balance the risks of a caesarean section following failed vacuum extraction with the
risks of forceps delivery following failed vacuum extraction.
Obstetricians should be aware of increased neonatal morbidity with failed operative vaginal delivery
and/or sequential use of instruments and should inform the neonatologist when this occurs to ensure
appropriate management of the baby.
The use of outlet/low-cavity forceps following failed vacuum extraction may be judicious in avoiding
a potentially complex caesarean section. Caesarean section in the second stage of labour is associated
with an increased risk of major obstetric haemorrhage, prolonged hospital stay and admission of the
baby to the special care baby unit compared with completed instrumental delivery.50
Evidence
level 2++
This must be balanced with the increased risk of neonatal trauma associated with sequential use of
instruments (risk of intracranial haemorrhage one in 256 deliveries for two instruments versus one
in 334 for failed forceps proceeding to caesarean section).68,7072
Evidence
levels
2+ to 3
A population-based retrospective analysis of 12 014 739 live births in the USA reported that
sequential use of vacuum and forceps compared with forceps alone was associated with an
increased risk of need for mechanical ventilation with an adjusted OR of 2.22 (1.243.97).The risk
of intracranial haemorrhage, retinal haemorrhage and feeding difficulty was also greater with
sequential use of instruments.72
Evidence
level 2+
10 of 19
The sequential use of instruments should not be attempted by an inexperienced operator without direct
supervision and should be avoided if possible.
5.6 What is the role of episiotomy for operative vaginal delivery?

In the absence of robust evidence to support routine use of episiotomy in operative vaginal delivery,
restrictive use of episiotomy, using the operators individual judgement, is supported.
A multicentre pilot randomised controlled study including 200 nulliparous women to evaluate the
role of episiotomy at operative vaginal deliveries failed to provide conclusive evidence that a policy
of routine episiotomy was better or worse than a restrictive policy.The incidence of obstetric anal
sphincter injury was similar in both groups (8.1% in 99 women randomised to the routine use of
episiotomy and 10.9% in 101 women randomised to restrictive use; OR 0.72; 95% CI 0.281.87).73
In this study, routine compared with restrictive use of episiotomy was not associated with a
statistically significant difference in anal sphincter tears for forceps delivery (OR 0.56; 95% CI
0.191.61) and the anal sphincter tears rate was low overall for vacuum deliveries. A review of 323
consecutive operative vaginal deliveries in a US setting evaluated the relationship between
episiotomy and significant perineal trauma (third- and fourth-degree tears).74 The use of episiotomy
did not influence the risk of significant perineal trauma for forceps delivery but was associated with
an increased risk of significant perineal trauma when vacuum delivery was performed. These data
are difficult to interpret in the UK context as midline episiotomy is preferred in the USA and
mediolateral episiotomy in the UK. A further study reported a lower frequency and severity of
perineal tears in forceps delivery when an episiotomy was performed, particularly for medio-lateral
episiotomy.75 A large observational study from the Netherlands of 28 732 operative vaginal deliveries
concluded that mediolateral episiotomy is protective against obstetric anal sphincter injury in both
vacuum extraction (9.40% versus 1.36%, OR 0.11, 95% CI 0.090.13) and forceps delivery (22.73%
versus 2.6%, OR 0.28, 95% CI 0.130.63).76 However, this is a retrospective study and the incidence
of obstetric anal sphincter injury is not comparable to that seen in a UK-based prospective cohort
study of 1360 operative vaginal deliveries.77 In the UK study episiotomy did not appear to protect
against obstetric anal sphincter injury in vacuum extraction (4.3% with episiotomy versus 5.5%
without episiotomy) and forceps delivery (11.7% versus 10.6%). However, episiotomy was
associated with a greater incidence of postpartum haemorrhage (28.4% versus 18.4%, OR 1.72, 95%
CI 1.212.45).This conflict in findings between the two studies may be due to variations in practice
of the threshold for episiotomy and use of different instruments.
Evidence
levels
1+ to 2-
5.7 Should prophylactic antibiotics be given?

There are insufficient data to justify the use of prophylactic antibiotics in operative vaginal delivery.
Good standards of hygiene and aseptic techniques are recommended.
A Cochrane review included only one randomised trial of 393 participants. There were seven
women with endometritis in the group given no antibiotics and none in the prophylactic antibiotic
group. This difference did not reach statistical significance, but the relative risk reduction was 93%
(RR 0.07; 95% CI 0.001.21).78,79
6.
Evidence
level 1++
Aftercare following operative vaginal delivery
6.1 Should thromboprophylaxis be given?

Women should be reassessed after an operative vaginal delivery for risk factors for venous
thromboembolism and, if appropriate, thromboprophylaxis should be prescribed.
11 of 19
Mid-cavity delivery, prolonged labour and immobility are risk factors for thromboembolism.Women should be
reassessed after delivery for risk factors for venous thromboembolism and considered for
thromboprophylaxis if necessary.80 The obstetrician should refer to the RCOG Green-top Guideline No. 37:
Reducing the risk of thrombosis and embolism during pregnancy and the puerperium.80
6.2 What analgesia should be given after delivery?

Regular paracetamol and diclofenac should be offered after an operative vaginal delivery in the absence
of contraindications.
Regular paracetamol and diclofenac have been shown to be beneficial after caesarean section and for perineal
pain.81 They should be considered (in the absence of contraindications) after an operative vaginal delivery.
6.3 What precautions should be taken for care of the bladder after delivery?
The timing and volume of the first void urine should be monitored and documented.
A post-void residual should be measured if retention is suspected.
Women who have had a spinal anaesthetic or an epidural that has been topped up for a trial may be at
increased risk of retention and should be recommended to have an indwelling catheter in place for at least
12 hours post-delivery to prevent asymptomatic bladder overfilling.
Women should be offered physiotherapy-directed strategies to prevent urinary incontinence.
Urine retention with bladder overdistension should be avoided, particularly in women who have
had spinal or dense epidural blocks. Operative delivery, prolonged labour and epidural analgesia
may predispose to postpartum urinary retention, which can be associated with long-term bladder
dysfunction.8284 There is considerable variation in practice in postpartum bladder management in
the UK.85 Further research is needed to develop evidence-based guidelines. However, at a minimum
the first void should be measured, and if retention is a possibility a post-void residual should be
measured to ensure that retention does not go unrecognised. Women who have had a spinal
anaesthetic or an epidural that has been topped up for a trial should be offered an indwelling
catheter for at least 12 hours post-delivery to prevent asymptomatic bladder overfilling followed by
fluid balance charts to ensure good voiding volumes.
Evidence
level 2+
Urinary incontinence is common after operative vaginal delivery. A physiotherapist-delivered

intervention designed to prevent urinary incontinence reduced incontinence from 38.4% to 31%
in a group of women who had had an operative vaginal birth and/or a baby over 4000 g.86
Evidence
level 1+
6.4 How can we reduce psychological morbidity for the mother?

There is no evidence to support the use of midwife-led debriefing in reducing maternal depression
following operative vaginal delivery.
The woman should be reviewed prior to hospital discharge to discuss the indication for operative
delivery, management of any complications and the prognosis for future deliveries. Best practice would
be for the woman to be reviewed by the obstetrician who conducted the delivery.
Operative vaginal delivery can be associated with fear of subsequent childbirth and in a severe form
may manifest as a post-traumatic stress-type syndrome termed tocophobia.8791 Follow-up of a
cohort at 3 years following operative delivery reported that 50% of women did not plan on having
12 of 19
Evidence
level 2+
a further child and almost half of these women reported fear of childbirth as the main reason for
avoiding pregnancy.92
Evidence
level 2+
Several studies have looked at debriefing approaches to reducing psychological morbidity following childbirth.93,94 There is no evidence to support the use of formal debriefing in reducing the risk
of subsequent postnatal depression for women who have experienced operative vaginal delivery.
Evidence
level 2-
Nonetheless, women report the need for a review following delivery to discuss the indication for
delivery, the management of any complications and the implications for future deliveries.87
Evidence
qualitative
The optimal timing, setting and healthcare professional for post-delivery review require further evaluation.
6.5 How should we advise women for future deliveries?

Women should be encouraged to aim for a spontaneous vaginal delivery in a subsequent pregnancy as
there is a high probability of success.
Care should be individualised for women who have sustained a third- or fourth-degree perineal tear.
Women who have experienced an operative vaginal delivery should be encouraged to aim for
spontaneous vaginal delivery in a subsequent pregnancy.The likelihood of achieving a spontaneous
vaginal delivery is approximately 80% even for women who have required more complex operative
vaginal deliveries in theatre.92,95,96
Evidence
level
2++ to 3
This discussion should take place at the earliest opportunity as there is evidence to suggest that
women decide on the future mode of delivery soon after delivery.97 The future plan of care should
be reviewed carefully with women who have experienced a third- or fourt-degree tear, particularly
if they are symptomatic, as they may be at increased risk of further anorectal damage with a
subsequent delivery.98
Evidence
level
2++
Women who sustain a third- or fourth-degree perineal tear should be counselled regarding the risk of
recurrence and implications for future childbirth.99
7.
Auditable standards
The following should be reviewed on a regular basis.

Maternity unit:
rate of operative vaginal delivery.
Maternity unit and individual operator:

percentage of women with failed operative vaginal delivery
rate of sequential instrument use
case notes review to audit appropriate management of women with failed operative vaginal delivery or
sequential instrument use, i.e. when to use a sequential instrument and when to abandon
percentage of women with third- and fourth-degree perineal tears
rate of neonatal morbidity, composite trauma (subgaleal haemorrhage/brachial plexus injury/fracture/facial

nerve palsy/cerebral haemorrhage), low Apgar <7 at 5 minutes and cord arterial pH <7.1
documentation of written or verbal consent for operative vaginal delivery
documentation of written consent for trial of operative vaginal delivery in operating theatre
accuracy of documentation.
13 of 19
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55. Alexander J, Anderson T, Cunningham S. An evaluation by focus
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57. OGrady JP, Pope CS, Patel SS. Vacuum extraction in modern
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58. Hayman R, Gilby J, Arulkumaran S. Clinical evaluation of a hand
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59. Attilakos G, Sibanda T, Winter C, Johnson N, Draycott T. A
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extraction device. BJOG 2005;112:15105.
60. Groom KM, Jones BA, Miller N, Paterson-Brown S. A prospective
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delivery. BJOG 2006;113:1839.
61. Baskett TF, Fanning CA,Young DC. A prospective observational
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device. J Obstet Gynaecol Can 2008;30:57380.
62. Chalmers JA, Chalmers I.The obstetric vacuum extractor is

the instrument of first choice for operative vaginal delivery.
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PW. Maternal and child health after assisted vaginal delivery:
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64. Suwannachat B, Lumbiganon P, Laopaiboon M. Rapid versus
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65. Department of Health, Welsh Office, Scottish Home and
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67. Whitby EH, Griffiths PD, Rutter S, Smith MF, Sprigg A, Ohadike
P, et al. Frequency and natural history of subdural
haemorrhages in babies and relation to obstetric factors.
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68. Towner D, Castro MA, Eby-Wilkens E, Gilbert WM. Effect of
mode of delivery in nulliparous women on neonatal
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69. NHS Litigation Authority. Clinical Negligence Scheme for
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70. Al-Kadri H, Sabr Y, Al-Saif S, Abulaimoun B, BaAqeel H, Saleh A.
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71. Ezenagu LC, Kakaria R, Bofill JA. Sequential use of instruments
at operative vaginal delivery: is it safe? Am J Obstet Gynecol
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of sequential use of vacuum and forceps for assisted vaginal
delivery on neonatal and maternal outcomes. Am J Obstet
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73. Murphy DJ, Macleod M, Bahl R, Goyder K, Howarth L, Strachan
B. A randomised controlled trial of routine versus restrictive
use of episiotomy at operative vaginal delivery: a multicentre
pilot study. BJOG 2008;115:1695702.
74. Robinson JN, Norwitz ER, Cohen AP, McElrath TF, Lieberman
ES. Episiotomy, operative vaginal delivery, and significant
perineal trauma in nulliparous women. Am J Obstet Gynecol
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75. Bodner-Adler B, Bodner K, Kimberger O, Wagenbichler O,
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severity of perineal trauma in women undergoing forceps
delivery. J Reprod Med 2003;48:23942.
76. de Leeuw JW, de Wit C, Kuijken JP, Bruinse HW. Mediolateral
episiotomy reduces the risk for anal sphincter injury during
operative vaginal delivery. BJOG 2008;115:1048.
77. Macleod M, Strachan B, Bahl R, Howarth L, Goyder K, Van de
Venne M, et al. A prospective cohort study of maternal and
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78. Heitmann JA, Benrubi GI. Efficacy of prophylactic antibiotics
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81. Peter EA, Janssen PA, Grange CS, Douglas MJ. Ibuprofen versus
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95. Mawdsley SD, Baskett TF. Outcome of the next labour in
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96. Bahl R, Strachan BK. Mode of delivery in the next pregnancy in
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stage of labor. Am J Obstet Gynecol 2003;188:5428.
98. Fynes M, Donnelly V, Behan M, OConnell PR, OHerlihy C.
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16 of 19
APPENDIX 1
OPERATIVE VAGINAL DELIVERY RECORD
Patient Details
Date..............................................................................
Operator
Name ...................................................... Grade ................
Supervisor
Name ...................................................... Grade ................
Indication(s) for delivery: ................................................................................................................................

Classification of OVD: outlet / low / midcavity
Rotation > 45: yes / no
Fetal wellbeing: CTG: normal / suspicious / pathological
Liquor: clear / meconium
Prerequisites:
Examination
Place of delivery: room / theatre
1/5th per abdomen: ............................................................
Analgesia: local / pudendal / regional
Dilatation:..............................................................................
Consent: verbal / written
Position: ................................................................................
Catheterised: yes / no
Station: ..................................................................................
Moulding:..............................................................................
Caput:....................................................................................
Procedure
Multiple instrument use: yes / no

Examination before second
instrument
Instrument used:
Vacuum extractor : silastic / Kiwi / metal anterior / metal posterior
1/5th per abdomen:............................
Forceps: rotational / non-rotational / outlet
Position: ..............................................
Number of pulls: ................................................
Station: ................................................
Traction: easy / moderate / strong
Moulding: ............................................
Maternal effort: minimal / moderate / good
Caput:..................................................
Placenta: CCT/ manual
Reasons for second instrument:
Episiotomy: yes / no
Perineal tear:
............................................................
1st degree
............................................................
2nd degree
............................................................
3rd / 4th degree
(complete pro forma)
Other
(complete suturing pro forma if necessary)
EBL: ....................................................................
Baby: M / F Birth weight: .......... (kg) Apgar: 1..... 5..... 10.....
Post-delivery care:
Level of care: routine / high dependency
Syntocinon infusion: yes / no
Catheter: yes / no
Remove ............................
Vaginal pack: yes / no Remove ............................
Diclofenac 100 mg PR: yes / no Analgesia prescribed: yes / no
Thromboembolic risk: low / medium / high
Thromboprophylaxis prescribed: yes / no
Cord pH: Arterial.......... Venous..........
Signature: ................................................................................................
17 of 19
Date: ............................................
APPENDIX II
Governance Advice No.1: Development of RCOG Green-Top Guidelines (available on the RCOG website
at http://www.rcog.org.uk/womens-health/clinical-guidance/development-rcog-green-top-guidelinespolicies-and-processes). These recommendations are not intended to dictate an exclusive course of
of clinical uncertainty where further research may be indicated.

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
18 of 19

development group
This guideline has been produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and
Gynaecologists by:
Dr R Bahl MRCOG, Bristol; Dr B K Strachan MRCOG, Bristol; and Professor D J Murphy MRCOG, Dublin, Ireland.
British Maternal and Fetal Medicine Society; Mr K T Moriarty MRCOG, Coventry; Ms S Paterson-Brown FRCOG,
London; Mr A D G Roberts FRCOG, Burton-on-Trent, Staffordshire; RCOG Consumers Forum; Royal College of
Midwives; Mr M Selinger FRCOG, Reading; Dr C Sparey MRCOG, Leeds; Dr A Vacca FRCOG, Queensland, Australia.
The Guidelines Committee lead reviewers were: Mr M Griffiths FRCOG, FFSRH, Luton and Dr J Shillito MRCOG, Leeds.
The guidelines review process will commence in 2014 unless evidence requires earlier review.
DISCLAIMER
health services.
19 of 19
Placenta Praevia, Placenta Praevia

Accreta and Vasa Praevia: Diagnosis
and Management
January 2011
Placenta Praevia, Placenta Praevia Accreta and Vasa Praevia:

Diagnosis and Management
This is the third edition of this guideline.The first, published in 2001, was entitled Placenta Praevia: Diagnosis
and Management; the second, published in 2005, was entitled Placenta Praevia and Placenta Praevia
Accreta: Diagnosis and Management.
1.
Purpose and scope
The purpose of this guideline is to describe the diagnostic modalities used for placenta praevia, vasa praevia
and a morbidly adherent placenta and how they are applied during the antenatal period. Clinical management will be described in the antenatal and peripartum period with specific reference to the anticipation,
planning and timing of surgery, as well as to the advanced techniques and interventions available for managing
placenta accreta. This guideline does not address the problems of a suspected morbidly adherent placenta
before fetal viability.
2.
2.1 Placenta praevia and placenta praevia accreta

Maternal and fetal morbidity and mortality from placenta praevia and placenta praevia accreta are
considerable111 and are associated with high demands on health resources. With the rising incidence of
caesarean sections combined with increasing maternal age, the number of cases of placenta praevia and its
complications, including placenta accreta, will continue to increase,7,8,1224 and updating the guideline for this
condition is timely. In addition, vasa praevia, while rare, is nonetheless associated with high perinatal
morbidity and mortality25 and is therefore included in this guideline for the first time.
Placenta praevia exists when the placenta is inserted wholly or in part into the lower segment of the uterus.
It is classified by ultrasound imaging according to what is relevant clinically: if the placenta lies over the
internal cervical os, it is considered a major praevia; if the leading edge of the placenta is in the lower uterine
segment but not covering the cervical os, minor or partial praevia exists.
A morbidly adherent placenta includes placenta accreta, increta and percreta as it penetrates through the
decidua basalis into and then through the myometrium, but for ease of description the term accreta will be
used in this guideline as a general term for all of these conditions.
2.2 Vasa praevia

Vasa praevia describes fetal vessels coursing through the membranes over the internal cervical os and below
the fetal presenting part, unprotected by placental tissue or the umbilical cord.26 This can be secondary to a
velamentous cord insertion in a single or bilobed placenta (vasa praevia type 1), or from fetal vessels running
between lobes of a placenta with one or more accessory lobes (vasa praevia type 2).27 The reported incidence
varies between one in 2000 and one in 6000 pregnancies,2730 but the condition may be under-reported in the
literature.31 Unlike placenta praevia, vasa praevia carries no major maternal risk, but is associated with
significant risk to the fetus. When the fetal membranes are ruptured, either spontaneously or artificially, the
unprotected fetal vessels are at risk of disruption with consequent fetal haemorrhage. Vasa praevia therefore
often presents with fresh vaginal bleeding at the time of membrane rupture and fetal heart rate abnormalities
such as decelerations, bradycardia, a sinusoidal trace or fetal demise.28,32,33 The mortality rate in this situation is
around 60%,25,28,34 although significantly improved survival rates of up to 97% have been reported where the
2 of 26
diagnosis has been made antenatally.25,34 More rarely, bleeding can occur in the absence of membrane rupture.
Because the fetal blood volume is around 80100 ml/kg, the loss of relatively small amounts of blood can have
major implications for the fetus, thus rapid delivery and aggressive resuscitation including the use of blood
transfusion if required are essential.35 Very rarely, fetal heart rate abnormalities in the absence of bleeding may
be present secondary to compression of the fetal vessels by the fetal presenting part.36
Risk factors for vasa praevia include placental anomalies such as a bilobed placenta or succenturiate lobes
where the fetal vessels run through the membranes joining the separate lobes together, a history of low-lying
placenta in the second trimester,37,38 multiple pregnancy39 and in vitro fertilisation,40,41 where the incidence of
vasa praevia has been reported to be as high as one in 300. The reasons for this association are not clear, but
disturbed orientation of the blastocyst at implantation, vanishing embryos and the increased frequency of
placental morphological variations in in vitro fertilisation pregnancies have all been postulated.42,43
3.
To update this guideline the Cochrane Library, Embase and Medline were searched for relevant randomised
controlled trials, systematic reviews and meta-analyses: for placenta praevia and accreta the search dated from
2004 to 2009 (the search for the previous guidelines was up to May 2004); the search for vasa praevia was
dated from 1950 to August 2009. The searches were performed using MeSH headings placenta praevia and
placenta accreta and vasa praevia. As with the previous editions of this guideline, the majority of publications
on placenta praevia and accreta are retrospective studies, case reports and reviews, with a paucity of
prospective studies and randomised trials or meta-analyses.This was also the case for vasa praevia. In addition
to the above the National Patient Safety Agency (NPSA), the RCOG and the Royal College of Midwives (RCM)
ran a pilot care bundle for placenta praevia and caesarean section during 2008 and information from this has
been included, although publication from this work postdated the end of the literature search.44
4.
Screening and diagnosis for placenta praevia/accreta
4.1 Can we diagnose placenta praevia clinically?

Clinical suspicion should be raised in all women with vaginal bleeding after 20 weeks of gestation. A
high presenting part, an abnormal lie and painless or provoked bleeding, irrespective of previous
imaging results, are more suggestive of a low-lying placenta but may not be present, and the definitive
diagnosis usually relies on ultrasound imaging.
While clinical acumen remains vitally important in suspecting and managing placenta praevia, the definitive
diagnosis of most low-lying placentas is now achieved with ultrasound imaging. Clinical suspicion should,
however, be raised in any woman with vaginal bleeding (classically painless bleeding, or bleeding provoked
by sexual intercourse) and a high presenting part or an abnormal lie, irrespective of previous imaging results.
4.2 Should we screen for placental localisation?

Routine ultrasound scanning at 20 weeks of gestation should include placental localisation.
The UK National Screening Committee does not recommend a national screening programme for
placenta praevia, but it supports the current local practices of identifying at the routine 20-week
antenatal screening ultrasound scan women whose placenta encroaches on the cervical os. This
practice is not supported by evidence from randomised controlled trials but is supported by the
RCOG and the National Institute for Health and Clinical Excellence (NICE).45
3 of 26
Evidence
level 4
4.3 How should we image for placental localisation?

Transvaginal scans improve the accuracy of placental localisation and are safe, so the suspected
diagnosis of placenta praevia at 20 weeks of gestation by abdominal scan should be confirmed by
transvaginal scan.
In the second trimester transvaginal sonography (TVS) will reclassify 2660% of cases where the
abdominal scan diagnosed a low-lying placenta,46,47 meaning fewer women will need follow-up. In
the third trimester,TVS changed the transabdominal scan diagnosis of placenta praevia in 12.5% of
32 women.48 Leerentveld et al.49 demonstrated high levels of accuracy of TVS in predicting placenta
praevia in 100 women suspected of having a low-lying placenta in the second and third trimester
(sensitivity 87.5%, specificity 98.8%, positive predictive value 93.3%, negative predictive value
97.6% and false negative rate 2.33%).
Evidence
level 2+
Numerous prospective observational trials have used TVS to diagnose placenta praevia and none
has experienced any haemorrhagic complications, thus confirming the safety of this technique.4650
There is still only one small randomised controlled trial (n=38)51 comparing transabdominal scan
and TVS for placenta praevia, which supports this safety profile and reports superior views,
especially for posteriorly situated placentas.
Evidence
level 1-
4.4 Which women need further imaging if the placenta is low at 20 weeks of gestation?
All women require follow-up imaging if the placenta covers or overlaps the cervical os at 20 weeks of
gestation.
Women with a previous caesarean section require a higher index of suspicion as there are two problems
to exclude: placenta praevia and placenta accreta. If the placenta lies anteriorly and reaches the cervical
os at 20 weeks, a follow-up scan can help identify if it is implanted into the caesarean section scar.
Placental apparent migration, owing to the development of the lower uterine segment, occurs
during the second and third trimesters,5254 but is less likely to occur if the placenta is posterior55 or
if there has been a previous caesarean section.35 In one study, only five of 55 women with a placenta
reaching or overlapping the cervical os at 1823 weeks of gestation (diagnosed by TVS) had
placenta praevia at birth and in all cases the edge of the placenta had overlapped 15 mm over the
os at 20 weeks of gestation.56 A previous caesarean section influences this: a large retrospective
review of 714 women with placenta praevia found that even with a partial praevia at 2023 weeks
(i.e. the edge of the placenta reached the internal cervical os), the chance of persistence of the
placenta praevia requiring abdominal delivery was 50% in women with a previous caesarean
section compared with 11% in those with no uterine scar.53
Evidence
level 2+
Conversely, although significant migration to allow vaginal delivery is unlikely if the placenta
substantially overlaps the internal os (by over 23 mm at 1114 weeks of gestation in one study,54
by over 25 mm at 2023 weeks of gestation in another52 and by over 20 mm at 26 weeks of
gestation in a third study57), such migration is still possible and therefore follow-up scanning should
be arranged.
4.5 When should further imaging occur?

Women who bleed should be managed individually according to their needs.
In cases of asymptomatic women with suspected minor praevia, follow-up imaging can be left until 36
weeks of gestation.
4 of 26
In cases with asymptomatic suspected major placenta praevia or a question of placenta accrete,
imaging should be performed at around 32 weeks of gestation to clarify the diagnosis and allow
planning for third-trimester management, further imaging and delivery. D
Asymptomatic women without a previous caesarean section whose placenta has just reached but
not covered the cervical os at the 20-week scan and in whom pregnancy is progressing normally
can be managed expectantly, with further imaging at 36 weeks of gestation.45
Women with major placenta praevia or placenta accreta are at high risk of preterm delivery and
severe morbidity58,59 and therefore clarification of the diagnosis earlier than 36 weeks is beneficial.
When the placenta has completely covered the cervix at the 20-week scan, making major placenta
praevia more likely, or if the placenta is anteriorly placed and reaching the os in a woman with a
previous caesarean section, making placenta accreta more likely, earlier follow-up imaging is
advised. Of those women in whom the placenta is still low at 32 weeks of gestation, the majority
(73%) will remain so at term, but 90% of major praevias at this gestation will persist.53 Imaging at
32 weeks therefore seems timely in enabling a fairly definitive diagnosis to be made alongside a
plan for further care, including follow-up imaging for possible accreta, counselling for delivery and
planning delivery.44
Evidence
level 4
4.6 How can a morbidly adherent placenta be diagnosed?

Women who have had a previous caesarean section who also have either placenta praevia or an anterior
placenta underlying the old caesarean section scar at 32 weeks of gestation are at increased risk of
placenta accreta and should be managed as if they have placenta accreta, with appropriate preparations
for surgery made.
Antenatal sonographic imaging can be complemented by magnetic resonance imaging in equivocal

cases to distinguish those women at special risk of placenta accreta.
Antenatal imaging techniques that can help to raise the suspicion of a morbidly adherent placenta should be
considered in any situation where any part of the placenta lies under the previous caesarean section scar, but
the definitive diagnosis can be made only at surgery. These techniques include ultrasound and magnetic
resonance imaging (MRI). Numerous ultrasound imaging techniques have been reported over the years
including greyscale, colour and/or three-dimensional power Doppler sonography.6069
Most recently, Shih et al. compared prospectively 3D power Doppler with greyscale and colour
Doppler techniques in 170 women of whom 72 had had a previous caesarean section.69 Thirty-eight
of the women with a previous caesarean section had placenta accreta identified at delivery.
Considering just the 72 women with previous caesarean section, the diagnostic performance of the
different ultrasound modalities are itemised in Table 1; in each case the results reported are when at
least one diagnostic criterion was present. It can be seen that three-dimensional power Doppler gives
the best overall results when an isolated criterion is found, but as multiple diagnostic criteria were
commonly found in the women with placenta accreta, these predictions can be improved upon.69
Evidence
level 2+
Table 1. Diagnostic performance of different ultrasound modalities

Sensitivity (%)
Specificity (%)
Positive predictive value (%)
Risk
Greyscale
95
76
82
93
Colour Doppler
92
68
76
89
Three-dimensional power
Doppler
100
85
88
100
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Ultrasound criteria for diagnosis were as follows:

Greyscale:
loss of the retroplacental sonolucent zone
irregular retroplacental sonolucent zone
thinning or disruption of the hyperechoic serosabladder interface
presence of focal exophytic masses invading the urinary bladder

abnormal placental lacunae.
Colour Doppler:
diffuse or focal lacunar flow
vascular lakes with turbulent flow (peak systolic velocity over 15 cm/s)
hypervascularity of serosabladder interface
markedly dilated vessels over peripheral subplacental zone.
Three-dimensional power Doppler:

numerous coherent vessels involving the whole uterine serosabladder junction (basal view)
hypervascularity (lateral view)
inseparable cotyledonal and intervillous circulations, chaotic branching, detour vessels (lateral view).
The role of MRI in diagnosing placenta accreta is still debated.Two recent comparative studies have
shown sonography and MRI to be comparable: in the first study 15 of 32 women ended up having
accreta70 (sensitivity 93% versus 80% and specificity 71% versus 65% for ultrasound versus MRI); in
the second study 12 of 50 women ended up having accreta and MRI and Doppler showed no
difference in detection (P=0.74), although MRI was better at detecting the depth of infiltration in
cases of placenta accreta (P<0.001).71 Many authors have therefore recommended MRI for women
in whom ultrasound findings are inconclusive.7274
Evidence
level 2+
The main MRI features of placenta accreta include:74

uterine bulging
heterogeneous signal intensity within the placenta
dark intraplacental bands on T2-weighted imaging.
5.
Antenatal management
Prevention and treatment of anaemia during the antenatal period is recommended.
5.1 Where should women with placenta praevia be cared for in the late third trimester?
Women with placenta praevia in the third trimester should be counselled about the risks of preterm
delivery and obstetric haemorrhage, and their care should be tailored to their individual needs.
Any home-based care requires close proximity to the hospital, the constant presence of a companion
and full informed consent by the woman.
The Cochrane systematic review, which has not been updated since November 2002,75 only
includes one randomised controlled trial comparing hospital versus home care.76 The trial by Wing
et al.76 compared 26 women who were allowed home with 27 women kept in hospital and the only
significant difference was a reduction in length of hospital stay.
Evidence
level 1-
In the previous version of this guideline it was stated that those with major praevia who have
previously bled should be admitted from approximately 34 weeks of gestation, while outpatient
care can be considered for those with minor praevia or those who are asymptomatic.There remains
a paucity of evidence to guide place of care. Since the last guidance, one retrospective observational
review has been published that considered the care of 161 women with placenta praevia in the
third trimester.77 It demonstrated that neither the likelihood of bleeding nor the need for rapid
Evidence
level 2+
6 of 26
delivery was associated with the degree of praevia. A small trial looking at whether cervical length
might help in the prediction of those at risk of early delivery was too small to allow conclusions to
be drawn.78
Evidence
level 2+
International opinion is similar, with the Royal Australian and New Zealand College of Obstetricians
and Gynaecologists recommending that all women at risk of major antepartum haemorrhage
should be encouraged to remain close to the hospital of confinement for the duration of the third
trimester of pregnancy.79
Evidence
level 4
Where possible, home-based care should be conducted within a research context.

If women are managed at home, they should be encouraged to ensure they have safety precautions in
place, including having someone available to help them should the need arise and, particularly, having
ready access to the hospital.
It should be made clear to any woman being managed at home that she should attend immediately she
experiences any bleeding, contractions or pain (including vague suprapubic period-like aches).
Decisions regarding blood availability during inpatient antenatal care should be based on clinical
factors relating to individual cases as well as on local blood bank services. Women with atypical
antibodies form a particularly high-risk group and discussions in these cases should involve the local
haematologist and blood bank.
5.2 Is there a place for cervical cerclage in these women?

The use of cervical cerclage to reduce bleeding and prolong pregnancy is not supported by sufficient
evidence to recommend this practice outside of a clinical trial.
There have been no new trials looking at this issue since the previous guidelines, which considered
two studies on cervical cerclage80,81 included in the Cochrane review.75 A total of 64 women were
randomised and three women were lost to follow-up. Only one of these trials showed a possible
benefit, with a reduction in the number of babies born before 34 weeks of gestation or weighing
less than 2 kg, although randomisation was by birth date and analysis was by treatment received,
not intention to treat.80
Evidence
level 1-
5.3.1 Is there a place for tocolytics in women who bleed?

Tocolysis for treatment of bleeding due to placenta praevia may be useful in selected cases. However,
beta-mimetics were used in the studies to date and, as these are known to be associated with significant
adverse effects, the agent and optimum regime are still to be determined: further research is needed in
this area.
The aetiology of bleeding in placenta praevia is due to the dynamics of the development of the
lower uterine segment, but may also be triggered by uterine activity. This has prompted
obstetricians to try conservative aggressive management of placenta praevia using tocolysis in this
situation.82,83 The previous version of these guidelines considered evidence from a prospective
randomised controlled trial of 60 women who presented with bleeding due to placenta praevia
between 28 and 34 weeks of gestation.84 Tocolysis using 10 mg of ritodrine every 6 hours by
intramuscular injections for 7 days was compared with no treatment. Treatment was associated
with prolongation of pregnancy (25.3317.7 days compared with 14.4720.33 days, P<0.05) and
an increased birth weight (2.270.59 kg compared with 1.950.55 kg). No adverse effects to
mother or baby were shown, and particularly no increased risk of bleeding was found. There have
been no new trials to consider for this guideline update.
7 of 26
Evidence
level 1+
Previous observational studies have reported similarly encouraging results. Besinger et al.85
conducted a prospective study on 112 women with acute vaginal bleeding and known placenta
praevia and gave tocolysis to 72 women who had significant uterine activity (85%). This group of
women had a prolongation of the interval from admission to delivery (39.2 days versus 26.9 days,
P<0.02) and an increase in birth weight (2.520 kg versus 2.124 kg, P<0.03) compared with the 40
women who were not given tocolysis. The largest series of cases where tocolysis was used for
bleeding in the third trimester, including in 76 of 105 women with placenta praevia, is reported in
a retrospective review by Towers et al.86 and has suggested no increased morbidity or mortality
associated with such use in a tertiary setting.
Evidence
level 2+
5.3.2 Is there a place for the use of prophylactic tocolytics in women to prevent bleeding?
Prophylactic terbutaline to prevent bleeding has not been found to benefit women with placenta
praevia.87
Evidence
level 2+
5.4 What precautions should be taken against venous thromboembolism for inpatients?
Prolonged inpatient care can be associated with an increased risk of thromboembolism; therefore,
mobility should be encouraged together with the use of thromboembolic deterrent stockings and
adequate hydration.
Prophylactic anticoagulation in women at high risk of bleeding can be hazardous and the decision to
use it should be taken on an individual basis considering the risk factors for thromboembolism. Limiting
anticoagulant thromboprophylaxis to those at high risk of thromboembolism seems reasonable.88
In the postnatal period, immobility, massive haemorrhage and operative delivery are all risk factors for
postnatal thromboembolism. Thromboprophylaxis should be considered according to Green-top Guideline
No. 37: Reducing the risk of thrombosis and embolism during pregnancy and the puerperium.88
6.
Preparations for delivery
Prior to delivery, all women with placenta praevia and their partners should have a discussion regarding
delivery, indications for blood transfusion and hysterectomy should be reviewed, and any concerns,
queries or refusals of treatment should be dealt with effectively and documented clearly.
6.1 In what situations can vaginal delivery be contemplated for women with a low-lying placenta?
The mode of delivery should be based on clinical judgement supplemented by sonographic information.
A woman with a placental edge less than 2 cm from the internal os in the third trimester is likely to need
delivery by caesarean section, especially if the placenta is thick, but the evidence for this is poor and
further research in this area is needed.
As the lower uterine segment continues to develop beyond 36 weeks of gestation, there is a place for
TVS if the fetal head is engaged prior to an otherwise planned caesarean section.
No new trials addressing this question have been published since the last guidelines. Making a
recommendation for a specific mode of delivery based on reports of ultrasound findings is difficult
because studies have largely been retrospective and observational, with the decisions being
influenced by knowledge of the ultrasound scan findings rather than being blind to them.
Oppenheimer et al.50 performed TVS in the third trimester on 127 women and 52 had placenta
praevia. In 31 cases there was major placenta praevia and only 21 were partial praevias. Of these
the mean distance from the leading placental edge to the cervical os was significantly different in
8 of 26
Evidence
level 2-
those delivered by caesarean section than those aiming for and achieving vaginal delivery, with a
cut-off distance of 2 cm (P=0.0004), but there was a 28% caesarean section rate in those in whom
the leading placental edge was over 2 cm from the os and 12.5% of those in whom the leading
placental edge was less than 2 cm away delivered vaginally.
Evidence
level 289
In another retrospective study of 121 cases, two of 40 women with placentas within 0.12.0 cm
of the cervical os delivered vaginally, while 22 of 39 with placentas further than 2 cm from the
internal os achieved vaginal delivery. No mention is made in this paper of whether the placentas
were anterior or posterior.
Decisions regarding the mode of delivery take into account clinical factors as well as ultrasound findings and the womans preferences, especially if the fetal head has entered the pelvis.
Ultrasound can add to this information in terms of where the fetal head is relative to the leading
edge of the placenta, and the thickness of the encroaching tongue of the placenta has been shown
to influence outcome: the thicker the placenta (over 1 cm), the greater the likelihood of abdominal delivery (P=0.02).90
Evidence
level 2+
6.2 At what gestation should elective delivery occur?

Elective delivery by caesarean section in asymptomatic women is not recommended before 38 weeks of
gestation for placenta praevia, or before 3637 weeks of gestation for suspected placenta accreta.
Although placenta praevia and placenta accreta are associated with preterm delivery, with 40% of
women delivering before 38+0 weeks of gestation,58,59 cases requiring delivery are unpredictable and
could only be avoided by a policy of delivery at 32 weeks of gestation. This would be unacceptable
due to neonatal morbidity,91 but equally waiting too long can increase the chance of neonatal
mortality.7 Individual characteristics should be considered, but with the planning needed for the
especially high-risk cases suspected of having placenta accreta, planned delivery at around 3637
weeks of gestation (with corticosteroid cover92) is a reasonable compromise, while in those with
uncomplicated placenta praevia delivery can be delayed until 3839 completed weeks of gestation.44,93
Evidence
level 4
6.3 What preparations should be made before surgery?

Placenta praevia without previous caesarean section carries a risk of massive obstetric haemorrhage
and hysterectomy and should be carried out in a unit with a blood bank and facilities for highdependency care.
The care bundle for suspected placenta accreta should be applied in all cases where there is a placenta
praevia and a previous caesarean section or an anterior placenta underlying the old caesarean scar scar.
In response to the findings of the confidential enquiry10 and the recognition of the severe morbidity
associated with placenta praevia and previous caesarean section,23 the NPSA in collaboration with the RCOG
and the RCM set up an expert working group to develop a care bundle for placenta praevia accreta.44 Six
elements of good care that were considered to be uncontroversial were agreed. The care bundle was then
tested in six units over a 5-month pilot study period and it was found to be both achievable and practical.
Clinical outcomes were monitored, confirming the high morbidity associated with this condition. The six
elements considered to be reflective of good care were:
consultant obstetrician planned and directly supervising delivery
consultant anaesthetist planned and directly supervising anaesthetic at delivery
blood and blood products available
multidisciplinary involvement in pre-op planning

discussion and consent includes possible interventions (such as hysterectomy, leaving the placenta in place,
cell salvage and intervention radiology)

local availability of a level 2 critical care bed.
9 of 26
The reasoning behind the choices for these elements of care together with relevant references were compiled
into a supportive document given to all pilot units and available on the NPSA/RCOG website.93 The view
regarding place of delivery is that women who decline blood products should be transferred to a centre
where cell salvage and interventional radiology are available.93
The unpredictable nature of this potentially high-risk surgery means that the need for a level 2
critical care bed should be confirmed before an elective procedure is embarked upon.10
Evidence
level 4
6.4 What blood products are needed?

6.4.1 Placenta praevia
Blood should be readily available for the peripartum period; whether ready cross-matched blood is
required and in what amount will depend on the clinical features of each individual case and the local
blood bank services available. When women have atypical antibodies, direct communication with the
local blood bank should enable specific plans to be made to match the individual circumstance.
The RCOG guidance on blood transfusion in obstetrics94 recommends red cells, fresh frozen plasma and
cryoprecipitate are all kept by blood banks supplying obstetric units.
There is no evidence to support the use of autologous blood transfusion for placenta praevia.
Dinsmoor et al.95 retrospectively reviewed 88 women who had placenta praevia and only 12 (14%)
would have been eligible for autologous blood donation/transfusion. Of the 12, only two were
transfused at delivery but required a total of 12 units and 18 units. Current European Union
legislation only permits blood establishments to perform this procedure96 and it is not supported
by the RCOG.94
Cell salvage may be considered in women at high risk of massive haemorrhage and especially in women
who would refuse donor blood. D
Cell salvage in obstetrics has increased in use since the early studies97101 and a NICE guideline102 has
been published since the previous version of this guideline. It has been used with success in
placenta praevia103 and in the USA anticipated difficulties with placenta praevia/accreta surgery are
an indication for considering the use of cell salvage technology, where available.104 The Obstetric
Anaesthetists Association (OAA) supports its use,105 as does the RCOG, which suggests it is
appropriate when anticipated blood loss exceeds 1500 ml.94
Evidence
level 2+
Evidence
level 4
6.4.2 Suspected placenta accreta

Cross-matched blood and blood products should be readily available in anticipation of massive
haemorrhage. Where available, cell salvage should be considered and if the woman refuses donor blood
it is recommended that she be transferred to a unit with a cell saver.
The use of cell salvage in obstetric units is increasing in the UK. During the pilot study for the
NSPA/RCOG/RCM care bundle, all units included had a cell saver on the labour ward.This had not
been a requirement for inclusion in the study.This study was too small to draw any conclusions or
comment on any effect on maternal morbidity.44 As more units acquire a cell saver and then become
familiar with its use more information will become available as to its usefulness, but its availability
does not remove the need to arrange for cross-matched blood.
10 of 26
Evidence
level 4
6.5 When is interventional radiology indicated?

Interventional radiology can be life saving for the treatment of massive postpartum haemorrhage, and
therefore having this facility available locally is desirable. If a woman is suspected of having placenta
accreta and she refuses donor blood, it is recommended that she be transferred to a unit with an
interventional radiology service.
The place of prophylactic catheter placement for balloon occlusion or in readiness for embolisation if
bleeding ensues requires further evaluation.
The treatment of severe postpartum haemorrhage using interventional radiology techniques and
selective embolisation has been well reported in case series,106110 but is unlikely to be subjected to
a randomised controlled trial. Uterine artery embolisation in cases of uncontrolled haemorrhage
can be life saving and uterus sparing and should be considered.
Evidence
level 3
Less clear is the value of prophylactic placement of arterial catheters in cases where placenta
accreta is suspected antenatally. This has not been subjected to a randomised controlled trial and
the evidence comprises a number of case series with variable results, from beneficial111113 through
equivocal107,114 to no benefit.115,116 Most recently, some casecontrol series have compared
prophylactic catheter placement with controls: Shrivastava et al.117 compared 19 cases of balloon
occlusion combined with hysterectomy with 50 cases of hysterectomy alone and found no
difference in outcome; Tan et al.118 compared 11 cases of prophylactic balloons with 14 historic
controls and found a reduction in operative time, blood loss and blood transfusion rates; a study
from Edinburgh119 found that six of 12 prophylactic catheter placements were unnecessary, four of
the remaining six women needed hysterectomy anyway, one woman bled after the catheter had
been removed post-delivery and the catheter may have been useful in one case.
Evidence
level 2+
There is a case report of a popliteal arterial thrombus requiring thromboembolectomy complicating

common iliac balloon catheterisation at caesarean hysterectomy.120 The current RCOG opinion is that further
work is required to establish the risks and benefits of this technique as a prophylactic measure before it can
be recommended.121
6.6 What anaesthetic is most appropriate for delivery of the baby?

The choice of anaesthetic technique for caesarean sections for placenta praevia and suspected placenta
accreta must be made by the anaesthetist conducting the procedure. There is insufficient evidence to
support one technique over another.
The data available on choice of anaesthetic technique for these cases has previously demonstrated
differing opinions from UK obstetric anaesthetists,122 while evidence from the USA has supported
regional anaesthesia.13 There have been no new trials since the previous guidelines, which
considered two trials adding to the evidence in support of regional anaesthesia.The first was a large
retrospective study of 350 cases of placenta praevia123 where 210 women who received regional
blockade were compared with 140 women who received general anaesthesia. There was more
blood loss and more transfusion requirements in those having a general anaesthetic, and the two
women who experienced major morbidity (one pulmonary embolus and one cerebral embolus)
both had general anaesthetics. Of the five womens with placenta accreta, four had regional
anaesthesia initially, but two required conversion to general anaesthesia. In this trial, general
anaesthetics were more commonly used in emergency situations and consultants were more likely
to give regional anaesthesia than their junior colleagues, especially in emergencies.
Evidence
level 2-
The second trial was a small randomised controlled trial of regional versus general anaesthesia for
placenta praevia124 where 12 women received general anaesthetic and 13 women received regional
Evidence
level 1-
11 of 26
blockade.The numbers were small and more women in the general anaesthetic group had placenta
praevia accreta (two versus one) or anterior praevia (four versus one), but outcomes were similar
for the babies. Blood transfusion requirements (although not estimated blood loss) were greater in
the general anaesthetic group.
Evidence
level 1-
6.7 What should be included in the consent form for caesarean section?
Any woman giving consent for caesarean section should understand the risks associated with
caesarean section in general and the specific risks of placenta praevia in terms of massive obstetric
haemorrhage, the need for blood transfusion and the chance of hysterectomy.
General procedures for discussing and obtaining consent for caesarean section are described in detail in
RCOG Consent Advice No.7: Caesarean section,125 but the risk of massive haemorrhage is approximately 12
times more likely with placenta praevia.121 This should be explained together with the possibility of needing
a blood transfusion. The risk of hysterectomy is also increased126 and rises when associated with previous
caesarean section.11 In the pilot series of the care bundle, of the 21 women with a low placenta and a previous
caesarean section, seven (33%) required a hysterectomy.44
Counselling women preoperatively before the diagnosis of placenta accreta is confirmed or dismissed can be
difficult, but a useful guide can be taken from Silver et al., who reported on over 30 000 women of whom 723
had placenta praevia, 143 had placenta accreta and 216 required hysterectomy.127 The risk of hysterectomy
increased with the number of previous caesarean sections the women had had, as shown in Table 2.
Table 2. Link between number of previous caesarean sections and risk of placenta accreta, placenta praevia
and hysterectomy127
Number of previous
caesarean section(s)
Number of
women
Number of women
with placenta accreta
Chance of placenta accreta

if placenta praevia
Number of
hysterectomies
6201
15 (0.24%)
3%
40 (0.65%)
15 808
49 (0.31%)
11%
67 (0.42%)
6324
36 (0.57%)
40%
57 (0.9%)
1452
31 (2.13%)
61%
35 (2.4%)
258
6 (2.33%)
67%
9 (3.49%)
89
6 (6.74%)
67%
8 (8.99%)
Any woman with suspected placenta praevia accreta should be reviewed by a consultant obstetrician in
the antenatal period. The different risks and treatment options should have been discussed and a plan
agreed, which should be reflected clearly in the consent form. This should include the anticipated skin
and uterine incisions and whether conservative management of the placenta or proceeding straight to
hysterectomy is preferred in the situation where accreta is confirmed at surgery. Additional possible
interventions in the case of massive haemorrhage should also be discussed, including cell salvage and
interventional radiology when available.
The anticipation and planning of surgery for suspected placenta accreta enables logical and timely decisions
to be made without the element of surprise and often without the urgency of massive haemorrhage.10 These
are described in section 7 on surgery for suspected placenta praevia accreta.To mention and gain consent for
the use of balloons, cell salvage and interventional radiology is recommended94,102,121 and is much easier done
before needed.
12 of 26
6.8 What grade of obstetrician should attend?

A junior doctor should not be left unsupervised when caring for these women and a senior experienced
obstetrician should be scrubbed in theatre.
As a minimum requirement during a planned procedure for placenta praevia, a consultant obstetrician
and anaesthetist should be present within the delivery suite. When an emergency arises, consultant
staff should be alerted and attend as soon as possible.
Any woman going to theatre electively with suspected placenta praevia accreta should be attended by
a consultant obstetrician and anaesthetist. If the delivery is unexpected, out-of-hours consultant staff
should be alerted and attend as soon as possible.
The most recent Confidential Enquiry into Maternal and Child Health stresses the importance of a
consultant-led multidisciplinary team at delivery in women at risk of placenta accreta.10 This
approach is the same as that in Australia and New Zealand and in the USA, where the respective
Colleges of Obstetrics and Gynaecology have issued a committee statement79 and an opinion104 that,
when hysterectomy is anticipated, consent should include that for hysterectomy and delivery
should involve specialised multidisciplinary personnel and occur where there are facilities for highvolume blood transfusion and availability of other blood products.
7.
Evidence
level 4
Surgery in the presence of placenta accreta, increta and percreta
7.1 What surgical approach should be used for suspected placenta praevia accreta?
Surgeons delivering the baby by caesarean section in the presence of a suspected placenta praevia
accreta should consider opening the uterus at a site distant from the placenta, and delivering the baby
without disturbing the placenta, in order to enable conservative management of the placenta or elective
hysterectomy to be performed if the accreta is confirmed. Going straight through the placenta to achieve
delivery is associated with more bleeding and a high chance of hysterectomy and should be avoided.
Conservative management of placenta accreta when the woman is already bleeding is unlikely to be
successful and risks wasting valuable time.
C/
D
The choice of skin and uterine incision needed to avoid the placenta will depend on the location of the
placenta. A low transverse skin incision allows access to the lower half of the uterus and is reasonable if the
upper margin of the anterior aspect of the placenta does not rise into the upper segment of the uterus. If,
however, the placenta is anterior and extending towards the level of the umbilicus, a midline skin incision
may be needed to allow for a high upper-segment longitudinal uterine incision. It is therefore useful for the
surgeon to perform an ultrasound scan before surgery to plot out the extent of placenta before starting. This
is surgical logic and not evidence based.
The antenatal diagnosis and surgical avoidance of the placenta, and its separation, may be associated with
reduced maternal morbidity.128,129 It allows for conservative management of the placenta, reducing the risk of
hysterectomy and of bleeding if the placenta is indeed found to be adherent. In cases of placenta percreta,
avoiding the placenta and leaving it attached to proceed with either hysterectomy or conservative
management is supported by current data described in more detail in sections 7.2 and 7.3 of this guideline;130
evidence has been summarised in the next section.
13 of 26
7.2 What should be done if the placenta does not separate after delivery of the baby?
If the placenta fails to separate with the usual measures, leaving it in place and closing, or leaving it in
place, closing the uterus and proceeding to a hysterectomy are both associated with less blood loss
than trying to separate it.
There are no randomised controlled trials comparing different surgical approaches for suspected
placenta praevia accreta, but a recent observational review of 57 cases of suspected accreta
demonstrated significantly reduced short-term morbidity (intensive care unit admission, massive
blood transfusion, coagulopathy, urological injury, re-laparotomy) if the placenta was left in place
and hysterectomy performed electively compared with attempting to remove the placenta first
(36% compared with 67%, P=0.038).129
C/
D
Evidence
level 2++
Clearly, this approach of elective hysterectomy would be unacceptable to women desiring uterine
preservation and in such cases leaving the placenta in place is another option.Attempting placental
separation risks hysterectomy in up to 100% of cases129 and therefore is illogical.Timmermans et al.
reviewed 60 case reports130 with successful preservation of the uterus in all but 12 women, while
six of a further 34 women who were conservatively managed also preserved their uterus,131136
supporting this practice.
The largest of these more recent case series reported on 26 patients receiving conservative
management of the placenta, which failed in five cases (19%); three women went on to have a
subsequent pregnancy.131 A further series of three cases on conservative management were
successful,132 while a further two women had a planned delayed straightforward hysterectomy after
having had arterial embolisation and conservative management of the placenta followed up with
methotrexate treatment.133 One case had a successful elective evacuation of retained products of
conception after 4 months,134 while two women had complications after conservative
management: one had partial accreta and had heavy bleeding requiring hysterectomy on day 3 postcaesarean section,135 while the other had recurrent problems with infection resulting in an
evacuation of retained products of conception followed by severe sepsis on day 33.136
Evidence
level 3
7.3 What happens if the placenta separates, or partially separates?

If the placenta separates, it needs to be delivered and any haemorrhage that occurs needs to be dealt
with in the normal way.
If the placenta partially separates, the separated portion(s) need to be delivered and any haemorrhage
that occurs needs to be dealt with in the normal way. Adherent portions can be left in place, but blood
loss in such circumstances can be large and massive haemorrhage management needs to follow in a
timely fashion.
The diagnosis of placenta accreta is made only if the placenta fails to separate at delivery; therefore,
if it comes away it is delivered as usual. If, however, it partially separates and partial accreta exists,
the associated blood loss can be large.Adherent portions should be left attached as trying to separate
them can cause severe bleeding.17,104 In the case review mentioned above,130 25 of the 60 cases had
partial placental separation; three of these women needed hysterectomy for failed conservative
treatment, and 12 others had secondary procedures to evacuate the uterus, which was conserved.
Evidence
level 3
7.4 How is massive haemorrhage best managed?

The surgical manoeuvres required in the face of massive haemorrhage associated with placenta praevia
caesarean sections should be performed by appropriately experienced surgeons. Calling for extra help
early should be encouraged and not seen as losing face.
14 of 26
Management of massive haemorrhage should occur in the normal way,121 including the use of
uterotonic agents, which can be very helpful in reducing the blood loss associated with bleeding
from the relatively atonic lower uterine segment.137 Advanced techniques may also be employed
and the use of bimanual compression or even aortic compression can buy time for extra help to
arrive, or for the anaesthetist to catch up haemodynamically in the unstable woman.
Evidence
level 3
The most recent Confidential Enquiry into Maternal and Child Health has reiterated the importance
of considering calling in another senior colleague(s) with superior gynaecological surgical skills
early in the process.10
Evidence
level 4
Specific techniques that have been described for accreta in retrospective reviews and case reports
include uterine and vaginal packing with gauze, which was successful in 45 of 48 women,138
balloon tamponade,139,140 the B-Lynch suture,141 vertical compression sutures142 and suturing an
inverted lip of cervix over the bleeding placenta bed.143 Uterine144 and internal iliac artery ligation145
have been reported but make subsequent access for intervention radiology techniques and
embolisation extremely difficult or impossible.
Evidence
level 3
8.
Follow-up of the woman after part or all of the placenta has been retained following
placenta accreta
8.1 How should the woman be managed after placental retention?

The woman should be warned of the risks of bleeding and infection postoperatively and prophylactic
antibiotics may be helpful in the immediate postpartum period to reduce this risk. Neither methotrexate
nor arterial embolisation reduces these risks and neither is recommended routinely.
A comprehensive review of all case reports published up to 2007 summarises the conservative
management of 60 women with placenta accreta and quantifies the risks of haemorrhage and
infectious complications.130 The outcomes for those women who received no additional treatment
was the same as those receiving either methotrexate or embolisation: of 26 women having no
additional measures, four required hysterectomy; of 22 receiving methotrexate, five required
hysterectomy; and of 12 having additional embolisation, three required hysterectomy. Infection
occurred in 11 of the 60 women (18%), bleeding in 21 (35%) and disseminated intravascular
coagulation in four (7%). Bleeding started a few hours after surgery up until 3 months post-delivery.
A more recent case report described severe sepsis after an evacuation of retained products of
conception on day 33.136
Follow-up of the woman using ultrasound should supplement serum beta-human chorionic
gonadotrophin measurements.
Evidence
level 3
The pattern of follow-up is not supported by randomised trials; however, owing to the protracted nature of
recovery with complications occurring months after delivery, local arrangements need to be made to ensure
regular review and, most importantly, ready access should the woman experience problems. Measuring serum
beta-human chorionic gonadotrophin on a weekly basis to check it falls continuously can reassure to some
extent, but low levels do not guarantee complete placental resolution and so this should be supplemented by
imaging.130
8.2 What chance of success can be quoted for a future pregnancy?

There are insufficient data at present to make any firm prognosis about future pregnancy. In two small series
each reporting three women with subsequent pregnancies, one group had 100% recurrence146 while the other
had 0% recurrence.130
15 of 26
9.
Vasa praevia
9.1 Can we diagnose vasa praevia clinically?

In the antenatal period, in the absence of vaginal bleeding, there is no method to diagnose vasa praevia
clinically.
In the intrapartum period, in the absence of vaginal bleeding, vasa praevia can occasionally be
diagnosed clinically by palpation of fetal vessels in the membranes at the time of vaginal examination.
This can be confirmed by direct visualisation using an amnioscope.
Without access to the fetal membranes, it is not possible to diagnose the intact vessels of vasa
praevia clinically. Once the cervix has started to dilate, these vessels may be felt digitally during a
vaginal examination.As the condition is rare, most clinicians will not be familiar with what they are
feeling, and it is therefore important for clinicians to have a high index of suspicion if they feel
something unusual and to confirm the diagnosis prior to membrane rupture if the consequences
of fetal haemorrhage are to be avoided. Direct visualisation using an amnioscope has some use,147
but this only gives visual access to the area of membranes exposed by the dilated cervix.
Evidence
level 3
Following delivery of the placenta, it is easy to confirm the presence of fetal vessels running through the
membranes by simple clinical examination, but it is more difficult to diagnose vasa praevia as the orientation
of the vessels in relation to the internal cervical os and fetal presenting part in utero is not certain after
delivery.
In the presence of vaginal bleeding, especially associated with membrane rupture and fetal
compromise, delivery should not be delayed to try and diagnose vasa praevia.
Because of the speed at which fetal exsanguination can occur and the high perinatal mortality rate
associated with ruptured vasa praevia, delivery should not be delayed while trying to confirm the
diagnosis if fetal wellbeing is compromised.
Evidence
level 4
9.2 Can we differentiate between fetal and maternal bleeding?

Various tests exist that can differentiate between fetal and maternal blood, but they are often not
applicable in the clinical situation.
The KleihauerBekte test148 and haemoglobin electrophoresis form part of routine obstetric
practice to accurately identify fetal cells in the maternal circulation and fetal haemoglobin. Both can
detect the presence of fetal haemoglobin in concentrations as low as 0.01%, and both can be used
to identify fetal cells in vaginal blood loss. The disadvantage of both of these is that they are
laboratory-based tests that take a significant amount of time before a result is obtained, thus
rendering them of little use in this clinical situation. The resistance of fetal haemoglobin to
denaturation with alkali has been used by various methods to identify fetal bleeding. The first of
these was the Apt test,149 but this requires the presence of at least 60% fetal haemoglobin to be
positive, and requires centrifugation. Modifications of the Apt test have been tried,150152 but all have
been too complicated or not sensitive enough for application in the clinical setting. Lindqvist and
Gren153 have recently described a much simpler bedside test using 0.14 M sodium hydroxide
solution, which denatures adult haemoglobin, turning it a brownish-green colour, while fetal
haemoglobin is resistant to denaturation and retains its red colour. This method may have some
applicability in the clinical situation but requires further validation.
16 of 26
Evidence
level 2+
9.3 Can vasa praevia be diagnosed using ultrasound?

Vasa praevia can be accurately diagnosed with colour Doppler ultrasound, often utilising the transvaginal route.
The antenatal diagnosis of vasa praevia using standard real-time ultrasound was first described in
1987.154 The ultrasound appearance of vasa praevia is of linear echolucent structures overlying the
cervix.155 In 1990, the use of colour Doppler in the diagnosis of vasa praevia was described,156 which
improved the diagnostic accuracy. Since then, there have been a few series published where
ultrasound has been used to diagnose vasa praevia antenatally.25,27,41,155,157,158 Fung and Lau25 reported
three cases of vasa praevia and reviewed 48 cases reported between 1980 and 1997. In 22 cases
the diagnosis was made antenatally, and this group had significantly better perinatal outcomes
compared with those diagnosed acutely. Catanzarite et al.27 described 11 cases of vasa praevia
diagnosed antenatally out of 33 208 women scanned over an 8-year period. The diagnosis was
confirmed in ten out of 11, giving a specificity of 91%, but the sensitivity could not be determined.
Baulies et al.41 described a retrospective study of 12 063 deliveries between 2000 and 2005 in a
single centre, during which nine cases were diagnosed with ultrasound in the antenatal period. All
nine were confirmed at delivery. Again, sensitivity could not be determined from this study. Lee et
al.155 diagnosed 18 cases of vasa praevia out of 93 874 women scanned, 15 of which were
confirmed, giving a specificity of 83%. Again, owing to the lack of outcome data in all cases
scanned, sensitivity could not be determined. Smorgick et al.30 described a retrospective study over
20 years on 110 684 women, in which 19 cases of vasa praevia were identified, ten of which were
diagnosed prenatally. The authors deliberately do not comment on the sensitivity/specificity of the
test or on perinatal outcome. It is clear that vasa praevia can be diagnosed with good specificity,
but owing to the low prevalence of the condition, numbers are small and sensitivity has not been
determined. Ultrasound diagnosis of vasa praevia is not without difficulty and factors such as
maternal obesity, scarring and fetal position can influence accuracy, and care must be taken not to
mistake cord presentation for vasa praevia.36,159 Using both the abdominal and vaginal routes of
scanning and changing maternal position can improve diagnostic accuracy.
Evidence
level 2+
9.4 Should we screen for vasa praevia?

At present, vasa praevia should not be screened for routinely at the time of the mid-trimester anomaly
scan, as it does not fulfil the criteria for a screening programme.
As the occurrence of vasa praevia in the absence of a velamentous cord insertion or a succenturiate
or bilobed placenta is minimal,39 screening for vasa praevia would involve detailed ultrasound
examination of the placenta and cord insertion to identify these placental and cord variants and
low-lying placentas. If any of these are present, colour Doppler assessment of the lower pole of the
uterus in the region of the internal cervical os should be carried out to identify any fetal vessels.36,159
This often requires TVS. Current recommendations from the RCOG and NICE27 include
identification of placental site and low-lying placenta only as part of routine ultrasound screening,
and although vasa praevia is now detectable by ultrasound, there remains insufficient information
on the case definition, natural history and epidemiology of the condition. The incidence of
velamentous cord insertion in an unselected population is around 1%,158 and that of bilobed or
succenturiate placenta is around 1.7%, two-thirds of which have a velamentous cord insertion.160
The reported coexistence of velamentous cord insertion and vasa praevia has been reported
between at 26%.161,162 Adding the other groups thought to be at increased risk of vasa praevia, i.e.
multiple pregnancies, in vitro fertilisation conceptions and those with a low-lying placenta, a
significant minority of women will be identified as being at increased risk of vasa praevia and
require further counselling and screening. The accuracy and practical application of the screening
test has not been elucidated in the general pregnant population, although some centres with an
interest have reported that identification of the cord insertion during the first or second trimester
17 of 26
Evidence
level 4
is easy and accurate, takes less than 1 minute and requires no additional scanning skills.158,163
Scanning for velamentous cord insertion and vasa praevia is not routinely taught during ultrasound
training courses in the UK, and the training implications of introducing such a screening
programme require careful consideration.The potential psychological impact of being identified as
being at high risk of vasa praevia and being diagnosed with vasa praevia must also be considered.
Furthermore, there is currently no agreed management pathway for those with confirmed vasa
praevia, although the Society of Obstetricians and Gynecologists of Canada has recently published
guidelines.164 Taking all of this into account, there is uncertainty about the balance of benefit versus
harm to be derived from screening all pregnant women with a view to offering caesarean section
to those at risk. The UK National Screening Committee has recently explored the topic and does
not recommend a national screening programme for vasa praevia.165
Evidence
level 4
However, some centres may feel that, based on their case mix, screening those with risk factors is
justifiable as recommended by some groups.31,36,159,166 This should be carefully audited and reported
to expand the evidence base regarding the sensitivity and specificity of screening, as well as
maternal and fetal/neonatal outcomes. For those who do wish to screen for vasa praevia, Jeantys
group have suggested a screening algorithm.31
Evidence
level 3
9.5 How should vasa praevia be managed?

In the presence of bleeding vasa praevia, delivery should be achieved by category 1 emergency
caesarean section.
Fetal wellbeing should be confirmed at the time of any antepartum or intrapartum haemorrhage,
and this is currently best achieved using the cardiotocograph.167 If signs of acute fetal compromise
are present, delivery should be achieved as soon as possible, usually by category 1 caesarean
section,168 to minimise the risk of fetal exsanguination. Delay to facilitate ultrasound or transfer to
another unit could result in fetal demise.
In cases of suspected vasa praevia, transvaginal colour Doppler ultrasonography should be carried out
to confirm the diagnosis.
If there is either an ultrasound or clinical suspicion of vasa praevia in the absence of fetal
compromise, a formal systematic assessment of the region of the internal cervical os should be
undertaken using transvaginal colour Doppler ultrasound.25,27,41,155,157,158,164
In confirmed cases of vasa praevia at term, delivery should be carried out by elective caesarean section
in a timely manner.
In view of the risk of fetal haemorrhage with the onset of labour or membrane rupture and the
minimal risks of neonatal lung disease, once vasa praevia has been confirmed at term, delivery
should be carried out by elective caesarean section as soon as is practicable.
In cases of vasa praevia identified in the second trimester, imaging should be repeated in the third
trimester to confirm persistence.
As gestation advances vasa praevia can resolve in up to 15% of cases.156 To avoid unnecessary
anxiety, admissions, prematurity and caesarean sections, it is essential to confirm persistence of vasa
praevia in the third trimester.165
18 of 26
Evidence
level 2+
Evidence
level 2+
Evidence
level 2+
P
Evidence
level 3
In cases of confirmed vasa praevia in the third trimester, antenatal admission from 28 to 32 weeks of
gestation to a unit with appropriate neonatal facilities will facilitate quicker intervention in the event of
bleeding or labour.
In view of the increased risk of preterm delivery, administration of corticosteroids for fetal lung maturity
should be considered.
In the presence of confirmed vasa praevia, elective caesarean section should be carried out prior to the
onset of labour.
In confirmed cases of vasa praevia where there is no bleeding, no trials have been performed to
identify optimal management, and numbers from individual centres will always be small. Suggested
management includes admission to a unit with appropriate neonatal facilities between 28 and 32
weeks of gestation,165 administration of corticosteroids for fetal lung maturity because of the risk of
preterm delivery93,165 and elective caesarean section between 35 and 37 weeks of gestation, when the
risks of prematurity have significantly decreased.36,37,160,165 Amniocentesis to establish fetal lung
maturity is used in some centres, mainly in the USA, but this practice is not commonplace in the
UK.37,160 Oleyese et al.37 have suggested that outpatient management is possible if there is no evidence
of cervical shortening on TVS and there are no symptoms of bleeding or preterm uterine activity.
Laser ablation in utero may have a role in the treatment of vasa praevia.
Evidence
level 3
Quintero et al.169 have described the successful use of in utero laser therapy to ablate the vessels of
vasa praevia type 2 in a case where the cord inserted into the dominant lobe of a bilobed placenta,
where the lobe being fed by the aberrant vessels accounted for 15% of the total placental mass.This
treatment modality may have a place in the management of such cases in the future.
Evidence
level 3
10. Clinical Governance
10.1 Debriefing
Postnatal follow-up should include debriefing with an explanation of what happened, why it happened and
any implications for future pregnancy or fertility.
10.2 Training
All staff should receive local training for obstetric emergencies, which should include massive haemorrhage
and acute fetal compromise.
Specific issues regarding raising the awareness of ultrasound staff to screen for placenta accreta are also worth
pursuing locally, including organising policies/guidelines for flagging up women at risk and arranging for
them to see a consultant after their 32-week scan.
Consideration should be given to ensuring appropriate training for ultrasound staff in the recognition of,
diagnosis of and screening for placental and cord variants such as bilobed placenta, velamentous cord
insertion and vasa praevia, particularly if screening is to be adopted locally.
10.3 Clinical incident reporting

Clinical incident forms should be completed for all adverse events. In the context of this guideline, this would
include all cases of massive haemorrhage, any peripartum hysterectomy, any case of ruptured vasa praevia and
any unexpected admission to the neonatal intensive care unit.
19 of 26
Any lack of compliance with the care bundle in a woman with a previous caesarean section and either
placenta praevia or a low anterior placenta should also be reported locally.
10.4 Auditable standards

Surgical support at caesarean sections on women with placenta praevia and placenta accreta has been
addressed in the reports of the Confidential Enquiries into Maternal Deaths.1,10 The substandard care
associated with these reports focuses us on areas that may be suitable for audit in everyday working practice,
with care given being compared with those standards identified in these reports.
Women with placenta praevia/placenta accreta could be subjected to clinical audit of the following:
Was the diagnosis anticipated? If so:
Was there adequate work-up (e.g. avoiding/treating anaemia)?
Was the antenatal imaging performed according to hospital policy?
Was the delivery plan appropriate for the clinical situation?

Were sufficiently experienced personnel present?
Were appropriate surgical measures taken?
Was resuscitation quick and effective?
Were appropriate fluids infused?

Was appropriate monitoring instituted?
Specifically for placenta accreta, were all elements of the care bundle satisfied before elective surgery?
consultant obstetrician planned and directly supervising delivery
consultant anaesthetist planned and directly supervising anaesthetic at delivery

blood and blood products available
multidisciplinary involvement in preoperative planning
discussion and consent includes possible interventions (such as hysterectomy, leaving the placenta in place,
cell salvage and interventional radiology)

local availability of a level 2 critical care bed.
With regard to vasa praevia, further information is required to establish the true incidence, associated risk
factors and the sensitivity and specificity of prenatal diagnosis with ultrasound. Any screening programme,
whether selective or universal, should therefore be audited and reported, including maternal and
fetal/neonatal outcomes. The following should be audited:
incidence of vasa praevia
sensitivity and specificity of ultrasound
false positive and false negative rates
incidence of antenatal admission

use of corticosteroids for fetal lung maturity
timing of delivery
mode of delivery
perinatal outcome
maternal morbidity.
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APPENDIX
Governance Advice No.1: Development of RCOG Green-Top Guidelines (available on the RCOG website
and limitations unique to the institution and variations in local populations. It is hoped that this process
of local ownership will help to incorporate these guidelines into routine practice. Attention is drawn to
areas of clinical uncertainty where further research may be indicated.

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
25 of 26

development group
Gynaecologists by:
Dr T A Johnston FRCOG, Birmingham and Miss S Paterson-Brown FRCS FRCOG, London.
and peer reviewed by: Dr L Bowyer FRCOG, Australia; Ms L M M Duley FRCOG, Bradford; Mr D I Fraser MRCOG,
Norwich; Mr H F Habeeb MRCOG, Gillingham; Dr S Macphail MRCOG, Newcastle Upon Tyne; Mr K T Moriarty
MRCOG, Coventry; Professor P J Steer FRCOG, London; Dr B K Strachan MRCOG, Bristol; Professor B Thilaganathan
MRCOG, London; Inner Vision Womens Ultrasound; International Vasa Previa Foundation; Obstetric Anaesthetists
Association; RCOG Consumers Forum; Royal College of Midwives; Royal College of Radiologists; Vasa Praevia Raising
Awareness
The Guidelines Committee lead reviewers were: Dr K R Langford FRCOG, London and Mrs C E Overton FRCOG,
Bristol.
The guidelines review process will commence in 2014 unless evidence requires an earlier review.
DISCLAIMER
This means that RCOG guidelines are unlike protocols or guidelines issued by employers, as they are not intended to
26 of 26
The Management of Third- and

Fourth-Degree Perineal Tears
June 2015
The Management of Third- and Fourth-Degree Perineal Tears

This is the third edition of this guideline, which was previously published in July 2001 and March 2007
under the same title.
Classification and terminology

How should obstetric anal sphincter injury be classified?
It is recommended that the classification outlined in this guideline be used when describing any
obstetric anal sphincter injury.
If there is any doubt about the degree of third-degree tear, it is advisable to classify it to the higher
degree rather than the lower degree.
Prediction and prevention of obstetric anal sphincter injury

Can obstetric anal sphincter injury be predicted?
Clinicians need to be aware of the risk factors for obstetric anal sphincter injuries (OASIS).
Clinicians should be aware, however, that risk factors do not allow the accurate prediction of OASIS.
P
D
Can obstetric anal sphincter injury be prevented?

Clinicians should explain to women that the evidence for the protective effect of episiotomy is
conflicting. [New 2015]
Mediolateral episiotomy should be considered in instrumental deliveries. [New 2015]
Where episiotomy is indicated, the mediolateral technique is recommended, with careful attention
to ensure that the angle is 60 degrees away from the midline when the perineum is distended.
Perineal protection at crowning can be protective. [New 2015]
Warm compression during the second stage of labour reduces the risk of OASIS. [New 2015]
Identification of obstetric anal sphincter injuries

How can the identification of obstetric anal sphincter injuries be improved?
All women having a vaginal delivery are at risk of sustaining OASIS or isolated rectal buttonhole
tears. They should therefore be examined systematically, including a digital rectal examination, to
assess the severity of damage, particularly prior to suturing.
Repair of OASIS
General principles
Repair of third- and fourth-degree tears should be conducted by an appropriately trained clinician
or by a trainee under supervision.
Repair should take place in an operating theatre, under regional or general anaesthesia, with good
lighting and with appropriate instruments. If there is excessive bleeding, a vaginal pack should
2 of 19
be inserted and the woman should be taken to the theatre as soon as possible. Repair of OASIS
in the delivery room may be performed in certain circumstances after discussion with a senior
obstetrician. [New 2015]
Figure of eight sutures should be avoided during the repair of OASIS because they are haemostatic
in nature and may cause tissue ischaemia. [New 2015]
A rectal examination should be performed after the repair to ensure that sutures have not been
inadvertently inserted through the anorectal mucosa. If a suture is identified it should be removed.
[New 2015]
P
P
Which techniques should be used to accomplish the repair of the anorectal mucosa?
The torn anorectal mucosa should be repaired with sutures using either the continuous or
interrupted technique. [New 2015]
Which techniques should be used to accomplish the repair of the internal anal sphincter?
Where the torn internal anal sphincter (IAS) can be identified, it is advisable to repair this separately
with interrupted or mattress sutures without any attempt to overlap the IAS.
Which techniques should be used to repair the external anal sphincter?

For repair of a full thickness external anal sphincter (EAS) tear, either an overlapping or an end-toend (approximation) method can be used with equivalent outcomes.
For partial thickness (all 3a and some 3b) tears, an end-to-end technique should be used. [New 2015]
Choice of suture materials

Which suture materials should be used to accomplish repair of obstetric anal sphincter injuries?
3-0 polyglactin should be used to repair the anorectal mucosa as it may cause less irritation and
discomfort than polydioxanone (PDS) sutures. [New 2015]
When repair of the EAS and/or IAS muscle is being performed, either monofilament sutures such as
3-0 PDS or modern braided sutures such as 2-0 polyglactin can be used with equivalent outcomes.
When obstetric anal sphincter repairs are being performed, the burying of surgical knots beneath
the superficial perineal muscles is recommended to minimise the risk of knot and suture migration
to the skin.
Surgical competence
Who should repair obstetric anal sphincter injury?
Obstetric anal sphincter repair should be performed by appropriately trained practitioners.
Formal training in anal sphincter repair techniques should be an essential component of obstetric
training.
Postoperative management
How should women with obstetric anal sphincter injury be managed postoperatively?
The use of broad-spectrum antibiotics is recommended following repair of OASIS to reduce the risk
of postoperative infections and wound dehiscence.
3 of 19
The use of postoperative laxatives is recommended to reduce the risk of wound dehiscence.
Bulking agents should not be given routinely with laxatives. [New 2015]
Local protocols should be implemented regarding the use of antibiotics, laxatives, examination
and follow-up of women with obstetric anal sphincter repair.
Women should be advised that physiotherapy following repair of OASIS could be beneficial.
Women who have undergone obstetric anal sphincter repair should be reviewed at a convenient
time (usually 612 weeks postpartum). Where possible, review should be by clinicians with a
special interest in OASIS.
If a woman is experiencing incontinence or pain at follow-up, referral to a specialist gynaecologist
or colorectal surgeon should be considered.
P
P
P
P
Prognosis
What is the prognosis following surgical repair?
Women should be advised that 6080% of women are asymptomatic 12 months following delivery
and EAS repair.
Future deliveries
What advice should women be given following an obstetric anal sphincter injury concerning future
pregnancies and mode of delivery?
All women who sustained OASIS in a previous pregnancy should be counselled about the mode of
delivery and this should be clearly documented in the notes.
The role of prophylactic episiotomy in subsequent pregnancies is not known and therefore an
episiotomy should only be performed if clinically indicated.
All women who have sustained OASIS in a previous pregnancy and who are symptomatic or have
abnormal endoanal ultrasonography and/or manometry should be counselled regarding the option
of elective caesarean birth.
Risk management
What processes and policies should be in place for women who have sustained obstetric OASIS?
Units should have a clear protocol for the management of OASIS. [New 2015]
Documentation of the anatomical structures involved, the method of repair and the suture materials
should be made.
The woman should be fully informed about the nature of her tear and the offer of follow-up should
be made, all supported by relevant written information.
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1.
Purpose and scope
The purpose of this guideline is to provide evidence-based guidance on the diagnosis, management
and treatment of third- and fourth-degree perineal tears (obstetric anal sphincter injuries, referred to
as OASIS).
2.
The reported rate of OASIS (in singleton, term, cephalic, vaginal first births) in England has tripled
from 1.8% to 5.9% from 2000 to 2012.1 The overall incidence in the UK is 2.9% (range 08%), with an
incidence of 6.1% in primiparae compared with 1.7% in multiparae.2
With increased awareness and training, there appears to be an increase in the detection of anal sphincter
injuries.1 A trend towards an increasing incidence of third- or fourth-degree perineal tears does not
necessarily indicate poor quality care. It may indicate, at least in the short term, an improved quality of
care through better detection and reporting.3
Obstetricians who are appropriately trained are more likely to provide a consistent, high standard of anal
sphincter repair and contribute to reducing the extent of morbidity and litigation associated with anal
sphincter injury.4
3.
The Cochrane Library was searched for relevant randomised controlled trials, systematic reviews and
meta-analyses. MEDLINE and EMBASE were also searched from 20062014 and the date of the last search
was November 2014. NICE Evidence Search, Trip and the National Guideline Clearinghouse were also
searched for relevant guidelines and reviews.
The databases were searched using the relevant Medical Subject Headings (MeSH), including all
subheadings, and this was combined with a keyword search that included the terms: human, female,
childbirth, obstetric, perineum, third degree, fourth degree, anal sphincter, tear, injury,
rupture, damage, incontinence, faecal, anal, repair, surgery and sutures.
Guidelines Network. Where possible, recommendations are based on and explicitly linked to the evidence
that supports them. Areas lacking evidence are highlighted and annotated as good practice points.
4.
Classification and terminology
4.1 How should obstetric anal sphincter injury be classified?

It is recommended that the classification outlined in this guideline be used when describing any
obstetric anal sphincter injury.
If there is any doubt about the degree of third-degree tear, it is advisable to classify it to the higher
degree rather than the lower degree.
The following classification described by Sultan5 has been adopted by the International
Consultation on Incontinence6 and the RCOG:
First-degree tear: Injury to perineal skin and/or vaginal mucosa.
Evidence
level 4
Second-degree tear: Injury to perineum involving perineal muscles but not involving the anal
sphincter.
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Third-degree tear: Injury to perineum involving the anal sphincter complex:

Grade 3a tear: Less than 50% of external anal sphincter (EAS) thickness torn.
Grade 3b tear: More than 50% of EAS thickness torn.
Grade 3c tear: Both EAS and internal anal sphincter (IAS) torn.
Fourth-degree tear: Injury to perineum involving the anal sphincter complex (EAS and IAS) Evidence
level 4
and anorectal mucosa.
The lining of the anal canal varies along its length due to its embryological derivation. The
proximal anal canal is lined with rectal mucosa (columnar epithelium) whereas the distal 11.5
cm of the anal canal is lined with modified squamous epithelium.7 To avoid confusion, the
term anorectal mucosa has been used instead of anal epithelium throughout this guideline.
Obstetric anal sphincter injuries (OASIS) encompass both third- and fourth-degree perineal tears.
Anal incontinence is defined as the complaint of involuntary loss of flatus and/or faeces affecting
quality of life.8
The IAS plays a role in the maintenance of continence. In a prospective study involving followup of 531 women after OASIS, those with a grade 3c/4 tear had a significantly poorer outcome
(P < 0.05) compared with women with a grade 3a/3b tear with respect to the development
of defaecatory symptoms, anal manometry results and the associated quality of life.9 Another
prospective follow-up study of 125 women who had OASIS reported a significantly increased
incidence of anal incontinence (P < 0.001) in women who had 3b and fourth-degree compared Evidence
with 3a tears.10 A third prospective study of 500 women followed up at 3 months showed that level 2+
IAS defect thickness (partial thickness defect greater than one quadrant or full thickness IAS
defect) was predictive of severe incontinence (OR 5.1, 95% CI 1.522.9).11 A retrospective,
descriptive cross-sectional study of 66 women who were followed up for a mean of 5 years
showed that women with combined IAS and EAS injury (n = 6) had worse faecal incontinence
(P < 0.05) and lower anal pressures (P = 0.04) than women with isolated EAS injury (n = 10).12
Inclusion of the IAS in the classification above would allow differentiation between future incontinence
related to IAS injury and that related to EAS injury alone. It is recognised that identification of the IAS
may be difficult in acute obstetric trauma, but every attempt should nonetheless be made to exclude
and document injury to the IAS. Recording the degree of EAS damage (more or less than 50%) should
be possible in all cases. If one is unsure whether it is more than 50% then it should be classified as 3b to
avoid underestimation.
Rectal buttonhole tear

If the tear involves the rectal mucosa with an intact anal sphincter complex, it is by definition
not a fourth-degree tear. This has to be documented as a rectal buttonhole tear. If not Evidence
level 4
recognised and repaired, this type of tear may lead to a rectovaginal fistula.13
5.
Prediction and prevention of obstetric anal sphincter injury
5.1 Can obstetric anal sphincter injury be predicted?

Clinicians need to be aware of the risk factors for OASIS.
Clinicians should be aware, however, that risk factors do not allow the accurate prediction of OASIS.
The following risk factors have been identified. There is, however, considerable difference in Evidence
level 3
the reported risks for the same risk factor.1,1416
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l Asian ethnicity1 (OR 2.27, 95% CI 2.142.41)

l nulliparity15 (relative risk [RR] 6.97, 95% CI 5.408.99)
l birthweight greater than 4 kg1 (OR 2.27, 95% CI 2.182.36)
l shoulder dystocia1 (OR 1.90, 95% CI 1.722.08)
l occipito-posterior position15 (RR 2.44, 95% CI 2.072.89)
l prolonged second stage of labour:15
duration of second stage between 2 and 3 hours (RR 1.47, 95% CI 1.201.79)
duration of second stage between 3 and 4 hours (RR 1.79, 95% CI 1.432.22)
m duration of second stage more than 4 hours (RR 2.02, 95% CI 1.622.51)
l instrumental delivery:1
m ventouse delivery without episiotomy (OR 1.89, 95% CI 1.742.05)
m ventouse delivery with episiotomy (OR 0.57, 95% CI 0.510.63)
m forceps delivery without episiotomy (OR 6.53, 95% CI 5.577.64)
m forceps delivery with episiotomy (OR 1.34, 95% CI 1.211.49).
m
Risk factors for OASIS were assessed in a retrospective study of 123 women who sustained
third- or fourth-degree tears and 123 controls without OASIS. The authors concluded that a Evidence
scoring system based on the reported risks from meta-analyses to identify women at risk is level 2
unlikely to be of practical use.16
There is limited evidence in relation to the risk of sustaining recurrent OASIS. A large
retrospective cohort study showed an odds ratio of 5.51 (95% CI 5.185.86) of sustaining
recurrent OASIS in the subsequent pregnancy.17 Risk factors for sustaining recurrent OASIS in Evidence
level 2++
the subsequent pregnancy include Asian ethnicity (OR 1.59, 95% CI 1.481.71), forceps delivery
(OR 4.02, 95% CI 3.514.60) and birthweight more than 4 kg (OR 2.29, 95% CI 2.162.43).
5.2 Can obstetric anal sphincter injury be prevented?

Clinicians should explain to women that the evidence for the protective effect of episiotomy
is conflicting.
Mediolateral episiotomy should be considered in instrumental deliveries.
Where episiotomy is indicated, the mediolateral technique is recommended, with careful attention
to ensure that the angle is 60 degrees away from the midline when the perineum is distended.
Perineal protection at crowning can be protective.
Warm compression during the second stage of labour reduces the risk of OASIS.
Episiotomy
The evidence that episiotomy prevents OASIS and/or anal incontinence is conflicting. Hospital
Episode Statistics data have shown that episiotomy is associated with the lowest risk of OASIS.1
Some studies have shown a protective effect while others have not.1820
Evidence
level 2
However, there is evidence that a mediolateral episiotomy should be performed with

instrumental deliveries as it appears to have a protective effect on OASIS.1,10
The angle of the episiotomy away from the midline has been shown to be important in reducing
the incidence of OASIS,21,22 with the National Institute for Health and Care Excellence (NICE)
recommending an angle of 4560 degrees from the midline.23 Nonetheless, a prospective Evidence
level 3
study by Kalis et al. suggests that a resultant suture angle of 4060 degrees is more important
than the incision angle of 4560 degrees.24
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However, this can be difficult to achieve at crowning when the perineum is fully stretched.
An episiotomy performed at 40 degrees results in a post-delivery angle of 22 degrees, which is
too close to the midline to be maximally protective. A 60-degree episiotomy from the centre
of the introitus results in a post-delivery angle of 45 degrees.24 A study has demonstrated
that doctors and midwives were unable to correctly estimate angles and lengths required Evidence
level 3
to perform safe mediolateral episiotomies.25 None of the midwives and only 22% of doctors
were able to perform a truly mediolateral episiotomy. Only 13% of episiotomies were at a postdelivery angle of 40 degrees or more.26 Special scissors designed to ensure an incision angle of
60 degrees have been shown to be effective in achieving the correct angle.27,28
Perineal protection
The NICE Intrapartum care guideline23 found no difference between hands poised and hands on the
perineum as prevention for OASIS. However, more recently there have been interventional studies using
programmes which have successfully reduced OASIS rates, all of which have described manual perineal
protection/hands on techniques.29,30
These include:
1. Left hand slowing down the delivery of the head.
2. Right hand protecting the perineum.
3. Mother NOT pushing when head is crowning (communicate).
4. Think about episiotomy (risk groups and correct angle).
Evidence
level 2+
The best method of perineal support/protection is unclear, with the Ritgen manoeuvre
(delivering the fetal head, using one hand to pull the fetal chin from between the maternal Evidence
anus and the coccyx and the other on the fetal occiput to control speed of delivery) no better level 1+
than standard care (not specifically defined but it included perineal protection/hands on).31
However, the positive effects of perineal support29,30 suggest that this should be promoted, as
opposed to hands off or poised, in order to protect the perineum and reduce the incidence Evidence
level 2+
of OASIS.
Warm compress
A Cochrane review has found the application of warm compresses during the second stage of
labour to have a significant effect on reducing OASIS.32 The analysis, comprising two studies
(1525 women), found that warm compresses significantly reduced the risk of third- and fourth- Evidence
level 1++
degree tears (RR 0.48, 95% CI 0.280.84). The intervention involves holding the compress on
the perineum continuously during and between contractions.
Perineal massage during antenatal period and in second stage of labour

Perineal massage during the last month of pregnancy has been suggested as a possible way of
enabling perineal tissue to expand more easily during birth. The Cochrane review33 of four
trials (2497 women) showed that perineal massage undertaken by the woman or her partner
was associated with an overall reduction in the incidence of trauma requiring suturing (four
trials, 2480 women, RR 0.91, 95% CI 0.860.96, number needed to treat to benefit [NNTB] 15 Evidence
[1036]). Women practising perineal massage were less likely to have an episiotomy (four trials, level 1
2480 women, RR 0.84, 95% CI 0.740.95, NNTB 21 [1275]). These findings were significant
for women without previous vaginal birth only. No differences were seen in the incidence of
first- or second-degree perineal tears or third-/fourth-degree perineal trauma (four trials, 2480
women, RR 0.81, 95% CI 0.561.18).
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The data regarding the protective effect of perineal massage in the second stage of labour are
inconclusive; a small randomised trial found that the rates of intact perineums, first- and seconddegree tears and episiotomies were similar in the massage and control groups. There were Evidence
level 1
fewer third-degree tears in the massage group (12 [1.7%] versus 23 [3.6%]; absolute risk 2.11,
RR 0.45, 95% CI 0.230.93), although the trial was underpowered to measure this outcome.32,34
6.
Identification of obstetric anal sphincter injuries
6.1 How can the identification of obstetric anal sphincter injuries be improved?
All women having a vaginal delivery are at risk of sustaining OASIS or isolated rectal buttonhole
tears. They should therefore be examined systematically, including a digital rectal examination, to
assess the severity of damage, particularly prior to suturing.
According to NICE perineal care guidance,23 before assessing for genital trauma, healthcare professionals should:
l explain to the woman what they plan to do and why
l offer inhalational analgesia
l ensure good lighting
l position the woman so that she is comfortable and so that the genital structures can be seen clearly.
The examination should be performed gently and may be done in the immediate period following
birth. If genital trauma is identified following birth, further systematic assessment should be carried out,
including a rectal examination.
Systematic assessment of genital trauma should include:13
l further explanation of what the healthcare professional plans to do and why
l confirmation by the woman that effective local or regional analgesia is in place
l visual assessment of the extent of perineal trauma to include the structures involved, the apex of
the injury and assessment of bleeding

l a rectal examination to assess whether there has been any damage to the external or internal anal
sphincter if there is any suspicion that the perineal muscles are damaged.
The woman should usually be in the lithotomy position to allow adequate visual assessment of the
degree of the trauma and for the repair itself. This position should only be maintained for as long as is
necessary for the systematic assessment and repair. The systematic assessment and its results should be
fully documented, preferably pictorially.
The woman should be referred to a more experienced healthcare professional if uncertainty exists as to
the nature or extent of the trauma sustained. All relevant healthcare professionals should attend handson training in perineal/genital assessment and repair and ensure that they maintain these skills.
Following vaginal delivery, anal sphincter and anorectal mucosal injury cannot be excluded
without performing a rectal examination. With increased awareness and training in Evidence
examination and diagnosis, there appears to be an increase in the detection of OASIS;4 one level 2+
observational study showed that increased vigilance can double the detection rate.35
Since the introduction of endoanal ultrasound, sonographic abnormalities of the anal sphincter
(occult injuries) have been identified in 33% of women following vaginal delivery.36 However,
when endoanal ultrasound was performed immediately following delivery, the detection
rate of OASIS was not significantly increased compared with clinical examination alone.37 Evidence
level 3
As there are current limitations in availability, image quality, interpretation skills and patient
acceptability, the use of endoanal ultrasound in detecting anal sphincter injuries immediately
after delivery should be viewed as a research tool.
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7.
Repair of OASIS
7.1 General principles

Repair of third- and fourth-degree tears should be conducted by an appropriately trained clinician
or by a trainee under supervision.
Repair should take place in an operating theatre, under regional or general anaesthesia, with
good lighting and with appropriate instruments. If there is excessive bleeding, a vaginal pack
should be inserted and the woman should be taken to the theatre as soon as possible. Repair
of OASIS in the delivery room may be performed in certain circumstances after discussion with
a senior obstetrician.
P
P
Figure of eight sutures should be avoided during the repair of OASIS because they are haemostatic
in nature and may cause tissue ischaemia.
A rectal examination should be performed after the repair to ensure that sutures have not been
inadvertently inserted through the anorectal mucosa. If a suture is identified it should be removed.
Involvement of a colorectal surgeon will be dependent on local protocols, expertise and

availability as the majority of colorectal surgeons are not familiar with acute OASIS.38 Repair
in an operating theatre will allow the repair to be performed under optimal conditions with Evidence
appropriate instruments, adequate light and an assistant. Regional or general anaesthesia will level 4
facilitate identification of the full extent of the injury and enable retrieval of the retracted ends
of the torn anal sphincter.13
7.2 Which techniques should be used to accomplish the repair of the anorectal mucosa?
The torn anorectal mucosa should be repaired with sutures using either the continuous or
interrupted technique.
Traditionally, the technique described to repair the torn anal mucosa was to insert interrupted
sutures with the knot tied within the anal canal. However, this was recommended when catgut
was in use to minimise tissue reaction and infection.39 With the availability of polyglactin Evidence
suture material this is no longer necessary as it dissolves by hydrolysis. Whichever technique level 4
is used, figure of eight sutures should be avoided during repair of the anal mucosa as they can
cause ischaemia.
7.3 Which techniques should be used to accomplish the repair of the internal anal sphincter?
Where the torn IAS can be identified, it is advisable to repair this separately with interrupted or
mattress sutures without any attempt to overlap the IAS.
In 1999, Sultan first described separate repair of the IAS during primary repair using the endto-end technique.40 Since then, a number of studies have demonstrated that a separate repair Evidence
level 2+
of the IAS improves the likelihood of subsequent anal continence.912
7.4 Which techniques should be used to repair the external anal sphincter?
For repair of a full thickness EAS tear, either an overlapping or an end-to-end (approximation)
method can be used with equivalent outcomes.
For partial thickness (all 3a and some 3b) tears, an end-to-end technique should be used.
A Cochrane review demonstrated no difference in outcomes between an end-to-end and an Evidence

overlap repair and therefore the end-to-end technique can be used for all external sphincter tears.41 level 1++
10 of 19
This Cochrane review on the method of repair for third- and fourth-degree tears examined six
trials involving 588 women.41 There was considerable heterogeneity in the outcome measures,
time points and reported results. Meta-analyses showed that there was no statistically significant
difference in perineal pain (RR 0.08, 95% CI 0.001.45, one trial, 52 women), dyspareunia
(average RR 0.77, 95% CI 0.481.24, two trials, 151 women) or flatus incontinence (RR 1.14, 95% CI
0.582.23, three trials, 256 women) between the two repair techniques at 12 months. However,
it showed a statistically significant lower incidence of faecal urgency (RR 0.12, 95% CI 0.020.86,
one trial, 52 women) and lower anal incontinence score (standardised mean difference [SMD]
0.70, 95% CI 1.26 to 0.14, one trial, 52 women) in the overlap group. The overlap technique
was also associated with a statistically significant lower risk of deterioration of anal incontinence Evidence
level 4
symptoms over 12 months (RR 0.26, 95% CI 0.090.79, one trial, 41 women). There was no
significant difference in quality of life. At 36 months follow-up, there was no difference in flatus
incontinence (average RR 1.12, 95% CI 0.631.99, one trial, 68 women) or faecal incontinence
(average RR 1.01, 95% CI 0.342.98, one trial, 68 women). The overlap technique can only be
used for full thickness external sphincter tears to allow the torn ends to be overlapped without
tension and this technique has only been described to repair full thickness EAS tears. As two
free ends of the muscle are needed for a proper overlap repair, overlapping of partial thickness
EAS tears would exert undue tension on the repair. Therefore an end-to-end repair should be
performed in a partial thickness EAS tear (3a and some 3b).40
8. Choice of suture materials
8.1 Which suture materials should be used to accomplish repair of obstetric anal sphincter
injuries?
3-0 polyglactin should be used to repair the anorectal mucosa as it may cause less irritation and
discomfort than polydioxanone (PDS) sutures.
When repair of the EAS and/or IAS muscle is being performed, either monofilament sutures such as
3-0 PDS or modern braided sutures such as 2-0 polyglactin can be used with equivalent outcomes.
When obstetric anal sphincter repairs are being performed, the burying of surgical knots beneath
the superficial perineal muscles is recommended to minimise the risk of knot and suture migration
to the skin.
The use of PDS sutures for repair of the anorectal mucosa should be avoided as they take Evidence
level 4
longer to dissolve and may cause discomfort in the anal canal.39
There are no systematic reviews available to evaluate the best suture material for the repair of
the EAS. The only randomised controlled trial comparing Vicryl (3-0 polyglactin; Ethicon,
Somerville, New Jersey, USA) and PDS reported no significant difference in suture-related
morbidity at 6 weeks and bowel symptoms at 6 and 12 months.42 There are no systematic
reviews or randomised studies available to evaluate the type of suture materials used in the
repair of the IAS. Similar to EAS repair, the use of fine suture sizes such as 3-0 PDS and 2-0
polyglactin (Vicryl) may cause less irritation and discomfort.
Evidence
level 1
Suture migration is recognised when a woman complains of irritation/pain around the

perineum after repair of OASIS. This may also be detected at the time of examination where
the exposed ends of suture material are seen or felt on digital examination. Exposed suture
ends can be trimmed in the outpatient setting under local anaesthesia. The reported incidence
of suture migration is about 7% and this can be reduced by trimming the suture ends and
burying the knots in the deep and superficial perineal muscles.42
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9.
Surgical competence
9.1 Who should repair obstetric anal sphincter injury?

Obstetric anal sphincter repair should be performed by appropriately trained practitioners.
Formal training in anal sphincter repair techniques should be an essential component of obstetric training.
Inexperienced attempts at anal sphincter repair may contribute to maternal morbidity,

especially subsequent anal incontinence. Published randomised controlled trials have
reported residual EAS defects in 1936% overall following repair.4345 The clinical relevance Evidence
level 1
of asymptomatic defects demonstrated by ultrasound is currently unclear, but it has been
suggested that this may be due to inadequate primary repair.9,46
In 2002, a survey of UK consultant obstetricians and trainee obstetricians in two regions
highlighted the deficiency in and their dissatisfaction with their training in the management Evidence
level 3
of third-degree tears.38,47
Repair of third- and fourth-degree perineal tears has now been incorporated in the module
on postpartum problems in the RCOG core training log book.48 Many regions now conduct Evidence
level 4
training workshops involving the use of simulation models.2
10. Postoperative management
10.1 How should women with obstetric anal sphincter injury be managed postoperatively?
The use of broad-spectrum antibiotics is recommended following repair of OASIS to reduce the risk
of postoperative infections and wound dehiscence.
The use of postoperative laxatives is recommended to reduce the risk of wound dehiscence.
Bulking agents should not be given routinely with laxatives.
Local protocols should be implemented regarding the use of antibiotics, laxatives, examination
and follow-up of women with obstetric anal sphincter repair.
Women should be advised that physiotherapy following repair of OASIS could be beneficial.
Women who have undergone obstetric anal sphincter repair should be reviewed at a convenient
time (usually 612 weeks postpartum). Where possible, review should be by clinicians with a
special interest in OASIS.
If a woman is experiencing incontinence or pain at follow-up, referral to a specialist gynaecologist
or colorectal surgeon should be considered.
P
P
P
P
A Cochrane review addressing antibiotic prophylaxis for third- and fourth-degree perineal
tears, comparing prophylactic antibiotics against placebo or no antibiotics, included only one
randomised controlled trial of 147 participants.49 Although the data suggested that prophylactic Evidence
antibiotics help to prevent perineal wound complications following third- or fourth-degree level 1
perineal tears, loss to follow-up was very high. The authors concluded that results should be
interpreted with caution as they are based on one small trial.
No systematic reviews were identified which evaluated the use of postoperative laxatives and
stool softeners. Laxatives are recommended during the postoperative period as passage of a Evidence
hard stool may disrupt the repair.40 Use of stool softeners such as lactulose is recommended level 2+
for about 10 days after the repair.
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One randomised controlled study compared laxatives and bulking agents in the postoperative
period following primary OASIS repair.50 In this study, women in the laxative group had a
significantly earlier and less painful bowel motion and earlier postnatal discharge. There was
no difference in the symptomatic or functional outcome of repair between the two regimens.
The dose of lactulose should be titrated to keep the stool soft but not loose. A randomised
controlled trial of lactulose alone versus lactulose with ispaghula husk (Fybogel, Reckitt
Benckiser, Hull, UK) demonstrated that incontinence in the immediate postpartum period Evidence
level 1
was more frequent (32.86% versus 18.18%; P = 0.03) with the latter regime and therefore
routine prescription of bulking agents and lactulose together is not recommended.51
There was one randomised controlled trial comparing early home biofeedback therapy and
pelvic floor exercises for women who sustained OASIS and this study showed that there was
no added value in using early home biofeedback therapy.52
As there are considerable variations in the use of antibiotics, laxatives and physiotherapy and in
available facilities for follow-up in different hospitals, the follow-up regimen is best designed according
to local facilities.
There were no systematic reviews or randomised controlled trials to indicate the optimal
method of follow-up after OASIS. It is appropriate to review women in the postnatal period
to discuss injury sustained during childbirth, assess symptoms and offer advice on how to
seek help if symptoms develop, offer treatment and/or referral if indicated and offer advice on
future mode of delivery. Use of a validated health-related quality of life questionnaire may be
useful for assessment of women who develop anal incontinence after sustaining OASIS.53 The Evidence
RCOG has produced a patient information leaflet on third- and fourth-degree perineal care level 4
and this, or a suitable alternative, should be given to all women who have had OASIS.54
If facilities are available and resources allow, follow-up of women with OASIS should be in a
dedicated perineal clinic with access to endoanal ultrasonography and anal manometry as this
can aid decision making regarding future delivery.55,56
11. Prognosis
11.1 What is the prognosis following surgical repair?

Women should be advised that 6080% of women are asymptomatic 12 months following delivery
and EAS repair.
Several randomised controlled studies carried out since 2000 comparing overlap and end-toend techniques of EAS repair have reported low incidences of anal incontinence symptoms in Evidence
level 1
both arms,4245 with 6080% of women described as asymptomatic at 12 months.4,42,44,45
12. Future deliveries
12.1 W hat advice should women be given following an obstetric anal sphincter injury
concerning future pregnancies and mode of delivery?
All women who sustained OASIS in a previous pregnancy should be counselled about the mode of
delivery and this should be clearly documented in the notes.
The role of prophylactic episiotomy in subsequent pregnancies is not known and therefore an
episiotomy should only be performed if clinically indicated.
13 of 19
All women who have sustained OASIS in a previous pregnancy and who are symptomatic or have
abnormal endoanal ultrasonography and/or manometry should be counselled regarding the option
of elective caesarean birth.
There were no systematic reviews or randomised controlled trials to suggest the best method
of delivery following OASIS. The risk of sustaining a further third- or fourth-degree tear after
a subsequent delivery is 57%.56,57 The risks of a subsequent vaginal delivery after a third- Evidence
degree tear have been assessed, with 17% of women developing worsening faecal symptoms level 4
after a second vaginal delivery.5861 This seemed to occur if there had been faecal incontinence
beyond 3 months but resolution by 6 months after the index delivery.60
There are no studies to suggest that prophylactic episiotomy in the subsequent delivery would prevent
OASIS. Hence the decision to perform an episiotomy during the subsequent delivery after previous
OASIS needs to be a clinical decision independent of the previous OASIS.
All women who have suffered OASIS should be counselled regarding the mode of delivery
and this should be clearly documented in the notes. If the woman is symptomatic or shows
abnormally low anorectal manometric pressures and/or endoanal ultrasonographic defects,
an elective caesarean section may be considered.39 One prospective study of pregnant women
who previously sustained OASIS evaluated a protocol in which women who had a sonographic Evidence
defect of the external sphincter of more than 30 degrees accompanied by an incremental level 4
squeeze pressure of less than 20 mmHg were offered a caesarean section. All other women
were advised to have a vaginal delivery. Short-term follow-up of this cohort of 73 women
showed that the women who underwent vaginal delivery suffered no significant deterioration
in anal sphincter function or quality of life.56
13. Risk management
13.1 W hat processes and policies should be in place for women who have sustained
obstetric OASIS?
Units should have a clear protocol for the management of OASIS.
Documentation of the anatomical structures involved, the method of repair and the suture materials
should be made.
P
P
The woman should be fully informed about the nature of her tear and the offer of follow-up should
be made, all supported by relevant written information.
There has been a rise in litigation related to OASIS. The majority of cases are related to failure to identify
the injury after delivery, leading to subsequent anal incontinence and rectovaginal and anovaginal
fistulae.62 From 1 April 2000 to 31 March 2010, there were 441 claims in England in which allegations of
negligence were made arising out of obstetric perineal trauma (the fourth highest number of claims in
obstetrics). The total value of those claims, including both damages and legal costs, was estimated to be
31.2 million and 85% of these claims were related to misdiagnosis of perineal trauma.62
At present, the occurrence of OASIS is not considered substandard care because it is a known complication
of vaginal delivery. However, failure to recognise anal sphincter damage or carry out an adequate repair
may be considered substandard care. A poor technique, poor selection of materials or poor healing may
cause a repair to fail.63
Clear documentation, preferably using a drawing, together with providing the woman with an explanation
and patient information leaflet, is important.54
14 of 19
14.
There is a lack of evidence to inform decision making regarding the optimal mode of delivery following
OASIS. This needs to be addressed by encouraging participation in multicentre randomised controlled trials.
Further research is required into patient acceptability of endoanal ultrasound and the interpretation of
endoanal ultrasound in detecting residual anal sphincter defects immediately after primary surgical repair.
The need for secondary surgery in women who have had OASIS should be investigated.
15.
Auditable topics
Organisations should audit the recognition of OASIS and institute a protocol for repair and follow-up.
Collected data should be audited against recommended/locally agreed standards.
l Incidence of OASIS compared with reported incidence of less than 3% in the UK.
l 100% evidence of adequate documentation of systematic examination of the vagina, perineum and
rectum prior to suturing of OASIS.

l 100% of OASIS repaired with documented evidence of type of analgesia, suture material, method of
repair and grade of operator.
l 100% of women with OASIS receiving postoperative advice as per local protocol and follow-up
appointment.
l 100% of doctors and midwives undertaking repair of OASIS have attended recognised training courses.
16.
l Bladder and Bowel Foundation [http://www.bladderandbowelfoundation.org/bowel/].

l Royal College of Obstetricians and Gynaecologists. A third- or fourth-degree tear during birth:
Information for you. London: RCOG; 2015.

References
1.
2.
3.
4.
5.
6.
7.
Gurol-Urganci I, Cromwell DA, Edozien LC, Mahmood TA,

Adams EJ, Richmond DH, et al. Third- and fourth-degree
perineal tears among primiparous women in England
between 2000 and 2012: time trends and risk factors. BJOG
2013;120:151625.
Thiagamoorthy G, Johnson A, Thakar R, Sultan AH. National
survey of perineal trauma and its subsequent management
in the United Kingdom. Int Urogynecol J 2014;25:16217.
Baghurst PA. The case for retaining severe perineal tears
as an indicator of the quality of obstetric care. Aust N Z J
Andrews V, Shelmeridine S, Sultan AH, Thakar R. Anal and
urinary incontinence 4 years after a vaginal delivery. Int
Urogynecol J 2013;24:5560.
Sultan AH. Obstetric perineal injury and anal incontinence.
Clin Risk 1999;5:1936.
Koelbl H, Igawa T, Salvatore S, Laterza RM, Lowry A, Sievert
KD, et al. Pathophysiology of urinary incontinence, faecal
incontinence and pelvic organ prolapse. In: Abrams P,
Cardozo L, Khoury S, Wein A, editors. Incontinence. 5th
ed. [place unknown]: ICUD-EAU; 2013. p. 261359.
Thakar R, Fenner DE. Anatomy of the Perineum and
the Anal Sphincter. In: Sultan AH, Thakar R, Fenner DE,
editors. Perineal and anal sphincter trauma. London:
Springer; 2007. p. 112.
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Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans

B, Lee J, et al.; International Urogynecological Association;
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for female pelvic floor dysfunction. Neurourol Urodyn
2010;29:420.
Roos AM, Thakar R, Sultan AH, Outcome of primary repair
of obstetric anal sphincter injuries (OASIS): does the grade
of tear matter? Ultrasound Obstet Gynecol 2010;36:36874.
De Leeuw JW, Vierhout ME, Struijk PC, Hop WC,
Wallenburg HC. Anal sphincter damage after vaginal
delivery: functional outcome and risk factors for fecal
incontinence. Acta Obstet Gynecol Scand 2001;80:8304.
Mahony R, Behan M, Daly L, Kirwan C, OHerlihy C,
OConnell PR. Internal anal sphincter defect inuences
continence outcome following obstetric anal sphincter
injury. Am J Obstet Gynecol 2007;196:217.e15.
Visscher AP, Lam TJ, Hart N, Felt-Bersma RJ. Fecal
incontinence, sexual complaints, and anorectal function
after third-degree obstetric anal sphincter injury (OASI):
5-year follow-up. Int Urogynecol J 2014;25:60713.
Sultan AH, Kettle C. Diagnosis of Perineal Trauma. In:
Sultan AH, Thakar R, Fenner DE, editors. Perineal and
anal sphincter trauma. London: Springer; 2007. p. 139.
14. Richter HE, Brumfield CG, Cliver SP, Burgio KL, Neely
CL, Varner RE. Risk factors associated with anal sphincter
tear: a comparison of primiparous patients, vaginal births
after cesarean deliveries, and patients with previous
vaginal delivery. Am J Obstet Gynecol 2002;187:11948.
15. McLeod NL, Gilmour DT, Joseph KS, Farrell SA, Luther ER.
Trends in major risk factors for anal sphincter lacerations:
a 10-year study. J Obstet Gynaecol Can 2003;25:58693.
16. Williams A, Tincello DG, White S, Adams EJ, Alfirevic
Z, Richmond DH. Risk scoring system for prediction of
obstetric anal sphincter injury. BJOG 2005;112:10669.
17. Edozien LC, Gurol-Urganci I, Cromwell DA, Adams EJ,
Richmond DH, Mahmood TA, et al. Impact of third- and fourthdegree perineal tears at first birth on subsequent pregnancy
outcomes: a cohort study. BJOG 2014;121:1695704.
18. Fritel X, Schaal JP, Fauconnier A, Bertrand V, Levet C,
Pign A. Pelvic floor disorders 4 years after first delivery:
a comparative study of restrictive versus systematic
episiotomy. BJOG 2008;115:24752.
19. de Vogel J, van der Leeuw-van Beek A, Gietelink D,
Vujkovic M, de Leeuw JW, van Bavel J, et al. The effect of a
mediolateral episiotomy during operative vaginal delivery
on the risk of developing obstetrical anal sphincter injuries.
Am J Obstet Gynecol 2012;206:404.e15.
20. Risnen S, Vehvilinen-Julkunen K, Heinonen S. Need for
and consequences of episiotomy in vaginal birth: a critical
approach. Midwifery 2010;26:34856.
21. Eogan M, Daly L, OConnell PR, OHerlihy C. Does the
angle of episiotomy affect the incidence of anal sphincter
injury? BJOG 2006;113:1904.
22. Stedenfeldt M, Pirhonen J, Blix E, Wilsgaard T, Vonen B,
ian P. Episiotomy characteristics and risks for obstetric
anal sphincter injuries: a case-control study. BJOG
2012;119:72430.
Intrapartum care: Care of healthy women and their
babies during childbirth. NICE clinical guideline 55.
Manchester: NICE; 2007.
24. Kalis V, Landsmanova J, Bednarova B, Karbanova J,
Laine K, Rokyta Z. Evaluation of the incision angle of
mediolateral episiotomy at 60 degrees. Int J Gynaecol
Obstet 2011;112:2204.
25. Tincello DG, Williams A, Fowler GE, Adams EJ, Richmond
DH, Alfirevic Z. Differences in episiotomy technique
between midwives and doctors. BJOG 2003;110:10414.
26. Andrews V, Thakar R, Sultan AH, Jones PW. Are mediolateral
episiotomies actually mediolateral? BJOG 2005;112:11568.
27. Freeman RM, Hollands HJ, Barron LF, Kapoor DS. Cutting
a mediolateral episiotomy at the correct angle: evaluation
of a new device, the Episcissors-60. Med Devices (Auckl)
2014;7:238.
28. Patel RP, Ubale SM. Evaluation of the angled Episcissors-60
episiotomy scissors in spontaneous vaginal deliveries. Med
Devices (Auckl) 2014:7;2536.
29. Hals E, ian P, Pirhonen T, Gissler M, Hjelle S, Nilsen EB,
et al. A multicenter interventional program to reduce
the incidence of anal sphincter tears. Obstet Gynecol
2010;116:9018.
30. Laine K, Skjeldestad FE, Sandvik L, Staff AC. Incidence of
obstetric anal sphincter injuries after training to protect
the perineum: cohort study. BMJ Open 2012;2:e001649.
31. Jnsson ER, Elfaghi I, Rydhstrm H, Herbst A. Modified
Ritgens maneuver for anal sphincter injury at delivery:
a randomized controlled trial. Obstet Gynecol
2008;112:2127.
32. Aasheim V, Nilsen AB, Lukasse M, Reinar LM. Perineal
techniques during the second stage of labour for
reducing perineal trauma. Cochrane Database Syst Rev
2011;(12):CD006672.
33. Beckmann MM, Stock OM. Antenatal perineal massage for
reducing perineal trauma. Cochrane Database Syst Rev
2013;(4):CD005123.
34. Stamp G, Kruzins G, Crowther C. Perineal massage in

labour and prevention of perineal trauma: randomised
controlled trial. BMJ 2001;322:127780.
35. Groom KM, Paterson-Brown S. Can we improve on the
diagnosis of third degree tears? Eur J Obstet Gynecol
Reprod Biol 2002;101:1921.
36. Sultan AH, Kamm MA, Hudson CN, Thomas JM, Bartram
CI. Anal-sphincter disruption during vaginal delivery. N
Engl J Med 1993;329:190511.
37. Andrews V, Sultan AH, Thakar R, Jones PW. Occult
anal sphincter injuriesmyth or reality? BJOG
2006;113:195200.
38. Fernando RJ, Sultan AH, Radley S, Jones PW, Johanson RB.
Management of obstetric anal sphincter injury: a systematic
review & national practice survey. BMC Health Serv Res
2002;2:9.
39. Sultan AH, Thakar R. Lower genital tract and anal
sphincter trauma. Best Pract Res Clin Obstet Gynaecol
2002;16:99115.
40. Sultan AH, Monga AK, Kumar D, Stanton SL. Primary
repair of obstetric anal sphincter rupture using the overlap
technique. Br J Obstet Gynaecol 1999;106:31823.
41. Fernando RJ, Sultan AH, Kettle C, Thakar R. Methods
of repair for obstetric anal sphincter injury. Cochrane
42. Williams A, Adams EJ, Tincello DG, Alfirevic Z, Walkinshaw
SA, Richmond DH. How to repair an anal sphincter injury
after vaginal delivery: results of a randomised controlled
trial. BJOG 2006;113:2017.
43. Fitzpatrick M, Behan M, OConnell PR, OHerlihy C. A
randomized clinical trial comparing primary overlap with
approximation repair of third-degree obstetric tears. Am J
44. Garcia V, Rogers RG, Kim SS, Hall RJ, Kammerer-Doak DN.
Primary repair of obstetric anal sphincter laceration: a
randomized trial of two surgical techniques. Am J Obstet
Gynecol 2005;192:1697701.
45. Fernando RJ, Sultan AH, Kettle C, Radley S, Jones P,
OBrien PM. Repair techniques for obstetric anal sphincter
injuries: a randomized controlled trial. Obstet Gynecol
2006;107:12618.
46. Pronk P, Van Leeuwen E, Albicher C, Dermout SM,
Doornbos JP, Engel AF. Temporal endosonographic
evaluation of anal sphincter integrity after primary repair
for obstetric ruptures: a case for specific training of
obstetricians. Colorectal Dis 2010;12:e1404.
47. Andrews V, Thakar R, Sultan AH. Structured hands-on
training in repair of obstetric anal sphincter injuries
(OASIS): an audit of clinical practice. Int Urogynecol J
Pelvic Floor Dysfunct 2009;20:1939.
48. Royal College of Obstetricians and Gynaecologists. Core
Module 12: Postpartum Problems (the Puerperium)
[https://w w w.rcog.org.uk/globalassets/documents/
careers-and-training/core-curriculum/2013-05-16_core_
module_12.pdf]. Accessed 2014 Oct 2.
49. Buppasiri P, Lumbiganon P, Thinkhamrop J, Thinkhamrop
B. Antibiotic prophylaxis for third- and fourth-degree
perineal tear during vaginal birth. Cochrane Database
Syst Rev 2010;(11):CD005125.
50. Mahony R, Behan M, OHerlihy C, OConnell PR.
Randomized, clinical trial of bowel confinement vs.
laxative use after primary repair of a third-degree obstetric
anal sphincter tear. Dis Colon Rectum 2004;47:127.
51. Eogan M, Daly L, Behan M, OConnell PR, OHerlihy
C. Randomised clinical trial of a laxative alone versus
a laxative and a bulking agent after primary repair of
obstetric anal sphincter injury. BJOG 2007;114:73640.
52. Peirce C, Murphy C, Fitzpatrick M, Cassidy M, Daly L,
OConnell PR, et al. Randomised controlled trial comparing
early home biofeedback physiotherapy with pelvic oor
exercises for the treatment of third-degree tears (EBAPT
Trial). BJOG 2013;120:12407.
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53. Bugg GJ, Kiff ES, Hosker G. A new condition-specific healthrelated quality of life questionnaire for the assessment of
women with anal incontinence. BJOG 2001;108:105767.
54. Royal College of Obstetricians and Gynaecologists. A thirdor fourth-degree tear during birth: Information for you.
London: RCOG; 2015.
55. Fowler G, Williams A, Murphy G, Taylor K, Wood C, Adams
E. How to set up a perineal clinic. The Obstetrician &
Gynaecologist 2009;11:12932.
56. Scheer I, Thakar R, Sultan AH. Mode of delivery after
previous obstetric anal sphincter injuries (OASIS)a
reappraisal? Int Urogynecol J Pelvic Floor Dysfunct
2009;20:1095101.
57. Harkin R, Fitzpatrick M, OConnell PR, OHerlihy C. Anal
sphincter disruption at vaginal delivery: is recurrence
predictable? Eur J Obstet Gynecol Reprod Biol
2003;109:14952.
58. Poen AC, Felt-Bersma RJ, Strijers RL, Dekker GA, Cuesta
MA, Meuwissen SG. Third-degree obstetric perineal tear:
long-term clinical and functional results after primary
repair. Br J Surg 1998;85:14338.
59. Goffeng AR, Andersch B, Andersson M, Berndtsson I,

Hulten L, resland T. Objective methods cannot predict
anal incontinence after primary repair of extensive anal
tears. Acta Obstet Gynecol Scand 1998;77:43943.
60. Bek KM, Laurberg S. Risks of anal incontinence from
subsequent vaginal delivery after a complete obstetric anal
sphincter tear. Br J Obstet Gynaecol 1992;99:7246.
61. Fynes M, Donnelly VS, OConnell PR, OHerlihy C. Cesarean
delivery and anal sphincter injury. Obstet Gynecol
1998;92:496500.
62. NHS Litigation Authority. Ten Years of Maternity Claims.
An Analysis of NHS Litigation Authority Data. London:
NHSLA; 2012.
63. Eddy A. Litigating and quantifying maternal damage
following childbirth. Clin Risk 1999;5:17880.
17 of 19
Appendix I: Explanation of guidelines and evidence levels


low risk of bias

randomised controlled trial rated as 1++, and

1++ or 1+

results; or
2++

low risk of bias
risk of bias
case series
4
Good practice point
Expert opinion
18 of 19

development group
Mr RJ Fernando FRCOG, London; Mr AH Sultan FRCOG, London; Professor RM Freeman FRCOG, Plymouth;
Dr AA Williams MRCOG, Bolton; and Dr EJ Adams FRCOG, Liverpool
Dr AAM Abdou MRCOG, Gloucester; British Maternal and Fetal Medicine Society; British Society of Urogynaecology;
Mrs AHD Diyaf MRCOG, Barnstaple; Mr O Eskandar FRCOG, Barnstaple; Mr DI Fraser FRCOG, Norwich;
Mrs E Hawkins FRCOG, Romford; Professor Emerita C Kettle, Staffordshire University, Stafford;
Mr B Kumar FRCOG, Wrexham; Dr MJ Perera MRCOG, Glasgow; RCOG Womens Network;
Dr S Rutter MRCOG, Rotherham; Dr JR Scott FRCOG, Salt Lake City, Utah, USA; Mr SS Sharma MRCOG, Kings Lynn;
and Mr C Spence-Jones FRCOG, London.
Committee lead reviewers were: Dr M Gupta MRCOG, London; Mrs G Kumar FRCOG, Wrexham;
Mr AT Leather FRCOG, Ipswich; and Dr P Owen FRCOG, Glasgow.
The chairs of the Guidelines Committee were: Dr M Gupta1 MRCOG, London; Dr P Owen2 FRCOG, Glasgow;
and Dr AJ Thomson1 MRCOG, Paisley.
1
co-chairs from June 2014 2 until May 2014.
All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any
conflicts of interest for this guideline is available from: https://www.rcog.org.uk/en/guidelines-researchservices/guidelines/gtg29/.
DISCLAIMER
19 of 19
Management of Genital Herpes

in Pregnancy
October 2014
Management of Genital Herpes in Pregnancy

Foley E, Clarke E, Beckett VA, Harrison S, Pillai A, FitzGerald M, Owen P, Low-Beer N, Patel R.
Guideline date: October 2014
Date of review: by 2018
Guideline development group:

Elizabeth Foley MB BS BSc FRCP FRCOG (lead author),
Consultant in Genitourinary and HIV Medicine, Solent NHS Trust
Emily Clarke BSc BM MSc MRCP (UK),
ST3 Genitourinary Medicine, Solent NHS Trust
Virginia Beckett MB BS BSc FRCOG (lead author on behalf of RCOG),
Consultant Obstetrician and Gynaecologist, Bradford Teaching Hospitals NHS Foundation Trust,
Honorary Senior Lecturer, University of Bradford
Sam Harrison MRCOG,
ST6 Obstetrics and Gynaecology, Bradford Teaching Hospitals NHS Foundation Trust
Anil Pillai MRCP,
Consultant Neonatologist, Bradford Teaching Hospitals NHS Foundation Trust
Mark FitzGerald FRCP,
Lead Editor, BASHH guideline on Management of Genital Herpes (2014),
BASHH Clinical Effectiveness Group,
Consultant Physician in Genitourinary Medicine, Musgrove Park Hospital, Taunton
Philip Owen MD FRCOG,
Chair (to May 2014), RCOG Guidelines Committee,
Consultant Obstetrician and Gynaecologist, Princess Royal Maternity, Glasgow
Naomi Low-Beer MBBS MD MRCOG MEd,
Consultant Gynaecologist, Chelsea and Westminster Hospital NHS Foundation Trust,
Honorary Senior Clinical Lecturer, Imperial College London
Rajul Patel FRCP,
Senior Lecturer, University of Southampton,
Consultant in Genitourinary and HIV Medicine, Solent NHS Trust
Contents
1.
Objective and scope
2.
Search strategy
3.
Background
4.
Management of pregnant women with first episode genital herpes
5.
Management of pregnant women with recurrent genital herpes
10
6.
Management of women with primary or recurrent genital lesions at the onset of labour
11
7.
Genital herpes in preterm prelabour rupture of membranes

(before 37+0 weeks of gestation)
13
8.
Management of HIV-positive women with HSV infection
14
9.
Management of the neonate
15
10. Prevention of postnatal transmission
17
11. Performance measures
18
12. About this guideline
19
References
21
Appendix I
25
Appendix II
26
Whats new in the 2014 Management of Genital Herpes in Pregnancy

guideline?
This guideline has been written as a consensus guideline between the British Association for Sexual
Health and HIV (BASHH) and the Royal College of Obstetricians and Gynaecologists (RCOG)
where previously there were two separate guidelines which in part gave conflicting advice.
Stronger recommendation to offer a vaginal delivery to women with recurrent
genital herpes in pregnancy.
New section on genital herpes in preterm prelabour rupture of membranes.
New section on the management of HIV-positive women with genital herpes.
Flow chart for management of herpes in mother and neonate (Appendix 1).

1. Objective and scope

In 2007, the British Association for Sexual Health and HIV (BASHH) published its guidance on the
management of genital herpes, including a section on management in pregnancy, and the Royal
College of Obstetricians and Gynaecologists (RCOG) published their Green-top Guideline on the
management of genital herpes in pregnancy.1,2 In 2010, a European guideline on the management of
genital herpes was published, which included a section on management in pregnancy.3
In order to achieve consensus, it was decided that a joint BASHH and RCOG guideline on the
management of herpes in pregnancy should be written to update the previous guidance from the two
organisations. For more detailed information on the general management of genital herpes infection
in nonpregnant patients, this guideline should be considered in conjunction with the 2014 BASHH
guideline on the management of genital herpes (currently undergoing consultation).
The scope of this guideline is the inpatient and outpatient management of genital herpes simplex
virus infection in the antenatal, intrapartum and postnatal periods. For the prevention of genital herpes
infection in uninfected mothers during pregnancy, please see the transmission prevention advice in
the 2014 BASHH guideline on the management of genital herpes (currently undergoing consultation).
The population covered by this guideline includes pregnant women with a suspected or confirmed
diagnosis of genital herpes simplex infection in primary or secondary care.
This guideline is aimed at healthcare professionals working in maternity units and departments offering
level 3 care in the management of sexually transmitted infections within the UK. However, the
principles of the recommendations should be adopted across all services, including community care.
Stakeholder involvement
Clinicians from the Herpes Special Interest Group of BASHH and the RCOG Guidelines Committee
have been involved in writing this guideline. The draft guideline was sent for consultation to the
Herpes Viruses Association (HVA) for patient involvement. The guideline was posted on the BASHH
and RCOG websites for 3 months for consultation, with a direct request to the Royal College of
Paediatrics and Child Health (RCPCH) for external peer review.

2. Search strategy
This document was produced in accordance with the guidance set out in the BASHH Clinical
Effectiveness Groups (CEGs) document Framework for guideline development and assessment
(available from: http://www.bashh.org/guidelines). A literature search was performed using
PubMed/MEDLINE, EMBASE, Google, The Cochrane Library and relevant guidelines from January
1981 to January 2014.
A MEDLINE/PubMed and EMBASE search was carried out from January 1981 to January 2014 using
the following search terms/Medical Subject Headings (MeSH): HSV/herpes, genital ulcers,
HSV/herpes pregnancy, neonatal HSV/herpes, HSV/herpes drugs, pregnancy complications:
infectious, Herpes genitalis and Herpes simplex diagnosis. The search was limited to humans and
the English language. For some specific recommendations, an additional MEDLINE/PubMed search
was performed when necessary.
A Google search was performed in January 2014 with the search term HSV guideline(s) and all
relevant documents of the first 150 search results were reviewed. A search of The Cochrane Library
included the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects
and Cochrane Central Register of Controlled Trials.
The following guidelines were reviewed in detail: 2010 European guideline for the management of
genital herpes; 2007 BASHH guidance on the management of genital herpes; and the 2007 RCOG
Green-top Guideline on the management of genital herpes in pregnancy.
The members of the guideline development group selected studies relevant to the scope of the
guideline. Article titles and abstracts were reviewed and if relevant the full-text article obtained.
Priority was given to randomised controlled trial and systematic review evidence and, where possible,
recommendations were made and graded on the basis of the best available evidence (Appendix 2).
In areas where evidence is lacking, recommendations based on consensus opinion within the writing
group have been made.

3. Background
Neonatal herpes is a very rare but serious viral infection with a high morbidity and mortality.4 It is
classified into three subgroups in the infant depending on the site of infection:
disease localised to skin, eye and/or mouth

local central nervous system (CNS) disease (encephalitis alone)
disseminated infection with multiple organ involvement.
Disease localised to skin, eye and/or mouth

Infants who present with symptoms localised to the skin, eye or mouth alone have the best prognosis
and represent approximately 30% of neonatal herpes infections.5 With appropriate antiviral treatment,
neurological and/or ocular morbidity is less than 2%.6
Local CNS disease and disseminated infection

70% of infants with neonatal herpes have disseminated and/or CNS infection and approximately 60%
of infants with local CNS and/or disseminated disease will present without skin, eye and/or mouth
infection.5 Infants with local CNS disease often present late (generally between 10 days and 4 weeks
of age). With antiviral treatment, mortality from local CNS disease is around 6% and neurological
morbidity (which may be lifelong) is 70%. Disseminated disease carries the worst prognosis; with
appropriate antiviral treatment, mortality is around 30% and 17% have long-term neurological
sequelae. The poor outcomes of disseminated and local CNS disease have been attributed to delays
between symptom onset and treatment.6
Neonatal infection occurs as the result of an infection at the time of birth; in contrast, congenital
herpes is extremely rare and occurs by transfer of infection in utero.
Incidence
Neonatal herpes is rare in the UK, in contrast to some other European countries and the USA. Active
surveillance by the British Paediatric Surveillance Unit (BPSU) between 1986 and 1991 found 76
cases over the five-and-a-half-year surveillance period with an incidence of 1.65/100 000 live births
annually (95% CI 1.32.0).7 Subsequent surveillance from 2004 to 2006 showed an approximate
doubling of incidence with 86 cases seen over the three-year surveillance period.5 This increase may
reflect the rise in the prevalence of sexually transmitted infections, demographic and social changes
within the general population and improvements in diagnostic techniques.5 Further published
incidence data are awaited.
The incidence in the UK is around 50% of that reported from other European countries.8 In the USA,
the average reported incidence is 1 in 15 000, but there is considerable variation between populations
and rates of up to 1 in 7500 have been reported in certain deprived inner-city populations.6,9
Aetiology
Neonatal herpes may be caused by herpes simplex virus type 1 (HSV-1) or herpes simplex virus type
2 (HSV-2) as either viral type can cause genital herpes in the mother. Approximately 50% of neonatal
herpes is due to HSV-1 and 50% due to HSV-2.5 Most cases of neonatal herpes occur as a result of
direct contact with infected maternal secretions, although in 25% of cases a possible source of
postnatal infection was identified, usually a close relative of the mother.5,7 Postnatal infection may
occur as a result of exposure to oro-labial herpes infection.
Transmission
Factors associated with transmission include the type of maternal infection (primary or recurrent),
the presence of transplacental maternal neutralising antibodies, the duration of rupture of membranes
before delivery, the use of fetal scalp electrodes and the mode of delivery.6,9 The risks are greatest
when a woman acquires a new infection (primary genital herpes) in the third trimester, particularly
within 6 weeks of delivery, as viral shedding may persist and the baby is likely to be born before the
development of protective maternal antibodies.6,9
Rarely, congenital herpes may occur as a result of transplacental intrauterine infection. Case reports
suggest that the skin, eyes and CNS may be affected and there may be fetal growth restriction or
fetal death.1012
Disseminated herpes is more common in preterm infants and occurs almost exclusively as a result of
primary infection in the mother.
Although recurrent genital herpes is associated with a very low risk of neonatal herpes, recurrent herpes
at the time of delivery, which is commonly asymptomatic or unrecognised, may cause the localised
forms of neonatal herpes: both local CNS disease and skin, eye and mouth infection. Transplacentally
acquired HSV antibodies do not prevent herpes virus spreading to the brain of the neonate.13
Data from the USA suggest that around 2% of women acquire genital HSV infection in pregnancy4
and most of these maternal infections are asymptomatic or unrecognised.4,9 However, acquisition in
the UK in pregnancy may vary markedly given differing rates of neonatal herpes between the UK and
USA. It may be difficult to distinguish clinically between recurrent and primary genital HSV infections,
as many first episode HSV infections are not true primary infections.14
Disseminated herpes infection in the mother

Disseminated herpes, which may present with encephalitis, hepatitis, disseminated skin lesions or a
combination of these conditions, is rare in adults. However, it has been more commonly reported in
pregnancy, particularly in the immunocompromised. The maternal mortality associated with this
condition is high.15 All immunocompromised women, such as those infected with the HIV virus, are
at increased risk of more severe and frequent symptomatic recurrent episodes of genital herpes during
pregnancy and of asymptomatic shedding of HSV at term.16,17 As co-infection with HSV and HIV
results in an increased replication of both viruses,18 there are concerns that genital reactivation of
HSV may increase the risk of perinatal transmission of both HIV and HSV,16,17 although this has not
been realised in practice in the UK.
For more detailed information on the diagnosis and management of HSV infection in the mother,
please refer to the 2014 BASHH guideline on the management of genital herpes.

4. Management of pregnant women

with first episode genital herpes
First or second trimester acquisition (until 27+6 weeks of gestation)
There is no evidence of an increased risk of spontaneous miscarriage with

primary genital herpes in the first trimester.
Women with suspected genital herpes should be referred to a genitourinary
medicine physician who will confirm or refute the diagnosis by viral
polymerase chain reaction (PCR), advise on management of genital herpes
and arrange a screen for other sexually transmitted infections.
Treatment, however, should not be delayed. Management of the woman
should be in line with her clinical condition and will usually involve the
use of oral (or intravenous for disseminated HSV) aciclovir in standard doses
(400 mg three times daily, usually for 5 days). The use of aciclovir is
associated with a reduction in the duration and severity of symptoms and a
decrease in the duration of viral shedding. Aciclovir is not licensed for use
in pregnancy but is considered safe and has not been associated with an
increased incidence of birth defects. Transient neonatal neutropenia1922 has
been reported but no clinically significant adverse maternal or neonatal
effects have been reported. Aciclovir is well tolerated in pregnancy.
For treatment courses no dose adjustment is necessary.23,24 There is no
evidence of an increased risk of birth defects with aciclovir, famciclovir
or valaciclovir if used in the first trimester.22
Safety data for aciclovir may be extrapolated to valaciclovir in late
pregnancy, as it is the valine ester, but as there is less experience with the
use of valaciclovir or famciclovir, they are not recommended as a firstline treatment.22
The obstetrician should be informed
Paracetamol and topical lidocaine 2% gel can be offered as symptomatic relief.
There is no evidence that either is harmful in pregnancy in standard doses.
Women with suspected genital herpes who are having midwifery-led care
should be referred for review by an obstetrician, ideally after review by a
genitourinary medicine physician.
Providing that delivery does not ensue within the next 6 weeks, the
pregnancy should be managed expectantly and vaginal delivery
anticipated. There is no evidence that HSV acquired in pregnancy is
associated with an increased incidence of congenital abnormalities.25
Following first or second trimester acquisition, daily suppressive aciclovir
400 mg three times daily from 36 weeks of gestation reduces HSV lesions
at term and hence the need for delivery by caesarean section.2631 It has also
been shown to reduce asymptomatic viral shedding (similar results have
been seen with valaciclovir, although valaciclovir is not recommended for
use in pregnancy in view of lack of experience with its use).27,32,33
Level of evidence
III
Level of evidence
IV
Level of evidence
III
Level of evidence
III
Level of evidence
Ib
Third trimester acquisition (from 28 weeks of gestation)

B
There is some evidence of increased perinatal morbidity (preterm labour and

low birthweight), together with stillbirth,4,34 however the data are conflicting4
so no additional monitoring of such pregnancies is recommended. There is
insufficient evidence to suggest an association between HSV and stillbirth
as a cause of fetal death35 with some studies demonstrating no association.36
Treatment should not be delayed. Management of the woman should be
in line with her clinical condition and will usually involve the use of oral
(or intravenous for disseminated HSV) aciclovir in standard doses (400 mg
three times daily, usually for 5 days). In the third trimester, treatment will
usually continue with daily suppressive aciclovir 400 mg three times daily
until delivery.
Caesarean section should be the recommended mode of delivery for all
women developing first episode genital herpes in the third trimester,
particularly those developing symptoms within 6 weeks of expected delivery,
as the risk of neonatal transmission of HSV is very high at 41%.4,3739
It can be difficult to distinguish clinically between primary and recurrent
genital HSV infections, as in up to 15% of cases where a woman presents
with a first episode of clinical HSV infection, it will actually be a recurrent
infection.14 For women presenting with first episode genital herpes in the
third trimester, particularly within 6 weeks of expected delivery, typespecific HSV antibody testing (immunoglobulin G [IgG] antibodies to
HSV-1 and HSV-2) is advisable. For these women, characterising the
infection will influence the advice given regarding mode of delivery and
risk of neonatal herpes infection. The presence of antibodies of the same
type as the HSV isolated from genital swabs would confirm this episode
to be a recurrence rather than a primary infection and elective caesarean
section would not be indicated to prevent neonatal transmission.
However, it should be noted that it may take 23 weeks for the results of
this test to become available. It is therefore recommended that an initial
plan of delivery should be based on the assumption that all first episode
lesions are primary genital herpes. This plan can then be modified if HSV
antibody test results subsequently confirm a recurrent, rather than primary,
infection. As interpretation of serology can be complicated, results should
be discussed with a virologist or genitourinary medicine physician.
Level of evidence
III
Level of evidence
IIb
Level of evidence
IV

5. Management of pregnant women

with recurrent genital herpes
B
10
Women with recurrent genital herpes should be informed that the risk of
neonatal herpes is low, even if lesions are present at the time of delivery
(03% for vaginal delivery).
Although there is no evidence that aciclovir is unsafe in early pregnancy,
the majority of recurrent episodes of genital herpes are short-lasting and
resolve within 710 days without antiviral treatment. Supportive treatment
measures using saline bathing and analgesia with standard doses of
paracetamol alone will usually suffice.
Vaginal delivery should be anticipated in the absence of other obstetric
indications for caesarean section.
Daily suppressive aciclovir 400 mg three times daily should be considered
from 36 weeks of gestation.
There is insufficient evidence to determine whether this reduces the
incidence of neonatal herpes; however, it reduces viral shedding and
recurrences at delivery so may reduce the need for caesarean section.
Limited information exists regarding the neonatal safety of prophylaxis.
The risks, benefits and alternatives to daily suppressive therapy should be
discussed with women who have a history and prophylaxis initiated for
women who desire intervention.33
This increase from the standard suppressive dose of 400 mg twice daily is
recommended in view of the greater volume of distribution of the drug
during pregnancy.26,40
Sequential PCR culture during late gestation to predict viral shedding at
term,17 or at delivery to identify women who are asymptomatically shedding
HSV, is not indicated.
There is no increased risk of preterm labour, preterm prelabour rupture of
membranes or fetal growth restriction associated with women seropositive
for HSV. The incidence of congenital abnormalities is not increased in the
presence of recurrent genital herpes infection.41
Level of evidence
III
Level of evidence
Ia
Level of evidence
IIa

6. Management of women with

primary or recurrent genital
lesions at the onset of labour
General management
C
Management of a woman with genital herpes at the onset of labour will

be based on clinical assessment as there will not be time for confirmatory
laboratory testing. The clinician must take a history in order to ascertain
whether this is a primary or recurrent episode. A viral swab from the
lesion(s) should nonetheless be taken, since the result may influence
management of the neonate.
The neonatologist should be informed.
Primary episode
B
Caesarean section should be recommended to all women presenting with

primary episode genital herpes lesions at the time of delivery, or within 6
weeks of the expected date of delivery, in order to reduce exposure of the
fetus to HSV which may be present in maternal genital secretions.9
There is some evidence to suggest that the benefit of caesarean section
reduces if the membranes have been ruptured for greater than 4 hours.42
However, there may be some benefit in performing a caesarean section
even after this time interval.
Intravenous aciclovir given intrapartum to the mother (5 mg/kg every 8
hours) and subsequently to the neonate (intravenous aciclovir 20 mg/kg
every 8 hours) may be considered for those mothers opting for vaginal
delivery.13,25 It is unknown whether intrapartum aciclovir reduces the risk
of neonatal HSV infection.
Where primary episode genital herpes lesions are present at the time of
delivery and the baby is delivered vaginally, the risk of neonatal herpes is
estimated to be 41%.4,3739
The risk of perinatal transmission depends on the timing of maternal
acquisition of HSV, with the highest risk in infants born to women who have
not completed HSV seroconversion during pregnancy (most commonly in
the third trimester, within 6 weeks of delivery).
Although vaginal delivery should be avoided if possible, in women who
deliver vaginally in the presence of primary genital herpes lesions, invasive
procedures (application of fetal scalp electrodes, fetal blood sampling,
artificial rupture of membranes and/or instrumental deliveries) should
be avoided.4,4345
Level of evidence
III
Level of evidence
IV
Level of evidence
III
11

Recurrent genital herpes
B
12
Women presenting with recurrent genital herpes lesions at the onset of

labour should be advised that the risk to the baby of neonatal herpes is
low (03% for vaginal delivery).1,38
Evidence from the Netherlands shows that a conservative approach,
allowing vaginal delivery in the presence of an anogenital lesion, has not
been associated with a rise in the number of neonatal HSV cases.46
Vaginal delivery should be offered to women with recurrent genital herpes
lesions at the onset of labour. A caesarean section delivery can be
considered but the risk to the mother and future pregnancies should be
set against the small risk of neonatal transmission of HSV with recurrent
disease (03% for vaginal delivery). The final choice of vaginal delivery
versus caesarean section should be made by the mother, who should base
her decision on the very low risk of transmission set against any other
obstetric risk factors and the risks associated with caesarean section.
It has been reported that invasive procedures (fetal blood sampling,
application of fetal scalp electrodes, artificial rupture of membranes and/or
instrumental deliveries) increase the risk of neonatal HSV infection.47
However, given the small background risk (03%) of transmission in this
group, the increased risk associated with invasive procedures is unlikely
to be clinically significant so they may be used if required.
Women should be managed in accordance with standard National
Institute for Health and Care Excellence (NICE) intrapartum guidelines.45
There is no evidence to guide the management of women with
spontaneous rupture of membranes at term, but many clinicians will
advise expediting delivery in an attempt to minimise the duration of
potential exposure of the fetus to HSV.
Level of evidence
III
Level of evidence
IV
Level of evidence
III
Level of evidence
IV

7. Genital herpes in preterm

prelabour rupture of membranes
(before 37+0 weeks of gestation)
Primary genital herpes in preterm prelabour rupture of membranes (PPROM)
There is limited evidence to inform best obstetric practice when PPROM

is complicated by primary HSV infection. Management should be guided
by multidisciplinary team discussion involving the obstetricians, neonatologists and genitourinary medicine physicians and will depend on the
gestation that PPROM occurred. If the decision is made for immediate
delivery then the anticipated benefits of caesarean section will remain. If
there is initial conservative management, the mother should be
recommended to receive intravenous aciclovir 5 mg/kg every 8 hours.
Prophylactic corticosteroids should be considered to reduce the
implications of preterm delivery upon the infant.48 If delivery is indicated
within 6 weeks of the primary infection, delivery by caesarean section may
still offer some benefit despite the prolonged rupture of membranes.4951
Level of evidence
IV
Recurrent genital herpes in PPROM
When PPROM is encountered in the presence of recurrent genital herpes

lesions, the risk of neonatal transmission is very small and may be outweighed
by the morbidity and mortality associated with premature delivery.
In the case of PPROM before 34 weeks there is evidence to suggest that
expectant management is appropriate, including oral aciclovir 400 mg
three times daily for the mother.49 After this gestation, it is recommended
that management is undertaken in accordance with relevant RCOG
guidelines on PPROM52 and antenatal corticosteroid administration53 to
reduce neonatal morbidity and mortality and is not materially influenced
by the presence of recurrent genital herpes lesions.49,54
Level of evidence
IV
13

8. Management of HIV-positive
women with HSV infection
Primary HSV infection
HIV-positive women with primary genital HSV infection in the last trimester
of pregnancy should be managed according to the recommendations for all
women with primary genital HSV infection.
Recurrent HSV infection
14
There is some evidence that HIV antibody positive women with genital
HSV ulceration in pregnancy are more likely to transmit HIV infection
independent of other factors.17,55 However, this is not a consistent finding
across all studies.56
Women who are HIV antibody positive and have a history of genital herpes
should be offered daily suppressive aciclovir 400 mg three times daily from
32 weeks of gestation to reduce the risk of transmission of HIV infection,
especially in women where a vaginal delivery is planned. Starting therapy
at this earlier gestation than usual should be considered in view of the
increased possibility of preterm labour in HIV-positive women.
The mode of delivery should be in line with the BHIVA HIV in pregnancy
guideline recommendations according to obstetric factors and HIV
parameters such as HIV viral load.42,57
There is currently no evidence to recommend daily suppressive treatment
of HSV for HIV antibody positive women who are HSV-1 or -2 seropositive
but have no history of genital herpes.56
Level of evidence
III
Level of evidence
IV

9. Management of the neonate

General management
C
In all cases the neonatal team should be informed.
Management of babies born by caesarean section in mothers with primary HSV

infection in the third trimester
C
These babies are at low risk of vertically transmitted HSV infection so conservative
management is recommended.
Liaise with the neonatal team.
Swabs from the neonate are not indicated.
No active treatment is required for the baby.
Normal postnatal care of the baby is advised with a neonatal examination
at 24 hours of age, after which the baby can be discharged from the
hospital if well and feeding is established.
Parents should be educated regarding good hand hygiene and due care
to reduce risk of postnatal infection.
Parents should be advised to seek medical help if they have concerns
regarding their baby. In particular, they should be advised to look for:
skin, eye and mucous membrane lesions, lethargy/irritability, poor feeding.
Management of babies born by spontaneous vaginal delivery in mothers with a primary

HSV infection within the previous 6 weeks
These babies are at high risk of vertically transmitted HSV infection.
If the baby is well:
Swabs of the skin, conjunctiva, oropharynx and rectum should be sent
for herpes simplex PCR.
A lumbar puncture is not necessary.
Empirical treatment with intravenous aciclovir (20 mg/kg every 8 hours)
should be initiated until evidence of active infection is ruled out.
Strict infection control procedures should be put in place for both
mother and baby.
Breastfeeding is recommended unless the mother has herpetic lesions
C
around the nipples.
Parents should be warned to report any early signs of infection such
as poor feeding, lethargy, fever or any suspicious lesions.
If the baby is unwell or presents with skin lesions:
Swabs of the skin, lesions, conjunctiva, oropharynx and rectum
should be sent for herpes simplex PCR.
A lumbar puncture should be performed even if CNS features are
not present.
15

Intravenous aciclovir (20 mg/kg every 8 hours) should be initiated until

evidence of active infection is ruled out.
Management of babies born to mothers with recurrent HSV infection in pregnancy with
or without active lesions at delivery
B
In the case of recurrent genital herpes infections in the mother, maternal

IgG will be protective in the baby and hence the infection risk is low.
Conservative management of the neonate is advised.55
Surface swabs from the neonate are not indicated.
No active treatment is advised for the baby.
Normal postnatal care of the baby is advised with a neonatal examination
at 24 hours of age, after which the baby can be discharged from the
hospital if well and feeding is established.
Parents should be educated regarding good hand hygiene and due care
to reduce risk of postnatal infection.
Parents should be advised to seek medical help if they have concerns
regarding their baby. In particular, they should be advised to look for:
skin, eye and mucous membrane lesions, lethargy/irritability, poor feeding.
Level of evidence
III
In cases where there are concerns regarding the neonate (clinical evidence of sepsis,
poor feeding)
C
Liaise with the neonatal team. In addition to considering bacterial sepsis, HSV infection
should be considered.
Surface swabs and blood for HSV culture and PCR.
Intravenous aciclovir (20 mg/kg every 8 hours) should be given while
awaiting cultures.
Further management by the neonatal team according to condition of the
baby and test results.
See Appendix 1 for flow chart of management.
16

10.
Prevention of postnatal
transmission
In 25% of cases a possible source of postnatal infection is responsible,

usually a close relative of the mother.2
Efforts to prevent postnatal transmission of HSV are therefore important
and advice should be given to the mother regarding this.
The mother and all those with herpetic lesions who may be in contact
with the neonate, including staff, should practice careful hand hygiene.
Those with oral herpetic lesions (cold sores) should not kiss the neonate.
Level of evidence IV
17

11.
18
Performance measures
1.
When a herpes antiviral drug is used against a previously undiagnosed genital herpes
episode, a swab for herpes PCR should be sent target 100%.
2.
In order that a discussion on the mode of delivery is undertaken with an obstetrician,

there must be documentation in the clinic notes that the obstetrician and/or GP have
been advised of this need and that the patient has also been informed of this need
target 100%.
3.
For women with suspected primary genital herpes in pregnancy diagnosed in level 1/2
services, primary care or obstetric services, referral to a genitourinary medicine
physician should be made (unless in labour) target 100%.
4.
Where a first episode diagnosis of genital herpes is made in the third trimester, the
womans case should be discussed between the obstetrician and neonatologist with
documentation of the agreed management target 100%.
5.
Pregnant women with genital herpes should be provided with written information on
genital herpes in pregnancy (e.g. the RCOG patient information leaflet) target 90%.

12.
About this guideline
Qualifying statement
The recommendations in this guideline may not be appropriate for use in all clinical situations.
Decisions to follow these recommendations must be based on the professional judgement of the
clinician and consideration of individual patient circumstances and available resources. All possible
care has been undertaken to ensure the publication of the correct dosage of medication and route of
administration. However, it remains the responsibility of the prescribing clinician to ensure the
accuracy and appropriateness of the medication they prescribe.
Editorial independence
This guideline was commissioned, edited and endorsed by the BASHH CEG and the RCOG without
external funding being sought or obtained.
Declarations of interest
All members of the guideline writing committee completed the BASHH conflict of interest declaration
at the time that the guidelines final draft was submitted to the CEG.
Dr Rajul Patel has received honoraria for talks and fees for consultancy from Novatis, Becton
Dickinson and Roche pharmaceutical and diagnostic companies.
Resource implications
The resource implications of this guideline will have little impact on current recommendations for
management of herpes in pregnancy. There may be a cost saving if women with recurrent genital
herpes simplex virus infection elect to have a vaginal delivery when herpetic lesions are present at
term rather than undergoing a caesarean section. The cost of suppressive aciclovir (400 mg three
times daily) for 1 month is 6.45*.
Membership of the writing group

EF and EC drafted the initial document and redrafts, VAB and SH drafted the obstetric component
and AP drafted the neonatal section. PO, NLB and RP commented on the drafts and redrafts of
the document.
Membership of the CEG
Dr Keith Radcliffe (Chair), Consultant Physician in Genitourinary Medicine,

Whittall Street Clinic
Dr David Daniels, Sexual Health Clinic, West Middlesex University
Hospital, West Middlesex University Hospital NHS Trust
Dr Mark FitzGerald, Consultant Physician in Genitourinary Medicine,
Musgrove Park Hospital
19

Dr Deepa Grover, Consultant in Genitourinary/HIV Medicine,

Barnet Hospital/Royal Free Hospital
Dr Stephen Higgins, Consultant Physician in Genitourinary Medicine,
North Manchester General Hospital, Manchester
Dr Margaret Kingston, Consultant Physician in Genitourinary Medicine,
Manchester Centre for Sexual Health
Dr Neil Lazaro, Associate Specialist in Genitourinary Medicine,
Royal Preston Hospital
Dr Louise Melvin, Faculty of Sexual & Reproductive Healthcare representative,
Consultant Sexual Health, Glasgow
Dr Ann Sullivan, Consultant Physician in Genitourinary Medicine,
Chelsea and Westminster Hospital NHS Foundation Trust.
Timescale for next review: 2018.
Acknowledgements
BASHH National Audit Group for suggesting the performance measures.
Dr Jolanta Bernatoniene and Dr Catherine OSullivan on behalf of the RCPCH for their expert review
of the neonatal sections of the guideline.
Marian Nicholson from the Herpes Viruses Association (HVA) for her invaluable input into this guideline.
*Source of costing: British National Formulary September 2014 (different prices may be negotiated by NHS hospital trusts).58
20

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Singhal P, Naswa S, Marfatia YS. Pregnancy and sexually transmitted viral infections. Indian J
Sex Transm Dis 2009;30:718.
Parvey LS, Chien LT. Neonatal herpes simplex virus infection introduced by fetal-monitor
scalp electrodes. Pediatrics 1980;65:11503.
Kimberlin DW, Baley J; Committee on Infectious Diseases; Committee on Fetus and
Newborn. Guidance on management of asymptomatic neonates born to women with active
genital herpes lesions. Pediatrics 2013;131:e63546.
Major CA, Towers CV, Lewis DF, Garite TJ. Expectant management of preterm premature
rupture of membranes complicated by active recurrent genital herpes. Am J Obstet Gynecol
2003;188:15514; discussion 15545.
Utley K, Bromberger P, Wagner L, Schneider H. Management of primary herpes in pregnancy
complicated by ruptured membranes and extreme prematurity: case report. Obstet Gynecol
1987;69(3 Pt 2):4713.
Dietrich YM, Napolitano PG. Acyclovir treatment of primary herpes in pregnancy
complicated by second trimester preterm premature rupture of membranes with term
delivery: case report. Am J Perinatol 2002;19:2358.
Pinninti SG, Kimberlin DW. Management of neonatal herpes simplex virus infection and
exposure. Arch Dis Child Fetal Neonatal Ed 2014;99:F2404.
Royal College of Obstetricians and Gynaecologists. Antenatal Corticosteroids to Reduce
Neonatal Morbidity and Mortality. Green-top Guideline No. 7. London: RCOG; 2010.
Ehsanipoor RM, Major CA. Herpes simplex and HIV infections and preterm PROM. Clin
Drake AL, John-Stewart GC, Wald A, Mbori-Ngacha DA, Bosire R, Wamalwa DC, et al.
Herpes simplex virus type 2 and risk of intrapartum human immunodeficiency virus
transmission. Obstet Gynecol 2007;109:4039.
23

56.
57.
58.
24
Chen KT, Tuomala RE, Chu C, Huang ML, Watts DH, Zorrilla CD, et al. No association
between antepartum serologic and genital tract evidence of herpes simplex virus-2
coinfection and perinatal HIV-1 transmission. Am J Obstet Gynecol 2008;198:399.e15.
British HIV Association. British HIV Association guidelines for the management of HIV
infection in pregnant women 2012 (2014 interim review). London: BHIVA; 2014.
NICE Evidence Services. British National Formulary September 2014. Aciclovir (Acyclovir)
[http://www.evidence.nhs.uk/formulary/bnf/current/5-infections/53-antiviral-drugs/532herpesvirus-infections/5321-herpes-simplex-and-varicellazoster-infection/aciclovir?q=
ACICLOVIR] Accessed 2014 Sep 16.

Appendix I
Algorithm for the management of herpes in pregnancy and care of neonate
Recurrent genital herpes
Primary acquisition of
genital herpes in first or
second trimester
Primary acquisition
of genital herpes in
third trimester
Treat episodes with

standard doses of
aciclovir if necessary
Treat primary episode

with standard doses
of aciclovir
Treat primary episode

with standard doses
of aciclovir
Consider aciclovir 400 mg tds from 36/40 gestation
Offer vaginal delivery
Normal
postnatal care
Genital HSV lesions

at delivery
Normal
postnatal care
Discharge home
if baby well at
24 hours
Advise parents
regarding later
management if
any concerns
If vaginal delivery
ensues inform
neonatologist
Baby well
Consider aciclovir
400 mg tds until delivery
Recommend planned CS
especially if within
6 weeks of delivery
Inform neonatologist
Normal postnatal care
Discharge home if
baby well at 24 hours
Advise parents
regarding later
management if
any concerns
Baby unwell
Perform
lumbar
puncture for
HSV PCR
Start aciclovir 20 mg/kg tds for

10 days while awaiting results
Abbreviations CS caesarean section; HSV herpes simplex virus; PCR polymerase chain reaction;
Abbreviations tds three times daily
25

Appendix II
Levels of evidence and grading of recommendations
Levels of evidence
Ia
Meta-analysis of randomised controlled trials
Ib At least one randomised controlled trial
IIa At least one well-designed controlled study without randomisation
IIb At least one other type of well-designed quasi-experimental study
III Well-designed non-experimental descriptive studies
IV Expert committee reports or opinions of respected authorities
Grading of recommendations
A
Evidence at level Ia or Ib
B
Evidence at level IIa, IIb or III
C
Evidence at level IV
26
The Investigation and Management of

the SmallforGestationalAge Fetus
2nd Edition | February 2013 | Minor revisions January 2014
The Investigation and Management of the

SmallforGestationalAge Fetus
This is the second edition of this guideline. It replaces the first edition which was published in November
2002 under the same title.
Executive Summary of Recommendations
Risk factors for a SGA fetus/neonate

All women should be assessed at booking for risk factors for a SGA fetus/neonate to identify those who
require increased surveillance.
Women who have a major risk factor (Odds Ratio [OR] > 2.0) should be referred for serial ultrasound
measurement of fetal size and assessment of wellbeing with umbilical artery Doppler from 2628
weeks of pregnancy (Appendix 1).
Women who have three or more minor risk factors should be referred for uterine artery Doppler at 2024
weeks of gestation (Appendix 1).
Second trimester DS markers have limited predictive accuracy for delivery of a SGA neonate.
A low level (< 0.415 MoM) of the first trimester marker PAPPA should be considered a major risk factor
for delivery of a SGA neonate.
In high risk populations uterine artery Doppler at 2024 weeks of pregnancy has a moderate predictive
value for a severely SGA neonate.
In women with an abnormal uterine artery Doppler at 2024 weeks of pregnancy, subsequent
normalisation of flow velocity indices is still associated with an increased risk of a SGA neonate.
Repeating uterine artery Doppler is therefore of limited value.
Women with an abnormal uterine artery Doppler at 2024 weeks (defined as a pulsatility index [PI]
> 95th centile) and/or notching should be referred for serial ultrasound measurement of fetal size and
assessment of wellbeing with umbilical artery Doppler commencing at 2628 weeks of pregnancy.
Women with a normal uterine artery Doppler do not require serial measurement of fetal size and serial
assessment of wellbeing with umbilical artery Doppler unless they develop specific pregnancy
complications, for example antepartum haemorrhage or hypertension. However, they should be offered
a scan for fetal size and umbilical artery Doppler during the third trimester.
Serial ultrasound measurement of fetal size and assessment of wellbeing with umbilical artery Doppler
should be offered in cases of fetal echogenic bowel.
Abdominal palpation has limited accuracy for the prediction of a SGA neonate and thus should not be
routinely performed in this context.
Serial measurement of symphysis fundal height (SFH) is recommended at each antenatal appointment
from 24 weeks of pregnancy as this improves prediction of a SGA neonate.
2 of 34
SFH should be plotted on a customised chart rather than a populationbased chart as this may improve
prediction of a SGA neonate.
Women with a single SFH which plots below the 10th centile or serial measurements which demonstrate
slow or static growth by crossing centiles should be referred for ultrasound measurement of fetal size.
Women in whom measurement of SFH is inaccurate (for example: BMI > 35, large fibroids, hydramnios)
should be referred for serial assessment of fetal size using ultrasound.
Optimum method of diagnosing a SGA fetus and FGR

Fetal abdominal circumference (AC) or estimated fetal weight (EFW) < 10th centile can be used to
diagnose a SGA fetus.
Use of a customised fetal weight reference may improve prediction of a SGA neonate and adverse
perinatal outcome. In women having serial assessment of fetal size, use of a customised fetal weight
reference may improve the prediction of normal perinatal outcome.
Routine measurement of fetal AC or EFW in the third trimester does not reduce the incidence of a SGA
neonate nor does it improve perinatal outcome. Routine fetal biometry is thus not justified.
Change in AC or EFW may improve the prediction of wasting at birth (neonatal morphometric indicators)
and adverse perinatal outcome suggestive of FGR.
When using two measurements of AC or EFW to estimate growth velocity, they should be at least
3 weeks apart to minimise falsepositive rates for diagnosing FGR. More frequent measurements of
fetal size may be appropriate where birth weight prediction is relevant outside of the context of
diagnosing SGA/FGR.
Where the fetal AC or EFW is < 10th centile or there is evidence of reduced growth velocity, women should
be offered serial assessment of fetal size and umbilical artery Doppler.
Investigations that are indicated in SGA fetuses

Offer referral for a detailed fetal anatomical survey and uterine artery Doppler by a fetal medicine
specialist if severe SGA is identified at the 1820 week scan.
Karyotyping should be offered in severely SGA fetuses with structural anomalies and in those detected
before 23 weeks of gestation, especially if uterine artery Doppler is normal.
Serological screening for congenital cytomegalovirus (CMV) and toxoplasmosis infection should be
offered in severely SGA fetuses.
Testing for syphilis and malaria should be considered in high risk populations.
Uterine artery Doppler has limited accuracy to predict adverse outcome in SGA fetuses diagnosed
during the third trimester.
3 of 34
Interventions to be considered in the prevention of SGA fetuses/neonates

Antiplatelet agents may be effective in preventing SGA birth in women at high risk of pre-eclampsia
although the effect size is small.
In women at high risk of pre-eclampsia, antiplatelet agents should be commenced at, or before, 16
weeks of pregnancy.
There is no consistent evidence that dietary modification, progesterone or calcium prevent birth of a
SGA infant. These interventions should not be used for this indication.
Interventions to promote smoking cessation may prevent delivery of a SGA infant. The health benefits
of smoking cessation indicate that these interventions should be offered to all women who are pregnant
and smoke.
Antithrombotic therapy appears to be a promising therapy for preventing delivery of a SGA infant in
high-risk women. However there is insufficient evidence, especially concerning serious adverse effects,
to recommend its use.
Interventions to be considered in the preterm SGA fetus

Women with a SGA fetus between 24+0 and 35+6 weeks of gestation, where delivery is being considered,
should receive a single course of antenatal corticosteroids.
Optimal method and frequency of fetal surveillance in SGA

In a highrisk population, the use of umbilical artery Doppler has been shown to reduce perinatal
morbidity and mortality. Umbilical artery Doppler should be the primary surveillance tool in the
SGA fetus.
When umbilical artery Doppler flow indices are normal it is reasonable to repeat surveillance every
14 days.
More frequent Doppler surveillance may be appropriate in a severely SGA fetus.
When umbilical artery Doppler flow indices are abnormal (pulsatility or resistance index > +2 SDs above
mean for gestational age) and delivery is not indicated repeat surveillance twice weekly in fetuses with
enddiastolic velocities present and daily in fetuses with absent/reversed enddiastolic frequencies.
CTG should not be used as the only form of surveillance in SGA fetuses.
Interpretation of the CTG should be based on short term fetal heart rate variation from computerised
analysis.
Ultrasound assessment of amniotic fluid volume should not be used as the only form of surveillance in
SGA fetuses.
Interpretation of amniotic fluid volume should be based on single deepest vertical pocket.
Biophysical profile should not be used for fetal surveillance in preterm SGA fetuses.
4 of 34
In the preterm SGA fetus, middle cerebral artery (MCA) Doppler has limited accuracy to predict
acidaemia and adverse outcome and should not be used to time delivery.
In the term SGA fetus with normal umbilical artery Doppler, an abnormal middle cerebral artery Doppler
(PI < 5th centile) has moderate predictive value for acidosis at birth and should be used to time delivery.
Ductus venosus Doppler has moderate predictive value for acidaemia and adverse outcome.
Ductus venosus Doppler should be used for surveillance in the preterm SGA fetus with abnormal
umbilical artery Doppler and used to time delivery.
The optimal gestation to deliver the SGA fetus

In the preterm SGA fetus with umbilical artery AREDV detected prior to 32 weeks of gestation, delivery
is recommended when DV Doppler becomes abnormal or UV pulsations appear, provided the fetus is
considered viable and after completion of steroids. Even when venous Doppler is normal, delivery is
recommended by 32 weeks of gestation and should be considered between 3032 weeks of gestation.
If MCA Doppler is abnormal, delivery should be recommended no later than 37 weeks of gestation.
In the SGA fetus detected after 32 weeks of gestation with an abnormal umbilical artery Doppler,
delivery no later than 37 weeks of gestation is recommended.
In the SGA fetus detected after 32 weeks of gestation with normal umbilical artery Doppler, a senior
obstetrician should be involved in determining the timing and mode of birth of these pregnancies.
Delivery should be offered at 37 weeks of gestation.
How the SGA fetus should be delivered

In the SGA fetus with umbilical artery AREDV delivery by caesarean section is recommended.
In the SGA fetus with normal umbilical artery Doppler or with abnormal umbilical artery PI but
enddiastolic velocities present, induction of labour can be offered but rates of emergency caesarean
section are increased and continuous fetal heart rate monitoring is recommended from the onset of
uterine contractions.
Early admission is recommended in women in spontaneous labour with a SGA fetus in order to instigate
continuous fetal heart rate monitoring.
1.
Purpose and scope
The purpose of this guideline is to provide advice that is based on the best evidence where available in order
to guide clinicians, regarding the investigation and management of the smallforgestational age (SGA) fetus.
The guideline reviews the risk factors for a SGA fetus and provides recommendations regarding screening,
diagnosis and management, including fetal monitoring and delivery.
1.1 Population and setting

Unselected pregnant women in community settings.
High-risk women (calculated on the basis of past obstetric history, current medical disorders or ultrasound
diagnosis) in the hospital setting.
The guideline does not address multiple pregnancies or pregnancies with fetal abnormalities.
5 of 34
1.2. Interventions to be studied

Comparison of modalities to screen for and diagnose a SGA fetus.
Comparison of modalities to monitor a SGA fetus.
2.
Definitions
Smallforgestational age (SGA) refers to an infant born with a birth weight less than the 10th centile.
Historically SGA birth has been defined using population centiles. But, the use of centiles customised for
maternal characteristics (maternal height, weight, parity and ethnic group) as well as gestational age at
delivery and infant sex, identifies small babies at higher risk of morbidity and mortality than those identified
by population centiles.12 With respect to the fetus, definitions of SGA birth and severe SGA vary. For the
purposes of this guideline, SGA birth is defined as an estimated fetal weight (EFW) or abdominal
circumference (AC) less than the 10th centile and severe SGA as an EFW or AC less than the 3rd centile.3 Other
definitions will be discussed where relevant.
Fetal growth restriction (FGR) is not synonymous with SGA. Some, but not all, growth restricted
fetuses/infants are SGA while 5070% of SGA fetuses are constitutionally small, with fetal growth appropriate
for maternal size and ethnicity.4 The likelihood of FGR is higher in severe SGA infants. Growth restriction
implies a pathological restriction of the genetic growth potential. As a result, growth restricted fetuses may
manifest evidence of fetal compromise (abnormal Doppler studies, reduced liquor volume). Low birth weight
(LBW) refers to an infant with a birth weight < 2500 g.
As some of the definitions used in the published literature vary, or as in the case of FGR, can be used
inappropriately, further clarification is given where necessary throughout the guideline when referring to
the evidence.
3.
Background
Small fetuses are divided into normal (constitutionally) small, nonplacenta mediated growth restriction, for
example; structural or chromosomal anomaly, inborn errors of metabolism and fetal infection, and placenta
mediated growth restriction. Maternal factors can affect placental transfer of nutrients, for example; low
prepregnancy weight, under nutrition, substance abuse or severe anaemia. Medical conditions can affect
placental implantation and vasculature and hence transfer, for example; pre-eclampsia, autoimmune disease,
thrombophilias, renal disease, diabetes and essential hypertension.
As a group, structurally normal SGA fetuses are at increased risk of perinatal mortality and morbidity but most
adverse outcomes are concentrated in the growth restricted group. Several studies have shown that neonates
defined as SGA by populationbased birthweight centiles but not customised centiles are not at increased risk
of perinatal morbidity or mortality.1,2,5
Clinical examination is a method of screening for fetal size, but is unreliable in detecting SGA fetuses.
Diagnosis of a SGA fetus usually relies on ultrasound measurement of fetal abdominal circumference or
estimation of fetal weight. Management of the SGA fetus is directed at timely delivery. A number of
surveillance tests are available, including cardiotocography, Doppler and ultrasound to assess biophysical
activity but there is controversy about which test or combination of tests should be used to time delivery,
especially in the fetus.
4.
This guideline was developed in accordance with standard methodology for producing RCOG Greentop
Guidelines. Medline, Pubmed, all EBM reviews (Cochrane CRCT, Cochrane database of Systematic Reviews,
6 of 34
methodology register, ACP journal club, DARE HTA, Maternity and Infant Care), EMBASE and TRIP were
searched for relevant randomised controlled trials (RCTs), systematic reviews, metaanalyses and cohort
studies. The search was restricted to articles published between 2002 and September 2011. Search words
included fetal growth retardation, fetal growth restriction, infant, small for gestational age, including all
relevant Medical Subject Heading (MeSH) terms.The search was limited to humans and the English language.
5.
What are the risk factors for a SGA fetus/neonate? What is the optimum method of
screening for the SGA fetus/neonate and care of at risk pregnancies?
Methods employed in the first and second trimesters, to predict the likelihood of a SGA fetus/neonate include:
medical and obstetric history and examination, maternal serum screening and uterine artery Doppler.
Methods of screening for the SGA fetus/neonate in the second and third trimester are abdominal palpation
and measurement of symphysis fundal height (SFH) (including customised charts).
5.1 History
All women should be assessed at booking for risk factors for a SGA fetus/neonate to identify those who
require increased surveillance.
Women who have a major risk factor (Odds Ratio [OR] > 2.0) should be referred for serial ultrasound
measurement of fetal size and assessment of wellbeing with umbilical artery Doppler from 2628
weeks of pregnancy (Appendix 1).
Women who have three or more minor risk factors should be referred for uterine artery Doppler at 2024
weeks of gestation (Appendix 1).
A table of risk factors and associated odds ratios (ORs) for the birth of a SGA neonate, where evidence is
consistent and not affected by adjustment for confounders, is presented in Appendix 1. It is acknowledged
that other risk factors may need to be considered on an individual basis.
Women that have previously had a SGA neonate have at least a twofold increased risk of a subsequent SGA
neonate.68 The risk is increased further after two SGA births.7 Classification of prior infant birthweight is best
done using customised centiles.12 This can be done using computer software that can be downloaded from the
internet.9 Women with a prior history of other placentamediated diseases are also at increased risk of a
subsequent SGA neonate.This includes prior pre-eclampsia8 and prior stillbirth,7 and in particular those with a
history of previous preterm unexplained stillbirth, due to the association with FGR.10 While termination of
pregnancy is not a risk factor for a SGA infant,11 the evidence regarding recurrent miscarriage is inconsistent.12,13
Maternal medical conditions associated with an increased risk of a SGA neonate are diabetes with vascular
disease,14 moderate and severe renal impairment (especially when associated with hypertension),15
antiphospholipid syndrome16 and chronic hypertension.17 Systemic lupus erythematosus18 and certain types
of congenital heart disease, in particular cyanotic congenital heart disease, are associated with increased
likelihood of a SGA neonate but there are no papers reporting ORs.19 The risk will therefore need to be
assessed on an individual basis. The evidence for an association with asthma, thyroid disease, inflammatory
bowel disease and depression is less convincing. Studies report a weak or nonsignificant association with
LBW but do not differentiate between the effect on SGA and preterm birth, and with confidence intervals
[CIs] often crossing one. Therefore, if uncomplicated and adequately treated, these are not considered to be
risk factors for a SGA fetus.20,21
Maternal risk factors associated with an increased risk of a SGA neonate are maternal age 35 years, with a
further increase in those 40 years old,22 African American23 or Indian/Asian ethnicity,2,24 nulliparity,25 social
deprivation,26 unmarried status,27 body mass index (BMI) < 20,2830 BMI > 25,28,29 maternal SGA,31 daily vigorous
7 of 34
exercise,32 a short (< 6 months) or long (> 60 months) interpregnancy interval33 and heavy vaginal bleeding
during the first trimester.34 The effect of some of these risk factors is reduced once adjusted for other
associated factors and thus they are not included in Appendix 1. Maternal exposure to domestic violence
during pregnancy has been shown in a systematic review to be associated with low birth weight (Adjusted
OR [AOR] 1.53, 95% CI 1.281.82).35 Low maternal weight gain has been shown to be associated with a SGA
infant in a preterm population (OR 4.9, 95% CI 1.912.6)13 but it is no longer recommended that women are
routinely weighed during pregnancy.36
Several maternal exposures have a seemingly causative relationship with a SGA infant, including moderate
alcohol intake,37 drug use (with cocaine use during pregnancy being the most significant)38 and cigarette
smoking.39 The effects of smoking are dose dependent.29
Other risk factors are maternal caffeine consumption 300 mg per day in the third trimester40 and a low fruit
intake prepregnancy, while a high green leafy vegetable intake prepregnancy has been reported to be protective
(AOR 0.44, 95% CI 0.240.81).32 Singleton pregnancies following IVF are also a risk factor for a SGA fetus.41
Changing paternity has been associated with an increased risk of a SGA infant,42 although a recent
systematic review demonstrated inconclusive evidence.43 A paternal history of SGA birth is a risk
factor for a SGA fetus.44
Evidence
level 3
There is insufficient evidence to determine how risk factors relate to each other in the individual woman and
consequently how these risk factors should be managed. This includes abnormal maternal Down syndrome
serum markers (see below). Further evidence may become available from the SCOPE study.45 This guideline
has therefore categorized risk factors into major and minor based on published ORs for the birth of a SGA
neonate. Major risk factors (OR > 2.0) should prompt referral for serial ultrasound measurement of fetal size
and assessment of wellbeing with umbilical artery Doppler. The presence of multiple minor risk factors is
likely to constitute a significant risk for the birth of a SGA neonate and there is a rationale for further screening
using uterine artery Doppler at 20 weeks (see below).
5.2 Biochemical markers used for Down Syndrome (DS) Screening

Second trimester DS markers have limited predictive accuracy for delivery of a SGA neonate.
A low level (< 0.415 MoM) of the first trimester marker PAPPA should be considered a major risk factor
for delivery of a SGA neonate.
Due to their placental origin, several biochemical markers have been investigated as screening tests for a
SGA fetus.
Two systematic reviews found low predictive accuracy for alpha fetoprotein (AFP) (> 2.5 MoM or
< 0.25 MoM), elevated hCG (> 3.0 MoM) and inhibin A ( 2.0 MoM), low unconjugated estriol (< 0.5
MoM) and the combined triple test to predict a SGA fetus.46,47 One review found methodological and
reporting limitations in all studies, resulting in great heterogeneity, concluding that serum markers
were only useful as a means of contributing to the overall assessment of risk for a pregnancy.47
Evidence
level
1+/2+
In women with elevated AFP, there is no evidence that increased fetal surveillance has any benefit.48
Similarly, there is a lack of evidence for the use of aspirin in women with raised hCG.49
Evidence
level 3
In a large series of 49 801 women at 11+0 to 13+6 weeks, low PAPPA (but not beta HCG) was inversely
associated with risk of being SGA. Using a 5th centile (0.415 MoM) cut off, ORs for A SGA infant (birthweight
< 10th centile) and severe SGA (birthweight < 3rd centile) were 2.7 and 3.66 respectively.50 A systematic review
8 of 34
found that an unexplained low first trimester PAPPA (< 0.4 MoM) and/or a low hCG (< 0.5 MoM) were
associated with an increased frequency of adverse obstetrical outcome including a SGA infant.47
There is some evidence that addition of fetal size at 1820 weeks of gestation or fetal growth
between 1114 and 1820 weeks of gestation to first trimester serum markers improves prediction
of a SGA infant.51,52 However, different ultrasound parameters have been used and it is unclear what
combination provides optimum prediction.
Evidence
level 2+
5.3 Uterine artery Doppler

In high risk populations uterine artery Doppler at 2024 weeks of pregnancy has a moderate predictive
value for a severely SGA neonate.
In women with an abnormal uterine artery Doppler at 2024 weeks of pregnancy, subsequent
normalisation of flow velocity indices is still associated with an increased risk of a SGA neonate.
Repeating uterine artery Doppler is therefore of limited value.
Women with an abnormal uterine artery Doppler at 2024 weeks (defined as a pulsatility index [PI]
> 95th centile) and/or notching should be referred for serial ultrasound measurement of fetal size and
assessment of wellbeing with umbilical artery Doppler commencing at 2628 weeks of pregnancy.
Women with a normal uterine artery Doppler do not require serial measurement of fetal size and serial
assessment of wellbeing with umbilical artery Doppler unless they develop specific pregnancy
complications, for example antepartum haemorrhage or hypertension. However, they should be offered
a scan for fetal size and umbilical artery Doppler during the third trimester.
SGA birth, particularly when severe (birth weight < 3rd centile) or necessitating delivery < 36 weeks of gestation,
is characterised by failure of trophoblast invasion of the myometrial uterine spiral arteries and reduced
uteroplacental blood flow. Nonpregnant and first trimester artery blood flow velocity waveforms are associated
with low enddiastolic velocities and an early diastolic notch. Persistent notching or abnormal flow velocity ratios
after 24 weeks of gestation are associated with inadequate trophoblast invasion of the myometrial spiral arteries.53
However reduced endovascular trophoblast invasion of decidual spiral arteries has been associated with the same
waveform abnormalities as early as 1014 weeks of pregnancy.54
A systematic review and metaanalysis summarised the results from 61 studies testing 41 131 pregnant women
with uterine artery Doppler (in both first and second trimesters) and assessed the value of different Doppler
flow velocity indices.55 SGA birth in low risk patients was best predicted by an increased pulsatility index (PI)
(defined as > 95th centile) with diastolic notching (positive likelihood ratio [LR+] 9.1, 95% CI 5.016.7; negative
likelihood ratio [LR] 0.89, 95% CI 0.850.93). Severe SGA (birthweight < 5th or < 3rd centile) in low risk
populations was best predicted in the second trimester by an increased PI (LR+ 13.7, 95% CI 10.316.9; LR
0.34, 95% CI 0.230.48) or an increased PI with notching (LR+ 14.6, 95% CI 7.826.3; LR 0.78, 95% CI
0.680.87). Uterine artery Doppler to predict a SGA infant in high risk populations overall showed low
predictive characteristics; an increased PI or notching in the second trimester best predicted a SGA infant (LR+
3.6, 95% CI 2.05.1; LR 0.40, 95% CI 0.140.65). Prediction of severe SGA showed moderate utility with the
best prediction by a resistance index (> 0.58 or > 90th centile) and notching in the second trimester (LR+ 10.9,
95% CI 10.411.4; LR 0.20, 95% CI 0.140.26). Although first trimester uterine artery Doppler studies suggest
a high specificity (9196%) and high negative predictive values (9199%), the low sensitivity (1225%) for a
SGA neonate suggest early screening cannot be recommended on current evidence.55
There were three studies included in this review that looked at prediction of early onset SGA, all
of which were in low risk/unselected populations.55 Increased PI in the second trimester has been
shown to be predictive of delivery of a SGA fetus < 34 weeks in two studies (LR+ 13.7, 95% CI
9 of 34
Evidence
level 1
11.316.7; LR 0.37, 95% CI 0.270.52) and < 32 weeks in one study (LR+ 14.6, 95% CI 11.518.7;
LR 0.31 0.180.53).
Evidence
level 1
In approximately 60% of cases with abnormal uterine artery Doppler at 2022 weeks of gestation, PI remains
increased at 2628 weeks.56 This group had the highest risk of a SGA infant (32%) compared to control women
with normal Doppler at 2022 weeks of gestation (1%). However, even when uterine artery PI normalised by 2628
weeks of gestation, the incidence of a SGA infant was higher than in controls (9.5%).Thus at present the evidence
suggests that repeating uterine artery Doppler later in the second trimester appears to be of limited value.
A systematic review assessing the effects on pregnancy outcome of routine uteroplacental
Doppler ultrasound in the second trimester showed no benefit to mother or baby. However this
review included only two studies involving 4993 participants and women were all low risk for
hypertensive disorders.57
Evidence
level 1++
The combination of uterine artery Doppler and maternal serum markers has been shown in
casecontrol and cohort studies to have an improved predictive ability for the SGA neonate, although
predictive values are still poor.5860 Use of combination testing in the second trimester appears to predict
adverse outcome related to placental insufficiency more effectively than first trimester screening.61
Evidence
level 2+
The developers interpretation of the evidence relating to uterine artery Doppler screening is that the LR is
insufficient to negate the risk associated with a major risk factor for a SGA neonate. In these women we would
not recommend uterine artery Doppler, as it would not change care.They should be offered serial assessment
of fetal size and umbilical artery Doppler from 2628 weeks of pregnancy. For women with multiple minor
risk factors, the developers consider there to be value in uterine artery Doppler screening at 2024 weeks of
pregnancy, with the institution of serial assessment of fetal size and umbilical artery Doppler from 2628
weeks of pregnancy in those with an abnormal result, given the LR+. In those with a normal result there may
still be value in a single assessment of fetal size and umbilical artery Doppler during the third trimester.
5.4 Fetal echogenic bowel

Serial ultrasound measurement of fetal size and assessment of wellbeing with umbilical artery Doppler
should be offered in cases of fetal echogenic bowel.
Fetal echogenic bowel has been shown to be independently associated with a SGA neonate (AOR 2.1, 95% CI
1.52.9) and fetal demise (AOR 9.6, 95% CI 5.815.9).62 Serial measurements of fetal size and umbilical artery
Doppler is indicated following confirmation of echogenic bowel.
An algorithm to assist in the screening of the SGA fetus is provided in Appendix 2. Risk should be assessed at
booking and then reassessed at 2024 weeks in the light of additional screening information, for example;
Down syndrome markers, 1820 week fetal anomaly scan. Several pregnancy complications (pre-eclampsia,7,17
pregnancyinduced hypertension,17 unexplained antepartum haemorrhage46 and abruption63) increase the
risk of a SGA neonate and are indications for serial assessment of fetal size and umbilical artery Doppler.
5.5 Clinical examination

Abdominal palpation has limited accuracy for the prediction of a SGA neonate and thus should not be
routinely performed in this context.
Serial measurement of symphysis fundal height (SFH) is recommended at each antenatal appointment
from 24 weeks of pregnancy as this improves prediction of a SGA neonate.
SFH should be plotted on a customised chart rather than a populationbased chart as this may improve
prediction of a SGA neonate.
10 of 34
Women with a single SFH which plots below the 10th centile or serial measurements which demonstrate
slow or static growth by crossing centiles should be referred for ultrasound measurement of fetal size.
Women in whom measurement of SFH is inaccurate (for example: BMI > 35, large fibroids, hydramnios)
should be referred for serial assessment of fetal size using ultrasound.
Cohort and casecontrol studies performed in low risk populations have consistently shown
abdominal palpation to be of limited accuracy in the detection of a SGA neonate (sensitivity
1921%, specificity 98%) and severely SGA neonate (< 2.3rd centile, sensitivity 28%).65,66 In mixed
risk populations, the sensitivity increases to 3244%.67,68 In high risk populations sensitivity is
reported as 37% for a SGA neonate and 53% for severe SGA.65
Evidence
level 2+
SFH should be measured from the fundus (variable point) to the symphysis pubis (fixed point) with the cm
values hidden from the examiner.68 Measurements should be plotted on a customised centile chart (see
below). Women with a single SFH which plots below the 10th centile or serial measurements which
demonstrate slow or static growth (i.e. they cross centiles in a downward direction) should be referred for
further investigation (Appendix 3). There is no evidence to determine the number of centiles to be crossed
to prompt referral.
A recent systematic review of five studies highlighted the wide variation of predictive accuracy of
SFH measurement for a SGA infant.69 Although early studies reported sensitivities of 5686% and
specificities of 8093% for SFH detection of a SGA neonate,7072 a large study of 2941 women
reported SFH to be less predictive with a sensitivity of 27% and specificity of 88% (LR+ 2.22, 95%
CI 1.772.78; LR 0.83, 95% CI 0.770.90).73 Maternal obesity, abnormal fetal lie, large fibroids,
hydramnios and fetal head engagement contribute to the limited predictive accuracy of SFH
measurement. SFH is associated with significant intra and interobserver variation69,74 and serial
measurement may improve predictive accuracy.75
Evidence
level 2++
The impact on perinatal outcome of measuring SFH is uncertain.A systematic review found only one trial with
1639 women which showed that SFH measurement did not improve any of the perinatal outcomes measured.76
A customised SFH chart is adjusted for maternal characteristics (maternal height, weight, parity and ethnic group).
Calculation of customised centiles requires computer software that can be downloaded from the Internet.9
No trials were identified that compared customised with noncustomised SFH charts and thus
evidence for their effectiveness on outcomes such as perinatal morbidity/mortality is lacking.
However observational studies suggest that customised SFH charts may improve the detection of a
SGA neonate. In one study, use of customised charts, with referral when a single SFH measurement
fell below the 10th centile or the last two measurements were above 10th centile but the slope was
flatter than the 10th centile line, resulted in improved sensitivity for a SGA neonate (48% versus 29%,
OR 2.2, 95% CI 1.14.5) compared to abdominal palpation.77 Use of customised charts was also
associated with fewer referrals for investigation and fewer admissions. An audit from the West
Midlands also showed that use of customised SFH charts detected 36% of SGA neonates compared
with only 16% when customised charts were not used.78
6.
Evidence
level 3
What is the optimum method of diagnosing a SGA fetus and FGR?
Fetal abdominal circumference (AC) or estimated fetal weight (EFW) < 10th centile can be used to
diagnose a SGA fetus.
11 of 34
Use of a customised fetal weight reference may improve prediction of a SGA neonate and adverse
perinatal outcome. In women having serial assessment of fetal size, use of a customised fetal weight
reference may improve the prediction of normal perinatal outcome.
Routine measurement of fetal AC or EFW in the third trimester does not reduce the incidence of a SGA
neonate nor does it improve perinatal outcome. Routine fetal biometry is thus not justified.
Change in AC or EFW may improve the prediction of wasting at birth (neonatal morphometric indicators)
and adverse perinatal outcome suggestive of FGR.
When using two measurements of AC or EFW to estimate growth velocity, they should be at least
3 weeks apart to minimise falsepositive rates for diagnosing FGR. More frequent measurements of
fetal size may be appropriate where birth weight prediction is relevant outside of the context of
diagnosing SGA/FGR.
Where the fetal AC or EFW is < 10th centile or there is evidence of reduced growth velocity, women should
be offered serial assessment of fetal size and umbilical artery Doppler (see Section 7).
6.1 Ultrasound biometry

Two systematic reviews have assessed the accuracy of ultrasound biometric measures, both as individual
measures, as ratios, and combined (as the EFW).3,79 Use of the 10th centile had better sensitivities and
specificities than other commonly used centiles.66 In a low risk population sensitivity varies from 010% and
specificity 6699% for any parameter. In a high risk population, fetal AC < 10th centile had sensitivity ranging
from 72.994.5% and specificity 50.683.8%. For EFW < 10th centile, sensitivity was 33.389.2% and specificity
53.790.9%.3,79 Metaanalysis was not performed in these systematic reviews due to the considerable clinical
and methodological heterogeneity within the included papers. The potential advantage of EFW is that
customised standards exist and accuracy can more easily be determined against birthweight.
A retrospective study has shown that among high risk patients, EFW and AC < 10th centile within
21 days of delivery better predicted a SGA infant than AC < 10th centile (80% versus 49%, OR 4.26,
95% CI 1.949.16).80 Adverse perinatal outcome was also highest when both measures were
< 10th centile.80 Kayem et al.81 found that measurement of AC in low risk women at term was a
better predictor of birth weight 2.5 kg than a single measurement of SFH (LR+ 9.9 versus 7.1,
LR 0.5 versus 0.6).
Evidence
level 2++
Several studies have compared various formulae for estimating fetal weight in unselected patients.
A prospective study compared 35 different formulae and found that most are relatively accurate at
predicting birth weight up to 3500 g.82 Another study found the Shepard and Aoki formulae to have
the best intraclass correlation coefficient, with EFW showing the smallest mean difference from
actual birth weight.83 Although formulae have been developed for SGA fetuses, there is little
evidence that accurate prediction of weight is substantially improved84,85 and in this population the
Hadlock formula86 may be most appropriate to use.
Evidence
level 2
There is no evidence to recommend one specific method of measuring AC (directly or derived from
abdominal diameters) nor which centile chart to use. The centile charts produced by Chitty et al.87 were
optimally constructed and are widely used.
The same maternal characteristics (maternal height, weight, parity and ethnic group) that affect
birth weight affect fetal biometric measures and fetal weight gain,88,89 providing a rationale for the
use of a customised AC or EFW chart.9 A customised EFW < 10th centile is predictive of a SGA
neonate (sensitivity 68%, specificity 89%).90 Use of customised fetal weight centiles to define SGA
12 of 34
Evidence
level 3
has also been shown to improve the prediction of adverse prenatal outcome;90,91 OR of adverse
outcomes (stillbirths, neonatal deaths, referral to higher level or special care unit or Apgar score <
7 at 5 minutes) for SGA neonates versus those not SGA was 1.59 (95% CI 1.531.66) for the
noncustomised fetal weight reference compared with 2.84 (95% CI 2.712.99) for the customised
reference.90 Prediction of perinatal mortality was also improved by the customised reference (OR
3.65, 95% CI 3.403.92 versus OR 1.77, 95% CI 1.651.89).91 A further study demonstrated that
individual growth trajectories of low risk fetuses with normal outcome were less likely to cross
below the 10th centile for fetal weight when using customised reference standards than when
unadjusted standards were used.92 However, no trials were identified that compared customised
with noncustomised EFW chartsp.
Evidence
level 3
A metaanalysis, including eight trials comprising 27 024 women, found no evidence that routine
fetal biometry (with or without assessment of amniotic fluid volume and placental grade) after
24 weeks of pregnancy improved perinatal outcome in a low risk population (SGA neonate relative
risk [RR] 0.98, 95% CI 0.741.28; perinatal mortality RR 0.94, 95% CI 0.551.61).93 The timing and
content of the ultrasound scan varied substantially between studies and the authors noted high
heterogeneity between studies in the reduction of the risk of a SGA neonate, mainly due to the
findings of one study in which routine estimation of fetal weight, amniotic fluid volume and
placental grading at 3032 and 3637 weeks of gestation was shown to result in the birth of fewer
SGA neonates (10.4% versus 6.9%, RR 0.67, 95% CI 0.500.89).94
Evidence
level 1+
The change in fetal size between two time points is a direct measure of fetal growth and hence
serial measurement of AC or EFW (growth velocities) should allow the diagnosis of FGR. However
the optimal method of using serial ultrasound measurements is not clear. Although eyeballing a
chart of individual AC or EFW measurements may give an impression of FGR a more objective
definition requires establishment of growth rate standards from longitudinally collected data.
Several standards have been reported,95,96 including conditional centiles for fetal growth,97 although
none has been adopted in clinical practice. Reported mean growth rates for AC and EFW after
30 weeks of gestation are 10 mm/14 days and 200 g/14 days although greater variation exists in the
lower limits (reflecting the methods used to derive the standard deviation [SD]).98 However a
change in AC of < 5mm over 14 days is suggestive of FGR.95 In a high risk population, identified as
being SGA, Chang et al.99,100 showed that a change in AC or EFW (defined as a change in SD score of
1.5) were better predictors of wasting at birth (ponderal index, midarm circumference/head
circumference ratio or subscapular skinfold thickness < 2 SD below mean) and adverse perinatal
outcome than the final AC or EFW before delivery.
Evidence
level 2+
Mongelli et al.101 used a mathematical model to estimate the impact of time interval between
examinations on the false positive rates for FGR (defined as no apparent growth in fetal AC between
two consecutive examinations). When the initial scan was performed at 32 weeks of gestation, the
false positive rates were 30.8%, 16.9%, 8.1% and 3.2% for intervals of 1,2,3 and 4 weeks respectively.
False positive rates were higher when the first scan was performed at 36 weeks of gestation (34.4%,
22.1%, 12.7%, 6.9% respectively).These findings suggest that if two measurements are to be used to
estimate velocity, they should be a minimum of 3 weeks apart to minimise falsepositive rates for
diagnosing FGR.This recommendation does not preclude more frequent ultrasound measurements
of AC/EFW to predict fetal size at birth but rather indicates which measurements should be used
to interpret growth.
Evidence
level 3
6.2 Biophysical tests

Biophysical tests, including amniotic fluid volume, cardiotocography (CTG) and biophysical scoring are poor
at diagnosing a small or growth restricted fetus.102104 A systematic review of the accuracy of umbilical artery
13 of 34
Doppler in a highrisk population to diagnose a SGA neonate has shown moderate accuracy (LR+ 3.76, 95%
CI 2.964.76; LR 0.52, 95% CI 0.450.61).105
7.
What investigations are indicated in SGA fetuses?
Offer a referral for a detailed fetal anatomical survey and uterine artery Doppler by a fetal medicine
specialist if severe SGA is identified at the 1820 week scan.
Karyotyping should be offered in severely SGA fetuses with structural anomalies and in those detected
before 23 weeks of gestation, especially if uterine artery Doppler is normal.
Serological screening for congenital cytomegalovirus (CMV) and toxoplasmosis infection should be
offered in severe SGA.
Testing for syphilis and malaria should be considered in high risk populations.
Uterine artery Doppler has limited accuracy to predict adverse outcome in SGA fetuses diagnosed
during the third trimester.
In severe SGA, the incidence of chromosomal abnormalities has been reported to be as high as
19%.104 Triploidy was the most common chromosomal defect in fetuses referred before 26 weeks of
gestation and trisomy 18 in those referred thereafter. Within this population, the risk of aneuploidy
was found to be higher in fetuses with a structural abnormality, a normal amniotic fluid volume, a
higher head circumference/AC ratio or a normal uterine artery Doppler.106,107 One small study
suggested that, in severely SGA fetuses, the rate of aneuploidy was 20% in fetuses presenting before
23 weeks of gestation, irrespective of the presence of structural anomalies, compared with 0% in
fetuses presenting between 2329 weeks of gestation.107
Evidence
level 2+
Fetal infections are responsible for up to 5% of SGA fetuses.108 The most common pathogens are reported to
be cytomegalovirus (CMV), toxoplasmosis, malaria and syphilis,108 although a recent multicentre study found
no association between congenital toxoplasmosis and incidence of a SGA infant.109 Malaria is a significant
cause of preterm birth and LBW worldwide and it should be considered in those from, or who have travelled
in, endemic areas.110
The predictive value of uterine artery Doppler in SGA fetuses diagnosed during the third trimester
is unclear and no systematic reviews on this topic were identified in the literature search for
this guideline. Severi et al.111 found that uterine artery RI > 0.50 and bilateral notching were
independently associated with emergency caesarean section in this population (OR 5.0, 95% CI
2.012.4; OR 12.2, 95% CI 2.074.3 respectively). Other studies have suggested that uterine artery
Doppler has no predictive value.112,113
8.
Evidence
level 2+
What interventions should be considered in the prevention of SGA fetuses/neonates?
Antiplatelet agents may be effective in preventing SGA birth in women at high risk of pre-eclampsia
although the effect size is small.
In women at high risk of pre-eclampsia, antiplatelet agents should be commenced at, or before, 16 weeks
of pregnancy.
There is no consistent evidence that dietary modification, progesterone or calcium prevent birth of a
SGA infant. These interventions should not be used for this indication.
14 of 34
Interventions to promote smoking cessation may prevent delivery of a SGA infant. The health benefits of
smoking cessation indicate that these interventions should be offered to all women who are pregnant
and smoke.
Antithrombotic therapy appears to be a promising therapy for preventing delivery of a SGA infant in
high-risk women. However, there is insufficient evidence, especially concerning serious adverse effects,
to recommend its use.
Antiplatelet agents have been extensively investigated in women at varying levels of risk for
pre-eclampsia, with SGA as an outcome in both an individual patient data (IPD) metaanalysis and
a Cochrane review.114,115 In all pregnant women, the RR of a SGA neonate with therapy was 0.90
(95% CI 0.830.98) and for high risk women was 0.89 (95% CI 0.741.08). In the IPD metaanalysis
for all pregnant women the RR was 0.90 (95% CI 0.811.01). The majority of the included papers
randomised women at risk of pre-eclampsia and therefore it is not possible to determine the RR for
aspirin in women at risk of a SGA neonate alone. The Cochrane review concluded that further
information was required to assess which women are most likely to benefit, when treatment is best
started and at what dose.115
Evidence
level 1++
A recent systematic review and metaanalysis of five trials, with 414 women, has suggested that, with respect
to women at risk of pre-eclampsia, the timing of commencement of aspirin is important.116 Where aspirin was
started at 16 weeks of gestation or less the RR of a SGA infant was 0.47 (95% CI 0.300.74) and the number
needed to treat was 9 (95% CI 5.017.0). No reduction in risk of a SGA infant was found when aspirin was
started after 16 weeks of gestation (RR 0.92, 95% CI 0.781.10).
A systematic review of nine trials of aspirin, in 1317 women with abnormal uterine artery Doppler,
concluded that aspirin started before 16 weeks of pregnancy reduced the incidence of
pre-eclampsia as well as SGA birth (RR 0.51, 95% CI 0.280.92); number needed to treat = 10 (95%
CI 550).117 Aspirin started after 20 weeks was not effective in reducing the risk of a SGA infant.
It is not possible to determine to what extent the effect of aspirin is due to the reduction of
pre-eclampsia in these women.
Dietary advice/modification interventions in pregnancy have yielded conflicting results in terms of
the incidence of SGA neonates. Based on thirteen trials in 4665 women, balanced energy/protein
supplementation has been associated with a modest increase in mean birth weight and a reduction
in the incidence of SGA neonates (RR 0.68, 95% CI 0.560.84).118 These effects did not appear greater
in undernourished women. In contrast, a review of two trials with 1076 women, showed
highprotein supplementation reduced mean birthweight.118 The impact on fetal growth of
multiplemicronutrient supplementation has been addressed in nine trials involving 15 378 low risk
women. Compared with supplementation of two or less micronutrients or no supplementation or a
placebo, multiple micronutrient supplementation resulted in a decrease in SGA neonates (RR 0.92,
95% CI 0.860.99). However, this difference lost statistical significance when multiple
micronutrient supplementation was compared with iron/folic acid supplementation alone.119
Although maternal nutrient supplementation has been attempted in suspected SGA/FGR (including
intraamniotic administration of nutrients), there is not enough evidence to evaluate the effects.120 A
systematic review of six trials, involving 2783 women, found that marine oil and other prostaglandin
precursor supplementation in low risk women did not alter the incidence of SGA neonates.121
Progesterone and calcium have also been used to prevent pre-eclampsia and its complications in
both high and low risk populations. In this context there is no evidence that either progesterone
(four trials, 1445 women)122 or calcium (four trials, 13 615 women)123 is effective in reducing the
incidence of SGA neonates.
15 of 34
Evidence
level 1+
Evidence
level 1+
Smoking increases the risk of SGA, and 21 trials involving over 20 000 women have addressed the
impact of interventions to promote smoking cessation in pregnancy.124 Overall interventions reduced
low birth weight (RR 0.83, 95% CI 0.730.95) and preterm birth but SGA was not reported in the
systematic review as an outcome. Trials using cognitive behavioural therapy and incentives as the
main intervention strategy demonstrated consistent improvements in birthweight.124 Women who are
able to stop smoking by 15 weeks of gestation can reduce the risk back to that of nonsmokers.39
Evidence
level 1+
Antithrombotic therapy has been used to improve outcome in women considered at risk of
placental dysfunction (primarily based on previous history of pre-eclampsia, FGR or stillbirth).
A systematic review of five studies involving 484 women, four of which compared heparin (either
alone or with dipyridamole) with no treatment, found that heparin reduced the incidence of SGA
neonates from 25% to 9% (RR 0.35, 95% CI 0.200.64) and also reduced the incidence of
pre-eclampsia.125 However, no differences were evident in perinatal mortality or preterm birth
below 34 weeks. The authors concluded that while this therapy appears promising, important
information about serious adverse effects and longterm childhood outcomes is unavailable.
Evidence
level 2+
Antihypertensive drug therapy for mild to moderate hypertension in pregnancy does not seem to
increase the risk of delivering a SGA neonate (19 trials, 2437 women, RR 1.02, 95% CI 0.891.16),126
but treatment with oral betablockers was associated with an increased risk of a SGA neonate (RR
1.36, 95% CI 1.021.82), partly dependent on one small outlying trial involving atenolol.127 Use of
atenolol is therefore best avoided but no recommendation can be made regarding the best agent
or target blood pressure to optimise fetal growth, especially when the fetus is known to be SGA.128
Evidence
level 1+
9.
What interventions should be considered in the preterm SGA fetus?
Women with a SGA fetus between 24+0 and 35+6 weeks of gestation, where delivery is being considered,
should receive a single course of antenatal corticosteroids.
Women with a SGA fetus between 24+0 and 35+6 weeks of gestation, where delivery is being
considered, should receive a single course of antenatal corticosteroids to accelerate fetal lung
maturation and reduce neonatal death and morbidity.129
Evidence
level 2
Bed rest in hospital for a suspected SGA infant has only been evaluated in one trial of 107 women that showed
no differences in any fetal growth parameters.130
Maternal oxygen administration has been investigated in three trials of SGA fetuses involving 94
women.131 Methodological problems were identified in two of the studies, both of which had
greater gestational ages of fetuses in the oxygen group. This may account for the increase in birth
weight in the intervention group. Oxygenation was associated with a lower perinatal mortality (RR
0.50, 95% CI 0.320.81). The authors of the systematic review concluded there was not enough
evidence to evaluate the benefits and risks of maternal oxygen therapy.131
Evidence
level 2
A proportion of growth restricted fetuses will be delivered prematurely and consequently be at an increased
risk of developing cerebral palsy. Maternally administered magnesium sulphate has a neuroprotective effect
and reduces the incidence of cerebral palsy amongst preterm infants. Australian guidelines recommend the
administration of magnesium sulphate when delivery is before 30 weeks of gestation.132,133
10. What is the optimal method and frequency of fetal surveillance in a SGA infant and
what is/are the optimal test/s to time delivery?
A variety of tests are available for surveillance of the SGA fetus.They vary in terms of the time and personnel
required to perform and interpret them. The purpose of surveillance is to predict fetal acidaemia thereby
16 of 34
allowing timely delivery prior to irreversible endorgan damage and intrauterine fetal death.
10.1 Umbilical artery Doppler

In a highrisk population, the use of umbilical artery Doppler has been shown to reduce perinatal
morbidity and mortality. Umbilical artery Doppler should be the primary surveillance tool in the
SGA fetus.
When umbilical artery Doppler flow indices are normal it is reasonable to repeat surveillance every
14 days.
More frequent Doppler surveillance may be appropriate in a severely SGA fetus.
When umbilical artery Doppler flow indices are abnormal (pulsatility or resistance index > +2 SDs above
mean for gestational age) and delivery is not indicated repeat surveillance twice weekly in fetuses with
enddiastolic velocities present and daily in fetuses with absent/reversed enddiastolic frequencies.
There is compelling evidence that umbilical artery Doppler is a useful tool in the management of the highrisk
pregnancy. A systematic review of 104 observational studies of accuracy, involving 19 191 fetuses, found that
umbilical artery Doppler predicted compromise of fetal/neonatal wellbeing with a pooled LR+ of 3.41 (95%
CI 2.684.34) and LR 0.55 (95% CI 0.480.62).134 The technique predicted fetal death (LR+ 4.37, 95% CI
0.8821.8; LR 0.25, 95% CI 0.070.91) and acidosis (LR+ 2.75, 95% CI 1.485.11; LR 0.58, 0.360.94).134
A systematic review of RCTs of effectiveness of umbilical artery Doppler as a surveillance tool in
high risk pregnancies (16 studies, testing 10 225 fetuses) found that use of umbilical artery Doppler
was associated with a reduction in perinatal deaths from 1.7% to 1.2% (RR 0.71, 95% CI 0.520.98),
number needed to treat was 203 (95% CI 1034352).135 There were also fewer inductions of labour
(RR 0.89, 95% CI 0.800.99) and fewer caesarean sections (RR 0.90, 95% CI 0.840.97). No
difference was found in operative vaginal births (RR 0.95, 95% CI 0.801.14) nor in Apgar scores
< 7 at 5 minutes (RR 0.92, 95% CI 0.691.24).135 Although not confined to SGA, this group of fetuses
made up a substantial proportion of the tested population. At present the recommendation from
the authors of this Cochrane review is that high risk pregnancies thought to be at risk of placental
insufficiency should be monitored with Doppler studies of the umbilical artery.
Evidence
level 1++
Several individual studies have also directly compared umbilical artery Doppler with other tests in the
management of the SGA fetus. Umbilical artery Doppler, but not biophysical profile or cardiotography (CTG),
predicted poor perinatal outcomes.136 Compared to CTG, use of umbilical artery Doppler is associated with
reduced use of antenatal resources (monitoring occasions, hospital admissions, inpatient stay), reduced
induction of labour and emergency caesarean section for fetal distress.137139
A variety of descriptor indices of umbilical artery Doppler waveform have been used to predict perinatal
outcome. The large systematic review of test accuracy could not comment on which waveform index to use
due to poor reporting in individual studies.134 Although PI has been widely adopted in the UK, an analysis
using receiver operator curves found that RI had the best discriminatory ability to predict a range of adverse
perinatal outcomes.140
When defined by customised fetal weight standards 81% of SGA fetuses have a normal umbilical
artery Doppler.141 Outpatient management is safe in this group142 and it may be reasonable to repeat
Doppler surveillance every 14 days; one small randomised trial involving 167 SGA fetuses with
normal umbilical artery Doppler investigated frequency of surveillance; twiceweekly compared to
two weekly monitoring resulted in earlier deliveries and more inductions of labour with no
difference in neonatal morbidity.143 Compared to SGA fetuses identified before delivery and
17 of 34
Evidence
level 2+
monitored with umbilical artery Doppler, unidentified SGA fetuses have a fourfold greater risk of
adverse fetal outcome (OR 4.1, 95% CI 2.56.8) and fetal/infant death (OR 4.2, 95% CI 2.18.5).144 In
this large series, SGA fetuses (defined as a birth weight deviation 2227% below the norm, equivalent
to 2 SDs) were monitored with two weekly umbilical artery Doppler. However, compared to
appropriate for gestational age (AGA) fetuses, SGA fetuses with a normal umbilical artery Doppler are
still at increased risk of neonatal morbidity (OR 2.26, 95% CI 1.044.39)141 and adverse
neurodevelopmental outcome.145
Evidence
level 2+
In SGA fetuses with abnormal umbilical artery Doppler where there is not an indication for delivery
the optimal frequency of surveillance is unclear. Until definitive evidence becomes available it is
reasonable to repeat surveillance twice weekly in fetuses with enddiastolic velocities present and
daily in fetuses with absent or reversed enddiastolic velocities (AREDV).
Evidence
level 4
In a low risk or unselected population, a systematic review of five trials, involving 14 185 women,
found no conclusive evidence that routine umbilical artery Doppler benefits mother or baby.146 As
such, umbilical artery Doppler is not recommended for screening an unselected population.
Evidence
level 1+
10.2 Cardiotocography (CTG)

CTG should not be used as the only form of surveillance in SGA fetuses.
Interpretation of the CTG should be based on short term fetal heart rate variation from computerised
analysis.
Antenatal CTG has been compared with no intervention in a Cochrane systematic review of RCTs.
Based on four trials (1627 fetuses) of high risk pregnancies there was no clear evidence that
antenatal CTG improved perinatal mortality (RR 2.05, 95% CI 0.954.42). The included trials all
employed visual analysis and only one trial was regarded as high quality.147
Evidence
level 1+
Unlike conventional CTG, which has high intra and interobserver variability, computerised
CTG (cCTG) is objective and consistent.148 Normal ranges for cCTG parameters throughout
gestation are available.149 Fetal heart rate (FHR) variation is the most useful predictor of fetal
wellbeing in SGA fetuses;150,151 a short term variation 3 ms (within 24 hours of delivery) has been
associated with a higher rate of metabolic acidaemia (54.2% versus 10.5%) and early neonatal death
(8.3% versus 0.5%).151
Evidence
level 2+
Comparison of cCTG with traditional CTG in the Cochrane review (two trials, 469 high risk fetuses)
showed a reduction in perinatal mortality with cCTG (4.2% versus 0.9%, RR 0.20, 95% CI 0.040.88)
but no significant difference in perinatal mortality excluding congenital anomalies (RR 0.23, 95%
CI 0.041.29), though the metaanalysis was underpowered to assess this outcome, or any other
measure of adverse perinatal outcome.147
Evidence
level 1
10.3 Amniotic fluid volume

Ultrasound assessment of amniotic fluid volume should not be used as the only form of surveillance in
SGA fetuses.
Interpretation of amniotic fluid volume should be based on single deepest vertical pocket.
Amniotic fluid volume is usually estimated by the single deepest vertical pocket (SDVP) or amniotic
fluid index (AFI) methods; although both correlate poorly with actual amniotic fluid volume.152 A
Cochrane systematic review (five trials, 3226 women) compared the two methods and concluded
18 of 34
Evidence
level 1+
that there was no evidence that one method was superior in the prevention of adverse perinatal
outcomes. However, compared to a SDVP < 2 cm, when an AFI 5 cm was used more cases of
oligohydramnios were diagnosed (RR 2.39, 95% CI 1.733.28) and more women had induction of
labour (RR 1.92, 95% CI 1.502.46) without an improvement in perinatal outcome.153
Evidence
level 1+
The incidence of an AFI 5 cm in a low risk population is 1.5%.154 Compared to cases with a normal AFI, the
risk of perinatal mortality and morbidity was not increased in cases with isolated oligohydramnios (RR 0.7,
95% CI 0.22.7) nor in those with associated conditions, including SGA fetuses (RR 1.6, 95% CI 0.92.6).
Notably over the 8 weeks after the initial diagnosis of oligohydramnios, mean EFW centile did not change
significantly (remaining on 3rd centile in SGA fetuses).154
Oligohydramnios is associated with labour outcome; a systematic review of 18 studies involving
10 551 women, found an AFI 5 cm was associated with an increased risk of caesarean section for
fetal distress (RR 2.2, 95% CI 1.53.4) and an Apgar score < 7 at 5 minutes (RR 5.2, 95% CI 2.411.3)
but not acidaemia.155 Although older studies in high risk pregnancies have shown that a reduced
SDVP is associated with increased perinatal mortality,156 limited information is available about the
accuracy of oligohydramnios to independently predict perinatal mortality and substantive perinatal
morbidity in nonanomalous SGA fetuses monitored with umbilical artery Doppler.
Evidence
level 1+
10.4 Biophysical profile (BPP)

Biophysical profile should not be used for fetal surveillance in preterm SGA fetuses.
The biophysical profile (BPP) includes four acute fetal variables (breathing movement, gross body movement,
tone and CTG, and amniotic fluid volume each assigned a score of 2 (if normal) or 0 (if abnormal). Reducing
BPP score is associated with lower antepartum umbilical venous pH and increasing perinatal mortality.157 The
BPP is time consuming and the incidence of an equivocal result (6/10) is high (1520%) in severely SGA
fetuses,158 although this rate can be reduced if cCTG is used instead of conventional CTG.150
A systematic review of the effectiveness of BPP as a surveillance tool in high risk pregnancies (five
studies, testing 2974 fetuses) found that the use of BPP was not associated with a reduction in
perinatal deaths (RR 1.33, 95% CI 0.602.98) or Apgar scores < 7 at 5 minutes (RR 1.27, 95% CI
0.851.92).159 Combined data from the two high quality trials suggested an increased risk of caesarean
section in the BPP group (RR 1.60, 95% CI 1.052.44) with no improvement in perinatal outcome.159
Evidence
level 1+
Early observational studies in high risk nonanomalous fetuses reported very low false negative
rates for antepartum acidaemia (0%) and perinatal death within 7 days of a normal test (0.2%).157,160
However more recent studies in preterm severely SGA fetuses suggest the BPP is not an accurate
predictor of fetal acidaemia150,161 and that the test has much higher false negative rates (11%) in this
group.161 BPP is not recommended for fetal surveillance in the preterm SGA fetus.
Evidence
level 2+
10.5 Middle cerebral artery (MCA) Doppler

In the preterm SGA fetus, middle cerebral artery (MCA) Doppler has limited accuracy to predict
acidaemia and adverse outcome and should not be used to time delivery.
In the term SGA fetus with normal umbilical artery Doppler, an abnormal middle cerebral artery Doppler
(PI < 5th centile) has moderate predictive value for acidosis at birth and should be used to time delivery.
Cerebral vasodilatation is a manifestation of the increase in diastolic flow, a sign of the brainsparing effect
of chronic hypoxia, and results in decreases in Doppler indices of the middle cerebral artery (MCA) such as
the PI. Reduced MCA PI or MCA PI/umbilical artery PI (cerebroplacental ratio) is therefore an early sign of
fetal hypoxia in SGA fetuses.162165
19 of 34
No systematic reviews of effectiveness of MCA Doppler as a surveillance tool in high risk or SGA
fetuses were identified. A systematic review of 31 observational studies (involving 3337 fetuses)
found that MCA Doppler had limited predictive accuracy for adverse perinatal outcome (LR+ 2.79,
95% CI 1.101.67; LR 0.56, 95% CI 0.430.72) and perinatal mortality (LR+ 1.36, 95% CI 1.101.67;
LR 0.51, 95% CI 0.290.89).165 Most studies investigating MCA Doppler as a predictor of adverse
outcome in preterm SGA fetuses have reported low predictive value,165167 especially when
umbilical artery Doppler is abnormal. In the largest study of predictors of neonatal outcome in SGA
neonates of less than 33 weeks gestational age (n = 604), although MCA PI < 2 SDs was associated
with neonatal death (LR 1.12, 95% CI 1.041.21) and major morbidity (LR 1.12, 95% CI 1.11.33),
it was not a statistically significant predictor of outcome on logistic regression.168 Initial findings of
a preterminal increase (reversal) of MCA PI have not been confirmed in subsequent reports.169,170
Evidence
level 1+
MCA Doppler may be a more useful test in SGA fetuses detected after 32 weeks of gestation where
umbilical artery Doppler is typically normal.171 Studies suggest an elevated MCA PI is associated
with emergency caesarean section and neonatal admission.172,173 In one study of 210 term SGA
fetuses with normal umbilical artery Doppler, MCA PI < 5th centile was predictive of caesarean
section for nonreassuring fetal status (OR 18.0, 95% CI 2.84750) and neonatal metabolic acidosis,
defined as umbilical artery pH < 7.15 and base deficit > 12 mEq/L (OR 9.0, 95% CI 1.25395).174
Based on this evidence it is reasonable to use MCA Doppler to time delivery in the term SGA fetus
with normal umbilical artery Doppler.
Evidence
level 2
10.6 Ductus venosus (DV) and umbilical vein (UV) Doppler

Ductus venosus Doppler has moderate predictive value for acidaemia and adverse outcome.
Ductus venosus Doppler should be used for surveillance in the preterm SGA fetus with abnormal
umbilical artery Doppler and used to time delivery.
The Ductus venosus (DV) Doppler flow velocity pattern reflects atrial pressurevolume changes during the
cardiac cycle. As FGR worsens velocity reduces in the DV awave owing to increased afterload and preload,
as well as increased enddiastolic pressure, resulting from the directs effects of hypoxia/acidaemia and
increased adrenergic drive.175 A retrograde awave and pulsatile flow in the umbilical vein (UV) signifies the
onset of overt fetal cardiac compromise.175
No systematic reviews of effectiveness of venous Doppler as a surveillance tool in high risk or
SGA fetuses were identified. A systematic review of 18 observational studies (involving 2267
fetuses) found that DV Doppler had moderate predictive accuracy for the prediction of perinatal
mortality in high risk fetuses with placental insufficiency with a pooled LR+ of 4.21 (95% CI
1.988.96) and LR of 0.43 (95% CI 0.300.61).175 For prediction of adverse perinatal outcome the
results were LR+ 3.15 (95% CI 2.194.54) and LR 0.49 (95% CI 0.400.59).176
Evidence
level 1+
Observational studies have identified venous Doppler as the best predictor of acidaemia.150,177 Turan
et al.150 reported an OR of 5.68 (95% CI 1.6719.32) for an increased DV PI for veins (PIV) and 45.0
(95% CI 5.0406.5) for UV pulsation compared to 2.12 (95% CI 0.666.83) for AREDV in the
umbilical artery. In the large study of predictors of neonatal outcome in preterm SGA neonates
referred to above, gestational age was the most significant determinant of intact survival until 29
weeks of gestation but DV Doppler alone predicted intact survival beyond this gestational age.168
Evidence
level 2
11.
What is the optimal gestation to deliver the SGA fetus?
In the preterm SGA fetus with umbilical artery AREDV detected prior to 32 weeks of gestation, delivery
is recommended when DV Doppler becomes abnormal or UV pulsations appear, provided the fetus is
20 of 34
considered viable and after completion of steroids. Even when venous Doppler is normal, delivery is
recommended by 32 weeks of gestation and should be considered between 3032 weeks of gestation.
If MCA Doppler is abnormal, delivery should be recommended no later than 37 weeks of gestation.
In the SGA fetus detected after 32 weeks of gestation with an abnormal umbilical artery Doppler,
delivery no later than 37 weeks of gestation is recommended.
In the SGA fetus detected after 32 weeks of gestation with normal umbilical artery Doppler, a senior
obstetrician should be involved in determining the timing and mode of birth of these pregnancies.
Delivery should be offered at 37 weeks of gestation.
At present there is no effective intervention to alter the course of FGR except delivery. Timing delivery is
therefore a critical issue in order to balance the risks of prematurity against those of continued intrauterine
stay; death and organ damage due to inadequate tissue perfusion.178
Gestational age is a critical determinant in decisionmaking. Various tools exist to predict survival in very
preterm births, such as the prematurity risk evaluation measure (PREM) score, which is a system derived from
UK cohorts and incorporates gestational age and EFW.179 In FGR detected prior to 33 weeks of gestation,
gestational age was found to be the most significant determinant of total survival until 27 weeks and intact
survival until 29 weeks.168
The second critical determinant in decisionmaking is the interpretation of surveillance tests which should
accurately predict perinatal outcomes of importance (death, major morbidity and neurodevelopmental delay).
Existing studies investigating the relationship between fetal surveillance tests and neurodevelopmental
outcome have recently been reviewed.185 Several studies have reported the sequence of changes in Doppler
and biophysical parameters as FGR worsens.170,181,182 While most fetuses showed a deterioration of arterial
Doppler indices before the occurrence of an abnormal DV PIV or biophysical abnormalities, the relationship
between venous Doppler and biophysical abnormalities was not consistent. For example, more than 50% of
fetuses delivered because of cCTG abnormalities had a normal DV PIV.181
11.1 Preterm SGA fetus

The RCT growth restriction intervention trial (GRIT) compared the effect of delivering early (after
completion of a steroid course) with delaying birth for as long as possible (i.e. until the obstetrician
was no longer uncertain).183 Between 2436 weeks of gestation, 588 fetuses were recruited. Median
timetodelivery was 0.9 days in the early group and 4.9 days in the delay group. There was no
difference in total deaths prior to discharge (10% versus 9%, OR 1.1, 95% CI 0.61.8), inferring
obstetricians are delivering sick preterm fetuses at about the correct time to minimise mortality.183
At 2 years overall rates of death (12% versus 11% respectively) or severe disability, defined as
a Griffiths developmental quotient 70 or presence of motor or perceptual severe disability
(7% versus 4%) were similar (OR 1.1, 95% CI 0.71.8).184 These findings are consistent with
observational studies suggesting that fetal deterioration does not have an independent impact on
neurodevelopment in earlyonset FGR.180
Evidence
level 1+
On the basis of GRIT, the evidence reviewed in Section 10 and that perinatal mortality increases
from 12% in fetuses with umbilical artery AREDV to 39% when DV PIV is increased (and 41% with
absence or reversal of DV Awave)178 it would seem reasonable to recommend delivery when the
DV Doppler becomes abnormal or UV pulsations are present, provided the fetus is considered
viable (usually when gestational age is 24 weeks and EFW is > 500 g)181, 185 and after completion
of steroids. Based on available evidence it is not known whether delivery should be recommended
as soon as the DV PIV becomes abnormal or whether delivery should be deferred until the DV
Evidence
level 4
21 of 34
Awave becomes absent/reversed. This key question is being addressed in the ongoing trial of
umbilical and fetal flow in a European RCT which aims to determine whether delivery based on
reduced short term variability on cCTG leads to better neurodevelopmental outcome in surviving
infants than delivery based on DV Doppler.186
By 31 weeks of gestation, neonatal mortality and disability rates in this population are low; in GRIT,
mortality and disability rates in fetuses delivered at 3136 weeks were 5% and 4% respectively183
while in the large series of early onset FGR reported by Baschat et al.,168 mortality was 8.6% in
fetuses delivered at 31 weeks and 2.6% in those delivered at 32 weeks. Given the mortality
associated with umbilical artery AREDV alone178 delivery should be considered based on this finding
alone after 30 weeks of gestation and recommended no later than 32 weeks of gestation.
Evidence
level 4
11.2 Near term / term SGA fetus

One randomised equivalence trial exists comparing the effect of induction of labour or expectant
monitoring in women beyond 36 weeks of gestation with suspected FGR (defined as a fetal AC or
EFW < 10th centile or flattening of the growth curve in the third trimester, as judged by the
clinician).187 Between 3641 weeks of gestation, 650 fetuses were recruited; 14 had umbilical artery
AREDV. Expectant monitoring consisted of twice weekly CTG and ultrasound examinations.
Induction group infants were delivered 9.9 (95% CI 8.611.3) days earlier and weighed 130 g (95%
CI 71188) less. A total of 5.3% infants in the induction group experienced adverse outcome
(defined as death, umbilical artery pH < 7.05 or admission to intensive care) compared to 6.1% in
the expectant monitoring group (difference 0.8%, 95% CI 4.33.2). Caesarean section was
performed in 14% of women in both groups.187 Based on these results, it is reasonable to offer
delivery in SGA infants at 37 weeks of gestation.
Evidence
level 1+
Given the evidence reviewed in Section 10 and the increased risk of adverse outcomes in term/
near term SGA fetuses with increased umbilical artery PI and those with a normal umbilical artery
Doppler but reduced MCA PI, delivery should be recommended by 37 weeks of gestation.
Evidence
level 2
An algorithm to assist in the management of the SGA fetus is provided in Appendix 3.
12. How should the SGA fetus be delivered?

In the SGA fetus with umbilical artery AREDV delivery by caesarean section is recommended.
In the SGA fetus with normal umbilical artery Doppler or with abnormal umbilical artery PI but
enddiastolic velocities present, induction of labour can be offered but rates of emergency caesarean
section are increased and continuous fetal heart rate monitoring is recommended from the onset of
uterine contractions.
Early admission is recommended in women in spontaneous labour with a SGA fetus in order to instigate
continuous fetal heart rate monitoring.
Compared to appropriateforgestational age fetuses, term and near term SGA fetuses are at increased risk of
FHR decelerations in labour, emergency caesarean section for suspected fetal compromise and metabolic
acidaemia at delivery. This reflects a lower prelabour pO2 and pH,188 greater cord compression secondary to
oligohydramnios189 and a greater fall in pH and higher lactate levels when FHR decelerations are present.190
Reported rates of emergency CS for suspected fetal compromise vary from 645% but a rate of ~15% is
probably reasonable for fetuses with an AC or EFW < 10th centile, with higher rates in those with serial AC or
EFW measurements suggestive of FGR.98,191,192 No RCTs of mode of delivery in the SGA fetus were identified.
22 of 34
Delivery in all recent studies reporting outcome of viable SGA fetuses with umbilical artery AREDV has been
by caesarean section and thus it is not possible to determine the likelihood of adverse outcome (including
emergency CS for suspected fetal compromise) associated with induced/spontaneous labour. Older series
report rates of intrapartum fetal heart decelerations necessitating CS of 7595%.193,194 More recent prospective
data on the outcome of labour in SGA fetuses with an abnormal umbilical artery Doppler but enddiastolic
velocities is also extremely limited; suspected fetal compromise (necessitating emergency CS) has been
reported in 1732% of such cases, compared to 69% in SGA fetuses with normal umbilical artery
Doppler.191,192,195 Although, it is acknowledged that knowledge of Doppler may lower obstetricians threshold
for emergency CS.196 The offer of induction of labour with continuous FHR monitoring is therefore reasonable
in term and near term fetuses, as well as SGA fetuses without umbilical artery AREDV. The procedures for
induction of labour should follow existing guidance.197

All units should audit their antenatal detection rate of the SGA neonate. Definition of a SGA neonate should
be based on customised birthweight standards. Suggested auditable standards are as follows:
All women should have a formal assessment of their risk of delivering a SGA neonate at booking.
All women with a major risk factor for a SGA neonate should be offered serial ultrasound measurement of
fetal size and assessment of wellbeing with umbilical artery Doppler.
All women with a SGA fetus should have serial ultrasound measurement of fetal size and assessment of
wellbeing with umbilical artery Doppler.
All women with a SGA fetus where delivery is considered between 24+0 and 35+6 weeks of gestation should
receive a single course of antenatal corticosteroids.
14. What are the areas for future research?

Research may be required to evaluate the effectiveness of/determine:
How combinations of risk factors for a SGA neonate (historical, biochemical and ultrasound) relate to each
other in the individual woman.

Interventions, specifically aspirin, in women classified as being at high risk of delivering a SGA neonate
based on combined historical, biochemical, and ultrasound marker screening in the first trimester.
Introducing customised SFH and EFW charts into clinical practice on substantive clinical endpoints
(perinatal mortality/morbidity and service utilisation).

Routine third trimester ultrasound assessment of fetal size combined with umbilical artery Doppler on
substantive clinical endpoints (perinatal mortality/morbidity and service utilisation).

Oxygen therapy in severe earlyonset SGA foetuses associated with umbilical artery AREDV on substantive
clinical endpoints (perinatal mortality/morbidity and service utilisation).

Optimal frequency and content of fetal surveillance in SGA fetuses with both a normal umbilical artery
Doppler and also an abnormal umbilical artery Doppler but with enddiastolic frequencies present.
Measuring amniotic fluid volume and MCA Doppler in the near term SGA fetuses with a normal umbilical
artery Doppler on substantive clinical endpoints (perinatal morbidity and service utilisation).
Potential health economic benefit of investment in maternity services to provide recommendations in this
guideline and future health outcomes of the children.
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Appendix I: Summary of Risk Factors for a SmallforGestationalAge Neonate.

Table A: Available from history at booking (usually prior to 12 weeks)
Risk category
Definition of risk
Definition of outcome
measure
Estimate
measure
Point estimate and

95% CI
Maternal age 35 years22
BW < 10th centile population
OR
1.4 (1.11.8)
Maternal age > 40 years22
OR
3.2 (1.95.4)
Nulliparity25
Maternal Risk Factors

Age
Parity
BMI
BW < 10th centile population*
OR
1.89 (1.821.96)
BMI
< 2028
BW < 10th centile customised
OR
1.2 (1.11.3)
BMI
2529.928
RR
1.2 (1.11.3)
RR
1.5 (1.31.7)
AOR
1.4 (1.21.7)
BW < 9.9th centile population
OR
1.54 (1.391.7)
Smoker 11 cigarettes per day
BW < 9.9th centile population
OR
2.21 (2.032.4)
Cocaine38
OR
3.23 (2.434.3)
BW < 10th centile
OR
1.6 (1.32.0)
AOR
3.3 (1.57.2)
AOR
1.9 (1.32.8)
OR
3.9 (2.147.12)
OR
6.4 (0.7852.56)
AOR
1.31 (1.191.44)
BMI 3028
Maternal substance
Exposure
Smoker32
Smoker 110 cigarettes per
day29
29
IVF
Exercise
Diet
IVF singleton pregnancy41

Daily vigorous
exercise32
Low fruit intake
prepregnancy32
Previous Pregnancy History

Previous SGA
Previous SGA baby8

stillbirth8
Previous Stillbirth
Previous
Previous pre-eclampsia
Pre-eclampsia9
Pregnancy Interval
Pregnancy interval < 6 months
SGA not defined*
AOR
1.26 (1.181.33)
Pregnancy interval 60 months33
SGA not defined*
AOR
1.29 (1.21.39)
Maternal SGA31
BW < 10th centile population*
OR
2.64 (2.283.05)
ARR
2.5 (2.12.9)
33
Maternal Medical History

SGA
Hypertension
Chronic
hypertension17
disease14
Diabetes
Diabetes with vascular
OR
6 (1.52.3)
Renal disease
Renal impairment15
AOR
5.3 (2.810)
APLS
Antiphospholipid syndrome16
FGR no definition
RR
6.22 (2.4316.0)
Paternal SGA43
OR
3.47 (1.1710.27)
Estimate
measure
Point estimate and

95% CI
Paternal Medical History

SGA
Table B: Current pregnancy complications/developments

Risk category
Definition of risk
Threatened miscarriage
Heavy bleeding similar to menses34 BW < 10th centile population
AOR
2.6 (1.25.6)
Ultrasound appearance
Echogenic bowel62
AOR
2.1 (1.52.9)
Pre-eclampsia
Pre-eclampsia8
AOR
2.26 (1.224.18)
Pregnancy induced
hypertension
Mild
Severe17
BW <10th centile population

RR
RR
1.3 (1.31.4)
2.5 (2.32.8)
Placental abruption
Placental abruption61
SGA not defined*
OR range
1.34.1
IUGR not defined
OR
5.6 (2.512.2)
OR
4.9 (1.912.6)
Unexplained APH
Definition of outcome
measure
17
Unexplained
APH44
gain13
Weight gain
Low maternal weight
Exposure
Caffeine 300 mg/day in

third trimester40
OR
1.9 (1.32.8)
DS marker
PAPPA < 0.4 MoM45
OR
2.6
* Denotes data from systematic review

Information regarding these risk factors may be unobtainable
Major risk factors are in bold
29 of 34
APPENDIX II: Screening for SmallforGestationalAge (SGA) Fetus

30 of 34
31 of 34
Delivery
Recommend delivery by 37 weeks
Consider steroids if delivery by CS
Consider delivery > 34 weeks if static growth
over 3 weeks
Recommend steroids if delivery is by CS
(as per RCOG guidance)
Repeat ultrasound
Weekly
Twice weekly
AC & EFW1,2
UA Doppler
PI or RI > 2 SDs, EDV present
UA Doppler
Fetal biometry
Single AC or EFW < 10th customised centile
Serial measurements indicative of FGR
Repeat ultrasound
Weekly
Daily
AC & EFW1,2
UA Doppler
DV Doppler
[cCTG]3
AREDV
Delivery
Recommend delivery before 32 weeks after
steroids if:
abnormal DV Doppler and/or cCTG
provided 24 weeks & EFW > 500 g
Recommend delivery by 32 weeks after steroids
Consider delivery at 3032 weeks even when
DV Doppler is normal
Refer for
fetal medicine
specialist
opinion
High risk of SGA fetus/neonate

Based on history, biochemistry or uterine
artery Doppler
Weekly measurement of fetal size is valuable in predicting birthweight and determining size-for-gestational age
If two AC/EFW measurements are used to estimate growth, they should be at least 3 weeks apart
3
Use cCTG when DV Doppler is unavailable or results are inconsistent recommend delivery if STV < 3 ms
Abbreviations: AC, abdominal circumference; EFW, estimated fetal weight; PI, pulsatility index; RI, resistance index; UA, umbilical artery; MCA, middle cerebral artery; DV ducts venosus;
SD, standard deviation; AREDV., Absent/reversed enddiastolic velocities; cCTG, computerised cardiotography; STV, short term variation; SFH, symphysisfundal height;
FGR, fetal growth restriction; EDV, enddiastolic velocities.
Delivery
Offer delivery by 37 weeks with the
involvement of a senior clinician
Recommend delivery by 37 weeks if
MCA Doppler PI < 5th centile
Consider delivery > 34 weeks if static growth
over 3weeks
Recommend steroids if delivery is by CS
(as per RCOG guidance)
Repeat ultrasound
(Fortnightly)
AC & EFW1,2 UA Doppler
MCA Doppler after 32 weeks
Normal
SFH
Single measurement < 10th customised centile
&/or serial measurements indicative of FGR
APPENDIX III: The Management of the SmallforGestationalAge (SGA) Fetus
APPENDIX IV: Glossary

AC
Abdominal circumference
AFI
Amniotic fluid index
AFP
Alpha fetoprotein
AGA
Appropriate for gestational age
AOR
Adjusted odds ratio
APH
Antepartum haemorrhage
AREDV
Absent or Reversed EndDiastolic Velocity
BMI
Body mass index
BPP
Biophysical profile
CI
Confidence interval
CTG
Cardiotocography
cCTG
Computerised cardiotocography
CMV
Cytomegalo virus
DS
Down Syndrome
DV
Ductus venosus
EDV
End-diastolic velocities
EFW
Estimated fetal weight
FGR
Fetal growth restriction
FHR
Fetal heart rate
GRIT
Growth restriction intervention trial
hCG
Human chorionic gonadotrophin
IPD
Individual patient data
LBW
Low birth weight
LR
Likelihood ratio
LR+
Positive likelihood ratio
LR
Negative likelihood ratio
MCA
Middle cerebral artery
MeSH
Medical subject heading
MoM
Multiples of the median
OR
Odds ratio
PAPPA
Pregnancy associated plasma proteinA
PI
Pulsatility Index
PIV
Pulsatility Index for veins
PREM
Prematurity risk evaluation measure
RCT
Randomised controlled trial
RR
Relative risk
SDVP
Single deepest vertical pocket
SFH
Symphysis fundal height
SGA
Smallforgestationalage
STV
Short term variation
TRUFFLE
Trial of umbilical and fetal flow in Europe
32 of 34
APPENDIX V: Explanation of Guidelines and Evidence Levels

Clinical guidelines are:systematically developed statements which assist clinicians and women in making
using a standardised methodology. Exact details of this process can be found in Clinical Governance
Advice No.1: Development of RCOG Green-top Guidelines (available on the RCOG website at
http://www.rcog.org.uk/greentopdevelopment). These recommendations are not intended to dictate an
exclusive course of management or treatment.They must be evaluated with reference to individual patient
needs, resources and limitations unique to the institution and variations in local populations. It is hoped
that this process of local ownership will help to incorporate these guidelines into routine practice.
Attention is drawn to areas of clinical uncertainty where further research might be indicated.

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
33 of 34

development group
This guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and Gynaecologists
by:
Professor SC Robson MRCOG, NewcastleuponTyne; Dr WL Martin FRCOG, Birmingham and Dr RK Morris MRCOG,
Birmingham.
Committee Lead Reviewers: Dr P Owen FRCOG, Glasgow, Scotland; Ms CJ Elson FRCOG, Leicestershire; Mr DJ Cruickshank
FRCOG, Middlesborough
and peerreviewed by: British Maternal and Fetal Medicine Society (BMFMS); British Medical Ultrasound Society (BMUS);
British Society of Urogenital Radiology (BSUR); Clinical Studies Group for Stillbirth (CSGS, hosted by SANDS); International
Society of Ultrasound in Obstetrics and Gynaecologist (ISUOG); Perinatal Institute; Dr UB Agarwal MRCOG, Liverpool;
Professor JC Dornan FRCOG, County Down, Northern Ireland; Dr MA Harper FRCOG, Belfast; Mr B Kumar FRCOG, Wrexham;
Dr AC McKelvey MRCOG, Norfolk; Professor LME McCowan, University of Auckland, New Zealand; Mr DJ Tuffnell FRCOG,
Bradford; Mr SA Walkinshaw FRCOG, Liverpool.
Conflicts of interest; none declared.
The final version is the responsibility of the Guidelines Committee of the RCOG
DISCLAIMER
health services.
34 of 34

UK National Guideline
for the Management of Pelvic Inflammatory Disease
2011
(updated June 2011)
Clinical Effectiveness Group
British Association for Sexual Health and HIV
Guideline development group:

Jonathan Ross MB ChB MD FRCP (lead author)
Gill McCarthy MB BS FRCP (lead editor on behalf of BASHH CEG)
What is new in the June 2011 update?
The dose of ceftriaxone has been increased to 500mg stat to reflect the reduced sensitivity of
Neisseria gonorrhoeae to cephalosporins and the current UK treatment guidelines for
uncomplicated gonorrhoea
NHS Evidence has accredited the process used by the British Association for Sexual Health &
HIV (BASHH) to produce UK national guidelines. Accreditation is valid for 3 years from January
2011 and is retrospectively applicable to guidance produced using the processes described in
the BASHH Framework for Guideline Development and Assessment dated September 2010.
More information on accreditation can be viewed at www.evidence.nhs.uk

Introduction and methodology
Objectives
This guideline offers recommendations on the diagnostic tests, treatment regimens and health
promotion principles needed for the effective management of pelvic inflammatory disease (PID)
covering the management of the initial presentation, as well as how to reduce transmission and future
infection.
It is aimed primarily at women aged 16 years or older (see specific guidelines for those under 16)
presenting to health care professionals working in departments offering level 3 care in STI
management within the United Kingdom. However, the principles of the recommendations should be
adopted across all levels - level 1 and 2 providers may need to develop local care pathways where
appropriate.
A PID patient information leaflet is currently being developed.
Search strategy
Five reference sources were used to provide a comprehensive basis for the guideline:
1. Medline and Embase Search
a.1987 January 2010
The search strategy comprised the following terms in the title or abstract: pelvic inflammatory
disease, adnexitis, oophoritis, parametritis, salpingitis, endometritis, PID (excluding primary
immune deficiency), adnexal disease or adnexal disease. 10422 citations were identified.
b.1963 - 1986
The search strategy comprised the following terms in the title or abstract: pelvic inflammatory
disease, adnexitis, oophoritis, parametritis, salpingitis or adnexal disease. The dataset was then
limited to AIM journals and human subjects, identifying 2321 citations.
2. 2010 CDC STD Treatment Guidelines (www.cdc.gov/std/)
3. 2009 RCOG Green Top Guidelines Management of Acute Pelvic Inflammatory Disease
(www.rcog.org.uk)
4. Royal College of Obstetrics and Gynaecology Working Group on PID Report 19961
PID guideline V4
page 2

5. Cochrane Collaboration Databases (www.cochrane.org)
Methods
Article titles and abstracts were reviewed and if relevant the full text article obtained. Priority was
given to randomised controlled trial and systematic review evidence, and recommendations made
and graded on the basis of best available evidence.
Piloting and feedback

The initial draft of the guideline including the patient information leaflet was piloted for validation by
the Clinical Effectiveness Group (CEG) of BASHH using a sample of UK genitourinary medicine
clinics. A standardised feed back form was completed by each pilot site and the guideline amended
by the CEG editor. The final guideline was then reviewed by the CEG using the AGREE instrument
before posting it on the BASHH website for external peer review for a 3 month period. Comments
received were collated by the CEG editor and sent to the guideline chair for review and action. The
final guideline was approved by the CEG and a review date agreed before publication on the BASHH
website.
Aetiology
PID is usually the result of infection ascending from the endocervix causing endometritis,
salpingitis, parametritis, oophoritis, tuboovarian abcess and/or pelvic peritonitis.
Neisseria gonorrhoeae and Chlamydia trachomatis have been identified as causative agents
1, 2
but account for only a quarter of cases in the UK, whilst Gardnerella vaginalis, anaerobes
(including Prevotella, Atopobium and Leptotrichia) and other organisms commonly found in the
vagina may also be implicated. Mycoplasma genitalium has also been associated with upper
genital tract infection in women3.
Clinical Features
Symptoms
The following features are suggestive of a diagnosis of PID1, 2, 4, 5:
lower abdominal pain which is typically bilateral
PID guideline V4
page 3

deep dyspareunia
abnormal vaginal bleeding, including post coital, inter-menstrual and menorrhagia
abnormal vaginal or cervical discharge which is often purulent
Signs
lower abdominal tenderness which is usually bilateral
adnexal tenderness on bimanual vaginal examination
cervical motion tenderness on bimanual vaginal examination
fever (>38C)
A diagnosis of PID, and empirical antibiotic treatment, should be considered and usually offered in
any young (under 25) sexually active woman who has recent onset, bilateral lower abdominal pain
associated with local tenderness on bimanual vaginal examination, in whom pregnancy has been
excluded.
Complications
Women with HIV may have more severe symptoms associated with PID but respond well to
standard antibiotic therapy6. No change in treatment recommendations compared to HIV
uninfected patients is required7-9. (Grade B [III])
The Fitz-Hugh-Curtis syndrome comprises right upper quadrant pain associated with perihepatitis
which occurs in some women with PID. Although laparoscopic division of hepatic adhesions has
been performed, there is insufficient clinical trial evidence to make specific recommendations for
treatment beyond those for uncomplicated PID.
The randomised controlled trial evidence for whether an intrauterine contraceptive device should
be left in situ or removed in women presenting with PID is limited10, 11. Removal of the IUD should
be considered and may be associated with better short term clinical outcomes10. The decision to
remove the IUD needs to be balanced against the risk of pregnancy in those who have had
otherwise unprotected intercourse in the preceding 7 days. Hormonal emergency contraception
may be appropriate for some women in this situation.
PID guideline V4
page 4
Diagnosis
PID may be symptomatic or asymptomatic. Even when present, clinical symptoms and signs lack
sensitivity and specificity (the positive predictive value of a clinical diagnosis is 65-90% compared
to laparoscopic diagnosis2, 4, 5)
Testing for gonorrhoea and chlamydia in the lower genital tract is recommended since a positive
result supports the diagnosis of PID. The absence of infection at this site does not exclude PID
however2, 4, 5
An elevated ESR or C reactive protein also supports the diagnosis but is non-specific 12.
The absence of endocervical or vaginal pus cells has a good negative predictive value (95%) for
a diagnosis of PID but their presence is non-specific (poor positive predictive value 17%)13.
The differential diagnosis of lower abdominal pain in a young woman includes:

ectopic pregnancy pregnancy should be excluded in all women suspected of having PID
acute appendicitis nausea and vomiting occurs in most patients with appendicitis but only 50% of
those with PID. Cervical movement pain will occur in about a quarter of women with appendicitis 14,
15
endometriosis the relationship between symptoms and the menstrual cycle may be helpful in
establishing a diagnosis
complications of an ovarian cyst e.g. torsion or rupture often of sudden onset
urinary tract infection often associated with dysuria and/or urinary frequency
functional pain may be associated with longstanding symptoms
Management
It is likely that delaying treatment increases the risk of long term sequelae such as ectopic pregnancy,
infertility and pelvic pain16. Because of this, and the lack of definitive diagnostic criteria, a low
threshold for empiric treatment of PID is recommended. Broad spectrum antibiotic therapy is required
PID guideline V4
page 5

to cover N. gonorrhoeae, C. trachomatis and a variety of aerobic and anaerobic bacteria commonly
isolated from the upper genital tract in women with PID1, 2.
Some of the best evidence for the effectiveness of antibiotic treatment in preventing the long term
complications of PID comes from the PEACH study where women were treated with cefoxitin followed
by doxycycline pregnancy rates after 3 years were similar or higher than those in the general
population 17, 18.
The choice of an appropriate treatment regimen may be influenced by:

robust evidence on local antimicrobial sensitivity patterns
robust evidence on the local epidemiology of specific infections in this setting
cost
patient preference and compliance
severity of disease
General Advice
Rest is advised for those with severe disease. (Grade C [IV])
Appropriate analgesia should be provided. (Grade C [IV])
Intravenous therapy is recommended for patients with more severe clinical disease (Grade C [IV])
e.g. pyrexia > 38oC, clinical signs of tubo-ovarian abcess, signs of pelvic peritonitis.
Patients should be advised to avoid unprotected intercourse until they, and their partner(s), have
completed treatment and follow-up (Grade C [IV]).
A detailed explanation of their condition with particular emphasis on the long term implications
for the health of themselves and their partner(s) should be provided, reinforced with clear and
accurate written information (Grade C [IV]). A patient information leaflet is included in
appendix 1 of this guideline.
When giving information to patients, the clinician should consider the following:
PID guideline V4
page 6
an explanation of what treatment is being given and its possible adverse effects
that following treatment fertility is usually maintained but there remains a risk of future
infertility, chronic pelvic pain or ectopic pregnancy
clinically more severe disease is associated with a greater risk of sequelae
repeat episodes of PID are associated with an exponential increase in the risk of infertility
the earlier treatment is given the lower the risk of future fertility problems.
future use of barrier contraception will significantly reduce the risk of PID
the need to screen her sexual contacts for infection to prevent her becoming reinfected
Outpatient therapy is as effective as inpatient treatment for patients with clinically mild to moderate
PID17. Admission for parenteral therapy, observation, further investigation and/or possible surgical
intervention should be considered in the following situations19:
a surgical emergency cannot be excluded
lack of response to oral therapy
clinically severe disease
presence of a tuboovarian abcess
intolerance to oral therapy
pregnancy
Further Investigation
All sexually active patients should be offered:
a pregnancy test
screening for sexually transmitted infections including HIV20
Treatment
The following antibiotic regimens are evidence based.
PID guideline V4
page 7
Recommended Regimens
All the recommended regimens are of similar efficacy.
Outpatient Regimens
i.m. ceftriaxone* 500mg single dose followed by oral doxycycline 100mg twice daily plus
metronidazole 400mg twice daily for 14 days
Grade A (Ib) 21-23
*
Clinical trial data support the use of cefoxitin for the treatment of PID but this agent is not easily
available in the UK so ceftriaxone, which has a similar spectrum of activity, is recommended.
oral ofloxacin 400mg twice daily plus oral metronidazole 400mg twice daily for 14 days
Grade A (Ib) 23-27
Metronidazole is included in some regimens to improve coverage for anaerobic bacteria. Anaerobes
are of relatively greater importance in patients with severe PID and metronidazole may be
discontinued in those patients with mild or moderate PID who are unable to tolerate it.
Ofloxacin and moxifloxacin should be avoided in patients who are at high risk of gonococcal PID
because of increasing quinolone resistance in the UK (e.g. when the patients partner has
gonorrhoea, in clinically severe disease, following sexual contact abroad). Quinolones should also be
avoided as first line empirical treatment for PID in areas where >5% of PID is caused by quinolone
resistant Neisseria gonorrhoeae.
Levofloxacin is the L isomer of ofloxacin28 and has the advantage of once daily dosing (500mg OD for
14 days). It may be used as a more convenient alternative to ofloxacin.29
Replacing intramuscular ceftriaxone with an oral cephalosporin (e.g. cefixime) is not recommended
because there is no clinical trial evidence to support its use, and tissue levels are likely to be lower
which might impact on efficacy. Reports of decreasing susceptibility of Neisseria gonorrhoeae to
PID guideline V4
page 8

cephalosporins also supports the use of parenteral based regimens when gonococcal PID is
suspected (to maximise tissue levels and overcome low level resistance).
Alternative Regimens
intramuscular ceftriaxone 500 mg immediately, followed by azithromycin 1 g/week for 2 weeks
Grade A (Ib)30, 31
Clinical trial evidence for this regimen is limited but it may be used when the treatments above are not
appropriate e.g. allergy, intolerance:
oral moxifloxacin 400mg once daily for 14 days

Grade A (Ib)29, 32, 33
Three large RCTs support the efficacy of moxifloxacin for PID but because of evidence of an
increased risk of liver reactions and other serious risks (such as QT interval prolongation), oral
moxifloxacin should be used only when it is considered inappropriate to use the other antibacterial
agents recommended for PID or when these have failed.
Inpatient Regimens
Intravenous therapy should be continued until 24 hours after clinical improvement and then switched
to oral. Intravenous doxycycline is not currently licensed in the UK but is available from IDIS world
medicines (01932 824100).
PID guideline V4
page 9

i.v. ceftriaxone 2g daily plus i.v. doxycycline 100mg twice daily (oral doxycycline may be used
if tolerated) followed by oral doxycycline 100mg twice daily plus oral metronidazole 400mg
twice daily for a total of 14 days
Grade A (Ib) 22, 23
i.v. clindamycin 900mg 3 times daily plus i.v. gentamicin (2mg/kg loading dose)
followed by 1.5mg/kg 3 times daily [a single daily dose of 7mg/kg may be substituted])
followed by either oral clindamycin 450mg 4 times daily or oral doxycycline 100mg twice daily
plus oral metronidazole 400mg twice daily to complete 14 days
Grade A (Ib) 22
Gentamicin levels need to be monitored if this regimen is used.
Alternative Regimens
Clinical trial evidence for the following regimens is more limited but they may be used when the
treatments above are not appropriate e.g. allergy, intolerance:
i.v. ofloxacin 400mg BD plus i.v. metronidazole 500mg TID for 14 days
Grade B (III) 23-25, 34
i.v. ciprofloxacin 200mg BD plus i.v. (or oral) doxycycline 100mg BD plus i.v. metronidazole
500mg TID for 14 days
Grade B (III) 24, 35
Allergy
There is no clear evidence of the superiority of any one of the suggested regimens over the others.
Therefore patients known to be allergic to one of the suggested regimens should be treated with an
alternative.
Pregnancy and Breastfeeding
PID guideline V4
page 10
PID in pregnancy is associated with an increase in both maternal and fetal morbidity,
therefore parenteral therapy is advised although none of the suggested evidence based
regimens are of proven safety in this situation.
There are insufficient data from clinical trials to recommend a specific regimen and empirical
therapy with agents effective against gonorrhoea, chlamydia and anaerobic infections should
be considered taking into account local antibiotic sensitivity patterns (e.g. i.m. ceftriaxone plus
oral or i.v. erythromycin, with the possible addition of oral or i.v. metronidazole 500mg 3 times
daily in clinically severe disease) (Grade C [IV]).
The risk of giving any of the recommended antibiotic regimens (listed above for non pregnant
women) in very early pregnancy (prior to a pregnancy test becoming positive) is justified by
the need to provide effective therapy and the low risk to the foetus (personal communication,
UK National Teratology Information Service 11.2.10).
Surgical Management
Laparoscopy may help early resolution of the disease by dividing adhesions and draining
pelvic abscesses36 but ultrasound guided aspiration of pelvic fluid collections is less invasive
and may be equally effective.37, 38
It is also possible to perform adhesiolysis in cases of perihepatitis although there is no

evidence whether this is superior to using only antibiotic therapy
Sexual Partners
Current male partners of women with PID should be contacted and offered health advice and
screening for gonorrhoea and chlamydia. Other recent sexual partners may also be offered
screening - tracing of contacts within a 6 month period of onset of symptoms is recommended
but this time period may be influenced by the sexual history (Grade C [IV]).
Gonorrhoea or chlamydia diagnosed in the male partner should be treated appropriately and
concurrently with the index patient. (Grade C [IV]).
PID guideline V4
page 11
Because many cases of PID are not associated with gonorrhoea or chlamydia, broad
spectrum empirical therapy should also be offered to male partners e.g. azithromycin 1g single
dose (Grade C [IV]).
If screening for gonorrhoea is not available additional specific antibiotics effective against
Neisseria gonorrhoeae should be offered e.g. i.m. ceftriaxone 500mg single dose (see also UK
National Guidelines for Gonorrhoea) (Grade C [IV]).
Partners should be advised to avoid intercourse until they and the index patient have
completed the treatment course (Grade C [IV]).
Follow Up
Review at 72 hours is recommended 5, particularly for those with a moderate or severe clinical
presentation, and should show a substantial improvement in clinical symptoms and signs (Grade C
[IV]). Failure to do so suggests the need for further investigation, parenteral therapy and/or surgical
intervention.
Further review 2-4 weeks (Grade C [IV]) after therapy may be useful to ensure:
adequate clinical response to treatment
compliance with oral antibiotics
screening and treatment of sexual contacts
awareness of the significance of PID and its sequelae
repeat pregnancy test, if clinically indicated
Repeat testing for gonorrhoea or chlamydia after 2 to 4 weeks is appropriate in those in whom
persisting symptoms, antibiotic resistance pattern (gonorrhoea only), compliance with antibiotics
and/or tracing of sexual contacts indicate the possibility of persisting or recurrent infection.
Auditable Outcome Measures

Appropriate short term audit outcomes include:
proportion of women receiving treatment with a recommended regimen target 95%
PID guideline V4
page 12

number of named male contacts screened for infection and/or treated target 0.4 (large urban
centres) or 0.6 (other centres) per index case39
Qualifying statement
The recommendations in this guideline may not be appropriate for use in all clinical situations.
Decisions to follow these recommendations must be based on the professional judgement of the
clinician and consideration of individual patient circumstances and available resources.
All possible care has been undertaken to ensure the publication of the correct dosage of medication
and route of administration. However, it remains the responsibility of the prescribing physician to
ensure the accuracy and appropriateness of the medication they prescribe.
Editorial independence
This guideline was commissioned, edited and endorsed by the BASHH CEG without external funding
being sought or obtained.
Declarations of interest
All members of the guideline writing committee completed the BASHH conflict of interest declaration
detailed below at the time the guidelines final draft was submitted to the CEG. JR has received
consultancy fees from Bayer pharma.
Author affiliation
Prof Jonathan Ross, Professor of Sexual Health and HIV, Whittall Street Clinic Whittall
Street B4 6DH
Dr Gill McCarthy, Consultant Physician Sexual Health an HIV, The Wolverton Centre,
Kingston Hospital NHS Trust, Galsworthy Road, Kingston upon Thames, KT2 7QB
Membership of the CEG
Dr Keith Radcliffe (Chair); Consultant Physician in Genitourinary Medicine Whittall Street

Clinic Whittall Street B4 6DH
PID guideline V4
page 13
Dr David Daniels, West Midllesex University Hospitals NHS Trust, Sexual Health Clinic
West Middlesex Hospital Twickenham Road, Isleworth, TW7 6AF
Dr Mark FitzGerald Consultant Physician in Genitourinary Medicine, Musgrove Park

Hospital, Taunton, TA1 5DA
Dr Margaret Kingston, Consultant Physician in GU Medicine, Manchester Centre for

Sexual Health, The Hathersage Centre, 280 Upper Brook Street, Manchester M13 0FH
Dr Neil Lazaro, Associate Specialist in GU Medicine, Royal Preston Hospital, Preston

PR2 9HT
Dr Gill McCarthy, Consultant Physician in GU Medicine, Kingston Hospital NHS Trust,

Wolverton Centre for Sexual Health Galsworthy Road, Kingston Upon Thames, KT2 7QB
Dr Ann Sullivan, Consultant Physician in Genitourinary Medicine, Chelsea & Westminster

Healthcare NHS Trust, John Hunter Clinic 2nd Floor St Stephens Centre 369 Fulham
Road SW10 9NH
Timescale for next revision

2015
Acknowledgements
None
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inflammatory disease. Am J Obstet Gynecol 1993;169(5):1143-1149.
13. Yudin MH, Hillier SL, Wiesenfeld HC, Krohn MA, Amortegui AA, Sweet RL. Vaginal
polymorphonuclear leukocytes and bacterial vaginosis as markers for histologic endometritis
among women without symptoms of pelvic inflammatory disease. American Journal of
Obstetrics and Gynecology 2003;188(2):318-323.
14. Bongard F, Landers DV, Lewis F. Differential diagnosis of appendicitis and pelvic inflammatory
disease. A prospective analysis. American Journal of Surgery 1985;150(1):90-96.
15. Lewis FR, Holcroft JW, Boey J, Dunphy JE. Appendicitis: a critical review of diagnosis and
treatment in 1000 cases. Archives of Surgery 1975;110:677-684.
16. Hillis SD, Joesoef R, Marchbanks PA et al. Delayed care of pelvic inflammatory disease as a
risk factor for impaired fertility. Am J Obstet Gynecol 1993;168(5):1503-1509.
17. Ness RB, Soper DE, Holley RL et al. Effectiveness of inpatient and outpatient treatment
strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory
Disease Evaluation and Clinical Health (PEACH) Randomized Trial. Am J Obstet Gynecol
2002;186(5):929-937.
18. Haggerty CL, Ness RB, Amortegui A et al. Endometritis does not predict reproductive morbidity
after pelvic inflammatory disease. Am J Obstet Gynecol 2003;188(1):141-148.
PID guideline V4
page 15

19. Ross JDC, Stewart P. Management of Acute Pelvic Inflammatory Disease.
http://www.rcog.org.uk/files/rcog-corp/uploadedfiles/T32PelvicInflamatoryDisease2008MinorRevision.pdf . 2009.
Ref Type: Generic
20. Ross JD, Ison CA. UK National Screening and Testing Guidelines for STIs. Sex Transm Infect
2006;82:Suppl IV.
21. Arredondo JL, Diaz V, Gaitan H et al. Oral clindamycin and ciprofloxacin versus intramuscular
ceftriaxone and oral doxycycline in the treatment of mild-to- moderate pelvic inflammatory
disease in outpatients. Clin Infect Dis 1997;24(2):170-178.
22. Hemsell DL, Little BB, Faro S et al. Comparison of three regimens recommended by the
Centers for Disease Control and Prevention for the treatment of women hospitalized with acute
pelvic inflammatory disease. Clin Infect Dis 1994;19(4):720-727.
23. Martens MG, Gordon S, Yarborough DR, Faro S, Binder D, Berkeley A. Multicenter randomized
trial of ofloxacin versus cefoxitin and doxycycline in outpatient treatment of pelvic inflammatory
disease. Ambulatory PID Research Group. Southern Medical Journal 1993;86(6):604-610.
24. Walker CK, Kahn JG, Washington AE, Peterson HB, Sweet RL. Pelvic inflammatory disease:
metaanalysis of antimicrobial regimen efficacy. J Infect Dis 1993;168(4):969-978.
25. Wendel GD, Jr., Cox SM, Bawdon RE, Theriot SK, Heard MC, Nobles BJ. A randomized trial of
ofloxacin versus cefoxitin and doxycycline in the outpatient treatment of acute salpingitis. Am J
Obstet Gynecol 1991;164(5 Pt 2):1390-1396.
26. Soper DE, Brockwell NJ, Dalton HP. Microbial etiology of urban emergency department acute
salpingitis: treatment with ofloxacin. Am J Obstet Gynecol 1992;167(3):653-660.
27. Peipert JF, Sweet RL, Walker CK, Kahn J, Rielly-Gauvin K. Evaluation of ofloxacin in the
treatment of laparoscopically documented acute pelvic inflammatory disease (salpingitis).
Infectious Diseases in Obstetrics & Gynecology 1999;7(3):138-144.
28. Isaacson DM, Fernadez JA, Frosco M et al. Levofloxacin: A review of its antibacterial activity.
Recent Res Devel in Antimicrob Agents & Chemotherapy 1996;1:391-439.
29. Judlin P, Liao Q, Liu Z, Reimnitz P, Hampel B, Arvis P. Efficacy and safety of moxifloxacin in
uncomplicated pelvic inflammatory disease: the MONALISA study. BJOG: An International
Journal of Obstetrics & Gynaecology 2010;117(12):1475-1484.
30. Savaris RF, Teixeira LM, Torres TG, Edelweiss MI, Moncada J, Schachter J. Comparing
ceftriaxone plus azithromycin or doxycycline for pelvic inflammatory disease: a randomized
controlled trial. Obstet Gynecol 2007;110(1):53-60.
31. Bevan CD, Ridgway GL, Rothermel CD. Efficacy and safety of azithromycin as monotherapy or
combined with metronidazole compared with two standard multidrug regimens for the treatment
of acute pelvic inflammatory disease. Journal of International Medical Research 2003;31(1):4554.
32. Heystek MJ, Ross JDC, PID Study Group. A randomised double-blind comparison of
moxifloxacin and doxycycline/metronidazole/ciprofloxacin in the treatment of acute,
uncomplicated pelvic inflammatory disease. Int J STD AIDS 2009;20:690-695.
33. Ross JDC, Cronje HS, Paszkowski T et al. Moxifloxacin versus ofloxacin plus metronidazole in
uncomplicated pelvic inflammatory disease: results of a multicentre, double blind, randomised
trial. Sex Transm Infect 2006;82:446-451.
PID guideline V4
page 16

34. Witte EH, Peters AA, Smit IB et al. A comparison of pefloxacin/metronidazole and
doxycycline/metronidazole in the treatment of laparoscopically confirmed acute pelvic
inflammatory disease. European Journal of Obstetrics, Gynecology, & Reproductive Biology
1993;50(2):153-158.
35. Heinonen PK, Teisala K, Miettinen A, Aine R, Punnonen R, Gronroos P. A comparison of
ciprofloxacin with doxycycline plus metronidazole in the treatment of acute pelvic inflammatory
disease. Scandinavian Journal of Infectious Diseases - Supplementum 1989;60:66-73.
36. Reich H, McGlynn F. Laparoscopic treatment of tuboovarian and pelvic abscess. J Reprod Med
1987;32(10):747-752.
37. Aboulghar MA, Mansour RT, Serour GI. Ultrasonographically guided transvaginal aspiration of
tuboovarian abscesses and pyosalpinges: an optional treatment for acute pelvic inflammatory
disease. Am J Obstet Gynecol 1995;172(5):1501-1503.
38. Corsi PJ, Johnson SC, Gonik B, Hendrix SL, McNeeley SG, Jr., Diamond MP. Transvaginal
ultrasound-guided aspiration of pelvic abscesses. Infectious Disease in Obstetrics and
Gynecology 1999;7(5):216-221.
39. Low N, Welch J, Radcliffe K. Developing national outcome standards for the management of
gonorrhoea and genital chlamydia in genitourinary medicine clinics. Sex Transm Infect
2004;80(3):223-229.
PID guideline V4
page 17

Appendix 1: Patient information leaflet on PID
See document on BASHH website (currently in preparation)
PID guideline V4
page 18
Long-term Consequences of
Polycystic Ovary Syndrome
November 2014
Long-term Consequences of Polycystic Ovary Syndrome

This is the third edition of this guideline, which was previously published under the same title in 2003 and 2007.
Diagnosis
How is polycystic ovary syndrome (PCOS) diagnosed?
PCOS should be diagnosed according to the Rotterdam consensus criteria.
Counselling
How should women with PCOS be counselled concerning the long-term implications of their condition and
by whom?
Women diagnosed with PCOS should be informed of the possible long-term risks to health that are
associated with their condition by their healthcare professional.
Long-term consequences
Metabolic consequences of PCOS
What is the risk of developing gestational diabetes in women with PCOS?
Clinicians may consider offering screening for gestational diabetes to women who have been diagnosed
as having PCOS before pregnancy. This should be performed at 2428 weeks of gestation, with referral
to a specialist obstetric diabetic service if abnormalities are detected.
How should women with PCOS be screened for type II diabetes?

Women presenting with PCOS who are overweight (body mass index [BMI] 25 kg/m2) and women with
PCOS who are not overweight (BMI < 25 kg/m2), but who have additional risk factors such as advanced
age (> 40 years), personal history of gestational diabetes or family history of type II diabetes, should
have a 2-hour post 75 g oral glucose tolerance test performed.
In women with impaired fasting glucose (fasting plasma glucose level from 6.1 mmol/l to 6.9 mmol/l)
or impaired glucose tolerance (plasma glucose of 7.8 mmol/l or more but less than 11.1 mmol/l after a
2-hour oral glucose tolerance test), an oral glucose tolerance test should be performed annually.
What is the risk of developing sleep apnoea in women with PCOS?

Women diagnosed with PCOS should be asked (or their partners asked) about snoring and daytime
fatigue/somnolence, informed of the possible risk of sleep apnoea and offered investigation and
treatment when necessary.
What is the risk of developing cardiovascular disease (CVD) in women with PCOS?
Clinicians need to be aware that conventional cardiovascular risk calculators have not been validated in
women with PCOS.
All women with PCOS should be assessed for CVD risk by assessing individual CVD risk factors (obesity,
lack of physical activity, cigarette smoking, family history of type II diabetes, dyslipidaemia,
hypertension, impaired glucose tolerance, type II diabetes) at the time of initial diagnosis.
In clinical practice, hypertension should be treated; however, lipid-lowering treatment is not

recommended routinely and should only be prescribed by a specialist.
2 of 15
What is the risk of having reduced health-related quality of life in women with PCOS?
Psychological issues should be considered in all women with PCOS. Depression and/or anxiety should
be routinely screened for and, if present, assessed. If a woman with PCOS is positive on screening,
further assessment and appropriate counselling and intervention should be offered by a qualified
professional.
Cancer and PCOS

What are the risks of cancer in women with PCOS and how should these women be screened?
Oligo- or amenorrhoea in women with PCOS may predispose to endometrial hyperplasia and later
carcinoma. It is good practice to recommend treatment with gestogens to induce a withdrawal bleed at
least every 3 to 4 months.
Transvaginal ultrasound should be considered in the absence of withdrawal bleeds or abnormal uterine
bleeding. In PCOS, an endometrial thickness of less than 7 mm is unlikely to be hyperplasia.
A thickened endometrium or an endometrial polyp should prompt consideration of endometrial biopsy

and/or hysteroscopy.
There does not appear to be an association with breast or ovarian cancer and no additional surveillance
is required.
Strategies for reduction of risk

Exercise and weight control
How should women with PCOS be advised on lifestyle issues?
It is recommended that lifestyle changes, including diet, exercise and weight loss, are initiated as the
first line of treatment for women with PCOS for improvement of long-term outcomes and should precede
and/or accompany pharmacological treatment.
Is drug therapy appropriate for long-term management of women with PCOS?

Insulin-sensitising agents have not been licensed in the UK for use in patients without diabetes.
Although a body of evidence has accumulated demonstrating the safety of these drugs, there is
currently no evidence that the use of insulin-sensitising agents confers any long-term benefit.
Use of weight reduction drugs may be helpful in reducing hyperandrogenaemia.
Ovarian electrocautery
What is the prognosis following electrocautery?
Ovarian electrocautery should be considered for selected anovulatory patients, especially those with a
normal BMI, as an alternative to ovulation induction.
Bariatric surgery
What is the prognosis following bariatric surgery?
Bariatric surgery may be an option for morbidly obese women with PCOS (BMI of 40 kg/m2 or more or 35
kg/m2 or more with a high-risk obesity-related condition) if standard weight loss strategies have failed.
3 of 15
1.
Purpose and scope
This guideline aims to provide information, based on clinical evidence, to assist clinicians who manage
women with polycystic ovary syndrome (PCOS) in advising these women about the long-term health
consequences of the syndrome. The advice should be targeted to the individual and the presenting
complaints.The delivery of the advice in this document to the patient will need to be done sensitively within
the framework of the patient presentation that will differ for each individual. This guideline does not cover
infertility associated with PCOS, which has been extensively reviewed elsewhere.1,2
2.
PCOS is a common disorder, often complicated by chronic anovulatory infertility and hyperandrogenism with
the clinical manifestations of oligomenorrhoea, hirsutism and acne.3,4 Many women with this condition are
obese and have a higher prevalence of impaired glucose tolerance, type II diabetes and sleep apnoea than is
observed in the general population.3 They exhibit an adverse cardiovascular risk profile, characteristic of the
cardiometabolic syndrome as suggested by a higher reported incidence of hypertension, dyslipidaemia,
visceral obesity, insulin resistance and hyperinsulinaemia.5,6 PCOS is frequently diagnosed by gynaecologists
and it is therefore important that there is a good understanding of the long-term implications of the diagnosis
in order to offer a holistic approach to the disorder.
PCOS is one of the most common endocrine disorders in women of reproductive age.79 Because of
differences in the diagnostic criteria employed, prevalence estimates vary widely, ranging from 2.2% to as high
as 26%.914 The prevalence of PCOS when diagnosed by the Rotterdam criteria was over twice that found
when the National Institutes of Health (NIH) criteria were used to diagnose PCOS.14
The prevalence of PCOS may be different according to ethnic background. For example, compared to
Caucasians, a higher prevalence is noted among women of south Asian origin, where it presents at a younger
age and has more severe symptoms.15,16
3.
Guidelines.The Cochrane Library (including the Cochrane Database of Systematic Reviews and the Database
of Abstracts of Reviews of Effects [DARE]), EMBASE, TRIP, MEDLINE and PubMed were searched for relevant
randomised controlled trials (RCTs), systematic reviews and meta-analyses. The search was restricted to
articles published between 2006 and August 2012. The databases were searched using the relevant Medical
Subject Headings (MeSH) terms including all subheadings and this was combined with a keyword search.The
MeSH heading search included polycystic ovary syndrome, metabolic, diabetes, cardiovascular and
cancer. The search was limited to humans and the English language. The computer search was
complemented by hand searching from original references and reviews. Where possible, recommendations
are based on and explicitly linked to the evidence that supports them. Areas lacking evidence are highlighted
and annotated as Good Practice Points.
4.
Diagnosis
4.1 How is PCOS diagnosed?

PCOS should be diagnosed according to the Rotterdam consensus criteria.
The 1990 NIH preliminary consensus definition has now been replaced by a more recent definition
by the Rotterdam European Society of Human Reproduction and Embryology (ESHRE)/American
Society for Reproductive Medicine (ASRM)-Sponsored PCOS Consensus Workshop Group.17
D
Evidence
level 4
The Rotterdam criteria17 have suggested a broader definition for PCOS, with two out of three of the following
criteria being diagnostic of the condition:
1. polycystic ovaries (either 12 or more follicles or increased ovarian volume [> 10 cm3])
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2. oligo-ovulation or anovulation
3. clinical and/or biochemical signs of hyperandrogenism.
It should be noted that the diagnosis of PCOS can only be made when other aetiologies for irregular cycles,
such as thyroid dysfunction, acromegaly or hyperprolactinaemia, have been excluded if there is clinical
suspicion. Women with non-Caucasian ethnicity might need different criteria to diagnose PCOS.18
Clinical features of hyperandrogenism include hirsutism characterised by excess facial and body
hair and midline hair growth.Although free and total testosterone is used in the diagnosis of PCOS,
the recommended baseline biochemical test for hyperandrogenism is free androgen index (total
testosterone divided by sex hormone binding globulin [SHBG] x 100).19 If there are signs of
virilisation (e.g. deep voice, reduced breast size, increased muscle bulk, clitoral hypertrophy),
rapidly progressing hirsutism (less than 1 year between hirsutism being noticed and seeking
medical advice) or high total testosterone levels (greater than 5 nmol/l or more than twice the
upper limit of normal reference range), androgen-secreting tumours and late-onset/nonclassical
congenital adrenal hyperplasia (CAH) should be excluded. 17-hydroxyprogesterone should be
measured in the follicular phase and will be raised in CAH. However, it is possible to have CAH
without the testosterone being greater than 5 nmol/l, particularly if the woman is heterozygous for
this condition. Hence measurement of 17-hydroxyprogesterone should be considered if there is a
high index of suspicion, for example, specific groups such as Ashkenazi Jews or those with a family
history of CAH, since the management of CAH is different than that of PCOS. If 17hydroxyprogesterone is borderline, it will have to be confirmed by an ACTH stimulation test to
diagnose CAH. If there is a clinical suspicion of Cushings syndrome or acromegaly, this should be
investigated as per local practice.20 Reference ranges for different methods and different
laboratories vary widely; clinical decisions should be guided by the reference ranges of the local
laboratory and the androgens should preferably be measured using tandem mass spectrometry.17,21,22
5.
Evidence
level 2+
Counselling
5.1 How should women with PCOS be counselled concerning the long-term implications of their condition
and by whom?
Women diagnosed with PCOS should be informed of the possible long-term risks to health that are
associated with their condition by their healthcare professional.
Women should be made aware of the long-term implications (as discussed in other sections) of
their condition, including their cardiovascular risk, by their healthcare professional, in a way that is
tailored to their individual circumstances. Women should be made aware of the positive effect of
lifestyle modification, including weight loss, for improving their symptoms, especially those who
are overweight or obese.23
Evidence
level 1+
Women should be counselled that there is no strong evidence that PCOS by itself can cause weight
gain or that having PCOS makes weight loss difficult or impossible. Many patients find great benefit
from support groups (e.g. http://www.verity-pcos.org.uk) and details of these, and sources of
information, should be provided.24
Evidence
level 4
6.
Long-term consequences
6.1 Metabolic consequences of PCOS

6.1.1 What is the risk of developing gestational diabetes in women with PCOS?
Clinicians may consider offering screening for gestational diabetes to women who have been diagnosed
as having PCOS before pregnancy. This should be performed at 2428 weeks of gestation, with referral
to a specialist obstetric diabetic service if abnormalities are detected.
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The prevalence of gestational diabetes mellitus is twice as high among women with PCOS
compared to control women.25 Clinicians may consider offering a 2-hour post 75 g oral glucose
tolerance test to all pregnant women with PCOS, similar as for screening in women with any other
risk factors for gestational diabetes.The diagnosis and treatment of gestational diabetes is discussed
in RCOG Scientific Impact Paper No. 23 in detail.26
Evidence
level 4
6.1.2 How should women with PCOS be screened for type II diabetes?
Women presenting with PCOS who are overweight (body mass index [BMI] 25 kg/m2) and women with
PCOS who are not overweight (BMI < 25 kg/m2), but who have additional risk factors such as advanced
age (> 40 years), personal history of gestational diabetes or family history of type II diabetes, should
have a 2-hour post 75 g oral glucose tolerance test performed.
In women with impaired fasting glucose (fasting plasma glucose level from 6.1 mmol/l to 6.9 mmol/l)
or impaired glucose tolerance (plasma glucose of 7.8 mmol/l or more but less than 11.1 mmol/l after a
2-hour oral glucose tolerance test), an oral glucose tolerance test should be performed annually.
Insulin resistance is present in around 6580% of women with PCOS, independent of obesity,27 and
is further exacerbated by excess weight.28 Insulin resistance has been shown to worsen
reproductive and metabolic features, type II diabetes and cardiovascular disease (CVD) risk in
PCOS.29 The highest incidence of metabolic abnormalities is seen in women with marked
hyperandrogenism and anovulation.6
Evidence
level 2+
There is an increased risk of impaired glucose tolerance and type II diabetes in PCOS independent
of obesity.30 Earlier onset hyperglycaemia and rapid progression to type II diabetes is also reported
in PCOS.31 PCOS is classified as a nonmodifiable risk factor for type II diabetes.32 Furthermore, type
II diabetes is a major CVD risk factor and lifestyle therapy has been shown to prevent or delay
progression to type II diabetes. Hence early screening and identification in this high-risk group of
women with PCOS is important. Women of non-Caucasian ethnicity (particularly south Asian
women) should have an oral glucose tolerance test regardless of their BMI, in view of their
propensity towards higher insulin resistance.33
Evidence
level 2++
Fasting blood glucose level alone has been shown to be inaccurate and results in underdiagnosis of
type II diabetes in PCOS.34 Use of an HbA1c of 6.5% or greater has been proposed for diagnosis of
diabetes. However, caution should be exercised as patients with type II diabetes may be missed34
and the utilisation of HbA1c for the diagnosis of diabetes in PCOS warrants better definition. Hence
an oral glucose tolerance test is considered to be appropriate for screening women with PCOS for
diabetes. However, it would be reasonable to carry out HbA1c measurements where women are
unwilling to have oral glucose tolerance tests or where the resources are not readily available.
Evidence
level 2+
6.2 What is the risk of developing sleep apnoea in women with PCOS?
Women diagnosed with PCOS should be asked (or their partners asked) about snoring and daytime
fatigue/somnolence, informed of the possible risk of sleep apnoea and offered investigation and
treatment when necessary.
The prevalence of obstructive sleep apnoea is increased in obese women with PCOS. Androgen
levels and insulin resistance are positively associated with obstructive sleep apnoea in PCOS.3538
Obstructive sleep apnoea contributes to insulin resistance in PCOS and continuous positive airway
pressure (CPAP) therapy improves insulin sensitivity in affected women.39
Evidence
level 2++
6.3 What is the risk of developing cardiovascular disease (CVD) in women with PCOS?
Clinicians need to be aware that conventional cardiovascular risk calculators have not been validated in
women with PCOS.
6 of 15
All women with PCOS should be assessed for CVD risk by assessing individual CVD risk factors (obesity,
lack of physical activity, cigarette smoking, family history of type II diabetes, dyslipidaemia,
hypertension, impaired glucose tolerance, type II diabetes) at the time of initial diagnosis.
In clinical practice, hypertension should be treated; however, lipid-lowering treatment is not

recommended routinely and should only be prescribed by a specialist.
CVD remains one of the leading causes of death in women. In women with PCOS, novel CVD risk
factors4042 and early onset cardiovascular dysfunction (endothelial dysfunction, arterial stiffness,
plaques and coronary artery calcification)5,43 have been noted and are related to insulin resistance and
obesity. High androgens and low SHBG have also been linked to increased CVD risk in both pre- and
postmenopausal women.44 A subset of the Womens Ischemia Syndrome Evaluation (WISE) study
confirmed increased cardiovascular events and deaths in postmenopausal women with PCOS.42
While it seems prudent to assess the cardiovascular risk factors of a woman with PCOS, including
measurement of blood pressure, cholesterol, triglycerides and high-density lipoprotein cholesterol,
it should be acknowledged that the conventional cardiovascular risk calculators have not been
validated in this group of women. Differences between PCOS and control women exist in several
CVD risk factors that are more profound in obese women with PCOS.45
Evidence
level 2++
Since lifetime risk for CVD is higher in women with PCOS4042 and mostly preventable, all women
with PCOS should be assessed for CVD risk by assessing individual CVD risk factors (obesity, lack
of physical activity, cigarette smoking, family history of type II diabetes, dyslipidaemia,
hypertension, impaired glucose tolerance, type II diabetes) at baseline and treated accordingly.
At the time of initial diagnosis, women with PCOS should be assessed for obesity with BMI and
waist circumference.
Blood pressure should be checked at the time of initial diagnosis and during oral contraceptive
therapy. In clinical practice, hypertension should be treated according to the Joint British Societies
guidelines46 which suggest that persistent blood pressures greater than or equal to 140 mmHg
systolic and/or 90 mmHg diastolic, not responding to lifestyle measures, need to be considered for
drug therapy (patients with diabetes or other high-risk factors with blood pressure greater than 130
mmHg systolic and/or 80 mmHg diastolic may require drug therapy). Women with hypertension
who need to start oral contraceptive therapy should be counselled regarding its risks and benefits
and should be monitored and treated as per the Joint British Societies guidelines.46
Evidence
level 4
There is emerging evidence that statins improve hyperandrogenaemia and the metabolic profile in
women with PCOS.47,48 However, lipid-lowering treatment is not recommended for treating
hyperandrogenaemia and should only be prescribed by a specialist.
Evidence
levels 1+
and 4
6.4 What is the risk of having reduced health-related quality of life in women with PCOS?
Psychological issues should be considered in all women with PCOS. Depression and/or anxiety should be
routinely screened for and, if present, assessed. If a woman with PCOS is positive on screening, further
assessment and appropriate counselling and intervention should be offered by a qualified professional.
Women with PCOS are at an increased risk of psychological and behavioural disorders as well as
reduced quality of life (QoL).4951 It has been shown that PCOS has a significant detrimental effect
on QoL compared with controls and weight issues were most likely to affect QoL in women with
PCOS.41 Women with PCOS are at a higher risk of developing psychological difficulties (such as
depression and/or anxiety), eating disorders and sexual and relationship dysfunction.51
Evidence
level 1+
Psychological issues, especially depression, should be screened for according to National Institute
for Health and Care Excellence guidelines:52,53
Evidence
level 1
7 of 15
Consider asking people who may have depression two questions specifically:
During the last month, have you often been bothered by feeling down, depressed or hopeless?
During the last month, have you often been bothered by having little interest or pleasure in doing things?
If a person answers 'yes' to either of the depression identification questions, but the practitioner is not
competent to perform a mental health assessment, they should refer the person to an appropriate
professional. If this professional is not the person's general practitioner (GP), inform the GP of the referral.
7.
Cancer and PCOS
7.1 What are the risks of cancer in women with PCOS and how should these women be screened?
Oligo- or amenorrhoea in women with PCOS may predispose to endometrial hyperplasia and later
carcinoma. It is good practice to recommend treatment with gestogens to induce a withdrawal bleed at
least every 3 to 4 months.
Transvaginal ultrasound should be considered in the absence of withdrawal bleeds or abnormal uterine
bleeding. In PCOS, an endometrial thickness of less than 7 mm is unlikely to be hyperplasia.
A thickened endometrium or an endometrial polyp should prompt consideration of endometrial biopsy

and/or hysteroscopy.
There does not appear to be an association with breast or ovarian cancer and no additional surveillance
is required.
It has been known for many years that oligo- and amenorrhoea in the presence of premenopausal
levels of estrogen can lead to endometrial hyperplasia and carcinoma.54 There are moderate quality
data to support the finding that women with PCOS have a 2.89-fold (95% CI 1.525.48) increased
risk for endometrial cancer.55 In women with PCOS, intervals between menstruation of more than
3 months (corresponding to fewer than four periods each year) may be associated with
endometrial hyperplasia.56 Regular induction of a withdrawal bleed with cyclical gestogens
gestogens for at least 12 days,57,58 oral contraceptive pills or endometrial protection gained by
exposure to gestogens by devices such as the Mirena (Bayer plc, Newbury, Berks, UK) intrauterine
system would be advisable in oligomenorrhoeic women with PCOS59 as part of good clinical
practice, but the most effective regimen is unclear due to a lack of randomised clinical trials.60
A prospective study of 56 consecutive amenorrhoeic women with PCOS who underwent
transvaginal ultrasound to assess the endometrial thickness concluded that the endometrial
thickness was positively correlated with endometrial hyperplasia; there were no cases of
endometrial hyperplasia when the endometrial thickness was less than 7 mm.56 McCormick et al.
found that, compared with 7 mm, a higher cut-off of 9 mm in patients with PCOS had comparable
sensitivity (100%), negative predictive value (100%) and positive predictive value (50%), but
superior specificity (56%); for every 1 mm increase in endometrial thickness, the odds ratio of
hyperplasia increased by 1.48 (95% CI 1.042.10).61
Evidence
level 4
Evidence
level 2+
Women with PCOS do not have a significant increase in their risk of developing breast cancer
compared to those without PCOS (RR 0.88, 95% CI 0.441.77).62 A small number of studies have
addressed the possibility of an association between PCOS and epithelial ovarian cancer risk; the
results are conflicting, but generally reassuring.6365 As there does not appear to be an association
with breast or ovarian cancer, no additional surveillance is required beyond routine screening.
8.
Strategies for reduction of risk
8.1 Exercise and weight control
8 of 15
8.1.1 How should women with PCOS be advised on lifestyle issues?

It is recommended that lifestyle changes, including diet, exercise and weight loss, are initiated as the
first line of treatment for women with PCOS for improvement of long-term outcomes and should precede
and/or accompany pharmacological treatment.
Lifestyle management including diet, exercise and weight loss is recommended as the first line of
treatment for women with PCOS;23 these changes should precede and/or accompany
pharmacological treatment. In women with PCOS and excess weight, a reduction of as little as 5%
of total body weight has been shown to reduce insulin resistance and testosterone levels as well as
improving body composition and cardiovascular risk markers.45
In the general population, motivational interviewing and established behaviour techniques appear
more effective than traditional advice giving for changes in weight, diet and/or exercise. Suggesting
ways to access support to help with weight loss and exercise, establishing self-monitoring
(including pedometer use), time management techniques, relapse prevention techniques, individual
tailoring, engaging social support and setting goals have all been shown to be useful. Individual,
group and mixed interventions have been shown to be effective.23,66,67 Also, a wide range of
providers (with appropriate training), including doctors, nurses, dietitians, nutritionists and exercise
specialists, can deliver effective interventions for changing diet and/or exercise.6669 Use of
behaviour change techniques and greater intensity, contact time and duration generate significantly
more weight loss.69
2
Lifestyle management targeting weight loss (in women with a BMI of 25 kg/m or more
[overweight/obese]) and prevention of weight gain (in women with a BMI of 18.524.9 kg/m2
[lean]) should include both reduced dietary energy (caloric) intake and exercise.This should be the
first-line therapy for all women with PCOS for managing long-term consequences.70 Prevention of
weight gain should be targeted in all women with PCOS through monitored caloric intake and in
the setting of healthy food choices, irrespective of diet composition. Behaviour change techniques
should target prevention of weight gain in all women with PCOS.71 Women who have failed to lose
weight with lifestyle strategies and who have a BMI of 40 kg/m2 or more or who have a BMI of 35
kg/m2 or more together with a high-risk obesity-related condition (such as hypertension or type II
diabetes) should be considered for bariatric surgery.72
Evidence
level 2++
Evidence
level 2+
8.2 Is drug therapy appropriate for long-term management of women with PCOS?
Insulin-sensitising agents have not been licensed in the UK for use in patients without diabetes.
Although a body of evidence has accumulated demonstrating the safety of these drugs, there is
currently no evidence that the use of insulin-sensitising agents confers any long-term benefit.
Use of weight reduction drugs may be helpful in reducing hyperandrogenaemia.
The demonstration of the potential long-term health consequences of PCOS has been accompanied
by the use of insulin-sensitising agents such as metformin and the thiazolidinediones to reduce
insulin resistance and thereby reduce the risk of developing diabetes and other metabolic sequelae.
However, there is no strong evidence regarding the long-term benefits for the use of sensitising
agents in women with PCOS.7375 Metformin7679 has been shown to have beneficial short-term
effects on insulin resistance and other cardiovascular risk markers in women with PCOS without
type II diabetes.80,81 There is evidence that metformin may modestly reduce androgen levels by
around 11% in women with PCOS compared to placebo82 and modest reductions in body weight
have been reported by some, but not all, studies.83 Women with a BMI of more than 37 kg/m2 may
not respond well to the standard dose of metformin therapy.84 It must be emphasised that both
metformin and the thiazolidinediones are unlicensed for use in PCOS and women should be
counselled before initiating therapy so that they can make an informed choice.
9 of 15
B
C
Evidence
level 2++
There is no current robust evidence to support the use of these drugs for the prevention of CVD
in PCOS and further research in this area is required. Inference from the diabetes prevention trial
that examined a cohort of patients who had similar metabolic profiles to women with PCOS
suggested that lifestyle intervention was superior to metformin in improving cardiometabolic risk
factors and progression to type II diabetes.85
Evidence
level 2++
Metformin can be considered in women with PCOS who are already undergoing lifestyle treatment
and do not have improvement in impaired glucose tolerance and in those women with impaired
glucose tolerance.68,7779 The use of metformin in induction of ovulation in women with PCOS will
not be discussed here as it is beyond the remit of this guideline.
Evidence
level 2+
Incretin hormone-based therapies such as exenatide have been shown to reduce weight and
improve insulin resistance in women with PCOS.86 However, the clinical experience with these
agents in PCOS is limited and significant side effects may occur; therefore, routine use of incretinbased therapies in PCOS is not recommended.
Evidence
level 4
Orlistat induces a small weight reduction and improves biochemical hyperandrogenaemia but
without changing glucoseinsulin homeostasis or lipid patterns.87
Evidence
level 2++
8.3 Ovarian electrocautery

8.3.1 What is the prognosis following electrocautery?
Ovarian electrocautery should be considered for selected anovulatory patients, especially those with a
normal BMI, as an alternative to ovulation induction.
Anovulation associated with PCOS has long been known to be amenable to surgical treatment. A
long-term cohort study has shown persistence of ovulation as well as normalisation of serum
androgens and SHBG up to 20 years after laparoscopic ovarian electrocautery in over 60% of
subjects, particularly if they have a normal BMI.88
Evidence
level 2+
However, no prospective studies have been powered to look at cardiovascular risk profiles and
ovarian electrocautery should be reserved for selected anovulatory patients with a normal BMI or
where a laparoscopy is required for other indications. It is also important to highlight that ovarian
surgery may adversely affect the reproductive capacity of the ovaries in the future.89
Evidence
level 2
8.4 Bariatric surgery

8.4.1 What is the prognosis following bariatric surgery?
Bariatric surgery may be an option for morbidly obese women with PCOS (BMI of 40 kg/m2 or more or
35 kg/m2 or more with a high-risk obesity-related condition) if standard weight loss strategies have failed.
Bariatric surgery may be indicated in selected women with PCOS and morbid obesity.90 Bariatric
surgery may induce a significant weight loss (up to 60% of excess weight) and improve diabetes,
hypertension and dyslipidaemia, reducing mortality from CVD and cancer when compared with
lifestyle modification.91,92 Long-term weight loss of 1425% may result.92,93 In women with PCOS,
bariatric surgery has been shown to be effective.90,94 In 12 morbidly obese women with PCOS, an
average postoperative weight loss of 41 kg in the first year improved hyperandrogenism, insulin
resistance, dyslipidaemia and hypertension and reversed the PCOS diagnosis.90
Evidence
level 2+
Bariatric surgery may be an option for morbidly obese women with PCOS in whom long-term dietbased strategies have failed. However, surgically induced weight loss must be balanced against the
risks of surgery. These risks include a 0.11.1% mortality rate, bowel obstruction, infection,
oesophagitis and nutritional abnormalities91 and hence bariatric surgery should be performed only
after standard weight loss strategies have failed in women with PCOS with a BMI of 40 kg/m2 or
more or a BMI of 35 kg/m2 or more together with a high-risk obesity-related condition.72
10 of 15
9.
In view of the paucity of evidence in this area, the following research topics are recommended:
large population-based studies on long-term consequences for non-Caucasian women

prospective long-term study on the development of type II diabetes and cardiovascular outcomes
elucidation of the long-term consequences for non-insulin resistant non-obese women with PCOS
better evidence that non-pharmaceutical interventions for young women with PCOS alter long-term
consequences
better evidence that bariatric procedures for women with PCOS alter long-term consequences
new, safe and effective pharmacological interventions to reduce cardiovascular outcomes, with long
term follow-up.
10. Auditable topics

Based on the above recommendations, the auditable standards are considered below:
1. 100% of women with PCOS should have an accurate diagnosis of PCOS as defined by at least two out of
three Rotterdam criteria.
2. 100% of overweight (BMI greater than or equal to 25) women with PCOS and lean PCOS subjects with
other risk factors such as advanced age (over 40 years old), personal history of gestational diabetes or
family history of type II diabetes should have a 2-hour post 75 g oral glucose tolerance test performed.
3. 100% of women with PCOS should be assessed for CVD risk by assessing individual CVD risk factors
(obesity, lack of physical activity, cigarette smoking, family history of type II diabetes, dyslipidaemia,
hypertension, impaired glucose tolerance, type II diabetes) at baseline.
4. 100% of women with PCOS should be assessed for obesity with measurement of the BMI and waist
circumference at every visit.
5. 100% of women with PCOS have their blood pressure checked routinely at every visit.
6. 100% of overweight women with PCOS should be provided with dietary and lifestyle advice.
7. Psychological issues should be considered and addressed in 100% of women with PCOS.
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Governance Advice No.1 Development of RCOG Green-top Guidelines (available on the RCOG website
formulated in a similar fashion with a standardised grading scheme
.

1+

low risk of bias

risk of bias

2+



case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
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development group
Professor WL Ledger FRCOG, Sydney, Australia; Professor SL Atkin BSc MB PhD FRCP, The Michael White Diabetes
Centre, University of Hull, Hull; and Dr T Sathyapalan MBBS MD FRCP, Hull York Medical School, University of York, York
Dr S Balakrishnan FRCOG, Trivandrum, Kerala, India; Professor AH Balen FRCOG, Leeds; Dr Y Chung, Research Fellow in
Social and Community Medicine, University of Bristol, Bristol; Dr A Eapen MBBS DRCOG, Clinical Lead, Midland Fertility,
Aldridge; Dr C Ekechi MRCOG, London; Mr R Faraj MRCOG, Rotherham; Professor N Finer, University College London;
Mr SA Fountain FRCOG, Salisbury; Mr DI Fraser FRCOG, Norwich; Dr WJ Jeffcoate, Nottingham; Dr J McManus FRCOG,
Belfast; Dr Y Mehmooda FRCOG, Islamabad, Pakistan; RCOG Womens Network; Dr P Sarkar FRCOG, Slough;
Dr DM Siassakos MRCOG, Bristol; Society for Endocrinology.
Committee lead reviewers were: Ms J Elson FRCOG, Leicester; Mrs G Kumar FRCOG,Wrexham: and Dr AJ Thomson MRCOG, Paisley.
Conflicts of interest: Professor WL Ledger has received payment for serving on the International Advisory Board for MSD and
Besins and has received research support from MSD, Ferring and SPD.
DISCLAIMER
15 of 15
Guideline No. 34
October 2003
Reviewed 2010
OVARIAN CYSTS IN POSTMENOPAUSAL WOMEN

1.
Aim
The aim of this guideline is to provide information, based on clinical evidence where available, on the
investigation and management of postmenopausal women with known ovarian cysts.
2.
Introduction and background
Ovarian cysts are common in postmenopausal women, although the prevalence is lower than in
premenopausal women. Of 20 000 healthy postmenopausal women screened in the Prostate, Lung, Colon and
Ovarian Cancer Screening Trial,1 21.2% had abnormal ovarian morphology, either simple or complex. The
greater use of ultrasound and other radiological investigations means that an increasing proportion of these
cysts will come to the attention of gynaecologists. Ovarian cysts may be discovered either as a result of
screening, as a result of investigations performed for a suspected pelvic mass or incidentally following
investigations carried out for other reasons.
Before ultrasound was routinely available, the finding of a pelvic mass or a palpable ovary2 in a
postmenopausal woman was considered to be an indication for surgery. However, the large numbers of
ovarian cysts now being discovered by ultrasound and the low risk of malignancy of many of these cysts
suggests that they need not all be managed surgically. The further investigation and management of these
women has implications for morbidity, mortality, resource allocation and tertiary referral patterns and, hence,
provides the need for clear guidelines in this area.
3.
A search of Medline, Embase from 1966 to 2001 and of the Cochrane Database of Systematic Reviews was
conducted, looking for relevant randomised controlled trials, meta-analyses, other clinical trials and systematic
reviews. The databases were searched using the relevant MeSH terms including all subheadings. This was
combined with a key word search using ovarian, cyst, neoplasm, pelvic mass and adnexal mass.
The definitions of the types of evidence used in this guideline originate from the US Agency for Health Care
Research and Quality. Where possible, recommendations are based on, and explicitly linked to, the evidence
that supports them.
4.
Diagnosis and assessment of ovarian cysts
The finding of an ovarian cyst in a postmenopausal woman raises two questions. First, what is the most
appropriate management and, second, where should this management take place?
1 of 8
The appropriate location for the management should reflect the new structure of cancer care in the UK.3,4
As the risk of malignancy increases, the appropriate location for management changes, so that while a general
gynaecologist might manage women with a low risk of malignancy, those at intermediate risk should be
managed in a cancer unit and those at high risk in a cancer centre.
The first aim should be to triage women in order to decide the most appropriate place for them to be
managed. A decision can then be made as to the most appropriate management.
It is recommended that ovarian cysts in postmenopausal women should be assessed using CA125 and transvaginal grey scale sonography. There is no routine role yet for Doppler, MRI, CT or PET.
In order to triage women, an estimate needs to be made as to the risk that the ovarian cyst is
malignant. This needs to be done using tests that are easily available in routine gynaecological
practice. At present, these tests are serum CA125 measurement and ultrasound. Serum CA125 is
well established, being raised in over 80% of ovarian cancer cases and, if a cut-off of 30 u/ml is used,
the test has a sensitivity of 81% and specificity of 75%.5 Ultrasound is also well established,
achieving a sensitivity of 89% and specificity of 73% when using a morphology index.6
Ovarian cysts should normally be assessed using transvaginal ultrasound, as this appears to provide
more detail and hence offers greater sensitivity than the transabdominal method.7 Larger cysts may
also need to be assessed transabdominally. It has also been suggested that colour-flow Doppler
sonography may be of benefit in assessing ovarian cysts.8 However, subsequent studies have not
consistently confirmed this, in particular finding that any small decrease in the false positive rate over
greyscale ultrasonography was at the cost of a large drop in sensitivity.9 There is therefore not yet a
clearly established role for colour-flow Doppler in assessing ovarian cysts in post-menopausal women.
Evidence
level IIa
The roles of other imaging modalities, such as magnetic resonance imaging (MRI), computed
tomography (CT) and positron emission tomography (PET), in the diagnosis of ovarian cancer have
yet to be clearly established. One study indicated that MRI may be superior to CT and ultrasound
in diagnosing an ovarian mass but there was no difference in the modalities ability to distinguish
between benign and malignant disease.10 In addition, in this study, there was little variation between
the modalities in their ability to provide accurate staging. Another study found that ultrasound had
greater sensitivity than either MRI or PET in distinguishing benign from malignant disease, at the
expense of some specificity,11 although the authors suggested that combining the imaging
techniques may provide some overall improvement. However the lack of clear evidence of benefit,
the relative expense and limited availability of these modalities, and the delay in referral and surgery
that can result, mean that their routine use cannot yet be recommended.
It is recommended that a risk of malignancy index should be used to select those women who require
primary surgery in a cancer centre by a gynaecological oncologist.
An effective way of triaging women into those who are at low, moderate, or high risk of malignancy
and who hence may be managed by a general gynaecologist, or in a cancer unit or cancer centre
respectively, is to use a risk of malignancy index. There are three well-documented risk of
malignancy indices1213 and Table 1 gives an example of one of these. This guideline is directed at
postmenopausal women and therefore all will be allocated the same score for menopausal status.
The best prognosis for women with ovarian cancer is offered if a laparotomy and full staging
procedure is carried out by a trained gynaecological oncologist.14 This procedure is likely to be
performed in a cancer centre. However, the large prevalence of ovarian cysts in the
postmenopausal population and the increase in their diagnosis means that it would not be feasible
2 of 8
Evidence
level IIa
for all women with ovarian cysts that require surgery, whether benign or malignant, to be referred
to a cancer centre.Women need to be triaged, so that a gynaecological oncologist in a cancer centre
operates on those at high risk of having ovarian cancer, a lead clinician in a cancer unit operates
on those at moderate risk, while those at low risk may be operated on by a general gynaecologist
or offered conservative management. The high specificity and sensitivity of the risk of malignancy
indices discussed makes them an ideal and simple way of triaging women for this purpose (Table
2 below gives an example of a reasonable protocol for triaging women using the risk of malignancy
index, RMI).The three risk of malignancy indices produce similar results.15 Using a cut off point of
250, a sensitivity of 70% and specificity of 90% can be achieved.Thus the great majority of women
with ovarian cancer will be dealt with by gynaecological oncologists in cancer centres, with only
a small number of referrals of women with benign conditions. However, as most of the cysts will
be benign, gynaecologists in units at more local level will perform the majority of surgery.
Evidence
level IIa
It should be appreciated, however, that no currently available tests are perfect, offering 100%
specificity and sensitivity. Ultrasound often fails to differentiate between benign and malignant
lesions, and serum CA125 levels, although raised in over 80% of ovarian cancers, is raised in only
50% of stage I cases. In addition, levels can be raised in many other malignancies and in benign
conditions, including benign cysts and endometriosis.
Those women who are at low risk of malignancy also need to be triaged into those where the risk of malignancy
is sufficiently low to allow conservative management, and those who still require intervention of some form.
Table 1. Calculating the risk of malignancy index (RMI); these are modifications of the original RMI using modified scores
RMI = U x M x CA125
U = 0 (for ultrasound score of 0); U = 1 (for ultrasound score of 1); U = 3 (for ultrasound score of 25)
Ultrasound scans are scored one point for each of the following characteristics: multilocular cyst;
evidence of solid areas; evidence of metastases; presence of ascites; bilateral lesions.
M = 3 for all postmenopausal women dealt with by this guideline
CA125 is serum CA125 measurement in u/ml
Table 2. An example of a protocol for triaging women using the risk of malignancy index (RMI); data
from validation of RMI by Prys Davies et al.16
Risk
Low
Moderate
High
5.
RMI
Women (%)
Risk of cancer (%)
< 25
25250
> 250
40
30
30
<3
20
75
Management of ovarian cysts
5.1. Conservative management
Simple, unilateral, unilocular ovarian cysts, less than 5cm in diameter, have a low risk of malignancy. It is
recommended that, in the presence of a normal serum CA125 levels, they be managed conservatively.
Numerous studies have looked at the risk of malignancy in ovarian cysts, comparing ultrasound
morphology with either histology at subsequent surgery or by close follow up of those women
managed conservatively. The risk of malignancy in these studies of cysts that are less than 5 cm,
3 of 8
Evidence
level IIa
unilateral, unilocular and echo-free with no solid parts or papillary formations is less than 1%.9,1730
In addition, more than 50% of these cysts will resolve spontaneously within three months.24 Thus,
it is reasonable to manage these cysts conservatively, with a follow-up ultrasound scan for cysts of
25 cm, a reasonable interval being four months. This, of course, depends upon the views and
symptoms of the woman and on the gynaecologists clinical assessment.
Evidence
level IIa
5.2. Surgical management

Those women who do not fit the above criteria for conservative management should be offered surgical
management in the most suitable location, and by the most suitable surgeon as determined by the risk of
malignancy index. Initial surgical management that has been assessed includes aspiration of the cyst,
laparoscopy and laparotomy.
5.2.1. Aspiration
Aspiration is not recommended for the management of ovarian cysts in postmenopausal women.
Cytological examination of ovarian cyst fluid is poor at distinguishing between benign and
malignant tumours, with sensitivities in most studies of around 25%.31,32 In addition, there is a risk
of cyst rupture and, if the cyst is malignant, there is some evidence that cyst rupture during surgery
has an unfavourable impact on disease free survival.33 Aspiration, therefore, has no role in the
management of asymptomatic ovarian cysts in postmenopausal women.
Evidence
level IIa
5.2.2. Laparoscopy
It is recommended that a risk of malignancy index should be used to select women for laparoscopic surgery,
to be undertaken by a suitably qualified surgeon.
The laparoscopic management of benign adnexal masses is well established. However, when
managing ovarian cysts in postmenopausal women, it should be remembered that the main reason
for operating is to exclude an ovarian malignancy. If an ovarian malignancy is present then the
appropriate management in the postmenopausal woman is to perform a laparotomy and a total
abdominal hysterectomy, bilateral salpingo-oophorectomy and full staging procedure. The
laparoscopic approach should therefore be reserved for those women who are not eligible for
conservative management but still have a relatively low risk of malignancy.Women who are at high
risk of malignancy, as calculated using the risk of malignancy index, are likely to need a laparotomy
and full staging procedure as their primary surgery. A suitably experienced surgeon may operate
laparoscopically on those women that fall below this cut-off point.
Evidence
level IV
It is recommended that laparoscopic management of ovarian cysts in postmenopausal women should

involve oophorectomy (usually bilateral) rather than cystectomy.
In a postmenopausal woman, the appropriate laparoscopic treatment for an ovarian cyst, which is
not suitable for conservative management, is oophorectomy, with removal of the ovary intact in a
bag without cyst rupture into the peritoneal cavity. This is the case even when the risk of
malignancy is low. In most cases this is likely to be a bilateral oophorectomy, but this will be
determined by the wishes of the woman. There is the risk of cyst rupture during cystectomy and,
as described above, cyst rupture into the peritoneal cavity may have an unfavourable impact on
disease-free survival in the small proportion of cases with an ovarian cancer. Women at
intermediate risk undergoing laparoscopic oophorectomy should be counselled preoperatively
that a full staging laparotomy would be required if evidence of malignancy is revealed.
4 of 8
Evidence
level IV
If a malignancy is revealed during laparoscopy or subsequent histology, it is recommended that the woman
is referred to a cancer centre for further management.
If an ovarian cancer is discovered at surgery or on histology, a subsequent full staging procedure is

likely to be required.
Evidence
level IV
A rapid referral to a cancer centre is recommended for those women who are found to have an ovarian
malignancy. Secondary surgery at a centre should be performed as quickly as feasible.
Evidence
level IIa
Secondary surgery should be performed as soon as feasible.3233
5.2.3. Laparotomy
All ovarian cysts that are suspicious of malignancy in a postmenopausal woman, as indicated by a high risk
of malignancy index, clinical suspicion or findings at laparoscopy are likely to require a full laparotomy and
staging procedure. This should be performed by an appropriate surgeon, working as part of a
multidisciplinary team in a cancer centre, through an extended midline incision, and should include:36
cytology: ascites or washings
laparotomy with clear documentation
biopsies from adhesions and suspicious areas
TAH, BSO and infra-colic omentectomy
The laparotomy and staging procedure may include bilateral selective pelvic and para-aortic
lymphadenectomy.
Further details of the management of ovarian cancer are beyond the scope of this guideline. For example,
some centres may make decisions about the extent of surgery on the basis of frozen section, according to
local cancer centre protocol, and others may alter the timing of surgery in relation to chemotherapy in
advanced cases, particularly with the advent of neoadjuvant chemotherapy.
In addition to the calculated risk of malignancy other factors will, of course, affect the decision as to whether
a woman has surgery, what type of surgery is performed and where this takes place.These include a womans
anxiety, her desire to retain her ovaries and any other medical conditions affecting the risk of surgery.
6.
Summary and suggested management protocol
LOW RISK: Less than 3% risk of cancer
Management in a gynaecology unit.

Simple cysts less than 5 cm in diameter with a serum CA125 level of less than 30 may be managed conservatively.
Conservative management should entail repeat ultrasound scans and serum CA125 measurement every four
months for one year.
If the cyst does not fit the above criteria or if the woman requests surgery then laparoscopic oophorectomy is
acceptable.
MODERATE RISK: approximately 20% risk of cancer
Management in a cancer unit.

Laparoscopic oophorectomy is acceptable in selected cases.
If a malignancy is discovered then a full staging procedure should be undertaken in a cancer centre.
HIGH RISK: greater than 75% risk of cancer
Management in a cancer centre.

Full staging procedure as described above.
5 of 8
7.
Topics suitable for audit

The proportion of women undergoing preoperative investigations with ultrasound and serum CA125 levels
with use of RMI.
The proportion of women managed at the correct location (gynaecological unit, cancer unit, cancer centre)
according to risk of malignancy.
The proportion of women in the cancer network with ovarian cancer referred to the cancer centre from
cancer or gynaecological units before surgery.
Flowchart for the management of ovarian cysts in postmenopausal women

Postmenopausal woman
Known ovarian cyst
TVS if not already performed

Serum CA125
Calculate RMI
RMI< 25
RMI 25250
Can be managed by a
general gynaecologist
RMI > 250
Laparoscopy or
laparotomy in
cancer unit
Simple unilateral cyst

< 5 cm diameter
Serum CA125<30
Other cysts
Conservative management
Normally
laparoscopy
Repeat TVS + serum CA125 (for max. of one year at four-monthly intervals)
Cyst resolved or
reduced in size
Discharge
No change in
cyst
Cyst increased in size or

developed suspicious features
If no change after one year

(three scans) then discharge
6 of 8
Laparotomy in
cancer centre
References
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associated with ovarian cancer risk factors: preliminary data from the prostate, lung, colon, and ovarian cancer screening trial. Am J
Barber HR, Graber EA.The PMPO syndrome (postmenopausal palpable ovary syndrome). Obstet Gynecol 1971;38:9213.
Whitehouse M. A policy framework for commissioning cancer services. BMJ 1995;310:14256.
Luesley D. Improving outcomes in gynaecological cancers. BJOG 2000;107:10613.
Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA125, ultrasound and
menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol 1990;97:9229.
DePriest PD, Varner E, Powell J, Fried A, Puls L, Higgins R, et al. The efficacy of a sonographic morphology index in identifying ovarian
cancer: a multi-institutional investigation. Gynecol Oncol 1994;55:1748.
Leibman AJ, Kruse B, McSweeney MB.Transvaginal sonography: comparison with transabdominal sonography in the diagnosis of pelvic
masses. Am J Roentgenol 1988;151:8992.
Bourne T, Campbell S, Steer C, Whitehead MI, Collins WP. Transvaginal colour flow imaging: a possible new screening technique for
ovarian cancer. BMJ 1989;299:136770.
Roman LD, Muderspach LI, Stein SM, Laifer-Narin S, Groshen S, Morrow CP. Pelvic examination, tumor marker level, and gray-scale and
Doppler sonography in the prediction of pelvic cancer. Obstet Gynecol 1997;89:493500.
Kurtz AB, Tsimikas JV, Tempany CM, Hamper UM, Arger PH, Bree RL. Diagnosis and staging of ovarian cancer: comparative values of
Doppler and conventional US, CT, and MR imaging correlated with surgery and histopathologic analysis: report of the Radiology
Diagnostic Oncology Group. Radiology 1999;212:1927.
Grab D, Flock F, Stohr I, Nussle K, Rieber A, Fenchel S, et al. Classification of asymptomatic adnexal masses by ultrasound, magnetic
resonance imaging, and positron emission tomography. Gynecol Oncol 2000;77:4549.
Tingulstad S, Hagen B, Skjeldestad FE, Onsrud M, Kiserud T, Halvorsen T. Evaluation of a risk of malignancy index based on serum CA125,
ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses. Br J Obstet Gynaecol 1996;103:82631.
Tingulstad S, Hagen B, Skjeldestad FE, Halvorsen T, Nustad K, Onsrud M.The risk-of-malignancy index to evaluate potential ovarian cancers
in local hospitals. Obstet Gynecol 1999;93:44852.
Junor EJ, Hole DJ, McNulty L, Mason M,Young J. Specialist gynaecologists and survival outcome in ovarian cancer: a Scottish national study
of 1866 patients. Br J Obstet Gynaecol 1999;106:11306.
Manjunath AP, Pratapkumar, Sujatha K, Vani R. Comparison of three risk of malignancy indices in evaluation of pelvic masses. Gynecol
Oncol 2001;81:2259.
Davies AP, Jacobs I,Woolas R, Fish A, Oram D.The adnexal mass: benign or malignant? Evaluation of a risk of malignancy index. Br J Obstet
Gynaecol 1993;100:92731.
Ekerhovd E,Wienerroith H, Staudach A, Granberg S. Preoperative assessment of unilocular adnexal cysts by transvaginal ultrasonography:
a comparison between ultrasonographic morphologic imaging and histopathologic diagnosis. Am J Obstet Gynecol 2001;184:4854.
Reimer T, Gerber B, Muller H, Jeschke U, Krause A, Friese K. Differential diagnosis of peri- and postmenopausal ovarian cysts. Maturitas
1999;31:12332.
Bailey CL, Ueland FR, Land GL, DePriest PD, Gallion HH, Kryscio RJ. The malignant potential of small cystic ovarian tumors in women
over 50 years of age. Gynecol Oncol 1998;69:37.
Kroon E, Andolf E. Diagnosis and follow-up of simple ovarian cysts detected by ultrasound in postmenopausal women. Obstet Gynecol
1995;85:2114.
Aubert JM, Rombaut C, Argacha P, Romero F, Leira J, Gomez-Bolea F. Simple adnexal cysts in postmenopausal women: conservative
management. Maturitas 1998;30:514.
Goldstein SR, Subramanyam B, Snyder JR, Beller U, Raghavendra BN, Beckman EM.The postmenopausal cystic adnexal mass: the potential
role of ultrasound in conservative management. Obstet Gynecol 1989;73:810.
Luxman D, Bergman A, Sagi J, David MP. The postmenopausal adnexal mass: correlation between ultrasonic and pathologic findings.
Levine D, Gosink BB, Wolf SI, Feldesman MR, Pretorius DH. Simple adnexal cysts: the natural history in postmenopausal women.
Radiology 1992;184:6539.
Andolf E, Jorgensen C. Cystic lesions in elderly women, diagnosed by ultrasound. Br J Obstet Gynaecol 1989;96:10769.
Hall DA, McCarthy KA.The significance of the postmenopausal simple adnexal cyst. J Ultrasound Med 1986;5:5035.
Shalev E, Eliyahu S, Peleg D,Tsabari A. Laparoscopic management of adnexal cystic masses in postmenopausal women. Obstet Gynecol
1994;83:5946.
Granberg S, Norstrom A, Wikland M.Tumors in the lower pelvis as imaged by vaginal sonography. Gynecol Oncol 1990;37:2249.
Valentin L, Sladkevicius P, Marsal K. Limited contribution of Doppler velocimetry to the differential diagnosis of extrauterine pelvic
tumors. Obstet Gynecol 1994;83:42533.
Strigini FA, Gadducci A, Del Bravo B, Ferdeghini M, Genazzani AR. Differential diagnosis of adnexal masses with transvaginal sonography,
color flow imaging, and serum CA 125 assay in pre- and postmenopausal women. Gynecol Oncol 1996;61:6872.
Higgins RV, Matkins JF, Marroum MC. Comparison of fine-needle aspiration cytologic findings of ovarian cysts with ovarian histologic
findings. Am J Obstet Gynecol 1999;180:5503.
Moran O, Menczer J, Ben-Baruch G, Lipitz S, Goor E. Cytologic examination of ovarian cyst fluid for the distinction between benign and
malignant tumors. Obstet Gynecol 1993;82:4446.
Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, Sevelda P, et al. Prognostic importance of degree of differentiation and cyst
rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001;357:17682.
Lehner R,Wenzl R, Heinzl H, Husslein P, Sevelda P. Influence of delayed staging laparotomy after laparoscopic removal of ovarian masses
later found malignant. Obstet Gynecol 1998;92:96771.
Kindermann G, Maassen V, Kuhn W. Laparoscopic preliminary surgery of ovarian malignancies. Experiences from 127 German
gynecologic clinics. Geburtshilfe Frauenheilkd 1995;55:68794.
Stratton JF,Tidy JA, Paterson ME.The surgical management of ovarian cancer. Cancer Treat Rev 2001;27:1118.
7 of 8
APPENDIX
Clinical guidelines are: systematically developed statements which assist clinicians and patients in making
using a standardised methodology. Exact details of this process can be found in Clinical Governance Advice
No. 1: Guidance for the Development of RCOG Green-top Guidelines (available on the RCOG website at
www.rcog.org.uk/clingov1). These recommendations are not intended to dictate an exclusive course of
management or treatment.They must be evaluated with reference to individual patient needs, resources and
limitations unique to the institution and variations in local populations. It is hoped that this process of local
clinical uncertainty where further research may be indicated.

Ia

Ib

IIa
Evidence obtained from at least one welldesigned controlled study without

randomisation.
IIb
Evidence obtained from at least one other

type of well-designed quasi-experimental
study.
III
IV
vidence obtained from well-designed nonexperimental descriptive studies, such as

comparative studies, correlation studies
and case studies.
Evidence obtained from expert committee
reports or opinions and/or clinical
experience of respected authorities.
Requires at least one randomised controlled trial

as part of a body of literature of overall good
quality and consistency addressing the specific
Requires the availability of well controlled clinical

studies but no randomised clinical trials on the
topic of recommendations. (Evidence levels IIa,
IIb, III)

committee reports or opinions and/or clinical
experiences of respected authorities. Indicates an
absence of directly applicable clinical studies of
good quality. (Evidence level IV)
Good practice point
Recommended best practice based on the clinical

experience of the guideline development group.
This Guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists and the British Society of Urogynaecology by:
Mr B D Rufford MRCOG, London and Professor I J Jacobs MRCOG, London.
Dr A A Ahmed MRCOG, Cambridge; Mr A J Farthing MRCOG, London; Mr J A Latimer MRCOG, Cambridge;
Mr A D B Lopes MRCOG, Gateshead; Mr J B Murdoch MRCOG, Bristol; Miss A Olaitan MRCOG, London;
The RCOG Consumers Forum; Dr G M Turner, consultant radiologist, Derby Cancer Centre, Derby City General Hospital.
The final version is the responsibility of the Guidelines and Audit Committee of the RCOG.
This guideline was reviewed in 2010. A literature review indicated there was no new evidence available
which would alter the recommendations and therefore the guideline review date has been extended until
2012, unless evidence requires earlier review.
8 of 8
The Prevention of Early-onset

Neonatal Group B
Streptococcal Disease
2nd edition I July 2012
The Prevention of Early-onset Neonatal Group B

Streptococcal Disease
This is the second edition of this guideline. The first edition was published in 2003 under the same title.
1.
Purpose and scope
The purpose of this guideline is to provide guidance for obstetricians, midwives and neonatologists on the
prevention of early-onset neonatal group B streptococcal (EOGBS) disease. Prevention of late-onset GBS and
treatment of established GBS disease is not considered beyond initial antibiotic therapy.
2.
Background
Group B streptococcus (Streptococcus agalactiae) is recognised as the most frequent cause of severe earlyonset (at less than 7 days of age) infection in newborn infants. However, there is still controversy about its
prevention. Surveys in 2001 and 2008 demonstrated that less than 1% of UK maternity units were performing
systematic screening for GBS1,2 and, to date, UK clinicians have not generally adopted the US and Canadian
practice of routine screening for GBS carriage.3,4 Extrapolation of practice from the USA to the UK may,
however, be inappropriate.The incidence of EOGBS disease in the UK in the absence of systematic screening
or widespread intrapartum antibiotic prophylaxis (IAP) is 0.5/1000 births,5 which is similar to that seen in the
USA after universal screening and IAP, despite comparable vaginal carriage rates.6 The incidence of cultureconfirmed early-onset disease in the USA has fallen in association with the introduction of screening pregnant
women for GBS.3 The current US guidelines7 advise that all women colonised with GBS at 3537 weeks of
gestation (or labouring before this time) should be offered IAP, usually in the form of high-dose intravenous
benzylpenicillin or ampicillin. IAP has been shown to significantly reduce the risk of culture-positive earlyonset but not late-onset disease (occurring 7 or more days after birth). There is also indirect evidence of an
impact on neonatal deaths. A review of sepsis-related neonatal mortality in the USA showed a decline in
mortality in the first week after birth, coinciding with the introduction of IAP.8 However, a Cochrane review
concluded that, while IAP for colonised mothers reduced the incidence of EOGBS disease, it has not been
shown to reduce all causes of mortality or GBS-related mortality.9 There have been no studies addressing
whether routine screening has had any impact on all-cause mortality. Antenatal screening and treatment may
carry disadvantages for the mother and baby. These include anaphylaxis,10 increased medicalisation of labour
and the neonatal period, and possible infection with antibiotic-resistant organisms, particularly when broadspectrum antibiotics such as amoxicillin are used for prophylaxis.11,12 The UK National Screening Committee
examined the issue of strategies for the prevention of EOGBS disease in November 2008 and recommended
that routine screening using bacteriological culture or near-patient testing techniques should not be
introduced into UK practice.13
3.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines.1416 The Cochrane Database of Systematic Reviews, DARE, EMBASE, Medline and PubMed
(electronic databases) were searched for relevant randomised controlled trials, systematic reviews and metaanalyses. The search was restricted to articles published between 2003 and August 2011. Search terms
included: group B streptococcus, Streptococcus agalactiae, group B streptococcus and pregnancy, beta
haemolytic streptococcus and pregnancy, and beta haemolytic streptococcus and neonatal, beta hemolytic
streptococcus and neonatal, GBS bacteriuria, and was limited to humans and the English language. The
National Library for Health and the National Guidelines Clearing House were also searched for relevant
guidelines and reviews. Studies relevant to the scope of the guideline were selected by the members of the
guideline development group. Where possible, recommendations are based on available evidence. Areas
lacking evidence are highlighted and annotated as good practice points.
2 of 13
4.
Antenatal screening
4.1 Should all pregnant women be offered bacteriological screening for GBS?
Routine bacteriological screening of all pregnant women for antenatal GBS carriage is not recommended.
Until it is clear that antenatal screening for GBS carriage does more good than harm and that the
benefits are cost-effective, the National Screening Committee does not recommend routine
screening in the UK.13 Initiating national swab-based screening for antenatal GBS carriage would
have a substantial impact on the provision of antenatal care within the UK. Major organisational
changes and new funding would be required to ensure an equitable and quality-assured service.
Evidence
level 4
4.2 If GBS is detected incidentally earlier in the pregnancy, should women be treated before the onset of labour?
Antenatal treatment with benzylpenicillin is not recommended.
Antenatal prophylaxis with oral benzylpenicillin for vaginal/rectal colonisation does not reduce the
likelihood of GBS colonisation at the time of delivery17 and so is not indicated in this situation. IAP
should be offered to GBS-colonised women (see section 5.2).
Evidence
level 2+
4.3 Should women be screened for GBS or receive IAP if GBS was detected in a previous pregnancy?
Current evidence does not support screening for GBS or the administration of IAP to women in whom
GBS carriage was detected in a previous pregnancy.
If GBS was detected in a previous pregnancy, the likelihood of carriage in a subsequent pregnancy
is around 38%.18 This gives a risk estimate of neonatal EOGBS disease of approximately 0.9
cases/1000 births versus a background risk of 0.5 cases/1000 births or 2.3 cases/1000 births in
women with GBS detected in the current pregnancy. The time interval between the two
pregnancies and the intensity of colonisation in the previous pregnancy are predictive of recurrent
GBS colonisation.18
5.
Evidence
level 3
Reducing the risk of neonatal GBS disease in women known to be colonised with GBS.
5.1 How should GBS bacteriuria in the current pregnancy be managed?

Clinicians should offer IAP to women with GBS bacteriuria identified during the current pregnancy.
GBS bacteriuria is associated with a higher risk of chorioamnionitis19 and neonatal disease.20 It is
not possible to accurately quantify these increased risks. These women should be offered IAP.
Women with GBS urinary tract infection (growth of greater than 105 cfu/ml) during pregnancy
should receive appropriate treatment at the time of diagnosis as well as IAP.
C
Evidence
level 3
5.2 Should women receive IAP if GBS is detected in the current pregnancy?
IAP should be offered if GBS is detected on a vaginal swab in the current pregnancy.
Vaginal swabs should not be taken during pregnancy unless there is a clinical indication to do so.
If GBS is present in a vaginal swab, it is likely that the risk of neonatal disease is increased. A risk of
disease of 2.3/1000 may be assumed (overall UK incidence 0.5/1000; approximately 21% women
are carriers).21
3 of 13
P
Evidence
level 3
5.3 How should women with known GBS colonisation undergoing planned caesarean section be managed?
Antibiotic prophylaxis specific for GBS is not required for women undergoing planned caesarean section
in the absence of labour and with intact membranes.
All women having caesarean section should receive antibiotic prophylaxis according to NICE guideline no. 132.22
Women undergoing planned caesarean delivery in the absence of labour or membrane rupture
do not require antibiotic prophylaxis for GBS, regardless of GBS colonisation status. The risk of
neonatal EOGBS disease is extremely low in this circumstance.23
Evidence
level 3
5.4 How should women known to be colonised with GBS who experience spontaneous rupture of membranes
at term be managed?
Immediate induction of labour and IAP should be offered to all women with prelabour rupture of
membranes at 37+0 weeks of gestation or more.
The NICE guideline on induction of labour 24 recommends that all women with prelabour rupture of
membranes at term (37 weeks + 0 days of gestation or greater) should be offered immediate induction
of labour, or induction after 24 hours. If GBS colonisation was identified earlier in the pregnancy (by
a swab taken for other reasons), immediate induction of labour and IAP should be offered.
Evidence
level 3
5.5 How should women with GBS colonisation and suspected chorioamnionitis be managed?
If chorioamnionitis is suspected, broad-spectrum antibiotic therapy including an agent active against
GBS should replace GBS-specific IAP and induction of labour should be considered.
Chorioamnionitis is known to be associated with maternal and neonatal morbidity including

sepsis,neonatal lung and brain injury and cerebral palsy.The risk of these complications is reduced
by broad-spectrum antibiotic therapy.25
6.
Evidence
level 1+
Management of labour (including rupture of membranes) to reduce the risk of neonatal

GBS disease in women without known GBS colonisation
6.1 Should women presenting in preterm labour with intact membranes be offered IAP?
Women presenting in established preterm labour with intact membranes with no other risk factors for
GBS should not routinely be offered IAP unless they are known to be colonised with GBS.
Although the risk of EOGBS infection is higher in preterm than in term infants (see Appendix I), there are
reasons to be cautious about widespread prescription of antibiotics for these women. Approximately 50% of
all women thought to be in preterm labour will not deliver preterm. Women presenting in uncomplicated
spontaneous preterm labour with intact membranes are the same group of women as those recruited to the
ORACLE trial, where there was evidence of harm in terms of adverse neurodevelopmental outcome including
cerebral palsy in their infants at 7 years of age in the absence of any demonstrable benefit in the short term.26
Although the antibiotics used in ORACLE are different from those used for IAP for GBS, there is no evidence
from long-term follow-up studies that other antibiotics, including penicillin, are safe. As the risk of EOGBS
infection in this group of infants is still low, prompt management of early-onset sepsis, if it occurs, is preferable
to IAP for large numbers of women.
There is currently no evidence to show that the subgroup of women in preterm labour with ruptured
membranes have greater benefit from IAP. The difficulty in balancing risks and benefits of IAP for women in
preterm labour could be resolved by a randomised controlled trial.
4 of 13
6.2 How should women with clinical risk factors such as a pyrexia (>38C) in labour be managed?
IAP should be offered to women who are pyrexial in labour (>38C).
Women who are pyrexial in labour should be offered broad-spectrum antibiotics including an antibiotic
for prevention of neonatal EOGBS disease.
Intrapartum pyrexia (>38C) is associated with a risk of EOGBS disease of 5.3/1000 (versus a
background risk of 0.5/1000).5,27 In view of this increased risk, IAP should be offered in the
presence of maternal pyrexia.
Evidence
level 3
6.3 How should women with term prelabour rupture of membranes be managed?
The evidence for IAP for women with term prelabour rupture of membranes is unclear and NICE
recommends that it is not given, unless there are other risk factors.
Women with prelabour rupture of membranes at term should be offered immediate induction of labour or
induction after 24 hours (in line with the NICE guideline on induction of labour24).
6.4 How should women with preterm prelabour rupture of membranes be managed to reduce the risk of
neonatal GBS disease?
Antibiotic prophylaxis for GBS is unnecessary for women with preterm rupture of membranes.
Women who experience preterm rupture of membranes should be managed according to the
RCOG Green-top Guideline Preterm Prelabour Rupture of Membranes.28 Antibiotic administration
specifically for GBS colonisation is not necessary prior to labour and should not be given just in
case.18,29 If these women are known to be colonised with GBS, IAP should be offered. Induction of
labour should be considered if there is suspicion of chorioamnionitis.
Evidence
level 3
6.5 Should women with a previous baby with neonatal GBS disease be offered IAP?
IAP should be offered to women with a previous baby with neonatal GBS disease.
Subsequent infants born to these women are likely to be at increased risk of GBS disease, although
this has not been accurately quantified. The probable increase in risk may be attributable to
persistence of low levels of maternal anti-GBS antibodies.30 Vaginal or rectal swabs are not helpful,
as IAP would be recommended even if these swabs were negative for GBS.
7.
D
Evidence
level 3
Which antibiotics should be given to prevent early-onset neonatal GBS disease?
For women who have accepted IAP, benzylpenicillin should be administered as soon as possible after
the onset of labour and given regularly until delivery.
Clindamycin should be administered to those women allergic to benzylpenicillin.
It is recommended that 3 g intravenous benzylpenicillin be given as soon as possible after the onset
of labour and 1.5 g 4-hourly until delivery. Clindamycin 900 mg should be given intravenously
8-hourly to those allergic to benzylpenicillin. Current clindamycin resistance rates in England and
Wales stand at 10%;31 thus, there is a chance that clindamycin might be less effective. An alternative
agent in this situation is vancomycin. It should be noted that dosage regimens are based on tradition
rather than evidence and the British National Formulary should be consulted for specific dose
recommendations. Broad-spectrum antibiotics such as ampicillin should be avoided if possible, as
concerns have been raised regarding increased rates of Gram-negative neonatal sepsis.11 To optimise
5 of 13
Evidence
level 3
the efficacy of IAP, the first dose should be given at least 2 hours prior to delivery.32,33 There is
evidence that benzylpenicillin levels in cord blood exceed the minimum inhibitory concentration
for GBS as early as 1 hour after maternal administration,34 but it is not known how this relates to
neonatal colonisation or disease. Oral antibiotics for IAP are not recommended because of variable
absorption in labour.
8.
Evidence
level 3
Should vaginal cleansing be performed in labour?
There is no evidence that intrapartum vaginal cleansing will reduce the risk of neonatal GBS disease.
Although vaginal cleansing with chlorhexidine has been shown to reduce the risk of neonatal GBS
colonisation,35 a recent large randomised controlled trial showed no impact on EOGBS disease.36
9.
C
Evidence
level 3
How should the newborn infant be managed?
The evidence base upon which to make treatment decisions for newborn infants is weak. Few randomised
controlled trials have been performed.3739 Previous guidelines have largely been based on consensus rather
than evidence. Published data permit risk estimates to be made which can be used to inform decision making
regarding the need for enhanced observation or investigation and initial treatment.There is no good evidence
to support routine blood tests to aid decision making about the management of these infants.40
The continuing management of infants with established disease is not within the scope of this guideline.
In a UK study of invasive GBS disease, 89% of early-onset cases were identified on day 1.41 Of those developing
clinical features on day 1, 97.6% were noted by 12 hours of age (where hour of onset was given).41 More recent
UK data from an infection surveillance network showed that 94% of early-onset cases occurred on day 1.42 Most
cases (6567%) have one or more risk factors prior to or during labour.41,42 A significant number will also have
had signs of fetal distress, an emergency delivery and low Apgar scores.The majority of early-onset cases in these
studies presented with sepsis (79.4%), 11.8% had meningitis, 7.8% had pneumonia and 1% focal infection.41
9.1 How should well infants at risk of EOGBS disease be monitored?

Well infants at risk of EOGBS should be observed for the first 1224 hours after birth with regular
assessments of general wellbeing, feeding, heart rate, respiratory rate and temperature.
The great majority of infants (8994%) who develop EOGBS infection develop signs within the first 24 hours
after birth and the majority of such infants (6567%) will have had one or more conventional risk factors
evident in or before labour. A significant number will also have had signs of fetal distress, an emergency
delivery and low Apgar scores. Clearly, any baby with clinical signs and symptoms compatible with sepsis
should be evaluated and commenced on antibiotics. Other infants without clinical signs but with other risk
factors should be observed closely for such signs over the first 24 hours after birth.
9.2 Should postnatal antibiotic prophylaxis be given to low-risk term infants?

Postnatal antibiotic prophylaxis is not recommended for asymptomatic term infants without known
antenatal risk factors.
The incidence of EOGBS disease in asymptomatic term infants without known antenatal risk factors in the
UK is estimated at 0.2 cases/1000 births.5 No randomised controlled trial has investigated treatment in this
group. If postnatal antibiotic treatment were completely effective and there were no adverse effects, 5000
infants would need to be treated to prevent a single case and at least 80 000 infants would have to be treated
to prevent a single death from EOGBS disease.
6 of 13
Evidence
level 3
Routine postnatal antibiotic prophylaxis is not recommended.
9.3 How should the well infant with one or more risk factors be treated?
Randomised controlled trials have not provided a sufficient evidence base for clear treatment
recommendations in well newborn infants.
Estimates of the risk of EOGBS disease in the presence of individual antenatal risk factors, before and after IAP,
are shown in Appendix I.
Some clinicians will recommend intravenous antibiotic treatment of well infants with risk factors (and stop
therapy when cultures are negative or after a defined period if IAP was given), while others will prefer to
observe infants because the balance of risks and benefits of treatment is uncertain. Around 90% of cases
present clinically before 24 hours of age,41,42 so the risk of disease in infants who remain well without
treatment beyond this time may not be substantially elevated above that of the infant with no risk factors.
Prolonged observation of well infants is therefore not indicated. The argument for using prophylactic
treatment in well infants is stronger in the presence of multiple maternal risk factors but is still unproven.
However, in well infants whose mothers had risk factors and received appropriate IAP, the risk of EOGBS is
significantly lower and these infants can be observed for 24 hours without treatment.
9.4 How should the neonate with clinical signs of EOGBS disease be managed?
Infants with clinical signs of EOGBS should be treated promptly with appropriate antibiotics.
Many infants with EOGBS disease have signs at or soon after birth.41 Neonatal sepsis may present
with subtle signs initially but can progress rapidly to death. Whether they received intrapartum
antibiotics or not, any newborn infant with clinical signs compatible with infection should be
investigated and treated promptly with antibiotics which are narrow spectrum but provide cover
against GBS and other common pathogens such as Escherichia coli 43 (for example, benzylpenicillin
and gentamicin). Blood cultures should always be obtained before antibiotic treatment is
commenced, and cerebrospinal fluid cultures should be considered unless the clinical condition
precludes a lumbar puncture. A lumbar puncture should be obtained at the earliest opportunity
once the clinical condition has stabilised.
Evidence
level 3
9.5 How should the infant of a mother with a previous infant with GBS disease be managed?
For a well infant whose mother has had a previous infant with GBS disease, either clinical evaluation
after birth and observation for around 24 hours are necessary, or blood cultures need to be obtained and
the infant treated with benzylpenicillin until the culture results are available. It is unclear whether
further action is necessary for the well infant.
The risk of GBS disease is unquantified but is probably significantly increased.27 The infant should
be evaluated clinically soon after birth and observed for at least 24 hours. It is unclear whether
further action is necessary, but an alternative approach would be to obtain blood cultures and treat
with benzylpenicillin until the culture results are available.There is insufficient evidence to suggest
that neonatal treatment should be given if IAP has been administered.
9.6 Are routine neonatal surveillance cultures of value?

It is not necessary to perform routine surface cultures or blood cultures on well infants.
Most infants who develop EOGBS disease present with illness soon after birth and 90% have
presented clinically by 24 hours of age, before culture results become available.41,43 Postnatal
antibiotic treatment has not been shown to eradicate carriage of GBS or to influence the risk of
7 of 13
Evidence
level 3
P
Evidence
level 3
late-onset GBS disease. It is therefore unnecessary to perform routine surface cultures or blood
cultures on well infants, whether they received IAP or not.
Evidence
level 3
9.7 Is there any need for breastfeeding to be avoided?

There is no evidence to discourage breastfeeding where there are concerns regarding the possible risk of
transmission of GBS disease.
Percentage of eligible women with various risk factors receiving IAP.

Percentage of women receiving IAP for at least 2 hours prior to delivery.
Percentage of women with pyrexia receiving broad-spectrum antibiotics.
Percentage of infants with risk factors being observed for 1224 hours.
Percentage of infants with signs of possible GBS disease receiving appropriate investigation and treatment.
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antimicrobial prophylaxis for prevention of group-Bstreptococcal disease on the incidence and ecology of earlyonset neonatal sepsis. Lancet Infect Dis 2003;3:20113.

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chemoprophylaxis for group B strep is not necessary with
elective cesarean section at term. Am J Obstet Gynecol
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24. National Institute for Health and Clinical Excellence. Induction
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26. Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, et
al. Childhood outcomes after prescription of antibiotics to
pregnant women with spontaneous preterm labour: 7-year
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27. Oddie S, Embleton ND. Risk factors for early onset neonatal
group B streptococcal sepsis: casecontrol study. BMJ
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28. Royal College of Obstetricians and Gynaecologsts. Preterm
prelabour rupture of membranes. Green-top Guideline No. 44.
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29. Alvarez JR, Williams SF, Ganesh VL, Apuzzio JJ. Duration of
antimicrobial prophylaxis for group B streptococcus in patients
with preterm premature rupture of membranes who are not in
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S. Early-onset neonatal group B streptococcal septicaemia in
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JA, et al.The effectiveness of risk-based intrapartum
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33. de Cueto M, Sanchez MJ, Sampedro A, Miranda JA, Herruzo AJ,
Rosa-Fraile M.Timing of intrapartum ampicillin and prevention
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34. Barber EL, Zhao G, Buhimschi IA, Illuzzi JL. Duration of
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35. Stade BC, Shah V, Ohlsson A. Vaginal chlorhexidine during labour
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38. Pyati SP, Pildes RS, Jacobs NM, Ramamurthy RS,Yeh TF, Raval DS,
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39. Patel DM, Rhodes PG, LeBlanc MH, Graves GR, Glick C, Morrison
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41. Heath PT, Balfour GF,Tighe H, Verlander NQ, Lamagni TL,
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45. Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et
al. Prenatal screening and treatment strategies to prevent group
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[http://www.hesonline.nhs.uk/Ease/servlet/ContentServer?siteI
D=1937&categoryID=1009].
9 of 13
APPENDIX I
Estimates of the risk of EOGBS disease in the presence of individual antenatal risk factors, with
and without IAP.
These estimates are based on an incidence of EOGBS disease in the UK of 0.5/1000,5 which is likely to be the
minimum incidence.
Risk factor
Risk of EOGBS
disease if IAP
not given
Risk of EOGBS
disease if full
IAP given
Risk of death from

EOGBS disease if
IAP not given
Risk of death from

EOGBS disease if
full IAP given
Intrapartum fever (>38C)
1:189
1:943
1:1783
1:8915
Prolonged rupture of
membranes (>18 hours)
at term
1:556
1:2777
1:9754
1:48 772
Prematurity
(<37+0 weeks of gestation)
1:435
1:2173
1:2377
1:11 885
Prematurity
(<35+0 weeks of gestation)
1:357
1:1786
1:1566
1:7829
Positive GBS swab in a

previous pregnancy
1:1105
1:5525
1:10 424
1:52 122
Positive GBS swab in

current pregnancy
1:434
1:2170
1:4094
1:20 471
EOGBS = early-onset group B streptococcus; IAP = intrapartum antibiotic prophylaxis.
The assumptions on which the figures in the table above are based are as follows:
Live birth rate in the UK in 2008: 793 38844
1.9% intrapartum fever >38C45
9.4% PROM at term45
7.9% <37 weeks of gestation46
4.0% <35 weeks of gestation46
Prevalence of maternal risk factors in infants with EOGBS disease:
19.9% intrapartum fever >38C41,45
34% PROM at term5
37% <37 weeks of gestation5
22% <35 weeks of gestation5
Incidence of EOGBS in the UK: 0.5/10005
Mortality of EOGBS in the UK is:
10.6% overall5
18.3% <37 weeks of gestation
22.8% <35 weeks of gestation
5.7% >37 weeks of gestation
80% effectiveness of IAP in preventing EOGBS12
It should be noted that GBS bacteriuria is a risk factor for neonatal disease but the magnitude of risk cannot
be quantified.
10 of 13
APPENDIX II
Indications for offering GBS-specific IAP:
Previous baby with invasive GBS infection.
GBS bacteriuria in the current pregnancy.
Vaginal swab positive for GBS in current pregnancy.
Pyrexia (>38C) in labour (give broad-spectrum antibiotics to include GBS cover).
Chorioamnionitis (give broad-spectrum antibiotics to include GBS cover).
IAP for GBS is not necessary if delivering by pre-labour lower segment caesarean section with intact
membranes.
11 of 13
APPENDIX III
Clinical guidelines are systematically developed statements which assist clinicians and women in making
http://www.rcog.org.uk/guidelines). These recommendations are not intended to dictate an exclusive
course of management or treatment. They must be evaluated with reference to individual patient needs,
resources and limitations unique to the institution and variations in local populations. It is hoped that this
process of local ownership will help to incorporate these guidelines into routine practice. Attention is
drawn to areas of clinical uncertainty where further research might be indicated.

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
12 of 21

development group
Gynaecologists by:
Dr RG Hughes FRCOG, Edinburgh; Professor P Brocklehurst FRCOG, Oxford; Dr P Heath FRACP FRCPCH,
Paediatrics Infectious Diseases Unit, St Georges Hospital, London; and Dr B Stenson FRCPCH FRCPE,
Neonatolog
y
Department, Simpson Centre for Reproductive Health, Edinburgh
and peer reviewed by: British Association of Perinatal Medicine; British Maternal and Fetal Medicine Society;
British Infection Association; Consumers Forum; Group B Strep Support; Womens Services Pharmacists Group, Leeds;
National Childbirth Trust; Royal College of Paediatrics and Child Health; UK National Screening Committee;
Department of Health; Mr FA Boret FRCOG, London; Dr N El Helali, Paris Saint-Joseph; Mr M J Heard FRCOG,
Winchester; Dr R Imtiaz MRCOG, Worcestershire; Dr G Kumar FRCOG, Chester; Dr PT Lynch MRCOG, Dundee;
Ms L Muir, Ayrshire Maternity Unit, Crosshouse Hospital, Kilmarnock; Dr J Sandoe, Leeds Teaching Hospitals NHS Trust,
Leeds General Infirmary; Dr A Simm MRCOG, Nottingham; Professor PJ Steer FRCOG, London.
Committee lead reviewers were: Mr M Griffiths FRCOG, Luton and Dr P Owen MRCOG, Glasgow.
DISCLAIMER
health services.
13 of 13
Reducing the Risk of

Venous Thromboembolism during
Pregnancy and the Puerperium
Green-top Guideline No. 37a
April 2015
Reducing the Risk of Venous Thromboembolism during

Pregnancy and the Puerperium
This is the third edition of this guideline, first published in 2004 under the title Thromboprophylaxis
during Pregnancy, Labour and after Vaginal Delivery and revised in 2009 under the title Reducing the
Risk of Thrombosis and Embolism during Pregnancy and the Puerperium.
Prepregnancy and antenatal risk assessment

What are the risk factors for venous thromboembolism (VTE) in pregnancy and the puerperium and
what is the magnitude of risk for these factors?
All women should undergo a documented assessment of risk factors for VTE in early pregnancy
or prepregnancy.
Risk assessment should be repeated if the woman is admitted to hospital for any reason or develops
other intercurrent problems.
Risk assessment should be repeated again intrapartum or immediately postpartum.
Any woman with four or more current risk factors shown in Appendix I and Table 1 (other than
previous VTE or thrombophilia) should be considered for prophylactic low-molecular-weight
heparin (LMWH) throughout the antenatal period and will usually require prophylactic LMWH for 6
weeks postnatally but a postnatal risk reassessment should be made. [New 2015]
Any woman with three current risk factors shown in Appendix I and Table 1 (other than previous
VTE or thrombophilia) should be considered for prophylactic LMWH from 28 weeks and will
usually require prophylactic LMWH for 6 weeks postnatally but a postnatal risk reassessment
should be made. [New 2015]
Any woman with two current risk factors shown in Appendix I and Table 1 (other than previous VTE
or thrombophilia) should be considered for prophylactic LMWH for at least 10 days postpartum.
[New 2015]
Women admitted to hospital when pregnant (including to the gynaecology ward with hyperemesis
gravidarum or ovarian hyperstimulation syndrome) should usually be offered thromboprophylaxis
with LMWH unless there is a specific contraindication such as risk of labour or active bleeding.
[New 2015]
The risk of VTE should be discussed with women at risk and the reasons for individual
recommendations explained. [New 2015]
Previous VTE
How should women with previous VTE be managed in pregnancy? (see Appendix IV)
Single previous VTE
Women with previous VTE should be offered prepregnancy counselling and a prospective
management plan for thromboprophylaxis in pregnancy made. Those who become pregnant before
receiving such counselling should be referred at the earliest opportunity in pregnancy to a clinician
with expertise in thrombosis in pregnancy.
RCOG Green-top Guideline No. 37a
2 of 40
Women with previous VTE (except those with a single previous VTE related to major surgery
and no other risk factors) should be offered thromboprophylaxis with LMWH throughout the
antenatal period. [New 2015]
Women with previous VTE should have a careful history documented. Where objective
documentation is not available, the previous diagnosis of VTE can be assumed in cases where
the woman gives a good history and received prolonged (greater than 6 weeks) therapeutic
anticoagulation. [New 2015]
Thrombophilia-associated VTE
Heritable thrombophilia
Women with previous VTE associated with antithrombin deficiency (who will often be on long-term
oral anticoagulation) should be offered thromboprophylaxis with higher dose LMWH (either 50%,
75% or full treatment dose) (see Appendix IV) antenatally and for 6 weeks postpartum or until
returned to oral anticoagulant therapy after delivery.
Management should be undertaken in collaboration with a haematologist with expertise in
thrombosis in pregnancy and consideration given to antenatal anti-Xa monitoring and the potential
for antithrombin replacement at initiation of labour or prior to caesarean section. [New 2015]
If anti-Xa levels are measured, a test that does not use exogenous antithrombin should be used
and 4-hour peak levels of 0.51.0 iu/ml aimed for. [New 2015]
Other heritable thrombophilic defects are lower risk and can be managed with standard doses of
thromboprophylaxis. [New 2015]
Acquired thrombophilia see also section 4.4

Women with VTE associated with the antiphospholipid syndrome (APS) (who will often be on longterm oral anticoagulation) should be offered thromboprophylaxis with higher dose LMWH (either
50%, 75% or full treatment dose) (see Appendix IV) antenatally and for 6 weeks postpartum or until
returned to oral anticoagulant therapy after delivery. [New 2015]
Pregnant women with APS and prior VTE or arterial thromboses should be managed in collaboration
with a haematologist and/or rheumatologist with expertise in this area. [New 2015]
Previous recurrent VTE

What extra advice is needed for women with previous recurrent VTE?
Advice regarding doses of LMWH in pregnancy should be sought from a clinician with expertise in
haemostasis and pregnancy. [New 2015]
Some women with previous recurrent VTE require higher doses of LMWH. [New 2015]
Women on long-term warfarin or other oral anticoagulants should be counselled about the risks of
these agents to the fetus (see section 8.6) and advised to stop their oral anticoagulant therapy and
change to LMWH as soon as pregnancy is confirmed, ideally within 2 weeks of the missed period
and before the sixth week of pregnancy. [New 2015]
Women not on warfarin or other oral anticoagulants should be advised to start LMWH as soon as
they have a positive pregnancy test. [New 2015]
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P
P
P
Stratification of women with previous VTE

How should women with previous VTE be stratified to determine management in pregnancy?
Women with VTE associated with either antithrombin deficiency or APS or with recurrent VTE (who
will often be on long-term oral anticoagulation) should be offered thromboprophylaxis with higher
dose LMWH (either 50%, 75% or full treatment dose) (see Appendix IV) antenatally and for 6 weeks
postpartum or until returned to oral anticoagulant therapy after delivery. These women require
specialist management by experts in haemostasis and pregnancy. [New 2015]
Women in whom the original VTE was unprovoked/idiopathic or related to estrogen (estrogen-containing
contraception/pregnancy) or related to a transient risk factor other than major surgery or who have
other risk factors should be offered thromboprophylaxis with LMWH throughout the antenatal period.
In women in whom the original VTE was provoked by major surgery from which they have recovered
and who have no other risk factors, thromboprophylaxis with LMWH can be withheld antenatally
until 28 weeks provided no additional risk factors are present (in which case they should be offered
LMWH). They require close surveillance for the development of other risk factors. [New 2015]
Testing for thrombophilia in women with prior VTE

Which women with prior VTE require thrombophilia testing?
Prior to testing for thrombophilia, women should be counselled regarding the implications for
themselves and family members of a positive or negative result. The results should be interpreted
by clinicians with specific expertise in the area.
Women with a family history of VTE and either antithrombin deficiency or where the specific
thrombophilia has not been detected should be tested for antithrombin deficiency. [New 2015]
Women with an unprovoked VTE should be tested for the presence of antiphospholipid antibodies.
[New 2015]
Asymptomatic heritable thrombophilia

How should women with asymptomatic thrombophilia be treated? (see Appendix IV)
Women should be stratified according to level of risk associated with their thrombophilia and the
presence or absence of a family history or other risk factors. [New 2015]
Women with asymptomatic antithrombin, protein C or S deficiency or those with more than one
thrombophilic defect (including homozygous factor V Leiden, homozygous prothrombin gene
mutation and compound heterozygotes) should be referred to a local expert and antenatal
prophylaxis considered. They should be recommended for six weeks postnatal prophylaxis even
in the absence of additional risk factors. [New 2015]
Heterozygosity for factor V Leiden or prothrombin gene mutation or antiphospholipid antibodies are
considered as risk factors for thrombosis in asymptomatic women (see Appendix I). In the presence
of three other risk factors such women may be considered for antenatal thromboprophylaxis, if there
are two other risk factors thromboprophylaxis should be considered from 28 weeks and if there is
one other risk factor postnatal thromboprophylaxis for 10 days should be considered. [New 2015]
Women with no personal history or risk factors for VTE but who have a family history of an
unprovoked or estrogen-provoked VTE in a first-degree relative when aged under 50 years should
be considered for thrombophilia testing. This will be more informative if the relative has a known
thrombophilia. [New 2015]
4 of 40
Antiphospholipid antibodies
How should women with antiphospholipid antibodies be treated?
Persistent antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin and/or
2-glycoprotein 1 antibodies) in women without previous VTE should be considered as a risk factor
for thrombosis (see Appendix I) such that if she has other risk factors she may be considered for
antenatal or postnatal thromboprophylaxis as above. [New 2015]
Timing of initiation of thromboprophylaxis

When should thromboprophylaxis be started?
Antenatal thromboprophylaxis for those with previous VTE should begin as early in pregnancy
as practical. [New 2015]
Women without previous VTE and without particular first trimester risk factors or admission to
hospital, but with four other risk factors, should be considered for antenatal prophylaxis throughout
pregnancy. [New 2015]
hospital, but with three other risk factors, can start antenatal prophylaxis at 28 weeks of gestation.
[New 2015]
First trimester risk factors

What are the first trimester risk factors for VTE and how should they be managed?
Women admitted with hyperemesis should be considered for thromboprophylaxis with LMWH and
can discontinue thromboprophylaxis when the hyperemesis resolves. [New 2015]
Women with ovarian hyperstimulation syndrome should be considered for thromboprophylaxis

with LMWH in the first trimester. [New 2015]
Women with an IVF pregnancy and three other risk factors should be considered for
thromboprophylaxis with LMWH starting in the first trimester. [New 2015]
Thromboprophylaxis during labour and delivery, including the use of regional analgesia
When should thromboprophylaxis be interrupted for delivery?
Women receiving antenatal LMWH should be advised that if they have any vaginal bleeding or once
labour begins they should not inject any further LMWH. They should be reassessed on admission
to hospital and further doses should be prescribed by medical staff.
Regional techniques should be avoided if possible until at least 12 hours after the previous
prophylactic dose of LMWH.
LMWH should not be given for 4 hours after use of spinal anaesthesia or after the epidural catheter
has been removed and the catheter should not be removed within 12 hours of the most recent injection.
When a woman presents while on a therapeutic regimen of LMWH, regional techniques should be
avoided if possible for at least 24 hours after the last dose of LMWH.
Women receiving antenatal LMWH having an elective caesarean section should receive a
thromboprophylactic dose of LMWH on the day prior to delivery and, on the day of delivery, any
morning dose should be omitted and the operation performed that morning.
5 of 40
The first thromboprophylactic dose of LMWH should be given as soon as possible after delivery
provided there is no postpartum haemorrhage and regional analgesia has not been used. [New 2015]
Women at high risk of haemorrhage with risk factors including major antepartum haemorrhage,
coagulopathy, progressive wound haematoma, suspected intra-abdominal bleeding and
postpartum haemorrhage may be managed with anti-embolism stockings (AES), foot impulse
devices or intermittent pneumatic compression devices. Unfractionated heparin (UFT) may also
be considered.
P
P
If a woman develops a haemorrhagic problem while on LMWH the treatment should be stopped and
expert haematological advice sought.
Thromboprophylaxis should be started or reinstituted as soon as the immediate risk of haemorrhage

is reduced.
Thromboprophylaxis after delivery

Assessment of risk
What are the risk factors for VTE after delivery?
All women with class 3 obesity (BMI greater than or equal to 40 kg/m2) should be considered for
prophylactic LMWH in doses appropriate for their weight for 10 days after delivery. [New 2015]
Women with two or more persisting risk factors listed in Table 1 should be considered for LMWH in
prophylactic doses appropriate for their weight for 10 days after delivery. [New 2015]
Previous VTE
Which women with previous VTE need postpartum thromboprophylaxis?
All women with a previous history of confirmed VTE should be offered thromboprophylaxis with
LMWH or warfarin for at least 6 weeks postpartum regardless of the mode of delivery.
Asymptomatic thrombophilia
Which women with thrombophilia without previous VTE need postpartum thromboprophylaxis?
Women with thrombophilia without previous VTE should be stratified according to both the level of
risk associated with their thrombophilia and the presence or absence of a family history or other
risk factors. [New 2015]
Women with a family history of VTE and an identified thrombophilia should be considered for
6 weeks postnatal thromboprophylaxis.
Caesarean section
What is the magnitude of risk of VTE after caesarean section?
All women who have had caesarean sections should be considered for thromboprophylaxis with
LMWH for 10 days after delivery apart from those having an elective caesarean section who should
be considered for thromboprophylaxis with LMWH for 10 days after delivery if they have any
additional risk factors (see Appendix I and Table 1). [New 2015]
6 of 40
For how long should thromboprophylaxis be continued after delivery?

Risk assessment should be performed in each woman at least once following delivery and before
discharge and arrangements made for LMWH prescription and administration (usually by the
woman herself) in the community where necessary. [New 2015]
Thromboprophylaxis should be continued for 6 weeks in high-risk women and for 10 days in
intermediate-risk women (see Appendix I). [New 2015]
In women who have additional persistent (lasting more than 10 days postpartum) risk factors, such
as prolonged admission, wound infection or surgery in the puerperium, thromboprophylaxis should
be extended for up to 6 weeks or until the additional risk factor/s is/are no longer present. [New 2015]
Which agents should be used for thromboprophylaxis?

Low-molecular-weight heparin (LMWH)
LMWHs are the agents of choice for antenatal and postnatal thromboprophylaxis.
Doses of LMWH are based on weight. For thromboprophylaxis the booking or most recent weight
can be used to guide dosing. [New 2015]
It is only necessary to monitor the platelet count if the woman has had prior exposure to
unfractionated heparin (UFH).
Monitoring of anti-Xa levels is not required when LMWH is used for thromboprophylaxis.
Doses of LMWH should be reduced in women with renal impairment.
LMWH is safe in breastfeeding.
Unfractionated heparin
In women at very high risk of thrombosis (see Appendix IV), UFH may be used peripartum in
preference to LMWH where there is an increased risk of haemorrhage or where regional anaesthetic
techniques may be required.
If UFH is used after caesarean section (or other surgery), the platelet count should be monitored
every 23 days from days 414 or until heparin is stopped. [New 2015]
Danaparoid
Potential use of danaparoid should be in conjunction with a consultant haematologist with
expertise in haemostasis and pregnancy.
Fondaparinux
Fondaparinux should be reserved for women intolerant of heparin compounds. [New 2015]
Fondaparinux use in pregnancy should be in conjunction with a consultant haematologist with
Low-dose aspirin
Aspirin is not recommended for thromboprophylaxis in obstetric patients. [New 2015]
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Warfarin
Warfarin use in pregnancy is restricted to the few situations where heparin is considered unsuitable,
e.g. some women with mechanical heart valves.
Women receiving long-term anticoagulation with warfarin can be converted from LMWH to warfarin
postpartum when the risk of haemorrhage is reduced, usually 57 days after delivery.
Warfarin is safe in breastfeeding.
Dextran
Dextran should be avoided antenatally and intrapartum because of the risk of anaphylactoid reaction.
Oral thrombin and Xa inhibitors

Non-vitamin K antagonist oral anticoagulants (NOACs) should be avoided in pregnant women.
[New 2015]
Use of NOACs is not currently recommended in women who are breastfeeding. [New 2015]
P
P
Anti-embolism stockings
The use of properly applied anti-embolism stockings (AES) of appropriate size and providing
graduated compression with a calf pressure of 1415 mmHg is recommended in pregnancy and the
puerperium for women who are hospitalised and have a contraindication to LMWH. These include
women who are hospitalised post-caesarean section (combined with LMWH) and considered to be at
particularly high risk of VTE (e.g. previous VTE, more than four risk factors antenatally or more than
two risk factors postnatally) and women travelling long distance for more than 4 hours. [New 2015]
Contraindications to LMWH
Which women should not be given thromboprophylaxis with LMWH?
LMWH should be avoided, discontinued or postponed in women at risk of bleeding after careful
consideration of the balance of risks of bleeding and thrombosis.
Women with previous or current allergic reactions to LMWH should be offered an alternative
preparation or alternative form of prophylaxis. [New 2015]
Further advice on the management of a woman with both VTE risk factors and bleeding risk factors
or LMWH allergy may be sought from a haematologist with expertise in the management of
thrombosis and bleeding disorders in pregnancy.
Risk scoring methodologies

A formal VTE risk assessment with numerical scoring for all pregnant and postpartum women is
recommended (see Appendix III). [New 2015]
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1.
Purpose and scope
The aim of this guideline is to provide advice, based on clinical evidence where available, regarding the
prevention of venous thromboembolism (VTE) during pregnancy, birth and following delivery. For the
diagnosis and management of acute VTE in pregnancy, please refer to Green-top Guideline No. 37b.1 For
anticoagulation for mechanical heart valves in pregnancy, the reader is directed to the chapter covering
this within the proceedings of the RCOG study group on heart disease.2 A summary of the guideline for
antenatal and postnatal thromboprophylaxis is given in Appendix I.
2.
Pulmonary embolism (PE) remains a leading direct cause of maternal death in the UK. There was a
significant fall in the maternal mortality rate from PE (from 1.56 [95% CI 1.432.63] per 100000
maternities in 20032005 [33 deaths] to 0.70 [95% CI 0.491.25] per 100 000 maternities in 20062008
[16 deaths]3,4) due largely to reductions in deaths from antenatal VTE (which fell from 11 to 3) and
deaths from VTE after vaginal delivery (which fell from 8 to 2) and attributed to the first version of this
guideline published in 2004.4
The National Institute for Health and Care Excellence (NICE) estimates that low-molecular-weight
heparin (LMWH) reduces VTE risk in medical and surgical patients by 60% and 70% respectively.5
Therefore it is reasonable to assume that it may substantially reduce the risk of VTE in obstetric patients.
A Scandinavian study6 found a relative risk reduction of VTE of 88% in obstetric patients with one
previous VTE given LMWH.
Seventy-nine percent and 89% of the women who died from PE in the UK between 2003 and 2005 and
between 2006 and 2008 respectively had identifiable risk factors3,4 and a similar proportion (70%) from
the UK Obstetric Surveillance System (UKOSS) cohort (n = 143) of fatal (3.5%) and nonfatal antenatal PE
also had identifiable risk factors.7
The UK incidence of antenatal PE calculated in the UKOSS study is 1.3 per 10000 maternities.7 Although
the relative risk of VTE in pregnancy is increased four- to six-fold8,9 and this is increased further
postpartum,911 the absolute risk is low with an overall incidence of VTE in pregnancy and the puerperium
of 12 per 1000.8,1217 Absolute incidence of VTE in pregnancy and the puerperium is 107 per 100000
person-years (95% CI 93122 per 100000 person-years) in the UK,9 107 per 100000 pregnancy-years
during pregnancy and 175 per 100000 puerperal-years during the puerperium in Denmark,17 and 175
per 100000 pregnancies (deep vein thrombosis [DVT] 121 per 100000, PE 54 per 100000) in Canada.16
Many fatal antenatal VTE events occur in the first trimester and therefore prophylaxis for women
with previous VTE should begin early in pregnancy.1820 The risk for VTE increases with gestational
age, reaching a maximum just after delivery.810,16,17 Caesarean section is a significant risk factor12,2124
but women having vaginal deliveries are also at risk.3 The relative risk postpartum is five-fold higher
compared to antepartum8 and a systematic review of risk of postpartum VTE found that the risk varied
from 21- to 84-fold from the baseline nonpregnant, nonpostpartum state in studies that included an
internal reference group.11 The absolute risk peaked in the first 3 weeks postpartum (421 per 100000
person-years; 22-fold increase in risk).9
As the absolute risk of VTE in pregnancy is low, some form of risk stratification is required to determine
which women warrant pharmacological thromboprophylaxis.25 The threshold for recommending
postpartum thromboprophylaxis is lower than that for recommending antenatal thromboprophylaxis
because the risk per day is higher and the duration of risk is shorter.26
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3.
This guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines. The Cochrane Library (including the Cochrane Database of Systematic Reviews, the
Cochrane Central Register of Controlled Trials and the Database of Abstracts of Reviews of Effects
[DARE]), EMBASE, the ACP Journal Club and MEDLINE, including in-process and other non-indexed
citations, were searched from 2009 to 2013 to identify all relevant randomised controlled trials, systematic
reviews and meta-analyses published since the previous edition of the guideline. The databases were
searched using the relevant Medical Subject Headings (MeSH) terms, including all subheadings. The
principal search terms used were: venous thromboembolism, thrombosis, pregnancy, postpartum,
puerperium, antenatal, prenatal. The search was limited to humans and the English language. The
National Library for Health and the National Guideline Clearinghouse were also searched for relevant
guidelines and reviews. A top-up search was performed in October 2014.
Current guidelines for the prevention of VTE in pregnancy and the puerperium were reviewed.2628 A
Cochrane systematic review29 of randomised trials comparing one method of thromboprophylaxis with
placebo or no treatment and randomised trials comparing two (or more) methods of thromboprophylaxis
concluded that there is insufficient evidence on which to base recommendations for thromboprophylaxis
during pregnancy and the early postnatal period. The current guidelines are therefore drawn up
recognising the limited evidence in this area.
4.
Prepregnancy and antenatal risk assessment
4.1 What are the risk factors for VTE in pregnancy and the puerperium and what is the
magnitude of risk for these factors?
All women should undergo a documented assessment of risk factors for VTE in early pregnancy or
prepregnancy.
Risk assessment should be repeated if the woman is admitted to hospital for any reason or develops
other intercurrent problems.
Risk assessment should be repeated again intrapartum or immediately postpartum.
Any woman with four or more current risk factors shown in Appendix I and Table 1 (other than
previous VTE or thrombophilia) should be considered for prophylactic LMWH throughout the
antenatal period and will usually require prophylactic LMWH for 6 weeks postnatally but a
postnatal risk reassessment should be made.
Any woman with three current risk factors shown in Appendix I and Table 1 (other than previous
VTE or thrombophilia) should be considered for prophylactic LMWH from 28 weeks and will
usually require prophylactic LMWH for 6 weeks postnatally but a postnatal risk reassessment
should be made.
Any woman with two current risk factors shown in Appendix I and Table 1 (other than previous VTE
or thrombophilia) should be considered for prophylactic LMWH for at least 10 days postpartum.
Women admitted to hospital when pregnant (including to the gynaecology ward with hyperemesis
gravidarum or ovarian hyperstimulation syndrome) should usually be offered thromboprophylaxis
with LMWH unless there is a specific contraindication such as risk of labour or active bleeding.
The risk of VTE should be discussed with women at risk and the reasons for individual
recommendations explained.
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The risk factors are listed in Table 1, Appendix II and Appendix III. For most risk factors the level of
evidence is 2+ but it varies from 2 to 2++ depending on the risk factor. Some women can be identified
to be at increased risk because of the presence of one or more well-documented risk factors.12,1416,2225,3035
Appendix II summarises the odds ratios (ORs) for VTE associated with each risk factor derived from
various studies. Women with multiple risk factors for VTE, even those who are not known to have a
thrombophilia or a previous VTE, may be at greatly increased risk of VTE in pregnancy, especially in
the third trimester and postpartum.9 Indeed, age greater than 35 years, obesity and caesarean section
contribute most substantially to the rates of VTE because of their high and increasing prevalence.36
4.1.1 Previous VTE or thrombophilia

Two well-recognised significant risk factors for VTE in pregnancy, identifiable before
pregnancy, are thrombophilia and previous VTE.15,16 Heritable thrombophilia is found in 20
50% of pregnancy-related VTE.37,38 A large retrospective study calculated an odds ratio of 24.8 Evidence
level 2+
(95% CI 17.136) for previous VTE.32 Previous VTE and thrombophilia are discussed in more
detail in sections 4.2 and 4.3 below.
4.1.2 Obesity
Sixty percent of women who died from PE in the UK between 2003 and 2008 were obese
(body mass index [BMI] 30 or higher)3,4 compared with the 20% prevalence of obesity in
women aged 1644 in the Health Survey for England 2010.39,40 Obesity is a risk factor for VTE in
pregnancy7,12,3133 and the risk is higher with increasing obesity.41 It is associated with a higher Evidence
level 2+
risk of PE (adjusted OR [aOR] 14.9, 95% CI 3.074.8) than of DVT (aOR 4.4, 95% CI 1.611.9).33
Being overweight (BMI 2529.9), too, is a weak risk factor for pregnancy-related VTE and is
extremely common, with a prevalence within the childbearing population of almost 50%.39
4.1.3 Age
Data for age are conflicting. Data from casecontrol studies (see Appendix II) have suggested a
modest increased relative risk of less than two-fold for women aged over 35 years.14,16,31 In a UK
study using a large population-based cohort,9 outside pregnancy, women in the oldest age band
(3544 years) had a 50% higher rate of VTE than women aged 2534 years. The rate of VTE did
not increase with age in the antepartum period; however, in the postpartum period women Evidence
level 2+
aged 35 and over had a 70% increase in risk compared to 2534 year olds (corresponding to
an excess absolute risk of 1.6 per 1000 person-years). A Korean study similarly found that
increased age was not associated with VTE in pregnancy.24 However, for simplicity we have
retained age greater than 35 years as a risk factor antenatally and postpartum.
4.1.4 Immobility and long-distance travel

For immobility and long-distance travel, data for pregnancy-related risk are limited and extrapolation
from studies in nonpregnant patients is necessary.34
The NICE guideline on antenatal care42 and the RCOG Scientific Impact Paper on air travel in
pregnancy43,44 state that long-haul air travel increases the risk of VTE; this guideline considers Evidence
all long-distance (more than four hours) travel (not exclusively by air) to be a risk factor for level 3
VTE in pregnancy.
Some studies have demonstrated interaction between the effects of the risk factors listed
in Table 1 and Appendix II. For example, in a Norwegian casecontrol study,12 BMI greater Evidence
level 2+
than 25 and antepartum immobilisation (defined as strict bed rest 1 week or more prior to
11 of 40
delivery) had a multiplicative effect on the risk for antepartum (aOR 62.3, 95% CI 11.5337.7) Evidence
level 2+
and postpartum VTE (aOR 40.1, 95% CI 8.0201.5).
4.1.5 Admission to hospital

Admission to hospital during pregnancy is associated with an 18-fold increased risk of first
VTE (adjusted incidence ratio 17.5, 95% CI 7.6940.0) compared with time outside hospital and
the risk remains increased after discharge, being six-fold higher in the 28 days after discharge. Evidence
The risk is higher in the third trimester and in women over 35 years old. The risk of VTE level 2+
during hospitalisation and after discharge are four-fold higher for admissions lasting less than
3 days but 12-fold higher if 3 days or longer.45
4.1.6 Other risk factors

Examples of comorbidities which have been shown to be associated with an increase in
the risk of VTE in pregnancy include active inflammatory bowel disease (IBD),22,46 urinary
tract infection,22 systemic lupus erythematosus (SLE), heart disease,16 pregnancy-induced
hypertension/pre-eclampsia15,24 and non-obstetric antenatal surgery.47
Recent data using a primary care database containing 376154 pregnancies between 1995 and Evidence
level 2+
2009 found that, in pregnancy, varicose veins, IBD, urinary tract infection and pre-existing
diabetes were associated with an increased risk for VTE (absolute risks [ARs] 139/100000
person-years; incidence rate ratios [IRRs] 1.8).22 Analysing data from 1475301 Scottish
maternity discharges, Kane et al.15 found that risk factors for VTE included three or more
previous pregnancies, obstetric haemorrhage, and pre-eclampsia.
An individual assessment of thrombotic risk should be undertaken before pregnancy, or in early
pregnancy, and at each hospital admission. Appendix III provides a suggested checklist for
documentation of this risk assessment. Early assessment is important in view of the increased
thrombotic risks associated with complications in the first trimester. For example, in one study
the odds ratio for VTE in women with hyperemesis gravidarum was 2.5 (95% CI 23.2) 32 (see Evidence
level 3
later for first trimester risk factors). This has implications for general practitioners, physicians
and gynaecologists since many fatal antenatal VTE events occur in the first trimester3,1820 and
booking often does not occur until the end of the first trimester, after the stage at which
thromboprophylaxis should have ideally begun.
Available evidence does not allow an accurate risk estimation of VTE to be determined from
combinations of the different risk factors listed in Table 1 and Appendix II. Neither is this list
exhaustive. There may be some conditions that increase the risk of VTE that are not listed. In Evidence
general, active autoimmune and inflammatory conditions should be considered as risk factors. level 2+
Multiple risk factors increase the risk of VTE.12 The risk of antenatal VTE is highest in the third
trimester9,17,48 (see below under section 5).
Therefore, as a pragmatic approach to women with risk factors (except previous VTE; see below and
Appendix I and Appendix III), it is suggested that thromboprophylaxis with LMWH be considered
antenatally if there are four or more risk factors, from 28 weeks if there are three risk factors and
postnatally if there are only two risk factors.
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Table 1. Risk factors for venous thromboembolism in pregnancy and the puerperium
See also Appendix I and Appendix II
Pre-existing
Previous VTE
Thrombophilia
Heritable
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin gene mutation
Acquired
Antiphospholipid antibodies
Persistent lupus anticoagulant and/or persistent
moderate/high titre anticardiolipin antibodies
and/or 2-glycoprotein 1 antibodies
Medical comorbidities e.g. cancer; heart failure; active SLE, inflammatory

polyarthropathy or IBD; nephrotic syndrome; type I diabetes mellitus with
nephropathy; sickle cell disease;49 current intravenous drug user
Age > 35 years
Obesity (BMI 30 kg/m2) either prepregnancy or in early pregnancy
Parity 3 (a woman becomes para 3 after her third delivery)
Smoking
Gross varicose veins (symptomatic or above knee or with associated phlebitis,
oedema/skin changes)
Paraplegia
Obstetric risk factors
Multiple pregnancy
Current pre-eclampsia
Caesarean section
Prolonged labour (> 24 hours)
Mid-cavity or rotational operative delivery
Stillbirth
Preterm birth
Postpartum haemorrhage (> 1 litre/requiring transfusion)
New onset/transient
These risk factors are potentially
reversible and may develop at later
stages in gestation than the initial
risk assessment or may resolve and
therefore what is important is an
ongoing individual risk assessment
Any surgical procedure in pregnancy or puerperium except immediate repair of the

perineum, e.g. appendicectomy, postpartum sterilisation
Bone fracture
Hyperemesis, dehydration
Ovarian hyperstimulation
syndrome (first trimester only)
Assisted reproductive technology (ART), in vitro

fertilisation (IVF)
Admission or immobility
( 3 days bed rest)
e.g. pelvic girdle pain restricting mobility
Current systemic infection

(requiring intravenous antibiotics or
admission to hospital)
e.g. pneumonia, pyelonephritis, postpartum

wound infection
Long-distance travel (> 4 hours)
4.2 Previous VTE

How should women with previous VTE be managed in pregnancy? (see Appendix IV)
4.2.1 Single previous VTE
Women with previous VTE should be offered prepregnancy counselling and a prospective
management plan for thromboprophylaxis in pregnancy made. Those who become pregnant before
receiving such counselling should be referred at the earliest opportunity in pregnancy to a clinician
with expertise in thrombosis in pregnancy.
Women with previous VTE (except those with a single previous VTE related to major surgery
and no other risk factors) should be offered thromboprophylaxis with LMWH throughout the
antenatal period.
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Women with previous VTE should have a careful history documented. Where objective documentation
is not available, the previous diagnosis of VTE can be assumed in cases where the woman gives a
good history and received prolonged (greater than 6 weeks) therapeutic anticoagulation.
Women with previous VTE have an increased risk of recurrence in pregnancy and
postpartum15,16,32 with reported recurrence rates of 211%.27,5053 A retrospective comparison of
the recurrence rate of VTE during pregnancy and the nonpregnant period revealed recurrence Evidence
rates of 10.9% during and 3.7% outside pregnancy, giving a relative risk during pregnancy of level 2+
3.5 (95% CI 1.67.8).50 The risk of recurrence appears to be constant over the whole period
of pregnancy.52,53
There are no randomised trials on which to base measures to prevent antenatal VTE in women
with prior VTE and decisions are therefore based on estimates from observational studies.
Evidence from prospective51 and retrospective53 studies suggests that the risk of antenatal Evidence
level 3
recurrence is very low if the prior VTE was provoked by a transient major risk factor that is no
longer present. Outside pregnancy, the recurrence risk is lower in those with VTE complicating
major surgery than in those provoked by other transient nonsurgical risk factors.54
All women with prior VTE should receive postpartum prophylaxis15,16,32 as this is the period Evidence
of greatest risk.
level 2+
4.2.2
Thrombophilia-associated VTE
Heritable thrombophilia
Women with previous VTE associated with antithrombin deficiency (who will often be on long-term
oral anticoagulation) should be offered thromboprophylaxis with higher dose LMWH (either 50%,
75% or full treatment dose) (see Appendix IV) antenatally and for 6 weeks postpartum or until
Management should be undertaken in collaboration with a haematologist with expertise in

thrombosis in pregnancy and consideration given to antenatal anti-Xa monitoring and the potential
for antithrombin replacement at initiation of labour or prior to caesarean section.
If anti-Xa levels are measured, a test that does not use exogenous antithrombin should be used
and 4-hour peak levels of 0.51.0 iu/ml aimed for.
Other heritable thrombophilic defects are lower risk and can be managed with standard doses of
thromboprophylaxis.
The evidence on which to base guidance on the prevention of recurrent VTE during
pregnancy in women with thrombophilia remains limited. However, since most women
with previous VTE will be offered thromboprophylaxis anyway, the presence of a heritable Evidence
level 4
thrombophilia generally makes little difference to management and, outside pregnancy,
heritable thrombophilias are at best weak predictors of recurrent VTE.55
Risks of recurrent VTE appear higher for those with a family history and deficiencies of
the naturally occurring anticoagulants, particularly type 1 antithrombin deficiency (both
activity and antigen reduced), than for those with heterozygous V Leiden or the prothrombin
variant.5660 Patients with prior VTE and type 1 antithrombin deficiency typically have a family Evidence
level 3
history of VTE and are often on long-term oral anticoagulant therapy. Heparins may not be
as effective in antithrombin deficiency as their mode of action is antithrombin-dependent.
Although evidence is limited,61 they are likely to require intermediate or therapeutic dose
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LMWH throughout pregnancy and this should be continued for a minimum of 6 weeks
postpartum or until converted back to long-term oral anticoagulation. Different subtypes of
antithrombin deficiency are associated with different levels of VTE risk and therefore advice Evidence
level 3
should be sought from a local expert in this area. Antithrombin replacement around the time
of delivery has been suggested61,62 and might be considered in individual cases.
Acquired thrombophilia see also section 4.4
Women with VTE associated with the antiphospholipid syndrome (APS) (who will often be on longterm oral anticoagulation) should be offered thromboprophylaxis with higher dose LMWH (either
50%, 75% or full treatment dose) (see Appendix IV) antenatally and for 6 weeks postpartum or until
Pregnant women with APS and prior VTE or arterial thromboses should be managed in collaboration
with a haematologist and/or rheumatologist with expertise in this area.
Women with antiphospholipid syndrome (APS) and previous VTE are at high risk of recurrent
VTE in pregnancy. A Canadian study found that APS was associated with an adjusted odds
ratio for PE of 12.9 (95% CI 4.438.0), and for DVT 5.1 (95% CI 1.814.3).16 Many women with
unprovoked or recurrent VTE diagnosed with APS will be on long-term oral anticoagulant Evidence
therapy. There are no randomised controlled trial data to support recommendations for level 3
particular doses of LMWH in pregnancy. Case series support high prophylactic doses,63,64 but
some authors recommend either intermediate (75%) or therapeutic full anticoagulant doses of
LMWH26,65 and this may be appropriate for APS with recurrent previous VTE or arterial events.
4.2.3
Previous recurrent VTE
What extra advice is needed for women with previous recurrent VTE?
Advice regarding doses of LMWH in pregnancy should be sought from a clinician with expertise in
haemostasis and pregnancy.
Some women with previous recurrent VTE require higher doses of LMWH.
Women on long-term warfarin or other oral anticoagulants should be counselled about the risks of
these agents to the fetus (see section 8.6) and advised to stop their oral anticoagulant therapy and
change to LMWH as soon as pregnancy is confirmed, ideally within 2 weeks of the missed period
and before the sixth week of pregnancy.
Women not on warfarin or other oral anticoagulants should be advised to start LMWH as soon as
they have a positive pregnancy test.
P
P
P
Individuals with recurrent VTE are at increased risk of further recurrence66,67 and many will
be on long-term oral anticoagulant therapy. Although data are lacking, it would be expected Evidence
level 4
that they would have a high risk of recurrence in pregnancy.
4.2.4
Stratification of women with previous VTE
How should women with previous VTE be stratified to determine management in pregnancy?
Women with VTE associated with either antithrombin deficiency or APS or with recurrent VTE (who
will often be on long-term oral anticoagulation) should be offered thromboprophylaxis with higher
dose LMWH (either 50%, 75% or full treatment dose) (see Appendix IV) antenatally and for 6 weeks
postpartum or until returned to oral anticoagulant therapy after delivery. These women require
specialist management by experts in haemostasis and pregnancy.
15 of 40
Women in whom the original VTE was unprovoked/idiopathic or related to estrogen (estrogencontaining contraception/pregnancy) or related to a transient risk factor other than major surgery
or who have other risk factors should be offered thromboprophylaxis with LMWH throughout the
antenatal period.
In women in whom the original VTE was provoked by major surgery from which they have recovered
and who have no other risk factors, thromboprophylaxis with LMWH can be withheld antenatally
until 28 weeks provided no additional risk factors are present (in which case they should be offered
LMWH). They require close surveillance for the development of other risk factors.
Administration of antenatal LMWH depending on categorisation of women with prior VTE

into higher and lower risk groups depending on the presence or absence of a temporary risk
factor and/or thrombophilia was associated with a low risk of recurrence in a prospective
German study.25
Evidence
level 2+
5,26,68
These data and recent international guidelines

support stratification of women with
previous VTE into different risk categories requiring different levels of thromboprophylaxis
(see Appendix I and Appendix IV).
4.2.5
Testing for thrombophilia in women with prior VTE
Which women with prior VTE require thrombophilia testing?

Prior to testing for thrombophilia, women should be counselled regarding the implications for
themselves and family members of a positive or negative result. The results should be interpreted
by clinicians with specific expertise in the area.
Women with a family history of VTE and either antithrombin deficiency or where the specific
thrombophilia has not been detected should be tested for antithrombin deficiency.
Women with an unprovoked VTE should be tested for the presence of antiphospholipid antibodies.
P
P
P
It is important to be aware of the effects of pregnancy on the results of thrombophilia tests.

These are described in another guideline.1 Thrombophilia testing should not be requested
inappropriately and only if the finding of a thrombophilia would alter the proposed management.
All women with prior VTE (see above) should be considered for thromboprophylaxis and
hence testing for heritable thrombophilia is not routinely required.
Recent reviews of risk assessment for recurrent venous thrombosis recommend against testing
routinely for thrombophilia.69,70 However, if thrombophilia testing is performed following
an episode of VTE (e.g. following an unprovoked VTE episode and with a family history),
it is preferable that this is done before pregnancy, both because pregnancy itself affects the
estimation of protein S in particular and because it allows decisions on thromboprophylaxis Evidence
level 4
to be considered in advance of pregnancy.
Women with previous VTE should not be screened for thrombophilia in pregnancy unless
the result will influence recommendations regarding thromboprophylaxis. Detection
of antithrombin deficiency or APS will alter the dose of thromboprophylaxis offered in
pregnancy and therefore screening for the former is indicated in women with previous
VTE and a family history of VTE and either antithrombin deficiency or where the
specific thrombophilia has not been detected and for APS in those with an unprovoked
VTE. APS is not diagnosed unless lupus anticoagulant and/or anticardiolipin and/or
2-glycoprotein 1 antibodies are positive on two occasions 12 weeks apart.71
16 of 40
4.3 Asymptomatic heritable thrombophilia

How should women with asymptomatic thrombophilia be treated? (see Appendix IV)
Women should be stratified according to level of risk associated with their thrombophilia and the
presence or absence of a family history or other risk factors.
Women with asymptomatic antithrombin, protein C or S deficiency or those with more than one
thrombophilic defect (including homozygous factor V Leiden, homozygous prothrombin gene
mutation and compound heterozygotes) should be referred to a local expert and antenatal
prophylaxis considered. They should be recommended for six weeks postnatal prophylaxis even
in the absence of additional risk factors.
Heterozygosity for factor V Leiden or prothrombin gene mutation or antiphospholipid antibodies are
considered as risk factors for thrombosis in asymptomatic women (see Appendix I). In the presence
of three other risk factors such women may be considered for antenatal thromboprophylaxis, if
there are two other risk factors thromboprophylaxis should be considered from 28 weeks and if
there is one other risk factor postnatal thromboprophylaxis for 10 days should be considered.
Women with no personal history or risk factors for VTE but who have a family history of an
unprovoked or estrogen-provoked VTE in a first-degree relative when aged under 50 years
should be considered for thrombophilia testing. This will be more informative if the relative has a
known thrombophilia.
The role of testing for heritable thrombophilias in women with a family history but no personal
history of VTE remains controversial, as does the management in pregnancy and following Evidence
level 4
childbirth of any thrombophilic tendency that is thereby identified.26,68,72
Family history itself in the absence of an identifiable thrombophilic tendency is associated
with an increased risk of VTE.7375 It may be reasonable to consider case finding in high-risk
thrombophilic families and in asymptomatic pregnant women with a family history of VTE
in a first-degree relative aged under 50 years where the episode has been unprovoked or
provoked by pregnancy, combined oral contraceptive exposure or the presence of a minor
risk factor.55,68 Testing is more informative if the thrombophilic tendency in the proband is
known. In contrast, thrombophilia testing is not required in pregnant women with other
clinical risk factors indicating a need for thromboprophylaxis.
Recent prospective and retrospective family studies support the view that deficiencies of
the naturally occurring anticoagulants (antithrombin, protein C and protein S) are of greater
clinical significance than heterozygous carriage of factor V Leiden or the prothrombin gene
mutation.59,76 Recent studies have been consistent with a higher risk of pregnancy-related Evidence
level 3
VTE in women who are antithrombin deficient or who are homozygous for factor V Leiden,
the prothrombin gene mutation or are compound heterozygotes for factor V Leiden and the
prothrombin gene mutation.61,62,77,78
Women should be stratified according to both the level of risk associated with their
thrombophilia (see Table 2) and the presence or absence of a family history or other risk
factors.79 The decision to offer antenatal thromboprophylaxis should be based on an estimate of
the absolute risk of VTE during the pregnancy (and of the bleeding risk of prophylaxis) and this
depends on the individual thrombophilic tendency, the details of the family history (number of
affected relatives, age at which thrombosis developed, whether it was pregnancy- or estrogenassociated and the presence or absence of additional risk factors in the affected relatives),80 the
presence of additional clinical risk factors and the wishes of the individual woman.
17 of 40
When LMWH is used for thromboprophylaxis in pregnancy in women with asymptomatic

thrombophilias, standard doses can be used, with the exception of antithrombin deficiency Evidence
level 4
where intermediate doses may be required.61
Antenatal thromboprophylaxis is not routinely required in women with a low-risk thrombophilic
tendency (heterozygosity of factor V Leiden or the prothrombin gene mutation) unless there are
additional clinical risk factors including a strong family history particularly of pregnancy-related VTE.
Homozygosity for a thermolabile variant of the gene for methylenetetrahydrofolate reductase
(MTHFR) is sometimes included in thrombophilia testing but there is no evidence of an Evidence
association with a clinically relevant increase in the risk of VTE in pregnancy and it should level 4
be ignored.81
Table 2. E
stimated absolute risk of pregnancy-associated VTE with different thrombophilic defects in women
with one or more symptomatic first-degree relative
Thrombophilic defect
Pregnancy
(%/pregnancy,
95% CI)
Antenatal
(%/pregnancy,
95% CI)
Postpartum
(%/pregnancy,
95% CI)
Antithrombin, protein C or protein S deficiency82
4.1 (1.78.3)
1.2 (0.34.2)
3.0 (1.36.7)
Antithrombin deficiency type 1 (range)8387*
1550
040
1128
V Leiden heterozygous
2.1 (0.74.9)
0.4 (0.12.4)
1.7 (0.74.3)
2.3 (0.85.3)
0.5 (0.12.6)
1.9 (0.74.7)
1.815.8
05
110
82
Prothrombin gene mutation heterozygous
82
V Leiden homozygous or compound heterozygosity

V Leiden and prothrombin gene mutation (range)88,89
*These data are from a population-based study, not a family-based study
4.4 Antiphospholipid antibodies

How should women with antiphospholipid antibodies be treated?
Persistent antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin and/or
2-glycoprotein 1 antibodies) in women without previous VTE should be considered as a risk factor
for thrombosis (see Appendix I) such that if she has other risk factors she may be considered for
antenatal or postnatal thromboprophylaxis as above.
Diagnostic criteria for APS, an acquired thrombophilic tendency, have been agreed.71 Management
recommendations in this guideline are limited to the prevention of VTE and not that of other adverse
pregnancy outcomes.
The risk of VTE in women with obstetric APS characterised by recurrent miscarriage or fetal
loss without prior VTE is unclear, but data from randomised trials suggest that the risk is
low. Antenatal heparin therapy administered to improve pregnancy outcome in these trials Evidence
was typically stopped between 35 weeks and delivery and no maternal VTE events were level 3
reported.90,91 In a series of 33 women with primary APS, there were no thromboses in women
with APS but without previous VTE given 35 days thromboprophylaxis postpartum only.63
Antiphospholipid antibodies are sometimes detected because of a coagulation disturbance or
connective tissue disorder in the absence of a history of thrombosis or obstetric problems.
The risks of VTE in women with a persistent lupus anticoagulant and/or anticardiolipin and/ Evidence
level 2+
or 2-glycoprotein 1 antibodies without prior thrombosis or recurrent miscarriage or fetal loss
(i.e. without APS) 92,93 are small but it is reasonable to consider this as a risk factor in the same
18 of 40
way as V Leiden or the prothrombin variant and consider LMWH thromboprophylaxis if other Evidence
level 2+
risk factors are present.
5.
Timing of initiation of thromboprophylaxis
5.1 When should thromboprophylaxis be started?

Antenatal thromboprophylaxis for those with previous VTE should begin as early in pregnancy
as practical.
Women without previous VTE and without particular first trimester risk factors or admission
to hospital, but with four other risk factors, should be considered for antenatal prophylaxis
throughout pregnancy.
hospital, but with three other risk factors, can start antenatal prophylaxis at 28 weeks of gestation.
Meta-analysis has shown that most VTE occurs antenatally with an equal distribution throughout
gestation,94 but two-thirds of antenatal fatal pulmonary VTE in 20032005 occurred in the
first trimester.3 Several studies have found that 4050% of antenatal VTE occurred before 15 Evidence
level 1+
weeks of gestation.1820 These data emphasise the need for risk assessment prepregnancy and
institution of prophylaxis if appropriate in early pregnancy.
However, recent studies have demonstrated that the risk of antenatal VTE is highest in the
third trimester. A Norwegian study48 found that, of all VTEs associated with pregnancy and
postpartum, 10% occurred in each of the first and second trimesters and 28% in the third
trimester; a UK study found that the rate of VTE during the third trimester was six times Evidence
higher than outside pregnancy (IRR 6.1, 95% CI 4.77.9). In contrast, both the first (IRR 1.6) level 2++
and second (IRR 2.1) trimesters conferred little increase in risk.9 In a Danish cohort study,17 the
absolute risk of VTE per 10 000 pregnancy-years increased from 4.1 (95% CI 3.25.2) during
the first trimester to 59.0 (95% CI 46.176.4) by week 40.
5.2 First trimester risk factors

What are the first trimester risk factors for VTE and how should they be managed?
Women admitted with hyperemesis should be considered for thromboprophylaxis with LMWH and
can discontinue thromboprophylaxis when the hyperemesis resolves.
Women with ovarian hyperstimulation syndrome should be considered for thromboprophylaxis

with LMWH in the first trimester.
Women with an IVF pregnancy and three other risk factors should be considered for
thromboprophylaxis with LMWH starting in the first trimester.
Certain additional risk factors may complicate the first trimester (Table 1 and Appendix II),
such as hyperemesis,16,32 ovarian hyperstimulation syndrome and IVF.12,24,95,96 In a Norwegian
casecontrol study12 assisted reproduction and multiple pregnancies had additive effects.
Evidence from a Swedish study suggests that not only does IVF double the risk of VTE
compared to natural conception, but the risk in the first trimester was four-fold higher Evidence
level 2+
and the risk of PE during the first trimester was seven times higher.97 Women with ovarian
hyperstimulation syndrome are particularly prone to VTE in the upper body.95,96 At present
it is unclear whether women undergoing surgical management of miscarriage and surgical
termination of pregnancy are at increased risk of VTE.
19 of 40
6.
Thromboprophylaxis during labour and delivery, including the use of regional analgesia
When should thromboprophylaxis be interrupted for delivery?

Women receiving antenatal LMWH should be advised that if they have any vaginal bleeding or once
labour begins they should not inject any further LMWH. They should be reassessed on admission
to hospital and further doses should be prescribed by medical staff.
Regional techniques should be avoided if possible until at least 12 hours after the previous
prophylactic dose of LMWH.
LMWH should not be given for 4 hours after use of spinal anaesthesia or after the epidural catheter
has been removed and the catheter should not be removed within 12 hours of the most recent
injection.
When a woman presents while on a therapeutic regimen of LMWH, regional techniques should be
avoided if possible for at least 24 hours after the last dose of LMWH.
Women receiving antenatal LMWH having an elective caesarean section should receive a
thromboprophylactic dose of LMWH on the day prior to delivery and, on the day of delivery, any
morning dose should be omitted and the operation performed that morning.
The first thromboprophylactic dose of LMWH should be given as soon as possible after delivery
provided there is no postpartum haemorrhage and regional analgesia has not been used.
Women at high risk of haemorrhage with risk factors including major antepartum haemorrhage,
coagulopathy, progressive wound haematoma, suspected intra-abdominal bleeding and postpartum
haemorrhage may be managed with anti-embolism stockings (AES), foot impulse devices or
intermittent pneumatic compression devices. Unfractionated heparin (UFT) may also be considered.
P
P
P
P
P
P
P
If a woman develops a haemorrhagic problem while on LMWH the treatment should be stopped and
expert haematological advice sought.
Thromboprophylaxis should be started or reinstituted as soon as the immediate risk of haemorrhage

is reduced.
The pregnancy-associated prothrombotic changes in the coagulation system are maximal

immediately following delivery. However, in order to allow for use of regional analgesia or
anaesthesia and minimise the risk of epidural haematoma,98 women are advised to discontinue
LMWH at the onset of labour or prior to planned delivery. Regional analgesia can be sited Evidence
only after discussion with a senior anaesthetist, in keeping with local obstetric anaesthetic level 4
protocols.1 It is important to discuss the implications of treatment with LMWH for regional
analgesia with the woman prior to labour or caesarean section. This could be undertaken in
an antenatal anaesthetic clinic.
If LMWH is routinely prescribed at 6 p.m., this allows for an elective caesarean section the next morning,
removal of the epidural catheter before 2 p.m. and a first postnatal dose of LMWH at 6 p.m. the same day.
In some women, particularly those on high-dose prophylactic or treatment doses of LMWH,
there may be an indication for induction of labour to help plan thromboprophylaxis around
delivery and facilitate a 24-hour window between the last dose of LMWH and regional Evidence
analgesia.99 If LMWH precludes regional techniques (in, for example, the woman who presents level 4
in spontaneous labour within 12 hours of taking a LMWH dose), alternative analgesia such as
opiate-based intravenous patient-controlled analgesia can be offered.
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7.
Thromboprophylaxis after delivery
7.1 Assessment of risk

What are the risk factors for VTE after delivery?
All women with class 3 obesity (BMI greater than or equal to 40 kg/m2) should be considered for
prophylactic LMWH in doses appropriate for their weight for 10 days after delivery.
Women with two or more persisting risk factors listed in Table 1 should be considered for LMWH in
prophylactic doses appropriate for their weight for 10 days after delivery.
Risk factors for VTE after delivery are summarised in Table 1, Appendix I and Appendix II.
Nearly all women7,8 dying from VTE following vaginal delivery in the 20032005 Confidential Evidence
level 3
Enquiry were overweight or obese or over the age of 40 years.
Additional risk factors relevant for postpartum thromboprophylaxis after delivery include
prolonged labour, immobility, infection, haemorrhage and blood transfusion (see Appendix
I, Table 1, Appendix II and Appendix III). Recent evidence supporting these obstetric
complications as risk factors for VTE comes from several large population-based studies.15,16,22
A Canadian population-based cohort study of around 7000 women with pregnancy-related
hospitalisations for VTE from 19911992 to 2005200616 identified major puerperal infection Evidence
(aOR for PE 4.1, 95% CI 3.05.6; aOR for DVT 6.1, 95% CI 5.07.5) and blood transfusion (aOR level 2++
for PE = 4.5, 95% CI 3.36.2; aOR for DVT 3.6, 95% CI 2.84.7) as risk factors for VTE. The
study by Sultan et al.22 found that the strongest risk factor was stillbirth (AR 2444/100000
person-years; IRR 6.2) and the risk was also significantly increased with preterm birth (AR
854/100000 person-years, 95% CI 6491124; IRR 2.69, 95% CI 1.993.65). These have therefore
been added as risk factors in this edition of the guideline.
7.2 Previous VTE

Which women with previous VTE need postpartum thromboprophylaxis?
All women with a previous history of confirmed VTE should be offered thromboprophylaxis with
LMWH or warfarin for at least 6 weeks postpartum regardless of the mode of delivery.
Since the risk of VTE is higher postpartum8,9,17,52,53,94 than antenatally, all women with previous
VTE need to continue their LMWH prophylaxis for 6 weeks postpartum. Those with recurrent Evidence
VTE on long-term oral anticoagulant therapy need to continue their LMWH until switched level 2++
back to warfarin or another oral agent.
7.3 Asymptomatic thrombophilia

Which women with thrombophilia without previous VTE need postpartum
thromboprophylaxis?
Women with thrombophilia without previous VTE should be stratified according to both the level of
risk associated with their thrombophilia and the presence or absence of a family history or other
risk factors.
Women with a family history of VTE and an identified thrombophilia should be considered for
6 weeks postnatal thromboprophylaxis.
See section 4.3 above.
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7.4 Caesarean section

What is the magnitude of risk of VTE after caesarean section?
All women who have had caesarean sections should be considered for thromboprophylaxis with
LMWH for 10 days after delivery apart from those having an elective caesarean section who should
be considered for thromboprophylaxis with LMWH for 10 days after delivery if they have any
additional risk factors (see Appendix I and Table 1).
Most women who suffer a VTE after caesarean section have other risk factors including twin
pregnancy, obesity, severe pre-eclampsia, reoperation, immobilisation and placenta praevia.100
Caesarean section is a risk factor for death from PE.3,4,101,102 Women delivered by elective caesarean
section have at least double the postpartum risk of VTE compared with vaginal birth.21 The risk Evidence
of postpartum VTE after an emergency caesarean section is twice that after an elective caesarean level 2+
section and four times that after a vaginal delivery.12,103 Studies exploring the risk of VTE
comparing all caesarean sections with vaginal delivery have found relative risks of 26.7.16,22,24,104
7.5 For how long should thromboprophylaxis be continued after delivery?

Risk assessment should be performed in each woman at least once following delivery and before
discharge and arrangements made for LMWH prescription and administration (usually by the
woman herself) in the community where necessary.
Thromboprophylaxis should be continued for 6 weeks in high-risk women and for 10 days in
intermediate-risk women (see Appendix I).
In women who have additional persistent (lasting more than 10 days postpartum) risk factors, such
as prolonged admission, wound infection or surgery in the puerperium, thromboprophylaxis should
be extended for up to 6 weeks or until the additional risk factor/s is/are no longer present.
The prothrombotic changes of pregnancy do not revert completely to normal until several weeks
after delivery. The time of greatest risk for VTE is the early puerperium and, although most VTE
occurs antenatally, the risk per day is greatest in the weeks immediately after delivery.8,9,17,52,53,94,105
For women at high risk of postpartum VTE, the recommended duration of thromboprophylaxis
is 6 weeks. Although laboratory evidence from thromboelastography (TEG) suggests correction
of hypercoagulability by 4 weeks,106 clinical data from observational studies in Sweden,107 the
USA,8,105 Norway48 and the Netherlands10 suggest that the increased risk of VTE persists for 6
weeks postpartum, albeit less during weeks 5 and 6. The triennial UK confidential enquiries
into maternal mortality between 1994 and 2005 suggest that the increased risk of fatal PE is
still present in weeks 5 and 6 (a total of 15 deaths compared to 21 in weeks 3 and 4) and all six
women who died from PE after caesarean section (20062008) died between 2 and 6 weeks Evidence
level 2+
after delivery, whereas fatal events after that are very rare.3,4,101,102,108
There is little evidence to support recommendations regarding duration of postpartum
thromboprophylaxis in women at intermediate risk of VTE. TEG data from 71 women post
normal delivery showed that all parameters remained abnormal at 1 week postpartum and the
authors suggested that 35 days thromboprophylaxis may be insufficient.106 The numbers of
VTEs after caesarean sections were similar in weeks 1, 2 and 3 in one study.12 This suggests
that caesarean section continues to be a significant risk factor for fatal PE and therefore it
is important to extend the duration of prophylaxis in the presence of additional persistent
(lasting more than 10 days postpartum) risk factors, such as prolonged admission (more than
or equal to 3 days) or wound infection, for up to 6 weeks or until the additional risk factor/s
is/are no longer present (see Appendix I).
22 of 40
8.
Which agents should be used for thromboprophylaxis?
8.1 Low-molecular-weight heparin (LMWH)

LMWHs are the agents of choice for antenatal and postnatal thromboprophylaxis.
Doses of LMWH are based on weight. For thromboprophylaxis the booking or most recent weight
can be used to guide dosing.
It is only necessary to monitor the platelet count if the woman has had prior exposure to
unfractionated heparin (UFH).
Monitoring of anti-Xa levels is not required when LMWH is used for thromboprophylaxis.
Doses of LMWH should be reduced in women with renal impairment.
LMWH is safe in breastfeeding.
LMWHs are as effective as and safer than unfractionated heparin (UFH) when used to prevent
VTE in pregnancy.21,109112 The risk of heparin-induced thrombocytopenia (HIT) is substantially
lower with LMWH.109,110,113 Guidelines recommend against monitoring platelet count where
LMWH is used and where there is no previous exposure to UFH.1,114 In a systematic review
of 2777 pregnancies there were no cases of HIT.109 Prolonged UFH use during pregnancy
may result in osteoporosis and fractures,115 but this risk is very low with LMWH.109,116119 A
systematic review of LMWH109 showed the incidence of osteoporotic fractures was 0.04%
(95% CI 0.010.2) and that of allergic skin reactions was 1.8% (95% CI 1.342.37). More recent
studies provide further evidence for the safety and efficacy of dalteparin,120 enoxaparin120
and tinzaparin121 for prophylaxis in pregnancy. In the study of tinzaparin,121 three women
developed bone fractures, but all had prior risk factors for osteoporosis (such as low BMI, Evidence
level 1++
previous osteoporosis, smoking, long-term steroid and/or other UFH/LMWH use).
Evidence for an increased risk of bleeding is more controversial. A systematic review found
significant bleeding, usually related primarily to obstetric causes, occurred in 1.98% (95% CI
1.52.57).109 This related to both treatment and prophylactic doses of LMWH and therefore the
risk of bleeding is likely to be less than 2% with prophylactic doses.109 There is an increased
risk of wound haematoma following caesarean section with LMWH of around 2%.6,109,122
Some have found an increased risk of postpartum haemorrhage6 but this is not supported by
other studies.123 A Cochrane review29 of UFH or LMWH for thromboprophylaxis in women
undergoing caesarean section found more bleeding or bruising episodes compared to women
not receiving heparin (risk ratio 5.15).
Table 3 gives suggested prophylactic and therapeutic subcutaneous doses of LMWH in pregnancy and
postpartum. There are no data to guide appropriate doses of LMWH for obese pregnant or puerperal
women. The doses in Table 3 are only suggestions and doses for obese women are not evidence-based.
In the UKOSS study,7 some overweight and obese women suffered a PE while receiving doses of LMWH
prophylaxis appropriate for women of weights 5090 kg.
Anti-Xa levels provide only a rough guide of the concentration of heparin present and provide Evidence
level 3
little or no evidence on the efficacy in relation to prevention of thrombosis.124
Lower doses of LMWH should be employed if the creatinine clearance is less than 30 ml/
minute (enoxaparin and dalteparin) or less than 20 ml/minute with tinzaparin.124 A creatinine Evidence
clearance of 30 ml/minute equates to a serum creatinine of about 200 mol/l for a 30-year-old level 2+
woman weighing 70 kg.
23 of 40
Table 3. Suggested thromboprophylactic doses for antenatal and postnatal LMWH

Weight
Enoxaparin
Dalteparin
Tinzaparin
(75 u/kg/day)
< 50 kg
20 mg daily
2500 units daily
3500 units daily
5090 kg
40 mg daily
5000 units daily
4500 units daily
91130 kg
60 mg daily*
7500 units daily
7000 units daily*
131170 kg
80 mg daily*
10 000 units daily
9000 units daily*
> 170 kg
0.6 mg/kg/day*
75 u/kg/day
75 u/kg/day*
High prophylactic dose for women weighing 5090 kg
40 mg 12 hourly
5000 units 12 hourly
4500 units 12 hourly
*may be given in 2 divided doses
LMWH is safe and easy to use postpartum and has the advantage of not requiring monitoring.
For those women receiving LMWH antenatally (and therefore for 6 weeks postpartum) or for Evidence
those requiring 10 days postpartum thromboprophylaxis, it is the agent of choice. Experience level 1+
of LMWH in the puerperium reports no problems during breastfeeding.109
8.2 Unfractionated heparin

In women at very high risk of thrombosis (see Appendix IV), UFH may be used peripartum in
preference to LMWH where there is an increased risk of haemorrhage or where regional anaesthetic
techniques may be required.
If UFH is used after caesarean section (or other surgery), the platelet count should be monitored
every 23 days from days 414 or until heparin is stopped.
The benefits of UFH are that it has a shorter half-life than LMWH and there is more complete
reversal of its activity by protamine sulfate.125 So, for example, if no LMWH has been given
for 24 hours but the woman has not yet delivered and there is concern about delaying further
doses of anticoagulants, a prophylactic dose of 5000 iu subcutaneously of UFH could be used Evidence
and repeated every 12 hours until LMWH can be resumed after delivery. The required interval level 3
between a prophylactic dose of UFH and regional analgesia or anaesthesia is less (4 hours)
than with LMWH (12 hours) 99 and there is less concern regarding neuraxial haematomas with
UFH.98 Any exposure to UFH is associated with an increased risk of HIT.126
8.3 Danaparoid
Potential use of danaparoid should be in conjunction with a consultant haematologist with
Danaparoid is a heparinoid that is mostly used in patients intolerant of heparin, either because
of HIT or a skin allergy to heparins. Experience in the use of this agent in a total of 91 pregnancies
has been reviewed.127,128 There were six maternal bleeding events, two of which were fatal due
to placental problems (praevia and abruption). Additionally there were seven early miscarriages
and one neonatal death following emergency caesarean section at 28 weeks for fetal growth
restriction. There were no adverse fetal outcomes attributed to danaparoid. Danaparoid seems Evidence
level 4
reasonable to use in pregnancy when there is a requirement for anticoagulant prophylaxis
or treatment and heparins cannot be used. The half-life of danaparoid is long (24 hours) and
regional anaesthesia should be avoided in women receiving it for thromboprophylaxis.99
Although direct evidence is limited, it seems likely that breastfeeding would be safe while on
danaparoid since little if any appears in breast milk129 and oral absorption is unlikely.
24 of 40
8.4 Fondaparinux
Fondaparinux should be reserved for women intolerant of heparin compounds.
Fondaparinux use in pregnancy should be in conjunction with a consultant haematologist with
Fondaparinux is a synthetic pentasaccharide that acts through inhibition of factor Xa

via antithrombin. It is licensed in the UK for the prevention and treatment of VTE outside
pregnancy and has a broadly similar efficacy to LMWH. There is limited experience of its
use in pregnancy but it has been used in the setting of heparin intolerance with no reported
hypersensitivity reactions or adverse effects on the fetus.130137 No placental passage of
fondaparinux was found in a human cotyledon model138 but anti-factor Xa activity about 10%
of that in maternal plasma was found in the umbilical cord plasma in newborns of four of Evidence
five mothers being treated with fondaparinux.139 No adverse effects were observed in the level 4
newborns. It does not seem necessary to alter the dose in pregnancy.131 It is unknown whether
fondaparinux is excreted in breast milk but oral absorption seems unlikely. The half-life of
fondaparinux is long (18 hours) and 3642 hours should pass following the previous dose
before it becomes acceptable to consider regional anaesthesia.99 Thus, although experience is
limited, it seems likely that fondaparinux would be a reasonable alternative when there is a
need for anticoagulant prophylaxis or treatment in pregnancy and heparins cannot be used.
8.5 Low-dose aspirin

Aspirin is not recommended for thromboprophylaxis in obstetric patients.
There are no controlled trials on the use of aspirin for thromboprophylaxis in pregnancy.
Conclusions about its efficacy have been extrapolated from trials in the nonpregnant population.
In the NICE guideline reviewing VTE prevention in hospitalised patients,5 300 mg or more of
aspirin daily reduced the risk of postoperative DVT in patients undergoing a variety of surgical
procedures. However, the benefit was modest in comparison to heparin and aspirin was not
Evidence
recommended for postoperative thromboprophylaxis. The Womens Health Study140 found low- level 3
dose aspirin no better than placebo for long-term primary prevention of VTE in older women.
In contrast, two recent trials outside pregnancy suggested that after completion of treatment
with warfarin, low-dose aspirin conferred a modest reduction compared to placebo in the risk
of recurrent VTE in patients with a first unprovoked event.141,142 Overall, any benefit of aspirin
in VTE prevention appears uncertain and significantly less than that of LMWH.
8.6 Warfarin
Warfarin use in pregnancy is restricted to the few situations where heparin is considered unsuitable,
e.g. some women with mechanical heart valves.
Women receiving long-term anticoagulation with warfarin can be converted from LMWH to warfarin
postpartum when the risk of haemorrhage is reduced, usually 57 days after delivery.
Warfarin is safe in breastfeeding.
Warfarin crosses the placenta leading to an increased risk of congenital abnormalities including
a characteristic warfarin embryopathy (hypoplasia of nasal bridge, congenital heart defects,
ventriculomegaly, agenesis of the corpus callosum, stippled epiphyses) in approximately 5% Evidence
of fetuses exposed between 6 and 12 weeks of gestation.143150 There is evidence that this level 2++
incidence is dose-dependent with a higher incidence in women taking greater than 5 mg/
day.147149 Other reported complications associated with warfarin therapy during pregnancy
25 of 40
include an increase in the risk of spontaneous miscarriage,146148,151,152 stillbirth,145,147,148,151 Evidence

level 2++
neurological problems in the baby153,154 and fetal and maternal haemorrhage.148,149
Warfarin can be safely used following delivery and in breastfeeding mothers, although it requires close
monitoring and visits to an anticoagulant clinic and carries an increased risk of postpartum haemorrhage
and perineal haematoma compared with LMWH. It is not appropriate for those women requiring only
10 days postpartum prophylaxis. However, it is appropriate for those on maintenance warfarin outside
pregnancy. Conversion from LMWH back to warfarin should be delayed for at least 57 days after delivery
to minimise the risk of haemorrhage during the period of overlap of LMWH and warfarin treatment.
8.7 Dextran
Dextran should be avoided antenatally and intrapartum because of the risk of anaphylactoid reaction.
Although dextran may reduce the risk of postoperative DVT outside pregnancy, the evidence
is weak, it is less effective than LMWH and it appears to increase the risk of bleeding.155 Evidence
Anaphylaxis to dextran has been associated with uterine hypertonus, fetal distress, fetal level 3
neurological abnormalities and death.156,157
8.8 Oral thrombin and Xa inhibitors

Non-vitamin K antagonist oral anticoagulants (NOACs) should be avoided in pregnant women.
Use of NOACs is not currently recommended in women who are breastfeeding.
P
P
Non-vitamin K antagonist oral anticoagulants (NOACs, previously known as new/novel oral anticoagulants)
such as dabigatran, rivaroxaban and apixaban work through direct inhibition of thrombin or factor Xa.
They are not licensed for use in pregnancy where there is no experience in their use.
9.
Anti-embolism stockings
The use of properly applied anti-embolism stockings (AES) of appropriate size and providing
graduated compression with a calf pressure of 1415 mmHg is recommended in pregnancy and the
puerperium for women who are hospitalised and have a contraindication to LMWH. These include
women who are hospitalised post-caesarean section (combined with LMWH) and considered to be
at particularly high risk of VTE (e.g. previous VTE, more than four risk factors antenatally or more
than two risk factors postnatally) and women travelling long distance for more than 4 hours.
There are no trials to support the use of AES in pregnancy and the puerperium and
recommendations are largely derived from extrapolation from studies using AES in the
hospitalised nonpregnant population158,159 Small studies have shown that AES significantly Evidence
improve venous emptying in pregnant women160 and increase the blood flow while decreasing level 3
the lumen diameter of the superficial femoral161 and common femoral162 veins in late pregnancy
and early postpartum patients.
Evidence from nonpregnant patients and other guidelines support the use of AES for patients
at high risk of bleeding (unable to receive pharmacological thromboprophylaxis), or where
there is a contraindication to anticoagulant thromboprophylaxis,26,163 or as an adjunct to
anticoagulant thromboprophylaxis in surgical patients.
Evidence
level 4
There are few data regarding the most efficacious length of AES to use in pregnancy and
advice in the nonpregnant population is contradictory.26,164167 More DVTs in pregnant women
are iliofemoral compared to the nonpregnant population where calf vein DVTs are more
26 of 40
common. Studies of AES in pregnancy have only concerned full-length stockings.162 However,
in the obstetric population, there is the added problem of full-length stockings becoming
bloodstained. Therefore, on balance, properly applied full-length AES are advocated for Evidence
level 4
pregnant women but knee-length AES should be considered if (as is often the case) full-length
AES are ill-fitting or compliance is poor.
The role of graduated compression stockings providing greater than 23 mmHg support at the ankle
for the prevention and/or treatment of the post-thrombotic syndrome rather than VTE prevention is
discussed in Green-top Guideline No. 37b.
10. Contraindications to LMWH
Which women should not be given thromboprophylaxis with LMWH?

LMWH should be avoided, discontinued or postponed in women at risk of bleeding after careful
consideration of the balance of risks of bleeding and thrombosis.
Women with previous or current allergic reactions to LMWH should be offered an alternative
preparation or alternative form of prophylaxis.
Further advice on the management of a woman with both VTE risk factors and bleeding risk factors
or LMWH allergy may be sought from a haematologist with expertise in the management of
thrombosis and bleeding disorders in pregnancy.
Risk factors for bleeding are summarised in Appendix III. LMWHs can increase bleeding if it
occurs and therefore should be delayed in women with active bleeding, coagulopathy or low Evidence
platelets (fewer than 75 x 109/l). LMWH is contraindicated in women with HIT. Women who level 4
develop allergic reactions to one LMWH will often be allergic to other LMWHs.5,26,109,115
11. Risk scoring methodologies
A formal VTE risk assessment with numerical scoring for all pregnant and postpartum women is
recommended (see Appendix III).
Compared with not using a formal assessment system, Shoenbeck et al. found there was a
significant increase in the rate of risk assessment, earlier treatment and greater consistency in Evidence
clinical decision making with the use of a numerical scoring system. This approach maintains level 3
a highly individualised assessment of VTE risk while achieving consistency in management.168
12. Recommendations for future research
l Doses of LMWH required in obese pregnant and puerperal women.
l At present it is unclear whether women undergoing surgical management of miscarriage and
surgical termination of pregnancy are at increased risk of VTE.

l How do risk factors for VTE interact in the antenatal and postpartum periods?
l How do we reduce/avoid the prevalence of risk factors for VTE?
l Should thromboprophylaxis vary with different heritable thrombophilias?

l Correct risk assessment at booking, on admission to antenatal ward, after delivery and at
discharge (100%).
l Correct dose of LMWH (based on weight) prescribed antenatally and postpartum (100%).
27 of 40
l LMWH prescribed and taken for 10 days postpartum in all women with class 3 obesity
(BMI greater than or equal to 40) (100%).

l LMWH prescribed and given for 6 weeks postpartum in all women with previous VTE (100%).
14. Useful links and support groups
l Royal College of Obstetricians and Gynaecologists. Information for you: Reducing the risk of
venous thrombosis in pregnancy and after birth. London: RCOG; 2011 [https://www.rcog.org.
uk/globalassets/documents/patients/patient-information-leaflets/pregnancy/pi-reducing-the-risk-ofvenous-thrombosis-in-pregnancy-and-after-birth.pdf].
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33 of 40
Fewer than
three risk
factors
Mobilisation and
avoidance of dehydration
LOWER RISK
Three risk factors:

prophylaxis from 28 weeks
Four or more risk factors:

prophylaxis from first trimester
APL = antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, 2 -glycoprotein 1 antibodies);

ART = assisted reproductive technology; BMI based on booking weight; DM = diabetes mellitus; FHx = family
history; gross varicose veins = symptomatic, above knee or associated with phlebitis/oedema/skin changes;
high-risk thrombophilia = antithrombin deficiency, protein C or S deficiency, compound or homozygous for low-risk
thrombophilias; IBD = inflammatory bowel disease; immobility = 3 days; IVDU = intravenous drug user; IVF = in
vitro fertilisation; LMWH = low-molecular-weight heparin; long-distance travel = > 4 hours; low-risk thrombophilia =
heterozygous for factor V Leiden or prothrombin G20210A mutations; OHSS = ovarian hyperstimulation syndrome;
PGP = pelvic girdle pain with reduced mobility; PPH = postpartum haemorrhage; thrombophilia = inherited or
acquired; VTE = venous thromboembolism.
Transient risk factors:

Dehydration/hyperemesis; current systemic
infection; long-distance travel
IVF/ART
Multiple pregnancy
Low-risk thrombophilia
Family history of unprovoked or

estrogen-provoked VTE in first-degree relative
Immobility, e.g. paraplegia, PGP
Gross varicose veins
Smoker
Parity 3
Age > 35
Obesity (BMI > 30 kg/m2)
OHSS (first trimester only)
Any surgical procedure e.g. appendicectomy
INTERMEDIATE RISK
Fewer than
two risk
factors
Two or
more risk
factors
Early mobilisation and

avoidance of dehydration
LOWER RISK
NB If persisting or > 3 risk factors

consider extending
thromboprophylaxis with LMWH
At least 10 days
postnatal prophylactic LMWH
INTERMEDIATE RISK
At least 6 weeks
HIGH RISK
Weight < 50 kg = 20 mg enoxaparin/2500 units dalteparin/3500 units tinzaparin daily

Weight 5090 kg = 40 mg enoxaparin/5000 units dalteparin/4500 units tinzaparin daily
Weight > 170 kg = 0.6 mg/kg/day enoxaparin/ 75 u/kg/day dalteparin/ 75 u/kg/day tinzaparin
Antenatal and postnatal prophylactic dose of LMWH
PPH > 1 litre or blood transfusion
Mid-cavity rotational or operative delivery
Stillbirth in this pregnancy
Preterm delivery in this pregnancy (< 37+0 weeks)
Multiple pregnancy
Immobility, e.g. paraplegia, PGP, longdistance travel
Low-risk thrombophilia
Family history of VTE
Elective caesarean section
Smoker
Parity 3
Obesity (BMI 30 kg/m2)
Age > 35 years
Medical comorbidities e.g. cancer, heart failure,

active SLE, IBD or inflammatory polyarthropathy;
nephrotic syndrome, type I DM with
nephropathy, sickle cell disease, current IVDU
Any surgical procedure in the puerperium except

immediate repair of the perineum
Readmission or prolonged admission ( 3 days)

in the puerperium
High-risk thrombophilia + no VTE
Consider antenatal prophylaxis

with LMWH
BMI 40 kg/m2
Medical comorbidities e.g. cancer, heart failure,

active SLE, IBD or inflammatory polyarthropathy, nephrotic syndrome, type I DM with
nephropathy, sickle cell disease, current IVDU
Caesarean section in labour
Low-risk thrombophilia + FHx
High-risk thrombophilia
Anyone requiring antenatal LMWH
Any previous VTE
Single previous VTE related to major surgery
Refer to trust-nominated thrombosis

in pregnancy expert/team
Requires antenatal prophylaxis

with LMWH
HIGH RISK
Postnatal assessment and

management (to be assessed
on delivery suite)
Hospital admission
Any previous VTE except a single event related

to major surgery
Antenatal assessment and

management (to be assessed at
booking and repeated if admitted)
Appendix I: Obstetric thromboprophylaxis risk assessment and management
Appendix II: Adjusted odds ratios for risk factors for VTE
Risk factor
aOR
95% CI
Previous VTE15,32
24.8
17.136
Age > 3514,16,31
1.314
1.01.7
n = 603
31
1.02.0
pn = 256
16
1.2
1.11.4
DVT
2.657
1.096.45
n = 143 an PE
33
2.113.5
n = 129
32
4.4
3.45.7
1.731
1.12.6
pn = 256
16
1.22.6
DVT
16
1.64.4
PE
12
1.8
1.32.4
an n = 268
2.412
1.73.3
pn n = 291
31
1.22.4
pn = 256
an
1.4
Obesity
BMI >/ 30
7,16,3133
5.3
1.8
2.7
BMI >/ 25
12,31
1.7
41
Comment
Weight 90120 kg
1.93
1.103.39
Weight > 120 kg
4.32
1.2614.84
Weight gain in pregnancy > 21 kg12

(compared to 721 kg)
1.6
1.12.6
pn n = 291
Parity 17
4.03
1.69.84
n = 143 an PE
14
1.5
1.11.9
n = 603
314
2.4
1.83.1
n = 603
12
1.33.4
an n = 268
12
3.4
2.05.5
pn n = 291
1.414
1.11.9
n = 603
35
1.34.7
n = 90
33
1.54.9
n = 129
Smoking
1030/day
2.1
12,14,35
2.5
33
Current smoker
2.7
Sickle cell32,49
6.732
4.410.1
2.549
1.54.1
DVT
49
1.7
0.93.1
PE
7.132
6.28.3
5.431
2.611.3
pn n = 256
3.2
2.24.6
DVT
43.416
35.053.9
PE
Heart disease16,31,32
16
16,32
Systemic lupus erythematosus
16,32
Anaemia
32
5.813
16
2.3
1.14.8
DVT
3.916
1.97.8
PE
32
2.22.9
16
1.41.9
DVT
16
PE
8.7
2.6
1.6
1.7
1.32.2
Varicose veins35
2.4
1.045.4
Immobility12
7.7
3.219
an
10.8
4.028.8
pn
2.914
2.13.9
3.112
1.85.3
Pre-eclampsia12,14
12
12
Pre-eclampsia plus FGR
5.8
2.116
Hyperemesis16,32
2.532
23.2
16
4.4
34 of 40
2.48.4
pn
DVT
Assisted reproductive technology12,24,97
Twins
12,14
16,31
Multiple pregnancy
4.312
2.09.4
4.224
1.511
1.897
1.42.2
12
2.6
1.16.2
an
1.814
1.13.0
n = 603
31
1.89.7
an n = 109
16
1.7
1.32.2
DVT
2.431
1.63.5
pn n = 256
4.2
Preterm delivery < 37 weeks22,31
22
2.69
1.993.65
Stillbirth (IRR)
6.24
2.7714.1
Antepartum haemorrhage32
2.3
1.82.8
22
14
Emergency caesarean section
14,16,24,31,32
Any caesarean section
2.7
1.84.1
14
3.04.3
32
1.82.4
2.031
1.52.7
pn n = 256
16
1.62.0
DVT
16
2.9
2.43.5
PE
3.424
1.39.0
4.1
2.37.3
3.6
2.1
1.8
PPH > 1 litre12

16
an
16
1.2
1.01.4
DVT
1.316
1.01.7
PE
12
3.936.9
Obstetric haemorrhage
1.171
Postpartum infection16,32
4.132
2.95.7
16
5.07.5
DVT
16
PE
PPH unspecified
PPH + surgery
12
35
6.1
4.1
3.05.6
Postpartum infection + caesarean section12
6.2
2.416.2
Transfusion16,32
7.632
6.29.4
16
3.6
2.84.7
DVT
4.516
3.36.2
PE
Abbreviations: an antenatal; aOR adjusted odds ratio; CI confidence interval; DVT deep venous thrombosis;
FGR fetal growth restriction; IRR incidence rate ratio; n number of cases in casecontrol study; PE pulmonary embolism; pn postnatal;
PPH postpartum haemorrhage; VTE venous thromboembolism.
35 of 40
Appendix III: Risk assessment for venous thromboembolism (VTE)

If total score 4 antenatally, consider thromboprophylaxis from the first trimester.
If total score 3 antenatally, consider thromboprophylaxis from 28 weeks.
If total score 2 postnatally, consider thromboprophylaxis for at least 10 days.
If admitted to hospital antenatally consider thromboprophylaxis.
If prolonged admission ( 3 days) or readmission to hospital within the puerperium consider thromboprophylaxis.
For patients with an identified bleeding risk, the balance of risks of bleeding and thrombosis should be discussed
in consultation with a haematologist with expertise in thrombosis and bleeding in pregnancy.
Risk factors for VTE
Pre-existing risk factors
Tick
Score
Previous VTE (except a single event related to major surgery)
Previous VTE provoked by major surgery
Known high-risk thrombophilia
Medical comorbidities e.g. cancer, heart failure; active systemic lupus

erythematosus, inflammatory polyarthropathy or inflammatory bowel disease;
nephrotic syndrome; type I diabetes mellitus with nephropathy; sickle cell disease;
current intravenous drug user
Family history of unprovoked or estrogen-related VTE in first-degree relative
Known low-risk thrombophilia (no VTE)
1a
Age (> 35 years)
1
1 or 2b
Obesity
Parity 3
Smoker
1
Obstetric risk factors
Pre-eclampsia in current pregnancy
ART/IVF (antenatal only)
Multiple pregnancy
Caesarean section in labour
Elective caesarean section
Mid-cavity or rotational operative delivery
PPH (> 1 litre or transfusion)
Preterm birth < 37 weeks in current pregnancy
Stillbirth in current pregnancy
+0
Transient risk factors

Any surgical procedure in pregnancy or puerperium except immediate repair of the
perineum, e.g. appendicectomy, postpartum sterilisation
Hyperemesis
OHSS (first trimester only)
Immobility, dehydration
TOTAL
Abbreviations: ART assisted reproductive technology; IVF in vitro fertilisation; OHSS ovarian hyperstimulation syndrome; VTE venous
thromboembolism.
a
If the known low-risk thrombophilia is in a woman with a family history of VTE in a first-degree relative postpartum thromboprophylaxis
should be continued for 6 weeks.
b
BMI 30 = 1; BMI 40 = 2
36 of 40
Contraindications/cautions to LMWH use

Known bleeding disorder (e.g. haemophilia, von Willebrands disease or acquired coagulopathy)
Active antenatal or postpartum bleeding
Women considered at increased risk of major haemorrhage (e.g. placenta praevia)
Thrombocytopenia (platelet count < 75 109/l)
Acute stroke in previous 4 weeks (haemorrhagic or ischaemic)
Severe renal disease (glomerular filtration rate [GFR] < 30 ml/minute/1.73m2)
Severe liver disease (prothrombin time above normal range or known varices)
Uncontrolled hypertension (blood pressure > 200 mmHg systolic or > 120 mmHg diastolic)
Clinical and laboratory thresholds are taken from the Department of Healths guidelines based on evidence from the nonpregnant
population.5
37 of 40
Appendix IV: S
ummary of guideline for thromboprophylaxis in women with previous VTE and/or
thrombophilia (also see Appendix I)
Very high risk
Previous VTE on long-term oral

anticoagulant therapy
Recommend antenatal high-dose LMWH

and at least 6 weeks postnatal LMWH or until
switched back to oral anticoagulant therapy
Antithrombin deficiency
Antiphospholipid syndrome with
previous VTE
These women require specialist

management by experts in haemostasis
and pregnancy
High risk
Any previous VTE (except a single VTE

related to major surgery)
Recommend antenatal and 6 weeks

Intermediate risk
Asymptomatic high-risk thrombophilia

homozygous factor V
Leiden/compound heterozygote
Protein C or S deficiency
Refer to local expert

Consider antenatal LMWH
Recommend postnatal prophylactic LMWH
for 6 weeks
Single previous VTE associated with

major surgery without thrombophilia,
family history or other risk factors
Consider antenatal LMWH (but not routinely

recommended)
Recommend LMWH from 28 weeks of
gestation and 6 weeks postnatal
prophylactic LMWH
Asymptomatic low-risk thrombophilia

(prothrombin gene mutation or
factor V Leiden)
Consider as a risk factor and score

appropriately (see Appendix III)
Recommend 10 days if other risk factor
postpartum (or 6 weeks if significant
family history) postnatal prophylactic LMWH
Low risk
38 of 40
Appendix V: Explanation of guidelines and evidence levels


low risk of bias


low risk of bias
risk of bias

1++ or 1+

results; or
2++

case series
4
Good practice point
Expert opinion

39 of 40

development group
Professor C Nelson-Piercy FRCP FRCOG, London; Dr P MacCallum MD FRCP FRCPath, Queen Mary University of London,
London; Dr L Mackillop MA FRCP Edin, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford
Dr M Bowers; British Committee for Standards in Haematology; Mr MAG Coleman FRCOG, Southampton;
Mrs AHD Diyaf MRCOG, Barnstaple; Kings Thrombosis Centre; Lifeblood: The Thrombosis Charity;
RCOG Womens Network; Dr N Singh MRCOG, Bolton.
Committee lead reviewers were: Dr M Gupta MRCOG, London; Mr AT Leather FRCOG, Ipswich; and Dr P Owen
FRCOG, Glasgow.
The developers acknowledge Dr Pensee Wu MRCOG, Stoke-on-Trent and Mr Christoph Lees FRCOG, London.
Conflicts of interest:
Professor Nelson-Piercy is a trustee for APEC, Action on Pre-eclampsia, and a patron of the Lauren Page Trust,
supporting the work of obstetric physicians. She is co-Editor-in-Chief of Obstetric Medicine: The Medicine of
Pregnancy, a quarterly journal published by SAGE, and receives an editorial stipend for this work. Professor NelsonPiercy has received commercial support for attending meetings/conferences from LEO Pharma and Sanofi-Aventis
(manufacturers of low-molecular-weight heparin).
Dr MacCallum has received commercial support for attending meetings/conferences from LEO Pharma and Pfizer
(manufacturers of low-molecular-weight heparin) and from Daiichi-Sankyo and Boehringer Ingelheim (manufacturers
of new oral anticoagulants). He has received honoraria from Bayer (a manufacturer of a new oral anticoagulant), LEO
Pharma, Boehringer Ingelheim and Daiichi-Sankyo. Dr MacCallum has received fees for providing expert testimony.
Dr Mackillop has received fees for reports as an expert witness and small honoraria for lectures.
DISCLAIMER
40 of 40
Thromboembolic Disease in
Pregnancy and the Puerperium:
Acute Management
Green-top Guideline No. 37b
April 2015
Thromboembolic Disease in Pregnancy and the Puerperium:

Acute Management
This is the third edition of this guideline. The first edition was published in April 2001 under the same
title (numbered Green-top Guideline No. 28) and the second edition was published in February 2007
and reviewed in 2010. Thromboprophylaxis during pregnancy and the puerperium is addressed in
Green-top Guideline No. 37a.
Diagnosis of acute venous thromboembolism (VTE)

How is acute VTE diagnosed in pregnancy?
Any woman with symptoms and/or signs suggestive of VTE should have objective testing performed
expeditiously and treatment with low-molecular-weight heparin (LMWH) given (see section 6)
until the diagnosis is excluded by objective testing, unless treatment is strongly contraindicated.
Individual hospitals should have an agreed protocol for the objective diagnosis of suspected VTE
during pregnancy. This may recommend the involvement of obstetricians, radiologists, physicians
and haematologists.
What investigations are needed for the diagnosis of an acute DVT?

Compression duplex ultrasound should be undertaken where there is clinical suspicion of DVT.
If ultrasound is negative and there is a low level of clinical suspicion, anticoagulant treatment can
be discontinued. If ultrasound is negative and a high level of clinical suspicion exists, anticoagulant
treatment should be discontinued but the ultrasound should be repeated on days 3 and 7. [New 2015]
What investigations are needed for the diagnosis of an acute pulmonary embolism (PE)?
Women presenting with symptoms and signs of an acute PE should have an electrocardiogram
(ECG) and a chest X-ray (CXR) performed. [New 2015]
In women with suspected PE who also have symptoms and signs of DVT, compression duplex
ultrasound should be performed. If compression ultrasonography confirms the presence of DVT,
no further investigation is necessary and treatment for VTE should continue. [New 2015]
In women with suspected PE without symptoms and signs of DVT, a ventilation/perfusion (V/Q) lung
scan or a computerised tomography pulmonary angiogram (CTPA) should be performed. [New 2015]
When the chest X-ray is abnormal and there is a clinical suspicion of PE, CTPA should be performed
in preference to a V/Q scan. [New 2015]
Alternative or repeat testing should be carried out where V/Q scan or CTPA is normal but the clinical
suspicion of PE remains. Anticoagulant treatment should be continued until PE is definitively
excluded.
Women with suspected PE should be advised that, compared with CTPA, V/Q scanning may carry
a slightly increased risk of childhood cancer but is associated with a lower risk of maternal breast
cancer; in both situations, the absolute risk is very small. [New 2015]
2 of 32
Where feasible, women should be involved in the decision to undergo CTPA or V/Q scanning.
Ideally, informed consent should be obtained before these tests are undertaken.
Should D-dimer testing be performed prior to objective diagnosis?

D-dimer testing should not be performed in the investigation of acute VTE in pregnancy.
What is the role of pretest probability assessment?

Clinicians should be aware that, at present, there is no evidence to support the use of pretest
probability assessment in the management of acute VTE in pregnancy. [New 2015]
Baseline blood investigations

What baseline blood investigations should be performed before initiating anticoagulant therapy?
Before anticoagulant therapy is commenced, blood should be taken for a full blood count,
coagulation screen, urea and electrolytes, and liver function tests.
Performing a thrombophilia screen prior to therapy is not recommended.
Initial anticoagulant treatment of VTE in pregnancy

What is the initial treatment of VTE in pregnancy?
In clinically suspected DVT or PE, treatment with low-molecular-weight heparin (LMWH) should be
commenced immediately until the diagnosis is excluded by objective testing, unless treatment is
strongly contraindicated.
What is the therapeutic dose of LMWH in pregnancy?

LMWH should be given in doses titrated against the womans booking or early pregnancy weight.
There is insufficient evidence to recommend whether the dose of LMWH should be given once daily
or in two divided doses. [New 2015]
There should be clear local guidelines for the dosage of LMWH to be used.
Should blood tests be performed to monitor heparin therapy in pregnancy?

Routine measurement of peak anti-Xa activity for patients on LMWH for treatment of acute VTE
in pregnancy or postpartum is not recommended except in women at extremes of body weight
(less than 50 kg and 90 kg or more) or with other complicating factors (for example, with renal
impairment or recurrent VTE).
Routine platelet count monitoring should not be carried out.
Obstetric patients who are postoperative and receiving unfractionated heparin should have
platelet count monitoring performed every 23 days from days 4 to 14 or until heparin is stopped.
[New 2015]
How should massive life-threatening PE in pregnancy and the puerperium be managed?

Collapsed, shocked women who are pregnant or in the puerperium should be assessed by a team
of experienced clinicians including the on-call consultant obstetrician.
3 of 32
Women should be managed on an individual basis regarding: intravenous unfractionated heparin,

thrombolytic therapy or thoracotomy and surgical embolectomy.
Management should involve a multidisciplinary team including senior physicians, obstetricians

and radiologists.
Intravenous unfractionated heparin is the preferred, initial treatment in massive PE with

cardiovascular compromise.
Maternity units should develop guidelines for the administration of intravenous unfractionated
heparin.
The on-call medical team should be contacted immediately. An urgent portable echocardiogram or
CTPA within 1 hour of presentation should be arranged. If massive PE is confirmed, or in extreme
circumstances prior to confirmation, immediate thrombolysis should be considered.
Additional therapies
Should graduated elastic compression stockings be employed in the acute management of VTE in pregnancy?
In the initial management of DVT, the leg should be elevated and a graduated elastic compression
stocking applied to reduce oedema. Mobilisation with graduated elastic compression stockings
should be encouraged.
What is the role of inferior vena cava filters in the management of VTE in pregnancy?
Consideration should be given to the use of a temporary inferior vena cava filter in the peripartum
period for patients with iliac vein VTE to reduce the risk of PE or in patients with proven DVT and
who have recurrent PE despite adequate anticoagulation.
Maintenance treatment of VTE

What is the maintenance treatment of DVT or PE?
Treatment with therapeutic doses of subcutaneous LMWH should be employed during the remainder
of the pregnancy and for at least 6 weeks postnatally and until at least 3 months of treatment has
been given in total.
Women should be taught to self-inject LMWH and arrangements made to allow safe disposal of
needles and syringes. Outpatient follow-up should include clinical assessment and advice with
monitoring of blood platelets and peak anti-Xa levels if appropriate (see sections 5 and 6.3).
Pregnant women who develop heparin-induced thrombocytopenia or have heparin allergy and
require continuing anticoagulant therapy should be managed with an alternative anticoagulant
under specialist advice.
Can vitamin K antagonists be used during pregnancy for the maintenance treatment of VTE?
Because of their adverse effects on the fetus, vitamin K antagonists, such as warfarin, should not
be used for antenatal VTE treatment.
Is there a role for the new anticoagulants in the treatment of VTE in pregnancy?
Consideration should be given to the use of newer anticoagulants (fondaparinux, argatroban or
r-hirudin) in pregnant women who are unable to tolerate heparin (LMWH or unfractionated heparin)
or danaparoid and who require continuing anticoagulant therapy. [New 2015]
4 of 32
Anticoagulant therapy during labour and delivery

Should anticoagulant therapy be altered during labour and delivery?
When VTE occurs at term, consideration should be given to the use of intravenous unfractionated
heparin which is more easily manipulated. [New 2015]
The woman on LMWH for maintenance therapy should be advised that once she is in established
labour or thinks that she is in labour, she should not inject any further heparin.
Where delivery is planned, either by elective caesarean section or induction of labour, LMWH
maintenance therapy should be discontinued 24 hours prior to planned delivery.
Regional anaesthetic or analgesic techniques should not be undertaken until at least 24 hours
after the last dose of therapeutic LMWH.
LMWH should not be given for 4 hours after the use of spinal anaesthesia or after the epidural
catheter has been removed, and the epidural catheter should not be removed within 12 hours of
the most recent injection. [New 2015]
Are specific surgical measures required for anticoagulated patients undergoing delivery by caesarean
section?
In patients receiving therapeutic doses of LMWH, wound drains (abdominal and rectus sheath)
should be considered at caesarean section and the skin incision should be closed with interrupted
sutures to allow drainage of any haematoma.
What anticoagulant therapy should be employed in women at high risk of haemorrhage?

Any woman who is considered to be at high risk of haemorrhage, and in whom continued heparin
treatment is considered essential, should be managed with intravenous unfractionated heparin
until the risk factors for haemorrhage have resolved.
Postnatal anticoagulation
How should anticoagulation be managed postnatally?
Therapeutic anticoagulant therapy should be continued for the duration of the pregnancy and for at
least 6 weeks postnatally and until at least 3 months of treatment has been given in total. Before
discontinuing treatment the continuing risk of thrombosis should be assessed.
Women should be offered a choice of LMWH or oral anticoagulant for postnatal therapy after
discussion about the need for regular blood tests for monitoring of warfarin, particularly during
the first 10 days of treatment.
Postpartum warfarin should be avoided until at least the fifth day and for longer in women at
increased risk of postpartum haemorrhage. [New 2015]
Women should be advised that neither heparin (unfractionated or LMWH) nor warfarin is
contraindicated in breastfeeding.
Prevention of post-thrombotic syndrome

What measures can be employed to prevent the development of post-thrombotic syndrome?
Women should be advised that prolonged use of LMWH (more than 12 weeks) is associated with a
significantly lower chance of developing post-thrombotic syndrome. [New 2015]
5 of 32
Following a DVT, graduated elastic compression stockings should be worn on the affected leg to
reduce pain and swelling. Clinicians should be aware that the role of compression stockings in the
prevention of post-thrombotic syndrome is unclear. [New 2015]
Postnatal clinic review

Postnatal review for patients who develop VTE during pregnancy or the puerperium should,
whenever possible, be at an obstetric medicine clinic or a joint obstetric haematology clinic.
Thrombophilia testing should be performed once anticoagulant therapy has been discontinued
only if it is considered that the results would influence the womans future management. [New 2015]
1.
Purpose and scope
The aim of this guideline is to provide information, based on clinical evidence where available, regarding
the immediate investigation and management of women in whom venous thromboembolism is suspected
during pregnancy or the puerperium.
2.
Venous thromboembolism (VTE) remains one of the main direct causes of maternal death in the UK1
and sequential reports on Confidential Enquiries into Maternal Deaths have highlighted failures in
obtaining objective diagnoses and employing adequate treatment.2 In recent years, there has been a
significant decline in maternal deaths from VTE in the UK (18 deaths between 2006 and 2008 compared
to 41 in 20032005), in part owing to better recognition of women at risk and more widespread use of
thromboprophylaxis.1
The subjective clinical assessment of deep venous thrombosis (DVT) and pulmonary embolism (PE) is
particularly unreliable in pregnancy and only a minority of women with clinically suspected VTE have
the diagnosis confirmed when objective testing is employed; the prevalence of ultimately diagnosed PE
in pregnant women with suspected PE is 26%.35 The risk of antenatal VTE is four- to five-fold higher
in pregnant women than in nonpregnant women of the same age,6,7 although the absolute risk remains
low at around 1 in 1000 pregnancies.8 Venous thromboembolism can occur at any stage of pregnancy
but the puerperium is the time of highest risk, with estimates of relative risk of approximately 20-fold.9
Acute VTE should be suspected during pregnancy in women with symptoms and signs consistent with
possible VTE, particularly if there are other risk factors for VTE (see Green-top Guideline No. 37a). The
majority of women with VTE in pregnancy have clinical symptoms.10 The symptoms and signs of DVT
include leg pain and swelling (usually unilateral) and lower abdominal pain (reflecting extension of
thrombus into the pelvic vessels and/or development of a collateral circulation) and the symptoms of PE
include dyspnoea, chest pain, haemoptysis and collapse. It is noteworthy that a low-grade pyrexia and
leucocytosis can occur with VTE.
3.
A search of MEDLINE and PubMed (electronic databases) from 20062013 was performed to identify
all relevant randomised controlled trials, systematic reviews and meta-analyses. Conference abstracts
published during this period that have since been superseded by full papers have been cited as the
latter, even when these were published outside the search dates. The databases were searched using
the relevant Medical Subject Headings (MeSH) terms including all subheadings. The principal terms
used were: venous thromboembolism, deep venous thrombosis, pulmonary thromboembolism and
pregnancy.
6 of 32
Where possible in this document, recommendations are based on and linked to the evidence that
supports them. Many of the guidelines for the management of VTE in nonpregnant patients are based on
level 1 evidence;11,12 however, level 1 evidence for the management of VTE during pregnancy is lacking13
and, in general, guideline recommendations for management of VTE during pregnancy are extrapolated
from studies in nonpregnant patients.
4.
Diagnosis of acute VTE
How is acute VTE diagnosed in pregnancy?

Any woman with symptoms and/or signs suggestive of VTE should have objective testing performed
expeditiously and treatment with low-molecular-weight heparin (LMWH) given (see section 6)
until the diagnosis is excluded by objective testing, unless treatment is strongly contraindicated.
Individual hospitals should have an agreed protocol for the objective diagnosis of suspected VTE
during pregnancy. This may recommend the involvement of obstetricians, radiologists, physicians
and haematologists.
Women presenting with symptoms and/or signs suggestive of VTE should have objective
testing performed expeditiously. If DVT remains untreated, 1524% of these patients will Evidence
develop PE. PE during pregnancy may be fatal in almost 15% of patients, and in 66% of these, level 2+
death will occur within 30 minutes of the embolic event.14,15
All hospitals should have a protocol for the diagnosis of suspected VTE in pregnancy which may require
multidisciplinary team involvement.
4.1 What investigations are needed for the diagnosis of an acute DVT?
Compression duplex ultrasound should be undertaken where there is clinical suspicion of DVT.
If ultrasound is negative and there is a low level of clinical suspicion, anticoagulant treatment can
be discontinued. If ultrasound is negative and a high level of clinical suspicion exists, anticoagulant
treatment should be discontinued but the ultrasound should be repeated on days 3 and 7.
Compression duplex ultrasound is the primary diagnostic test for DVT.16,17 If ultrasound Evidence
level 2++
confirms the diagnosis of DVT, anticoagulant treatment should be continued.
If ultrasound is negative and a high level of clinical suspicion exists, anticoagulant treatment
should be discontinued but the ultrasound repeated on days 3 and 7.18 If repeat testing is
negative, no further treatment is required; if repeat testing confirms the presence of DVT,
anticoagulant treatment should be recommenced and continued. This strategy has been Evidence
evaluated in a prospective cohort study of 221 pregnant women who presented with suspected level 2+
DVT. The sensitivity of serial compression ultrasonography with Doppler imaging was 94.1%
(95% CI 69.299.7%), the negative predictive value was 99.5% (95% CI 96.9100%) and the
negative likelihood ratio was 0.068 (95% CI 0.010.39).18
When iliac vein thrombosis is suspected (back and buttock pain and swelling of the entire
limb), Doppler ultrasound of the iliac vein, magnetic resonance venography or conventional Evidence
contrast venography may be considered,16 although in practice, because of the extensive level 3
nature of these thrombi, ultrasound venography will often suffice.
4.2 What investigations are needed for the diagnosis of an acute PE?
Women presenting with symptoms and signs of an acute PE should have an electrocardiogram
(ECG) and a chest X-ray (CXR) performed.
7 of 32
In women with suspected PE who also have symptoms and signs of DVT, compression duplex
ultrasound should be performed. If compression ultrasonography confirms the presence of DVT,
no further investigation is necessary and treatment for VTE should continue.
In women with suspected PE without symptoms and signs of DVT, a ventilation/perfusion (V/Q)
lung scan or a computerised tomography pulmonary angiogram (CTPA) should be performed.
When the chest X-ray is abnormal and there is a clinical suspicion of PE, CTPA should be performed
in preference to a V/Q scan.
Alternative or repeat testing should be carried out where V/Q scan or CTPA is normal but the clinical
suspicion of PE remains. Anticoagulant treatment should be continued until PE is definitively
excluded.
Women with suspected PE should be advised that, compared with CTPA, V/Q scanning may carry
a slightly increased risk of childhood cancer but is associated with a lower risk of maternal breast
cancer; in both situations, the absolute risk is very small.
Where feasible, women should be involved in the decision to undergo CTPA or V/Q scanning.
Ideally, informed consent should be obtained before these tests are undertaken.
In the diagnosis of PE in the nonpregnant individual, both the electrocardiogram (ECG)

and arterial blood gas (ABG) measurement are of limited diagnostic value.19,20 However, in
pregnancy and the puerperium, one study found that the ECG was abnormal in 41% of women
with acute PE; the most common abnormalities were T wave inversion (21%), S1Q3T3 pattern
(15%) and right bundle branch block (18% during pregnancy and 4.2% in the puerperium).21 Evidence
Given the increasing incidence of ischaemic heart disease in pregnancy, the ECG may also level 2+
be helpful in identifying alternative diagnoses. In the same cohort of women, ABG analysis
showed that only 10% had arterial PO2 levels less than 60 mmHg and 2.9% had oxygen
saturation levels less than 90%.21 These findings indicate a diagnostic role for ECG in women
with suspected acute PE, and that ABG analysis is of limited diagnostic value.
Chest X-ray (CXR) may identify other pulmonary disease such as pneumonia, pneumothorax
or lobar collapse.22 While the CXR is normal in over half of pregnant patients with objectively
proven PE,21 abnormal features caused by PE include atelectasis, effusion, focal opacities,
regional oligaemia or pulmonary oedema.23 The radiation dose to the fetus from a CXR Evidence
performed at any stage of pregnancy is negligible (less than 0.01 mSv).24,25 A CXR should be level 3
performed before deciding upon further diagnostic tests; a normal CXR prior to V/Q scanning
improves the likelihood of a definitive V/Q result.26 If the CXR is abnormal with a clinical
suspicion of PE, CTPA should be performed.
Pregnant women with suspected PE who have symptoms and signs of DVT should have
bilateral compression duplex ultrasound leg studies performed. A diagnosis of DVT may
indirectly confirm a diagnosis of PE and since anticoagulant therapy is the same for both
conditions, further investigation may not be necessary. This would limit the radiation doses
given to the mother and her fetus.27 While several studies have investigated the use of lower
limb ultrasonography in the investigation of nonpregnant patients with suspected PE,2831 the Evidence
role of ultrasound leg studies in pregnant women with suspected PE and without symptoms level 2+
and signs of DVT is unclear. In one case series, Chan et al. found no cases of DVT in 67
women presenting with suspected PE.4 Given the higher incidence of isolated iliac vein DVT
in pregnancy,32 it would be anticipated that there would be an increased likelihood of falsenegative results with this strategy. Therefore, while a positive result is of value, a negative
investigation does not help to exclude a PE.
8 of 32
The choice of technique for definitive diagnosis (V/Q scan or CTPA) will depend on local
availability, and individual hospitals should have an agreed protocol for the objective diagnosis
of suspected PE during pregnancy. A matched casecontrol study in the UK investigated the
management of 143 women with antenatal PE; ninety-one women (65%) had a V/Q scan, 42
(30%) had CTPA performed, 22 (16%) had echocardiography and 16 (11%) were diagnosed by
angiography.33 Forty women (28%) were diagnosed using a combination of techniques. With Evidence
regard to V/Q lung scanning, during pregnancy the ventilation component can often be omitted level 2+
thereby minimising the radiation dose for the fetus. Studies have compared V/Q or low-dose
perfusion (Q) scans with CTPA for the detection of PE in pregnancy and have found comparable
negative predictive values (99% and 100% for CTPA and Q scans respectively) and no significant
difference between the number of positive, nondiagnostic and normal scans.5,34,35 One study
reported a higher rate of nondiagnostic scans with CTPA (37.5%) compared with V/Q scanning
(4%) in pregnancy,36 although this may be related to the imaging protocol employed.
CTPA has potential advantages over V/Q imaging including: CTPA is more readily available,37,38
delivers a low radiation dose to the fetus (see section below) and can identify other pathology
including pneumonia (57%), pulmonary oedema (26%) and rarely aortic dissection.5,35 Despite
these potential advantages of CTPA, many authorities continue to recommend V/Q scanning as
first-line investigation in pregnancy because of its high negative predictive value in this situation
and its substantially lower radiation dose to pregnant breast tissue (see section below).39,40
Clinicians arranging imaging scans for suspected PE in pregnancy should be aware of the
potential risks surrounding fetal and maternal radiation exposure.41 CTPA exposes the fetus to Evidence
similar or lower amounts of radiation as V/Q scanning, although studies have been confounded level 4
by the type and model of scanners used, the imaging protocols employed and the methods used
to estimate radiation exposure.42 With both techniques, the doses employed are well below
accepted thresholds for teratogenicity, fetal death and fetal growth restriction, and the main
concern for the fetus is a very small increased risk of childhood cancer.43 The International
Commission on Radiological Protection has estimated an increased risk of fatal childhood
cancer to the age of 15 following in utero radiation exposure of 0.006% per mGy, which equates
to a risk of 1 in 17000 per mGy.44 The fetal radiation exposure associated with CTPA and V/Q is
approximately 0.1 mGy and 0.5 mGy respectively, although quoted figures vary considerably.25,43,45
While CTPA is associated with a low risk of radiation for the fetus, this must be offset by the
relatively high radiation dose (up to 20 mGy) to the mothers breast tissue, which is associated
with an increased risk of breast cancer. The dose estimate for CTPA is 20 to 100 times greater
than for V/Q scanning. The radiation dose depends on breast size, the technique used and
the age of the woman the risk of cancer being greater in younger women.46 Estimates of the
increased risk of breast cancer associated with CTPA in pregnancy vary considerably and are
based on modelling or extrapolated data. The delivery of 10 mGy of radiation to a womans breast
has been estimated to increase her lifetime risk of developing breast cancer by 13.6% above her
background risk47 and this figure has been cited widely. For a 25-year-old whose background Evidence
risk of developing breast cancer in the following 10 years is 0.1%, the extra risk from 10mGy of level 3
radiation increases the risk by 13.6% of 0.1%, which is 0.0136% extra. Furthermore, Allen and
Demetriades48 have suggested that even this small risk is an overestimate. Nevertheless, breast
tissue is especially sensitive to radiation exposure during pregnancy because of hormonally
induced increased glandular activity.49 The breast doses associated with CTPA can be reduced
by 2040% by the use of bismuth shields placed over the breasts.50 It would be prudent to
recommend that lung perfusion scans should be considered the investigation of first choice for
young women, especially if there is a family history of breast cancer or the patient has had a
previous chest CT scan.45
9 of 32
An algorithm for the investigation of suspected PE in pregnancy and the puerperium is given in Appendix I.
There is a theoretical risk of hypothyroidism for neonates who have been exposed in utero to
iodinated contrast medium (such as that employed during CTPA), although this has not been Evidence
level 3
borne out in a study of over 300 neonates.51
Newer imaging techniques for the diagnosis of PE have been developed but have not been fully evaluated
in pregnancy; these include: magnetic resonance pulmonary angiogram, digital subtraction angiography
and ventilation and perfusion single-photon emission computed tomography (V/QSPECT ).52
4.3 Should D-dimer testing be performed prior to objective diagnosis?

D-dimer testing should not be performed in the investigation of acute VTE in pregnancy.
In the nonpregnant individual, D-dimer testing is used successfully in the investigation of

acute VTE, having a high sensitivity, moderate specificity and high negative predictive value.53
In pregnancy, there is a progressive rise in D-dimer levels with advancing gestation and levels
become abnormal at term and in the postnatal period in most healthy pregnant women.54,55
D-dimer levels are increased further in multiple pregnancies,56 following caesarean section
and in major postpartum haemorrhage57 and if there is concomitant pre-eclampsia.58 Thus a
positive D-dimer test in pregnancy is not necessarily consistent with VTE. The role of D-dimer Evidence
level 4
testing in the investigation of acute VTE in pregnancy remains controversial.59 Guidelines from
the European Society of Cardiology recommend testing D-dimer levels, proposing that normal
D-dimer levels can exclude PE in pregnancy just as for other patients, even though normal
levels are less likely to be found in pregnancy.60 In contrast, guidelines from the American
Thoracic Society/Society of Thoracic Radiology recommend that D-dimer should not be used
to exclude PE in pregnancy.39
Evidence regarding the safety and clinical use of D-dimer concentrations in the diagnosis of
suspected PE in pregnancy is lacking. A retrospective study of pregnant women with suspected
PE who had both V/Q scans and D-dimer testing found a negative likelihood ratio of 1.8,
suggesting that a negative D-dimer is inadequate to exclude PE in pregnancy.61 Furthermore,
case reports have described negative D-dimer levels in pregnant women with acute VTE.6264
In current practice, measurements of D-dimer levels in the nonpregnant should be combined Evidence
level 3
with validated tests to assign a pretest probability before PE can be excluded without imaging,
and these tests do not currently exist in pregnancy. Several studies have described the use
of gestation-specific, higher cut-off values in the diagnosis of suspected VTE in pregnancy;
all, however, conclude that further prospective studies are required before D-dimer testing in
pregnancy can be recommended.6568
4.4 What is the role of pretest probability assessment?

Clinicians should be aware that, at present, there is no evidence to support the use of pretest
probability assessment in the management of acute VTE in pregnancy.
In the UK, national guidelines recommend that nonpregnant patients presenting with suspected
VTE should have a two-level Wells score (a pretest probability assessment) performed.12 Various
modifications of the Wells score have been described and combine presenting symptoms and
signs to stratify risk and determine the need for further investigations. Studies have reported Evidence
on the performance of pretest probability assessment in pregnancy.6971 Chan et al.69 found level 3
that subjective assessment of pretest probability by VTE experts could exclude DVT when
the pretest probability is low. Furthermore they reported on three variables that may improve
the diagnostic accuracy of DVT in pregnancy (left leg [L], calf circumference difference of at least
10 of 32
2 cm [E for edema] and first trimester presentation [Ft] the LEFt rule). Righini et al.,71 in a post
hoc analysis of 157 pregnant women with suspected DVT, applied the LEFt rule and found that a
negative score accurately identifies pregnant women in whom the proportion of confirmed DVT
is very low. OConnor et al.70 examined the use of the modified Wells score (MWS) in pregnancy Evidence
as a risk stratification tool in the diagnosis of PE. They found that a MWS of 6 or higher was 100% level 2+
sensitive and 90% specific with a positive predictive value of 36% for PE on CTPA. No woman
with a MWS of less than 6 had a PE, giving a negative predictive value of 100%. In each of these
studies, the authors conclude that prospective trials are required to validate their findings.
5.
Baseline blood investigations
What baseline blood investigations should be performed before initiating anticoagulant therapy?
Before anticoagulant therapy is commenced, blood should be taken for a full blood count, coagulation
screen, urea and electrolytes, and liver function tests.
Performing a thrombophilia screen prior to therapy is not recommended.
The use of anticoagulant therapy can be influenced by renal and hepatic function, and can
influence the platelet count, and blood should be taken to confirm that these are normal Evidence
level 4
before commencing treatment.11
Almost half of all women who have an episode of VTE in pregnancy will have an underlying
heritable or acquired thrombophilia.72,73 In the nonpregnant individual, the presence of
thrombophilia does not alter the acute management of VTE with regards to the choice of
anticoagulant agent, intensity of treatment or duration of therapy,74 and therefore testing for
thrombophilia is not recommended.11 Furthermore, the physiological changes of pregnancy and Evidence
pathophysiology of acute thrombus can influence the results of a thrombophilia screen. Levels level 1++
of antithrombin and protein C may fall, particularly if the thrombus is extensive. In addition,
protein S levels fall in normal pregnancy and an acquired activated protein C resistance is found
in around 40% of pregnancies.75,76 It is recommended therefore that a thrombophilia screen
should not be performed in pregnant women on presentation with suspected VTE.
6.
Initial anticoagulant treatment of VTE in pregnancy
6.1 What is the initial treatment of VTE in pregnancy?

In clinically suspected DVT or PE, treatment with low-molecular-weight heparin (LMWH) should be
commenced immediately until the diagnosis is excluded by objective testing, unless treatment is
strongly contraindicated.
Meta-analyses of randomised controlled trials indicate that LMWHs are more effective, are
associated with a lower risk of haemorrhagic complications and are associated with lower
mortality than unfractionated heparin in the initial treatment of DVT in nonpregnant
patients.77,78 A meta-analysis of randomised controlled trials has shown equivalent efficacy
of LMWH to unfractionated heparin in the initial treatment of PE.79 A Cochrane review of Evidence
22 studies had over 8000 patients of whom 75% had DVT and 25% PE without evidence of level 1++
DVT; compared with unfractionated heparin, LMWH treatment was associated with lower
rates of VTE recurrence or extension (3.6% versus 5.4%; OR 0.68, 95% CI 0.550.84), lower
mortality (4.5% versus 6.0%; OR 0.76, 95% CI 0.630.92) and less major bleeding during the
initial treatment period (1.2% versus 2.0%; OR 0.57, 95% CI 0.390.83).80
With regard to safety, there is substantial accumulating evidence with the use of LMWHs, Evidence
both in pregnant and nonpregnant patients, for the prevention and treatment of VTE.81 There level 2++
11 of 32
is evidence that LMWHs do not cross the placenta.82 While a Cochrane review concluded that
there is no evidence from randomised controlled trials on the effectiveness of anticoagulation
for DVT in pregnancy,13 systematic reviews and large series of cases have concluded that
LMWH is a safe and effective alternative to unfractionated heparin as an anticoagulant during
pregnancy.8387 These have demonstrated a low risk of recurrent VTE when therapeutic doses
of LMWH were used to manage VTE in pregnancy; for example, Greer and Nelson-Piercy
identified a risk of recurrent VTE of 1.15% in women managed with LMWH.84 This compares
favourably with recurrence rates of 58% reported in trials carried out in nonpregnant
patients treated with LMWH or unfractionated heparin followed by coumarin therapy who
are followed up for 36 months.88,89
Evidence
One of the advantages of LMWH over unfractionated heparin is the potential reduced risk of level 2++
bleeding. This is of particular relevance in obstetric practice where obstetric haemorrhage
remains the most common cause of severe obstetric morbidity.90 LMWHs are not associated
with an increased risk of severe postpartum haemorrhage (defined as a blood loss of 1000 ml
or more) in vaginal delivery.91 In one retrospective study85 the observed rate of massive
postpartum haemorrhage (more than 1500 ml) was 1.1%, which compares favourably with the
rate of massive haemorrhage (0.7%) from one prospective study without the use of LMWH.92 It
is known that the risk of heparin-induced thrombocytopenia (HIT) is substantially lower with
LMWH use compared with unfractionated heparin and in the 2777 pregnancies treated with
LMWH and reviewed by Greer and Nelson-Piercy, no cases of HIT associated with thrombosis
were reported.84
Data on LMWH also substantiate a lower risk of LMWH compared with unfractionated heparin
for heparin-induced osteoporosis; the overall risk of this complication on systematic review
was 0.04% (compared with 2% for unfractionated heparin).84,93 A randomised controlled trial Evidence
investigating bone mineral density in pregnant women receiving long-term dalteparin in level 1+
pregnancy found no significant difference in bone density between LMWH-treated patients
and controls.94
In clinically suspected VTE, LMWH should be postponed until objective testing has confirmed
the diagnosis in women at risk of bleeding after careful consideration of the balance of risks
of haemorrhage and clotting. The risk factors for bleeding are summarised in Green-top Evidence
level 4
Guideline No. 37a. Women who are known to be allergic to LMWH should be offered an
alternative anticoagulant preparation (see section 8.3).
6.2 What is the therapeutic dose of LMWH in pregnancy?

LMWH should be given in doses titrated against the womans booking or early pregnancy weight.
There is insufficient evidence to recommend whether the dose of LMWH should be given once daily
or in two divided doses.
There should be clear local guidelines for the dosage of LMWH to be used.
In nonpregnant patients, the recommended therapeutic doses of LMWH vary according to

the manufacturer (enoxaparin 1.5 mg/kg once daily; dalteparin 1000018000 units once
daily depending on body weight; tinzaparin 175 units/kg once daily). During pregnancy,
changes in volume of distribution and renal glomerular filtration rate result in alterations
in the pharmacokinetics of LMWHs.9599 Previous editions of this guideline (2001 and 2007) Evidence
level 3
recommended a twice-daily dosage regimen for enoxaparin and dalteparin in the treatment of
VTE in pregnancy (enoxaparin 1 mg/kg twice daily; dalteparin 100 units/kg twice daily). This
recommendation was based on anti-Xa activity and a paucity of reports on safety and efficacy
of once-daily dosing.100 Since then, a prospective multicentre observational study has found
12 of 32
that 60% of practitioners use once-daily dosing of enoxaparin and dalteparin for treatment of Evidence
level 3
VTE in pregnancy.101
A national casecontrol study on the management of antenatal PE using the UK Obstetric Evidence
Surveillance System found that 49% of women were managed with a once-daily dosage schedule.33 level 2+
Further, a large, international retrospective study on the use of tinzaparin in pregnancy (with
254 pregnancies receiving treatment doses and 94.1% of these in a once-daily regimen) has Evidence
level 3
provided reassuring data on safety and efficacy of once-daily dosing.85
Recommendations on the treatment of pregnancy-associated VTE from clinicians in New
Zealand and Australia concluded that there is insufficient evidence to favour one dose regimen Evidence
over the other, and that treatment of acute VTE in pregnancy can be with LMWH administered level 4
either once daily or twice daily.40
A recent pharmacokinetic study involving 123 pregnant women found that the half-life
of enoxaparin is prolonged with the progression of pregnancy; the authors conclude that Evidence
their study provides further support for the use of once-daily enoxaparin for treatment of VTE level 2+
in pregnancy.102
The doses of different LMWHs are given in Tables 1ac below.
Table 1a. Initial dose of enoxaparin is determined as follows:
Booking or early pregnancy weight
Initial dose of enoxaparin
< 50 kg
40 mg twice daily or 60 mg once daily
5069 kg
7089 kg
90109 kg
110125 kg
> 125 kg
Discuss with haematologist
Table 1b. Initial dose of dalteparin is determined as follows:

Booking or early pregnancy weight
Initial dose of dalteparin
< 50 kg
5000 iu twice daily or 10 000 iu once daily
5069 kg
7089 kg
90109 kg
110125 kg
12000 iu twice daily or 24 000 iu daily
> 125 kg
Discuss with haematologist
Table 1c. Initial dose of tinzaparin is determined as follows:

Initial dose of tinzaparin (based on booking or early pregnancy weight)
175 units/kg once daily
Lower doses of LMWH should be employed if the creatinine clearance is less than 30 ml/minute
(enoxaparin and dalteparin) or less than 20 ml/minute with tinzaparin.103,104
13 of 32
6.3 Should blood tests be performed to monitor heparin therapy in pregnancy?

Routine measurement of peak anti-Xa activity for patients on LMWH for treatment of acute VTE
in pregnancy or postpartum is not recommended except in women at extremes of body weight
(less than 50 kg and 90 kg or more) or with other complicating factors (for example, with renal
impairment or recurrent VTE).
Routine platelet count monitoring should not be carried out.
Obstetric patients who are postoperative and receiving unfractionated heparin should have
platelet count monitoring performed every 23 days from days 4 to 14 or until heparin is stopped.
Initial experience with enoxaparin for the treatment of VTE in pregnancy indicated that
satisfactory anti-Xa levels (peak anti-Xa activity, 3 hours post-injection, of 0.51.2 u/ml) were
obtained using a weight-based regimen.105 A recent case series of 13 pregnant women treated
with therapeutic doses of tinzaparin found that 11 required dose adjustments to maintain the antiXa activity, assessed 4 hours post-injection, in the therapeutic range.99 However, a retrospective
casecontrol study from Denmark assessed 166 women managed with prophylactic and Evidence
therapeutic doses of LMWH in pregnancy without anti-Xa monitoring and reported excellent level 2+
clinical outcomes.106 Monitoring of anti-Xa is therefore not routinely required in patients with
VTE on therapeutic doses of LMWH, particularly as there are concerns over the accuracy of
anti-Xa monitoring.107,108 There may be a case for monitoring levels at extremes of body weight
(less than 50 kg and 90 kg or more) and in women with other complicating factors including
renal disease and recurrent VTE.109
Guideline documents recommend that routine platelet count monitoring is not required in
obstetric patients who receive heparin,110,111 as the risk of HIT is low; one case report of HIT
with thrombosis was identified in a pregnancy managed with enoxaparin.112 The platelet count
should be checked after 24 hours of initiating treatment if the patient has previously received
heparin (unfractionated or LMWH) in the last 100 days.111 The frequency of HIT is greater in Evidence
level 4
surgical than medical patients, and is more likely with unfractionated heparin. It is therefore
recommended that obstetric patients who are postoperative and receiving unfractionated
heparin should have platelet count monitoring performed every 23 days from days 4 to 14 or
until heparin is stopped.110
6.4 How should massive life-threatening PE in pregnancy and the puerperium be managed?
Collapsed, shocked women who are pregnant or in the puerperium should be assessed by a team
of experienced clinicians including the on-call consultant obstetrician.
Women should be managed on an individual basis regarding: intravenous unfractionated heparin,

thrombolytic therapy or thoracotomy and surgical embolectomy.
Management should involve a multidisciplinary team including senior physicians, obstetricians

and radiologists.
Intravenous unfractionated heparin is the preferred, initial treatment in massive PE with

cardiovascular compromise.
Maternity units should develop guidelines for the administration of intravenous unfractionated
heparin.
The on-call medical team should be contacted immediately. An urgent portable echocardiogram or
CTPA within 1 hour of presentation should be arranged. If massive PE is confirmed, or in extreme
circumstances prior to confirmation, immediate thrombolysis should be considered.
14 of 32
Massive PE may present with shock, refractory hypoxaemia and/or right ventricular dysfunction on
echocardiogram and is a medical emergency. Collapsed, shocked women who are pregnant or in the
puerperium should be assessed by a multidisciplinary resuscitation team of experienced clinicians including
the on-call consultant obstetrician, who should decide on an individual basis whether a woman receives
intravenous unfractionated heparin, thrombolytic therapy or thoracotomy and surgical embolectomy.
Maternal resuscitation should commence following the principles of ABC and if cardiac arrest
occurs, cardiopulmonary resuscitation should be performed with the woman in a left lateral Evidence
level 4
tilt. A perimortem caesarean section should be performed by 5 minutes if resuscitation is
unsuccessful and the pregnancy is more than 20 weeks.113
Intravenous unfractionated heparin is the preferred, initial treatment in massive PE because Evidence
of its rapid effect, extensive experience of its use in this situation and since it can be adjusted level 1+
more readily if thrombolytic therapy is administered.11
One regimen for the administration of intravenous unfractionated heparin is:114
l loading dose of 80 units/kg, followed by a continuous intravenous infusion of 18 units/kg/hour
l if a patient has received thrombolysis (see below), the loading dose of heparin should be omitted
and an infusion started at 18 units/kg/hour

l it is mandatory to measure activated partial thromboplastin time (APTT) level 46 hours after the
loading dose, 6 hours after any dose change and then at least daily when in the therapeutic range.
The therapeutic target APTT ratio is usually 1.52.5 times the average laboratory control value.
(This will depend on the APTT reagent used in the laboratory and, when unfractionated heparin is
employed, the advice of a haematologist should be sought)
l using this weight-adjusted regimen, the infusion rate should be adjusted according to the APTT as
described in Table 2.
Table 2. Adjustments in the infusion rate of unfractionated heparin according to the APTT
APTT ratio
Dose change (units/kg/hour)
Additional action
Next APTT (hour)
< 1.2
+4
Re-bolus 80 units/kg
1.21.5
+2
Re-bolus 40 units/kg
1.52.5
no change
24
2.53.0
> 3.0
Stop infusion 1 hour
It is recognised that APTT monitoring of unfractionated heparin is technically problematic,

particularly in late pregnancy when an apparent heparin resistance occurs due to increased
fibrinogen and factor VIII which influence the APTT.115,116 This can lead to unnecessarily high
doses of heparin being used with subsequent haemorrhagic problems. Where such problems Evidence
are considered to exist, haematologists should be involved in the patients management. It may level 2+
be useful to determine the anti-Xa level as a measure of heparin dose. With unfractionated
heparin, a lower level of anti-Xa is considered therapeutic (target range 0.350.7 u/ml or
0.51.0 u/ml for patients with life-threatening PE).117
In massive life-threatening PE with haemodynamic compromise (or with limb- or life-threatening
ischaemic complications from extensive iliofemoral vein thrombosis), thrombolytic therapy should
be considered as anticoagulant therapy alone will not reduce the obstruction in the circulation. After
thrombolytic therapy has been given, an infusion of unfractionated heparin can be given, but the loading
dose (outlined above) should be omitted.
15 of 32
A meta-analysis of randomised controlled trials using thrombolytic agents for PE has established
that thrombolytic therapy is more effective than heparin therapy in reducing clot burden and
improving haemodynamics.118 These studies, however, have not shown any impact on longterm survival over and above that of conventional therapy with heparin or LMWH, and no
thrombolytic agent has been shown to be superior to any of the others.118 However, when Wan et Evidence
level 1++
al. restricted their analysis to those trials with massive PE, they identified a significant reduction in
recurrent PE or death from 19.0% with heparin alone to 9.4% with thrombolysis (OR 0.45, 95% CI
0.220.90).118 Current recommendations suggest that thrombolytic therapy should be reserved
for patients with severe pulmonary thromboembolism with haemodynamic compromise.119
There are now a large number of published case reports and case series on the use of thrombolytic
therapy in pregnancy,120123 including cases treated with: streptokinase,123125 urokinase,126
recombinant tissue plasminogen activator (rtPA; alteplase)121,127,128 and tenecteplase.129 A major
concern regarding the use of thrombolytic therapy in pregnancy is fetal and maternal bleeding.
In one literature review, Ahearn et al.121 reported on 172 women treated with thrombolytic
therapy (167 of whom had DVT or PE); problems associated with treatment included five Evidence
level 3
nonfatal maternal bleeding complications (2.9%) and three fetal deaths (1.7%). No maternal
deaths associated with thrombolytic therapy have been reported. More recently, te Raa et al.123
reported on 13 cases of massive PE during pregnancy four had haemorrhagic complications
and there were two fetal deaths. Most bleeding events occur around catheter and puncture
sites and, in pregnant women, there have been no reports of intracranial bleeding.
If the patient is not suitable for thrombolysis or is moribund, a discussion with the cardiothoracic
surgeons with a view to urgent thoracotomy should be had.112
7.
Additional therapies
7.1 Should graduated elastic compression stockings be employed in the acute management of
VTE in pregnancy?
In the initial management of DVT, the leg should be elevated and a graduated elastic compression
stocking applied to reduce oedema. Mobilisation with graduated elastic compression stockings
should be encouraged.
Patients with acute DVT have traditionally been recommended bed rest and immobilisation
for fear of dislodging an unstable thrombus and causing PE, and by the belief that rest relieves
pain and swelling. However, randomised controlled trials have shown that early ambulation,
with leg compression, does not increase the risk of PE, does not increase thrombus
propagation, and that pain and swelling improved faster compared to those patients who
had their mobility restricted.130138 This approach may also prevent the development of postthrombotic syndrome (see section 11). A randomised controlled trial comparing knee-length
with thigh-length hosiery concluded that thigh-length compression elastic stockings do not Evidence
offer better protection against post-thrombotic syndrome than below-knee hosiery and are level 1+
less well tolerated.139 National guidance in the UK recommends that patients with proximal
DVT should be offered below-knee compression stockings with an ankle pressure greater
than 23 mmHg and that hosiery does not need to be worn on the unaffected leg.12 Accurate
fitting and careful instruction in the correct application of the hosiery is essential to avoid
discomfort and assist rather than prevent venous return. A pilot audit of compliance with
graduated compression stockings in pregnancy showed poor levels of compliance related to
discomfort and side effects.140
16 of 32
7.2 What is the role of inferior vena cava filters in the management of VTE in pregnancy?
Consideration should be given to the use of a temporary inferior vena cava filter in the peripartum
period for patients with iliac vein VTE to reduce the risk of PE or in patients with proven DVT and
who have recurrent PE despite adequate anticoagulation.
Placement of a temporary inferior vena cava (IVC) filter in obstetric practice is indicated when
recurrent thromboembolism occurs despite adequate anticoagulation, or when anticoagulation
is contraindicated (such as the peripartum period). Case reports and case series have reported
favourable outcomes with regard to safety and effectiveness on the use of IVC filters in Evidence
level 3
pregnancy.141145 The long-term safety of IVC filters is uncertain and the main complications
associated with vena cava filters are migration, an increased risk of lower limb DVT and caval
thrombosis and, rarely, infection.12
8.
Maintenance treatment of VTE
8.1 What is the maintenance treatment of DVT or PE?

Treatment with therapeutic doses of subcutaneous LMWH should be employed during the remainder
of the pregnancy and for at least 6 weeks postnatally and until at least 3 months of treatment has
been given in total.
Women should be taught to self-inject LMWH and arrangements made to allow safe disposal of
needles and syringes. Outpatient follow-up should include clinical assessment and advice with
monitoring of blood platelets and peak anti-Xa levels if appropriate (see sections 5 and 6.3).
Pregnant women who develop heparin-induced thrombocytopenia or have heparin allergy and
require continuing anticoagulant therapy should be managed with an alternative anticoagulant
under specialist advice.
Women with antenatal VTE can be managed with subcutaneous therapeutic doses of LMWH
for the remainder of the pregnancy7779,81,8387 (see section 6.2). If LMWH therapy requires Evidence
monitoring (e.g. extremes of body weight or renal impairment, see section 6.3), the aim is to level 3
achieve a peak anti-Xa activity, 3 hours post-injection, of 0.51.2 u/ml.
The rationale for recommending therapeutic doses of LMWH (rather than reduced, prophylactic
doses) throughout the remainder of the pregnancy is based on the continuing risk of recurrent
VTE during this time arising from: pregnancy-related changes in the coagulation system,
reduced venous flow velocity, a higher incidence of isolated iliac vein DVT in pregnancy and in Evidence
at least 50% of patients a thrombophilia will be present. A high recurrence rate of VTE (9 of 35 level 1+
patients) was reported in a prospective randomised controlled trial in nonpregnant patients,
when thromboprophylactic doses of unfractionated heparin (5000 iu every 12 hours) were
employed after initial management with intravenous unfractionated heparin.146
In their observational study on the management of antenatal VTE in Britain and Ireland, Voke
et al.101 found that doses of LMWH were reduced in 22% of women after initial treatment; the Evidence
reasons given included clinical improvement several weeks after diagnosis and transfer from level 3
twice- to once-daily injections.
It is not yet established whether the dose of LMWH or unfractionated heparin can be reduced
to an intermediate dose after an initial period of therapeutic anticoagulation. In view of the
compelling safety data for LMWHs,8387 we continue to recommend continuation of therapeutic Evidence
level 2++
doses based on the patients weight throughout pregnancy. Reducing to an intermediate dose
may be useful in pregnant women at increased risk of bleeding or osteoporosis.
17 of 32
Women should be taught to self-inject and can then be managed as outpatients until delivery;
arrangements should be made to allow safe disposal of needles and syringes. A clinical audit Evidence
and a prospective cohort study have shown good levels of compliance with LMWH self- level 2+
injection therapy during the antenatal period.147,148
Prolonged unfractionated heparin use during pregnancy may result in osteoporosis and
fractures.93,149 As discussed previously (section 6.1), the risk of osteoporosis with LMWH is much Evidence
level 2++
less than with unfractionated heparin, with one systematic review reporting a risk of 0.04%.84
Allergic skin reactions to heparin can occur and may require the heparin preparation to be
changed.150 A prospective observational study of 111 pregnant women receiving heparin
treatment (94 had LMWH and 17 had unfractionated heparin) found heparin-induced skin Evidence
level 2
reactions in 22 (19.8%).151 All lesions were caused by allergic delayed-type hypersensitivity
reactions and the median time of onset was 50.5 days (range 5184 days).
In women who are unable to tolerate heparin, usually because of allergic skin reactions without
evidence of HIT, an alternative LMWH can be prescribed, although the cross-reactivity rate to
different heparin preparations is 33.3%.151 Where the problem persists or in women with HIT, Evidence
the use of danaparoid, a low-molecular-weight heparinoid, can be considered. A review of 91 level 3
pregnancies in 83 women concluded that danaparoid is an effective and safe antithrombotic
in pregnancy for women who are intolerant of heparin.152
8.2 Can vitamin K antagonists be used during pregnancy for the maintenance treatment of VTE?
Because of their adverse effects on the fetus, vitamin K antagonists, such as warfarin, should not
be used for antenatal VTE treatment.
Vitamin K antagonists cross the placenta readily and are associated with adverse pregnancy
outcomes including miscarriage, prematurity, low birthweight, neurodevelopmental problems Evidence
and fetal and neonatal bleeding. They are also associated with a characteristic embryopathy level 2+
following fetal exposure in the first trimester.153,154
8.3 Is there a role for the new anticoagulants in the treatment of VTE in pregnancy?
Consideration should be given to the use of newer anticoagulants (fondaparinux, argatroban or
r-hirudin) in pregnant women who are unable to tolerate heparin (LMWH or unfractionated heparin)
or danaparoid and who require continuing anticoagulant therapy.
Case reports and case series have described the use of newer anticoagulants in pregnancy
following the development of HIT or skin allergy to heparins; these preparations are
administered parenterally and include fondaparinux (a selective factor-Xa inhibitor),112,155,156
argatroban (a direct thrombin inhibitor)157160 and r-hirudin (a direct thrombin inhibitor).161165 Evidence
While these drugs are not licensed for use in pregnancy, preliminary data regarding their level 3
safety and efficacy in pregnancy are reassuring; fondaparinux has been recommended by a
group of experts (the Pregnancy and Thrombosis Working Group) as an alternative to LMWH
when HIT occurs in pregnancy.166
There are no reports on the use of the non-vitamin K antagonist oral anticoagulants (NOACs,
previously called new or novel oral anticoagulants, e.g. rivaroxaban, apixaban, betrixaban and Evidence
dabigatran) in pregnancy or the puerperium and as they are likely to cross the placenta and level 4
have potential direct fetal effects, they should therefore be avoided in the antenatal period.154
18 of 32
9.
Anticoagulant therapy during labour and delivery
9.1 Should anticoagulant therapy be altered during labour and delivery?

When VTE occurs at term, consideration should be given to the use of intravenous unfractionated
heparin which is more easily manipulated.
The woman on LMWH for maintenance therapy should be advised that once she is in established
labour or thinks that she is in labour, she should not inject any further heparin.
Where delivery is planned, either by elective caesarean section or induction of labour, LMWH
maintenance therapy should be discontinued 24 hours prior to planned delivery.
Regional anaesthetic or analgesic techniques should not be undertaken until at least 24 hours
after the last dose of therapeutic LMWH.
LMWH should not be given for 4 hours after the use of spinal anaesthesia or after the epidural
catheter has been removed, and the epidural catheter should not be removed within 12 hours of
the most recent injection.
Where possible, anticoagulant therapy should be altered to avoid an unwanted anticoagulant effect
during delivery. Women should be advised not to inject any further heparin if they are in established
labour or think they are in labour.
For elective delivery, LMWH should be stopped 24 hours before induction of labour or caesarean
section. Subcutaneous unfractionated heparin should be discontinued 12 hours before and
intravenous unfractionated heparin stopped 6 hours before induction of labour or regional
anaesthesia.167 Women who present in labour shortly after injecting LMWH can be reassured that
bleeding complications are very uncommon with LMWH (see section 6.1). If spontaneous labour
occurs in women receiving therapeutic doses of subcutaneous unfractionated heparin, careful
monitoring of the APTT is required (see above for use of APTT in pregnancy). If it is markedly
prolonged near delivery, protamine sulfate may be required to reduce the risk of bleeding.
When VTE occurs at term, the risk of recurrent thrombosis may be increased if anticoagulant
therapy is discontinued to allow a planned induction of labour or caesarean section; one study
suggested that the risk of recurrent VTE is higher within 2 weeks of the initial thrombosis.168
Consideration can be given to the use of intravenous unfractionated heparin which is more easily
manipulated and, because of its shorter half-life, minimises the duration without anticoagulant
therapy. However, as noted previously, there are issues in monitoring unfractionated heparin in Evidence
pregnancy using the APTT. One approach to the use of anticoagulant therapy in this situation level 4
has been described by McLintock et al.40
The incidence of spinal haematoma after regional anaesthesia (with or without antithrombotic
therapy) in the obstetric population is unknown. It is considered that obstetric patients have
a lower incidence of spinal haematoma than elderly patients.169,170 Epidural anaesthesia can be
sited in obstetric patients undergoing treatment for VTE only after discussion with a senior
anaesthetist, in keeping with local anaesthetic protocols. When a woman presents while on a
therapeutic regimen of LMWH, regional techniques should not be employed for at least 24 hours
after the last dose of LMWH. LMWH should not be given for at least 4 hours after the epidural
catheter has been removed and the catheter should not be removed within 12 hours of the most
recent injection.167
For delivery by elective caesarean section, the treatment doses of LMWH should be omitted
for 24 hours prior to surgery. A thromboprophylactic dose of LMWH (enoxaparin 40 mg;
19 of 32
dalteparin 5000 iu; tinzaparin 75 iu/kg) should be given 4 hours postoperatively (at least 4 hours
after removal of the epidural catheter, if appropriate) and the treatment dose recommenced Evidence
level 4
8 to 12 hours later.
9.2 Are specific surgical measures required for anticoagulated patients undergoing delivery
by caesarean section?
In patients receiving therapeutic doses of LMWH, wound drains (abdominal and rectus sheath)
should be considered at caesarean section and the skin incision should be closed with interrupted
sutures to allow drainage of any haematoma.
Measures should be taken to allow drainage of any haematoma, including the use of drains and
interrupted skin sutures. A casecontrol study has reported an increased incidence of wound Evidence
complications in women receiving peripartum anticoagulation.171 The incidence of wound level 2+
haematoma was 9.1% in women receiving anticoagulation and 1.3% in controls.
9.3 What anticoagulant therapy should be employed in women at high risk of haemorrhage?
Any woman who is considered to be at high risk of haemorrhage, and in whom continued heparin
treatment is considered essential, should be managed with intravenous unfractionated heparin
until the risk factors for haemorrhage have resolved.
Unfractionated heparin has a shorter half-life than LMWH and its activity is more completely
reversed with protamine sulfate. It should therefore be used in situations when anticoagulation
is required but concerns exist regarding bleeding; these situations include: antepartum
haemorrhage, coagulopathy, progressive wound haematoma, suspected intra-abdominal
bleeding, and postpartum haemorrhage. One regimen for the administration of unfractionated Evidence
heparin is given in section 6.4. If a woman develops a haemorrhagic problem while on LMWH, level 3
the treatment should be stopped and advice sought from a haematologist. Protamine sulfate
reverses the anti-IIa fraction of LMWH, but does not fully reverse the anti-Xa effect; case series
have shown that it is useful in the management of bleeding associated with LMWH in some,
but not all, patients.172
10. Postnatal anticoagulation
How should anticoagulation be managed postnatally?

Therapeutic anticoagulant therapy should be continued for the duration of the pregnancy and for at
least 6 weeks postnatally and until at least 3 months of treatment has been given in total. Before
discontinuing treatment the continuing risk of thrombosis should be assessed.
Women should be offered a choice of LMWH or oral anticoagulant for postnatal therapy after
discussion about the need for regular blood tests for monitoring of warfarin, particularly during
the first 10 days of treatment.
Postpartum warfarin should be avoided until at least the fifth day and for longer in women at
increased risk of postpartum haemorrhage.
Women should be advised that neither heparin (unfractionated or LMWH) nor warfarin is
contraindicated in breastfeeding.
National guidelines in the UK recommend that in nonpregnant patients anticoagulant therapy

should be continued for at least 3 months for proximal DVT or PE and longer if the risk of Evidence
recurrent VTE is considered to be high.12 The presence of continuing prothrombotic factors level 4
that are a feature of pregnancy (see section 8.1) and the safety of LMWH have led authorities
20 of 32
to propose that, in the management of VTE in pregnancy, anticoagulant therapy should be

continued for the duration of the pregnancy and until at least 6 weeks postpartum and to
allow a total duration of treatment of at least 3 months.81 Both heparin and warfarin are Evidence
satisfactory for use postpartum. NOACs (see section 8.3) could be considered in women who level 4
are not breastfeeding, although no reports were identified of their use in the puerperium.
Before discontinuing treatment the continuing risk of thrombosis should be assessed.
Women should be offered a choice of LMWH or oral anticoagulant for postnatal therapy after discussion
about the need for regular blood tests for monitoring of warfarin. If the woman chooses to continue
with LMWH postnatally, then the doses and dosage schedule that were employed antenatally should
be continued.
A prospective cohort study has shown that womens adherence to LMWH therapy decreases
postnatally (mean percentage adherence to LMWH antenatally was 97.92% and 93.37% Evidence
postnatally). The authors conclude that healthcare workers should reinforce the necessity of level 2+
adherence to LMWH treatment during the postpartum period.148
If the woman chooses to commence warfarin postpartum, this should be avoided until at least the
fifth postnatal day. Daily testing of the international normalised ratio (INR) is recommended during
the transfer from LMWH to warfarin to avoid over-anticoagulation. Warfarin administration should be
delayed in women considered to be at risk of postpartum haemorrhage.
A systematic review on dosage regimens for initiating warfarin found no evidence to suggest a
10 mg loading dose is superior to 5 mg, although no studies in that review involved obstetric Evidence
level 2++
patients.173
A casecontrol study investigated the number of days and total warfarin dose required to
achieve therapeutic INR in a group of postpartum women compared to a group of matched
nonpregnant women.174 The postpartum women required larger doses of warfarin and took Evidence
significantly longer to reach therapeutic INR; the authors propose that the coagulation changes level 2+
that occur in pregnancy and persist into the puerperium antagonise warfarin and may justify
higher loading doses.
The regimen for commencing warfarin should be based on nomograms developed with
haematologists175 (for an example, see Appendix II). The INR should be checked on day two of Evidence
warfarin treatment and subsequent warfarin doses titrated to maintain the INR between 2.0 and level 4
3.0; heparin treatment should be continued until the INR is greater than 2.0 for at least 24 hours.176
Neither heparin (unfractionated or LMWH) nor warfarin is contraindicated in breastfeeding.
There is little published data on whether LMWHs are secreted in breast milk; in a case series of
15 women receiving LMWH after caesarean section, small amounts of heparin were detected
in the breast milk of 11 patients.177 Since neither unfractionated heparin nor LMWH is orally Evidence
level 3
active, no clinical effect would be anticipated in the infant.178 Warfarin does not pass into
breast milk to any measurable degree; it is 99% bound to serum proteins which results in
minimal transfer to breast milk.179,180
11. Prevention of post-thrombotic syndrome
What measures can be employed to prevent the development of post-thrombotic syndrome?

Women should be advised that prolonged use of LMWH (more than 12 weeks) is associated with a
significantly lower chance of developing post-thrombotic syndrome.
21 of 32
Following a DVT, graduated elastic compression stockings should be worn on the affected leg to
reduce pain and swelling. Clinicians should be aware that the role of compression stockings in the
prevention of post-thrombotic syndrome is unclear.
The post-thrombotic syndrome (PTS) is characterised by chronic persistent leg swelling, pain,
a feeling of heaviness, dependant cyanosis, telangiectasis, chronic pigmentation, eczema,
associated varicose veins and in the most severe cases, venous ulceration. A casecontrol
study from Norway found a prevalence of PTS of 42% following DVT in pregnancy; proximal
postnatal thrombosis, smoking and age greater than 33 years were independent predictors of
the development of PTS.181 Other recognised risk factors include: recurrent ipsilateral DVT and
obesity.182 A randomised controlled trial of long-term use of LMWH (tinzaparin for more than Evidence
12 weeks) versus tinzaparin for 5 days then warfarin for 12 weeks in patients with proximal level 1+
DVT reported a significantly lower rate of PTS in patients allocated to prolonged LMWH.183 A
subanalysis has shown that the benefits of prolonged LMWH are even greater for iliac vein
DVT (OR 0.53, 95% CI 0.330.83) than with non-iliac DVT (OR 0.79, 95% CI 0.670.93).184
While this study was conducted in nonpregnant subjects, the results may be relevant to the
pregnant population where iliac vein DVT is more common and prolonged use of LMWH is
standard treatment.
Graduated elastic compression stockings have been shown in meta-analyses of randomised
controlled trials to offer substantial protection against the development of PTS in the nonpregnant
(relative risk 0.54)185 and national guidelines recommend that compression hosiery (more than
23 mmHg) should be worn on the affected leg for at least 2 years.12 More recently, the benefits
of compression stockings in preventing PTS have been questioned. A high-quality randomised Evidence
level 1++
controlled trial of over 800 patients with proximal DVT has reported the effectiveness of 3040
mmHg (class II) compression stockings compared to a placebo stocking worn daily for 2 years
on the incidence of PTS; compression stockings did not prevent the occurrence of PTS after a
first proximal DVT and did not influence the severity of PTS or rate of recurrent VTE.186
12. Postnatal clinic review
Postnatal review for patients who develop VTE during pregnancy or the puerperium should,
whenever possible, be at an obstetric medicine clinic or a joint obstetric haematology clinic.
Thrombophilia testing should be performed once anticoagulant therapy has been discontinued
only if it is considered that the results would influence the womans future management.
At the postnatal review, an assessment should be made of post-thrombotic venous damage and
advice should be given on the need for thromboprophylaxis in any future pregnancy and at
other times of increased risk (see Green-top Guideline No. 37a). Thrombophilia testing should
be performed once anticoagulant therapy has been discontinued and only if it is considered Evidence
that the results would influence the womans future management; testing will not alter the level 4
duration and intensity of acute treatment but may alter prophylaxis in subsequent pregnancy
(Green-top Guideline No. 37a). Hormonal contraception should be discussed with reference
to guidance from the Faculty of Sexual and Reproductive Healthcare.187
l The role of D-dimer testing and pretest probability scoring in the diagnosis of VTE in pregnancy
require further investigation.

l The maternal and fetal radiation risks of tests used in the diagnosis of PE in pregnancy need to be
clarified.
22 of 32
l The role of newer diagnostic modalities (e.g. V/QSPECT ) in the diagnosis of PE in pregnancy needs
l
l
l
l
l
l
further evaluation.
The optimum dosage regimen of LMWH for treatment of VTE in pregnancy (once daily versus two
divided doses) merits further investigation.
Doses of LMWH required in obese pregnant and puerperal women.
The value and role of anti-Xa monitoring, including measurement of trough anti-Xa activity, of
LMWH treatment in pregnancy needs further study.
Studies are required to establish the safety and efficacy of newer anticoagulant agents in pregnancy.
Studies are required to determine whether thrombophilia status alters the risk of recurrence of
VTE and whether thrombophilia status requires an alteration in the duration of treatment.
Strategies to prevent and treat post-thrombotic syndrome following DVT in pregnancy are required.

l Documentation of risks of VTE investigations and management (100%).
l Correct therapeutic management of suspected and proven VTE (100%).
l Appropriate interval for administration of postpartum anticoagulant therapy (100%).
l Documentation of postpartum management plan (100%).
l Attendance for postnatal review and appropriate thrombophilia testing (100%).

l Royal College of Obstetricians and Gynaecologists. Information for you: Treatment of venous
thrombosis in pregnancy and after birth. London: RCOG; 2011 [https://www.rcog.org.uk/en/

patients/patient-leaflets/treatment-of-venous-thrombosis-in-pregnancy-and-after-birth/].
l Lifeblood: The Thrombosis Charity. Thrombosis and pregnancy. Llanwrda: Lifeblood: The
Thrombosis Charity; 2013 [http://www.thrombosis-charity.org.uk/perch/resources/thrombosispregnancy-crystal-mark-feb-2013.pdf].
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2009 (revised 2010).
28 of 32
Appendix I: Algorithm for the investigation and initial management of suspected PE in pregnancy
and the puerperium
Suspected PE:
clinical assessment
perform CXR and ECG
test FBC, U&E, LFTs
commence LMWH (unless treatment is contraindicated)
Symptoms and signs of DVT
YES
NO
Perform compression
duplex ultrasound
Compression ultrasound
confirms DVT
NO
Is the CXR normal?
YES
YES
Continue therapeutic
doses of LMWH
Perform V/Q scan
NO
Perform CTPA
PE confirmed
NO
If the clinical suspicion of PE is low, discontinue

LMWH and consider alternative diagnoses
If the clinical suspicion of PE is high, consider
alternative or repeat testing and continue LMWH
YES
Continue therapeutic
doses of LMWH
Abbreviations
CTPA computerised tomography pulmonary angiogram; CXR chest X-ray; DVT deep venous thrombosis; ECG electrocardiogram;
FBC full blood count; LFTs liver function tests; LMWH low-molecular-weight heparin; PE pulmonary embolism;
U&Es urea and electrolytes; V/Q scan ventilation/perfusion scan.
29 of 32
Appendix II: Suggested nomogram for commencing warfarin treatment in the puerperium
Day of warfarin treatment
International normalised ratio (INR)
First
7.0
Second
Third
Fourth
Warfarin dose (mg)

7.0
< 2.0
7.0
2.02.1
5.0
2.22.3
4.5
2.42.5
4.0
2.62.7
3.5
2.82.9
3.0
3.03.1
2.5
3.23.3
2.0
3.4
1.5
3.5
1.0
3.64.0
0.5
> 4.0
0.0
< 1.4
> 8.0
1.4
8.0
1.5
7.5
1.61.7
7.0
1.8
6.5
1.9
6.0
2.02.1
5.5
2.22.3
5.0
2.42.6
4.5
2.73.0
4.0
3.13.5
3.5
3.64.0
3.0
4.14.5
omit next days dose then give 2 mg
> 4.5
omit two days doses then give 1 mg
30 of 32
Appendix III: Explanation of guidelines and evidence levels


low risk of bias


low risk of bias
risk of bias

1++ or 1+

results; or
2++

case series
4
Good practice point
Expert opinion

31 of 32

development group
Dr AJ Thomson MRCOG, Paisley and Professor IA Greer FRCOG, Liverpool
British Committee for Standards in Haematology; Mrs AHD Diyaf MRCOG, Barnstaple; Kings Thrombosis Centre;
RCOG Womens Network.
Committee lead reviewers were: Dr M Gupta MRCOG, London; Mr AT Leather FRCOG, Ipswich; and
Dr P Owen FRCOG, Glasgow.
Conflicts of interest:
Dr Thomson was provided with a travel grant by LEO Pharma to attend an overseas conference in March 2014.
Professor Greer: none declared.
DISCLAIMER
32 of 32
The Management of Gestational

Trophoblastic Disease
February 2010
The Management of Gestational Trophoblastic Disease

This is the third edition of this guideline. It replaces The Management of Gestational Trophoblastic Neoplasia,
which was published in 2004.
1.
Definitions
Gestational trophoblastic disease (GTD) forms a group of disorders spanning the conditions of complete and
partial molar pregnancies through to the malignant conditions of invasive mole, choriocarcinoma and the very
rare placental site trophoblastic tumour (PSTT). There are reports of neoplastic transformation of atypical
placental site nodules to placental site trophoblastic tumour.
If there is any evidence of persistence of GTD, most commonly defined as a persistent elevation of beta human
chorionic gonadotrophin (hCG), the condition is referred to as gestational trophoblastic neoplasia (GTN).
2.
Purpose and scope
The purpose of this guideline is to describe the presentation, management, treatment and follow-up of GTD
and GTN. It also provides advice on future pregnancy outcomes and the use of contraception.
3.
Molar pregnancies can be subdivided into complete (CM) and partial moles (PM) based on genetic and
histopathological features. Complete moles are diploid and androgenic in origin, with no evidence of fetal
tissue. Complete moles usually (7580%) arise as a consequence of duplication of a single sperm following
fertilisation of an empty ovum. Some complete moles (2025%) can arise after dispermic fertilisation of an
empty ovum. Partial moles are usually (90%) triploid in origin, with two sets of paternal haploid genes and
one set of maternal haploid genes. Partial moles occur, in almost all cases, following dispermic fertilisation of
an ovum. Ten percent of partial moles represent tetraploid or mosaic conceptions. In a partial mole, there is
usually evidence of a fetus or fetal red blood cells.
GTD (hydatidiform mole, invasive mole, choriocarcinoma, placental-site trophoblastic tumour) is a rare event
in the UK, with a calculated incidence of 1/714 live births.1 There is evidence of ethnic variation in the
incidence of GTD in the UK, with women from Asia having a higher incidence compared with non-Asian
women (1/387 versus 1/752 live births). However, these figures may under represent the true incidence of
the disease because of problems with reporting, particularly in regard to partial moles. GTN may develop
after a molar pregnancy, a non-molar pregnancy or a live birth. The incidence after a live birth is estimated at
1/50 000. Because of the rarity of the problem, an average consultant obstetrician and gynaecologist may deal
with only one new case of molar pregnancy every second year.
In the UK, there exists an effective registration and treatment programme. The programme has achieved
impressive results, with high cure (98100%) and low (58%) chemotherapy rates.
4.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines. Medline, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Control
Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews and Effects (DARE), the
American College of Physicians ACP Journal Club and Ovid database, including in-process and other nonindexed citations, were searched using the terms molar pregnancy, hydatidiform mole, gestational
trophoblastic disease, gestational neoplasms, placental site trophoblastic tumour, invasive mole,
choriocarcinoma and limited to humans and English language. The date of the last search was July 2008.
2 of 12
Royal College of Obstetricians and Gynaecologists 2010
Selection of articles for analysis and review was then made based on the relevance to the objectives. Further
documents were obtained by the use of free text terms and hand searches. The National Library for Health
and the National Guidelines Clearing House were also searched for relevant guidelines and reviews.
The level of evidence and the grade of the recommendations used in this guideline originate from the
guidance by the Scottish Intercollegiate Guidelines Network Grading Review Group, which incorporates
formal assessment of the methodological quality, quantity, consistency and applicability of the evidence base.
Owing to the rarity of the condition, there are no randomised controlled trials comparing interventions with
the exception of first-line chemotherapy for low risk GTN. There are a large number of casecontrol studies,
case series and case reports.
5.
How do molar pregnancies present to the clinician?
Clinicians need to be aware of the symptoms and signs of molar pregnancy:
The classic features of molar pregnancy are irregular vaginal bleeding, hyperemesis, excessive
uterine enlargement and early failed pregnancy.
Clinicians should check a urine pregnancy test in women presenting with such symptoms.
Rarer presentations include hyperthyroidism, early onset pre-eclampsia or abdominal distension

due to theca lutein cysts. Very rarely, women can present with acute respiratory failure or
neurological symptoms such as seizures; these are likely to be due to metastatic disease.
6.
Evidence
level 4
How are molar pregnancies diagnosed?
Ultrasound examination is helpful in making a pre-evacuation diagnosis but the definitive diagnosis is
made by histological examination of the products of conception.
The use of ultrasound in early pregnancy has probably led to the earlier diagnosis of molar
pregnancy. Soto-Wright et al. demonstrated a reduction in the mean gestation at presentation from
16 weeks, during the time period 196575, to 12 weeks between 198893.2 The majority of
histologically proven complete moles are associated with an ultrasound diagnosis of delayed
miscarriage or anembryonic pregnancy.3,4 In one study, the accuracy of pre-evacuation diagnosis of
molar pregnancy increased with increasing gestational age, 3540 % before 14 weeks increasing to
60% after 14 weeks.4 A further study suggested a 56% detection rate for ultrasound examination.5
The ultrasound diagnosis of a partial molar pregnancy is more complex; the finding of multiple soft
markers, including both cystic spaces in the placenta and a ratio of transverse to anterioposterior
dimension of the gestation sac of greater than 1.5, is required for the reliable diagnosis of a partial
molar pregnancy.6,7 Estimation of hCG levels may be of value in diagnosing molar pregnancies: hCG
levels greater than two multiples of the median may help.5.
7.
Evidence
level 2+
Evacuation of a molar pregnancy
7.1 What is the best method of evacuating a molar pregnancy?

Suction curettage is the method of choice of evacuation for complete molar pregnancies.
Suction curettage is the method of choice of evacuation for partial molar pregnancies except when the
size of the fetal parts deters the use of suction curettage and then medical evacuation can be used.
P
P
A urinary pregnancy test should be performed 3 weeks after medical management of failed pregnancy
if products of conception are not sent for histological examination.
Anti-D prophylaxis is required following evacuation of a molar pregnancy.
3 of 12
Complete molar pregnancies are not associated with fetal parts, so suction evacuation is the
method of choice for uterine evacuation. For partial molar pregnancies or twin pregnancies when
there is a normal pregnancy with a molar pregnancy, and the size of the fetal parts deters the use
of suction curettage, then medical evacuation can be used.
Evidence
level 4
Medical evacuation of complete molar pregnancies should be avoided if possible.8,9 There is

theoretical concern over the routine use of potent oxytocic agents because of the potential to
embolise and disseminate trophoblastic tissue through the venous system. In addition, women with
complete molar pregnancies may be at an increased risk for requiring treatment for persistent
trophoblastic disease, although the risk for women with partial molar pregnancies needing
chemotherapy is low (0.5%).10,11
Evidence
level 2+
Data from the management of molar pregnancies with mifepristone and misoprostol are limited.9
Evidence
level 3
Evacuation of complete molar pregnancies with these agents should be avoided at present since it
increases the sensitivity of the uterus to prostaglandins.
Because of poor vascularisation of the chorionic villi and absence of the anti-D antigen in complete
moles, anti-D prophylaxis is not required. It is, however, required for partial moles. Confirmation of
the diagnosis of complete molar pregnancy may not occur for some time after evacuation and so
administration of anti-D could be delayed when required, within an appropriate timeframe.
Evidence
level 4
7.2 Is it safe to prepare the cervix prior to surgical evacuation?

Preparation of the cervix immediately prior to evacuation is safe.
In a casecontrol study of 219 patients there was no evidence that ripening of the cervix prior to
uterine evacuation was linked to a higher risk for needing chemotherapy. However, the study did
show a link with increasing uterine size and the subsequent need for chemotherapy.12
Evidence
level 2+
Prolonged cervical preparation, particularly with prostaglandins, should be avoided where possible
to reduce the risk of embolisation of trophoblastic cells.
Evidence
level 4
7.3 Can oxytocic infusions be used during surgical evacuation?

Excessive vaginal bleeding can be associated with molar pregnancy and a senior surgeon directly
supervising surgical evacuation is advised.
The use of oxytocic infusion prior to completion of the evacuation is not recommended.
P
P
If the woman is experiencing significant haemorrhage prior to evacuation, surgical evacuation should
be expedited and the need for oxytocin infusion weighed up against the risk of tumour embolisation.
Excessive vaginal bleeding can be associated with molar pregnancy. There is theoretical concern
over the routine use of potent oxytocic agents because of the potential to embolise and
disseminate trophoblastic tissue through the venous system. This is known to occur in normal
pregnancy, especially when uterine activity is increased, such as with accidental haemorrhage.13 The
contraction of the myometrium may force tissue into the venous spaces at the site of the placental
bed. The dissemination of this tissue may lead to the profound deterioration in the patient, with
embolic and metastatic disease occurring in the lung.To control life threatening bleeding oxytocic
infusions may be used.
8.
Evidence
level 3
Histological examination of the products of conception in the diagnosis of GTD
8.1 Should products of conception from all miscarriages be examined histologically?

The histological assessment of material obtained from the medical or surgical management of all failed
pregnancies is recommended to exclude trophoblastic neoplasia.
4 of 12
In view of the difficulty in making a diagnosis of a molar pregnancy before evacuation, it is

recommended that, in failed pregnancies, products of conception are examined histologically.14
As persistent trophoblastic neoplasia may develop after any pregnancy, it is recommended that
products of conception, obtained after all repeat evacuations, should also undergo histological
examination.
Ploidy status and immunohistochemistry staining for P57 may help in distinguishing partial from
complete moles.15
Evidence
level 4
Evidence
level 3
8.2 Should products of conception be sent for examination after surgical termination of pregnancy?
There is no need to routinely send products of conception for histological examination following
therapeutic termination of pregnancy, provided that fetal parts have been identified on prior ultrasound
examination.
Seckl et al. reviewed the risk of GTN developing after confirmed therapeutic termination.16 The rate
is estimated to be 1/20 000. However, the failure to diagnose of GTD at time of termination leads to
adverse outcomes with a significantly higher risk of life threatening complications, surgical
intervention, including hysterectomy and multi-agent chemotherapy.
Guidance from the RCOG recommends the use of ultrasound prior to termination of pregnancy to
exclude non-viable and molar pregnancies. There is no indication to send products of conception
from a terminated viable pregnancy routinely for histological examination.17
Evidence
level 3
Evidence
level 4
The Royal College of Pathologists recommends that specimens should not be routinely sent for
examination if fetal parts are visible.18
9.
How should persisting gynaecological symptoms after an evacuation for molar

pregnancy be managed?
Consultation with the relevant trophoblastic screening centre is recommended prior to second
evacuation.
There is no clinical indication for the routine use of second uterine evacuation in the management of molar
pregnancies.
If symptoms are persistent, evaluation of the patient with hCG estimation and ultrasound
examination is advised. Several case series have found that there may be a role for second
evacuation in selected cases when the hCG is less than 5000 units/litre.19,20,21
Evidence
level 2+
10. Which women should be investigated for persistent GTN after a non-molar pregnancy?
Any woman who develops persistent vaginal bleeding after a pregnancy event is at risk of having GTN.
A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after
a pregnancy event.
Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely.
Several case series have shown that vaginal bleeding is the most common presenting symptom of
GTN diagnosed after miscarriage, therapeutic termination of pregnancy or postpartum.22,23,24,25,26
The prognosis for women with GTN after non-molar pregnancies may be worse, in part owing to
delay in diagnosis or advanced disease, such as liver or CNS disease, at presentation.22,23,24,25,26
5 of 12
Evidence
level 2+
11. How is twin pregnancy of a fetus and coexistent molar pregnancy managed?
When there is diagnostic doubt about the possibility of a combined molar pregnancy with a viable
fetus, advice should be sought from the regional fetal medicine unit and the relevant trophoblastic
screening centre.
In the situation of a twin pregnancy where there is one viable fetus and the other pregnancy is molar,
the woman should be counselled about the increased risk of perinatal morbidity and outcome for GTN.
Prenatal invasive testing for fetal karyotype should be considered in cases where it is unclear if the
pregnancy is a complete mole with a coexisting normal twin or a partial mole. Prenatal invasive testing
for fetal karyotype should also be considered in cases of abnormal placenta, such as suspected
mesenchymal hyperplasia of the placenta.
The outcome for a normal pregnancy with a coexisting complete mole is poor, with approximately
a 25% chance of achieving a live birth. There is an increased risk of early fetal loss (40%) and
premature delivery (36%). The incidence of pre-eclampsia is variable, with rates as high as 20%
reported. However, in the large UK series, the incidence was only 4% and there were no maternal
deaths.27,28 In the same UK series, there was no increase in the risk of developing GTN after such a
twin pregnancy and outcome after chemotherapy was unaffected.27,28
Evidence
level 3
12. Which women should be registered at GTD screening centres?

All women diagnosed with GTD should be provided with written information about the condition and the
need for referral for follow-up to a trophoblastic screening centre should be explained.
Registration of women with GTD represents a minimum standard of care.
Women with the following diagnoses should be registered and require follow-up as determined by the
screening centre:
complete hydatidiform mole
partial hydatidiform mole
twin pregnancy with complete or partial hydatidiform mole
limited macroscopic or microscopic molar change suggesting possible partial or early complete molar change
choriocarcinoma
placental-site trophoblastic tumour
atypical placental site nodules: designated by nuclear atypia of trophoblast, areas of necrosis, calcification and
increased proliferation (as demonstrated by Ki67 immunoreactivity) within a placental site nodule.
Recent reports suggest that a proportion of atypical placental-site nodules may transform into placental-site
trophoblastic tumours so all women with this condition should be registered with the GTD screening service.
After registration, follow-up consists of serial estimation of hCG levels, either in blood or urine specimens.
In the UK, there exists an effective registration and treatment programme. The programme has
achieved impressive results, with high cure (98100%) and low (58%) chemotherapy rates.29
Evidence
level 3
Registration forms can be obtained from the listed screening centres or registration can be made online at
http://www.hmole-chorio.org.uk.
13. What is the optimum follow-up following a diagnosis of GTD?

Follow up after GTD is increasingly individualised.
If hCG has reverted to normal within 56 days of the pregnancy event then follow up will be for 6 months
from the date of uterine evacuation.
If hCG has not reverted to normal within 56 days of the pregnancy event then follow-up will be for 6
months from normalisation of the hCG level.
6 of 12
P
D
D
All women should notify the screening centre at the end of any future pregnancy, whatever the outcome
of the pregnancy. hCG levels are measured 6-8 weeks after the end of the pregnancy to exclude disease
recurrence.
Two large case series of just under 9000 cases have shown that, once hCG has normalised, the
possibility of GTN developing is very low.30,31 GTN can occur after any GTD event, even when
separated by a normal pregnancy.10
Evidence
level 3
14. What is the optimum treatment for GTN?

Women with GTN may be treated either with single-agent or multi-agent chemotherapy for GTN.
Treatment used is based on the FIGO 2000 scoring system for GTN following assessment at the
treatment centre.
The need for chemotherapy following a complete mole is 15% and 0.5 % after a partial mole. The
development of postpartum GTN requiring chemotherapy occurs at a rate of 1/50 000 births.11
Evidence
level 3
Women are assessed before chemotherapy using the FIGO 2000 scoring system (Table 1).32 Women with
scores 6 are at low risk and are treated with single-agent intramuscular methotrexate alternating daily with
folinic acid for 1 week followed by 6 rest days. Women with scores 7 are at high risk and are treated with
intravenous multi-agent chemotherapy, which includes combinations of methotrexate, dactinomycin,
etoposide, cyclophosphamide and vincristine. Treatment is continued, in all cases, until the hCG level has
returned to normal and then for a further 6 consecutive weeks.
The cure rate for women with a score 6 is almost 100%; the rate for women with a score 7 is
95%.11
Evidence
level 3
Placental site trophoblastic tumour is now recognised as a variant of gestational trophoblastic neoplasia. It
may be treated with surgery because it is less sensitive to chemotherapy.
15. When can women whose last pregnancy was a complete or partial hydatidiform molar
pregnancy try to conceive in the future and what is the outcome of subsequent
pregnancies?
Women should be advised not to conceive until their follow-up is complete.
Women who undergo chemotherapy are advised not to conceive for 1 year after completion of treatment.
The risk of a further molar pregnancy is low (1/80): more than 98% of women who become
pregnant following a molar pregnancy will not have a further molar pregnancy nor are they at
increased risk of obstetric complications. If a further molar pregnancy does occur, in 6880% of
cases it will be of the same histological type.33
Evidence
level 3
Table 1 FIGO Scoring system32

FIGO SCORING
Age (years)
< 40
40
Antecedent pregnancy
Mole
Abortion
Term
<4
4<7
7 < 13
Interval months from end of index pregnancy to treatment

Pretreatment serum hCG (iu/l)
Largest tumour size, including uterus (cm)
Site of metastases
< 10
103
< 104
104
< 105
13
105
<3
3<5
Lung
Spleen, kidney
Gastro-intestinal
Liver, brain
Number of metastases
14
58
>8
Previous failed chemotherapy
Single drug
2 or more drugs
7 of 12
In a study of 230 women who conceived within 12 months of completing chemotherapy, there was
an increased risk of miscarriage and higher rate of termination in women who received multi-agent
chemotherapy. The rate of congenital abnormality was low (1.8%), irrespective of the type of
chemotherapy used.34 The rate of stillbirth was elevated compared with the normal population
(18.6/1000 births).35
Evidence
level 3
16. What is the long-term outcome of women treated for GTN?

Women who receive chemotherapy for GTN are likely to have an earlier menopause.
Women with high-risk GTN who require multi-agent chemotherapy which includes etoposide should be
advised that they may be at increased risk of developing secondary cancers.
The age at menopause for women who receive single-agent chemotherapy is advanced by 1 year
and by 3 years if they receive multi-agent chemotherapy.36
An early study of 1377 women treated between 1958 and 1990 showed a 16.6 relative risk of
developing acute myeloid leukaemia.There was also a 4.6 relative risk for developing colon cancer,
3.4 relative risk for melanoma and 5.79 relative risk for breast cancer in women surviving for more
than 25 years.37 If combination chemotherapy is limited to less than 6 months there appears to be
no increased risk of secondary cancers.38
Evidence
level 3
17. What is safe contraception following a diagnosis of GTD and when should it be
commenced?
Women with GTD should be advised to use barrier methods of contraception until hCG levels revert to
normal.
Once hCG level have normalised, the combined oral contraceptive pill may be used. There is no evidence
as to whether single-agent progestogens have any effect on GTN.
If oral contraception has been started before the diagnosis of GTD was made, the woman can be advised
to remain on oral contraception but she should be advised that there is a potential but low increased
risk of developing GTN.
Intrauterine contraceptive devices should not be used until hCG levels are normal to reduce the risk of
uterine perforation.
Two randomised controlled trials using the combined oral contraceptive pill have demonstrated no
increased risk of developing GTN.39 A much larger UK case series reported a 1.19 relative risk for
developing GTN.8
Evidence
level 1+
18. Is hormone replacement therapy safe for women to use after GTD?
Hormone replacement therapy may be used safely once hCG levels have returned to normal.
There is no evidence of risk that the use of hormone replacement therapy affects the outcome of
GTN.
P
Evidence
level 4
19. Auditable outcomes

1. The proportion of women with GTN registered with the relevant screening centre. This would include:
complete hydatidiform mole
partial hydatidiform mole
twin pregnancy with complete or partial hydatidiform mole
limited macroscopic or microscopic molar change suggesting possible partial or early complete molar change
choriocarcinoma
8 of 12
placental site trophoblastic tumour

atypical placental site nodules.
2. The proportion of women with a histological diagnosis of molar pregnancy who have an ultrasound
diagnosis of molar pregnancy prior to uterine evacuation.
3. The proportion of women who undergo medical management for evacuation of products of conception
with an ultrasound diagnosis of molar pregnancy.
20. Screening centres

Trophoblastic Tumour Screening and Treatment Centre
Department of Medical Oncology
Charing Cross Hospital
Fulham Palace Road
London W6 8RF
Tel: +44 (20) 8846 1409
Fax: +44 (20) 8748 5665
Website: www.hmole-chorio.org.uk
Trophoblastic Screening and Treatment Centre
Weston Park Hospital
Whitham Road
Sheffield S10 2SJ
Tel: +44 (0) 114 226 5205
Fax: +44 (0) 114 226 5511
Website: www.chorio.group.shef.ac.uk/index.html
Hydatidiform Mole Follow-up (Scotland)
Department of Obstetrics and Gynaecology
Ninewells Hospital
Dundee DD1 9SY
Tel: +44 (0) 1382 632748
Fax: +44 (0) 1382 632096
9 of 12
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results from a cohort of 272 patients. J Clin Oncol
1997;15:263643.
24. Nugent D, Hassadia A, Everard J, Hancock BW,Tidy JA. Postpartum
choriocarcinoma: presentation, management and survival. J
Reprod Med 2006;51:81924.
25. Powles T,Young A, Sammit A, Stebbing J, Short D, Bower M, et al.
The significance of the time interval between antecedent
pregnancy and diagnosis of high risk gestational trophoblastic
tumours. Br J Cancer 2006;95:11457.
26. Ma Y, Xiang Y, Wan XR, Chen Y, Feng FZ, Lei CZ, et al.The
prognostic analysis of 123 post partum choriocarcinoma cases.
Int J Gynecol Cancer 2008;18:1097101.
27. Sebire NJ, Foskett M, Paradinas FJ, Fisher RA, Francis RJ, Short D,
et al. Outcome of twin pregnancies with complete hydatidi-form
mole and healthy co-twin. Lancet 2002;359:21656.
28. Wee L, Jauniaux E. Prenatal diagnosis and management of twin
pregnancies complicated by a co-existing molar pregnancy.
Prenat Diagn 2005;25:7726.
29. Hancock BW. Differences in management and treatment: a
critical appraisal. In: Hancock BW, Newlands ES, Berkowitz RS,
Cole LA, editors. Gestational Trophoblastic Disease. 3rd ed.
Disease; 2003 [www.isstd.org/isstd/book.html]. p. 44759.
30. Pisal N,Tidy J, Hancock B. Gestational trophoblastic disease: is
intensive follow up essential in all women? BJOG
2004;111:144951.
31. Sebire NJ, Foskett M, Short D, Savage P, Stewart W,Thomson M, et
al. Shortened duration of human chorionic gonadotrophin
surveillance following complete or partial hydatidiform mole:
evidence for revised protocol of a UK regional trophoblastic
disease unit. BJOG 2007;114:760-762.
32. International Federation of Obstetrics and Gynecology Oncology
Committee. FIGO staging for gestational trophoblastic neoplasia
2000. Int J Gynecol Obstet 2002;77:2857.
33. Sebire NJ, Fisher RA, Foskett M, Rees H, Seckl MJ, Newlands ES.
Risk of recurrent hydatidiform mole and subsequent pregnancy
outcome following complete or partial hydatidiform molar
pregnancy. BJOG 2003;110:226.
34. Blagden SP, Foskett MA, Fisher RA, Short D, Fuller S, Newlands ES,
Seckl MJ.The effect of early pregnancy following chemotherapy
on disease relapse and foetal outcome in women treated for
gestational trophoblastic tumours. Br J Cancer 2002;86: 2630.
35. Woolas RP, Bower M, Newlands ES, Seckl MJ, Short D, Holden L.
Influence of chemotherapy for gestational trophoblastic disease
on subsequent pregnancy outcome. Br J Obstet Gynaecol
1998;105:10325.
36. Seckl MJ, Rustin GJS. Late toxicity after therapy for gestational
trophoblastic tumours. In: Hancock BW, Newlands ES, Berkowitz
RS, Cole LA, editors. Gestational Trophoblastic Disease. 3rd ed.
Disease; 2003 [www.isstd.org/isstd/book.html]. p. 47084.
37. Rustin GJS, Newlands ES, Lutz JM, Holden L, Bagshawe KD,
Hiscox JG, et al. Combination but not single agent
chemotherapy for gestational trophoblastic tumours (GTT)
increases the incidence of seconds tumours. J Clin Oncol
1996;14:276973.
38. McNeish IA, Strickland S, Holden L, Rustin GJS, Foskett M, Seckl
MJ, et al. Low risk persistent gestational trophoblastic disease:
outcome following initial treatment with low dose methotrexate
and folinic acic 19922000. J Clin Oncol 2002;20:183844.
39. Costa HLFF, Doyle P. Influence of oral contraceptives in the
development of post molar trophoblastic neoplasia: a systematic
review. Gynecol Oncol 2006;100:57985.
APPENDIX
at www.rcog.org.uk/womens-health/clinical-guidance/development-rcog-green-top-guidelines-policies-andprocesses). These recommendations are not intended to dictate an exclusive course of management or
treatment. They must be evaluated with reference to individual patient needs, resources and limitations
unique to the institution and variations in local populations. It is hoped that this process of local
clinical uncertainty where further research may be indicated within the appropriate health services.

risk of bias
1+

low risk of bias

risk of bias

2+
3
4

case series

1++ or 1+
results; or
2++
2+
Good practice point
Expert opinion

population; or
11 of 12

development group
This Guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Mr John Tidy FRCOG, Sheffield, and Professor BW Hancock FRCP, Sheffield.
This guideline was peer-reviewed by:
Mr DI Fraser MRCOG, Norwich; Professor ERM Jauniaux MRCOG, London; Professor YSH Ngan FRCOG, Hong Kong;
Dr NJ Sebire MRCOG, London.
The Guideline Committee lead reviewers were P Hilton FRCOG, Newcastle upon Tyne, and S Leeson FRCOG, Bangor,
Wales.
The Guidelines review process will commence in 2013
DISCLAIMER
health services.
guidelines should be fully documented in the patients case notes at the time the relevant decision is taken. Once
adapted for local use, these guidelines are no longer representative of the RCOG.
12 of 12
Faculty of Sexual & Reproductive Healthcare

Statement
Venous Thromboembolism (VTE) and Hormonal Contraception
November 2014
Background
This statement updates and replaces the Royal College of Obstetricians and
Gynaecologists (RCOG) Green-top Guideline No. 40 on the same topic. It
summarises Faculty of Sexual and Reproductive Healthcare (FSRH)
recommendations and relevant information found within FSRH clinical
guidance.1-5
Hormonal contraceptives contain either a combination of estrogen and
progestogen (combined hormonal contraceptives (CHC)), or progestogen
alone (progestogen-only contraceptives). In the UK, the majority of combined
hormonal contraceptives contain the synthetic estrogen, ethinylestradiol. A
combined oral contraceptive (COC) product containing mestranol is also
available, with 50g of mestranol roughly equating to 35g of ethinylestradiol.
More recently, COC products have been introduced onto the market that
contain the naturally occurring human hormone, estradiol, either as estradiol
valerate or as estradiol hemihydrate.
Progestogens are often grouped according to the time they were first marketed
as constituents of COCs and may be referred to by generation.
Examples of progestogens according to their classified generation
Generation of progestogen
Examples of Progestogen
First generation
Norethisterone, norethisterone acetate
Second generation
Levonorgestrel
Third generation
Desogestrel, gestodene, norgestimate
Fourth generation
Drospirenone, dienogest, nomegestrol acetate
This summary document examines the VTE risk associated with hormonal
contraception and the relevant risk factors to consider when choosing a
combined hormonal contraceptive.
Risk of venous thromboembolism

The term venous thromboembolism (VTE) includes deep vein thrombosis (DVT),
pulmonary embolism, and cerebral venous sinus thrombosis. Most studies of
venous thrombosis and hormonal contraceptive use relate to DVT and
pulmonary embolism. The true background incidence of VTE in women of
reproductive age is difficult to quantify but recently published figures suggest it is
in the range of 2 per 10,000 women in 1 year.6
Concerns about the role of hormonal contraceptives in mediating thrombosis risk
are not new and have been ongoing since the introduction of hormonal
contraceptives in the 1960s. Non-randomized studies have consistently reported
an increased risk of VTE associated with combined hormonal contraceptive
use,7-19 suggesting that this effect is real.
What is the venous thromboembolism risk associated with different

combined hormonal contraceptives (pill, patch and vaginal ring)?
Combined oral contraception
Data10;18 suggest that COCs containing the third generation progestogens
gestodene or desogestrel are associated with an increased risk of venous
thromboemolism (VTE) when compared with those containing the second
generation progestogens levonorgestrel or norethisterone. The first publications
to show differences in VTE risk led to the UK pill scare in 1995 and a reduction in
oral contraceptive use with a corresponding increase in unintended
pregnancies.20;21
Since the publications in the 1990s, debate has continued about the effect of
newly introduced progestogens on VTE risk. Some studies have reported no
increased risk for fourth generation drospirenone-containing COCS;14,15;22 others
have demonstrated an increased risk along with other newer progestogens.12;13;23
The biological mechanism is not fully understood but different progestogens
appear to modify the thrombogenic effects of estrogen to different extents, for
example, acquired resistance to activated protein C is more pronounced during
use of COCs containing desogestrel than levonorgestrel.24 Although bias and
confounding cannot be excluded, the consistency of recent studies coupled
with evidence supporting biological plausibility suggests that this is a true effect.
In 2013 the European Medicines Agency (EMA) initiated a review of the risk of
VTE associated with use of CHC. This review concluded that there was good
evidence to suggest that the risk of VTE associated with different COCs was
influenced by progestogen type, with those containing levonorgestrel,

norethisterone or norgestimate having the lowest risk (5-7 per 10,000 women) and
those containing drospirenone, desogestrel or gestodene having the highest risk
(9-12 per 10,000 women).6 The risk of VTE with use of CHC was therefore reported
to range from 5-12 per 10,000 women years, compared with 2 per 10,000 nonusers. However the EMA noted that the benefits of CHC use generally
outweighed the risk of venous thrombosis, which is low overall and is lower than
the VTE risk associated with pregnancy and the postpartum period (29 per 10,
000 woman-years and 300400 per 10,000 woman-years, respectively).25 Despite
evidence of more favourable effects on lipid profiles and carbohydrate
metabolism, there is no evidence to suggest that the newer, less androgenic
progestogens are any safer in terms of arterial thrombosis risk than older
progestogens.26
A Cochrane review27 examined the findings of 26 studies and concluded that
the risk of VTE with use of 30-35g ethinylestradiol oral contraceptives was similar,
regardless of whether they contained gestodene, desogestrel, cyproterone
acetate or drospirenone, but that these oral contraceptives were associated
with a 50-80% increased risk than 30-35g ethinylestradiol oral contraceptives
containing levonorgestrel.
Newer synthetic hormones such as estradiol valerate, estradiol hemihydrate,
dienogest, and nomegestrol acetate are being incorporated into COC
products. Long-term safety data for these new formulations are not yet
available. Therefore, the risks and benefits of use must be assumed to be as for
other CHCs.28;29
Combined transdermal patch and vaginal ring
Long-term data on VTE risk with the combined ethinylestradiol and
norelgestromin transdermal patch are limited. Those studies comparing the risk
associated with transdermal patch use to oral contraceptives containing second
generation progestogens have reported mixed results. Some observational
studies of the transdermal patch have reported a similar level of venous
thromboembolism (VTE) risk30-32 to COCs containing second generation
progestogens, whereas other studies have suggested an increased risk.33-35
There is less available data for the vaginal ring which contains ethinylestradiol
and etonogestrel. A national registry-based study35, which sought to assess the
risk of VTE in users of non-oral contraceptives, reported that compared to nonusers use of the ring conferred a relative risk of 6.5 (95% CI 4.7-8.9) with a
corresponding incidence rate of 7.8 per 10,000 exposure years. A prospective
cohort study that examined the short and long-term cardiovascular risks
associated with use of the combined vaginal ring, and COC in new users from
the United States and five European countries, reported an incidence rate for
the vaginal ring of 8.3 per 10,000 woman-years.36
In 2014 the Medicines and Healthcare Regulatory Authority (MHRA) produced
updated advice for UK prescribers based on the EMAs estimates of VTE risk for

different products (see table 2).6 The advice suggested a risk of 6-12 per 10,000
women over a year for CHCs containing norelgestromin or etonogestrel.6
Table 2: Risk of venous thromboembolism (VTE) associated with non-use,
combined hormonal contraception (CHC) use over the course of 1 year
(adapted from
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/11
/news_detail_001969.jsp&mid=WC0b01ac058004d5c1)
Risk of VTE per 10,000 healthy women

over one year
Non contraceptive users and not
pregnant
levonorgestrel, norgestimate or
norethisterone
CHC containing etonogestrel (ring) or
norelgestromin (patch)
gestodene, desogestrel or
drospirenone
2
5-7
6-12
9-12
Cyproterone-containing combined oral contraceptives

Co-cyprindiol (brands in the UK include Dianette, Clairette, Cicafem and
Acnocin) is a product containing the anti-androgen cyproterone acetate 2mg
in combination with ethinylestradiol 35 micrograms. It is licensed for the
treatment of acne that has not responded to antibiotics and while it can be
used as a contraceptive, it should not be used solely for this purpose.
Observational studies have suggested that cyproterone containing COCs may
be associated with an increased risk of VTE compared with levonorgestrel
COCs.12;13;37 The VTE risk initially appeared to be four-fold higher than
levonorgestrel COCs38, which conferred the highest VTE risk of all COCs available
in the UK at that time. The Committee on Safety of Medicines (CSM) previously
advised that co-cyprindiol should be discontinued 3-4 months after the
complete resolution of symptoms.39
In 2008 the Medicines and Healthcare Products Regulatory Agency (MHRA) and
the Commission on Human Medicines (CHM formerly the CSM) endorsed this
advice but acknowledged that in women with severe hyperandrogenism
symptoms usually recur when treatment is stopped.40 The MHRA advised that for
these women co-cyprindiol could be continued until symptoms are judged
unlikely to recur and that in all women co-cyprindiol could be re-started at any
time if acne or hirsutism recurs on stopping treatment.40

Following reported deaths from VTE in women prescribed co-cyprindiol in France,
the EMAs Pharmacovigilance Risk Assessment Committee (PRAC) conducted an
evaluation of the risk of venous and arterial thromboembolism (VTE and ATE)
associated with use of cyproterone-containing products.41 A review of postmarketing data suggested that in some of the reported cases of death, women
had been using Dianette as well as CHCs. In 2013 the PRAC42 report concluded
that the incidence of VTE is 1.5 to 2 times higher in users of co-cyprindiol than in
users of levonorgestrel-containing COCs and that there may be similar risk to that
associated with desogestrel / gestodene / drospirenone-containing COCs41.
In response to the PRAC report, the MHRA issued updated advice for health
professionals in the UK42:
The benefits of co-cyprindiol outweigh the risks in women of reproductive

age for the treatment of:
o Skin conditions related to androgen sensitivity (for example, severe
acne with or without seborrhoea)
o Hirsutism
Co-cyprindiol provides effective contraception in these women. An
additional hormonal contraceptive should not be used in combination
with co-cyprindiol.
The need to continue treatment should be evaluated periodically by the
treating physician.
The risk of VTE is rare but this remains an important side effect, and
healthcare professionals should themselves be vigilant for signs and
counsel patients to remain vigilant for signs and symptoms.
Duration of use
The risk of VTE is highest in the four months following initiation of CHC43 or when
restarting after a break of at least one month. The risk then reduces over the next
year and remains stable thereafter.14;19;44-46 Although the risk is high in the first few
months of CHC use and then falls, it remains higher than in non-users.
B
Health professionals should be aware that compared to non-users, the risk

of VTE with use of CHC is approximately doubled but that the absolute risk
remains very low.
Health professionals prescribing CHCs should be guided by a womans

own personal preference, risk of VTE, any contraindications, possible noncontraceptive benefits, and experience with other contraceptive
formulations.
A personal history of VTE or having a known thrombogenic mutation

represents an unacceptable health risk to CHC use.
For women with a family history of VTE, a negative thrombophillia screen

does not necessarily exclude all thrombogenic mutations

C
A thrombophillia screen is not recommended routinely before prescribing

CHC
Do progestogen-only methods of contraception (pill, injectable, implant

and intrauterine system) increase the risk of VTE?
There are fewer data on VTE risk with progestogen-only methods of
contraception and, although a lack of evidence does not necessarily suggest an
absence of effect, data12;47 do not generally support an increased risk.
Data from a WHO study suggested that there was little or no increased risk of VTE
associated with use of oral or injectable progestogen-only methods.47 The odds
ratio for progestogen-only pill (POP) users was 1.74 (95% CI 0.76-3.99) and for
progestogen-only injectable users 2.19 (95% CI 0.66-7.26).47 More recently a casecontrol study48 reported a 3.6-fold (95% CI, 1.8- to 7.1-fold) increased risk of
venous thrombosis associated with use of the injectable compared with nonusers
of hormonal contraceptives. A meta-analysis of eight observational studies,
designed to investigate the risk of VTE associated with progestogen-only
methods, noted that from the small amount of available data the relative risk of
a VTE event for users of the progestogen-only injectable was increased
compared with non-users (2.67 (95% CI, 1.29 to 5.53).49 However, the studies
included in the analysis had small sample sizes and bias and confounding
cannot be excluded.
Norethisterone and norethisterone acetate have been shown to be partly
metabolised to ethinylestradiol.50;51 At an oral dose of 5mg a conversion ratio of
about 0.4+/-0.4 was found. This approximated to equate to an oral dose
equivalent of 4g of ethinylestradiol per 1mg of norethisterone, although the
authors noted that they could not rule out individual variations.51 While
therapeutic doses of norethisterone used for gynaecological treatment should
perhaps be prescribed with care in women with risk factors or contraindications
to estrogen, POPs in the UK only contain 350g of norethisterone, and therefore
this conversion is not likely to be clinically significant.
The progestogen-only injectable Noristerat contains norethisterone enanthate
(NET-EN). The degree of conversion to ethinylestradiol after intramuscular
injection (IM) of NET-EN is unknown. However, if the conversion rate is assumed to
be the same as for oral administration then levels similar to a combined oral
product would be expected during the first 4 weeks of use (personal
communication with Bayer Healthcare Pharmaceuticals). An open label oneway crossover pharmacokinetic study designed to assess the in vivo formation of
EE following administration of IM NET-EN is currently ongoing.
No statistically significant increased risk has been observed for the levonorgestrel
intrauterine system35;48 or the progestogen-only implant.35

There is no evidence to suggest that use of progestogen-only emergency
contraception is associated with an increased risk of VTE.
Progestogen-only methods of contraception do not appear to be

associated with an increased risk of venous thromboembolism.
What conditions increase the risk of VTE in women considering

hormonal contraception?
There is synergism between acquired risk factors associated with venous
thrombosis, such as, CHC use, antiphospholipid syndrome, pregnancy, surgery,
trauma, immobilisation, malignancy52 and high altitude53, and genetic factors,
such as, factor V Leiden mutation, prothombin 20210A, protein C or protein S
deficiency, and antithrombim III deficiency. The use of hormonal contraceptives,
in particular CHC, in women with such conditions may negatively affect the
balance of risk and therefore contraindicate the use of such methods.
The UK Medical Eligibility Criteria for Contraceptive Use (UKMEC) provides
consensus-based recommendations to allow health professionals and individuals
to select the most appropriate method of contraception, without imposing
unnecessary restrictions. On the balance of the available evidence and
consensus opinion of experts, conditions are assigned one of four categories for
each category of contraceptive method (see table 3).
Table 3: Definitions of UK Medical Eligibility Criteria categories for contraceptive
use54
UKMEC Category
Definition
1
2
3
A condition for which there is no restriction for the use of

the contraceptive method
A condition for which the advantages of using the
method generally outweigh the theoretical or proven
risks
A condition where the theoretical or proven risks usually
outweigh the advantages of using the method. The
provision of a method requires expert clinical judgement
and/or referral to a specialist contraceptive provider,
since use of the method is not usually recommended
unless other more appropriate methods are not
available or not acceptable.
A condition which represents an unacceptable health
risk if the method is used.
A clinical history should identify any conditions which fall within the categories 3
or 4 for use of hormonal contraception. Since progestogen-only methods do not
increase the risk of VTE most of the risk assessment relates to CHC use. UKMEC is
updated following each update of the World Health Organisation Medical
Eligibility Criteria (WHOMEC). Health professionals should refer to the current
version of UKMEC, available via the FSRH website www.fsrh.org
Summary of UKMEC categories relevant to VTE risk
CHC
POP
DMPA/NETEN
History of VTE
4
2
2
PO
Implant
2
LNG-IUS
Cu-IUD
Current VTE (on

anticoagulants)
Family history of
VTE in a first
degree relative
aged under 45
Family history of
VTE in a first
degree relative
aged 45 or over
Major surgery
with prolonged
immobilisation
Major surgery
without
prolonged
immobilisation
Minor surgery
without
immobilisation
Immobility
unrelated to
surgery (e.g.
wheelchair use,
debilitating
illness)
Known

thrombogenic
mutation
(Factor
V
Leiden,
Prothrombin
mutation,
Protein
S,
Protein C, and
Antithrombin
deficiencies)
BMI 3034kg/m2
BMI 35kg/m2
Smoking aged
< 35 years
3
2
1
1
1
1
1
1
1
1
1
1
Smoking less
than 15
cigarettes/day
aged >35years
Smoking > 15
cigarettes/day
aged >35years
Aged > 35 and

stopped
smoking < 1
year ago
Aged >35 and

stopped
smoking a year
or more ago
Postpartum
(non
breastfeeding)1
<21 days
21 days
WHOMEC55 and USMEC56 are more restrictive than UKMEC depending on whether there
are other risk factors
1

While the advantages of using the progestogen-only implant, injectable and
intrauterine methods generally outweigh the theoretical or proven risks in women
who are anticoagulated, the CEU would advise ensuring that coagulation has
been monitored recently. FSRH guidance57 advises that there is generally no
need to alter anticoagulant therapy if the woman is anticoagulated within the
target therapeutic range. A community setting for fitting implants and
intrauterine contraceptives is generally appropriate providing there are no other
risks, for example, severe vasovagal reaction. However, it is recommended that
an experienced clinician performs the procedure with careful attention to
haemostasis, and application of a pressure bandage following implant
procedures. Subcutaneous administration of the progestogen-only injectable
(Sayana-Press) can be considered as an alternative to IM injection, although
any advantage in terms of bleeding is currently unproven.
While women with reduced levels of naturally occurring anticoagulants (antithrombin III, Protein C or Protein S) factor V Leiden, or prothrombin gene
mutations (G20210A) are predisposed to VTE58 FSRH guidance1 does not
recommend the need for routine thrombophillia screening prior to use of CHC,
as a negative screen may not exclude all types of thrombophilia.
The United Kingdom Medical Eligibility Criteria for Contraceptive Use

provides
consensus-based
recommendations
for
the
use
of
contraception. A clinical history should be taken to identify any relevant
medical conditions which may influence contraceptive choice.
A thrombophillia screen is not recommended routinely before use of CHC
Summary
Although the relative risk of VTE does increase with CHC use, the absolute risk in
women of reproductive age is very low. Other hormonal contraceptives do not
appear to be associated with an increased risk of VTE, although more evidence
is required, particularly for high risk groups. Clinicians advising women on
hormonal contraceptive use should be able to convey the risk of VTE and
provide information on overall risks and benefits to help women judge the level
of risk that is acceptable to them.
10

References
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http://www.fsrh.org/pdfs/CEUGuidanceCombinedHormonalContraceptio
n.pdf.2(Accessed:30/10/14).
(2) Faculty of Sexual and Reproductive Health Care. Progestogen-only
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11

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(16) Parkin, L., Sharples, K., Hernandex RK, and Jick S. Risk of venous
thromboembolism in users of oral contraceptives containing drospirenone
or levonorgestrel: nested case-control study based on UK general
practice research database. BMJ 2011; 342: 1-7.
(17) Jick, H., Kaye, J. A., Vasilakis-Scaramozza, C., and Jick, S. S. Risk of venous
thromboembolism among users of third generation oral contraceptives
compared with users of oral contraceptives with levonorgestrel before
and after 1995: cohort and case-control analysis. British Medical Journal
2000; 321:1190-1195.
(18) Jick, H., Jick, S. S., Gwewich, K., and et al. Risk of idiopathic cardiovascular
death and non fatal venous thromboembolism in women using oral
contraceptives with differing progestogen components. Lancet 1995;
346:1589-1593.
(19) Bloemenkamp, K. W. M., Rosendaal, F. R., Helmerhorst, F. M., and et al.
Enhancement by Factor V Leiden mutation of risk of deep venous
12

thrombosis associated with oral contraceptives containing a third
generation progestogen. Lancet 1995; 346:1593-1596.
(20) Szarewski, A. and Mansour, D. The 'pill scare': the responses of authorities,
doctors and patients using oral contraception. [Review] [57 refs]. Human
Reproduction Update 1999; 5(6):627-632.
(21) Furedi, A. The public health implications of the 1995 'pill scare'.
Hum.Reprod.Update. 1999; 5(6):621-626.
(22) Dinger, J., Bardenheuer, K., and Heinemann, K. Cardiovascular and
general safety of a 24-day regimen of drospirenone-containing combined
oral contraceptives: Final results from the International Active Surveillance
Study of Women Taking Oral Contraceptives. Contraception 2014;
89(4):April.
(23) Stegeman, B. H., de, Bastos M., Rosendaal, F. R., van, Hylckama, V,
Helmerhorst, F. M., Stijnen, T., and Dekkers, O. M. Different combined oral
contraceptives and the risk of venous thrombosis: systematic review and
network meta-analysis. BMJ 2013; 347:f5298.
(24) Odlind, V., Milsom, I., Persson, I., and Victor, A. Can changes in sex
hormone binding globulin predict the risk of venous thromboembolism
with combined oral contraceptive pills? Acta Obstet Gynecol Scand
2002; 81(6):482-490.
(25) Reid, R. L., Westhoff, C., Mansour, D., de Vries, C., Verhaeghe, J.,
Boschitsch, E., Gompel, A., Birkhauser, M., Krepelka, P., Dulicek, P.,
Iversen.O-E., Khamoshina, M., Dezman, L. V., Fruzzetti, F., Szarewski, A.,
Wilken-Jensen, C., Seidman, D., Kaaja, R., and Shapiro, S. Oral
contraceptives and venous thromboembolism: Consensus opinion from
an international workshop. Journal of Family Planning and Reproductive
Healthcare 2010; 36(3):117-122.
(26) Lidegaard, O., Lokkegaard, E., Jensen, A., Skovlund, C. W., and Keiding, N.
Thrombotic stroke and myocardial infarction with hormonal
contraception. New England Journal of Medicine 2012; 366(24):2257-2266.
(27) de Bastos M., Stegeman BH, Rosendaal FR, Van Hylckama Vlieg,
Helmerhorst FM, and Stijnen T. Combined oral contraceptives: venous
thrombosis. Cochrane Database of Systematic Review 2014;(3):Art. No.:
CD010813. DOI: 10.1002/14651858.CD010813.pub2.
(28) Faculty of Sexual and Reproductive Health Care. The estradiol valerate /
dienogest combined pill, Qlaira. 2009. Available at:
http://www.fsrh.org/admin/uploads/CEU_Qlaira.pdf. (Accessed:
30/10/14).
13

(29) Faculty of Sexual and Reproductive Healthcare. Estradiol/Nomegestrol
Combined Pill, Zoely. 2013. Available at:
http://www.fsrh.org/pdfs/CEUstatementZoely.pdf. (Accessed: 30/10/14).
(30) Jick S.S, Kaye J.A, Russmann S, and Jick, H. Risk of nonfatal venous
thromboembolism in women using a contraceptive transdermal patch
and oral contraceptives containing norgestimate and 35ug of ethinyl
estradiol. Contraception 2006; 73:223-228.
(31) Jick, S. S., Hagberg, K. W., Hernandez, R. K., and Kaye, J. A. Postmarketing
study of ORTHO EVRA and levonorgestrel oral contraceptive containing
hormonal contraceptives with 30mcg of ethinylestradiol in relation to
nonfatal venous thromoembolism. Contraception 2010; 81:16-21.
(32) Jick, S., Kaye, J. A., Li, L., and Jick, H. Further results on the risk of nonfatal
venous thromboemolism in users of the contraceptive transdermal patch
compared to users of oral contraceptive containing norgestimate and
35ug of ethinyl estradiol. Contraception 2007; 76:4-7.
(33) Cole, J. A., Norman, H., Doherty, M., and Walker, A. M. Venous
Thromboembolism, Myocardial Infaction, and Stroke Among Transdermal
Contraceptive System Users. American Journal of Obstetrics and
Gynecology 2007; 109(2):339-346.
(34) Dore, D. D., Norman H., Loughlin, J., and Seeger, J. D. Extended casecontrol study results on thromboembolic outcomes among transdermal
contraceptive users. Contraception 2010; 81:408-413.
(35) Lidegaard O, Nielson L, Skovlund CW, and Lokkegaard E. Venous
thrombosis in users of non-oral hormonal contraception: follow-up study,
Denmark 2001-10. BMJ 2012; 344:e2990.
(36) Dinger, Jurgen MD, Mohner, Sabine PhD, and Heinemann, Klaas MD.
Cardiovascular Risk Associated With the Use of an EtonogestrelContaining Vaginal Ring. [Article]. Obstetrics & Gynecology 2013;
122(4):800-808.
with cyproterone or levonorgestrel contraceptives. Lancet 2001;
358(9291):1427-1429.
with cyproterone or levonorgestrel contraceptives. Lancet 27-10-2001;
358(9291):1427-1429.
Cyproterone acetate (Dianette): risk of venous thromboembolism (VTE).
Current Problems in Pharmacovigilance 2002; 28(October):9-10.
14

(40) Medicines Control Agency Committee on Safety of Medicines. Combined
hormonal contraceptives: venous thromboembolism - update. Drug
Safety Update 2008; 1(9):3-4.
(41) European Medicines Agency Pharmacovigillance Risk Assessment
Committee. Cyproterone and ethinylestradiol containing medicinal
products. 2013. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_doc
ument/cyproterone_ethinylestradiol_107i/Position_provided_by_CMDh/W
C500143778.pdf. (Accessed: 30/10/14).
Cyproterone acetate with ethinyloestradiol (co-cyprindiol) balance of
benefits and risks remains positive. Drug Safety Update 2013; 6(11):A3.
(43) Farley, T. M., Meirik, O., Chang, C. L., Marmot, M. G., and Poulter, N. R.
Effect of different progestagens in low oestrogen oral contraceptives on
venous thromboembolic disease. World Health Organization
Collaborative Study of Cardiovascular Disease and Steroid Hormone
Contraception. Lancet 1995; 346(8990):1582-1588.
(44) Farmer, R. D. T., Lawrenson, R. A., Todd, J. C., Williams, T. J., MacRae, K. D.,
Tyrer, F., and Leydon, G. M. A comparison of the risks of venous
thromboembolic disease in association with different combined oral
contraceptives. British Journal of Cinical Pharmacology 2000; 49:580-590.
(45) Suissa, S, Blais, L, Spitzer, W. O., Cusson, J, Lewis, M, and Heinemann, L. FirstTime Use of Newer Oral Contraceptives and the Risk of Venous
Thromboembolism. Contraception 1997; 56:141-146.
(46) Lidegaard, O., Edstrom, B., and Kreiner, S. Oral contraceptives and venous
thromboembolism: a five year national case-control study. Contraception
2002; 65(3):187-196.
(47) World Health Organization Collaborative Study of Cardiovascular Disease
and Steroid Hormone Contraception. Cardiovascular disease and use of
oral and injectable progestogen-only contraceptives and combined
injectable contraceptives. Contraception 1998; 57:315-324.
(48) van, Hylckama, V, Helmerhorst, F. M., and Rosendaal, F. R. The risk of deep
venous thrombosis associated with injectable depotmedroxyprogesterone acetate contraceptives or a levonorgestrel
intrauterine device. Arteriosclerosis, Thrombosis & Vascular Biology 2010;
30(11):2297-2300.
(49) Mantha, S., Karp, R., Raghavan, V., Terrin, N., Bauer, K. A., and Zwicker, J. I.
Assessing the risk of venous thromboembolic events in women taking
progestin-only contraception: a meta-analysis. [Review]. BMJ 2012;
345:e4944.
15

(50) Chu, M. C., Zhang, X., Gentzschein, E., Stanczyk, F. Z., and Lobo, R. A.
Formation of ethinyl estradiol in women during treatment with
norethindrone acetate. J Clin Endocrinol Metab 2007; 92(6):2205-2207.
(51) Kuhnz, W., Heuner, A., Humpel, M., Seifert, W., and Michaelis, K. In vivo
conversion of norethisterone and norethisterone acetate to ethinyl
etradiol in postmenopausal women. Contraception 1997; 56(6):379-385.
(52) Rosendaal, F. R. Venous thrombosis: a multicausal disease. Lancet 1993;
353:1167-1173.
(53) Hillebrandt D, Meijer H. Contraception and Period Control at Altitude:
Consensus Statement of the UIAA Medical Commission. Standard No 14.
2009.
(54) Faculty of Sexual and Reproductive Health Care. UK Medical Eligibility
Criteria for Contraceptive Use. (UKMEC 2009). Available at:
http://www.fsrh.org/admin/uploads/UKMEC2009.pdf. (Accessed:
30/10/14).
(55) World Health Organization. Medical Eligibility Criteria for Contraceptive
Use 4th Edition 2009. [4th Edition]. Geneva, Switzerland: WHO, 2009.
Available at:
http://www.who.int/reproductivehealth/publications/family_planning/978
9241563888/en/index.html. (Accessed: 30/10/14).
(56) Centre for Disease Control and Prevention. U.S. Medical Eligibility Criteria
for Contraceptive Use 2010. MMWR 2010; 59(RR4):1-85.
(57) Faculty of Sexual and Reproductive Healthcare. Contraceptive Choices
for Women with Cardiac Disease. 2014. Available at:
http://www.fsrh.org/pdfs/CEUGuidanceContraceptiveChoicesWomenCar
diacDisease.pdf. (Accessed: 30/10/14).
(58) Vandenbroucke, J. P., van der Meer, Felix, Helmerhorst, F M, and
Rosendaal, F R. Family history and risks of venous thromboembolism with
oral contraception. British Medical Journal 2001; 323:752.
COMMENTS AND FEEDBACK ON PUBLISHED GUIDANCE
All comments on published statements can be sent directly to the Faculty of
Sexual and Reproductive Healthcare (FSRH) at: [email protected]
FSRH are unable to respond individually to all feedback. However, FSRH will
review all comments and provide an anonymised summary of comments and
responses, which are reviewed by the Clinical Effectiveness Committee and any
necessary amendments made.
16
The InitialManagement of Chronic

Pelvic Pain
May 2012
The Initial Management of Chronic Pelvic Pain

This is the second edition of this guideline.The first edition was published in 2005 under the same title.
1.
Purpose and scope
The purpose of this guideline is to provide an evidence-based summary for the generalist to facilitate
appropriate investigation and management of women presenting for the first time with chronic pelvic
pain.
2.
Chronic pelvic pain can be defined as intermittent or constant pain in the lower abdomen or pelvis of a
woman of at least 6 months in duration,not occurring exclusively with menstruation or intercourse and not
associated with pregnancy. It is a symptom not a diagnosis. Chronic pelvic pain presents in primary care as
frequently as migraine or low-back pain1 and may significantly impact on a womans ability to function.2
Living with any chronic pain carries a heavy economic and social burden.Aiming for accurate diagnosis and
effective management from the first presentation may help to reduce the disruption of the womans life and
may avoid an endless succession of referrals,investigations and operations.This guideline provides an evidencebased framework for the initial assessment of women with chronic pelvic pain. It is intended for the general
gynaecologist but may be of use to the general practitioner in deciding when to refer and to whom.
3.
The Cochrane Library and the Cochrane Register of Controlled Trials were searched for relevant
randomised controlled trials, systematic reviews and meta-analyses.A search of Medline from 1966 to July
2011 was also carried out.The database was searched using the MeSH terms pelvic pain,dysmenorrhoea
and chronic disease including all sub-headings.This was combined with a keywords search using the
terms chronic pelvic pain and dysmenorrhoea.
The definitions of types of evidence used in this guideline are detailed in RCOG Clinical Governance
Advice No. 1ac.35 Where possible, recommendations are based on, and explicitly linked to, the evidence
that supports them although, unfortunately, little good-quality evidence exists.Areas lacking evidence are
highlighted and annotated as good practice points.
4.
What are the possible aetiological factors in the genesis of chronic pelvic pain?
There is frequently more than one component to chronic pelvic pain. Assessment should aim to identify
contributory factors rather than assign causality to a single pathology.
At the initial assessment, it may not be possible to identify confidently the cause of the pain.
Pain is,by definition,a sensory and emotional experience associated with actual or potential tissue damage
or described in those terms.6 The experience of pain will inevitably be affected by physical, psychological
and social factors.The woman is often aware of these influences but may choose not to discuss them,
fearing that her pain will be dismissed as psychological or that non-gynaecological symptoms will be
considered irrelevant.
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Careful scrutiny of the womans history and physical findings will frequently reveal factors that may be
contributing to the pain and can therefore be at least partially treated.Given the incomplete understanding
of the genesis of pelvic pain, it may be necessary to keep an open mind about the cause and consider
unusual diagnoses, such as hernias or retroperitoneal tumours, or consider causes which until recently
might have been dismissed as rarities, such as musculoskeletal pain. It is important not to leave the woman
with the feeling that nothing more can be done to help her.
4.1 Central and peripheral nervous system

Acute pain reflects fresh tissue damage and resolves as the tissues heal. In chronic pain, additional factors
come into play and pain may persist long after the original tissue injury or exist in the absence of any
such injury. Major changes are seen in both afferent and efferent nerve pathways in the central and
peripheral nervous systems.
Local factors, such as tumour necrosis factor alpha (TNF-) and chemokines, may change peripheral nerve
function and/or stimulate normally quiescent fibres, resulting in altered sensation over a wider area than
that originally affected.A persistent barrage of pain may lead to changes within the central nervous system,
which magnify the original signal.7
Descending information from the central nervous system,possibly influenced by previous experiences and
current circumstances, may modify pain perception and visceral function.Alteration in visceral sensation
and function, provoked by a variety of neurological factors, has been termed visceral hyperalgesia. Nerve
damage following surgery, trauma, inflammation, fibrosis or infection may play a part in this process.8,9
Pain as a result of changes in the nerve itself is termed neuropathic pain and is characteristically, but not
exclusively, burning, aching or shooting in nature.10
Possible contributory factors are separated out for the purposes of discussion but the problem must be
seen as a whole by both the woman and her doctor.
4.2 Endometriosis and adenomyosis

Pelvic pain which varies markedly over the menstrual cycle is likely to be attributable to a hormonally
driven condition such as endometriosis.
Pelvic pain which varies markedly over the menstrual cycle is likely to be attributable to a
hormonally driven condition such as endometriosis.The cardinal symptoms of dysmenorrhoea,
dyspareunia and chronic pelvic pain are said to be characteristic of endometriosis or
adenomyosis.11 In a prospective study of 90 women undergoing laparoscopy or laparotomy, the
combination of clinical examination and transvaginal ultrasound accurately identified ovarian
endometriosis but not peritoneal disease. Symptoms alone were a poor predictor of finding
endometriosis at surgery,12 but a causal association between the disease and severe dysmenorrhoea probably exists.13 In a recent casecontrol study comparing symptoms among 255
women undergoing hysterectomy,pain symptoms predicted a higher likelihood of adenomysosis
and fibroids rather than fibroids alone being found on histology.14 It is important that dysmenorrhoea in adolescents is not overlooked as adenomyosis and endometriosis certainly occurs in
the group.15
Evidence
level
2+ to 4
The existence of pelvic venous congestion as a cause of chronic pelvic pain remains controversial.A recent
systematic review of diagnosis and management of this condition found no valid diagnostic tests, although
ovarian suppression was effective in treating pelvic pain symptoms. In women suspected of having this
condition,both progestins and gonadotrophin-releasing hormone (GnRH) agonists were shown in randomised
controlled trials to effectively decrease pain during therapy, with GnRH agonists showing higher efficacy.16
3 of 16
Although many symptom complexes such as irritable bowel syndrome (IBS) and pain perception itself17
may vary a little with the menstrual cycle (with 50% of women experiencing a worsening of their
symptoms in association with their period18),strikingly cyclical pain is likely to be gynaecological in nature.
4.3 Adhesions
There is no evidence to support the division of fine adhesions in women with chronic pelvic pain.
Division of dense vascular adhesion should be considered as this is associated with pain relief.
Adhesions may be a cause of pain, particularly on organ distension or stretching. Dense vascular
adhesions may cause chronic pelvic pain. However, adhesions may be asymptomatic. Evidence
to demonstrate that adhesions cause pain or that laparoscopic division of adhesions relieves
pain is lacking. However, in a randomised controlled trial, 48 women with chronic pelvic pain
underwent laparotomy with or without division of adhesions. Although overall there was no
difference between the two groups, a subset analysis showed that division of dense, vascular
adhesions produced significant pain relief.19 In a 2003 study of 100 women,no difference in pain
scores was found between a group undergoing laparoscopic adhesiolysis and those having
laparoscopy alone.20

Evidence
level 1+
Adhesions may be caused by endometriosis, previous surgery or previous infection.Two distinct forms of
adhesive disease are recognised: residual ovary syndrome (a small amount of ovarian tissue inadvertently
left behind following oophorectomy which may become buried in adhesions) and trapped ovary syndrome
(in which a retained ovary becomes buried in dense adhesions post-hysterectomy). Removal of all ovarian
tissue or suppression using a GnRH analogue may relieve pain.
4.4 IBS and interstitial cystitis

Symptoms suggestive of IBS or interstitial cystitis are often present in women with chronic pelvic pain.
These conditions may be a primary cause of chronic pelvic pain, a component of chronic pelvic pain or a
secondary effect caused by efferent neurological dysfunction in the presence of chronic pain (see section
3.4).
In a study of 798 women attending a gynaecology clinic,50% of women referred because of pain
had symptoms suggestive of IBS compared with 28% of women attending ear, nose and throat
or dermatology clinics.21 In three observational studies of women with chronic pelvic pain
presenting to secondary care, 3884% had symptoms suggestive of interstitial cystitis.2224
Evidence
level 2+
4.5 Musculoskeletal
Musculoskeletal pain may be a primary source of pelvic pain or an additional component resulting from
postural changes.
Pain may arise from the joints in the pelvis or from damage to the muscles in the abdominal wall or pelvic
floor.Pelvic organ prolapse may also be a source of pain.25 Increasing interest is also being shown in trigger
points localised areas of deep tenderness in a tight band of muscle, the aetiology of which is not fully
understood. It may relate to chronic contraction of the muscle, with the stimulus coming from misalignment of the pelvis or a discrete pain such as endometriosis.The pain from a trigger point may then become
self-perpetuating.26,27 Clear evidence regarding diagnostic tests and therapeutic options is lacking.
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In a consecutive series of 26 women with laparoscopy-negative chronic pelvic pain undergoing

magnetic resonance imaging (MRI), 20 were found to have injuries to the levator ani. In a painfree control group undergoing MRI, none of the 20 nulliparous and two of the 32 multiparous
women had such injuries.28 Spasm of the muscles of the pelvic floor is proposed as a cause of
pelvic pain which can be reduced by botulinum toxin injections.29,30 A number of controlled and
non-controlled observational studies have demonstrated a high prevalence of primary or
secondary musculoskeletal abnormalities in women with chronic pelvic pain.3134
Evidence
level
1+ to 3
4.6 Nerve entrapment

Nerve entrapment in scar tissue, fascia or a narrow foramen may result in pain and dysfunction in the
distribution of that nerve.
The incidence of nerve entrapment (defined as highly localised, sharp, stabbing or aching pain,
exacerbated by particular movements, and persisting beyond 5 weeks or occurring after a painfree interval) after one Pfannenstiel incision is 3.7%.35,36
Evidence
level 3/4
4.7 Psychological and social issues

Enquiry should be made regarding psychological and social issues which commonly occur in association
with chronic pelvic pain; addressing these issues may be important in resolving symptoms.
Depression and sleep disorders are common in women with chronic pain. This may be a
consequence rather than a cause of their pain, but specific treatment may improve the womans
ability to function.37 Similarly,women with chronic pelvic pain tend to suppress their unwanted
thoughts and feelings either as a cause or consequence of their pain.38
Evidence
level
1+/3
The relationship between chronic pelvic pain and sexual or physical abuse is complex. Studies
are difficult to interpret because many have a retrospective design and are performed in
secondary care. In this secondary care population it appears that women with chronic pain in
general are more likely to report physical or sexual abuse as children than pain-free women.
Those who experience chronic pelvic pain specifically are more likely to report sexual abuse
than women with another chronic pain complaint.3942 However, using multiple regression
analysis, it appears that child sexual abuse may be a marker for continuing abuse and the
development of depression,anxiety or somatisation,which then predispose the individual to the
development or presentation of chronic pelvic pain.43,44 In a primary care population, 26% of
women reported child sexual abuse and 28% reported adult sexual abuse, but only those
reporting both were more likely to have increased pain symptoms (dysmenorrhoea,dyspareunia
or chronic pelvic pain) than women reporting no abuse.45 Interestingly, in a prospective study
of young adults who had been abused there was no increase in medically unexplained
symptoms (albeit the study subjects were only followed into their 20s) compared with those not
known to have been abused, but those who did have unexplained symptoms were more likely
to report their history of abuse.46
Evidence
level 3
In summary, it may be that, for some individuals, child sexual abuse may initiate a cascade of events or
reactions which make an individual more vulnerable to the development of chronic pelvic pain as an
adult. Women who continue to be abused are particularly at risk.
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5.
What should underline the initial assessment of chronic pelvic pain?
Adequate time should be allowed for the initial assessment of women with chronic pelvic pain. They
need to feel that they have been able to tell their story and that they have been listened to and believed.
Many women present because they want an explanation for their pain. Often they already have a theory
or a concern about the origin of the pain. These ideas should ideally be discussed in the initial consultation.

It has been shown that consultations which elicit the patients ideas will result in a better doctorpatient
relationship and improved concordance with investigation and treatment.47 Women with chronic pelvic
pain want their experience to be heard and validated and they want to receive personal care to help them
understand and manage their pain.4850
Particularly if they have had negative experiences previously, women may need to be encouraged to talk
about their symptoms and ideas, allowing them to influence and shape the doctorpatient relationship as
a partnership.In a study of 105 consecutive referrals to a university gynaecology clinic,a favourable patient
rating at the initial consultation was associated with complete recovery at follow-up.51
The multifactorial nature of chronic pelvic pain should be discussed and explored from the start. The aim
should be to develop a partnership between the clinician and the woman to plan a management
programme.
In the only study of its kind, 106 women with chronic pelvic pain were randomised to an
integrated approach or standard treatment,which involved exclusion of organic causes followed
by a laparoscopy. If the laparoscopy was negative, attention was then given to psychological
factors. In the integrated approach, equal attention was devoted to possible organic,
psychological, dietary and environmental causes of the pain. In this group, laparoscopy was not
routinely performed; a consultation with a physiotherapist was included and provocation tests
were performed.After 1 year, the integrated approach group reported significantly greater pain
relief than the standard treatment group.52
Evidence
level 1+
In a meta-analysis of pain management in a related condition involving over 3000 women, a

multidisciplinary approach to chronic back pain has been shown to be effective both in
reducing subjective pain measures and in improving work and social functioning.53 When an
interdisciplinary approach is adopted for the management of chronic pelvic pain, improvement
is seen only when all components of the programme are in place.54
Evidence
level
1+ to 3
In a study of 53 women with chronic pelvic pain undergoing weekly psychological and physiotherapy-based treatment in small groups over 10 weeks, significant and sustained improvement
was seen in pain scores,analgesia intake,use of health service resources and ability to work.Over
the course of treatment, women seemed to develop greater self-knowledge and to take more
responsibility for, and control over, their own health.55
Evidence
level 2+
Many women with chronic pelvic pain can be managed in primary care. General practitioners might
consider referral when the pain has not been explained to the womans satisfaction or when pain is
inadequately controlled.
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5.1 History
The initial history should include questions about the pattern of the pain and its association with other
problems, such as psychological, bladder and bowel symptoms, and the effect of movement and posture
on the pain.
Symptoms alone may be used to diagnose IBS positively in this group (see Appendix 1).

B
On taking the womans history, special note should be taken of any red flag symptoms (see Appendix 2)
which may need further investigation and referral to a specialist. If the situation allows, it may be helpful
to ask directly about past or present sexual assault, particularly intimate partner violence.The doctor must
be prepared to listen and accept these experiences as stated and know where to access specialist support.
Completing a daily pain diary for two to three menstrual cycles may help the woman and the doctor
identify provoking factors or temporal associations.The information may be useful in understanding the
cause of the pain.
It may be helpful to establish the womans level of function at the start of treatment (e.g. time off work,
avoiding activities), both to monitor progress and to emphasise the value of functional goals.Asking which
drugs have been used previously, and whether or not they helped, may be helpful both to aid diagnosis
and to plan effective management.
Symptom-based diagnostic criteria can be used with confidence to make the diagnosis of IBS
with a positive predictive value of 98%.56,57 Long-term follow-up of women in whom a positive
diagnosis of IBS is made suggests that the diagnosis is unlikely to be changed.58
Evidence
level
2++ to 4
A number of validated symptom-based tools are also available for the detection of psychological
comorbidity. However, simply enquiring generally about things at home and symptoms such as sleep or
appetite disturbance and tearfulness may be enough.
If the history suggests to the woman and doctor that there is a specific non-gynaecological component
to the pain, referral to the relevant healthcare professional such as gastroenterologist, urologist,
genitourinary medicine physician, physiotherapist, psychologist or psychosexual counsellor should
be considered, usually via the GP.
5.2 Examination
The examination is most usefully undertaken when there is time to explore the womans fears and
anxieties. The examiner should be prepared for new information to be revealed at this point.
The assessment should include abdominal and pelvic examination,looking particularly for focal tenderness,
enlargement, distortion or tethering, or prolapse. Highly localised trigger points may be identified in the
abdominal wall and/or pelvic floor. The sacroiliac joints or the symphysis pubis may also be tender,
suggestive of a musculoskeletal origin to the pain.
6.
What investigations should be undertaken?
6.1 Screening for infection

Suitable samples to screen for infection, particularly Chlamydia trachomatis and gonorrhoea, should be
taken if there is any suspicion of pelvic inflammatory disease (PID).
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All sexually active women with chronic pelvic pain should be offered screening for sexually transmitted
infections (STIs).
A positive endocervical sample supports but does not prove the diagnosis of PID.The absence
of a result positive for Chlamydia trachomatis or gonococcus does not rule out the diagnosis
of PID.59
Evidence
level 4
If PID is suspected clinically, this condition is best managed in conjunction with a genitourinary
medicine physician in order that up-to-date microbiological advice and contact tracing can be
arranged.Sexually active women with chronic pelvic pain should be offered screening for STIs.60
Evidence
level 4
6.2 Transvaginal scanning (TVS) and MRI

TVS is an appropriate investigation to identify and assess adnexal masses.
TVS and MRI are useful tests to diagnose adenomyosis.
The role of MRI in diagnosing small deposits of endometriosis is uncertain.
A systematic review of the value of TVS in the diagnosis of endometriosis found that endometriomas may be accurately distinguished from other adnexal masses.61

Evidence
level 2++
It is also useful in identifying structural abnormalities such as hydrosalpinges or fibroids, which may be
relevant even if not the cause of the pain.
TVS is of little value for the positive identification of other causes of chronic pelvic pain,
including peritoneal endometriosis.However,in a study of 120 consecutive women with chronic
pelvic pain undergoing TVS prior to laparoscopy, the presence of soft markers such as
tenderness or poor ovarian mobility improved the prelaparoscopy probability of identifying
relevant pathology at laparoscopy from 58% to 73% (likelihood ratio [LR] 1.9, 95% CI 1.23.1).
In the absence of soft markers, the prelaparoscopy likelihood of pathology fell to 20% (LR 0.18,
95% CI 0.090.34).TVS may therefore have a role in identifying those women who are less likely
to obtain a positive diagnosis from a diagnostic laparoscopy.62
Evidence
level 2+
The sensitivities of MRI and TVS for the diagnosis of adenomyosis are comparable in the best
hands. Sensitivities of 7078% and specificities of 8693% for MRI, with figures of 6568% and
6598% for TVS, were achieved in two prospective blinded studies of consecutive patients
undergoing hysterectomy and in a systematic review, using histopathology as the gold
standard.6366A systematic review of 14 trials examining the diagnostic accuracy of TVS for
diagnosing adenomyosis found a sensitivity of 82.5% and specificity of 84.6%.64
Evidence
level
1++/2++
While MRI lacks sensitivity in the detection of endometriotic deposits, it may be useful in the
assessment of palpable nodules in the pelvis or when symptoms suggest the presence of
rectovaginal disease.67 It may also reveal rare pathology.
Evidence
level 4
6.3 Diagnostic laparoscopy

Diagnostic laparoscopy has been regarded in the past as the gold standard in the diagnosis of chronic
pelvic pain. It may be better seen as a second-line investigation if other therapeutic interventions fail.
Diagnostic laparoscopy may have a role in developing the womans beliefs about her pain.
8 of 16
Diagnostic laparoscopy is the only test capable of reliably diagnosing peritoneal endometriosis
and adhesions. Gynaecologists have therefore seen it as an essential tool in the assessment of
women with chronic pelvic pain. However, it carries significant risks: an estimated risk of death
of approximately 1 in 10 000, and a risk of injury to bowel, bladder or blood vessel of approximately 2.4 in 1000, of whom two-thirds will require laparotomy.6870
Evidence
level 3/4
Clearly, conditions such as IBS and adenomyosis are not visible at laparoscopy, but there is also
a risk that some forms of endometriosis will be missed. Endometriosis is a disease with a large
variety of appearances and many authorities consider that it is significantly underdiagnosed at
laparoscopy.Some recommend that all suspicious areas should be biopsied.It is well known that
the existing scoring systems do not correlate with severity of pain and that deeply infiltrating
endometriosis, which is strongly correlated with pain, may be misinterpreted as minimal
disease.71
Evidence
level 4
One-third to one-half of diagnostic laparoscopies will be negative and much of the pathology
identified is not necessarily the cause of pain.There may be adverse consequences of a negative
laparoscopy. Many women may feel disappointed that no diagnosis has been made.72 This set of
events may lead to disengagement with the medical process.49
Evidence
level 4
The risks and benefits of diagnostic laparoscopy and the possibility of negative findings should be
discussed before the decision is made to perform a laparoscopy. Perhaps it should be performed only
when the index of suspicion of adhesive disease or endometriosis requiring surgical intervention is high,
or when the patient has specific concerns which could be addressed by diagnostic laparoscopy such as
the existence of endometriosis or adhesions potentially affecting her fertility.
Microlaparoscopy orconscious pain mappinghas been proposed as an alternative to diagnostic
laparoscopy under general anaesthetic.Although the technique seems to provide an opportunity
to confirm particular lesions as the source of the patients pain, it has not been widely adopted,
and questions remain as to the acceptability, reproducibility and validity of this technique.73 In
a recent study of 43 women undergoing conscious pain mapping,39 had a successful procedure,
but in only seven was a different diagnosis or treatment suggested by the awake laparoscopy
compared with one performed under general anaesthetic.74
Evidence
level 2+/3
In a postal questionnaire study of 63 women following a diagnostic laparoscopy, their subsequent pain experience and quality of life were not affected by the result of the laparoscopy.75
Similarly, in a prospective study of 71 women undergoing laparoscopy for chronic pelvic pain,
women were interviewed before and after their operation.The only factor identified through
regression analysis which predicted an improvement in pain scores was a change in health
beliefs as a result of having a laparoscopy. This finding applied to women with positive or
negative findings at laparoscopy.76 Simply showing women a photograph of their pelvis does not
seem to affect their health beliefs or their pain outcome.77
Evidence
level
1+ to 3
6.4 CA125
Women reporting any of the following symptoms persistently or frequently (more than 12 times per
month) bloating, early satiety, pelvic pain or urinary urgency or frequency should have a serum CA125
measurement taken.Particularly in women over the age of 50 years,any new IBS symptoms should prompt
such action.78
9 of 16
7.
What therapeutic options are available?
Women with cyclical pain should be offered a therapeutic trial using hormonal treatment for a period of
36 months before having a diagnostic laparoscopy.
Women with IBS should be offered a trial with antispasmodics.
Women with IBS should be encouraged to amend their diet to attempt to control symptoms.
Women should be offered appropriate analgesia to control their pain even if no other therapeutic
manoeuvres are yet to be initiated. If pain is not adequately controlled, consideration should be given to
referral to a pain management team or a specialist pelvic pain clinic.
Ovarian suppression can be an effective treatment for cyclical pain associated with endometriosis. The effect can be achieved with the combined oral contraceptive, progestogens,
danazol or GnRH analogues, all of which are equally effective but have differing adverse effect
profiles.67,79 The levonorgestrel-releasing intrauterine system (Mirena; Bayer) could also be
considered, even in adolescents.80 Non-endometriosis-related cyclical pain also appears to be
well controlled by these treatments.8183
Evidence
level
1+ to 4
In a randomised controlled trial, 100 women with clinically suspected endometriosis received
either a GnRH analogue or placebo without a pretreatment laparoscopy. After 12 weeks, the
treatment group had significantly less pain than women taking placebo.84 This trial is the only
study in which the effectiveness of this treatment approach has been evaluated. However, there
is a growing consensus which supports this strategy.11,8486 An economic evaluation of the use
of GnRH analogues as empirical treatment for cyclical pain prior to laparoscopy demonstrated
improved patient and physician satisfaction at reduced cost.87
Evidence
level
1+ to 4
For further advice on the management of IBS, please see NICE clinical guideline 61.88
A systematic review has concluded that smooth-muscle relaxants such as mebeverine
hydrochloride are beneficial in the treatment of IBS where abdominal pain is a prominent
feature.The efficacy of bulking agents has not been established but they are commonly used.57,89
Evidence
level
1++/4
In a study of 200 women suffering from IBS using an exclusion diet, 36% were able to identify
one or more dietary components, the avoidance of which led to sustained improvement in
symptoms.The most commonly implicated foods were dairy products and grains.90
Evidence
level
3
Dietary manipulation may therefore be worth considering for an individual woman but evidence is lacking.
Regular non-steroidal anti-inflammatory drugs with or without paracetamol may be particularly useful in
this context. Compound analgesics such as co-dydramol may be appropriate. For the general gynaecologist
it is probably unwise to prescribe opioids for regular use in women with chronic pelvic pain.91 Adjuvant
treatments such as amitriptyline or gabapentin may be useful in the treatment of neuropathic pain.92 For
further information on the management of neuropathic pain, please see NICE clinical guideline 96.93 Nonpharmacological modalities such as transcutaneous nerve stimulation, acupuncture and other
complementary therapies may be helpful for some women. Dietary modification may also relieve pain.
Laparoscopic uterosacral nerve ablation (LUNA) is ineffective in the management of chronic pelvic
pain.94,95
10 of 16
Voluntary organisations such as Endometriosis UK can be an important source of information and support
for some patients. A list of such organisations is given in section 10. Self-management techniques as
suggested by the Department of Healths Expert Patient Initiative may also be of value to some women.
8.
Summary
Chronic pelvic pain is common, affecting perhaps one in six of the adult female population.96 Much
remains unclear about its aetiology, but chronic pelvic pain should be seen as a symptom with a number
of contributory factors rather than as a diagnosis in itself.As with all chronic pain it is important to consider
psychological and social factors as well as physical causes of pain. Many non-gynaecological conditions
such as nerve entrapment or IBS may be relevant.Women often present because they seek an explanation
for their pain.
The assessment process should allow enough time for the woman to be able to tell her story.This may be
therapeutic in itself.A pain diary may be helpful in tracking symptoms or activities associated with the pain.
Where pain is strikingly cyclical and no abnormality is palpable at vaginal examination, a therapeutic trial
of ovarian suppression may be more helpful than a diagnostic laparoscopy. Other conditions such as IBS
require specific treatment. Even if no explanation for the pain can be found initially, attempts should be
made to treat the pain empirically and to develop a management plan in partnership with the woman.
9.

What proportion of sexually active women with chronic pelvic pain are tested for STIs?
What proportion of women have an ultrasound scan performed prior to diagnostic laparoscopy?
What proportion of women with cyclical chronic pelvic pain are offered a therapeutic trial of
hormonal treatment for 36 months before having a diagnostic laparoscopy?
10. Organisations providing further information and/or support
Endometriosis UK [www.endometriosis-uk.org]
IBS Network [www.theibsnetwork.org]
Cystitis and Overactive Bladder foundation [www.cobfoundation.org]
Womens Health [www.womens-health.co.uk] or [womenshealth.gov]
Pelvic Pain Support Network [www.pelvicpain.org.uk]
Department of Health Expert Patient Initiative [www.expertpatients.co.uk/]
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nice.org.uk/CG96/NICEguidance/pdf/English].
94. Daniels J, Gray R, Hills RK, Latthe P, Buckley L, Gupta J, et al.;
LUNA Trial Collaboration. Laparoscopic uterosacral nerve
ablation for alleviating chronic pelvic pain: a randomized
controlled trial. JAMA 2009;302:95561.
95. National Institute for Health and Clinical Excellence. Laparoscopic uterine nerve ablation (LUNA) for chronic pelvic pain.
Interventional procedure guidance 234. London: NICE; 2007
[http://www.nice.org.uk/guidance/IPG234/Guidance/pdf].
96. Zondervan KT,Yudkin PL,Vessey MP, Jenkinson CP, Dawes MG,
Barlow DH,et al. The community prevalence of chronic pelvic
pain in women and associated illness behaviour. Br J Gen
Pract 2001;51:5417.
APPENDIX 1: Rome III criteria for the diagnosis of IBS

Continuous or recurrent abdominal pain or discomfort on at least 3 days a month in the last 3 months,with
the onset at least 6 months previously, associated with at least two of the following:
improvement with defecation
onset associated with a change in frequency of stool
onset associated with a change in the form of stool.

Symptoms such as abdominal bloating and the passage of mucus are commonly present and are suggestive
of IBS. Extraintestinal symptoms such as lethargy, back ache, urinary frequency and dyspareunia may also
occur in association with IBS.
APPENDIX 2: Red flag symptoms and signs
Bleeding per rectum

New bowel symptoms over 50 years of age
New pain after the menopause
Pelvic mass
Suicidal ideation
Excessive weight loss
Irregular vaginal bleeding over 40 years of age
Postcoital bleeding
14 of 16
APPENDIX 3
1+

low risk of bias

risk of bias

2+
2-

is not causal

case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
15 of 16

development group
Gynaecologists by:
Ms SJ Moore MRCOG, Oxford and Mr SH Kennedy MRCOG, Oxford
and peer reviewed by: Dr U Krishnamoorthy, East Lancashire; College of Emergency Medicine; Consumers Forum;
Obstetric AnaesthetistsAssociation (OAA); Royal College of Midwives (RCM);Womens Health Pharmacist Group.
The Guidelines Committee lead reviewers were: Dr AJ Thomson MRCOG Paisley, Scotland and Dr KR Harding FRCOG,
London.
DISCLAIMER
16 of 16
Shoulder Dystocia

2nd Edition I March 2012
Shoulder Dystocia
This is the second edition of this guideline. The first edition was published in 2005 under the same title.
1.
Background
Shoulder dystocia is defined as a vaginal cephalic delivery that requires additional obstetric manoeuvres to
deliver the fetus after the head has delivered and gentle traction has failed.1 An objective diagnosis of a
prolongation of head-to-body delivery time of more than 60 seconds has also been proposed2,3 but these data
are not routinely collected. Shoulder dystocia occurs when either the anterior, or less commonly the posterior,
fetal shoulder impacts on the maternal symphysis, or sacral promontory, respectively.
There is a wide variation in the reported incidence of shoulder dystocia.4 Studies involving the
largest number of vaginal deliveries (34 800 to 267 228) report incidences between 0.58% and
0.70%.510
Evidence level
2+ and Evidence
level 3
There can be significant perinatal morbidity and mortality associated with the condition, even
when it is managed appropriately.7 Maternal morbidity is increased, particularly the incidence of
postpartum haemorrhage (11%) as well as third and fourth-degree perineal tears (3.8%). Their
incidences remain unchanged by the number or type of manoeuvres required to effect delivery.11,12
Evidence
level 2+
Brachial plexus injury (BPI) is one of the most important fetal complications of shoulder dystocia,
complicating 2.3% to 16% of such deliveries.7,11,13,14
Evidence level
2+ and Evidence
level 3
Most cases of BPI resolve without permanent disability, with fewer than 10% resulting in permanent
neurological dysfunction.15 In the UK and Ireland, the incidence of BPI was 0.43 per 1000 live
births.16 However, this may be an underestimate as the data were collected by paediatricians, and
some babies with early resolution of their BPI might have been missed.
Evidence
level 2+
There is evidence to suggest that where shoulder dystocia occurs, larger infants are more likely to
suffer a permanent BPI after shoulder dystocia.17,18
Evidence
level 4
A retrospective review of all BPIs in one American hospital reported an incidence of 1 in 1000 births, with a
permanent injury rate of 0.1 per 1000.19 Another review of 33 international studies reported an incidence of
BPI of 1.4 in 1000 births, with a permanent injury rate of 0.2 per 1000 births.20
Neonatal BPI is the most common cause for litigation related to shoulder dystocia and the third
most litigated obstetric-related complication in the UK.21
Evidence
level 3
The NHSLA (NHS Litigation Authority) has reported that 46% of the injuries were associated with
substandard care.21 However, they also emphasised that not all injuries are due to excess traction
by healthcare professionals, and there is a significant body of evidence suggesting that maternal
propulsive force may contribute to some of these injuries.22,23
Evidence
level 3
and 4
Moreover, a substantial minority of BPIs are not associated with clinically evident shoulder
dystocia.24,25 In one series, 4% of injuries occurred after a caesarean section,26 and in another series
12% of babies with a BPI were born after an uncomplicated caesarean section.27 When BPI is
discussed legally, it is important to determine whether the affected shoulder was anterior or
posterior at the time of delivery, because damage to the plexus of the posterior shoulder is
considered unlikely to be due to action by the healthcare professional.22
Evidence
level 4
2 of 18
2.
Purpose and scope
The purpose of this guideline is to review the current evidence regarding the possible prediction, prevention
and management of shoulder dystocia; it does not cover primary prevention of fetal macrosomia associated
with gestational diabetes mellitus. The guideline provides guidance for skills training for the management of
shoulder dystocia, but the practical manoeuvres are not described in detail. These can be found in standard
textbooks and course manuals such as PROMPT (PRactical Obstetric Multi-Professional Training),28 ALSO
(Advanced Life Support in Obstetrics),108 MOET (Managing Obstetric Emergencies and Trauma)61 and others.
3.
This RCOG guideline was revised in accordance with standard methodology for producing RCOG Green- top
Guidelines. A search was performed in the OVID database, which included Medline, Embase, the Cochrane
Database of Systematic Reviews, the Cochrane Control Register of Controlled Trials (CENTRAL), the Database
of Abstracts of Reviews and Effects (DARE), the ACP Journal Club, the National Guidelines Clearing House and
the Confidential Enquiry into Maternal and Child Health (CEMACH) reports. The search was restricted to
articles published between January 1980 and May 2011 and limited to humans and the English language.
Search terms included: shoulder dystocia, macrosomia, McRoberts manoeuvre, obstetric manoeuvres,
complications, labour/delivery, brachial plexus injury, Erbs palsy, Klumpkes palsy, symphysiotomy,
Zavanelli manoeuvre,skill drills,rehearsal of obstetric emergencies and medical simulation. Reference lists
of the articles identified were hand-searched for additional articles and some experts within the field were
contacted. Relevant key original papers published prior to 1980 were also obtained and are referenced within
this guideline.
Owing to the emergency nature of the condition, most published series examining procedures for the
management of shoulder dystocia are retrospective case series or case reports. Areas lacking evidence are
annotated as good practice points.
4.
Prediction
4.1 Can shoulder dystocia be predicted?

Clinicians should be aware of existing risk factors in labouring women and must always be alert to the
possibility of shoulder dystocia.
Risk assessments for the prediction of shoulder dystocia are insufficiently predictive to allow prevention
of the large majority of cases.
D
C
A number of antenatal and intrapartum characteristics have been reported to be associated with shoulder
dystocia (table 1), but statistical modelling has shown that these risk factors have a low positive predictive
value, both singly and in combination.29,30 Conventional risk factors predicted only 16% of shoulder dystocia
that resulted in infant morbidity.29 There is a relationship between fetal size and shoulder dystocia,13 but it is
not a good predictor: partly because fetal size is difficult to determine accurately, but also because the large
majority of infants with a birth weight of 4500g do not develop shoulder dystocia.31 Equally important, 48%
of births complicated by shoulder dystocia occur with infants who weigh less than 4000g.6
Infants of diabetic mothers have a two- to four-fold increased risk of shoulder dystocia compared
with infants of the same birth weight born to non-diabetic mothers.13,29
Evidence level
2+ and Evidence
level 3
A retrospective case-control study to develop a predictive model of risk for shoulder dystocia with injury was
published in 2006.33 The authors reported that the best combination of variables to identify neonatal injury
associated with shoulder dystocia were maternal height and weight, gestational age and parity and birthweight.
3 of 18
A score over 0.5 detected 50.7% of the shoulder dystocia cases with BPI, with a false positive rate of 2.7%.33
However, the statistical modelling for this prediction tool was based on actual birth weight and not estimated
fetal weight. Clinical fetal weight estimation is unreliable and third-trimester ultrasound scans have at least a 10%
margin for error for actual birth weight and a sensitivity of just 60% for macrosomia (over 4.5 kg).34,35 The use
of shoulder dystocia prediction models cannot therefore be recommended.9,35
Table 1. Factors associated with shoulder dystocia
Pre-labour
Intrapartum
Previous shoulder dystocia
Prolonged first stage of labour
Macrosomia >4.5kg
Secondary arrest
Diabetes mellitus
Prolonged second stage of labour
Maternal body mass index >30kg/m2
Oxytocin augmentation
Induction of labour
Assisted vaginal delivery
5.
Prevention of shoulder dystocia
5.1 Management of suspected fetal macrosomia

5.1.1 Does induction of labour prevent shoulder dystocia?
Induction of labour does not prevent shoulder dystocia in non-diabetic women with a suspected
macrosomic fetus.
Induction of labour at term can reduce the incidence of shoulder dystocia in women with gestational
diabetes.
There are a number of evidence-based reviews that have demonstrated that early induction of
labour for women with suspected fetal macrosomia, who do not have gestational diabetes, does not
improve either maternal or fetal outcome.36,37
Evidence
level 4
A systematic review and meta-analysis of randomised controlled trials of the effect of treatment in
women with gestational diabetes38 concluded that the incidence of shoulder dystocia is reduced
with early induction of labour.
Evidence
level 2+
The NICE diabetes guideline recommends that pregnant women with diabetes who have a normally grown
fetus should be offered elective birth through induction of labour, or by elective caesarean section if
indicated, after 38 completed weeks.39
5.1.2 Should elective caesarean section be recommended for suspected fetal macrosomia to prevent
brachial plexus injury (BPI)?
Elective caesarean section should be considered to reduce the potential morbidity for pregnancies
complicated by pre-existing or gestational diabetes, regardless of treatment, with an estimated fetal
weight of greater than 4.5 kg.
Infants of diabetic mothers have a two- to four-fold increased risk of shoulder dystocia compared
with infants of the same birth weight born to non-diabetic mothers.13,29 A decision-analysis model
estimated that in diabetic women with an EFW > 4.5kg, 443 caesarean sections would need to be
performed to prevent one permanent BPI. In comparison, 3695 caesarean sections would be
required to prevent one permanent BPI in the non-diabetic population.34
4 of 18
Evidence
level 3
Estimation of fetal weight is unreliable and the large majority of infants over 4.5kg do not
experience shoulder dystocia.32 In the USA, a decision-analysis model estimated that in non-diabetic
women with an EFW of >4kg, an additional 2345 caesarean deliveries would be required, at a cost
of US$4.9 million, to prevent one permanent injury from shoulder dystocia.34 However, there is
some difficulty in grouping all fetuses with an expected weight of >4.5 kg together: some fetuses
will be much larger than this.The American College of Obstetricians and Gynecologists (ACOG) has
recommended that an estimated fetal weight of over 5 kg should prompt consideration of delivery
by caesarean section,40 inaccuracy of methods of fetal size estimation notwithstanding.
Evidence
level 4
The National Institute for Health and Clinical Excellence states that ultrasound estimation of fetal
size for suspected large-for-gestational-age unborn babies should not be undertaken in a low-risk
population.41
5.2 What are the recommendations for future pregnancy?

What is the appropriate mode of delivery for the woman with a previous episode of shoulder dystocia?
Either caesarean section or vaginal delivery can be appropriate after a previous shoulder dystocia. The
decision should be made jointly by the woman and her carers.
The rate of shoulder dystocia in women who have had a previous shoulder dystocia has been
reported to be 10 times higher than the rate in the general population.42 There is a reported
recurrence rate of shoulder dystocia of between 1% and 25%.6,10,30,4246 However, this may be an
underestimate owing to selection bias, as caesarean section might have been advocated for
pregnancies after severe shoulder dystocia, particularly with a neonatal poor outcome.
Evidence
level 3
There is no requirement to recommend elective caesarean birth routinely but factors such as the
severity of any previous neonatal or maternal injury, predicted fetal size and maternal choice should
all be considered and discussed with the woman and her family when making plans for the next
delivery.
Evidence
level 4
6.
Management of shoulder dystocia
6.1 Preparation in labour: what measures should be taken when shoulder dystocia is anticipated?
All birth attendants should be aware of the methods for diagnosing shoulder dystocia and the
techniques required to facilitate delivery.
6.2 How is shoulder dystocia diagnosed?

Birth attendants should routinely look for the signs of shoulder dystocia.
Timely management of shoulder dystocia requires prompt recognition. The attendant health carer should
routinely observe for:
difficulty with delivery of the face and chin
the head remaining tightly applied to the vulva or even retracting (turtle-neck sign)
failure of restitution of the fetal head
failure of the shoulders to descend.

Routine traction in an axial direction can be used to diagnose shoulder dystocia but any other traction
should be avoided.
5 of 18
Routine traction is defined as that traction required for delivery of the shoulders in a normal vaginal delivery
where there is no difficulty with the shoulders.47 Axial traction is traction in line with the fetal spine i.e.
without lateral deviation.
Evidence from cadaver studies suggests that lateral and downward traction, and rapidly applied
traction,48 are more likely to cause nerve avulsion. In a Swedish series, downward traction on the
fetal head was strongly associated with obstetric BPI, and had been employed in all cases of residual
BPI at 18 months old.48 Therefore, downward traction on the fetal head should be avoided in the
management of all births.
Evidence
level 3
There is no evidence that the use of the McRoberts manoeuvre before delivery of the fetal head
prevents shoulder dystocia.49 Therefore, prophylactic McRoberts positioning before delivery of the
fetal head is not recommended to prevent shoulder dystocia.
6.3.1 How should shoulder dystocia be managed?
Shoulder dystocia should be managed systematically (see appendix 1).
Immediately after recognition of shoulder dystocia, additional help should be called.
The problem should be stated clearly as this is shoulder dystocia to the arriving team.
Fundal pressure should not be used.
McRoberts manoeuvre is a simple, rapid and effective intervention and should be performed first.
Suprapubic pressure should be used to improve the effectiveness of the McRoberts manoeuvre.
An episiotomy is not always necessary.
The Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) report on shoulder dystocia identified
that 47% of the babies that died did so within five minutes of the head being delivered; however, in a very
high proportion of cases, the fetus had a pathological cardiotocograph (CTG) prior to the shoulder dystocia.50
A group from Hong Kong have recently reported that in their series there was a very low rate of hypoxic
ischaemic injury if the head-to-body delivery time was less than five minutes.51 It is important, therefore, to
manage the problem as efficiently as possible to avoid hypoxic acidosis, and as carefully as possible to avoid
unnecessary trauma.
Managing shoulder dystocia according to the RCOG algorithm (see appendix 2) has been associated
with improved perinatal outcomes.14
Evidence
level 3
Help should be summoned immediately. In a hospital setting, this should include further midwifery
assistance, including the labour ward coordinator or an equivalent experienced midwife, an
experienced obstetrician, a neonatal resuscitation team and an anaesthetist.52
Evidence
level 4
Stating the problem early has been associated with improvements in outcomes in shoulder
dystocia53 and improved performance in other obstetric emergencies.54
Evidence
level 3
Maternal pushing should be discouraged, as this may exacerbate impaction of the shoulders.55
Fundal pressure should not be used during the management of shoulder dystocia.50 It is associated
with a high neonatal complication rate47 and may result in uterine rupture.31
6 of 18
Evidence
level 3
The McRoberts manoeuvre is flexion and abduction of the maternal hips, positioning the maternal
thighs on her abdomen.56 It straightens the lumbosacral angle, rotates the maternal pelvis towards
the mothers head and increases the relative anterior-posterior diameter of the pelvis.57 The
McRoberts manoeuvre is an effective intervention, with reported success rates as high as 90%.8,11,58,59
It has a low rate of complication and is one of the least invasive manoeuvres, and therefore, if
possible, should be employed first.
Evidence
level 2+
and
Evidence
level 3
The woman should be laid flat and any pillows should be removed from under her back. With one
assistant on either side, the womans legs should be hyperflexed. If the woman is in the lithotomy
position, her legs will need to be removed from the supports. Routine traction (the same degree of
traction applied during a normal delivery) in an axial direction should then be applied to the fetal
head to assess whether the shoulders have been released.
If the anterior shoulder is not released with the McRoberts position and routine axial traction,
another manoeuvre should be attempted.
Suprapubic pressure can be employed together with the McRoberts manoeuvre to improve
success rates.11 Suprapubic pressure reduces the fetal bisacromial diameter and rotates the anterior
fetal shoulder into the wider oblique pelvic diameter.The shoulder is then freed to slip underneath
the symphysis pubis with the aid of routine axial traction.58
Evidence
level 4
Suprapubic pressure should ideally be applied by an assistant from the side of the fetal back in a
downward and lateral direction just above the maternal symphysis pubis. This reduces the fetal
bisacromial diameter by pushing the posterior aspect of the anterior shoulder towards the fetal
chest. There is no clear difference in efficacy between continuous pressure and rocking
movement. Only routine traction should be applied to the fetal head when assessing whether the
manoeuvre has been successful. Again, if the anterior shoulder is not released with suprapubic
pressure and routine traction, then another manoeuvre should be attempted.
An episiotomy will not relieve the bony obstruction of shoulder dystocia but may be required to
allow the healthcare professional more space to facilitate internal vaginal manoeuvres. The use of
an episiotomy does not decrease the risk of BPI with shoulder dystocia.60
Evidence
level 3
An episiotomy should therefore only be considered if internal vaginal access of the healthcare
professionals whole hand cannot easily be achieved to facilitate manoeuvres such as delivery of
the posterior arm or internal rotation of the shoulders.61
Evidence
level 4
6.3.2 What measures should be undertaken if simple techniques fail?

Internal manoeuvres or all-fours position should be used if the McRoberts manoeuvre and suprapubic
pressure fail.
If simple measures (the McRoberts manoeuvre and suprapubic pressure) fail, then there is a choice to be
made between the all-fours position and internal manipulation.
Gaining access to the vagina for internal manoeuvres: the most spacious part of the pelvis is in the
sacral hollow; therefore vaginal access should be gained posteriorly, into the sacral hollow. The
whole hand should be entered posteriorly to perform internal rotation or delivery of the posterior
arm.62 The woman should be brought to the end of the bed, or the end of the bed should be
removed, to make vaginal access easier. Delivery can then be facilitated by rotation into an oblique
diameter or when possible by a full 180 degree rotation of the fetal trunk,63,64 or by delivery of the
posterior arm.65
7 of 18
Evidence
level 4
Internal rotational manoeuvres were originally described by Woods64 and Rubin.63 Rotation can be
most easily achieved by pressing on the anterior or posterior aspect of the posterior shoulder.
Pressure on the posterior aspect of the posterior shoulder has the additional benefit of reducing
the shoulder diameter by adducting the shoulders.63 The shoulders should be rotated into the wider
oblique diameter, resolving the shoulder dystocia. If pressure on the posterior shoulder is
unsuccessful, an attempt should be made to apply pressure on the posterior aspect of the anterior
shoulder to adduct and rotate the shoulders into the oblique diameter.
Evidence
level 4
Delivering the posterior arm reduces the diameter of the fetal shoulders by the width of the arm.
The fetal wrist should be grasped and the posterior arm should be gently withdrawn from the
vagina in a straight line.61 Delivery of the posterior arm is associated with humeral fractures with a
reported incidence between 2% and 12%7,14 but the neonatal trauma may be a reflection of the
refractory nature of the case, rather than the procedure itself.8
Evidence
level 3
There are no randomised comparative studies available comparing delivery of the posterior arm
and internal rotation. Some authors favour delivery of the posterior arm over other manoeuvres,59,66
particularly where the mother is large.67 Others have reported that rotational methods and
posterior arm delivery were similarly successful, but rotational manoeuvres were associated with
reductions in both BPI and humeral fractures68 compared to delivery of the posterior arm.
Therefore, healthcare professionals should base their decision on their training, clinical experience
and the prevailing circumstances.
Evidence
level 4
All-fours technique: the all-fours position has been described, with an 83% success rate in one
case series.69
Evidence
level 3
The individual circumstances should guide the healthcare professional as to whether to try the allfours technique before or after attempting internal rotation and delivery of the posterior arm. For a slim
mobile woman without epidural anaesthesia and with a single midwifery attendant, the all-fours
position is probably more appropriate, and clearly this may be a useful option in a community setting.
For a less mobile woman with epidural anaesthesia in place, internal manoeuvres are more appropriate.
Evidence
level 4
6.3.3 Persistent failure of first- and second-line manoeuvres: what measures should be taken if first- and
second-line manoeuvres fail?
Third-line manoeuvres should be considered very carefully to avoid unnecessary maternal morbidity
and mortality, particularly by inexperienced practitioners.
It is difficult to recommend an absolute time limit for the management of shoulder dystocia as there
are no conclusive data available, but there appears to be a very low rate of hypoxic ischaemic injury
up to five minutes.51
P
Evidence
level 3
Several third-line methods have been described for those cases resistant to all standard measures. These
include cleidotomy (surgical division of the clavicle or bending with a finger), symphysiotomy (dividing the
anterior fibres of symphyseal ligament) and the Zavanelli manoeuvre. It is rare that these are required.
Vaginal replacement of the head (Zavanelli manoeuvre), and then delivery by caesarean section has
been described70,71 but success rates vary.72 Intuitively, the Zavanelli manoeuvre may be most
appropriate for rare bilateral shoulder dystocia, where both the shoulders impact on the pelvic
inlet, anteriorly above the pubic symphysis and posteriorly on the sacral promontory.The maternal
safety of this procedure is unknown, however, and this should be borne in mind, knowing that a
high proportion of fetuses have irreversible hypoxia-acidosis by this stage, and it may not reduce
the risk of BPI.73
8 of 18
Evidence
level 4
Similarly, symphysiotomy has been suggested as a potentially useful procedure, both in the
developing74,75 and developed world.76 However, there is a high incidence of serious maternal
morbidity and poor neonatal outcome.77 Serious consideration should be given to these facts,
particularly where practitioners are not trained in the technique.
Evidence
level 4
Other techniques, including the use of a posterior axillary sling, have been recently reported but
there are few data available.78,79
6.4 What is the optimal management of the woman and baby after shoulder dystocia?
Birth attendants should be alert to the possibility of postpartum haemorrhage and severe perineal tears.
There is significant maternal morbidity associated with shoulder dystocia, particularly postpartum
haemorrhage (11%) and third and fourth degree perineal tears (3.8%).11 Other reported
complications include vaginal lacerations,80 cervical tears, bladder rupture, uterine rupture,
symphyseal separation, sacroiliac joint dislocation and lateral femoral cutaneous neuropathy.81,82
The baby should be examined for injury by a neonatal clinician.
P
Evidence
level 2+
and
Evidence
level 3
BPI is one of the most important complications of shoulder dystocia, complicating 2.3% to 16% of such
deliveries.7,11,13,14
Other reported fetal injuries associated with shoulder dystocia include fractures of the humerus
and clavicle, pneumothoraces and hypoxic brain damage.15,83,84
An explanation of the delivery should be given to the parents (see section 9).
7.
Evidence
level 3
Risk management
7.1 Training
7.1.1 What are the recommendations for training?
All maternity staff should participate in shoulder dystocia training at least annually. Grade D
The fifth CESDI report recommended that a high level of awareness and training for all birth
attendants should be observed.50 Annual skill drills, including shoulder dystocia, are recommended
jointly by both the Royal College of Midwives and the RCOG85 and are one of the requirements in
the Clinical Negligence Scheme for Trusts (CNST) maternity standards.86
Evidence
level 4
Where training has been associated with improvements in neonatal outcome, all staff received
annual training.14
Evidence
level 3
One study looked at retention of skill for up to one year following training using simulation. If staff
had the ability to manage a severe shoulder dystocia immediately following training, the ability to
deliver tended to be maintained at one year.87
Evidence
level 2-
7.1.2 What is the evidence for the effectiveness of shoulder dystocia training?
Practical shoulder dystocia training has been shown to improve knowledge,88 confidence89 and
management of simulated shoulder dystocia.9093 Training has also been shown to improve the actorpatients perception of their care during simulated shoulder dystocia.94
9 of 18
Evidence
level 1-
The effect of training on actual perinatal outcomes have been variable: an eight year retrospective
review of shoulder dystocia management before and after the introduction of annual shoulder
dystocia training for all staff in one UK hospital demonstrated a significant reduction in neonatal
injury at birth following shoulder dystocia (9.3% pre-training, 2.3% post-training).14 There are other
reports of improvements after training,53,95 although in one recent USA study95 there was increase
in the caesarean section rate - from a pre-training rate of 29.90% to a post-training rate of 40.14% which could account for at least some of the effect.
Evidence
level 3
However, training has also been associated with no change in outcome96 or even deterioration in
neonatal outcome;97 hospitals should therefore monitor the neonatal injury rate after the
introduction of training to ensure it is effective.
7.1.3 What measures can be taken to ensure optimal management of shoulder dystocia?
Manoeuvres should be demonstrated in direct view, as they are complex and difficult to understand by
description alone.
Higher fidelity training equipment should be used.
Practical training using mannequins has been associated with improvements in management in simulation9093
and in real life.14
The largest trial of shoulder dystocia training found that before training only 43% of midwives and doctors
could successfully manage a severe shoulder dystocia simulation within five minutes.91 Three weeks after a 40
minute simulation training session 83% of staff were able to successfully complete the delivery. Training on a
high fidelity mannequin was more successful than training with lower fidelity rag doll and pelvis with a
significantly higher successful delivery rate (95% versus 72%), a shorter head-to-body interval and a lower total
applied force successful delivery rate.91
Moreover, the traction used in simulated shoulder dystocia can be excessive98,99 but training using models with
force monitoring can reduce the traction used in simulated shoulder dystocia.98,100,101
Shoulder dystocia training associated with improvements in clinical management and neonatal outcomes was
multi-professional, with manoeuvres demonstrated and practiced on a high fidelity mannequin.14 Teaching
used the RCOG algorithm (see appendix 2) rather than staff being taught mnemonics (e.g. HELPERR) or
eponyms (e.g. Rubins and Woods screw).
7.2 Documentation
Documentation should be accurate and comprehensive. GPP
The sixth CESDI annual report highlighted inadequate documentation in obstetrics, with potential
medico-legal consequences.102 Poor documentation of shoulder dystocia management has been
highlighted103,104 and it has been suggested that documentation should be included in shoulder
dystocia training.103 The use of a structured pro forma has been suggested to improve accurate
record keeping in the clinical setting5 and there is some evidence that they are effective.106
Evidence
level 2+
An example is provided in appendix 3.

It is important to record within the birth record the:
time of delivery of the head and time of delivery of the body
anterior shoulder at the time of the dystocia
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manoeuvres performed, their timing and sequence

maternal perineal and vaginal examination
estimated blood loss
staff in attendance and the time they arrived
general condition of the baby (Apgar score)
umbilical cord blood acid-base measurements
neonatal assessment of the baby.104,106
It is particularly important to document the position of the fetal head at delivery as this facilitates
identification of the anterior and posterior shoulder during the delivery.
8.
9.

incident reporting of shoulder dystocia (CNST standard)
critical analysis of manoeuvres used in the management of shoulder dystocia
neonatal team called at diagnosis of shoulder dystocia
documentation of the event (see above)
performance of cord blood gas analysis
monitoring neonatal injury (BPI bony fractures) following shoulder dystocia
staff attendance at annual training
discussion of events with parents.
Support
An information leaflet for parents A difficult birth: what is shoulder dystocia? produced by the RCOG is
available online (http://www.rcog.org.uk/womens-health/clinical-guidance/difficult-birth-what-shoulderdystocia).
The Erbs Palsy Group (www.erbspalsygroup.co.uk) provides an excellent support network for children and
families affected by BPI.
References
1.
Resnick R. Management of shoulder dystocia girdle. Clin Obstet

Gynecol 1980;23:559-64.
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shoulder dystocia: a prospective evaluation. Am J Obstet
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of the obstetric nightmare. Clin Obstet Gynecol
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49. Poggi SH, Allen RH, Patel CR, Ghidini A, Pezzullo JC, Spong CY.
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52. Hope P, Breslin S, Lamont L, Lucas A, Martin D, Moore I, et al.
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53. Grobman WA, Miller D, Burke C, Hornbogen A,Tam K, Costello
R. Outcomes associated with introduction of a shoulder
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54. Siassakos D, Bristowe K, Draycott TJ, Angouri J, Hambly H,
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and relationship to team behaviours: a multisite cross-sectional
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55. Gonik B, Zhang N, Grimm MJ. Defining forces that are
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Allen LM, Allen RH. Episiotomy versus fetal manipulation in
managing severe shoulder dystocia: a comparison of outcomes.
61. Hinshaw K. Shoulder dystocia. In: Johanson R, Cox C, Grady K,
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62. Crofts JF, Fox R, Ellis D, Winter C, Hinshaw K, Draycott TJ.
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63. Rubin A. Management of shoulder dystocia. JAMA
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64. Woods CE, Westbury NYA. A principle of physics as applicable
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65. Barnum CG. Dystocia due to the shoulders. Am J Obstet
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66. Hoffman MK, Bailit JL, Branch DW, Burkman RT, Van Veldhusien
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67. Poggi SH, Spong CY, Allen RH. Prioritizing posterior arm
delivery during severe shoulder dystocia. Obstet Gynecol
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68. Leung TY, Stuart O, Suen SS, Sahota DS, Lau TK, Lao TT.
Comparison of perinatal outcomes of shoulder dystocia
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alleviated by different type and sequence of manoeuvres: a

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Bruner JP, Drummond SB, Meenan AL, Gaskin IM. All-fours
maneuver for reducing shoulder dystocia during labor. J
Reprod Med 1998;43:43943.
Sandberg EC.The Zavanelli maneuver: a potentially
revolutionary method for the resolution of shoulder dystocia.
Vaithilingam N, Davies D. Cephalic replacement for shoulder
dystocia: three cases. BJOG 2005;112:6745
Spellacy WN.The Zavanelli maneuver for fetal shoulder
dystocia.Three cases with poor outcomes. J Reprod Med
1995;40:5434.
Gherman RB, Ouzounian JG, Chauhan S. Posterior arm
shoulder dystocia alleviated by the Zavanelli maneuver. Am J
Perinatol 2010;27:74951.
Van Roosmalen J. Shoulder dystocia and symphysiotomy. Eur J
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Wykes CB, Johnston TA, Paterson-Brown S, Johanson RB.
Symphysiotomy: a lifesaving procedure. BJOG
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Goodwin TM, Banks E, Millar LK, Phelan JP. Catastrophic
shoulder dystocia and emergency symphysiotomy. Am J Obstet
Gynecol 1997;177:4634.
Gherman R. Posterior axillary sling traction: another empiric
technique for shoulder dystocia alleviation? Obstet Gynecol
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Hofmeyr GJ, Cluver CA. Posterior axilla sling traction for
intractable shoulder dystocia. BJOG 2009;116:181820.
Sheiner E, Levy A, Hershkovitz R, Hallak M, Hammel RD, Katz
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dystocia: a population-based study. Eur J Obstet Gynecol
Gherman RB. Shoulder dystocia: prevention and management.
Obstet Gynecol Clin North Am 2005;32:297305.
Heath T, Gherman RB. Symphyseal separation, sacroiliac joint
dislocation and transient lateral femoral cutaneous neuropathy
associated with McRoberts' maneuver. A case report. J Reprod
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Ouzounian JG, Korst LM, Phelan JP. Permanent Erb palsy: a
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Nocon JJ, McKenzie DK,Thomas LJ, Hansell RS. Shoulder
dystocia: an analysis of risks and obstetric maneuvers. Am J
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a Joint Working Party. London: RCOG Press; 1999.
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Management of shoulder dystocia: skill retention 6 and 12
months after training. Obstet Gynecol 2007;110:106974.
Crofts JF, Ellis D, Draycott TJ, Winter C, Hunt LP, Akande VA.
Change in knowledge of midwives and obstetricians following
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2007;114:1534-41.
Srensen JL, Lkkegaard E, Johansen M, Ringsted C, Kreiner S,
McAleer S.The implementation and evaluation of a mandatory
multi-professional obstetric skills training program. Acta Obstet
Goffman D, Heo H, Pardanani S, Merkatz IR, Bernstein PS.
Improving shoulder dystocia management among resident and
attending physicians using simulations. Am J Obstet Gynecol
2008;199:294.e15.
Crofts JF, Bartlett C, Ellis D, Hunt LP, Fox R, Draycott TJ.Training
for shoulder dystocia: a trial of simulation using low-fidelity and
high-fidelity mannequins. Obstet Gynecol 2006;108:147785.
92. Crofts JF, Attilakos G, Read M, Sibanda T, Draycott TJ. Shoulder

dystocia training using a new birth training mannequin. BJOG
2005;112:9979.
93. Deering S, Poggi S, Macedonia C, Gherman R, Satin AJ.
Improving resident competency in the management of
shoulder dystocia with simulation training. Obstet Gynecol
2004;103:12248.
94. Crofts JF, Bartlett C, Ellis D, Winter C, Donald F, Hunt LP,
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95. Inglis SR, Feier N, Chetiyaar JB, Naylor MH, Sumersille M,
Cervellione KL, Predanic M. Effects of shoulder dystocia
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96. Walsh JM, Kandamany N, Ni Shuibhne N, Power H, Murphy JF,
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97. MacKenzie IZ, Shah M, Lean K, Dutton S, Newdick H,Tucker
DE. Management of shoulder dystocia: trends in incidence and
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98. Crofts JF, Ellis D, James M, Hunt LP, Fox R, Draycott TJ. Pattern
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99. Deering SH, Weeks L, Benedetti T. Evaluation of force applied
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103. Deering S, Poggi S, Hodor J, Macedonia C, Satin AJ. Evaluation of
residents' delivery notes after a simulated shoulder dystocia.
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106. Crofts JF, Bartlett C, Ellis D, Fox R, Draycott TJ. Documentation
of simulated shoulder dystocia: accurate and complete? BJOG
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108. Advanced Life Support in Obstetrics (UK) [www.also.org.uk].
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APPENDIX 1
Figure 1. The McRoberts' manoeuvre (from the SaFE study)
Figure 2 Suprapubic pressure (from SaFE study)
Figure 3 Delivery of the posterior arm (from the SaFE study)
14 of 18
APPENDIX 2
15 of 18
APPENDIX 3
16 of 18
APPENDIX 4

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
17 of 18

development group
Dr J Crofts MRCOG, Bristol; Professor TJ Draycott MRCOG, Bristol; Dr I Montague FRCOG, Plymouth;
Ms C Winter, Midwife, Bristol; and Mr R Fox FRCOG, Taunton.
BMFMS; Consumers Forum; Erbs Palsy Group; RCM; Dr HM Cameron FRCOG, Sunderland;
Mr D I Fraser FRCOG, Norwich; Mr IZ MacKenzie FRCOG, Oxford; Mr KT Moriarty MRCOG, Wirral, Merseyside; and
Mr DJ Tuffnell FRCOG, Bradford.
The guidelines committee lead reviewers were: Dr R Ashe FRCOG, County Antrim, Northern Ireland and Mr M
Griffiths FRCOG, Luton.
Conflicts of interest; none declared.
The final version is the responsibility of the guidelines committee of the RCOG.
DISCLAIMER
health services.
18 of 18
Obstetric Cholestasis

April 2011
Obstetric Cholestasis
This is the second edition of this guideline.The first edition was published in 2006 under the same title.
1.
Purpose and scope
This guideline summarises the evidence for the fetal risks associated with obstetric cholestasis and provides
guidance on the different management choices and the options available for its treatment.The wide range
of definitions of obstetric cholestasis and the absence of agreed diagnostic criteria make comparisons of
the published literature challenging and limit the ability to provide detailed recommendations for specific
aspects of care.Areas of uncertainty are highlighted along with recommendations for future research in
this field.
2.
Background
In England, obstetric cholestasis (also referred to as intrahepatic cholestasis of pregnancy) affects 0.7% of
pregnancies in multiethnic populations1 and 1.21.5% of women of IndianAsian or PakistaniAsian
origin.2 Prevalence is influenced by genetic and environmental factors and varies between populations
worldwide. For example, in Chile, 2.4% of all pregnancies are affected, with a 5% prevalence in women of
AraucanianIndian origin.3
Obstetric cholestasis is a multifactorial condition of pregnancy characterised by pruritus in the absence
of a skin rash with abnormal liver function tests (LFTs), neither of which has an alternative cause and both
of which resolve after birth. Most authorities accept elevations of any of a wide range of LFTs beyond
pregnancy-specific limits.4 Investigations to exclude other causes of pruritus and of abnormal LFTs should
be performed.
The clinical importance of obstetric cholestasis lies in the potential fetal risks, which may include
spontaneous preterm birth, iatrogenic preterm birth and fetal death.There can also be maternal morbidity
in association with the intense pruritus and consequent sleep deprivation.
3.
Guidelines.Medline,Embase,the Cochrane library including the Cochrane Database of Systematic Reviews,
the Cochrane Control Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews and
Effects (DARE), the ACP Journal Club and Ovid database, including in-process and other non-indexed
citations, were searched using the relevant MeSH terms, including all subheadings, between 2003 and
January 2010.This was combined with a keyword search. Search words included cholestasis;intrahepatic,
cholestasis;ursodeoxycholic acid,s-adenosylmethionine,vitamin K,bile pigments,pruritus,bilirubin,
transminases, pregnancy complications, dexamethasone, congenital and neonatal diseases and
abnormalities;embryo and fetal development,developmental disabilities,newborn disease,prenatal
disorder,nervous system disorder,liver function tests,bile acids and salt and amniotransferase.The
search was limited to humans and the English language. Selection of articles for analysis and review was
then made based on relevance to the objectives.
The National Library for Health and the National Guidelines Clearing House were also searched for relevant
guidelines and reviews. Only one other guideline was identified.5
Where possible, recommendations are based on available evidence.The areas where evidence is lacking
are annotated as good practice points.
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4.
How is obstetric cholestasis diagnosed?
Obstetric cholestasis is diagnosed when otherwise unexplained pruritus occurs in

pregnancy and abnormal liver function tests (LFTs) and/or raised bile acids occur in
the pregnant woman and both resolve after delivery. Pruritus that involves the palms
and soles of the feet is particularly suggestive.
Pregnancy-specific reference ranges for LFTs should be used.
Other causes of itching and of liver dysfunction should be excluded.
Women with persistent pruritus and normal biochemistry should have LFTs repeated
every 12 weeks.
Postnatal resolution of pruritus and abnormal LFTs should be confirmed.
C
C
Pruritus in pregnancy is common, affecting 23% of pregnancies, of which a small proportion will have
obstetric cholestasis.1 The pruritus of obstetric cholestasis is typically worse at night, is often widespread
and may involve the palms of the hands and/or the soles of the feet.1 Other causes of pruritus must be
excluded.The skin should be inspected and care must be taken to differentiate dermatographia artefacta
(skin trauma from intense scratching),which may be seen in obstetric cholestasis,from other common skin
conditions such as eczema or atopic eruption of pregnancy (previously referred to as eczema of pregnancy,
prurigo and pruritic folliculitis).6,7 If a rash is present, polymorphic eruption of pregnancy or pemphigoid
gestations (blisters) should be considered.
Other evidence of cholestasis should be sought, including pale stool, dark urine and jaundice, and other
risk factors identified such as a personal or family history of obstetric cholestasis, multiple pregnancy,
carriage of hepatitis C and presence of gallstones.
In clinical practice, otherwise unexplained abnormalities in transaminases, gamma-glutamyl transferase
and/or bile salts are considered sufficient to support the diagnosis of obstetric cholestasis.The increase in
alkaline phosphatase in pregnancy is usually placental in origin and so does not normally reflect liver
disease. A thorough history and examination should be carried out, including a drug history, before
abnormal LFTs are determined to be otherwise unexplained. Bilirubin is raised only infrequently and most
women will have increased levels of one or more of the remaining LFTs.Although a wide variety of cutoff points have been used for defining abnormality in LFTs810 and bile salts, the upper limit of
pregnancy-specific ranges should be applied. For transaminases, gamma-glutamyl transferase and bilirubin,
the upper limit of normal throughout pregnancy is 20% lower than the non-pregnant range.4 Many laboratories will use pregnancy-specific ranges for bile salts, but this should not be assumed. Bile acid levels can
rise significantly after a meal, so while fasting might give lower values and help the diagnosis to be avoided
in a few women with otherwise normal LFT, in the majority of studies and in clinical practice random
levels are generally used. Some women will have pruritus for days or weeks before the development of
abnormal liver function: in those with persistent unexplained pruritus and normal biochemistry, LFTs
should be measured every 12 weeks.11 Isolated elevation of bile salts may occur but this is uncommon;
normal levels of bile salts do not exclude the diagnosis.8,10,1217
Other causes of pruritus and abnormal LFTs should be sought.This may include carrying out a viral screen
for hepatitis A, B, and C, Epstein Barr and cytomegalovirus, a liver autoimmune screen for chronic active
hepatitis and primary biliary cirrhosis (for example,anti-smooth muscle and antimitochondrial antibodies)
and liver ultrasound.810 Pre-eclampsia and acute fatty liver of pregnancy are pregnancy-specific causes of
abnormal LFTs that might form part of the differential diagnosis in atypical or early cases.
3 of 14
5.
How should obstetric cholestasis be monitored?
Once obstetric cholestasis is diagnosed, it is reasonable to measure LFTs weekly until

delivery.
Postnatally, LFTs should be deferred for at least 10 days.

D
Typically, transaminases will range from just above the upper limit of normal to several hundreds. Regular
LFTs, along with a general review, blood pressure measurement and urine check, allow monitoring of the
condition and exclusion of other diagnoses. If LFTs return to normal, obstetric cholestasis is not likely to
be the correct diagnosis. If LFTs escalate very rapidly, additional diagnoses need to be considered and the
frequency of monitoring increased: although this situation can be consistent with obstetric cholestasis, it
is not typical.A coagulation screen should be performed.
Postnatal resolution of symptoms and of biochemical abnormalities is required to secure the
diagnosis.810,13,14,16 In normal pregnancy, LFTs may increase in the first 10 days of the
puerperium.18 In a pregnancy complicated by obstetric cholestasis, routine measurement of
LFTs should be deferred beyond this time, and can usually be performed before to the postnatal
follow-up visit.
6.
What is the risk of stillbirth for pregnancies complicated by obstetric cholestasis?
In a hospital setting, the current additional risk of stillbirth in obstetric cholestasis

above that of the general population has not been determined but is likely to be small.
Stillbirth is the major concern for those involved in the management of obstetric cholestasis.
Perinatal mortality of six deaths from 56 cases (107/1000) was described from a single Australian
centre between 1965 and 1974.12 When the same hospital re-reported their results a decade
later, the perinatal mortality rate was lower, at 35/1000.15 When more recent studies are
considered,the perinatal mortality rate from obstetric cholestasis is 11/1000 (17 fetal or neonatal
deaths from all causes in 1538 pregnancies beyond 24 weeks of gestation and live births).810,15
17,1921
When only studies between 2001 and 2011 are considered, the perinatal mortality rate is
5.7/1000 (four deaths in 697 pregnancies).8,20,21 Where the data are unclear, neonatal deaths
have been assumed to occur in the first week of life; if this is an incorrect assumption, the
perinatal mortality rate is falsely elevated. It seems most likely that some of this fall in the
perinatal mortality rate is secondary to general improvements in obstetric and neonatal care
and in womens overall health and socio-economic status. The contributions of active
management, case selection (it is possible that more recent series include less severe cases) and
reporting bias are unknown.These rates are comparable to whole population figures over the
same time period: for England and Wales in 1980, the perinatal mortality rate was 13.4, 8.3 in
200222 and 5.4 in 2008.23 This fall should be balanced against the increase in case ascertainment
over this period of time, which may include milder forms of the disease.
7.
Evidence
level 3
Evidence
level 2+
What additional risks are associated with pregnancies complicated by obstetric

cholestasis?
Obstetricians should be aware (and should advise women) that the incidence of
premature birth, especially iatrogenic, is increased.
Women should be advised of the increased likelihood of meconium passage in

pregnancies affected by obstetric cholestasis.
4 of 14
Women with obstetric cholestasis should be booked in under consultant-led, teambased care and give birth in a hospital unit.
Obstetric cholestasis has been linked with an increased incidence of passage of meconium, premature
delivery, fetal distress, delivery by caesarean section and postpartum haemorrhage.The evidence comes
from six case series8,10,12,13,15,21 and six casecontrol studies,9,14,16,17,19,20 totalling 1621 pregnancies, which
have reported outcome in obstetric cholestasis pregnancies since 1965. All studies, except the earliest
two,12,14 practised some form of active surveillance and/or elective early delivery, so outcomes are a
reflection of both the disease process and its management. No studies stated how pregnancy was dated,
so gestational age may not have been accurately assessed.
Much of the prematurity (range 725%) is iatrogenic (the result of a medical decision to deliver
the baby rather than spontaneous onset of labour),8,1517 with the risk of spontaneous preterm
delivery being at most only slightly increased compared with the general population (range 4
12%).810,12,1517,19,20 Passage of meconium is more common in preterm obstetric cholestasis
pregnancies than in term obstetric cholestasis pregnancies (25% compared with 12%)8 and
preterm controls (18% compared with 3%),17 although not all studies show this.9 Meconium
passage may be more common in those with severe cholestasis (defined as bile acids over 40
micromoles/litre, 49 women) compared with mild cholestasis (bile acids under 20
micromoles/litre, 34 women) (10% compared with 0%, P = 0.02).21 These authors conclude that
risk of meconium passage increases linearly with a 19.7% increase for each 10 micromoles/litre
increase in total bile acid concentration (P = 0.001). In the study by Glantz et al., meconiumstained liquor was present in 44% of women with bile acids over 40 micromoles/litre (96
women).20
Evidence
level 2+
Caesarean section rates are high, ranging from 10% to 36%. It is difficult to establish the relative roles
played of obstetric cholestasis itself, of induction of labour/other obstetric indications and of
obstetrician/patient anxiety.
Despite physiological reasons (see section 9) and a high caesarean section rate, which might suggest an
increased risk of postpartum haemorrhage,evidence from current practice does not show this.Postpartum
haemorrhage is reported in only five case series, with rates ranging from 2% to 22%.8,10,12,13,21
8.
Can fetal death be predicted and prevented?
Poor outcome cannot currently be predicted by biochemical results and delivery

decisions should not be based on results alone.
No specific method of antenatal fetal monitoring for the prediction of fetal death can
be recommended.
Ultrasound and cardiotocography are not reliable methods for preventing fetal death
in obstetric cholestasis.
Continuous fetal monitoring in labour should be offered.
There is some evidence, mainly from in vitro work, that bile salts may play a role in fetal
demise.15,2428 However, in clinical practice it is unclear whether bile acid concentrations are
related to fetal outcome and, if so, whether total bile salt, differential bile salt or fetal bile salt
concentration is most relevant. High bile acid levels have been linked with fetal death,10,29
passage of meconium,20,21,29 abnormal cardiotocograph,2931 prematurity20,32 and non-fatal
asphyxial events.20,33 A study of 60 women studied retrospectively found that serum bile acids
5 of 14
Evidence
level 2+
and early gestation at onset of pruritus were independent predictors of preterm birth (OR 2.13,
95% CI 1.133.25 and OR 1.7, 95% CI 1.232.95, respectively).32 A large study20 of 937 women
with pruritus in pregnancy, of whom 505 had fasting bile acid concentrations 10
micromoles/litre and were diagnosed with obstetric cholestasis, demonstrated that fetal
compromise (preterm delivery, asphyxial events,meconium staining [see section 7] of amniotic
fluid and membranes) increased by 12% for each additional micromole/litre of bile acid
concentration; further statistical analysis suggested that, compared with control pregnancies,
these rates increased significantly at bile acid levels 40 micromoles/litre,which was defined as
four times the upper limit of normal in that laboratory.The management of the cases of obstetric
cholestasis analysed was at the discretion of the attending obstetrician, not subject to a uniform
protocol and not revealed.There remained one stillbirth in a twin pregnancy with bile acid
levels of 27 micromoles/litre.The authors in subsequent correspondence attribute this to a true
knot in the umbilical cord. There were two stillbirths in the group with bile acids over 40
micromoles/litre (one of a twin and one of a singleton). In a later paper by the same authors
describing an intervention arm of the study, there was a stillbirth in a woman with obstetric
cholestasis receiving placebo and with bile acids of 16 micromoles/litre.34 While these data are
interesting,this was not a randomised controlled trial and should not be used to dictate practice.
Other studies applying such cut-off values retrospectively have not shown differences in adverse
obstetric outcomes.21 The former study does not support full reassurance to a woman with
obstetric cholestasis and bile acids under 40 micromoles/litre, nor does it justify intervention
at bile acids over 40 micromoles/litre, or four times the laboratory upper limit of normal. It may
be that rates of fetal death are too low for a robust assessment of the relationship of this complication with bile acid levels.There are currently insufficient data available to inform decisions
about the best intervention to prevent fetal death, but a relationship with bile acid levels is
suspected and remains the focus of much research.
Evidence
level 2+
There are also conflicting data relating to prediction of fetal death and liver enzyme concentrations, with
one study reporting more fetal distress with high alanine aminotransferase35 and another showing no
correlation.12
Until the pathophysiology of obstetric cholestasis and fetal death is more clearly defined and the level of
risk is clarified, prediction and prevention of fetal death will remain challenging. Genetically inherited
abnormalities in bile acid transport proteins are the focus of much research.36,37 The proposed genetic
heterogeneity of the condition, differing genetic aetiology between individuals and populations and
sampling at earlier or later points in the disease process all complicate the interpretation of published
results within and between individuals and populations.
A continuing multicentre randomised controlled trial (ISRCTN37730443) that includes an early and a late
intervention (delivery) arm may help to define which fetuses are at risk from the disease and which are
at risk from our interventions.
A large number of techniques have been used to monitor fetuses in the hope that fetal death can be
predicted.These include cardiotocography,ultrasound,amniocentesis for presence of meconium or mature
lecithin sphingomyelin ratio,17 transcervical amnioscopy for identification of meconium after 36 weeks of
gestation17 and monitoring of fetal movement patterns by the pregnant woman. None has been subjected
to rigorous study.
In general, the lack of predictability of future fetal wellbeing of a normal cardiotocograph is a
major limitation of the use of this modality. Individual cases have been reported where routine
cardiotocography has detected preterminal patterns,15,16,19 which has allowed emergency
caesarean section to be performed. Many would consider amniocentesis to be too invasive in
the absence of robust evidence that the results obtained are useful. Maternal detection of
6 of 14
Evidence
level 3
movements is simple, inexpensive and not time consuming for women or staff, but its role in
monitoring pregnancy complicated by obstetric cholestasis has not been assessed.
Evidence
level 3
Fetal death is usually sudden. There is no evidence of placental insufficiency. Fetal growth
restriction and oligohydramnios are not features of the disease10,13,16,19,38 and umbilical artery
Doppler assessments are not different compared with those taken in other pregnancies.39
Evidence
level 2+
9.
Should women with obstetric cholestasis be offered elective early delivery?
A discussion should take place with women regarding induction of labour after 37+0
weeks of gestation.
Women should be informed of the increased risk of perinatal morbidity from early
intervention (after 37+0 weeks of gestation).
Women should be informed that the case for intervention (after 37+0 weeks of
gestation) may be stronger in those with more severe biochemical abnormality
(transaminases and bile acids).
Women should be informed of the increased risk of maternal morbidity from

intervention at 37+0 weeks of gestation.
Women should be informed of the inability to predict stillbirth if the pregnancy

continues.
Stillbirths in obstetric cholestasis have been reported across all gestations.As gestation advances, the risk
of delivery (prematurity, respiratory distress, failed induction) versus the uncertain fetal risk of continuing
the pregnancy (stillbirth) may justify offering women induction of labour after 37+0 weeks of pregnancy.
The decision should be made after careful counselling.The case for intervention at this gestation may be
stronger in those with more severe biochemical abnormality.
In over 1500 actively managed obstetric cholestasis pregnancies,most of which were diagnosed
before 37 weeks of gestation, 13 of 18 stillbirths occurred before 37 weeks of gestation and five
were at 3738 weeks of gestation.1217,19,20,22 The study reporting the highest incidence of
stillbirth was derived from a population of women contacting an obstetric cholestasis support
group and must be interpreted with this potential bias in mind.40 However, 227 women (352
pregnancies) suffered 20 deaths in singleton pregnancies, of which 18 were at over 37 weeks
of gestation, although only in two women was the diagnosis reached prior to the fetal death
occurring;in the others the diagnosis was made retrospectively either on blood tests taken after
the fetal death or when obstetric cholestasis occurred in a subsequent pregnancy (n=8).The
number of stillbirths rises with increasing gestation41 within antenatal populations,and whether
obstetric cholestasis represents an increase in excess of this is unclear.While it is certain that
delivery at 37 weeks of gestation will prevent a stillbirth beyond that gestation, it is not known
how high the risk of such a stillbirth might be.The widely adopted practice of offering delivery
at 37 weeks of gestation,42 or at diagnosis if this is after 37 weeks of gestation, is not evidence
based.Therefore,the iatrogenic consequences of elective delivery must be considered.In general
obstetrics, elective early delivery results in increased respiratory morbidity compared with later
delivery.The risk of admission to a special care baby unit following an elective caesarean section
is 711% at 37 weeks of gestation, 6% at 38 weeks of gestation and 1.5% at 39 weeks of
gestation.43,44 Data in obstetric cholestasis pregnancy suggest that the risks may be similar.8
7 of 14
Evidence
level 2++
10. What treatment, if any, should be used to treat obstetric cholestasis and what benefit
can be expected?
There is no evidence that any specific treatment improves fetal or neonatal outcomes.All such therapies
should be discussed with the individual woman with this in mind.
10.1 Topical emollients

Topical emollients are safe but their efficacy is unknown.
Bland topical options include Diprobase (Schering-Plough, Welwyn Garden City, UK), Balneum Plus
(Crookes Healthcare,Nottingham,UK),calamine lotion and aqueous cream with menthol.There are no trial
data to support or refute the use of these products.They are safe in pregnancy and clinical experience
suggests that for some women they may provide slight temporary relief of pruritus.
10.2 Systemic treatment

Systemic treatments aimed at relieving pruritus include colestyramine,a poorly tolerated bile acid-chelating
agent,which may improve pruritus in some women45 but may also exacerbate vitamin K deficiency (which
has been associated with fetal intracranial haemorrhage).46 Colestyramine has not been subjected to
randomised trials and is not in clinical use. Antihistamines such as chlorphenamine may provide some
welcome sedation at night but do not have a significant impact on pruritus.Activated charcoal47 and guar
gum48 do not relieve pruritus.
10.3 S-adenosyl methionine

There is insufficient evidence to demonstrate whether S-adenosyl methionine (SAMe)
is effective for either control of maternal symptoms or for improving fetal outcome,
and it is not recommended.
In human pregnancy, there have been four clinical studies comparing SAMe with placebo,
totalling only 86 patients;4952 meta-analysis is not possible.53 Three studies reported no difference
in pregnancy outcome and the effect on pruritus and LFTs was inconsistent. Its administration
as a twice-daily and usually intravenous infusion makes SAMe unacceptable in the UK to women
and to healthcare professionals.
Evidence
level 1+
10.4 Ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) improves pruritus and liver function in women with
obstetric cholestasis.
Women should be informed of the lack of robust data concerning protection against
stillbirth and safety to the fetus or neonate.
In obstetric cholestasis,the proposed mechanism of action of UDCA is displacement of more hydrophobic

endogenous bile salts from the bile acid pool. This may protect the hepatocyte membrane from the
damaging toxicity of bile salts, enhance bile acid clearance across the placenta from the fetus54 and protect
in vitro rat cardiomyocytes from damage by endogenous bile salts.55
There have been several small observational studies on the use of UDCA in pregnancy
complicated by obstetric cholestasis,5661 and four randomised controlled trials totalling 186
patients.36,52,62,63 In the largest, 47 of 130 women received UDCA; improvement in pruritus and
bile acid concentrations were observed only in those with bile acids over 40 micromoles/litre
(34 women).36 The remaining three randomised controlled trials, which randomised eight,62
8 of 14
Evidence
level 1+
eight63 and 1652 women to receive UDCA, suggested an improvement in pruritus, transaminases
and bile acids. In one study the placebo improved pruritus.62 Three randomised studies,totalling
78 patients,have compared SAMe with UDCA.52,61,64 These studies do not clarify the effectiveness
of these medications, as one study showed UDCA to be better, one showed SAMe to be better
and the third showed no difference.Meta-analysis of these studies has not been possible.53 UDCA
is a commonly prescribed agent in the UK for relief of pruritus in obstetric cholestasis;however,
its effect on fetal outcome remains to be determined. As the pathophysiology of obstetric
cholestasis and the mechanism of fetal demise are uncertain, the possible role of UDCA is
unclear. Further larger studies are required to determine this.
Evidence
level 1+
10.5 Dexamethasone
Dexamethasone should not be first-line therapy for treatment of obstetric cholestasis,
nor should it be used outside of a randomised controlled trial without a thorough
consultation with the woman.
There have been three observational reports on the use of dexamethasone (10 mg orally for 7
days and then stopping over 3 days) in 23 women for the treatment of obstetric cholestasis.6567
The results are conflicting, with some improvement in symptoms and biochemistry in some
women.The small numbers of women reported in these studies and the general concern about
adverse fetal and neonatal neurological effects of repeated courses of maternally administered
dexamethasone (as used for fetal lung maturation) limit the potential use of dexamethasone.68
11.
Evidence
level 3
What is the role of vitamin K?
A discussion should take place with the woman regarding the use of vitamin K.
Women should be advised that where the prothrombin time is prolonged, the use of
water-soluble vitamin K (menadiol sodium phosphate) in doses of 510 mg daily is
indicated.
Women should be advised that when prothrombin time is normal, water-soluble
vitamin K (menadiol sodium phosphate) in low doses should be used only after
careful counselling about the likely benefits but small theoretical risk.
As vitamin K is fat soluble, women with fat malabsorption especially biliary obstruction or
hepatic disease may become deficient in vitamin K. For oral administration to prevent vitamin
K deficiency in malabsorption syndromes, a water-soluble preparation (menadiol sodium
phosphate) must be used with a usual dose of 10 mg daily. However, the British National
Formulary advises avoiding therapy in late pregnancy and labour because of a risk of neonatal
haemolytic anaemia,hyperbilirubinaemia and kernicterus.69 Local difficulties with implementing
the previous version of this guideline in light of this advice has necessitated a revision in this
version of the guideline.The evidence for the advice in the British National Formulary appears
largely historical. The first of several case reports of kernicterus and haemolytic anaemia
following large doses of water-soluble vitamin K analogues given to premature babies (30 mg)
and parenterally to women in labour (72 mg) to prevent haemolytic disease of the newborn was
published in 1955.70 Little detail is available and the vitamin K and absorption status of the
mothers is not known. One author in the field concluded at the time that no toxic effect would
be anticipated following small adequate clinical doses (5 mg, or 12 mg to the newborn).71
9 of 14

D
Evidence
level 3
Although the data to support the antenatal use of vitamin K in obstetric cholestasis are sparse,
there are good physiological reasons why this treatment may be beneficial.Obstetric cholestasis
can result in reduced absorption of dietary fats owing to failure of excretion of bile salts into
the gastrointestinal tract and reduced micelle formation. Increased fat excretion in women with
obstetric cholestasis may be subclinical (but demonstrable on faecal fat assay) or clinically
apparent as steatorrhoea, and both have been reported to affect the absorption of fat-soluble
vitamins including vitamin K,72 which is required for the manufacture of coagulation factors
11,V11, 1X and X.Water-soluble vitamin K has been prescribed widely in the management of
obstetric cholestasis.The usual dose is 10 mg daily by mouth, aiming to improve both maternal
and neonatal levels, which are assumed to be deficient, and therefore reduce postpartum
haemorrhage and fetal or neonatal bleeding. Postnatal vitamin K must be offered to the babies
in the usual way. Prothrombin time is rarely reported but, in one series, four of 50 women (8%)
had abnormal times that were corrected by parenteral vitamin K (dose and frequency of
administration not stated).10 Kenyon et al.8 found that postpartum haemorrhage was more
common in those women who had not taken vitamin K compared with those who had (45%
compared with 12%).There have been no randomised controlled trials in this area.
Evidence
level 4
Data from pregnant women taking antiepileptic medications (who are at risk of vitamin K deficiency
because of liver enzyme induction) show greater levels of vitamin K in the offspring of those who took
oral supplements before delivery compared with the offspring of those who did not.73
12. What follow-up should be offered to women who have had a pregnancy affected by
obstetric cholestasis?
Women should be offered follow-up with a healthcare professional with the necessary
skills and expertise to provide appropriate counselling and to ensure that LFTs have
returned to normal.
As a minimum,healthcare practitioners must ensure that LFTs return to normal,pruritus resolves,all investigations carried out during the pregnancy have been reviewed and the mother has fully understood the
implications of obstetric cholestasis. The latter will include reassurance about the lack of long-term
sequelae for mother and baby and discussion of the high recurrence rate (4590%),74 contraceptive choices
(usually avoiding estrogen-containing methods) and the increased incidence of obstetric cholestasis in
family members. Local policy will dictate how this is best organised, but LFTs at 6 weeks after delivery and
an appointment at 8 weeks is a suggested model.Appropriate follow-up should be arranged by a medical
practitioner with appropriate skills.
Both the RCOG75 and The British Liver Trust76 have patient information leaflets on obstetric cholestasis.
There is also an Obstetric Cholestasis Patient Support Group (http://www.ocsupport.org.uk/).
13. Future research

There are many areas that require further investigation, in particular:
the pathophysiology of obstetric cholestasis

the mechanism of fetal death and improved detection of at-risk pregnancies
the magnitude of risk of fetal death and its prevention
the role of UDCA, its safety profile and whether it reduces the risk of fetal death.
drug therapies.
Well organised randomised controlled trials of available therapies and fetal surveillance schemes are
required.
10 of 14
A multicentre double-blind,randomised,controlled factorial design trial (PITCH:ISRCTN37730443) funded

by the NHS Research for Patient Benefit Programme is currently in its pilot phase in the UK.This trial will
compare UDCA with placebo and early with late delivery.The protocol is available from http://www.
biomedcentral.com/1471-2393/9/19.
Heparin, rifampicin and nor-UDCA are all currently under investigation for use in obstetric cholestasis. For
more information, visit http://www.britishlivertrust.org.uk/home/research/british-liver-trust-fundedresearch/ongoing-research.aspx.
Percentage of women with prolonged prothrombin time who are offered vitamin K.
Percentage of women receiving vitamin K.
Number of women with a case of diagnosed obstetric cholestasis.
Perinatal outcome of cases of obstetric cholestasis.
Gestational age at delivery.
Percentage of women receiving documentation of appropriate counselling.
Percentage of women with postnatal follow-up completed.
Percentage of women offered hospital follow-up.
Percentage of women with iatrogenic delivery for obstetric cholestasis at less than 37 weeks of
gestation.
Percentage of women receiving documentation of risks and benefits of UDCA.
Percentage of women with appropriate investigations performed before confirmation of diagnosis.
Documentation of appropriate counselling.
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41. Reddy UM, Ko CW,Willinger M. Maternal age and the risk of
stillbirth throughout pregnancy in the United States. Am J
42. Saleh MM,Abdo KR. Consensus on the management of
obstetric cholestasis: national UK survey. BJOG 2007;
114:99103.
43. Morrison JJ, Rennie JM, Milton PJ. Neonatal respiratory
morbidity and mode of delivery at term: influence of timing
of elective caesarean section. Br J Obstet Gynaecol
1995;102:1016.
44. Stuchfield P,Whitaker R, Russell I;Antenatal Steroids for Term
Elective Caesarean Section (ASTECS) Research Team.
Antenatal betamethasone and incidence of neonatal
respiratory distress after elective caesarean section:
pragmatic randomised trial. BMJ 2005;331:662.
45. Jenkins JK, Boothby LA.Treatment of itching associated with

intrahepatic cholestasis of pregnancy. Ann Pharmacother
2002;36:14625.
46. Sadler LC, Lane M, North R. Severe fetal intracranial
haemorrhage during treatment with cholestyramine for
intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol
1995;102:16970.
47. Kaaja RJ, Kontula KK, Rih A, Laatikainen T.Treatment of
cholestasis of pregnancy with peroral activated charcoal.A
preliminary study. Scand J Gastroenterol 1994;29:17881.
48. Riikonen S, Savonius H, Gylling H, Nikkil K,Tuomi AM,
Miettinen TA. Oral guar gum, a gel-forming dietary fiber
relieves pruritus in intrahepatic cholestasis of pregnancy.
49. Frezza M, Pozzato G, Chiesa L, Stramentinoli G, di Padova C.
Reversal of intrahepatic cholestasis of pregnancy in women
after high dose S-adenosyl-L-methionine administration.
Hepatology 1984;4:2748.
50. Frezza M, Centini G, Cammareri G, Le Grazie C, Di Padova C.
S-adenosylmethionine for the treatment of intrahepatic
cholestasis of pregnancy. Results of a controlled clinical trial.
Hepatogastroenterology 1990;37 Suppl 2:1225.
51. Ribalta J, Reyes H, Gonzalez MC, Iglesias J,Arrese M,
Poniachik J, et al. S-adenosyl-L-methionine in the treatment of
patients with intrahepatic cholestasis of pregnancy: a
randomized, double-blind, placebo-controlled study with
negative results. Hepatology 1991;13:10849.
52. Nicastri PL, Diaferia A,Tartagni M, Loizzi P, Fanelli N.A
randomised placebo-controlled trial of ursodeoxycholic acid
and S-adenosylmethionine in the treatment of intrahepatic
cholestasis of pregnancy. Br J Obstet Gynaecol
1998;105:12057.
53. Burrows RF, Clavisi O, Burrows E. Interventions for treating
cholestasis in pregnancy. Cochrane Database Syst Rev
2001;(4):CD000493.
54. Serrano MA, Brites D, Larena MG, Monte MJ, Bravo MP,
Oliviera N, et al. Beneficial effect of ursodeoxycholic acid on
alterations induced by cholestasis of pregnancy in bile acid
transport across the human placenta. J Hepatol
1998;28:82939.
55. Gorelik J, Shevchuk AI, Diakonov I, de Swiet M, Lab M,
Korchev Y, et al. Dexamethasone and ursodeoxycholic acid
protect against the arrhythmogenic effect of taurocholate in
an in vitro study of rat cardiomyocytes. BJOG 2003;110:
46774.
56. Floreani A, Paternoster D, Grella V, Sacco S, Gangemi M,
Chiaramonte M. Ursodeoxycholic acid in intrahepatic
cholestasis of pregnancy. Br J Obstet Gynaecol
1994;101:645.
57. Brites D, Rodrigues CM, Oliveira N, Cardoso MD Graa LM.
Correction of maternal serum bile acid profile during
ursodeoxycholic acid therapy in cholestasis of pregnancy.
J Hepatol 1998;28:918.
58. Palma J, Reyes H, Ribalta J, Iglesias J, Gonzalez MC, Hernandez
I, et al. Effects of ursodeoxycholic acid in patients with
intrahepatic cholestasis of pregnancy. Hepatology
1992;15:10437.
59. Davies MH, da Dilva RC, Jones SR,Weaver JB, Elias E. Fetal
mortality associated with cholestasis of pregnancy and the
potential benefit of therapy with ursodeoxycholic acid. Gut
1995;37:5804.
60. Mazzella G, Rizzo N,Azzaroli F, Simoni P, Bovicelli L, Miracolo
A, et al. Ursodeoxycholic acid administration in patients with
cholestasis of pregnancy: effects on primary bile acids in
babies and mothers. Hepatology 2001;33:5048.
61. Floreani A, Paternoster D, Melis A, Grella PV. S-adenosylmethionine versus ursodeoxycholic acid in the treatment of
intrahepatic cholestasis of pregnancy: preliminary results of
a controlled trial. Eur J Obstet Gynecol Reprod Biol
1996;67:10913.
62. Diaferia A, Nicastri PL,Tartagni M, Loizzi P, Iacovizzi C, Di Leo
A. Ursodeoxycholic acid therapy in pregnant women with
cholestasis. Int J Gynecol Obstet 1996;52:13340.
12 of 14
63. Palma J, Reyes H, Ribalta J, Hernndez I, Sandoval L,Almuna R,

et al. Ursodeoxycholic acid in the treatment of cholestasis of
pregnancy: a randomized, double-blind study controlled with
placebo. J Hepatol 1997;27:10228.
64. Roncaglia N, Locatelli A,Arreghini A,Assi F, Cameroni I,
Pezzullo JC, et al.A randomised controlled trial of
ursodeoxycholic acid and S-adenosyl-l-methionine in the
treatment of gestational cholestasis. BJOG 2004;111:1721.
65. Hirvioja M,Tuimala R,Vuori J.The treatment of intrahepatic
cholestasis of pregnancy by dexamethasone. Br J Obstet
Gynaecol 1992;99:10911.
66. Kretowicz E, McIntyre D. Intrahepatic cholestasis of
pregnancy, worsening after dexamethasone. Aust N Z J
67. Diac M, Kenyon A, Nelson-Piercy C, Girling J, Cheng F,Tribe
RM, et al. Dexamethasone in the treatment of obstetric
cholestasis: a case series. J Obstet Gynaecol 2006;26:1104.
68. Vidaeff AC, Mastrobattista JM. Controversies in the use of
antenatal steroids for fetal maturation. Semin Perinatol
2001;25:38596.
69. British Medical Association, Pharmaceutical Society of Great
Britain.Vitamin K. British National Formulary. London:
British Medical Association, Pharmaceutical Society of Great
Britain, 2010.
70. Finkel MJ.Vitamin K1 and the vitamin K analogues.

Clin Pharmacol Ther 1961;2:794814.
71. Wynn RM.The obstetric significance of factors affecting the
metabolism of bilirubin, with particular reference to the role
of vitamin K. Obstet Gynecol Surv 1963;18:33354.
72. Reyes H, Radrigan ME, Gonzalez MC, Latorre R, Ribalta J,
Segovia N, et al. Steatorrhea in patients with intrahepatic
cholestasis of pregnancy. Gastroenterology 1987;93:58490.
73. Cornelissen, M, Steegers-Theunissen R, Kolle L, Eskes T,
Motohara K, Monnens L. Supplementation of vitamin K in
pregnant women receiving anticonvulsant therapy prevents
neonatal vitamin K deficiency. Am J Obstet Gynecol
1993;168:8848.
74. Shaw D, Frohlich J,Wittmann BAK,Willms M.A prospective
study of 18 patients with cholestasis of pregnancy.
75. Royal College of Obstetricians and Gynaecologists. Obstetric
cholestasis (itching liver disorder): information for you.
London: RCOG; 2007 http://www.rcog.org.uk/
womens-health/clinical-guidance/obstetriccholestasis-itching-liver-disorder-information-you].
76. British Liver Trust. Obstetric cholestasis. Ringwood: British
Liver Trust; 2011 [http://www.britishlivertrust.org.uk/
home/the-liver/liver-diseases/obstetric-cholestasis.aspx].
Appendix
1+

low risk of bias

risk of bias

2+
2-

is not causal

case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
13 of 14

development group
Gynaecologists by:
Dr AP Kenyon MRCOG, London and Ms JC Girling FRCOG, Middlesex
and peer reviewed by: British Maternal and Fetal Medicine Society; British Liver Trust; Foundation for Liver Research; OC
Support UK;RCOG ConsumersForum;RCPCH;Dr JE Brennand FRCOG,Glasgow;Mr AJ Kelly MRCOG,Brighton;Professor
C Nelson-Piercy FRCOG,London;Dr MM Ramsay FRCOG,Nottingham;Dr AJThomson MRCOG,Paisley,Scotland;Professor
JG Thornton FRCOG, Nottingham; Mr SA Walkinshaw FRCOG, Liverpool; Professor C Williamson, Professor of Obstetric
Medicine, London.
Committee lead peer reviewers were: Mr Griffiths FRCOG, Luton and Dr Siddiqui FRCOG, Glasgow, Scotland.
DISCLAIMER
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Preterm Prelabour Rupture of

Membranes
November 2006 I Minor amendment October 2010
Preterm Prelabour Rupture of Membranes

This is the first edition of this guideline, which was reviewed in 2010 and has received minor amendments
to section 4 and section 5.
1.
Aim
The aim of this guideline is to make recommendations relating to the diagnosis, investigation and
management of preterm prelabour rupture of membranes (PPROM). The guideline evaluates various
antenatal tests in helping to predict the fetus at risk from intrauterine infection.The role of prophylactic
antibiotics, steroids and tocolytic agents and the optimum gestation to deliver women with pregnancies
complicated by PPROM is examined and recommendations are provided based on published evidence.
2.
Background
PPROM complicates only 2% of pregnancies but is associated with 40% of preterm deliveries and can
result in significant neonatal morbidity and mortality.13 The three causes of neonatal death associated with
PPROM are prematurity,sepsis and pulmonary hypoplasia.Women with intrauterine infection deliver earlier
than non-infected women and infants born with sepsis have a mortality four times higher than those
without sepsis.4 In addition, there are maternal risks associated with chorioamnionitis.
There is evidence demonstrating an association between ascending infection from the lower genital tract
and PPROM.In patients with PPROM,about one-third of pregnancies have positive amniotic fluid cultures5,6
and studies have shown that bacteria have the ability to cross intact membranes.7,8
3.
This guideline was developed using the standard methodology for producing RCOG Green-top Guidelines.
The Cochrane Library and Medline were searched for the following terms in the title or abstract:preterm
prelabour rupture of membranes,amnioinfusion,sealing amniotic membranes,intraamniotic infection,
Nitrazine,amniocentesis,antenatal corticosteroids and tocolytics. Previous guidelines on this subject
were obtained using the sites recommended in the RCOG Clinical Governance Advice No. 1c.9
The recommendations given in this guideline have been graded according to the guidance for the
development of RCOG Green-top Guidelines.
4.
How is the diagnosis of PPROM best achieved?
The diagnosis of spontaneous rupture of the membranes is best achieved by maternal

history followed by a sterile speculum examination.
Ultrasound examination is useful in some cases to help confirm the diagnosis.
The presence of a pool of fluid in the vagina at sterile speculum examimation is highly suggestive of
amniorrhexis.A range of tests have been used to confirm membrane rupture; the most widely used has
been the Nitrazine test, which detects pH change.10,11 Other tests which have been used include
microscopic examination of the vaginal fluid for the characteristic ferning of the crystalline pattern of
dried amniotic fluid owing to its sodium chloride and protein content,12,13 examination for lanugo hair12
and fetal epithelial cells stained with Nile blue.14
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A study evaluating the various tests in the diagnosis of membrane rupture examined 100
consecutive women in labour with either intact or ruptured membranes.15 The best results were
obtained with the Nitrazine and ferning tests,with a sensitivity of 90%.The false-positive rate was
17% for the Nitrazine test, owing to contamination with urine, blood or semen, and 6% for the
ferning test, owing to contamination with cervical mucus.A similar sensitivity and false-positive
rate was achieved by obtaining a history of rapid passage of fluid from the vagina. Ultrasound
examination demonstrating oligohydramnios is also used to help confirm the diagnosis of
spontaneous rupture of the membranes.1619 AmniSure (AmniSure International LLC, Boston,
MA, USA), a rapid immunoassay, has been shown to be accurate in the diagnosis of ruptured
membranes with a sensitivity and specificity of 98.9% and 100%, respectively.20
The diagnosis is made by a history suggestive of spontaneous rupture of membranes followed by
a sterile speculum examination demonstrating pooling of fluid in the posterior vaginal fornix; a
Nitrazine test is not necessary. Digital vaginal examination is best avoided unless there is a strong
suspicion that the woman may be in labour.This is because micro-organisms may be transported
from the vagina into the cervix leading to intrauterine infection,prostaglandin release and preterm
labour. Indeed, a retrospective study reported that the latency interval between spontaneous
rupture of membranes and delivery in those who had a digital vaginal examination was significantly shorter than if a sterile speculum examination only was performed.21
Evidence
level IIb
Evidence
level IIb
4.1 What antenatal tests should be performed?

Women should be observed for signs of clinical chorioamnionitis.

Weekly high vaginal swab need not be performed.

It is not necessary to carry out weekly maternal full blood count or C-reactive protein
because the sensitivity of these tests in the detection of intrauterine infection is low.
Cardiotogography is useful and indeed fetal tachycardia is used in the definition of
clinical chorioamnionitis. Biophysical profile score and Doppler velocimetry can be
carried out, but women should be informed that these tests are of limited value in
predicting fetal infection.

B
The criteria for the diagnosis of clinical chorioamnionitis include maternal pyrexia, tachycardia,
leucocytosis, uterine tenderness, offensive vaginal discharge and fetal tachycardia. During observation, the
woman should be regularly examined for such signs of intrauterine infection and an abnormal parameter
or a combination of them may indicate intrauterine infection.The frequency of maternal temperature,
pulse and fetal heart rate auscultation should be between every 4 and 8 hours.16,17,22
Maternal pyrexia, offensive vaginal discharge and fetal tachycardia indicate clinical chorioamnionitis. There is variation in the literature regarding the accuracy of the laboratory tests of
leucocytosis and raised C-reactive protein in the prediction of chorioamnionitis.The sensitivities
and false-positive rates for leucocytosis in the detection of clinical chorioamnionitis range from
29% to 47% and from 5% to 18%, respectively.16,22 The specificity of C-reactive protein is 38
55%.16,23,24 Although weekly culture of swabs from the vagina is often performed as part of the
clinical management of women with PPROM, the data evaluating this practice do not show
conclusively that it is beneficial. It has been shown that positive genital tract cultures predict
53% of positive amniotic fluid cultures with a false-positive rate of 25%.25
Evidence
level IIa
There have also been publications describing non-invasive antenatal fetal assessments with the aim of
differentiating fetuses that are not infected and will benefit from remaining in utero from those who are
3 of 12
at risk of infection or infected and need to be delivered. Several studies have examined the value of the
biophysical profile score,fetal tachycardia,non-reactive non-stress test and Doppler studies of the placental
and fetal circulation in the prediction of intrauterine infection. As with maternal assessment, there is a
wide range of true and false-positive results, which may partly be a consequence of the different endpoints
used for the diagnosis of intrauterine infection such as clinical chorioamnionitis, histological chorioamnionitis or positive amniotic fluid cultures.
Abnormal biophysical profile scores and increased systolic/diastolic ratios in the umbilical artery
have been shown to be markers of intrauterine infection.26 The true and false-positive rates for
an abnormal biophysical profile score in the prediction of clinical chorioamnionitis range from
30% to 80% and from 2% to 9%, respectively.2731 Another data set using positive amniotic fluid
and positive fetal blood cultures as endpoints for infection found that the biophysical profile
score or Doppler studies of the placental or fetal circulation did not provide accurate distinction
between infected and non-infected cases.18,32 Fetal tachycardia predicts 2040% of cases of
intrauterine infection with a false-positive rate of about 3%.16,18,33 Cardiotocography is useful
because a fetal tachycardia, if present, may represent a late sign of infection and is frequently
used in the clinical definition of chorioamnionitis in studies.
Evidence
level IIa
There are no randomised controlled trials to support the premise that pregnancy outcome is improved by
the use of frequent biophysical or Doppler assessment.The disparity in the literature evaluating these noninvasive tests of fetal wellbeing suggests that, although some studies have shown benefit, overall the tests
are of limited value in differentiating between fetuses with and without infection.
4.2 What is the role of amniocentesis?

Although there are data documenting an association between subclinical intrauterine
infection and adverse neonatal outcome, the role of amniocentesis in improving
outcome remains to be determined. There is insufficient evidence to recommend the
use of amniocentesis in the diagnosis of intrauterine infection.
Intrauterine infection, as defined by positive amniotic fluid cultures, is found in 36% of women
with PPROM.Most infections are subclinical without obvious signs of chorioamnionitis.5 Positive
amniotic fluid cultures increase the risks of preterm delivery,neonatal sepsis,respiratory distress
syndrome,chronic lung disease,periventricular leukomalacia, intraventricular haemorrhage and
cerebral palsy.3436
Evidence
level IIa
Current evidence suggests that infection is a cause rather than a consequence of amniorrhexis.37
Amniocentesis has the potential to detect subclinical infection before the onset of maternal
signs of chorioamnionitis and before the onset of fetal sepsis,allowing appropriate intervention
such as administration of antibiotics in infected cases and/or delivery depending on the
gestation, and expectant management for patients with negative amniotic fluid cultures. Rapid
tests on amniotic fluid such as Gram stain and assay of cytokines such as interleukins 6 and
18,36,38,39 which indicate intrauterine infection, may be performed.
Evidence
level IIa
Although prophylactic antibiotic therapy in cases of PPROM has been shown to have benefits,proponents
for clinical management using amniocentesis argue that treatment should be targeted to appropriate
women because a potential adverse effect of prolonged antibiotic therapy in PPROM includes superinfection with virulent organisms.40 It remains to be determined in future studies whether amniocentesis
improves outcomes.Amniocentesis should be performed in specialised units.
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5.
Management
5.1 Treatment
5.1.1 Are prophylactic antibiotics recommended?
Erythromycin should be given for 10 days following the diagnosis of PPROM.
Twenty-two trials involving over 6000 women with PPROM before 37 weeks of gestation were
included in a meta-analysis.41 The use of antibiotics following PPROM is associated with a statistically significant reduction in chorioamnionitis (RR 0.57; 95% CI 0.370.86). There was a
significant reduction in the numbers of babies born within 48 hours (RR 0.71;95% CI 0.580.87)
and 7 days (RR 0.80; 95% CI 0.710.90). Neonatal infection was significantly reduced in the
babies whose mothers received antibiotics (RR 0.68; 95% CI 0.530.87). There was also a
significant reduction in the number of babies with an abnormal cerebral ultrasound scan prior
to discharge from hospital (RR 0.82; 95% CI 0.680.98).There was no significant reduction in
perinatal mortality, although there was a trend for reduction in the treatment group.
Evidence
level Ia
There was variation in the choice of antibiotics used and the duration of therapy in the studies examined
in the meta-analysis.41 Ten trials tested broad-ppectrum penicillin, either alone or in combination, five
tested macrolide antibiotics (erythromycin) either alone or in combination and one trial tested clindamycin
and gentamycin.The duration of treatment varied between two doses and 10 days.Any penicillin (except
co-amoxiclav) or erythromycin versus placebo was associated with a significant reduction in the numbers
of babies born within 48 hours and who had positive blood cultures. Co-amoxiclav versus placebo was
associated with an increase in the numbers of babies born with necrotising enterocolitis.
This review shows that routine antibiotic administration reduces maternal and neonatal
morbidity.Antibiotic therapy also delays delivery, thereby allowing sufficient time for prophylactic prenatal corticosteroids to take effect.The data also showed that prenatal co-amoxiclav
increased the risk of neonatal necrotising enterocolitis and this antibiotic is best avoided.
Erythromycin or penicillin appears the antibiotic of choice. Erythromycin may be used in
women who are allergic to penicillin.
Evidence
level Ia
If group B streptococcus is isolated in cases of PPROM, antibiotics should be given in line with
the recommendation for routine intrapartum prophylaxis.As indicated in the RCOG Green-top
Guideline No.36:Prevention of early onset neonatal group B streptococcal disease,42 penicillin
should be administered, or clindamycin in women who are allergic to penicillin.
Evidence
level IV
5.1.2 What is the role of antenatal corticosteroids?

Antenatal corticosteroids should be administered in women with PPROM.
A meta-analysis of 15 randomised controlled trials involving more than 1400 women with
preterm rupture of the membranes demonstrated that antenatal corticosteroids reduce the risk
of respiratory distress syndrome (RR 0.56; 95% CI 0.4670), intraventricular haemorrhage (RR
0.47;95% CI 0.310.70) and necrotising enterocolitis (RR 0.21;95% CI 0.050.82).They may also
reduce the risk of neonatal death (RR 0.68; 95% CI 0.431.07).They do not appear to increase
the risk of infection in either mother (RR 0.86; 95% CI 0.611.20) or baby (RR 1.05; 95% CI
0.661.68).43
Evidence
level Ia
As stated in the RCOG Green-top Guideline No.7: Antenatal corticosteroids to reduce neonatal
morbidity,44 indications for antenatal corticosteroid therapy include women with PPROM between 24
and 34 weeks of gestation.
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5.1.3 Should tocolytic agents be used?

Tocolysis in women with PPROM is not recommended because this treatment does
not significantly improve perinatal outcome.
5.1.4 Prophylactic tocolysis

Three randomised studies on a total of 235 patients with PPROM reported that the proportion
of women remaining undelivered 10 days after membrane rupture were not significantly higher
in those receiving tocolysis compared with those receiving none.4547
Evidence
level Ib
A retrospective casecontrol study showed that tocolysis after PPROM did not increase the
interval between membrane rupture and delivery or reduce neonatal morbidity.48
Evidence
level IIa
5.1.5 Therapeutic tocolysis

A randomised trial involving 30 women demonstrated that delivery can be inhibited for 24 hours by
intravenous ritodrine.49 After 24 hours there was no difference in the duration of pregnancy in either group.
A randomised study involving 109 women showed that, for premature labour associated with premature
rupture of the membranes after 28 weeks of gestatation, there were no significant differences between
treatment groups in intrauterine time after the onset of regular contractions.50 The results of another
randomised study of 79 patients with contractions following PPROM did not suggest that there is benefit
of tocolysis in terms of prolonging the interval to delivery or in reducing perinatal morbidity or mortality.51
A casecontrol study involving 193 women found that aggressive tocolysis after PPROM did not increase
latency or decrease neonatal morbidity compared with either limited tocolysis or no tocolysis at all.19
Tocolytic treatment for women in preterm labour is the subject of RCOG Green-top Guideline No. 1(B):
Tocolytic drugs for women in preterm labour.52
In the absence of clear evidence that tocolysis improves neonatal outcome following PPROM, it is
reasonable not to use it.Additionally,with PPROM in the presence of uterine contractions,it is possible that
tocolysis could have adverse effects, such as delaying delivery from an infected environment, since there
is an association between intrauterine infection, prostaglandin and cytokine release and delivery.
5.2 When is the appropriate time to deliver the baby?

Delivery should be considered at 34 weeks of gestation. Where expectant management is considered beyond this gestation, women should be informed of the
increased risk of chorioamnionitis and the decreased risk of respiratory problems in
the neonate.
The decision to deliver or manage expectantly in cases of PPROM requires an assessment of the risks
related to the development of intrauterine infection in those pregnancies managed expectantly compared
with the gestational age-related risks of prematurity in pregnancies delivered earlier.
A retrospective study examining 430 women with PPROM demonstrated that composite
neonatal minor morbidity such as hyperbilirubinaemia and transient tachypnoea of the newborn
was significantly higher among pregnancies delivered at 34 weeks of gestation or less compared
with those delivered at 36 weeks.53 Composite major neonatal morbidity including respiratory
distress syndrome and intraventricular haemorrhage was not significantly different.
Evidence
level III
A randomised trial assigning 93 women with PPROM between 32 and 36 weeks and 6 days of
gestation to either immediate or delayed delivery showed that the incidence of respiratory
distress syndrome, intraventricular haemorrhage and confirmed neonatal sepsis was not signif-
Evidence
level Ib
6 of 12
icantly different in the two groups.54 Although in the expectantly managed group the 27.7%
incidence of chorioamniotis was higher than the 10.9% in the induced group,this difference did
not reach statistical significance.
Evidence
level Ib
In another report, 129 women with PPROM between 30 and 34 weeks of gestation were
randomly assigned to either immediate delivery or expectant management.55 The mean
gestational age at delivery was 31.7 weeks in the immediate delivery group and 32 weeks in the
group managed expectantly.Although the incidence of chorioamniotis was significantly less in
the immediate delivery group (2%) compared with the expectant management group (15%;
P < 0.05), there were no significant differences between the groups with regard to neonatal
morbidity.
Evidence
level Ib
In a prospective randomised study of 120 women with PPROM between 34 and 37 weeks of
gestation, the expectantly managed group had a higher incidence of chorioamnionitis (16%)
compared with the immediate delivery group (2%; P < 0.05).The incidence of sepsis was 5% in
the expectantly managed group and 0% in the immediate delivery group, but this was not statistically significant.There was no difference in the risk of respiratory distress syndrome.56
Evidence
level Ib
A retrospective series examining neonatal outcome following cases with PPROM between 32 and 36 weeks
showed that the specific gestation for reduced morbidity was 34 weeks.57 The incidence of respiratory
distress syndrome and the length of hospital stay were reduced in infants delivered after 34 weeks of
gestation.The incidence of respiratory distress syndrome was 22.5% and 5.8% at 33 and 34 weeks, respectively. Although the incidence of RDS beyond 34 weeks was relatively low, the condition affected infants
into the 36th week, with incidences of 10.4% and 1.5% at 35 and 36 weeks, respectively.
Many studies have demonstrated benefits of conservative management for gestations of less than 34 weeks,
whereas the management of pregnancies complicated by PPROM between 34 and 37 weeks continues to
be a contentious issue.56 Proponents of delivery at 34 weeks argue that, because of the lack of significant
neonatal benefit with prolongation of the pregnancy until 37 weeks, early delivery is justified to reduce the
risk of chorioamnionitis. Data from existing studies call for further research to elucidate the optimal
gestational age at delivery for women with PPROM between 34 and 37 weeks of gestation.A large randomised
trial of induction compared with expectant management of women with PPROM between these gestations
is needed.There are currently two randomised controlled trials comparing intentional delivery versus conservative management in women with PPROM between 32 and 35 weeks of gestation.58,59
Until the results of these trials become available, published data question the benefit of continued
expectant management beyond 34 weeks of gestation.There is little evidence that intentional delivery
after 34 weeks adversely affects neonatal outcome.There is a suggestion from these studies that expectant
management beyond 34 weeks is associated with an increased risk of chorioamnionitis.A longer latency
interval with expectant management may allow time for clinical chorioamnionitis, which either is
subclinical at the time of membrane rupture or develops with ascending bacterial infection subsequent
to membrane rupture.
A Cochrane review of planned early birth versus expectant management for women with PPROM before
37 weeks of gestation was published in 2010.The conclusions were that there is insufficient evidence to
guide clinical practice on the benefits and harms of immediate delivery compared with expectant
management.60
5.3 Can women be monitored at home?

In a randomised study of home versus hospital management,outcomes were comparable in the two groups
with a similar latency period and gestational age at delivery.16 There were no significant differences in the
7 of 12
frequencies of chorioamnionitis, respiratory distress syndrome or neonatal sepsis. However, only 18% of
the patients were eligible and agreed to randomisation.The patients were randomised after 72 hours in
hospital and 57% and 74% of those in the home and hospital groups, respectively, had an amniocentesis
for Gram stain and culture.This study does not support routine home management in patients with PPROM
but supports rigorous individual selection of women for this treatment.
There are insufficient data to make recommendations for home and outpatient monitoring
rather than continued hospital admission in women with PPROM.The decision to allow the
woman home should incorporate the finding that women presenting with PPROM and
subclinical intrauterine infection deliver earlier than non-infected patients. It would be
considered reasonable to keep the woman in hospital for at least 48 hours before a decision is
made to allow her to go home. This method of management should be individualised and
restricted to certain women. Women should be instructed to take regular temperature
recordings at home every 48 hours.
Evidence
level III
5.4. Should amnioinfusion in labour be carried out?

Amnioinfusion during labour is not recommended in women with preterm rupture
of membranes.
PPROM places the fetus at risk of umbilical cord compression. Amnioinfusion has been
described as a method of preventing this complication.Amnioinfusion during labour has been
the subject of a Cochrane review,61 which examined one randomised controlled trial involving
66 women with spontaneous rupture of membranes between 26 and 35 weeks of gestation
who received amnioinfusion during labour.62 The results showed no significant differences
between amnioinfusion and no amnioinfusion for caesarean section, low Apgar scores and
neonatal death.The implication is that there is insufficient evidence to guide clinical practice
concerning the use of amnioinfusion.
Evidence
level Ib
5.5 What is the role of transabdominal amnioinfusion in the prevention of pulmonary hypoplasia?
There is insufficient evidence to recommend amnioinfusion in very preterm PPROM
as a method to prevent pulmonary hypoplasia.
A published trial of 65 women with PPROM between 24 and 33 weeks of gestation who were
randomised to amnioinfusion or expectant management showed that the risk of postnatal death
from pulmonary hypoplasia was similar in both groups.63
Evidence
level Ib
Another casecontrol study involving 24 women reported no difference in the incidence of

pulmonary hypoplasia between controls and treated women.64
Evidence
level IIa
Another study involving 71 women with PPROM before 26 weeks of gestation demonstrated
that the percentage of intrauterine fetal survival was higher in the treated group than in the
control group (64.8% versus 32.3%; P < 0.01).65
Evidence
level IIa
A randomised controlled trial is under way comparing expectant management with serial amnioinfusions
in women with early second-trimester PPROM.66
5.6 What is the role of fibrin glue in the sealing of chorioamniotic membranes to prevent pulmonary
hypoplasia?
There is insufficient evidence to recommend fibrin sealants as routine treatment for
second-trimester oligohydramnios caused by PPROM.
8 of 12
There are publications involving small numbers of women with midtrimester PPROM describing
transvaginal or transabdominal injection of fibrin into the amniotic fluid with the aim of sealing
the membranes.6769 The amniopatch resulted in an increase in amniotic fluid volume in some
cases. Larger studies are needed examining neonatal outcome before this treatment can be
recommended as routine practice.
6.
Evidence
level III
Possible audit topics

Proportion of women with PPROM receiving erythromycin for 10 days.
Proportion of women with PPROM receiving a complete course of antenatal corticosteroids.
Proportion of women with PPROM being delivered at 34 weeks of gestation.
Proportion of women with PPROM delivered after 34 weeks of gestation with documented advice of
increased risk of chorioamnionitis and decreased risk of neonatal respiratory problems.
References
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18. Carroll SG, Papiaoannou S, Nicolaides KH.Assessment of
fetal activity and amniotic fluid volume in the prediction
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19. Combs CA, McCune M, Clark R, Fishman A.Aggressive
tocolysis does not prolong pregnancy or reduce neonatal
morbidity after preterm premature rupture of the
20. Cousins LM, Smok DP, Lovett SM, Poelter DM.AmniSure
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21. Lewis DF, Major CA,Towers CV,Asrat T, Harding JA, Garite TJ.
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22. Romem Y,Artal R. C-reactive protein as a predictor for
chorioamnionitis in cases of premature rupture of the
23. Watts DH, Krohn MA, Hillier SL,Wener MH, Kiviat NB,
Eschenbach DA. Characteristics of women in preterm labour
associated with elevated C-reactive protein levels. Obstet
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24. Kurki T,Teramo K,Ylikorkala O, Paavonen J. C-reactive protein
in preterm premature rupture of the membranes. Arch
25. Carroll SG, Papaioannou S, Ntumazah IL, Philpott-Howard J,
Nicolaides KH. Lower genital tract swabs in the prediction
of intrauterine infection in preterm prelabour rupture of the
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26. Ycel N,Ycel O,Yekeler H.The relationship between
umbilical artery Doppler findings, fetal biophysical score and
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27. Vintzileos AM, Campbell WA, Nochimson DJ,Weinbaum PJ,
Mirochnick MH, Escoto DT. Fetal biophysical profile versus
amniocentesis in predicting infection in preterm premature
rupture of the membranes. Obstet Gynecol 1986;68:48894.
28. Goldstein I, Romero R, Merrill S,Wan M, OConnor WM, Mazor
M, et al. Fetal body and breathing movements as predictors of
intraamniotic infection in preterm premature rupture of
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29. Roussis P, Rosemond RL, Glass C, Boehm F. Preterm

premature rupture of membranes: detection of infection.
Am J Obstet Gynecol 1991;165:1099104
30. Del Valle GO, Joffe GM, Izquierdo LA, Smith JF, Gilson GJ,
Curet LB.The biophysical profile and the nonstress test:
poor predictors of chorioamnionitis and fetal infection in
prolonged preterm premature rupture of membranes.
31. Gauthier DW, Meyer WJ, Bieniarz A. Biophysical profile as a
predictor of amniotic fluid culture results. Obstet Gynecol
1992;80:1025.
32. Carroll SG, Papiaoannou S, Nicolaides KH. Doppler studies
of the placental and fetal circulation in pregnancies with
preterm prelabour amniorrhexis. Ultrasound Obstet
Gynecol 1995;5:1848.
33. Ferguson MG, Rhodes PG, Morrison JC, Puckett CM.
Clinical amniotic fluid infection and its effect on the
neonate. Am J Obstet Gynecol 1995;151:105861.
34. Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, et al.
Amniotic fluid inflammatory cytokines (interleukin-6,
interleukin-1beta, and tumor necrosis factor-alpha), neonatal
brain white matter lesions, and cerebral palsy. Am J Obstet
Gynecol 1997;177:1926.
35. Yoon BH, Romero R, Jun JK, Park KH, Park JD, Ghezzi F, et al.
Amniotic fluid cytokines (interleukin-6, tumor necrosis
factor-alpha, interleukin-1 beta, and interleukin-8) and the
risk for the development of bronchopulmonary dysplasia.
36. Yoon BH, Park CW, Chaiorapongsa T. Intrauterine infection
and the development of cerebral palsy. BJOG 2003;110
Suppl 20:1247.
37. Carroll SG,Ville Y, Greenough A, Gamsu H, Patel B, PhilpottHoward J, et al. Preterm prelabour amniorrhexis: intrauterine
infection and interval between membrane rupture and
delivery. Arch Dis Child Fetal Neonatal Ed 1995;72:F436.
38. Jacobsson B, Holst RM, Mattsby-Baltzer I, Nikolaitchouk N,
Wennerholm UB, Hagberg H. Interleukin-18 in cervical
mucus and amniotic fluid: relationship to microbial invasion
of the amniotic fluid, intra-amniotic inflammation and
preterm delivery. BJOG 2003;110:598603.
39. Coultrip LL, Grossman JH. Evaluation of rapid diagnostic
tests in the detection of microbial invasion of the amniotic
cavity. Am J Obstet Gynecol 1992;167:123142.
40. Blackwell SC, Berry SM. Role of amniocentesis for the
diagnosis of subclinical intra-amniotic infection in preterm
premature rupture of the membranes. Curr Opin Obstet
Gynecol 1999;11:5417.
41. Kenyon S, Boulvain M, Neilson J.Antibiotics for preterm
rupture of membranes. Cochrane Database Syst Rev
2003;(2):CD001058.
42. Royal College of Obstetricians and Gynaecologists. Greentop Guideline No. 36: Prevention of early onset neonatal
group B streptococcal disease. London: RCOG; 2003.
43. Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal
corticosteroids help in the setting of preterm rupture of
membranes? Am J Obstet Gynecol 2001;184:1319.
44. Royal College of Obstetricians and Gynaecologists. Greentop Guideline No. 7: Antenatal corticosteroids to reduce
neonatal morbidity and mortality. London: RCOG; 2010.
45. How HY, Cook CR, Cook VD, Miles DE, Spinnato JA. Preterm
premature rupture of membranes: aggressive tocolysis versus
expectant management. J Matern Fetal Med 1998;7:812.
46. Levy D,Warsof SL. Oral ritodrine and preterm premature
rupture of membranes. Obstet Gynecol 1985;66:6213.
47. Dunlop PDM, Crowley PA, Lamont RF, Hawkins DF. Preterm
ruptured membranes, no contractions. J Obstet Gynecol
1986;7:926.
48. Jazayeri A, Jazayeri MK, Sutkin G.Tocolysis does not improve

neonatal outcome in patients with preterm rupture of
membranes. Am J Perinatol 2003;20:18993.
49. Christensen KK, Ingemarsson I, Leiderman T, Solum H,
Svenningsen N. Effect of ritodrine on labor after premature
rupture of the membranes. Obstet Gynecol 1980;55:18790.
50. Weiner CP, Renk K, Klugman M.The therapeutic efficacy and
cost-effectiveness of aggressive tocolysis for premature labor
associated with premature rupture of the membranes.
51. Garite TJ, Keegan KA, Freeman RK, Nageotte MP.A randomized
trial of ritodrine tocolysis versus expectant management in
patients with premature rupture of membranes at 25 to 30
weeks of gestation. Am J Obstet Gynecol 1987;157:38893.
52. Royal College of Obstetricians and Gynaecologists. Greentop Guideline No. 1(B): Tocolytic drugs for women in
preterm labour. London: RCOG; 2002.
53. Lieman JM, Brumfield CG, Carlo W, Ramsey PS. Preterm
premature rupture of membranes: is there an optimal
gestational age for delivery? Obstet Gynecol 2005;105:127.
54. Mercer BM, Crocker LG, Boe NM, Sibai BM. Induction versus
expectant management in premature rupture of the
membranes with mature amniotic fluid at 32 to 36 weeks:
a randomized trial. Am J Obstet Gynecol 1993;169:77582.
55. Cox S, Leveno KJ. Intentional delivery versus expectant
management with preterm ruptured membranes at 3034
weeks gestation. Obstet Gynecol 1995;86:8759.
56. Naef RW 3rd,Allbert JR, Ross EL,Weber BM, Martin RW,
Morrison JC. Premature rupture of membranes at 34 to 37
weeks gestation: aggressive versus conservative
management. Am J Obstet Gynecol 1998;178:12630.
57. Neerhof MG, Cravello C, Haney EI, Silver RK.Timing of labor
induction after premature rrupture of membranes between
32 and 36 weeks gestation. Am J Obstet Gynecol
1999;180:34952.
58. Lacaze-Masmonteil T, Chari R. Safety and Efficacy Study of
Intentional Delivery in Women with Preterm and Prelabour
Rupture of the Membranes. Clinical Trials.gov identifier
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59. Morris J. Immediate delivery versus expectant care in
women with ruptured membranes close to term.
ISRCTN44485060.
60. Buchanan SL, Crowther CA, Levett KM, Middleton P, Morris J.
Planned early birth versus expectant management for
women with preterm prelabour rupture of membranes prior
to 37 weeks gestation for improving pregnancy outcome.
61. Hofmeyr GJ.Amnioinfusion for preterm rupture of membranes.
62. Nageotte MP, Freedman RK, Garite TJ, Dorchester W.
Prophylactic intrapartum amnioinfusion in patients with
preterm premature rrupture of membranes. Am J Obstet
Gynecol 1985;153:55762.
63. Tranquilli AL, Giannubilo SR, Bezzeccheri V, Scagnoli C.
Transabdominal amnioinfusion in preterm premature
rupture of membranes: a randomised controlled trial. BJOG
2005;112:75963.
64. Ogunyemi D,Thompson W.A case controlled study of serial
transabdominal amnioinfusions in the management of
second trimester oligohydramnios due to premature rupture
of membranes. Eur J Obstet Gynceol Reprod Biol
2002;102:16772.
65. De Santis M, Scavo M, Noia G, Masini L, Piersigilli F,
Romagnoli C, et al.Transabdominal amnioinfusion treatment
of severe oligohydramnios in preterm premature rupture of
membranes at less than 26 gestational weeks. Fetal Diagn
Ther 2003;18:4127.
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66. Roberts D.Amnio infusion in preterm premature rupture of

membranes. ISRCTN 81932589.
67. Quintero RA, Morales WJ,Allen M, Bornick PW,Arroyo J, Le
Parc G.Treatment of iatrogenic previable premature rupture
of membranes with intra-amniotic infection of platelets and
cryoprecipitate (amniopatch): a preliminary experience. Am
68. Sciscione AC, Manley JS, Pollock M, Maas B, Shlossman PA,

Mulla W, et al. Intracervical fibrin sealants: a potential
treatment for early preterm premature rupture of the
69. Young BK, Roqu H,Abdelhak YE, Poiolek D, Demopulos R,
Lockwood CJ. Minimally invasive endoscopy in the
treatment of preterm premature rupture of membranes by
application of fibrin sealant. J Perinat Med 2000;28:32630.
APPENDIX
Clinical guidelines are:systematically developed statements which assist clinicians and patients in making
using a standardised methodology.Exact details of this process can be found inClinical Governance Advice
No 1: Guidance for the development of RCOG green-top guidelines (available on the RCOG website at
www.rcog.org.uk/guidelines).These recommendations are not intended to dictate an exclusive course of
management or treatment.They must be evaluated with reference to individual patient needs, resources
and limitations unique to the institution and variations in local populations. It is hoped that this process
of local ownership will help to incorporate these guidelines into routine practice.Attention is drawn to
areas of clinical uncertainty where further research may be indicated.

Ia
Evidence obtained from meta-analysis

of randomised controlled trials.
Ib

IIa

well-designed controlled study without
randomisation.
IIb

other type of well-designed quasiexperimental study.
III
Evidence obtained from well-designed

non-experimental descriptive studies,
such as comparative studies,
correlation studies and case studies.
IV
Evidence obtained from expert

clinical experience of respected
authorities.
Requires at least one randomised controlled

trial as part of a body of literature of overall
good quality and consistency addressing the
specific recommendation. (Evidence levels
Ia, Ib)
Requires the availability of well controlled

clinical studies but no randomised clinical
trials on the topic of recommendations.
(Evidence levels IIa, IIb, III)

clinical experiences of respected authorities.
Indicates an absence of directly applicable
clinical studies of good quality. (Evidence
level IV)
Good practice point
11 of 12

development group.
This guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by
Dr S G M Carroll FRCOG, Dublin, Ireland
and peer-reviewed by
Dr N C Smith FRCOG; Dr Devender Roberts MRCOG; Ms Sara Kenyon; Royal College of Midwives; British Association of
Perinatal Medicine; Professor D J Taylor FRCOG; Mr Jonathan Morris; Professor David Edwards; Mr John Wyatt; RCOG
Consumers Forum.
DISCLAIMER
12 of 12
Birth After Previous

Caesarean Birth
October 2015
Birth After Previous Caesarean Birth

This is the second edition of this guideline. The first edition was published in 2007 under the same title.1
Antenatal care schedule

What is the recommended schedule of antenatal care for pregnant women with previous caesarean
delivery?
Implementation of a vaginal birth after previous caesarean delivery (VBAC) versus elective repeat
caesarean section (ERCS) checklist or clinical care pathway is recommended to facilitate best
practice in antenatal counselling, shared decision making and documentation. [New 2015]
Suitability for planned VBAC

Which women are best suited to have a planned VBAC?
Planned VBAC is appropriate for and may be offered to the majority of women with a singleton
pregnancy of cephalic presentation at 37+0 weeks or beyond who have had a single previous lower
segment caesarean delivery, with or without a history of previous vaginal birth.
What are the contraindications to VBAC?

Planned VBAC is contraindicated in women with previous uterine rupture or classical caesarean scar
and in women who have other absolute contraindications to vaginal birth that apply irrespective of
the presence or absence of a scar (e.g. major placenta praevia).
In women with complicated uterine scars, caution should be exercised and decisions should be
made on a case-by-case basis by a senior obstetrician with access to the details of previous surgery.
Can women with two or more prior caesareans be offered planned VBAC?
Women who have had two or more prior lower segment caesarean deliveries may be offered VBAC
after counselling by a senior obstetrician. This should include the risk of uterine rupture and
maternal morbidity, and the individual likelihood of successful VBAC (e.g. given a history of prior
vaginal delivery). Labour should be conducted in a centre with suitable expertise and recourse to
immediate surgical delivery. [New 2015]
What factors are associated with an increased risk of uterine rupture in women undergoing VBAC?
An individualised assessment of the suitability for VBAC should be made in women with factors
that increase the risk of uterine rupture.
Antenatal counselling
What are the overall aims of antenatal counselling?
The antenatal counselling of women with a previous caesarean birth should be documented in
the notes.
A final decision for mode of birth should be agreed upon by the woman and member(s) of the
maternity team before the expected/planned date of delivery.
When a date for ERCS is being arranged, a plan for the event of labour starting before the scheduled
date should be documented in the notes.
2 of 31
The routine use of VBAC checklists during antenatal counselling should be considered, as they
would ensure informed consent and shared decision making in women undergoing VBAC. [New 2015]
A patient information leaflet should be provided with the consultation.
What are the risks and benefits of planned VBAC versus ERCS from 39
P
+0
weeks of gestation?
Women should be made aware that successful VBAC has the fewest complications and therefore
the chance of VBAC success or failure is an important consideration when choosing the mode of
delivery.
Women should be made aware that the greatest risk of adverse outcome occurs in a trial of VBAC
resulting in emergency caesarean delivery.
Women should be informed that planned VBAC is associated with an approximately 1 in 200 (0.5%)
risk of uterine rupture.
Women should be informed that the absolute risk of birth-related perinatal death associated with
VBAC is extremely low and comparable to the risk for nulliparous women in labour.
Women should be informed that ERCS is associated with a small increased risk of placenta
praevia and/or accreta in future pregnancies and of pelvic adhesions complicating any future
abdominopelvic surgery.
The risk of perinatal death with ERCS is extremely low, but there is a small increase in neonatal
respiratory morbidity when ERCS is performed before 39+0 weeks of gestation. The risk of respiratory
morbidity can be reduced with a preoperative course of antenatal corticosteroids.
What is the likelihood of VBAC success?

Women should be informed that the success rate of planned VBAC is 7275%.
What factors determine the individualised likelihood of VBAC success?

Women with one or more previous vaginal births should be informed that previous vaginal delivery,
particularly previous VBAC, is the single best predictor of successful VBAC and is associated with a
planned VBAC success rate of 8590%. Previous vaginal delivery is also independently associated
with a reduced risk of uterine rupture.
Intrapartum management of planned VBAC

What delivery setting is appropriate for conducting planned VBAC?
Women should be advised that planned VBAC should be conducted in a suitably staffed and
equipped delivery suite with continuous intrapartum care and monitoring with resources available
for immediate caesarean delivery and advanced neonatal resuscitation.
Women with an unplanned labour and a history of previous caesarean delivery should have a
discussion with an experienced obstetrician to determine feasibility of VBAC. [New 2015]
Epidural analgesia is not contraindicated in a planned VBAC, although an increasing requirement

for pain relief in labour should raise awareness of the possibility of an impending uterine rupture.
Women should be advised to have continuous electronic fetal monitoring for the duration of
planned VBAC, commencing at the onset of regular uterine contractions.
How should women with a previous caesarean birth be advised in relation to induction or augmentation
of labour?
3 of 31
Women should be informed of the two- to three-fold increased risk of uterine rupture and around
1.5-fold increased risk of caesarean delivery in induced and/or augmented labour compared with
spontaneous VBAC labour.
A senior obstetrician should discuss the following with the woman: the decision to induce labour,
the proposed method of induction, the decision to augment labour with oxytocin, the time intervals
for serial vaginal examination and the selected parameters of progress that would necessitate
discontinuing VBAC.
Clinicians should be aware that induction of labour using mechanical methods (amniotomy or
Foley catheter) is associated with a lower risk of scar rupture compared with induction using
prostaglandins.
Planning and conducting ERCS

What elements are involved in the perioperative, intraoperative and postoperative care for ERCS?
ERCS delivery should be conducted after 39+0 weeks of gestation.
Antibiotics should be administered before making the skin incision in women undergoing ERCS.
[New 2015]
All women undergoing ERCS should receive thromboprophylaxis according to existing RCOG
guidelines. [New 2015]
Early recognition of placenta praevia, adopting a multidisciplinary approach and informed consent
are important considerations in the management of women with placenta praevia and previous
caesarean delivery. [New 2015]
How should women in special circumstances be cared for?

Clinicians should be aware that there is uncertainty about the safety and efficacy of planned
VBAC in pregnancies complicated by post-dates, twin gestation, fetal macrosomia, antepartum
stillbirth or maternal age of 40 years or more. Hence, a cautious approach is advised if VBAC is
being considered in such circumstances.
Women who are preterm and considering the options for birth after a previous caesarean delivery
should be informed that planned preterm VBAC has similar success rates to planned term VBAC but
with a lower risk of uterine rupture.
1.
Purpose and scope
The purpose of this guideline is to provide evidence-based information to inform the antenatal and
intrapartum care of pregnant women who have had previous caesarean delivery, with the options for
delivery being either planned vaginal birth after previous caesarean delivery (VBAC) or elective repeat
caesarean section (ERCS).
2.
There has been continued debate about defining an acceptable caesarean delivery rate and what rate
achieves optimal maternal and infant outcomes. The overall caesarean delivery rate in England for 2012
2013 was 25.5%2; the majority were emergency (14.8%) rather than elective (10.7%) caesarean births.
The caesarean delivery rates for Wales,3 Northern Ireland4 and Scotland5 in 20122013 were 27.5%, 29.8%
and 27.3% respectively. Hence, counselling women for and managing birth after caesarean delivery are
important issues.
4 of 31
There is a consensus (National Institute for Health and Care Excellence [NICE],6 Royal College of
Obstetricians and Gynaecologists [RCOG],1 American College of Obstetricians and Gynecologists [ACOG]/
National Institutes of Health [NIH]79) that planned VBAC is a clinically safe choice for the majority of
women with a single previous lower segment caesarean delivery. Such a strategy is also supported by
health economic modelling6,10 and would also at least limit any escalation of the caesarean delivery
rate and maternal morbidity associated with multiple caesarean deliveries.1115 This guideline provides
evidence-based recommendations on best practice for the antenatal and intrapartum management of
women undergoing planned VBAC and ERCS. The terms used in this guideline are defined in Appendix I.
3.
Guidelines. MEDLINE, PubMed, all Evidence-Based Medicine (EBM) Reviews (Cochrane Central Register
of Controlled Trials, Cochrane Database of Systematic Reviews, Methodology Register, ACP Journal
Club, Database of Abstracts of Reviews of Effects [DARE], Health Technology Assessment database
[HTA], Maternity and Infant Care), EMBASE and Trip were searched for relevant randomised controlled
trials, systematic reviews, meta-analyses and cohort studies. The search was restricted to articles
published between 2003 and February 2015. Search words included VBAC, TOLAC, vaginal birth
after caesarean, previous caesarean, prior caesarean and all relevant Medical Subject Headings (MeSH)
terms. This guideline assesses the quality of evidence and determines the strength of recommendations
in accordance with Scottish Intercollegiate Guidelines Network criteria.
4.
Identified studies and limitations of data
Notable publications within the last 10 years have included evidence-based systematic reviews,9,16,17 clinical
guidelines from the UK (RCOG 20071 and NICE 20116) and the USA (ACOG 20107; NIH 2010 Consensus
report8) and a study by the US National Institute of Child Health and Human Development (NICHD, 2004;
17 898 planned VBACs, 15 801 planned ERCSs at 37+041+0 weeks of gestation18). Important attributes
of the NICHD study18 include its large sample size, prospective strict case ascertainment and reporting
outcomes according to planned VBAC and planned ERCS antenatal decisions rather than observed
modes of delivery. Many of the recent studies vary in their case ascertainment and outcome criteria.
These include an Australian multicentre patient preference cohort trial (2012; 1237 planned VBACs,
1108 planned ERCSs at 38 +039 +0 weeks of gestation),19 a UK national casecontrol study (20122013;
UK Obstetric Surveillance System)12,13,20 and Scottish (2013),21 Australian (2010)22 and Dutch (2009) 23
population-based studies. Importantly, although planned ERCS is recommended to be conducted from
39 +0 weeks of gestation,6 most studies have reported ERCS outcomes for deliveries that have occurred
between 37+0 and 40 +0 weeks of gestation.
5.
Antenatal care schedule
5.1 What is the recommended schedule of antenatal care for pregnant women with previous
caesarean delivery?
Implementation of a VBAC versus ERCS checklist or clinical care pathway is recommended to
facilitate best practice in antenatal counselling, shared decision making and documentation.
The antenatal care schedule should comply with that recommended by the NICE antenatal
care guideline,24 with specific reviews as shown in Appendices II and III. NICE25 pathways
may also be used as guides when devising appropriate local clinical care pathways.
Evidence
level 4
In the majority of cases, counselling for mode of delivery could be conducted by a member
of the maternity team soon after the womans midtrimester ultrasound, assuming that there
5 of 31
were no contraindications to planned VBAC. An obstetrician should be involved in any of

the following situations: the woman had contraindications that precluded VBAC, she was
uncertain of mode of delivery, she specifically requested ERCS, she required induction
of labour (e.g. more than 41+0 weeks of gestation) or she developed specific pregnancy
complications (e.g. pre-eclampsia, breech presentation, fetal growth restriction, macrosomia).
After initial counselling, some more complex cases may need senior support. In most cases,
the decision regarding mode of delivery should be finalised by 36 +0 weeks of gestation. Having Evidence
well-structured evidence-based patient information leaflets that list key points, including the level 4
probability of the woman having successful VBAC, is likely to improve the informed decisionmaking process on mode of birth after caesarean delivery26 (see Appendix IV).
Use of specialist antenatal clinics designed to guide and support women through the informed
decision-making process on mode of birth after a primary caesarean delivery has been found
to improve VBAC attempt rates in Australia.27
6.
Suitability for planned VBAC
6.1 Which women are best suited to have a planned VBAC?

Planned VBAC is appropriate for and may be offered to the majority of women with a singleton
pregnancy of cephalic presentation at 37+0 weeks or beyond who have had a single previous lower
segment caesarean delivery, with or without a history of previous vaginal birth.
There is a consensus, endorsed by evidence-based systematic reviews9,16,17 and clinical

guidelines,1,68 that planned VBAC is a safe and appropriate mode of delivery for the majority Evidence
level 2++
of pregnant women with a single previous lower segment caesarean delivery.
However, a review of the previous caesarean delivery records and current pregnancy is recommended
to identify contraindications to VBAC.
6.2 What are the contraindications to VBAC?

Planned VBAC is contraindicated in women with previous uterine rupture or classical caesarean scar
and in women who have other absolute contraindications to vaginal birth that apply irrespective of
the presence or absence of a scar (e.g. major placenta praevia).
In women with complicated uterine scars, caution should be exercised and decisions should be
made on a case-by-case basis by a senior obstetrician with access to the details of previous surgery.
Women with the following risk factors are considered to be at increased risk of adverse maternal and/or
perinatal outcome as a consequence of VBAC.
Previous uterine rupture

Based on limited observational data,2830 women who have experienced a previous uterine
rupture are reported to have a higher risk (5% or higher) of recurrent uterine rupture with Evidence
level 3
labour. Hence previous uterine rupture is considered a contraindication to VBAC.
Type of previous uterine incision

Based on limited observational data,31,32 there is insufficient evidence to support the safety
of VBAC in women with previous inverted T or J incisions, low vertical uterine incisions or
significant inadvertent uterine extension at the time of primary caesarean; hence caution Evidence
should be exercised in these women and decisions should be made by a senior obstetrician level 3
on a case-by-case basis. VBAC is contraindicated in women with previous classical caesearean
delivery due to the high risk of uterine rupture.33
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Previous uterine surgery

Although previous uterine surgery is not within the scope of this guideline, there is uncertainty
whether women who have undergone laparoscopic or abdominal myomectomy, particularly
where the uterine cavity has been breached, are at increased risk of uterine rupture.3441 Uterine Evidence
rupture after hysteroscopic resection of uterine septum is considered a rare complication.42,43 level 3
Given this uncertainty, women who have had such uterine surgery should be considered to
have delivery risks at least equivalent to those of VBAC and managed similarly in labour.
Placenta praevia
A major degree of placenta praevia (and some cases of minor or partial placenta praevia)
is a contraindication to vaginal delivery, including VBAC (see RCOG Green-top Guideline
No. 27).44 A systematic review reported that women with one, two, or three or more previous
caesarean deliveries experience a 1%, 1.7% or 2.8% risk respectively of placenta praevia in
subsequent pregnancies,9 concurring with the findings of a recent UK population study and Evidence
meta-analysis.45 Placenta accreta occurs in 1114% of women with placenta praevia and one prior level 2++
caesarean delivery and in 2340% of women with placenta praevia and two prior caesarean
deliveries. In women with placenta praevia and five or more prior caesarean deliveries, the
incidence of placenta accreta is up to 67%.9 In view of these associations, the RCOG and NICE
have produced recommendations for women with a previous caesarean delivery which can be
found in RCOG Green-top Guideline No. 2744 and the NICE guideline.6
6.3 Can women with two or more prior caesareans be offered planned VBAC?
Women who have had two or more prior lower segment caesarean deliveries may be offered VBAC
after counselling by a senior obstetrician. This should include the risk of uterine rupture and
maternal morbidity, and the individual likelihood of successful VBAC (e.g. given a history of prior
vaginal delivery). Labour should be conducted in a centre with suitable expertise and recourse to
immediate surgical delivery.
A multivariate analysis of the NICHD study showed that there was no significant difference
in the rates of uterine rupture in VBAC with two or more previous caesarean births (9/975,
92/10000) compared with a single previous caesarean birth (115/16 915, 68/10000).46 These
findings concur with other observational studies, which, overall, have shown similar rates of
VBAC success with two previous caesarean births (VBAC success rates of 6275%) and single Evidence
level 2+
prior caesarean birth.4750 It is notable that more than half of the women with two previous
caesarean deliveries had also had a previous vaginal birth and 40% had a previous VBAC.
Hence, caution should be applied when extrapolating these data to women with no previous
vaginal delivery.
A systematic review51 has suggested that women with two previous caesarean deliveries
who are considering VBAC should be counselled about the success rate (71.1%), the uterine
rupture rate (1.36%) and the comparable maternal morbidity to the repeat caesarean delivery
option. The rates of hysterectomy (56/10000 compared with 19/10000) and transfusion
(1.99% compared with 1.21%) were increased in women undergoing VBAC after two previous Evidence
caesarean births compared with one previous caesarean birth. Therefore, provided that level 2++
the woman has been fully informed by a senior obstetrician of the increased risks and a
comprehensive individualised risk analysis has been undertaken of the indication for and the
nature of the previous caesarean deliveries, then planned VBAC may be supported in women
with two or more previous lower segment caesarean deliveries.
Women seeking multiple (e.g. three or more) future pregnancies should be counselled Evidence
that opting for ERCS may expose themselves to greater surgical risks for future pregnancies level 3
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(particularly placenta praevia, placenta accreta and hysterectomy) associated with repeated ERCS Evidence
level 3
delivery1113,44,52,53 and therefore greater consideration ought to be given to attempting VBAC.
6.4 What factors are associated with an increased risk of uterine rupture in women
undergoing VBAC?
An individualised assessment of the suitability for VBAC should be made in women with factors
that increase the risk of uterine rupture.
Factors that potentially increase the risk of uterine rupture include short inter-delivery interval
(less than 12 months since last delivery), post-date pregnancy, maternal age of 40 years or
more, obesity, lower prelabour Bishop score, macrosomia and decreased ultrasonographic
lower segment myometrial thickness.20,22,23,5457 A recent retrospective study58 involving 3176 Evidence
patients evaluated the safety of women undergoing VBAC with a short inter-delivery interval. level 3
The study concluded that a short inter-delivery interval (less than 12 months) is not a risk factor
for major complications such as uterine rupture and maternal death, but that it is for preterm
delivery. Further data are needed before the safety of such an approach can be confirmed.
There is uncertainty in how to incorporate this knowledge in antenatal counselling and
therefore the presence of these risk factors does not contraindicate VBAC. However, such Evidence
factors may be considered during the decision-making process, particularly if considering level 2
induction or augmentation of VBAC labour (see section 8.2).
A recent meta-analysis59 has suggested that measurement of lower uterine segment (LUS)
thickness antenatally in women with a previous caesarean delivery could be used to predict
the occurrence of a uterine defect (scar dehiscence or scar rupture) in women undergoing
VBAC. According to the study, a myometrial thickness (the minimum thickness overlying
the amniotic cavity at the level of the uterine scar) cut-off of 2.14.0 mm provided a strong
negative predictive value for the occurrence of a uterine defect during VBAC, whereas a Evidence
myometrial thickness cut-off between 0.6 and 2.0 mm provided a strong positive predictive level 1+
value for the occurrence of a uterine defect. However, the study could not define an ideal LUS
thickness cut-off value usable in clinical practice. This meta-analysis provides support for the
use of antenatal LUS measurements in the prediction of a uterine defect in women undergoing
VBAC; however, clinical applicability needs be assessed in prospective observational studies
using a standardised method of measurement.
7.
Antenatal counselling
7.1 What are the overall aims of antenatal counselling?

The antenatal counselling of women with a previous caesarean birth should be documented in
the notes.
A final decision for mode of birth should be agreed upon by the woman and member(s) of the
maternity team before the expected/planned date of delivery.
When a date for ERCS is being arranged, a plan for the event of labour starting before the scheduled
date should be documented in the notes.
The routine use of VBAC checklists during antenatal counselling should be considered, as they
would ensure informed consent and shared decision making in women undergoing VBAC.
A patient information leaflet should be provided with the consultation.
8 of 31
Ideally, discussion should be individualised to the womans medical circumstances and consider her
individual chance of VBAC success and future reproductive preferences. The antenatal counselling
process should be documented in the medical records. Where possible, outcomes from women who give
birth at term (37+042+0 weeks of gestation) should be used for the purposes of antenatal counselling and
are used throughout this guideline. As up to 10% of women scheduled for ERCS go into labour before
39 +0 weeks, it is good practice to discuss and document a plan for delivery if labour starts prior to the
scheduled date.
Clinical trials have shown decision aids, specific patient information literature and VBAC
checklists, which encompass such information, may facilitate the decision-making process Evidence
by lowering decisional conflict, improving level of knowledge, improving satisfaction and level 1
increasing the perception of having made an informed choice.6066
Documentation of the counselling process (for example, using a standardised VBAC checklist or
clinical care pathway) and provision of a patient information leaflet67 are recommended.6062,68 Evidence
level 1+
An example checklist is provided in Appendix IV.
7.2 What are the risks and benefits of planned VBAC versus ERCS from 39 +0 weeks of
gestation?
Women should be made aware that successful VBAC has the fewest complications and therefore
the chance of VBAC success or failure is an important consideration when choosing the mode of
delivery.
Women should be made aware that the greatest risk of adverse outcome occurs in a trial of VBAC
resulting in emergency caesarean delivery.
Women should be informed that planned VBAC is associated with an approximately 1 in 200 (0.5%)
risk of uterine rupture.
Women should be informed that the absolute risk of birth-related perinatal death associated with
VBAC is extremely low and comparable to the risk for nulliparous women in labour.
Women should be informed that ERCS is associated with a small increased risk of placenta
praevia and/or accreta in future pregnancies and of pelvic adhesions complicating any future
abdominopelvic surgery.
The risk of perinatal death with ERCS is extremely low, but there is a small increase in neonatal
respiratory morbidity when ERCS is performed before 39+0 weeks of gestation. The risk of
respiratory morbidity can be reduced with a preoperative course of antenatal corticosteroids.
The maternal and fetal risks of planned VBAC and ERCS from 39 +0 weeks of gestation are summarised
in Table 1.
Planned VBAC adverse maternal outcomes

Uterine rupture
The NICHD study18 showed that planned VBAC, compared with ERCS, had a higher risk of
uterine rupture (0.7% versus 0%). The US Agency for Healthcare Research and Quality (AHRQ)
meta-analysis and studies from the UK, Australia and Ireland reported a VBAC uterine rupture
risk of 0.5%,9 0.2%,20 0.33%22 and 0.2%73 respectively. Rates of uterine rupture differ according Evidence
level 2
to whether VBAC labour is spontaneous (0.150.4%), induced (0.541.4%) or augmented
(0.91.91%)18,20,22 (Appendix V). In the UK cohort study, two women with uterine rupture died
(uterine rupture case fatality 1.3%, 95% CI 0.24.5%).20
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Table 1. Risks and benefits of opting for VBAC versus ERCS from 39+0 weeks of gestation
Maternal outcomes
Planned VBAC
ERCS from 39+0 weeks
7275% chance of successful VBAC. If

successful, shorter hospital stay and recovery.
A
ble to plan a known delivery date in select
patients. This may however change based
on circumstances surrounding maternal
and fetal wellbeing in the antenatal period.
Approximately 0.5% risk of uterine scar rupture.

If occurs, associated with maternal morbidity
and fetal morbidity/mortality.
V
irtually avoids the risk of uterine rupture
(actual risk is extremely low: less than
0.02%).
Longer recovery.
R
educes the risk of pelvic organ prolapse
and urinary incontinence in comparison
with number of vaginal births (dose
response effect) at least in the short term.69
O
ption for sterilisation if fertility is no
longer desired. Evidence suggests that the
regret rate is higher and that the failure
rate from sterilisation associated with
pregnancy may be higher than that from an
interval procedure. If sterilisation is to be
performed at the same time as a caesarean
delivery, counselling and agreement
should have been given at least 2 weeks
prior to the procedure.70
Increases likelihood of future vaginal birth.
F uture pregnancies likely to require

caesarean delivery, increased risk of
placenta praevia/accreta and adhesions
with successive caesarean deliveries/
abdominal surgery.
Risk of anal sphincter injury in women

undergoing VBAC is 5% and birthweight is
the strongest predictor of this. The rate of
instrumental delivery is also increased up to
39%.71
Infant outcomes
Risk of maternal death with planned VBAC of

4/100000 (95% CI 1/100000 to 16/100000).9
R
isk of maternal death with ERCS of
13/100000 (95% CI 4/100000 to
42/100000).9
Risk of transient respiratory morbidity of 23%.
R
isk of transient respiratory morbidity of
45% (6% risk if delivery performed at 38
instead of 39 weeks). The risk is reduced
with antenatal corticosteroids, but there
are concerns about potential long-term
adverse effects.72
10 per 10000 (0.1%) prospective risk of

antepartum stillbirth beyond 39 +0 weeks
while awaiting spontaneous labour (similar to
nulliparous women).
8 per 10000 (0.08%) risk of hypoxic ischaemic
encephalopathy (HIE).
<
1 per 10000 (< 0.01%) risk of deliveryrelated perinatal death or HIE.
4 per 10000 (0.04%) risk of delivery-related

perinatal death. This is comparable to the risk
for nulliparous women in labour.
The estimates of risk for adverse maternal or fetal events in VBAC are based on women receiving continuous electronic
monitoring during their labour.
Hysterectomy and other morbidities

The rates of hysterectomy, thromboembolic disease, transfusion and endometritis did not
differ significantly between planned VBAC and ERCS according to the AHRQ meta-analysis9 Evidence
level 2+
and another meta-analysis.74 However, the NICHD study showed unsuccessful compared with
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successful VBAC increased the risk of uterine rupture (2.3% versus 0.1%), hysterectomy (0.5%
versus 0.1%), transfusion (3.2% versus 1.2%) and endometritis (7.7% versus 1.2%).18 Meta- Evidence
level 2+
analysis has shown that hysterectomy was required in 1433% of uterine rupture cases.9
A review of Maternal-Fetal Medicine Units Network publications75 suggests that, at term,
women undergoing VBAC as compared with ERCS have a significantly greater incidence of Evidence
level 3
blood transfusion (2% versus 1%), but the likelihood of hysterectomy is not increased.
Planned VBAC adverse perinatal outcomes

Antepartum stillbirth
Planned VBAC is associated with an additional 10 per 10000 prospective risk of antepartum
stillbirth beyond 39 +0 weeks of gestation (recommended timing for ERCS delivery) while
awaiting spontaneous labour.76 The pathophysiology of the increased risk of stillbirth Evidence
associated with VBAC is unexplained, but this increased risk is evident in women with level 2
previous caesarean delivery compared with no prior caesarean delivery despite correcting for
gestation and other factors.76,77
Delivery-related perinatal death
In the NICHD study, planned VBAC is associated with a 4 per 10000 risk of term perinatal death
(i.e. intrapartum stillbirth or neonatal death), with around one-third (1.4 per 10000 overall) of deaths
due to uterine rupture.18 In contrast, ERCS is associated with a risk of delivery-related perinatal Evidence
level 2
death of 1 per 10000 or less. The risk of perinatal death arising from uterine rupture during
VBAC was reported as 4.5% in a Dutch population study23 and 216% in the AHRQ meta-analysis.9
Neonatal hypoxic ischaemic encephalopathy (HIE)
In the NICHD study, HIE affected 8 per 10000 planned VBACs and, of these, 60% of cases Evidence
level 2+
(7/12) were due to uterine rupture.18
ERCS and adverse maternal and perinatal outcomes

Maternal mortality
Both the NICHD18 study and AHRQ9 meta-analysis showed an increased risk of maternal
mortality with ERCS compared with planned VBAC (13/100000 versus 4/100000),9 although Evidence
data were conflicting on whether the differences were statistically significant. Absolute risks level 1
are extremely low for either mode of delivery.
Neonatal respiratory morbidity
ERCS compared with planned VBAC increased the risks of transient tachypnoea of the newborn
(45% versus 23%) and respiratory distress syndrome (0.5% versus less than 0.05%).9,18,7881 Evidence
The Antenatal Steroids for Term Elective Caesarean Section (ASTECS) trial82 reported that level 2+
respiratory morbidity was 11.4%, 6.2% and 1.5% at 37, 38 and 39 weeks of gestation respectively.
Long-term outcomes of planned VBAC versus ERCS

There are no data reporting on long-term maternal or infant outcomes of planned VBAC versus
ERCS cohort groups.9 There are considerable data to show that repeated ERCS is associated Evidence
with an increased risk of placenta praevia, placenta accreta and surgical complications at the level 2
time of subsequent pregnancy and delivery, such as hysterectomy.1113,44,45,52,53
Perinatal outcomes of planned VBAC versus ERCS

The NICHD observational study showed that there was around a three-fold increase (0.38%
versus 0.13%, OR 2.90, 95% CI 1.744.81) for one or more serious composite adverse perinatal Evidence
outcomes (which include perinatal mortality and HIE) for planned VBAC at term compared level 2
with ERCS. Another prospective cohort study in Australia used a broader composite of adverse
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perinatal outcomes (perinatal mortality, HIE, neonatal intensive care unit admission, neonatal
acidosis, birth trauma, neonatal sepsis) and also found an approximately three-fold risk for Evidence
level 2
women attempting VBAC.19
A review of Maternal-Fetal Medicine Units Network publications75 suggests that, at term,
in women undergoing VBAC as compared with ERCS, there were similar rates of neonatal Evidence
level 3
seizures and perinatal mortality.
Summary of outcomes of planned VBAC versus ERCS

A reasonable summary of the evidence is that planned VBAC exposes the woman to a very low
(0.25%) additional risk for experiencing perinatal mortality or serious neonatal morbidity and
an additional 1.5% risk of any significant morbidity compared with opting for ERCS from 39 +0 Evidence
weeks of gestation. Nevertheless, it may be helpful to emphasise to women that the absolute level 2+
risk of delivery-related perinatal death associated with VBAC is extremely low (4 per 10000
[0.04%]) and comparable to the risk for nulliparous women in labour.83,84
Cochrane reviews8587 suggest that there are benefits and risks associated with planned ERCS
and planned induction of labour in women with a prior caesarean delivery. There is a paucity of
randomised controlled trials that would provide the most reliable evidence and help women to Evidence
make an informed choice. The related evidence for the established care pathways is potentially level 1++
biased, as it is drawn from nonrandomised studies. Hence, the results and conclusions should
be interpreted with caution and the uncertainties should be discussed with women.
7.3 What is the likelihood of VBAC success?

Women should be informed that the success rate of planned VBAC is 7275%.
88,89
Meta-analysis
(n = 103 188 VBAC labours) reported a pooled VBAC labour success rate of
74% (95% CI 7275%), while the NICHD study reported a 73% VBAC labour success rate (n =
17898 VBAC labours). A recent Australian cohort trial reported a VBAC success rate of 43%
(535/1237 planned VBAC at 37 weeks), although excluding those women who required elective
caesarean after opting for VBAC, the study showed a VBAC success rate of 59% (535/903 VBAC Evidence
level 2+
labours).19 There are often differences in VBAC success rates between centres and published
studies, so consideration should be given to counselling women using locally derived VBAC
success rates given the pragmatic differences in population, induction/non-induction VBAC
policies and healthcare provision.
7.4 What factors determine the individualised likelihood of VBAC success?

Women with one or more previous vaginal births should be informed that previous vaginal delivery,
particularly previous VBAC, is the single best predictor of successful VBAC and is associated with a
planned VBAC success rate of 8590%. Previous vaginal delivery is also independently associated
with a reduced risk of uterine rupture.
Several pre-admission- and admission-based multivariate models have been published to

predict the individualised likelihood of VBAC success.9093 Importantly, women at increased
risk of unsuccessful VBAC are also at increased risk of uterine rupture, including catastrophic
rupture leading to perinatal death.92,9496 Research is exploring the value of transvaginal/
Evidence
transabdominal ultrasonographic assessment of myometrial scar thickness to predict VBAC level 2
success and uterine scar rupture (see section 6.4).57,59,9799 Although prediction models ought to
be intuitively beneficial, such models have not been routinely applied in the decision-making
process and their precise role is yet to be established. A 2013 meta-analysis of these studies has
concluded that further prospective research is required.59
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A VBAC score100 has been used by some authors to predict the success of women attempting
VBAC. The retrospective VBAC score was created by examining five features: admission
Bishop score, age, previous caesarean delivery indication, body mass index (BMI) and previous Evidence
vaginal birth. The higher the VBAC score, the higher the success rate; the success rate of level 2
women with a VBAC score of more than 16 was greater than 85%, in contrast to those with a
VBAC score of 10 who had a 49% success rate.
The use of specific population-based models to predict VBAC success needs further data,101,102 Evidence
level 2+
although initial results are promising.
Induced labour, no previous vaginal delivery, BMI greater than 30 and previous caesarean
for labour dystocia are associated with an increased risk of unsuccessful VBAC. If all of these
factors are present, successful VBAC is achieved in 40% of cases.18,103
Previous vaginal delivery, particularly previous successful VBAC, is the single best predictor
for successful VBAC and is associated with a planned VBAC success rate of 8590%.103 Previous
vaginal delivery is also independently associated with a reduced risk of uterine rupture.54,96,104,105
Greater maternal height, maternal age less than 40 years, BMI less than 30, gestation of less
than 40 weeks and infant birthweight less than 4 kg (or similar/lower birthweight than index
caesarean delivery106) are associated with an increased likelihood of successful VBAC.90,93,107110
In addition, spontaneous onset of labour, vertex presentation, fetal head engagement or a
lower station, and higher admission Bishop score also increase the likelihood of successful
VBAC.91,94,103,108,111 Successful VBAC is more likely among women with previous caesarean for
fetal malpresentation (84%) compared with women with previous caesarean for either labour
dystocia (64%) or fetal distress (73%) indications.18,103 Younger women and those of white Evidence
level 2
ethnicity experienced the highest success rate, in contrast to women of black ethnicity who
experienced a lower success rate. Those who had an emergency caesarean delivery in their
first birth also had a lower VBAC success rate, in particular those who experienced a failed
induction of labour.112 Despite a degree of data inconsistency, successful VBAC appears more
likely among women with previous caesarean for dystocia at 8 cm or more compared with
women with previous caesarean for dystocia at less than 8 cm.113115 A retrospective study
concluded that the success rate for VBAC in women who had a prior caesarean delivery due to
an unsuccessful instrumental delivery was high (61.3%). The risk factors that were associated
with a failed VBAC in these women were occiput posterior position and prolonged second
stage as the indication for instrumental vaginal delivery in the index pregnancy, maternal age
older than 30 years at the time of subsequent delivery and a birthweight in the subsequent
pregnancy that is higher than the birthweight in the index pregnancy. This information and
the risk factors for VBAC failure can be used when counselling these women regarding mode
of delivery in subsequent pregnancy.116
8.
Intrapartum management of planned VBAC
8.1 What delivery setting is appropriate for conducting planned VBAC?

Women should be advised that planned VBAC should be conducted in a suitably staffed and
equipped delivery suite with continuous intrapartum care and monitoring with resources available
for immediate caesarean delivery and advanced neonatal resuscitation.
Women with an unplanned labour and a history of previous caesarean delivery should have a
discussion with an experienced obstetrician to determine feasibility of VBAC.
Epidural analgesia is not contraindicated in a planned VBAC, although an increasing requirement

for pain relief in labour should raise awareness of the possibility of an impending uterine rupture.
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Women should be advised to have continuous electronic fetal monitoring for the duration of
planned VBAC, commencing at the onset of regular uterine contractions.
There should be continuous monitoring of the labour to ensure prompt identification of maternal or
fetal compromise, labour dystocia or uterine scar rupture. Consequently, all women in established VBAC
labour should receive:
l supportive one-to-one care
l intravenous access with full blood count and blood group and save
l continuous electronic fetal monitoring
l regular monitoring of maternal symptoms and signs
l regular (no less than 4-hourly) assessment of their cervicometric progress in labour.
For all labours, a meta-analysis showed that epidural analgesia increased the risk of second
stage delay and operative instrumental vaginal delivery.117 It is appropriate to consider early
placement of the epidural catheter so that it can be used later for labour analgesia or for
anaesthesia should an operative delivery become necessary.118
One study (NICHD103) suggested that planned VBAC success rates were higher among women
receiving epidural analgesia; two other studies reported the opposite finding.23,54 A recent
casecontrol study showed frequent epidural dosing to be an independent risk factor for
impending uterine rupture in VBAC labour.119 The increasing pain and analgesia requirement
that is likely to precede uterine rupture may explain the association between uterine rupture Evidence
level 3
and increasing epidural dosing in VBAC labour that progresses to uterine rupture.
The presence of any of the features in the list below is suggestive of uterine rupture. Abnormal
cardiotocography (CTG) is the most consistent finding in uterine rupture and is present in
6676% of these events. However, over half of cases present with a combination of findings
(most often abnormal CTG and abdominal pain).20,23,120 The diagnosis is made at emergency
caesarean delivery or postpartum laparotomy. Most uterine ruptures (more than 90%) occur
during labour (the peak incidence being at 45 cm cervical dilatation), with around 18%
occurring in the second stage of labour and 8% being identified post vaginal delivery.23
The clinical features associated with uterine scar rupture include:
l abnormal CTG
l severe abdominal pain, especially if persisting between contractions
l acute onset scar tenderness
l abnormal vaginal bleeding
l haematuria
l cessation of previously efficient uterine activity
l maternal tachycardia, hypotension, fainting or shock
l loss of station of the presenting part
l change in abdominal contour and inability to pick up fetal heart rate at the old
transducer site.
The risk of uterine rupture in an unscarred uterus is extremely rare at 2 per 10000 (0.02%)
deliveries and this risk is mainly confined to multiparous women in labour.20,23,121 The risk of
uterine rupture in planned VBAC is approximately 2050 per 10000 (0.20.5%) and in ERCS
the risk is 2 per 10000 (0.02%) (Appendix V).9,20,22,73 Early diagnosis of uterine scar dehiscence Evidence
or rupture followed by expeditious laparotomy and neonatal resuscitation are essential to level 3
reduce associated morbidity and mortality. An observational study indicated a potential upper
limit for nonhypoxic neonatal delivery of 18 minutes from suspected uterine rupture to
delivery.122 It is important to note that scar dehiscence may be asymptomatic in up to 48% of
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women, and the classic triad of a complete uterine rupture (pain, vaginal bleeding, fetal heart Evidence
level 3
rate abnormalities) may present in less than 10% of cases.123
8.2 How should women with a previous caesarean birth be advised in relation to induction
or augmentation of labour?
Women should be informed of the two- to three-fold increased risk of uterine rupture and around
1.5-fold increased risk of caesarean delivery in induced and/or augmented labour compared with
spontaneous VBAC labour.
A senior obstetrician should discuss the following with the woman: the decision to induce labour,
the proposed method of induction, the decision to augment labour with oxytocin, the time intervals
for serial vaginal examination and the selected parameters of progress that would necessitate
discontinuing VBAC.
Clinicians should be aware that induction of labour using mechanical methods (amniotomy or
Foley catheter) is associated with a lower risk of scar rupture compared with induction using
prostaglandins.
Although induction and augmentation are not contraindicated in women with previous
caesarean delivery, there remains considerable disagreement among clinicians on their use.
Induction (particularly in women with an unfavourable cervix or by prostaglandin method) or
augmentation of VBAC labour are associated with a two- to three-fold increased risk of uterine
rupture and around a 1.5-fold increased risk of caesarean delivery compared with spontaneous
VBAC labour (Appendix V). Studies evaluating oxytocin use in VBAC labour have not recorded
the indication for oxytocin use. However, it would seem plausible to assume that uterine Evidence
level 3
rupture would be more likely to occur if oxytocin was used to overcome delayed progress
when uterine activity appeared to be adequate (appropriate strength/frequency uterine
contractions) compared with when uterine activity was absent or inadequate (infrequent/
weak strength contractions). Furthermore, a casecontrol study has shown that utilising
higher dose oxytocin (exceeding 20 milliunits/minute) during VBAC augmentation increases
the risk of uterine rupture by four-fold or greater.124,125
The decision to induce or augment VBAC labour should be determined following careful obstetric
assessment and be made by senior obstetricians in consultation with the women. As part of informed
consent, women should be made aware of the increased risks (uterine rupture and emergency caesarean
delivery) associated with induction and/or augmentation of VBAC labour, and of the alternative option of
caesarean delivery. Women who are contemplating many future pregnancies may be prepared to accept
the additional risks associated with induction and/or augmentation in an effort to avoid the potential
long-term surgical risks associated with multiple repeat caesarean deliveries.
Women with previous caesarean delivery who have not previously given birth vaginally
and those who have labour induced with prostaglandins are at increased risk of uterine
rupture and the same two factors are associated with an increased risk of perinatal death
due to uterine rupture.105 In the NICHD study,18 prostaglandin induction compared with nonprostaglandin induction (e.g. amniotomy or intracervical Foley catheter) was associated with
a higher uterine rupture risk (87 per 10000 [0.87%] versus 29 per 10000 [0.29%]) and a Evidence
level 3
higher risk of perinatal death due to uterine rupture (11.2 per 10000 [0.11%] versus 4.5 per
10000 [0.045%]). Hence, careful consideration should be given to using prostaglandins and,
if prostaglandins are to be used, to restricting the dose of total prostaglandin exposure in
accordance with locally agreed guidelines, or considering another method of induction, such
as an intracervical Foley catheter.126
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Two retrospective studies127,128 have suggested that low-dose prostaglandin E2 is a safe option
for induction of labour in women undergoing VBAC, with no appreciable increase in rates of
uterine rupture or maternal and perinatal mortality when compared with women undergoing Evidence
a spontaneous VBAC. However, a Cochrane review129 suggested that there is insufficient level 2
evidence from randomised controlled trials to determine the lowest risk method of induction
of labour with a previous caesarean delivery.
9.
Planning and conducting ERCS
9.1 What elements are involved in the perioperative, intraoperative and postoperative care
for ERCS?
ERCS delivery should be conducted after 39+0 weeks of gestation.
Antibiotics should be administered before making the skin incision in women undergoing ERCS.
All women undergoing ERCS should receive thromboprophylaxis according to existing RCOG guidelines.
Early recognition of placenta praevia, adopting a multidisciplinary approach and informed consent
are important considerations in the management of women with placenta praevia and previous
caesarean delivery.
P
P
Recommended practice relating to planning and conducting ERCS is provided in the NICE caesarean
section guideline.6 In addition to standard perioperative measures for conducting ERCS, there are further
specific issues that warrant discussion.
Women considering ERCS should be counselled that delaying delivery by 1 week from 38 +0 to
39 +0 weeks enables around a 5% reduction (6% versus 1%) in the risk of respiratory morbidity
(particularly reducing the risk of transient tachypnoea of the newborn),7881,130 but this delay
may be associated with a 5 per 10000 (0.05%) increase in the risk of antepartum stillbirth.76
Should there be a need to perform ERCS prior to 39 weeks, consideration should be given to
administering maternal corticosteroids.6,130 A randomised controlled trial demonstrated a 50%
reduction in respiratory morbidity by administering prophylactic betamethasone to women
having elective caesarean deliveries beyond 37+0 weeks (steroid versus control 2.4% versus
5.1%; relative risk 0.46, 95% CI 0.230.93) and this treatment effect was still apparent at 39 +0
weeks of gestation (steroid versus control, 0.6% versus 1.5%).82
However, the current RCOG Green-top Guideline on antenatal corticosteroids130 raises a
caution that there is an absence of evidence available for the safety of antenatal corticosteroids
in babies born after 36 +0 weeks of gestation; some research suggests the existence of potential Evidence
long-term adverse effects in infants of mothers who received antenatal corticosteroids.72,131 level 1+
A follow-up study from the trial of steroids prior to term caesarean delivery demonstrated
no long-term benefit of steroids, but found that glucocorticoid-exposed children were twice
as likely to be identified as being in the lowest achievement group at school compared with
controls (33/186 [17.7%] versus 14/164 [8.5%] respectively, relative risk 2.1, 95% CI 1.13.7, P =
0.01).132 These issues should be discussed with women prior to the use of steroids and efforts
should be directed to avoiding ERCS prior to 39 +0 weeks rather than a more liberal use of
earlier delivery and antenatal steroids.
Perioperative preincision antibiotics achieve a greater reduction in the risk of maternal infection
than prophylactic antibiotics administered after making the skin incision. No detrimental effects
on the baby have been demonstrated. Ideally, the chosen antibiotic should protect against
endometritis and urinary tract and wound infections: i.e. cefuroxime and metronidazole.6
16 of 31
Concerns about the use of co-amoxiclav in pregnancy were raised by the Overview of the Role
of Antibiotics in Curtailing Labour and Early Delivery (ORACLE) studies, which demonstrated an
increased incidence of necrotising enterocolitis when it was given in preterm prelabour rupture
of membranes133 and a nonsignificant increase when used during spontaneous preterm labour.134 Evidence
level 1+
Extrapolating from these data, the NICE Guideline Development Group advise against its use as
prophylaxis before skin incision or before cord clamping at the time of caesarean delivery, citing
a hypothetical increased risk of necrotising enterocolitis by fetal exposure to co-amoxiclav.135
The choice of method of thromboprophylaxis should be as per the RCOG guidance.136
The RCOG has published guidance on the diagnosis and management of placenta praevia in Evidence
level 4
association with a caesarean delivery and placenta accreta45 and its recommendations should
be followed in women with a previous caesarean delivery and placenta praevia.
10. How should women in special circumstances be cared for?
Clinicians should be aware that there is uncertainty about the safety and efficacy of planned
VBAC in pregnancies complicated by post-dates, twin gestation, fetal macrosomia, antepartum
stillbirth or maternal age of 40 years or more. Hence, a cautious approach is advised if VBAC is
being considered in such circumstances.
Women who are preterm and considering the options for birth after a previous caesarean delivery
should be informed that planned preterm VBAC has similar success rates to planned term VBAC but
with a lower risk of uterine rupture.
41+0 weeks of gestation

The NICE induction of labour guideline recommends induction of labour from 41+0 weeks as
this reduces perinatal mortality without an increase in caesarean delivery rates.137 There are
no adequate data to recommend whether such an approach is equally valid in women with
previous caesarean delivery. The risk of stillbirth at or after 39 weeks is between 1.5- and
two-fold higher in women with previous caesarean delivery compared with women without Evidence
previous caesarean delivery (absolute risks 11 per 10000 [0.11%] versus 5 per 10000 [0.05%]).76 level 3
Hence, the reduction in risk of perinatal death that occurs by delivering from 41 weeks is likely
to be greater among women with previous caesarean delivery. However, in such women,
induction of labour compared with spontaneous labour is associated with increased risks of
emergency caesarean delivery (by 1.5-fold) and uterine scar rupture (by two- to three-fold).
A reasonable approach would be for women who planned VBAC to have a review by a senior obstetrician
at 41+0 weeks of gestation if spontaneous onset of labour has not ensued (Appendix II). Such a review
should assess her likelihood of successful VBAC (for example, favourable cervix, previous vaginal
birth, absence of any obstetric or fetal complications), her understanding of the increased maternal and
perinatal risks if induction is chosen, her preference for membrane sweep, spontaneous VBAC, induced
(amniotomy or prostaglandin) VBAC or ERCS, and her future reproductive preferences. In practice, this
may mean scheduling a provisional ERCS at around 40 +10 weeks and converting to induction of labour
depending on further clinical and cervical assessment at 40 +10 weeks.
Twin gestation
Various studies, including the NICHD study (n = 186 twin pregnancies)138 and three US
retrospective studies (n = 535,139 n = 1850,140 n = 25141 twin pregnancies), have reported similar Evidence
level 3
successful rates of VBAC in twin pregnancies (4584%) to those in singleton pregnancies.
17 of 31
Suspected fetal macrosomia

In relation to VBAC labour, birthweight of 4 kg or more is associated with an increased
risk of uterine rupture (OR 2.62, 95% CI 1.0016.85), unsuccessful VBAC (OR 2.47, 95% CI
1.823.34), shoulder dystocia (OR 25.13, 95% CI 9.3167.86) and third- and fourth-degree
perineal laceration (OR 2.64, 95% CI 1.664.19).110 For women with no prior vaginal delivery
undergoing VBAC labour when neonatal birthweight was 4 kg or higher, the VBAC success Evidence
rate was reported as less than 50% and the uterine rupture rate was 3.6%.142 A subgroup level 2
analysis of the NICHD study showed that, among women with previous caesarean delivery
for dystocia, greater birthweight in the subsequent planned VBAC labour (relative to the first
birthweight) was associated with a decreased likelihood of successful VBAC.108 However, third
trimester ultrasound is a poor predictor of macrosomia in decision making regarding VBAC.
Women with an antepartum stillbirth and a previous caesarean delivery undergo labour with
a high VBAC success rate (87%). The care of these women should be in line with national Evidence
guidelines.143 However, because a proportion of cases required induction and/or augmentation, level 3
one study reported a uterine rupture rate of 2.4%.144
Maternal age of 40 years or more

Maternal age of 40 years or more is an independent risk factor for stillbirth145 and unsuccessful
VBAC.103,146,147 Published advice suggests consideration of delivery of women aged 40 years
or more by 39 +040 +0 weeks to reduce the risk of adverse perinatal outcome (particularly
stillbirth).145 However, given the likely additive effects of previous caesarean delivery and Evidence
level 4
raised maternal age on the risk of stillbirth, careful consideration should be given to the
timing of the delivery in women aged 40 years or above who plan VBAC. There is insufficient
evidence to recommend optimum timing of delivery in this subgroup of women.
Preterm VBAC
The NICHD study showed planned VBAC success rates for preterm and term pregnancies
were similar (72.8% versus 73.3%). However, the rates of uterine rupture (34 per 10000 versus
74 per 10000 respectively) and dehiscence (26 per 10000 versus 67 per 10000 respectively) Evidence
level 2
were significantly lower in preterm compared with term VBAC.148 Perinatal outcomes were
similar with preterm VBAC and preterm ERCS.
l Development, validation and pragmatic clinical evaluation of an antenatal- and/or intrapartum-
based scoring system to identify women at high or low risk of unsuccessful VBAC.
l Determine the clinical value of antenatal and intrapartum ultrasound to predict the likelihood of
successful VBAC or uterine rupture using specific (e.g. ultrasonographically measured myometrial
scar thickness) or combination parameters.
l Investigate the aetiology and prevention (e.g. specific antenatal monitoring strategies, timing
of delivery) of the increased risk of stillbirth in women with previous caesarean delivery in the
presence or absence of other previous complications (e.g. pre-eclampsia, preterm delivery, small
for gestational age).
l Investigate cervicometric progress in VBAC labour and determine the value of timing interventions
to maximise VBAC success and minimise uterine rupture.
l Research into factors that may explain the regional and unit-based variation in uptake of VBAC
and the factors that impact most on women accepting or declining VBAC (e.g. patient information
18 of 31
leaflet, previous childbirth experiences, desired family size, understanding the risk analysis during
counselling, how to reduce any decisional conflict, variation in case mix).
l Investigate the use of mechanical dilators for induction of VBAC labour.
l Documented discussion of risks and benefits of VBAC versus ERCS/use of VBAC checklists (100%).
l Proportions of women experiencing successful versus unsuccessful spontaneous and induced
planned VBAC (particularly with reference to the induction method).

l 100% reporting of serious maternal (e.g. uterine rupture, peripartum hysterectomy, mortality) and
neonatal (e.g. antepartum stillbirth, HIE, intrapartum and neonatal mortality) morbidity/mortality
consequent to VBAC versus ERCS via a local incident reporting system.
l Effectiveness of antenatal screening for placenta praevia and accreta, including frequency of
missed antenatal diagnoses against locally agreed standards.
l Use of continuous electronic fetal monitoring during VBAC labour (100%).
l Documentation of senior obstetrician involvement in induction and augmentation of VBAC
labour (100%).
l Caesarean Birth and VBAC Information [http://caesarean.org.uk].
l Royal College of Obstetricians and Gynaecologists. Birth after a caesarean section: Information
for you. London: RCOG; 2015.

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Appendix I: Definitions of terms

Planned VBAC
Planned VBAC (vaginal birth after previous caesarean delivery) refers to the
intended mode of delivery of any woman who has experienced a prior caesarean
birth who plans to deliver vaginally rather than by elective repeat caesarean
section (ERCS).
Successful and unsuccessful

planned VBAC
A vaginal delivery (spontaneous or assisted) in a woman undergoing planned

VBAC indicates a successful VBAC. Delivery by emergency caesarean during
the labour indicates an unsuccessful VBAC.
Uterine rupture
Disruption of the uterine muscle extending to and involving the uterine serosa or
disruption of the uterine muscle with extension to the bladder or broad ligament.
Uterine dehiscence
Disruption of the uterine muscle with intact uterine serosa.
Perinatal mortality
Combined number of stillbirths (antepartum and intrapartum) and neonatal

deaths between 20 weeks of gestation and 28 days of life per 10000 live
births and stillbirths. Perinatal mortality rate will exclude deaths due to fetal
malformation unless otherwise stated.
Term delivery-related perinatal

death
Term delivery-related perinatal death is defined as the combined number of

intrapartum stillbirths and neonatal deaths per 10000 live births and stillbirths
at or beyond 37+0 weeks of gestation. Birth-related perinatal mortality rates
exclude antepartum stillbirths and deaths due to fetal malformation unless
otherwise stated.
Neonatal respiratory morbidity
Combined rate of transient tachypnoea of the newborn and respiratory distress

syndrome.
24 of 31
Appendix II: Example of a schedule of antenatal care

12+0 weeks
Provision of written patient information on delivery options (VBAC and ERCS).
1821+0 weeks
Ultrasonographer to perform midtrimester scan for fetal anomaly and placental localisation.
Reschedule ultrasound at 3234 weeks for women identified to have a low-lying placenta with a
history of previous caesarean delivery.
2128 weeks
Antenatal counselling appointment for women with uncomplicated singleton pregnancies and
single previous lower segment caesarean delivery. Documented counselling of risks and benefits
of VBAC versus ERCS (facilitated by use of decision aid, pro forma or checklist). A review of the
previous caesarean delivery, with access to the womans previous obstetric medical record, should
take place. Counselling should be undertaken by member(s) of the maternity team.
Midwifery review for all pregnant women. Undertake routine reviews and completion of 28-week
screening tests (e.g. full blood count, ABO rhesus D group status, administration of anti-D if
appropriate).
3234 weeks
Obstetrician-led assessment of women with previous caesarean delivery who are identified to have
a low-lying placenta at 3234-week obstetric ultrasound. The aim is to provide adequate time for
investigation and management of possible placenta accreta.
Midwifery review for women with normally sited placenta. Establish womans preference for
planned VBAC or ERCS and ensure suitability for planned VBAC (i.e. cephalic presentation, no other
obstetric complications).
By 36 weeks
Obstetrician-led assessment to determine mode of delivery for women who opted for ERCS, are
undecided on mode of delivery or have complicating obstetric and medical disorders (e.g. multiple
pregnancy, delivery of a macrosomic infant [birthweight of 4 kg or more], small for gestational age
and/or fetal growth restriction, pre-eclampsia).
Midwifery review to confirm suitability and maternal preference for planned VBAC (i.e. woman
understands all risks/benefits, has normally grown fetus with cephalic presentation, no other
obstetric complications).
After 39 weeks
Performing ERCS
If ERCS is required prior to 39 +0 weeks for obstetric or medical indications then prophylactic
antenatal corticosteroids may be considered to reduce the risk of neonatal respiratory morbidity
(transient tachypnoea of the newborn, respiratory distress syndrome). However, concerns
regarding the long-term safety should be discussed with the mother.
41+0 weeks
Senior obstetrician-led assessment for women who had opted for planned VBAC but have not gone
into spontaneous labour. Risks and benefits of various options are discussed and documented.
Options include membrane sweep, prostaglandin, amniotomy or Foley catheter induction of labour,
ERCS or expectant management.
25 of 31
Appendix III: Clinical management of pregnant women who have had one or more caesarean birth(s)
Management of pregnant women who have one or more caesarean birth(s)
Any contraindications to VBAC
l Placental localisation exclude praevia accreta.

l Review previous record and operative notes.
l Medical or obstetric conditions that preclude VBAC.
Antenatal counselling and shared decision-making process
l E xplain risks and benefits of planned VBAC versus ERCS, including the individualised likelihood of VBAC success.
m For example, women with previous vaginal births should be informed that previous vaginal delivery, particularly
previous VBAC, is the single best predictor of successful VBAC and is associated with planned VBAC success rates of
8590%.
m Greater maternal height, maternal age less than 40 years, BMI less than 30, gestation of less than 40 weeks and
infant birthweight less than 4 kg (or similar/lower birthweight to/than index caesarean delivery) are associated with
an increased likelihood of successful VBAC.
m In addition, spontaneous onset of labour, vertex presentation, fetal head engagement or a lower station, and higher
admission Bishop score also increase the likelihood of successful VBAC.
m Successful VBAC is more likely among women with prior caesarean for fetal malpresentation (84%).
l Elicit maternal choice for mode of delivery and how it fits with future reproductive preferences.
Intrapartum care for VBAC
l Delivery setting, monitoring, analgesia.

l Recognising failure to progress and/or uterine rupture.
l Caution if induction and/or augmentation is/are considered necessary.
Intrapartum care for ERCS
l Preferred gestational timing to conduct caesarean (from 39 +0 weeks).

l Perioperative management.
Management of women in special circumstances
l VBAC in the presence of high-risk obstetric factors.
26 of 31
Appendix IV: Birth choices after caesarean delivery pathway

Likelihood of
Overall
Successful VBAC (one previous caesarean delivery, no previous vaginal birth)
3 out of 4 or 7275%
Successful VBAC (one previous caesarean delivery, at least one previous

vaginal birth)
Almost 9 out of 10 or
up to 8590%
Tick when
discussed
Unsuccessful VBAC more likely in:

Induced labour, no previous vaginal delivery, body mass index (BMI) greater than 30 and previous
caesarean for labour dystocia. If all of these factors are present, successful VBAC is achieved in 40%
of cases.
Likelihood of
VBAC
ERCS
Maternal
Uterine rupture
5 per 1000/0.5%
< 2 per 10000/< 0.02%
Blood transfusion
2 per 100/2%
1 per 100/1%
Endometritis
No significant difference in risk
Serious complications
in future pregnancies
Not applicable if successful

VBAC
Increased likelihood of placenta praevia/

morbidly adherent placenta
Maternal mortality
4 per 100000/0.004%
13 per 100000/0.013%
Fetal/newborn
Transient respiratory
morbidity
23 per 100/23%
46 per 100/46% (risk reduced with

corticosteroids, but there are concerns
about potential long-term adverse effects)
beyond 39 +0 weeks
while awaiting
spontaneous labour
10 per 10000/0.1%
Not applicable
Hypoxic ischaemic
encephalopathy (HIE)
8 per 10000/0.08%
< 1 per 10000/< 0.01%
Information leaflet(s) provided:
VBAC
ERCS
Other
Discussed:
Continuous electronic fetal monitoring at the onset of regular uterine contractions
Birth on the labour suite
Need for intravenous (IV) access in labour
Comments:
27 of 31
Management plan in the event of:

Preterm labour (< 37+0 weeks)
VBAC
Emergency caesarean delivery
Spontaneous labour before

ERCS date
VBAC
Caesarean delivery
No spontaneous labour after

41 weeks discussed with
senior obstetrician
Sweep
I nduction of labour (give details of agreed plan below)
D
epends on stage of
labour details below
ERCS
Use of oxytocin in labour

discussed with senior
obstetrician
Details of induction of labour:
ERCS booking details:
Additional comments:
28 of 31
Appendix V: VBAC success and uterine rupture risks of planned VBAC labours
Spontaneous
Induced
Augmented
VBAC success
*74% (95% CI
7275%)
63% (95% CI
5967%)
68% (95% CI
6472%)
Uterine rupture
*0.47% (95% CI
0.280.68%)
1.2% (95% CI
0.71.9%)
1.1% (95% CI
0.91.5%)
NICHD study18,103
(n = 17898 VBACs)
VBAC success
80.6%
67.4%
73.9%
Uterine rupture
0.36%
1.02%
0.87%
Australian population study22

(n = 10958 VBACs)
VBAC success
52.6%
51.4%
61.6%
Uterine rupture
0.15%
0.68%
1.91%
UK Obstetric Surveillance System

casecontrol study20
Uterine rupture
0.13%
0.36%
0.28%
AHRQ meta-analysis9
*refers to overall rates when spontaneous, induced and augmented labours are combined, although the large majority of data
are derived from spontaneous labour.
29 of 31
Appendix VI: Explanation of guidelines and evidence levels


low risk of bias


1++ or 1+

results; or
2++

low risk of bias
risk of bias
case series
4
Good practice point
Expert opinion
30 of 31

development group
Professor JK Gupta FRCOG, Birmingham; Professor GCS Smith FRCOG, Cambridge; and Mr RR Chodankar MRCOG,
Camberley
Professor Z Alfirevic FRCOG, Liverpool; Ms SM Baines, midwifery lecturer and supervisor of midwives,
Wrightington, Wigan and Leigh NHS Foundation Trust; Dr S Bewley FRCOG, London; British Maternal and
Fetal Medicine Society; Dr AA Elkady FRCOG, Greater Cairo, Egypt; Mr UI Esen FRCOG, South Shields;
Dr M Formosa FRCOG, Msida, Malta; Mr DI Fraser FRCOG, Norwich; Mr M Griffiths FRCOG, Luton; Dr S Hamilton
FRCOG, Huntingdon; Dr KR Harding FRCOG, London; Mr DW Irons FRCOG, Durham; Dr SI Kayani FRCOG,
Sabah Al-Salem, Kuwait; Dr R Malhas MRCOG, Walsall; Mr CN Nzewi MRCOG, Guernsey; Mr SOU Orife FRCOG,
South Shields; Dr MAK Perera, Avissawella, Sri Lanka; RCOG Ethics Committee; RCOG Womens Network;
Royal College of Midwives; Dr S Rutter MRCOG, Rotherham; Dr P Sarkar FRCOG, Slough; Dr JR Scott FRCOG,
Salt Lake City, Utah, USA; Dr M Sinha MRCOG, Chichester; Mrs P Sinha FRCOG, St Leonards-on-Sea; Dr CY Spong,
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of
Health, Bethesda, Maryland, USA; The Royal College of Radiologists; Dr CL Tower MRCOG, Manchester;
Dr AU Ukpong, Port Harcourt, Nigeria; Mr DP Webster MRCOG, Poole; and Dr SNE Webster MRCOG,
Newcastle upon Tyne.
Committee lead reviewers were: Mrs G Kumar FRCOG, Wrexham; Dr P Owen FRCOG, Glasgow; and
Dr AJ Thomson MRCOG, Paisley.
The chairs of the RCOG Guidelines Committee were: Dr M Gupta1 MRCOG, London; Dr P Owen2 FRCOG, Glasgow;
1
conflicts of interest for this guideline is available from: https://www.rcog.org.uk/en/guidelines-research-services/
guidelines/gtg45/.
DISCLAIMER
31 of 31
Post-Hysterectomy
Vaginal Vault Prolapse
RCOG/BSUG Joint Guideline | July 2015
Post-Hysterectomy Vaginal Vault Prolapse

This is the second edition of this guideline, previously published in 2007 as a joint guideline with the
British Society of Urogynaecology as The Management of Post Hysterectomy Vaginal Vault Prolapse.
Diagnosis and investigation

What is the preferred classification for vault/pelvic organ prolapse?
Standardised classification systems should be used for the assessment and documentation of
pelvic organ prolapse (POP), including vault prolapse.
When is urodynamic testing required?

Routine urodynamic assessment is not recommended in women with post-hysterectomy vaginal
vault prolapse (PHVP). [New 2015]
In what setting should a patient with PHVP be assessed?

Clinicians should work as part of a pelvic floor multidisciplinary team (MDT). [New 2015]
Are quality of life (QoL) measures of value?

Patient assessment should address QoL issues using standardised tools.
Prevention
What preventive techniques are of value at hysterectomy?
McCall culdoplasty at the time of vaginal hysterectomy is effective in preventing subsequent PHVP.
Suturing the cardinal and uterosacral ligaments to the vaginal cuff at the time of hysterectomy is
effective in preventing PHVP following both abdominal and vaginal hysterectomies.
Sacrospinous fixation (SSF) at the time of vaginal hysterectomy should be considered when the
vault descends to the introitus during closure.
Does subtotal hysterectomy have a place in the prevention of PHVP?

Subtotal hysterectomy is not recommended for the prevention of PHVP. [New 2015]
Are there preferred suture materials for vault support at the time of hysterectomy?
There is inadequate and conflicting evidence over the use of permanent sutures in the short term
and no evidence of benefit in the long term; they can be associated with high suture exposure
rates. [New 2015]
Is pelvic floor therapy of value in the management of PHVP?
Pelvic floor muscle training (PFMT) is an effective treatment option for women with stage III
vaginal prolapse, including PHVP. [New 2015]
RCOG/BSUG Green-top Guideline No. 46
2 of 21
What is the place of vaginal devices?

Vaginal pessaries are an alternative treatment option for women with stage IIIV PHVP. [New 2015]
Surgical management
What are the indications for surgery?
Surgical treatment should be offered to women with symptomatic PHVP after appropriate
counselling. [New 2015]
Who should undertake surgery?

PHVP surgery should be performed by an RCOG-accredited subspecialist urogynaecologist, or
gynaecologists who can demonstrate an equivalent level of training or experience. [New 2015]
What is an acceptable successful result after surgical treatment?

Patient-reported outcomes, including patient-reported success rates and relief of presenting
symptoms, should be the primary assessment outcomes. [New 2015]
Objective cure is important as it correlates to symptoms of vaginal bulge; a Pelvic Organ Prolapse
Quantification (POP-Q) stage of I or O in the apical compartment seems to be acceptable and widely
used as the optimum postoperative result. [New 2015]
What surgical procedures are available for the treatment of PHVP?

The type of operation performed should be tailored to the individual patients circumstances.
A comparison of surgical procedures

Open abdominal sacrocolpopexy (ASC) versus vaginal SSF
Women should be aware that both ASC and SSF are effective treatments for primary PHVP.
ASC is associated with significantly lower rates of recurrent vault prolapse, dyspareunia and
postoperative stress urinary incontinence (SUI) when compared with SSF. However, this is not
reflected in significantly lower reoperation rates or higher patient satisfaction.
SSF is associated with earlier recovery compared with ASC.
SSF may not be appropriate in women with short vaginal length and should be carefully considered
in women with pre-existing dyspareunia.
Laparoscopic and robotic sacrocolpopexy (LSC and RSC)

LSC can be equally effective as ASC in selected women with primary PHVP. LSC can include mesh
extension or be combined with other vaginal procedures to correct other compartment prolapse.
There is limited evidence on the effectiveness of RSC; therefore, it should only be performed in the
context of research or prospective audit following local governance procedures. [New 2015]
High uterosacral ligament suspension (HUSLS)

HUSLS should only be offered as first-line management in women with PHVP within the context of
research or prospective audit following local governance procedures.
Clinicians should be aware of the risk of ureteric injury, especially in the laparoscopic approach.
3 of 21
Under what circumstances would transvaginal mesh (TVM) kits/grafts be considered?

The limited evidence on TVM kits does not support their use as first-line treatment of PHVP.
If TVM is considered, women should be fully informed of the permanent nature of the mesh and
potential mesh complications, some of which are serious and have long-term effects that can be
difficult to treat. [New 2015]
If TVM is considered, women should be fully informed of alternative surgical and nonsurgical
options and referral to other surgeons/units arranged as appropriate. [New 2015]
TVM should only be performed by an appropriately trained urogynaecologist, after discussion of

each individual case in an MDT meeting. [New 2015]
The results of all surgical procedures involving mesh should be prospectively audited and
submitted to a national surgical database (e.g. British Society of Urogynaecology [BSUG]) and
any mesh complications reported to the Medicines and Healthcare Products Regulatory Agency
(MHRA). [New 2015]
When should colpocleisis be used?

Colpocleisis is a safe and effective procedure that can be considered for frail women and/or women
who do not wish to retain sexual function.
Is there an indication for concomitant surgery for occult SUI?

Colposuspension performed at the time of sacrocolpopexy is an effective measure to reduce
postoperative symptomatic SUI in previously continent women. [New 2015]
Is there an indication for concomitant surgery for PHVP and overt SUI?
Colposuspension at the time of ASC does not appear to be effective treatment for SUI. [New 2015]
Concomitant mid-urethral sling surgery may be considered when vaginal surgical approaches are
used for the treatment of PHVP. [New 2015]
What is the optimal treatment of recurrent vault prolapse?

The management of recurrent vault prolapse should be through a specialist MDT with experience
and training in this field. [New 2015]
Clinical governance
National databases, such as the BSUG surgical database, should be used to document surgical
outcomes and complications. [New 2015]
The International Urogynecological Association (IUGA)/International Continence Society (ICS)
terminology and classification of complications should be used for the documentation of graftrelated complications. [New 2015]
All complications related to the use of devices and mesh should be reported to the MHRA. [New 2015]
4 of 21
P
P
P
1.
Purpose and scope
This guideline aims to assist generalist and subspecialist gynaecologists in the management of posthysterectomy vaginal vault prolapse (PHVP). The management of urinary incontinence is not covered in
this guideline; however, the role of concomitant continence procedures at the time of surgery for vault
prolapse is addressed.
2.
There is no precise definition of PHVP; however, the International Urogynecological Association (IUGA)/
International Continence Society (ICS) joint report on female pelvic floor dysfunction defines it as
descent of the apex of the vagina (vaginal vault or cuff scar after hysterectomy).1 The vaginal cuff
scar corresponds to point C on the Pelvic Organ Prolapse Quantification (POP-Q) grid (Appendix I).2
Prolapse of the vaginal vault after hysterectomy may occur when the structures that support the top of
the vagina and uterus are not reattached at the time of the initial procedure or due to weakening of these
supports over time.
Case series dating back to 1960 have identified the incidence of PHVP as ranging from 0.2% to 43%.35
More recently, PHVP has been reported to follow 11.6% of hysterectomies performed for prolapse and
1.8% for other benign diseases.6 A large study from Austria estimated the frequency of PHVP requiring
surgical repair to be between 6% and 8%.7
3.
A search of MEDLINE, EMBASE and The Cochrane Library from 20062013 for relevant systematic
reviews, meta-analyses, randomised controlled trials (RCTs) and other clinical trials was conducted.
A top-up search was performed in January 2015 for more recent evidence. The main Medical Subject
Headings (MeSH) and non-MeSH terms used included uterine prolapse, vault prolapse, pelvic organ
prolapse and hysterectomy with text words: sacrocolpopexy, sacrospinous fixation/suspension,
intravaginal slingplasty (IVS), posterior IVS, infracoccygeal sacropexy, colpocleisis, uterosacral
ligament suspension/plication, prolift, perigee, apogee, elevate, capio, i-stitch and avaulta.
4.
Diagnosis and investigation
4.1 What is the preferred classification for vault/pelvic organ prolapse?

Standardised classification systems should be used for the assessment and documentation of
pelvic organ prolapse (POP), including vault prolapse.
A number of classification systems for POP are used in both research and clinical settings.1,2,8,9
The use of standardised terminology is recommended as it enables assessment of outcomes for Evidence
level 4
individual women and facilitates the comparison of results for audit and research purposes.
The ICS POP-Q system is the most comprehensive and widely used.2
4.2 When is urodynamic testing required?

Routine urodynamic assessment is not recommended in women with PHVP.
Performing preoperative urodynamic testing with and without prolapse reduction in continent women
undergoing POP surgery does not always predict postoperative stress incontinence. Prophylactic
treatment for women thought to have occult stress urinary incontinence (SUI) will result in unnecessary
treatment for some women. Clinical assessment remains the most important assessment tool.
5 of 21
In the Colpopexy and Urinary Reduction Efforts (CARE) trial,1012 patients undergoing
sacrocolpopexy, who were asymptomatic for SUI, were randomised to undergo either a
concomitant Burch colposuspension or no Burch colposuspension (control group). The group
demonstrated that the preoperative incidence of urodynamic stress incontinence (USI) increased
from 3.7% to 19% following manual prolapse reduction, while using pessaries or speculum Evidence
reduction for prolapse was associated with detection rates of 6% and 30% respectively.13 level 1+
Women who demonstrated preoperative USI were at higher risk of postoperative SUI, even if
they underwent a concomitant Burch colposuspension. Preoperative urodynamic testing did
not, however, accurately predict USI in all cases, with 38% of women with negative testing in
the control group and 21% in the Burch group still developing symptomatic postoperative SUI.
The role of concomitant assessment and management of symptomatic SUI in women with POP, including
PHVP, is outwith the scope of this guideline.
4.3 In what setting should a patient with PHVP be assessed?

Clinicians should work as part of a pelvic floor multidisciplinary team (MDT).
Clinicians involved in the management of patients with PHVP should demonstrate an

appropriate level of training and clinical practice. Involvement of other specialties (e.g. Evidence
coloproctology or urology) or allied health professionals may be useful in the management of level 4
PHVP in patients with concomitant bladder/bowel symptoms.14
4.4 Are quality of life (QoL) measures of value?

Patient assessment should address QoL issues using standardised tools.
Many standardised and validated QoL assessment tools exist for use in women with vaginal
prolapse, but not specifically for use in women with PHVP. Some QoL tools are condition
specific and address symptom complexes (e.g. Pelvic Organ Prolapse/Urinary Incontinence
Sexual Questionnaire -12, International Consultation on Incontinence Modular Questionnaire
[ICIQ]-Vaginal Symptoms, ICIQ-Urinary Incontinence)15,16 while others look at the impact of Evidence
level 2+
the condition on patients activities (e.g. Pelvic Floor Distress Inventory, Pelvic Floor Impact
Questionnaire, ColorectalAnal Distress Inventory, Incontinence Impact Questionnaire,
Urogenital Distress Inventory).1719 Using these will require time and resources, such as
preprinted questionnaires and/or the availability of computers in clinics.
QoL questionnaires are useful audit and research tools that help with patient-centred assessment
and goals,20 but their use can be time consuming and may require additional resources that Evidence
level 4
may not alter patient outcomes.
5.
Prevention
5.1 What preventive techniques are of value at hysterectomy?

McCall culdoplasty at the time of vaginal hysterectomy is effective in preventing subsequent PHVP.
Suturing the cardinal and uterosacral ligaments to the vaginal cuff at the time of hysterectomy is
effective in preventing PHVP following both abdominal and vaginal hysterectomies.
Sacrospinous fixation (SSF) at the time of vaginal hysterectomy should be considered when the
vault descends to the introitus during closure.
A small RCT compared vaginal Moschcowitz-type operation, McCall culdoplasty and peritoneal Evidence
closure of the cul-de-sac as preventive measures against the development of enterocele. It level 1+
6 of 21
showed that McCall culdoplasty was more effective than vaginal Moschcowitz or simple
closure of the peritoneum in preventing enterocele at 3 years follow-up.21
McCall culdoplasty involves approximating the uterosacral ligaments using continuous Evidence
sutures, so as to obliterate the peritoneum of the posterior cul-de-sac as high as possible.22 A level 1+
similar approach has been described for abdominal hysterectomy.23,24 No comparative studies
are available to assess the value of such a step at the time of abdominal hysterectomy, which
is often carried out for indications other than prolapse.
A retrospective study evaluated the anatomical and functional results of the McCall culdoplasty
in a total of 185 patients undergoing vaginal hysterectomy for mild or moderate uterine
prolapse. At 24 months follow-up, the vaginal vault was well supported in 99.2%, with 89.2%
showing stage 0 vaginal vault prolapse and 10% showing stage I prolapse that did not require
revision surgery. Functional analysis showed satisfactory sexual function at 24 months post
surgery for 81.2% of patients.25
Attaching the uterosacral and cardinal ligaments to the vaginal cuff and high circumferential Evidence
level 2+
obliteration of the pouch of Douglas have been shown to prevent PHVP and subsequent
enterocele formation.26 No cases of vault prolapse or enterocele were recorded among 112
patients over a follow-up period extending from 742 months.
One observational study showed that incorporation of the cardinaluterosacral ligaments into
the vaginal cuff margins at the time of total abdominal hysterectomy may help to minimise
subsequent apical vault prolapse.27
A systematic review28 of vaginal uterosacral ligament suspension provided a meta-analysis of
anatomical outcomes and a summary of subjective outcomes. In the apical compartment, the Evidence
level 1++
pooled rates for a successful outcome were 98.3%.
Prophylactic SSF has been suggested at the time of vaginal hysterectomy for marked uterovaginal
prolapse,29 when the vault (point C on the POP-Q system) could be pulled to the introitus at
the end of anterior vaginal wall closure. A small retrospective study reported only one case of
recurrent PHVP in 48 patients with a mean follow-up of 2 years.29 In this series, twenty women Evidence
level 2+
complained of right buttock pain; all resolved spontaneously by 6 weeks follow-up, while five
women subsequently developed de novo anterior vaginal wall prolapse. No information was
provided about sexual dysfunction in this study.
5.2 Does subtotal hysterectomy have a place in the prevention of PHVP?

Subtotal hysterectomy is not recommended for the prevention of PHVP.
There is no evidence to support the role of subtotal hysterectomy in preventing PHVP. A metaanalysis showed that although subtotal hysterectomy is quicker to perform and there are fewer Evidence
intra- and postoperative complications, more women suffered with urinary incontinence and level 1+
prolapse compared with women who had a total hysterectomy.30
5.3 Are there preferred suture materials for vault support at the time of hysterectomy?
There is inadequate and conflicting evidence over the use of permanent sutures in the short term
and no evidence of benefit in the long term; they can be associated with high suture exposure rates.
In a retrospective analysis of 248 patients who underwent uterosacral ligament suspension, Evidence
permanent (2-0 Ti-Cron, Covidien, Dublin, Ireland) and delayed absorbable polydioxanone level 2+
7 of 21
(0-Maxon, Covidien, Dublin, Ireland) sutures were compared for failure of anatomical
support. In the short term, the use of permanent sutures for uterosacral ligament suspension
of the vaginal apex was associated with a lower failure rate than delayed absorbable sutures, Evidence
but there were 16 cases of permanent suture exposure that required removal.31 Another study level 2+
found that permanent sutures do not offer significantly better apical support at short-term
follow-up and are also associated with a high rate of suture erosion.32
6.
6.1 Is pelvic floor therapy of value in the management of PHVP?

Pelvic floor muscle training (PFMT) is an effective treatment option for women with stage III
vaginal prolapse, including PHVP.
No trials looking specifically at the role of PFMT in women with PHVP were identified.
A large multicentre RCT (the Pelvic Organ Prolapse PhysiotherapY [POPPY] trial) 33 showed
that one-to-one PFMT for prolapse is effective for the improvement of prolapse symptoms. Evidence
level 1+
This study included, but did not exclusively address, women with PHVP.
There is growing evidence, including a small number of RCTs, to indicate that PFMT has a
positive effect on prolapse symptoms and severity3436 in women with POP-Q stage III vaginal Evidence
level 1
prolapse compared with no treatment. These trials included, but were not specific to, PHVP.
Both the National Institute for Health and Care Excellence and the American College of
Obstetricians and Gynecologists list PFMT as a treatment option in women with all types of Evidence
level 4
vaginal prolapse.3740
6.2 What is the place of vaginal devices?

Vaginal pessaries are an alternative treatment option for women with stage IIIV PHVP.
A randomised crossover trial (the PESSRI study) compared two different vaginal pessaries
(Gellhorn versus ring) in women with stage IIIV prolapse and showed clinically significant Evidence
improvements in prolapse symptoms with both types of pessaries, but no significant differences level 1+
between pessary groups.41
Pessaries should be considered in all women with POP, including PHVP.3740 Consideration
needs to be given to sexual function, regular pessary changes and possible complications such Evidence
level 4
as ulceration, vaginal bleeding and a small risk of fistula formation.
7.
Surgical management
7.1 What are the indications for surgery?

Surgical treatment should be offered to women with symptomatic PHVP after appropriate
counselling.
The decision to offer surgical treatment for PHVP should primarily be determined by the womans
symptoms, her response to conservative treatment, the impact of PHVP on her QoL and daily activities
and also on her fitness for surgery. The planned procedure should be fully discussed, including success
rates, recurrence, potential complications, and the impact of treatment and potential complications on
womens QoL and sexual function.
8 of 21
7.2
Who should undertake surgery?
PHVP surgery should be performed by an RCOG-accredited subspecialist urogynaecologist, or

gynaecologists who can demonstrate an equivalent level of training or experience.
No studies were identified that evaluated the level of training and/or experience that a surgeon is
required to achieve prior to undertaking PHVP surgery, nor the workload per year that is required to
maintain skills. In the UK at the present time, PHVP surgery is not part of the urogynaecology Advanced
Training Skills Module, but is part of subspecialty training in urogynaecology. There will of course be
established consultants who completed their training prior to the creation of such programmes who will
be able to demonstrate equivalent training and experience if they undertake such surgery.
For all surgeons, an adequate workload of each procedure per year is required to maintain skills;
however, there is no robust evidence to advise on the volume of such workload. A clear referral pathway
should be in place to refer the patient to the appropriate surgeon to undertake the required procedure.
7.3 What is an acceptable successful result after surgical treatment?

Patient-reported outcomes, including patient-reported success rates and relief of presenting
symptoms, should be the primary assessment outcomes.
Objective cure is important as it correlates to symptoms of vaginal bulge; a POP-Q stage of I or O in

the apical compartment seems to be acceptable and widely used as the optimum postoperative result.
The primary aims of surgical treatment are the restoration of normal vaginal anatomy,
improvement in vaginal bulge symptoms and the restoration/maintenance of normal bladder,
bowel and sexual function. Most of the studies in the literature, however, have used the
anatomical outcome as the primary outcome, with POP-Q stages I or 0 defined as the anatomical
cure.42 A recent qualitative study based on patient interviews showed that women are most
affected by the actual physical symptoms of prolapse (bulge, pain and bowel problems) as
well as by the impact that prolapse has on their sexual function.43 The prevalence of pelvic
floor dysfunction symptoms was found to be quite high 6 years after primary POP surgery:
urinary leakage (once or more/week, 41%), vaginal bulge (18%), faecal incontinence (15%) and
Evidence
refraining from sexual intercourse (15%).44
level 2+
A number of studies have showed that vaginal descent distal to the hymen (point C greater
than 0 cm) accurately predicts the symptoms of prolapse bulging/protrusion; however, these
studies failed to identify a threshold of prolapse severity that predicted other pelvic floor
symptoms.4547 An updated definition of objective failure was therefore proposed in the longterm outcome of a large RCT;48 which defined failure as point C greater than (two-thirds x
total vaginal length), i.e. the vaginal apex descending below the upper third of the vagina, or
one of points Ba or Bp being greater than 0 cm, i.e. the anterior (Ba) or posterior (Bp) vaginal
wall prolapsing beyond the hymen.
The outcome reporting scheme proposed by IUGA/ICS is recommended.49
Evidence
level 4
7.4 What surgical procedures are available for the treatment of PHVP?
The type of operation performed should be tailored to the individual patients circumstances.
A variety of procedures exist for surgical treatment of PHVP in women who are deemed fit for
surgery. There is no robust evidence to guide the clinician as to the best surgical technique Evidence
for a particular patient. The type of operation performed should be tailored to the individual level 4
patients circumstances, such as concomitant prolapse in other compartment(s), sexual
9 of 21
activity, previous abdominal surgery, previous prolapse surgery, the total vaginal length,
and associated comorbidities. Women with multiple compartment prolapse and/or a history
of extensive abdominal surgery can be quite challenging with the abdominal/laparoscopic
approach and a vaginal approach may be appropriate. An abdominal approach would be Evidence
level 4
more appropriate in women with short vaginal length50 and those undergoing concomitant
abdominal surgery. An elderly, sexually inactive woman or a woman unfit for a long surgical
operation would be a candidate for colpocleisis.
7.4.1
A comparison of surgical procedures
7.4.1.1 Open abdominal sacrocolpopexy (ASC) versus vaginal sacrospinous fixation (SSF)
Women should be aware that both ASC and SSF are effective treatments for primary PHVP.
ASC is associated with significantly lower rates of recurrent vault prolapse, dyspareunia and
postoperative SUI when compared with SSF. However, this is not reflected in significantly lower
reoperation rates or higher patient satisfaction.
SSF is associated with earlier recovery compared with ASC.
SSF may not be appropriate in women with short vaginal length and should be carefully considered
in women with pre-existing dyspareunia.
The Cochrane review42 included three RCTs that compared ASC versus SSF (also known as
vaginal sacrospinous colpopexy [VSC]). Its meta-analysis showed that ASC was associated with
significantly (i) lower rates of recurrent vault prolapse (risk ratio [RR] 0.23, 95% CI 0.070.77),
(ii) less postoperative SUI (RR 0.55, 95% CI 0.320.95) and (iii) less postoperative dyspareunia Evidence
(RR 0.39, 95% CI 0.180.86). There were no statistically significant differences in patient level 1+
satisfaction, the number of women reporting prolapse symptoms, objective failure at any site,
reoperation rates for SUI and reoperation rates for prolapse. SSF resulted in a reduction in operative
time, it was less expensive to perform and women had an earlier return to their daily activities.
ASC involves apical suspension of the vault with a permanent mesh fixed to the longitudinal
ligament of the sacrum; typically, the mesh is attached to the anterior and posterior aspects
of the vault with possible mesh extension to correct prolapse in other compartments.51 A Evidence
systematic review of observational studies reported long-term success rates of 78100%. Mesh level 2++
erosion was observed in 211%.52,53 Serious complications such as bowel injury, sacral myelitis
and severe bleeding have an estimated incidence of 2% (range 08%).
A recent high quality RCT with 7 years follow-up after ASC48 showed that POP and SUI failure
rates gradually increased over the follow-up period; however, of the 10% anatomical POP
failures, one-half of the women were asymptomatic and were not retreated. Conversely, 9%
were symptomatic failures, of which one-half did not meet the anatomical failure criteria.
The estimated probability of mesh erosion was 10.5% and the reoperation rate was 16.7%
divided almost equally into one-third for POP, one-third for SUI and one-third for mesh-related
complications. Surgery for SUI was doubled in women who did not undergo concomitant
colposuspension. The authors of the trial concluded that as a gold standard for the surgical Evidence
level 1+
treatment of POP, abdominal sacrocolpopexy is less effective than desired, with nearly onethird of women meeting their composite failure definition by 5 years. They also highlighted
that although 95% had no retreatment for POP, one explanation may be related to other health
issues taking priority over the vaginal bulge as patients grow older.
SSF involves unilateral anchoring of the vaginal vault to the sacrospinous ligament (usually the
right side) using either absorbable or non-absorbable sutures and can be done bilaterally.54,55
10 of 21
Several systematic reviews have shown that SSF is a highly effective therapy for vault prolapse,
with low recurrence and complication rates and good patient satisfaction. One concern is the
high incidence (830%) of postoperative anterior compartment prolapse and SUI, presumably
due to posterior fixation of the upper vagina which predisposes the anterior compartment to
excess intra-abdominal pressure.5660 Postoperative buttock pain has an estimated incidence of
18%,61,62 although this usually resolves within 23 months and rarely requires any additional
treatment apart from analgesics and anti-inflammatory agents. There are case reports of Evidence
pudendal nerve injury with SSF,63 primarily owing to the anatomical variations in the course of level 1+
the pudendal nerve on crossing the ischial spine. However, placing the SSF sutures 1.52 cm
medial to the ischial spines is recommended.63,64 One large study showed temporary irritation of
the sciatic nerve in 7.5% and temporary partial ureteral obstruction in 5.5% of 200 women who
underwent SSF.65 There is no evidence that bilateral SSF or using permanent suture material
is associated with better success rates. Long-term follow-up studies showed patient-reported
prolapse symptoms in 16% of women at 215 years follow-up.66
7.4.1.2 Laparoscopic and robotic sacrocolpopexy (LSC and RSC)
LSC can be equally effective as ASC in selected women with primary PHVP. LSC can include mesh
extension or be combined with other vaginal procedures to correct other compartment prolapse.
There is limited evidence on the effectiveness of RSC; therefore, it should only be performed in the
context of research or prospective audit following local governance procedures.
A number of observational studies have shown good anatomical cure rates (more than 90%) in
women undergoing LSC at 12 years follow-up.6771 However, one study showed an 8% recurrence
of vault prolapse and a 42% recurrence/persistence of other compartment prolapse at 5 years Evidence
follow-up. In this study, 70% reported their symptoms to be cured or improved; however, 38% level 2+
still had symptoms of prolapse. The authors concluded that, for every two women who were
cured of their urinary or bowel symptoms, one woman developed worse symptoms.72
One relatively small multicentre RCT73 compared ASC versus LSC in women with PHVP with
or without other compartment prolapse. The results showed significant improvement in
the objective outcome in both groups with no significant difference between groups. At 12 Evidence
months, 67% of the ASC group and 54% of the LSC group reported themselves to be very much level 1
better. The potential advantages of LSC were ascertained with significantly less intraoperative
blood loss (P < 0.01) and shorter hospital stays (P = 0.02).
The robotic approach is available in only a limited number of centres in the UK, being expensive
to set up. A recent prospective cohort study of 90 women with POP-Q stage III undergoing
RSC, with an additional procedure in 71 cases (either subtotal hysterectomy, adnexectomy,
adhesiolysis or rectopexy), showed a mean operative time of 246 minutes (180415 minutes) Evidence
level 2+
and a mean hospital stay of 3.48 days (211 days). Surgical complications were rare: one case
of sigmoidal perforation and two cases of bowel hernia through port sites. At a mean follow-up
of 15 months, six patients (6%) had persistent stage II prolapse.74
One prospective single-blinded RCT75 compared the outcomes of LSC (n = 33) versus RSC
(n = 35) in patients with stages IIIV PHVP. The primary outcome measure was operative
time from incision to closure. Results showed that LSC had a shorter operating time (199
46 minutes versus 265 50 minutes) and less use of postoperative analgesia and that it was Evidence
level 1
significantly less expensive compared with RSC. At 1 year, both groups reported significant
and similar improvements in objective assessment and functional outcomes; however, the
study was not powered to show significant differences in cure rates.
11 of 21
7.4.1.3 High uterosacral ligament suspension (HUSLS)

HUSLS should only be offered as first-line management in women with PHVP within the context of
research or prospective audit following local governance procedures.
Clinicians should be aware of the risk of ureteric injury, especially in the laparoscopic approach.
HUSLS can be done vaginally, abdominally or laparoscopically and involves bilateral suspension of the
vaginal vault, using sutures, to the uterosacral ligaments near the level of the ischial spine.
The evidence regarding the value of HUSLS as first-line management in women with vault
prolapse is limited and contradictory. One small prospective RCT76 compared ASC (n = 54)
versus HUSLS (n = 56) in women with point C greater than 1 cm beyond the introitus. With a
loose definition of objective success at 1 year (point C less than 1 cm), they reported 100%
versus 82.5% success in ASC and HUSLS respectively. Recurrence in the anterior or posterior
compartments (5.3% versus 33.3% and 0% versus 6.2% respectively) and the reoperation rate
for prolapse were significantly lower in the ASC versus HUSLS groups. Both intraoperative
complications and postoperative complications were higher in the HUSLS versus ASC groups Evidence
level 1+
(3.7% versus 0%, P = 0.15 and 20.4% versus 7.3%, P = 0.047 respectively).
An RCT (the Operations and Pelvic Muscle Training in the Management of Apical Support Loss
[OPTIMAL] trial)77 has compared HUSLS versus SSF (both with mid-urethral slings) in women
with PHVP and USI. The 2-year results showed no difference in success rates (HUSLS 59.2%
versus SSF 60.5%), serious adverse event rates (HUSLS 16.5% versus SSF 16.7%) or prolapse
scores at 24 months. This well-designed RCT concluded that neither HUSLS nor SSF was
significantly superior to the other for anatomical, functional or adverse event outcomes.
In a systematic review and meta-analysis28 of transvaginal uterosacral ligament suspension, the
pooled rates for a successful outcome in the anterior, apical and posterior compartments were
81.2%, 98.3% and 87.4% respectively. Outcomes, with respect to subjective symptoms, were Evidence
level 1++
reassuring; however, it was not possible to pool data because of methodological differences
between studies.
Complications of HUSLS include ureteric injury, the incidence of which can be as high as
10.9%, bladder injury, urinary tract infection, blood transfusion and small bowel injury.7880 Evidence
Placing the sutures into the deep dorsal aspect of the ligament is reported to reduce the level 2+
incidence of ureteric injury,81 especially in the laparoscopic approach. Suture erosion was
noted with permanent sutures; a similar risk has been reported with laparoscopic HUSLS.82
7.5 Under what circumstances would transvaginal mesh (TVM) kits/grafts be considered?
The limited evidence on TVM kits does not support their use as first-line treatment of PHVP.
If TVM is considered, women should be fully informed of the permanent nature of the mesh and
potential mesh complications, some of which are serious and have long-term effects that can be
difficult to treat.
If TVM is considered, women should be fully informed of alternative surgical and nonsurgical
options and referral to other surgeons/units arranged as appropriate.
TVM should only be performed by an appropriately trained urogynaecologist, after discussion of

each individual case in an MDT meeting.
12 of 21
The results of all surgical procedures involving mesh should be prospectively audited and submitted
to a national surgical database (e.g. British Society of Urogynaecology [BSUG]) and any mesh
complications reported to the Medicines and Healthcare Products Regulatory Agency (MHRA).
TVM has mesh arms that bilaterally anchor the vaginal vault to both sacrospinous ligaments, achieving
level I support. These were originally delivered with trocars through anatomical landmarks via the
obturator membrane/ischiorectal fossa; however, more recently they have been anchored through
single vaginal incisions.
A systematic review and meta-analysis83 evaluated the efficacy and safety of TVM in the
treatment of apical vaginal prolapse in 30 observational studies with a total of 2653 women; Evidence
they showed objective success rates of 8795% with short-term follow-up (618 months). Mesh level 2++
erosion occurred in 4.610.7% and reoperation rates were 0.46.0%.
One RCT84 compared LSC versus TVM in women with PHVP with 2 years follow-up. The
results showed that the women in the LSC group had a longer operating time, a shorter
hospital stay and a quicker return to daily activities compared with the TVM group. At 2 years
follow-up, the objective success rate and mean patient satisfaction were significantly higher in
the LSC group. Women in the TVM group had a shorter postoperative total vaginal length, a
trend towards higher vaginal mesh erosions (13% versus 2%, P = 0.07) and higher reoperation Evidence
level 1+
rates (22% versus 5%, P = 0.006).
One RCT85 compared TVM versus SSF with 12 months follow-up and showed POP recurrence
rates of 16.9% versus 39.4% respectively (P = 0.002). The mesh exposure rate was 20.8%.
There was no significant difference in QoL improvement, de novo SUI and overactive bladder
between the two groups.
A large study has reported concerns on the safety and potentially serious complications (1%) Evidence
level 2+
associated with TVM, including serious infection and major haemorrhage.86
Similar concerns were voiced by the US Food and Drug Administration87 who proposed to
reclassify these devices to class III (high-risk devices).88 The MHRA has produced a report on
Evidence
TVM in prolapse and urinary incontinence.89,90
level 4
7.6 When should colpocleisis be used?

Colpocleisis is a safe and effective procedure that can be considered for frail women and/or women
who do not wish to retain sexual function.
Colpocleisis entails closure of the vagina. The outcomes and complications of colpocleisis
have been reviewed elsewhere.91 Different techniques have been described, including
vaginectomy,92 purse-string closure,93 colpocleisis after performing standard anterior and
posterior vaginal wall repair,94 purse-string closure of enterocele followed by approximation
of perivesical and rectovaginal fascia and high levator plication95 and LeFort colpocleisis,96
where a bridge of tissue is created between the anterior and posterior vaginal wall to stop the
Evidence
vault prolapse from protruding.
level 2+
Colpocleisis has a short operating time and a low incidence of complications.9395 One published
study included 33 women and a second included 92 women. Success rates of 97% and above
have been reported.9397 The procedure can also be performed under local anaesthesia, which
suits frail women who may be difficult to anaesthetise, as demonstrated in a study that included
30 women having tension-free vaginal tape sling insertion carried out under local anaesthetic.98
13 of 21
7.7
Is there an indication for concomitant surgery for occult SUI?
Colposuspension performed at the time of sacrocolpopexy is an effective measure to reduce

postoperative symptomatic SUI in previously continent women.
A large RCT of 322 women11 comparing ASC versus ASC and colposuspension in women
with occult SUI stopped recruitment at the first interim analysis due to the significantly
low incidence of postoperative SUI in the group of women who underwent concomitant
colposuspension (44.1% versus 23.8%, P < 0.01). The results were maintained at 7 years Evidence
level 1+
follow-up, with the incidence of continence surgery almost halved in the group of women
who underwent concomitant colposuspension. A meta-analysis that included two RCTs11,99
confirmed the benefit of concomitant colposuspension.42
There have been no clinical trials to assess delayed minimally invasive mid-urethral sling surgery, when
required, after ASC and whether that would have led to higher overall continence rates.
There are no trials that evaluated performing prophylactic mid-urethral sling surgery at the time of SSF
or ASC/LSC for occult SUI.
7.8 Is there an indication for concomitant surgery for PHVP and overt SUI?
Colposuspension at the time of ASC does not appear to be effective treatment for SUI.
Concomitant mid-urethral sling surgery may be considered when vaginal surgical approaches are
used for the treatment of PHVP. [New 2015]
In a small RCT of women with PHVP and concomitant SUI, 54.2% were still incontinent after
combined ASC and Burch colposuspension, compared with 39.1% following ASC alone. Burch Evidence
colposuspension does not provide any additional benefit in PHVP repair in patients with pre- level 1+
existing SUI.100
A 2013 Cochrane review assessed 16 RCTs, not specific to PHVP, which included data on
bladder symptoms and concluded that Women undergoing prolapse surgery may have Evidence
benefited from having continence surgery performed concomitantly, especially if they had level 1++
[overt] stress urinary incontinence (RR 7.4, 95% CI 4.0 to 14).42
A single RCT evaluated concomitant mid-urethral sling at the time of vaginal prolapse surgery
(not specifically PHVP); combination surgery signicantly reduced the risk of postoperative Evidence
level 1+
SUI at 1 year of follow-up (21% versus 59%).101
7.9 What is the optimal treatment of recurrent vault prolapse?

The management of recurrent vault prolapse should be through a specialist MDT with experience
and training in this field.
A number of case series have reported good outcomes after vaginal HUSLS102 and LSC103 for
recurrent vault prolapse. Evidence in relation to other management options, including PFMT Evidence
and the use of pessaries, is very limited.104 Patients should be counselled about the likely level 3
benefits and potential risks of each management option.
These patients should be assessed by those with expertise in the management of recurrent vaginal
vault prolapse, ideally a subspecialist urogynaecologist (or those with equivalent experience) working
within MDTs.
14 of 21
8.
Clinical governance
National databases, such as the BSUG surgical database, should be used to document surgical
outcomes and complications.
The IUGA/ICS terminology and classification of complications should be used for the documentation
of graft-related complications.
All complications related to the use of devices and mesh should be reported to the MHRA.
Reporting of the complications of surgery for PHVP should describe the nature of the complication in
terms of category, time and site. It should also describe any involvement of adjacent structures, such as
the urinary tract or bowel, as well as any systemic effect.
The use of a standard method to report the outcome of surgery, including complications, for
POP enables comparison for audit and research. Utilising the schemes proposed by IUGA/
ICS facilitates the standardisation of terminology and the comparison of results for audit and
Evidence
research purposes.105,106
level 4
The BSUG registry (https://nww.bsug.nhs.uk) allows the use of these schemes and enables
personal audit. Reporting can be made through medical device liaison officers or directly to
the MHRA online (https://yellowcard.mhra.gov.uk/).
9.
l The role of concomitant continence surgery in patients with PHVP.

l The correlation of surgical workload and outcome.
l Robotic versus other abdominal and vaginal procedures for the treatment of PHVP.
l The use of mesh in the treatment of PHVP.

l Documentation of management options offered including provision of patient information (100%).
l Documentation of the discussion of conservative measures (PFMT/pessaries) prior to surgery (100%).
l Compliance with relevant database, e.g. BSUG (100%).
l Documentation of the MDT discussion prior to surgery for recurrent prolapse (100%).
l Outcome following various surgical procedures for PHVP.
l Development of SUI following surgery for PHVP.

l Association for Pelvic Organ Prolapse Support (APOPS)
[http://www.pelvicorganprolapsesupport.org/].
l British Society of Urogynaecology. Patient Information
[http://www.bsug.org.uk/patient-information.php].
l International Continence Society [http://www.ics.org/].
l International Urogynecological Association [http://www.iuga.org/].
15 of 21
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Int Urogynecol J 2012;23:142933.
103.
Schmid C, ORourke P, Maher C. Laparoscopic
sacrocolpopexy for recurrent pelvic organ prolapse
after failed transvaginal polypropylene mesh surgery. Int
104. Toh VV, Bogne V, Bako A. Management of recurrent vault
prolapse. Int Urogynecol J 2012;23:2934.
105. Haylen BT, Freeman RM, Swift SE, Cosson M, Davila
GW, Deprest J, et al. An International Urogynecological
Association (IUGA) / International Continence Society (ICS)
joint terminology and classification of the complications
related directly to the insertion of prostheses (meshes,
implants, tapes) & grafts in female pelvic floor surgery. Int
106. Haylen BT, Freeman RM, Lee J, Swift SE, Cosson M, Deprest
J, et al. An International Urogynecological Association
(IUGA)/International Continence Society (ICS) joint
terminology and classification of the complications related
to native tissue female pelvic floor surgery. Int Urogynecol
J 2012;23:51526.
18 of 21
Appendix I: POP-Q exam reference guide

The pelvic organ prolapse quantification (POP-Q) exam is used to quantify, describe and stage pelvic support.
l There are 6 points measured at the vagina with respect to the hymen.
l Points above the hymen are negative numbers; points below the hymen are positive numbers.
l All measurements except tvl are measured at maximum valsalva.
D
C
Bp
Ba
tvl
Ap
Aa
gh
pb
Point
Description
Range of values
Aa
Anterior vaginal wall 3 cm proximal to the hymen
3 cm to +3 cm
Ba
Most distal position of the remaining upper anterior vaginal wall
3 cm to +tvl
Most distal edge of cervix or vaginal cuff scar
Posterior fornix (N/A if post hysterectomy)
Ap
Posterior vaginal wall 3 cm proximal to the hymen
3 cm to +3 cm
Bp
Most distal position of the remaining upper posterior vaginal wall
3 cm to +tvl
Genital hiatus (gh) measured from middle of external urethral meatus to posterior midline hymen
Perineal body (pb) measured from posterior margin of gh to middle of anal opening
Total vaginal length (tvl) depth of vagina when point D or C is reduced to normal position
POP-Q staging criteria
Stage O
Aa, Ap, Ba, Bp = 3 cm and C or D (tvl 2) cm
Stage I
Stage O criteria not met and leading edge < 1 cm
Stage II
Leading edge 1 but +1 cm
Stage III
Leading edge > +1 cm but < + (tvl 2) cm
Stage IV
Leading edge + (tvl 2) cm
Reference: Bump RC, Mattiasson A, B K, Brubaker LP, DeLancey JO, Klarskov P, et al. The standardization of terminology of
female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996;175:107.
19 of 21
Appendix II: Explanation of guidelines and evidence levels


low risk of bias


1++ or 1+

results; or
2++

low risk of bias
risk of bias
case series
4
Good practice point
Expert opinion
20 of 21

development group
This guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists and the British
Society of Urogynaecology by:
Mr AM El Naqa FRCOG, Wolverhampton; Miss KL Guerrero FRCOG, Glasgow; and Mr MS Abdel Fattah FRCOG,
Aberdeen
British Society for Gynaecological Endoscopy; Mr DCY Chou MRCOG, Australia; Mrs AHD Diyaf MRCOG, Barnstaple;
Dr LM Dolan FRCOG, Belfast; Dr AA Elkady FRCOG, Greater Cairo, Egypt; Professor CMA Glazener FRCOG,
Aberdeen; Mr P Hilton FRCOG, Newcastle upon Tyne; Dr A Khunda FRCOG, Middlesbrough; Mr CJ Mayne FRCOG,
Leicester; Professor A Ostrzenski, USA; Mrs CMA Ramage FRCOG, Bradford; RCOG Womens Network;
Dr JR Scott FRCOG, Salt Lake City, Utah, USA; Dr JA Short MRCOG, Christchurch, New Zealand; Mrs P Sinha FRCOG,
St Leonards-on-Sea; Dr B Thomas MRCOG, Thrissur, India; and Mr PM Toozs-Hobson FRCOG, Birmingham.
RCOG Guidelines Committee lead reviewers were: Dr CJ Crowe MRCOG, London and Dr M Gupta MRCOG, London.
The chairs of the RCOG Guidelines Committee were: Dr M Gupta1 MRCOG, London; Dr P Owen2 FRCOG, Glasgow;
1
guidelines/gtg46/.
DISCLAIMER
21 of 21
Blood Transfusion in Obstetrics

May 2015
Blood Transfusion in Obstetrics

This is the second edition of this guideline, which was previously published under the same title in 2007.
How can the risk of transfusion be reduced?

Optimisation of haemoglobin in the antenatal period
Diagnosis
Anaemia in pregnancy is defined as first trimester haemoglobin (Hb) less than 110 g/l, second/third
trimester Hb less than 105 g/l, and postpartum Hb less than 100 g/l, in line with British Committee
for Standards in Haematology (BCSH) guidance.
For normocytic or microcytic anaemia, a trial of oral iron should be considered as the first step and
further tests should be undertaken if there is no demonstrable rise in Hb at 2 weeks and compliance
has been checked.
Pregnant women should be offered screening for anaemia at booking and at 28 weeks. Women
with multiple pregnancies should have an additional full blood count done at 2024 weeks.
P
P
Treatment and management

Oral iron should be the preferred first-line treatment for iron deficiency.
Parenteral iron is indicated when oral iron is not tolerated or absorbed or patient compliance is in
doubt or if the woman is approaching term and there is insufficient time for oral supplementation
to be effective.
Women should receive information on improvement of dietary iron intake and factors affecting
absorption of dietary iron.
The role of recombinant human erythropoietin (rHuEPO) for non-end-stage renal anaemia is still
to be established and it should only be used in the context of a controlled clinical trial or on the
expert advice of the haematologist.
Active management of the third stage of labour is recommended to minimise blood loss.
Women at high risk of haemorrhage should be advised to deliver in hospital.
General principles of blood transfusion

Consent for blood transfusion
Valid consent should be obtained where possible prior to administering a blood transfusion.
In an emergency, where it is not feasible to get consent, information on blood transfusion should
be provided retrospectively.
The reason for transfusion and a note of the consent discussion should be documented in the
patients case notes.
2 of 23
Requirements for group and screen samples and cross-matching

All women should have their blood group and antibody status checked at booking and at 28 weeks
of gestation.
Group and screen samples used for provision of blood in pregnancy should be less than 3 days old.
In a woman at high risk of emergency transfusion, e.g. placenta praevia, and with no clinically
significant alloantibodies, group and screen samples should be sent once a week to exclude or
identify any new antibody formation and to keep blood available if necessary. Close liaison with
the hospital transfusion laboratory is essential.
Women should have a group and screen sample taken in line with clear locally agreed protocols
for provision of blood.
Blood product specification in pregnancy and the puerperium

ABO-, rhesus D- (RhD-) and K- (Kell-) compatible red cell units should be transfused.
If clinically significant red cell antibodies are present, then blood negative for the relevant antigen
should be cross-matched before transfusion; close liaison with the transfusion laboratory is
essential to avoid delay in transfusion in life-threatening haemorrhage.
Cytomegalovirus- (CMV-) seronegative red cell and platelet components should be provided for
elective transfusions during pregnancy.
What are the strategies to minimise the use of banked blood?

Is there a role for preoperative/predelivery autologous blood deposit?
Predelivery autologous blood deposit is not recommended.
Is there a role for intraoperative cell salvage (IOCS)?

Cell salvage is recommended for patients where the anticipated blood loss is great enough to
induce anaemia or expected to exceed 20% of estimated blood volume.
Consent should be obtained for IOCS where possible and its use in obstetric patients should be
subject to audit and monitoring.
Cell salvage should only be performed by multidisciplinary teams who develop regular experience
of IOCS.
Where IOCS is used during caesarean section in RhD-negative, previously nonsensitised women
and where cord blood group is confirmed as RhD positive (or unknown), a minimum dose of 1500 iu
anti-D immunoglobulin should be administered following the reinfusion of salvaged red cells.
A maternal blood sample should be taken for estimation of fetomaternal haemorrhage 3040
minutes after reinfusion in case more anti-D is indicated.
Management of obstetric haemorrhage with blood components

There should be a clear local protocol on how to manage major obstetric haemorrhage.
3 of 23
The protocol should be updated annually and practised in skills drills to inform and train relevant
personnel.
Are there mechanical strategies that can be employed?

Clinicians should familiarise themselves with mechanical strategies that can be employed to
reduce postpartum blood loss.
What blood components can be used for obstetric haemorrhage?

When should red cells be used?
There are no firm criteria for initiating red cell transfusion. The decision to provide blood transfusion
should be made on clinical and haematological grounds.
In an extreme situation and when the blood group is unknown, group O RhD-negative red cells
should be given (although they may be incompatible for patients with irregular antibodies).
Staff working in obstetric units should be aware of the location of the satellite blood fridge (where
available) and should ensure that access is possible for blood collection.
In what circumstances should fresh frozen plasma (FFP) and cryoprecipitate be used?
FFP at a dose of 1215 ml/kg should be administered for every 6 units of red cells during major
obstetric haemorrhage. Subsequent FFP transfusion should be guided by the results of clotting
tests if they are available in a timely manner, aiming to maintain prothrombin time (PT) and
activated partial thromboplastin time (APTT) ratios at less than 1.5 x normal.
It is essential that regular full blood counts and coagulation screens (PT, APTT and fibrinogen) are
performed during the bleeding episode.
Cryoprecipitate at a standard dose of two 5-unit pools should be administered early in major
obstetric haemorrhage. Subsequent cryoprecipitate transfusion should be guided by fibrinogen
results, aiming to keep levels above 1.5 g/l.
The FFP and cryoprecipitate should ideally be of the same group as the recipient. If unavailable,
FFP of a different ABO group is acceptable providing that it does not have a high titre of anti-A or
anti-B activity.
No anti-D prophylaxis is required if a RhD-negative woman receives RhD-positive FFP or

cryoprecipitate.
When should platelets be used?

Aim to maintain the platelet count above 50 x 109/l in the acutely bleeding patient.
A platelet transfusion trigger of 75 x 10 /l is recommended to provide a margin of safety.
9
The platelets should ideally be group compatible. RhD-negative women should also receive RhDnegative platelets.
P
D
Is there a role for near patient testing of coagulation?

Centres that are using thromboelastography (TEG, Haemonetics, Braintree, Massachusetts, USA)
or rotation thromboelastometry (ROTEM, Tem, Munich, Germany) for guiding blood transfusion
during major obstetric haemorrhage must ensure that their transfusion algorithm protocol has
been validated and that quality assurance measures are followed.
4 of 23
Pharmacological strategies for management of major obstetric haemorrhage

Is there a role for recombinant factor VIIa (rFVIIa) therapy?
The use of rFVIIa may be considered as a treatment for life-threatening postpartum haemorrhage
(PPH), but should not delay or be considered a substitute for a live-saving procedure such as
embolisation or surgery, or transfer to a referral centre.
Is there a role for fibrinogen concentrate therapy?

Fibrinogen concentrate is not licensed in the UK for the management of acquired bleeding disorders.
Thus, its use in PPH should be considered only in the context of clinical trials.
Is there a role for antifibrinolytics?

For those centres not participating in clinical trials, consideration should be given to using
tranexamic acid during major obstetric haemorrhage.
How should intrapartum anaemia be managed?

In addition to major haemorrhage guidelines, obstetric units should have guidelines on criteria for
red cell transfusion in anaemic women who are not actively bleeding. If the Hb is less than 70 g/l in
labour or in the immediate postpartum period, the decision to transfuse should be made according
to the individuals medical history and symptoms.
How should women with postpartum anaemia be managed in the postnatal period?
If the Hb is less than 70 g/l in the postnatal period, where there is no ongoing or threat of bleeding,
the decision to transfuse should be made on an informed individual basis.
How should women who decline blood products be managed?

Hb should be optimised prior to delivery to prevent avoidable anaemia.
Consent/refusal of blood and components or other transfusion-sparing techniques should be

discussed and documented during the antenatal period.
Use of pharmacological, mechanical and surgical procedures to avert the use of banked blood and
blood components should be considered early.
IOCS has a role in the management of patients who refuse allogeneic blood transfusion.
1.
Purpose and scope
Obstetric conditions associated with the need for blood transfusion may lead to morbidity and mortality
if not managed correctly. The increasingly important issues in blood transfusion are adverse events
associated with transfusion, including potential infection and potential transmission of prions, rising
costs and the possible future problems of availability.
The aim of this guideline is to update the previous guidance about the appropriate use of blood products
that neither compromises the affected woman nor exposes her to unnecessary risk. Strategies to
maximise the haemoglobin (Hb) level at delivery as well as to minimise blood loss are also discussed.
5 of 23
2.
Obstetric haemorrhage remains a major cause of maternal mortality in the UK and is now the third
leading cause of direct maternal deaths, accounting for approximately 10% of direct deaths. This does not
represent a significant increase in mortality as deaths have decreased overall. Substandard management
continues to be a significant contributor to mortality from haemorrhage.1 It is estimated that there are
more than 4000 cases of severe haemorrhage each year in the UK. The majority of these women will
need blood transfusion.
Retrospective analyses of the clinical scenarios often criticise the employment of blood transfusion as
too little, too late. Women at high risk of losing greater than 1000 ml should be strongly advised to
deliver in a setting where blood transfusion and intensive care facilities are available.2
Blood transfusion may be a life-saving procedure but it is not without risk. Recipients may rarely develop
transfusion-transmitted infections or suffer immunological sequelae such as red cell alloimmunisation.
The major risk, however, of blood transfusion is of a patient receiving an incorrect blood component.3
Strict adherence to correct sampling, cross-match and administration procedures is therefore of
paramount importance, even in an emergency.
3.
This guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines. The Cochrane Library (including the Cochrane Database of Systematic Reviews and the
Database of Abstracts of Reviews of Effects [DARE]), EMBASE, Trip, MEDLINE and PubMed (electronic
databases) were searched for relevant randomised controlled trials, systematic reviews and metaanalyses. The search was restricted to articles published between 2003 and March 2013. The databases
were searched using the relevant Medical Subject Headings (MeSH) terms, including all subheadings,
and this was combined with a keyword search. A top-up search was performed in December 2014.
Terms and keyword search words included obstetrics and blood transfusion, tranexamic acid, factor
VIIa, cell salvage, antifibrinolytics, fibrinogen concentrate, haematinics, autologous transfusion,
transfusion triggers and platelet. The search was limited to humans and the English language. The
National Library for Health and the National Guideline Clearinghouse were also searched for relevant
guidelines and reviews. Guidelines and recommendations produced by organisations such as the British
Committee for Standards in Haematology (BCSH) and various national bodies were considered. Where
possible, recommendations are based on available evidence and the areas where evidence is lacking are
annotated as good practice points.
4.
How can the risk of transfusion be reduced?
4.1 Optimisation of haemoglobin in the antenatal period

4.1.1 Diagnosis
Anaemia in pregnancy is defined as first trimester haemoglobin (Hb) less than 110 g/l, second/third
trimester Hb less than 105 g/l, and postpartum Hb less than 100 g/l, in line with BCSH guidance.
For normocytic or microcytic anaemia, a trial of oral iron should be considered as the first step and
further tests should be undertaken if there is no demonstrable rise in Hb at 2 weeks and compliance
has been checked.
Pregnant women should be offered screening for anaemia at booking and at 28 weeks. Women
with multiple pregnancies should have an additional full blood count done at 2024 weeks.
6 of 23
P
P
The BCSH has defined what it considers to be adequate Hb levels at different stages of
pregnancy.4 The intrapartum and postpartum thresholds for Hb are derived from the World Evidence
Health Organization with a modification suggested by the US Centers for Disease Control and level 2+
Prevention because of the plasma expansion seen in the second trimester.57
If the Hb is less than 110 g/l in the first trimester or less than 105 g/l in the second or third trimester,
consider haematinic deficiency once haemoglobinopathies have been excluded.
Iron deficiency can be difficult to diagnose. The signs and symptoms are generally nonspecific.
Serum ferritin is the most useful test for diagnosing iron deficiency but it is an acute phase Evidence
level 2++
reactant.4 Other laboratory parameters also have their limitations.8
Anaemia not due to haematinic deficiency (for example, haemoglobinopathies and bone marrow failure
syndromes) should be managed by blood transfusion where appropriate in close conjunction with a
haematologist.
In line with the National Institute for Health and Care Excellence (NICE),9,10 screening for
anaemia should be offered at booking and at 28 weeks, with an additional full blood count at Evidence
level 4
2024 weeks for women with multiple pregnancies.
4.1.2 Treatment and management
Oral iron should be the preferred first-line treatment for iron deficiency.
Parenteral iron is indicated when oral iron is not tolerated or absorbed or patient compliance is in
doubt or if the woman is approaching term and there is insufficient time for oral supplementation
to be effective.
Women should receive information on improvement of dietary iron intake and factors affecting
absorption of dietary iron.
The role of recombinant human erythropoietin (rHuEPO) for non-end-stage renal anaemia is still
to be established and it should only be used in the context of a controlled clinical trial or on the
expert advice of the haematologist.
Women at high risk of haemorrhage should be advised to deliver in hospital.
A meta-analysis of randomised trials on the antenatal use of iron, with or without folic acid, Evidence
level 1++
showed a 50% reduction in the risk of anaemia in the third trimester or at delivery.11
A Cochrane review of studies comparing iron supplementation with no iron or placebo found
that iron supplementation decreased the incidence of low birthweight babies and prevented
maternal anaemia and iron deficiency anaemia.12 A second Cochrane review comparing Evidence
intermittent versus daily iron supplementation showed that intermittent supplementation level 1+
produced a similar risk of anaemia at term, prematurity and low birthweight babies, but was
associated with fewer side effects.13
Parenteral therapy offers a shorter duration of treatment and a quicker response than oral
therapy.14 It is, however, more invasive and expensive to administer. Severe allergic reactions
are possible with all iron preparations. Intravenous iron products should only be administered Evidence
level 2+
when staff trained to evaluate and manage anaphylactic or anaphylactoid reactions, as well as
resuscitation facilities, are immediately available.
7 of 23
Rich sources of dietary iron are red meat, fish and poultry. These provide haem iron that is
more easily absorbed than non-haem iron but the latter forms the vast majority of iron taken Evidence
through the diet.15 Vitamin C enhances the absorption of non-haem iron whereas tea and level 2+
coffee inhibit iron absorption from food.15
rHuEPO is mostly used in the anaemia of end-stage renal disease. rHuEPO has been used both
antenatally and postpartum in patients without end-stage renal disease without any maternal,
fetal or neonatal adverse effects.16,17 Its use in clinical practice for non-end-stage renal anaemia Evidence
level 1
is still to be established and should only be used in the context of a controlled clinical trial
and/or under haematological advice.
Clear evidence from randomised trials supports the active management of the third stage of Evidence
level 1+
labour as a method of decreasing postpartum blood loss.1820
Maternal deaths from haemorrhage in the UK have fallen over the years and one contributor
is considered to be the hospitalisation for delivery of women at higher risk of haemorrhage
(older women, grand multiparae and those with pre-eclampsia). Analysis of such deaths has Evidence
level 3
led to a recommendation that women at high risk of haemorrhage should not be delivered in
units without immediate access to consultant-led care, blood products and intensive care.2
5.
General principles of blood transfusion
5.1 Consent for blood transfusion

Valid consent should be obtained where possible prior to administering a blood transfusion.
In an emergency, where it is not feasible to get consent, information on blood transfusion should
be provided retrospectively.
The reason for transfusion and a note of the consent discussion should be documented in the
patients case notes.
The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO), following
a consultation exercise looking at consent for blood transfusion, recommended that valid
consent for blood transfusion should be obtained wherever possible before administering a Evidence
transfusion. While this does not entail specific written consent, valid consent does require the level 4
provision of information to patients on risks and benefits together with alternatives available
with clear documentation in the clinical records.21
Where transfusion of all or specific blood components is refused, or an advance directive exists, this
should be documented in the patients clinical records and communicated to all relevant healthcare
professionals (see section 11).
Patients who require an emergency blood transfusion may not be able to give valid consent
prior to the transfusion. Transfusion should not be delayed, but attempts should be made to
provide information retrospectively.21 Patient information leaflets on blood transfusion are
available from the UK blood transfusion services (see section 14).
The decision process leading to transfusion including indication for transfusion and obtaining
valid consent should be documented in the patients clinical record.22,23 There is some limited
evidence24 that when the decision or reason for transfusion is documented there is a lower rate
of inappropriate transfusion.
8 of 23
Evidence
level 4
5.2
Requirements for group and screen samples and cross-matching
All women should have their blood group and antibody status checked at booking and at 28 weeks
of gestation.
Group and screen samples used for provision of blood in pregnancy should be less than 3 days old.
In a woman at high risk of emergency transfusion, e.g. placenta praevia, and with no clinically
significant alloantibodies, group and screen samples should be sent once a week to exclude or
identify any new antibody formation and to keep blood available if necessary. Close liaison with
the hospital transfusion laboratory is essential.
Women should have a group and screen sample taken in line with clear locally agreed protocols
for provision of blood.
Maternal red cell antibodies are relatively common.25 These can cause haemolytic disease of
the fetus and newborn (HDFN) and will also have implications for the selection of blood for
transfusion in the mother to avoid the risk of haemolytic transfusion reactions. Accordingly, Evidence
level 3
the blood group and antibody status of the mother should be tested at booking and at 28
weeks of gestation.26,27
When red cell antibodies are detected in the booking sample, further testing of maternal blood
should be undertaken to determine the specificity and the level of antibody or antibodies
and to assess the likelihood of HDFN,25 with early referral to a specialist fetal medicine unit
depending on the nature of the antibody, level and previous history. Further details on the
assessment and management of women with red cell antibodies during pregnancy are covered
in the RCOG Green-top Guideline.25
Transfusion or pregnancy may stimulate the production of unexpected antibodies against
red cell antigens through either a primary or secondary immune response.28 To ensure that
the specimen used for compatibility testing is representative of a patients current immune
status, serological studies should be performed using blood collected no more than 3 days in
advance of the actual transfusion when the patient has been transfused or pregnant within
the preceding 3 months.28
A formal deviation to the 3-day rule may be used in pregnant women with no clinically
significant alloantibodies who require blood standing by for potential obstetric emergencies, Evidence
e.g. placenta praevia,28 with samples sent once a week to the transfusion laboratory for testing. level 4
Fetomaternal haemorrhage constitutes a smaller stimulus than transfusion because the number
of foreign antigens is limited and in many pregnancies the volume of red cells transferred from
fetus to mother is too small to stimulate a primary response.29
The majority of laboratories in the UK now use automated testing for blood grouping and
antibody testing with advanced information technology systems for documentation and
reporting of results. The hospital transfusion laboratory can readily provide red cells that are
ABO and rhesus D (RhD) compatible using electronic issue with no cross-matching needed,
provided that the patient does not have any antibodies and there are robust automated systems
in place for antibody testing and identification of the patient.28 In this setting, since blood can
be readily issued, there is no need to reserve units for individual cases. Where electronic issue
is not available, a locally agreed maximum surgical blood ordering schedule should be used to
decide how many red cell units should be reserved and available for particular cases, based on
the obstetric diagnosis. In patients with red cell antibodies, cross-match between the patients
blood and the red cell units to be transfused is essential to ensure compatibility.
9 of 23
It should be borne in mind that many hospitals send antenatal serology off-site for economies of scale. If
hospitals send antenatal serology samples for testing off-site, it is advised that the results of the grouping
and antibody screen should be made readily available for the local unit. If laboratory provision is off-site,
there should be robust systems in place for local arrangements for the provision of blood, and components
if required, taking into account transport times and whether or not the woman has red cell antibodies.
Unless secure electronic patient identification systems are in place, a second sample should be
requested for confirmation of the ABO group of a first-time patient prior to transfusion, where Evidence
level 4
this does not impede the delivery of urgent red cells or other components.28
5.3 Blood product specification in pregnancy and the puerperium

ABO-, RhD- and K- (Kell-) compatible red cell units should be transfused.
If clinically significant red cell antibodies are present, then blood negative for the relevant antigen
should be cross-matched before transfusion; close liaison with the transfusion laboratory is
essential to avoid delay in transfusion in life-threatening haemorrhage.
Cytomegalovirus- (CMV-) seronegative red cell and platelet components should be provided for
elective transfusions during pregnancy.
Pregnant women (and women of childbearing age) who are RhD negative must only receive
RhD-negative blood to avoid the risk of RhD alloimmunisation.28 Previous blood transfusion is
an important cause for alloimmunisation with antibodies other than anti-D, in particular anti-K, Evidence
level 2+
which can cause severe HDFN.25 Accordingly, unless a woman is known to be K positive, only
K-negative blood should be used for transfusion in women of childbearing age.28
Major obstetric haemorrhage protocols must include the provision of emergency blood with immediate issue
of group O, RhD-negative and K-negative units, with a switch to group-specific blood as soon as feasible.
The aim of antibody screening is to determine the presence of atypical red cell antibodies
of likely clinical significance. When the antibody screen is positive, further testing is
required to identify the relevant antibody or antibodies and the laboratory should select
red cell units negative for the relevant antigen for cross-matching.28 However, in a major
obstetric haemorrhage there should be no delay in the provision of blood with the initial use
of group O-negative units if needed, with subsequent transfusion of cross-matched antigennegative units when available.30 Close liaison with the transfusion laboratory is essential, with
input if needed from the clinical haematology team and specialist advice from the national Evidence
level 4
blood service.
In 2012, SaBTO stated that CMV-seronegative red cells and platelets should be provided, where
possible, for pregnant women.31 The UK policy of universal leucocyte depletion substantially
reduces the risk of CMV transmission.32 In an emergency, such as major haemorrhage, standard
leucocyte-depleted components should be given to avoid delay and CMV-negative blood or
platelets are not needed for transfusion during delivery or in the postpartum period.31
6.
What are the strategies to minimise the use of banked blood?
6.1 Is there a role for preoperative/predelivery autologous blood deposit?

Predelivery autologous blood deposit is not recommended.
A Cochrane review on preoperative autologous donations33 considered randomised controlled Evidence

trials and concluded that the studies were of poor quality, with insufficient numbers of level 1
10 of 23
patients and high transfusion rates. None of the studies were conducted on pregnant women.
Preoperative/predelivery deposit of autologous blood is not a service that is available routinely Evidence
level 1
in the UK.
6.2 Is there a role for intraoperative cell salvage (IOCS)?

Cell salvage is recommended for patients where the anticipated blood loss is great enough to
induce anaemia or expected to exceed 20% of estimated blood volume.
Consent should be obtained for IOCS where possible and its use in obstetric patients should be
subject to audit and monitoring.
Cell salvage should only be performed by multidisciplinary teams who develop regular experience
of IOCS.
Where IOCS is used during caesarean section in RhD-negative, previously nonsensitised women
and where cord blood group is confirmed as RhD positive (or unknown), a minimum dose of 1500 iu
anti-D immunoglobulin should be administered following the reinfusion of salvaged red cells.
A maternal blood sample should be taken for estimation of fetomaternal haemorrhage 3040
minutes after reinfusion in case more anti-D is indicated.
In general, intraoperative cell salvage (IOCS) has been recommended for nonobstetric patients
undergoing elective or emergency surgical procedures where the anticipated blood loss is
great enough to induce anaemia or expected to exceed 20% of estimated blood volume.3436
Therefore, IOCS would not be required for most caesarean sections if a similar threshold
were to be adopted.
Evidence
level 2+
IOCS has been used during caesarean section in a number of case reports and case series
without any reported complications related to receiving salvaged blood.37 Although current
evidence supports the use of IOCS in obstetrics,38,39 evidence from large randomised controlled
trials are needed to support the routine practice of IOCS in obstetrics.
Preoperative discussions on blood transfusion should be undertaken according to SaBTO
guidance,21 as outlined in the section above. These discussions should include oral and written
information on cell salvage, if it is available in the facility where the woman is to give birth.
More information for staff and patients is available from the UK Cell Salvage Action Group
website (see section 14 for link details).
Evidence
level 4
The NICE guideline on IOCS in obstetrics states that this procedure should only be performed
by multidisciplinary teams who have regular experience of IOCS.37 UK centres with high
levels of experience of IOCS in obstetrics have developed this experience by training staff to
use cell salvage during elective routine low-risk caesarean sections.
Using disposables for low-risk cases to ensure that theatre staff are trained requires financial resource.
If a hospital trust/maternity service provider cannot afford to purchase disposables to train staff in the
elective, low-risk setting, then they cannot provide cell salvage in an emergency setting.
IOCS, together with the use of modern leucocyte depletion filters, has been shown to be
effective at removing the common markers of amniotic fluid contamination.40 However, it Evidence
will not remove fetal blood cells and therefore adequate anti-D immunisation (as determined level 2+
by Kleihauer test 3040 minutes after the procedure) will be required to prevent rhesus
immunisation in RhD-negative women.41
11 of 23
7. Management of obstetric haemorrhage with blood components

There should be a clear local protocol on how to manage major obstetric haemorrhage.
The protocol should be updated annually and practised in skills drills to inform and train relevant
personnel.
In October 2010, the National Patient Safety Agency (NPSA) reported 94 incidents (23 obstetric
cases) where there was a delay in accessing blood components for life-threatening bleeding
patients, resulting in unacceptable morbidity and mortality.42 The report highlighted the
need for local protocols that allow provision of emergency blood (including out of hours) in Evidence
patients with major haemorrhage. These protocols should waive restrictions on special blood level 3
components, such as irradiated blood components or CMV, in order to avoid unnecessary
delays of red blood cell (RBC) provision and to allow for rapid delivery of uncross-matched
blood (i.e. group O RhD and K negative).42
A randomised controlled trial found that practical, multidisciplinary, obstetric emergency
training increased midwives and doctors knowledge of obstetric emergency management, Evidence
including postpartum haemorrhage (PPH);43 thus, the major haemorrhage protocol should be level 1+
practised in skills drills and updated annually so as to inform and train relevant personnel.
7.1 Are there mechanical strategies that can be employed?

Clinicians should familiarise themselves with mechanical strategies that can be employed to
reduce postpartum blood loss.
The mechanical strategies that can be employed to minimise blood loss during PPH are outlined in
RCOG Green-top Guideline No. 53, Prevention and Management of Postpartum Haemorrhage.30
7.2 What blood components can be used for obstetric haemorrhage?

7.2.1 When should red cells be used?
There are no firm criteria for initiating red cell transfusion. The decision to provide blood transfusion
should be made on clinical and haematological grounds.
In an extreme situation and when the blood group is unknown, group O RhD-negative red cells
should be given (although they may be incompatible for patients with irregular antibodies).
Staff working in obstetric units should be aware of the location of the satellite blood fridge (where
available) and should ensure that access is possible for blood collection.
There are no firm criteria for initiating red cell transfusion.44 The decision to perform blood
transfusion should be made on both clinical and haematological grounds. Blood transfusion is
almost always required when the Hb is less than 60 g/l and it is rarely required when the Hb is
greater than 100 g/l.44 It should also be remembered that patients with acute haemorrhage can have
normal Hb; hence the clinical evaluation of the patient in this situation is extremely important.
Between October 2006 and September 2010, the Rapid Response Report from the NPSA reported
11 deaths and 83 incidents where the patient suffered harm as a result of delays in the provision
of blood. One of the reasons for the delay in blood transfusion during life-threatening bleeding
episodes was a lack of understanding concerning the term cross-matched, whereby clinicians
frequently request cross-matched blood without realising that this could take some time, which
12 of 23
Evidence
level 4
is not optimal in an emergency.42 Thus, in the event of life-threatening haemorrhage, even if a

woman has RBC alloantibodies, the transfusion of group O RhD-negative red cells, or groupspecific red cells, must not be delayed.
In order to facilitate the immediate provision of uncross-matched group O red cell units for Evidence
level 4
patients who suffer massive haemorrhage, some National Health Service (NHS) organisations
have introduced satellite blood fridges in different clinical areas. Medical staff working in these
organisations and who are involved in the management of major bleeding should be aware of
the fridge location and should ensure that access is possible for blood collection.42
7.2.2 In what circumstances should fresh frozen plasma (FFP) and cryoprecipitate be used?
FFP at a dose of 1215 ml/kg should be administered for every 6 units of red cells during major
obstetric haemorrhage. Subsequent FFP transfusion should be guided by the results of clotting
tests if they are available in a timely manner, aiming to maintain prothrombin time (PT) and
activated partial thromboplastin time (APTT) ratios at less than 1.5 x normal.
It is essential that regular full blood counts and coagulation screens (PT, APTT and fibrinogen) are
performed during the bleeding episode.
Cryoprecipitate at a standard dose of two 5-unit pools should be administered early in major
obstetric haemorrhage. Subsequent cryoprecipitate transfusion should be guided by fibrinogen
results, aiming to keep levels above 1.5 g/l.
The FFP and cryoprecipitate should ideally be of the same group as the recipient. If unavailable,
FFP of a different ABO group is acceptable providing that it does not have a high titre of anti-A or
anti-B activity.
No anti-D prophylaxis is required if a RhD-negative woman receives RhD-positive FFP or

cryoprecipitate.
Observational studies in military combat casualties have suggested that early administration of
FFP in high ratios improves clinical outcomes of trauma bleeding patients.4547 However, due
to the lack of randomised controlled trials, the optimum FFP-to-RBC ratio for management of
major bleeding remains unknown.4851 Further, no studies have evaluated the optimum dose
of FFP during major bleeding. Until further evidence becomes available, we recommend that
FFP at a dose of 1215 ml/kg should be administered for every 6 units of red cells during a
major obstetric bleed.30
Subsequent FFP transfusion should be guided by the results of clotting tests (if they are available
in a timely manner), aiming to maintain PT and APTT ratios at less than 1.5 x normal.52
52
Once the FFP has been ordered, it takes at least 30 minutes to thaw and issue. During this time,
resuscitation should be continued with volume expanding fluids or red cells as appropriate.
Evidence
level 4
It should be borne in mind that, at present in the UK, most units of FFP (as is the case with red
cells, platelets and cryoprecipitate) are not virally inactivated and that transfusion with these
products offers a small risk of transfusion-transmitted infection.52
Full blood counts play an important role in guiding red cell and platelet transfusion during
major haemorrhage, while PT/APTT and fibrinogen results should be used to guide FFP and
cryoprecipitate transfusion respectively.53
13 of 23
Observational studies have indicated that a fibrinogen level of less than 2.9 g/l is associated
with increased risk of PPH.54 One study showed that the decrease in fibrinogen levels was
an early predictor of PPH and that the risk for severe PPH was 2.63-fold higher for each 1 g/l
decrease in fibrinogen, with the positive predictive value being 100% if the fibrinogen level Evidence
level 3
was 2 g/l or less.55 It is important to recognise that during pregnancy fibrinogen levels increase
above normal ranges (varying between 3.5 and 6.5 g/l) and the above studies have indicated
that during PPH a fibrinogen level of 2.0 g/l or less is abnormally low.
Although the above studies have indicated that fibrinogen levels reduce significantly during PPH, no
clinical studies have looked into the timing of when to introduce fibrinogen replacement therapy
during PPH and what the minimum fibrinogen level should be when managing PPH. Cryoprecipitate
at a standard dose of two 5-unit pools should be administered early in major obstetric haemorrhage
and subsequent cryoprecipitate transfusion should be guided by fibrinogen results, aiming to keep a
fibrinogen level of more than 1.5 g/l.
In order to avoid the low risk of ABO-associated haemolysis, FFP and cryoprecipitate should
ideally be of the same blood group as the recipient. If this is not possible, FFP of a different Evidence
level 3
group may be acceptable if it does not possess high-titre anti-A or anti-B activity.52
Sensitisation following the administration of RhD-positive FFP or cryoprecipitate to RhDnegative patients is most unlikely; hence no anti-D prophylaxis is required if a RhD-negative Evidence
level 2
woman receives RhD-positive FFP or cryoprecipitate.52
7.2.3 When should platelets be used?
Aim to maintain the platelet count above 50 x 109/l in the acutely bleeding patient.
A platelet transfusion trigger of 75 x 10 /l is recommended to provide a margin of safety.
9
The platelets should ideally be group compatible. RhD-negative women should also receive RhDnegative platelets.
P
D
The platelet count should not be allowed to fall below 50 x 109/l in the acutely bleeding
patient as this represents the critical level for haemostasis. Such a low platelet count may be Evidence
anticipated when approximately two blood volumes have been replaced by fluid or blood level 4
components.56 A platelet transfusion trigger of 75 x 109/l is recommended in a patient with
ongoing bleeding, so as to provide a margin of safety.57
Platelets may not be on-site in many units; therefore their need should be anticipated and good
communication with the transfusion laboratory maintained.
Platelet concentrates should ideally be of the same ABO group as the recipient. ABO-nonidentical
platelet transfusions have been associated with poorer platelet count increments in some studies,
but this is not usually clinically significant in terms of the haemostatic effectiveness of the
platelet transfusion.58 Administration of ABO-nonidentical platelets is an acceptable transfusion
practice, in particular, when platelet concentrates are in short supply or when human leucocyte
antigen (HLA)-matched platelets are required and the best match is not ABO compatible.58
Evidence
level 3
In order to avoid the development of anti-D antibodies, RhD-negative platelet concentrates

should be given where possible to RhD-negative women of childbearing potential.58
If RhD-positive platelets are transfused to a RhD-negative woman of childbearing potential, anti-D
immunoglobulin should be administered. A dose of 250 iu anti-D immunoglobulin is sufficient to
14 of 23
cover five adult therapeutic doses of platelets given within a 6-week period. This may be given Evidence
level 3
subcutaneously to minimise bruising and haematomas in thrombocytopenic women.58
Platelets may be given via an unused blood giving set, although a platelet giving set reduces Evidence
wastage because it has less dead space. Transfusion of platelets through a giving set previously level 4
used for red cells is not recommended.59
7.2.4 Is there a role for near patient testing of coagulation?
Centres that are using thromboelastography (TEG, Haemonetics, Braintree, Massachusetts, USA)
or rotation thromboelastometry (ROTEM, Tem, Munich, Germany) for guiding blood transfusion
during major obstetric haemorrhage must ensure that their transfusion algorithm protocol has
been validated and that quality assurance measures are followed.
TEG and ROTEM are viscoelastic whole-blood assays that provide information on the
coagulation process through the graphic display of clot initiation, propagation and lysis.
Experiences in cardiac and liver surgery have suggested that TEG or ROTEM can be used
to guide transfusion of blood components, although currently there is no validated transfusion
algorithm for TEG/ROTEM. NHS Quality Improvement Scotland (now known as Healthcare Evidence
level 1
Improvement Scotland) has reviewed the evidence on the clinical and cost effectiveness of
TEG/ROTEM in liver and cardiac surgery; the report concluded that this intervention is costeffective (assuming a usage of 200 tests annually) since it reduces inappropriate transfusions,
thus improving transfusion management and patients clinical outcome.60
There are no randomised controlled trials on the use of TEG or ROTEM in major obstetric
haemorrhage. At the current time, unless a centre has special expertise in the use of TEG/ROTEM,
conventional testing should be performed regularly during major obstetric haemorrhage to guide
transfusion of blood components.
If hospitals are using TEG or ROTEM for guiding blood transfusion during major obstetric Evidence
haemorrhage, it is important that the transfusion algorithm protocol has been validated and level 2
that quality assurance measures are followed.61
8. Pharmacological strategies for management of major obstetric haemorrhage
8.1 Is there a role for recombinant factor VIIa (rFVIIa) therapy?

The use of rFVIIa may be considered as a treatment for life-threatening PPH, but should not delay or
be considered a substitute for a live-saving procedure such as embolisation or surgery, or transfer
to a referral centre.
Factor VIIa has a pivotal role in initiating the process of blood coagulation. Recombinant
factor VIIa (rFVIIa) is licensed for treatment of inherited bleeding disorders. Outside of these Evidence
settings, a review of 35 randomised controlled trials that used rFVIIa on an off-licence basis level 1+
demonstrated that rFVIIa significantly increased the risk of arterial thrombosis.62
There have been no randomised controlled trials to assess the efficacy of rFVIIa in PPH. A
number of case series and national registries have indicated that administration of rFVIIa during
PPH might reduce bleeding and transfusion requirements. However, none of these reports were Evidence
powered to assess the safety of rFVIIa. Moreover, these studies vary significantly with respect to level 3
the timing and dosing of rFVIIa administration.6365 The incidence of thrombotic complications
in a review of 272 women with PPH who had received rFVIIa was reported to be 2.5%.66
15 of 23
There is no evidence to support the prophylactic use of rFVIIa to reduce blood loss for caesarean sections.
In order to ensure the maximum effect of rFVIIa on clot formation, attempts should be made Evidence
level 4
to correct thrombocytopenia, acidosis and hypofibrinogenaemia.67
In the event of intractable obstetric haemorrhage, the administration of rFVIIa may be an option to be
discussed with the haematologists. It is important that each unit or hospital prepares local guidance on
indications for rFVIIa in managing intractable obstetric haemorrhage. A protocol should be available for
how to procure it urgently.
8.2 Is there a role for fibrinogen concentrate therapy?

Fibrinogen concentrate is not licensed in the UK for the management of acquired bleeding disorders.
Thus, its use in PPH should be considered only in the context of clinical trials.
The main advantages of fibrinogen concentrate compared with cryoprecipitate are faster
reconstitution, ease of use and not requiring thawing or ABO compatibility. No randomised
controlled trials or prospective clinical studies have assessed the efficacy of fibrinogen concentrate
in obstetric haemorrhage. One retrospective study compared the clinical outcomes of 20 and 14 Evidence
level 2
women with PPH who had received fibrinogen concentrate and cryoprecipitate respectively.68
There were no significant differences between the two groups with regard to estimated blood
loss, RBC transfusion, FFP transfusion and high dependency unit or intensive therapy unit stay.
8.3 Is there a role for antifibrinolytics?

For those centres not participating in clinical trials, consideration should be given to using
tranexamic acid during major obstetric haemorrhage.
The main antifibrinolytic agent used in the UK is tranexamic acid. Tranexamic acid is a synthetic
derivative of the amino acid lysine that reversibly binds to the lysine-binding sites of the
plasminogen molecule. In doing so, it prevents activation of plasminogen to plasmin, leading to Evidence
level 1
inhibition of fibrinolysis. The CRASH-2 study showed that tranexamic acid reduces mortality in
bleeding trauma patients without an increase in the rate of venous thromboembolism.69
In obstetric settings, several small randomised trials have compared the use of tranexamic acid
with placebo7072 or no treatment.7376 Apart from one study,75 all others were performed in women
undergoing caesarean section. The overall conclusion was that tranexamic acid significantly Evidence
reduces blood loss.77 However, none of these trials were statistically powered to assess mortality level 2
rates and the safety of tranexamic acid. Further, they were heterogenous in their definition of
PPH, the dosing of tranexamic acid and the timing when blood loss was measured.
9.
How should intrapartum anaemia be managed?
In addition to major haemorrhage guidelines, obstetric units should have guidelines on criteria for
red cell transfusion in anaemic women who are not actively bleeding. If the Hb is less than 70 g/l in
labour or in the immediate postpartum period, the decision to transfuse should be made according
to the individuals medical history and symptoms.
Concerns about the safety and availability of donor blood have promoted greater scrutiny
of blood transfusion practice with a focus on restrictive transfusion triggers and avoidance
strategies where available. Outside the context of major haemorrhage, there is little evidence Evidence
level 4
of the benefit of blood transfusion in fit, healthy, asymptomatic patients. The decision to
transfuse must be based on careful clinical assessment in conjunction with the Hb level.
16 of 23
Transfusion will be indicated in women with continued bleeding or at risk of further bleeding, Evidence
level 4
imminent cardiac compromise or significant symptoms requiring urgent correction.4
10. How should women with postpartum anaemia be managed in the postnatal period?
If the Hb is less than 70 g/l in the postnatal period, where there is no ongoing or threat of bleeding,
the decision to transfuse should be made on an informed individual basis.
Audits indicate that a high proportion of blood transfusions administered in the postpartum
period may be inappropriate, with underutilisation of iron supplements.78,79 Prompt recognition
of iron deficiency in the antenatal period followed by iron therapy may reduce the subsequent Evidence
need for blood transfusion.4 If, after careful consideration, elective transfusion is required, level 4
women should be fully counselled about the potential risks. Written information should be
provided and valid informed consent should be obtained before the transfusion is administered.
11. How should women who decline blood products be managed?
Hb should be optimised prior to delivery to prevent avoidable anaemia.
Consent/refusal of blood and components or other transfusion-sparing techniques should be

discussed and documented during the antenatal period.
Use of pharmacological, mechanical and surgical procedures to avert the use of banked blood and
blood components should be considered early.
IOCS has a role in the management of patients who refuse allogeneic blood transfusion.
There are additional challenges in the management of pregnancy in mothers refusing blood
transfusion, including for religious reasons, i.e. Jehovahs Witnesses (JW), with a higher risk
of morbidity and mortality.8082 Accordingly, all women declining blood transfusion require Evidence
careful multidisciplinary planning with senior clinician input during pregnancy to minimise level 2
anaemia and to manage blood loss. Early use of iron replacement is indicated with, if needed,
use of intravenous iron.83,84
Antenatal planning is essential and haematinic deficiencies should be corrected if the Hb is less than
105 g/l for all women before delivery.
The treating clinician will need to establish which blood components or blood-sparing techniques (e.g.
clotting factor products) are acceptable. An example of a suggested care plan for managing women refusing
blood transfusion is available at: http://www.transfusionguidelines.org.uk/transfusion-handbook/12management-of-patients-who-do-not-accept-transfusion/12-2-jehovah-s-witnesses-and-blood-transfusion.
The woman should have an opportunity to discuss consent alone (witnessed) with an experienced
clinician. Treating clinicians should ensure that the woman is fully informed of the risks of refusing
transfusion and of maternal mortality data for JW compared with non-JW women.80 This needs to be
handled sensitively to avoid any possibility of coercion.
An advance directive should be completed and carried in the hand-held notes, although a woman should
always be given the opportunity to change her mind about the use of blood products.
The woman may wish to wear a no blood wristband to make it clear to all members of the treating team
that blood transfusion is not to be used.
17 of 23
The use of a Patient Blood Management (PBM) programme is recommended by AABB

(formerly the American Association of Blood Banks), the Australian National Blood Authority
and the National Blood Transfusion Committee, which covers England and North Wales (see
section 14). PBM involves an all-encompassing approach to avoid unnecessary transfusion by Evidence
level 4
optimising preoperative/predelivery Hb, avoiding overtransfusion, using cell salvage where
appropriate, accepting evidence-based lower transfusion triggers and using intravenous or oral
iron supplements in women who are not actively bleeding and are cardiovascularly stable.85
The Code of Practice for the Surgical Management of Jehovahs Witnesses by the Royal College of
Surgeons of England and Management of Anaesthesia for Jehovahs Witnesses by the Association of
Anaesthetists of Great Britain and Ireland provide useful information.86,87
Evidence from orthopaedic and cardiac surgery supports the premise that use of autologous
blood from IOCS decreases the requirement for allogeneic transfusion. In one study with 68
patients included in the review by NICE, the mean postoperative Hb level was significantly
greater in the group that had blood cell salvage compared with the control group (104 [SD Evidence
15] versus 81 [SD 14] g/l). Also, 2.9% (1/34) of patients who received cell salvage required level 2+
an allogeneic blood transfusion compared with 23.5% (8/34) of the control group.88 Current
evidence supports the use of IOCS in obstetrics, which has been endorsed by several bodies
and is likely to become increasingly commonplace.37
l Define the coagulation abnormalities during major obstetric haemorrhage and investigate the
role of point of care testing (i.e. TEG or ROTEM) in the diagnosis and management of
obstetric haemorrhage.
l Determine the optimal dose and timing of cryoprecipitate and FFP transfusion during major
l Randomised controlled trials are needed to determine the role of fibrinogen concentrate during
major haemorrhage. The WOMAN study (Clinicaltrials.gov ID: NCT00872469), a large, international,
randomised, double-blind, placebo-controlled trial, will be addressing the role of tranexamic acid in
women with a clinical diagnosis of PPH and data collection is due to finish in 2016.
Standards for audit of documentation:
l Provision of local protocols for the management of massive obstetric haemorrhage in all obstetric
l
l
l
l
hospitals (100%).
100% of the staff members, including clinicians, midwives, biomedical scientists and porters, are
familiar with this local protocol.
Provision of local guidelines for red cell transfusion in anaemic women who are not actively
bleeding (100%).
Provision of local guidelines for the treatment of antenatal and postnatal anaemia (100%).
Documentation of the reasons for transfusion in all patients receiving blood products (100%).
Standards for audit of practice:

l Proportion of cases of major obstetric haemorrhage that were incident reported (100%).
l All cases of major obstetric haemorrhage to be reviewed to ensure that the communication chain
worked and that there was no delay in the provision of blood products (100%).
l Provision of written information on the risks of blood transfusion to women who are transfused (100%).
l All women who have had a blood transfusion should have their post-transfusion Hb checked (100%).
18 of 23
14.
l NHS Blood and Transplant. Patient Information Leaflets [http://hospital.blood.co.uk/

l
l
patient-services/patient-blood-management/patient-information-leaflets/].
NHS Choices. Blood transfusion [http://www.nhs.uk/Conditions/Blood-transfusion/Pages/
Introduction.aspx].
Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional
Advisory Committee. UK Cell Salvage Action Group [http://www.transfusionguidelines.org.uk/
transfusion-practice/uk-cell-salvage-action-group].
Patient Blood Management
m AABB. Patient Blood Management [http://www.aabb.org/pbm/Pages/default.aspx].
m National Blood Authority Australia. Patient Blood Management Guidelines [http://www.
blood.gov.au/pbm-guidelines].
m Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Services Professional
Advisory Committee. Patient Blood Management [http://www.transfusionguidelines.org.uk/
uk-transfusion-committees/national-blood-transfusion-committee/patient-blood-management].
The Royal College of Surgeons of England. Code of Practice for the Surgical Management of
Jehovahs Witnesses. London: The Royal College of Surgeons of England; 2002 [http://www.rcseng.
ac.uk/publications/docs/jehovahs_witness.html].
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44. Murphy MF, Wallington TB, Kelsey P, Boulton F, Bruce

M, Cohen H, et al.; British Committee for Standards in
Haematology, Blood Transfusion Task Force. Guidelines
for the clinical use of red cell transfusions. Br J Haematol
2001;113:2431.
45. Borgman MA, Spinella PC, Perkins JG, Grathwohl KW,
Repine T, Beekley AC, et al. The ratio of blood products
transfused affects mortality in patients receiving massive
transfusions at a combat support hospital. J Trauma
2007;63:80513.
46. Spinella PC, Perkins JG, Grathwohl KW, Beekley AC, Niles
SE, McLaughlin DF, et al. Effect of plasma and red blood cell
transfusions on survival in patients with combat related
traumatic injuries. J Trauma 2008;64 Suppl 1:S6977.
47. Stinger HK, Spinella PC, Perkins JG, Grathwohl KW, Salinas
J, Martini WZ, et al. The ratio of fibrinogen to red cells
transfused affects survival in casualties receiving massive
transfusions at an army combat support hospital. J Trauma
2008;64 Suppl 1:S7985.
48. Rajasekhar A, Gowing R, Zarychanski R, Arnold DM, Lim
W, Crowther MA, et al. Survival of trauma patients after
massive red blood cell transfusion using a high or low
red blood cell to plasma transfusion ratio. Crit Care Med
2011;39:150713.
49. Curry N, Stanworth S, Hopewell S, Dore C, Brohi K, Hyde C.
Trauma-induced coagulopathya review of the systematic
reviews: is there sufficient evidence to guide clinical
transfusion practice? Transfus Med Rev 2011;25:21731.e2.
50. Phan HH, Wisner DH. Should we increase the ratio of
plasma/platelets to red blood cells in massive transfusion:
what is the evidence? Vox Sang 2010;98:395402.
51. Murad MH, Stubbs JR, Gandhi MJ, Wang AT, Paul A, Erwin
PJ, et al. The effect of plasma transfusion on morbidity
and mortality: a systematic review and meta-analysis.
52. OShaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M,
Thomas D, Yates S, et al.; British Committee for Standards
in Haematology, Blood Transfusion Task Force. Guidelines
for the use of fresh-frozen plasma, cryoprecipitate and
cryosupernatant. Br J Haematol 2004;126:1128.
53. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J,
Fernndez-Mondjar E, et al. Management of bleeding
and coagulopathy following major trauma: an updated
European guideline. Crit Care 2013;17:R76.
54. Simon L, Santi TM, Sacquin P, Hamza J. Pre-anaesthetic
assessment of coagulation abnormalities in obstetric
patients: usefulness, timing and clinical implications. Br J
Anaesth 1997;78:67883.
55. Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B,
Keita H, et al.; PPH Study Group. The decrease of fibrinogen
is an early predictor of the severity of postpartum
hemorrhage. J Thromb Haemost 2007;5:26673.
56. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and
replacement of major blood loss with plasma-poor red cell
concentrates. Anesth Analg 1995;81:3605.
57. Fakhry SM, Sheldon GF. Massive transfusion in the
surgical patient. In: Jeffries LC, Brecher ME, editors.
Massive Transfusion. Bethesda, Maryland, USA: American
Association of Blood Banks; 1994.
58. British Committee for Standards in Haematology, Blood
Transfusion Task Force. Guidelines for the use of platelet
transfusions. Br J Haematol 2003;122:1023.
59. British Committee for Standards in Haematology, Stainsby D,
MacLennan S, Thomas D, Isaac J, Hamilton PJ. Guidelines
on the management of massive blood loss. Br J Haematol
2006;135:63441.
60. NHS Quality Improvement Scotland. HTA Programme:
Health Technology Assessment Report 11. The clinical
and cost effectiveness of thromboelastography/
thromboelastometry. Glasgow: NHS QIS; 2008.
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61. Medicines and Healthcare Products Regulatory Agency.

Management and use of IVD point of care test devices.
London: MHRA; 2013.
62. Levi M, Levy JH, Andersen HF, Truloff D. Safety of
recombinant activated factor VII in randomized clinical
trials. N Engl J Med 2010;363:17911800.
63. Phillips LE, McLintock C, Pollock W, Gatt S, Popham
P, Jankelowitz G, et al.; Australian and New Zealand
Haemostasis Registry. Recombinant activated factor VII
in obstetric hemorrhage: experiences from the Australian
and New Zealand Haemostasis Registry. Anesth Analg
2009;109:190815.
64. Bomken C, Mathai S, Biss T, Loughney A, Hanley
J. Recombinant activated factor VII (rFVIIa) in the
management of major obstetric haemorrhage: a case series
and a proposed guideline for use. Obstet Gynecol Int
2009;2009:364843.
65. Alfirevic Z, Elbourne D, Pavord S, Bolte A, Van Geijn H,
Mercier F, et al. Use of recombinant activated factor VII in
primary postpartum hemorrhage: the Northern European
registry 2000-2004. Obstet Gynecol 2007;110:12708.
66. Franchini M, Franchi M, Bergamini V, Montagnana M,
Salvagno GL, Targher G, et al. The use of recombinant
activated FVII in postpartum hemorrhage. Clin Obstet
Gynecol 2010;53:21927.
67. Vincent JL, Rossaint R, Riou B, Ozier Y, Zideman D, Spahn
DR. Recommendations on the use of recombinant activated
factor VII as an adjunctive treatment for massive bleeding
a European perspective. Crit Care 2006;10:R120.
68. Ahmed S, Harrity C, Johnson S, Varadkar S, McMorrow S,
Fanning R, et al. The efficacy of fibrinogen concentrate
compared with cryoprecipitate in major obstetric
haemorrhage--an observational study. Transfus Med
2012;22:3449.
69. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista
R, Caballero J, Coats T, et al. Effects of tranexamic acid on
death, vascular occlusive events, and blood transfusion
in trauma patients with significant haemorrhage
(CRASH-2): a randomised, placebo-controlled trial. Lancet
2010;376:2332.
70. Sekhavat L, Tabatabaii A, Dalili M, Farajkhoda T, Tafti
AD. Efficacy of tranexamic acid in reducing blood loss
after cesarean section. J Matern Fetal Neonatal Med
2009;22:725.
71. Gungorduk K, Yildirim G, Asicioglu O, Gungorduk OC,
Sudolmus S, Ark C. Efficacy of intravenous tranexamic acid
in reducing blood loss after elective cesarean section: a
prospective, randomized, double-blind, placebo-controlled
study. Am J Perinatol 2011;28:23340.
72. Movafegh A, Eslamian L, Dorabadi A. Effect of intravenous
tranexamic acid administration on blood loss during
and after cesarean delivery. Int J Gynaecol Obstet
2011;115:2246.
73. Gai MY, Wu LF, Su QF, Tatsumoto K. Clinical observation
of blood loss reduced by tranexamic acid during and after
caesarian section: a multi-center, randomized trial. Eur J
74. Gohel M, Patel P, Gupta A, Desai P. Efficacy of tranexamic

acid in decreasing blood loss during and after cesarean
section: a randomized case controlled prospective study. J
Obstet Gynaecol India 2007;57:22730.
75. Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud
C, Keita-Meyer H, et al.; EXADELI Study Group. Highdose tranexamic acid reduces blood loss in postpartum
haemorrhage. Crit Care 2011;15:R117.
76. Xu J, Gao W, Ju Y. Tranexamic acid for the prevention
of postpartum hemorrhage after cesarean section: a
double-blind randomization trial. Arch Gynecol Obstet
2013;287:4638.
77. Novikova N, Hofmeyr GJ. Tranexamic acid for preventing
postpartum haemorrhage. Cochrane Database Syst Rev
2010;(7):CD007872.
78. Parker J, Thompson J, Stanworth S. A retrospective oneyear single-centre survey of obstetric red cell transfusions.
Int J Obstet Anesth 2009;18:30913.
79. Butwick AJ, Aleshi P, Fontaine M, Riley ET, Goodnough LT.
Retrospective analysis of transfusion outcomes in pregnant
patients at a tertiary obstetric center. Int J Obstet Anesth
2009;18:3028.
80. Singla AK, Lapinski RH, Berkowitz RL, Saphier CJ. Are
women who are Jehovahs Witnesses at risk of maternal
death? Am J Obstet Gynecol 2001;185:8935.
81. Massiah N, Athimulam S, Loo C, Okolo S, Yoong W. Obstetric
care of Jehovahs Witnesses: a 14-year observational study.
82. Van Wolfswinkel ME, Zwart JJ, Schutte JM, Duvekot JJ, Pel M,
Van Roosmalen J. Maternal mortality and serious maternal
morbidity in Jehovahs witnesses in The Netherlands. BJOG
2009;116:11038.
83. Khalafallah AA, Dennis AE, Ogden K, Robertson I, Charlton
RH, Bellette JM, et al. Three-year follow-up of a randomised
clinical trial of intravenous versus oral iron for anaemia in
pregnancy. BMJ Open 2012;2:e000998.
84. Froessler B, Cocchiaro C, Saadat-Gilani K, Hodyl N, Dekker
G. Intravenous iron sucrose versus oral iron ferrous
sulfate for antenatal and postpartum iron deficiency
anemia: a randomized trial. J Matern Fetal Neonatal Med
2013;26:6549.
85. Goodnough LT, Shander A. Patient blood management.
86. The Royal College of Surgeons of England. Code of Practice
for the Surgical Management of Jehovahs Witnesses.
London: The Royal College of Surgeons of England; 2002.
87. The Association of Anaesthetists of Great Britain and
Ireland. Management of Anaesthesia for Jehovahs
Witnesses. 2nd ed. London: AAGBI; 2005.
88. Rainaldi MP, Tazzari PL, Scagliarini G, Borghi B, Conte
R. Blood salvage during caesarean section. Br J Anaesth
1998;80:1958.
21 of 23


low risk of bias


1++ or 1+

results; or
2++

low risk of bias
risk of bias
case series
4
Good practice point
Expert opinion
22 of 23

development group
Dr L Green, Consultant Haematologist, NHS Blood and Transplant and Barts Health NHS Trust, London;
Dr C Connolly, Consultant Anaesthetist, Ninewells Hospital, Dundee, Scotland; Dr TK Cooper MRCOG, Livingston;
Dr G Cho, Consultant Haematologist, Central Middlesex Hospital; and Dr S Allard, Consultant Haematologist,
NHS Blood and Transplant and Barts Health NHS Trust, London
Dr J Bamber, Cambridge; British Maternal and Fetal Medicine Society; Mr UI Esen FRCOG, South Shields; Dr R Fox
MRCOG, Shropshire; Mr DI Fraser FRCOG, Norwich; Dr S Hamilton FRCOG, Huntingdon; Hospital Information
Services for Jehovahs Witnesses; Dr TA Mahmood FRCOG, Kirkcaldy; RCOG Ethics Committee; RCOG Womens
Network; Dr F Regan FRCP FRCPath, Imperial College Healthcare NHS Trust and NHS Blood and Transplant, London;
Dr S Robinson, Guys and St Thomas NHS Foundation Trust, London; Royal College of Midwives; Dr S Rutter MRCOG,
Rotherham; Dr B Thomas MRCOG, Thrissur, India.
Committee lead reviewers were: Dr PS Arunakumari FRCOG, Basildon; Mr DJ Cruikshank FRCOG, Middlesbrough; and
Dr M Gupta MRCOG, London.
guidelines/gtg47/.
DISCLAIMER
23 of 23
Female Genital Mutilation

and its Management
July 2015
Female Genital Mutilation and its Management

This is the second edition of this guideline, which was previously published under the same title in
2009. Prior to this, an RCOG statement with the same title was published in 2003.
Complications of female genital mutilation (FGM)

Clinicians should be aware of the short- and long-term complications of FGM.
The legal and regulatory responsibilities of health professionals

FGM and UK law
All health professionals must be aware of the Female Genital Mutilation Act 2003 in England,
Wales and Northern Ireland and the Prohibition of Female Genital Mutilation (Scotland) Act 2005
in Scotland. Both Acts provide that:
1. FGM is illegal unless it is a surgical operation on a girl or woman irrespective of her age:
(a) which is necessary for her physical or mental health; or
(b) she is in any stage of labour, or has just given birth, for purposes connected with the
labour or birth.
2. It is illegal to arrange, or assist in arranging, for a UK national or UK resident to be taken
overseas for the purpose of FGM.
3. It is an offence for those with parental responsibility to fail to protect a girl from the risk
of FGM.
4. If FGM is confirmed in a girl under 18 years of age (either on examination or because the
patient or parent says it has been done), reporting to the police is mandatory and this
must be within 1 month of confirmation. [New 2015]
Female genital cosmetic surgery (FGCS) may be prohibited unless it is necessary for the patients
physical or mental health. All surgeons who undertake FGCS must take appropriate measures to
ensure compliance with the FGM Acts. [New 2015]
Re-infibulation is illegal; there is no clinical justification for re-infibulation and it should not be
undertaken under any circumstances. [New 2015]
What are the legal and regulatory responsibilities of health professionals in their evaluation of women
with FGM?
When a woman with FGM is identified:
The health professional must explain the UK law on FGM. [New 2015]
The health professional must understand the difference between recording (documenting FGM in
the medical records for data collection) and reporting (making a referral to police and/or social
services) and their responsibilities with regards to these (Appendix I). [New 2015]
The health professional must be familiar with the requirements of the Health and Social Care
Information Centre (HSCIC) FGM Enhanced Dataset and explain its purpose to the woman. The
requirement for her personal data to be submitted without anonymisation to the HSCIC, in order
to prevent duplication of data, should be explained. However, she should also be told that all
personal data are anonymised at the point of statistical analysis and publication. [New 2015]
2 of 26
The health professional should be aware that it is not mandatory to report all pregnant women to
social services or the police. An individual risk assessment should be made by a member of the
clinical team (midwife or obstetrician) using an FGM safeguarding risk assessment tool (an example
of such a tool can be found at https://www.gov.uk/government/publications/safeguarding-womenand-girls-at-risk-of-fgm). If the unborn child, or any related child, is considered at risk then a report
should be made. [New 2015]
What are the principles of FGM management in obstetric and gynaecological practice?
All acute trusts/health boards should have a designated consultant and midwife responsible for
the care of women with FGM (Appendix II).
All gynaecologists, obstetricians and midwives should receive mandatory training on FGM and its
management, including the technique of de-infibulation. They should complete the programme of
FGM e-modules developed by Health Education England. [New 2015]
Specialist multidisciplinary FGM services should be led by a consultant obstetrician and/or
gynaecologist and be accessible through self-referral. These services should offer: information and
advice about FGM; child safeguarding risk assessment; gynaecological assessment; de-infibulation;
and access to other services.
Health professionals should ensure that, in consultations with women affected by FGM, the
consultation and examination environment is safe and private, their approach is sensitive and
nonjudgemental and professional interpreters are used where necessary. Family members should
not be used as interpreters.
P
P
P
How should recent FGM be managed?

Healthcare professionals should be vigilant and aware of the clinical signs and symptoms of recent
FGM, which include pain, haemorrhage, infection and urinary retention. [New 2015]
Examination findings should be accurately recorded in the clinical records. Some type 4 FGM,
where a small incision or cut is made adjacent to or on the clitoris, can leave few, if any, visible
signs when healed. Consideration should be given to photographic documentation of the findings
at acute presentation. [New 2015]
Legal and regulatory procedures must be followed (Appendix I); all women and girls with acute or
recent FGM require police and social services referral. [New 2015]
How should FGM be managed in gynaecological practice?

What should the referral pathway be for women with FGM?
Women may be referred by their general practitioner (GP) to a hospital gynaecology clinic. The
referral should be directed to FGM services, if available, or to the designated consultant obstetrician
and/or gynaecologist responsible for the care of women and girls with FGM.
Women should be able to self-refer. [New 2015]
P
P
All children with FGM or suspected FGM should be seen within child safeguarding services.
[New 2015]
How should women with FGM be assessed in gynaecological practice?

Women with FGM may present with symptoms directly attributable to their FGM or with
co-existing gynaecological morbidity. Gynaecologists should ask all women from communities
that traditionally practise FGM whether they have had the procedure. [New 2015]
3 of 26
Clinicians should be aware that psychological sequelae and impaired sexual function can occur
with all types of FGM.
Examination should include inspection of the vulva to determine the type of FGM and whether
de-infibulation is indicated, as well as to identify any other FGM-related morbidities, e.g.
epidermoid inclusion cysts. [New 2015]
All women should be offered referral for psychological assessment and treatment, testing for HIV,
hepatitis B and C and sexual health screening. Where appropriate, women should be referred to
gynaecological subspecialties, e.g. psychosexual services, urogynaecology, infertility. [New 2015]
Gynaecologists should be aware that narrowing of the vagina due to type 3 FGM can preclude
vaginal examination for cervical smears and genital infection screens. De-infibulation may be
required prior to gynaecological procedures such as surgical management of miscarriage (SMM)
or termination of pregnancy (TOP).
P
P
P
What is the role of de-infibulation in gynaecological practice?

Women who are likely to benefit from de-infibulation should be counselled and offered the
procedure before pregnancy, ideally before first sexual intercourse.
Women offered de-infibulation should have the option of having the procedure performed under
local anaesthetic in the clinic setting in a suitable outpatient procedures room (Appendix III).
What is the role of clitoral reconstruction?

Clitoral reconstruction should not be performed because current evidence suggests unacceptable
complication rates without conclusive evidence of benefit. [New 2015]
How should FGM be managed in pregnancy?

What level of care do women with FGM require?
Women with FGM are more likely to have obstetric complications and consultant-led care is
generally recommended. However, some women with previous uncomplicated vaginal deliveries
may be suitable for midwifery-led care in labour.
How should women with FGM be identified in pregnancy?

All women, irrespective of country of origin, should be asked for a history of FGM at their booking
antenatal visit so that FGM can be identified early in the pregnancy. This should be documented in
the maternity record. [New 2015]
Women identified as having FGM should be referred to the designated consultant obstetrician or
midwife with responsibility for FGM patients. Local protocols will determine which elements of care
should be undertaken by these individuals and which may be undertaken by other appropriately
trained midwives or obstetricians (Appendix IV).
P
P
What antenatal documentation is required to demonstrate that legal and regulatory processes have been
adhered to?
The midwife or obstetrician should ensure that all relevant information is documented in the
clinical records (Appendix I). [New 2015]
How should antenatal care be managed?

Referral for psychological assessment and treatment should be offered.
4 of 26
The vulva should be inspected to determine the type of FGM and whether de-infibulation is
indicated. If the introitus is sufficiently open to permit vaginal examination and if the urethral
meatus is visible, then de-infibulation is unlikely to be necessary.
Screening for hepatitis C should be offered in addition to the other routine antenatal screening
tests (hepatitis B, HIV and syphilis). [New 2015]
De-infibulation may be performed antenatally, in the first stage of labour or at the time of delivery
and can usually be performed under local anaesthetic in a delivery suite room. It can also be
performed perioperatively after caesarean section (Appendix III).
P
P
P
The midwife or obstetrician should discuss, agree and record a plan of care (see Appendix IV). This
may be documented in a preformatted sheet.
Women should be informed that re-infibulation will not be undertaken under any circumstances.
[New 2015]
How should intrapartum care be managed?

If a woman requires intrapartum de-infibulation, the midwife and obstetrician caring for her should
have completed training in de-infibulation or should be supervised appropriately.
If de-infibulation planned for the time of delivery is not undertaken because of recourse to caesarean
section, then the option of perioperative de-infibulation (i.e. just after caesarean section) should
be considered and discussed with the woman. [New 2015]
Labial tears in women with FGM should be managed in the same manner as in women without
FGM. Repairs should be performed where clinically indicated, after discussion with the woman and
using appropriate materials and techniques.
How should intrapartum care be managed for women identified as having FGM in pregnancy for whom
there has been no agreed documented plan of care?
The impact of FGM on labour and delivery should be sensitively discussed and a plan of care
agreed. [New 2015]
How should postnatal care be managed?

A woman whose planned de-infibulation was not performed because of delivery by caesarean
section should have follow-up in a gynaecology outpatient or FGM clinic so that de-infibulation
can be offered before a subsequent pregnancy. [New 2015]
The discharging midwife should ensure that all legal and regulatory processes have been adhered
to prior to discharge (Appendix I). [New 2015]
1.
P
P
Purpose and scope
The purpose of this guideline is to provide evidence-based guidance on the management of women with
female genital mutilation (FGM) and those who are considered to be at risk. It covers the clinical care of
women before, during and after pregnancy, including the legal and regulatory responsibilities of health
professionals. The focus of this guideline is on practice in the UK. Although much of the content is
applicable to all four constituent countries, the regulatory framework in Scotland and Northern Ireland
differs to that described here; further information is available elsewhere.1,2
For a global perspective on FGM, further information is available from other sources.3,4
5 of 26
2.
2.1 Definition and classification

Female genital mutilation, also known as female genital cutting, female genital mutilation/cutting or
cutting, refers to all procedures involving partial or total removal of the external female genitalia or
other injury to the female genital organs for non-medical reasons.3,5 The widely accepted classification
of FGM developed by the World Health Organization (WHO) in 1995 and updated in 2007 is shown in
Table 1. FGM is practised for a variety of complex reasons, usually in the belief that it is beneficial for the
girl.4 It has no health benefits and harms girls and women in many ways. FGM is a human rights violation
and a form of child abuse, breaching the United Nations Convention on the Rights of the Child,4 and is a
severe form of violence against women and girls.6
Table 1. WHO FGM classification3
Type 1:
Partial or total removal of the clitoris and/or the prepuce (clitoridectomy).
Type 2:
Partial or total removal of the clitoris and the labia minora, with or without excision of the labia majora
(excision).
Type 3:
arrowing of the vaginal orifice with creation of a covering seal by cutting and appositioning the labia minora
N
and/or the labia majora, with or without excision of the clitoris (infibulation).
Type 4:
ll other harmful procedures to the female genitalia for non-medical purposes, for example: pricking, piercing,
A
incising, scraping and cauterization.
2.2 Global epidemiology

UNICEF estimates that worldwide over 125 million women and girls have undergone FGM.4 It is a
traditional cultural practice in 29 African countries. FGM prevalence by country is shown in Figure 1.
Outside Africa, FGM is also practised in Yemen, Iraqi Kurdistan and parts of Indonesia and Malaysia. Far
smaller numbers have been recorded in India, Pakistan, Sri Lanka, the United Arab Emirates, Oman, Peru
and Colombia.
The type of FGM varies between countries. FGM type 3 (infibulation) is practised almost exclusively in
Africa, with the highest prevalence in northeastern Africa, including Somalia, Sudan, Ethiopia, Eritrea
and Djibouti. FGM prevalence also varies within countries, where it may be associated with particular
ethnic groups. FGM is almost always carried out on girls between infancy and the age of 15, but the age
at which girls are mutilated varies considerably between countries. It is estimated that in over half of
countries practising FGM, girls are cut under the age of 5 years. In some communities adult women may
undergo re-infibulation following childbirth.
Those performing FGM are usually traditional practitioners with no formal medical training, who practise
without anaesthetics using crude instruments such as knives, scissors or razor blades. However, in some
countries health professionals undertake a substantial number of FGM procedures. These include Egypt,
where doctors undertake the majority of FGM procedures, Sudan and Kenya. Globally, the trend towards
medicalisation of FGM is increasing.4
As a result of migration, there has been a substantial increase in the number of girls and women with
FGM living in North America, Australia, New Zealand and Europe.4
2.3 UK epidemiology
It has been estimated that 137000 women and girls in England and Wales, born in countries where
FGM is traditionally practised, have undergone FGM, including 10000 girls aged under 15 years.
These provisional interim estimates were derived by combining published data on FGM prevalence
in FGM-practising countries with census and birth registration data in England and Wales.7 There are
6 of 26
Figure 1. P
revalence of FGM. Percentage of girls and women aged 1549 who have undergone FGM, by region/
country. Source: UNICEF4
98% Somalia
96% Guinea
93% Djibouti
91% Egypt
89% Eritrea
89% Mali
88% Sierra Leone
88% Sudan
76% Gambia
76% Burkina Faso
74% Ethiopia
69% Mauritania
66% Liberia
50% Guinea-Bissau
44% Chad
38% Cte dIvoire
27% Kenya
27% Nigeria
26% Senegal
24% Central African Republic
23% Yemen
15% United Republic of Tanzania
13% Benin
8% Iraq
4% Ghana
4% Togo
2% Niger
1% Cameroon
1% Uganda
Above 80%
51% 80%
26% 50%
10% 25%
Less than 10%
FGM/C is not
concentrated in
these countries
This map is
stylized and
not to scale. It
does not reflect
a position by
UNICEF on the
legal status of
any country or
territory or the
delimitation of
any frontiers.
The final
boundary
between the
Republic of the
Sudan and the
Republic of
South Sudan
has not yet been
determined.
FGM/C female genital mutilation/cutting
no published studies on the prevalence of FGM in Scotland or Northern Ireland. There is anecdotal
evidence that girls are taken from the UK to their country of origin to undergo FGM and that FGM also
takes place in the UK.8
In order to capture data about numbers of women with FGM receiving care from the National Health
Service in England, the Department of Health implemented an FGM data set in 2014. In April 2015, an
enhanced data set was introduced, requiring all acute trusts, general practices and mental health trusts
to record FGM data and return patient-identifiable data to the Health and Social Care Information Centre
(HSCIC). Information can be found on the HSCIC website: http://www.hscic.gov.uk/fgm.
3.
Guidelines. MEDLINE, EMBASE and the Cochrane Library were searched. The search was restricted to
articles published between 2007 and January 2014 and limited to humans and the English language. A
top-up literature search was performed in April 2015. The databases were searched using the relevant
Medical Subject Headings (MeSH) terms, including all subheadings, and this was combined with
a keyword search. Search terms included FGM, female genital cutting, female genital mutilation,
circumcision, infibulation, deinfibulation, de-infibulation, clitoridectomy and defibulation. The
National Guideline Clearinghouse, National Institute for Health and Care Excellence (NICE) Evidence
Search, Trip, Guidelines International Network and the Geneva Foundation for Medical Education and
Research website were also searched for relevant guidelines. The websites of the WHO, UNICEF, United
Nations Population Fund (UNFPA), the Population Council, the Population Reference Bureau, FORWARD
7 of 26
(Foundation for Womens Health Research and Development), Rainbo and the UK Government were
searched for relevant reports. Where possible, recommendations are based on available evidence. Areas
lacking evidence are highlighted and annotated as good practice points.
4.
Complications of FGM
Clinicians should be aware of the short- and long-term complications of FGM.
4.1 Short-term complications

A systematic review by Berg9 found that the most common immediate complications from
FGM were haemorrhage (562%), urinary retention (853%) and genital swelling (227%), Evidence
although there were additional studies reporting infection and fever, and three deaths directly level 2+
attributed to FGM. The methodological quality of these studies was generally poor.
There is concern that some type 4 FGM procedures, where a small cut is made adjacent to the clitoris,
may now be performed more frequently.4 This may leave little in the way of long-term scarring and so
contemporaneous recording of all findings is crucial.
4.2 Long-term complications

Reported long-term complications of FGM are listed below. The systematic review by Berg9 demonstrated
an association of FGM with urinary tract infection, dyspareunia and bacterial vaginosis. Cohort
studies and case reports have also found associations with other sequelae. Most studies are of poor
methodological quality.
Genital scarring
Genital scarring after FGM can be unsightly and painful. Keloid scarring has been reported
in up to 3% of women. Epidermoid inclusion cysts and sebaceous cysts may need surgical Evidence
level 4
excision.10 Neuroma of the clitoris causing pain has been described.1113
Urinary tract complications

Lower urinary tract symptoms are more common in women with FGM, particularly those
with type 2 or type 3 FGM.14 Poor urinary flow beneath the infibulation scar may result in
symptoms of urinary obstruction, and stasis of urine may lead to recurrent urinary tract Evidence
level 2+
infection (relative risk [RR] 3.01, CI 1.426.38) 9 and to urinary or vaginal calculi.15 The
recommended treatment is de-infibulation.
Damage to the urethra during FGM of any type may result in a urinary stricture or fistulae. These require
assessment by a urologist or urogynaecologist.
There is no evidence that FGM directly increases the long-term risk of genital prolapse or Evidence
level 3
incontinence.16 However, vaginal narrowing may hamper urodynamic investigation.
Dyspareunia, apareunia and impaired sexual function

Dyspareunia may occur as a result of vaginal narrowing and painful scar tissue (RR 1.53, 95%
CI 1.201.97). Apareunia and vulvovaginal lacerations during sexual intercourse have also
been reported.9
Evidence
level 2+
The removal of sexually sensitive tissue such as the clitoris and labia minora may reduce
sexual sensation, while scarring over the clitoris may be painful. Numerous reports exist of
8 of 26
various sexual consequences of FGM, including a reduction in desire and arousal, reduced Evidence
frequency of orgasm or anorgasmia, decreased lubrication and poorer sexual satisfaction.1719 level 2+
Psychological sequelae
It is accepted that FGM has psychological effects, and flashbacks, anxiety20 and post-traumatic
stress disorder have been reported.21 FGM has been linked to an increased incidence of Evidence
level 3
domestic violence in Africa22,23 but there are no European or UK data on this.
Menstrual difficulties
Haematocolpos due to FGM has been reported. Dysmenorrhoea has also been reported among Evidence
level 3
women with FGM, although the underlying mechanisms are unclear.13
Genital infection and pelvic inflammatory disease

FGM has been associated with an increased risk of bacterial vaginosis9 and herpes simplex
virus type 2.24 However, currently there is no conclusive epidemiological evidence to support
an increased risk of pelvic inflammatory disease as a consequence of FGM. One casecontrol Evidence
level 2+
study from Sudan showed similar rates of chlamydia, gonorrhoea and syphilis in women with
and without FGM.25
Infertility
At present, there are no well-planned studies that confirm whether or not FGM leads to
infertility. Potential factors could include lack of sexual intercourse (apareunia, dyspareunia, Evidence
impaired sexual function) and ascending infections caused by the FGM procedure. One case level 2
control study showed an association between primary infertility and FGM.26
HIV and hepatitis B infection

Many FGM-practising countries are hepatitis B endemic27 and some have a high prevalence of HIV.28
Although mechanisms by which FGM may increase the risk of transmission of hepatitis B, hepatitis C
and HIV have been proposed (i.e. sharing of non-sterile instruments and cutting in groups), there is
currently no conclusive epidemiological evidence to support this.
Obstetric complications
Research into the obstetric complications of FGM has been hampered by patchy methodology and the
fact that in Africa, where FGM is typically practised, maternal and perinatal mortality and morbidity are
already high due to other factors. Obstetric complications have been described with all types of FGM.
However, the risks are greater with greater tissue damage.
Maternal complications associated with FGM have been described in Africa, North America
and Europe. One large prospective study by the WHO investigated both maternal and
perinatal outcomes in 28000 women in six African countries.29 A meta-analysis by Berg et al.30
reviewed maternal outcomes and included some studies from Western countries (USA and
Europe), although the majority were from Africa. The meta-analysis reported an increased
risk of prolonged labour, postpartum haemorrhage and perineal trauma. The WHO study also Evidence
level 2
found an increased risk of caesarean section and demonstrated an increased need for neonatal
resuscitation and risk of stillbirth and early neonatal death.
There are no good quality European or UK studies investigating FGM and perinatal outcomes.
However, evidence from epidemiological studies of non-European migrants in Europe has
9 of 26
shown a higher incidence of stillbirth31,32 and neonatal death,31 so women in the UK from FGM- Evidence
level 2
practising countries may be at higher risk.
Although fistulae have been associated with FGM, studies have not demonstrated that a history Evidence
level 4
of FGM increases the risk of subsequent obstetric fistulae due to obstructed labour.33
Other obstetric consequences that have been described include fear of childbirth, difficulty
in intrapartum monitoring (including application of fetal scalp electrodes and fetal blood Evidence
level 2+
sampling), difficulty in catheterisation during labour, wound infection and retention of lochia.29
5.
The legal and regulatory responsibilities of health professionals
5.1 FGM and UK law

All health professionals must be aware of the Female Genital Mutilation Act 2003 in England,
Wales and Northern Ireland and the Prohibition of Female Genital Mutilation (Scotland) Act 2005
in Scotland. Both Acts provide that:
1. FGM is illegal unless it is a surgical operation on a girl or woman irrespective of her age:
(a) which is necessary for her physical or mental health; or
(b) she is in any stage of labour, or has just given birth, for purposes connected with the
labour or birth.
2. It is illegal to arrange, or assist in arranging, for a UK national or UK resident to be taken
overseas for the purpose of FGM.
3. It is an offence for those with parental responsibility to fail to protect a girl from the risk
of FGM.
4. If FGM is confirmed in a girl under 18 years of age (either on examination or because the
patient or parent says it has been done), reporting to the police is mandatory and this
must be within 1 month of confirmation.
Female genital cosmetic surgery (FGCS) may be prohibited unless it is necessary for the patients
physical or mental health. All surgeons who undertake FGCS must take appropriate measures to
ensure compliance with the FGM Acts.
Re-infibulation is illegal; there is no clinical justification for re-infibulation and it should not be
undertaken under any circumstances.
Health professionals must have a clear understanding of the law on FGM so that they can
explain it to their patients and so that they understand the basis for reporting concerns to the Evidence
level 4
police and/or social care.34
FGM is illegal in England, Wales and Northern Ireland under the Female Genital Mutilation Act 2003 and
in Scotland under the Prohibition of Female Genital Mutilation (Scotland) Act 2005. Both Acts make it
an offence for any person:
(a) to excise, infibulate or otherwise mutilate the whole or any part of a persons labia majora, labia
minora or clitoris; or
(b) to aid, abet, counsel or procure the performance by another person of any of those acts on that
other persons own body, or
(c) to aid, abet, counsel or procure a person to excise, infibulate or otherwise mutilate the whole or
any part of her own labia majora, labia minora or clitoris.
Both Acts also make it a criminal offence to carry out FGM abroad, and to aid, abet, counsel or procure
the carrying out of FGM abroad, including in countries where the practice is legal. Both Acts permit
10 of 26
surgical procedures that may fall within these categories (carried out by an appropriately registered
practitioner) if necessary for the physical or mental health of the woman or if performed during labour
or immediately postpartum for purposes connected with the labour or birth. It should be noted that
the FGM Acts apply to adult women as well as children.
The Serious Crime Act 2015 reinforced existing FGM legislation and introduced mandatory reporting of
FGM in girls under 18 years by healthcare workers, teachers and social workers to the police.35
All health professionals should be aware of the Department of Healths guidance on FGM risk assessment
and safeguarding.5
FGCS refers to non-medically indicated cosmetic surgical procedures, which change the
structure and appearance of the healthy external genitalia of women (or internally in the case
of vaginal tightening). UK guidance on FGCS is available and this includes the recommendation
that FGCS should not normally be carried out on those under 18.36 The legal status of some
FGCS procedures has been called into question and it is likely to be illegal unless necessary to
Evidence
safeguard the patients physical or mental health (the section 1(2)(a) exemption).
level 4
Re-infibulation refers to the resuturing (usually after childbirth) of the incised scar tissue in a
woman with FGM type 2 or 3. Previously there was uncertainty as to whether re-infibulation
was covered by the FGM Acts.6 However, it is now accepted that re-infibulation is illegal and
should not be performed in any circumstances.
5.2 What are the legal and regulatory responsibilities of health professionals in their
evaluation of women with FGM?
When a woman with FGM is identified:
The health professional must explain the UK law on FGM.
The health professional must understand the difference between recording (documenting FGM in
the medical records for data collection) and reporting (making a referral to police and/or social
services) and their responsibilities with regards to these (Appendix I).
The health professional must be familiar with the requirements of the HSCIC FGM Enhanced Dataset
and explain its purpose to the woman. The requirement for her personal data to be submitted
without anonymisation to the HSCIC, in order to prevent duplication of data, should be explained.
However, she should also be told that all personal data are anonymised at the point of statistical
analysis and publication.
The health professional should be aware that it is not mandatory to report all pregnant women to
social services or the police. An individual risk assessment should be made by a member of the
clinical team (midwife or obstetrician) using an FGM safeguarding risk assessment tool (an example
of such a tool can be found at https://www.gov.uk/government/publications/safeguarding-womenand-girls-at-risk-of-fgm). If the unborn child, or any related child, is considered at risk then a report
should be made.
To assist health professionals in explaining the law on FGM to their patients, women should be referred
to information provided in the Health Passport.38 This document is available in a range of languages.39
The legal and regulatory responsibilities of health professionals are summarised in Appendix I.
11 of 26
Recording (see Appendix I)

Recording must be in accordance with the requirements of the HSCIC FGM Enhanced Dataset, which
was implemented primarily to improve services for those with FGM. It requires all acute trusts, general
practices and mental health trusts to record demographic, clinical and family information for all women
with FGM and for these data to be submitted, without anonymisation, to the HSCIC. This should be
explained to the woman. However, she should also be told that all personal data are anonymised at
the point of statistical analysis and publication. According to Department of Health guidance (http://
www.nhs.uk/NHSEngland/AboutNHSservices/sexual-health-services/Documents/2903740%20DH%20
FGM%20Leaflet%20Acessible%20-%20English.pdf), women who object to use of their data in this way
should go to http://www.hscic.gov.uk/patientconf for more details.
In accordance with the Enhanced Dataset, when a patient with FGM is identified, the fact that they
have had FGM must be documented in the medical records regardless of whether FGM is the reason for
presentation. A clinical examination may be indicated to determine the type of FGM and clinicians are
required to use the WHO FGM classification (Table 1). For this reason genital piercings must be included
as type 4 FGM. The woman should be informed that her personal data will be transmitted to the HSCIC
for the purpose of FGM prevalence monitoring and that the data will not be anonymised. Some services,
such as sexual health services, are likely to be exempt from returning identifiable FGM data on adult
women due to their specific legal obligations regarding confidentiality.
Reporting (see Appendix I)

Reporting means making a referral to the police or social services and guidance from the Department
of Health is available.5
The requirement to report depends on whether an adult or a child is affected. FGM is child abuse and
any child with confirmed or suspected FGM, or a child considered to be at risk of FGM, must be reported,
if necessary without the consent of the parents. Information should also be shared with the general
practitioner (GP) and health visitor. This is in accordance with section 47 of the Children Act 1989.
Local Safeguarding Children Boards (LSCBs) have responsibility for developing inter-agency protocols
and procedures for safeguarding. If in any doubt, health professionals must contact their named lead for
safeguarding who will advise. The urgency of the referral will vary depending on the type of risk.
There is no requirement to report a nonpregnant adult woman aged 18 or over to the police or social
services unless a related child is at risk. The patients right to confidentiality must be respected if they do
not wish any action to be taken. No reports to social care or the police should be made in these cases.5,34
It is not mandatory to report every pregnant woman identified as having had FGM to social services or
the police. An individual risk assessment must be made by a member of the clinical team caring for the
woman during her pregnancy. If the unborn child, or any related child, is considered to be at risk of
FGM, then a report must be made to childrens social care or the police.
Healthcare professionals must record identified FGM in antenatal notes, screening returns and
immunisation notes. Notes should also include whether the woman has been de-infibulated and, where
appropriate, referred to further specialist care. A list of specialist FGM clinics is available (please note
that this list only covers England).40
Following birth, relevant information about the mothers FGM should be recorded in the maternity
discharge documentation so that GPs and health visitors are aware of the mothers history. The family
history of FGM should also be recorded in the babys personal child health record (Red Book).41
12 of 26
Where appropriate, healthcare professionals should educate women on how FGM is illegal in the UK Evidence
and how the practice has serious long-term physical, psychological and emotional consequences.4 level 4
6.
What are the principles of FGM management in obstetric and gynaecological practice?
All acute trusts/health boards should have a designated consultant and midwife responsible for
the care of women with FGM (Appendix II).
All gynaecologists, obstetricians and midwives should receive mandatory training on FGM and its
management, including the technique of de-infibulation. They should complete the programme of
FGM e-modules developed by Health Education England.
Specialist multidisciplinary FGM services should be led by a consultant obstetrician and/or
gynaecologist and be accessible through self-referral. These services should offer: information and
advice about FGM; child safeguarding risk assessment; gynaecological assessment; de-infibulation;
and access to other services.
Health professionals should ensure that, in consultations with women affected by FGM, the
consultation and examination environment is safe and private, their approach is sensitive and
nonjudgemental and professional interpreters are used where necessary. Family members should
not be used as interpreters.
P
P
P
Each trust/health board should have a designated obstetrician and/or gynaecologist responsible for FGM
care. These individuals should be aware of local and/or regional specialist multidisciplinary FGM services.
They should remain competent and up to date in all aspects of FGM (including child safeguarding protocols).
The programme of FGM e-modules developed by Health Education England is available free to
all healthcare professionals (http://www.e-lfh.org.uk/programmes/female-genital-mutilation). Use of a
de-infibulation bench-top trainer as an aid to learning may be considered.
Most UK specialist FGM services are in major cities and may be located in a hospital or
community clinic (e.g. GP surgery or sexual health clinic). All FGM specialist services should
offer information and advice regarding FGM as well as gynaecological assessment and access
to de-infibulation. Some may also offer antenatal care. Specialist FGM services should offer
access to psychological assessment and treatment, sexual health screening and treatment and
gynaecological subspecialties such as urogynaecology, psychosexual services and infertility.
They should work collaboratively with other healthcare providers, including GPs and acute
trusts, voluntary sector organisations, the police, social services and schools. Currently referral
pathways, clinic hours and service provision vary and there is a need to develop national Evidence
minimum quality assurance standards for establishing and operating these services.42
level 4
Guidance about the professional approach to take when women with FGM attend for
consultation is available.34 Health professionals should be nonjudgemental, pointing out the
illegality and health risks of the practice without appearing to blame the woman. Appropriate
language should be used. Although the term FGM may be understood and accepted by some,
referring to being cut, closed or circumcised may be more acceptable to many women.34 A
list of local/traditional terms for FGM is available in the Department of Health Female Genital
Mutilation Risk and Safeguarding guidance.5
7.
How should recent FGM be managed?
Healthcare professionals should be vigilant and aware of the clinical signs and symptoms of recent
FGM, which include pain, haemorrhage, infection and urinary retention.
13 of 26
Examination findings should be accurately recorded in the clinical records. Some type 4 FGM,
where a small incision or cut is made adjacent to or on the clitoris, can leave few, if any, visible
signs when healed. Consideration should be given to photographic documentation of the findings
at acute presentation.
Legal and regulatory procedures must be followed (Appendix I); all women and girls with acute or
recent FGM require police and social services referral.
Healthcare professionals should be aware of the clinical signs and symptoms of FGM and record their
examination findings accurately in the clinical records. The legal and regulatory procedures are outlined
in Appendix I.
8. How should FGM be managed in gynaecological practice?
8.1 What should the referral pathway be for women with FGM?
Women may be referred by their GP to a hospital gynaecology clinic. The referral should be directed
to FGM services, if available, or to the designated consultant obstetrician and/or gynaecologist
responsible for the care of women and girls with FGM.
Women should be able to self-refer.
All children with FGM or suspected FGM should be seen within child safeguarding services.
P
P
P
All hospitals are expected to identify women with FGM and assess appropriately. In areas of low
prevalence there must be clear pathways for referral to FGM services, including self-referral.
8.2 How should women with FGM be assessed in gynaecological practice?

Women with FGM may present with symptoms directly attributable to their FGM or with coexisting gynaecological morbidity. Gynaecologists should ask all women from communities that
traditionally practise FGM whether they have had the procedure.
Clinicians should be aware that psychological sequelae and impaired sexual function can occur
with all types of FGM.
Examination should include inspection of the vulva to determine the type of FGM and whether deinfibulation is indicated, as well as to identify any other FGM-related morbidities, e.g. epidermoid
inclusion cysts.
All women should be offered referral for psychological assessment and treatment, testing for HIV,
hepatitis B and C and sexual health screening. Where appropriate, women should be referred to
gynaecological subspecialties, e.g. psychosexual services, urogynaecology, infertility.
Gynaecologists should be aware that narrowing of the vagina due to type 3 FGM can preclude
vaginal examination for cervical smears and genital infection screens. De-infibulation may be
required prior to gynaecological procedures such as surgical management of miscarriage (SMM)
or termination of pregnancy (TOP).
P
C
P
P
P
The clinical management of women with FGM in gynaecological practice is summarised in Appendix II.
8.3 What is the role of de-infibulation in gynaecological practice?

Women who are likely to benefit from de-infibulation should be counselled and offered the
procedure before pregnancy, ideally before first sexual intercourse.
14 of 26
Women offered de-infibulation should have the option of having the procedure performed under
local anaesthetic in the clinic setting in a suitable outpatient procedures room (Appendix III).
De-infibulation is a minor surgical procedure to divide the scar tissue sealing the vaginal introitus in
type 3 FGM. The need for de-infibulation can be determined on inspection of the external genitals by an
experienced health professional. De-infibulation is sometimes termed a reversal of FGM; however, this
is incorrect as it does not replace genital tissue or restore normal genital anatomy and function.
De-infibulation is recommended if the introitus is not sufficiently open to permit normal urinary and
menstrual flow, vaginal examination, comfortable sexual intercourse and safe vaginal delivery. It may also
be necessary to permit cervical smears, sexual health screens and gynaecological surgery (e.g. SMM, TOP).
In practice it will be required for most women with type 3 FGM, as the vaginal introitus will be narrowed.
De-infibulation can usually be performed under local anaesthetic in an appropriately equipped room for
minor procedures or in a delivery suite room. Occasionally a spinal or general anaesthetic is required.
One recommended method of de-infibulation is shown in Appendix III.
8.4 What is the role of clitoral reconstruction?

Clitoral reconstruction should not be performed because current evidence suggests unacceptable
complication rates without conclusive evidence of benefit.
Several publications, including a large retrospective study,43 claim that reconstructive clitoral
surgery can restore clitoral function. However, surgery cannot replace clitoral tissue removed
at FGM and it is also possible that surgical exploration of the clitoral area may result in further
damage to the clitoral nerves and vasculature and loss of sensation. It is debatable that these
procedures improve clitoral sensation, although improving the genital appearance may have Evidence
benefits for some women. Existing studies are retrospective with poor follow-up and they lack level 3
standardised assessment of sexual function. In the study by Folds,43 2938 women underwent
surgery but only 29% attended for follow-up and 4% required hospital readmission because of
surgical complications. There is a need for well-designed clinical trials to investigate the safety
and effectiveness of this procedure.
9.
How should FGM be managed in pregnancy?
9.1 What level of care do women with FGM require?

Women with FGM are more likely to have obstetric complications and consultant-led care is
generally recommended. However, some women with previous uncomplicated vaginal deliveries
may be suitable for midwifery-led care in labour.
Women with FGM are more likely to have obstetric complications and consultant-led care is generally
recommended. However, some women who have previously had one or more uncomplicated pregnancies
and have delivered vaginally may be considered low risk, provided that they have no history of postdelivery re-infibulation.
9.2 How should women with FGM be identified in pregnancy?

All women, irrespective of country of origin, should be asked for a history of FGM at their booking
antenatal visit so that FGM can be identified early in the pregnancy. This should be documented in
the maternity record.
15 of 26
Women identified as having FGM should be referred to the designated consultant obstetrician or
midwife with responsibility for FGM patients. Local protocols will determine which elements of care
should be undertaken by these individuals and which may be undertaken by other appropriately
trained midwives or obstetricians (Appendix IV).
Pregnancy is a time when the majority of women engage with healthcare services. It presents
a key opportunity to identify women with FGM, provide information and advice, address
healthcare needs and assess the risk to the unborn child and to other female family members.
In the UK, it is normal practice to defer vaginal examination of pregnant women until the
onset of labour, unless there is a clinical indication. For this reason, early identification of FGM Evidence
level 4
in pregnancy is best achieved by asking all women booking for antenatal care whether they
have a history of FGM.41 It is good practice if possible to obtain such a clinical history from the
patient in the absence of a partner or other family member. It might be important to consider
that some women may not know if they have been exposed to FGM.
The clinical management of pregnant women is summarised in Appendix II.
9.3 What antenatal documentation is required to demonstrate that legal and regulatory
processes have been adhered to?
The midwife or obstetrician should ensure that all relevant information is documented in the
clinical records (Appendix I).
The information in the clinical records should include documentation that FGM has been recorded in
accordance with the HSCIC Enhanced Dataset, as well as other information as shown in Appendix I.
9.4 How should antenatal care be managed?

Referral for psychological assessment and treatment should be offered.
The vulva should be inspected to determine the type of FGM and whether de-infibulation is
indicated. If the introitus is sufficiently open to permit vaginal examination and if the urethral
meatus is visible, then de-infibulation is unlikely to be necessary.
Screening for hepatitis C should be offered in addition to the other routine antenatal screening
tests (hepatitis B, HIV and syphilis).
De-infibulation may be performed antenatally, in the first stage of labour or at the time of delivery
and can usually be performed under local anaesthetic in a delivery suite room. It can also be
performed perioperatively after caesarean section (Appendix III).
The midwife or obstetrician should discuss, agree and record a plan of care (see Appendix IV). This
may be documented in a preformatted sheet.
Women should be informed that re-infibulation will not be undertaken under any circumstances.
P
P
P
P
P
D
For women with type 3 FGM, where adequate vaginal assessment in labour is unlikely to be possible,
de-infibulation should be recommended antenatally, usually in the second trimester, typically at around
20 weeks of gestation. Antenatal de-infibulation as an elective procedure ensures that the procedure
is performed by an appropriately trained midwife or obstetrician. However, women may prefer
de-infibulation during labour, as this is the usual practice in some countries where FGM is prevalent.
There have been no randomised trials conducted on measures that may improve outcomes for pregnant
women with a history of FGM.44 However de-infibulation (when the introitus is narrowed) and selective
episiotomy (depending on assessment at the time of delivery) may improve clinical outcomes.
16 of 26
Women should be informed that re-infibulation will not be undertaken under any
circumstances.37 They should also be informed of the health consequences of re-infibulation Evidence
level 4
and the benefits of not re-infibulating.
9.5 How should intrapartum care be managed?

If a woman requires intrapartum de-infibulation, the midwife and obstetrician caring for her should
have completed training in de-infibulation or should be supervised appropriately.
If de-infibulation planned for the time of delivery is not undertaken because of recourse to caesarean
section, then the option of perioperative de-infibulation (i.e. just after caesarean section) should
be considered and discussed with the woman.
Labial tears in women with FGM should be managed in the same manner as in women without
FGM. Repairs should be performed where clinically indicated, after discussion with the woman and
using appropriate materials and techniques.
P
P
D
Women with FGM should generally be delivered in units with immediate access to emergency obstetric
care and should have intravenous access established in labour and blood taken for full blood count and
group and save. However, in certain circumstances women with FGM may be considered low risk and
midwifery-led care in labour may be appropriate (see section 9.1).
The technique of de-infibulation at delivery is similar in principle to de-infibulation performed at other
times (see Appendix III). However, in contrast to de-infibulation prepregnancy, antenatally or in the first
stage of labour, when either a scalpel or scissors may be used, at delivery the incision should be made
with scissors (rather than a scalpel) just before crowning of the fetal head. Lidocaine without adrenaline
(epinephrine) should be used. Once the procedure has been performed, the need for episiotomy should
be assessed; this is commonly required (irrespective of FGM type) due to scarring and reduced skin
elasticity of the introitus.
In women for whom intrapartum de-infibulation was planned to permit safe vaginal delivery, emergency
caesarean section may result in the woman having an ongoing need for de-infibulation during a subsequent
pregnancy. If feasible from the perspective of maternal and fetal wellbeing, the option of perioperative
de-infibulation, after safe caesarean delivery of the baby, should be discussed with the woman prior to
transfer to theatre. This scenario may be discussed with women antenatally.
Guidance for repair of perineal and genital trauma is available45 and should be followed for Evidence
level 4
women with FGM, for example, in the case of labial tears.
9.6 How should intrapartum care be managed for women identified as having FGM in
pregnancy for whom there has been no agreed documented plan of care?
The impact of FGM on labour and delivery should be sensitively discussed and a plan of care agreed.
If vaginal examination is not possible or intrapartum procedures and urinary catheterisation are not
feasible, then de-infibulation in the first stage of labour should be recommended. An epidural should be
offered to cover the procedure and for subsequent examinations and delivery. If vaginal access is adequate
then de-infibulation can be performed at the time of delivery under local anaesthetic (see section 9.5).
9.7 How should postnatal care be managed?

A woman whose planned de-infibulation was not performed because of delivery by caesarean
section should have follow-up in a gynaecology outpatient or FGM clinic so that de-infibulation
can be offered before a subsequent pregnancy.
17 of 26
The discharging midwife should ensure that all legal and regulatory processes have been adhered
to prior to discharge (Appendix I).
The designated consultant obstetrician or named specialist midwife may consider a postnatal debrief
with the patient and her partner, regardless of whether intrapartum procedures were undertaken or
not. This represents a further opportunity to educate the family on FGM. All the appropriate legal and
regulatory processes should be documented as shown in Appendix I. The discharging midwife should
ensure that the documentation is complete.
l The rates of stillbirth and neonatal death in women with FGM.
l Interventional trials to assess the role of de-infibulation in improving pregnancy outcomes and the
optimal timing of de-infibulation.

l Clinical trials to investigate the safety and effectiveness of clitoral reconstruction.
l The role of psychological assessment and treatment in the antenatal care of women with FGM.
l The proportion of women asked about FGM at booking (100%).
l The proportion of healthcare professionals who are familiar with the HSCIC FGM Enhanced
l
l
l
l
l
Dataset (100%).
The proportion of healthcare workers (gynaecologists, obstetricians and midwives) who have
received training on FGM and its management (100%).
The proportion of pregnant women identified as having FGM who are referred to a designated
consultant obstetrician or specialist midwife with responsibility for FGM patients (100%).
The proportion of women identified as having FGM who are offered screening for hepatitis B,
hepatitis C, HIV and syphilis (100%).
The quality of documentation of FGM in the medical records, including ensuring information is
transferred to the community.
Number of referrals made to social services and/or police.

l Department of Health. Commissioning services to support women and girls with female genital
l
l
l
mutilation. London: DH; 2015 [https://www.gov.uk/government/publications/services-for-womenand-girls-with-fgm].

Department of Health. Female Genital Mutilation Risk and Safeguarding. Guidance for
professionals. London: DH; 2015 [https://www.gov.uk/government/publications/safeguardingwomen-and-girls-at-risk-of-fgm].
Patient information leaflets may be ordered from the Department of Health [https://www.orderline.
dh.gov.uk/ecom_dh/public/saleproduct.jsf?catalogueCode=2903740].
FORWARD (Foundation for Womens Health Research and Development) [http://www.forwarduk.
org.uk].
Multi-agency practice guidelines have been produced by the Home Office and the Department for
Education to support front-line professionals to prevent FGM [https://www.gov.uk/government/
publications/female-genital-mutilation-guidelines].
NHS Choices. Female genital mutilation
m For patients: [http://www.nhs.uk/Conditions/female-genital-mutilation/Pages/Introduction.aspx].
m For professionals: [http://www.nhs.uk/nhsengland/aboutnhsservices/sexual-health-services/
pages/fgm-for-professionals.aspx].
Orchid Project (a charity dedicated to ending female genital cutting) [http://orchidproject.org/].
18 of 26
References
1. Baillot H, Murray N, Connelly E, Howard N; Scottish
Refugee Council; London School of Hygiene and Tropical
Medicine. Tackling Female Genital Mutilation in
Scotland. A Scottish model of intervention. Glasgow:
Scottish Refugee Council; 2014.
2. [Department of Finance and Personnel, Northern
Ireland]. Multi-agency practice guidelines: female
genital mutilation. [Bangor, Northern Ireland]: [DFP];
[2014] [http://www.dfpni.gov.uk/multi-agency-practiceguidelines-on-female-genital-mutilation.pdf].
Accessed
2015 May 29.
3. World Health Organization. Eliminating female genital
mutilation: an interagency statement. Geneva: World
Health Organization; 2008.
4. United Nations Childrens Fund. Female Genital Mutilation/
Cutting: A statistical overview and exploration of the
dynamics of change. New York: UNICEF; 2013.
5. Department of Health. Female Genital Mutilation Risk
and Safeguarding. Guidance for professionals. London:
DH; 2015.
6. Royal College of Midwives, Royal College of Nursing, Royal
College of Obstetricians and Gynaecologists, Equality
Now, Unite. Tackling FGM in the UK: Intercollegiate
recommendations for identifying, recording and
reporting. London: RCM; 2013.
7. Macfarlane A, Dorkenoo E. Female Genital Mutilation in
England and Wales. Updated statistical estimates of the
numbers of affected women living in England and Wales
and girls at risk. Interim report on provisional estimates.
London: City University London; 2014.
8. House of Commons Home Affairs Committee. Female
genital mutilation: the case for a national action plan.
Second Report of Session 201415 Report, together
with formal minutes relating to the report. HC 201
[Incorporating HC 1091, 201314]. London: The Stationery
Office; 2014.
9. Berg RC, Underland V, Odgaard-Jensen J, Fretheim A, Vist
GE. Effects of female genital cutting on physical health
outcomes: a systematic review and meta-analysis. BMJ
Open 2014;4:e006316.
10. Asante A, Omurtag K, Roberts C. Epidermal inclusion cyst
of the clitoris 30 years after female genital mutilation. Fertil
Steril 2010;94:1097.e13.
11. Abdulcadir J, Pusztaszeri M, Vilarino R, Dubuisson JB,
Vlastos AT. Clitoral neuroma after female genital mutilation/
cutting: a rare but possible event. J Sex Med 2012;9:12205.
12. Fernndez-Aguilar S, Nol JC. Neuroma of the clitoris after
female genital cutting. Obstet Gynecol 2003;101:10534.
13. Kaplan A, Forbes M, Bonhoure I, Utzet M, Martn M,
Manneh M, et al. Female genital mutilation/cutting in The
Gambia: long-term health consequences and complications
during delivery and for the newborn. Int J Womens Health
2013;5:32331.
14. Amin MM, Rasheed S, Salem E. Lower urinary tract
symptoms following female genital mutilation. Int J
15. Yusuf L, Negash S. Vaginal calculus following severe form
of female genital mutilation: a case report. Ethiop Med J
2008;46:1858.
16. Peterman A, Johnson K. Incontinence and trauma: sexual
violence, female genital cutting and proxy measures of
gynecological fistula. Soc Sci Med 2009;68:9719.
17. Berg RC, Denison E. Does female genital mutilation/cutting
(FGM/C) affect womens sexual functioning? A systematic
review of the sexual consequences of FGM/C. Sex Res
Social Policy 2012;9:4156.
18. Andersson SH, Rymer J, Joyce DW, Momoh C, Gayle CM.
Sexual quality of life in women who have undergone
female genital mutilation: a casecontrol study. BJOG
2012;119:160611.
19. Alsibiani SA, Rouzi AA. Sexual function in women with

female genital mutilation. Fertil Steril 2010;93:7224.
20. Vloeberghs E, van der Kwaak A, Knipscheer J, van den
Muijsenbergh M. Coping and chronic psychosocial
consequences of female genital mutilation in The
Netherlands. Ethn Health 2012;17:67795.
21. Behrendt A, Moritz S. Posttraumatic stress disorder and
memory problems after female genital mutilation. Am J
Psychiatry 2005;162:10002.
22. Salihu HM, August EM, Salemi JL, Weldeselasse H, Sarro YS,
Alio AP. The association between female genital mutilation
and intimate partner violence. BJOG 2012;119:1597605.
23. Peltzer K, Pengpid S. Female genital mutilation and intimate
partner violence in the Ivory Coast. BMC Womens Health
2014;14:13.
24. Morison L, Scherf C, Ekpo G, Paine K, West B, Coleman R,
et al. The long-term reproductive health consequences of
female genital cutting in rural Gambia: a community-based
survey. Trop Med Int Health 2001;6:64353.
25. Elmusharaf S, Elkhidir I, Hoffmann S, Almroth L. A case
control study on the association between female genital
mutilation and sexually transmitted infections in Sudan.
BJOG 2006;113:46974.
26. Almroth L, Elmusharaf S, El Hadi N, Obeid A, El Sheikh MA,
Elfadil SM, et al. Primary infertility after genital mutilation
in girlhood in Sudan: a case-control study. Lancet
2005;366:38591.
27. Hwang EW, Cheung R. Global epidemiology of hepatitis B
virus (HBV) infection. N Am J Med Sci (Boston) 2011;4:713.
28. Duri K, Stray-Pedersen B. HIV/AIDS in Africa: trends, missing
links and the way forward. J Virol Antivir Res 2013;2(1).
29. WHO study group on female genital mutilation and
obstetric outcome, Banks E, Meirik O, Farley T, Akande
O, Bathija H, et al. Female genital mutilation and obstetric
outcome: WHO collaborative prospective study in six
African countries. Lancet 2006;367:183541.
30. Berg RC, Odgaard-Jensen J, Fretheim A, Underland V, Vist
G. An updated systematic review and meta-analysis of
the obstetric consequences of female genital mutilation/
cutting. Obstet Gynecol Int 2014;2014:542859.
31. Gissler M, Alexander S, Macfarlane A, Small R, StrayPedersen B, Zeitlin J, et al. Stillbirths and infant deaths
among migrants in industrialized countries. Acta Obstet
32. Small R, Gagnon A, Gissler M, Zeitlin J, Bennis M, Glazier
R, et al. Somali women and their pregnancy outcomes
postmigration: data from six receiving countries. BJOG
2008;115:163040.
33. Browning A, Allsworth JE, Wall LL. The relationship
between female genital cutting and obstetric fistulae.
34. HM Government. Multi-Agency Practice Guidelines: Female
Genital Mutilation. [London]: HM Government; 2014.
35. Ministry of Justice, Home Office. Serious Crime Act 2015.
Factsheet female genital mutilation. [London]: Ministry
of Justice; 2015 [https://www.gov.uk/government/uploads/
system/uploads/attachment_data/file/416323/ Fact_
sheet_-_FGM_-_Act.pdf]. Accessed 2015 May 29.
36. Royal College of Obstetricians and Gynaecologists. Ethical
considerations in relation to female genital cosmetic
surgery (FGCS). Ethical opinion paper. London: RCOG; 2013.
37. World Health Organization. Global strategy to stop healthcare providers from performing female genital mutilation
UNAIDS, UNDP, UNFPA, UNHCR, UNICEF, UNIFEM, WHO,
FIGO, ICN, IOM, MWIA, WCPT, WMA. Geneva: WHO; 2010.
38. HM Government. A Statement Opposing Female Genital
Mutilation. [London]: HM Government; 2014.
39. Statement opposing female genital mutilation [https://
w w w.gov.u k /gover n ment/publ icat ion s /st atementopposing-female-genital-mutilation]. Accessed 2015 Apr 20.
19 of 26
40. Department of Health. NHS Specialist Services for Female

Genital Mutilation. [London]: DH; 2014 [http://www.
nhs.uk/NHSEngland/AboutNHSservices/sexual-healthservices/Documents/List%20of%20FGM%20Clinics%20
Mar%2014%20FINAL.pdf]. Accessed 2015 Apr 20.
41. Health and Social Care Information Centre. Female Genital
Mutilation (FGM) Enhanced Dataset. Requirements
Specification. [Leeds]: HSCIC; 2015.
42. FORWARD. Reviewing Access to FGM Specialist Services
in England (2011). Research Brief No. 2. London:
FORWARD; 2011.
43. Folds P, Cuzin B, Andro A. Reconstructive surgery after

female genital mutilation: a prospective cohort study.
Lancet 2012;380:13441.
44. Balogun OO, Hirayama F, Wariki WM, Koyanagi A, Mori R.
Interventions for improving outcomes for pregnant women
who have experienced genital cutting. Cochrane Database
Syst Rev 2013;(2):CD009872.
45. National Institute for Health and Care Excellence.
Intrapartum care: care of healthy women and their
babies during childbirth. NICE clinical guideline 190.
[Manchester]: NICE; 2014.
20 of 26
Appendix I: Legal and regulatory responsibilities of health professionals

1. Data recording (http://www.hscic.gov.uk/fgm)
l Data recording is mandatory for all women identified as having FGM.
l Document FGM diagnosis in medical records (even if FGM is not the reason for presentation).
l If genital examination is performed and type of FGM is identified, record FGM type (WHO
classification).*
l Document further details in accordance with the HSCIC FGM Enhanced Dataset.
l Explain to the woman that her personal data will be transmitted to the HSCIC for the purpose of
FGM prevalence monitoring and that the data will not be anonymised.
2. Reporting to police and/or social services in the event of risk to a child
(https://www.gov.uk/government/publications/safeguarding-women-and-girls-at-risk-of-fgm)
l Children under 18:
m If FGM is confirmed (on examination or if the patient or parent says it has been done), refer as
a matter of urgency to the police and this should be done within 1 month of confirmation.
m If FGM is suspected (but not confirmed) or the girl is at risk (but has not had FGM), refer to
social services or the police. The urgency of the referral depends on the degree of risk.
l Nonpregnant women with FGM: no requirement to report unless a related child is at risk.
l Pregnant women:
m A member of the clinical team (midwife or obstetrician) must make an individual risk
assessment using an FGM safeguarding risk assessment tool and if the unborn child, or any
other child in the family, is considered to be at risk of FGM then reporting to social services or
the police must occur.
m Document maternal history of FGM in the personal child health record (Red Book) prior to
postnatal discharge.
m If delivery of a baby girl, notify the designated child protection midwife, who should inform
the GP and health visitor.
*Genital piercings should be classified as type 4 FGM in accordance with the WHO FGM classification.
21 of 26
Appendix II: Clinical management of adult women with FGM in obstetric and gynaecological practice
1. All acute trusts/health boards should have a designated consultant and midwife responsible for the
care of women with FGM
2. All women in obstetric and gynaecological practice
l Explain law on FGM, documenting the discussion and referring her to information provided in the
Health Passport (https://www.gov.uk/government/publications/statement-opposing-female-genitalmutilation).
l Provide interpreter if required (not a family member).
l Offer referral for psychological assessment and treatment.
l Offer specialist referral as appropriate, e.g. sexual health, urology.
l Make a clinical assessment of FGM (symptoms, examination) and need for de-infibulation.
l Record data in accordance with the HSCIC FGM Enhanced Dataset. These include age at FGM,
country where FGM was performed, date of entry to UK (if applicable) and past history of
de-infibulation and/or re-infibulation.
l If de-infibulation is indicated, offer before pregnancy it can usually be performed on an
outpatient basis.
l Reporting to social services or the police is only required if a related child is considered to be at
risk.
3. Additional management in pregnant women
l Refer to designated consultant obstetrician or specialist midwife with responsibility for women
with FGM.
l Local protocols will determine which elements of care (child safeguarding risk assessment, data
recording, clinical management) should be undertaken by the designated midwife or obstetrician
and which may be undertaken by other appropriately trained midwives or obstetricians.
l Discuss and clearly document a plan of care preformatted pro formas may be used.
l Make an individual risk assessment using an FGM safeguarding risk assessment tool (an example
of such a tool can be found at https://www.gov.uk/government/publications/safeguarding-womenand-girls-at-risk-of-fgm). If the unborn child or any related child is considered to be at risk then
reporting to social services or the police must occur.
l Offer screening for hepatitis C in addition to routine screening for hepatitis B, HIV and syphilis.
l If de-infibulation is indicated, discuss, agree and document the timing (antenatal or intrapartum).
Inform the woman that re-infibulation after delivery will not be performed under any
circumstances.
l Manage as high obstetric risk (increased risk of haemorrhage, perineal trauma and caesarean
section), except for women who have had previous pregnancies with uncomplicated vaginal
deliveries and no history of post-delivery re-infibulation.
l Document maternal history of FGM in the personal child health record (Red Book) prior to
postnatal discharge.
l If delivery of a baby girl, notify the designated child protection midwife, who should inform the GP
and health visitor.
l Offer postnatal follow-up if de-infibulation performed intrapartum or if planned de-infibulation did
not occur because of delivery by caesarean section.
22 of 26
Appendix III: One recommended method of performing de-infibulation
1) Type 3 FGM (infibulation)
2) I nfiltration of midline scar with

local anaesthetic
Infiltration of the
infibulation scar with
local anaesthetic should
be undertaken with surgical
forceps placed behind the
scar to prevent injury to
underlying tissues.
3) Incision of midline scar
4) Suturing of cut edges with

absorbable suture
The cut edges may be oversewn with a fine

absorbable suture and a paraffin gauze
dressing applied.
The incision should be made either with scissors or
a knife and extended anteriorly until the external
urethral meatus is visible.
23 of 26
Appendix IV: Plan of care for women with FGM in pregnancy
Woman with FGM in pregnancy:

Referral to designated midwife and/or
obstetrician with responsibility for FGM*
Consultant-led care
Child safeguarding risk

assessment by midwife or
obstetrician:
Use risk assessment tool
Explain law on FGM
Report to social services or the
police if unborn child or related
child at risk
Antenatal
1. U
se professional interpreter if
required (not family member)
and explain law on FGM
2. O
ffer referral for
psychological assessment
and screening for hepatitis
C, in addition to routine
antenatal screening
3. M
ake clinical assessment
of FGM. If de-infibulation is
required, agree timing and
explain that re-infibulation
will not be performed
4. A
ssess other obstetric
risk factors and action
appropriately
5. A
gree and document plan for
antenatal, intrapartum and
postpartum care
Data recording:
Clinical management plan:
Ensure compliance with HSCIC

Enhanced Dataset
Ensure clear documentation
Document FGM diagnosis,

including FGM type
(WHO classification)
Intrapartum
Preformatted pro formas may

be used
Postpartum
1. G
enerally manage as high
risk for caesarean section,
haemorrhage and perineal
trauma
1. Document maternal history of

FGM in personal child health
record (Red Book)
2. I f delivery of baby girl, notify
safeguarding midwife who
should inform the GP and
health visitor
2. S
ome women may be
considered low risk and
suitable for midwifery-led
care if history of previous
uncomplicated vaginal
delivery
3. I f de-infibulation is required,
ensure that the midwife
and obstetrician caring for
the woman have received
appropriate training
4. P
erineal tears in women with
FGM should be managed
in the same manner as in
women without FGM
3. Offer postnatal follow-up

if de-infibulation performed
intrapartum or if planned
de-infibulation did not occur
because of delivery by
caesarean section
4. Ensure all data required for
HSCIC Enhanced Dataset
have been recorded
* Local protocols will determine which elements of care (child safeguarding risk assessment, data recording, clinical management plan) should be undertaken by the designated midwife or obstetrician responsible for women with FGM and which may be
undertaken by other appropriately trained midwives or obstetricians
24 of 26


low risk of bias


1++ or 1+

results; or
2++

low risk of bias
risk of bias
case series
4
Good practice point
Expert opinion
25 of 26

development group
Dr NM Low-Beer MRCOG, London and Professor SM Creighton FRCOG, London
Dr J Abdulcadir, University Hospitals of Geneva, Geneva, Switzerland; Dr F Abu Amna MRCOG, Preston;
Ms J Albert, London; Dr MM Amin, Kobe University Graduate School of Medicine, Kobe, Japan;
Dr IA Babarinsa MRCOG, Doha, Qatar; Ms O Balogun, National Center for Child Health and Development, Tokyo,
Japan; Dr RC Berg, Norwegian Knowledge Centre for the Health Services, Oslo, Norway; Miss P Buck FRCOG,
Lancashire; Crown Prosecution Service; Department of Health; Professor A Macfarlane, City University London;
Dr R Mori, National Center for Child Health and Development, Tokyo, Japan; RCOG Womens Network;
Professor AA Rouzi, King Abdulaziz University Hospital, Jeddah, Saudi Arabia; Royal College of Midwives;
Dr SMA Saad MRCOG, Paisley; Mr E Vloeberghs, Pharos, Utrecht, The Netherlands; Dr AL Wright FRCOG, London;
Dr AEA Yagoub MRCOG, Blackpool; and Professor L Yusuf, Addis Ababa University College of Health, Addis Ababa,
Ethiopia.
Committee lead reviewers were: Dr M Gupta MRCOG, London; Dr M Ledingham MRCOG, Glasgow;
Dr AJ Thomson MRCOG, Paisley; and Mr RC Wimalasundera FRCOG, London.
The chairs of the Guidelines Committee were: Dr M Gupta1 MRCOG, London; Dr P Owen2 FRCOG, Glasgow;
1
guidelines/gtg53/.
DISCLAIMER
26 of 26
The prevention of malaria in pregnancy
Greentop Guideline No. 54a

April 2010
The prevention of malaria in pregnancy

This is the first edition of this guideline.
1.
Purpose and scope
The aim of this guideline is to provide clinicians with evidenced based, up-to-date information about the
prevention of malaria in pregnancy in situations that are likely to be encountered in UK medical facilities (that
is, UK-based residents visiting malaria endemic areas). These guidelines are not necessarily appropriate for
those residing in endemic areas.1 This guideline covers malaria prevention travel recommendations in:
women planning a pregnancy

those already pregnant or breast feeding.
Drug recommendations for malaria prophylaxis can change, owing to resistance, and up-to-date information
on drugs can be obtained using online resources as described in this guideline.
2.
Background
Malaria can be life-threatening but it is preventable. Malaria is caused by the bite of the female Anopheles
mosquito, which results in infection of the red blood cell. The species determines the pattern of the disease.
The species of the 1370 imported infections reported in the UK in 2008 were: 79.3% (1087) P. falciparum,
12.9% (170) P. vivax, 5.5% (76) P. ovale, 2.1% (20) P. malariae, one unspecified infection and, of all these, nine
were mixed infections.2 In 2006, there was one case report of primate malaria (P. knowlesi) in a UK traveller
returning from Brunei.2 In 2008, there were six deaths reported in the UK from malaria.2 By far the heaviest
burden of malaria in travellers from the UK is P. falciparum from Africa (mainly West Africa, particularly
Nigeria and Ghana).3 P. falciparum is the most dangerous species of malaria and causes the vast majority of
deaths worldwide. In UK travellers to Asia, particularly to the Indian subcontinent, infection with P. vivax is
more likely and this can cause a relapsing type of malaria. P. ovale can also cause relapsing malaria and P.
malariae is unique, owing to late recrudescence after many years. Other places where UK travellers have
acquired malaria include South and Central America (including Great Exuma in the Bahamas), Hispaniola,
Oceania and the Middle East.2 In the UK, the majority of travellers with imported malaria report visiting
friends and relatives in their families country of origin, especially in West Africa.47 The uptake of chemoprophylaxis among people residing in the UK who present with malaria in the UK is low.8 Special effort to tailor
malaria prevention messages to migrant groups could reduce the risk of travel-associated malaria significantly.8
Pregnant women are not specifically identified in the UK surveillance data.2 A report published by the Health
Protection Agency does not mention pregnancy.8 Most of the literature on imported malaria worldwide is
based on a few reports of isolated cases911 with the most comprehensive series of 14 pregnant women
reported by French investigators in Marseille.12 Perhaps the message contained in this limited literature is
found in surveillance from the USA: pregnant women comprised 1.6% of malaria cases (24/1505) during 2008
and none had adhered to a complete preventive drug regimen.13
3.
A literature search was performed using Medline (1983 to November 2009). The keywords used were
malaria, prevention, travellers, UK, imported malaria, pregnancy and breast feeding. Reference lists of
the articles identified were hand searched for additional articles. Other sources included malaria-related pages
from the websites of the Health Protection Agency [www.hpa.org.uk/HPA], the National Travel Health
Network and Centre [www.nathnac.org], European Network on Imported Infectious Disease Surveillance
[www.tropnet.net], Centers for Disease Control and Prevention [www.cdc.gov/Malaria] and TOXBASE, the
primary clinical toxicology database of the National Poisons Information Service [www.toxbase.org].
2 of 14
4.
What are the medical complications of malaria in pregnancy?
Malaria infection in pregnancy carries significant risks to mother and baby.
UK-based residents have low premunition and high susceptibility to malaria infection.
Malaria infection in pregnancy may result in reduced birth weight in the fetus and this may have health
consequences in later life.
Malaria in pregnancy adversely affects the mother and fetus (Table 1).14,15 Maternal mortality or
pregnancy loss from miscarriage, stillbirth and premature labour are the main complications of
malaria in women with low premunition and complications are likely to be equivalent or worse in
women who are not immune.1618 The principal effect of malaria in pregnancy in women from
endemic countries is low birth weight and this could have consequences on health in adulthood.19
The extent of this effect in returned travellers has not been well documented.12 In endemic areas,
pregnant women are twice as likely to be bitten by anopheline mosquitoes20,21 and to contract and
die from malaria22,23 than their non-pregnant counterparts.The clinical manifestations in pregnancy
depend on premunition; that is, the degree of naturally acquired host immunity to malaria (Table
1).14,18,24,25 Premunition depends on repeated exposure to infectious anopheline bites, so UK-based
residents will have low or no premunition.
5.
Evidence
level 2++
Prevention of malaria infection in pregnancy
5.1 What advice should pregnant women be given if they are considering travel to a malaria endemic area?
Pregnant women should consider the risks of travel to malaria endemic countries and consider
postponing their trip, unless travel is unavoidable.
A health professional advising a prospective UK resident who is pregnant or thinking about becoming
pregnant and who is intending to go to a malaria endemic area should suggest that the woman considers not
going or postponing their trip until they are no longer pregnant (Table 1).26
Table 1. Summary of the main consequences of malaria in pregnancy in non-immune female UK-based
residents, with different levels of premunition to malaria (severity indicated by + when known)
Consequence
Severity
Premunition
Low
High
Susceptibility to infection
++++
+++
++
Risk of illness
++++
+++
Not known
+++
+++
++++
+++
Severe anaemia
Severe/cerebral malaria
Maternal and fetal mortality (woman dies with the baby undelivered)
Reduction of birth weight
Miscarriage, premature birth, stillbirth
Gravida at risk
Placental parasitaemia
3 of 14
++++
+++
Not known
++
++
++++
++++
All
All
Primiparous
Not known
+++
5.2 If travel is unavoidable what advice should pregnant women receive about preventing malaria infection?
Advise the woman to seek guidance from a centre with expertise on malaria risks and avoidance
strategies.
Advise women that a fever or flu-like illness while travelling or upon returning home, up to 1 year or
more, may indicate malaria and requires medical attention.
Advise the woman on the risk of being exposed to malaria at her intended area of travel.
There are no measures specific to pregnancy that can be taken to prevent malaria beyond those that nonpregnant travellers can apply.27,28
The ABCD of malaria prevention is a useful formula to remember the components of malaria prevention:
Awareness of risk (see Section 5.2.1)

Bite prevention (see Section 5.3)
Chemoprophylaxis (see Section 5.4)
Diagnosis and treatment which must be prompt (see 5.5).
Women need to be educated about possible measures and, where possible, provided with written information
in their own language.1
The Department of Health produces Think Malaria leaflets (order code MAL/1) which are available in 11
different languages and can be obtained from DH Publications by writing to: DH Publications Orderline, PO
Box 777, London SE1 6XH, or by telephoning 03001231002, or by email to [email protected] or for further
information see the Department of Health website [www.orderline.dh.gov.uk].
5.2.1 What needs to be done to raise pregnant travellers awareness of the risk of malaria?
The risk of malaria is dependent on a variety of factors, including the level of transmission in the area(s) of
travel and the time of year (rainy or dry season), the presence of drug resistant strains of P. falciparum or P.
vivax, whether rural or urban sleepovers are planned, length of travel and the availability and the likelihood
of uptake of malaria prevention interventions.29 For example, if a woman proposes to go to urban tourist areas
of Southeast Asia, such as Bangkok and Phuket, and stay in air-conditioned hotels, the risks are considered
minimal for malaria, whereas urban travel in sub-Saharan Africa and New Guinea (Papua New Guinea and
Papua) constitutes a significant risk of infection. For UK residents, the risk remains disproportionately high in
the African Diaspora of travellers visiting friends and relatives in West Africa, particularly Nigeria, Ghana and
Uganda.8 The risk of contracting malaria during a 1 month stay without chemoprophylaxis (regardless of
country of residence of the traveller) has been estimated from retrospective studies of large numbers of
travellers (Table 2).3032
Table 2. Risk of contracting malaria during a 1-month stay without chemoprophylaxis

Area
Risk
Oceania (Papua New Guinea, Papua, Solomon Islands and Vanuatu)
1:20
Sub-Saharan Africa
1:50
Indian subcontinent
1:500
Southeast Asia
1:500
South America
1:2500
Central America and the Caribbean
1:10 000
4 of 14
A suggested template of a comprehensive medical and travel history is available on Page 14 of the 2007
edition of the HPA Malaria Guidelines, available at [http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/
HPAweb_C/1203496943315].Using this template will ensure that the physician is aware of background
medical problems which may affect the choice of chemoprophylactic agent.1
Despite applying effective anti-mosquito measures and good compliance to chemoprophylaxis, women can
still contract malaria. Education about the symptoms of malaria (such as a fever or flu-like illness) is beneficial
to travellers: it enables them to realise that they need to seek medical attention without delay and to state that
they have travelled to a malarious area. Worryingly, some migrant groups and their families do not access
effective antimalarial prophylaxis.8 Adults travellers born in Africa were reported to hold a belief that malaria
was trivial or that they were protected from severe malaria.33,34 It is important to challenge and advise on
misconceptions. Awareness of the risk is vital. Women may find the websites listed in Box 1 useful to learn
about malaria for travellers and to reinforce the points already made to them.
5.3 How should bites be prevented?

Inform women about bite prevention measures, including skin repellents, knock-down mosquito sprays,
insecticide-treated bed nets, clothing and room protection.
The anopheline mosquito has different preferred biting times in different parts of the world but making the
assumption that the risk period is from dawn to dusk will suffice.35,36 In pregnancy, other mosquito-borne
diseases, such as dengue, which is caused by a daytime-biting mosquito, should be prevented, so applying
mosquito bite prevention measures 24 hours a day is advisable.
Repellents the evidence favours skin repellents containing 50% DEET
A solution of 20% DEET (N,N-diethyl-m-toluamide or N,N-diethly-3-methyl-benzamide) was applied
to the exposed areas of the arms and legs twice daily in pregnant women (second and third
trimesters) as part of a randomised controlled trial of prevention of malaria.37,38 Pregnancies were
followed prospectively and there were no adverse effects noted for the woman or fetus but DEET
was detected in 8% of cord bloods examined after spontaneous birth.There are no specific data on
the safety of DEET in the first trimester of pregnancy but it is estimated to have been used by
millions since 1956 and about 30% of the American population every year with no apparent
adverse effects.39,40 In addition, there is no evidence of reproductive or developmental toxicity in
rats.41 As the consequences of malaria in pregnancy can be devastating and higher concentrations
Evidence
level 1+
Box 1. Websites for pregnant (or intending to become pregnant) travellers to learn about malaria
Patient UK [www.patient.co.uk/health/Malaria-Prevention.htm]
Supports the measures recommended by the Advisory Committee on Malaria Prevention in UK Travellers and the Health Protection Agency
and is available in a patient friendly format with printouts.
Health Protection Agency [www.hpa.org.uk/HPA/Topics/InfectiousDiseases/InfectionsAZ/1191942128239]
General information, news and guidelines.
Centers for Disease Control and Prevention, USA [www.cdc.gov/malaria]
Various informative resources. The website also presents a realistic cautionary tale of a pregnant woman of 19 weeks on a trip from USA to
Sierra Leone for a family crisis. [http://www.cdc.gov/malaria/stories/malaria_travel_pregnancy.html ]. There is also an interactive malaria
map[http://cdc-malaria.ncsa.uiuc.edu/].
Health Link British Columbia [www.healthlinkbc.ca/healthfiles/hfile41f.stm]
Gives good general advice on travel for pregnant women and is available in English, French, Chinese, Punjabi, Spanish, Vietnamese.
Malaria Hotspots [www.malariahotspots.co.uk/facts-maphotspots.asp]
Dynamic website with interactive malaria world map, malaria myths, FAQs and even a test of knowledge. Not specific for pregnancy but good
general principles.
Nobel Prize.org [http://nobelprize.org/educational_games/medicine/malaria]
An interactive malaria games and a brief about malaria. Not specific to pregnancy.
5 of 14
give longer protection, 50% DEET is recommended.1 In a sweaty environment, the effect of
repellent is lowered and more frequent applications are required. There are few alternatives when
50% DEET is not tolerated, including PMD [p-methane 3,8 diol], IR3535 [3-ethlyaminopropionate],
picaridin 20% [KBR3023(2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1-methylpropylester)] and
these are all less effective than DEET and require more frequent applications.4245 Evidence
demonstrates that not wearing repellent in a group where others do puts a person at more risk of
being bitten.46
Evidence
level 1+
Knock-down mosquito sprays: permethrin and pyrethroids sprays kill resting and flying mosquitoes
Whether women stay in air-conditioned hotel rooms or tents, a can of insect spray active against
mosquitoes is useful to help clear the room of mosquitoes. Pyrethroids will quickly kill mosquitoes
and are the preferred ingredient in sprays,4750 while permethrin will both repel and kill mosquitoes
when used regularly in the same room.5154
Evidence
level 2+
Insecticide treated bed nets: long lasting pyrethroid-impregnated bed nets offer significant protection
Women sleeping outdoors or in unscreened accommodation should use long-lasting pyrethroidimpregnated nets. If the net is not long-lasting it needs reimpregnating every 6 months, starting
from the first date on which the net is used after purchase.The use of bed nets by pregnant women
in endemic areas has been studied for both efficacy and safety in large numbers of women,5561 with
reassuring results. Nets are now recommended by the World Health Organization for all pregnant
women in malaria-endemic areas.62 Long pyrethroid insecticide treated bed nets, without tears and
well tucked in under mattresses or mats, are estimated to offer a protective efficacy of 50%.63 Again,
travellers in groups where some have nets and others in the room do not are likely to be at higher
risk of being bitten.64 Permethrin-impregnated hammocks are another possibility.65,66
Evidence
level 1++
Clothing that covers the body and forms a barrier from biting mosquitoes will reduce the risk of
malaria
After sunset, long sleeves, long trousers, loose-fitting clothing and socks, regardless of colour, are
recommended. Clothes can be impregnated with permethrin or permethrin or DEET can be spayed
on to the clothes.6772 Studies by the military demonstrate absorption of permethrin from clothes
but levels are within safe limits.73
Evidence
level 1-
Room protection: electrically heated mats will kill mosquitoes in the room
If electricity can be relied upon, an electrically heated device that vaporises synthetic pyrethroids
from a mat tablet can kill mosquitoes.74,75 A supply of mats is required, as new mat is needed each
night. While mosquito coils could be used as an alternative, they are not as effective and not
recommended indoors.
Evidence
level 2+
There is a growing trend among pregnant women to use herb-based remedies for many aspects of pregnancy
care.7678 There is no evidence that any of the following offers sufficient protection from malaria to advocate
their use: herbal remedies, homeopathy, buzzers, wrist and ankle bands, vitamin B1, garlic, yeast extracts, tea
tree oil and bath oils.1,29 While citronella has repellent properties, the effects are too short-lasting to
recommend its use.79
5.4 Which drug can be recommended for malaria prevention in pregnancy?

Inform women (and their general practitioner) of the risks and benefits of chemoprophylaxis versus the
risks of malaria.
Remind women that there is no malaria prophylaxis regimen that is 100% protective.
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The choice of drug and advice about chemoprophylaxis in pregnant women depends on the level of
chloroquine-resistant P. falciparum and P. vivax malaria and the trimester of pregnancy. There are malaria
prevention guidelines produced for travellers who are UK residents and these are detailed: by country and
popular destination and updated regularly.1 It is not the aim of this guideline to reproduce these guidelines
here.They can be directly accessed on the Health Protection Agency website [www.hpa.org.uk/HPA/Topics/
InfectiousDiseases/InfectionsAZ] and clicking on malaria. Updates to guidelines, such as change in resistance
or transmission, can be found at the same place.
Chemoprophylaxis for malaria can be causal or suppressive. Causal prophylaxis is directed against
liver schizont stage, which takes approximately 7 days to develop so these drugs (for example,
atovaquone-proguanil (Malarone) need to be continued for 7 days after leaving a malarious area.80
Suppressive prophylaxis (such as mefloquine) is directed against the red blood cell stages of the
malaria parasite and so should be continued for 4 weeks after leaving a malarious area.81 The full
listings of drug actions, dosages, adverse effects, interactions and contraindications is contained in
the British National Formulary [www.bnf.org] and will not be repeated here. Women should be
warned that drugs purchased in endemic countries or over the internet may be cheaper but they
may be fake.8284
Evidence
level 1+
5.4.1 Chemoprophylaxis for women planning a pregnancy

Women planning pregnancy and travelling to a destination where there is a risk of contracting malaria should
be advised there may be harmful consequences for the pregnancy. Prophylaxis is not 100% effective and
malaria is associated with increased risk of miscarriage. Women should be advised not to travel or to choose
an alternative destination. If it not possible to delay either the pregnancy or the travel plan, advice from a
specialist with current experience of malaria should be sought (Box 2). Chloroquine and proguanil are not
efficacious in chloroquine-resistant areas and cannot be recommended because of this.85 There are very few
chloroquine-sensitive areas remaining.
To avoid completely any potential adverse drug effects from preconceptual and first-trimester exposure, it is
advisable to wait for complete excretion of the drug, if it was taken for prophylaxis, before becoming
pregnant (Table 3). Nevertheless, unplanned conception while taking malaria prophylaxis is not considered a
reason to recommend termination of pregnancy, owing to the low risk of teratogenicity.
5.4.2 Chemoprophylaxis for pregnant or breastfeeding women
Mefloquine (5mg/kg once a week) is the recommended drug of choice for prophylaxis in the second and third
trimesters for chloroquine-resistant areas. With very few areas in the world free from chloroquine resistance,
mefloquine is essentially the only drug considered safe for prophylaxis in pregnant travellers (Table 4).7
The majority of observational and clinical data, mostly second and third trimesters, suggest that the
drug does not result in an increased risk of stillbirth or congenital malformation at prophylactic
doses.104,108,109 One study found an association with increased risk of still birth at treatment doses (25
mg/kg) for chloroquine-resistant P. falciparum malaria110 but other studies where the drug has been
Evidence
level 1-
Box 2. Expert centres in the UK on chemoprophylaxis

Malaria Reference Laboratory [www.malaria-reference.co.uk]
Possible to send risk assessment via fax (template available on website) and receive results in 3 days.
Tel: 020 763 70248.
National Travel Health Network and Centre [www.nathnac.org]
Advice line for healthcare professionals.
Tel. 0845 602 6712.
Liverpool School of Tropical Medicine [www.liv.ac.uk/lstm]
TRAVAX: the AZ of Healthy Travel (Health Protection Scotland and NHS Scotland) [www.travax.nhs.uk]
7 of 14
Table 3. Suggested waiting times before becoming pregnant, with animal and human first-trimester data on
teratogenicity
Drug
Estimated half life Excretion time
Data
Animal
Human
Mefloquine
1421 days
3 months
Skeletal and muscular

malformation in rats at 520
times the therapeutic dose87
Post-marketing surveillance
system of the manufacturer
(Hoffman-LaRoche) or case
reports focusing on the effects of
mefloquine prophylaxis8890 do
not support the hypothesis that
mefloquine is associated with
embryo toxicity even in the first
trimester [Evidence level 1]
Doxycycline
1224 hours
1 week
Chick embryos: abnormal

skeletal development and
reduced fetal growth;91 rats:
discolouration of the lens92
Disturbances of bone growth of

the fetus; congenital cataract92
[Evidence level 3]
Malarone
Atovaquone
23 days
2 weeks
Proguanil
1421 hours
1 week
Chloroquine
12 months
Not applicable
Three women inadvertently

exposed at the time of conception,
all with normal pregnancy outcomes94
[Evidence level 3]
No teratogenicity shown in
animal studies with the combination
of both drugs93
Embryotoxicity in rat culture at

doses close to therapeutic range,
including developmental
abnormalities of neural tube;
micro-ophthalmia and optic
primordium;97 altered cranial
neural tube development and
morphology of neural crest
cells98,99
Proguanil as chemoprophylaxis in
pregnant women demonstrated no
evidence of toxic fetal effects after
decades of use;95 cycloguanil, the
active metabolite of proguanil, is toxic
at the stage of cleavage of the ovum96
[Evidence level 3]
No adverse effects in first trimester
reported from malaria literature100-107
nor from a meta-analysis on women
treated with high doses of
hydroxychloroquine for
autoimmune disease108
Evidence level 1++]
used for treatment or intermittent preventive treatment or in combination with artesunate have not
reported this association.109114 The use of mefloquine in the first trimester may still be justified in
areas of high risk of acquiring falciparum malaria. In the UK, this can be discussed with a specialist
with current experience of managing malaria (Box 2). There are strict contraindications to
mefloquine, including current or previous history of depression, neuropsychiatric disorders,
epilepsy or hypersensitivity to quinine or mefloquine.1
Evidence
level 1-
Table 4. Dosing regimen for chemoprophylaxis in pregnancy

Regimen
Dose for chemoprophylaxis
Usual amount/tablet (mg)
P. falciparum resistance n
Mefloquine
1 tablet weekly
250
Chloroquine resistant
Atovaquone-proguanila
1 tablet daily
250 atovaquone + 100 proguanil
Chloroquine resistant & mefloquine

not tolerated or contraindicated
OR
Mefloquine resistant
Proguanila plus chloroquine
2 tablets daily plus

2 tablets weekly
100 proguanil + 150

(chloroquine; base)
No chloroquine resistance
a Folic acid supplements (5 mg daily) need to be taken if proguanil is used in those who are pregnant or seeking to become pregnant
8 of 14
Atovaquone and proguanil (Malarone) is potentially a good candidate for prophylaxis in the
second and third trimesters but it is not recommended, owing to insufficient data on its safety in
pregnancy.115 To date, only treatment data on pregnant women have been published; the drug was
effective and well tolerated with no adverse effects detected.93,116119 If travel to a chloroquineresistant area is essential in pregnancy and mefloquine cannot be tolerated or is contraindicated,
atovaquone and proguanil use can be considered in consultation with a specialist with current
experience of managing malaria (Box 2).7
Evidence
level 3
Doxycycline and primaquine are contraindicated as chemoprophylaxis in pregnant women.

Doxycyline has been reported to disturb bone growth of the fetus120 and to cause irreversible teeth
coloration when given in the third trimester121 and congenital cataract has been reported.122
Primaquine can cause haemolysis, particularly in G6PD deficiency. Fetal red blood cells are more
sensitive to haemolysis and the G6PD status of the fetus cannot be determined.123,124
While chloroquine and proguanil are safe, they are no longer efficacious in areas of chloroquine
resistance and provide women with suboptimal prophylaxis if recommended.1
Evidence
level 1+
Recommendations for breastfeeding mothers are the same as for pregnancy.There are few data on
the use mefloquine during breastfeeding125 and, while it is excreted into breast milk in small
amounts, there are not enough data to draw conclusions regarding harm.126
Evidence
level 3
Atovaquone and proguanil may also be considered in consultation with an infectious diseases physician for a
pregnant woman travelling to a mefloquine-resistant area.7
5.5 Emergency standby treatment in pregnancy?

Written instructions should be given to a pregnant traveller regarding emergency standby malaria
treatment in the event of suspected malaria without access to medical care.
Suspected malaria is a medical emergency and women should seek diagnosis and treatment at a
health facility at the earliest opportunity.1,28 Early diagnosis and stand-by emergency treatment have
been promoted in the event of remote travel without access to medical care within 24 hours of
symptoms. In theory, this should be an extremely rare situation in pregnant women, as this type of
travel could be hazardous in pregnancy. Owing to reports of the misuse of standby treatment127,128
and the importance that it is given correctly, written instructions should be issued. An example
template is available from the Health Protection Agency Malaria Guideline, on page 54 of the 2007
edition [www.hpa.org.uk/webw/HPAweb&HPAwebStandard/HPAweb_C/1203496943315?p=124
9920576136].1
Evidence
level 3
Standby treatment should be started if malaria is suspected (flu-like illness) and temperature is 38C or above.
Medical treatment for a full medical evaluation and, in the event that the fever has another cause, must be sought
at the earliest possibility. Antipyretics should be used for fever. The only recommended treatment in the UK for
pregnant women is quinine (300 mg tablets, two tablets three times a day for 7 days) and clinda-mycin (150 mg
capsules, three capsules three times a day for 57 days). If a dose is vomited within 30 minutes, the full dose
should be repeated and if the dose is vomited after 3060 minutes, half the dose should be repeated. The
treatment should be finished and mefloquine should be commenced 1 week after the last treatment dose.
Drugs that are highly efficacious and well tolerated are likely to be the best candidate drugs for stand-by
emergency treatment. Quinine may be efficacious in most parts of the world but it is not well tolerated. Coartem (Riamet) or atovaquone-proguanil (Malarone) (if not used as prophylaxis) could be used as standby emergency treatment and evidence to support the use of these drugs in uncomplicated malaria in
pregnancy is detailed in Part B of this guideline.129
9 of 14
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58. Mnyika SK, Kabalimu TK, Mbaruku G, Masisila R, MpanjuShumbusho W. Randomised trial of alternative malaria
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Kigoma,Tanzania: II. Results from baseline studies. East Afr
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59. Shulman CE, Dorman EK,Talisuna AO, Lowe BS, Nevill C, Snow
RW, et al. A community randomized controlled trial of
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anaemia among primigravid women on the Kenyan coast. Trop
Med Int Health 1998;3:197204.
60. Gamble C, Ekwaru JP, ter Kuile FO. Insecticide-treated nets for
preventing malaria in pregnancy. Cochrane Database Syst Rev
2006:CD003755.
61. Gamble C, Ekwaru PJ, Garner P, ter Kuile FO. Insecticide-treated
nets for the prevention of malaria in pregnancy: a systematic
review of randomised controlled trials. PLoS Med 2007;4:e107.
62. Breman JG. Eradicating malaria. Sci Prog 2009;92:138.
63. Petersen E. Malaria chemoprophylaxis: when should we use it

and what are the options? Expert Rev Anti Infect Ther
2004;2:11932.
64. Lines JD, Myamba J, Curtis CF. Experimental hut trials of
permethrinimpregnated mosquito nets and eave curtains
against malaria vectors in Tanzania. Med Vet Entomol
1987;1:3751.
65. Hougard JM, Martin T, Guillet PF, Coosemans M, Itoh T, Akogbeto
M, et al. Preliminary field testing of a long-lasting insecticidetreated hammock against Anopheles gambiae and Mansonia
spp. (Diptera: Culicidae) in West Africa. J Med Entomol
2007;44:6515.
66. Magris M, Rubio-Palis Y, Alexander N, Ruiz B, Galvan N, Frias D,
et al. Community-randomized trial of lambdacyhalothrintreated hammock nets for malaria control in Yanomami
communities in the Amazon region of Venezuela. Trop Med Int
Health 2007;12:392403.
67. Deparis X, Frere B, Lamizana M, N'Guessan R, Leroux F, Lefevre
P, et al. Efficacy of permethrin-treated uniforms in combination
with DEET topical repellent for protection of French military
troops in Cote d'Ivoire. J Med Entomol 2004;41:91421.
68. Faulde M, Uedelhoven W. A new clothing impregnation method
for personal protection against ticks and biting insects. Int J
Med Microbiol 2006;296 Suppl 40:2259.
69. Kimani EW, Vulule JM, Kuria IW, Mugisha F. Use of insecticidetreated clothes for personal protection against malaria: a
community trial. Malar J 2006;5:63.
70. Lane RS.Treatment of clothing with a permethrin spray for
personal protection against the western black-legged tick,
Ixodes pacificus (Acari: Ixodidae). Exp Appl Acarol
1989;6:34352.
71. Schreck CE, Snoddy EL, Spielman A. Pressurized sprays of
permethrin or deet on military clothing for personal
protection against Ixodes dammini (Acari: Ixodidae). J Med
Entomol 1986;23:3969.
72. Snodgrass HL. Permethrin transfer from treated cloth to the
skin surface: potential for exposure in humans. J Toxicol
Environ Health 1992;35:91105.
73. Rossbach B, Appel KE, Mross KG, Letzel S. Uptake of
permethrin from impregnated clothing. Toxicol Lett 2009.
74. Amalraj DD, Sivagnaname N, Boopathidoss PS, Das PK.
Bioefficacy of mosquito mat, coil and dispenser formulations
containing allethrin group of synthetic pyrethroids against
mosquito vectors. J Commun Dis 1996;28:8593.
75. Holzer RB. [Malaria prevention without drugs]. Schweiz
Rundsch Med Prax 1993;82:13943.
76. Low Dog T.The use of botanicals during pregnancy and
lactation. Altern Ther Health Med 2009;15:548.
77. Marcus DM, Snodgrass WR. Do no harm: avoidance of herbal
medicines during pregnancy. Obstet Gynecol 2005;105:111922.
78. Refuerzo JS, Blackwell SC, Sokol RJ, Lajeunesse L, Firchau K,
Kruger M, et al. Use of over-the-counter medications and
herbal remedies in pregnancy. Am J Perinatol 2005;22:3214.
79. Fradin MS, Day JF. Comparative efficacy of insect repellents
against mosquito bites. N Engl J Med 2002;347:138.
80. Chulay JD. Challenges in the development of antimalarial drugs
with causal prophylactic activity. Trans R Soc Trop Med Hyg
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81. Franco-Paredes C, Santos-Preciado JI. Problem pathogens:
prevention of malaria in travellers. Lancet Infect Dis
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82. Atemnkeng MA, De Cock K, Plaizier-Vercammen J. Quality
control of active ingredients in artemisinin-derivative
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Health 2007;12:6874.
83. Newton PN, McGready R, Fernandez F, Green MD, Sunjio M,
Bruneton C, et al. Manslaughter by fake artesunate in Asia: will
Africa be next? PLoS Med 2006;3:e197.
84. Newton PN, Fernandez FM, Plancon A, Mildenhall DC, Green
MD, Ziyong L, et al. A collaborative epidemiological
investigation into the criminal fake artesunate trade in South
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85. Hogh B, Clarke PD, Camus D, Nothdurft HD, Overbosch D,

Gunther M, et al. Atovaquone-proguanil versus chloroquineproguanil for malaria prophylaxis in non-immune travellers: a
randomised, double-blind study. Malarone International Study
Team. Lancet 2000;356:188894.
86. Cantor GH, Pontzer CH, Palmer GH. Opsonization of
Anaplasma marginale mediated by bovine antibody against
surface protein MSP1. Vet Immunol Immunopathol
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87. Phillips-Howard PA, Steffen R, Kerr L, Vanhauwere B,
Schildknecht J, Fuchs E, et al. Safety of mefloquine and other
antimalarial agents in the first trimester of pregnancy. J Travel
Med 1998;5:1216.
88. Smoak BL, Writer JV, Keep LW, Cowan J, Chantelois JL.The
effects of inadvertent exposure of mefloquine
chemoprophylaxis on pregnancy outcomes and infants of US
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89. Vanhauwere B, Maradit H, Kerr L. Post-marketing surveillance
of prophylactic mefloquine (Lariam) use in pregnancy. Am J
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90. Cohlan SQ.Teratogenic agents and congenital malformations. J
Pediatr 1963;63:6509.
91. Westring DW, Pisciotta AV. Anemia, cataracts, and seizures in
patient with glucose-6-phosphate dehydrogenase deficiency.
Arch Intern Med 1966;118:38590.
92. GlaxoSmithKline Inc. Malarone. GSK Product Monograph.
Research Triangle Park, NC: GSK; 2009.
93. McGready R, Keo NK, Villegas L, White NJ, Looareesuwan S,
Nosten F. Artesunate-atovaquone-proguanil rescue treatment of
multidrug-resistant Plasmodium falciparum malaria in
pregnancy: a preliminary report. Trans R Soc Trop Med Hyg
2003;97:5924.
94. Phillips-Howard PA, Wood D.The safety of antimalarial drugs in
pregnancy. Drug Saf 1996;14:13145.
95. Cutting W. Antifertility effects of biguanides. Antibiot
Chemother 1962;12:6715.
96. Tagoe CN, Ofori-Adjei D. Effects of chloroquine and its
enantiomers on the development of rat embryos in vitro.
Teratology 1995;52:13742.
97. Ambroso JL, Harris C. Chloroquine embryotoxicity in the postimplantation rat conceptus in vitro. Teratology 1993;48:21326.
98. Ambroso JL, Harris C. Chloroquine accumulation and
alterations of proteolysis and pinocytosis in the rat conceptus
in vitro. Biochem Pharmacol 1994;47:67988.
99. Drouin J, Rock G, Jolly EE. Plasmodium falciparum malaria
mimicking autoimmune hemolytic anemia during pregnancy.
Can Med Assoc J 1985;132:2657.
100. Hart CW, Naunton RF.The ototoxicity of chloroquine
phosphate. Arch Otolaryngol 1964;80:40712.
101. Levy M, Buskila D, Gladman DD, Urowitz MB, Koren G.
Pregnancy outcome following first trimester exposure to
chloroquine. Am J Perinatol 1991;8:1748.
102. Nosten F, McGready R, Simpson JA,Thwai KL, Balkan S, Cho T, et
al. Effects of Plasmodium vivax malaria in pregnancy. Lancet
1999;354:5469.
103. Singh N, Mehra RK, Srivastava N. Malaria during pregnancy and
infancy, in an area of intense malaria transmission in central
India. Ann Trop Med Parasitol 2001;95:1929.
104. Steketee RW, Wirima JJ, Slutsker L, Khoromana CO, Heymann
DL, Breman JG. Malaria treatment and prevention in pregnancy:
indications for use and adverse events associated with use of
chloroquine or mefloquine. Am J Trop Med Hyg 1996;55:506.
105. Villegas L, McGready R, Htway M, Paw MK, Pimanpanarak M,
Arunjerdja R, et al. Chloroquine prophylaxis against vivax
malaria in pregnancy: a randomized, double-blind, placebocontrolled trial. Trop Med Int Health 2007;12:20918.
106. Wolfe MS, Cordero JF. Safety of chloroquine in
chemosuppression of malaria during pregnancy. Br Med J
1985;290:14667.
107. Sperber K, Hom C, Chao CP, Shapiro D, Ash J. Systematic review
of hydroxychloroquine use in pregnant patients with
autoimmune diseases. Pediatr Rheumatol Online J 2009;7:9.
109. Nosten F, ter Kuile F, Maelankiri L, Chongsuphajaisiddhi T,

Nopdonrattakoon L,Tangkitchot S, et al. Mefloquine
prophylaxis prevents malaria during pregnancy: a double-blind,
placebo-controlled study. J Infect Dis 1994;169:595603.
109. Steketee RW, Wirima JJ, Slutsker L, Roberts JM, Khoromana CO,
Heymann DL, et al. Malaria parasite infection during pregnancy
and at delivery in mother, placenta, and newborn: efficacy of
chloroquine and mefloquine in rural Malawi. Am J Trop Med
Hyg 1996;55:2432.
110. Nosten F, Vincenti M, Simpson J,Yei P,Thwai KL, de Vries A, et al.
The effects of mefloquine treatment in pregnancy. Clin Infect
Dis 1999;28:80815.
111. Briand V, Bottero J, Noel H, Masse V, Cordel H, Guerra J, et al.
Intermittent treatment for the prevention of malaria during
pregnancy in Benin: a randomized, open-label equivalence trial
comparing sulfadoxinepyrimethamine with mefloquine. J
Infect Dis 2009;200:9911001.
112. Harinasuta T, Kietinun S, Somlaw S, Bunnag D, Sheth UK,
Wernsdorfer W. A clinical trial of mefloquine on multi-resistant
falciparum malaria in pregnant women in Thailand. Bull Soc Fr
Parasitol 1990:429.
113. McGready R, Brockman A, Cho T, Cho D, van Vugt M,
Luxemburger C, et al. Randomized comparison of mefloquineartesunate versus quinine in the treatment of multidrugresistant falciparum malaria in pregnancy. Trans R Soc Trop
Med Hyg 2000;94:68993.
114. McGready R, Cho T, Hkirijaroen L, Simpson J,
Chongsuphajaisiddhi T, White NJ, et al. Quinine and mefloquine
in the treatment of multidrug-resistant Plasmodium
falciparum malaria in pregnancy. Ann Trop Med Parasitol
1998;92:64353.
115. Boggild AK, Parise ME, Lewis LS, Kain KC. Atovaquoneproguanil: report from the CDC expert meeting on malaria
chemoprophylaxis (II). Am J Trop Med Hyg 2007;76:20823.
116. McGready R, Stepniewska K, Edstein MD, Cho T, Gilveray G,
Looareesuwan S, et al.The pharmacokinetics of atovaquone
and proguanil in pregnant women with acute falciparum
malaria. Eur J Clin Pharmacol 2003;59:54552.
117. Na-Bangchang K, Manyando C, Ruengweerayut R, Kioy D,
Mulenga M, Miller GB, et al.The pharmacokinetics and pharmacodynamics of atovaquone and proguanil for the treatment of
uncomplicated falciparum malaria in third-trimester pregnant
women. Eur J Clin Pharmacol 2005;61:57382.
118. McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung
R, et al. A randomized comparison of artesunate-atovaquoneproguanil versus quinine in treatment for uncomplicated
falciparum malaria during pregnancy. J Infect Dis
2005;192:84653.
119. Okoyeh JN, Lege-Oguntoye L, Emembolu JO, Sarki U. Sensitivity
of Plasmodium falciparum to reduced dose of mefloquine in
pregnant women in Nigeria. Acta Trop 1996;61:18.
120. Cohlan SQ, Bevelander G,Tiamsic T. Growth inhibition of
prematures receiving tetracycline. Am J Dis Child
1963;105:45361.
121. Manson JD.Tetracyclines and the teeth. Lancet 1966;1:1104.
122. Krejci L, Brettschneider I. Congenital cataract due to
tetracycline. Ophthalmic Paediatr Genet 1983;3:5960.
123. Rietveld AE. Special groups: pregnant women, infants and
young children. In: Schlagenhauf-Lawlor O, editor. Malaria. 1st
ed. Hamilton, BC: Decker Inc; 2001. p. 30323.
124. National Travel Health Network and Centre. Use of Mefloquine
During Breastfeeding. London: NaTHNaC; 2009
[www.nathnac.org/pro/factsheets/mefloquine_breastfeeding06
0709.htm].
125. Clyde DF. Clinical problems associated with the use of
primaquine as a tissue schizontocidal and gametocytocidal
drug. Bull World Health Organ 1981;59:3915.
126. Edstein MD, Veenendaal JR, Hyslop R. Excretion of mefloquine
in human breast milk. Chemotherapy 1988;34:1659.
127. Chen LH, Keystone JS. New strategies for the prevention of
malaria in travelers. Infect Dis Clin North Am
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128. Swales CA, Chiodini PL, Bannister BA. New guidelines on

malaria prevention: A summary. J Infect 2007;54:10710.

Diagnosis and Treatment of Malaria in Pregnancy. Greentop Guideline No. 54B. London: RCOG; 2010.
APPENDIX

risk of bias
1+

low risk of bias

risk of bias

2+


case series
Expert opinion

population; or
1++ or 1+
results; or
2++
2+
Good practice point
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development group
This Guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and
Gynaecologists by: Dr R McGready PhD Dip RANZCOG, Mae Sot, Thailand; Dr EA Ashley PhD, London; Professor F
Nosten MD PhD, Mae Sot, Thailand; Dr M Rijken MD PhD, Mae Sot, Thailand.
It was peer reviewed by: Dr A Diaf MRCOG, Birmingham; RCOG Consumers Forum; Mr SA Walkinshaw MRCOG,
Liverpool; Dr C Whitty FRCP, London; the Advisory Committee on Malaria Prevention in UK Travellers: Dr BA Bannister
FRCP, London; Dr D Lalloo FRCP, Liverpool; Professor P Chiodini FRCP, London.
The Guidelines Committee lead peer reviewers were: Dr ALM David MRCOG, London, and Professor F McAuliffe
FRCOG, Dublin.
DISCLAIMER
health services.
adapted for local use, these guidelines no longer represent the views of the RCOG.
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The diagnosis and treatment of malaria

in pregnancy
April 2010
The diagnosis and treatment of malaria in pregnancy

1.
Purpose and scope
The aim of this guideline is to provide clinicians with up-to-date, evidence-based information on the diagnosis
and treatment of malaria in pregnancy, in situations that are likely to be encountered in UK medical practice.
For initial rapid assessment and management, see Appendix 1.
2.
Background
Malaria is the most important parasitic infection in humans and is the tropical disease most commonly
imported into the UK, with approximately 1500 cases reported each year and rising, apart from 2008.1
Approximately 75% of cases are caused by Plasmodium falciparum and there is an average of 515 deaths a
year (mortality rate approximately 0.51.0%).1 Immigrants and second- and third-generation relatives
returning home assuming they are immune from malaria are by far the highest risk group. They may take no
prophylaxis or may be deterred by the cost, may not adhere to advice, may receive poor advice or some
combination of these factors.2,3 Prevention of malaria is covered in Green-top Guideline No. 54A.4
In the UK, the prevalence of imported malaria in pregnancy is unknown. A review of the burden of
malaria in pregnancy estimated that about one in four women in sub-Saharan Africa in areas of stable
transmission has malaria at the time of birth.5 Online and telephone enquiries with the Health Protection
Agency (www.hpa.org.uk) and Eurosurveillance archives (www.eurosurveillance.org) and reviews of
published reports failed to uncover a report of maternal death from malaria in UK for the past 10 years.6
Maternal deaths from malaria are unlikely to be reported when they occur in endemic countries.
Malaria in pregnancy is detrimental to the woman and her fetus and collective data demonstrate that the risk
of adverse effects from untreated malaria in pregnancy outweigh those of treatment.5,610 The protozoan
parasites P. falciparum, P. vivax, P. malariae and P. ovale (extremely rarely P. knowlesi),11 are transmitted by
the bite of a sporozoite-bearing female anopheline mosquito. After a period of pre-erythrocytic development
in the liver, the blood stage infection, which causes the disease, begins. Parasitic invasion of the erythrocyte
consumes haemoglobin and alters the red cell membrane. This allows P. falciparum infected erythrocytes to
cytoadhere (or stick) inside the small blood vessels of brain, kidneys and other affected organs. Cytoadherence
and rosetting (adherence of uninfected red blood cells) interfere with microcirculatory flow and metabolism
of vital organs. The hallmark of falciparum malaria in pregnancy is parasites sequestered in the placenta.
Sequestered parasites evade host defence mechanisms: splenic processing and filtration. Sequestration is not
known to occur in the benign malarias due to P. vivax, P. ovale and P. malariae. In pregnancy, the adverse
effects of malaria infection result from:
the systemic infection, comparable to the effects of any severe febrile illness in pregnancy: maternal and fetal
mortality, miscarriage, stillbirth and premature birth
the parasitisation itself: fetal growth restriction and low birth weight, maternal and fetal anaemia, interaction
with HIV, susceptibility of the infant to malaria.
P. falciparum causes greater morbidity (maternal and fetal, principally low birth weight and anaemia) and
mortality than non-falciparum infections5,710 but there is mounting evidence that P. vivax is not as benign as
had been previously thought.1214 Response to antimalarial treatment is multifactorial but is associated with
the degree of prior immunity acquired from repeated exposures in childhood and the background level of
drug resistance.The higher the transmission of malaria, the greater the degree of prior immunity and the more
likely the woman will respond favourably to a drug treatment.15,16
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3.
A literature search was performed using Medline (November 2009). Keywords used were severe malaria,
uncomplicated malaria, burden malaria, congenital malaria, anaemia malaria, pregnancy, treatment,
antimalarials artesunate, artemether, artemether-lumefantrine, atovaquone-proguanil, chloroquine,
clindamycin,dihyroartemisinin-piperaquine,mefloquine,quinine,primaquine,UK,epidemics,maternal
mortality,pharmacokinetic and pregnancy. Reference lists of the articles identified were hand searched for
additional articles. Other sources used in the development of this guideline included UK malaria treatment
guidelines, published3 and online at the Health Protection Agency, international guidelines from the World
Health Organization17 and websites covering malaria and pregnancy. Areas lacking evidence are highlighted
and annotated as good practice points. Articles on intermittent preventive treatment were specifically
excluded, as this practice is not recommended in the UK.
4.
Limitations of the data used in this guidelines
There is no published evidence of treatment efficacy for malaria in pregnant women in the UK or any other
non-endemic country.18,19 There are no randomised controlled trials of antimalarials in the first trimester of
pregnancy.18 The evidence for best treatment in pregnancy is gained from endemic areas17,19,20 and is not
supported by the availability of drugs or licensing regulations within the UK. Treatment response in UK
pregnant women can only be extrapolated from, and is likely to be worse than, treatment responses in semiimmune women. Treatment responses are likely to be closest to those observed in areas of low and unstable
malaria transmission, where malaria in pregnancy is usually symptomatic. Data on malaria in pregnancy,
especially epidemic malaria, where the severe effects on pregnant women were recorded, is historical.21,22 In
this guideline, the best available evidence for treatment in pregnancy is published in parallel with UK
treatment guidelines,3 with comments on the guidelines. Availability of drugs within the UK can change and
this guideline promotes the use of evidence-based prescription choices in this vulnerable group.
Overall, 13 randomised controlled trials on the treatment of uncomplicated P. falciparum in pregnancy were
completed in the past 20 years in eight different countries (Africa and Asia) and have included 2254 women
from high and low transmission areas and a total of 16 different antimalarial drug regimens.2335 Seventy-seven
percent (10/13) of the trials followed the women post-treatment until delivery but 46% (6/13) attempted to
evaluate the infants at 1 year of life. A 2009 Cochrane meta-analysis concluded that data on uncomplicated
malaria in pregnancy were scant and, while some combinations appeared effective, data on safety were lacking.36
5.
Definition of terms used in this guideline
5.1 Severe and complicated malaria

The severe signs of malaria are non-specific and other causes must be excluded before assigning the signs and
symptoms to malaria (Box 1). The parasitaemia of severe malaria can be less than 2%. Pregnant women with
2% or more parasitised red blood cells are at higher risk of developing severe malaria and should be treated
with the severe malaria protocol.3
5.2 Uncomplicated malaria

Uncomplicated malaria in the UK is defined as fewer than 2% parasitised red blood cells in a woman with no
signs of severity and no complicating features.3
5.3 Congenital malaria

Congenital malaria in the very young infant or newborn results from the passage of parasites or infected red
blood cells from the mother to the newborn while in utero or during delivery and not by the bite of the
female anopheline mosquito.
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Box 1. Clinical and laboratory findings of severe or complicated malaria in adults

(reproduced with permission from the World Health Organization)16
Clinical manifestations
Prostration
Impaired consciousness
Respiratory distress (acidotic breathing, acute respiratory distress syndrome)*
Pulmonary oedema (including radiological)*
Multiple convulsions
Circulatory collapse, shock (blood pressure < 90/60 mmHg)
Abnormal bleeding, disseminated intravascular coagulopathy
Jaundice
Haemoglobinuria (without G6PD deficiency)
Laboratory tests
Severe anaemia (Haemoglobin < 8.0 g/dl)
Thrombocytopaenia
Hypoglycaemia (< 2.2 mmol/l)*
Acidosis (pH < 7.3)
Renal impairment (oliguria < 0.4 ml/kg body weight/hour or creatinine > 265 mol/l)
Hyperlactataemia (correlates with mortality)
Hyperparasitaemia (> 2% parasitised red blood cells)
Algid malaria - Gram-negative septicaemia*
Lumbar puncture to exclude meningitis
* Common features in pregnant women with severe or complicated malaria
5.4 Artemisinin combination therapy

Artemisinin combination therapy is a combination of artemisinin or one of its derivatives with an antimalarial
or antimalarials of a different class.
5.5 Resistance
Resistance is defined as the ability of a parasite strain to survive and multiply despite the administration and
absorption of a medicine given in doses equal to or higher than those usually recommended but within the
tolerance of the subject, with the caveat that the form of the drug active against the parasite must be able to
gain access to the parasite or the infected red blood cell for the duration of time necessary for its normal action.37
6. Diagnosis of malaria in pregnancy
6.1 Why is malaria diagnosis difficult?

There are no specific symptoms or signs and malaria infection may present with a flu-like illness.
A history of travel to a malaria endemic area should be sought in a pregnant woman with pyrexia of
unknown origin.
Suspicion of malaria requires prompt confirmation by malaria blood film (Appendix 2), as there are no clinical
algorithms that permit accurate diagnosis by signs and symptoms (see Section 6.2). In its early stages, the
symptoms and signs of malaria can mimic influenza and other common viral infections (Box 2).
4 of 29
Box 2. Symptoms and signs of malaria

Symptoms
Fever/chills/sweats
Headache
Muscle pain
Nausea
Vomiting
Diarrhea
Cough
General malaise
Signs
Jaundice
Elevated temperature
Perspiration
Pallor
Splenomegaly
Respiratory distress
Misdiagnosis has been reported to occur when the leading symptoms are jaundice or respiratory3840 and
possibly gastrointestinal (certainly in children) in nature. Misdiagnosis and delay of treatment are the most
common reasons cited for death from malaria in Europe41,42 and the USA.43 For the non-falciparum malarias,
the history of travel may be more than 1 year before the onset of symptoms3,43 and, for any woman who has
taken prophylaxis, compliance does not rule out the diagnosis of malaria. In the only case series of imported
malaria in pregnant women in Europe (Marseille, France), the majority (14 of 18) had fever and the four
women who did not, had thrombocytopenia or anaemia associated with splenomegaly.44
A history of travel to the tropics and the non-specific nature of the symptoms and signs will lead clinicians to
consider investigating other travel-related diagnoses, according to the region visited; for example, influenzalike illnesses including H1N1, severe acute respiratory syndrome, avian influenza, HIV, meningitis/encephalitis
and viral haemorrhagic fevers, hepatitis, dengue fever, scrub and murine typhus and leptospirosis. However,
for malaria diagnosis a blood film is vital.
6.2 How should malaria in pregnancy be diagnosed?

Microscopic diagnosis allows species identification and estimation of parasitaemia, so that appropriate
antimalarials can be prescribed.
Rapid detection tests may miss low parasitaemia, which is more likely in pregnant women, and rapid
detections tests are relatively insensitive in P. vivax malaria.
Microscopy and rapid diagnostic tests are the standard tools available. The diagnosis of malaria in pregnancy,
as in non-pregnant patients, relies on microscopic examination (the current gold standard) of thick and thin
blood films for parasites (Appendix 2) or the use of rapid diagnostic tests which detect specific parasite
antigen or enzyme. Rapid diagnostic tests are less sensitive than malaria blood film.45,46 A positive rapid
diagnostic test should be followed by microscopy to quantify the number of infected red blood cells
(parasitaemia) and to confirm the species and the stage of parasites. The rapid diagnostic tests should not
replace blood films, which should always be prepared, even if they cannot immediately be read (assistance
can be provided in the UK; Box 3).
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Box 3. Assistance for reading malaria blood films sent urgently by courier or taxi
HPA Malaria Reference Laboratory
Website: www.hpa.org.uk/HPA
For advice on laboratory diagnosis: tel: 020 7927 2427
Send in the risk assessment template by fax and receive results within 3 days; fax: 020 7637 0248
Patient data requirements (risk assessment template Malaria Request Form) available to download as a PDF file:
www.hpa.org.uk/HPA/ProductsServices/InfectiousDiseases/LaboratoriesAndReferenceFacilities/1200660023262/
Send samples to:
HPA Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT
For advice for health professionals over the phone, please contact the National Travel Health Network and Centre: tel: 0845 602 6712
Hospital for Tropical Diseases, London

Website information for doctors: www.thehtd.org/Fordoctors.aspx
General practitioners or hospitals requiring information or clinical advice should telephone: 0845 1555 000 ext. 5414/5418
Send films by courier or cab to:
Hospital for Tropical Diseases, Department of Parasitology, Mortimer Market Centre, Capper St, London WC1E 6AU
After 17:00 or at the weekend, the sample should be addressed to:
SHO on call, T8, University College Hospital, 253 Euston Road, London NW1 2BU
Tel. 08451555000 bleep 5840
Liverpool School of Tropical Medicine, Liverpool

Patient data requirements (HPA risk assessment template Malaria Request Form) available to download as a PDF file :
www.liv.ac.uk/lstm/travel_health_services/diagnos_lab.htm
Sample requirements: original (EDTA) blood sample plus two unstained thick films and two unstained, methanol fixed, thin films. Samples
should be sent by first class mail, or courier to:
Clinical Diagnostic Parasitology Laboratory, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA
or, if in the Hays DX scheme:
Liverpool School of Tropical Medicine, Diagnostic Laboratory, DX 6966301, Liverpool 92L
A charge is made for all laboratory services; for current prices please telephone laboratory staff on 0151 705 3220. Please note that the
laboratory opening hours are 08.3017.00 Monday to Friday. The laboratory is closed at weekends and on Bank Holidays. For technical advice
regarding samples/tests and for interpretation of results please contact the Diagnostic Laboratory 0151 705 3220/3290
In a febrile patient, three negative malaria smears 1224 hours apart rules out the diagnosis of malaria.
In a case series of pregnant women from France, all women were identified as positive for malaria by
microscopy.44 There are occasions for suspicions to remain high and expert advice should be sought in such
circumstances. Women who have taken prophylaxis may have their parasitaemia suppressed below the level
of microscopic detection (total biomass 108 parasites) and details of prophylaxis (name, where it was bought
in case of fake drug dosing and adherence) should be sought. Stop prophylaxis on admission to hospital.
Pregnant women with a high background immune level may have negative peripheral blood thick films but
parasites sequestered in the placenta (for example, a recently arrived woman from a high malaria-endemic
country with an unexplained anaemia).47
Other important prognostic factors that should be reported on a peripheral blood smear result are:
the presence and count of mature trophozoites and schizonts of P. falciparum

finding malaria pigment in more than 5% of the polymorphonuclear leucocytes in the peripheral blood
film.48,49
6 of 29
6.3 Is the severity of malaria a useful aid in managing the infection?

Women with malaria in pregnancy should have the severity of their condition assessed and documented
as an aid to management.
The clinical condition is the most important indicator of severity and should be assessed promptly (Box 1). A
helpful summary of the key points for use in the emergency department has been made available via the
British Infection Society website (www.britishinfectionsociety.org). The severity of malaria determines the
treatment and predicts the case fatality rate. In uncomplicated malaria, fatality rates are low: approximately
0.1% for P. falciparum. In severe malaria, particularly in pregnancy, fatality rates are high (1520% in
nonpregnant women compared with 50% in pregnancy).17,38,50,51 Brabin estimated mortality to be 210 times
higher in pregnant women than in non-pregnant women in endemic areas.52 The non-falciparum species are
rarely fatal but caution should still be observed.12,53
Once the disease has been classified as severe/complicated (as defined in Section 5.1 and Box 1 of this
guideline) or uncomplicated malaria (as defined in Section 5.2 of this guideline) prompt treatment should be
instituted.
7.
How is malaria infection treated during pregnancy?
Treat malaria in pregnancy as an emergency.
Admit pregnant women with uncomplicated malaria to hospital and pregnant women with severe and
complicated malaria to an intensive care unit.
Intravenous artesunate is the treatment of choice for severe falciparum malaria. Use intravenous
quinine if artesunate is not available.
Use quinine and clindamycin to treat uncomplicated P. falciparum (or mixed, such as P. falciparum and
P. vivax).
Use chloroquine to treat P. vivax, P. ovale or P. malariae.
Primaquine should not be used in pregnancy.
Seek advice from infectious diseases specialists, especially for severe and recurrent cases.
Do not persist with oral therapy if vomiting is persistent.
Treat the fever with antipyretics.
Screen women with malaria for anaemia and treat appropriately.
Write a management plan for follow-up, to ensure detection of relapse.
7.1 Drug treatment

Delay in diagnosis and treatment is associated with death from severe malaria.42,5456 Use the treatment
guidelines shown in Table 1. For a summary of the published evidence see Appendix 3.
7 of 29
Table 1. UK treatment guidelines in pregnancy3

Severity
Indication
Drug and dosage
Severe or complicated
malariaa
Any species (for specific cases after

expert consultation; see Table 2)
Artesunate IV 2.4 mg/kg at 0, 12 and 24 hours, then daily thereafter.

When the patient is well enough to take oral medication she can be
switched to oral artesunate 2 mg/kg (or IM artesunate 2.4 mg/kg)
once daily, plus clindamycin. If oral artesunate is not available, use a
3-day course of Riamet (GSK) or atovaquone-proguanil (Malarone,
Novartis) or a 7-day course of quinine and clindamycin at 450 mg
3 times a day 7 days.
ALTERNATIVELY
Any species
Quinine IV 20 mg/kg loading dose (no loading dose if patient already

taking quinine or mefloquine) in 5% dextrose over 4 hours and then
10 mg/kg IV over 4 hours every 8 hours plus clindamycin IV 450 mg
every 8 hours (max. dose quinine 1.4 g). When the patient is well
enough to take oral medication she can be switched to oral quinine
600 mg 3 times a day to complete 57 days and oral clindamycin
450 mg 3 times a day 7 days (an alternative rapid quinine-loading
regimen is 7 mg/kg quinine dihyrochloride IV over 30 minutes using an
infusion pump followed by 10 mg/kg over 4 hours).
Note: quinine dosing should be reduced to 12-hourly dosing if IV
therapy extends more than 48 hours or if the patient has renal or
hepatic dysfunction.56 Quinine is associated with severe and
recurrent hypoglycaemia in late pregnancy.57
Uncomplicated malariab
Non-falciparum malariac
P. falciparum
Oral quinine 600 mg 8 hourly and oral clindamycin 450 mg 8 hourly

for 7 days (can be given together)
or Riamet 4 tablets/dose for weight > 35 kg, twice daily for 3 days
(with fat)
or atovaquone-proguanil (Malarone) 4 standard tablets daily for
3 days.
Vomiting but no signs of severe or

complicated malaria
Quinine 10 mg/kg dose IV in 5% dextrose over 4 hours every 8 hours

plus IV clindamycin 450 mg every 8 hours. When the patient is well
enough to take oral medication she can be switched to oral quinine
600 mg 3 times a day to complete 57 days and oral clindamycin can
if needed be switched to 450 mg 3 times a day 7 days.
P. vivax, P. ovale, P. malariae
Oral chloroquine (base) 600 mg followed by 300 mg 68 hours later.

Then 300 mg on day 2 and again on day 3.
Resistant P. vivax
As for uncomplicated malaria P. falciparum
Preventing relapse DURING pregnancy
Chloroquine oral 300 mg weekly until delivery
Preventing relapse AFTER delivery
Postpone until 3 months after delivery and G6PD testing
P. ovale
Oral primaquine 15 mg single daily dose for 14 days
P. vivax
Oral primaquine 30 mg single daily dose for 14 days
G6PD (mild) for P. vivax or P. ovale
Primaquine oral 4560 mg once a week for 8 weeks
Severe and complicated malaria published evidence, see Appendix 3.1;

Uncomplicated malaria published evidence, see Appendix 3.2;
c Non-falciparum malaria published evidence, see Appendix 3.3; IM = intramuscular, IV = intravenous
a
7.2 Who should prescribe treatment for malaria infection in pregnancy?

In the UK, treatment prescription is limited to physicians. Treatment in pregnancy, particularly of severe and
recurrent malaria, is best given with expert advice (Table 2).
7.3 Where should treatment of uncomplicated malaria infection take place?

In the UK, it is advisable to hospitalise all pregnant women with P. falciparum, as the clinical condition can
deteriorate rapidly.3,5962 Blood films are usually monitored every 24 hours but clinical deterioration is an
indication for a repeat blood film.
8 of 29
Table 2. Contact details for intravenous artesunate or specialist advice in cases of severe malaria
Organisation
Contact details
Hospital for Tropical Diseases, London

[http://thehtd.org/Emergencies.aspx]
HTD will send artesunate to other hospitals dealing with severe
cases if there is going to be a delay in transferring the patient to
HTD (do not delay IV treatment in the interim)
FOR ADVICE/IV ARTESUNATE

Ask for the on-call tropical medicine registrar (24-hour service).
Use the University College London Hospital switchboard;
tel: 08451 555000
Oxford Hospital for Tropical Diseases

Ask for the infectious diseases consultant on call at the John Warin
Ward. Use Churchill Hospital Switchboard; tel: 01865 741841
Note: the drug can be sent during the daytime and services at the
weekend are limited.
Liverpool School Tropical Medicine

Tropical Medicine Services for Health Professionals
[www.liv.ac.uk/lstm/travel_health_services/health_profs.htm]

Tropical doctor on call in working hours; tel: 0151 705 3100,
0151 706 2000 (at other times ask for the infectious disease/tropical
doctor on call at the Royal Hospital)
Birmingham Heartlands Hospital

Infectious Diseases Unit
Department of Infection and Tropical Medicine

Birmingham Heartlands Hospital
Birmingham B9 5ST
Tel: 0121 424 1137
Outside working hours tel: 0121 424 2000 for the switchboard
Idis Pharma [www.idispharma.com]

Despite the fact that artesunate has not achieved good
manufacturing practice certification, it has received the
orphan medicinal products designation from the European
Medicines Agency.132
Product details: oral artesunate guilin, 50-mg tablets 1 x 12;
IV artesunate 60-mg powder/solution for injection 1 x 8
FOR IV or ORAL ARTESUNATE

Contact details in the UK: tel: 01932 824100; fax: 01932 824300;
email: [email protected]
The 7-day course of quinine has significant adverse effects, principally cinchonism,19 which includes tinnitus,
headache, nausea, diarrhoea, altered auditory acuity and blurred vision. This can lead to non-compliance,
which frequently leads to failure.16,6366 For this reason, hospitalisation can be useful, as compliance with each
dose of quinine and clindamycin can be observed and this may lead to improved cure rates.65,67
While non-falciparum malaria can be managed on an outpatient basis, admission ensures compliance and any
risk of vomiting or rapid deterioration is minimised and allows time for planning post-treatment prophylaxis.
7.4 What happens if the patient vomits?

Vomiting is a symptom of malaria and a known adverse effect of quinine.6870 It is associated with
antimalarial treatment failure.16
Evidence
level 2+
If the patient vomits, use an antiemetic.There are no studies of their efficacy in malaria17 but metoclopramide
is considered safe, even in the first trimester.71 After the antiemetic has had time to take effect, repeat the dose.
Repeat vomiting after antiemetic is an indication for parenteral therapy.
7.5 What other medication should be provided alongside treatment of uncomplicated malaria infection?
The fever of malaria has been associated with premature labour53,72 and fetal distress.73 Prompt
treatment with antipyretics (paracetamol at the standard dose) is fundamental to the treatment of
fever from malaria in pregnancy. Evidence for the efficacy of paracetamol arises mostly from studies
in children.7478
Evidence
level 1
An estimated 400 000 pregnant woman developed severe anaemia as a result of malaria in sub-Saharan Africa
in 1995.79 Despite the massive burden of malaria-related anaemia in pregnancy, there are very few studies that
9 of 29
have directly addressed the question of routine iron and folate supplementation as part of uncomplicated
malaria treatment. In P. falciparum malaria treatment trials in women with low premunition, 90% of women
developed anaemia (haemoglobin less than 10 g/dl), either on admission or during follow-up.80 Premunition
is the degree of naturally acquired host immunity to malaria. It depends on repeated exposure to infectious
anopheline bites, so most UK-based residents will have low or no premunition. Mild and moderate malariaassociated anaemia is treated with ferrous sulphate and folic acid at the usual doses.
7.6 Does pregnancy affect the efficacy of malaria treatments?

Treatments in pregnancy may have lower efficacy than in non-pregnant patients but this apparent effect could
result from lowered concentrations of antimalarials in pregnancy.26,30,32 Women should be advised of the risk
of recurrence and a suitable follow-up plan devised; for example, if symptoms or fever return, a repeat blood
film is necessary. Alternatively, weekly screening by blood film can provide early detection and treatment of
malaria. This has been shown to reduce maternal death from malaria in Thailand.10 There is no evidence of
weekly blood film use in the UK but Thailand is a low endemic area so immune levels would not be much
higher than those in women from the UK who were not immune.
Malaria in pregnancy is unique and the ability of P. falciparum to sequester in the placenta challenges the
normal way antimalarial drug efficacy is assessed.37 Polymerase chain reaction (PCR)-confirmed prolonged
submicroscopic carriage with subsequent recurrence has been reported in pregnant women for months
following drug treatment for uncomplicated P. falciparum. Most recurrence is around day 2842 but latereported recurrence, so far unique to pregnancy, has been reported to occur at 85 days with quinine,28 98 days
with artesunate, 63 days with artemether-lumefantrine30 and 121 days with mefloquine.81 Weekly screening by
blood film until delivery allows these women to be detected positive before becoming symptomatic.10
7.7 How should recurrence be treated?

The treatment efficacy of antimalarials for recurrent malaria in pregnancy has been described in only a handful of trials.30,8284 The cure rates for uncomplicated malaria with quinine fell from 77.0% to 61.0% (P = 0.03)
and for mefloquine from 72.0% to 62.5% (P > 0.05) when these drugs were used to treat primary and
recurrent infections.82 The alternative regimen for recurrent malaria at that time (19951997) was artesunate
monotherapy, which had a cure rate of 84%. In another study, the PCR-confirmed cure rates of women treated
in the second and third trimesters of pregnancy were highest when the infection on admission to the study
was primary (the first for the pregnancy) and lowest when the infection was recrudescent (failure of previous
drug treatment in pregnancy).82 Infections that recur following treatment are likely to be intrinsically less
sensitive to the drugs used against them. A highly effective 7-day treatment has more chance of curing the
patient. All the trials of recurrent malaria in pregnancy rely on artemisinin derivatives.
Unfortunately, the options for treatment of recurrent infection in pregnancy in the UK are limited but, if
quinine and clindamycin has failed as first-line treatment, an alternative should be considered. Atovaquoneproguanil-artesunate83 and dihydroartemisinin-piperaquine84 have been used in pregnant women with
multiple recurrent infections with good effect. Atovaquone-proguanil (Malarone, GlaxoSmithKline) is
available in the UK and, as noted earlier, was highly effective against uncomplicated P. falciparum malaria even
when it was not combined with artesunate.85 Note that oral artesunate can be obtained from IDIS Pharma
(Table 2). The World Health Organization recommended regimen of 7 days of artesunate (2 mg/kg/day or
100 mg daily for 7 days) and clindamycin (450 mg three times daily for 7 days) could be given.
8.
How are pregnancy-related complications of severe malaria managed?
Monitor for hypoglycaemia regularly, as it can be profound and persistent in malaria in pregnancy and
can be exacerbated by quinine.
10 of 29
Prevent mortality from pulmonary oedema and acute respiratory distress syndrome by clinical
assessment of jugular venous or central venous pressure, aimed at keeping right arterial pressure less
than 10 cm H2O.
Women who are severely anaemic should be transfused slowly, preferably with packed cells and
intravenous frusemide 20 mg. Alternatively, exchange transfusion may be considered in centres where
this can be performed safely.
Secondary bacterial infection should be suspected if the patient becomes hypotensive.
Severe malaria in pregnancy is a medical emergency and women should be treated in a high-dependency or
intensive care unit, according to their condition and without delay. The World Health Organizations 2006
malaria treatment guidelines detail the treatment of severe malaria and do not need to be repeated here.17
Common clinical manifestations and management of severe malaria have been summarised (Table 3).17,50 While
hypoglycaemia, pulmonary oedema, severe anaemia and secondary bacterial infection can occur in severe
malaria in non-pregnant patients, they are more common and severe in pregnant women.3,39,40,50,86
Hypoglycaemia is commonly asymptomatic, although it may be associated with fetal bradycardia
and other signs of fetal distress. In the most severely ill women, it is associated with lactic acidosis
and high mortality.68 In patients who have been given quinine, abnormal behaviour, sweating and
sudden loss of consciousness are the usual manifestations.The hypoglycaemia of quinine is caused
by hyperinsulinaemia and remains the most common and important adverse effect of this drug.87
The hypoglycaemia may be profound, recurrent and intractable in pregnancy73,87,88 and regular
monitoring of glucose is required while under quinine treatment. It may present late in the disease
when the patient appears to be recovering. Quinine at treatment doses does not induce abortion
or labour.73,89
Evidence
level 2
Table 3. Supportive clinical care in severe malaria

Manifestation or complication
Management
Coma (cerebral malaria)
Monitor using Glasgow Coma Score. Maintain airway, place patient on her left side, exclude
treatable causes of coma (e.g. hypoglycaemia, bacterial meningitis)
Hyperpyrexia
Administer tepid sponging, fanning and antipyretic drugs
Convulsions
Maintain airway; treat promptly with intravenous or rectal diazepam
Hypoglycaemia
(blood glucose < 2.2 mmol/l or
< 40 mg/100 ml)
Check blood glucose regularly, correct hypoglycaemia and maintain with glucose-containing
infusion. Quinine induced hypoglycaemia can occur quite late in the course even after the
patient appears to be recovering
Severe anaemia
(haemoglobin < 8 g/100 ml or
packed cell volume < 24%)
Transfuse with packed red cells
Acute pulmonary oedema

(possible overlay of acute respiratory
distress syndrome)
Prevent by monitoring jugular venous pressure(JVP)/central venous pressure (CVP) to keep

right arterial pressure < 10 cm H2O. Treat by propping patient up at an angle of 45 degrees,
give oxygen, give a diuretic, stop intravenous fluids, intubate and add positive end-expiratory
pressure/continuous positive airway pressure in life-threatening hypoxaemia
Renal failure
Exclude pre-renal causes, check fluid balance and urinary sodium; if in established renal failure,
add haemofiltration or haemodialysis or, if unavailable, peritoneal dialysis. The benefits of
diuretics/dopamine in acute renal failure are not proven
Spontaneous bleeding and

coagulopathy
Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets
if available); give Vitamin K by injection
Metabolic acidosis
Prevent by careful fluid balance; observation of JVP/CVP by central venous access helps
optimise fluid balance and avoids overfilling. Exclude or treat hypoglycaemia, hypovolaemia
and septicaemia. If severe, add haemofiltration or haemodialysis
Shock
Suspect septicaemia, take blood for cultures; give parenteral broad-spectrum antimicrobials,
correct haemodynamic disturbances
11 of 29
Pulmonary oedema may be present on admission or may develop suddenly and unexpectedly. It
may develop immediately after childbirth.38 Pulmonary oedema is a grave complication of severe
malaria, with a high mortality of over 50%.39,40,86,9093 The first indication of impending pulmonary
oedema is an increase in the respiratory rate, which precedes the development of other chest signs.
Ensure that the pulmonary oedema has not resulted from iatrogenic fluid overload and monitor the
central venous pressure and urine output. In some women, acute respiratory distress syndrome can
occur in addition to the pulmonary oedema. Once this syndrome develops, the patient needs fluid
restriction.
Evidence
level 2+
Severe anaemia is associated with maternal morbidity, an increased risk of postpartum

haemorrhage and perinatal mortality.8,39,51,52,90,9396 Women who go into labour when severely anaemic
or fluid-overloaded may develop acute pulmonary oedema after separation of the placenta. Monitor
haemoglobin and transfuse as necessary. Exchange transfusion may be considered but there is no
clear evidence base.97
Evidence
level 2++
Secondary bacterial infection, principally Gram-negative septicaemia, has been reported; the patient
is collapsed with a systolic blood pressure less than 80 mmHg in the supine position.55,98,99 Blood
cultures should be taken if the patient shows signs of shock or fever returns after apparent fever
clearance, Broad-spectrum antibiotics (such as ceftriaxone) should be started immediately. Once
the results of blood culture and sensitivity testing are available, give the appropriate antibiotic.
Evidence
level 3
9.
Obstetric management specific to malaria infection in pregnancy
9.1 Common obstetric problems with acute symptomatic malaria

Preterm labour, fetal growth restriction and fetal heart rate abnormalities can occur in malaria in
pregnancy.
In severe malaria complicated by fetal compromise, a multidisciplinary team approach (intensive care
specialist, infectious disease specialist, obstetrician, neonatologist) is required to plan optimal
management of mother and baby.
Stillbirth and premature delivery in malaria in pregnancy are best prevented with prompt and effective
antimalarial treatment.
Uncomplicated malaria in pregnancy is not a reason for induction of labour.
Pharmacological thromboprophylaxis should be weighed up against the risk of haemorrhage and

should be withheld if the platelet count is falling or less than 100, indicating thrombocytopenia.
Peripartum malaria is an indication for placental histology and placenta, cord and baby blood films to
detect congenital malaria at an early stage.
Inform women of the risk of vertical transmission and, in the presence of positive placental blood films,
that fever in the infant could indicate malaria; a blood film from the baby is required for confirmation.
Commonsense obstetrics applies to the management of the adverse effects of malaria in pregnancy.
Efficacious and prompt treatment of malaria in the woman reduces the systemic effects of parasitaemia and
reduces the adverse effects on the fetus, such as fetal distress.
In severe malaria, cardiotocograph monitoring may reveal fetal tachycardia, bradycardia or late
decelerations in relation to uterine contractions, indicating fetal distress, particularly in the
12 of 29
Evidence
level 4
presence of fever.72 Paracetamol 1 g every 46 hours (to a maximum of 4 g/day) is safe and effective
and should be prescribed. Maternal hypoglycaemia should be excluded as the cause of fetal distress,
particularly if treatment is with quinine. Tocolytic therapy and prophylactic steroid therapy at the
usual obstetric doses should be considered if there are no contraindications.100
Evidence
level 4
Historic records indicate a high fetal loss rate with malaria in pregnancy.101,102 In a more recent
study from the Kenyan coast, Dorman et al.103 found that the risk of preterm delivery in women
with histological evidence of past placental malaria infection compared with women without
infection was more than twice as high (relative risk [RR] 2.33; 95% confidence interval [CI]
1.314.13; P = 0.004).
Evidence
level 2-
Abnormalities in fetal and placental circulation have been noted on Doppler studies. In one study,
23 women with acute malaria reported that the umbilical artery resistance index increased by 5 to
20% (P < 0.05), with evidence of cerebral redistribution.103,104 In the second observational study in
Kenya, malaria infection at 3235 weeks of gestation was associated with abnormal uterine artery
flow velocity waveforms on the day of blood testing (RR 2.11; 95% CI 1.243.59; P = 0.006).103
In women with severe malaria, obstetric advice should be sought at an early stage.The paediatrician
should be alerted and the mothers blood glucose checked frequently, particularly when
intravenous quinine is administered. Fetal distress is common and has been related to malaria fever:
late (type II) decelerations of the fetal heart rate were recorded in six women before treatment but,
in most women, signs of fetal distress diminished as the maternal temperature fell.73 Standard
obstetric principles apply: the life of the woman comes first. There are no formal studies but
instrumental birth in the second stage of labour in the presence of maternal or fetal distress is
indicated, if there are no contraindications. In severe malaria, the role of early caesarean section for
the viable fetus is unproven.
Evidence
level 3
Acute malaria can cause thrombocytopenia in pregnancy.105 Two studies have examined the effects
on postpartum haemorrhage, which was reported to be higher in malarious areas compared with
non-malarious areas of Papua New Guinea.106 One further trial found an increased mean blood loss
in women with malaria but no increased risk of postpartum haemorrhage.107
In more than 3000 pregnant women who have participated in uncomplicated malaria treatment
trials7,24,2629,43,53,80,8284,108121 and have been prospectively followed from diagnosis of malaria through
treatment and birth, no routine induction of labour occurred unless it was indicated on obstetric
grounds.
Evidence
level 1++
There is usually no need for pregnant women with malaria infection to receive thromboprophylaxis. Acute malaria causes thrombocytopenia105 and, in severe malaria, can cause disseminated
intravascular coagulation.50 Thrombocytopenia recovers with treatment: 90% by day 7 and 100% by
day 14, irrespective of the type of antimalarial treatment.105
Evidence
level 3
Antimalarial drugs can clear peripheral parasitaemia more quickly than from the placenta.122
Maternal malaria close to delivery can result in congenital malaria, which can cause significant
mortality.123 Congenital malaria may present in the first weeks to months of life.A negative placental
blood film at delivery in a woman who has had malaria in pregnancy eliminates the risk of
congenital malaria significantly. Placenta- and cord-positive blood films result in a higher chance of
congenital malaria than placenta-positive, cord-negative blood films. Send the placenta for
histopathology, as it is more sensitive than microscopy for detection of placental parasites.124,125
Evidence
level 2+
13 of 29
9.2 What antenatal care after recovery from an episode of malaria in pregnancy is advised?
Regular antenatal care, including assessment of maternal haemoglobin, platelets, glucose and fetal
growth scans, is advised following recovery from an episode of malaria in pregnancy.
Regular fetal growth assessment is advised and, if growth restriction is identified, routine obstetric
management for this condition applies (See RCOG Green-top Guideline No. 31: Investigation and
Management of Small-for-Gestational-Age Fetus).126
Inform the woman about the risk of relapse, try to prevent it and develop a clear plan with the woman
in the event of symptom recurrence.
In endemic settings, malaria in pregnancy is responsible for over 50% of fetal growth restriction but most
babies born to women with infection during pregnancy will be of normal birth weight.5 No additional fetal
surveillance will prevent the growth restriction. If growth restriction is identified, routine obstetric protocols
for this condition apply. Effective antimalarial treatment which clears the placenta of parasites is the most
important step in preventing this complication (Table 1) followed by prophylaxis to prevent relapse
(Appendix 3), such as weekly chloroquine for P. vivax.The chances of recurrence are low when a woman has
completed an effective course of antimalarials. Nevertheless, it is useful for women to be aware that malaria
can recur (and is more likely with P. vivax or P. ovale). Should symptoms return, prompt screening by malaria
blood film, preferably at the same hospital where treatment was first given, is essential.
The post-malaria treatment course for women treated for malaria can be complicated by anaemia,
which will be detected in routine antenatal screening. There are malaria-endemic countries where
the risk of pre-eclampsia is increased significantly in women with placental malaria.127 The situation
for women in these countries is different from that of a pregnant woman treated for malaria in the
UK because malaria is endemic, diagnosis and case management tends to be weak, impregnated
bed nets and prophylaxis are the main stay of malaria control in pregnancy and the risk of
reinfection is high. The risk of pre-eclampsia in UK pregnant women treated for malaria is not
known but may be lower than in malaria endemic countries.
Evidence
level 3
10. What is the risk of vertical transmission of malaria infection to the baby?
Vertical transmission to the fetus can occur particularly when there is infection at the time of birth and
the placenta and cord are blood film positive for malaria (Appendix 2).
All neonates whose mothers developed malaria in pregnancy should be screened for malaria with
standard microscopy of thick and thin blood films at birth and weekly blood films for 28 days.
Vertical transmission of malaria occurs when malaria parasites cross the placenta, either during
pregnancy or at the time of birth (Appendix 4).128 In a non-endemic country, congenital malaria can
be diagnosed by finding parasites in the neonate if they have not travelled in an endemic area.128132
The reported prevalence of congenital malaria varies from 8% to 33%.5 One or the largest series of
congenital malaria in a non-endemic country comes from the USA.133 P. vivax was the predominant
infecting species and the most common error in the treatment of these infants was the
administration of primaquine, which is unnecessary in this group. Infection of the newborn can
occur despite appropriate treatment in the mother during pregnancy. If the placenta is positive for
parasites, weekly screening of the newborn for 28 days is useful to allow early detection and
treatment of congenital malaria.
14 of 29
Evidence
level 3
11.
Disease reporting
Does a case of malaria in pregnancy in the UK need reporting?

In the UK, malaria in pregnancy must be reported to the public health authorities and the Health Protection
Agency (www.hpa.org.uk) and slides, plus a blood aliquot, should be sent to the Malaria Reference Laboratory
for confirmation, which is performed free of charge.3
Health Protection Agency Central Office
7th Floor
Holborn Gate
330 High Holborn
London, WC1V 7PP
Tel: 020 7759 2700 / 2701
Fax: 020 7759 2733
Email: [email protected]
OR
Health Protection Agency Centre for Infections

61 Colindale Avenue
London NW9 5EQ
Tel: 020 8200 4400
Fax: 020 8200 7868
Email: [email protected]
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Chemoprophylaxis is not 100% effective

Pregnant women with malaria can deteriorate very rapidly
Expert advice with a specialist with current experience in management of malaria is strongly advised
Notify all cases to the local health protection unit, send blood film to reference laboratory
19 of 29
Management of malaria in pregnancy

Commence antimalarials immediately,
according to species and severity
Admit to HDU or ICU and seek expert
advice
Careful fluid balance avoid over-hydration
and hypovolaemia; consider CVP line
Complicated malaria: one or more of

following:
Impaired consciousness (measure GCS and
NSQ) or seizures
Hypoglycaemia
Pulmonary oedema or ARDS
Hyperparasitaemia ( 2% parasitised RBC
but can be lower in severe malaria)
Severe anaemia (Hb < 8.0 g/dl)
Regular blood glucose monitoring

4-hourly observations (pulse, BP, RR, JVP,
SaO2, urine output, GCS)
Repeat daily: parasite count, FBC,
clotting, U&E, LFT
Shock treat for Gram-negative
bacteraemia
Abnormal bleeding/DIC
Haemoglobinuria (without G6PD
deficiency)
Renal impairment/electrolyte disturbance
(acidosis pH < 7.3)
Hyperlactataemia (correlates with
mortality)
Shock (algid malaria) consider Gramnegative septicaemia
Uncomplicated malaria dosing:

Quinine 600 mg orally 8-hourly and clindamycin
450 mg orally 8-hourly for 7 days (drug of choice
EGA < 13 weeks)
Or
Riamet 4 tablets/day for weight > 35 kg for 3 days
Or
Proguanil with atovaquone (Malarone ,
GlaxoSmithKline) four standard tablets daily for
3 days
Non-falciparum malaria
Chloroquine (base) 600 mg orally followed by
300 mg 68 hours later. Then 300 mg day 2, and
again day 3
To prevent relapse (P. vivax/ovale) after treatment
during pregnancy: chloroquine oral 300 mg weekly
until delivery
To prevent relapse after delivery: postpone until
3 months after delivery and G6PD testing. Use
primaquine
Key: ARDS = acute respiratory distress syndrome, BP = blood pressure, CVP = central venous pressure, DIC = disseminated intravascular coagulation, EGA = estimated gestational age, FBC = full blood count,
GCS = Glasgow Coma Score, Hb = haemoglobin, HDU = high-dependency unit, ICU = intensive care unit, JVP = jugular venous pressure, LFT = liver function test, NSQ = Neuroticism Scale Questionnaire,
RBC = red blood cells, RR = respiratory rate, SaO2 = oxygen saturation, U&E = urea and electrolytes
Expert advice/IV artesunate: local infectious unit or London 08451 555000; Liverpool 0151 706 2000; Oxford 08165 7418415; IDIS pharma 01932 824100.
Useful information: www.hpa.org.uk/HPA/ProductsServices/InfectiousDiseases/LaboratoriesAndReferenceFacilities/1200660023262/ and www.who.int/malaria/publications/atoz/9241546948/en/index.html
Complicated malaria dosing:

Artesunate IV 2.4 mg/kg at 0, 12 and 24 hours
& daily thereafter. Drug of choice regardless of
EGA
Or
Quinine IV 20 mg/kg loading dose (no loading
dose if woman already taking quinine or
mefloquine) in 5% dextrose over 4 hours and
then 10 mg/kg IV over 4 hours every 8 hours+
Oral when the patient can swallow (see
uncomplicated malaria dosing)
Malaria unlikely if 3 negative blood films

Finish chemoprohylaxis
Repeat blood film daily 2 days
Stop prophylaxis until malaria excluded

Avoid empirical therapy unless severe illness:
seek expert advice
Falciparum malaria
(mixed or species not characterised)
Admit to hospital; assess severity immediately
Blood film shows
Urgent investigations: All women should have thick and thin blood films and malaria rapid antigen tests. Send to a laboratory immediately and ask for a result in 1 hour. FBC, blood glucose
(imparied consciousness or seizures), U&E, LFT, blood culture, urine dipstick; if indicated, stool test, chest X-ray (precautions apply), obstetric ultrasound (EGA)
History and examination no symptoms or sign can accurately predict malaria. Flu-like illness with fever/chills/sweats, headache, muscle pain, nausea, vomiting, diarrhea, cough, general malaise
Early diagnosis, assessment of severity and treatment is vital to avoid malaria deaths
Febrile or ill pregnant women with a history of travel or residence in a malaria area (tropics or
sub-tropics) should be assessed urgently (incubation for non-falciparum malaria may occasionally
be > 6 months)
Recent return (3 weeks): check infection control requirements with microbiologist e.g. viral
haemorrhagic fever, avian influenza or severe acute respiratory syndrome
No evidence of malaria
(Single negative test does not exclude malaria)
Suspect malaria
APPENDIX I: Initial rapid diagnosis, assessment and treatment of malaria in pregnancy
APPENDIX II: Preparing a blood film for malaria and taking a section of placenta for
histopatholgy.
Blood films are also commonly called malaria slide, thick
and thin films, malaria smear or blood slide. A few drops
of the patients blood are required for the test. A brief
summary is provided in Figure 1.
There are many useful websites (including videos) on how
to prepare a thick and thin blood film. For detailed
instructions, try: www.dpd.cdc.gov/dpdx/HTML/Malaria.
htm or www.helid.desastres.net select Parasitic and Vector
Borne Disease from the topic list (Basic Malaria Microscopy,
Learning Unit 4) or see the laboratory handout from:
www.shoklo-unit.com/lab.shoklo-unit.com/index.html.
Step 1. Put 3 drops of blood onto the slide
Cord blood film or placental blood films require a few drops

of blood collected from those sites.
Cord specimens can be obtained before delivery of the
placenta. Hold the clamped end of the cord above the level
of the umbilicus. Wipe the cord clean, puncture the cord
with a syringe and needle (small gauge) and withdraw blood
from the vessel (0.2 ml is plenty) and reclamp the cord
above the puncture site. The blood obtained needs to go
directly onto the glass slide before it clots (see Figure 1).
Step 2. Use another slide to spread the drop
Placental blood can be obtained by placing the placenta

maternal surface upward. Choose a site midway between the
edge of the placenta and the cord, wipe it clean with gauze,
make an incision about 1 cm deep and 34 cm in length
with a scalpel blade (do not pierce the fetal surface) and use
a syringe and needle (or haematocrit tube) to withdraw
blood that pools in the incised area. Place this blood onto the
glass slide before it clots.
Label all blood films clearly with the site from which they
were obtained (for example, mother, cord, placenta or baby)
before sending to the laboratory. This histopathological
section can be obtained from the same site on the placenta
by cutting a 1 1 1 cm (or smaller) block from the
maternal surface through to the fetal surface and placing it
in fixative.
Figure 1. Summary of steps involved in making a blood film
20 of 29
Step 3. Stir the thick drop
Step 4. Allow the slide to dry before staining
APPENDIX III: Summary of the published evidence on pregnancy treatment recommendations
Severe and complicated malaria.

The first line of treatment in the UK for severe malaria in pregnancy is intravenous quinine1 while the World
Health Organization (WHO) and an increasing number of countries throughout the world recommend
intravenous (IV) artesunate as the preferred first-line drug for all severe malaria in adults including pregnant
women.2 This recommendation was based partly on two WHO informal consultations on the safety of
artemisinins in pregnancy.3 The first of these reported normal pregnancy outcomes in 124 women exposed
in the first trimester. The conclusions were that there was insufficient evidence to support the use of
artemisinin in the first trimester but that it should not be withheld if the life of the woman was endangered
or if other antimalarials were considered unsuitable.The recommendation also relied upon a meta-analysis of
artemisinins for severe malaria4 and a large, multicentre, open-label randomised controlled trial (RCT) of
severe malaria carried out mostly in adults (including pregnant women) in South East Asia, where the trial was
stopped prematurely because of a significantly increased risk of mortality in the intravenous quinine group
(22% compared with 15% in the IV artesunate group).5 Mortality was reduced by 34.7% (95% confidence
interval 18.547.6; P = 0.002) when IV artesunate was used or, for every 13 people treated with IV artesunate
rather than IV quinine, one death was averted. In the same trial, quinine use was associated with
hypoglycaemia (relative risk 3.9, P = 0.002). This is pertinent in pregnancy, since severe and recurrent
hypoglycaemia associated with severe malaria pregnancy is exacerbated by quinine use, which stimulates
insulin secretion.6,7 These effects are more likely in the second and third trimesters of pregnancy and it is in
these trimesters that the efficacy and safety data of use of artemisinin derivatives are reassuring.8 A metaanalysis of all RCTs comparing parenteral quinine with artesunate indicated that artesunate was associated
with a 35% reduction in mortality.4 Artesunate kills circulating ring-stage parasites and so prevents
sequestration, which quinine does not, and it is this mechanism of action,9 not quinine resistance, that has
been proposed for the significant reduction in mortality with IV artesunate compared when compared with
IV quinine.5 Every effort should be made to obtain IV artesunate (see Table 2 of the main report for contact
details) for pregnant women with severe malaria, regardless of trimester, in an effort to prevent maternal
death. Parenteral quinine should be given without delay if artesunate is unavailable but treatment should be
switched to artesunate as soon as possible.
Parenteral artesunate is not currently licensed in the UK.The IV artesunate used in the multicentre study was
not made to internationally recognised good manufacturing practice standards.5 Good manufacturing practice
IV artesunate is still not available and has not been licensed in the UK.1 TropNetEurop has advocated strongly
for the use of IV artesunate for severe malaria.10 It can be made available in the UK from specialist tropical
disease centres in London, Oxford and Liverpool or commercially from and Idis Pharma, who can send IV and
oral artesunate to patients who need it (see Table 2 of the main report for contact details).
Treatment of malaria should never be delayed (IV quinine should be used promptly while obtaining IV
artesunate). The UK guidelines explain expert consultation is required before the artesunate will be issued.1
Severe malaria in pregnancy provides an urgent and pressing reason for artesunate to be issued (although this
is not in the current guidelines).1 IV clindamycin is a very slow-acting antimalarial and it is unlikely to add any
additional value to IV artesunate, which is the fastest acting of all antimalarial drugs. In endemic countries, the
treatment course when the patient is well enough to eat and drink would be any artemisinin combination
therapy.2 The only artemisinin available in the UK is Riamet (Novartis; also known as Coartem in some
countries), which can be used at standard doses, alternatively, a treatment course of atovaquone-proguanil
(Malarone, GlaxoSmithKline), four standard tablets daily for 3 days could be prescribed. Artesunate can
be given intramuscularly at 2.4 mg/kg/24 hours (or oral artesunate at 2 mg/kg when available) to complete
7 days, with oral clindamycin for 7 days. Although not ideal, quinine and clindamycin can be given at the
standard dose for 7 days (see Table 1 of the main report) if the preferred treatment is not available.
21 of 29
Uncomplicated malaria
Quinine is not thought to be teratogenic.1014 There is no RCT on quinine efficacy in pregnancy from Africa,
where most UK patients acquire their malaria infection. Quinine is assumed to be safe and efficacious, based
on historical data15,16 and on published trials, mostly from women from South East Asia.17 Unacceptably high
failure rates have been reported with quinine monotherapy when treatment has been given in the context of
an RCT. In six trials from Thailand and Burma,1824 in all except one,18 there were 186 women who received
quinine monotherapy and it is no longer recommended.2 Clindamycin augments the efficacy of quinine
significantly.22 The single RCT on the effectiveness of 5 days of quinine in pregnancy resulted in failure rates
greater than 30%.24 As quinine is a rapidly eliminated antimalarial,25 cure rates are improved with 7 day
regimens, although they are poorly complied with. Note that the 5 day recommendation in the UK guidelines
is for non-pregnant adults and should not be used in pregnancy.1 Patients may deteriorate under treatment, at
which point, management should be upgraded to account for severity.
The safety of clindamycin in pregnancy has been established in non-malaria studies.2633 It has been shown to
be effective when used in combination against falciparum malaria in numerous settings,3436 including in
pregnancy.22,3739
WHO recommends artemisinin-based combination therapy in the second and third trimesters,2,8 ahead
of quinine and clindamycin, principally because of the adverse effects and risk of non-compliance with the
7-day regimen. There are now reassuring data on more than 2000 pregnancy outcomes with the use of
artemisinins,5,2022,40,4160 principally for uncomplicated malaria in pregnancy. Most of these studies have been
RCTs in pregnant women from Africa and Asia.20,21,4044 This means there is now more published evidence on
artemisinins in pregnancy than there is for quinine. Only one of these highly effective therapies is available in
the UK (Riamet, Novartis). For nonpregnant adults in the UK, malaria treatment guidelines prescribe three
oral regimens for uncomplicated malaria, including oral quinine and doxycycline; atovaquone-proguanil, four
standard tablets daily for 3 days; and Riamet, four tablets/day for weight over 35 kg. While doxycycline can be
replaced with clindamycin and combined with quinine, the other two regimens have no alternatives but have
been studied in the context of RCTs in the second and third trimesters of pregnancy.
Atovaquone-proguanil alone (n = 26)61 and atovaquone-proguanil-artesunate (n = 100)20,47,49,61 were safe and
efficacious for uncomplicated P. falciprum in the second and third trimesters. Tinnitus was reported in 79.3%
of those on quinine compared with 24.1% of those treated with atovaquone-proguanil-artesunate (P < 0.001)
in the RCT.20 Of the 126 women treated, most were followed through until pregnancy outcome and no
adverse effects for the mother or fetus were observed.The product information sheet for Malarone says that,
while there are no adequate and well-controlled studies of atovaquone and/or proguanil hydrochloride in
pregnant women, Malarone may be used if the potential benefit justifies the potential risk to the fetus62.The
same product information sheet also ignores the largest single site study ever performed on Malarone, which
included 1596 nonpregnant patients randomised to receive atovaquone-proguanil, atovaquone-proguanilartesunate or artesunate-mefloquine for uncomplicated malaria and followed-up for 42 days.63 Adding
artesunate to atovaquone-proguanil reduced the risk of failure three-fold (95% CI 1.18.2) although the cure
rate of atovaquone-proguanil (without the addition of artesunate) was very high, 97.2% (95% CI 95.498.4).
Atovaquone-proguanil (with or without artesunate) is likely to be a useful 3-day treatment in the treatment of
P. falciparum in the second and third trimesters if it has not been used for prophylaxis (see Green-top
Guideline No. 54A).64
At the time of writing, there is only one published RCT on artemether-lumefantrine treatment in pregnancy
(n = 125) and, while the drug was well tolerated with no adverse effects on the mother or fetus, the efficacy
was disappointing, with a cure rate (by delivery or day 42 if later) of 82.0% (95% CI 74.889.3; P = 0.054).42
Pharmacokinetic data demonstrated lowered concentrations of artemether and lumefantrine in pregnancy.57
Polymerase chain reaction confirmed that failures were as early as day 14 and 53% (9/17) had occurred at 3
weeks. Mathematical modelling has suggested an increase in the dose and length of treatment would result in
22 of 29
higher cure rates.65 Two abstracts presented at the American Society of Tropical Medicine and Hygiene Annual
Meeting in December 2008 analysed:
1001 pregnant women (artemether and lumefantrine treated, n = 495 and sulfadoxine-pyrimethamine
treated, n = 506) and their fetuses or newborns (artemether and lumefantrine treated, n = 470 and
sulfadoxine-pyrimethamine, n = 477) and reported no adverse effects on the fetus55
preliminary results on 304 women who received artemether-lumefantrine or quinine as part of an RCT in
Uganda on uncomplicated malaria in the second and third trimesters, which demonstrated high efficacy and
no adverse effects on the fetus.
The product information sheet applies the usual pharmaceutical safeguard statement that it should not be
withheld in life-threatening situations, where no other effective antimalarials are available. During the second
and third trimester, treatment should only be considered if the expected benefit to the mother outweighs the
risk to the fetus, until dose optimisation studies are completed.66 However, given the reassuring data on nearly
1000 pregnant women, and the fact that it is available in the UK, it can be recommended in second and third
trimesters.
Chloroquine and sulfadoxine-pyrimethamine are no longer recommended for P. falciparum treatment, owing
to resistance,1 with supporting data from poor efficacy in RCTs in pregnant women.41,43,67,68
Non-falciparum malaria
The first step in the treatment in the UK of the non-falciparum infections P. vivax, P. ovale and P. malariae (and
P. knowlesi) is chloroquine to treat the symptoms caused by blood-stage infection (see Table 1 of the main
text).1 For P. vivax and P. ovale, there is a second step: the treatment of the liver-stage hypnozoites (radical
cure), which causes relapse, sometimes years later. In nonpregnant adults, a course of primaquine is normally
prescribed.69 In the UK, more than 10% of patients with imported P. vivax treated with chloroquine followed
by unsupervised primaquine 15 mg/day for 14 days relapse70 and higher-dose primaquine 30 mg/day for 14
days has been found to be more effective.71,72 Hence, there are different dosing schedules for P. ovale and P.
vivax. Primaquine is contraindicated in pregnancy, as it could induce haemolysis and methaemo-globinaemia
in the fetus.73,74 Therefore, radical cure in pregnancy is not recommended until after delivery. There are no data
on primaquine in breast milk. Fetal red blood cells are almost entirely replaced by adult red blood cells by 6
months of life. It is advisable to wait for some replacement of fetal red blood cells with adult red blood cells,
which are less sensitive to haemolysis, before radical cure with primaquine in the mother. There are no
published data on the use of primaquine treatment in young infants, so a cut-off age cannot be recommended,
but 3 months of age is likely to be safe. To prevent relapse of P. vivax or P. ovale before delivery, weekly
chloroquine (300 mg) can be given (see Table 1 of the main report). It is safe and effective and has been
studied in a large RCT involving 1000 women. Infants were followed to 1 year of life and no adverse effects
for the mother or fetus were observed.75
Evidence from nonpregnant patients has demonstrated that chloroquine-resistant P. vivax should be treated
in the same way as chloroquine resistant P. falciparum.45,7679 However, the UK guidelines recommend
chloroquine and alternative treatment if there are persistent parasites or symptoms present. In pregnant
women, this could result in the onset of premature labour, whereas effective first-line treatment can prevent
this outcome.The combination of quinine and clindamycin is likely to have higher cure rates than chloroquine
for women with P. vivax infection and a history of travel in Indonesia or Papua New Guinea.45,78,79
Where blood or plasma concentrations of antimalarial drugs have been measured in late pregnancy, they have
usually been found to be reduced, indicating under-dosing. For artemether, dihyroartemisinin, atovaquone,
proguanil and lumefantrine, the reductions have been substantial and are likely to have contributed to poor
therapeutic responses.80,81
23 of 29
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malaria. Antimicrob Agents Chemother 2009;53:383746.
66. Novartis Pharmaceuticals UK Ltd. Riamet 20/120mg tablets.
Summary of Product Characteristics. electronic Medicines
Compendium; 2009
(http://emc.medicines.org.uk/medicine/9196/SPC/Riamet+20+
120mg+tablets/#PREGNANCY).
67. Keuter M, van Eijk A, Hoogstrate M, Raasveld M, van de Ree M,
Ngwawe WA, et al. Comparison of chloroquine, pyrimethamine
and sulfadoxine, and chlorproguanil and dapsone as treatment
for falciparum malaria in pregnant and non-pregnant women,
Kakamega District, Kenya. Br Med J 1990;301:46670.
68. Tagbor H, Bruce J, Browne E, Randal A, Greenwood B,
Chandramohan D. Efficacy, safety, and tolerability of
amodiaquine plus sulphadoxinepyrimethamine used alone or
in combination for malaria treatment in pregnancy: a
randomised trial. Lancet 2006;368:134956.
69. Arnold J, Alving AS, Hockwald RS, Clayman CB, Dern RJ, Beutler
E, et al.The effect of continuous and intermittent primaquine
therapy on the relapse rate of Chesson strain vivax malaria. J
Lab Clin Med 1954;44:42938.
70. Doherty JF, Day JH, Warhurst DC, Chiodini PL.Treatment of
Plasmodium vivax malaria: time for a change? Trans R Soc Trop
Med Hyg 1997;91:76.
71. Fryauff DJ, Baird JK, Basri H, Sumawinata I, Purnomo, Richie TL,
et al. Randomised placebo-controlled trial of primaquine for
prophylaxis of falciparum and vivax malaria. Lancet
1995;346:11903.
72. Hill DR, Baird JK, Parise ME, Lewis LS, Ryan ET, Magill AJ.
Primaquine: report from CDC expert meeting on malaria
chemoprophylaxis I. Am J Trop Med Hyg 2006;75:40215.
25 of 29

74. Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug
Saf 2004;27:2561.
75. Villegas L, McGready R, Htway M, Paw MK, Pimanpanarak M,
Arunjerdja R, et al. Chloroquine prophylaxis against vivax
malaria in pregnancy: a randomized, doubleblind, placebocontrolled trial. Trop Med Int Health 2007;12:20918.
76. Baird JK, Basri H, Purnomo, Bangs MJ, Subianto B, Patchen LC,
et al. Resistance to chloroquine by Plasmodium vivax in Irian
Jaya, Indonesia. Am J Trop Med Hyg 1991;44:54752.
77. Pukrittayakamee S, Clemens R, Chantra A, Nontprasert A,
Luknam T, Looareesuwan S, et al.Therapeutic responses to
antibacterial drugs in vivax malaria. Trans R Soc Trop Med Hyg
2001;95:5248.
78. Ratcliff A, Siswantoro H, Kenangalem E, Wuwung M, Brockman
A, Edstein MD, et al.Therapeutic response of multidrugresistant Plasmodium falciparum and P. vivax to chloroquine
and sulfadoxine-pyrimethamine in southern Papua, Indonesia.
79. Ratcliff A, Siswantoro H, Kenangalem E, Maristela R, Wuwung

RM, Laihad F, et al.Two fixed-dose artemisinin combinations for
drug-resistant falciparum and vivax malaria in Papua, Indonesia:
an open-label randomised comparison. Lancet
2007;369:75765.
80. White NJ, McGready RM, Nosten FH. New medicines for
tropical diseases in pregnancy: catch-22. PLoS Med
2008;5:e133.
81. Ward SA, Sevene EJ, Hastings IM, Nosten F, McGready R.
Antimalarial drugs and pregnancy: safety, pharmacokinetics,
and pharmacovigilance. Lancet Infect Dis 2007;7:13644.
26 of 29
APPENDIX IV: Persistence of Plasmodium falciparum in the placenta after apparently

effective quinidine-clindamycin therapy
The persistence of Plasmodium falciparum in the placenta after apparently adequate therapy with quinine
has been described.1 This phenomenon is described in the placenta of a 19-year-old woman with falciparum
malaria, who was treated with a combination of quinidine and clindamycin. Although this therapy was
effective and diminished (her peripheral blood parasitemia from 3% at presentation to almost undetectable at
the time of delivery) vast numbers of P. falciparum-infected erythrocytes were present in the maternal
sinusoids of the placenta. This sequestration of infected erythrocytes produced a local parasitaemia in the
placenta of 7080%. Additionally, rare Plasmodium-infected erythrocytes were also seen in the fetal blood of
the placenta. Malaria in pregnancy and parasitic involvement of the placenta are reviewed and it is
emphasised that Plasmodium-infected erythrocytes may persist in the placenta even after clearance of
parasites from the peripheral blood.
Reference
1.
Procop GW, Jessen R, Hyde SR, Scheck DN. Persistence of Plasmodium falciparum in the placenta after apparently effective
quinidine/clindamycin therapy. J Perinatol 2001;21:12830.
27 of 29
APPENDIX V

risk of bias
1+

low risk of bias

risk of bias

2+
3
4

case series

1++ or 1+
results; or
2++
2+
Good practice point
Expert opinion

population; or
28 of 29

development group
This Guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and
Gynaecologists by: Dr R McGready PhD Dip RANZCOG, Mae Sot, Thailand; Dr EA Ashley PhD, London; Professor F
Nosten MD PhD, Mae Sot, Thailand; Dr M Rijken MD PhD, Mae Sot, Thailand; A Dundorp MD PhD, Bangkok, Thailand.
This guideline was peer reviewed by: Dr A Diaf MRCOG, Birmingham; RCOG Consumers Forum; Mr SA Walkinshaw
MRCOG, Liverpool; Dr C Whitty FRCP, London; the Advisory Committee on Malaria Prevention in UK Travellers: Dr BA
Bannister FRCP, London; Dr D Lalloo FRCP, Liverpool; Professor P Chiodini FRCP, London.
The Guidelines Committee lead peer reviewers were: Dr ALM David MRCOG, London, and Professor F McAuliffe
FRCOG, Dublin.
DISCLAIMER
health series.
adapted for local use, these guidelines no longer represent the views of the RCOG.
29 of 29
Late Intrauterine Fetal Death and

Stillbirth
October 2010
Late Intrauterine Fetal Death and Stillbirth

1.
Purpose and scope
To identify evidence-based options for women (and their relatives) who have a late intrauterine fetal death
(IUFD: after 24 completed weeks of pregnancy) of a singleton fetus. To incorporate information on general
care before, during and after birth, and care in future pregnancies. The guidance is primarily intended for
obstetricians and midwives but might also be useful for women and their partners, general practitioners and
commissioners of healthcare.
This guideline does not include the management of multiple pregnancies with a surviving fetus, stillbirth
following late fetocide, late delivery of fetus papyraceous or the management of specific medical conditions
associated with increased risk of late IUFD. Recommendations about the psychological aspects of late IUFD
are focused on the main principles of care to provide a framework of practice for maternity clinicians. The
full psychological and social aspects of care have been reviewed by Sands (Stillbirth and neonatal death
society).1 The section on postmortem examination covers clinical aspects required for obstetricians and
midwives caring for women who have suffered a stillbirth. More detail can be found in a Joint Report by the
Royal College of Obstetricians and Gynaecologists (RCOG) and the Royal College of Pathologists.2
2.
Background
The Perinatal Mortality Surveillance Report (CEMACH)3 defined stillbirth as a baby delivered with no signs of
life known to have died after 24 completed weeks of pregnancy. Intrauterine fetal death refers to babies with
no signs of life in utero.
Stillbirth is common, with 1 in 200 babies born dead.3 This compares with one sudden infant death per 10 000
live births.3 There were 4037 stillbirths in the UK and Crown Dependencies in 2007, at a rate of 5.2 per 1000
total births.The overall adjusted stillbirth rate was 3.9 per 1000. Rates ranged from 3.1 in Northern Ireland to
4.6 in Scotland. Scotland had a significantly higher stillbirth rate than the other nations.3 Overall, over onethird of stillbirths are small-for-gestational-age fetuses with half classified as being unexplained.3,4 The 8th
Annual Report of the Confidential Enquiries into Stillbirths and Deaths in Infancy (CESDI) identified
suboptimal care as being evident in half of the pregnancies.5
The stillbirth rate has remained generally constant since 2000. It has been speculated that rising obesity rates
and average maternal age might be behind the lack of improvement;4 a systematic review identified these as
the more prevalent risk factors for stillbirth.6
In addition to any physical effects, stillbirth often has profound emotional, psychiatric and social effects on
parents, their relatives and friends.
3.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines.A search was performed in the OVID database, which included Medline, Embase, the Cochrane
Database of Systematic Reviews, the Cochrane Control Register of Controlled Trials (CENTRAL), the Database
of Abstracts of Reviews and Effects (DARE) and the ACP Journal Club.The National Guidelines Clearing House,
Sands publications, CEMACH reports, ISI Web, the Cochrane Methodology Register, the TRIP databse and EBM
Reviews including Health Technology Assessment and the NHS Economic Evaluation Database were also
2 of 33
searched. Search terms included stillbirth, intrauterine, fetal death, intrauterine, lactation suppression,
induction of labour and intrauterine fetal death,intrauterine death and intrauterine death and diagnosis.The
search was limited to 1 January 1980 to 5 June 2008 and to humans after 24 completed weeks of pregnancy.
Duplicates were removed and filtered on Reference Manager for systematic reviews, randomised controlled
trials, cohort studies, casecontrol studies and reviews. Six hundred and forty-nine manuscripts were
obtained. Further documents were obtained by the use of free text terms and hand searches.The search was
updated in June 2010 for vaginal birth after caesarean (VBAC) and induction of labour.
The levels of evidence and the grade of recommendations used in this guideline originate from the guidance
by the Scottish Intercollegiate Guidelines Network Grading Review Group,7 which incorporates formal
assessment of the methodological quality, quantity, consistency and applicability of the evidence base. For the
latter, we have used studies that report findings relevant to either stillbirths or deaths in utero. Findings of
other studies have been extrapolated only after consideration of applicability.
4.
Diagnosis
4.1 What is the optimal method for diagnosing late IUFD?

Auscultation and cardiotocography should not be used to investigate suspected IUFD.
Real-time ultrasonography is essential for the accurate diagnosis of IUFD.
Ideally, real-time ultrasonography should be available at all times.
A second opinion should be obtained whenever practically possible.
Mothers should be prepared for the possibility of passive fetal movement. If the mother reports passive
fetal movement after the scan to diagnose IUFD, a repeat scan should be offered.
Auscultation of the fetal heart by Pinard stethoscope or Doppler ultrasound is insufficiently

accurate for diagnosis. In a series of 70 late pregnancies in which fetal heart sounds were inaudible
on auscultation, 22 were found to have viable fetuses.7
Evidence
level 2+
Auscultation can also give false reassurance; maternal pelvic blood flow can result in an apparently normal
fetal heart rate pattern with external Doppler.
Real-time ultrasound allows direct visualisation of the fetal heart. Imaging can be technically difficult,
particularly in the presence of maternal obesity, abdominal scars and oligohydramnios, but views can often be
augmented with colour Doppler of the fetal heart and umbilical cord.
In addition to the absence of fetal cardiac activity, other secondary features might be seen: collapse
of the fetal skull with overlapping bones,8 hydrops, or maceration resulting in unrecognisable fetal
mass. Intrafetal gas (within the heart, blood vessels and joints) is another feature associated with
IUFD that might limit the quality of real-time images.9,10
Evidence
level 3
The ultrasound findings of severe maceration and gross skin oedema can be discussed with the parents.
Although evidence of occult placental abruption might also be identified, the sensitivity can be as
low as 15%. Even large abruptions can be missed.10
Evidence
level 3
After the diagnosis of late IUFD, mothers sometimes continue to experience (passive) fetal movement.
3 of 33
4.2 What is the best practice for discussing the diagnosis and subsequent care?
If the woman is unaccompanied, an immediate offer should be made to call her partner, relatives or
friends.
Discussions should aim to support maternal/parental choice.
Parents should be offered written information to supplement discussions.
Many strategies have been described for discussing bad news. Late IUFD poses particular difficulties
as it is often sudden and unexpected. A crucial component is to determine the emotional feelings
and needs of the mother and her companions.11 This empathetic approach seeks to identify and
understand womens thoughts and wishes but without trying to shape them.Women with an IUFD
and their partners value acceptance and recognition of their emotions highly.12
Evidence
level 3
Empathetic techniques, which can enhance recovery, can be learned and retained as a skill.13
Evidence
level 4
Pregnancy loss can quickly result in vulnerability; imposing care can worsen the psychological
impact.14
Evidence
level 2++
A study of 808 families who had suffered an IUFD found that decisions about care varied widely
from individual to individual.15
Evidence
level 3
The developers concluded that carers should neither persuade parents nor make assumptions
that would limit parental choice. Initial discussions can be used to emphasise choice in decision
making.16
Evidence
level 2
Continuity of caregiver and supplementary written information are valued by pregnant women
with adverse events.17
Evidence
level 3
5. Investigation of the cause of late IUFD
5.1 What are the general principles of investigation?

Clinical assessment and laboratory tests should be recommended to assess maternal wellbeing
(including coagulopathy) and to determine the cause of death, the chance of recurrence and possible
means of avoiding further pregnancy complications.
Parents should be advised that no specific cause is found in almost half of stillbirths.
Parents should be advised that when a cause is found it can crucially influence care in a future
pregnancy.
Carers should be aware that an abnormal test result is not necessarily related to the IUFD; correlation
between blood tests and postmortem examination should be sought. Further tests might be indicated
following the results of the postmortem examination.
Systems that use customised weight charts and capture multiple contributing factors should be used to
categorise late IUFDs.
Tests aim to identify the cause of late IUFD and so provide the answer to the parents question why?
In a study of 314 women, 95% stated that it was important emotionally to have an explanation of
their babys death.18
4 of 33
Evidence
level 2+
Another important purpose of investigation is to assess maternal wellbeing and ensure prompt
management of any potentially life-threatening maternal disease.This includes a detailed history of
events during pregnancy and clinical examination for pre-eclampsia, chorioamnionitis and
placental abruption. There is also a moderate risk of maternal disseminated intravascular
coagulation (DIC): 10% within 4 weeks after the date of late IUFD, rising to 30% thereafter.This can
be tested for by clotting studies, blood platelet count and fibrinogen measurement.19
Evidence
level 3
Tests should be repeated twice weekly in women who choose expectant management.
Evidence
level 4
It is important to recognise that there is a distinction between the underlying cause of the death
(the disease process), the mode of death (for example asphyxia) and the classification of the death
(for example growth restriction). Conventional diagnostic systems fail to identify a specific cause
in about half of IUFDs.3 The proportion of unclassified late IUFDs can be significantly reduced with
systems that use customised weight-for-gestational-age charts,20 such as the relevant condition at
death (ReCoDe) system,21 or systems that capture multiple and/or sequential contributing factors,
such as Tulip, Perinatal Society of Australia and New Zealand Perinatal Death Classification
(PSANZ-PDC) or Causes Of Death and Associated Conditions (CODAC).22
Evidence
level 2++
Further research is required to determine the optimal classification method and tools.
An abnormal result might not be linked to the IUFD but rather be simply an incidental finding; for example,
factor V Leiden is present in about 5% of the general population and will often be an incidental finding.23
Comprehensive investigation can be important even though one cause is particularly suspected. With a very
obvious cause such as massive abruption, nonlethal fetal malformations might be identified at postmortem
that would only have been revealed had the baby lived.
5.2 Are there any special recommendations for women with an IUFD who are rhesus D-negative?
Women who are rhesus D (RhD)-negative should be advised to have a Kleihauer test undertaken
urgently to detect large fetomaternal haemorrhage (FMH) that might have occurred a few days earlier.
Anti-RhD gammaglobulin should be administered as soon as possible after presentation.
If there has been a large FMH, the dose of anti-RhD gammaglobulin should be adjusted upwards and
the Kleihauer test should be repeated at 48 hours to ensure the fetal red cells have cleared.
If it is important to know the babys blood group; if no blood sample can be obtained from the baby or
cord, RhD typing should be undertaken using free fetal DNA (ffDNA) from maternal blood taken shortly
after birth.
Major FMH is a silent cause of IUFD and a Kleihauer test is recommended for all women to diagnose
the cause of death (Table 1). In those women who are RhD-negative, the potentially sensitising
bleed might have occurred days before the death is recognised, threatening the window for optimal
timing of anti-RhD gammaglobulin administration (72 hours).24 Anti-RhD gammaglobulin provides
reduced benefit when given beyond 72 hours, up to 10 days after the sensitising event.2527
Evidence
level 2+
Persistent positivity of the Kleihauer is often because the babys group is also RhD-negative, but
might occur with very large RhD-positive FMHs. If it is important to distinguish between the two,
the babys blood group can be typed using conventional serology on cord blood.Typing with ffDNA
from maternal blood is also available. In one series of 226 pregnancies with an informative result,
fetal RhD status was correctly predicted in 223 women whose babies had not received intrauterine
transfusions.28
Evidence
level 3
extrapolated
5 of 33
In a series of 14 women with pre-eclampsia, one woman with an IUFD had significantly higher levels of ffDNA
compared with women with live fetuses.29
5.3 What tests should be recommended to identify the cause of late IUFD?
Tests should be directed to identify scientifically proven causes of late IUFD.
Commonly associated antepartum conditions include congenital malformation, congenital fetal

infection, antepartum haemorrhage, pre-eclampsia and maternal disease such as diabetes mellitus.3,4
The common causes of intrapartum death include placental abruption, maternal and fetal infection,
cord prolapse, idiopathic hypoxiaacidosis and uterine rupture.3,4
A
Evidence
level 3
Transplacental infections associated with IUFD include cytomegalovirus30 (Evidence level 2+), syphilis3134
(Evidence level 1+) and parvovirus B1934,35 (Evidence level 2++) as well as listeria36,37 (Evidence level 2+),
rubella38 (Evidence level 3), toxoplasmosis33,34 (Evidence level 2+), herpes simplex30 (Evidence level 2+),
coxsackievirus, leptospira, Q fever, and Lyme disease.39 Malaria parasitaemia has also been associated with
stillbirth (OR 2.3, 95% CI 1.34.1)40 (Evidence level 2++).
Ascending infection, with or without membrane rupture, with Escherichia coli, Klebsiella, Group B
Streptococcus, Enterococcus, mycoplasma/ureaplasma, Haemophilus influenzae and Chlamydia
are the more common infectious causes in developed countries.3234,41
Evidence
level 2+
Other infections are either historical causes or common only in developing countries.39
Evidence
level 1++
Table 14276 summarises the diagnostic tests available, their indications and value and the evidence to support
their use.
Table 1. Tests recommended for women with a late IUFD

Test
Reason(s) for test
Maternal standard
haematology and
biochemistry including
CRPs and bile salt
Pre-eclampsia and its

complications
Evidence level Reference(s)
Additional comments
3, 19, 42
Platelet count to test for occult DIC

(repeat twice weekly)
19
Not a test for cause of late IUFD
Multi-organ failure in sepsis

or haemorrhage
Obstetric cholestasis
Maternal coagulation times

and plasma fibrinogen
DIC
Maternal sepsis, placental abruption

and pre-eclampsia increase the
probability of DIC
Especially important if woman desires
regional anaesthesia
Kleihauer
Lethal fetomaternal
haemorrhage
To decide level of requirement

for anti- RhD gammaglobulin
25, 43
Fetomaternal haemorrhage is a cause of

IUFD43
Kleihauer should be recommended for all
women, not simply those who are
RhD-negative (ensure laboratory aware if
a woman is RhD-positive)
Tests should be undertaken before birth
as red cells might clear quickly from
maternal circulation
In RhD-negative women, a second
Kleihauer test also determines whether
sufficient anti-RhD has been given
6 of 33
Table 1 (continued). Tests recommended for women with a late IUFD

Test
Reason(s) for test
Maternal bacteriology:
blood cultures
midstream urine
vaginal swabs
cervical swabs
Suspected maternal bacterial

infection including Listeria
monocytogenes and
Chlamydia spp.

1++
3234, 39
41, 44, 45
Additional comments
Indicated in the presence of:
maternal fever
flu-like symptoms
abnormal liquor
(purulent appearance/offensive odour)
prolonged ruptured membranes before
late IUFD
Abnormal bacteriology is of doubtful

significance in the absence of clinical or
histological evidence of chorioamnionitis46
(Evidence level 3)
In one study, amniotic fluid culture was
positive in only 1 of 44 women with IUFD
despite evidence of chorioamnionitis in a
further 9 women47 (Evidence level 3)
Also used to direct maternal antibiotic therapy
Maternal serology:
viral screen
syphilis
tropical infections
Occult maternalfetal
infection
2+
30, 3235,
48
Stored serum from booking tests can

provide baseline serology
Parvovirus B19, rubella (if nonimmune at
booking), CMV, herpes simplex and
Toxoplasma gondii (routinely)
Hydrops not necessarily a feature of
parvovirus-related late IUFD
Treponemal serology usually known already
Others if presentation suggestive,
e.g. travel to endemic areas
Maternal random blood

glucose
Occult maternal diabetes mellitus
49, 50
Rarely a woman will have incidental

type 1 diabetes mellitus, usually with severe
ketosis
Women with gestational diabetes mellitus
return to normal glucose tolerance within a
few hours after late IUFD has occurred
Maternal HbA1c
Gestational diabetes
mellitus
2+
3, 4, 5153
Most women with gestational diabetes

mellitus have a normal HbA1c
Need to test for gestational diabetes mellitus
in future pregnancy
Might also indicate occult type 1 and type 2
diabetes
Maternal thyroid function
Occult maternal
thyroid disease
Maternal thrombophilia
screen
Maternal thrombophilia
54, 55
TSH, FT4 and FT3
1++
5658
Indicated if evidence of fetal growth

restriction or placental disease
The association between inherited thrombophilias and IUFD is weak, and management in
future pregnancy is uncertain56,58
Most tests are not affected by pregnancy
if abnormal, repeat at 6 weeks
Antiphospholipid screen repeated if
abnormal
Anti-red cell antibody

serology
Immune haemolytic disease
5962
Indicated if fetal hydrops evident

clinically or on postmortem
Maternal anti-Ro and

anti-La antibodies
Occult maternal autoimmune

disease
63
Indicated if evidence of hydrops,

endomyocardial fibro-elastosis or
AV node calcification at postmortem
Maternal alloimmune
antiplatelet antibodies
Alloimmune thrombocytopenia
64
Indicated if fetal intracranial

haemorrhage found on postmortem
7 of 33
Table 1 (continued). Tests recommended for women with a late IUFD

Test
Reason(s) for test
Parental bloods for karyotype Parental balanced translocation

Parental mosaicism
6567
Additional comments
Indicated if:
fetal unbalanced translocation
other fetal aneuploidy, e.g. 45X
(Turner syndrome)
fetal genetic testing fails and history
suggestive of aneuploidy (fetal abnormality
on postmorterm, previous unexplained
IUFD,
recurrent miscarriage)
Maternal urine for cocaine

metabolites
Occult drug use
1++
68
With consent, if history and/or

presentation are suggestive
Fetal and placental:

microbiology
fetal blood
fetal swabs
placental swabs
Fetal infections
2+
3
33, 34, 69
More informative than maternal

serology for detecting viral infections
Cord or cardiac blood (if possible)
in lithium heparin
Written consent advisable for cardiac
bloods
Need to be obtained using clean
technique
Fetal and placental tissues

for karyotype (and possible
single-gene testing):
deep fetal skin
fetal cartilage
placenta
Aneuploidy
2+
7074
Absolutely contraindicated if parents

do not wish (written consent essential)
Single gene disorders
Send several specimens cell cultures

might fail
See section 5.4 on sexing
Culture bottles must be kept on labour

ward in a refrigerator stored
separately from formalin preservation
bottles
Genetic material should be stored if a
single-gene syndrome is suspected
Postmortem examination:
external
autopsy
microscopy
X-ray
placenta and cord
See section 5.6
3, 4, 75, 76
Absolutely contraindicated if parents

do not wish (written consent essential)
External examination should include
weight and length measurement
IUGR is a significant association for
late IUFD
Some tests should be taken before birth. Tests below the bold line are fetal. Shaded tests are selective.
AV = atrioventricular; CMV = cytomegalovirus; CRP = C-reactive protein; DIC = disseminated intravascular coagulation;
FT3 = free triiodothyronine; FT4 = free thyroxin index; HbA1c = glycated haemoglobin; IUFD = intrauterine fetal death;
IUGR = intrauterine growth restriction; RhD = rhesus D; TSH = thyroid-stimulating hormone
5.4 What precautions should be taken when sexing the baby?

Parents can be advised before birth about the potential difficulty in sexing the baby, when appropriate.
Two experienced healthcare practitioners (midwives, obstetricians, neonatologists or pathologists)
should inspect the baby when examining the external genitalia of extremely preterm, severely
macerated or grossly hydropic infants.
If there is any difficulty or doubt, rapid karyotyping should be offered using quantitative fluorescent
polymerase chain reaction (QF-PCR) or fluorescence in situ hybridisation (FISH).
Females can be mistaken for males, and vice versa. Errors in fetal sexing can result in severe
emotional harm for parents. Some practitioners who have incorrectly determined the sex on external
inspection probably had no doubt at the time. Extreme prematurity, maceration and hydrops can all
make the diagnosis difficult. If the sex cannot be determined clinically or if there is any difficulty or
8 of 33
P
P
B
Evidence
level 3
doubt, the genetic sex can be tested rapidly on skin (or placental) tissue, even of macerated babies.77
Evidence
level 3
QF-PCR with additional Y chromosome markers can provide a highly accurate result within two
working days in more than 99.9% of samples.78 Sexing can also be performed rapidly and reliably
by FISH. If these techniques fail, sex can be determined on cell culture or at postmortem, but these
methods can take longer.
Evidence
level 2++
extrapolated from
prenatal and
level 2++
If the genital sex is not clear and the parents do not wish for postmortem testing in any form, they might wish
to judge the sex themselves for registration purposes, perhaps based on an earlier scan, or ask the midwife or
doctor to make a judgement. Other parents might choose not to sex the baby and give a neutral name.
Stillborn babies can be registered as having indeterminate sex (see section 8.4).
5.5 What is best practice guidance for cytogenetic analysis of the baby?
Written consent should be taken for any fetal samples used for karyotyping.
Samples from multiple tissues should be used to increase the chance of culture.
More than one cytogenetic technique should be available to maximise the chance of informative results.
Culture fluid should be stored in a refrigerator and thawed thoroughly before use.
Karyotyping is important as about 6% of stillborn babies will have a chromosomal abnormality.8082
Evidence
level 3
Some abnormalities are potentially recurrent and can be tested for in future pregnancies. Culture
potentially provides the greatest range of genetic information (trisomies, monosomies, translocations, major deletions and marker chromosomes). Microdeletions have to be requested specifically,
usually according to the result of any postmortem examination. If all cultures fail, QF-PCR can be
performed on extracted DNA.83,84
Evidence
level 2+
extrapolated
Many laboratories are moving towards DNA-based methods for routine chromosome analysis,
avoiding the need for cell culture. It is a reliable (<0.01% failure rate), efficient and cheap technique
for detecting common aneuploidies.78 It provides slightly less detailed limited genetic information
and is unreliable for the detection of translocations and marker chromosomes.
Evidence
level 2++
extrapolated
A range of tissue types can be used (see below), but all cell cultures can fail.71,85
Contamination with bacteria is an avoidable reason for failure to obtain results.78
Evidence level 3
Evidence level 2++

extrapolated
Culture fluid containing antibiotics can reduce this risk. Perinatal specimens suitable for
karyotyping include skin, cartilage and placenta. Skin specimens are associated with a higher rate
of culture failure (~60%), twice that of other tissues, including placenta. Placenta usually has the
advantages of being the most viable tissue and of more rapid cell culture, but the disadvantages of
maternal contamination and placental pseudomosaicism.86 The next best is cartilage, e.g. patella, but
cartilage is harder to sample.87 Amniocentesis can also provide cytogenetic results if the mother
chooses expectant management,1,71,73,74 but patient acceptability and safety (infection) of amniocentesis has not been investigated in this setting.
Evidence
level 3
Placental biopsy (approximately 1 cm diameter) should be taken from the fetal surface close to the cord
insertion (to avoid tissue of maternal origin2). Skin biopsy should be deep to include underlying muscle2
(about 1 cm in length from the upper fleshy part of the thigh). The skin can be closed with wound adhesive
strips and tissue adhesives, but this is less successful when the baby is severely macerated.
9 of 33
5.6 What is the guidance on perinatal postmortem examination for maternity clinicians?
Parents should be offered full postmortem examination to help explain the cause of an IUFD.
Parents should be advised that postmortem examination provides more information than other (less
invasive) tests and this can sometimes be crucial to the management of future pregnancy.
Attempts to persuade parents to choose postmortem must be avoided; individual, cultural and religious
beliefs must be respected.
Written consent must be obtained for any invasive procedure on the baby including tissues taken for
genetic analysis. Consent should be sought or directly supervised by an obstetrician or midwife trained
in special consent issues and the nature of perinatal postmortem, including retention of any tissues for
clinical investigation, research and teaching.
Parents should be offered a description of what happens during the procedure and the likely
appearance of the baby afterwards. This should include information on how the baby is treated with
dignity and any arrangements for transport. Discussions should be supplemented by the offer of a
leaflet.
Postmortem examination should include external examination with birth weight, histology of relevant
tissues and skeletal X-rays.
Pathological examination of the cord, membranes and placenta should be recommended whether or not
postmortem examination of the baby is requested.
The examination should be undertaken by a specialist perinatal pathologist.
Parents who decline full postmortem might be offered a limited examination (sparing certain organs),
but this is not straightforward and should be discussed with a perinatal pathologist before being
offered.
Less invasive methods such as needle biopsies can be offered, but these are much less informative and
reliable than conventional postmortem.
Ultrasound and magnetic resonance imaging (MRI) should not yet be offered as a substitute for
conventional postmortem.
MRI can be a useful adjunct to conventional postmortem.
It is essential to offer conventional postmortem examination to all parents but in a way that allows
free choice; it is now agreed that the quality of the consent process is paramount and not the rate
of uptake.2
The 8th CESDI report recommended that all practitioners who discuss postmortems with parents
have a responsibility to understand the process so that consent is fully informed. It was also
recommended that the consent form should include sections on the purpose of the postmortem;
the extent of the examination; possible organ/tissue retention and purpose; what should happen to
tissues/organ after postmorten; and research and education.5
10 of 33
Evidence
level 4
Postmortem examination of the baby and placenta has the highest diagnostic yield of all investigations.69 Postmortem examination might reveal the cause(s) and time of death, inform discussions
of relevance to the risk of recurrence and provide information for any medico-legal proceedings.8082
A study of 1477 stillbirths demonstrated that autopsy alone provided a classification of death in
45.9% of cases. When combined with other diagnostic tests, it offered information relevant to
recurrence risk in 40.1% of cases and to management of next pregnancy in 51%. Important information that affected management of next pregnancy was elicited in 10% of stillborn infants with
no recognisable cause of death from other clinical or laboratory investigations.88 In an analysis of
168 perinatal deaths, an autopsy was not requested in 26.2% and was uninformative in 24.2%. Of
the 94 examinations that provided a conclusive autopsy, in 55.3% the pathological diagnosis
confirmed the clinical diagnosis, but in 44.7% the findings changed or significantly added to it.89
Evidence
level 3
Postmortem may also identify coincidental structural anomalies.About one-tenth of stillborn babies
have congenital malformations, some of which are not related to the cause of death but can help
plan future care.3,4
There are published standards for the conduct of perinatal autopsies. Autopsies must include
external examination and measurement of the baby.2
Evidence
level 4
Independently of full autopsy, placental pathology is useful and should be offered even if a postmortem examination of the baby is declined. A retrospective review of 120 autopsy reports of
stillborn babies and placentas showed that in 88% a major contributor to death was found in the
placentas.76
Evidence
level 3
More restricted conventional postmortem examinations can be undertaken, but these are of very
limited value unless there is a specific question about the organs the parents will allow to be
examined. Limited postmortems are technically difficult and run the risk that the pathologist can
inadvertently fail to comply with parents wishes. For example, if permission to examine the heart
is given, the parents have to be aware that in order to do this not only the heart but also the thymus
and lungs need to be removed from the babys body.
Evidence
level 4
Medical imaging can act as an adjunct to full postmortem, particularly of the brain and spinal cord.
In one series, 100 stillborn babies underwent a postmortem MRI, limited to the brain and spinal
cord. In 54, there was a complete agreement between the MRI and autopsy findings. In 24, the MRI
added valuable information to the autopsy, but if MRI had been the only investigation, essential
information would have been lost in 17% of the perinatal deaths.90
Evidence
level 2+
X-rays can show skeletal defects that are difficult to identify or categorise on dissection.91
Evidence
level 3
Some parents are less uncomfortable with the notion of noninvasive or minimally invasive testing.
Clinically useful information might be obtained from less invasive methods including
transcutaneous tissue biopsy, body-cavity aspiration and medical imaging, particularly whole-body
X-ray.2 Currently, these techniques, alone or in combination, are of limited availability, and are
significantly less informative than conventional postmortem.2
Evidence
level 4
MRI is currently being evaluated (MaRIAS trial) but is not yet suitable for clinical service. Ultrasound
has been used to visualise fetal brain, cardiac, lung and renal development when consent to autopsy
has been withheld, but the use of ultrasound in such a context has not been subject to rigorous
evaluation.92
Evidence
level 3
11 of 33
6.
Labour and birth
6.1 What are the recommendations for timing and mode of birth?
Recommendations about labour and birth should take into account the mothers preferences as well as
her medical condition and previous intrapartum history.
Women should be strongly advised to take immediate steps towards delivery if there is sepsis, preeclampsia, placental abruption or membrane rupture, but a more flexible approach can be discussed if
these factors are not present.
Well women with intact membranes and no laboratory evidence of DIC should be advised that they are
unlikely to come to physical harm if they delay labour for a short period, but they may develop severe
medical complications and suffer greater anxiety with prolonged intervals. Women who delay labour for
periods longer than 48 hours should be advised to have testing for DIC twice weekly (Table 1).
If a woman returns home before labour, she should be given a 24-hour contact number for information
and support.
Women contemplating prolonged expectant management should be advised that the value of
postmortem may be reduced.
Women contemplating prolonged expectant management should be advised that the appearance of the
baby may deteriorate.
Vaginal birth is the recommended mode of delivery for most women, but caesarean birth will need to be
considered with some.
More than 85% of women with an IUFD labour spontaneously within three weeks of diagnosis.93,94 If
the woman is physically well, her membranes are intact and there is no evidence of pre-eclampsia,
infection or bleeding, the risk of expectant management for 48 hours is low.9396 There is a 10% chance
of maternal DIC within 4 weeks from the date of fetal death and an increasing chance thereafter.19
Evidence
level 3
A Swedish study of 380 women with stillbirth and 379 controls with a live healthy child showed that
an interval of 24 hours or more from the diagnosis of death in utero to the start of labour was
associated with an increased risk of moderately severe anxiety or worse (OR 4.8, 95% CI 1.515.9).97
Vaginal birth can be achieved within 24 hours of induction of labour for IUFD in about 90% of
women.98 Vaginal birth carries the potential advantages of immediate recovery and quicker return
to home. Caesarean birth might occasionally be clinically indicated by virtue of maternal condition.
The woman herself might request caesarean section because of previous experiences or a wish to
avoid vaginal birth of a dead baby. Vaginal birth was described as emotionally distressing by 47% of
314 women with an intrauterine death compared with just 7% of 322 matched controls.18
Evidence
level 2+
This demands a careful and sensitive discussion and joint decision making. The implications of caesarean
delivery for future childbearing should be discussed.99
6.2 How should labour be induced for a woman with an unscarred uterus?
A combination of mifepristone and a prostaglandin preparation should usually be recommended as the
first-line intervention for induction of labour.
12 of 33
Misoprostol can be used in preference to prostaglandin E2 because of equivalent safety and efficacy
with lower cost but at doses lower than those currently marketed in the UK.
Women should be advised that vaginal misoprostol is as effective as oral therapy but associated with
fewer adverse effects.
In a study of a case series of 96 women with a late IUFD, the combination of mifepristone and
misoprostol gave an average duration of labour of 8 hours. The addition of mifepristone appeared
to reduce the time interval by about 7 hours compared with published regimens not including
mifepristone, but there was no other apparent benefit.98
Evidence
level 3
A single 200 mg dose of mifepristone is appropriate for this indication.

A randomised controlled trial comparing intravenous oxytocin alone with intravaginal misoprostol
(a prostaglandin E1 analogue) for induction of labour in women with an IUFD showed that
misoprostol was more effective.100
Evidence
level 1+
Two randomised controlled trials comparing prostaglandin E2 with low-dose misoprostol for
women with a live fetus found misoprostol to be efficacious in cervical ripening and labour
induction. The studies demonstrated a similar maternal safety profile for both groups.101,102
Evidence
level 1+
extrapolated
For third- (and second-) trimester IUFD, a systematic review found that vaginal misoprostol for
induction of labour appears equally effective as gemeprost but is much cheaper.103
Evidence
level 1+
The average cost per treatment is also much lower for misoprostol than for prostaglandin E2.
Evidence
level 1+
extrapolated
The use of misoprostol for induction of labour in women with IUFD has been endorsed by NICE.94
NICE recommended that the choice and dose of vaginal prostaglandins should take into account
the clinical circumstances, availability of preparations and local protocols. A review of misoprostol
use for late IUFD recommended that the dose should be adjusted according to gestational age
(100 micrograms 6-hourly before 26+6 weeks, 2550 micrograms 4-hourly at 27+0 weeks or more,
up to 24 hours).105
Evidence
level 3
102,104
Misoprostol use in pregnancy is off-label in the UK,106 and the doses used in these studies are not currently
marketed in Britain. Two phase III trials have recently been completed for lower-dose formulations for
induction of labour.101,102 The current 200 microgram tablet can be divided in half by pharmacists or dissolved
in water and administered as measured aliquots.107
Two randomised controlled trials compared oral and vaginal misoprostol. In the first, the mean
induction to birth interval was shorter with vaginal use by 7.9 hours (P<0.05) and there was a
reduced need for oxytocin augmentation.108 In the other, there was no difference in mean induction
to birth interval for gestations of more than 28 weeks.109 In both studies the systemic adverse effects
(diarrhoea, vomiting, shivering and pyrexia) were more common with oral misoprostol.
Evidence
level 1+
6.3 What is best practice for induction of labour for a woman with a history of lower segment caesarean
section (LSCS)?
A discussion of the safety and benefits of induction of labour should be undertaken by a consultant
obstetrician.
Mifepristone can be used alone to increase the chance of labour significantly within 72 hours (avoiding
the use of prostaglandin).
13 of 33
Mechanical methods for induction of labour in women with an IUFD should be used only in the context
of a clinical trial.
Women with a single lower segment scar should be advised that, in general, induction of labour with
prostaglandin is safe but not without risk.
Misoprostol can be safely used for induction of labour in women with a single previous LSCS and an
IUFD but with lower doses than those marketed in the UK.
Women with two previous LSCS should be advised that in general the absolute risk of induction of
labour with prostaglandin is only a little higher than for women with a single previous LSCS.
Women with more than two LSCS deliveries or atypical scars should be advised that the safety of
induction of labour is unknown.
A randomised controlled trial of oral mifepristone alone (200 mg three times a day for 2 days) was
compared with placebo in women with an IUFD. Labour occurred within 72 hours in significantly
more women in the mifepristone group (63% versus 17%, P<0.001).110
Evidence
level 1+
Use of mifepristone in this context is off-label.106 Mifepristone 600 mg once daily for 2 days can also
be used.106
Evidence
level 4
A transcervical balloon catheter technique was used to induce labour for a small series of 37 women
with a live fetus and an unfavourable cervix who had previously undergone a caesarean section.
There were no complications and 79% achieved vaginal birth.111
Evidence
level 3
In another large retrospective study of women with one previous caesarean section, induction
of labour with mechanical methods resulted in uterine rupture rates (5 in 862, 0.58%) that were
significantly lower than with prostaglandins (18 in 1130, 1.59%) and similar to spontaneous labour
(51 in 9239, 0.55%).112
Evidence
level 2+
Mechanical methods of induction might increase the risk of ascending infection in the presence
of IUFD.113
Evidence
level 1++
No studies were found on the safety and effectiveness of induction of labour after IUFD in women
with a single caesarean section scar. In general maternity care, the RCOG Green-top Guideline on
VBAC recommends that women should be informed that there is a higher risk of uterine rupture
with induction of labour with prostaglandins.114 The more frequent serious risks of induction of
labour with VBAC relate to the fetus, however. In the National Institute of Child Health (NICH)
study of 17 898 women with a live fetus undergoing VBAC, the maternal morbidity associated with
VBAC (including induced and augmented labours) was a higher risk of endometritis (OR 1.62,
CI 1.401.87), blood transfusion (OR 1.71, CI 1.412.08) and scar dehiscence/rupture (0.7%).
There was no evidence of an increased rate of hysterectomy or maternal death. Of a subset of
4708 women who had had labour induced, 48 had scar problems (1%).115
Evidence
level 2++
The Society of Obstetricians and Gynaecologists of Canada recommended that misoprostol

is contraindicated in women with previous caesarean delivery because of a high rate of
uterine rupture.116 A more recent narrative review of induction of labour for late IUFD
concluded that misoprostol can be used safely at lower doses for women with a previous
caesarean (2550 micrograms).105
Evidence
level 4
14 of 33
Misoprostol is off-label for this indication, however, and is not currently marketed in the UK at the doses
recommended.These lower doses can be prepared in-house by dissolving a 200 microgram tablet in water.107
No studies were found on the safety of induction of labour in women with two caesarean births
and IUFD.A retrospective cohort database study of 3970 women with a live fetus and two previous
LSCS compared outcome with those for 20 175 women who had undergone a single procedure.
Thirty percent of labours were induced in both groups.The chance of successful vaginal birth was
almost identical (~75%). The chance of major maternal morbidity, including rupture, was higher in
the multiple LSCS group, but the absolute risk remained low: 3.23% overall (rupture 1.8%) versus
2.12% overall (rupture 0.9%, adjusted OR 1.61, 95% CI 1.112.33).117
Evidence
level 2++
Another retrospective multicentre study of 975 women with two previous LSCS and 16 915 with
one LSCS reported similar results: uterine rupture rates of 0.9% versus 0.7% (P=0.37), hysterectomy
0.6% versus 0.2% (P=0.23) and transfusion 3.2% versus 1.6% (P<0.001). Induction of labour (all
types combined) was a significant risk factor for rupture (1% rate for induction versus 0.70.9%
overall; OR 1.78, 95% CI 1.242.56 in univariate analysis; OR 2.712.8, 95% CI 1.565.22 in
multivariate models).118
No studies were found into the safety of induction of labour in women with three or more
caesarean sections and IUFD.VBAC is not ordinarily recommended for women with three previous
caesarean sections, previous uterine rupture or upper segment incisions.114
Evidence
level 4
In a prospective study of 89 women who attempted VBAC after three or more caesareans, including
29 inductions of labour, there were no cases of uterine rupture or of major maternal morbidity, but
the upper 95% confidence interval for zero incidence extends to 4% (calculated by guideline
developers).119
Evidence
level 2+
No data were found on the maternal safety of VBAC with an IUFD in the presence of atypical uterine scars.
6.4 What are considered suitable facilities for labour?

Women should be advised to labour in an environment that provides appropriate facilities for
emergency care according to their individual circumstances.
Maternity units should aim to develop a special labour ward room for well women with an otherwise
uncomplicated IUFD that pays special heed to emotional and practical needs without compromising
safety. This can include a double bed for her partner or other companion to share, away from the sounds
of other women and babies.
Care in labour should given by an experienced midwife.
The physical priorities of women with an IUFD vary greatly according to their individual clinical findings.
6.5 What are the recommendations for intrapartum antimicrobial therapy?

Women with sepsis should be treated with intravenous broad-spectrum antibiotic therapy (including
antichlamydial agents).
Routine antibiotic prophylaxis should not be used.
Intrapartum antibiotic prophylaxis for women colonised with group B streptococcus is not indicated.
15 of 33
Infection is a common association of late IUFD and the mother can develop severe sepsis from a
wide range of bacteria, including severe systemic chlamydial infection.120 Regardless of the primary
cause of death, the fetus can act as a focus for severe secondary sepsis, including gas-forming
clostridial species, which can result in severe DIC.121,122 In one study, 3.1% of women with an IUFD
developed signs of sepsis during induction of labour.98
Evidence
level 3
It has been suggested that artificial rupture of membranes may facilitate ascending infection, but no
studies were found on this aspect of care. It should be remembered that prostaglandins, given to
induce labour, are associated with pyrexia.123
Evidence
level 1+
No studies were found on routine intrapartum antibiotic prophylaxis in this specific circumstance.
No studies were found on the use of antibiotics for the prevention of maternal infection in women
with a late IUFD. Intrapartum antibiotic prophylaxis for carriers of group B streptococcus is primarily
intended to reduce the risk of neonatal infection.A large prospective study of group B streptococcus
carriers in the USA showed that 2.0% of women developed postpartum endometritis.124
Evidence
level 3
6.6 Are there any special recommendations for pain relief in labour?
Diamorphine should be used in preference to pethidine.
Regional anaesthesia should be available for women with an IUFD.
Assessment for DIC and sepsis should be undertaken before administering regional anaesthesia.
Women should be offered an opportunity to meet with an obstetric anaesthetist.
Analgesia is particularly important for women with an IUFD. A study of 314 women with an IUFD
and 322 with a live fetus revealed that labour and delivery were assessed as physically insufferably
hard by 17% of the affected women compared with 10% of controls.Analgesia was more frequently
used during labour for stillbirth.18
Evidence
level 2+
All usual modalities should be available including regional anaesthesia and patient-controlled anaesthesia. Diamorphine and morphine have greater analgesic qualities and longer duration of action
than pethidine.They were rated more highly by labouring women in the National Birthday Study.125
DIC increases the chance of subdural and epidural haematomata with regional anaesthesia.126,127
Evidence
level 3
Maternal sepsis can result in epidural abscess formation.
6.7 What are the recommendations for women labouring with a scarred uterus?
Women undergoing VBAC should be closely monitored for features of scar rupture.
Oxytocin augmentation can be used for VBAC, but the decision should be made by a consultant
obstetrician.
Fetal heart rate abnormality, usually the most common early sign of scar dehiscence, does not apply
in this circumstance. Other clinical features include maternal tachycardia, atypical pain, vaginal
bleeding, haematuria on catheter specimen and maternal collapse.114
Evidence
level 4
No studies were found into the safety and effectiveness of oxytocin augmentation in VBAC with
IUFD. Women with previous caesarean section and a live fetus who need augmentation of labour
have a 73.9% of achieving vaginal delivery.128
Evidence
level 2++
16 of 33
The RCOG Green-top Guideline on VBAC recommends that the decision to augment with oxytocin
should be discussed with a consultant.114
7.
Evidence
level 4
Puerperium
7.1 Where should women receive care before returning home?

Women should be cared for in an environment that provides adequate safety according to individual
clinical circumstance.
Women with no critical care needs should ideally be able to choose between facilities which provide
adequate privacy.
Some women have acute medical problems after birth, e.g. sepsis, pre-eclampsia, etc., with continuing critical
care needs. Women without acute medical issues who do not want to return home immediately might wish
to receive care within the hospital but away from the maternity unit if such a facility is available.
7.2 What are the criteria for thromboprophylaxis?

Women should be routinely assessed for thromboprophylaxis, but IUFD is not a risk factor.
Heparin thromboprophylaxis should be discussed with a haematologist if the woman has DIC.
Established guidelines should be followed for thromboprophylaxis.129 Given the association of late IUFD with
obesity, advanced maternal age, infection and maternal disease,3,4,6,130,131 it is likely that many women with an
IUFD fall into the moderate- or high-risk categories.
7.3 What are the options for suppression of lactation?

Women should be advised that almost one-third of those that choose nonpharmacological measures are
troubled by excessive discomfort.
Women should be advised that dopamine agonists successfully suppress lactation in a very high
proportion of women and are well tolerated by a very large majority; cabergoline is superior to
bromocriptine.
Dopamine agonists should not be given to women with hypertension or pre-eclampsia.
Estrogens should not be used to suppress lactation.
Suppression of lactation is of psychological importance for some women following IUFD. Up to

one-third of women who use simple measures such as a support brassire, ice packs and analgesics
experience severe breast pain.132
Evidence
level 1++
A placebo-controlled randomised controlled trial showed that bromocriptine inhibited lactation in

more than 90% of women with few adverse effects.133 A second randomised controlled trial found
bromocriptine to be significantly more effective than breast binders.134
Evidence
level 1+
A double-blind randomised controlled trial of 272 women requesting lactation suppression

compared a single dose of cabergoline (1 mg) with bromocriptine (2.5 mg twice daily) for 14 days.
The two regimens had very similar effectiveness, but cabergoline was simpler to use and had
significantly lower rates of rebound breast activity and adverse events.135
Evidence
level 1++
17 of 33
Dopamine agonists are contraindicated in women with hypertension or pre-eclampsia.136 They can
increase blood pressure and have been associated with intracerebral haemorrhage.137 Estrogen is of
unproven benefit for lactation suppression and it increases thromboembolic risk.138
Evidence
level 3
7.4 Who should be informed of events?

All key staff responsible for care of the woman during pregnancy and afterwards should be informed of
events.
All existing appointments should be cancelled maternity units should keep a list of likely departments
that need to be contacted.
All key staff groups must be informed to ensure cancellation of existing appointments and continuity of
follow-up. This includes the community midwives, health visitor, antenatal class coordinator and general
practitioner. Other existing carers such as psychiatrists, secondary care specialists and drug workers should
also be contacted. It should also include voluntary groups who distribute free items to new mothers, but
specific details should not be released to maintain confidentiality.Appointments for antenatal clinics (hospital
and community), ultrasound scans and preoperative assessment should be cancelled.
8.
Psychological and social aspects of care
8.1 What psychological problems can follow late IUFD?

Carers must be alert to the fact that mothers, partners and children are all at risk of prolonged severe
psychological reactions including post-traumatic stress disorder but that their reactions might be very
different.
Perinatal death is associated with increased rates of admission owing to postnatal depression.139
Unresolved normal grief responses can evolve into post-traumatic stress disorder.140,141 Women with
poor social support are particularly vulnerable.142
Evidence
level 3
Partners of women with an IUFD can also suffer from severe grief responses, but the prevalence of
such psychological disorders in partners is not precisely known. Men demonstrate less guilt,
anxiety and depression than women themselves, but they can also develop post-traumatic stress
disorder.143 Discordant grief reactions between partners are more common after IUFD than after
neonatal death and this is a risk factor for prolonged and abnormal grief reactions.144
Evidence
level 2+
Parental relationships have a 40% higher risk of dissolving after stillbirth compared with live birth.145
8.2 What is best practice for use of interventions that might aid psychological recovery?
Carers should be aware of and responsive to possible variations in individual and cultural approaches
to death.
Counselling should be offered to all women and their partners.
Other family members, especially existing children and grandparents, should also be considered for
counselling.
Debriefing services must not care for women with symptoms of psychiatric disease in isolation.
Parents should be advised about support groups.
18 of 33
Bereavement officers should be appointed to coordinate services.
Some parents develop prolonged psychological problems after stillbirth. This appears to be much
more likely if professional support is not given,146 but there is a paucity of evidence from randomised
trials that address the benefits and pitfalls of psychological interventions after perinatal death.147
Evidence
level
1+/1++
An interview survey of women after an IUFD found that many wanted their carers to understand
and acknowledge the nature of perinatal grief.148
Evidence
level 2+
Guilt is a common emotion but is not necessarily voiced.149 Carers should carefully seek to identify false
assumptions made by parents and communicate these to counsellors.
Other members of the family can also be severely affected by bereavement. A 10-year study of 843
parents who experienced a stillbirth, newborn death or sudden unexpected death in infancy
included extended family members; primarily grandparents, but also existing children. The most
common response of grandparents was a profound need to protect their own child. The study
found that grandparents need information on how they can help their children recover from their
loss, how long grief lasts and the differences between mens and womens grief responses. Existing
children often felt a need to help the family heal.150
Evidence
level 3
Their grief responses are influenced by their ability to conceptualise death and their parents
responses.151
Evidence
level 2+
Childparent relationships can be adversely affected if the parents have great difficulty coping with their loss.
Some parents wish to have guidance on how to explain the death to siblings and how to help them mourn.
Some UK maternity units have developed debriefing services for parents who have experienced
traumatic events in relation to childbirth. One systematic review analysed eight random-allocation
trials. There was no evidence of benefit in six studies and possible evidence of harm in a seventh.
The authors emphasised the essential need to differentiate between parents who perceive their
experience of childbirth as emotionally traumatic and those who develop symptoms of depression
or post-traumatic stress disorder (for whom specific psychiatric treatment might be required).152
Evidence
level 1+
Support groups, such as Sands (Stillbirth and neonatal death society), have been developed to offer
help to both partners. In an observational study of 23 women who attended pregnancy loss groups,
interviews showed that the primary focus for women was the need to seek recognition and
acceptance of their grief.12 The introduction of bereavement support officers has been shown to
improve the management of perinatal loss.153
Evidence
level 3
8.3 What is the evidence for seeing, holding, naming and mementos?
Carers should avoid persuading parents to have contact with their stillborn baby, but should strongly
support such desires when expressed.
Parents who are considering naming their baby should be advised that after registration a name cannot
be entered at a later date, nor can it be changed.
If parents do decide to name their baby, carers should use the name, including at followup meetings.
Parents should be offered, but not persuaded, to retain artefacts of remembrance.
19 of 33
Maternity units should have the facilities for producing photographs, palm and foot prints and locks of
hair with presentation frames.
Verbal consent should be sought from the parents and information governance regulations should be
complied with for clinical photography.
If the parents do not wish to have mementos, staff should offer to store them securely in the maternal
case record for future access.
It should be explained that clothes on a macerated baby might become stained.
P
Evidence
level 3
Many parents expressly wish to see and hold their baby.15

A study of 309 women found an overall beneficial effect, in terms of better sleep and less chance
of getting a headache, after having a stillborn baby.154
However, another study showed that practices that actively promoted contact with the stillborn
baby are associated with worse outcomes. Women who had held their stillborn baby were more
depressed than those who only saw the baby, while those who did not see the baby were least
likely to be depressed (39% versus 21% versus 6%, P=0.03). Women who had seen their stillborn
baby had greater anxiety (P=0.02) and more symptoms of post-traumatic stress disorder than those
who had not (P=0.02), and their next-born babies were more likely to show disorganised
attachment behaviour (42% versus 8%, P=0.04).14
Evidence
level 2+
Some parents may wish to name their baby, but others may decide not to do so. Either option is allowable in
law, but once the stillbirth has been registered, names cannot be added or changed (Births and Deaths
Registration Act 1953; amended by the Still-Birth (Definition) Act 1992).155
Keeping mementoes has not been associated with adverse outcomes,14 and qualitative studies have
shown that many parents value them highly.97,156
Evidence
level 3
8.4 What are the legal requirements for medical certification of stillbirth?
Obstetricians and midwives should be aware of the law related to stillbirth.
The following practice guidance is derived from statute and code of practice.
Stillbirth must be medically certified by a fully registered doctor or midwife; the doctor or midwife must have
been present at the birth or examined the baby after birth. (Statute)
HM Coroner must be contacted if there is doubt about the status of a birth. (Statute)
Police should be contacted if there is suspicion of deliberate action to cause stillbirth. (Statute)
Fetal deaths delivered later than 24 weeks that had clearly occurred before the end of the 24th week do not
have to be certified or registered. (Code of Practice)

The baby can be registered as indeterminate sex awaiting further tests. (Code of Practice)
The parents are responsible in law for registering the birth but can delegate the task to a healthcare
professional. (Statute)
The current law on stillbirth registration is set out in the Births and Deaths Registration Act 1953 (amended
by the Still-Birth (Definition) Act 1992).155 The legal definition of stillbirth is: any child expelled or issued forth
from its mother after the 24th week of pregnancy that did not breathe or show any other signs of life.
Legal advisors for the Department of Health and the Office for National Statistics have agreed that a fetus that
is expelled after 24 weeks of pregnancy, provided it was no longer alive at the 24th week of pregnancy (this fact
being either known or provable from the stage of development reached by the dead fetus), does not fall within
20 of 33
the category of births to be registered as a stillbirth under the above Acts. This interpretation is also accepted
by the General Register Office for Scotland and the General Register Office for Northern Ireland.155 When the
gestational age is not known before the birth, with unbooked pregnancies for example, the decision about the
status of the birth should be made on the basis of the stage of development of the baby on examination.
The doctor or midwife attending the stillbirth is required to issue a Medical Certificate of Stillbirth that
enables the birth to be registered. The cause and sequence of medical events leading to the IUFD should be
given in as much detail as possible. Nonspecific terms such as anoxia, prematurity and so on should be
avoided. Certification should not be delayed for the results of the postmortem.
The mother (or father if the couple were married at the time of birth) is responsible for registering the
stillbirth, normally within 42 days (21 days in Scotland) but with a final limit of 3 months for exceptional
circumstances. This responsibility can be delegated to health professionals, including a midwife or doctor
present at the birth or a bereavement support officer. The person registering the birth has to be able to
provide the following:
the place and date of birth of the baby

if the parents wish to name the baby, the name and surname
the sex of the baby (but can be registered as indeterminate and later changed if tests show a clear result)
the names, surnames, places of birth and occupations of the parents
the mothers maiden name (if applicable)
in Scotland, the marriage certificate of the parents is required.
The Registrar of Births will meet with the parents in private. The birth is entered onto the Stillbirth Register,
which is separate from the standard Register of Births. The parents are then issued with a Certificate of
Stillbirth and the documentation for burial or cremation. A certificate for cremation cannot be issued before
the registration.
If the couple were not married at the time of the birth, the fathers details can be added only if one of the
following is fulfilled:
the mother and father go to the register office and sign the stillbirth register together or
where the father is unable to go to the register office with the mother, the father may make a statutory
declaration acknowledging his paternity, which the mother must produce to the Registrar (this form can be
obtained from any Registrar of Births) or
where the mother is unable to go to the register office with the father, the mother might make a statutory
declaration acknowledging the fathers paternity, which the father must produce to the Registrar (this form
can be obtained from any Registrar of Births).
If information about the father is not recorded initially, it is possible for the birth to be re-registered to include
his details later.
Most local authorities have websites on the registering of stillbirth. There are no fees for registration, but
additional certificates do carry a charge (3.50 per copy as of January 2010).
HM Coroner does not normally have jurisdiction over stillbirth, even if the cause of death is not known, but
contact should be made for an apparently fresh stillbirth not attended by a healthcare professional. HM
Coroner also has discretion to be involved if the death followed a criminal act such as common assault and
can then request for any postmortem to be expedited. Twenty-one stillbirths were referred to HM Coroner
Services for England and Wales in 2007 and 13 in 2008. If there is suspicion of actions taken deliberately to
cause a stillbirth, the police service should be contacted.
8.5 What are the recommendations for spiritual guidance, burial, cremation and remembrance?
Maternity units should have arrangements with elders of all common faiths and nonreligious spiritual
organisations as a source of guidance and support for parents.
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The legal responsibility for the childs body rests with the parents but can be delegated to hospital
services.
Parents should be allowed to choose freely about attendance at a funeral service.
A leaflet about the options should be available.
Maternity units should provide a book of remembrance for parents, relatives and friends.
Carers should offer parents the option of leaving toys, pictures and messages in the coffin.
Parents might wish to seek guidance from a spiritual leader or religious elder. Funeral options including burial
and cremation should be discussed with parents, taking into account religious and cultural considerations.
Practical issues should be discussed with the parents, at a time and to an extent that suits them.
Having a funeral service for the infant was associated with slower resolution of womens psychological distress in one study.157
Evidence
level 2+
An observational study found that most women appreciate rapid arrangements for the funeral or
cremation.158
Evidence
level 3
Some parents choose to leave messages, toys and photographs in the coffin.
If the parents request cremation they have to complete Cremation Form 3 (application for cremation of
remains of a stillborn child).Together with a copy of the Stillbirth Certificate (known also as Cremation Form
9), they submit CF3 to the Medical Referee, who issues Cremation Form 10 (authorisation to cremate a
stillborn child). Cremation Form 2 is the equivalent of CF3 for retained body parts of a stillborn child when
the body has already been cremated.
8.6 What advice should be given about fertility?

Information about fertility and contraception should be offered to mothers before returning home.
Mothers are vulnerable to psychological disorders when conception occurs soon after the loss.141,143
With suppression of lactation, ovulation returns more quickly. This can be as early as day 18.159
C
Evidence
level 2+
Some women might not be aware that they might conceive before their first menstrual period.
9.
Follow-up
9.1 What are the options for follow-up meetings?

The wishes of the woman and her partner should be considered when arranging follow-up.
Before the visit, it is essential to ensure that all available results are readily to hand.
There is no evidence to support home visits over clinic follow-up, or to indicate the optimum timing and
frequency of such appointments, but it is recognised that some parents find it very distressing to return to the
unit where their baby was stillborn. If practicable, the option of home visits should be offered to parents.
Office consultation has the potential advantages over clinic follow-up of preventing waits and allowing
flexible duration. Six to eight weeks is common practice for the timing of the appointment, when the
placental and the postmortem histology results usually become available, but a flexible approach is
appropriate according to the needs of the parents and the range of tests performed.
22 of 33
9.2 What are the recommendations for the content of the follow-up appointment?
Parents should be advised about the cause of late IUFD, chance of recurrence and any specific means of
preventing further loss.
Women should be offered general prepregnancy advice, including support for smoking cessation.
Women should be advised to avoid weight gain if they are already overweight (body mass index over
25) and to consider weight loss.
An offer should be made to discuss the potential benefit of delaying conception until severe
psychological issues have been resolved.
Carers should be aware that while mothers tend to experience greater anxiety when conception occurs
soon after a fetal loss, partners are more likely to suffer anxiety if conception is delayed.
Parents can be advised that the absolute chance of adverse events with a pregnancy interval less than
6 months remains low and is unlikely to be significantly increased compared with conceiving later.
The meeting should be documented for the parents in a letter that includes an agreed outline plan for
future pregnancy.
Women might wish to keep a written log of questions and comments. Some women/couples might wish to
use this to help set the agenda themselves at the start of the meeting. As well as an opportunity to ask about
the physical and emotional wellbeing of the mother and her partner, the meeting allows parents time to
discuss the results of tests and the likely cause of late IUFD.The meeting can also focus on the prognosis and
options for future pregnancies. The discussion should cover general preparation for pregnancy: lifestyle, folic
acid supplementation and rubella vaccination. Parents often desire an open, honest discussion with an
opportunity to make comments and the chance to raise any concerns they might have. If care has been
suboptimal, parents might want this to be acknowledged, lessons to be learned and care in the future to be
improved.
Vulnerability to depression and anxiety in the next pregnancy is related to time since stillbirth, with
more recently bereaved women at significantly greater risk than controls.160 In contrast to mothers
vulnerability to psychological disorder when conception occurs soon after the loss, fathers tend to
experience greater problems when pregnancy is delayed.161
Evidence
level 2+
Two medium-sized studies focusing on women with previous stillbirth have not shown any
association between inter-pregnancy interval and pregnancy outcome.162,163
Evidence
level 2++
Recent larger studies and a meta-analysis164,165 of the general maternity population suggested that
there is a higher rate of adverse events with shorter inter-pregnancy intervals but the absolute risk
remained low. Inter-pregnancy intervals shorter than 6 months were associated with increased risks
of preterm birth, low birth weight and small-for-gestational-age babies (adjusted OR [95% CI] 1.40
[1.241.58], 1.61 [1.391.86] and 1.26 [1.181.33], respectively).164
Evidence
level 1++
extrapolated
The odds ratio for stillbirth for women who smoke is 1.6 (95% CI 1.22.3). Women who stop
smoking have equivalent stillbirth rates to women who have never smoked.166
Evidence
level 2+
In two large studies, the odds ratio for stillbirth for women with a prepregnancy body mass index
(BMI) over 30 kg/m ranged from 1.4 to 2.6 (Evidence level 2+)131,167 and in a systematic review it
was 2.12.8.6
Evidence
level 1++
23 of 33
Another study of 151 025 women, including 666 with stillbirth, showed that the risk of adverse
outcomes in the next pregnancy increased linearly for women who gained three or more BMI units
after birth compared with women whose BMI did not change by more than one unit between
pregnancies.The increased risk included stillbirth for women with a BMI over 25 before the weight
increase (OR 1.63, 95% CI 1.202.21).168
Evidence
level 2++
10. Pregnancy following unexplained stillbirth
10.1 What recommendations should be made for pregnancy following unexplained late IUFD?
The history of stillbirth should be clearly marked in the case record and carers should ensure they read
all the notes thoroughly before seeing the woman.
Women with a previous unexplained IUFD should be recommended to have obstetric antenatal care.
Women with a previous unexplained IUFD should be recommended to have screening for gestational
diabetes.
For women in whom a normally formed stillborn baby had shown evidence of being small for gestational
age, serial assessment of growth by ultrasound biometry should be recommended in subsequent
pregnancies.
Small studies169 have shown no difference in stillbirth recurrence, but a large retrospective study of
947 women and 261 384 controls showed that women with a history of stillbirth (but otherwise
low-risk) had a 12-fold increased risk of intrapartum stillbirth (95% CI 4.533.7).170 A study that
compared outcomes in the second pregnancy for 364 women with previous stillbirth versus
33 715 with previous live birth showed an increased risk of pre-eclampsia (OR 3.1, 95% CI 1.75.7)
and placental abruption (OR 9.4, 95% CI 4.519.7).171
Evidence
level 2+
Another study of 71 315 women showed that there was an increased risk of ischaemic placental
disease (OR 1.6, 95% CI 1.22.1), fetal distress (OR 2.8, 95% CI 1.74.5), chorioamnionitis (OR 2.3,
95% CI 1.54.3), extreme preterm birth (OR 4.2, 95% CI 1.89.9) and early neonatal mortality
(OR 8.3, 95% CI 3.718.6) in pregnancies after stillbirth versus pregnancies after live birth.162
Evidence
level 2++
The increased risk was independent of recurrent maternal conditions and fetal congenital anomalies.172
An observational study of 316 consecutive pregnancies in women with a history of unexplained
stillbirth revealed a rate of gestational diabetes four times higher than expected.173 A significant
proportion of unexplained IUFDs are reclassified as fetal growth restriction when customised
charts and different classification systems are used.20,21
Evidence
level 2+
There are no prospective outcome studies of serial sonography in the next pregnancy after an IUFD, but it is
a prudent action that can provide reassurance to most women and partners. The optimum timing and
frequency of scans are not known.
10.2 What recommendations should be made for the management of future delivery after unexplained
stillbirth?
Previous unexplained IUFD is an indication to recommend birth at a specialist maternity unit.
Previous IUFD related to a known nonrecurrent cause merits individual assessment for place of birth.
24 of 33
Maternal request for scheduled birth should take into account the gestational age of the previous IUFD,
previous intrapartum history and the safety of induction of labour.
A large retrospective study of 947 women after an IUFD and 261 384 controls showed that history
of stillbirth conferred a greater risk of subsequent early IUFDs between 20 and 28 weeks (HR 10.3,
95% CI 6.117.2) than of late IUFDs (over 29 weeks) (HR 2.5, 95% CI 1.06.0).170 There have been
no studies that adequately tested fetal benefit from intervention by routine induction of labour.
A study of intrapartum events in 364 pregnancies following unexplained stillbirth has shown
higher rates for induction of labour (OR 3.2, 95% CI 2.44.2).This was associated with higher rates
of instrumental delivery (OR 2.0, 95% CI 1.43.0) and emergency caesarean deliveries (OR 2.1,
95% CI 1.53.0) compared with controls.171 Others have shown similar findings.173
Evidence
level 2+
These complications were probably iatrogenic, the result of obstetric intervention.174
Evidence
level 3
10.3 What recommendations should be made for maternal care after the next birth?
Carers should be vigilant for postpartum depression in women with a previous IUFD.
Carers should be aware that maternal bonding can be adversely affected.
The birth of a healthy baby does not compensate for a previous loss and can trigger a resurgence
of grief; women might feel happy one moment and sad the next. Depression in the third trimester
is highly predictive of depression one year after subsequent birth, particularly for women who
conceive within less than 12 months from an IUFD.160 Unresolved maternal grief may result in
disorganisation of attachment with future babies.175
11.
Evidence
level 2+
Clinical governance
11.1 Are there any risk management standards for IUFD?

Maternity units should be aware of specific standards for IUFD and stillbirth.
National Health Service Litigation Authority risk management maternity standards include expectations for
care specific to intrauterine death and stillbirth. These vary from edition to edition.
11.2 What are the standards for documentation?

Standardised checklists can be used to ensure that all appropriate care options are offered and that the
response to each is recorded.
Consent for perinatal postmortem examination should be documented using the nationally
recommended form.
All stillbirths should be reviewed in a multiprofessional meeting using a standardised approach to

analysis for substandard care and means of future prevention. Results of the discussion should be
recorded in the mothers case record and discussed with the parents.
All stillbirths should be reported to the Centre for Maternal and Child Enquiries (CMACE).
11.3 Information leaflets

All women (and partners) should be offered leaflets that provide information on the following issues:
named carers
local contact points
25 of 33
postmortem nature, benefits and choice

expectations for physical recovery
lactation suppression
registering the birth including web addresses of local authority site
details of national and local parent support groups, e.g. Sands
guidance on fertility and contraception
plan for follow-up.
11.4 What is best practice for care of staff?

A system should be in place to give clinical and psychological support for staff involved with an IUFD.
Occupational Health should be contacted for advice if there are particular concerns about fitness to
work.
In a survey of 804 doctors experiences and attitudes in dealing with perinatal death, 75% of
respondents reported that caring for a patient with a stillbirth took a large emotional toll on them
personally. Nearly one in ten obstetricians reported they had considered giving up obstetric
practice because of the emotional difficulty in caring for a woman with a stillbirth. Talking
informally with colleagues (87%) or friends/family (56%) had been the most common strategies
used by doctors to cope. Confidentiality is important. Improved bereavement training can help staff
care for grieving families but can also help staff cope with their own emotions.176
Evidence
level 2+
11.5 What are important auditable standards?
Proportion of stillbirths reported as a clinical incident (requirement for the Clinical Negligence Scheme for
Trusts).
Completion of investigations for the cause of late IUFD.
Proportion of parents offered postmortem examination.
Proportion of parents declining full postmortem who were offered alternative tests.
Proportion of parents who have postmortem consent undertaken by an appropriately trained obstetrician or
midwife.
Proportion of women offered suppression of lactation.
Proportion of women given fertility and contraceptive advice.
Proportion of parents offered follow-up with a senior obstetrician.
Proportion of women and families offered counselling follow-up.
11.6 What are the important aspects of training?
Seminars on the causes and care of late IUFD.

Skills training for the ultrasound diagnosis of late IUFD.
Training for discussions with parents about late IUFD.
Training on the postmortem examination, including consent.
Additional training in IUFD for bereavement counsellors.
Quarterly multidisciplinary clinicpathology meetings for critical analysis of stillbirths.
Role play of follow-up appointments for obstetric trainees.
12. Future research
12.1 What are the recommendations for future research?
The optimal system for classification of stillbirth.

Safety and efficacy of methods for induction of labour with a previous caesarean section.
The optimal dose of misoprostol for induction of labour according to gestational age.
The diagnostic power and accuracy of MRI for postmortem investigation.
The optimal psychological care of women and their partners.
A comparison of hospital and home follow-up appointments.
26 of 33
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31 of 33
APPENDIX

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
32 of 33

development group
Gynaecologists by:
Dr D Siassakos MRCOG, Bristol; Dr R Fox MRCOG, Taunton; Dr T Draycott FRCOG, Bristol;
and Mrs C Winter RM, Bristol.
RCOG Consumers Forum; British Association of Perinatal Medicine; British Maternal and Fetal Medicine Society; Mr D
I Fraser MRCOG, Norwich; Mr R B Beattie FRCOG, Cardiff; Dr A C G Breeze MRCOG, Nottingham; Professor E S
Draper, Professor of Perinatal and Paediatric Epidemiology, University of Leicester; Dr P Cox, Consultant Perinatal
Pathologist, Birmingham Womens Hospital; The Child Bereavement Charity; Centre for Maternal and Child Enquiries;
Mrs J Frohlich, Deputy Head of Midwifery, Ashford and St Peters NHS Trust, Chertsey; Professor G C S Smith MRCOG,
Cambridge; Professor J Gardosi, Director, Perinatal Institute; Dr A E P Heazell MRCOG, Manchester; Dr A G Howatson,
Consultant Paediatric and Perinatal Pathologist, Royal Hospital for Sick Children, Glasgow, Scotland; Dr I Jeffrey,
Perinatal Pathology Service, St Georges Hospital, London; Sands; Dr E J Treloar MRCOG, Bristol; Royal College of
Paediatrics and Child Health; Obstetric Anaesthetists Association.
Committee lead peer reviewers were: Mrs C E Overton FRCOG, Dr J Thomas MRCOG, Dr S K Surendran FRCOG and
Dr P Owen MRCOG.
DISCLAIMER
health services.
33 of 33
Maternal Collapse in Pregnancy and

the Puerperium
January 2011
Maternal Collapse in Pregnancy and the Puerperium

1.
Purpose and scope
Maternal collapse is a rare but life-threatening event with a wide-ranging aetiology. The outcome, primarily
for the mother but also for the fetus, depends on prompt and effective resuscitation.The purpose of this guideline is to discuss the identification of women at increased risk of maternal collapse and the different causes of
maternal collapse, to delineate the initial and continuing management of maternal collapse and to review maternal and neonatal outcomes. It covers both hospital and community settings, and includes all gestations and the
postpartum period.The resuscitation team and equipment and training requirements will also be covered.
2.
Maternal collapse is defined as an acute event involving the cardiorespiratory systems and/or brain, resulting
in a reduced or absent conscious level (and potentially death), at any stage in pregnancy and up to six weeks
after delivery. While there is a robust and effective system for maternal mortality audit in the UK in the form
of the Confidential Enquiry into Maternal and Child Health (CEMACH), now the Centre for Maternal and Child
Enquiries (CMACE), the incidence of maternal collapse or severe maternal morbidity is unknown as morbidity
data are not routinely collected.There are drivers to improve this situation, but resources are limited.1 The UK
Obstetric Surveillance System (UKOSS), run by the National Perinatal Epidemiology Unit (NPEU), has made a
significant contribution towards the study of rare events and maternal morbidity.2 Severe maternal morbidity
data was collected Scotland-wide for 5 years and published in 2007.3 A woman was defined as having had a
severe maternal morbidity event if there was a risk of maternal death without timely intervention. The data
showed a severe maternal morbidity rate of 6/1000 (600/100 000) maternities, but not all cases of severe
maternal morbidity involved maternal collapse (although all cases of collapse were included in the figures). A
recent publication from Dublin showed a severe maternal morbidity rate of 3.2/1000 (320/100 000) births.4 In
the last triennium in the UK the maternal mortality rate was 14/100 000 births,1 but again not all maternal
deaths are preceded by maternal collapse. Thus, the true rate of maternal collapse lies somewhere between
0.14 and 6/1000 (14 and 600/100 000) births. As it is such a rare event, with potentially devastating consequences, it is essential that caregivers are skilled in initial effective resuscitation techniques and are able to
investigate and diagnose the cause of the collapse to allow appropriate, directed continuing management.
Unfortunately, in reports regarding morbidity3,4 and in the CEMACH report,1 areas of substandard care continue
to be identified, including poor resuscitation skills, but it should also be remembered that death and disability
may result despite excellent care.1 It should be noted that vasovagal attacks and the postictal state following
an epileptic seizure are the most common causes of maternal collapse and are not covered by this guideline.
3.
Guidelines.5 The Cochrane Library (including the Cochrane Database of Systematic Reviews, DARE and
EMBASE), TRIP, Medline and PubMed were searched for relevant randomised controlled trials, systematic
reviews and meta-analyses. The search was restricted to articles published between 1960 and 2010. The
databases were searched using the relevant MeSH terms, including all subheadings, and this was combined
with a keyword search. Search words included amniotic fluid embolism,cardiac arrest and pregnancy,DVT
and pregnancy, hypovolaemia and pregnancy, hypoxia and pregnancy, massive haemorrhage, maternal
collapse and resuscitation and pregnancy. The search was also limited to humans and the English language.
guidelines and reviews.
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4.
Clinical issues
4.1 Can women at risk of impending collapse be identified early?

An obstetric early warning score chart should be used routinely for all women, to allow early recognition
of the woman who is becoming critically ill.
In some cases maternal collapse occurs with no prior warning, although there may be existing risk
factors that make this more likely. Antenatal care for women with significant medical conditions at
risk of maternal collapse should include multidisciplinary team input with a pregnancy and
delivery management plan in place. Often there are clinical signs that precede collapse. In the latest
CEMACH report,1 substandard care was often identified where these signs and symptoms were not
recognised and acted upon. The report recommended that a national obstetric early warning
scoring system should be introduced and used for all obstetric women, including those being cared
for outside the obstetric setting.1
Evidence
level 4
The first early warning scoring (EWS) systems6 were introduced on the basis that a deterioration in
simple physiological vital signs will precede significant clinical deterioration, and that early
intervention will reduce morbidity.711 EWS systems are now extensively used in acute settings and
critical care,1214 although it has not been possible to identify the optimal system.15
Evidence
level 1+
Despite this, EWS systems have not been demonstrated to be highly effective, even when their use has triggered
input from a specialised medical emergency team,16 and although their use is recommended by the National
Institute for Health and Clinical Excellence (NICE),17 this is based on informal consensus rather than evidence.
The physiological changes of pregnancy may render the existing EWS systems inappropriate,18 and no
validated system for use in the pregnant woman currently exists. Because of this, many maternity hospitals
have developed their own modified EWS system, and there is continuing work in the UK to try and develop
a national obstetrics EWS system. However, this should be subjected to rigorous scrutiny to ensure that it is
effective before it is universally implemented.
4.2 What are the causes of maternal collapse?

There are many causes of collapse, and these may be pregnancy-related or result from conditions not related
to pregnancy and possibly existing before pregnancy. Systematic consideration of the causes of collapse can
enable skilled rescuers to identify the cause of collapse in the hospital setting and, where the cause is
reversible, survival can be improved.19 The common reversible causes of collapse in any woman can be
remembered using the well known aide memoire employed by the Resuscitation Council (UK) of the 4 Ts
and the 4 Hs.19 In the pregnant woman, eclampsia and intracranial haemorrhage should be added to this list,
and obstetric-specific causes are clearly more likely and must also be considered systematically (Figure 1).
Owing to the lack of robust morbidity data regarding collapse, maternal deaths are often used as a reference
point. The common causes of maternal collapse are discussed below, but this is not an exhaustive list, as this
is beyond the scope of this guideline.
4.2.1 Haemorrhage
This is the most common cause of maternal collapse, and was responsible for 17 maternal deaths in the last
triennium.1 Major obstetric haemorrhage has an estimated incidence of 3.7/1000 maternities.20 Causes of major
obstetric haemorrhage include postpartum haemorrhage, major antepartum haemorrhage from placenta praevia/
accreta, placental abruption, uterine rupture and ectopic pregnancy. In most cases of massive haemorrhage
leading to collapse, the cause is obvious, but concealed haemorrhage should not be forgotten, including following
caesarean section and ruptured ectopic pregnancy. Other rarer causes of concealed haemorrhage include splenic
artery rupture21 and hepatic rupture. Blood loss is often underestimated,22,23 especially slow, steady bleeding, and
fit healthy women can tolerate significant loss prior to showing signs of decompensation.
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Figure 1. Causes of maternal collapse

Eclampsia
Intracranial haemorrhage
Anaphylaxis
Pulmonary embolism
Amniotic fluid embolism
Aortic dissection
Drugs: magnesium sulphate

local anaesthetic
illicit drugs
Cardiac causes: arrhythmias

myocardial infarction
cardiomyopathy
Hypoglycaemia
Haemorrhage: splenic artery rupture

hepatic rupture
uterine (antepartum
haemorrhage/
postpartum
haemorrhage)
Sepsis
Reversible cause
4 Hs
Cause in pregnancy
Hypovolaemia
Bleeding (may be concealed) (obstetric/other) or relative hypovolaemia of dense

spinal block; septic or neurogenic shock
Hypoxia
Pregnant patients can become hypoxic more quickly

Cardiac events: peripartum cardiomyopathy, myocardial infarction, aortic dissection,
large-vessel aneurysms
4 Ts
Hypo/hyperkalaemia and other

electrolyte disturbances
No more likely
Hypothermia
No more likely
Thromboembolism
Amniotic fluid embolus, pulmonary embolus, air embolus, myocardial infarction
Toxicity
Local anaesthetic, magnesium, other
Tension pneumothorax
Following trauma/suicide attempt
Tamponade (cardiac)
Following trauma/suicide attempt
Eclampsia and pre-eclampsia
Includes intracranial haemorrhage
4.2.2 Thromboembolism
In the last CEMACH report1 there were 41 deaths from thromboembolism (33 pulmonary embolism and eight
cerebral vein thrombosis), making it the most common cause of direct maternal death. Appropriate use of
thromboprophylaxis has improved maternal morbidity and mortality, but improvements in clinical risk
assessment and prophylaxis are still required.1,24
4.2.3 Amniotic fluid embolism
The estimated frequency of amniotic fluid embolism (AFE) lies somewhere between 1.25/100 000 and
12.5/100 000 maternities, with the most recent UK data giving an incidence of 2/100 000 maternities.25
Survival rates seem to have improved significantly over time, from 14% in 197926 to around 30% in 200527 and
80% in 2010,25 although neurological morbidity in survivors is well recognised.28 The perinatal mortality
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rate in cases of AFE is 135/1000 total births.25 AFE presents as collapse during labour or delivery or within
30 minutes of delivery in the form of acute hypotension, respiratory distress and acute hypoxia.29 Seizures
and cardiac arrest may occur. There are different phases to disease progression,28,30 which clearly impacts
on maternal survival. Initially, pulmonary hypertension may develop secondary to vascular occlusion either
by debris or by vasoconstriction. This often resolves and left ventricular dysfunction or failure develops.
Coagulopathy often develops if the mother survives long enough, often giving rise to massive postpartum
haemorrhage. If AFE occurs prior to delivery, profound fetal distress develops acutely.29 The underlying pathophysiological process has been compared to anaphylaxis or severe sepsis.28 Diagnosis in nonfatal cases is
clinical, as there is no established accurate diagnostic test premortem.31
4.2.4 Cardiac disease
Cardiac disease was the most common overall cause of maternal death in the CEMACH report,1 being
responsible for 48 maternal deaths.The majority of deaths secondary to cardiac causes occur in women with
no previous history.32 The main cardiac causes of death are myocardial infarction, aortic dissection and
cardiomyopathy.1 The incidence of primary cardiac arrest in pregnancy is much rarer at around 1/30 000
maternities, and most cardiac events have preceding signs and symptoms. Aortic root dissection can present
in otherwise healthy women, and signs and symptoms such as central chest or interscapular pain, a wide pulse
pressure, mainly secondary to systolic hypertension, and a new cardiac murmur must prompt referral to a
cardiologist and appropriate imaging. The incidence of congenital and rheumatic heart disease in pregnancy
is increasing secondary to increased survival rates owing to improved management of congenital heart
disease and increased immigration.1 These cases should be managed by an appropriately skilled and
experienced multidisciplinary team, usually in regional centres. Other cardiac causes include dissection of the
coronary artery, acute left ventricular failure, infective endocarditis and pulmonary oedema.
4.2.5 Sepsis
Sepsis has been recognised for centuries as a significant cause of maternal morbidity and mortality, and
substandard care continues to feature in the cases that result in death.1 Bacteraemia, which can be present in
the absence of pyrexia or a raised white cell count, can progress rapidly to severe sepsis and septic shock
leading to collapse;33 the most common organisms implicated in obstetrics are the streptococcal groups A, B
and D, pneumococcus and Escherichia coli.
4.2.6 Drug toxicity/overdose
Drug toxicity/overdose should be considered in all cases of collapse, and illicit drug overdose should be
remembered as a potential cause of collapse outside of hospital. In terms of therapeutic drug toxicity, the
common sources in obstetric practice are magnesium sulphate in the presence of renal impairment and local
anaesthetic agents injected intravenously by accident.
Toxic effects associated with local anaesthetics usually result from excessively high plasma concentrations.
Effects initially include a feeling of inebriation and lightheadedness followed by sedation, circumoral
paraesthesia and twitching; convulsions can occur in severe toxicity. On intravenous injection, convulsions
and cardiovascular collapse may occur very rapidly. Local anaesthetic toxicity resulting from systemic
absorption of the local anaesthetic may occur some time after the initial injection. Signs of severe toxicity
include sudden loss of consciousness, with or without tonicclonic convulsions, and cardiovascular collapse:
sinus bradycardia, conduction blocks, asystole and ventricular tachyarrhythmias can all occur.34
In terms of local anaesthetics, total spinal block or high spinal/epidural block are rarer and usually easily
recognised causes of collapse.
4.2.7 Eclampsia
Eclampsia as the cause of maternal collapse is usually obvious in the inpatient setting, as often the diagnosis
of pre-eclampsia has already been made and the seizure witnessed. Epilepsy should always be considered in
cases of maternal collapse associated with seizure activity.
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4.2.8 Intracranial haemorrhage

Intracranial haemorrhage is a significant complication of uncontrolled, particularly systolic, hypertension, but
can also result from ruptured aneurysms and arteriovenous malformations. The initial presentation may be
maternal collapse, but often severe headache precedes this.
4.2.9 Anaphylaxis
Anaphylaxis is a severe, life-threatening generalised or systemic hypersensitivity reaction35 resulting in respiratory,
cutaneous and circulatory changes and, possibly gastrointestinal disturbance and collapse. There is significant
intravascular volume redistribution, which can lead to decreased cardiac output. Acute ventricular failure and
myocardial ischaemia may occur. Upper airway occlusion secondary to angioedema, bronchospasm and mucous
plugging of smaller airways all contribute to significant hypoxia and difficulties with ventilation. Common
triggers are a variety of drugs, latex, animal allergens and foods.The incidence is between 3 and 10/1000, with a
mortality rate of around 1%.36 Anaphylaxis is likely when all of the following three criteria are met:
sudden onset and rapid progression of symptoms
life-threatening airway and/or breathing and/or circulation problems
skin and/or mucosal changes (flushing, urticaria, angioedema).
Exposure to a known allergen for the woman supports the diagnosis, but many cases occur with no previous
history. Mast cell tryptase levels can be useful.
4.2.10 Other causes
Other causes of maternal collapse include hypoglycaemia and other metabolic/electrolyte disturbances, other
causes of hypoxia such as airway obstruction secondary to aspiration/foreign body, air embolism, tension
pneumothorax, cardiac tamponade secondary to trauma and hypothermia. There will be other very unusual
and rare causes of maternal collapse, but detailed discussion of all causes is beyond the scope of this guideline.
4.3 What are the physiological and anatomical changes in pregnancy that affect resuscitation?
It is essential that anyone involved in the resuscitation of pregnant women is aware of the physiological
differences. This includes paramedics and emergency room staff.
The pregnant woman undergoes a variety of physiological changes that accelerate the development of hypoxia and acidosis and make ventilation more difficult.37 The cardiovascular changes
also promote rapid blood loss and reduced oxygen-carrying capacity. These changes are listed in
Table 138 and, combined with other physical changes, make resuscitation during pregnancy more
challenging. It is essential that anyone involved in the resuscitation of a pregnant woman is aware
of these differences. This includes paramedics and emergency room staff.
4.3.1 Aortocaval compression
Aortocaval compression significantly reduces cardiac output from 20 weeks of gestation onwards.
From around 20 weeks of gestation onwards, in the supine position the gravid uterus can compress
the inferior vena cava and aorta (to a much lesser extent), thus reducing venous return and, as a
consequence, cardiac output by up to 3040%, causing what is known as supine hypotension.39
Supine hypotension itself can precipitate maternal collapse, which is usually reversed by turning the
woman into the left lateral position.
Evidence
level 2+
Aortocaval compression significantly reduces the efficacy of chest compressions during resuscitation.
When cardiopulmonary arrest occurs, chest compressions are needed to produce a cardiac output.
In nonpregnant women, chest compressions achieve around 30% of the normal cardiac output.4042
Aortocaval compression further reduces cardiac output to around 10% that achieved in nonpregnant women.43 Cardiopulmonary resuscitation (CPR) is less likely to be effective in a woman who
is 20 weeks pregnant or more.
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Table 1. Physiological and physical changes in pregnancy

Changes in pregnancy
Impact on resuscitation
Plasma volume
Increased by up to 50%
Dilutional anaemia
Reduced oxygen-carrying capacity
Heart rate
Increased by 1520 bpm
Increased CPR circulation demands
Cardiac output
Increased by 40%
Significantly reduced by pressure of gravid
uterus on IVC
Uterine blood flow
10% of cardiac output at term
Potential for rapid massive haemorrhage
Systemic vascular resistance
Decreased
Sequesters blood during CPR
Arterial blood pressure
Decreased by 1015 mmHg
Decreased reserve
Venous return
Decreased by pressure of gravid uterus on IVC

Decreased reserve
Respiratory rate
Increased
Decreased buffering capacity, acidosis more likely
Oxygen consumption
Increased by 20%
Hypoxia develops more quickly
Residual capacity
Decreased by 25%
Arterial PCO2
Decreased
Laryngeal oedema
Increased
Difficult intubation
Gastric motility
Decreased
Increased risk of aspiration
Lower oesophageal sphincter
Relaxed
Increased risk of aspiration
Uterus
Enlarged
Diaphragmatic splinting reduces residual capacity

and makes ventilation more difficult
Cardiovascular system
Respiratory system
Other changes
Aortocaval compression causes supine hypotension,

reduces venous return and significantly impairs CPR
Weight
Increases
Large breasts may interfere with intubation

Makes ventilation more difficult
CPR = cardiopulmonary resuscitation; IVC = inferior vena cava; PCO2 = partial pressure of carbon dioxide
4.3.2 Respiratory changes

Changes in lung function, diaphragmatic splinting and increased oxygen consumption make the
pregnant woman become hypoxic more readily and make ventilation more difficult.
The increased progesterone level in pregnancy increases the respiratory drive,44,45 leading to an
increase in tidal volume and minute ventilation. Splinting of the diaphragm by the enlarged uterus
reduces the functional residual capacity and also makes ventilation more difficult. These factors,
along with the markedly increased oxygen consumption of the fetoplacental unit, mean that the
pregnant woman becomes hypoxic much more rapidly during periods of hypoventilation.
Evidence
level 2+
4.3.3 Intubation
Difficult intubation is more likely in pregnancy.
Weight gain in pregnancy, large breasts inhibiting the working space and laryngeal oedema can all
contribute to make intubation more difficult.
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Evidence
level 3
4.3.4 Aspiration
Pregnant women are at an increased risk of aspiration.
The pregnant woman is at a significantly higher risk of regurgitation and aspiration secondary to the
progesterone effect relaxing the lower oesophageal sphincter and delayed gastric emptying, along
with the raised intra-abdominal pressure secondary to the gravid uterus. Aspiration pneumonitis in
the pregnant woman, known as Mendelson syndrome,46 can be severe, particularly as the gastric pH
is lower than in the nonpregnant population. Early intubation with effective cricoid pressure and
the use of H2 antagonists and antacids prophylactically in all women considered to be at high risk
of obstetric intervention during labour is advised.
4.3.5 Circulation
The increased cardiac output and hyperdynamic circulation of pregnancy mean that large volumes
of blood can be lost rapidly, especially from the uterus, which receives 10% of the cardiac output at
term. Otherwise healthy women tolerate blood loss remarkably well, and can lose up to 35% of their
circulation before becoming symptomatic. Blood loss is tolerated less well if there is a pre-existing
maternal anaemia, and clotting is less efficient if there is a significant anaemia. Concealed bleeding
and underestimation of loss mean that intervention is often delayed. Where signs of hypovolaemia
have been subtle, hypovolaemia as the cause of maternal cardiopulmonary arrest may go unrecognised, particularly where blood loss has been concealed.
Evidence
level 2+
Evidence
level 3
4.4 What is the optimal initial management of maternal collapse?

Maternal resuscitation should follow the Resuscitation Council (UK) guidelines using the standard A, B,
C approach, with some modification.
In the UK, resuscitation is conducted according to the UK Resuscitation Council Guidelines: basic
life support (BLS), adult advanced life support (ALS) and automated external defibrillation (AED)
algorithms and recommendations.47,48 These guidelines were updated in 2010 by international
experts under the auspices of the International Liaison Committee on Resuscitation49 and are used
in the resuscitation of the pregnant woman.
Evidence
level 1++
It is recognised that the divisions into basic and advanced life support are somewhat arbitrary in the hospital
setting.5052
In the community setting, basic life support should be administered and rapid transfer arranged, unless
appropriate personnel and equipment are available.
In the pregnant woman of 20 weeks or more gestation, adaptations are made to the resuscitation process.
There are also algorithms for special patient groups. While algorithms for generic, paediatric and neonatal life
support are available in standardised posters, adaptations for maternal resuscitation are addressed but are not
available in algorithmic and poster form. For this reason, the Resuscitation Council (UK) algorithm for
advanced life support has been modified by the authors (Appendix 2).
There are essential adaptations to the management of the collapsed pregnant woman because of the
physiological and anatomical changes of pregnancy.
4.4.1 Tilt
From 20 weeks of gestation onwards, the pressure of the gravid uterus must be relieved from the inferior
vena cava and aorta.
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A left lateral tilt of 150 on a firm surface will relieve aortocaval compression in the majority of pregnant
women and still allow effective chest compressions to be performed.53
A left lateral tilt of 15 can be achieved on an operating table using a Cardiff wedge54 by having
someone kneel on the right side of the woman with their knees under the womans thorax, although
this has the disadvantage of the tilt being removed for defibrillation;54,55 alternatives are using an
upturned chairback or using manual displacement of the uterus to the left.
Evidence
level 2+
In cases of major trauma, the wedge should be placed under the spinal board. In the absence of a spinal board,
manual displacement of the uterus should be used. Using soft surfaces such as a bed or objects such as pillows
or blankets is not nearly as effective and compromises effective chest compressions, but is better than leaving
the woman supine.
4.4.2 Airway
The airway should be protected as soon as possible by intubation with a cuffed endotracheal tube.
In pregnancy, the airway is more vulnerable because of the increased risk of regurgitation and aspiration. For
this reason it is important to clear and protect the airway as early as possible. Intubation should then be performed as soon as possible. This will protect the airway, ensure good oxygen delivery and facilitate more
efficient ventilation. Intubation can be more difficult in pregnancy, so this should be undertaken by someone
with the appropriate skills. During cardiac arrest in the nonpregnant patient it is acceptable to use a supraglottic device such as the laryngeal mask airway as an alternative to the tracheal tube.49 However, it should be
emphasised that the pregnant woman is more likely to regurgitate and aspirate in the absence of a secured
airway (tracheal tube) than the nonpregnant patient, and that the early involvement of an appropriately skilled
anaesthetist remains best practice. Capnography is recurrent in the intubated patient.49
Box 1. Suggested equipment for airway management56

Recommended equipment for routine airway management:
Facemasks
Oropharyngeal airways: three sizes
Nasopharyngeal airways: three sizes
Laryngeal mask airways
Tracheal tubes in a range of sizes
Two working laryngoscope handles
Macintosh blades: sizes 3 and 4
Tracheal tube introducer (gum-elastic bougie)
Malleable stylet
Magill forceps
Recommended equipment for management of unanticipated difficult intubation
Difficult Airway Society guidelines algorithm flowcharts (or modified local version)
Equipment list for restocking
At least one alternative blade (e.g. straight, McCoy)
Intubating laryngeal mask airway (ILMA) set (sizes 3, 4 and 5 with dedicated tubes and pusher)
Tracheal tubes reinforced and microlaryngeal, sizes 5 mm and 6mm
Flexible fibreoptic laryngoscope (with portable/battery light source)
Proseal laryngeal mask airway (ProSeal LMA)
Cricothyroid cannula (e.g. Ravussin) with a high-pressure jet ventilation system (e.g. Manujet) or large-bore cricothyroid cannula
(e.g. Quicktrac)
Surgical cricothyroidotomy kit
(Scalpel with no. 20 blade, tracheal hook, 6/7 mm tracheal and tracheostomy tubes)
Alternative specialised techniques of proven value57

Bullard-type laryngoscope
Trachlight
Aintree intubation catheter
Combitub
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Box 1 lists suggested equipment that should be available for cases where airway management may be
difficult.56,57
4.4.3 Breathing
Supplemental oxygen should be administered as soon as possible.
Because of the increased oxygen requirements and rapid onset of hypoxia in pregnancy, it is important to
ensure optimal oxygen delivery by adding high-flow 100% oxygen to whatever method of ventilation is being
employed.
Bag and mask ventilation should be undertaken until intubation can be achieved.
Ventilation, by face mask, by a supraglottic airway device and self-inflating bag or by a cuffed endotracheal
tube, may be more difficult because of the physiological changes of pregnancy described above. It can also
be difficult to see the chest rise.
4.4.4 Circulation
In the absence of breathing despite a clear airway, chest compressions should be commenced
immediately.
Chest compressions should not be delayed by palpating for a pulse, but should be commenced
immediately in the absence of breathing and continued until the cardiac rhythm can be checked
and cardiac output confirmed. Compressions may be made difficult because of obesity and the
tilted position. Hand position should be over the centre of the chest, and it is important to ensure
that the direction of compression is perpendicular to the chest wall, thus the angle of tilt must be
taken into account. Compressions should be performed at a ratio of 30:2 ventilations unless the
woman is intubated, in which case chest compressions and ventilations should be desynchronised,
with compressions being performed at a rate of 100/minute and ventilations at a rate of
10/minute.19 Because chest compressions are not as effective after 20 weeks of gestation, there
should be early recourse to delivery of the fetus and placenta if CPR is not effective.
Evidence
level 2++
Two wide-bore cannulae should be inserted as soon as possible.
There should be an aggressive approach to volume.
Haemorrhage is the most common cause of maternal collapse and a consequence of other causes of collapse.
There must be a high index of suspicion for bleeding and awareness of the limitations of clinical signs. Caution
must be exercised in the presence of severe pre-eclampsia and eclampsia, where fluid overload can contribute
to poor outcome. In the case where both significant haemorrhage and pre-eclampsia/eclampsia exist, careful
fluid management is essential.
Abdominal ultrasound by a skilled operator can assist in the diagnosis of concealed haemorrhage.
Very occasionally, ultrasound by a skilled operator can aid diagnosis in cases of massive abruption and
intra-abdominal bleeding, although laparotomy should not be delayed if the findings are negative or
the index of suspicion is high.58,59 However, this should not interfere with the resuscitation process.
The same defibrillation energy levels should be used as in the nonpregnant patient.
If defibrillation is required, the same settings should be used as in the nonpregnant patient as there
is no change in thoracic impedance.60 Adhesive defibrillator pads are preferable to defibrillator
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C
Evidence
level 2+
B
Evidence
level 2++
paddles, and the left defibrillation pad should be applied lateral to the left breast. The energy from
the defibrillation shock is directed across the heart and there is no evidence that shocks from a
direct current defibrillator have an adverse effect on the fetus. Uterine monitors should be removed
before shock delivery.
Evidence
level 2++
4.4.5 Drugs
There should normally be no alteration in algorithm drugs or doses.
Common, reversible causes of maternal cardiopulmonary arrest should be considered throughout the
resuscitation process.
Throughout the resuscitation process, consideration should be given to the cause of the collapse,
so that continuing therapy can be directed towards the specific cause to optimise outcome.19
Resuscitation efforts should be continued until a decision is taken by the consultant obstetrician, and
consultant anaesthetist in consensus with the cardiac arrest team.
Evidence
level 4
4.5 When, where and how should perimortem caesarean section be performed?
If there is no response to correctly performed CPR within 4 minutes of maternal collapse or if
resuscitation is continued beyond this in women beyond 20 weeks of gestation, delivery should be
undertaken to assist maternal resuscitation. This should be achieved within 5 minutes of the collapse.
The concept of perimortem caesarean section was introduced in 1986,61 along with the recommendation that it be initiated after 4 minutes of maternal cardiopulmonary arrest if resuscitation is
ineffective, and be achieved within 5 minutes of collapse. The rationale for this timescale is that the
pregnant woman becomes hypoxic more quickly than the nonpregnant woman, and irreversible brain
damage can ensue within 46 minutes. The gravid uterus impairs venous return and reduces cardiac
output secondary to aortocaval compression. Delivery of the fetus and placenta reduces oxygen
consumption, improves venous return and cardiac output, facilitates chest compressions and makes
ventilation easier. It also allows the heart to be compressed easily through the diaphragm against the
chest wall by placing the hand behind the heart (with the diaphragm closed) and compressing it
against the posterior aspect of the anterior chest wall. This improves cardiac output beyond that
achieved with closed chest compressions.62 Before 20 weeks of gestation there is no proven benefit
from delivery of the fetus and placenta. Perimortem caesarean section should be considered a
resuscitative procedure to be performed primarily in the interests of maternal, not fetal, survival.
Evidence
level 4
Delivery within 5 minutes of maternal collapse improves the chances of survival for the baby, but this is not
the reason for delivery. If maternal resuscitation continues beyond 4 minutes of the collapse, delivery of the
fetus and placenta should be performed as soon as possible to aid this, even if the fetus is already dead.There
is, of course, the possibility that the outcome could be that of a severely damaged surviving child, but the
interests of the mother must come first.
Perimortem caesarean section should not be delayed by moving the woman it should be performed
where resuscitation is taking place.
Time should not be wasted by moving the woman to an operating theatre; a perimortem caesarean section
can be performed anywhere, with a scalpel being the only essential equipment required. With no circulation,
blood loss is minimal and no anaesthetic is required. If resuscitation is successful following delivery, there
should be prompt transfer to an appropriate environment at that point, as well as anaesthesia and sedation,
to control ensuing haemorrhage and complete the operation.The doctrine of the best interests of the patient
would apply to conduct of this procedure being carried out without consent.
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The operator should use the incision that will facilitate the most rapid access.
In terms of the best incision to use, a midline abdominal incision and a classic uterine incision will give the
most rapid access, but many will be unfamiliar with this approach and, as delivery can be achieved rapidly with
a transverse approach, the operator should use the approach they are most comfortable with. If resuscitation
is successful, the uterus and abdomen should be closed in the usual way to control blood loss and minimise
the risk of infection. Where the outcome is not successful, the case should be discussed with the coroner/
procurator fiscal to determine whether a postmortem is required before any medical devices such as lines and
endotracheal tubes are removed, as per the Royal College of Pathologists recommendations.63,64
A perimortem caesarean section tray should be available on the resuscitation trolley in all areas where
maternal collapse may occur, including the accident and emergency department.
To ensure there are no delays in executing a perimortem caesarean section when indicated, the equipment
necessary should be immediately available on the resuscitation trolley. All that is required is a fixed blade
scalpel and two clamps for the cord. In the absence of a specific tray, a scalpel alone will enable delivery of
the fetus and placenta and cutting the cord, which can then be manually compressed until a clamp is found
if the baby is alive.
4.6 What does the continuing management consist of?

Senior staff with appropriate experience should be involved at an early stage.
Transfer should be supervised by an adequately skilled team with appropriate equipment.
Continuing management depends very much on the underlying cause of the collapse, and appropriate senior
staff must be involved early. It is essential the woman is transferred to an appropriate environment to ensure
optimal contiuing care. This would usually mean transfer to a high-dependency/critical care area with
appropriate staff and monitoring facilities.65
4.6.1 Haemorrhage
The continuing management of major postpartum haemorrhage is comprehensively covered in the RCOG
Green-top Guideline No. 52: Prevention and Management of Postpartum Haemorrhage.66
In the case of maternal collapse secondary to antepartum haemorrhage, the fetus and placenta should
be delivered promptly to allow control of the haemorrhage.
In the case of massive placental abruption, caesarean section may occasionally be indicated even if the
fetus is dead to allow rapid control of the haemorrhage.
Management of collapse secondary to massive haemorrhage as a result of placenta praevia should be managed
in accordance with the RCOG Green-top Guideline No. 27: Placenta Praevia, Placenta Praevia Accreta and
Vasa Praevia: Diagnosis and Management.67
4.6.2 Venous thromboembolism
The specific management of massive pulmonary embolism is covered in the RCOG Green-top Guideline No.
28: Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management.68
4.6.3 Amniotic fluid embolism
The management of AFE is supportive rather than specific, as there is no proven effective therapy.2
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Early involvement of senior experienced staff, including obstetrician, anaesthetist, haematologist and
intensivist, is essential to optimise outcome.
On top of resuscitation and supportive measures, arrhythmias may develop and will require standard
treatment. Inotropic support is likely to be needed and measurement of cardiac output may help direct
therapy and avoid fluid overload, as this will exacerbate pulmonary oedema and increases the risk of acute
respiratory distress syndrome. High filling pressures are indicative of a failing left ventricle.
Coagulopathy needs early, aggressive treatment, including aggressive use of fresh frozen plasma.
If undelivered, delivery of the fetus and placenta should be performed as soon as possible.The incidence of uterine
atony is increased in this condition and contributes to the postpartum haemorrhage.This should be managed as
stated in the RCOG Green-top Guideline No. 52: Prevention and Management of Postpartum Haemorrhage.66
Various other therapies have been tried, including steroids, heparin, plasmapheresis and haemofiltration,
usually in single cases. As such, there is no robust evidence to support their use.27
4.6.4 Cardiac disease
After successful resuscitation, cardiac cases should be managed by an expert cardiology team.
After initial resuscitation, the continuing management of cardiac disease is similar to that in the
nonpregnant state, although in many cases delivery will be necessary to facilitate this.
Although thrombolysis can be associated with significant bleeding from the placental site, it should
be given to women with acute coronary insufficiency, although caution should be exercised in the
perioperative period.69 If available, percutaneous angioplasty allows accurate diagnosis and definitive therapy.
Evidence
level 4
4.6.5 Sepsis
Septic shock should be managed in accordance with the Surviving Sepsis Campaign guidelines.
The Surviving Sepsis Campaign has updated the management of sepsis and septic shock.70 The speed and
appropriateness of therapy administered in the initial hours after severe sepsis develops are likely to influence
outcome with early resuscitation improving survival rates. A multidisciplinary team approach is required
including midwives, consultant obstetricians, consultant anaesthetists, consultant haematologists, consultant
intensivists and consultant microbiologists. The following care bundle should be applied immediately or
within 6 hours, and has been shown to significantly improve survival rates:7173
1. Measure serum lactate.
2. Obtain blood cultures/culture swabs prior to antibiotic administration.
3. Administer broad-spectrum antibiotic(s) within the first hour of recognition of severe sepsis and
septic shock according to local protocol
4. In the event of hypotension and/or lactate >4 mmol/l:
a) deliver an initial minimum of 20 ml/kg of crystalloid/ colloid
b) once adequate volume replacement has been achieved, a vasopressor (norepinephrine,
Evidence
epinephrine) and/or an inotrope (e.g. dobutamine) may be used to maintain mean arterial
level 1+
pressure over 65 mmHg.
Further management consists of:
5. In the event of hypotension despite fluid resuscitation (septic shock) and/or lactate over 4 mmol/l:
a) achieve a central venous pressure of at least 8 mmHg (or over 12 mmHg if the woman is
mechanically ventilated) with aggressive fluid replacement
b) consider steroids.
6. Maintain oxygen saturation with facial oxygen. Consider transfusion if haemoglobin is below 7g/dl.
13 of 24
Continuing management involves continued supportive therapy, removing the septic focus, administration of
blood products if required and thromboprophylaxis.71
4.6.6 Drug overdose/toxicity
Many drug overdoses have specific therapy dependent on the drug in question, and appropriate help should
be sought in the management of such cases. In obstetric practice, the two main drugs that can give rise to
overdose or toxic problems are magnesium sulphate and local anaesthetic agents.
4.6.6.1 Magnesium sulphate
The antidote to magnesium toxicity is 10 ml 10% calcium gluconate given by slow intravenous injection.
4.6.6.2 Local anaesthetic agents

If local anaesthetic toxicity is suspected, stop injecting immediately.
Lipid rescue should be used in cases of collapse secondary to local anaesthetic toxicity.
Intralipid 20% should be available in all maternity units.
Treatment of cardiac arrest with lipid emulsion34,73 consists of an intravenous bolus injection of
Intralipid 20% 1.5 ml.kg-1 over 1 minute (100 ml for a 70 kg woman) followed by an intravenous
infusion of Intralipid 20% at 0.25 ml.kg-1 min-1 (400 ml over 20 minutes for a 70 kg woman). The
bolus injection can be repeated twice at 5-minute intervals if an adequate circulation has not been
restored (a further two boluses of 100 ml at 5-minute intervals for a 70 kg woman). After another 5
minutes, the infusion rate should be increased to 0.5 ml.kg-1 min-1 if adequate circulation has not
been restored. CPR should be continued throughout this process until an adequate circulation has
been restored, and this may take over an hour.
Manage arrhythmias as usual, recognising that they may be very refractory to treatment.
Evidence
level 2+
Prolonged resuscitation may be necessary, and it may be appropriate to consider other options. The firstline treatment should be lipid emulsion, but if the facilities are available, some may consider the use of cardiopulmonary bypass.
A copy of the guidance that can be put on the wall locally can be found at http://www.aagbi.org/publica
tions/guidelines/docs/latoxicity07.pdf.
All cases of lipid rescue should be reported to the National Patient Safety Agency (www.npsa.nhs.uk)
and to the Lipid Rescue site (www.lipidrescue.org).
4.6.7 Eclampsia
Eclampsia should be managed in accordance with the RCOG Green-top Guideline No. 10(A): The Management of Severe Pre-eclampsia/Eclampsia.74
4.6.8 Intracranial haemorrhage
Expert neuroradiology is required to establish an accurate diagnosis. Management is the same as in the
nonpregnant state, although delivery may be necessary to facilitate this. The appropriate experts should be
involved at the earliest opportunity.
4.6.9 Anaphylaxis
In cases of anaphylaxis, all potential causative agents should be removed, and the A, B, C, D, E approach
followed.36,75
14 of 24
If the anaphylactic reaction occurs in the community, the woman should receive basic life support and be
transferred to a hospital setting as quickly as possible, unless a suitably trained healthcare professional
is present with appropriate equipment/drugs, in which case definitive resuscitation and treatment should
be commenced.
The definitive treatment for anaphylaxis is 500 micrograms (0.5 ml) of 1:1000 adrenaline intramuscularly. PLEASE NOTE THIS DOSE IS FOR INTRAMUSCULAR USE ONLY.
Adrenaline treatment can be repeated after 5 minutes if there is no effect.36,75 In experienced hands
it can be given intravenously as a 50 microgram bolus (0.5 ml of 1:10 000 solution).Adjuvant therapy
consists of chlopheniramine 10 mg and hydrocortisone 200 mg. Both are given intramuscularly or
by slow intravenous injection.36,75
Evidence
level 1+
4.7 What are the outcomes for mother and baby?

Owing to the lack of robust population data, it is not possible to be accurate regarding outcomes. It is widely
accepted that there is significant selection bias in publications relating to the topic.The Confidential Enquiries
into Maternal Death have given robust data when resuscitation was not successful, and the Scottish Maternal
Morbidity data3 and the Dublin study4 report maternal survival figures for severe maternal morbidity, but not
for collapse per se.These data do give near miss to death ratios of 56:13 and 79:1.4 For some conditions such
as AFE, the maternal survival figures are more robust, but accurate data collection is required for maternal
collapse as a whole.
In 2005, Katz et al. reviewed maternal and fetal outcomes for perimortem caesarean section over an 18-year
period from 1986 to 2004.76 There were 38 procedures, 30 of which resulted in surviving babies between
25 and 42 weeks of gestation, with intact survival most likely with a collapse to delivery interval of 5 minutes
or less. In 18 cases, the cause of the collapse was felt to be irreversible. Of the 20 cases in which the cause of
collapse was known and felt to be reversible, 13 women survived, giving a survival rate of 65%.The paper also
demonstrated the positive effect of the delivery on the maternal circulation, supporting their original advice
of achieving delivery within 5 minutes of collapse if CPR is ineffective,61 which was based on theory and a
single case report.
The latest CEMACH report1 details the neonatal outcomes of the 52 perimortem or postmortem sections that
were performed in which the mothers did not survive. Fifty-four percent were liveborn, although eight out of
these 28 babies died in the early neonatal period. Neonatal survival is associated with advanced gestation and
delivery within a delivery suite or critical care setting, and not the emergency department.
There have been successful cases of somatic support after maternal brain death to facilitate neonatal
outcome,77 the longest being from 15 weeks to delivery at 32 weeks.78 This process is not without difficulties,
both in medical terms and ethically,79 and what is not known is how many such cases have not been
successful. In view of the complex nature of such cases, a multidisciplinary discussion, including the family,
should be conducted in each case.
4.8 Who should be on the team?

In addition to the general arrest team, there should be a senior midwife, an obstetrician and an obstetric
anaesthetist included in the team in cases of maternal collapse.
If the maternity unit is an integral part of a general hospital, the maternal cardiopulmonary resuscitation team
should be the hospital cardiopulmonary arrest team with the addition of:
a senior midwife
the most senior resident obstetrician usually ST 37

a resident anaesthetist who has recognised skills in obstetric anaesthesia usually ST 37.
15 of 24
This will mean that the request needs to be specific with common terminology, so that the switchboard
operators know exactly who to call. While managing the arrest, there must be dialogue between the team
leader, the obstetrician and the obstetric anaesthetist as to how best to manage the pregnant woman.
In stand-alone consultant-led maternity units, or those that are geographically distant from the main general
hospital, the entire arrest team is often made up of staff from within the maternity unit. In this case, the team
is usually made up of senior midwifery staff, operating department practitioners, resident obstetric staff and
the resident obstetric anaesthetist.
The consultant obstetrician and consultant obstetric anaesthetist should be summoned at the time of
the cardiopulmonary arrest call.
The neonatal team should be called early if delivery is likely (antepartum collapse over 22 weeks of
gestation).
Where the woman survives, a consultant intensivist should be involved as soon as possible.
In a stand-alone midwifery unit or a homebirth environment, the midwifery staff should provide life support
and call a 999 ambulance to transfer the woman to the nearest appropriate environment. Maternity services
that include a stand-alone midwifery unit should ensure that there is a written agreement with the ambulance
service confirming the emergency status of a 999 call from the midwifery unit, which must not be considered
a place of safety as an NHS facility
5.
Clinical governance
5.1 Documentation
Accurate documentation in all cases of maternal collapse, whether or not resuscitation is successful, is
essential.
Poor documentation remains a problem in all aspects of medicine, and can have potential medico-legal
consequences.80 Contemporaneous note-keeping is difficult in a resuscitation situation, unless someone is
scribing. Those involved should then write full notes as soon as possible after the event.
5.2 Incident reporting

All cases of maternal collapse should generate a clinical incident form and the care should be reviewed
through the clinical governance process.
Maternal collapse is a rare and potentially devastating event, and substandard care continues to be highlighted.14 In all cases of maternal collapse, care should be reviewed to ensure individual and organisational
learning, and also to reassure staff and the family when care has been optimal.
In view of the significant reduction in maternal mortality over the years, robust population-based data
regarding maternal collapse through a national reporting system would render valuable information about
management and outcomes.
All cases of maternal death should be reported to CMACE.
National reporting and scrutiny of maternal deaths continues to provide valuable information and learning.
16 of 24
Evidence
level 1+
5.3 Training
All generic life support training should make mention of the adaptation of CPR in the pregnant woman.
All front-line staff must be aware of the adaptations for CPR in pregnancy.This includes paramedics who will
deal with collapse in the community setting and accident and emergency department personnel as well as
staff within a maternity unit.
All maternity staff should have annual formal training in generic life support and the management of
maternal collapse.
The RCOG, the Royal College of Midwives and CEMACH1 recommend that all staff undergo annual training in
obstetric emergencies, and this is now included in the NHS Litigation Authority,81 Clinical Negligence and
Other Risks (Non-clinical) Indemnity Scheme82 and Welsh Pool Risk83 maternity standards.
Life support training reduces morbidity and mortality.
Small-group interactive practical training is recommended.
A systematic review of life support training showed a significant reduction in morbidity and
mortality,84 and there is now a wealth of evidence emerging to show that multidisciplinary training
in obstetric emergencies improves outcomes.8588
Evidence
level 1+
The best method of training is not clear,89 although there is evidence to support small-group interactive
training.90 Various courses exist,5052 and have been evaluated well by those undertaking them.91 When asked,
those who participated felt that such courses significantly increased their confidence in managing obstetric
emergencies.92 Where outcomes have been seen to improve after the introduction of training, it appears that
the elements of multiprofessional training of all staff and integrating teamwork training with clinical teaching
are important.87,88,93,94 The ideal frequency of training is not clear, but this should occur at least annually for all
staff.95,96 Despite all this evidence in support of training, it cannot be assumed that the presence of training
equates to the receipt of training,97 and this remains a challenge.
5.4 Debriefing
Debriefing is recommended for the woman, her family and the staff involved in the event.
Maternal collapse can be associated with post-traumatic stress disorder, postnatal depression and tocophobia.
Family and staff members should not be forgotten. Debriefing is an important part of holistic maternity care
and should be offered by a competent professional.98
Proportion of staff undergoing annual training in life support.

Proportion of staff undergoing annual training in maternal collapse.
Audit of the management of maternal collapse.
Compliance with incident reporting.
Achievement of perimortem caesarean section within 5 minutes of collapse on hospital premises where
there is no response to resuscitation.
Presence of a perimortem caesarean section tray on resuscitation trolleys.
17 of 24
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82. Scottish Executive. Health Department. Directorate of Finance.
Clinical Negligence and Other Risks (Non-clinical) Indemnity
Scheme (CNORIS). Edinburgh: NHS MEL; 1999
[http://www.sehd.scot.nhs.uk/mels/1999_86.htm].
19 of 24
83. Welsh Risk Pool. Standard 15: Maternity services; 2005.

84. Jabbour M, Osmond MH, Klassen TP. Life support courses: are
they effective? Ann Emerg Med 1996;28:6908.
85. Draycott T, Sibanda T, Owen L, Akande V, Winter C, Reading S, et
al. Does training in obstetric emergencies improve neonatal
outcome? BJOG 2006;113:17782.
86. Draycott TJ, Crofts JF, Ash JP, Wilson LV,Yard E, Sibanda T, et al.
Improving neonatal outcome through practical shoulder
dystocia training. Obstet Gynecol 2008;112:1420.
87. Sibanda T, Crofts JF, Barnfield S, Siassakos D, Epee MJ, Winter C,
et al. PROMPT education and development: saving mothers
and babies lives in resource poor settings. BJOG 2009;4:8689.
88. Siassakos D, Hasafa Z, Sibanda T, Fox R, Donald F, Winter C, et al.
Retrospective cohort study of diagnosis-delivery interval with
umbilical cord prolapse: the effect of team training. BJOG
2009;116:108996.
89. Black RS, Brocklehurst P. A systematic review of training in
acute obstetric emergencies. BJOG 2003;110:83741.
90. Baskett P. Progress of the advanced life support courses in
Europe and beyond. Resuscitation 2004;62:3113.
91. Johanson R, Cox C, ODonnell E, Grady K, Howell C, Jones P.
Managing obstetric emergencies and trauma (MOET).
Structured skills training using models and reality-based
scenarios. TOG 1999;1:4652.
92. Taylor HA, Kiser WR. Reported comfort with obstetrical

emergencies before and after participation in the advanced life
support in obstetrics course. Fam Med 1998:30:1037.
93. Ellis D, Crofts JF, Hunt LP, Read M, Fox R, James M. Hospital,
simulation center, and teamwork training for eclampsia
management: a randomized controlled trial. Obstet Gynecol
2008;111:72331.
94. Siassakos D, Crofts J, Winter C, Weiner CP, Draycott TJ.The active
components of effective training in obstetric emergencies.
BJOG 2009;116:102832.
95. Crofts JF, Bartlett C, Ellis D, Hunt LP, Fox R, Draycott TJ.
Management of shoulder dystocia: skill retention 6 and 12
months after training. Obstet Gynecol 2007;110:106974.
96. Crofts JF, Ellis D, Draycott TJ, Winter C, Hunt LP, Akande VA.
2007;114:153441.
97. Dijkman A, Huisman CM, Smit M, Schutte JM, Zwart JJ, Van
Roosemalen, et al. Cardiac arrest in pregnancy: increasing use
of perimortem caesarean section due to emergency skills
training? BJOG 2010;117:2827.
98. Weston R. When birth goes wrong. Pract Midwife 2001;4:102.
20 of 24
APPENDICES
APPENDIX 1 Post-collapse management algorithm
Patient alive?
Yes
No
Continue treatment
Inform coroner
Transfer to critical care setting
Inform CMACE
Ensure accurate documentation
Debrief patient (if alive) and relatives
Offer staff support and debriefing
Review case through

clinical governance process
21 of 24
APPENDIX 2 Maternal collapse algorithm

Put into left lateral position
Call for help if appropriate
Check maternal obs
Assess fetal wellbeing
Call for obstetric review
No
Call neonatal team if

>22 weeks of gestation
Unresponsive?
Yes
Open airway
Look for signs of life
Call obstetric
resuscitation team
Wedge/tilt patient
If no response to CPR after

4 minutes, proceed to
delivery/perimortem
caesarean section
CPR 30:2
Until defibrillator/monitor
attached
Call consultant
obstetrician and
anaesthetist
100% supplemental O2
Intubate early
Insert two IV cannulae
(wide-bore)
Assess rhythm
Shockable
(VF/pulseless VT)
Non-shockable
(PEA/asystole)
1 shock
150360 J biphasic or
360 J monophasic
Return of
spontaneous
circulation
Immediately resume
CPR for 2 minutes
minimise interruptions
Immediate postcardiac arrest

treatment
Use ABCDE approach
Controlled oxygenation and
ventilation
12-lead ECG
Treat precipitating cause
Temperature
control/therapeutic
hypothermia
During CPR:
Ensure high-quality CPR: rate,
depth, recoil
Plan actions before interrupting CPR
Give oxygen
Consider advanced airway and
capnography
Continuous chest compressions
when advanced airway in place
Vascular access (intravenous,
intraosseus)
Give adrenaline every 35 minutes
Correct reversible causes
Immediately resume
CPR for 2 minutes
minimise interruptions
Reversible causes:
Hypoxia
Hypovolaemia
Hypo/hyperkalaemia/metabolic
Hypothermia
Thrombosis coronary or
pulmonary
Tamponade cardiac
Toxins
Tension pneumothorax
KEY
ABCDE = airway, breathing, circulation, disability, exposure; CPR = cardiopulmonary resuscitation;
RCG = electrocardiogram; PEA = pulseless electrical activity; VF = ventricular fibrillation; VT = ventricular tachycardia
22 of 24
APPENDIX 3
Governance Advice No.1: Development of RCOG Green-top Guidelines (available on the RCOG website
of clinical uncertainty where further research may be indicated.

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
23 of 24

development group
Gynaecologists by:
Dr TA Johnston FRCOG, Birmingham and Dr K Grady BSc FRCA FFPMRCA, Consultant in Pain Medicine
and Anaesthesia, Department of Anaesthesia, University Hospital of South Manchester Foundation Trust.
and peer reviewed by the British Maternal and Fetal Medicine Society; the Centre for Maternal and Child Enquiries;
the College of Emergency Medicine; the Obstetric Anaesthetists Association; the Resuscitation Council (UK);
the Royal College of Anaesthetists; the Royal College of Midwives; the Royal College of Pathologists;
the British Society for Haematology; the Intensive Care National Audit & Research Centre;
the Joint Royal Colleges Ambulance Liaison Committee.
The Guidelines Committee lead peer reviewers were: Mr M Griffiths FRCOG, Luton and
Mr SK Surendran FRCOG, London.
DISCLAIMER
This means that RCOG guidelines are unlike protocols or guidelines issued by employers, as they are not intended to
24 of 24
Reduced Fetal Movements

February 2011
Reduced Fetal Movements

1.
Purpose and scope
The purpose of this guideline is to provide advice to guide clinicians, based on the best evidence where
available, regarding the management of women presenting with reduced fetal movements (RFM) during
pregnancy.This guideline reviews the risk factors for RFM in pregnancy and factors influencing maternal
perception. It provides recommendations as to how women presenting in both the community and
hospital settings should be managed. This guideline excludes the management of RFM in multiple
pregnancy.As is apparent from the low grading of the evidence for many of the recommendations, they
have been developed to provide a broad practical guide for midwives and obstetricians in clinical practice.
However, it is recognised that in individual women alternative approaches may be reasonable
1.1 Population and setting

Pregnant women in community or hospital settings reporting RFM in singleton pregnancies.
1.2 Interventions to be studied

Comparison of modalities to detect and manage women perceiving RFMs.
2.
Background
Maternal perception of fetal movement is one of the first signs of fetal life and is regarded as a manifestation
of fetal wellbeing.1,2 Movements are first perceived by the mother between 18 and 20 weeks of gestation
and rapidly acquire a regular pattern.Fetal movements have been defined as any discrete kick,flutter,swish
or roll.3 A significant reduction or sudden alteration in fetal movement is a potentially important clinical
sign. It has been suggested that reduced or absent fetal movements may be a warning sign of impending
fetal death. Studies of fetal physiology using ultrasound have demonstrated an association between RFM
and poor perinatal outcome.4,5 The majority of women (55%) experiencing a stillbirth perceived a
reduction in fetal movements prior to diagnosis.6 A number of studies of fetal deaths in Norway and the
UK identified that an inappropriate response by clinicians to maternal perception of RFM was a common
contributory factor in stillbirth.7,8
3.
Guidelines.Medline, Pubmed, all EBM reviews (Cochrane CRCT, Cochrane Database of Systematic Reviews,
Methodology register, ACP journal club, DARE, HTA, Maternity and Infant Care), EMBASE and TRIP were
searched for relevant randomised controlled trials,systematic reviews and meta-analyses,cohort studies and
case studies.The search was restricted to articles published between 1980 and November 2008. Search
words included fetal activity, fetal movement + detection, reduced fetal movement, fetal cardiotocography,fetal heart auscultationandumbilical artery Doppler,including all relevant MeSH terms.The
search was limited to humans and the English language.The National Library for Health and the National
Guidelines Clearing House were also searched for relevant guidelines.Where possible, recommendations
are based on available evidence; areas where evidence is lacking are annotated as good practice points
(designated by a tick).
3.1 Limitations of data used in this guideline

Interpreting studies of women perceiving RFM is complicated by multiple definitions of normal and
abnormal fetal movements (discussed in detail in section 5 of this guideline) and a paucity of large-scale
2 of 16
(over 1000 participants) descriptive or intervention studies.There are no randomised controlled trials
addressing the management of RFM.The main outcome of interest stillbirth is relatively uncommon and
adequately powered studies of different management protocols would require large numbers of participants. Consequently, many studies have limitations in terms of definition of RFM and outcomes,
ascertainment bias and selection bias.
4.
What are considered normal fetal movements during pregnancy?
Most women are aware of fetal movements by 20 weeks of gestation.
Clinicians should be aware (and should advise women) that although fetal movements tend to plateau
at 32 weeks of gestation, there is no reduction in the frequency of fetal movements in the late third
trimester.
Perceived fetal movements are defined as the maternal sensation of any discrete kick,flutter, swish or roll.3
Such fetal activity provides an indication of the integrity of the central nervous and musculoskeletal
systems.The normal fetus is active and capable of physical movement, and goes through periods of both
rest and sleep.The majority of women perceive fetal movements and intuitively view their experience of
fetal activity as normal.
From 1820 weeks of gestation, most pregnant women become aware of fetal activity, although
some multiparous women may perceive fetal movements as early as 16 weeks of gestation and
some primiparous women may perceive movement much later than 20 weeks of gestation.1
The number of spontaneous movements tends to increase until the 32nd week of pregnancy.9
11
From this stage of gestation, the frequency of fetal movements plateaus until the onset of
labour; however, the type of fetal movement may change as pregnancy advances in the third
trimester.913 By term, the average number of generalised movements per hour is 31 (range 16
45),with the longest period between movements ranging from 50 to 75 minutes.Changes in the
number and nature of fetal movements as the fetus matures are considered to be a reflection of
the normal neurological development of the fetus. From as early as 20 weeks of gestation, fetal
movements show diurnal changes. The afternoon and evening periods are periods of peak
activity.14,15 Fetal movements are usually absent during fetal sleep cycles, which occur regularly
throughout the day and night and usually last for 2040 minutes.5,16 These sleep cycles rarely
exceed 90 minutes in the normal, healthy fetus.1618
Evidence
level 2
Because of the paucity of robust epidemiological studies on fetal activity patterns and maternal perception
of fetal activity in normal pregnancies, there is currently no universally agreed definition of RFM.
5.
Are there factors which influence a womans perception of this activity?
Women should be advised of the need to be aware of fetal movements up to and including the onset of
labour and should report any decrease or cessation of fetal movements to their maternity unit.
Fetal activity is influenced by a wide variety of factors.There is some evidence that women perceive most
fetal movements when lying down, fewer when sitting and fewest while standing.15 It is therefore not
surprising that pregnant women who are busy and not concentrating on fetal activity often report a misperception of a reduction of fetal movements.12,17 Johnson demonstrated that when attention is paid to fetal
activity in a quiet room and careful recordings are made, fetal movements that were not previously
perceived are often recognised clearly.19,20
Prior to 28+0 weeks of gestation, an anteriorly positioned placenta may decrease a womans
perception of fetal movements.21
3 of 16
Evidence
level 2
Sedating drugs which cross the placenta such as alcohol,benzodiazepines,methadone and other
opioids can have a transient effect on fetal movements.22,23
Evidence
level 3
Several observational studies have demonstrated an increase in fetal movements following the elevation
of glucose concentration in maternal blood, although other studies refute these findings.24,25 From 30
weeks of gestation onwards, the level of carbon dioxide in maternal blood influences fetal respiratory
movements, and some authors report that cigarette smoking is associated with a decrease in fetal
activity.22,26,27
The administration of corticosteroids to enhance fetal lung maturation has been reported by
some authors to decrease fetal movements and fetal heart rate variability detected by
cardiotocography (CTG) over the 2 days following administration.2830 The pathophysiology of
corticosteroid changes in fetal movement and fetal heart rate variability is still unclear and has
not been definitely proven.2831 Evidence level 2-
Evidence
level 2
Fetuses with major malformations are generally more likely to demonstrate reduced fetal activity.31
However,normal or excessive fetal activity has been reported in anencephalic fetuses.32,33 A lack of vigorous
motion may relate to abnormalities of the central nervous system, muscular dysfunction or skeletal
abnormalities.34
Fetal presentation has no effect on perception of movement.35
Evidence
level 2+
Fetal position might influence maternal perception: 80% of fetal spines lay anteriorly in women
who were unable to perceive fetal movements despite being able to visualise them when an
ultrasound scan was performed.36
6.
Evidence
level 2
How can fetal movements be assessed?
Fetal movements should be assessed by subjective maternal perception of fetal movements.
Fetal movements are most commonly assessed by maternal perception alone. Studies on the
correlation between maternal perception of fetal movements and fetal movements concurrently
detected on ultrasound scans show wide variation, with correlation ranging from 37 to 88%
and large body movements and those lasting more than 7 seconds most likely to be felt.3743
The greatest number of fetal movements are noted when the mother is lying down, and the
number appears to be greatest in the evening.12 This may be an effect of concentrating on fetal
movements.The difference in mean time to perceive 10 movements varied between 21 minutes
for focused counting to 162 minutes with unfocused perception of fetal movements.4,17
Evidence
level 2
Objective assessments of fetal movements use Doppler or real-time ultrasound to detect fetal
movement.These studies report slightly increased sensitivity for fetal movements recorded by
ultrasound, with 31.457.2% of all movements recorded compared with 30.8% for maternally
perceived fetal movements.44,45 However, the duration of recording is restricted to 2030
minutes with the mother in a semi-recumbent position. There are no studies which have
evaluated the use of longer periods of fetal movement counting by Doppler ultrasound or
whether this method can detect fetuses at risk of stillbirth. Given the potential detection of
false-positive signals from maternal abdominal wall movements such as coughing, this may not
be a useful means to objectively measure fetal movements in all pregnant women.46
Evidence
level 2
4 of 16
7.
Should fetal movements be counted routinely in a formal manner?
There is insufficient evidence to recommend formal fetal movement counting using specified alarm limits.
Women should be advised to be aware of their babys individual pattern of movements. If they are
concerned about a reduction in or cessation of fetal movements after 28+0 weeks of gestation, they should
contact their maternity unit.
Women who are concerned about RFM should not wait until the next day for assessment of fetal
wellbeing.
If women are unsure whether movements are reduced after 28+0 weeks of gestation, they should be
advised to lie on their left side and focus on fetal movements for 2 hours. If they do not feel 10 or more
discrete movements in 2 hours, they should contact their midwife or maternity unit immediately.
Clinicians should be aware that instructing women to monitor fetal movements is potentially associated
with increased maternal anxiety.

C
Formal fetal movement counting relies on a woman counting fetal movements and, if she perceives fewer
movements than a specified alarm limit, contacting her care provider.There are a number of problems
with this strategy. First, there is a wide range of normal fetal movements, leading to wide variability among
mothers. Second, the most frequently used alarm limit was developed in high-risk patients who counted
fetal movements while hospital inpatients;therefore,these observations may not be applicable to a general
population.47 Ideally, an alarm limit would be developed using the whole obstetric population and then
be proved to reduce stillbirth rates in a prospective study.48
There have been five studies evaluating maternal assessment of fetal movements. Grant et al.
published a multicentre study randomising women (n=68 654) to counting fetal movements
using the count-to-ten chart or a non-counting group. These groups were contaminated as
women in the non-counting group were also instructed to count fetal movements if they were
deemed high risk.4 There was no reduction in perinatal mortality in the group randomised to
counting fetal movements, although the number of women presenting initially with a live fetus
that was subsequently stillborn was greater in the counting cohort (11 versus six).The studys
authors acknowledged that these intrauterine deaths may have been preventable,resulting from
false reassurance from CTG and clinical error. Importantly, the perinatal mortality rate for the
whole study population fell to 2.9 per 1000 compared with 4.0 per 1000 reported prior to the
study, suggesting that participation in the trial may have been beneficial (the Hawthorne
effect).49
Evidence
level 2
In a smaller randomised trial (n=2250), patients were randomised to focus on fetal movements
for 2 hours three times a week or given no information.3 There were eight intrauterine deaths,
all in the control group, leading to a significant decrease in perinatal mortality in women who
formally counted fetal movements.Over 75% of this study population were classified as high risk.
Evidence
level 2+
Moore and Piacquadio used a retrospective casecontrol design.17 In a period when women
counted fetal movements for 2 hours a day but were not given any alarm limits, the perinatal
mortality rate was 8.7 per 1000 (n=2519).The study was then extended to 5758 women who
were instructed to present for further investigation if they had not felt 10 movements after 2
hours of focused counting.50 During this period the perinatal mortality rate was 3.6 per 1000.
This extension of the study was associated with increased hospital attendances, rates of
induction of labour (7.9% versus 4.4%) and emergency caesarean birth for fetal distress (2.4%
versus 0.8%). Evidence level 2-
Evidence
level 2
5 of 16
Westgate and Jamieson compared the rates of stillbirth before and after the introduction of the
count-to-ten charts in New Zealand.51 They describe a significant reduction in the stillbirth rate
from 10.8 to 8.2 per 1000 total births. Other service improvements introduced over this period
may also have had an impact on the perinatal mortality rate.
Evidence
level 2
In Norway, a comparison was made between the incidence of stillbirth before and after women
were given written information about decreased fetal movements and a standard protocol for
the management of RFM was introduced.52 The incidence of stillbirth fell from 3.0 to 2.0 per
1000 during the intervention period. In women perceiving RFM, the rate dropped from 42 to
24 per 1000.
Evidence
level 2+
While normal perception of fetal movements is associated with a positive effect on maternal
fetal attachment,52,53 the effect of monitoring fetal movements is equivocal. Two studies
(including one randomised controlled trial) reported no adverse effects.54,55 A small retrospective
cohort found that 23% of women reported anxiety and a further 16% felt that monitoring fetal
movements was useless and a nuisance.56 Perception of RFM itself is associated with increased
maternal anxiety.57,58 Clinicians should be aware that the risk of stillbirth (in the absence of
congenital anomaly) in the UK is less than one in 250 births. Any study of the utility of fetal
movements as a screening test must take account of the potentially deleterious effects of
maternal stress and anxiety.
Evidence
level 2+
8.
What is the optimal management of women with RFM?
The initial goal of antenatal fetal surveillance in cases of RFM is to exclude fetal death. Subsequent to this,
the aim is to exclude fetal compromise and to identify pregnancies at risk of adverse pregnancy outcome
while avoiding unnecessary interventions. A large cross-sectional survey revealed wide variations in
knowledge and practice among both obstetricians and midwives with regard to management of women
presenting with RFM. Although most clinicians recognised the association with fetal growth restriction
(FGR), this did not translate into practice as professionals seldom undertook further assessment to identify
FGR.59
8.1 What should be included in the clinical history?

Upon presenting with RFM, a relevant history should be taken to assess a womans risk factors for
stillbirth and FGR.
All clinicians should be aware of the potential association of decreased fetal movements with key risk
factors such as FGR, small-for-gestational-age (SGA) fetus, placental insufficiency and congenital malformations.
If after discussion with the clinician it is clear that the woman does not have RFM, there are no other risk
factors for stillbirth and there is the presence of a fetal heart rate on auscultation, she can be reassured.
However, if the woman still has concerns, she should be advised to attend her maternity unit.
Women noticing a sudden change in fetal activity or in whom other risk factors for stillbirth are identified
should report to their maternity unit for further investigation (see section 6.3).

C
A history of RFM should be taken, including the duration of RFM, whether there has been absence of fetal
movements and whether this is the first occasion the woman has perceived RFM.The history must include
a comprehensive stillbirth risk evaluation, including a review of the presence of other factors associated
with an increased risk of stillbirth, such as multiple consultations for RFM, known FGR, hypertension,
diabetes, extremes of maternal age, primiparity, smoking, placental insufficiency, congenital malformation,
obesity, racial/ethnic factors, poor past obstetric history (e.g. FGR and stillbirth), genetic factors and issues
6 of 16
with access to care. Clinicians should be aware that a womans risk status is fluid throughout pregnancy
and that women should be transferred from low-risk to high-risk care programmes if complications occur.60
If after discussion with the clinician it is clear that the woman does not have RFM,in the absence of further
risk factors and the presence of a normal fetal heart rate on auscultation,there should be no need to follow
up with further investigations.
8.2 What should be covered in the clinical examination?

If a woman presents with RFM in the community setting with no facility to auscultate the fetal heart, she
should be referred immediately to her maternity unit for auscultation.
When a woman presents with RFM in the community or hospital setting, an attempt should be made to
auscultate the fetal heart using a handheld Doppler device to exclude fetal death.
Clinical assessment of a woman with RFM should include assessment of fetal size with the aim of detecting SGA
fetuses.
The key priority when a woman presents with RFM is to confirm fetal viability. In most cases, a
handheld Doppler device will confirm the presence of the fetal heart beat. This should be
available in the majority of community settings in which a pregnant woman would be seen by
a midwife or general practitioner. The fetal heart beat needs to be differentiated from the
maternal heart beat.This is easily done in most cases by noting the difference between the fetal
heart rate and the maternal pulse rate. If the presence of a fetal heart beat is not confirmed,
immediate referral for ultrasound scan assessment of fetal cardiac activity must be undertaken.
If the encounter with the woman has been over the telephone and there is thus no additional
reassurance of auscultation of the fetal heart, the woman should be advised to report for further
assessment.
Evidence
level 2+
Methods employed to detect SGA fetuses include abdominal palpation, measurement of symphysisfundal
height and ultrasound biometry.The RCOG guidelines on the investigation and management of the SGA
fetus recommend use of a customised fundal height chart.61 Consideration should be given to the judicious
use of ultrasound to assess fetal size in women in whom clinical assessment is likely to be less accurate,
for example those with a raised body mass index. As pre-eclampsia is also associated with placental
dysfunction, it is prudent to measure blood pressure and test urine for proteinuria in women with RFM.
8.3 What is the role of CTG?

After fetal viability has been confirmed and history confirms a decrease in fetal movements, arrangements
should be made for the woman to have a CTG to exclude fetal compromise if the pregnancy is over 28+0
weeks of gestation.
CTG monitoring of the fetal heart rate, initially for at least 20 minutes, provides an easily
accessible means of detecting fetal compromise. The presence of a normal fetal heart rate
pattern (i.e. showing accelerations of fetal heart rate coinciding with fetal movements) is
indicative of a healthy fetus with a properly functioning autonomic nervous system. Interpretation of the CTG fetal heart rate pattern is assisted by adopting the National Institute for Health
and Clinical Excellence classification of fetal heart rate patterns.62 The fetal heart rate accelerates
with 9297% of all gross body movements felt by the mother.63,64 Computer systems for interpretation of CTG provide objective data, reduce intra- and inter-observer variation and are more
accurate than clinical experts in predicting umbilical acidosis and depressed Apgar scores.
However, further evaluation of this technology is required before clinical recommendations can
be made.65
7 of 16
Evidence
level 3
Several studies have concluded that if the term fetus does not experience a fetal heart rate
acceleration for more than 80 minutes, fetal compromise is likely to be present.6668 However, a
systematic review in the Cochrane Database of Systematic Reviews did not confirm or refute any
benefits of routine CTG monitoring of at risk pregnancies.69 The authors acknowledged several
limitations, including limited numbers of women (four trials and 1588 women) and serious
methodological concerns, such as the fact that the trials were conducted in the early 1980s
when CTG monitoring was just being introduced into routine clinical practice.
Evidence
level 2
In a Norwegian study of 3014 women who presented with RFM,a CTG was performed in 97.5%
of cases, with an abnormality such as FGR, fetal distress, oligohydramnios or malformations
detected in 3.2% of cases.58 In a different observational study of women presenting with RFM
who had an initial CTG and an ultrasound scan, 21% had an abnormality detected that required
action and 4.4% were admitted for immediate delivery.70 Another study showed that stillbirth
rates (corrected for lethal congenital anomalies) after a reactive or non-reactive CTG were 1.9
and 26 per 1000 births,respectively.71 Lastly,a relatively small study reported that 56% of women
with a high-risk pregnancy who reported RFM had an abnormal CTG.This was associated with
an unfavourable perinatal outcome in nine out of ten cases.40
Evidence
level 2+
8.4 What is the role of ultrasound scanning?

Ultrasound scan assessment should be undertaken as part of the preliminary investigations of a woman
presenting with RFM after 28+0 weeks of gestation if the perception of RFM persists despite a normal
CTG or if there are any additional risk factors for FGR/stillbirth.
If an ultrasound scan assessment is deemed necessary, it should be performed when the service is next
available preferably within 24 hours.
Ultrasound scan assessment should include the assessment of abdominal circumference and/or
estimated fetal weight to detect the SGA fetus, and the assessment of amniotic fluid volume.
Ultrasound should include assessment of fetal morphology if this has not previously been performed
and the woman has no objection to this being carried out.
There are no randomised controlled trials of ultrasound scan versus no ultrasound scan in
women with RFM.Froen et al.conducted a prospective population-based cohort study of 46 132
births in eastern Norway and Bergen over a 17-month period from 2006 to 2007.57 In the
prospective cohort of 3014 women presenting with RFM, ultrasound scanning was performed
in 94% of cases and detection of an abnormality such as FGR,reduced amniotic fluid volume and
abnormal fetal morphology or Doppler of the umbilical artery was reported in 11.6% of cases.
Umbilical artery Doppler alone did not provide uniquely valuable information in any case.
Evidence
level 2+
In a recent quality improvement programme in Norway, a prospective before and after study
design was used to evaluate the combined impact of providing women with information on
RFM and clinicians with clinical practice guidelines.13,34,72 After an initial period of study (n=19
407), an investigation protocol of CTG and ultrasound scan was introduced in the management
of women with RFM (n=46 143). The guideline recommended that both investigations be
performed within 2 hours if women reported no fetal movements, and within 12 hours if they
reported RFM.The ultrasound scan was conducted to assess amniotic fluid volume,fetal size and
fetal anatomy; the addition of Doppler studies to the investigation protocol did not show any
additional benefit.There was a significant reduction in all stillbirths from 3.0 to 2.0 per 1000,
and from 4.2% to 2.4% of women presenting with RFM.The study reported no increase in the
number of preterm births, infants requiring transfer to neonatal care or infants with severe
neonatal depression or FGR.There was more than a doubling in the number of ultrasound scans
Evidence
level 2
8 of 16
(OR 2.64; 95% CI 2.023.45), but this seemed to be compensated by a reduction in additional
follow-up consultations and admissions for induction of labour.
Evidence
level 2
In a study of 489 women with RFM, Ahn et al. demonstrated that women with RFM but no
additional pregnancy risk factors did not require further follow-up once the CTG and the
amniotic fluid volume were confirmed to be normal.73 However, the study found a 3.7 times
greater likelihood of diminished amniotic fluid volume on scan in their study population.
Evidence
level 2
8.5 Is there any role for the biophysical profile (BPP)?

There may be a role for the selective use of BPP in the management or investigation of RFM.
The basis of the BPP is the observed association between hypoxia (low levels of oxygen) and
alterations of measures of central nervous system performance such as fetal heart rate patterns,
fetal movement and fetal tone, which have been observed in both human and animal fetuses.74
A systematic review of the use of BPP in women with high-risk pregnancies, including women
with RFM, included five poor-quality studies with fewer than 3000 patients.75 The systematic
review concluded that the available evidence from randomised controlled trials does not
support the use of BPP as a test of fetal wellbeing in high-risk pregnancies. It should be noted,
however, that there is evidence from uncontrolled observational studies that BPP in high-risk
women has good negative predictive value; that is, fetal death is rare in women in the presence
of a normal BPP.76
9.
Evidence
level 1
What is the optimal surveillance method for women who have presented with RFM in
whom investigations are normal?
Women should be reassured that 70% of pregnancies with a single episode of RFM are uncomplicated.
There are no data to support formal fetal movement counting (kick charts) after women have perceived
RFM in those who have normal investigations.
Women who have normal investigations after one presentation with RFM should be advised to contact
their maternity unit if they have another episode of RFM.
The majority of women (approximately 70%) who perceive a reduction in fetal movements will
have a normal outcome to their pregnancy.7779 There are no studies of the follow-up of women
who have normal investigations. Some practitioners advocate commencing formal fetal
movement counting in this situation.57 There is no evidence to support this strategy. Formal
fetal movement counting in this situation is subject to the same difficulties as in the general
obstetric population.
Evidence
level 2/+
In a single retrospective cohort study, perinatal outcome was worse in women who had
presented on more than one occasion with RFM.79 If a woman experiences a further episode
of definite RFM, she should be referred for hospital assessment to exclude signs of compromise
through the use of CTG and ultrasound, as outlined in section 8.
Evidence
level 2
10. What is the optimal management of the woman who presents recurrently with reduced
RFM?
When a woman recurrently perceives RFM, her case should be reviewed to exclude predisposing causes.
When a woman recurrently perceives RFM, ultrasound scan assessment should be undertaken as part of
the investigations.
9 of 16
Caregivers should be aware of the increased risk of poor perinatal outcome in women presenting with
recurrent RFM.
Women who present on two or more occasions with RFM are at increased risk of a poor
perinatal outcome (stillbirth, FGR or preterm birth) compared with those who attend on only
one occasion (OR 1.92; 95% CI 1.213.02).79 There are no studies to determine whether
intervention (e.g. delivery or further investigation) alters perinatal morbidity or mortality in
women presenting with recurrent RFM.Therefore,the decision whether or not to induce labour
at term in a woman who presents recurrently with RFM when the growth, liquor volume and
CTG appear normal must be made after careful consultant-led counselling of the pros and cons
of induction on an individualised basis.
11.
Evidence
level 2
What is the optimal management of RFM before 24+0 weeks of gestation?
If a woman presents with RFM prior to 24+0 weeks of gestation, the presence of a fetal heartbeat should
be confirmed by auscultation with a Doppler handheld device.
If fetal movements have never been felt by 24 weeks of gestation, referral to a specialist fetal medicine
centre should be considered to look for evidence of fetal neuromuscular conditions.
There are no studies looking at the outcome of women who present with RFM before 24+0 weeks of
gestation.While placental insufficiency rarely presents before the first trimester, the fetal heartbeat should
be auscultated to exclude fetal demise.There is limited evidence from a number of case reports that women
who present having failed to feel fetal movements at all may have a fetus with an underlying neuromuscular
condition.8084 A routine full antenatal check-up should be carried out, including listening to the fetal heart.
12. What is the optimal management of RFM between 24+0 and 28+0 weeks of gestation?
If a woman presents with RFM between 24+0 and 28+0 weeks of gestation, the presence of a fetal heartbeat
should be confirmed by auscultation with a Doppler handheld device.
There are no studies looking at the outcome of women who present with RFM between 24+0 and 28+0
weeks of gestation.The fetal heartbeat should be confirmed to check fetal viability. History must include
a comprehensive stillbirth risk evaluation, including a review of the presence of other risk factors
associated with an increased risk of stillbirth. Clinicians should be aware that placental insufficiency may
present at this gestation.There is no evidence to recommend the routine use of CTG surveillance in this
group. If there is clinical suspicion of FGR, consideration should be given to the need for ultrasound
assessment.There is no evidence on which to recommend the routine use of ultrasound assessment in this
group.
13. What should we document in the maternal records?

It is important that full details of assessment and management are documented. It is also important to
record the advice given about follow-up and when/where to present if a further episode of RFM is
perceived. Accurate record keeping is needed in sufficient detail to ensure that the consultation and
outcome can be easily audited and continuity of care provided.
Existence of a guideline on RFM.

Percentage of women over 28+0 weeks of gestation in whom history confirms RFM having a CTG to
exclude fetal compromise.
10 of 16
Percentage of women having ultrasound scan assessment as part of the preliminary investigation of
women presenting with confirmed RFM if the perception of RFM persists despite a normal CTG or
if there are any additional risk factors for FGR/stillbirth.
Percentage of women presenting with recurrent RFM referred for a growth scan and liquor volume
assessment.
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58. Saastad E,Ahlborg T, Fren JF. Low maternal awareness of
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Appendix 1
Attends with first presentation of reduced fetal movements (RFM) at >28+0 weeks of gestation
Detailed clinical history including risk factors for stillbirth and fetal growth restriction (FGR)
History confirms RFM
History does not confirm RFM
Auscultate with handheld Doppler to exclude

intrauterine fetal death (IUFD)
FH not present on
auscultation
FH present on
auscultation
Immediate
ultrasound to
exclude/diagnose
IUFD
Offer to auscultate fetal heart (FH)

Routine antenatal assessment
Give advice re: further episodes of RFM
If unsure whether fetal movements are reduced, focus on fetal
movements for 2 hours
If they do not feel more than 10 movements in 2 hours, contact
healthcare provider
Cardiotocograph to exclude imminent fetal

compromise
Normal fetal heart rate pattern
Suspicious or pathological fetal

heart rate pattern
IUFD
Manage as per unit

protocol
Abnormality detected on scan
Continue with RFM or risk factors

for FGR/stillbirth
Perception of RFM resolved and no risk

factors for FGR/stillbirth
Ultrasound for amniotic fluid

volume/abdominal
circumference/estimated fetal
weight
Reassure
Give advice re: further episodes of RFM
If unsure whether fetal movements are
reduced, focus on fetal movements for
2 hours
If they do not feel more than 10
movements in 2 hours, contact
maternity unit
Normal scan
14 of 16
Appendix 2
using a standardised methodology.Exact details of this process can be found in Clinical Governance Advice
No.1: Development of RCOG Green-Top Guidelines (available on the RCOG website at http://www.rcog.
org.uk/womens-health/clinical-guidance/development-rcog-green-top-guidelines-policies-and-processes).
These recommendations are not intended to dictate an exclusive course of management or treatment.
They must be evaluated with reference to individual patient needs,resources and limitations unique to the
institution and variations in local populations. It is hoped that this process of local ownership will help to
incorporate these guidelines into routine practice.Attention is drawn to areas of clinical uncertainty where
further research may be indicated.

1+

low risk of bias

risk of bias

2+
2-

is not causal

case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
15 of 16

development group
This guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and Gynaecologists by:
Dr MK Whitworth MRCOG, Manchester, Professor M Fisher, Exeter and Dr A Heazell MRCOG, Manchester
and peer-reviewed by: the British Maternal and Fetal Medicine Society (BMFMS); RCOG Consumers Forum; Professor Sir
S Arulkumaran FRCOG, London; Mrs A Diyaf MRCOG, Birmingham; Mr D Fraser FRCOG, Norfolk; Dr T Kay MRCOG,Exeter;
Mr TG Overton FRCOG, Bristol; Dr S Yong MRCOG, Hong Kong.
The Guidelines Committee lead reviewers were: Mr M Griffiths FRCOG, Luton and Dr P Owen MRCOG, Glasgow.
DISCLAIMER
16 of 16

March 2011
Best Practice in
Outpatient Hysteroscopy
RCOG/BSGE Joint Guideline
Best Practice in Outpatient Hysteroscopy


Service provision
All gynaecology units should provide a dedicated outpatient hysteroscopy service to
aid management of women with abnormal uterine bleeding. There are clinical and
economic benefits associated with this type of service.
Outpatient hysteroscopy should be conducted outside of the formal operating theatre
setting in an appropriately sized, equipped and staffed treatment room with adjoining, private changing facilities and toilet.
Outpatient hysteroscopy should be performed in an appropriately sized and fully
equipped treatment room. This may be a dedicated hysteroscopy suite or a multipurpose facility.

The healthcare professional should have the necessary skills and expertise to carry
out hysteroscopy.
There should be a nurse chaperone regardless of the gender of the clinician.
Written patient information should be provided before the appointment and consent
for the procedure should be taken.
Analgesia
Routine use of opiate analgesia before outpatient hysteroscopy should be avoided as
it may cause adverse effects.
Women without contraindications should be advised to consider taking standard

doses of non-steroidal anti-inflammatory agents (NSAIDs) around 1 hour before their
scheduled outpatient hysteroscopy appointment with the aim of reducing pain in the
immediate postoperative period.
Cervical preparation
Routine cervical preparation before outpatient hysteroscopy should not be used in
the absence of any evidence of benefit in terms of reduction of pain, rates of failure
or uterine trauma.
Type of hysteroscope
Miniature hysteroscopes (2.7 mm with a 33.5 mm sheath) should be used for diagnostic outpatient hysteroscopy as they significantly reduce the discomfort experienced
by the woman.
2 of 22
There is insufficient evidence to recommend 0 or fore-oblique optical lenses (i.e.

12, 25 or 30 off-set lenses) for routine outpatient hysteroscopy. Choice of hysteroscope should be left to the discretion of the operator.
Flexible hysteroscopes are associated with less pain during outpatient hysteroscopy
compared with rigid hysteroscopes. However, rigid hysteroscopes may provide better
images, fewer failed procedures, quicker examination time and reduced cost. Thus,
there is insufficient evidence to recommend preferential use of rigid or flexible
hysteroscopes for diagnostic outpatient procedures. Choice of hysteroscope should
be left to the discretion of the operator.

B
Distension medium
For routine outpatient hysteroscopy, the choice of distension medium between
carbon dioxide and normal saline should be left to the discretion of the operator as
neither is superior in reducing pain, although uterine distension with normal saline
appears to reduce the incidence of vasovagal episodes.
Uterine distension with normal saline allows improved image quality and allows
outpatient diagnostic hysteroscopy to be completed more quickly compared with
carbon dioxide.
Operative outpatient hysteroscopy, using bipolar electrosurgery, requires the use of

normal saline to act as both the distension and conducting medium.
Local anaesthesia and cervical dilatation

Blind cervical dilatation to facilitate insertion of the miniature outpatient hysteroscope is unnecessary in the majority of procedures. Routine cervical dilatation is
associated with pain, vasovagal reactions and uterine trauma and should be avoided.
Cervical dilatation generally requires administration of local cervical anaesthesia.
Standard protocols regarding the type, maximum dosage and route of administration
of anaesthesia should be developed and implemented to help both recognise and
prevent rare but potentially serious adverse effects resulting from systemic vascular
absorption.
Instillation of local anaesthetic into the cervical canal does not reduce pain during
diagnostic outpatient hysteroscopy but may reduce the incidence of vasovagal
reactions.
Topical application of local anaesthetic to the ectocervix should be considered where

application of a cervical tenaculum is necessary.
Application of local anaesthetic into or around the cervix is associated with a reduction of the pain experienced during outpatient diagnostic hysteroscopy. However, it
is unclear how clinically significant this reduction in pain is. Consideration should
be given to the routine administration of intracervical or paracervical local
anaesthetic, particularly in postmenopausal women.
3 of 22
Miniaturisation of hysteroscopes and increasing use of the vaginoscopic technique

may diminish any advantage of intracervical or paracervical anaesthesia. Routine
administration of intracervical or paracervical local anaesthetic should be used where
larger diameter hysteroscopes are being employed (outer diameter greater than
5mm) and where the need for cervical dilatation is anticipated (e.g. cervical stenosis).
Routine administration of intracervical or paracervical local anaesthetic is not
indicated to reduce the incidence of vasovagal reactions.
Conscious sedation
Conscious sedation should not be routinely used in outpatient hysteroscopic
procedures as it confers no advantage in terms of pain control and the womans
satisfaction over local anaesthesia.
Life-threatening complications can result from the use of conscious sedation. Appropriate monitoring and staff skills are mandatory if procedures are to be undertaken
using conscious sedation.
Vaginoscopy
Vaginoscopy reduces pain during diagnostic rigid outpatient hysteroscopy.
Vaginoscopy should be the standard technique for outpatient hysteroscopy, especially
where successful insertion of a vaginal speculum is anticipated to be difficult and
where blind endometrial biopsy is not required.
4 of 22
1.
Purpose and Scope
The aim of this guideline is to provide clinicians with up-to-date, evidence-based information regarding
outpatient hysteroscopy, with particular reference to minimising pain and optimising the womans
experience.
2.
Background
Outpatient hysteroscopy is an established diagnostic test13 that is in widespread use across the UK.46
The procedure involves the use of miniaturised endoscopic equipment to directly visualise and examine
the uterine cavity, without the need for formal theatre facilities or general or regional anaesthesia.
Outpatient hysteroscopy is indicated primarily in the assessment of women with abnormal uterine
bleeding,13 but is also employed in the diagnostic work-up of reproductive problems. More recently,
advances in endoscopic technology and ancillary instrumentation have facilitated the development of
operative hysteroscopic procedures in an outpatient setting with or without the use of local anaesthesia.
Common procedures include endometrial polypectomy,68 removal of small submucous fibroids,9
endometrial ablation,1013 removal of lost intrauterine devices and transcervical sterilisation.14
Outpatient hysteroscopy, whether diagnostic1,15 or operative,614 is successful, safe and well tolerated.
However, as with any procedure requiring instrumentation of the uterus, outpatient hysteroscopy can be
associated with significant pain,16,17 anxiety and embarrassment.18 This not only impacts upon womens
satisfaction with their experience, but also limits the feasibility and possibly the safety, accuracy and
effectiveness of the procedure.To minimise pain and discomfort, variations in hysteroscopic equipment,
adaptations to the technique and use of pharmacological agents have been advocated. This guideline
assesses these components along with issues relating to optimal service provision.
3.
Four databases were systematically searched: MEDLINE (from 1950 to September 2008), EMBASE (from
1980 to September 2008), CINAHL (from 1981 to September 2008) and the Cochrane library. No
restrictions were placed on the searches in an attempt to reduce selection bias. The databases were
searched using the relevant MeSH terms and keywords.The main keywords used were hysteroscopy and
vaginoscopy, which were used with combinations of the following words depending upon the area of
hysteroscopy being examined: anaesthesia, analgesia, distension media, flexible, rigid, cervical
preparation,conscious sedation,prostaglandins and laminaria.The results of the searches were systematically reviewed.
Systematic reviews of the literature were conducted, with meta-analyses where possible, to assess pain
and feasibility of outpatient hysteroscopy.The definitions of the types of evidence used in this guideline
originate from the US Agency for Healthcare Research and Quality.Where possible, recommendations are
based on, and explicitly linked to, the evidence that supports them.Areas lacking evidence are highlighted
and annotated as good practice points.
4.
Service provision
4.1 What is the ideal setting for performing hysteroscopy?

All gynaecology units should provide a dedicated outpatient hysteroscopy service to
aid management of women with abnormal uterine bleeding. There are clinical and
economic benefits associated with this type of service.
5 of 22
Outpatient hysteroscopy should be conducted outside of the formal operating theatre

setting in an appropriately sized, equipped and staffed treatment room with
adjoining, private changing facilities and toilet.
An outpatient hysteroscopy service offers a safe, convenient and cost-effective means of
diagnosing and treating abnormal uterine bleeding as well as aiding the management of other
benign gynaecological conditions (e.g.fertility control,subfertility and miscarriage and abnormal
glandular cervical cytology).19 A randomised controlled trial reported more rapid mobilisation
postoperatively (0 minutes [range 05] versus 105 minutes [range 80120], P < 0.001) and
quicker recovery to preoperative levels (2 days [range 12.7] versus 3 days [range 24],P < 0.05)
favouring diagnostic outpatient hysteroscopy compared with traditional day-case hysteroscopy
under general anaesthesia.20 The same study demonstrated high and equivalent levels of
womens satisfaction with outpatient hysteroscopy in conscious women compared with daycase procedures under general anaesthesia.There were also economic benefits for women, the
health service and society at large. Compared with day-case procedures under general
anaesthesia, women undergoing outpatient hysteroscopy required significantly less time off
work compared with the day-case group (0.8 days versus 3.3 days, P < 0.001) and experienced
reduced loss of income and reduced travel costs. Costs per woman to the National Health
Service were estimated to be substantially less for outpatient procedures.21
Evidence
level 1+
4.2 What are the requirements for running an effective outpatient hysteroscopy service?
Outpatient hysteroscopy should be performed in an appropriately sized and fully
equipped treatment room. This may be a dedicated hysteroscopy suite or a multipurpose facility.
The healthcare professional should have the necessary skills and expertise to carry
out hysteroscopy.
There should be a nurse chaperone regardless of the gender of the clinician.
Written patient information should be provided before the appointment and consent
for the procedure should be taken.
Outpatient hysteroscopy should be performed in an appropriately sized and fully equipped treatment
room.This may be a dedicated hysteroscopy suite or a multipurpose facility. Outpatient hysteroscopy can
be associated with substantial anxiety,18 so the treatment room should be private and patient friendly, with
a separate, and ideally adjoining, changing area with a toilet. Adequate resuscitation facilities should be
available, as should a comfortable recovery area with refreshment-making facilities. Access to onsite or
offsite decontamination facilities of an appropriate standard is necessary. Outpatient hysteroscopy should
not be performed in a formal operating theatre setting because this environment is likely to provoke
anxiety in the woman and negate the economic advantages associated with avoiding use of expensive
operating theatres.Appropriate staffing levels are required;these will vary according to local circumstances
(patient populations, numbers seen per clinic) and the type of service offered (concomitant pelvic
ultrasound, pure diagnostic service or diagnostic and therapeutic service). In general, there will be a
complement of up to three support staff consisting of at least one registered general nurse and healthcare
assistants. When possible, one of the staff members should act as the womans advocate during the
procedure to provide reassurance, explanation and support. Communication with the woman in this way
may help alleviate anxiety and divert their attention, thereby minimising pain and embarrassment (the socalled vocal local).
6 of 22
Adequate, clear and simple written patient information should be provided with the
appointment letter.The information will vary according to local circumstances and the type of
service offered. Where simultaneous treatments are offered (see and treat services), it is
important that this fact is reflected in the patient literature to facilitate informed choice. It is
good clinical practice to obtain formal consent for outpatient hysteroscopy before the
procedure. Practice should conform to recommendations on consent from the General Medical
Council and the RCOG.The RCOG has produced Consent Advice No.1:Diagnostic hysteroscopy
under general anaesthesia,22 which should be used in conjunction with RCOG Clinical
Governance Advice No. 6: Obtaining valid consent.23 Women should be able to access advice
following any intervention (e.g. a direct line to the clinic and an out-of-hours contact number).
Consideration should be given to allow direct access for GPs according to locally developed
criteria and selected groups of women to aid streamlining of the service.
5.
Evidence
level 4
Analgesia
5.1 Do analgesics given before diagnostic hysteroscopy reduce the pain felt by women during the procedure?
Routine use of opiate analgesia before outpatient hysteroscopy should be avoided as
it may cause adverse effects.
Women without contraindications should be advised to consider taking standard
doses of non-steroidal anti-inflammatory agents (NSAIDs) around 1 hour before their
scheduled outpatient hysteroscopy appointment with the aim of reducing pain in the
immediate postoperative period.
B
B
A systematic review24 identified six studies which examine the use of analgesics compared with controls
before outpatient hysteroscopy.2530 All of these studies were randomised controlled trials.Three of the
studies examined the use of opiate drugs2527 and three examined NSAIDs.2830
Two of the opiate studies examined the use of 100 mg tramadol administered approximately 50
minutes before the outpatient hysteroscopy, one study giving the tramadol intramuscularly25
and the second giving it as an intravenous infusion.26 The first study found that the women who
had received tramadol had significantly less pain at the end of the procedure than women in the
intracervical block group and the women who received no medication (P = 0.001 and P < 0.001,
respectively).25 Although this was a low-quality study, the result was supported by those from
the second, high-quality study which reported significantly lower pain scores in the tramadol
group compared with placebo both during (P < 0.012) and 15 minutes after (P < 0.008) the
procedure.26 The third opiate study examined the use of sublingual buprenorphine 0.2 mg 40
minutes before the procedure compared with placebo.There was no significant pain reduction
with the use of buprenorphine overall and when stratified for menopausal status and parity.30
Two studies reported adverse effects.26,30 The tramadol study found no significant difference
between the groups in terms of incidence of nausea, vomiting or bradycardia.26 Conversely, in
the buprenorphine study there was a high incidence of adverse effects (nausea, vomiting and
drowsiness) in the intervention group (38.8%) and none in the control group.30
Three trials examined the use of NSAIDs before outpatient hysteroscopy.2830 One of these
studies assessed the use of 50 mg oral diclofenac 12 hours before the procedure and found that
it did not significantly reduce the pain experienced compared with placebo: mean (standard
deviation) in the diclofenac group 3.0 (2.5) versus 3.0 (2.9) in the control group.30 Vasovagal
reactions were not reduced in the diclofenac group compared with the placebo group (four
reactions and five reactions, respectively). The only adverse effects were in the diclofenac
treatment group, but these were mild and self-limiting (one woman reported drug rash and one
complained of epigastric pain). The second NSAID study compared the use of 500 mg oral
7 of 22
Evidence
level 1
Evidence
level 1
mefenamic acid 1 hour before the procedure with placebo.29 This study found that mefenamic
acid did not significantly reduce the pain of the hysteroscopy;however,it did significantly reduce
the pain experienced at 30 minutes (P < 0.01) and 60 minutes (P < 0.05).Adverse effects were
not reported for either group.The final study examined the use of ketorolac 30 mg intramuscularly given with an intracervical block 45 minutes before the procedure, compared with
cervical block alone.28 The paper reports a significant reduction in pain with the addition of
ketorolac; however, it does not report P values and there were only 12 women in each arm of
the study, making it difficult to draw strong conclusions from the results.
Evidence
level 1
No studies were identified addressing the issue of timing of analgesia before outpatient
hysteroscopy.The onset of action of these drugs means that to be effective they need to be
given in advance of the womans appointment. Optimal timing depends upon the agent used
(half-life, rate of absorption, etc.) and the route of administration, but in general simple, nonopioid analgesics given orally, such as 1000 mg paracetamol or 400 mg ibuprofen, should be
taken around 1 hour before the scheduled appointment time. Thus, it is likely to be more
practical to advise women to take simple analgesics in advance of their appointment rather
than administer them in hospital. Routine patient information leaflets posted to the woman
with details of their appointment can advise them to consider taking simple analgesics before
they attend their appointment, with the proviso that they have taken them before without ill
effects.This approach is likely to be of more benefit in those units offering simultaneous hysteroscopic diagnosis and treatment (i.e. the see and treat clinic), where the levels of discomfort
experienced are likely to be increased.
Evidence
level 4
6.
Cervical preparation
6.1 Does cervical preparation reduce uterine trauma, failure to access the uterine cavity or pain associated
with outpatient hysteroscopy?
Routine cervical preparation before outpatient hysteroscopy should not be used in
the absence of any evidence of benefit in terms of reduction of pain, rates of failure
or uterine trauma.
Uterine trauma (lacerations to the cervix or uterine perforation) is recognised with blind and endoscopic
instrumentation of the uterus,1,3134 with an estimated perforation incidence of 0.0021.7%.The incidence
of uterine trauma is low for diagnostic outpatient hysteroscopy performed with small-diameter endoscopes
(outer sheath diameter under 5.5 mm) under direct vision.1 Factors associated with uterine trauma include
the need for blind dilatation, cervical stenosis (e.g. atrophy, cervical surgery, previous caesarean section,
nulliparity), a tortuous cervical canal (e.g. in association with fibroids) and a deviated uterine cavity (e.g.
acute flexion, pelvic adhesions, fibroids).15,19
Prostaglandin or misoprostol administration before diagnostic hysteroscopy performed under general
anaesthesia is associated with a reduction in cervical resistance and need for cervical dilatation in premenopausal women3537 compared with placebo, although no such benefit was noted in postmenopausal
women.41,41
A systematic review of the use of cervical preparation before outpatient hysteroscopy identified
five randomised controlled trials,4246 with administration of prostaglandin regimens varying
from 4 hours to 30 hours before hysteroscopy.47 No reduction in the incidence of lacerations
to the cervix with the use of vaginal prostaglandins was demonstrated in the three trials42,43,46
assessing this outcome (OR 0.59, 95% CI 0.221.55).47
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Evidence
level 1+
Prostaglandins are associated with gastrointestinal adverse effects and are contraindicated in
severe uncontrolled asthma, chronic adrenal failure, acute porphyria, renal or hepatic
impairment and breastfeeding.48 Four heterogeneous trials assessed the incidence of genital
tract bleeding associated with vaginal prostaglandins before outpatient hysteroscopy42,4446 and
found no increased risk with the use of prostaglandins (OR 1.32, 95% CI 0.523.40).47
Evidence
level 1+
The main reason for failure to successfully perform an outpatient hysteroscopy is inability to
access the uterine cavity as a result of cervical stenosis; this is most commonly encountered in
the postmenopausal population.19 Two randomised controlled trials43,44 have assessed the
feasibility of outpatient hysteroscopy after vaginal prostaglandins and a meta-analysis showed
no reduction in failure rates (OR 2.12, 95% CI 0.647.04).47
Evidence
level 1+
One randomised controlled trial included in the systematic review examined the use of oral
mifepristone.There were no failed hysteroscopies in the study.47
Evidence
level 1+
Two studies examined the use of misoprostol 400 micrograms given vaginally before hysteroscopy to premenopausal women.The drugs were administered 4 hours before hysteroscopy in
one of the studies42 and 6 hours before hysteroscopy in the other.45 The low-quality study42
found that pain during cervical dilatation was significantly reduced after the use of prostaglandin
compared with placebo (P < 0.05); however, the other, high-quality study45 found no significant
reduction in pain during the hysteroscopy with the use of misoprostol (P = 0.72).
Evidence
level 1+
One study43 examined the use of misoprostol 200 micrograms given vaginally 8 hours before
hysteroscopy to postmenopausal women.The median pain scores as the hysteroscope passed
through the cervical os were five in the intervention group and seven in the placebo group
(P = 0.02).When the pain severity was assessed by comparing the number of women scoring
more than six on the visual analogue scale (i.e.considerable pain),there were significantly fewer
in the intervention group (P = 0.0132). However, no significant difference between the groups
was identified when assessing the presence of pain during clamping of the cervix (P = 0.74),
during the examination (P = 0.32) or during the endometrial biopsy (P = 0.19).
Evidence
level 1+
Two studies included both pre- and postmenopausal women in their study populations.44,46 One
of the studies42 gave misoprostol 400 micrograms vaginally 46 hours before the hysteroscopy
and found that pain at the end of the procedure was significantly less in the intervention group
compared with the group receiving no medication (P = 0.03).This was judged to be a lowquality study owing to the lack of blinding.The second study46 gave the same dose of misoprostol
1224 hours before the procedure and assessed pain after the cervix was dilated to 6 mm. Pain
was found to be significantly less in the misoprostol group (P = 0.004; when adjusted for
baseline pain score P = 0.01).This study subgrouped the women according to menopausal status
and found that there was a significant reduction in pain for postmenopausal women given
misoprostol (P = 0.004;when adjusted for baseline scores P = 0.006) but not for premenopausal
women (P = 0.56; when adjusted for baseline scores P = 0.77).This was a high-quality study.
Evidence
level 1+
One trial assessed oral mifepristone in premenopausal women49 and found no benefit in terms
of reduction in pain experienced during outpatient hysteroscopy (mean pain score 33.4 23.5
versus 37.0 30.0, P = 0.60).
Evidence
level 1+
No comparative studies were identified for other methods of cervical dilatation before outpatient hysteroscopy (e.g. local/systemic administration of estrogens or osmotic agents).
9 of 22
7.
Type of hysteroscope
7.1 What size and angle of hysteroscope should be used in the outpatient setting?
Miniature hysteroscopes (2.7 mm with a 33.5 mm sheath) should be used for diagnostic outpatient hysteroscopy as they significantly reduce the discomfort experienced
by the woman.
There is insufficient evidence to recommend 0 or fore-oblique optical lenses (i.e.
12, 25 or 30 off-set lenses) for routine outpatient hysteroscopy. Choice of hysteroscope should be left to the discretion of the operator.
Four randomised controlled trials have examined how the diameter of hysteroscopes with an
outer sheath affects pain during outpatient hysteroscopy.5053 One of the studies looked
exclusively at postmenopausal women and found that there was significantly less pain associated
with outpatient hysteroscopy when a 3.5 mm diameter hysteroscopy system as opposed to a
5 mm diameter system was used (P < 0.01), although the procedural success rate was not significantly increased.52 The remaining three papers compared 5 mm hysteroscopy assemblies with
3 mm,53 3.3 mm51 or 3.5 mm50 mini-hysteroscopy set-ups. Procedural pain was significantly
reduced with the smaller-diameter hysteroscopes in two of the trials (P < 0.0001 in both
studies);50,51 however,the third trial found no significant difference.53 One of the studies reported
the procedural success rate and visualisation of the cavity to be significantly better with minihysteroscopy (P < 0.0001);50 by contrast,the procedural success rate was not significantly better
in the other trial reporting this outcome.53
Evidence
level 1+
No studies were identified that compared 0 hysteroscopes with off-set distal lenses (e.g. 12,
30). Off-set lenses offer a wider field of view, a property that can be advantageous in visualising
the corneal recesses and tubal ostia within the uterine cavity with minimal external movement
of the hysteroscope. Fore-oblique lenses facilitate visualisation of ancillary instrumentation and
so are advantageous for operative hysteroscopy. However, 0 hysteroscopes are more intuitive,
facilitating entry into the uterine cavity through the cervical canal, which may reduce the need
for cervical dilatation as well as minimising discomfort and uterine trauma.
Evidence
level 4
7.2 Should rigid or flexible hysteroscopes be used routinely in the outpatient setting?
Flexible hysteroscopes are associated with less pain during outpatient hysteroscopy
compared with rigid hysteroscopes. However, rigid hysteroscopes may provide better
images, fewer failed procedures, quicker examination time and reduced cost. Thus,
there is insufficient evidence to recommend preferential use of rigid or flexible
hysteroscopes for diagnostic outpatient procedures. Choice of hysteroscope should
be left to the discretion of the operator.
Two small randomised controlled trials compared the pain experienced during outpatient
hysteroscopy with the use of a flexible hysteroscope versus a rigid hysteroscope.54,55 Neither
study presented data according to menopausal state or parity. Both studies found that use of the
flexible hysteroscope significantly reduced the womans pain experience during the procedure
(P = 0.0001 and P < 0.001, respectively). One of the studies reported no difference between the
flexible and rigid groups in terms of procedure time and image view. There were no failed
hysteroscopies in either group.54 The other study found that rigid scopes gave significantly better
image quality (P < 0.001) and significantly shortened the time taken to perform the procedure
(P = 0.003). There were two failed hysteroscopies in the flexible group owing to cervical
stenosis and these women were excluded from the analysis. Five more women in the flexible
group had to be changed to a rigid hysteroscope because of inability to negotiate the cervical
10 of 22
Evidence
level 1+
canal or inadequate visualisation.There were no failed hysteroscopies or change to flexible

scopes in the rigid group.This study also reported that rigid hysteroscopes were cheaper to
purchase and easier to sterilise and maintain than flexible hysteroscopies.55
Evidence
level 1+
Operative outpatient hysteroscopy using miniature mechanical and electrosurgical equipment is becoming
more established.These technologies generally require the use of rigid hysteroscopies.19 Units offering
both hysteroscopic diagnosis and treatment in the outpatient setting should consider the versatility of
respective hysteroscopes and relative resource implications when planning the composition of endoscopic
equipment.
8.
Distension medium
8.1 Which uterine distension medium should be used during outpatient hysteroscopy?
For routine outpatient hysteroscopy, the choice of distension medium between
carbon dioxide and normal saline should be left to the discretion of the operator as
neither is superior in reducing pain, although uterine distension with normal saline
appears to reduce the incidence of vasovagal episodes.
Uterine distension with normal saline allows improved image quality and allows
outpatient diagnostic hysteroscopy to be completed more quickly compared with
carbon dioxide.
Operative outpatient hysteroscopy, using bipolar electrosurgery, requires the use of

normal saline to act as both the distension and conducting medium.
8.2 Does the type of distension medium affect pain experience during outpatient hysteroscopy?
A systematic review identified seven studies5662 that looked at whether normal saline or carbon
dioxide uterine distension media were associated with less pain during outpatient hysteroscopy.62 One study was considered a duplication of data61 from an earlier study by the same
group.56 Therefore, six studies were included in the meta-analysis.5660,62 The meta-analysis
showed there to be no significant difference between the pain experienced with the use of
carbon dioxide versus normal saline for outpatient hysteroscopy (standard mean difference
[SMD] 0.34, 95% CI 0.12 to 0.80).63
Evidence
level 1++
Uterine distension pressures need to be sufficient to allow systematic inspection of the entire
uterine cavity. However, care is needed to ensure that pressures are minimised to avoid overdistension of the uterus and consequent pain.
Evidence
level 4
8.3 Which distension medium causes the fewest vasovagal episodes during outpatient hysteroscopy?
The incidence of vasovagal episodes was reported in three of the randomised controlled
trials.57,59,60 A meta-analysis of these results showed there to be significantly fewer vasovagal
episodes with the use of normal saline compared with carbon dioxide (OR 3.24, 95% CI 1.23
8.54).63
11 of 22
Evidence
level 1++
8.4 Which distension medium produces the best image quality during outpatient hysteroscopy?
Four randomised controlled trials evaluated image quality for each of the distension
media.56,57,59,62 Three studies reported no significant difference in image quality between carbon
dioxide and normal saline;56,57,59 however,one of these studies reported changing the distension
medium from carbon dioxide to normal saline in eight (10.1%) women.One study found a statistically significant increased risk of unsatisfactory view on hysteroscopy (RR 4.75, 95% CI
1.6116.4) with the use of carbon dioxide.This was mainly attributed to bubbles and bleeding.
Of the 19 women who had an unsatisfactory view at hysteroscopy using carbon dioxide, 17
were changed to normal saline and an improved view was reported in 11 (64.7%).62 Normal
saline produces lavage of the cavity and so washes away any blood or mucus which otherwise
might obscure the view.
Evidence
level 1+
8.5 Which distension medium allows the quickest procedure?

Four randomised controlled trials compared procedure times between normal saline and carbon
dioxide.5659 All four found that hysteroscopies using normal saline were significantly quicker.
This remained significant when the results were meta-analysed (SMD 1.32, 95% CI 1.171.48).63
Evidence
level 1++
8.6 Which distension medium should be used for operative procedures?

Normal saline should be used as the distension medium when bipolar intrauterine equipment
is used for hysteroscopic surgery.Thus, it is more practical to perform diagnostic procedures
with normal saline in units offering simultaneous diagnosis and treatment as this avoids having
to swap distension media should operative procedures need to be carried out. Hysteroscopic
sterilisation requires fluid distension medium; the choice of normal saline or glycine depends
upon the specific technology adopted.
9.
Evidence
level 4
Local anaesthesia and cervical dilatation
9.1 Should routine dilatation of the cervical canal be used before insertion of the hysteroscope
in an outpatient setting?
Blind cervical dilatation to facilitate insertion of the miniature outpatient hysteroscope is unnecessary in the majority of procedures. Routine cervical dilatation is
associated with pain, vasovagal reactions and uterine trauma and should be avoided.
Cervical dilatation generally requires administration of local cervical anaesthesia.
Standard protocols regarding the type, maximum dosage and route of administration
of anaesthesia should be developed and implemented to help both recognise and
prevent rare but potentially serious adverse effects resulting from systemic vascular
absorption.
Blind dilatation of the cervix to instrument the uterine cavity is commonly performed under
general anaesthesia and is associated with cervical and uterine trauma.1,3134 In addition, in the
conscious woman,dilatation of the cervix causes pain and discomfort and generally requires the
use of local anaesthesia.19 No randomised controlled trials or large comparative observational
studies examining the routine or selective use of blind cervical dilatation before outpatient
hysteroscopy were identified.
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Evidence
level 4
9.2 Should topical local anaesthetic be administered before outpatient hysteroscopy?

Instillation of local anaesthetic into the cervical canal does not reduce pain during diagnostic outpatient hysteroscopy but may reduce the incidence of vasovagal reactions.
Topical application of local anaesthetic to the ectocervix should be considered where

application of a cervical tenaculum is necessary.
A systematic review identified three randomised controlled trials comparing the application of
topical local anaesthetic to the ectocervix.6466 Two of these studies were meta-analysed.65,66
One used lidocaine 5% spray on the ectocervix and canal,65 while the other used 2% lignocaine
gel rubbed over the surface of the cervix;66 both used a placebo as a control. Meta-analysis of
these two studies found that there was no significant pain reduction with the use of topical
application of local anaesthetic to the cervix (SMD 0.32, 95% CI 0.97 to 0.33).67 Another
randomised controlled trial using lignocaine 2% aerosol spray, which could not be included in
the meta-analysis as it reported its results as medians rather than means, demonstrated a
reduction in pain as measured on a 100 mm visual analogue scale when applying a cervical
tenaculum as part of the hysteroscopy procedure using a rigid 5.5 mm diagnostic hysteroscope
(visual analogue scale score 9 versus 18, P = 0.005), but no significant reduction in the pain
associated with the hysteroscopic procedure itself.64
Evidence
level 1++
A systematic review identified five randomised controlled trials comparing the transcervical
application of local anaesthetic.62,6871 Three trials injected the anaesthetic through the cervical
canal into the uterine cavity.68,69,71 Two of these studies used 5 ml of 2% lignocaine69,71 and one
used 2 ml of 2% mepivacaine.68 All three used normal saline as their control substance.Two of
the studies mixed lignocaine with the distension medium. One used 18 ml of lignocaine
(strength not stated) per 250 ml of normal saline combined with an intracervical block and
compared it with normal saline as the distension medium with an intracervical block.70 The
second study used 40 ml of 2% lignocaine per 500 ml of normal saline and compared it with
normal saline as the distension medium.62 No significant reduction in pain during hysteroscopy
was demonstrated (SMD 0.11, 95% CI 0.31 to 0.10).67
Evidence
level 1++
Vasovagal episodes were significantly reduced with the use of topical anaesthesia (Peto OR 0.35,
95% CI 0.150.79), but this apparent reduction was limited to the use of transcervical topical
application only (Peto OR 0.29, 95% CI 0.120.74).67
Evidence
level 1++
9.3 Should injectable local anaesthetic be administered to the cervix and/or paracervix before outpatient
hysteroscopy?
Application of local anaesthetic into or around the cervix is associated with a
reduction of the pain experienced during outpatient diagnostic hysteroscopy.
However, it is unclear how clinically significant this reduction in pain is. Consideration should be given to the routine administration of intracervical or paracervical
local anaesthetic, particularly in postmenopausal women.
Miniaturisation of hysteroscopes and increasing use of the vaginoscopic technique
may diminish any advantage of intracervical or paracervical anaesthesia. Routine
administration of intracervical or paracervical local anaesthetic should be used where
larger diameter hysteroscopes are being employed (outer diameter greater than
5mm) and where the need for cervical dilatation is anticipated (e.g. cervical stenosis).
Routine administration of intracervical or paracervical local anaesthetic is not
indicated to reduce the incidence of vasovagal reactions.
13 of 22
A systematic review identified five randomised controlled trials comparing the use of direct
intracervical injection of local anaesthetic before outpatient hysteroscopy with control (placebo,
vaginoscopy or nil).25,7275 No significant reduction in pain was noted in the four trials25,72,73,75
included in the meta-analysis (SMD 0.05, 95% CI 0.71 to 0.60).67 However, intracervical
injection of local anaesthetic was found to reduce pain with hysteroscopy (SMD 0.36, 95% CI
0.61 to 0.10) when the trial comparing local anaesthesia with vaginoscopy was excluded.75
Evidence
level 1++
A systematic review identified six randomised controlled trials comparing the use of
paracervical injection of local anaesthetic before outpatient hysteroscopy with control (placebo
or nil).52,7680 Meta-analysis showed a significant reduction in pain (SMD 1.28, 95% CI 2.22 to
0.35),67 although the studies were heterogenous. If the analysis was stratified by menopausal
status, the heterogeneity between studies remained, but a significant reduction in pain was
observed in the two studies with a purely postmenopausal population52,78 (SMD 1.12, 95% CI
2.23 to 0.01).67
Evidence
level 1++
The same systematic quantitative review did not find a reduction in vasovagal reactions
associated with diagnostic outpatient hysteroscopy with the use of injectable cervical
anaesthetics52,74,7779 (OR 0.89, 95% CI 0.541.46).67 However, the heterogeneity of study
populations and variations in the definition of vasovagal episodes are likely to have affected
this finding. Larger-scale studies of homogeneous populations with standardised interventions
(equipment, technique, etc.) and definitions of vasovagal episodes are required to confirm or
refute these findings.
Evidence
level 1+
10. Conscious sedation
10.1 Should conscious sedation be used to reduce pain associated with outpatient hysteroscopic procedures?
Conscious sedation should not be routinely used in outpatient hysteroscopic procedures as it confers no advantage in terms of pain control and the womans satisfaction
over local anaesthesia.
Life-threatening complications can result from the use of conscious sedation. Appropriate monitoring and staff skills are mandatory if procedures are to be undertaken
using conscious sedation.
Conscious sedation is used widely in outpatient endoscopic procedures of the gastrointestinal

system. It is less commonly employed in outpatient hysteroscopy. One randomised controlled
trial reported the use of conscious sedation using 0.25 mg fentanyl intravenous with 0.5 mg
atropine and 2 mg midazolam immediately before operative outpatient hysteroscopy
polypectomy, myomectomy, septoplasty and adhesiolysis using the Versapoint (Ethicon Inc.)
bipolar electrode intrauterine system compared with paracervical anaesthesia with 10 ml 1%
mepivacaine hydrochloride without sedation.There were no significant differences between
local anaesthesia and conscious sedation in terms of pain control during the procedure, postoperative pain or the womans satisfaction.78
Evidence
level 1+
Sedative drugs (anaesthetics, anxiolytics and opioids) are administered by oral, intravenous,
transmucosal or inhalational routes.Any drug that depresses the central nervous system has the
potential to impair respiration, circulation or both. Close monitoring of the woman must be
undertaken by a designated staff member to ensure maintenance of continuous verbal contact
and adequate oxygen saturation.Monitoring of blood pressure and electrocardiogram should be
considered in high-risk cases and staff trained in acute airway management and anaesthetic
support should be immediately available.
Evidence
level 4
14 of 22
11.
Vaginoscopy
11.1 Does a vaginoscopic approach to outpatient hysteroscopy reduce pain and increase the feasibility of the
procedure?
Vaginoscopy reduces pain during diagnostic rigid outpatient hysteroscopy.
Vaginoscopy should be the standard technique for outpatient hysteroscopy, especially

where successful insertion of a vaginal speculum is anticipated to be difficult and
where blind endometrial biopsy is not required.
Vaginoscopy or the no touch approach to hysteroscopy refers to a technique where the
hysteroscope is introduced into the vagina, through the cervical canal and into the uterine
cavity without the need for a vaginal speculum or cervical instrumentation.A systematic review
identified six small randomised controlled trials comparing the vaginoscopic versus traditional
outpatient hysteroscopy.75,8185 There were no significant differences in feasibility (failed
procedures) between the techniques (OR 1.28, 95% CI 0.742.24), but vaginoscopy was
associated with significantly less procedural pain (SMD 0.44, 95% CI 0.65 to 0.22)86 in the
four studies evaluating this outcome.75,81,82,84
Evidence
level 1++
Larger studies are indicated to better assess the feasibility of vaginoscopy in relation to the characteristics
of the woman (e.g.body mass index,menopausal status,parity,caesarean section) and type of hysteroscope
(size, angle, rigid/flexible endoscopes) and the risk of ascending pelvic infection. Vaginoscopy allows
increased external movement of the hysteroscope. Future studies should assess whether this manoeuvrability improves the feasibility and effectiveness of operative hysteroscopy.
Patient satisfaction with elements of the outpatient hysteroscopy service.

Complications (e.g. infection, vasovagal reactions, uterine trauma) of diagnostic and operative
outpatient hysteroscopy.
Failure rate of diagnostic and operative outpatient hysteroscopy and reasons for failures.
Rates of cervical dilatation in outpatient hysteroscopy stratified by parity and menopausal status.
Standards of documentation.
Use of analgesia post-procedure.
Percentage of women provided with written information and asked for written consent.
13. Recommendations for research
Optimal type and timing of analgesia in diagnostic and operative outpatient hysteroscopy.
Effect of cervical preparation with prostaglandins and/or local estrogens on pain relief and feasibility
of outpatient hysteroscopy in postmenopausal women.
Safety and acceptability of hysteroscopy according to angle of distal optical lens.
Effect of local anaesthetic on pain reduction according to menopausal status and parity.
Effectiveness of vaginoscopic approach to outpatient hysteroscopy in relieving pain compared with
traditional approaches with and without local anaesthesia.
Feasibility and safety of vaginoscopy in relation to the womans characteristics and type of
hysteroscope.
Effect of vaginoscopy and local anaesthesia on the incidence of vasovagal episodes associated with
diagnostic and operative outpatient hysteroscopy.
Effectiveness of warming fluid distension media on relieving pain in outpatient hysteroscopy.
15 of 22
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60. Paschopoulos M, Kaponis A, Makrydimas G, Zikopoulos K,
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62. Shankar M, Davidson A,Taub N, Habiba M. Randomised
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64. Davies A, Richardson RE, OConnor H, Baskett TF, Nagele F,
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66. Wong AY,Wong K,Tang LC. Stepwise pain score analysis of
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69. Costello MF, Horrowitz SD,Williamson M.A prospective
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72. Broadbent JA, Hill NC, Molnr BG, Rolfe KJ, Magos AL.
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Coutinho E.The efficacy of intracervical lidocaine in
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74. Makris N, Xygakis A, Dachlythras M, Prevedourakis C,
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78. Guida M, Pellicano M, Zullo F,Acunzo G, Lavitola G,
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anaesthesia in outpatient hysteroscopy: a randomised
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BJOG 2010;117:1440.
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APPENDIX 1
Terminology
Conscious sedation
Conscious sedation refers to an arousable but drowsy state in which a woman can communicate and
maintain an airway.Sedation techniques aim to make potentially unpleasant interventions more acceptable.
However, there is potential for the drugs to impair respiration, circulation or both.This dictates that the
operator should have advanced training in airway management and anaesthesia.
Direct intracervical cervical anaesthesia

Local anaesthetic is injected directly into the cervix (intracervical or direct cervical block). The
anaesthetic solution should be distributed equally to all cervical quadrants.The majority of the anaesthetic
should be injected at the deepest possible point in each quadrant, with some distributed evenly along the
length of the cervix as the needle is withdrawn.
Outpatient hysteroscopy (office/ambulatory)

The term outpatient hysteroscopy encompasses office and ambulatory hysteroscopy.
Paracervical anaesthesia
Local anaesthetic is injected into the vaginal mucosa at the cervicovaginal junction. One to two millilitres
of anaesthetic is injected to produce swelling and blanching of the tissue around the cervix.The needle is
then advanced into the vaginal vault and the anaesthetic is delivered to a depth of 12.5 cm. Care should
be taken to aspirate before injection to avoid inadvertent intravascular injection.The injection site may be
tracked by injecting as the needle progresses.The standard bilateral injections are at the 4 oclock and 8
oclock positions, although 3 oclock and 9 oclock positions are often used.
Procedural pain
For the purpose of this guideline,procedural pain is defined as an overall, global assessment of pain
associated with outpatient hysteroscopy. If a global score was not given, the pain experienced during
inspection of the cavity was used.
Topical anaesthesia/transcervical
Anaesthetic gels such as Instillagel (Clinined Ltd, High Wycombe, UK: lidocaine hydrochloride 2% and
chlorhexidine gluconate solution 0.25%),creams such as emla (AstraZeneca Pty Ltd,North Ryde,Australia:
lidocaine 2.5% and prilocaine 2.5%) or sprays such as xylocaine (lidocaine 10%) are applied to the
ectocervix, cervical canal or into the uterine cavity.Absorption through mucous membranes may be slow
and unreliable, so sufficient time should be allowed for the anaesthetic to work.
Vaginoscopy
The vaginoscopic or no-touch technique involves introducing the hysteroscope into the vagina without
a speculum or cervical instrumentation. The labia minora are then held closed and the table tilted
backwards to keep the distension medium inside the vagina.The hysteroscope is slowly advanced to
visualise the cervix and identify the cervical os.The scope then traverses the cervical canal and passes into
the uterine cavity.
19 of 22
Vasovagal reaction
Vasovagal reactions are caused by stimulation of the parasympathetic nervous system.The cervix receives
parasympathetic innervation from the sacral nerves. Manipulation and dilatation of the cervix can lead to
stimulation of the parasympathetic nervous system,which causes hypotension and bradycardia and causes
women to feel sick and faint.They may display clinical signs such as pallor,sweating and reduced conscious
state. Most women will recover rapidly if the procedure is stopped and instruments removed and they are
put in the supine or recovery position. Cool fanning, fluids and reassurance will hasten recovery. In rare
cases, atropine may need to be given.
20 of 22
Appendix 2
using a standardised methodology.Exact details of this process can be found in Clinical Governance Advice
No.1: Development of RCOG Green-Top Guidelines (available on the RCOG website at http://www.
rcog.org.uk/womens-health/clinical-guidance/development-rcog-green-top-guidelines-policies-andprocesses).These recommendations are not intended to dictate an exclusive course of management or
treatment.They must be evaluated with reference to individual patient needs, resources and limitations
unique to the institution and variations in local populations.It is hoped that this process of local ownership
will help to incorporate these guidelines into routine practice. Attention is drawn to areas of clinical
uncertainty where further research may be indicated.

1+

low risk of bias

risk of bias

2+
2-

is not causal

case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
21 of 22

development group
This guideline was produced on behalf of the British Society of Gynaecological Endoscopists and the Royal College of
Obstetricians and Gynaecologists by:
Mr TJ Clark MRCOG, Birmingham, Dr NAM Cooper, Birmingham, Mr C Kremer FRCOG, Wakefield.
and peer reviewed by: Mr PM Flynn MRCOG, Swansea; Dr MW Rodger FRCOG, Glasgow.
The Guidelines Committee lead reviewers were: Mrs CE Overton FRCOG, Bristol and Dr J Shillito MRCOG, Leeds.
The final version is the responsibility of both the Guidelines Committee of the RCOG and the Guidelines and Audit
Committee of the British Society of Gynaecological Endoscopists.
DISCLAIMER
The British Society of Gynaecological Endoscopists produces guidelines as an educational aid to good clinical practice.
gynaecologists and other relevant health professionals.The ultimate judgement regarding a particular clinical procedure
or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient
and the diagnostic and treatment options available.This means that BSGE guidelines are unlike protocols or guidelines
issued by employers,not being intended to be prescriptive directions defining a single course of management.Departure
from the local prescriptive protocols or guidelines should be fully documented in the patients case notes at the time the
relevant decision is taken.
22 of 22
Cervical Cerclage

May 2011
Cervical Cerclage
1.
Purpose and scope
Since the 1960s, the use of cerclage has expanded to include the management of women considered to be at
high risk of mid-trimester loss and spontaneous preterm birth by virtue of factors such as multiple pregnancy,
uterine anomalies, a history of cervical trauma (e.g. conisation or operations requiring forced dilatation of the
cervical canal) and cervical shortening seen on sonographic examination. However, the use and efficacy of
cerclage in these different groups is highly controversial since there is contradiction in the results of
individual studies and meta-analyses.
Cerclage remains a commonly performed prophylactic intervention used by most obstetricians despite the
absence of a well-defined population for whom there is clear evidence of benefit. Furthermore, there is little
consensus on the optimal cerclage technique and timing of suture placement. The role of amniocentesis
before emergency (rescue) cerclage insertion and the optimal management following insertion are also
poorly defined. Complications are not well documented and often difficult to separate from risks inherent to
the underlying condition.The purpose of this guideline is to review the literature and provide evidence-based
guidance on the use of cerclage.
2.
Background
Prematurity is the leading cause of perinatal death and disability. Preterm birth before 37+0 weeks of gestation
accounted for 7.6% of all live births in England and Wales in 2005. Although preterm birth is defined as
delivery before 37+0 weeks of gestation, the majority of prematurity-related adverse outcomes relate to birth
before 33+0 weeks of gestation. Mortality increases from about 2% for infants born at 32 weeks of gestation to
more than 90% for those born at 23 weeks of gestation.1 Two-thirds of preterm births are the consequence of
spontaneous preterm labour and/or preterm prelabour rupture of membranes (PPROM). The rate of
spontaneous preterm birth continues to rise globally despite efforts to the contrary, and interventions aimed
at reducing preterm birth have been largely disappointing.
Cervical cerclage was first performed in 1902 in women with a history of mid-trimester abortion or
spontaneous preterm birth suggestive of cervical incompetence, with the aim of preventing recurrent loss.
Cervical incompetence is an imprecise clinical diagnosis frequently applied to women with such a history
where it is assumed that the cervix is weak and unable to remain closed during the pregnancy. However,
recent evidence suggests that rather than being a dichotomous variable, cervical competence is likely to be
a continuum influenced by factors related not solely to the intrinsic structure of the cervix but also to
processes driving premature effacement and dilatation. While cerclage may provide a degree of structural
support to a weak cervix, its role in maintaining the cervical length and the endocervical mucus plug as a
mechanical barrier to ascending infection may be more important.
All decisions about cerclage are difficult and should be made with senior involvement. A doctor with the
necessary skills and expertise to perform cerclage should carry out the procedure.
3.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines.24 The Cochrane Library (including the Cochrane Database of Systematic Reviews), DARE,
EMBASE,TRIP, Medline and PubMed (electronic databases) were searched for relevant randomised controlled
trials, systematic reviews and meta-analyses.The search was restricted to articles published between 1980 and
November 2008. The databases were searched using the relevant MeSH terms, including all subheadings, and
this was combined with a keyword search. Search words included cervical cerclage, cervical suture,
2 of 21
midtrimester miscarriage, McDonald cerclage, Shirodkar cerclage, infection and cerclage, tocolytics and
cerclage and inflammatory mediators and cerclage, and the search was limited to humans and the English
language.The National Library for Health and the National Guidelines Clearing House were also searched for
4.
Definitions
Previous terminology (prophylactic, elective, emergency, urgent, rescue) of cervical sutures (cerclage) can be
ambiguous. More appropriate nomenclature based on indication for cervical suture is recommended. The
terms below are increasingly used in the scientific literature.
History-indicated cerclage
Insertion of a cerclage as a result of factors in a womans obstetric or gynaecological history which increase
the risk of spontaneous second-trimester loss or preterm delivery. A history-indicated suture is performed as
a prophylactic measure in asymptomatic women and normally inserted electively at 1214 weeks of
gestation.
Ultrasound-indicated cerclage
Insertion of a cerclage as a therapeutic measure in cases of cervical length shortening seen on transvaginal
ultrasound. Ultrasound-indicated cerclage is performed on asymptomatic women who do not have exposed
fetal membranes in the vagina. Sonographic assessment of the cervix is usually performed between 14 and 24
weeks of gestation.
Rescue cerclage
Insertion of cerclage as a salvage measure in the case of premature cervical dilatation with exposed fetal
membranes in the vagina. This may be discovered by ultrasound examination of the cervix or as a result of a
speculum/physical examination performed for symptoms such as vaginal discharge, bleeding or sensation of
pressure.
Transvaginal cerclage (McDonald)
A transvaginal purse-string suture placed at the cervicovaginal junction, without bladder mobilisation.5
High transvaginal cerclage (Shirodkar)
A transvaginal purse-string suture placed following bladder mobilisation, to allow insertion above the level of
the cardinal ligaments.6
Transabdominal cerclage
A suture performed via a laparotomy or laparoscopy, placing the suture at the cervicoisthmic junction.7
Occlusion cerclage
Occlusion of the external os by placement of continuous non-absorbable suture. The theory behind the
potential benefit of occlusion cerclage is retention of the mucus plug.8
5.
History-indicated cerclage
5.1 When should a history-indicated cerclage be offered?

History-indicated cerclage should be offered to women with three or more previous preterm births
and/or second-trimester losses.
History-indicated cerclage should not be routinely offered to women with two or fewer previous preterm
births and/or second-trimester losses.
Characteristics of the previous adverse event, such as painless dilatation of the cervix or rupture of the
membranes before the onset of contractions, or additional risk factors, such as cervical surgery, are not
helpful in the decision to place a history-indicated cerclage.
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There is insufficient evidence to recommend the use of prepregnancy diagnostic techniques aimed at
diagnosing cervical weakness in women with a history of preterm birth and/or second-trimester loss
in the decision to place a history-indicated cerclage. Such techniques include assessment of cervical
resistance index, hysterography or insertion of cervical dilators.
Three randomised controlled trials (RCTs) have been conducted comparing history-indicated cerclage with
expectant management.911 The largest trial, coordinated by the Medical Research Council and Royal College
of Obstetricians and Gynaecologists, was an international multicentre trial which recruited 1292 women
whose obstetrician was uncertain as to whether a cerclage would be of benefit (71% of the study population
had a history of second-trimester loss or preterm birth before 37 weeks of gestation). Randomisation allocated
647 women to cerclage and 645 to no cerclage.11 Overall, there were fewer deliveries before 33 weeks of
gestation in the cerclage group compared with the controls (13% versus 17%; RR 0.75; 95% CI 0.580.98),
which was compatible with the prevention of one delivery before 33 weeks of gestation for every 25 cerclage
insertions. There was no significant difference between the two groups in fetal/neonatal outcome (total
numbers of miscarriages, stillbirths and deaths following live birth 55 [8.5%] in the cerclage group compared
with 68 [10.5%] in the control group; OR 0.79; 95% CI 0.541.14). However, two of the eight infant deaths in
the cerclage group were ascribed to conditions subsequent to preterm birth, compared with seven of the 14
in the control group.There were insufficient data to allow any conclusions to be drawn as to whether women
were more likely to benefit if the previous loss had features suggestive of cervical incompetence (e.g. painless
cervical dilatation or rupture of the membranes before the onset of contractions). Of six prespecified
subgroup analyses, only women with a history of three or more pregnancies ending before 37 weeks of
gestation (n = 104) benefitted from cerclage, which halved the incidence of preterm delivery before 33 weeks
of gestation (15% versus 32%, P < 0.05). No effect was observed in those with only one (delivery before 33
weeks of gestation in the cerclage group 14% versus 17% in the expectant group) or two previous early
deliveries (delivery before 33 weeks of gestation in the cerclage group 12% versus 14% in the expectant
group), previous cervical surgery or first-trimester loss/uterine anomaly; however, the authors concluded that
the relatively small numbers in each group limited the reliability of these results.
One further trial of 506 women considered at moderate risk of cervical incompetence, based on a
scoring system to assess risk factors, randomised 268 to a McDonald cerclage and 238 to a policy
of no cerclage. Women with prior second-trimester losses of a live fetus were excluded. There was
no significant difference in preterm delivery (6.7% in the cerclage group versus 5.5% in the
expectant group), although those with cerclage were more likely to be admitted to hospital and
receive tocolytics.9 A third trial recruited 194 women who had had at least two previous preterm
deliveries before 37 weeks of gestation (or one or more preterm delivery before 34 weeks of
gestation); 96 women were randomised to McDonald cerclage and 98 to expectant management.
There was no difference in outcome, with 34% delivering before 37 weeks of gestation in the
cerclage group and 34% in the no cerclage group.10
Evidence
level 1+
No studies provide sufficient data to examine the influence of additional risk factors such as cervical surgery
or the characteristics of the previous delivery/miscarriage on the effect of history-indicated cerclage.
The studies that have examined the use of prepregnancy techniques (e.g. hysterography, cervical resistance
indices, insertion of cervical dilators) to assess cervical weakness were observational and not designed to test
the hypothesis that their use optimised the selection of women for history-indicated cerclage.12,13 The largest
study of cervical resistance indices (force required to dilate the cervix to 8 mm) reported that 175 women
with a history of mid-trimester loss had a lower cervical resistance index than 123 parous women with no
such history (P < 0.001). However, in this study all women with a history of low cervical resistance index had
a suture inserted, with a successful pregnancy outcome in 75%.This rate is no higher than that expected with
expectant management11 and the absence of a control group makes it inappropriate to draw any evidencebased conclusions on the usefulness of this technique.13
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6. Ultrasound-indicated cerclage
6.1 When should an ultrasound-indicated cerclage be offered?

6.1.1 Women with a singleton pregnancy and no history of spontaneous mid-trimester loss or
preterm birth
The insertion of an ultrasound-indicated cerclage is not recommended in women without a history of
spontaneous preterm delivery or second-trimester loss who have an incidentally identified short cervix
of 25 mm or less.
To et al. screened 47 123 women at 2224 weeks of gestation using transvaginal ultrasound to
measure cervical length. In 470 women (1%), the cervix was 15 mm or less. Of these women, 253
(54%) agreed to participate in a randomised study comparing Shirodkar cerclage (n = 127) with
expectant management (n = 126).The incidence of preterm delivery before 33 weeks of gestation
was similar in both groups, at 22% (28 of 127) in the cerclage group versus 26% (33 of 126) in the
control group (RR 0.84; 95% CI 0.541.3; P = 0.44), with no significant differences in perinatal or
maternal morbidity or mortality.14
Evidence
level 1++
This was further confirmed in an individual patient data (IPD) meta-analysis of four RCTs of
cerclage versus expectant management in women with a short cervix (in which women from the
previously discussed RCT were included). This meta-analysis reported no overall evidence of
benefit of cerclage in women with cervical length less than 25 mm who had no other risk factors
for spontaneous preterm birth.15
6.1.2 Women with a singleton pregnancy and a history of spontaneous mid-trimester loss or
preterm birth
Women with a history of one or more spontaneous mid-trimester losses or preterm births who are
undergoing transvaginal sonographic surveillance of cervical length should be offered an ultrasoundindicated cerclage if the cervix is 25 mm or less and before 24 weeks of gestation.
An ultrasound-indicated cerclage is not recommended for funnelling of the cervix (dilatation of the
internal os on ultrasound) in the absence of cervical shortening to 25 mm or less.
An RCT of ultrasound-indicated cerclage involving 302 women with singleton pregnancies with a
history of spontaneous preterm birth between 17+0 and 33+6 weeks of gestation, who were found
to have a cervical length of less than 25 mm detected during serial sonographic examinations
between 16+0 and 21+6 weeks of gestation, reported that when compared with expectant
management, cerclage reduced previable birth (at less than 24+0 weeks of gestation: 6.1% versus
14%; P = 0.03) and perinatal death (8.8% versus 16%; P = 0.046) but did not prevent birth at less
than 35 weeks of gestation (32% versus 42%; OR = 0.67; 95% CI 0.421.07) unless cervical length
was less than 15 mm (OR 0.23; 95% CI 0.080.66).16
Evidence
level 1++
Similar results were reported from a meta-analysis that included 607 pregnancies from four RCTs
of ultrasound-indicated cerclage.15 This study reported that in the subgroup of women with
singleton pregnancies with a history of preterm second-trimester loss (1623 weeks of gestation)
or birth before 36 weeks of gestation, when compared with expectant management, cerclage
resulted in a significant reduction in delivery before 35 weeks of gestation (RR 0.57; 95% CI
0.330.99 and RR 0.61; 95% CI 0.400.92, respectively), which was of a similar magnitude to the
reduction observed in the previous study.16
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There are no studies evaluating ultrasound-indicated cerclage performed solely on the presence of
funnelling. However, studies have demonstrated that funnelling is a function of cervical shortening
and does not appear to independently add to the risk of preterm birth associated with cervical
length.17,18
Evidence
level 2++
6.2 Who should be offered serial sonographic surveillance ultrasound-indicated cerclage?

Women with a history of spontaneous second-trimester loss or preterm delivery who have not
undergone a history-indicated cerclage may be offered serial sonographic surveillance, as there is
evidence to suggest that those who experience cervical shortening are at an increased risk of
subsequent second-trimester loss/preterm birth and may benefit from ultrasound-indicated cerclage
(see 6.1), while those whose cervix remains long have a low risk of second-trimester loss/premature
delivery.
Women should be informed that expectant management is a reasonable alternative since there is a
lack of direct evidence to support serial sonographic surveillance over expectant management.
Furthermore, the majority of women with a history of second-trimester loss/preterm delivery will
deliver after 33 weeks of gestation.
In studies where serial sonographic surveillance of cervical length has been carried out in women
with a history of second-trimester loss and/or spontaneous preterm delivery, between 40% and 70%
of women maintain a cervical length of more than 25 mm before 24+0 weeks of gestation.11,16,1921 In
three of these studies which reported the outcome of pregnancy in those who maintained a
cervical length of more than 25 mm and hence did not receive cerclage, more than 90% of women
delivered after 34 weeks of gestation. This suggests that serial sonographic surveillance may
differentiate between women with a prior second-trimester loss/preterm birth who might benefit
from cerclage and women who do not need intervention.
Evidence
level 2+
In the Medical Research Council/RCOG randomised study, women with a history of one, two or
three or more previous second-trimester losses or spontaneous preterm births had an 83%, 86% and
68% chance, respectively, of delivery after 33 weeks of gestation when managed expectantly.11 Given
that there are no randomised studies directly comparing a policy of serial sonographic surveillance
ultrasound-indicated cerclage with expectant management in women with a history of one or
more spontaneous preterm births/mid-trimester losses, and given the significant chance of delivery
after 33 weeks of gestation in such women, expectant management is a reasonable alternative.
Evidence
level 4
7.
Can cervical cerclage be recommended in any other groups considered at increased risk
of spontaneous preterm delivery?
7.1 Multiple pregnancies

The insertion of a history- or ultrasound-indicated cerclage in women with multiple pregnancies is not
recommended, as there is some evidence to suggest it may be detrimental and associated with an
increase in preterm delivery and pregnancy loss.
In a meta-analysis, subgroup examination of 39 twin pregnancies demonstrated a doubling in

delivery rates before 35 weeks of gestation with the use of ultrasound-indicated cerclage compared
with expectant management in women with a cervical length less than 25 mm (RR 2.15; 95% CI
1.154.01).15 Insertion of cerclage may also be associated with increased perinatal mortality,
although this was not statistically significant (RR 2.66; 95% CI 0.838.54).
6 of 21
Evidence
level 1++
A prospective cohort study of 147 twin pregnancies identified 37 women with cervical length less
than 25 mm between 18 and 26 weeks of gestation, of whom 21 underwent insertion of McDonald
cerclage and 12 did not.22 Insertion of cervical cerclage was not associated with any significant
improvement in preterm delivery at 34 weeks of gestation or less (42.9% in the cerclage group
versus 50% in the non-cerclage group). Small numbers and lack of randomised design limit the
conclusions that can be drawn from this study. Furthermore, those women who underwent
cerclage had a significantly shorter mean cervical length compared with those who did not.
Evidence
level 2++
There is only one RCT of history-indicated cerclage in twin pregnancies. This study examined the
effect of cerclage (n = 25) versus no cerclage (n = 23) in twins conceived following ovulation
induction, and demonstrated that cerclage was not effective in prolonging gestation or improving
fetal outcome.23
Several studies of cervical cerclage have included a subgroup of multiple pregnancies; however,
they were of insufficient number to enable conclusions to be drawn regarding the effect of cerclage
in preventing preterm birth. In an IPD meta-analysis,24 data for multiple gestations were available in
66 mothers from three randomised studies.11,25,26 The use of cervical cerclage in multiple gestations
was associated with a substantial increase in pregnancy loss or death before discharge from
hospital (OR 5.88; 95% CI 1.1430.19); however, the results should be interpreted with caution
owing to the relatively small number of women included.
Evidence
level 1+
7.2 Uterine anomalies and cervical trauma

History- or ultrasound-indicated cerclage cannot be recommended in other high-risk groups such as
women with mllerian anomalies, previous cervical surgery (cone biopsy, large loop excision of the
transformation zone or destructive procedures such as laser ablation or diathermy) or multiple
dilatation and evacuation.
The existing published studies are either inadequately controlled or include insufficient numbers
to be able to make evidence-based recommendations in the vast majority of the groups mentioned
above. In the IPD meta-analysis of ultrasound-indicated cerclage,15 subgroup analysis of those
women with a history of cone biopsy (n = 64) or more than one dilatation and evacuation (n =
131) showed no difference in preterm birth before 35 weeks of gestation in the cerclage group
compared with the expectantly managed group (RR 1.18; 95% CI 0.572.45 and RR 0.91; 95% CI
0.571.47, respectively); however, the authors concluded that that the results should be interpreted
with caution owing to the small numbers of women. There were insufficient women with
mllerian anomalies or diethylstilbestrol exposure to perform subgroup analyses.
Evidence
level 1+
The Medical Research Council/RCOG study of history-indicated cerclage reported that in a

subgroup analysis of women with a history of cone biopsy or cervical amputation (n = 138), there
was no significant difference in delivery before 33+0 weeks of gestation in the cerclage group
compared with the expectant group (19% versus 22%).11
7.2.1 Radical trachelectomy
The decision to place a concomitant cerclage at radical trachelectomy should be individualised.
There are several case series27 reporting successful pregnancy outcomes with the use of
concomitant cerclage placement at radical trachelectomy; however, the absence of a control group
makes it impossible to provide evidence-based guidelines on the use of this technique.
7 of 21
P
Evidence
level 3
8.
Transabdominal cerclage
8.1 When should a transabdominal cerclage be considered?

In women with a previous failed transvaginal cerclage, insertion of a transabdominal cerclage may be
considered, but this procedure may be associated with increased maternal morbidity.
Transabdominal cerclage can be performed preconceptually or in early pregnancy.
A transabdominal cerclage is usually inserted following a failed vaginal cerclage or extensive

cervical surgery. There are no randomised studies comparing the effectiveness of transabdominal
cerclage with that of expectant management or transvaginal cerclage. The evidence is limited to a
systematic review including 13 case series and one controlled non-randomised study of
transabdominal versus transvaginal cerclage in women with a prior failed transvaginal cerclage.This
systematic review reported a lower risk of perinatal death/delivery before 24 weeks of gestation
(6% versus 12.5%) in those women who had undergone transabdominal cerclage (n = 117)
compared with those who had a repeat insertion of transvaginal cerclage (n = 40).28 However, there
was a higher incidence (3.4% versus 0%) of serious operative complications (bleeding requiring
transfusion, injury to bladder/bowel/uterine artery, anaesthesia problems). Davis et al., in their
controlled non-randomised study in women with a prior failed transvaginal cerclage, reported that
the incidence of delivery before 33 weeks of gestation was lower in the 40 women with a
transabdominal suture compared with the 24 women with a transvaginal suture insertion (10%
versus 38%; P = 0.01).29
Evidence
level 2-/3
There are no studies directly comparing the insertion of a preconceptual transabdominal cerclage with
insertion in early pregnancy. However, preconceptual insertion should be considered when possible because
of the technical advantage of operating on the uterus of a woman who is not pregnant. Furthermore, there is
no evidence that preconceptual transabdominal cerclage has any detrimental impact on fertility or
management of early miscarriage. Abdominal cerclage can be safely left in place if a further pregnancy is a
possibility.
8.2 Should an abdominal cerclage be performed laparoscopically?

There is no evidence to support a laparoscopic approach over laparotomy in the insertion of an
abdominal cerclage.
One small study making a retrospective comparison in 19 women demonstrated a viable infant in
nine of 12 women who received a laparoscopic procedure compared with five of seven who
received an abdominal procedure.30
Evidence
level 3
8.3 How should a delayed miscarriage or fetal death be managed in women with an abdominal cerclage?
Management decisions in cases of delayed miscarriage or fetal death in women with an abdominal
cerclage can be difficult and should be made with senior involvement. A doctor with the necessary skills
and expertise to perform the procedure should carry out the procedure.
Successful evacuation through the stitch by suction curettage or by dilatation and evacuation (up to 18
weeks of gestation) has been described; alternatively, the suture may be cut, usually via a posterior
colpotomy. Failing this, a hysterotomy may be required or caesarean section may be necessary.
There are no studies evaluating the management of pregnancy termination in the event of fetal
demise or the need to terminate a pregnancy. Success using the techniques described above has
been reported by experienced clinicians.
8 of 21
Evidence
level 4
9.
Rescue cerclage
9.1 When should a rescue cerclage be considered?

The decision to place a rescue suture should be individualised, taking into account the gestation at
presentation, as even with rescue cerclage the risks of severe preterm delivery and neonatal mortality
and morbidity remain high. A senior obstetrician should be involved in making the decision.
Insertion of a rescue cerclage may delay delivery by a further 5 weeks on average compared with
expectant management/bed rest alone. It may also be associated with a two-fold reduction in the
chance of delivery before 34 weeks of gestation. However, there are only limited data to support an
associated improvement in neonatal mortality or morbidity.
Advanced dilatation of the cervix (more than 4 cm) or membrane prolapse beyond the external os
appears to be associated with a high chance of cerclage failure.
There has been one RCT evaluating rescue cerclage and bed rest against bed rest alone.31 This trial
included only 23 women (16 with singleton pregnancies and seven with twin pregnancies) who
were confirmed to have cervical dilatation and prolapse of the membranes on speculum
examination at a mean gestation of 2223 weeks. No data are given on degree of cervical dilatation.
All women, irrespective of random allocation, were hospitalised and on bed rest until 30 weeks of
gestation and received 1 week of broad-spectrum antibiotics. In addition, those undergoing
cerclage received perioperative indometacin. Eight of 13 women in the cerclage group required
emergency removal of the suture for maternal or fetal reasons before 36 weeks of gestation.Women
in the cerclage group delivered on average 4 weeks later than those in the bed rest group (mean
interval between randomisation and delivery 54 days versus 20 days) and there was a significant
reduction in delivery before 34 weeks of gestation (53% versus 100%; P = 0.02).There was a trend
towards improvement in neonatal survival (56% versus 28%) and a significant reduction in
compound neonatal morbidity (defined as neonatal admission to intensive care unit and/or
neonatal death: 71% versus 100%; RR 1.6; 95% CI 1.12.3).The authors did not provide any data on
the incidence of chorioamnionitis or neonatal morbidity.
Evidence
level 1-
In a prospective non-randomised study of 46 asymptomatic low-risk women found to have a dilated cervix
(mean 4 cm) with bulging membranes between 18 and 26 weeks of gestation (mean 2223 weeks) during
routine preterm delivery screening, the insertion of a rescue cerclage was associated with a mean
prolongation of pregnancy of 8.8 weeks (range 017) compared with 3.1 weeks (range 011) in women who
received bed rest alone.32 This prolongation resulted in a three-fold reduction in the number of births before
32 weeks of gestation (31% versus 94%; RR 0.33; 95% CI 0.190.57), a doubling in the number of live births
(86% versus 41%) and an almost 40% improvement in neonatal survival (96% versus 57%; RR 0.59; 95% CI
0.00.76). No comparative data are provided regarding evidence of infection in the two groups.
The findings from one further prospective non-randomised study of 37 women with cervical
dilatation of 4 cm or greater (mean 6 cm) between 20 and 27 weeks of gestation (mean 2223
weeks) reported that the insertion of a rescue cerclage in 22 cases prolonged pregnancy for on
average 4 weeks more than the 15 pregnancies managed with bed rest alone.33 The mean age at
delivery was 334.4 weeks of gestation in the cerclage group and 284.3 weeks of gestation in the
bed rest group.There was no significant difference in perinatal survival (73% in the cerclage group
versus 67% in the bed rest group). All women in this study received 48 hours of tocolytics
(indometacin or ritodrine) and women in the cerclage group received 5 days of antibiotics and
hospitalisation.Women in the bed rest group were hospitalised for the duration of their pregnancy.
The rate of clinical chorioamnionitis was similar in the two groups (9% versus 13%), but no data
were given on the neonatal infection rate.
9 of 21
Evidence
level 2++
There is no clear evidence that the gestation at which the cerclage is inserted affects the magnitude
of prolongation in gestation; however, consideration should be given to the fact that, in cases
presenting before 20 weeks of gestation, insertion of a rescue cerclage is highly likely to result in a
preterm delivery before 28 weeks of gestation. Furthermore, the decision to place a rescue cerclage
beyond 24 weeks of gestation should be individualised and take into account the local gestational
age of viability. Improvements in neonatal intensive care have advanced the gestational age of
viability to 24 weeks of gestation in most developed countries and, given the potential risk of
iatrogenic membrane rupture and subsequent preterm delivery, rescue cerclage can rarely be
justified after this gestation.
Evidence
level 4
The aforementioned studies have not provided an analysis of prolongation of pregnancy in relation
to cervical dilatation. However, several other uncontrolled studies have suggested that the presence
of membrane prolapse beyond the external os and/or cervical dilatation greater than 4 cm are
significant predictors of cerclage failure. In view of the absence of a control group in these studies,
it is not clear whether this observation relates to treatment failure or a more advanced underlying
process that makes this group of women inherently more likely to deliver.3436
Evidence
level 3
10. What are the contraindications to cerclage insertion?

The contraindications to cerclage insertion are:
active preterm labour
clinical evidence of chorioamnionitis
continuing vaginal bleeding
PPROM
evidence of fetal compromise
lethal fetal defect
fetal death.
11.
What information should be given to women before cerclage insertion?
Before history- or ultrasound-indicated cerclage insertion, a woman should be given information about the
potential complications, which should include the following:
Cerclage insertion is associated with a doubling in risk of maternal pyrexia but no apparent increase in
chorioamnionitis.
Cerclage insertion is not associated with an increased risk of PPROM, induction of labour or caesarean
section.
The insertion of a cervical suture is not associated with an increased risk of preterm delivery or secondtrimester loss.
Before any type of cerclage insertion, women should be informed of the following:
There is a small risk of intraoperative bladder damage, cervical trauma, membrane rupture and bleeding
during insertion of cervical cerclage.
Shirodkar cerclage usually requires anaesthesia for removal and therefore carries the risk of an
additional anaesthetic.
Cervical cerclage may be associated with a risk of cervical laceration/trauma if there is spontaneous
labour with the suture in place.
10 of 21
Although women are often routinely informed of a number of potential complications associated
with cerclage insertion, including PPROM, miscarriage, preterm labour, infection, bleeding and
bladder or cervical damage, there is little published evidence to support this. None of the
randomised studies of cervical cerclage has been designed or adequately powered to assess the risk
of maternal morbidity and, to date, none of the larger studies of history- or ultrasound-indicated
cerclage has reported an increase in PPROM, preterm delivery or second-trimester loss.11,16,25
Intraoperative complications including bladder damage, cervical trauma, membrane rupture and
bleeding are reported but are rare (<1%).11,14,16
Evidence
level 1++
An IPD meta-analysis of seven randomised studies of cerclage insertion (combining data from
studies of both history-indicated and ultrasound-indicated cerclage) found that cerclage was
associated with an increased risk of maternal pyrexia (OR 2.35; 95% CI 1.374.05), but there was
no evidence of increase in chorioamnionitis (OR 0.73; 95% CI 0.361.46), PPROM (OR 0.92; 95%
CI 0.621.35), induction of labour or caesarean section (OR for spontaneous labour for no cerclage
0.81; 95% CI 0.651.02).24
In a retrospective review of 251 cerclages (including 49 rescue and 202 history-indicated sutures)
over a 7.5-year period, cervical laceration requiring suturing at the time of delivery was reported in
11% of Shirodkar and 14% of McDonald procedures, which was higher than that reported in 55 688
other deliveries occurring during the same period (2%). Although this was statistically significant
(P < 0.025), this result is highly susceptible to reporting bias.
Evidence
level 2
Several case series have reported high risks of membrane rupture and infection associated with rescue
cerclage; however, the lack of a control group makes it difficult to separate the procedure-related risk from
that inherent to the underlying condition.
12. Pre operative management
12.1 What investigations should be performed before insertion of cervical cerclage?

It is good practice to offer a first-trimester ultrasound scan and screening for aneuploidy before the
insertion of a history-indicated suture to ensure both viability and the absence of lethal/major fetal
abnormality. Before ultrasound-indicated or rescue cerclage, it is good practice to ensure an anomaly
scan has been performed recently.
The use of routine maternal white cell count and C-reactive protein to detect subclinical
chorioamnionitis before insertion of a rescue cerclage is not recommended. The decision to perform
these tests should be based on the overall clinical picture, but in the absence of clinical signs of
chorioamnionitis, the decision for rescue cerclage need not be delayed.
Although several studies have linked a raised maternal C-reactive protein level with histological
evidence of chorioamnionitis in cases of preterm labour or PPROM, the sensitivity and specificity
are considered to be too poor to be clinically useful.37,38 In an uncontrolled retrospective review of
17 cases of rescue cerclage, the authors reported that a preoperative C-reactive protein value below
4.0 mg/dl and a maternal white cell count less than 14 000/microlitre were associated with
prolongation of pregnancy compared with women with values above these cut-offs. Interpretation
of these results was confounded by the degree of cervical dilatation, such that those women with
higher values also had more advanced cervical dilatation.
Evidence
level 2
12.2 Should amniocentesis to detect infection be performed before rescue or ultrasound-indicated cerclage?
There is insufficient evidence to recommend routine amniocentesis before rescue or ultrasoundindicated cerclage as there are no clear data demonstrating that it improves outcome.
11 of 21
In selected cases where there is suspicion of intra-amniotic infection, amniocentesis may be performed
to aid the decision about rescue cerclage, as the presence of infection is associated with a poor
prognosis.
Amniocentesis before rescue cerclage does not appear to increase the risk of preterm delivery before 28
weeks of gestation.
Several studies have reported an association between poor pregnancy outcome and the presence
of intra-amniotic infection/inflammation, diagnosed by amniocentesis, in women presenting with a
dilated cervix, whether or not they undergo rescue cerclage.39,40 However, none of these studies was
randomised and they are hence susceptible to selection bias, with the majority of women
undergoing amniocentesis at the discretion of the individual physician. Rates of intra-amniotic
infection vary from 13% to 51% depending on the criteria used to define a positive result and the
population selected.4143 Furthermore, the low specificity of amniocentesis could deny women
cerclage who may have benefited from the procedure.The incidence of intra-amniotic infection in
ultrasound-indicated cerclage is about 12%.
Evidence
level 3
Airoldi et al.41 identified 122 women between 15+0 and 25+6 weeks of gestation with a dilated cervix
(14 cm). Twenty-four (20%) of these had an amniocentesis performed. Following multivariate
regression analysis, the authors concluded that an amniocentesis did not independently contribute
to preterm birth before 28 weeks of gestation (P = 0.90).
Evidence
level 2+
12.2.1 Is amnioreduction before rescue cerclage recommended?

There is an absence of data to either refute or support the use of amnioreduction before insertion of a
rescue cerclage.
Several small studies have reported successful prolongation of pregnancy using amnioreduction
before cerclage, but the absence of a valid control group makes it impossible to draw any evidencebased conclusion as to its contribution to the outcome.4446
Evidence
level 3
12.2.2 Should a latency period be observed between presentation and insertion of rescue or
ultrasound-indicated cerclage?
There are no studies to support immediate versus delayed cerclage insertion in either rescue or
ultrasound-indicated procedures, but as delay can only increase the risk of infection, immediate
insertion is likely to supersede the benefits of waiting to see if infection manifests clinically.
The interval between presentation and suture insertion varies between studies, with some authors advocating
a period of observation to ensure that preterm labour, abruption and infection are excluded. Others argue that
delayed insertion has the potential to increase the risk of ascending infection; however, no comparative
studies of the two strategies exist.
12.2.3 Should routine genital tract screening for infection be carried out before cerclage
insertion?
There is an absence of data to support genital tract screening before cerclage insertion.
In the presence of a positive culture from a genital swab, a complete course of sensitive antimicrobial
eradication therapy before cerclage insertion would be recommended.
There are no studies evaluating the benefit of screening for genital tract infection before insertion of a
cerclage.
12 of 21
13. Operative issues
13.1 Should perioperative tocolysis be used for insertion of cerclage?

There is no evidence to support the use of routine perioperative tocolysis in women undergoing
insertion of cerclage.
In most of the existing randomised studies, the majority of women allocated cerclage also received
perioperative tocolysis, most commonly indometacin. Consequently, there is no control group
available for comparison. However, a retrospective cohort study involving 101 women who
underwent ultrasound-indicated cerclage reported that the rate of preterm birth before 35 weeks
of gestation was not significantly different in women who received indometacin for 48 hours
following the procedure compared with those who did not (39% versus 34%).47
Evidence
level 2+
13.2 Should perioperative antibiotics be given?

The decision for antibiotic prophylaxis at the time of cerclage placement should be at the discretion of
the operating team.
There are no studies of perioperative antibiotic use in women undergoing cervical cerclage.
13.3 What method of anaesthesia should be employed for the insertion of cerclage?
The choice of anaesthesia should be at the discretion of the operating team.
There are no studies comparing general with regional anaesthesia for insertion of cervical cerclage and hence
the decision should be made on a case-by-case basis.
13.4 Can cerclage be performed as a day-case procedure?

Elective transvaginal cerclage can safely be performed as a day-case procedure.
Women undergoing ultrasound-indicated or rescue cerclage, given the higher risk of complications such
as PPROM, early preterm delivery, miscarriage and infection, may benefit from at least a 24-hour
postoperative period of observation in hospital. Cases should be managed on an individual basis.
In women undergoing insertion of transabdominal cerclage via laparotomy, an inpatient stay of at least
48 hours is recommended.
Golan et al. retrospectively compared 125 cases of elective outpatient cerclage with 101 cases of
inpatient cerclage, during which women received complete bed rest in hospital for 48 hours
postoperatively.48 There was no significant difference in short-term complications or pregnancy
outcome, but hospital stay was significantly shorter for those managed as planned day cases.
Evidence
level 2+
13.5 Which technique and material should be used?

The choice of suture material should be at the discretion of the surgeon.
The choice of transvaginal cerclage technique (Shirodkar versus McDonald) should be at the discretion
of the surgeon.
There is no current evidence to support the placement of two purse-string sutures over a single suture.
There is no current evidence to support the placement of a cervical occlusion suture in addition to the
primary cerclage.
13 of 21
There is insufficient evidence to support any specific technique for cerclage insertion. In a
secondary analysis of singleton pregnancy data from four randomised trials of cervical cerclage in
women with a short cervix, there was no significant difference in the rate of delivery before 33
weeks of gestation in those with a McDonald cerclage compared with those with a Shirodkar
suture, once adjusted for confounding factors (OR 0.55; 95% CI 0.21.3).49 These results should be
interpreted with caution since the study was not sufficiently powered to detect a statistically
significant difference in this outcome.
Evidence
level 2-
A retrospective analysis of 169 women having McDonald procedures and 82 women having
Shirodkar procedures did not reveal any significant differences in fetal survival or major
postoperative morbidity between the two techniques.50 In a subgroup of women with one previous
second-trimester loss, there was a significant increase in fetal survival in those with a high vaginal
cerclage (100% versus 63%; P < 0.05). However, a similar effect was not observed in those with a
previous preterm birth or those with more than one previous second-trimester loss.
Evidence
level 3
In a small retrospective cohort study involving 150 women who had either an ultrasound-indicated
(n = 43) or an elective (n = 107) cerclage, 112 were managed with a single purse-string suture and
38 with a double suture.There was no significant difference in preterm delivery or pregnancy loss.
However, the study is limited by being retrospective and non-randomised and also underpowered
to detect a significant difference in the primary outcomes.51
Evidence
level 2-
There are no controlled studies on the use of a cervical occlusion suture in addition to the primary cerclage;
however, this is the subject of a continuing randomised trial.8
14. Adjuvant management
14.1 Bed rest

Bed rest in women who have undergone cerclage should not be routinely recommended, but the
decision should be individualised, taking into account the clinical circumstances and the potential
adverse effects that bed rest could have on women and their families in addition to increased costs for
the healthcare system.
There are no studies comparing bed rest with no bed rest in women undergoing cervical cerclage.A Cochrane
review of bed rest in women at high risk of preterm delivery identified only one randomised cluster study of
uncertain methodological quality. A comparison was made between 432 women prescribed bed rest and 834
women prescribed no intervention/placebo. Preterm birth before 37 weeks of gestation was similar in both
groups (7.9% in the intervention group versus 8.5% in the control group: RR 0.92; 95% CI 0.621.37).52
14.2 Sexual intercourse

Abstinence from sexual intercourse following cerclage insertion should not be routinely recommended.
There are no studies evaluating the effect of sexual intercourse on the risk of second-trimester loss or preterm
delivery in women with cervical cerclage. Furthermore, there is no evidence that sexual intercourse in early
pregnancy increases the risk of preterm delivery in women with a previous preterm birth. In a secondary
analysis of an observational study of transvaginal sonographic examinations performed at 1618 weeks of
gestation on 187 women with singleton gestations with a prior spontaneous preterm birth before 32 weeks
of gestation, women who reported infrequent sexual intercourse during early pregnancy had an incidence of
recurrent spontaneous preterm birth of 28% compared with 38% in those women who reported some
intercourse (P = 0.35).53
14 of 21
14.3 Is there a role for post-cerclage serial sonographic surveillance of cervical length?
While routine serial sonographic measurement of the cervix is not recommended, it may be useful in
individual cases following ultrasound-indicated cerclage to offer timely administration of steroids or in
utero transfer.
Several studies have shown a significant increase in cervical length following the insertion of elective,
ultrasound-indicated and rescue cerclage.5457 A postoperative upper cervical length (closed cervix above the
cerclage) of less than 10 mm before 28 weeks of gestation appears to provide the best prediction of
subsequent preterm delivery before 36 weeks of gestation following the placement of an ultrasound-indicated
cerclage.55,58
14.4 Is there a role for repeat cerclage when cervical shortening is seen post-cerclage?
Placement of an ultrasound-indicated cerclage in the presence of cervical length shortening cannot be
recommended as, compared with expectant management, it may be associated with an increase in both
pregnancy loss and delivery before 35 weeks of gestation.
The decision to place a rescue cerclage following an elective or ultrasound-indicated cerclage should be
made on an individual basis, taking into account the clinical circumstances.
In a retrospective cohort study involving 24 women with a history-indicated cerclage and

subsequent cervical length shortening to less than 25 mm on ultrasound, 19 women were managed
expectantly and five women underwent insertion of a reinforcing cerclage.59 Repeat suture
insertion was associated with a significantly earlier gestational age at delivery (21 versus 33 weeks
of gestation; P = 0.002) and an increased miscarriage rate (80% versus 16%; P = 0.01). However, the
selection criteria for choosing expectant management over repeat suture insertion were not
defined and hence these results may be subject to bias.
Evidence
level 2-
In a further retrospective cohort, Fox et al. followed 12 women with an elective cerclage who had
cervical length shortening of more than 2 cm or prolapse of the membranes below the suture
before 28 weeks of gestation, and who underwent between one and four repeat cerclage
procedures.60 The median gestation at delivery was 34 weeks (range 2239), with 75% of women
delivering before 37 weeks of gestation.
Evidence
level 3
14.5 Is fetal fibronectin testing useful following insertion of a cervical cerclage?

Routine fetal fibronectin testing is not recommended post-cerclage. However, the high negative
predictive value of fetal fibronectin testing for subsequent delivery at less than 30 weeks of gestation
in asymptomatic high-risk women with a cerclage in place may provide reassurance to women and
clinicians in individual cases. However, the increased false-positive rate of fetal fibronectin testing in
such women makes the finding of a positive result less useful.
In a retrospective observational study involving 910 asymptomatic women at high risk of preterm
birth, including 159 with a cervical cerclage in place, fetal fibronectin testing for the prediction of
delivery before 30 weeks of gestation was shown to have a similar negative predictive value in both
groups (over 98%) but a significantly lower specificity (77% versus 90%; P < 0.001) in those with a
suture.61
Evidence
level 2+
14.6 Should women receive supplemental progesterone following cerclage?

Routine use of progesterone supplementation following cerclage is not recommended.
15 of 21
The RCOG guidance currently recommends that in women at high risk of preterm delivery, progesterone
administration be restricted to clinical trials which aim to determine whether its use is associated with
improved fetal, neonatal and/or infant outcome.62
There are no comparative studies on the use of progesterone in woman who have undergone cerclage. In an
RCT of ultrasound-indicated cerclage involving 302 women with singleton pregnancies and a history of
spontaneous preterm birth between 17+0 and 33+6 weeks of gestation, an analysis of the womans recorded
intention to use supplemental progesterone did not appear to have any effect on delivery before 35+0 weeks
of gestation (OR 0.97; 95% CI 0.61.6).16
15. When should the cerclage be removed?

A transvaginal cervical cerclage should be removed before labour, usually between 36+1 and 37+0 weeks
of gestation, unless delivery is by elective caesarean section, in which case suture removal could be
delayed until this time.
In women presenting in established preterm labour, the cerclage should be removed to minimise
potential trauma to the cervix.
There are no studies comparing elective removal of transvaginal cerclage with removal in labour. However, in
the absence of preterm labour, elective removal at 3637 weeks of gestation is advisable owing to the
potential risk of cervical injury in labour and the minimal risk to a neonate born at this gestation.
A Shirodkar suture will usually require anaesthesia for removal.
There are no studies regarding the use of anaesthesia in the removal of a Shirodkar suture but, given that the
technique involves burial of the suture, an anaesthetic is likely to be necessary for removal.
All women with a transabdominal cerclage require delivery by caesarean section, and the abdominal
suture may be left in place following delivery.
There are no published studies on long-term outcome comparing a policy of removing a transabdominal
cerclage to it remaining in place. However, if further pregnancies are contemplated, it is reasonable to
recommend leaving the cerclage in place.
15.1 Should the cerclage be removed following PPROM?

In women with PPROM between 24 and 34 weeks of gestation and without evidence of infection or
preterm labour, delayed removal of the cerclage for 48 hours can be considered, as it may result in
sufficient latency that a course of prophylactic steroids for fetal lung maturation is completed and/or in
utero transfer arranged.
Delayed suture removal until labour ensues or delivery is indicated is associated with an increased risk
of maternal/fetal sepsis and is not recommended.
Given the risk of neonatal and/or maternal sepsis and the minimal benefit of 48 hours of latency in
pregnancies with PPROM before 23 and after 34 weeks of gestation, delayed suture removal is unlikely
to be advantageous in this situation.
Jenkins et al. retrospectively studied 62 women, approximately 50% of whom had an elective
cerclage in place and the remainder a rescue cerclage in place, who had PPROM between 24 and
34 weeks of gestation but no signs of preterm labour or infection.63 In 37 women there was
16 of 21
Evidence
level 2+
immediate removal (less than 24 hours) of the suture and in 25 women removal was delayed (over
24 hours) based on clinician preference. The duration of latency from PPROM to delivery was
significantly longer in the delayed-removal group (10.1 days versus 5.0 days; P < 0.001), but there
was no significant difference in gestational age at delivery. Delayed removal was associated with
significantly more women delivering more than 48 hours after presentation (96% versus 54%;
P < 0.001) compared with immediate removal, accompanied by a trend towards lower neonatal
mortality (4% versus 11%).There was no significant trend towards a higher rate of maternal infection
(44% versus 22%) and neonatal sepsis (16% versus 5%) in the delayed-removal group. Prolongation
of time to removal of cerclage to more than 48 hours in the delayed-removal group compared with
the immediate group (206.87.4 hours versus 5.40.2 hours) may have contributed to the observed
trend towards an increase in infectious complications.There was no obvious difference in outcome
in those with a history-indicated, ultrasound-indicated or rescue cerclage.
Evidence
level 2+
Ludmir et al. retrospectively studied 30 women with an elective cerclage in place and PPROM between 24
and 32 weeks of gestation where all cases were managed expectantly but in 20 cases there was immediate
removal of the suture and in 10 cases there was retention of the cerclage until delivery.64 Significantly more
women with retained cerclage had delivery delayed for at least 48 hours compared with women who had
immediate cerclage removal (90% versus 50%), but there was no overall difference in gestation at delivery.
Although there was no difference in the reported rate of chorioamnionitis prompting delivery in the retained
cerclage versus the removed cerclage groups, there was a significantly higher neonatal mortality rate in the
retained cerclage group (70% versus 10%), the majority of deaths in the former group being attributed to
neonatal sepsis.
Both of these studies lack a randomised approach to the allocated management strategy and are hence subject
to selection bias. Furthermore, there may be significant differences between the effects and complications
associated with delayed removal in women with rescue, ultrasound-indicated and elective cerclage.
Number of women referred to a consultant obstetrician (or a specialist prematurity clinic) before 12 weeks
of gestation as a proportion of those eligible for history-indicated cerclage.
Review of the indications for cerclage in women having undergone a procedure in line with local protocol.
Proportion of women receiving aneuploidy screening before history-indicated cerclage insertion.
Pregnancy loss rate at less than 24 weeks of gestation and preterm delivery at 2432 weeks of gestation
following cervical cerclage insertion.
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7. Benson RC, Durfee RB.Transabdominal cervico uterine
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To MS, Palaniappan V, Skentou C, Gibb D, Nicolaides KH.
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Berghella V, Haas S, Chervoneva I, Hyslop T. Patients with prior
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Newman RB, Krombach RS, Myers MC, McGee DL. Effect of
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Dor J, Shalev J, Mashiach S, Blankstein J, Serr DM. Elective
cervical suture of twin pregnancies diagnosed ultrasonically in
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Jorgensen AL, Alfirevic Z,Tudur Smith C, Williamson PR;
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Berghella V, Odibo AO,Tolosa JE. Cerclage for prevention of
preterm birth in women with a short cervix found on transvaginal ultrasound examination: a randomized trial. Am J
Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting
the short cervix detected by transvaginal ultrasound in the
second trimester: why cerclage therapy may not help. Am J
Jolley JA, Battista L, Wing DA. Management of pregnancy after
radical trachelectomy: case reports and systematic review of
the literature. Am J Perinatol 2007;24:5319.
Zaveri V, Aghajafari F, Amankwah K, Hannah M. Abdominal
versus vaginal cerclage after a failed transvaginal cerclage: a
systematic review. Am J Obstet Gynecol 2002;187:86872.
Davis G, Berghella V,Talucci M, Wapner RJ. Patients with a prior
failed transvaginal cerclage: a comparison of obstetric
outcomes with either transabdominal or transvaginal cerclage.
30. Carter JF, Soper DE, Goetzl LM, Van Dorsten JP. Abdominal
cerclage for the treatment of recurrent cervical insufficiency:
laparoscopy or laparotomy? Am J Obstet Gynecol
2009;201:111.e14.
31. Althuisius SM, Dekker GA, Hummel P, van Geijn HP; Cervical
incompetence prevention randomized cerclage trial. Cervical
incompetence prevention randomized cerclage trial:
emergency cerclage with bed rest versus bed rest alone. Am
32. Daskalakis G, Papantoniou N, Mesogitis S, Antsaklis A.
Management of cervical insufficiency and bulging fetal
33. Olatunbosun OA, al-Nuaim L,Turnell RW. Emergency cerclage
compared with bed rest for advanced cervical dilatation in
pregnancy. Int Surg 1995;80:1704.
34. Schorr SJ, Morales WJ. Obstetric management of incompetent
cervix and bulging fetal membranes. J Reprod Med
1996;41:2358.
35. Kokia E, Dor J, Blankenstein J, Seidman DS, Lipitz S, Serr DM,
et al. A simple scoring system for the treatment of cervical
incompetence diagnosed during the second trimester.
Gynecol Obstet Invest 1991;31:126.
36. Terkildsen MF, Parilla BV, Kumar P, Grobman WA. Factors
associated with success of emergent second-trimester
cerclage. Obstet Gynecol 2003;101:5659.
37. Trochez-Martinez RD, Smith P, Lamont RF. Use of C-reactive
protein as a predictor of chorioamnionitis in preterm
prelabour rupture of membranes: a systematic review. BJOG
2007;114:796801.
38. Wiwanitkit V. Maternal C-reactive protein for detection of
chorioamnionitis: an appraisal. Infect Dis Obstet Gynecol
2005;13:17981.
39. Weiner CP, Lee KY, Buhimschi CS, Christner R, Buhimschi IA.
Proteomic biomarkers that predict the clinical success of
rescue cerclage. Am J Obstet Gynecol 2005;192:7108.
40. Mays JK, Figueroa R, Shah J, Khakoo H, Kaminskly S,Tejani N.
Amniocentesis for selection before rescue cerclage. Obstet
Gynecol 2000;95:6525.
41. Airoldi J, Pereira L, Cotter A, Gomez R, Berghella V,
Prasertcharoensuk W, et al. Amniocentesis prior to physical
exam-indicated cerclage in women with midtrimester
cervical dilation: results from the expectant management
compared to physical exam-indicated cerclage international
cohort study. Am J Perinatol 2009;26:638.
42. Lee SE, Romero R, Park CW, Jun JK,Yoon BH.The frequency
and significance of intraamniotic inflammation in patients
with cervical insufficiency. Am J Obstet Gynecol
2008;198:633.e18.
43. Romero R, Gonzalez R, Sepulveda W, Brandt F, Ramirez M,
Sorokin Y, et al. Infection and labor. VIII. Microbial invasion of
the amniotic cavity in patients with suspected cervical
incompetence: prevalence and clinical significance. Am J
44. Cerqui AJ, Olive E, Bennett MJ, Challis D. Emergency cervical
cerclage. Is there a role for amnioreduction? Aust N Z J
45. Makino Y, Makino I,Tsujioka H, Kawarabayashi T.
Amnioreduction in patients with bulging prolapsed
membranes out of the cervix and vaginal orifice in cervical
cerclage. J Perinat Med 2004;32:1408.
46. Locatelli A, Vergani P, Bellini P, Strobelt N, Arreghini A,
Ghidini A. Amnioreduction in emergency cerclage with
prolapsed membranes: comparison of two methods for
reducing the membranes. Am J Perinatol 1999;16:737.
47. Visintine J, Airoldi J, Berghella V. Indomethacin administration
at the time of ultrasound-indicated cerclage: is there an
association with a reduction in spontaneous preterm birth?
48. Golan A, Wolman I, Barnan R, Niv D, David MP. Outpatient
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49. Odibo AO, Berghella V,To MS, Rust OA, Althuisius SM, Nicolaides
KH. Shirodkar versus McDonald cerclage for the prevention of
preterm birth in women with short cervical length. Am J
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50. Harger JH. Comparison of success and morbidity in cervical
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51. Woensdregt K, Norwitz ER, Cackovic M, Paidas MJ, Illuzzi JL.
Effect of 2 stitches vs 1 stitch on the prevention of preterm
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52. Sosa C, Althabe F, Belizn JM, Bergel E. Bed rest in singleton
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63. Jenkins TM, Berghella V, Shlossman PA, McIntyre CJ, Maas BD,
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19 of 21
APPENDIX

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
20 of 21

development group
Gynaecologists by:
Professor AH Shennan FRCOG, London and Ms MS To MRCOG, London
and peer-reviewed by: BLISS (Babies Born too Soon, too Small, too Sick); RCOG Consumers Forum; Royal College of
Midwives; Mrs A Diyaf MRCOG, Nottingham; Ms LMM Duley FRCOG, Leeds; Mr RG Farquharson FRCOG, Liverpool;
Ms SK Flint FRCOG, Tunbridge Wells; Mr KT Moriarty MRCOG, Warwickshire; Dr NC Smith FRCOG, Aberdeen.
The Guidelines Committee lead reviewers were: Mr M Griffiths FRCOG, Luton and Dr K Langford FRCOG, London.
DISCLAIMER
health services.
21 of 21
Management of Sickle Cell Disease

in Pregnancy
July 2011
Management of Sickle Cell Disease in Pregnancy

1.
Purpose and scope
The purpose of this guideline is to describe the management of pregnant women with sickle cell disease
(SCD). It will include preconceptual screening and antenatal, intrapartum and postnatal management. It will
not cover the management of women with sickle cell trait.
2.
SCD is a group of inherited single-gene autosomal recessive disorders caused by the sickle gene, which affects
haemoglobin structure.1 SCD has its origins in sub-Saharan Africa and the Middle East,2,3 hence it is most
prevalent in individuals of African descent as well as in the Caribbean, Middle East, parts of India and the
Mediterranean, and South and Central America. Owing to population migration, SCD is now of increasing
importance worldwide and there are increasing numbers of affected individuals in Europe and the USA.47
The term SCD includes sickle cell anaemia (HbSS) and the heterozygous conditions of haemoglobin S and other
clinically abnormal haemoglobins.These include combination with haemoglobin C (giving HbSC), combination
with beta thalassaemia (giving HbSB thalassaemia) and combination with haemoglobin D, E or O-Arab. All of
these genotypes will give a similar clinical phenotype of varying severity.3 Haemoglobin S combined with
normal haemoglobin (A), known as sickle trait (AS), is asymptomatic, except for a possible increased risk of
urinary tract infections and microscopic haematuria, and is not considered further in this guideline.
SCD is the most common inherited condition worldwide. About 300 000 children with SCD are born each
year;8,9 two-thirds of these births are in Africa.10 In the UK, it is estimated that there are 12 00015 000 affected
individuals and over 300 infants born with SCD in the UK each year who are diagnosed as part of the neonatal
screening programme.7 There are approximately 100200 pregnancies in women with SCD per year in the
UK; pregnancy outcome in this group is currently being assessed by the UK Obstetric Surveillance System
[https://www.npeu.ox.ac.uk/ukoss/completed-surveillance].
The pathophysiology of SCD is a consequence of polymerisation of the abnormal haemoglobin in low-oxygen
conditions, which leads to the formation of rigid and fragile sickle-shaped red cells. These cells are prone to
increased breakdown, which causes the haemolytic anaemia, and to vaso-occlusion in the small blood vessels,
which causes most of the other clinical features, including acute painful crises. Other complications of SCD
include stroke, pulmonary hypertension, renal dysfunction, retinal disease, leg ulcers, cholelithiasis and
avascular necrosis (which commonly affects the femoral head and may necessitate hip replacement). SCD was
previously associated with a high early mortality rate, but now the majority of children born with SCD in the
UK live to reproductive age and average life expectancy is at least the mid-50s.11,12
3.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines.1315 Medline, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Control
Register of Controlled Trials (CONTROL), the Database of Abstracts of Reviews and Effects (DARE), the ACP
Journal Club and the Ovid database were searched for relevant randomised controlled trials, systematic reviews
and meta-analyses between 1980 and August 2009. Search terms included: sickle cell, hydroxycarbamide,
antenatal, pregnancy, intrapartum, penicillin prophylaxis, ACE inhibitor, transfusion, ultrasound,
Doppler, echocardiogram, anticoagulation, prophylaxis, sickle cell and risk factors, preconceptual and
sickle cell crisis and included all relevant MeSH terms and subheadings.The search was limited to humans and
2 of 20
the English language. The National Library for Health and the National Guidelines Clearing House were also
searched for relevant guidelines. Where possible, recommendations are based on available evidence; areas
where evidence is lacking are annotated as good practice points (designated by a tick).
4.
Preconception care
4.1 What are the additional risks to the woman and baby?
SCD is associated with both maternal and fetal complications and is associated with an increased incidence
of perinatal mortality,1621 premature labour,1622 fetal growth restriction1623 and acute painful crises during
pregnancy.1719,24,25 Some studies also describe an increase in spontaneous miscarriage,22 antenatal
hospitalisation,23 maternal mortality,26 delivery by caesarean section,23,26 infection, thromboembolic events27
and antepartum haemorrhage.26 An increased risk of pre-eclampsia and pregnancy-induced hypertension has
been described in some studies16,18,19,23,26 but not in others.17,20,22 In HbSC there are fewer reported adverse
outcomes, but there is evidence of an increased incidence of painful crises during pregnancy,28 fetal growth
restriction, antepartum hospital admission and postpartum infection.21
4.2 What is the importance of planning pregnancy and how can outcomes for the woman and baby be
improved?
From adolescence, the intentions of women with SCD regarding pregnancy and contraception should be
documented at each contact with their sickle care team.
Women with SCD should be seen preconceptually by a sickle specialist to receive information about how
SCD affects pregnancy and how pregnancy affects sickle cell disease, and how to improve outcomes for
mother and baby. This consultation should include optimisation of management and screening for end
organ damage.
Primary care physicians have a key role in preconceptual screening, including the provision of
contraceptive advice. Women with SCD should receive not only the general preconceptual care which is
given to all women but also additional advice about vaccinations, medications and crisis avoidance.
Advise women to have a low threshold for seeking medical help.
Reproductive planning and contraceptive choice should be part of the regular outpatient consultation in the
sickle cell clinic.
SCD is a chronic, lifelong condition and there are recommendations for clinical care which apply to all patients,
including women planning to become pregnant.26 Women should be reviewed at least annually by a specialist
sickle service for the monitoring of chronic disease complications and the imparting of information.29
Information that is particularly relevant for women planning to conceive includes:
the role of dehydration, cold, hypoxia, overexertion and stress in the frequency of sickle cell crises
how nausea and vomiting in pregnancy can result in dehydration and the precipitation of crises
the risk of worsening anaemia, the increased risk of crises and acute chest syndrome (ACS) and
the risk of increased infection (especially urinary tract infection) during pregnancy
the increased risk of having a growth-restricted baby, which increases the likelihood of fetal
distress, induction of labour and caesarean section16,17,18,22,23
the chance of their baby being affected by SCD
an up-to-date assessment for chronic disease complications.
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Evidence
level 4
The assessment for chronic disease complications should include:
Screening for pulmonary hypertension with echocardiography. The incidence of pulmonary

hypertension is increased in patients with SCD and is associated with increased mortality.30 A
tricuspid regurgitant jet velocity of more than 2.5 m/second is associated with a high risk of
pulmonary hypertension.31 Screening should be performed if this has not been carried out in the
last year.29
Blood pressure and urinalysis should be performed to identify women with hypertension and/or
proteinuria. Renal and liver function tests should be performed annually to identify sickle
nephropathy and/or deranged hepatic function.29
Retinal screening. Proliferative retinopathy is common in patients with SCD, especially patients
with HbSC, and can lead to loss of vision.32 There is no randomised evidence on whether routine
screening should be performed or if patients should be screened only if they experience visual
symptoms, but we recommend that women are screened preconceptually.
Screening for iron overload. In women who have been multiply transfused in the past or who
have a high ferritin level, T2* cardiac magnetic resonance imaging may be helpful to assess body
iron loading. Aggressive iron chelation before conception is advisable in women who are
significantly iron loaded.
Screening for red cell antibodies. Red cell antibodies may indicate an increased risk of haemolytic
disease of the newborn.
Evidence
level 4
4.3 What is the importance of genetic screening and what procedure(s) are involved?
Women and men with SCD should be encouraged to have the haemoglobinopathy status of their partner
determined before they embark on pregnancy. If identified as an at risk couple, as per National
Screening Committee guidance, they should receive counselling and advice about reproductive options.
General practitioners have a key role to play in partner screening and genetic counselling. Women should be
encouraged to have the haemoglobinopathy status of their partner tested. If a partner is a carrier of, or
affected by, a major haemoglobinopathy, the couple should receive appropriate counselling regarding the risk
of having affected offspring (Table 1).33 The methods and risks of prenatal diagnosis and termination of
pregnancy should be discussed with the couple.34 In addition, they should receive counselling about the
availability of preimplantation genetic diagnosis and referred for this if appropriate. Partners will not always
be available or willing to undergo preconceptual testing. Women with SCD should be aware that if their
partners status is unknown, the fetus should be treated as high risk for a haemoglobinopathy.33 Sperm donors
should also be screened for haemoglobinopathies for couples considering in vitro fertilisation.
Further information can be obtained from the NHS Sickle Cell & Thalassaemia Screening Programme website33
or the Programmes Handbook for Laboratories.35
Table 1. Conditions requiring counselling when the mother is affected by SCD35

Condition
HbS
Carrier state in partner which requires referral for counselling and offer of prenatal diagnosis
thalassaemia
O-Arab
HbC
D-Punjab
DB thalassaemia
Carrier state in partner which requires counselling and may need further investigation
Lepore
HbE
Hereditary persistence of
fetal hemoglobin (HPFH)
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4.4 What is the importance of antibiotic prophylaxis and immunisation?

Penicillin prophylaxis or the equivalent should be prescribed.
Vaccination status should be determined and updated before pregnancy.
Patients with SCD are hyposplenic and are at risk of infection, in particular from encapsulated
bacteria such as Neisseria meningitides, Streptococcus pneumonia and Haemophilus influenzae.
There is clear evidence that penicillin prophylaxis is of benefit in young children with SCD,36 but
there is no randomised trial evidence in older patients or pregnant women. UK guidance is that daily
penicillin prophylaxis is given to all patients with SCD, in line with the guidelines for all hyposplenic
patients.29,37 People who are allergic to penicillin should be recommended erythromycin.
Evidence
level 4
In addition, women should be given H. influenza type b and the conjugated meningococcal C
vaccine as a single dose if they have not received it as part of primary vaccination. The
pneumococcal vaccine (Pneumovax, Sanofi Pasteur MSD Limited, Maidenhead, UK) should be
given every 5 years.38
Evidence
level 1
Hepatitis B vaccination is recommended and the womans immune status should be determined
preconceptually. Women with SCD should be advised to receive the influenza and swine flu
vaccine annually.29
Evidence
level 4
Penicillin prophylaxis and vaccinations are usually monitored and administered in primary care, but
should be reviewed by the specialist haematologist/obstetrician during pregnancy.
4.5 What vitamin supplements should be given?

Folic acid (5 mg) should be given once daily both preconceptually and throughout pregnancy.
Folic acid is recommended in all pregnant women to prevent neural tube defects.39
Evidence
level 1
Folic acid at a dosage of at least 1 mg daily is recommended for women with SCD outside
pregnancy in view of their haemolytic anaemia, which puts them at increased risk of folate
deficiency.40
Evidence
level 3
Folic acid 5 mg daily should be prescribed during pregnancy to reduce the risk of neural tube
defect and to compensate for the increased demand for folate during pregnancy.41
Evidence
level 4
4.6 What medications should be reviewed preconceptually?

Hydroxycarbamide (hydroxyurea) should be stopped at least 3 months before conception.
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be stopped before
conception.
Hydroxycarbamide has been demonstrated to decrease the incidence of acute painful crises and
ACS in individuals with severe clinical manifestations of SCD.42 Hydroxycarbamide is teratatogenic
in animals and, consequently, current UK advice is that women with SCD on hydroxycarbamide
should use effective contraception and stop taking hydroxycarbamide 3 months before they
conceive.There are published reports of women receiving hydroxycarbamide both for SCD and for
other indications becoming pregnant, some of whom have continued the medication throughout
pregnancy without adverse effects on the baby. While pregnancy should be avoided in women on
hydroxycarbamide, these case reports provide help when counselling women: if they become
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Evidence
level 3
pregnant while taking hydroxycarbamide, it should be stopped and a level 3 ultrasound performed
to look for structural abnormality, but termination is not indicated based on exposure to
hydroxycarbamide alone.43,44
Evidence
level 3
Renal dysfunction, proteinuria and microalbuminuria are common in SCD. Angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers are used routinely in patients with SCD with significant
proteinuria (proteincreatinine ratio of more than 50 mg/mmol), since there is evidence that these agents
reduce proteinuria and microalbuminuria.45,46 These drugs are not safe in pregnancy and should be stopped
in women who are trying to conceive.
5.
Antenatal care
5.1 General aspects

This section should be read in conjunction with National Institute for Health and Clinical Excellence (NICE)
clinical guideline no. 62: Antenatal care. Routine care for the healthy pregnant woman.47
Antenatal care should be provided by a multidisciplinary team including an obstetrician and midwife
with experience of high-risk antenatal care and a haematologist with an interest in SCD.
Women with SCD should undergo medical review by the haematologist and be screened for end organ
damage (if this has not been undertaken preconceptually).
Women with SCD should aim to avoid precipitating factors of sickle cell crises such as exposure to
extreme temperatures, dehydration and overexertion.
Persistent vomiting can lead to dehydration and sickle cell crisis and women should be advised to seek
medical advice early.
The influenza vaccine should be recommended if it has not been administered in the previous year.
Many women become pregnant without preconceptual care. Therefore, all of the actions outlined in section
4, including vaccinations, review of iron overload and red cell autoantibodies, should take place as early as
possible during antenatal care. Live attenuated vaccines should be deferred until after delivery.
The development of multidisciplinary care seems to be associated with an improvement in
maternal and fetal outcomes. The establishment of comprehensive sickle cell centres in the USA
was associated with decreases in the spontaneous miscarriage and perinatal death rates and
incidence of preterm labour.24 Active prenatal management in an African setting, which included
providing information and education about SCD, improving nutritional status, malaria prevention
and early detection of bacterial infection, has also been shown to have a positive impact on SCDrelated morbidity and mortality.48 A retrospective nationwide data analysis of all pregnancy-related
discharges with the diagnosis of SCD for 20002003 in the USA also demonstrated improved
outcomes, principally as a result of committed multidisciplinary care.26
Evidence
level 2-
In UK practice, provision of multidisciplinary care is complicated by the wide variation in prevalence of SCD
in different parts of the country. If there is a relevant multidisciplinary team available within reasonable
travelling distance, women should go there. If this is not available, women should be cared for by high-risk
teams who have shared care arrangements and shared protocols with the specialist teams.
Women with HbSC experience fewer adverse outcomes, but there is still evidence of an increased incidence
of painful crises during pregnancy,28 fetal growth restriction, antepartum hospital admission and postpartum
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infection.21 Although outcomes among women with HbSC are better than in women with HbSS, some do have
serious, unpredictable complications, and women with HbSC should therefore be monitored in the same way
as those with HbSS. There is a paucity of data on pregnancy outcomes in women with HbSB thalassaemia,
HbSD, HbSE or HbSO-Arab, but anecdotal evidence indicates that such women should also be monitored and
treated with the same level of vigilance and care.
5.2 Antenatal haemoglobinopathy screening

If the woman has not been seen preconceptually, she should be offered partner testing. If the partner is
a carrier, appropriate counselling should be offered as early as possible in pregnancy ideally by 10
weeks of gestation to allow the option of first-trimester diagnosis and termination if that is the
womans choice.
It is essential that any woman who has a potentially affected infant (i.e. their partner is a carrier or is affected
by a significant haemoglobinopathy) is aware of this and receives appropriate counselling. Prenatal diagnosis
should be offered as early in pregnancy as possible. Partner status and subsequent counselling should be
clearly documented in the notes. Further information can be obtained on the NHS Sickle Cell & Thalassaemia
Screening Programme website,33 which includes information about the laboratories that can perform prenatal
diagnostic testing. The objective of the screening programme is to ensure that screening tests are offered by
810 weeks of pregnancy by primary care or maternity services.
5.3 What medication should be given during pregnancy?

If women have not undergone a preconceptual review, they should be advised to take daily folic acid and
prophylactic antibiotics (if not contraindicated). Drugs that are unsafe in pregnancy should be stopped
immediately.
Iron supplementation should be given only if there is laboratory evidence of iron deficiency.
Women with SCD should be considered for low-dose aspirin 75 mg once daily from 12 weeks of gestation
in an effort to reduce the risk of developing pre-eclampsia.
Women with SCD should be advised to receive prophylactic low-molecular-weight heparin during
antenatal hospital admissions.
While older studies demonstrated iron deficiency to be common in SCD, a more recent study examining a
small number of pregnant women with SCD showed no evidence of iron deficiency, and some of these
women were iron overloaded.49,50 Iron status should be assessed and iron supplementation should be
recommended only if there is evidence of iron deficiency.
Women who are at increased risk of pre-eclampsia are advised to take low-dose aspirin 75 mg from 12 weeks
of gestation, unless they have aspirin sensitivity. While there is no specific evidence that aspirin decreases the
risk of pre-eclampsia in women with SCD, such women are probably at increased risk of developing preeclampsia.51,52 SCD should be considered a mild risk factor and aspirin prophylaxis recommended according
to NICE guidance.52
There is some evidence that the incidence of venous thromboembolism is increased among pregnant women
with SCD.A study from Bahrain examining maternal deaths between 1977 and 1989 reported that 5/12 deaths
among women with SCD were attributed to pulmonary embolism.27 Thromboprophylaxis advice should be
based on the RCOG Green-top Guideline for women with additional risk factors.53 The use of graduated
compression stockings of appropriate strength is recommended in pregnancy for women considered to be
at risk of venous thromboembolism, as discussed in the RCOG Green-top Guideline on thromboprophylaxis.53
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It is recommended that women receive low-molecular-weight heparin during hospital admission.

Non-steroidal anti-inflammatory drugs (NSAIDs) should be prescribed only between 12 and 28 weeks of
gestation owing to concerns regarding adverse effects on fetal development
5.4 What additional care should be provided during the antenatal appointment?
Antenatal appointments for women with SCD should provide routine antenatal care as well as care
specifically for women with SCD.45
Blood pressure and urinalysis should be performed at each consultation, and midstream urine for
culture performed monthly.
Women with SCD probably have an increased risk of pregnancy-induced hypertension;16,18,19,23,26

therefore, blood pressure and the presence of proteinuria should be assessed at each visit. Women
with pre-existing proteinuria or known renal impairment will require more frequent monitoring.
Women with SCD often have a low blood pressure, so an upward trend in blood pressure, even if
modest, should be monitored carefully. Studies have also demonstrated an increase in the incidence
of urinary tract infection and asymptomatic bacteriuria,26 so urinalysis should be performed at each
antenatal visit and midstream urine should be sent for culture and sensitivity monthly.
Evidence
level 2+
At each appointment, opportunities should be offered for information and education. The womans housing
and work circumstances should be reviewed, and interventions which may reduce the potential provocation
of acute crises (e.g. improved heating, allowance for increased hospital visits) should be encouraged. Table 2
outlines the recommended frequency and content of antenatal appointments for women with SCD.
5.5 What is the recommended schedule of ultrasound scanning during pregnancy?

Women should be offered a viability scan at 79 weeks of gestation.
Women should be offered the routine first-trimester scan (1114 weeks of gestation) and a detailed
anomaly scan at 20 weeks of gestation. In addition, women should be offered serial fetal biometry
scans (growth scans) every 4 weeks from 24 weeks of gestation.
A number of studies suggest that women with SCD are at risk of fetal growth restriction21,26,28 as well
as pre-eclampsia. Serial growth scans allow early detection of fetal growth restriction and hence aid
appropriate timing of delivery to reduce perinatal mortality and morbidity.54
Evidence
level 2+
5.6 What is the role of blood transfusion during pregnancy?

Routine prophylactic transfusion is not recommended during pregnancy for women with SCD.
If acute exchange transfusion is required for the treatment of a sickle complication, it may be
appropriate to continue the transfusion regimen for the remainder of the pregnancy.
Blood should be matched for an extended phenotype including full rhesus typing (C, D and E) as well
as Kell typing.
Blood used for transfusion in pregnancy should be cytomegalovirus negative.
Early studies recommended prophylactic transfusion during pregnancy as there was a decrease in
maternal morbidity and perinatal mortality among transfused women compared with historical
controls.5557 There are appreciable risks associated with transfusion in this heavily transfused
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Evidence
level 1-
patient cohort, including alloimmunisation,25,58 delayed transfusion reactions,58 transmission of

infection and iron overload. A randomised controlled trial59 and a retrospective study25 have
demonstrated that prophylactic transfusion decreased the incidence of maternal painful crises but
did not influence fetal or maternal outcome. A systematic review60 indicated that there is
insufficient evidence to draw conclusions about the role of transfusion in pregnancy.
Evidence
level 1-
Table 2. Specific antenatal care for women with SCD

Appointment
Care for women with SCD during pregnancy
What should happen at

at the first appointment?
Offer information, advice and support in relation to optimising general health (D)
Primary care or
hospital appointment
Offer partner testing if not already done; review partner results if available and discuss PND if
appropriate (D)
Take a clinical history to establish extent of SCD and its complications
Review medications and its complications; if taking hydroxycarbamide, ACE inhibitors or ARBs,
these should be stopped (D)
Women should already be taking 5 mg folic acid and antibiotic prophylaxis if no contraindication (D)
Discuss vaccinations (D)
Offer retinal and/or renal and/or cardiac assessments if these have not been performed in the
previous year (D)
Document baseline oxygen saturations and blood pressure
Send MSU for culture
79 weeks
Confirm viability in view of the increased risk of miscarriage (D)
What should happen at

the booking appointment?
Discuss information, education and advice about how SCD will affect pregnancy (D)
See midwife with experience

in high-risk obstetrics if possible
Review partner results and discuss PND if appropriate (D)

Baseline renal function test, urine protein/creatinine ratio, liver function test and ferritin should be
performed (D)
Extended red cell phenotype if not previously performed (D)
Confirm that all actions from first visit are complete (D)
Consider low-dose aspirin from 12 weeks of gestation (D)
16 weeks: see midwife plus

multidisciplinary review
Routine as per NICE; repeat MSU

Multidisciplinary review (consultant obstetrician and haematologist)
20 weeks : see midwife plus

multidisciplinary team
Detailed ultrasound as per NICE antenatal guideline

Repeat MSU
Repeat FBC
24 weeks: see multidisciplinary

team
Ultrasound monitoring of fetal growth and amniotic fluid volume.

Repeat MSU
26 weeks: see midwife
Routine check including blood pressure and urinalysis

team
Ultrasound monitoring of fetal growth and amniotic fluid volume

Repeat MSU
Repeat FBC and group and antibody screen
30 weeks: see midwife and offer

antenatal classes
Routine check including blood pressure and urinalysis

team
Routine check
Repeat MSU and FBC
Routine check including blood pressure and urinalyis

team
Routine check
Offer information and advice about:
timing, mode and management of the birth
analgesia and anaesthesia; arrange anaesthetic assessment
care of baby after birth
38 weeks: see midwife and

obstetrician
Routine check
Recommend induction of labour or caesarean section between 38 and 40 weeks of gestation
Routine check and recommend delivery by 40 weeks of gestation
40 weeks: see obstetrician
Routine check and offer fetal monitoring if the woman declines delivery by 40 weeks of gestation
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; FBC = full blood count (for the woman); MSU = midstream urine;
NICE = National Institute for Health and Clinical Excellence; PND = prenatal diagnosis; SCD = sickle cell disease
9 of 20
Top-up transfusion is indicated for women with acute anaemia.29 Acute anaemia may be
attributable to transient red cell aplasia, acute splenic sequestration or the increased haemolysis and
volume expansion encountered in SCD. There is no absolute level at which transfusion should be
undertaken and the decision must be made in conjunction with clinical findings, but haemoglobin
under 6 g/dl or a fall of over 2 g/dl from baseline is often used as a guide to transfusion requirement.
Evidence
level 4
Exchange transfusion for ACS was demonstrated to be effective in one prospective randomised trial
and is accepted as best practice.29,61
Evidence
level 1-
Exchange transfusion is also indicated for acute stroke.16
Evidence
level 4
The decision to recommend transfusion should be made by an experienced haematologist and obstetrician.
Indications for transfusion are summarised in Table 3.
Alloimmunisation (the formation of antibodies to red cell antigens) is common in SCD, occurring in
1836% of patients. Alloimmunisation is clinically important as it can lead to delayed haemolytic
transfusion reactions or haemolytic disease of the newborn62 and can render patients
untransfusable. The most common antibodies are to the C, E and Kell antigens. The risk of
alloimmunisation is significantly reduced by giving red cells matched for the C, E and Kell antigens,61
and this should be standard practice for all patients with SCD whether they are pregnant or not.
Evidence
level 1
5.7 What is the optimal management of acute painful crisis during pregnancy?
Women with SCD who become unwell should have sickle cell crisis excluded as a matter of urgency.
Pregnant women presenting with acute painful crisis should be rapidly assessed by the
multidisciplinary team and appropriate analgesia should be administered. Pethidine should not be
used because of the associated risk of seizures.
Women admitted with sickle cell crisis should be looked after by the multidisciplinary team, involving
obstetricians, midwives, haematologists and anaesthetists.
The requirement for fluids and oxygen should be assessed, and fluids and oxygen administered if
required.
Thromboprophylaxis should be given to women admitted to hospital with acute painful crisis.
Table 3. Indications for blood transfusion in pregnancy complicated by SCD

Indication
Comments
Women with previous serious medical, obstetric or fetal

complications
Exchange or top-up transfusion may be indicated depending on

clinical indications and should be decided in the multidisciplinary
clinic setting
Women who are on a transfusion regimen before pregnancy for

primary or secondary stroke prevention or for the prevention of
severe disease complications
Transfusion should be continued during pregnancy
Twin pregnancies
Prophylactic transfusion should be considered owing to the high rate

of complications in these women25
Acute anaemia
Top-up transfusion
Acute chest syndrome or acute stroke
Exchange transfusion
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Painful crisis is the most frequent complication of SCD during pregnancy, with between 27% and 50% of
women having a painful crisis during pregnancy,17,19,24,25 and it is the most frequent cause of hospital
admission.24 Avoidance of precipitants such as a cold environment, excessive exercise, dehydration and stress
is important. There are no randomised controlled trials examining the management of painful crisis in
pregnant women with SCD,63 so treatment of acute pain in pregnant women should follow national
recommendations applicable to non-pregnant women.64
Mild pain may be managed in the community with rest, oral fluids and paracetamol or weak opioids. NSAIDs
should be used only between 12 and 28 weeks of gestation. Primary care physicians should have a low
threshold for referring women to secondary care; all women with pain which does not settle with simple
analgesia, who are febrile, have atypical pain or chest pain or symptoms of shortness of breath should be
referred to hospital.
On presentation, the woman in sickle crisis should be assessed rapidly for medical complications requiring
intervention such as ACS, sepsis or dehydration. History should ascertain if this is typical sickle pain or not,
and if there are precipitating factors. Examination should focus on the site of pain, any atypical features of the
pain and any precipitating factors, in particular whether there are any signs of infection. Initial investigations
should include full blood count, reticulocyte count and renal function. Other investigations will depend on
the clinical scenario but may include blood cultures, chest X-ray, urine culture and liver function tests.
Initial analgesia should be given within 30 minutes of arriving at hospital and effective analgesia
should be achieved within 1 hour.64
Evidence
level 4
The World Health Organization analgesic ladder should be used, starting with paracetamol for mild pain;
NSAIDs can be used for mild to moderate pain between 12 and 28 weeks of gestation. Weak opioids such as
co-dydramol, co-codamol or dihydrocodeine can be used for moderate pain, and stronger opiates such as
morphine can be used for severe pain. Morphine or diamorphine can be given by the oral, subcutaneous,
intramuscular or intravenous route depending on the womans preference and local expertise. Parenteral
opiates can be given by intermittent bolus or patient-controlled administration systems. Pethidine should be
avoided because of the risk of toxicity and pethidine-associated seizures in patients with SCD.64
Women presenting with pain should initially be monitored at 20-minute intervals for pain severity, respiratory
rate and sedation. Women whose pain settles following oral analgesia can be discharged home. If the women
need strong opiate therapy, they will need to be admitted to hospital: to a medical ward in early pregnancy,
or to a level 2 antenatal bed in later pregnancy, under the joint care of obstetricians and haematologists.
Ideally, care should be provided by doctors and midwives who are familiar with SCD, but this is not always
possible for geographical reasons and in this situation shared care arrangements and protocols should exist
with specialist centres.Assessments of pain score, sedation score and oxygen saturation should be performed
at least 2-hourly using a modified obstetric early warning chart.6466 While women are receiving parenteral
opiates, they should be nursed in an area where they can undergo hourly observations (Box 1).
Box 1. Outline of management of acute pain64
Rapid clinical assessment
If pain is severe and oral analgesia is not effective, give strong opioids (e.g. morphine)
Give adjuvant non-opioid analgesia: paracetamol, NSAID (if 1228 weeks of gestation)
Prescribe laxatives, antipruritic and antiemetic if required
Monitor pain, sedation, vital signs, respiratory rate and oxygen saturation every 2030 minutes until pain is controlled and signs are stable,
then monitor every 2 hours (hourly if receiving parenteral opiates)
Give a rescue doses of analgesia if required
If respiratory rate is less than 10/minute, omit maintenance analgesia; consider naloxone
Consider reducing analgesia after 23 days and replacing injections with equivalent dose of oral analgesia
Discharge the woman when pain is controlled and improving without analgesia or on acceptable doses of oral analgesia
Arrange any necessary home care and outpatient follow-up appointment.
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Fluid intake of at least 60ml/kg/24 hours should be ensured; this can be taken either orally or intravenously
if the woman is not able to take adequate oral fluids. There is a risk of fluid overload in women with preeclampsia; senior experienced staff should be involved in managing the fluid balance of these women.
Oxygen saturations should be monitored and facial oxygen should be prescribed if oxygen saturation falls
below the womans baseline or below 95%.64 There should be early recourse to intensive care if satisfactory
oxygen saturation cannot be maintained by facial or nasal prong oxygen administration.
The woman should be assessed for infection. Therapeutic antibiotics should be prescribed if the woman is
febrile or there is a high clinical suspicion of infection. White blood cell counts are often raised in SCD and
do not necessarily indicate infection. Thromboprophylaxis should be provided to women with SCD who are
admitted to hospital with painful crises. Other adjuvants may be required to treat the adverse effects of
opiates, such as antihistamines to treat itching or laxatives to prevent opiate-induced constipation, and antiemetics may be required. As the painful crisis resolves, most women are able to reduce their opiate
requirement rapidly, but this should be guided by the womans previous experience.
Opiates are not associated with teratogenicity or congenital malformation but may be associated with
transient suppression of fetal movement and a reduced baseline variability of the fetal heart rate. Where a
mother has received prolonged administration of opiates in late pregnancy, the neonate should be observed
for signs of opioid withdrawal.
5.8 What are the other acute complications of SCD and how are they treated?
All patients, carers, medical and nursing staff should be aware of the other acute complications of SCD,
including ACS, acute stroke and acute anaemia.
Each hospital should have a protocol in place for the management of ACS in pregnancy, including the
use of transfusion therapy.
SCD is associated with other acute complications including ACS, stroke and acute anaemia. In the pregnant
woman, these complications should be managed in the multidisciplinary setting by an obstetrician and a
haematologist, and guidance on the management of these complications can be found in the relevant UK
standards.29
After acute pain, ACS is the most common complication, reported in 720% of pregnancies.18,22,25 ACS is
characterised by respiratory symptoms such as tachypnoea, chest pain, cough and shortness of breath in the
presence of a new infiltrate on the chest X-ray. The signs and symptoms of ACS are the same as those of
pneumonia, so both should be treated simultaneously. Acute severe infection with the H1N1 virus in
pregnancy can cause a similar clinical picture, and investigation and treatment for this should be instituted.
Early recognition of ACS is key. Treatment is with intravenous antibiotics, oxygen and blood
transfusion, as in non-pregnant women.29 Top-up blood transfusion may be required if the
haemoglobin is falling, and certainly if the haemoglobin is less than 6.5 g/dl, but in severe hypoxia,
and if the haemoglobin level is maintained, exchange transfusion will be required. If ACS is
suspected, the woman should be reviewed urgently by the haematology team to advise on
transfusion. If the woman has hypoxia, she should be reviewed by the critical care team and
ventilatory support may be required.
Evidence
level 4
There is an increased risk of pulmonary embolism among women with SCD. In women presenting with acute
hypoxia, there should be a low threshold for considering pulmonary embolism. In this situation, therapeutic
low-molecular-weight heparin should be commenced until the woman has been reviewed by senior staff and
definitive investigations have been undertaken.
12 of 20
Acute stroke, both infarctive and haemorrhagic, is associated with SCD67 and this diagnosis should
be considered in any woman with SCD who presents with acute neurological impairment. Acute
stroke is a medical emergency and a rapid-exchange blood transfusion can decrease long-term
neurological damage. If a stroke is suspected, the woman should have urgent brain imaging and the
haematologist should be called for consideration of urgent exchange transfusion. Thrombolysis is
not indicated in acute stroke secondary to SCD.29
Acute anaemia in women with SCD may be attributable to erythrovirus infection. Infection with
erythrovirus in SCD causes a red cell maturation arrest and an aplastic crisis characterised by a
reticulocytopenia. Therefore, a reticulocyte count should be requested in any woman presenting
with an acute anaemia and, if low, may indicate infection with erythrovirus.Treatment is with blood
transfusion and the woman must be isolated. With erythrovirus infection there is the added risk of
vertical transmission to the fetus, which can result in hydrops fetalis, hence a review by a fetal
medicine specialist is indicated.68 Women with SCD can develop anaemia owing to bleeding or any
other causes of anaemia incidental to the SCD. Rare causes of anaemia in SCD include malaria and,
occasionally, splenic sequestration in women with a mild phenotype.
6.
Evidence
level 4
Intrapartum care
This section should be read in conjunction with NICE clinical guideline no. 55: Intrapartum care. Care of
healthy women and their babies during childbirth.69
6.1 What is the optimal timing and mode of delivery?

Pregnant women with SCD who have a normally growing fetus should be offered elective birth through
induction of labour, or by elective caesarean section if indicated, after 38+0 weeks of gestation.
SCD should not in itself be considered a contraindication to attempting vaginal delivery or vaginal birth
after caesarean section.
Blood should be cross-matched for delivery if there are atypical antibodies present (since this may
delay the availability of blood), otherwise a group and save will suffice.
In women who have hip replacements (because of avascular necrosis) it is important to discuss suitable
positions for delivery.
There are no randomised controlled trials to dictate the appropriate timing of delivery. Studies from the USA,
UK, Jamaica and Africa have highlighted increased perinatal mortality, particularly during the later stages of
pregnancy, in part owing to the complications of SCD.2126 The risks of abruption, pre-eclampsia, peripartum
cardiomyopathy and acute sickle cell crisis are increased and unpredictable. It is the opinion of the developers
that, like most high-risk conditions, delivery of the baby at 3840 weeks of gestation will prevent late
pregnancy complications and associated adverse perinatal events.
Some older studies questioned vaginal delivery as the optimal mode of delivery for women with
SCD. However, other studies demonstrating improved clinical outcomes21,22,24,26 all support vaginal
delivery as the recommended mode of delivery with the need for caesarean section based on
obstetric indications.70
Evidence
level 2+
6.2 What is the optimum care and place of birth for a woman with SCD?
Women with SCD should be advised to give birth in hospitals that are able to manage both the
complications of SCD and high-risk pregnancies.
13 of 20
The relevant multidisciplinary team (senior midwife in charge, senior obstetrician, anaesthetist and
haematologist) should be informed as soon as labour is confirmed.
Women should be kept warm and given adequate fluid during labour.
Continuous intrapartum electronic fetal heart rate monitoring is recommended owing to the increased
risk of fetal distress which may necessitate operative delivery.
There are no randomised controlled trials with regard to place of birth for women with SCD.There
is an increased frequency of sickle cell crisis and ACS in the intrapartum period. There is an
increased risk of painful crisis with protracted labour (more than 12 hours), but this is often
secondary to dehydration. In this situation, if the woman is well hydrated and labour is progressing,
the labour should be carefully supervised; caesarean section should be considered if labour is not
progressing well and delivery is not imminent.26
Evidence
level 2+
During labour, if oral hydration is not tolerated or is inadequate, intravenous fluids should be
administered using a fluid balance chart to prevent fluid overload. Venous access can be difficult,
especially if they have had multiple previous admissions, and as such anaesthetic
review/intravenous access should be obtained early.The demand for oxygen is increased during the
intrapartum period and the use of pulse oximetry to detect hypoxia in the mother is appropriate
during labour. Arterial blood gas analysis should be performed and oxygen therapy instituted if
oxygen saturation is 94% or less.
Evidence
level 4
Routine antibiotic prophylaxis in labour is currently not supported by evidence, but hourly observations of
vital signs should be performed.A raised temperature (over 37.5C) requires investigation.The clinician should
have a low threshold to commence broad-spectrum antibiotics.
There are no randomised controlled trials with regard to interventions during labour for women
with SCD. Experience reported in cohort observational studies from sickle cell centres in Jamaica,22
the USA18,21,24 and the UK16,25 recommend close observation, as described above. Continuous
electronic fetal heart rate monitoring is recommended because of the increased rate of stillbirth,
placental abruption and compromised placental reserve.71,72
Evidence
level 2+
6.3 What is the optimal mode of analgesia and anaesthesia?

Women with SCD should be offered anaesthetic assessment in the third trimester of pregnancy.
Avoid the use of pethidine, but other opiates can be used.
Regional analgesia is recommended for caesarean section.
Pregnant women with SCD are at risk of end organ damage as well as experiencing a higher rate of caesarean
section. General anaesthesia carries additional risks beyond the normal obstetric case and should be avoided
where possible. Regional anaesthesia during labour may reduce the necessity of general anaesthesia for
delivery. It is also likely to reduce the need for high doses of opioids if the woman has sickle-related pain in
the lower body. An anaesthetic assessment in the third trimester is warranted. Pethidine should be avoided
because of the risk of seizures when administered to a woman with SCD.64 Other opiates can be used (see
section 5.7). Indications for epidural analgesia in labour are the same as per NICE intrapartum guidelines and
are determined by the level of pain experienced, maternal choice and the absence of contraindications.69
Sickle cell crisis in labour should be treated as per the guidance for antepartum crisis above (section 5.7).
14 of 20
7.
Postpartum care
7.1 What should be the optimum care post-delivery?

In pregnant women where the baby is at high risk of SCD (i.e. the partner is a carrier or affected), early
testing for SCD should be offered. Capillary samples should be sent to laboratories where there is
experience in the routine analysis of SCD in newborn samples. This will usually be at a regional centre.
Maintain maternal oxygen saturation above 94% and adequate hydration based on fluid balance until
discharge.
Low-molecular-weight heparin should be administered while in hospital and 7 days post-discharge

following vaginal delivery or for a period of 6 weeks following caesarean section.
The same level of care and vigilance should be maintained as has been described for antenatal care,
since acute crisis and other complications of SCD remain a risk in the puerperium.
Antithrombotic stockings are recommended in the puerperium, as per RCOG Green-top Guideline No. 37a.53
Routine care should be provided as per the NICE guideline on postnatal care.73
The risk of sickle cell crisis remains increased: in one study it occurred in 25% of women and was more
common following general anaesthesia.74 Hydration and oxygenation should be maintained and early
mobilisation encouraged. Crises should be managed as for non-pregnant women. NSAIDs are routinely
administered in the postpartum period and can be used during breastfeeding. Breastfeeding should be
encouraged, as in women without SCD.
Thromboprophylaxis in the form of low-molecular-weight heparin is recommended while the
pregnant woman is in hospital and for 7 days following vaginal delivery or for a period of 6 weeks
following caesarean section.
Evidence
level 4
7.2 What postpartum contraceptive advice should women be given?

This section should be read in conjunction with the Faculty of Sexual & Reproductive Healthcare guidance
on postnatal hormonal contraception.75 Contraceptive advice will often be the responsibility of primary care.
Progestogen-containing contraceptives such as the progesterone only pill (Cerazette, Organon
Laboratories Ltd, Hoddesdon, UK), injectable contraceptives (Depo-Provera, Pfizer Ltd, New York,
USA) and the levenorgestrel intrauterine system (Mirena, Bayer Schering Pharma AG, Berlin,
Germany) are safe and effective in SCD.
Estrogen-containing contraceptives should be used as second-line agents.
Barrier methods are as safe and effective in women with SCD as in the general population.There is
only limited safety evidence on hormonal contraception in SCD; a Cochrane review76 identified one
randomised trial which showed that women taking intramuscular depo-medroxyprogesterone
acetate (DMPA) were less likely to have a painful episode.77 Evidence level 1-
Evidence
level 1-
A systematic review analysing randomised and non-randomised studies demonstrated progestogens

to be effective and safe in SCD.78 One further study which randomly assigned women to DMPA or
Microgynon (combined oral contraceptive pill; Bayer Schering Pharma AG, Berlin, Germany)
showed a decrease in painful episodes in both groups, but to a greater degree in the DMPA group.79
Evidence
level
2+/3
15 of 20
Prescribers have been reluctant to recommend the combined oral contraceptive in women with
SCD because of the concern about an increased risk of venous thromboembolism, but there is no
evidence using definitive outcome points of venous thromboembolism to confirm this. The UK
Medical Eligibility Criteria80 are based on the World Health Organization criteria classifying
contraceptive use and define the combined oral contraceptive and copper intrauterine device as
category 2, indicating that the advantages outweigh the disadvantages.80 Other methods of
contraception, such as the progestogen only pill, Depo-Provera, the levonorgestrel intrauterine
system (Mirena) and emergency contraception, are rated level 1, indicating there is no restriction
on their use.
8.
Evidence
level 4
Clinical governance
Each hospital should have a protocol for the management of pregnant women with SCD. This should
identify a multidisciplinary team which has responsibility for the care of pregnant women with SCD,
including an obstetrician with expertise in managing high-risk pregnancies and a haematologist.
All staff involved in maternity care should receive training in the care of pregnant women with SCD.
Areas with a low prevalence of SCD should be linked to a specialist centre or care network for shared
care arrangements and shared protocols.
9.

The proportion of staff who receive appropriate training.
The proportion of women receiving folic acid.
The proportion of women receiving penicillin prophylaxis.
The proportion of women receiving preconception advice.
The latter three standards could be audited within primary care.
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18 of 20
APPENDIX

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
19 of 20

development group
Gynaecologists by:
Dr E Oteng-Ntim FRCOG, Consultant Obstetrician, London and Dr J Howard, Consultant Haematologist,
Guys and St Thomas NHS Foundation Trust, London.
Professor E Anionwu, Emeritus Professor of Nursing, Thames Valley University and Sickle Cell Society; Mr I Babarinsa
MRCOG, Gloucester; Dr C Bagot, Consultant Haematologist, Glasgow; Mr DI Fraser MRCOG, Norwich; Dr Jane Preston
FRCOG; Dr KER Ryan, Manchester and General Haematology Task Force, British Committee for Standards in
Haematology; Ms S Tuck FRCOG, London; British Committee for Standards in Haematology; British Maternal and Fetal
Medicine Society; Dr Allison Streetly, National Screening Committee; Obstetric Anaesthetists Association; Royal College
of General Practitioners; RCOG Consumers Forum; Royal College of Midwives; World Health Organization.
The Guideline Committee lead reviewers were: Dr J Shillito MRCOG, Leeds and Dr SK Surendran FRCOG, London.
DISCLAIMER
health services.
20 of 20
Management of Suspected Ovarian

Masses in Premenopausal Women
RCOG/BSGE Joint Guideline I November 2011
Management of Suspected Ovarian Masses in

Premenopausal Women
1.
Purpose and scope
This guideline has been produced to provide information, based on clinical evidence, to assist clinicians with
the initial assessment and appropriate management of suspected ovarian masses in the premenopausal
woman. It aims to clarify when ovarian masses can be managed within a benign gynaecological service and
when referral into a gynaecological oncological service should occur.
The ongoing management of borderline ovarian tumours is outside the remit of this guideline. The
laparoscopic management of highly suspicious or known ovarian malignancies is also outside the scope of
this guideline. In addition, the guideline does not specifically address the acute presentation of ovarian cysts
or the management of ovarian cysts in pregnant women.
This guideline should be read in conjunction with Green-top Guideline No. 24 The Investigation and
Management of Endometriosis.1 The diagnosis of ovarian cysts has been addressed in the National Institute
for Health and Clinical Excellence (NICE) Clinical guidelines on the recognition and initial management of
ovarian cancer.2 The American College of Obstetricians and Gynecologists and the Society of Obstetricians
and Gynecologists of Canada have also produced guidelines for the management of women with an ovarian
mass (see section 5.3).3,4
2.
Up to 10% of women will have some form of surgery during their lifetime for the presence of an ovarian mass.
In premenopausal women almost all ovarian masses and cysts are benign. The overall incidence of a
symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1000 increasing to
3:1000 at the age of 50.
Preoperative differentiation between the benign and the malignant ovarian mass in the premenopausal
woman can be problematic with no test or algorithm being clearly superior in terms of accuracy. Exceptions
are germ cell tumours with elevations of specific tumour markers such as alphafetoprotein (-FP) and human
chorionic gonadotrophin (hCG).
Ten percent of suspected ovarian masses are ultimately found to be non-ovarian in origin (Table 1).6
The underlying management rationale is to minimise patient morbidity by:
conservative management where possible

use of laparoscopic techniques where appropriate, thus avoiding laparotomy where possible
referral to a gynaecological oncologist where appropriate.
Many ovarian masses in the premenopausal woman can be managed conservatively. Functional or simple
ovarian cysts (thin-walled cysts without internal structures) which are less than 50 mm maximum diameter
usually resolve over 23 menstrual cycles without the need for intervention.
If surgery is indicated, a laparoscopic approach is generally considered to be the gold standard for the
management of benign ovarian masses.610 Laparoscopic management is also cost-effective because of the
associated earlier discharge from hospital.11,12 Mini-laparotomy may be considered for occasional very large
2 of 14
Table 1. Types of adnexal masses

Benign ovarian
Functional cysts
Endometriomas
Serous cystadenoma
Mucinous cystadenoma
Mature teratoma
Benign non-ovarian
Paratubal cyst
Hydrosalpinges
Tubo-ovarian abscess
Peritoneal pseudocysts
Appendiceal abscess
Diverticular abscess
Pelvic kidney
Primary malignant ovarian
Germ cell tumour

Epithelial carcinoma
Sex-cord tumour
Secondary malignant ovarian
Predominantly breast and gastrointestinal carcinoma.
cysts of benign appearance. On rare occasions the laparoscopic approach may be specifically contraindicated
in an individual patient.
It is important to consider borderline ovarian tumours as a histological diagnosis when undertaking any
surgery for ovarian masses and, when such a histological diagnosis is made or strongly suspected, referral to
a gynaecological oncology unit is recommended. Preoperative diagnosis can be difficult with radiological and
serum markers being relatively insensitive, especially in their differentiation from stage I ovarian epithelial
cancers. Although up to 20% of borderline ovarian tumours appear as simple cysts on ultrasonography the
majority of such tumours will have suspicious ultrasonographic finding.
Mean survival time for women with ovarian malignancy is significantly improved when managed within a
specialised gynaecological oncology service. Hence early diagnosis and referral is important.13
3.
This guideline was developed using standard methodology for developing RCOG Green-top Guidelines.1416
The Cochrane Library (including the Cochrane Database of Systematic Reviews, DARE and EMBASE), TRIP,
Medline and PubMed (electronic databases) were searched for relevant papers. The search was restricted to
articles published between 1966 and May 2011 and performed by the British Society for Gynaecological
Endoscopy (BSGE) using RCOG methodology.The databases were searched using the relevant medical subject
heading terms including all subheadings and this was combined with a keyword search.The medical subject
heading search included adnexa, ovary and management. The search was limited to humans and papers in
the English language. Relevant guidelines were also searched using the same criteria in the National
Guidelines Clearinghouse, the National electronic Library for Health, the Organising Medical Networked
Information (OMNI) and the Canadian Medical Association (CMA) Infobase.
4.
Preoperative assessment of women with ovarian masses
4.1 What is the role of history and examination in the assessment of women with suspected ovarian masses?
A thorough medical history should be taken from the woman with specific attention to risk factors or
protective factors for ovarian malignancy and a family history of ovarian or breast cancer. Symptoms
suggestive of endometriosis should be specifically considered17 along with any symptoms suggesting possible
3 of 14
ovarian malignancy: persistent abdominal distension, appetite change including increased satiety, pelvic or
abdominal pain, increased urinary urgency and/or frequency.18,19
A careful physical examination of the woman is essential and should include abdominal and vaginal
examination and the presence or absence of local lymphadenopathy. In the acute presentation with pain the
diagnosis of accident to the ovarian cyst should be considered (torsion, rupture, haemorrhage).
Although clinical examination has poor sensitivity in the detection of ovarian masses (1551%) its importance
lies in the evaluation of mass tenderness, mobility, nodularity and ascites.19,20
4.2 What blood tests should be performed?

A serum CA-125 assay does not need to be undertaken in all premenopausal women when an
ultrasonographic diagnosis of a simple ovarian cyst has been made.2123
Lactate dehydrogenase (LDH), -FP and hCG should be measured in all women under age 40 with a
complex ovarian mass because of the possibility of germ cell tumours.
CA-125 is unreliable in differentiating benign from malignant ovarian masses in premenopausal

women because of the increased rate of false positives and reduced specificity.This is as a result of
CA-125 being raised in numerous conditions including fibroids, endometriosis, adenomyosis and
pelvic infection. Consequently a raised serum CA-125 should be interpreted cautiously. However, it
is important to note that only in stage IIIIV endometriosis is it likely to be raised to several
hundreds or thousands of units/ml.21 It is also important to note that CA-125 is primarily a marker
for epithelial ovarian carcinoma and is only raised in 50% of early stage disease.22
Evidence
level 2++
A serum CA-125 assay is not necessary when a clear ultrasonographic diagnosis of a simple ovarian cyst has
been made.2326
If a serum CA-125 assay is raised and less than 200 units/ml, further investigation may be appropriate to
exclude/treat the common differential diagnoses (see Table 1).
When serum CA-125 levels are raised, serial monitoring of CA-125 may be helpful as rapidly rising levels are
more likely to be associated with malignancy than high levels which remain static.3
If serum CA-125 assay more than 200 units/ml, discussion with a gynaecological oncologist is recommended.3
Guidelines from the United Kingdom2 and the USA3 recommend that -FP and hCG should be measured in all
women under 40 with a complex ovarian mass because of the possibility of germ cell tumours. Guidelines
from the USA also recommend measuring LDH in these women.
4.3 What imaging should be employed in the assessment of suspected ovarian masses?
4.3.1 What is the role of ultrasound in the assessment of suspected ovarian masses?
A pelvic ultrasound is the single most effective way of evaluating an ovarian mass with transvaginal
ultrasonography being preferable due to its increased sensitivity over transabdominal ultrasound.
In some cases, a combination of the transvaginal and transabdominal routes may be appropriate for
the assessment of larger masses and extra-ovarian disease.3 The use of colour flow Doppler has
generally not been shown to significantly improve diagnostic accuracy2729 but the combined use of
the transvaginal route in combination with colour flow mapping and 3D imaging may improve
sensitivity, particularly in complex cases.30,31 Pattern recognition of specific ultrasound findings can
produce sensitivity and specificity equivalent to logistic regression models, especially when
performed by more experienced clinicians specialising in womens imaging.32 This could
potentially reduce the number of unnecessary staging laparotomies.33 This evidence derives from
centres with particular expertise in this field and the extent to which this can safely be
extrapolated into other centres is not clear.
4 of 14
Evidence
level 2++
Repeating ultrasound assessment in the postmenstrual phase may be helpful in cases of doubt and
endometrial views may contribute to diagnosis in cases of estrogen-secreting tumours of the ovary. It is
important to note that no single ultrasound finding differentiates categorically between benign and malignant
ovarian masses.
4.3.2 What is the role of the routine use of computed tomography and magnetic resonance
imaging (MRI) in the assessment of suspected ovarian masses?
At the present time the routine use of computed tomography and MRI for assessment of ovarian masses
does not improve the sensitivity or specificity obtained by transvaginal ultrasonography in the detection
of ovarian malignancy.
There is no clear consensus regarding the need for further imaging beyond transvaginal ultrasound
in the presence of apparently benign disease. However, these additional imaging modalities will
have a place in the evaluation of more complex lesions (see section 6.1).34 If, from the clinical
picture and ultrasonographic findings, malignant disease is a possibility, onward referral to a
gynaecological oncology multidisciplinary team is appropriate.
5.
Evidence
level 2+
What is the best way to estimate the risk of malignancy?
An estimation of the risk of malignancy is essential in the assessment of an ovarian mass.
At present the Risk of Malignancy Index (RMI) is the most widely used model but recent studies
have shown a specific model of ultrasound parameters, the ultrasound rules derived from the
International Ovarian Tumor Analysis (IOTA) Group, to have increased sensitivity and specificity.26
The simple rules have recently been externally validated in 1983 women from 19 ultrasound
centres in 8 countries.35
Evidence
level 2++
An estimation of the risk of malignancy is essential in the assessment of an ovarian mass. This has been
assessed using over 80 different models.36
Simple models involve using discrete cut-off values such as CA-125, pulsatility index, resistance index.
Intermediate models include morphology scoring systems and the risk of malignancy index.27,37
Advanced models include artificial neural networks and multiple logistic regression models a method for
determining whether each of a set of independent variables has a unique predictive relationship to a
dichotomous dependent variable.38
Unfortunately, many studies do not look specifically at the premenopausal woman. As such, reported results
may not be applicable to this specific patient group.The routine use of a CA-125 assay in the investigation of
the premenopausal woman with an ovarian mass has not been shown to be useful because of its relatively
poor specificity.38,39
5.1 Which RMI should be used?

A systematic review of diagnostic studies concluded that the RMI I is the most effective for women with
suspected ovarian cancer.
Risk of Malignancy Index

The RMI was first described by Jacobs in 199040 and has since evolved into RMI II,41 RMI III42 and RMI IV.43 To
date only RMI I and RMI II have been sufficiently validated.The RMI is simple to use and reproducible but its
utility is negatively affected in the premenopausal woman. This is primarily because of the incidence of
5 of 14
endometriomas, borderline ovarian tumours, non-epithelial ovarian tumours and other pathologies increasing
the level of CA-125 in this group.3
A systematic review of diagnostic studies concluded that the RMI I was the most effective for
women with suspected ovarian malignancy.36 The NICE guideline on ovarian cancer2 recommends
that for women with suspected ovarian malignancy the RMI I score should be calculated and used
to guide the womans management.
Evidence
level 1+
Calculation of the RMI I

RMI I combines three presurgical features: serum CA-125 (CA-125); menopausal status (M); and ultrasound
score (U). The RMI is a product of the ultrasound scan score, the menopausal status and the serum CA-125
level (IU/ml) as follows:
RMI = U x M x CA-125.
The ultrasound result is scored 1 point for each of the following characteristics: multilocular cysts, solid areas,
metastases, ascites and bilateral lesions. U = 0 (for an ultrasound score of 0), U = 1 (for an ultrasound score of
1), U = 3 (for an ultrasound score of 25).
The menopausal status is scored as 1 = premenopausal and 3 = postmenopausal.
Postmenopausal can be defined as women who have had no period for more than one year or women over
the age of 50 who have had a hysterectomy.
Serum CA-125 is measured in IU/ml and can vary between zero to hundreds or even thousands of units.
A recent systematic review36 showed the pooled sensitivities and specificities of an RMI I score of 200 in the
detection of ovarian malignancies to be:
RMI I sensitivity 78% (95% CI 71-85%), specificity 87% (95% CI 83-91%).4450
5.2 Is there another way to estimate accurately a risk of malignancy in premenopausal women without using
a CA-125?
There are simple ultrasound rules derived from the IOTA Group. The use of specific ultrasound
morphological findings without CA-125 has been shown to have high sensitivity, specificity and
likelihood ratios.26,35
If not clearly classifiable from these rules, further investigation by a specialist in gynaecological
ultrasound is appropriate.35
The IOTA Group has published the largest study to date investigating the use of ultrasound in
differentiating benign and malignant ovarian masses. Using data derived from the IOTA Group,38,51
simple ultrasound rules were developed to help classify masses as benign (B-rules) or malignant (Mrules) (see Table 2). Using these rules the reported sensitivity was 95%, specificity 91%, positive
likelihood ratio of 10.37 and negative likelihood ratio of 0.06.
Evidence
level 2++
Table 2. IOTA Group ultrasound rules to classify masses as benign (B-rules) or malignant (M-rules)38,51
B-rules
M-rules
Unilocular cysts
Irregular solid tumour
Presence of solid components where the largest solid component <7 mm
Ascites
Presence of acoustic shadowing
At least four papillary structures
Smooth multilocular tumour with a largest diameter <100 mm
Irregular multilocular solid tumour with largest diameter 100 mm
No blood flow
Very strong blood flow
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Women with an ovarian mass with any of the M-rules ultrasound findings should be referred to a
gynaecological oncological service.
5.3. What other current guidelines are in use?

The American College of Obstetricians and Gynecologists and the Society of Obstetricians and Gynaecologists
of Canada have guidelines for the management of premenopausal women with a pelvic mass.3,4 They consider
the following features suspicious for ovarian malignancy and their presence would warrant referral to a
gynaecological oncologist: serum CA-125 of more than 200 units/ml; ascites; evidence of abdominal or distant
metastasis; a first-degree relative with breast or ovarian cancer. In the largest study validating these guidelines
30% of premenopausal women with ovarian cancer would not have been regarded as high risk.49
6.
Management of ovarian masses presumed to be benign in non-emergency situations
6.1 Can asymptomatic women with simple ovarian cysts be managed expectantly?
Women with small (less than 50 mm diameter) simple ovarian cysts generally do not require follow-up
as these cysts are very likely to be physiological and almost always resolve within 3 menstrual cycles.
Women with simple ovarian cysts of 5070 mm in diameter should have yearly ultrasound follow-up and
those with larger simple cysts should be considered for either further imaging (MRI) or surgical
intervention.
With the widespread use of ultrasound in clinical practice incidental finding of simple ovarian cysts has
become commonplace. In one study 4% of women, with a median age of 26 years, had an ovarian cyst greater
than 30 mm in diameter in their luteal phase.52
One generally accepted definition of an ovarian cyst is: a fluid-containing structure more than 30
mm in diameter. Women with simple cystic structures less than 50 mm generally do not require
follow-up as these cysts are very likely to be physiological and almost always resolve within 3
menstrual cycles.53 The Society of Radiologists in Ultrasound published a consensus statement
concluding that asymptomatic simple cysts 3050 mm in diameter do not require follow-up, cysts
5070 mm require follow-up, and cysts more than 70 mm in diameter should be considered for
either further imaging (MRI) or surgical intervention due to difficulties in examining the entire cyst
adequately at time of ultrasound.54
Evidence
level 4
6.2 How should persistent, asymptomatic ovarian cysts be managed?

Ovarian cysts that persist or increase in size are unlikely to be functional and may warrant surgical
management.
Ovarian cysts that persist or increase in size after several cycles are unlikely to be functional.5557
Mature cystic teratomas (dermoid cysts) have been shown to grow over time,5859 increasing the risk
of pain and ovarian accidents. Surgical management is therefore usually appropriate, with
preoperative assessment using RMI 1 or ultrasound rules (IOTA Group).There is no evidence-based
consensus on the size above which surgical management should be considered. Most studies have
used an arbitrary maximum diameter of 5060 mm among their inclusion criteria to offer
conservative management.5859
Evidence
level 4
6.3 Does the use of combined oral contraceptives help in the treatment of functional ovarian cysts?
The use of the combined oral contraceptive pill does not promote the resolution of functional ovarian
cysts.
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A recent Cochrane review of the effects of the oral contraceptive pill in the treatment of functional
ovarian cysts concluded that there was no earlier resolution in the treatment group compared to
the control group.60 However, these trials were small with significant heterogeneity.
Evidence
level 1++
6.4 Is the laparoscopic approach better for the elective surgical management of ovarian masses?
The laparoscopic approach for elective surgical management of ovarian masses presumed to be benign
is associated with lower postoperative morbidity and shorter recovery time and is preferred to
laparotomy in suitable patients.710
Laparoscopic management is cost-effective because of the associated earlier discharge and return to
work.11
In the presence of large masses with solid components (for example large dermoid cysts) laparotomy
may be appropriate.
A systematic review of six randomised controlled trials compared the laparoscopic approach with
laparotomy in a total of 324 women undergoing removal of ovarian cysts. Laparoscopy was
associated with reduced febrile morbidity, less postoperative pain, lower rates of postoperative
complications, earlier discharge from hospital and lower overall cost.61
Evidence
level 1++
The maximum cyst size above which laparotomy should be considered is controversial. In one trial
comparing mini-laparotomy with laparoscopy for the surgical management of benign ovarian tumours, cyst
rupture occurred more often in the laparoscopy group, but only in a subgroup of women with cysts larger
than 70 mm.9
Although reports of successful laparoscopic management of very large or even giant benign ovarian tumours
exist in the literature,62,63 there is currently insufficient evidence to recommend this approach. It is likely that
drainage or removal of large ovarian cysts will require significant extension of the laparoscopic port incision,
in which case the advantages of laparoscopic approach would be reduced. Some of these reports required a
mini-laparotomy for drainage or removal of the cyst.64
6.5 Who should perform laparoscopic surgery for a presumed benign ovarian cyst?
Laparoscopic management of presumed benign ovarian cysts should be undertaken by a surgeon with
suitable experience and appropriate equipment, whenever local facilities permit.
The appropriate route for the surgical management of ovarian masses depends on several factors related to
the woman (including suitability for laparoscopy and her wishes), the mass (size, complexity, likely nature)
and the setting (including surgeons skills and equipment). A decision should be made after careful clinical
assessment and counselling considering the above factors. Where appropriately trained staff and equipment
are unavailable then consideration should be given to referral to another provider.
6.6 Should an ovarian cyst be aspirated?

Aspiration of ovarian cysts, either vaginally or laparoscopically, is less effective and is associated with
a high rate of recurrence.
Randomised controlled trials have shown the resolution rates of simple ovarian cysts to be similar
whether expectant management or ultrasound guided needle aspirations were used (46% versus
44.6% respectively).65 The recurrence rates after laparoscopic needle aspiration of simple cysts
range from 53% to as high as 84%.65,66
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Evidence
level 2++
For highly selected cases, following discussion between the woman and her clinician, transvaginal or
laparoscopic aspiration may be an appropriate intervention.67
6.7 Is it important to avoid unplanned rupture of the cyst?

Spillage of cyst contents should be avoided where possible as preoperative and intraoperative
assessment cannot absolutely preclude malignancy.
Consideration should be given to the use of a tissue bag to avoid peritoneal spill of cystic contents
bearing in mind the likely preoperative diagnosis.
It is preferable to avoid spillage of cyst contents because the apparently benign characteristics of a cyst on
preoperative and intraoperative assessment cannot absolutely preclude malignancy.68
Chemical peritonitis due to spillage of dermoid cyst contents has been reported in different series to occur
in less than 0.2% of cases.6971 If inadvertent spillage does occur, meticulous peritoneal lavage of the peritoneal
cavity should be performed using large amounts of warmed fluid. Use of cold irrigation fluid may not only
cause hypothermia, but it will also make retrieval of the contents more challenging by solidifying the fat-rich
contents. Any solid content should be removed using an appropriate bag.
The RCOG Green-top Guideline on the investigation and management of endometriosis1 recommends in the
case of endometrioma (greater than 30 mm in diameter) that histology should be obtained to identify
endometriosis and to exclude rare cases of malignancy. Obtaining such histology using the standard surgical
technique will inevitably cause peritoneal spill of cyst contents.There is always the potential to inadvertently
upstage a tumour if the suspected endometrioma is actually a malignant tumour.This is rare: a leading centre
reported no cases of malignancy in 814 women with consecutive endometriomas of greater than 30 mm in
diameter.72 As there is no effective preoperative discriminator between an endometrioma and some rare cases
of ovarian cancer such upstaging may be inevitable. Consideration of the possibility of rare underlying
malignancy should be managed on an individual basis through multidisciplinary team meetings.
6.8 When should an oophorectomy be performed?

The possibility of removing an ovary should be discussed with the woman preoperatively.
This discussion should be in the context of it being either an expected or unexpected part of the procedure.
The pros and cons of electively removing an ovary should be discussed, taking into consideration the
womans preference and the specific clinical scenario.
6.9 How should an ovarian mass be removed?

Where possible removal of benign ovarian masses should be via the umbilical port. This results in less
postoperative pain and a quicker retrieval time than when using lateral ports of the same size.
Various types of laparoscopic tissue retrieval bags have been described, both specifically designed
products and innovatively used pre-existing equipment. The use of tissue retrieval bags is
commonplace but there is no general consensus for their routine use.
Evidence
level 2-
Removing tissue in a tissue retrieval bag via the umbilical port has been investigated in a
randomised73 and a large prospective trial.74 Removal of benign ovarian masses via the umbilical
port should be utilised where possible as this results in less postoperative pain and a quicker
retrieval time. Avoidance of extending accessory ports is beneficial in reducing postoperative pain,
as well as reducing incidence of incisional hernia and incidence of epigastric vessel injury. It also
leads to improved cosmesis.
Evidence
level 1-
9 of 14
7.

The percentage of women with unexpected malignancy after elective laparoscopic surgery for ovarian cysts.
Ultrasound reporting of ovarian cyst characteristics.
Laparotomy for ovarian cysts presumed to have an increased risk of malignancy preoperatively, where the
ultimate diagnosis is benign.
The percentage of women with complications following laparoscopic surgery for ovarian cysts.
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imaging. BMJ 1993;306:10259.
38. Timmerman D,Testa AC, Bourne T, Ferrazzi E, Ameye L,
Konstantinovic ML, et al. Logistic regression model to
distinguish between the benign and malignant adnexal mass
before surgery: a multicenter study by the International
Ovarian Tumor Analysis Group. J Clin Oncol
2005;23:8794801.
39. Dearking AC, Aletti GD, McGree ME, Weaver AL, Sommerfield
MK, Cliby WA. How relevant are ACOG and SGO guidelines for
referral of adnexal mass? Obstet Gynecol 2007;110:8418.
40. Jacobs I, Oram D, Fairbanks J,Turner J, Frost C, Grudzinskas JG.
A risk of malignancy index incorporating CA 125, ultrasound
and menopausal status for the accurate preoperative diagnosis
of ovarian cancer. Br J Obstet Gynaecol 1990;97:9229.
41. Tingulstad S, Hagen B, Skjeldestad FE, Onsrud M, Kiserud T,
Halvorsen T, et al. Evaluation of a risk of malignancy index
based on serum CA-125, ultrasound findings and menopausal
status in the pre-operative diagnosis of pelvic masses. Br J
42. Tingulstad S, Hagen B, Skjeldestad FE, Halvorsen T, Nustad K,
Onsrud M.The risk-of-malignancy index to evaluate potential
ovarian cancers in local hospitals. Obstet Gynecol
1999;93:44852.
43. Torres JC, Derchain SF, Faundes A, Gontijo RC, Martinez EZ,
Andrade LA. Risk-of-malignancy index in preoperative
evaluation of clinically restricted ovarian cancer. Sao Paulo
Med J. 2002;120:726.
44. Morgante G, la Marca A, Ditto A, De Leo V. Comparison of two
malignancy risk indices based on serum CA125, ultrasound
score and menopausal status in the diagnosis of ovarian
masses. Br J Obstet Gynaecol 1999;106:5247.
45. Aslam N,Tailor A, Lawton F, Carr J, Savvas M, Jurkovic D.
Prospective evaluation of three different models for the preoperative diagnosis of ovarian cancer. BJOG
2000;107:134753.
46. Mol BW, Boll D, De Kanter M, Heintz AP, Sijmons EA, Oei SG, et
al. Distinguishing the benign and malignant adnexal mass: an
external validation of prognostic models. Gynecol Oncol
2001;80:1627.
47. Manjunath AP, Pratapkumar, Sujatha K, Vani R. Comparison of
three risk of malignancy indices in evaluation of pelvic masses.
48. Ma S, Shen K, Lang J. A risk of malignancy index in preoperative
diagnosis of ovarian cancer. Chin Med J (Engl) 2003;116:3969.
49. Andersen ES, Knudsen A, Rix P, Johansen B. Risk of malignancy
index in the preoperative evaluation of patients with adnexal
masses. Gynecol Oncol 2003;90:10912.
50. Van Holsbeke C, Van Calster B, Valentin L,Testa AC, Ferrazzi E,
Dimou I, et al. External validation of mathematical models to
distinguish between benign and malignant adnexal tumors: a
multicenter study by the International Ovarian Tumor Analysis
Group. Clin Cancer Res 2007;13:44407.
51. Timmerman D, Valentin L, Bourne TH, Collins WP, Verrelst H,

Vergote I; International Ovarian Tumor Analysis (IOTA) Group.
Terms, definitions and measurements to describe the
sonographic features of adnexal tumors: a consensus opinion
from the International Ovarian Tumor Analysis (IOTA) Group.
52. Teichmann AT, Brill K, Albring M, Schnitker J, Wojtynek P, Kustra
E.The influence of the dose of ethinylestradiol in oral
contraceptives on follicle growth. Gynecol Endocrinol
1995;9:299305.
53. MacKenna A, Fabres C, Alam V, Morales V. Clinical management
of functional ovarian cysts: a prospective and randomized
study. Hum Reprod 2000;15:25679.
54. Levine D, Brown DL, Andreotti RF, Benacerraf B, Benson CB,
Brewster WR, et al. Management of asymptomatic ovarian and
other adnexal cysts imaged at US: Society of Radiologists in
Ultrasound Consensus Conference Statement. Radiology
2010;256:94354.
55. Ben-Ami M, Geslevich Y, Battino S, Matilsky M, Shalev E.
Management of functional ovarian cysts after induction of
ovulation. A randomized prospective study. Acta Obstet
56. Steinkampf MP, Hammond KR, Blackwell RE. Hormonal
treatment of functional ovarian cysts: a randomized,
prospective study. Fertil Steril 1990;54:7757.
57. Turan C, Zorlu CG, Ugur M, Ozcan T, Kaleli BG, Gkmen O.
Expectant management of functional ovarian cysts: an
alternative to hormonal therapy. Int J Gynaecol Obstet
1994;47:25760.
58. Alczar JL, Castillo G, Jurado M, Garcia GL. Is expectant
management of sonographically benign adnexal cysts an
option in selected asymptomatic premenopausal women?
Hum Reprod 2005;20:32314.
59. Caspi B, Appelman Z, Rabinerson D, Zalel Y,Tulandi T, Shoham
Z.The growth pattern of ovarian dermoid cysts: a prospective
study in premenopausal and postmenopausal women. Fertil
Steril 1997;68:5015.
60. Grimes DA, Jones LB, Lopez LM, Schulz KF. Oral contraceptives
for functional ovarian cysts. Cochrane Database Syst Rev
2009;(2):CD006134.
61. Medeiros LR, Stein AT, Fachel J, Garry R, Furness S. Laparoscopy
versus laparotomy for benign ovarian tumor: a systematic
review and meta-analysis. Int J Gynecol Cancer
2008;18:38799.
62. Ghezzi F, Cromi A, Bergamini V, Uccella S, Siesto G, Franchi M, et
al. Should adnexal mass size influence surgical approach? A
series of 186 laparoscopically managed large adnexal masses.
BJOG 2008;115:10207.
63. Sagiv R, Golan A, Glezerman M. Laparoscopic management of
extremely large ovarian cysts. Obstet Gynecol
2005;105:131922.
64. Dolan MS, Boulanger SC, Salameh JR. Laparoscopic
management of giant ovarian cyst. JSLS 2006;10:2546.
65. Zanetta G, Lissoni A,Torri V, Dalla Valle C,Trio D, Rangoni G, et
al. Role of puncture and aspiration in expectant management
of simple ovarian cysts: a randomised study. BMJ
1996;313:11103.
66. Marana R, Caruana P, Muzii L, Catalano GF, Mancuso S.
Operative laparoscopy for ovarian cysts. Excision vs. aspiration.
J Reprod Med 1996;41:4358.
67. Testa AC, van Holsbeke C, Mascilini F,Timmerman D. Dynamic
and interactive gynecological ultrasound examination.
68. Maiman M, Seltzer V, Boyce J. Laparoscopic excision of ovarian
neoplasms subsequently found to be malignant. Obstet
Gynecol 1991;77:56365.
69. Koak M, Dilbaz B, Ozturk N, Dede S, Altay M, Dilbaz S, Haberal
A. Laparoscopic management of ovarian dermoid cysts: a
review of 47 cases. Ann Saudi Med 2004;24:35760.
70. Nezhat CR, Kalyoncu S, Nezhat CH, Johnson E, Berlanda N,
Nezhat F. Laparoscopic management of ovarian dermoid cysts:
ten years' experience. JSLS 1999;3:17984.
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71. Shawki O, Ramadan A, Askalany A, Bahnassi A. Laparoscopic

management of ovarian dermoid cysts: potential fear of
dermoid spill, myths and facts. Gynecol Surgery
2007;4;25560.
72. Donnez J, Nisolle M, Gillet N, Smets M, Bassil S, Casanas-Roux F.
Large ovarian endometriomas. Hum Reprod 1996;11:64145.
73. Chou LY, Sheu BC, Chang DY, Huang SC, Chen SY, Hsu WC, et
al. Comparison between transumbilical and transabdominal
ports for the laparoscopic retrieval of benign adnexal masses: a
randomized trial. Eur J Obstet Gynecol Reprod Biol
2010;153:198202.
74. Ghezzi F, Cromi A, Uccella S, Siesto G, Bergamini V, Bolis P.
Transumbilical surgical specimen retrieval: a viable refinement
of laparoscopic surgery for pelvic masses. BJOG 2008
115:131620.
12 of 14
APPENDIX

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
13 of 14

development group
This guideline has been produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and
Gynaecologists and the British Society of Gynaecological Endoscopy by:
Mr PD Kaloo MRCOG, Cheltenham, Mr KA Louden FRCOG, Winchester, Mr S Khazali MRCOG, Winchester,
Dr D Hoy MB, BS Cheltenham, Mr S Sadoon MRCOG, Gillingham.
And peer reviewed by:
RCOG Consumers Forum
British Medical Ultrasound Society (BMUS)
Mr D Jurkovich MRCOG, London
Professor IJ Jacobs FRCOG, London
Dr U Menon FRCOG, London
Dr NA Siddiqui FRCOG, Glasgow
British Society for Gynaecological Endoscopy (BSGE)
British Gynaecological Cancer Society (BGCS)
Mr R Naik FRCOG, Newcastle
Mrs SS Sundar MRCOG, Birmingham
Dr KA Burton MRCOG, Glagow
Royal College of Radiologists (RCR)
International Society of Ultrasound in Obstetrics and Gynaecology
The Guideline Committee lead reviewers were: Dr AJ Thomson MRCOG, Paisley, Scotland and Dr RG Ashe FRCOG,
County Antrim, Northern Ireland.
The final version is the responsibility of the Guidelines Committee of the RCOG and the BSGE.
DISCLAIMER
health services.
14 of 14
Antepartum Haemorrhage

November 2011
Antepartum Haemorrhage
1.
Purpose and scope
Antepartum haemorrhage (APH) is defined as bleeding from or in to the genital tract, occurring from 24+0
weeks of pregnancy and prior to the birth of the baby.The most important causes of APH are placenta praevia
and placental abruption, although these are not the most common.APH complicates 35% of pregnancies and
is a leading cause of perinatal and maternal mortality worldwide.1 Up to one-fifth of very preterm babies are
born in association with APH, and the known association of APH with cerebral palsy can be explained by
preterm delivery.
This guideline has been developed primarily for clinicians working in obstetric units in the UK;
recommendations may be less appropriate for other settings where facilities, resources and routine practice
differ. This guideline does not include specific recommendations for the management of women who refuse
blood transfusion. The Centre for Maternal and Child Enquiries (CMACE)2 and the RCOG3 have published
guidance regarding the management of pregnancy in women who decline blood products. The code of
practice for the surgical management of Jehovahs Witness patients by the Royal College of Surgeons
(England) and Management of Anaesthesia for Jehovahs Witnesses by the Association of Anaesthetists of Great
Britain and Ireland provide useful additional information.4,5
2.
Introduction and background
Obstetric haemorrhage remains one of the major causes of maternal death in developing countries and is the
cause of up to 50% of the estimated 500 000 maternal deaths that occur globally each year.6 In the UK,
deaths from obstetric haemorrhage are uncommon. In the 200608 report of the UK Confidential Enquiries
into Maternal Deaths,7 haemorrhage was the sixth highest direct cause of maternal death (9 direct deaths;
3.9 deaths/million maternities) a decline from the 14 that occurred in the previous triennium
(6.6 deaths/million maternities).8 There were 4 deaths from APH in the more recent report.7 In the 200507
report of the Confidential Enquiries into Maternal Deaths in South Africa, obstetric haemorrhage was the third
most common cause of death accounting for 12.4% of all deaths; there were 108 deaths from APH and 74 of
these (68.5%) were considered to be clearly avoidable.9 Haemorrhage emerges as the major cause of severe
maternal morbidity in almost all near miss audits in both developed and developing countries.10
Obstetric haemorrhage encompasses both antepartum and postpartum bleeding. This green-top guideline is
restricted in scope to the management of APH. The causes of APH include: placenta praevia, placental
abruption and local causes (for example bleeding from the vulva, vagina or cervix). It is not uncommon to fail
to identify a cause for APH when it is then described as unexplained APH.
Green-top guidelines that are relevant to this topic and are cited in this guideline include:
RCOG Green-top Guideline No. 47 Blood Transfusions in Obstetrics3
RCOG Green-top Guideline No. 22 The Use of Anti-D Immunoglobulin for Rhesus D Prophylaxis11
RCOG Green-top Guideline No. 27 Placenta Praevia, Placenta Praevia Accreta and Vasa Praevia:
Diagnosis and Management12
RCOG Green-top Guideline No. 52 Prevention and Management of Postpartum Haemorrhage13
RCOG Green-top Guideline No. 56 Maternal Collapse in Pregnancy and the Puerperium14
RCOG Green-top Guideline No. 55 Late Intrauterine Fetal Death and Stillbirth15
RCOG Green-top Guideline No. 7 Antenatal Corticosteroids to Reduce Neonatal Morbidity16
RCOG Green-top Guideline No. 1b Tocolysis for Women in Preterm Labour17
2 of 23
RCOG Green-top Guideline No. 37b The Acute Management of Thrombosis and Embolism During
Pregnancy and the Puerperium.18
There are no consistent definitions of the severity of APH. It is recognised that the amount of blood lost is
often underestimated and that the amount of blood coming from the introitus may not represent the total
blood lost (for example in a concealed placental abruption). It is important therefore, when estimating the
blood loss, to assess for signs of clinical shock. The presence of fetal compromise or fetal demise is an
important indicator of volume depletion.19
For the purposes of this guideline, the following definitions have been used:
Spotting staining, streaking or blood spotting noted on underwear or sanitary protection
Minor haemorrhage blood loss less than 50 ml that has settled
Major haemorrhage blood loss of 501000 ml, with no signs of clinical shock
Massive haemorrhage blood loss greater than 1000 ml and/or signs of clinical shock.
Recurrent APH is the term used when there are episodes of APH on more than one occasion.
3.
Guidelines.2022 Cochrane reviews on interventions for suspected placenta praevia23 and for treating placental
abruption have highlighted the lack of evidence to guide practice.24
3.1 Search strategy

The Cochrane Library (including the Cochrane Database of Systematic Reviews, DARE and EMBASE), TRIP,
Medline and PubMed (electronic databases) were searched for relevant randomised controlled trials,
systematic reviews and meta-analyses. The search was restricted to articles published between 1966 and
February 2011. The databases were searched using the relevant MeSH terms, including all subheadings, and
this was combined with a keyword search. Search words included antepartum haemorrhage, placental
abruption, placenta praevia, placenta previa, vasa praevia, vasa previa, obstetric haemorrhage, obstetric
hemorrhage, fetal haemorrhage, fetal hemorrhage, fetomaternal haemorrhage, fetomaternal hemorrhage,
antenatal bleeding,pregnancy,disseminated intravascular coagulopathy, and the search limited to humans
and the English language.
guidelines and reviews (with no results). Guidelines and recommendations produced by organisations such
as NHS Health Trusts were therefore considered. Where possible, recommendations are based on available
evidence and the areas where evidence is lacking are annotated as good practice points.
4.
Prediction and prevention of antepartum haemorrhage?
4.1 What are the risk factors for placental abruption?

A number of clinical and epidemiological studies have identified predisposing risk factors for placental
abruption.2531 The most predictive is abruption in a previous pregnancy. A large observational study from
Norway reported a 4.4% incidence of recurrent abruption (adjusted OR 7.8, 95% CI 6.59.2).32 Abruption
recurs in 1925% of women who have had two previous pregnancies complicated by abruption.33 Other risk
factors for placental abruption include: pre-eclampsia, fetal growth restriction, non-vertex presentations,
polyhydramnios, advanced maternal age, multiparity, low body mass index (BMI), pregnancy following assisted
reproductive techniques, intrauterine infection, premature rupture of membranes, abdominal trauma (both
accidental and resulting from domestic violence), smoking and drug misuse (cocaine and amphetamines)
during pregnancy.31,34
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First trimester bleeding increases the risk of abruption later in the pregnancy. A retrospective cohort study
from Denmark found that threatened miscarriage increases the risk of placental abruption from 1.0% to 1.4%
(OR 1.48, 95% CI 1.301.68).35 A systematic review reported first trimester bleeding to be associated with an
increased risk of placental abruption (OR 1.6, 95% CI 1.12.6); when an intrauterine haematoma is identified
on ultrasound scan in the first trimester, the risk of subsequent placental abruption is increased (RR 5.6, 95%
CI 2.811.1).36
Maternal thrombophilias have been associated with placental abruption. In a systematic review, Robertson et
al.37 identified seven studies that evaluated the association between thrombophilias and placental abruption.
Overall, thrombophilias were associated with an increased risk of placental abruption, but significant
associations were only observed with heterozygous factor V Leiden (OR 4.70, 95% CI 1.1319.59) and
heterozygous prothrombin 20210A (OR 7.71, 95% CI 3.0119.76). More recently, a systematic review and
meta-analysis of prospective cohort studies investigating the relationship between factor V Leiden, the
prothrombin gene mutation and placental abruption reported only a weak association (pooled OR estimate
for placental abruption in women with factor V Leiden was 1.85 [95% CI 0.923.70], and prothrombin
20210A was 2.02 [95% CI 0.815.02]).38
While these and other risk factors for placental abruption are recognised, causal pathways remain largely
speculative.39 Women should be assessed for these factors at each antenatal contact. This information may be
used to assign women to high-risk or low-risk antenatal care.
4.2 What are the risk factors for placenta praevia?

A number of risk factors for placenta praevia have been described, some of which are listed in Table 1.4043,4547
In a comparison of maternal risk factors for placenta praevia and placental abruption,Yang et al.44 concluded
that abruption is more likely to be related to conditions occurring during pregnancy and placenta praevia is
more likely to be related to conditions existing prior to pregnancy.
Table 1. Risk factors for placenta praevia4043,4547
Previous placenta praevia (adjusted OR 9.7)4547
Previous caesarean sections (RR 2.6, 95% CI 2.33.0 with a background rate of 0.5%)46
One previous caesarean section OR 2.2 (95% CI 1.43.4 with a background rate of 1%)47
Two previous caesarean sections OR 4.1 (95% CI 1.98.8)
Three previous caesarean sections OR 22.4 (95% CI 6.478.3)
Previous termination of pregnancy
Multiparity
Advanced maternal age (>40 years)
Multiple pregnancy
Smoking
Deficient endometrium due to presence or history of:
uterine scar
endometritis
manual removal of placenta
curettage
submucous fibroid
Assisted conception
4.3 Can APH be predicted?

APH has a heterogeneous pathophysiology and cannot reliably be predicted.
A number of risk factors for APH have been described (see sections 4.1 and 4.2).
4 of 23
APH has a heterogeneous pathophysiology and cannot be predicted. In a study investigating risk
factors for placental abruption, the authors concluded that abruption is usually a sudden and
unexpected obstetric emergency, not predictable by means of known reproductive risk factors.48
They found that approximately 70% of cases of placental abruption occur in low-risk pregnancies.
Another study aiming to predict placental abruption in women with previous caesarean section
concluded that models combining risk factors were too inefficient to be useful.49
Evidence
level 2++
4.4. Can APH be prevented?

Women should be advised, encouraged and helped to change modifiable risk factors (such as smoking
and drug misuse).
There is limited evidence to support interventions to prevent APH.

4.4.1 Placental abruption
In view of the known associations between placental abruption and tobacco use, cocaine and amphetamine
misuse, women should be advised and encouraged to modify these risk factors. No evidence was identified
that specifically investigated smoking cessation and APH. A Cochrane review concluded that smoking
cessation programmes in pregnancy reduce the proportion of women who continue to smoke, and reduce
low birthweight and preterm birth.The pooled trials have inadequate power to detect reductions in perinatal
mortality or very low birthweight and did not specifically analyse rates of APH.51 The management of cocaine
and amphetamine misuse involves a combination of symptomatic interventions during the withdrawal phase
and psychosocial interventions. There has been very little systematic research into the effectiveness of this
approach in pregnant women.52,53
A systematic review of folic acid supplements in pregnancy (involving a re-analysis of a large randomised
controlled trial and update of a Cochrane review) found no conclusive evidence of benefit (including risk of
placental abruption) in women who took folic acid supplements.54 In contrast, an observational study
conducted in Norway investigating vitamin supplementation and risk of placental abruption found that
women who use folic acid and multivitamins during pregnancy are significantly less likely than non-users to
develop placental abruption (adjusted OR 0.74, 95% CI 0.650.84).55
There are no good data to support a role for antithrombotic therapy (low dose aspirin +/ low molecular
weight heparin) in the prevention of abruption in women with thrombophilia.56
A pilot study investigating the effects of antithrombotic therapy (the low molecular weight
heparin, enoxaparin) in women with a previous placental abruption reported that women
randomised to receive enoxaparin in the subsequent pregnancy experienced fewer placental
vascular complications (including abruption, pre-eclampsia or low birthweight; adjusted hazard
ratio = 0.37, 95% CI 0.180.77).57 The authors conclude that their study findings are preliminary and
are currently being evaluated in larger multicentre trials to ensure their findings can be generalised.
Evidence
level 4
4.4.2 Haemorrhage from placenta praevia

It is considered good practice to avoid vaginal and rectal examinations in women with placenta praevia,
and to advise these women to avoid penetrative sexual intercourse.
RCOG Green-top Guideline No. 27 recommends that in cases of placenta praevia, cervical cerclage
to prevent or reduce bleeding and prolong pregnancy is not supported by sufficient evidence to
recommend this practice outside a clinical trial.12
Evidence
level 1
RCOG Green-top Guideline No. 27 indicates that there is no place for the use of prophylactic
tocolytics in women with placenta praevia to prevent bleeding.12
Evidence
level 1+
5 of 23
Table 2. Complications of APH

Maternal complications
Fetal complications
Anaemia
Fetal hypoxia
Infection
Small for gestational age and fetal growth restriction
Maternal shock
Prematurity (iatrogenic and spontaneous)
Renal tubular necrosis
Fetal death
Consumptive coagulopathy
Postpartum haemorrhage
Prolonged hospital stay
Psychological sequelae
Complications of blood transfusion
5.
Is APH associated with any specific pregnancy complications and outcomes?
Health professionals should be aware that domestic violence in pregnancy may result in APH.
Health professionals should be aware that domestic violence in pregnancy may result in APH.50 Women with
repeated presentations that may include APH should be asked about this.
Antepartum haemorrhage is associated with maternal and perinatal morbidity and mortality. Clinicians
managing women with APH should be aware of these potential consequences.
APH is associated with complications for the mother and her fetus (Table 2).58 Complications are more likely
to occur when haemorrhage is due to a placental cause (abruption or placenta praevia), when the bleeding
is heavy and when the bleeding occurs at early gestations.59
5.1 Unexplained APH

Pregnancies complicated by unexplained APH are also at increased risk of adverse maternal and
perinatal outcomes. A meta-analysis of unexplained APH identified 10 relevant studies in the
previous 38 years, with a limited number of cases; preterm delivery (OR 3.17), stillbirth (OR 2.09),
and fetal anomalies (OR 1.42) appear to be increased in frequency.60 More recently, a retrospective
observational study from Australia found that women with unexplained APH are at greater risk of
preterm delivery and of undergoing induction of labour at term, and their babies are more likely to
be admitted to neonatal intensive care units and develop hyperbilirubinaemia.61 Furthermore,
women with unexplained APH were more likely to have smaller babies (2940g versus 3325g,
p < 0.001), and this difference remained statistically significant when the birthweight was adjusted
for gestational age at delivery and other confounders (p = 0.026).
Evidence
levels
1 to 2+
6. Where should the woman presenting with APH be managed?

It is recommended that women be advised to report all vaginal bleeding to their antenatal care provider.
Women with APH presenting to a midwifery-led maternity unit, a general practitioner or to an accident
and emergency department should be assessed, stabilised if necessary and transferred to a hospital
maternity unit with facilities for resuscitation (such as anaesthetic support and blood transfusion
resources) and performing emergency operative delivery.
A multidisciplinary team including midwifery and obstetric staff, with immediate access to laboratory,
theatre, neonatal and anaesthetic services, should provide clinical assessment.
6 of 23
Sequential reports investigating maternal deaths in the UK have highlighted the importance of
multidisciplinary protocols for the management of obstetric haemorrhage. These should be updated and
rehearsed regularly in conjunction with transfusion services. All members of staff, including those working in
the blood bank, should be aware of the processes which are in place to ensure that blood and blood products
can be delivered in a timely manner.These reports have recommended that women known to be at high risk
of haemorrhage should be managed in centres with facilities for blood transfusion, intensive care and other
interventions.7,8,62,63
7. What is the role of clinical assessment in women presenting with APH?

The role of clinical assessment in women presenting with APH is first to establish whether urgent
intervention is required to manage maternal or fetal compromise. The process of triage includes history
taking to assess coexisting symptoms such as pain, an assessment of the extent of vaginal bleeding,
the cardiovascular condition of the mother, and an assessment of fetal wellbeing.
Women presenting with a major or massive haemorrhage that is persisting or if the woman is unable to
provide a history due to a compromised clinical state, an acute appraisal of maternal wellbeing should be
performed and resuscitation started immediately.The mother is the priority in these situations and should be
stabilised prior to establishing the fetal condition.
If there is no maternal compromise a full history should be taken.
The clinical history should determine whether there is pain associated with the haemorrhage.
Placental abruption should be considered when the pain is continuous. Labour should be considered if the
pain is intermittent.
Risk factors for abruption and placenta praevia should be identified.
The woman should be asked about her awareness of fetal movements and attempts should be made to
auscultate the fetal heart.
If the APH is associated with spontaneous or iatrogenic rupture of the fetal membranes, bleeding from a
ruptured vasa praevia should be considered.
Previous cervical smear history may be useful in order to assess the possibility of a neoplastic lesion of the
cervix as the cause of bleeding. The presentation of cervical cancer in pregnancy depends on the stage at
diagnosis and lesion size; most women with International Federation of Gynecology and Obstetrics (FIGO)
stage I cancer are asymptomatic; symptomatic pregnant women usually present with APH (mostly postcoital)
or vaginal discharge.64 In a Swedish population study, the incidence of cervical cancer was 7.5 cases per
100 000 deliveries; in over half of these cases, the women had an abnormal cervical smear history.65
Examination of the woman should be performed to assess the amount and cause of APH.
The basic principles of resuscitation should be adhered to in all women presenting with collapse or major
haemorrhage. These should follow the principles outlined in Green-top Guideline No.56 Maternal Collapse
in Pregnancy and the Puerperium14 and in Green-top Guideline No.52 Prevention and Management of
Postpartum Haemorrhage.13 The primary survey should follow the structured approach of airway (A),
breathing (B) and circulation (C). Following initial assessment and commencement of resuscitation, causes for
haemorrhage or collapse should be sought.
All women presenting with APH should have their pulse and blood pressure recorded.
7.1 Abdominal palpation

The woman should be assessed for tenderness or signs of an acute abdomen.The tense or woody feel to the
uterus on abdominal palpation indicates a significant abruption. Abdominal palpation may also reveal uterine
contractions. A soft, non-tender uterus may suggest a lower genital tract cause or bleeding from placenta or
vasa praevia.
7 of 23
7.2 Speculum examination

A speculum examination can be useful to identify cervical dilatation or visualise a lower genital
tract cause for the APH. In a prospective observational study of 564 women presenting with APH,
521 (92.4%) underwent an admission speculum examination; 389 women (69%) had a normal
cervix, 120 (21%) had cervical ectropion and 12 (2%) had a dilated cervix. 66
Evidence
level 3
If the woman presents with a clinically suspicious cervix she should be referred for colposcopic
evaluation in line with guidelines from the British Society for Colposcopy and Cervical Pathology.67
Evidence
level 4
7.3 Digital vaginal examination

If placenta praevia is a possible diagnosis (for example, a previous scan shows a low placenta, there is a high
presenting part on abdominal examination or the bleed has been painless), digital vaginal examination should
not be performed until an ultrasound has excluded placenta praevia. Digital vaginal examination can provide
information on cervical dilatation if APH is associated with pain or uterine activity.
8.
What investigations should be performed in women presenting with APH?
8.1 Maternal investigations

Investigations should be performed to assess the extent and physiological consequences of the APH.
The maternal investigations performed will depend on the amount of bleeding.
The Kleihauer test should be performed in rhesus D (RhD)-negative women to quantify fetomaternal
haemorrhage (FMH) in order to gauge the dose of anti-D immunoglobulin (anti-D Ig) required.
The Kleihauer test is not a sensitive test for diagnosing abruption.
Ultrasound can be used to diagnose placenta praevia but does not exclude abruption.
Placental abruption is a clinical diagnosis and there are no sensitive or reliable diagnostic tests
available. Ultrasound has limited sensitivity in the identification of retroplacental haemorrhage.
8.1.1 Blood tests

In cases of major or massive haemorrhage, blood should be analysed for full blood count and coagulation
screen and 4 units of blood cross-matched. Urea, electrolytes and liver function tests should be assayed. The
initial haemoglobin may not reflect the amount of blood lost and therefore clinical judgement should be used
when initiating and calculating the blood transfusion required. In such circumstances a point of care test
(bedside test) to assess haemoglobin may be useful. The platelet count, if low, may indicate a consumptive
process seen in relation to significant abruption; this may be associated with a coagulopathy.
In minor haemorrhage, a full blood count and group and save should be performed. A coagulation screen is
not indicated unless the platelet count is abnormal.
In all women who are RhD-negative, a Kleihauer test should be performed to quantify FMH to
gauge the dose of anti-D Ig required.11
Evidence
level 4
The Kleihauer test is not a sensitive test for diagnosing placental abruption.68,69
Evidence
level 2+
8.1.2 Ultrasound scan

Women presenting with APH should have an ultrasound scan performed to confirm or exclude placenta
praevia if the placental site is not already known. Ultrasound scanning is well established in determining
placental location and in the diagnosis of placenta praevia.12,70
8 of 23
The sensitivity of ultrasound for the detection of retroplacental clot (abruption) is poor. Glantz and
colleagues71 reported the sensitivity, specificity, and positive and negative predictive values of
ultrasonography for placental abruption to be 24%, 96%, 88% and 53% respectively. Thus,
ultrasonography will fail to detect three-quarters of cases of abruption. However, when the
ultrasound suggests an abruption, the likelihood that there is an abruption is high.
Evidence
level 3
8.2 Fetal investigation

An assessment of the fetal heart rate should be performed, usually with a cardiotocograph (CTG) in
women presenting with APH once the mother is stable or resuscitation has commenced, to aid decision
making on the mode of delivery.
Whenever possible, CTG monitoring should be performed where knowledge of fetal condition will
influence the timing and mode of delivery.
Ultrasound should be carried out to establish fetal heart pulsation if fetal viability cannot be detected
using external auscultation.
APH, particularly major haemorrhage and that associated with placental abruption, can result in fetal
hypoxia and abnormalities of the fetal heart rate pattern. If the fetal heart rate cannot be heard on
auscultation, then an ultrasound scan should be performed to exclude an intrauterine fetal death.15
Ultrasound imaging can be technically difficult, particularly in the presence of maternal obesity,
abdominal scars and oligohydramnios, but views can often be augmented with colour Doppler.
Evidence
level 3
Guidance directly relevant to monitoring the fetal heart rate at the extreme of viability can be
reasonably extrapolated from advice on the management of women in extremely preterm labour
(less than 26+0 weeks) from the British Association of Perinatal Medicine.72 The results of this working
group suggest If active obstetric intervention in the interests of the fetus is not planned, for example
at gestations less than 26+0 weeks, continuous monitoring of the fetal heart rate is not advised.72
Evidence
level 4
There is a lack of published evidence regarding the role and usefulness of fetal heart-rate monitoring in
women presenting with APH. In one study, the fetal heart-rate pattern (CTG) was abnormal in 69% of women
presenting with placental abruption.73 Whilst conservative (expectant) management appears to be safe in
preterm pregnancies with placental abruption and a normal CTG, an abnormal CTG is associated with poor
fetal outcome and delivery should be expedited to save the fetus.74 Clinical judgement is required in these
circumstances since women presenting with bleeding that may indicate a catastrophic event such as
placental abruption, constitute a group where the fetus is more likely to be exposed to severe hypoxia and
acidaemia.75 In such circumstances, the CTG can reasonably be expected to be informative.
In the context of suspected vasa praevia various tests exist that can differentiate between fetal and
maternal blood, but are often not applicable. (See Green-top Guideline No. 27 Placenta Praevia,
Placenta Accreta and Vasa Praevia: Diagnosis and Management.12)
Evidence is lacking concerning the validity of point of care tests to differentiate between fetal and
maternal blood. In the event of a significant bleed related to vasa praevia, signs of fetal compromise
would be identifiable on fetal heart rate monitoring and delivery would be indicated irrespective
of the results of such a test. Commercial kits to perform such tests are currently unavailable and the
tests are considered to be complicated and lacking in accuracy.
9.
Evidence
level 2+
Should women with APH be hospitalised, and if so, for how long?
Recommendations about hospitalisation for women with placenta praevia are presented in RCOG Green-top
Guideline No. 27.12
9 of 23
Women presenting with spotting who are no longer bleeding and where placenta praevia has been
excluded can go home after a reassuring initial clinical assessment.
All women with APH heavier than spotting and women with ongoing bleeding should remain in hospital
at least until the bleeding has stopped.
At present, there is no evidence to support recommendations regarding duration of inpatient management

following APH.Where the bleeding has been spotting and has settled, and tests of fetal and maternal wellbeing
are reassuring, the woman can go home. She should be encouraged to contact the maternity unit if she has
any further bleeding, pain or a reduction in fetal movements. Further measures such as a telephone
consultation between the woman and the hospital the following day may provide further reassurance.
Each woman must be assessed on an individual basis and sound clinical judgment applied. For example, if a
woman presents with spotting and has a past history of intrauterine fetal death resulting from placental
abruption, then hospitalisation would be appropriate.
10. Should corticosteroids be administered to women who present with APH before term?
Clinicians should offer a single course of antenatal corticosteroids to women between 24+0 and 34+6
weeks of gestation at risk of preterm birth.
In women presenting with spotting, where the most likely cause is lower genital tract bleeding, where
imminent delivery is unlikely, corticosteroids are unlikely to be of benefit, but could still be considered.
RCOG Green-top Guideline No. 7 Antenatal Corticosteroids to Reduce Neonatal Morbidity states
that antenatal corticosteroids should be given to all women at risk of iatrogenic or spontaneous
preterm birth up to 34+6 weeks of gestation.16 Antenatal corticosteroids are associated with a
significant reduction in rates of neonatal death, respiratory distress syndrome and intraventricular
haemorrhage.
Evidence
level 1++
In women with APH and no immediate indication to deliver the baby, an assessment should be made
in each individual case. If bleeding is associated with pain suggestive of uterine activity or abruption,
the risk of preterm birth is increased and therefore steroids may be of benefit. Women presenting
with spotting which has stopped (particularly an identified lower genital tract cause such as
postcoital from a cervical ectropion) and no abdominal pain or tenderness may not require steroids.
Evidence
level 4
11.
Should tocolytic therapy be used in women presenting with APH who have uterine activity?
Tocolysis should not be used to delay delivery in a woman presenting with a major APH, or who is
haemodynamically unstable, or if there is evidence of fetal compromise.
A senior obstetrician should make any decision regarding the initiation of tocolysis in the event of an APH.
Women most likely to benefit from use of a tocolytic drug are those who are very preterm, those
needing transfer to a hospital that can provide neonatal intensive care and those who have not yet
completed a full course of corticosteroids. RCOG Green-top Guideline No. 1b states that tocolytic
therapy is contraindicated in placental abruption and is relatively contraindicated in mild
haemorrhage due to placenta praevia.17
Evidence
level 4
Towers et al.76 reviewed 236 cases of APH, which included 131 cases of placental abruption and
105 cases of placenta praevia. Tocolysis had been used in 95 women with abruption and in 76
women with placenta praevia. The authors concluded that no adverse maternal or fetal effects of
Evidence
level 2
10 of 23
tocolysis occurred, but that a prospective randomised trial was necessary to determine whether
tocolytic use carries any benefits.
Evidence
level 2
If tocolysis is employed, then the drug of choice in a woman with a history of APH should have fewest
maternal cardiovascular side effects. The calcium antagonist nifedipine has been associated with cases of
maternal hypotension and is probably best avoided.77
12. Should the antenatal care of a woman be altered following APH?

Following single or recurrent episodes of APH from a cervical ectropion, subsequent antenatal care need
not be altered.
Following APH from placental abruption or unexplained APH, the pregnancy should be reclassified as
high risk and antenatal care should be consultant-led. Serial ultrasound for fetal growth should be
performed.
If placenta praevia is diagnosed, subsequent antenatal care should be in line with RCOG Green-top Guideline
No 27.12
Women with pregnancies complicated by APH (including unexplained APH) are at increased risk
of adverse perinatal outcomes including small for gestational age fetus (see section 5) and fetal
growth restriction. Serial ultrasound for fetal growth should be performed. The pregnant woman
should be reclassified as high-risk at least until serial ultrasound scans demonstrate normal fetal
growth and amniotic fluid volume. An epidemiological study of women with unexplained APH
demonstrated an increased risk of oligohydramnios (OR 6.2), premature rupture of membranes (OR
3.4), fetal growth restriction (OR 5.6), preterm labour and caesarean delivery (OR 4.0).The authors
concluded that women who have experienced APH should have increased fetal surveillance
throughout the pregnancy.78
Evidence
level 2+
13. Labour and delivery
13.1 When should women with APH be delivered and what mode of delivery should be employed in women
whose pregnancies have been complicated by APH?
If fetal death is diagnosed, vaginal birth is the recommended mode of delivery for most women
(provided the maternal condition is satisfactory), but caesarean birth will need to be considered for
some. This is addressed in Green-top Guideline No. 55.15
If the fetus is compromised, a caesarean section is the appropriate method of delivery with concurrent
resuscitation of the mother.
Women with APH and associated maternal and/or fetal compromise are required to be delivered
immediately.
The optimum timing of delivery of women presenting with unexplained APH and no associated maternal
and/or fetal compromise is not established. A senior obstetrician should be involved in determining the
timing and mode of birth of these women.
In women with APH secondary to placenta praevia, intrapartum management is described in Green-top
Guideline No. 27.12
APH associated with maternal or fetal compromise is an obstetric emergency. Management should include
maternal resuscitation and delivery of the fetus to control the bleeding (see section 15). Delivery in this
11 of 23
situation will usually be by caesarean section, unless the woman is in established labour. Similarly, if there is
evidence of fetal distress, resuscitation of the mother should commence and arrangements made to deliver
the baby by caesarean section once the woman is stabilised.
No studies were identified to support recommendations regarding the optimum timing of delivery of women
presenting with APH in the absence of maternal or fetal compromise. In women presenting with APH before
37+0 weeks of gestation, where there is no maternal or fetal compromise and bleeding has settled, there is no
evidence to support elective premature delivery of the fetus.
If the woman presents after 37+0 weeks of gestation, it is important to establish if the bleeding is an APH or
blood stained show; if the APH is spotting or the blood is streaked through mucus it is unlikely to require
active intervention. However, in the event of a minor or major APH, induction of labour with the aim of
achieving a vaginal delivery should be considered in order to avoid adverse consequences potentially
associated with a placental abruption.
13.2 What intrapartum fetal monitoring should be employed for women whose pregnancies were complicated
by APH?
Women in labour with active vaginal bleeding require continuous electronic fetal monitoring.
In women who are in preterm labour whose pregnancies have been complicated by major APH or
recurrent minor APH, or if there has been any clinical suspicion of an abruption, then continuous
electronic fetal monitoring should be recommended.
In women who have experienced one episode of minor APH, in which there have been no subsequent
concerns regarding maternal or fetal wellbeing, intermittent auscultation is appropriate.
Women with minor APH with evidence of placental insufficiency (such as fetal growth restriction or
oligohydramnios) should be recommended to undergo continuous electronic fetal monitoring.
The monitoring of the fetal heart rate in labour aims to identify hypoxia before it leads to perinatal death or
impaired neurological development.There is a lack of evidence to support recommendations on intrapartum
fetal monitoring after APH.
Guidelines commissioned by the National Institute for Health and Clinical Excellence (NICE) on
intrapartum care recommend that continuous electronic fetal heart rate monitoring should be
performed when women have active vaginal bleeding.79 Pregnancies complicated by co-existing
severe morbidity are outside the remit of the guideline.
Evidence
level 4
Extrapolating advice from the NICE guidelines on intrapartum care, it seems reasonable to recommend that
women whose pregnancies have been complicated by major APH or recurrent, minor APH, who are in
preterm labour or if there has been any clinical suspicion of an abruption, should be recommended to
undergo continuous electronic fetal monitoring. Since NICE recommends that intermittent auscultation of the
fetal heart rate is appropriate for low-risk women in established labour,79 it would be reasonable practice to
employ intermittent auscultation of the fetal heart in women who have experienced spotting or one episode
of minor APH, in which there have been no subsequent concerns regarding maternal or fetal wellbeing.
13.3 What is the optimal mode of anaesthesia for women who have experienced APH?
Regional anaesthetic is recommended for operative delivery unless there is a specific contraindication.
In a case of APH where maternal or fetal condition is compromised and caesarean section required, a general
anaesthetic should be considered to facilitate control of maternal resuscitation and to expedite delivery.
12 of 23
A consultant anaesthetist should be involved in the intrapartum care of women with APH with
associated compromise.
The Sixth Report of the Confidential Enquiries into Maternal and Child Health in the UK63 highlighted the
relative safety of regional versus general anaesthesia for operative delivery. Specific contraindications to
regional anaesthesia relevant to APH include maternal cardiovascular instability and coagulopathy.The choice
of anaesthesia for each case requires an individual assessment by a senior anaesthetist; if the woman is
haemodynamically stable, the magnitude of active bleeding should determine the appropriateness of regional
anaesthesia.
In the case of severe fetal compromise but with a stable mother, it is reasonable to perform a general
anaesthetic in the fetal interest to expedite rapid delivery. The optimal mode of anaesthesia will depend on
the skill, expertise and experience of the individual anaesthetist. In this situation good communication is
required between the obstetric and anaesthetic staff. Sequential reports investigating maternal deaths in the
UK have highlighted the importance of senior (consultant) anaesthetic involvement in the care of women at
high risk of haemorrhage.8,62,63
13.4 What is the appropriate management of the third stage of labour in women with APH?
Postpartum haemorrhage (PPH) should be anticipated in women who have experienced APH.
Women with APH resulting from placental abruption or placenta praevia should be strongly
recommended to receive active management of the third stage of labour.
Consideration should be given to the use of ergometrine-oxytocin (Syntometrine [Alliance,

Chippenham, Wilts]) to manage the third stage of labour in women with APH resulting from placental
abruption or placenta praevia in the absence of hypertension (see Green-top Guideline No.52).
APH arising from placental abruption and placenta praevia is associated with an increased risk of
postpartum haemorrhage.80,81 Active versus expectant management of the third stage of labour
reduces the risk of PPH (blood loss greater than 1000 ml) and need for blood transfusion.82 NICE
guidelines on intrapartum care79 recommend that women with risk factors for PPH (including APH)
should have these highlighted in their notes and a care plan covering the third stage of labour
should be made and discussed with the women.
Evidence
level 1++
A Cochrane review addressing prophylactic ergometrine-oxytocin versus oxytocin for the third
stage of labour reported that the addition of ergometrine to oxytocin was associated with a small
reduction in the risk of PPH using the definition of PPH of blood loss of at least 500 ml (OR 0.82,
95% CI 0.710.95).83
Consideration should therefore be given to the use of ergometrine-oxytocin for the third stage of labour in
women with APH resulting from placental abruption or placenta praevia.
14. Should women presenting with APH who are RhD-negative be given anti-D Ig?
Anti-D Ig should be given to all non-sensitised RhD-negative women after any presentation with APH,
independent of whether routine antenatal prophylactic anti-D has been administered.
In the non-sensitised RhD-negative woman in the event of recurrent vaginal bleeding after 20+0 weeks
of gestation, anti-D Ig should be given at a minimum of 6-weekly intervals.
13 of 23
In the non-sensitised RhD-negative woman for all events after 20+0 weeks of gestation, at least 500 iu
anti-D Ig should be given followed by a test to identify FMH greater than 4 ml red blood cells; additional
anti-D Ig should be given as required.
Recommendations regarding the administration of anti-D Ig for RhD prophylaxis are presented in RCOG
Green-top Guideline No.22.11
15. How should massive APH be managed and who should be included in the resuscitation team?
The management of massive APH should follow locally devised multidisciplinary protocols for massive
The management team should include a consultant obstetrician, anaesthetist, haematologist and
midwifery labour ward coordinator. Laboratory staff and portering staff should be alerted.
The CEMACH report, Saving Mothers Lives 200305, stated that dealing with ill, bleeding women requires
skilled teamwork between obstetric and anaesthetic teams with appropriate help from other specialists
including haematologists, vascular surgeons and radiologists. Senior staff should be involved as early as
possible, and should have appropriate experience.7,8 A multidisciplinary haemorrhage protocol should be
available in all units and be updated regularly.62,63
The principles of management of massive APH are outlined in Appendix 1.
16. What blood products should be ordered and made available for women with APH?
The principles of fluid replacement and administration of blood products are the same for APH as they are
for PPH.These are presented in detail in the RCOG Green-top Guideline No. 52 Prevention and Management
of Postpartum Haemorrhage13 and are summarised in Appendix 2.
Data regarding transfusion of blood products in APH are limited. In the management of military trauma, a
decrease in coagulopathy and improved survival is reported with a high fresh frozen plasma (FFP) to packed
red cell (PRC) transfusion ratio of 1:1 to 1:1.4.84,85 An observational population-based study compared the
transfusion of whole blood versus PRCs in obstetric haemorrhage.86 Women who were transfused with PRCs
developed acute tubular necrosis more often than women given whole blood, while pulmonary oedema was
more commonly seen in women given whole blood. Prospective randomised trials are required before
recommendations can be made on whole blood transfusion in obstetric haemorrhage.87
16.1 How should the woman presenting with an APH who develops a coagulopathy be managed?
In women who have experienced a massive blood loss or a major abruption, the development of a
disseminated intravascular coagulation (DIC) should be considered. Clotting studies and a platelet
count should be urgently requested and advice from a haematologist sought. Up to 4 units of FFP and
10 units of cryoprecipitate may be given whilst awaiting the results of the coagulation studies.
RCOG Green-top Guideline No. 52 states that: While acknowledging the general principle that
results of coagulation studies and the advice of a haematologist should be used to guide transfusion
of coagulation factors, up to 1 litre (equivalent to 4 units) of FFP and 10 units of cryoprecipitate
(two packs) may be given empirically in the face of relentless bleeding, while awaiting the results
of coagulation studies. 13
Evidence
level 4
In cases of placental abruption and associated intrauterine fetal death, coagulopathy and hypovolaemic shock
are not uncommon.70 Resuscitation of the woman should follow the framework in Appendix 2, working
closely with haematology and anaesthetic colleagues.
14 of 23
16.2 How should the woman presenting with an APH who is taking anticoagulant therapy be managed?
Women receiving antenatal anticoagulant therapy (usually low molecular weight heparin or warfarin)
should be advised that if they have any vaginal bleeding they should not take any more doses of
anticoagulant medication. They should attend hospital urgently, be assessed on admission and further
doses should only be administered after consultation with medical staff.
If a woman develops a haemorrhagic problem while on anticoagulant therapy, the treatment should
be reviewed urgently and expert haematological advice sought.18
Any woman who is considered to be at high risk of haemorrhage and in whom continued heparin
treatment is considered essential should be managed with intravenous, unfractionated heparin until
the risk factors for haemorrhage have resolved.18
Evidence
level 4
17. In women whose pregnancy is complicated by APH, how should the neonate be
managed and by whom?
Major or massive APH may result in fetal anaemia and fetal compromise. The neonate should be
assessed by a senior paediatrician/neonatologist.
In minor APH, clinical judgement should be used. With continuing haemorrhage, it would be appropriate
to request paediatric support at the time of delivery.
17.1 Major APH

17.1.1 Abruption and vasa praevia
The principal concern in these circumstances is neonatal anaemia and therefore these babies should be
managed by an experienced paediatrician/neonatologist. Neonatal staff should be present at the time of
delivery and be informed of the likely diagnosis and extent of the blood loss so that arrangements for early
neonatal blood transfusion can be made if necessary.
The obstetrician should ensure that, in cases of vasa praevia, the umbilical cord is clamped as soon as possible
after delivery, leaving the longer part attached to the neonate so that umbilical artery catheterisation is
facilitated if required.
17.1.2 Placenta praevia
Anterior placenta praevia that necessitates incising the placenta at the time of caesarean section is an
indication for attendance by an experienced paediatrician/neonatologist.
17.2 Minor APH

Clinical judgement should be used in these circumstances. It would be appropriate to inform paediatric staff
of the anticipated delivery.
18. How should the woman with an extremely preterm pregnancy (24+0 to 26+0 weeks of
gestation) and APH be managed?
Regardless of the gestation, the mothers life should take priority. She should be resuscitated and
stabilised before any decision is made regarding delivery of the baby.
A senior paediatrician/neonatologist should be involved in the counselling of women when extreme

preterm birth is likely.
15 of 23
Conservative management is usually appropriate when APH occurs in the extremely preterm pregnancy (less
than 26+0 weeks of gestation) and the mothers condition is stable.
When the bleeding is considered life-threatening for the woman or there is evidence of
cardiovascular compromise that fails to respond to resuscitation, consideration should be given to
delivery of the fetus. At these gestations experienced neonatologists should be involved in the
counselling of the woman and her partner.88 The use of practical, clinical guidelines in these
situations aids consistency and promotes informed, supportive and responsible choices.89 The
British Association of Perinatal Medicine have produced a framework for the management of babies
born extremely preterm (less than 26+0 weeks of gestation).72
Evidence
level 4
19. What are the postnatal issues that need to be addressed in women whose pregnancies
are complicated by APH?
The postnatal management of pregnancies complicated by major or massive APH should include
thromboprophylaxis, debriefing and clinical incident reporting.
Following a major APH or when the outcome for either the mother or baby/babies was suboptimal, it is
important that an experienced obstetrician debriefs the woman and her partner. The visit should take place
at the earliest possible time following delivery when the woman is able to comprehend and communicate.
The events should be discussed and the woman and her family given the opportunity to ask questions. A
follow-up appointment 4 to 6 weeks following birth should be offered and contact numbers for access to
medical and psychological support should be provided as appropriate.
Where the APH has resulted in fetal demise, good communication between the maternity unit and
the womans general practitioner and community midwife is crucial. These issues are addressed in
RCOG Green-top Guideline No. 55 Late Intrauterine Fetal Death and Stillbirth.15 It may be
appropriate for the consultant to contact the general practitioner by telephone.7
Evidence
level 4
Haemorrhage and blood transfusion are risk factors for venous thromboembolism therefore
thromboprophylaxis should be commenced or reinstituted as soon as the immediate risk of haemorrhage is
reduced. Women at high risk of further haemorrhage (for example women with a coagulopathy) or women
with continuing haemorrhage and in whom thromboprophylaxis is indicated, may be more appropriately
managed with unfractionated heparin and/or graduated compression stockings.18
Risk management in obstetric practice aims to improve quality of care and patient safety. The RCOG
recommend that a major obstetric haemorrhage should be reported through clinical incident systems.90
20. What is the role of obstetric skill drills to improve the management of APH?
Management of a major APH should be included in obstetric skill drills.
CEMACH, the RCOG and the Royal College of Midwives have recommended obstetric drills or skill drills
which includes maternal collapse. These drills are also now one of the requirements in the new Maternity
Clinical Negligence Scheme for Trusts standards.91
Sequential reports investigating maternal deaths in the UK have highlighted the importance of
obstetric haemorrhage skill drills.7,8,62,63 Management of a major APH should be included in obstetric
skill drills9294 A prospective randomised trial from the UK demonstrated that practical, multiprofessional training in the management of obstetric emergencies increases midwives and doctors
knowledge.95 Skill drills should ensure all members of staff, including those involved in blood
transfusion services, know exactly what to do, ensuring that appropriate blood products are
16 of 23
Evidence
levels
2+ to 4
delivered to the labour ward. A multidisciplinary approach to treatment should promote effective
teamworking and ensure prompt and efficient management in such an emergency.
Evidence
levels
2+ to 4

1. The administration of corticosteroids to women presenting with APH less than 34+6 weeks of gestation.
2. Administration of anti-D Ig to non-sensitised RhD-negative women presenting with APH.
3. Percentage of women with APH (recurrent episodes of minor APH, a major APH that has resolved or
unexplained APH) referred for serial growth scans.
4. Management of the third stage of labour in women who had a major APH.
5. Appropriate training of the multidisciplinary team.
22. Areas for future research

1. Randomised controlled trials of sufficient power are required to assess interventions (for example diet,
vitamin supplements and antithrombotic therapy) to prevent placental abruption.
2. Studies are required to determine the optimum timing of delivery in women presenting with unexplained
APH and no associated maternal and/or fetal compromise.
3. Data regarding transfusion of blood products in APH are limited. Studies are required to determine
maternal and fetal outcomes following use of PRCs, FFP and whole blood in the management of APH.
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the risk of placenta previa. Acta Obstet Gynecol Scand
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46. Ananth CV, Smulian JC, Vintzileos AM.The association of
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47. Hendricks MS, Chow YH, Bhagavath B, Singh K. Previous
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placenta previa. J Obstet Gynaecol Res 1999;25:13742.
48. Toivonen S, Heinonen S, Anttila M, Kosma VM, Saarikoski S.
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49. Odibo AO, Cahill AG, Stamilio DM, Stevens EJ, Peipert JF,
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50. Campbell JC. Health consequences of intimate partner
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51. Lumley J, Chamberlain C, Dowswell T, Oliver S, Oakley L,
Watson L. Interventions for promoting smoking cessation
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52. Day E, George S. Management of drug misuse in pregnancy.
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54. Charles DH, Ness AR, Campbell D, Smith GD, Whitley E, Hall
MH. Folic acid supplements in pregnancy and birth outcome:
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55. Nilsen RM, Vollset SE, Rasmussen SA, Ueland PM, Daltveit AK.
Folic acid and multivitamin supplement use and risk of
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Epidemiol 2008;167:86774.
56. Rodger MA, Paidas M. Do thrombophilias cause placentamediated pregnancy complications? Semin Thromb Hemost
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57. Gris JC, Chauleur C, Faillie JL, Baer G, Mars P, Fabbro-Peray P,
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58. Calleja-Agius J, Custo R, Brincat M, Calleja N. Placental
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Anaesthesia 2009;103:i47i56.
60. Magann EF, Cummings JE, Niederhauser A, RodriguezThompson D, McCormack R, Chauhan SP. Antepartum bleeding
of unknown origin in the second half of pregnancy: a review.
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Newnham JP. Antepartum bleeding of unknown origin in the
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cervix in pregnancy. A study of the incidence and treatment in
the Western region of Sweden 1973 to 1992. Acta Obstet
66. Chilaka VN, Konje JC, Clarke S,Taylor DJ. Practice observed: is
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[http://www.cancerscreening.nhs.uk/cervical/publications/nhs
csp20.html].
68. Emery CL, Morway LF, Chung-Park M, Wyatt-Ashmead J, Sawady
J, Beddow TD.The Kleihauer-Betke test. Clinical utility,
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69. Dhanraj D, Lambers D.The incidences of positive KleihauerBetke test in low-risk pregnancies and maternal trauma
patients. Am J Obstet Gynecol 2004;190:14613.
70. Oyelese Y. Placenta previa: the evolving role of ultrasound.
71. Glantz C, Purnell L. Clinical utility of sonography in the
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74. Manolitsas T, Wein P, Beischer NA, Sheedy MT, Ratten VJ. Value of
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shows ominous features? Aust N Z J Obstet Gynaecol
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75. Ananth CV, Berkowitz GS, Savitz DA, Lapinski RH. Placental
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77. Khan K, Zamora J, Lamont RF, Van Geijn Hp H, Svare J, SantosJorge C, et al. Safety concerns for the use of calcium channel
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78. Harlev A, Levy A, Zaulan Y, Koifman A, Mazor M, Wiznitzer A, et
al. Idiopathic bleeding during the second half of pregnancy as
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babies during childbirth. London: RCOG Press; 2007.
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obstetric haemorrhage. Eur J Obstet Gynecol Reprod Biol
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81. Schuurmans N, MacKinnon C, Lane C, Etches D. Prevention and
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86. Alexander JM, Sarode R, McIntire DD, Burner JD, Leveno KJ.
Whole blood in the management of hypovolemia due to
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87. Mercier FJ, Bonnet MP. Use of clotting factors and other
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89. Kaempf JW,Tomlinson M, Arduza C, Anderson S, Campbell B,
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premature infants. Pediatrics 2006;117;229.
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RCOG; 2009.
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its impact on outcome. Fetal Matern Med Rev
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93. Sorensen SS. Emergency drills in obstetrics: reducing risk of
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94. Grunebaum A. Error reduction and quality assurance in
obstetrics. Clin Perinatol 2007;34:489502.
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2007;114:153441.
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APPENDIX 1
Principles of management of massive APH (blood loss greater than 1000 ml and/or signs of clinical shock)
Personnel required:
call experienced midwife (in addition to midwife in charge)
call obstetric middle grade and alert consultant
call anaesthetic middle grade and alert consultant
alert consultant clinical haematologist on call
alert blood transfusion laboratory
call porters for delivery of specimens/blood
designate one member of the team to record events, fluids, drugs and vital signs.
Initial management:
Initial management should follow the ABCD pathway.
A and B assess airway and breathing

A high concentration of oxygen (1015 litres/minute) via a facemask should be administered.
C evaluate circulation
Establish two 14-gauge intravenous lines; a 20 ml blood sample should be taken and sent for diagnostic tests,
including full blood count and assessment of FMH if RhD-negative, coagulation screen, urea and electrolytes
and cross match (4 units)
D assess the fetus and decide on delivery
The four pillars of management:

communication between all members of the multidisciplinary team
resuscitation (see Appendix 2)
monitoring and investigation
arrest bleeding by arranging delivery of the fetus (see section 14).
These management strategies have been adapted from RCOG Green-top Guideline No. 52 Prevention and
Management of Postpartum Haemorrhage.12 The differences in management options between APH and PPH
are that there are two individuals to care for (should the fetus still be alive) and that a very specific method
of controlling the haemorrhage is available in the event of an APH (delivery of the fetus and placenta).
Delivery of the fetus and placenta will control bleeding by allowing the uterus to contract and stop bleeding
from the site of placental separation, and will also remove placental tissue, a source of production of
coagulation activators which predisposes to the development of DIC.
20 of 23
APPENDIX 2
The principles of fluid replacement and administration of blood products (from RCOG Green-top Guideline No. 5212)
Basic measures for haemorrhage up to 1000 ml with no clinical shock:

intravenous access (14-gauge cannula x 1)
commence crystalloid infusion.
Full protocol for massive haemorrhage (blood loss > 1000 ml or clinical shock):
assess airway
assess breathing
evaluate circulation
oxygen by mask at 1015 litres/minute
intravenous access (14-gauge cannula x 2)
position left lateral tilt
keep the woman warm using appropriate available measures
transfuse blood as soon as possible
until blood is available, infuse up to 3.5 litres of warmed crystalloid Hartmanns solution (2 litres) and/or
colloid (12 litres) as rapidly as required

the best equipment available should be used to achieve rapid warmed infusion of fluids
special blood filters should not be used, as they slow infusions.
Fluid therapy and blood product transfusion:

Crystalloid
Colloid
Blood
Fresh frozen plasma
Platelets concentrates
Cryoprecipitate
up to 2 litres Hartmanns solution

up to 12 litres colloid until blood arrives
cross-matched
if cross-matched blood unavailable and the clinical situation is urgent, give uncrossmatched group-specific blood or give O RhD-negative blood
consider the use of red-cell salvage if available
4 units of FFP (1215 ml/kg or total 1 litre)
(i) for every 6 units of red cells or
(ii) if prothrombin time and/or activated partial thromboplastin time (PT and aPTT) are
greater than 1.5 x mean control
if platelet count < 50 x 109/l
if fibrinogen < 1 g/l.
With continuing massive haemorrhage and whilst awaiting coagulation studies, up to 4 units of FFP and 10
units of cryoprecipitate (two packs) may be given empirically.
Apply clinical judgement in each situation.
The main therapeutic goal of the management of massive blood loss as outlined in Green-top Guideline No. 52
summarises the main therapeutic goal of management of massive blood loss is to maintain:
haemoglobin > 8 g/dl
platelet count > 75 x 109/l
prothrombin time < 1.5 x mean control
activated partial prothromboplastin time < 1.5 x mean control
fibrinogen > 1.0 g/l.
21 of 23
APPENDIX 3

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
22 of 23

development group
Gynaecologists by:
Dr AJ Thomson MRCOG, Paisley, Scotland and Dr JE Ramsay MRCOG, Kilmarnock, Scotland; with input
from Miss D Rich FRCOG, Wales at the scope and first draft stage
Sir S Arulkumaran FRCOG, London; Mr KT Moriarty MRCOG, Northampton; Mr DI Fraser MRCOG, Norwich; Mr AK
Ash FRCOG, London; Dr G Kumar FRCOG, BMFMS, RCGP, BCSH.
Committee lead peer reviewers were:
Dr P Owen MRCOG, Glasgow, Scotland and Dr K Harding FRCOG, London
DISCLAIMER
health services.
23 of 23
Bacterial Sepsis in Pregnancy
Greentop Guideline No. 64a

April 2012
Bacterial Sepsis in Pregnancy

1.
Purpose and scope
The need for a guideline on the management of sepsis in pregnancy was identified by the 2007 Confidential
Enquiry into Maternal Deaths.1 The scope of this guideline covers the recognition and management of serious
bacterial illness in the antenatal and intrapartum periods, arising in the genital tract or elsewhere, and its
management in secondary care. Sepsis arising due to viral, fungal or other infectious agents is outside the
scope of this guideline. Bacterial sepsis following pregnancy in the puerperium is the subject of a separate
Green-top Guideline. The population covered by this guideline includes pregnant women suspected of, or
diagnosed with, serious bacterial sepsis in primary or secondary healthcare.
2.
Sepsis in pregnancy remains an important cause of maternal death in the UK.1,2 In 20032005 there were 13
direct deaths from genital tract sepsis in pregnancy, five related to pregnancy complications prior to 24
weeks of gestation and eight related to sepsis from 24 weeks of gestation, arising before or during labour.
Sadly, substandard care was identified in many of the cases, in particular lack of recognition of the signs of
sepsis and a lack of guidelines on the investigation and management of genital tract sepsis.1 Between 2006
and 2008 sepsis rose to be the leading cause of direct maternal deaths in the UK, with deaths due to group
A streptococcal infection (GAS) rising to 13 women.2 Severe sepsis with acute organ dysfunction has a
mortality rate of 20 to 40%, which increases to 60% if septic shock develops.1 Studies in the non-pregnant
population have found that the survival rates following sepsis are related to early recognition and initiation
of treatment.3-5
Sepsis may be defined as infection plus systemic manifestations of infection. Severe sepsis may be defined as
sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Septic shock is defined as the
persistence of hypoperfusion despite adequate fluid replacement therapy.3
3.
This RCOG guideline was developed in accordance with standard methodology for producing RCOG Greentop Guidelines. The Cochrane Database of Systematic Reviews, DARE, EMBASE, Medline and PubMed
(electronic databases) were searched for relevant randomised controlled trials, systematic reviews and metaanalyses. The search was restricted to articles published between 1980 to May 2011. Search terms included:
sepsis and pregnancy, bacterial infection and pregnancy, antenatal bacterial infection, bacterial sepsis,
intrapartum septic shock,intrapartum infection,maternal pyrexia,maternal fever,systemic inflammatory
response syndrome, chorioamnionitis, genital tract sepsis, listeria infection, group A Streptococcus,
Streptococcus pyogenes, Streptococcus and pregnancy, and the search limited to humans and English
language.The NHS Evidence, Health Information Resources and the National Guidelines Clearing House were
also searched for relevant guidelines and reviews. Studies relevant to the scope of the guideline were selected
by the members of the guideline development group. Where possible, recommendations are based on
available evidence. Areas where evidence is lacking are annotated as good practice points.
4.
Which women are at risk of sepsis in pregnancy?
Multiple risk factors for severe sepsis have been identified by the Confidential Enquiries into Maternal
Deaths (CEMD) (see table 1).
2 of 14
Risk factors for sepsis identified from the women who died in the 2003-2005 and 2006-2008
triennia are shown in table 1. Many of the women who died had one or more risk factors. Urinary
tract infection and chorioamnionitis are common infections associated with septic shock in the
pregnant patient.5
Evidence
level 3
Table 1. Risk factors for maternal sepsis in pregnancy as identified by the Confidential Enquiries into
Maternal Deaths1,2
Obesity
Impaired glucose tolerance / diabetes
Impaired immunity/ immunosuppressant medication
Anaemia
Vaginal discharge
History of pelvic infection
History of group B streptococcal infection
Amniocentesis and other invasive procedures
Cervical cerclage
Prolonged spontaneous rupture of membranes
GAS infection in close contacts / family members
Of black or other minority ethnic group origin
5.
What should prompt recognition of sepsis in the pregnant woman?
All healthcare professionals should be aware of the symptoms and signs of maternal sepsis and critical
illness and of the rapid, potentially lethal course of severe sepsis and septic shock. Suspicion of
significant sepsis should trigger an urgent referral to secondary care.
Clinical signs suggestive of sepsis include one or more of the following: pyrexia, hypothermia,
tachycardia, tachypnoea, hypoxia, hypotension, oliguria, impaired consciousness and failure to respond
to treatment. These signs, including pyrexia, may not always be present and are not necessarily related
to the severity of sepsis.
Regular observations of all vital signs (including temperature, pulse rate, blood pressure and
respiratory rate) should be recorded on a Modified Early Obstetric Warning Score (MEOWS) chart.
All staff taking observations should have annual training in the use of the MEOWS chart.
The signs and symptoms of sepsis in pregnant women may be less distinctive than in the nonpregnant population and are not necessarily present in all cases;4 therefore, a high index of
suspicion is necessary. Clinical features suggestive of sepsis are shown in table 2. Healthcare
professionals should be aware of the symptoms and signs of maternal sepsis and critical illness.
Disease progression may be much more rapid than in the non-pregnant state. Genital tract sepsis
may present with constant severe abdominal pain and tenderness unrelieved by usual analgesia,
and this should prompt urgent medical review.1 Severe infection may be associated with preterm
labour. Toxic shock syndrome caused by staphylococcal or streptococcal exotoxins can produce
confusing symptoms including nausea, vomiting and diarrhoea; exquisite severe pain out of
proportion to clinical signs due to necrotising fasciitis; a watery vaginal discharge; generalised rash;
and conjunctival suffusion.
3 of 14
Evidence
level 4
Diagnostic criteria for sepsis and severe sepsis are provided in appendix 1 and features of toxic shock
syndrome are listed in appendix 2.
Table 2. Clinical features suggestive of sepsis. Modified from references 1 and 3.
Fever or rigors
Diarrhoea or vomiting - may indicate exotoxin production (early toxic shock)
Rash (generalised streptococcal maculopapular rash or purpura fulminans)
Abdominal /pelvic pain and tenderness
Offensive vaginal discharge (smelly suggests anaerobes; serosanguinous suggests streptococcal infection)
Productive cough
Urinary symptoms
6.
What are the appropriate investigations when sepsis is suspected?
Blood cultures are the key investigation and should be obtained prior to antibiotic administration;
however, antibiotic treatment should be started without waiting for microbiology results.
Serum lactate should be measured within six hours of the suspicion of severe sepsis in order to guide
management. Serum lactate 4 mmol/l is indicative of tissue hypoperfusion.
Any relevant imaging studies should be performed promptly in an attempt to confirm the source of
infection.
Blood cultures and other samples as guided by clinical suspicion of the focus of infection (e.g.
throat swabs, mid-stream urine, high vaginal swab, or cerebrospinal fluid) should be obtained prior
to starting antibiotic therapy as they may become uninformative within a few hours of
commencing antibiotics but must not delay antibiotic therapy.3 If the methicillin-resistant
Staphylococcus aureus (MRSA) status is unknown, a pre-moistened nose swab may be sent for rapid
MRSA screening where such testing is available.The results of these tests should be reviewed when
they become available to allow subsequent optimisation of the antibiotic regime. Similarly, prompt
imaging may identify the source of the infection, allowing early definitive treatment, and should not
be deferred on the grounds of pregnancy.3
Evidence
level 4
Use of the resuscitation bundle developed as part of the Surviving Sepsis Campaign is
recommended (see table 3) and includes measurement of serum lactate within six hours of
suspicion of severe sepsis with the result being used to guide management.3 Arterial blood gas
measurement should be undertaken to assess for hypoxia. Laboratory findings suggestive of a
diagnosis of sepsis are outlined in appendix 1.
Table 3. Tasks to be performed within the first six hours of the identification of severe sepsis. Modified from
the Surviving Sepsis Campaign Resuscitation Bundle (group of therapies)3
Obtain blood cultures prior to antibiotic administration
Administer broad-spectrum antibiotic within one hour of recognition of severe sepsis
Measure serum lactate
In the event of hypotension and/or a serum lactate >4mmol/l deliver an initial minimum 20ml/kg of crystalloid or an equivalent. Apply
vasopressors for hypotension that is not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) >65mmHg
In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate >4mmol/l
a. Achieve a central venous pressure (CVP) of 8mmHg
b. Achieve a central venous oxygen saturation (ScvO2) 70% or mixed venous oxygen saturation (ScvO2) 65%
4 of 14
7.
Who should be involved in the collaborative care of women with sepsis?
If sepsis is suspected, regular frequent observations should be made. The use of a MEOWS chart is
recommended. There should be an urgent referral to the critical care team in severe or rapidly
deteriorating cases, and the involvement of a consultant obstetrician.
The expert advice of a consultant microbiologist or infectious disease physician should be sought
urgently when serious sepsis is suspected.
A MEOWS chart should be used for all maternity inpatients to identify seriously ill pregnant women
and refer them to critical care and obstetric anaesthetic colleagues according to local guidelines.1
Evidence
level 3
Early, goal-directed resuscitation has been shown to improve survival for non-pregnant patients
presenting with septic shock.6
Evidence
level 1+
The Surviving Sepsis Campaign Resuscitation Bundle recommends that this is commenced pending
transfer to an intensive care unit (ICU).3 See table 3 for details of the bundle.
The decision to transfer to intensive care should be decided by the critical care team in conjunction
with the obstetric consultant and the consultant obstetric anaesthetist.7 Cardiac output monitoring,
ventilatory support requiring intubation, and renal support would all require transfer to ICU in the
majority of units (see table 4).
Evidence
level 4
Table 4. Indications for transfer to ICU. Adapted from Plaat and Wray (2008)8
System
Indication
Cardiovascular
Hypotension or raised serum lactate persisting despite fluid resuscitation, suggesting the need for
inotrope support
Respiratory
Pulmonary oedema
Mechanical ventilation
Airway protection
Renal
Renal dialysis
Neurological
Significantly decreased conscious level
Miscellaneous
Multi-organ failure
Uncorrected acidosis
Hypothermia
8.
What are the commonly identified organisms, including hospital acquired infection?
The most common organisms identified in pregnant women dying from sepsis are Lancefield group
A beta-haemolytic Streptococcus and E.Coli.1, 2
Mixed infections with both Gram-positive and Gram-negative organisms are common, especially in
chorioamnionitis. Coliform infection is particularly associated with urinary sepsis, preterm
premature rupture of membranes, and cerclage.1 Anaerobes such as Clostridium perfringens (the
cause of gas gangrene) are less commonly seen nowadays, with Peptostreptococcus and Bacteroides
spp. predominating.9
Evidence
level 3
9. What empirical and specific antimicrobial therapy should be used to treat the woman?
Administration of intravenous broad spectrum antibiotics is recommended within one hour of suspicion
of severe sepsis, with or without septic shock.
5 of 14
If genital tract sepsis is suspected, prompt early treatment with a combination of high-dose broadspectrum intravenous antibiotics may be lifesaving.
Administration of intravenous broad spectrum antibiotics are recommended within one hour of suspicion of
severe sepsis in the woman, with or without septic shock, as part of the Surviving Sepsis Campaign
Resuscitation Bundle.3
Empirically, broad spectrum antimicrobials active against Gram-negative bacteria, and capable of
preventing exotoxin production from Gram-positive bacteria, should be used according to local
microbiology policy, and therapy narrowed once the causative organism(s) has been identified.
Evidence
level 4
The 20032005 CEMACH report1 referred to the use of cefuroxime and metronidazole for genital tract
sepsis. However, cefuroxime is no longer part of many hospital formularies because of the association with
C. difficile. Neither agent provides any MSRA, Pseudomonas or extended-spectrum beta-lactamases (ESBL)
cover (see appendix 3 for range of activity of common antibiotics). Information on antimicrobials which may
aid in guiding choice is provided in table 5; however, hospital guidelines differ, and local guidance should be
followed as the incidence of resistant organisms varies throughout the UK.
In addition to antimicrobial therapy, the source of sepsis should be sought and dealt with if
possible: for example, by delivery of the baby.1
Evidence
level 3
Table 5. Antimicrobial choices and limitations of antimicrobial.

Co-amoxiclav
Does not cover MRSA or Pseudomonas, and there is concern about an increase in the risk of necrotising
enterocolitis in neonates exposed to co-amoxiclav in utero.10
Metronidazole
Only covers anaerobes.
Clindamycin
Covers most streptococci and staphylococci, including many MRSA, and switches off exotoxin production
with significantly decreased mortality.11,12 Not renally excreted or nephrotoxic.
Piperacillintazobactam
(Tazocin) and carbapenems
Covers all except MRSA and are renal sparing (in contrast to aminoglycosides).
Gentamicin (as a single dose

of 35mg/kg)
Poses no problem in normal renal function but if doses are to be given regularly serum levels must be
monitored.
10. What is the role of intravenous immunoglobulin (IVIG)?

IVIG is recommended for severe invasive streptococcal or staphylococcal infection if other therapies
have failed.
IVIG has an immunomodulatory effect, and in staphylococcal and streptococcal sepsis it also
neutralises the superantigen effect of exotoxins, and inhibits production of tumour necrosis factor
(TNF) and interleukins.The Department of Health has recommendations regarding the use of IVIG
for invasive streptococcal and staphylococcal infection.13
Evidence
level 4
High dose IVIG has been used in pregnant women14 and is effective in exotoxic shock (i.e. toxic
shock due to streptococci and staphylococci) but with little evidence of benefit in Gram-negative
(endotoxin related) sepsis. The main contraindication to IVIG use is a congenital deficiency of
immunoglobulin A. Its use in women with severe staphylococcal and streptococcal sepsis should
be discussed with infectious disease colleagues or medical microbiologists.
Evidence
level 3
IVIG is available from the blood transfusion department, and all commercial brands of IVIG available in the
UK contain antibodies to streptococcal and staphylococcal exotoxins. Actual administration of IVIG should
6 of 14
be through a blood warming device, and hospital protocols for replacement therapy in haematology patients
may be used.
11.
How should the fetus be monitored and when and how should the baby be delivered?
In a critically ill pregnant woman, birth of the baby may be considered if it would be beneficial to the
mother or the baby or to both. A decision on the timing and mode of birth should be made by a senior
obstetrician following discussion with the woman if her condition allows.
If preterm delivery is anticipated, cautious consideration should be given to the use of antenatal
corticosteroids for fetal lung maturity in the woman with sepsis.
During the intrapartum period, continuous electronic fetal monitoring is recommended. Changes in
cardiotocography (CTG), such as changes in baseline variability or new onset decelerations, must
prompt reassessment of maternal mean arterial pressure, hypoxia and acidaemia.
Epidural/spinal anaesthesia should be avoided in women with sepsis and a general anaesthetic will
usually be required for caesarean section.
The effects of maternal sepsis on fetal wellbeing include the direct effect of infection in the fetus,
the effect of maternal illness/shock and the effect of maternal treatment. The risk of neonatal
encephalopathy and cerebral palsy is increased in the presence of intrauterine infection.15
Evidence
level 2+
If preterm delivery is anticipated the use of antenatal corticosteroids for fetal lung maturity in the
woman with sepsis can be considered.16,17 See RCOG Green-top Guideline No.7, Antenatal
Corticosteroids to Reduce Neonatal Morbidity.16
Evidence
level 4
During the intrapartum period, continuous electronic fetal monitoring is recommended in the
presence of maternal pyrexia (defined as a temperature >38.0 C once, or 37.5 C on two occasions
2 hours apart)18 and this should also apply to sepsis without pyrexia.
Objective evidence of intrauterine infection is associated with abnormal fetal heart monitoring;
however, electronic fetal monitoring is not a sensitive predictor of early onset neonatal sepsis.19,20
Evidence
level 2+
Changes in CTG, such as changes in baseline variability or new onset decelerations, must also prompt
reassessment of maternal mean arterial pressure, hypoxia and acidaemia. These changes may serve
as an early warning sign for derangements in maternal end-organ systems.17 There is insufficient
evidence regarding fetal blood sampling in the presence of maternal sepsis to guide practice.
Evidence
level 4
Attempting delivery in the setting of maternal instability increases the maternal and fetal mortality
rates unless the source of infection is intrauterine.21 The decision on mode of delivery should be
individualised by the consultant obstetrician with consideration of severity of maternal illness,
duration of labour, gestational age and viability.17
12. What prophylaxis should be considered for the neonate, other family members and
healthcare workers?
Local and national guidelines should be followed in consultation with the local health protection unit or
lead for communicable disease control.
When a mother has been found to have invasive group A streptococcal infection in the peripartum
period, the neonatologist should be informed and prophylactic antibiotics administered to the baby.
7 of 14
Close household contacts of women with group A streptococcal infection should be warned to seek
medical attention should symptoms develop, and the situation may warrant antibiotic prophylaxis.
Healthcare workers who have been exposed to respiratory secretions of women with group A
streptococcal infection should be considered for antibiotic prophylaxis.
The Health Protection Agency have produced detailed guidelines for the investigation, control and prevention
of the spread of group A streptococcal infection in healthcare settings in the United Kingdom.22
As well as the specific recommendation for group A streptococcal disease, any baby of a mother
found to have sepsis in the peripartum period should be discussed with neonatology colleagues so
that prophylactic antibiotic administration to the baby can be considered.22
Evidence
level 4
13. What infection control issues should be considered?

Group A -haemolytic Streptococcus and MRSA are easily transmitted via the hands of healthcare
workers and via close contact in households. Local infection control guidelines should be followed for
hospitalspecific isolation and contact precautions.
Invasive group A streptococcal infections are notifiable and the infection control team and the
consultant for communicable diseases should be informed.
Women suspected of or diagnosed with group A Streptococcus sepsis should be isolated in a single room with
en suite facilities to minimise the risk of spread to other women. Local advice from infectious control
colleagues should always be sought.
The existence of locally based guidelines for the investigation and management of genital tract sepsis in the
maternity unit.
The use of a version of a MEOWS chart to aid the identification of seriously ill pregnant women1 in the
maternity unit.
The proportion of pregnant women with suspected severe sepsis who had serum lactate measured within
six hours of presentation.
8 of 14
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Lewis G, editor. Saving Mothers Lives: reviewing maternal

deaths to make motherhood safer 2003-2005. The Seventh
Report on Confidential enquiries into Maternal Deaths in
the United Kingdom. London: RCOG Press; 2007.
[http://www.oaa-anaes.ac.uk/assets/_managed/editor/File/
Reports/2003-2005_saving_mothers_full_report.pdf]
Centre for Maternal and Child Enquiries (CMACE). Saving
Mothers Lives: reviewing maternal deaths to make
motherhood safer: 2006-2008. BJOG 2011; 118(suppl. 1):1-203.
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R
et al. Surviving Sepsis Campaign: International guidelines for
2008;36:296327 [published correction appears in Crit Care
Med 2008;36:1394-1396].
Fein AM, DuVivier R. Sepsis in Pregnancy. Clin Chest Med
1992;13:70922.
McDonald NS.The care of the critically ill obstetric patient.
CPD Anaesthesia 2004;6:6167.
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B,
et al. Early goal-directed therapy in the treatment of severe
sepsis and septic shock. N Engl J Med 2001;345:136877.
Mukherjee S, Brett SJ. On the response to acutely deteriorating
patients. In Vincent JL, editor. Yearbook of Intensive Care
and Emergency Medicine 2010 pp531-538. New York:
Springer; 2010.
Plaat F, Wray S. Role of the anaesthetist in obstetric critical care.
Best Pract Res Clin Obstet Gynaecol 2008;22: 91735.
Topiel MS, Simon GL. Peptococcaceae bacteraemia. Diagn
Microbiol Infect Dis 1986;4:10917.
Kenyon S,Taylor DJ,Tarnow-Mordi W. Broad-spectrum
antibiotics for spontaneous preterm labour: the Oracle II
randomised trial. The Lancet 2001;357:989994.
Schuitemaker N, van Roosmalen J, Dekker G, van Dongen P, van
Geijn H, Gravenhorst JB. Increased maternal mortality in The
Netherlands from group A streptococcal infections. Eur J
Stevens DL. Streptococcal toxic-shock syndrome: spectrum of
disease, pathogenesis and new concepts in treatment. Emerg
Infect Dis 1995;1:6978.
Department of Health. Clinical guidelines for immunoglobulin use (Second Edition). 2008 [http://www.dh.gov.uk/
en/Publicationsandstatistics/Publications/PublicationsPolicyAn
dGuidance/DH_085235]
14. Ooe K, Udagawa H. A new type of fulminant group A

streptococcal infection in obstetric patients; report of 2 cases.
Hum Pathol 1997;28:509-512.
15. Yoon BH, Romero R, Park JS, Kim CJ, Kim SH, Choi JH et al.
Fetal exposure to an intra-amniotic inflammation and the
development of cerebral palsy at the age of three years. Am J
Corticosteroids to Reduce Neonatal Morbidity. Green Top
17. American College of Obstetricians and Gynaecologists
Committee on Obstetric Practice. ACOG Practice Bulletin
No.100: Critical care in pregnancy. Obstet Gynecol
2009;113:44350.
Health. Intrapartum care: Care of healthy women and their
babies during childbirth. London: RCOG Press; 2007. [http://
www.nice.org.uk/nicemedia/pdf/CG55FullGuideline.pdf]
19. Buhimschi CS, Abdel-Razeq S, Cackovic M, Pettker CM, Dulay
AT, Bahtiyar MO et al. Fetal heart rate monitoring patterns in
women with amniotic fluid proteomic profiles indicative of
inflammation. Am J Perinatol 2008;25;35972.
20. Aina-Mumuney AJ, Althaus JE, Henderson JL, Blakemore MC,
Johnson EA, Graham EM. Intrapartum electronic fetal
monitoring and the identification of systemic fetal
inflammation. J Reprod Med 2007;52:7628.
21. Sheffield JS. Sepsis and septic shock in pregnancy. Crit Care
Clin 2004;20:65160.
22. Health Protection Agency, Group A Streptococcus Working
Group. Interim UK guidelines for management of close
community contacts of invasive group A streptococcal disease.
Commun Dis Public Health 2004;7:35461.
23. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D et
al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis
Definitions Conference. Crit Care Med 2003;31:12506.
24. Lappin E, Ferguson AJ. Gram-positive toxic shock syndromes.
9 of 14
APPENDIX 1
Diagnostic criteria for sepsis modified from Levy et al (2003)23 for pregnant women using references 1 and 2
where pregnancy specific parameters are available.
Infection, documented or suspected, and some of the following:
General variables:
Fever (>38C)
Hypothermia (core temperature <36C)
Tachycardia (>100 beats per minute)
Tachypnoea (>20 breaths per minute)
Impaired mental state
Significant oedema or positive fluid balance (>20ml/kg over 24 hours)
Hyperglycaemia in the absence of diabetes (plasma glucose >7.7 mmol/l)
Inflammatory variables:
White blood cell (WBC) count >12 x 109/l (note that a transient leucocytosis is common in labour)
Leucopenia (WBC count <4 x 109/l)
Normal WBC count with >10% immature forms
Plasma C-reactive protein >7mg/l
Haemodynamic variables:
Arterial hypotension (systolic blood pressure <90mmHg; mean arterial pressure <70mmHg or systolic blood pressure decrease >40mmHg)
Tissue perfusion variables:
Raised serum lactate 4 mmol/l
Decreased capillary refill or mottling
Organ dysfunction variables:
Arterial hypoxaemia (PaO2 (arterial oxygen partial pressure) /FIO2 (fraction of inspired oxygen) <40kPa). Sepsis is severe if <33.3kPa in the
absence of pneumonia or <26.7kPa in the presence of pneumonia.
Oliguria (urine output <0.5ml/kg/hr for at least two hours, despite adequate fluid resuscitation)
Creatinine rise of >44.2mol/l. Sepsis is severe if creatinine level >176mol/l
Coagulation abnormalities (International Normalised Ratio [INR] >1.5 or activated partial thromboplastin time [APTT] >60s)
Thrombocytopaenia (platelet count <100 x 109/l)
Hyperbilirubinaemia (plasma total bilirubin> 70mol/l)
Ileus (absent bowel sounds)
10 of 14
APPENDIX 2
Staphylococcal and streptococcal toxic shock syndrome clinical disease definition.12,23
Staphylococcal toxic shock24
Streptococcal toxic shock syndrome12,24
1. Fever > /= 39.9C
A. Isolation of beta-haemolytic group A Streptococcus from:
2. Rash diffuse macular erythroderma
1. normally sterile site blood, CSF, peritoneal fluid, tissue biopsy
3. Desquamation 10 to 14 days after onset of illness,
2. non-sterile site throat, vagina, sputum
especially palms and soles

4. Hypotension systolic BP < 90 mm Hg adults
5. Multisystem involvement
B. Clinical case definition
Three or more of the following systems affected:
Multi-organ involvement characterised by:
Gastrointestinal vomiting or diarrhoea at onset illness
Muscular severe myalgia or elevated creatinine phosphokinase
Mucous membranes vaginal, oro-pharyngeal or conjunctival
2. Two or more of the following:
hyperaemia
Renal impairment creatinine >176mol/l
Renal creatinine twice the upper limit of normal
Coagulopathy platelets < 100 x 109/l or disseminated intravascular
Hepatic total bilirubin twice the upper limit of normal
Haematological platelets < /= 100 x
Central nervous system disorientation or alterations in
109/l
consciousness without focal neurological signs
1. Hypotension
plus
coagulation
Liver involvement alanine transaminase or aspartame

transaminase or bilirubin levels twice the normal upper limit for age
Acute respiratory distress syndrome
Generalised erythematous macular rash (present in 10%) may

desquamate
Soft tissue necrosis including necrotising fasciitis, myositis or

gangrene
Case classification:
Probable four of the five clinical findings positive
Probable meets clinical case definition (above) plus isolation from

non-sterile site
Confirmed case with all five clinical findings
Definite meets clinical case definition (above) plus isolation of group

A Streptococcus from a normally sterile site
11 of 14
APPENDIX 3
Antibiotic spectra for obstetrics and gynaecology.
Dr Marina S Morgan, 2012
Solid lines represent roughly the proportion of the bacteria sensitive to that antibiotic.
NB: Tazocin may not be effective against some ESBL producing Gram-negative bacteria, and carbapenemase
producing organisms will be resistant to carbapenems.
12 of 14
APPENDIX 4

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
13 of 14

development group
Dr D Pasupathy MRCOG, London; Dr M Morgan MB ChB FRCPath, Consultant Microbiologist,
Royal Devon & Exeter NHS Foundation Trust; Dr FS Plaat MA MB BS FRCA, Consultant, Department of
Anaesthesia, Hammersmith Hospital, London; and Dr KS Langford FRCOG, London.
Mr DI Fraser MRCOG, Norwich; Dr MA Harper FRCOG, Belfast; Dr R Daniels, Heart of England NHS Foundation Trust,
Birmingham; Mr I Babarinsa MRCOG, Gloucester; Centre for Maternal and Child Enquiries (CMACE); Health Protection
Agency; Obstetric Anaesthetists Association (OAA); RCOG Consumers Forum; Royal College of General Practitioners;
Royal College of Midwives.
The Guideline Committee lead reviewers were: Mr M Griffiths FRCOG, Luton; Dr AJ Thomson MRCOG, Paisley,
Scotland; and Dr KR Harding FRCOG, London.
DISCLAIMER
health services.
14 of 14
Bacterial Sepsis following Pregnancy

April 2012
Bacterial Sepsis following Pregnancy

1.
Purpose and scope
The purpose of this guideline is to provide guidance on the management of sepsis in the puerperium (i.e. sepsis
developing after birth until 6 weeks postnatally), in response to the findings of the Centre for Maternal and Child
Enquiries (CMACE) Eighth Report on Confidential Enquiries into Maternal Deaths in the United Kingdom.1
This topic is particularly relevant as there has been a dramatic rise in maternal deaths attributable to group A
beta-haemolytic streptococci (GAS) (three in 200020022 and 13 in 20062008).1 The most common site of
sepsis in the puerperium is the genital tract and in particular the uterus, resulting in endometritis. This
guideline covers the recognition of febrile bacterial illness in the postpartum period including postabortion
sepsis arising in the genital tract or elsewhere, investigations to identify and characterise sepsis in the
puerperium, and management strategies. The population covered includes women in the puerperium (i.e.
within 6 weeks of giving birth) with suspected or diagnosed bacterial sepsis in primary or secondary care.
Sepsis in pregnancy is covered by a parallel guideline. Sepsis arising owing to viral or parasitic agents is
outside the scope of this guideline. This guideline excludes mild to moderate illness in primary care.
2.
Despite significant advances in diagnosis, medical management and antimicrobial therapy, sepsis in the
puerperium remains an important cause of maternal death, accounting for around 10 deaths per year in the
UK.1 Severe sepsis with acute organ dysfunction has a mortality rate of 2040%, rising to around 60% if
septicaemic shock develops.3
Sepsis may be defined as infection plus systemic manifestations of infection; severe sepsis may be defined as
sepsis plus sepsis-induced organ dysfunction or tissue hypoperfusion. Septic shock is defined as the
persistence of hypoperfusion despite adequate fluid replacement therapy.3
Symptoms of sepsis (see section 7) may be less distinctive than in the non-pregnant population and are not
necessarily present in all cases; therefore, a high index of suspicion is necessary.
Disease progression may be rapid. Genital tract sepsis may present with constant severe abdominal pain and
tenderness unrelieved by usual analgesia, and this should prompt urgent medical review.1
3.
Guidelines. The Cochrane Database of Systematic Reviews, DARE, EMBASE, Medline and PubMed (electronic
databases) were searched for relevant randomised controlled trials, systematic reviews and meta-analyses.The
search was restricted to articles published between 1980 and May 2011. Search terms included: postpartum
sepsis, postpartum infection, septic shock, postpartum, puerperal sepsis, puerperal pyrexia, puerperal
fever,genital tract sepsis,bacterial sepsis,toxic shock,activated protein C and postpartum,Streptococcus
infection and puerperium, group A streptococcus, Streptococcus pyogenes, beta haemolytic Streptococcus
and puerperium.The search was limited to humans and the English language.The National Library for Health
and the National Guidelines Clearing House were also searched for relevant guidelines and reviews. Studies
relevant to the scope of the guideline were selected by the members of the guideline development group.
Where possible, recommendations are based on available evidence. Areas lacking evidence are highlighted
and annotated as good practice points (tick).
2 of 21
4.
Who is at increased risk of sepsis in the puerperium?
Multiple risk factors for maternal sepsis have been identified by CMACE (Table 1).1,2 Many of those who died
in the UK CMACE survey 20052008 had one or more risk factors.
Table 1. Risk factors for maternal sepsis as identified by the Confidential Enquiries into Maternal Deaths1,2
Obesity
Impaired glucose tolerance / diabetes
Impaired immunity / immunosuppressant medication
Anaemia
Vaginal discharge
History of pelvic infection
Amniocentesis and other invasive procedures
Cervical cerclage
Prolonged spontaneous rupture of membranes
Vaginal trauma, caesarean section, wound haematoma
Retained products of conception
GAS infection in close contacts / family members
Black or minority ethnic group origin
Another recognised risk factor for sepsis in the puerperium is acquisition or carriage of invasive organisms,
especially GAS.1,2,4,5
5.
What are the common organisms causing sepsis in the puerperium, including hospitalacquired infection?
The major pathogens causing sepsis in the puerperium are:

GAS, also known as Streptococcus pyogenes
Escherichia coli
Staphylococcus aureus
Streptococcus pneumoniae
meticillin-resistant S. aureus (MRSA), Clostridium septicum and Morganella morganii.
GAS is increasingly causing invasive infections worldwide and was directly responsible for 13 of the 29 maternal
deaths from infection in the UK during 20062008.1
Since the 20032005 survey,2 MRSA carriage and infection has increased worldwide, with rates of 2.1%
reported in mothers in the puerperium in the USA.6 The CMACE report identified one maternal death from
PantonValentine leukocidin (PVL)-producing MRSA following caesarean section.1
Gram-negative bacteria that produce extended-spectrum beta-lactamases (ESBL) are an increasingly common
cause of co-amoxiclav- and cephalosporin-resistant urinary tract infections and caused one of the maternal
deaths in the CMACE report.1 Since 2003, the UK incidence of ESBL-producing bacteria has increased to more
than 12% of coliform bacteria.This may have implications for use of cephalosporins for infections in penicillinallergic women. Clostridium spp. remain uncommon causes of death from sepsis in the puerperium, with one
case of C. septicum reported post-termination of pregnancy.1
6.
What are the likely causes of sepsis outside the genital tract and how might they be identified?
A general history and examination should be carried out to try and identify the source of sepsis.
Women should be assessed clinically and, if unwell or with dehydration or vomiting, admission should
be considered.
3 of 21
Mastitis, urinary tract infection, pneumonia, skin and soft-tissue infection, gastroenteritis and pharyngitis are
likely causes of sepsis other than the genital tract. Rarer causes include bacterial meningitis.
6.1 Mastitis
Mastitis is easily overlooked clinically, but may lead to breast abscesses,710 necrotising fasciitis1,10 and toxic
shock syndrome.1,10 During 20052008, two women died of mastitis-related sepsis, one with necrotising
mastitis attributable to GAS and the other with S.aureus.1 Outbreaks of PVL-producing MRSA in neonatal units
have been associated with maternal carriage and vertical transmission during breastfeeding.11,12 Immediate
referral to hospital is indicated if the woman with mastitis is clinically unwell, if there is no response to oral
antibiotics within 48 hours, if mastitis recurs or if there are very severe or unusual symptoms.1
6.2 Urinary tract infection

Gram-negative bacterial infections are particularly associated with the urinary tract. Acute pyelonephritis
should be treated aggressively. Although not all women may warrant hospital admission, those with signs of
sepsis, those who are unable to remain hydrated and those who are vomiting should be admitted.13,14 The ESBLproducing coliforms are resistant to commonly used antimicrobials such as cephalosporins and co-amoxiclav
and may necessitate usage of carbapenems or more unusual intravenous antimicrobials such as colistin.
Identification of urinary sepsis is primarily clinical but the presence of leucocytes, protein and blood in a midstream specimen of urine may be suggestive of current infection and a specimen should be sent for culture.
6.3 Pneumonia
Severe pneumonia should be managed in consultation with a respiratory physician and a medical
microbiologist. A beta-lactam antibiotic together with a macrolide antibiotic is used to cover typical and
atypical organisms.15 Haemoptysis may be a feature of pneumococcal pneumonia. Severe haemoptysis and
low peripheral white cell count suggest PVL-associated staphylococcal necrotising pneumonia, which has a
mortality rate of more than 70% in young, fit people.16
Identification of the cause of pneumonia is by submitting a sample of sputum to the laboratory for culture. In
some hospitals a urinary sample may be tested for pneumococcal antigen when sputum is not easily available.
6.4 Skin and soft-tissue infection

Any woman with suspected bacterial sepsis should be carefully examined for skin and soft-tissue infection,
particularly looking at intravenous cannulae or injection sites and caesarean or episiotomy wounds. Swabs
should be taken of any discharge. If drains, vascular access devices or other indwelling devices are suspected
as the source of infection, they should be removed as soon as is practicable. The location of intravenous
cannula sites should be recorded and inspected twice daily. Skin and soft-tissue infections are particularly
associated with toxic shock syndromes.5,10,1720 Recurrent abscess formation, including labial abscesses, is a
feature of PVL-producing staphylococci.21
Septicaemic seeding of streptococci from a uterine focus may give rise to a secondary focus in a limb,
simulating a venous thrombosis.1,20 Early necrotising fasciitis occurs deep in the tissues; therefore, in early
necrotising fasciitis there may be no visible skin changes. As the necrotising process ascends to the skin, late
infection produces blisters and obvious necrosis. The cardinal feature of necrotising fasciitis is of agonising
pain, typically necessitating increasing amounts of strong analgesia culminating in use of opiates.20
Women with suspected thrombosis who are systemically unwell with any features of sepsis should be
examined very carefully. Presence of shock or other organ dysfunction mandates rapid referral to critical care.
4 of 21
6.5 Gastroenteritis
Salmonella and Campylobacter rarely cause severe systemic infection and should be managed
symptomatically unless features of bacteraemia are present. Diarrhoea and vomiting may be features of toxic
shock syndrome4,5,10,1719 together with features of profound sepsis. C. difficile is rare but increasingly found in
obstetric patients.22
6.6 Pharyngitis
Most cases of pharyngitis are viral, but approximately 10% of cases in adults are attributable to GAS. If three
of the four Centor criteria23 (fever, tonsillar exudate, no cough, tender anterior cervical lymphadenopathy) are
present, treatment with an antibiotic is appropriate.
6.7 Infection related to regional anaesthesia

Spinal abscess is a very rare complication after regional anaesthesia in obstetric patients.24,25 The usual
organism responsible is S. aureus, with streptococci, Gram-negative rods and sterile specimens accounting for
15% each.25 It is vital to consider the diagnosis, investigate and treat in a timely manner as permanent spinal
cord or cauda equina damage may result if neural compression is prolonged.
7.
What should prompt recognition of sepsis in the puerperium?
All health professionals should be aware of the symptoms and signs of maternal sepsis and critical
illness and of the rapid, potentially lethal course of severe sepsis and septic shock. Suspicion of
significant sepsis should trigger urgent referral to secondary care.
Clinical signs suggestive of sepsis include one or more of the following: pyrexia, hypothermia,
tachycardia, tachypnoea, hypoxia, hypotension, oliguria, impaired consciousness and failure to respond
to treatment. These signs, including pyrexia, may not always be present and are not necessarily related
to the severity of sepsis.
Mastitis must never be overlooked.
Abdominal pain, fever (greater than 38C) and tachycardia (greater than 90 beats/minute in the
puerperium) are indications for intravenous antibiotics and senior clinical review.
Non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided for pain relief in cases of sepsis as
they impede the ability of polymorphs to fight GAS infection.
Sepsis should be considered in all recently delivered women who feel unwell and have pyrexia or hypothermia.1
The common symptoms of sepsis in the puerperium include fever, diarrhoea, vomiting, abdominal
pain, generalised maculopapular rash (staphylococcal or streptococcal sepsis), offensive vaginal
discharge and signs of infection in caesarean wounds.1,2 Evidence level 3
Evidence
level 3
Agonising pain out of proportion to the clinical signs suggests a deep infection, and necrotising
fasciitis/myositis must be considered.9,17,18,20
Table 2 details common symptoms of sepsis in the puerperium.
A pain scoring system is useful in charting progress. Since NSAIDs significantly impede the ability of
polymorphs to fight infection caused by GAS, they should be avoided for pain relief in cases of sepsis.20,26
5 of 21
Table 2. Common symptoms of sepsis in the puerperium1,2

Fever, rigors (persistent spiking temperature suggests abscess). Beware: normal temperature may be attributable to antipyretics or NSAIDs
Diarrhoea or vomiting may indicate exotoxin production (early toxic shock)
Breast engorgement / redness
Rash (generalised maculopapular rash)
Abdominal / pelvic pain and tenderness
Wound infection spreading cellulitis or discharge
Offensive vaginal discharge (smelly: suggestive of anaerobes; serosanguinous: suggestive of streptococcal infection)
Productive cough
Urinary symptoms
Delay in uterine involution, heavy lochia
General non-specific signs such as lethargy, reduced appetite.
Some cases of sepsis in the puerperium may present initially only with severe abdominal pain, in the absence
of fever and tachycardia.18,19
Any widespread rash should suggest early toxic shock syndrome, especially if conjunctival hyperaemia or
suffusion is present.5,9,1719 A generalised macular rash is present in most cases of staphylococcal toxic shock
syndrome but in only 10% of cases of streptococcal toxic shock syndrome. Conjunctival suffusion is a classic
sign of toxic shock syndrome.9,18,26 See Appendix 1 for a definition and classification of toxic shock syndrome.
8.
What is the optimum way to monitor women with suspected sepsis in the puerperium?
Monitoring of the woman with suspected severe sepsis or established sepsis should be
multidisciplinary but preferably under the leadership of a single consultant. A senior obstetrician
should be involved, in consultation with an intensivist, microbiologist or infectious disease clinician.
Regular observations of all vital signs (including temperature, pulse rate, blood pressure and
respiratory rate) should be recorded on a modified early obstetric warning score (MEOWS) chart.
P
P
While MEOWS charts have become widespread since the recommendations of the CEMACH 2 report,
unfortunately there is no standardisation. (An example from the Obstetric AnaesthetistsAssociation is available.27)
Swanton et al. have developed a MEOWS chart taking into account the variations in charts used by individual
hospitals.28 Abnormal scores should not just be recorded but should also trigger an appropriate response.1
All women who are unwell during the puerperium require regular and frequent observation. Handover
arrangements should be robust. Regular contact with family members is required.
9.
What infectious disease history/information should be noted?
Any recent illness or exposure to illness in close contacts, particularly streptococcal infections, should
be noted.
A history of recent sore throat or prolonged (household) contact with family members with known
streptococcal infections (pharyngitis, impetigo, cellulitis) has been implicated in cases of GAS sepsis.1,17,18 In
the CMACE report, five of six women with GAS admitted to hospital with septic shock had a history of recent
sore throat or respiratory infection.1
Intravenous drug misuse carries a high risk of staphylococcal and streptococcal sepsis as well as generalised
immunosuppression of chronic disease, endocarditis and blood-borne viruses.1
6 of 21
Recent febrile illnesses, especially if associated with chills and rigors, suggest bacteraemia.
Gastrointestinal symptoms such as diarrhoea and vomiting may be attributable to food-borne pathogens, C.
difficile infection or early toxic shock.10,19,20
Prior carriage of or infection with multiresistant organisms such as ESBL-producing Gram-negative bacteria,
vancomycin-resistant enterococci and MRSA should be noted on admission as empirical antimicrobial choice
will be affected in the event of sepsis. Appropriate infection control precautions may need to be instituted.
Any inter-current illness warranting antimicrobials should be noted on admission.
Ingestion of unpasteurised milk products raises the possibility of infection with Salmonella, Campylobacter
or Listeria. Chlamydophila psittaci is acquired by contact with aborting sheep or infected birds or by crossinfection from washing contaminated clothing. Q fever is caused by Coxiella burnetii after inhalation of
infectious particles from birthing animals or contaminated dust.
Recent foreign travel or hospitalisation abroad is associated with a high carriage rate of multiresistant
organisms and hence should prompt discussions with a microbiologist to ensure isolation procedures and
diagnostic tests are appropriate.
10. What are the appropriate triggers or features of sepsis in the puerperium that should
prompt hospital admission?
Community carers should be aware of the importance of early referral to hospital of recently delivered
women who feel unwell and have pyrexia, and should be aware of the possibility of sepsis in the
puerperium (see Table 2).
If sepsis is suspected in the community, urgent referral to hospital is indicated.
Red flag signs and symptoms (see below) should prompt urgent referral for hospital assessment and, if the
woman appears seriously unwell, by emergency ambulance:
pyrexia more than 38C
sustained tachycardia more than 90 beats/minute
breathlessness (respiratory rate more than 20 breaths/minute; a serious symptom)
abdominal or chest pain
diarrhoea and/or vomiting
uterine or renal angle pain and tenderness
woman is generally unwell or seems unduly anxious or distressed.1

Early presentation of sepsis (less than 12 hours post-birth) is more likely to be caused by streptococcal
infection, particularly GAS, and severe continuous pain suggests necrotising fasciitis.1,10,20
Infection must also be suspected and actively ruled out when a recently delivered woman has persistent
vaginal bleeding and abdominal pain. If there is any concern, the woman must be referred back to the
maternity unit as soon as possible.1
The speed of onset or deterioration in symptoms and signs is important. Early treatment with antibiotics,
whether oral or parenteral, may be crucial in determining the outcome. Abdominal pain, fever (greater than
38C) and tachycardia (greater than 90 beats/minute) are indications for admission for intravenous antibiotics.1
In hospital, high-dose intravenous broad-spectrum antibiotics should be started immediately, without waiting
for the results of investigations, because once infection becomes systemic the womans condition can
deteriorate extremely rapidly, with death ensuing within a few hours if untreated.1
7 of 21
11.
What are the appropriate triggers for involvement of other specialties?
All cases of sepsis in the puerperium should be discussed with a clinical microbiologist or infectious
diseases physician. Appropriate specimens should be sent for urgent examination. Antimicrobials
should be started within 1 hour of recognition of severe sepsis.
Women with previously documented carriage of or infection with multiresistant organisms (e.g. ESBLproducing organisms, MRSA, GAS or PVL-producing staphylococci) should prompt notification of the
infection control team.
Suspicion of necrotising fasciitis should prompt involvement of intensive care physicians and referral for
surgical opinion, ideally from plastic and reconstructive surgeons if available.22
It is important that the expertise of other specialist teams is sought early in cases of suspected sepsis in the
puerperium. There may be a need to consider infections less commonly seen, and appropriate advice needs
to be sought as early as possible to expedite the appropriate investigations or management.
12. What investigations should be performed?

Blood cultures are the key investigation and should be obtained prior to antibiotic administration;
however, antibiotic treatment should be started without waiting for microbiology results.
Serum lactate should be measured within 6 hours of the suspicion of severe sepsis to guide
management. Serum lactate 4 mmol/l is indicative of tissue hypoperfusion.
Any relevant imaging studies should be performed promptly in an attempt to confirm the source of
infection. This could include a chest X-ray, pelvic ultrasound scan or computed tomography scan if pelvic
abscess is suspected.
Other samples taken should be guided by the clinical suspicion of focus of infection as appropriate.
Routine blood tests should include full blood count, urea, electrolytes and C-reactive protein (CRP).
Any woman with symptoms of tonsillitis/pharyngitis should have a throat swab sent for culture.
If the MRSA status of the woman is unknown, a premoistened nose swab may be sent for rapid MRSA
screening where such testing is available.
Blood cultures and other samples taken should be guided by clinical suspicion of focus of infection, such as
throat swabs, mid-stream urine, high vaginal swab, throat swab, placental swabs, sputum, cerebrospinal fluid,
epidural site swab, caesarean section or episiotomy site wound swabs and expressed breast milk, and should
ideally be obtained prior to starting antibiotic therapy as the results may become uninformative within a few
hours of commencing antibiotics. Antibiotics should be given as soon as possible. Results of laboratory tests
should be checked and recorded regularly and the medical microbiologist consulted to ensure specimens are
processed appropriately and results communicated directly to the clinician at the earliest opportunity. Gram
stain, culture results and sensitivities should be used to tailor antimicrobial therapy.
If diarrhoea is particularly offensive following antimicrobial therapy, a stool sample should be submitted for
C. difficile toxin testing.22 A history of diarrhoea warrants routine culture (e.g. Salmonella, Campylobacter).
The laboratory should be informed if there is a clinical indication for investigations for unusual pathogens
such as Listeria monocytogenes (consumption of soft cheese or cured meats) or if there is a history of foreign
travel (parasites, typhoid or cholera).
8 of 21
Bacterial numbers may be scanty or not seen on initial Gram staining of swabs, fluids or debrided tissue.
However, organisms seen on Gram staining will guide empirical prescribing. A paucity of leucocytes and the
presence of Gram-positive cocci in chains indicate streptococcal infection. Mixed organisms (i.e. mixed
Gram- negative and -positive organisms) would suggest the possibility of gut organisms, including anaerobes,
as part of a synergistic infection.
Diagnostic criteria for sepsis are available in Appendix 2 (in the absence of specific criteria for women in the
puerperium).
Thrombocytosis (high platelet count) with a rising CRP and a swinging pyrexia usually indicates a collection
of pus or an infected haematoma in the woman.
Table 3 indicates tasks which should be performed within the first 6 hours of the identification of severe sepsis.
Table 3. Tasks to be performed within the first 6 hours of the identification of severe sepsis; modified from
the Surviving Sepsis Campaign Resuscitation Bundles3
Obtain blood cultures prior to antibiotic administration
Administer broad-spectrum antibiotic within 1 hour of recognition of severe sepsis
Measure serum lactate
In the event of hypotension and/or a serum lactate greater than 4 mmol/l:
Deliver an initial minimum 20 ml/kg of crystalloid or an equivalent
Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure above 65 mmHg
In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or serum lactate greater than 4 mmol/l:
Achieve a central venous pressure of 8 mmHg
Achieve a central venous oxygen saturation 70% or mixed venous oxygen saturation 65%
13. How should sepsis in the puerperium be managed?

The focus of infection should be sought and dealt with. This may be by uterine evacuation or by drainage
of a breast, wound or pelvic abscess. Broad-spectrum antibiotics should be given to cover these procedures.
13.1 Which antibiotics should be used?

Administration of intravenous broad-spectrum antibiotics within 1 hour of suspicion of severe sepsis,
with or without septic shock, is recommended as part of the Surviving Sepsis resuscitation care bundle.
If genital tract sepsis is suspected, prompt early treatment with a combination of high-dose broadspectrum intravenous antibiotics may be life saving.
A combination of either piperacillin/tazobactam or a carbapenem plus clindamycin provides one of the

broadest ranges of treatment for severe sepsis.
MRSA may be resistant to clindamycin, hence if the woman is or is highly likely to be MRSA-positive, a
glycopeptide such as vancomycin or teicoplanin may be added until sensitivity is known.
Breastfeeding limits the use of some antimicrobials, hence the advice of a consultant microbiologist
should be sought at an early stage.
Antibiotic therapy should be guided by the Gram stain of any aspirate or biopsy; however, in
practice the patient is usually so sick there is no time to wait, hence initial empirical prescribing of
broad-spectrum antibiotics is essential. Intravenous broad-spectrum antibiotics should be given
within 1 hour of suspicion of severe sepsis.3
9 of 21
Evidence
level 4
Clindamycin is not nephrotoxic and switches off the production of superantigens and other
exotoxins.18,20,29 Therefore, together with either piperacillin/tazobactam or a carbapenem,
clindamycin provides broad cover in severe sepsis.
The 20032005 CEMACH report2 referred to the use of cefuroxime and metronidazole for sepsis in
the puerperium. However, cefuroxime is no longer part of many hospital formularies because of
the association with C. difficile. Neither agent provides any protection against MRSA, Pseudomonas
or ESBL (see Appendix 3).
Evidence
level 4
In ESBL infection, piperacillin/tazobactam is likely to be ineffective.

Information on antimicrobials which may aid in guiding choice is given in Table 4, but hospital guidelines
differ and local guidance should be followed since the incidence of resistant organisms varies throughout the
UK.The decision as to which antimicrobials to include in the hospital formulary and maternity unit guidelines
for severe sepsis in the puerperium should be agreed by clinicians and the hospital microbiologist.
National guidelines for the management of community-acquired pneumonia,30 PVL-producing
S. aureus31 and MRSA-associated infections32,33 should be consulted where necessary.
Evidence
level 4
Table 4. Antimicrobial choices and limitations of antimicrobials

Antimicrobial
Limitations
Co-amoxiclav
Does not cover MRSA, Pseudomonas or ESBL-producing organisms
Metronidazole
Only covers anaerobes
Clindamycin
Covers most streptococci and staphylococci, including many MRSA, and switches off exotoxin
production with significantly decreased mortality18,29,34
Not renally excreted or nephrotoxic
Piperacillin/tazobactam and carbapenems
Covers most organisms except MRSA and are renal sparing (in contrast to aminoglycosides)
Piperacillin/tazobactam does not cover ESBL producers
Gentamicin (as a single dose of 35 mg/kg)
Poses no problem in normal renal function but if doses are to be given regularly serum levels
must be monitored35
13.2 What are some of the adverse effects of treatment?

Treatment with any antimicrobial can cause allergic reactions, including skin rashes. However, it should be
remembered that, particularly in toxic shock, a maculopapular or blanching erythema may be exotoxin related
and not an allergy to the therapy.
Diarrhoea, particularly if offensive or developing after any antimicrobial therapy, should be sent for C. difficile
toxin testing. The organism does not infect neonates but can cause up to 30% mortality in mothers if
untreated.22 Pending the result of testing, oral metronidazole or oral vancomycin are used empirically where
clinically justified.
13.3 What is the role of intravenous immunoglobulin (IVIG)?

IVIG is recommended for severe invasive streptococcal or staphylococcal infection if other therapies
have failed.
IVIG has an immunodulatory effect and in staphylococcal and streptococcal sepsis also neutralises the superantigen effect of exotoxins and inhibits production of tumour necrosis factor and interleukins.
10 of 21
High-dose IVIG has been used in pregnant and postpartum women3639 and is effective in exotoxic
shock (i.e. toxic shock attributable to streptococci and staphylococci),4044 but there is little
evidence of benefit in Gram-negative (endotoxin-related) sepsis.The main contraindication to IVIG
use is a congenital deficiency of immunoglobulin A.46
Evidence
level 3
There are now many case reports3643 and some small series44,46 where dramatic improvement
resulted after administration of IVIG.
IVIG is available from the blood transfusion department. All commercial brands of IVIG available in
the UK contain antibodies to streptococcal and staphylococcal exotoxins. Actual administration of
IVIG should be through a blood warming device and hospital guidelines/protocols for replacement
therapy in haematology patients may be used. However, when faster replacement is necessary in
severely ill patients, the Mount Sinai hospital protocol may be helpful.47
Evidence
level 4
13.4 Where should women with sepsis be cared for?

Women with sepsis in the puerperium are best managed in a hospital where diagnostic services are
easy to access and intensive care facilities are readily available.
Early referral to hospital may be life saving.
Sepsis in the puerperium may have an insidious onset but then a fulminating course. Early discharge from the
delivery unit means that some women will develop infection after they return home, or they may have given
birth at home.
The CEMACH 20022005 report noted that some women who died were managed in units ill equipped to
deal with them.2
13.5 What are the indications for admission to the intensive care unit (ICU)?
The presence of shock or other organ dysfunction in the woman is an indication for admission to the ICU.
The diagnosis of sepsis should trigger discussion with the critical care team. Features of severe sepsis which
are likely to require admission to the ICU are shown in Table 5.
Table 5. Indications for admission of the woman to the ICU;3 adapted from Plaat and Wray, 200848
System
Indication
Cardiovascular
Hypotension or raised serum lactate persisting despite fluid resuscitation suggesting the need for inotrope support
Respiratory
Pulmonary oedema
Mechanical ventilation
Airway protection
Renal
Renal dialysis
Neurological
Significantly decreased conscious level
Miscellaneous
Multiorgan failure
Uncorrected acidosis
Hypothermia
The treatment of hypotension and oliguria in non-pregnant septic patients involves aggressive fluid
replacement. However, postpartum women may be more susceptible to the development of pulmonary
oedema than non-pregnant patients after circulatory fluid overload. Achieving the correct balance between
these potentially conflicting aims is exceedingly difficult, and central venous pressure monitoring and
11 of 21
vasopressor treatment are likely to be required on the ICU. It is important to involve the anaesthetic and
critical care teams early to advise on early management and subsequent transfer.
13.6 How should a drug-misusing woman be managed?

Women with a history of substance misuse are usually monitored under multiagency care. The local
drugs advisory specialist team and existing hospital guidelines for care of substance misusers /drug
users should be consulted.
Any injection-site lesions should be swabbed and an MRSA screen performed.
A history of intravenous drug use and features of sepsis of unknown site requires a search for bacterial
endocarditis or abscesses spread via the bloodstream. Current or former intravenous drug users usually have
very difficult vascular access. Alternative access devices such as a central venous catheter or peripherally
inserted central catheter are more likely to be required for long-term intravenous antibiotic treatment, and
early referral of the woman to a vascular access team or equivalent is desirable.
Effects on breastfeeding and other practical management issues necessitate the involvement of neonatologists
and the local specialist drugs team.
14. What are the infection control issues?

The woman should be isolated in a single room with en suite facilities to reduce the risk of transmission
of infection.
Healthcare workers (defined as doctors, midwives, nurses, anaesthetists and members of the wound
care team) should wear personal protective equipment including disposable gloves and aprons when in
contact with the woman, equipment and their immediate surroundings.
Breaks in the skin of the woman or carer must be covered with a waterproof dressing.
Fluid-repellent surgical masks with visors must be used at operative debridement /change of dressings
of GAS necrotising fasciitis and for other procedures where droplet spread is possible.
Visitors should be offered suitable information and relevant personal protective equipment while the
woman is isolated.
Mothers or neonates infected or colonised with high-risk organisms such as GAS, MRSA or PVL-producing
staphylococci may generate outbreaks within the healthcare setting, especially for other babies in nursery units
and staff.4951 The local infection control team should be informed of any such cases and appropriate isolation
precautions followed. Healthcare workers should wear personal protective equipment including disposable
gloves and aprons when in contact with the woman, equipment and their immediate surroundings.49,52
Isolation in a single room with en suite facilities is recommended since numerous streptococcal outbreaks
have occurred in maternity units, some involving shared toilet and shower facilities.51
MRSA and GAS are easily transmitted via the hands of healthcare workers and via close contact in
households.49 Local infection control guidelines should be followed for hospital-specific isolation and contact
precautions. PVL-associated infections should be managed in accordance with national guidelines.32,52
Non-maternity isolations of GAS for example, when known about before the patient is admitted, or diagnosed
in a healthcare worker should be reported to the infection control team/director of infection prevention and
12 of 21
control/occupational health, as appropriate. Strict infection control precautions should be applied, both to
delivery procedures and during the hospital stay.49,52
15. What are the neonatal issues if sepsis develops in the puerperium?
The baby is especially at risk of streptococcal and staphylococcal infection during birth and during
breastfeeding. The umbilical area should be examined and a paediatrician consulted in the event of
sepsis in the puerperium.
If either the mother or the baby is infected with invasive GAS in the postpartum period, both should be
treated with antibiotics.
GAS and PVL-producing S. aureus infections have been transmitted to babies during breastfeeding,
causing severe infection.11 GAS poses the highest risk of sepsis in the neonate, with numerous cases
where both mother and baby have been affected.49 Hence, antimicrobial prophylaxis should be
given routinely to neonates of mothers with GAS infection.52
Evidence
level 4
The infant of a mother colonised with Group B Streptococci should be managed as per RCOG
Green-top Guideline No.36: Prevention of early onset neonatal group B streptococcal disease.53
16. What are the indications for prophylaxis to family/staff?

Close household contacts should be warned about the symptoms of GAS infection and told to seek
medical attention should symptoms develop. Asymptomatic contacts may warrant prophylaxis.
Local and national guidelines should be followed in consultation with the local health protection unit or
consultant for communicable disease control.
Only the meningococcus (Neisseria meningitidis) and GAS merit consideration of prophylaxis for family or staff.
MRSA and PVL-producing S. aureus are transmitted during breastfeeding and close contact. Although routine
prophylaxis is not indicated, the neonate should be observed closely and liaison with the infection control
team is advised.
The Health Protection Agency has produced detailed guidelines for investigation, control and
prevention of spread of GAS infection in healthcare settings in the UK.52 Generally, prophylaxis for
GAS organisms would be administered in the event of close contact (kissing or household contacts)
and for healthcare workers with exposure to respiratory secretions (e.g. suctioning).49
Evidence
level 4
17. Can sepsis in the puerperium be prevented or detected earlier?

All pregnant and recently delivered women should be informed of the signs and symptoms of genital
tract infection and how to prevent its transmission.
Any GAS identified during pregnancy should be treated aggressively.
All pregnant and recently delivered women need to be informed of the signs and symptoms of genital tract
infection and how to prevent its transmission. Advice to all women should include verbal and written
information about its prevention, signs and symptoms and the need to seek advice early if concerned, as well
as the importance of good personal hygiene. This includes avoiding contamination of the perineum by
washing hands before and after using the lavatory or changing sanitary towels. It is especially necessary when
the woman or her family or close contacts have a sore throat or upper respiratory tract infection. 1
13 of 21
All clinical staff must undertake regular, written, documented and audited training for the identification and
initial management of serious obstetric conditions or emerging potential emergencies, such as sepsis, which
need to be distinguished from commonplace symptoms in pregnancy.1
Any GAS identified during pregnancy should be treated aggressively. Several cases of women with known GAS
infection have been reported where GAS was not treated, resulting in maternal death.1
Any signs of infection or necessity to administer antibiotics noted during a womans hospital stay should be
reported directly to her community carers (GP, midwives and health visitors) when she is discharged so that
appropriate follow-up visits may be arranged and the significance of developing symptoms recognised.
Number of women admitted to hospital within 6 weeks of delivery for sepsis.

Number of postpartum women admitted to the ICU with sepsis as the primary diagnosis.
Rate of hospital-acquired infection in the maternity unit.
Rate of wound infection after caesarean section.
Number of women with specific infections: MRSA, GAS, Clostridia sepsis.
Percentage of women who had antibiotic therapy started within 1 hour of recognition of bacterial sepsis
after pregnancy. Target: 100% within 1 hour.1
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randomized, double-blind, placebo-controlled trial. Clin Infect
Dis 2003;37:33340.
47. McGeer A. Recommendations for investigation and
chemophrophylaxis related to invasive gas cases, including
streptococcal toxic shock and necrotizing fasciitis
[http://microbiology.mtsinai.on.ca/protocols/pdf/k5a.pdf].
48. Plaat F, Wray S. Role of the anaesthetist in obstetric critical
care. Best Pract Res Clin Obstet Gynaecol 2008;22:91735.
49. Steer JA, Lamagni T, Healy B, Morgan M, Dryden M, Rao B, et al.
Guidelines for prevention and control of group A
streptococcal infection in acute healthcare and maternity
settings in the UK. J Infect 2012;64:118.
50. Greenberg D, Leibovitz E, Shinnwell ES,Yagupsky P, Dagan R.
Neonatal sepsis caused by Streptococcus pyogenes: resurgence
of an old etiology? Ped Infect Dis J 1999;18:47981.
51. Claesson BE, Claesson UL. An outbreak of endometritis in a
maternity unit caused by spread of group A streptococci from
a showerhead. J Hosp Inf 1985;6:30411.
52. Health Protection Agency, Group A Streptococcus Working
Group. Interim UK guidelines for management of close
community contacts of invasive group A streptococcal disease.
Comm Dis Publ Health 2004;4:35461.
of Early Onset Neonatal Group B Streptococcal Disease. Greentop Guideline No. 36. London: RCOG; 2003 [http://www.rcog.
org.uk/womens-health/clinical-guidance/prevention-early-onsetneonatal-group-b-streptococcal-disease-green-].
54. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et
al.; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/
ATS/SIS International Sepsis Definitions Conference. Crit Care
Med 2003;31:12506.
15 of 21
APPENDIX 1
Staphylococcal and streptococcal toxic shock syndrome: clinical disease definition.
Staphylococcal toxic shock syndrome (TSS)17
Streptococcal toxic shock syndrome (STSS)17,26
1. Fever > /= 39.9C
A. Isolation of group A Streptococcus from:
2. Rash: diffuse macular erythema
1. normally sterile site: blood, cerebrospinal fluid, peritoneal fluid,

tissue biopsy
3. Desquamation: 1014 days after onset of illness,
2. non-sterile site: throat, vagina, sputum
especially palms and soles

4. Hypotension: systolic BP < 90 mmHg (adults)
5. Multisystem involvement: Three or more of the following
B. Clinical case definition
systems affected:
Multi-organ involvement characterised by:
gastrointestinal: vomiting or diarrhoea at onset of illness
1. hypotension
muscular: severe myalgia or elevated creatinine phosphokinase
plus
mucous membranes: vaginal, oropharyngeal or conjunctival
2. two or more of the following:
hyperaemia
renal impairment creatinine >176mol/l
renal: creatinine twice the upper limit of normal
coagulopathy platelets < 100 x 109/l or disseminated intravascular
hepatic: total bilirubin twice the upper limit of normal

109/l
haematological platelets /= 100 x
central nervous system disorientation or alterations in

consciousness without focal neurological signs
coagulation
liver involvement: alanine transaminase or aspartame transaminase

or bilirubin levels twice the normal upper limit for age
acute respiratory distress syndrome
generalised erythematous macular rash (present in 10%):

may desquamate
soft tissue necrosis including necrotising fasciitis, myositis or

gangrene
Probable: 4 of the 5 clinical findings positive
Probable: meets clinical case definition (above) plus isolation from

non-sterile site
Confirmed: case with all 5 clinical findings
Definite: meets clinical case definition (above) plus isolation of group

A Streptococcus from a normally sterile site
16 of 21
APPENDIX 2
Diagnostic criteria for sepsis modified from Levy et al.,54 using CMACE1 and Lewis2 where pregnancy-specific
parameters available.
Infection, documented or suspected, and some of the following:
General variables:
Fever (> 38C)
Hypothermia (core temperature < 36C)
Tachycardia (> 90 beats/minute)
Tachypnoea (> 20 breaths/minute)
Impaired mental state, altered conscious level
Considerable oedema or positive fluid balance (> 20ml/kg over 24 hours)
Hyperglycaemia in the absence of diabetes (plasma glucose > 7.7 mmol/l)
Bruising or discoloration of skin suggests late fasciitis (often pain receding as cutaneous anaesthesia supervenes as nerves die)
Inflammatory variables:
White blood cell (WBC) count > 12 x 109l
Leucopenia (WBC count < 4 x 109l)
Normal WBC count with > 10% immature forms
Plasma C-reactive protein > 7mg/l (usually significantly higher in bacterial sepsis)
Haemodynamic variables:
Arterial hypotension (systolic blood pressure < 90mmHg; mean arterial pressure < 70mmHg; or systolic blood pressure decrease > 40mmHg)
Tissue perfusion variables:
Raised serum lactate 4 mmol/l
Decreased capillary refill or mottling
Organ dysfunction variables:
Arterial hypoxaemia (PaO2 (partial pressure of oxygen in arterial blood) /F IO2 (fraction of inspired oxygen) < 40kPa); sepsis is severe if
< 33.3kPa in the absence of pneumonia or < 26.7kPa in the presence of pneumonia
Oliguria (urine output < 0.5ml/kg/hr for at least two hours, despite adequate fluid resuscitation)
Creatinine rise of > 44.2mol/l; sepsis is severe if creatinine level > 176mol/l
Coagulation abnormalities (International Normalised Ratio [INR] > 1.5 or activated partial thromboplastin time [APTT] > 60 seconds)
Thrombocytopaenia (platelet count < 100 x109/l)
Hyperbilirubinaemia (plasma total bilirubin > 70mol/l)
Ileus (absent bowel sounds)
17 of 21
APPENDIX 3
Suggested empirical antimicrobials for use in bacterial sepsis after pregnancy.
Condition
Organisms
Antimicrobial
If allergic
Notes
Mastitis
MSSA
Streptococci
Flucloxacillin +
clindamycin
Vancomycin +
clindamycin
Trough level
vancomycin 520 mg/l
necessary
Mastitis
MRSA
Streptococci
Vancomycin +
clindamycin
Clindamycin/teicoplanin
are alternatives
Caesarean section
MRSA
Vancomycin +
Clindamycin/teicoplanin
wound infection or
intravenous cannula
site infection
Streptococci
clindamycin
are alternatives
Caesarean section
wound infection or
intravenous cannula
site infection
MSSA
Streptococci
Flucloxacillin +
clindamycin
Vancomycin +
clindamycin
Endometritis
Gram-negative anaerobes
Streptococci
Gentamicin one
dose immediately +
cefotaxime
+ metronidazole
Gentamicin +
clindamycin +
ciprofloxacin
Acute pyelonephritis
Gram-negative bacteria
Cefotaxime +
gentamicin (gentamicin
administered
once only)
Gentamicin +
ciprofloxacin
ESBLs:
gentamicin +
meropenem
Flucloxacillin +
clindamycin +
gentamicin
Vancomycin +
clindamycin +
immediately gentamicin
Regimen must contain an

antitoxin agent such as
clindamycin28 or linezolid
Consider IVIG44
Occasionally
staphylococci and
streptococci
Toxic shock syndrome
Staphylococci
Streptococci
(gentamicin
(gentamicin
administered
once only )
administered
once only)
For MRSA use

vancomycin instead
of flucloxacillin
or
Linezolid + gentamicin
(gentamicin
administered
once only)
Severe sepsis, no focus
MRSA, streptococci,
Gram-negatives
(including ESBL
producers +
Pseudomonas)
and anaerobes
Meropenem +
clindamycin +
gentamicin
(gentamicin usually
administered
once only)
Clindamycin +
gentamicin +
metronidazole +
ciprofloxacin
In those with severe

penicillin allergy,
carbapenems are
contraindicated
ESBL = extended-spectrum beta-lactamase; IVIG = intravenous immunoglobulin; MRSA = meticillin-resistant Staphylococcus aureus;
MSSA = meticillin-sensitive Staphylococcus aureus.
Note: these are suggestions, and local guidelines should be consulted since policies and sensitivities differ between hospitals.
All complex cases or unusual allergies should be discussed with a microbiologist and therapy should be rationalised as soon as possible.
18 of 21
APPENDIX 4
Antibiotic spectra for obstetrics and gynaecology.
Dr Marina S Morgan, 2012

Solid lines represent roughly the proportion of the bacteria sensitive to that antibiotic.
Produced by Marina Morgan 2012.
19 of 21
APPENDIX 5

1+

low risk of bias

risk of bias

2+
2-


case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
20 of 21

development group
Dr M Morgan, Consultant Microbiologist, Royal Devon & Exeter Hospital, Exeter; Dr RG Hughes MRCOG,
Edinburgh, Scotland; and Dr SM Kinsella, Consultant Obstetric Anaesthetist, Bristol.
Mr DI Fraser MRCOG, Norwich, Norfolk; Dr MA Harper FRCOG, Belfast; Dr R Daniels, Heart of England NHS
Foundation Trust, Birmingham; Mr I Babarinsa, Gloucestershire Royal Hospital, Gloucester; Centre for Maternal and
Child Enquiries (CMACE); Health Protection Agency; Obstetric Anaesthetists Association (OAA); RCOG Consumers
Forum; Royal College of General Practitioners; Royal College of Midwives.
The Guideline Committee lead reviewers were: Mr M Griffiths FRCOG, Luton and Dr KS Langford FRCOG, London.
Conflicts of interest; none declared
DISCLAIMER
health services.
21 of 21
The Management of Women with Red

Cell Antibodies during Pregnancy
May 2014
The Management of Women with Red Cell Antibodies

during Pregnancy
Prepregnancy counselling
Women with red cell antibodies, particularly if there is a risk of fetal anaemia or if compatible donor red
cells for transfusion may be difficult to obtain, should attend for prepregnancy counselling with a
clinician with knowledge and expertise of this condition.
Red cell antibodies in pregnancy

What red cell antibodies are clinically significant (maternal and fetal) during pregnancy?
All women should have their blood group and antibody status determined at booking and at 28 weeks
of gestation (Appendix 2).
What are the implications for the fetus and neonate from red cell antibodies?
Clinicians should be aware that severe fetal anaemia can result in hydrops which significantly worsens
the perinatal outcome.
When and how should paternal and fetal genotyping be performed?

Non-invasive fetal genotyping using maternal blood is now possible for D, C, c, E, e and K antigens. This
should be performed in the first instance for the relevant antigen when maternal red cell antibodies
are present.
For other antigens, invasive testing (chorionic villus sampling [CVS] or amniocentesis) may be considered
if fetal anaemia is a concern or if invasive testing is performed for another reason (e.g. karyotyping).
Is karyotyping contraindicated in the presence of maternal red cell antibodies?

Invasive testing is not contraindicated if alloimmunisation has occurred.
Anti-D prophylaxis should be given to cover invasive testing if the mother is rhesus D (RhD) negative
and is not sensitised.
If the fetus is at risk of anaemia, when should referral to a fetal medicine specialist take place?
Referral to a fetal medicine specialist should occur when there are rising antibody levels/titres, a
level/titre above a specific threshold (see section 6.7) or ultrasound features suggestive of fetal anaemia.
Referral should take place if there is a history of unexplained severe neonatal jaundice, neonatal
anaemia requiring transfusion or exchange transfusion, in order to exclude haemolytic disease of the
fetus and newborn (HDFN) as the cause.
2 of 26
P
P
For antibodies other than anti-D, anti-c and anti-K, the following should prompt referral to a fetal medicine
specialist: a history of previous significant HDFN or intrauterine transfusion (IUT), or a titre of 32 or above,
especially if the titre is rising as rising titres correlate with increasing risk and severity of anaemia.
What thresholds should be used for the various antibodies that could cause fetal anaemia to trigger referral
for further investigation or monitoring?
An anti-D level of > 4 iu/ml but < 15 iu/ml correlates with a moderate risk of HDFN and an anti-D level
of > 15 iu/ml can cause severe HDFN. Referral for a fetal medicine opinion should therefore be made
once anti-D levels are > 4 iu/ml.
An anti-c level of > 7.5 iu/ml but < 20 iu/ml correlates with a moderate risk of HDFN, whereas an antic level of > 20 iu/ml correlates with a high risk of HDFN. Referral for a fetal medicine opinion should
therefore be made once anti-c levels are > 7.5 iu/ml.
For anti-K antibodies, referral should take place once detected, as severe fetal anaemia can occur even
with low titres.
The presence of anti-E potentiates the severity of fetal anaemia due to anti-c antibodies so that referral
at lower levels/titres is indicated (unless the fetus has only one of these antigens).
Once detected how often should antibody levels be monitored during pregnancy?
Anti-D and anti-c levels should be measured every 4 weeks up to 28 weeks of gestation and then every
2 weeks until delivery.
Although anti-K titres do not correlate well with either the development or severity of fetal anaemia,
titres should nevertheless be measured every 4 weeks up to 28 weeks of gestation, then every 2 weeks
until delivery.
For all other antibodies, retesting at 28 weeks is advised with the exception of women who have a
previous history of pregnancies affected with HDFN when early referral to a fetal medicine specialist is
also recommended.
For antibodies that could potentially cause problems with cross-matching or issues with the availability
of appropriate blood, discussion with the blood transfusion service is required regarding the frequency
of antenatal testing. This may depend on the type of antibody as well as the likelihood of requiring
blood at short notice.
P
P
How should pregnancies at risk of fetal anaemia be monitored?

The cause of the alloimmunisation, relevant past history and pregnancy outcomes should be
ascertained in order to generate an assessment of risk of HDFN.
If the fetus carries the corresponding antigen for a maternal antibody which is capable of causing fetal
anaemia and if the antibody levels/titres rise beyond the levels detailed in section 6.7 then the
pregnancy should be monitored weekly by ultrasound, specifically assessing the fetal middle cerebral
artery peak systolic velocities (MCA PSV).
3 of 26
P
B
Referral to a fetal medicine specialist for consideration of invasive treatment should take place if
the MCA PSV rises above the 1.5 multiples of the median (MoM) threshold or if there are other signs of
fetal anaemia.
P
P
Fetal monitoring is required (as above) once anti-K is detected.
If fetal transfusion is required what type of donor blood should be used?

Red cell preparations for IUT should be group O (low titre haemolysin) or ABO identical with the fetus
(if known) and negative for the antigen(s) corresponding to maternal red cell antibodies.
IUTs should be performed only in fetal medicine units that have the requisite invasive skills and
appropriate perinatal haematology expertise.
What are the implications for the mother from red cell antibodies?
For antibodies other than anti-D, anti-c, anti-C, anti-E or anti-K, maternity staff should liaise with their
local transfusion laboratory to assess and plan for any possible transfusion requirements, as obtaining
the relevant blood may take longer.
How often should pregnant women with red cell antibodies who are at high risk of requiring a transfusion
(placenta praevia, sickle cell disease etc.) be tested?
Pregnant women with red cell antibodies, who are assessed as being at high risk of requiring a blood
transfusion, should have a cross-match sample taken at least every week.
If maternal transfusion is required, what type of donor blood or blood components should be used?
Red cell components of the same ABO group and RhD type, and that are K negative and cytomegalovirus
(CMV) negative, should be selected.
Should RhD-negative women who have anti-D or non-anti-D antibodies receive routine antenatal or postnatal
prophylaxis?
Anti-D immunoglobulin should be given to RhD-negative women with non-anti-D antibodies for routine
antenatal prophylaxis, for potential antenatal sensitising events and postnatal prophylaxis.
If immune anti-D is detected, prophylaxis is no longer necessary.
B
D
Discussion and liaison with the transfusion laboratory are essential in determining whether anti-D
antibodies are immune or passive in women who have previously received anti-D prophylaxis.
Requirements for blood

What are the logistics of obtaining blood or blood components for the woman, fetus or neonate?
Blood or blood components for the woman.
Close collaboration between the maternity, neonatology and haematology staff is essential.
When blood is required for women with multiple antibodies or antibodies against high prevalence
antigens, planning is required as rare blood donors may need to be called up to donate, or frozen blood
may need to be obtained from the National Frozen Blood Bank in Liverpool.
4 of 26
P
P
Local blood transport time and time for cross-match should be taken into account when the decision for
transfusion is made.
Blood for intrauterine transfusion (IUT)

Clinicians should be aware that blood for IUT has the same requirements as blood for neonatal
exchange (see 7.1.3), except that plasma is removed by the blood centre to increase the haematocrit to
0.700.85 and it is always irradiated.
Blood for neonatal exchange

Blood should be ABO compatible with the neonate and mother (to avoid ABO HDFN from the womans
anti-A or -B antibodies present), RhD negative (or RhD identical with neonate), K negative, negative for
the corresponding antigen to which the woman has an antibody and cross-match compatible with the
womans blood sample.
Blood should be less than 5 days old (to ensure low supernatant potassium levels), CMV negative and
irradiated unless the risk to the baby of delaying exchange transfusion while obtaining irradiated blood
outweighs this. It should be plasma reduced (rather than in saline-adenine-glucose-mannitol [SAGM]
additive solution), with a haematocrit of 0.500.60.
Blood for neonatal small volume (top-up) transfusion

anti-A or -B antibodies present), RhD negative (or RhD identical with neonate), K negative and negative
for the corresponding antigen to which the woman has an antibody and cross-match compatible with
the womans blood sample.
Blood should be CMV negative but does not need to be irradiated unless the neonate has had a previous
IUT and blood can be stored in SAGM (rather than plasma reduced) and be up to 35 days old (as a topup transfusion is a much smaller volume than an exchange transfusion).
Clinicians considering transfusion in a neonate must check if the baby has had an IUT, as if so, blood
must be irradiated to prevent transfusion-associated graft-versus-host disease.
What blood or blood components can be administered in the emergency situation to a woman known to have
red cell antibodies?
The decision to use ABO-, RhD- and K-compatible blood that is not matched for other antibodies (or O
negative, where the womans ABO and RhD groups are unknown) should be made on the balance of risks
(severe haemorrhage versus a haemolytic transfusion reaction).
Transfusion should not be delayed in the event of life-threatening haemorrhage. Close liaison with the
transfusion laboratory is essential.
P
P
Birth
What is the optimum mode, place and timing of birth?
Timing of delivery for women with red cell antibodies that can cause fetal anaemia will depend on the
antibody levels/titres, rate of rise as well as if any fetal therapy has been required. The mode, timing
and place of delivery are otherwise dependent on standard obstetric grounds.
5 of 26
If a woman is at risk of requiring significant amounts of transfused blood either antenatally, intrapartum
or postnatally, consideration should be given to transferring her care to a centre capable of processing
cross-match samples and providing appropriate compatible blood rapidly.
As these are high-risk pregnancies, continuous electronic fetal heart monitoring is advised during labour.
P
P
Cord blood investigations

What cord blood investigations should be performed?
If a woman has clinically significant antibodies (Appendix 1) then cord samples should be taken for a
direct antiglobulin test (DAT), haemoglobin and bilirubin levels.
Management
How should the neonate be managed?
This depends on the risk of haemolysis or anaemia conferred by the relevant red cell antibody. The
neonate should have regular clinical assessment of its neurobehavioural state and be observed for the
development of jaundice and/or anaemia.
Regular assessment of bilirubin and haemoglobin levels should be made and early discharge is
not advisable.
The mother should be encouraged to feed the baby regularly to guard against dehydration, since
dehydration can increase the severity of jaundice.
Clinicians should be aware that if bilirubin levels rise rapidly or above the interventional threshold,
phototherapy and/or exchange transfusion may be required.
Pregnancies complicated by red cell alloimmunisation with a minimal or no risk of fetal or neonatal
anaemia require no specific treatment.
Future Risks
What is the risk of recurrence in a future pregnancy?
A woman with a history of a pregnancy or infant affected by HDFN should be referred for early
assessment to a fetal medicine specialist in all further pregnancies.
Long-term consequences of red cell antibodies to women and their offspring

What are the long-term health consequences for the woman?
Women can be advised that there are no long-term adverse health consequences associated with the
presence of red cell antibodies.
What are the long-term health concerns for the children of women with red cell antibodies during pregnancy?
Clinicians should be aware that some infants may experience anaemia persisting for a few weeks
following birth.
Clinicians should be aware that some infants may develop late anaemia which is usually due to
hyporegenerative anaemia.
6 of 26
1.
Purpose and scope
The purpose of this guideline is to provide guidance on the management of pregnant women with red cell
antibodies predating the pregnancy or those developing antibodies during pregnancy. The guideline also
includes the management of fetal anaemia caused by red cell antibodies, as well as the early management of
the neonate at risk of anaemia and/or hyperbilirubinaemia. It does not address the management of the
pregnant woman with anti-platelet antibodies or other autoimmune or alloimmune antibodies.
2.
The presence of maternal red cell antibodies during pregnancy is a relatively common finding and requires
close collaboration between the blood transfusion laboratory, obstetric and neonatal care providers. A
population study from the Netherlands found that red cell antibodies were detected in 1.2% of pregnancies,
while the prevalence of clinically significant antibodies was placed at 0.4% (Appendix 1).1
The presence of red cell antibodies signifies alloimmunisation that has occurred as a result of previous
pregnancy, transfusion or transplantation. Haemolytic disease of the fetus and newborn (HDFN) is a condition
in which transplacental passage of maternal immunoglobulin G (IgG) antibodies results in immune
haemolysis of fetal/neonatal red cells. Some antibodies (including anti-D, anti-K (-Kell) and anti-c) confer
significant fetal and neonatal risks such as anaemia requiring intrauterine or neonatal transfusion, jaundice or
perinatal loss. There are many antibodies that are unlikely to significantly affect the fetus but can cause
neonatal anaemia and hyperbilirubinaemia, while others may cause problems for the screening and provision
of appropriate blood or blood components to the mother or fetus/neonate when required (Appendix 1).
Anti-D is the most commonly encountered antibody during pregnancy. Before routine antenatal anti-D
prophylaxis, late immunisation during a first pregnancy was responsible for 1827% of cases. Immunisation
during a second or subsequent pregnancy probably accounts for a similar proportion of cases, although it is
often impossible to distinguish late sensitisation from failure of prophylaxis at the end of the preceding
pregnancy.2 Antibodies of the ABO blood group system can also cause mild to moderate anaemia and jaundice
in the neonate and occasionally in the fetus. In particular, anti-A and anti-B antibodies of the IgG subclass in a
group O mother can cross the placenta and cause haemolysis of fetal erythrocytes.
3.
EMBASE, TRIP, MEDLINE and PubMed (electronic databases) were searched for relevant randomised
controlled trials, systematic reviews, meta-analyses and other studies. The search was restricted to articles
published between 1960 and July 2013. The databases were searched using the relevant MeSH terms,
including all subheadings, and this was combined with a keyword search. Search terms included: red cell
antibody, red blood cell antigen, erythroblastosis fetalis, blood group incompatibility, haemolytic disease of
newborn, anti-D, anti-c, anti-E, anti-K, Kidd, Duffy, Diego alloimmunisation. The search was limited to humans
and the English language. NHS Evidence and the National Guideline Clearinghouse were also searched for
4.
Prepregnancy counselling
4.1 Is prepregnancy counselling necessary for women known to have red cell antibodies prior to pregnancy?
Women with red cell antibodies, particularly if there is a risk of fetal anaemia or if compatible donor red
cells for transfusion may be difficult to obtain, should attend for prepregnancy counselling with a
clinician with knowledge and expertise of this condition.
7 of 26
Routine prepregnancy screening for red cell antibodies is not indicated. Most women would have had
antibodies detected in a previous pregnancy, screening prior to blood transfusion/donation or fortuitously for
some other indication. Women with clinically significant red cell antibodies should be given information
regarding the possible implications (maternal and fetal) to the pregnancy.This will clearly depend on the type
of antibody present. Counselling should be by a clinician with knowledge and expertise of this condition and
in most cases this will be a fetal medicine specialist.
A guideline issued by the British Committee for Standards in Haematology (BCSH)3 on antibodies in
pregnancy recommends that women with clinically significant antibodies should be issued with a card giving
details of the antibody.
5.
Assisted reproductive techniques (ART)
5.1 Do assisted reproductive techniques (ART) increase the risk of red cell antibodies developing?
There is no evidence that ART increases the risk of red cell alloimmunisation. However, if donor eggs are used
for a mother with an alloantibody and the donor red cell antigen status is not known, fetal genotyping may
be required.
6.
Red cell antibodies in pregnancy
6.1 What is the incidence of red cell antibodies in pregnancy?

In a population study conducted in the Netherlands, the prevalence of positive antibody screens
was 1:80, with a 1:300 prevalence of clinically significant alloantibodies other than anti-D.1
Evidence
level 2++
Previous blood transfusion is an important cause for alloimmunisation with antibodies other than
anti-D implicated in HDFN.4
Evidence
level 2+
6.2 What red cell antibodies are clinically significant (maternal and fetal) during pregnancy?
All women should have their blood group and antibody status determined at booking and at 28 weeks
of gestation (Appendix 2).
Relevant antibodies are presented in Appendix 1. Antibodies to many of the red cell antigens have
the potential to be clinically significant and will have implications for the selection of blood for
transfusion in the mother to avoid the risk of haemolytic transfusion reactions (HTRs). For this
reason, the blood group and antibody status of the mother should be tested at booking and at 28
weeks of gestation.5 In addition to the risk of fetal anaemia, the presence of maternal red cell
antibodies can hinder the timely provision of blood and blood components because of difficulty in
obtaining antigen-negative blood and/or cross-matching issues.3
Evidence
level 4
The risk of fetal anaemia is greatest with anti-D, anti-c and anti-K antibodies. Other antibodies that
potentially cause significant fetal anaemia include anti-E, -Fya, -Jka, -C and -Ce.69 There are numerous
other antibodies that usually only cause mild haemolysis that is only rarely significant (Appendix 1).
Evidence
level 3
6.3 What are the implications for the fetus and neonate from red cell antibodies?
Clinicians should be aware that severe fetal anaemia can result in hydrops which significantly worsens
the perinatal outcome.
Fetal anaemia, hyperbilirubinaemia and neonatal jaundice can result from red cell antibodies that
cause haemolysis or impaired erythropoiesis in utero. Untreated, severe fetal anaemia can result in
hydrops, preterm birth or perinatal death.The overall perinatal survival in pregnancies complicated
8 of 26
D
Evidence
level 3
by red cell antibodies causing fetal anaemia following treatment was reported to be 84%, with
nonhydropic fetuses having better survival (94%) than hydropic fetuses (74%).10
Evidence
level 3
Anti-K causes anaemia secondary to erythroid suppression and immune destruction of early
erythroid progenitor cells, but hyperbilirubinaemia is not a prominent feature.11 Severe fetal
anaemia can occur even at relatively low antibody titres.12
Evidence
level 2+
6.4 When and how should paternal and fetal genotyping be performed?
Non-invasive fetal genotyping using maternal blood is now possible for D, C, c, E, e and K antigens.
This should be performed in the first instance for the relevant antigen when maternal red cell antibodies
are present.
For other antigens, invasive testing (chorionic villus sampling [CVS] or amniocentesis) may be considered
if fetal anaemia is a concern or if invasive testing is performed for another reason (e.g. karyotyping).
Where clinically significant maternal red cell antibodies are detected, the paternal phenotype can be ascertained
by serology. However with the rhesus D (RhD) antigen specifically, in an antigen-positive father, while a likely
phenotype can be deduced, genotyping is required to determine whether he is homozygous or heterozygous
for the RHD gene. If the father is homozygous for the red cell antigen then all pregnancies are potentially at risk.
It is also reasonable to omit paternal testing and proceed directly to fetal genotyping to avoid issues
of nonpaternity. It is now possible to determine the fetal genotype non-invasively from maternal
blood.13 Using polymerase chain reaction techniques, the fetal RHD status can be detected with
great sensitivity using free fetal DNA (ffDNA) extracted from maternal plasma.The fetal C, c, E, e and
K genotype can also be detected using this method (with an accuracy of fetal RhC/c and RhE/e
genotype estimations from maternal blood between 9698%, which compares well with the
reported accuracy of fetal RhD of > 95%).14,15 Genotyping can be undertaken from 16 weeks of
gestation for all except K which can be undertaken from 20 weeks, due to the risk of a falsenegative result if performed earlier in pregnancy. However, in some cases, results are inconclusive
as it is not possible to confirm that fetal DNA, as well as maternal DNA, is present in the sample. In
these cases, consideration may need to be given to repeating the non-invasive test, performing an
amniocentesis or managing the pregnancy as one that is at risk. It is also reasonable not to perform
fetal genotyping until the antibody reaches a level that would warrant fetal middle cerebral artery
(MCA) Doppler monitoring.
Evidence
level 2+
Of note, in dizygotic twins, a maternal blood test for fetal genotyping will not differentiate between the twins:
just that at least one has the corresponding gene. If fetal monitoring for anaemia is indicated, each twin would
need to be monitored separately.
Non-invasive genotyping is not possible for some red cell antigens. In these cases invasive testing (CVS or
amniocentesis) may be considered. However, the risks of the procedure (miscarriage, worsening of
alloimmunisation) need to be balanced against the benefit that knowledge of the fetal genotype brings to the
management of the pregnancy. It would normally only be indicated if there was a history of a significant
problem with HDFN, or MCA Doppler ultrasound suggested developing fetal anaemia and intrauterine
transfusion (IUT) was being considered.
6.5 Is karyotyping contraindicated in the presence of maternal red cell antibodies?

Invasive testing is not contraindicated if alloimmunisation has occurred.
Anti-D prophylaxis should be given to cover invasive testing if the mother is RhD negative and is not
sensitised.
9 of 26
Invasive testing solely for the purposes of fetal genotyping is seldom required as this can be undertaken using
maternal blood in the majority of cases. However, if karyotyping is necessary for a separate indication,
concomitant genotyping can be performed.
In addition to the procedure-related risks, any invasive procedure will further increase the risk of
alloimmunisation, through either the increasing of antibody levels or the development of further
antibodies. If the mother is RhD negative and is not sensitised, anti-D prophylaxis should be given
to cover invasive testing.16
Evidence
level 4
6.6 If the fetus is at risk of anaemia, when should referral to a fetal medicine specialist take place?
Referral to a fetal medicine specialist should occur when there are rising antibody levels/titres, a
level/titre above a specific threshold (see section 6.7) or ultrasound features suggestive of fetal
anaemia.
Referral should take place if there is a history of unexplained severe neonatal jaundice, neonatal
anaemia requiring transfusion or exchange transfusion, in order to exclude HDFN as the cause.
For antibodies other than anti-D, anti-c and anti-K, the following should prompt referral to a fetal
medicine specialist: a history of previous significant HDFN or IUT, or a titre of 32 or above, especially if
the titre is rising as rising titres correlate with increasing risk and severity of anaemia.
Referral to a fetal medicine specialist will depend on the type of antibody and its levels or titres.
The risk of fetal anaemia is greatest with anti-D, anti-c and anti-K. In addition to these antibodies,
other antibodies may rarely cause fetal anaemia (Appendix 1) and referral may be indicated.1,3 Once
alloimmunisation has occurred, the fetus may be at risk from anaemia and the risk appears to
correlate with increasing antibody titres.
Evidence
level 4
6.7 What thresholds should be used for the various antibodies that could cause fetal anaemia to trigger
referral for further investigation or monitoring?
An anti-D level of > 4 iu/ml but < 15 iu/ml correlates with a moderate risk of HDFN and an anti-D level
of > 15 iu/ml can cause severe HDFN. Referral for a fetal medicine opinion should therefore be made
once anti-D levels are > 4 iu/ml.
An anti-c level of > 7.5 iu/ml but < 20 iu/ml correlates with a moderate risk of HDFN, whereas an antic level of > 20 iu/ml correlates with a high risk of HDFN. Referral for a fetal medicine opinion should
therefore be made once anti-c levels are > 7.5 iu/ml.
For anti-K antibodies, referral should take place once detected, as severe fetal anaemia can occur even
with low titres.
The presence of anti-E potentiates the severity of fetal anaemia due to anti-c antibodies so that referral
at lower levels/titres is indicated (unless the fetus has only one of these antigens).
An anti-D level < 4 iu/ml or an anti-c level of < 7.5 iu/ml correlates with a low risk of fetal anaemia
and therefore referral to a fetal medicine specialist is not immediately indicated (Appendix 3).3,17,18
Serial monitoring of antibody levels is necessary. Once referral to a fetal medicine specialist has
been made for assessment of pregnancy at moderate or high risk of HDFN, the value of subsequent
quantitation of anti-D and anti-c levels is doubtful. Further testing is however required at 28 weeks
for the development of additional red cell antibodies. Caution is required however if there is a
history of a severely affected previous pregnancy even if the antibody levels are low in the current
pregnancy. For such cases early referral to a fetal medicine specialist should be made so that an
10 of 26
Evidence
level 2+
expert assessment of risk can be undertaken. For these women, ultrasound monitoring may be
required even with low antibody levels.
Evidence
level 2+
Anti-K titres appear to correlate poorly with the severity of disease with fetal anaemia occurring at titres as
low as 8.19
The presence of anti-E potentiates the severity of fetal anaemia due to anti-c antibodies so, unless the fetus
has only one of these antigens, referral at lower levels/titres is indicated.
6.8 Once detected how often should antibody levels be monitored during pregnancy?
Anti-D and anti-c levels should be measured every 4 weeks up to 28 weeks of gestation and then every
2 weeks until delivery.
Although anti-K titres do not correlate well with either the development or severity of fetal anaemia,
titres should nevertheless be measured every 4 weeks up to 28 weeks of gestation, then every 2 weeks
until delivery.
For all other antibodies, retesting at 28 weeks is advised with the exception of women who have a
previous history of pregnancies affected with HDFN when early referral to a fetal medicine specialist is
also recommended.
For antibodies that could potentially cause problems with cross-matching or issues with the availability
of appropriate blood, discussion with the blood transfusion service is required regarding the frequency
of antenatal testing. This may depend on the type of antibody as well as the likelihood of requiring
blood at short notice.
P
P
Blood samples from women with immune anti-D, anti-c or anti-K should be tested at least monthly
until 28 weeks of gestation and every 2 weeks thereafter until delivery to monitor the level of
antibody and to identify any additional antibodies that may have developed.3
When red cell antibodies are detected in the booking sample, further testing of maternal blood
should be undertaken to determine the specificity and level of antibody or antibodies, and to assess
the likelihood of HDFN.3 The levels of anti-D and anti-c antibodies are quantified using an automated
analyser whereas the titre of other antibodies is determined by titration using doubling dilution.
Evidence
level 4
6.9 How should pregnancies at risk of fetal anaemia be monitored?

The cause of the alloimmunisation, relevant past history and pregnancy outcomes should be
ascertained in order to generate an assessment of risk of HDFN.
If the fetus carries the corresponding antigen for a maternal antibody which is capable of causing fetal
anaemia and if the antibody levels/titres rise beyond the levels detailed in section 6.7 then the
pregnancy should be monitored weekly by ultrasound, specifically assessing the fetal middle cerebral
artery peak systolic velocities (MCA PSV).
Referral to a fetal medicine specialist for consideration of invasive treatment should take place if
the MCA PSV rises above the 1.5 multiples of the median (MoM) threshold or if there are other signs of
fetal anaemia.
Fetal monitoring is required (as above) once anti-K is detected.
11 of 26
P
B
P
P
The cause of the alloimmunisation should be ascertained: for example, inadequate or omitted antiD prophylaxis or a previous blood transfusion. Details of previously affected pregnancies,
particularly IUTs and the gestation at which they were commenced, neonatal anaemia, gestation at
delivery and the need for exchange transfusions or phototherapy, should also be obtained. This
information enables a risk assessment of the pregnancy to be made. Ultrasound monitoring should
commence once there is a moderate or severe risk of fetal anaemia.20
Evidence
level 2+
If the fetus is antigen positive, it will be at risk of anaemia and the pregnancy needs to be serially monitored.
Pregnancies at risk should be monitored on a weekly basis looking specifically at the MCA PSV. Other signs
that might suggest fetal anaemia include polyhydramnios, skin oedema and cardiomegaly. Although the risks
of fetal anaemia are well known for anti-D, anti-c and anti-K antibodies and weekly monitoring is advisable,
the risks for other less common antibodies is difficult to precisely quantify. A reasonable approach would be
ultrasound monitoring every 12 weeks using the MCA PSV.
Ultrasound monitoring should be performed by a professional with appropriate expertise to reliably perform
MCA Doppler assessment (see International Society of Ultrasound in Obstetrics and Gynecology practice
guidelines for the use of Doppler ultrasonography in obstetrics21). If the MCA PSV rises beyond the
interventional threshold then referral to a fetal medicine specialist with expertise in IUT should be made.
MCA PSV monitoring is predictive of moderate or severe fetal anaemia with 100% sensitivity and a
false positive rate of 12%.20
Evidence
level 2+
If monitoring of the MCA indicates anaemia (MCA PSV > 1.5 MoM), fetal blood sampling (FBS) and possibly
IUT are indicated. Monitoring with MCA PSV should be used with caution after 36 weeks as its sensitivity for
the detection of fetal anaemia decreases. If there are concerns beyond this gestation because of raised MCA
PSV, further advice should be sought from a fetal medicine specialist experienced in managing fetal anaemia.
Further management should also be discussed with a fetal medicine specialist if MCA PSV levels are normal
despite high or increasing antibody levels beyond 36 weeks of gestation.The risk of fetal loss following an FBS
is 13%, but is higher if the fetus is hydropic.10
The procedure is carried out under continuous ultrasound guidance with facilities for immediate analysis of
the fetal blood haemoglobin and haematocrit. The risks and benefits of IUT should always be discussed with
the woman who should be made aware of the consequences of untreated severe fetal anaemia (i.e. hydrops,
preterm birth, perinatal death, severe neonatal jaundice and kernicterus) as well as the risks of neonatal
exchange transfusion.
6.10 If fetal transfusion is required what type of donor blood should be used?
Red cell preparations for IUT should be group O (low titre haemolysin) or ABO identical with the fetus
(if known) and negative for the antigen(s) corresponding to maternal red cell antibodies.
IUTs should be performed only in fetal medicine units that have the requisite invasive skills and
appropriate perinatal haematology expertise.
Blood should be IAT (indirect antiglobulin test) cross-match compatible with maternal plasma and
negative for the relevant antigen(s) determined by maternal antibody status.22 K-negative blood is
recommended to reduce additional maternal alloimmunisation risks. It should also be less than 5 days
old and in citrate phosphate dextrose (CPD) anticoagulant, cytomegalovirus (CMV) seronegative,
irradiated and transfused within 24 hours of irradiation. Blood packs should have a haematocrit
(packed cell volume, PCV) of 0.700.85.23 Blood for IUT should never be transfused straight from 4C
storage.22 In exceptional cases, it will be necessary to give O RhD-positive, c-negative blood, for example
in HDFN because of anti-c alloimmunisation, where giving RhD-negative blood would be harmful.22
12 of 26
Evidence
level 4
As the number of cases of fetal anaemia due to red cell alloimmunisation is decreasing, fewer fetal medicine
specialists will have the necessary skills to perform IUTs. These cases should be referred to tertiary units
where the appropriate intrauterine invasive skills and perinatal haematology expertise are available. If FBS is
being performed for suspected fetal anaemia, the appropriate blood pack for an IUT should be immediately
available. This will require prior liaison with the transfusion laboratory. It is not good practice to perform a
diagnostic FBS and then defer the IUT to a later time because suitable blood is not available.
While 24 hours notice may be requested for planned IUTs, in an emergency, blood for IUT can be provided
in less time following discussion with the blood transfusion service; in a dire emergency, discussion should be
undertaken with the relevant consultant haematologist regarding the best compromise of blood available.
6.11 What are the implications for the mother from red cell antibodies?
For antibodies other than anti-D, anti-c, anti-C, anti-E or anti-K, maternity staff should liaise with their
local transfusion laboratory to assess and plan for any possible transfusion requirements, as obtaining
the relevant blood may take longer.
The implications relate to possible transfusion problems for the mother in terms of the availability and
provision of compatible blood.
6.12 How often should pregnant women with red cell antibodies who are at high risk of requiring a
transfusion (placenta praevia, sickle cell disease etc.) be tested?
Pregnant women with red cell antibodies, who are assessed as being at high risk of requiring a blood
transfusion, should have a cross-match sample taken at least every week.
Current BCSH guidelines require a sample no more than 72 hours old for providing compatible blood in
pregnancy,24 but do allow a deviation to the 3-day rule for individual cases such as high-risk women with
placenta praevia without red cell antibodies where weekly samples can be taken, as long as a risk assessment
is made and recorded in each individual case. In high-risk women with red cell antibodies where a sample
every 72 hours is not feasible, a sample should be taken once a week and if transfusion is required a new
sample should be taken immediately, to exclude new antibody development. However, in the event of lifethreatening haemorrhage, urgent transfusion should not be delayed (see section 7.2) and close liaison with
the hospital transfusion laboratory is vital.
6.13 If maternal transfusion is required, what type of donor blood or blood components should be used?
Red cell components of the same ABO group and RhD type, and that are K negative and CMV negative,
should be selected.
If group ABO-identical blood is not available for group A, B or AB patients, group O blood should
be used. Pregnant women and women of childbearing age who are RhD negative should receive
RhD-negative blood. The transfused blood should also be K negative. Blood which has been
phenotyped and found negative for the antigen corresponding to the maternal antibody should
be provided. Antigen-negative red cells should also be selected when a clinically significant
antibody has previously been identified, but cannot be detected in the most recent cross-match
sample. An IAT cross-match must be used if the womans plasma contains or has previously
contained clinically significant red cell alloantibodies (see section 7.2).24 For planned antenatal
transfusions, CMV-negative blood should be transfused.25 Screening for CMV should not delay
transfusion in an emergency situation; all blood in the UK also undergoes leucodepletion which
significantly reduces risk of CMV transmission by blood.25
13 of 26
Evidence
level 4
6.14 Should RhD-negative women who have anti-D or non-anti-D antibodies receive routine antenatal or
postnatal prophylaxis?
Anti-D immunoglobulin should be given to RhD-negative women with non-anti-D antibodies for routine
antenatal prophylaxis, for potential antenatal sensitising events and postnatal prophylaxis.
If immune anti-D is detected, prophylaxis is no longer necessary.
Discussion and liaison with the transfusion laboratory are essential in determining whether anti-D
antibodies are immune or passive in women who have previously received anti-D prophylaxis.
Anti-D immunoglobulin prophylaxis is given to prevent RhD-negative women forming anti-D

antibodies in the event of a potentially sensitising event during pregnancy and/or as part of routine
antenatal anti-D prophylaxis (RAADP).16,26 It is important to remember to administer anti-D
prophylaxis to RhD-negative women who have other red cell antibodies, as this will still prevent
the formation of immune anti-D.
Women who are already sensitised, i.e. have immune anti-D, should not be given anti-D prophylaxis.3
Evidence
level 2++
Evidence
level 4
In the non-RhD-sensitised woman, if fetal genotyping indicates that the fetus is RhD negative or if the father
is confirmed to be RhD negative then anti-D prophylaxis is not required.
Women given anti-D immunoglobulin may have a positive antibody screen on subsequent testing
and it may be difficult to determine if this anti-D is passive following administration of a
prophylactic dose or immune as result of sensitisation. It is essential to liaise with the transfusion
laboratory to discuss appropriate interpretation.3
7.
Evidence
level 4
Requirements for blood
7.1 What are the logistics of obtaining blood or blood components for the woman, fetus or neonate?
7.1.1 Blood or blood components for the woman
Close collaboration between the maternity, neonatology and haematology staff is essential.
When blood is required for women with multiple antibodies or antibodies against high prevalence
antigens, planning is required as rare blood donors may need to be called up to donate, or frozen blood
may need to be obtained from the National Frozen Blood Bank in Liverpool.
Local blood transport time and time for cross-match should be taken into account when the decision for
transfusion is made.
P
P
P
An assessment and discussion of the likelihood of the need for blood, as well as all appropriate preventative
measures to reduce the likelihood of transfusion should take place as early in pregnancy as feasible between
the maternity and haematology staff. This will optimise the use of rare blood, taking account of the needs of
the patient together with the scarcity of the blood. Any haematinic deficiency should be corrected.
Multidisciplinary planning of delivery should take place to reduce blood loss and intra-operative cell salvage
should be available where appropriate.
The appropriate management of transfusion in the mother and the baby requires essential communication
not only between teams within a hospital but also between hospitals if cases are referred to tertiary centres.
Blood can usually be sourced from hospital stocks for women with anti-D, -c, -C, -E or -K as all units are labelled
14 of 26
with full Rh and K antigen status. For antibodies other than anti-D, -c, -C, -E and -K, blood will most likely need
to be obtained from the regional blood transfusion centre, so additional transport time may be required. For
antibodies where compatible blood is rare, a national search for compatible blood may be required. If
insufficient blood is available, blood may need to be obtained from the National Frozen Blood Bank in
Liverpool, or rare blood donors called up to donate. Obtaining frozen blood entails a delay of approximately
46 hours for 2 units to be thawed, multiply washed and processed to remove glycerol, with a further 2 hours
for each additional 2 units plus additional transportation time.
The shelf life of frozen units, once thawed, is 72 hours and they cannot be refrozen. Calling up rare donors to
donate requires advance notification where possible. There may be additional delays because of necessary
virology testing and other processing which may take up to 1 working day. The timing of obtaining
appropriate donor blood should take account of when the woman is most likely to need that blood.
7.1.2 Blood for intrauterine transfusion (IUT)

Clinicians should be aware that blood for IUT has the same requirements as blood for neonatal
exchange (see 7.1.3), except that plasma is removed by the blood centre to increase the haematocrit to
0.700.85 and it is always irradiated.
Blood for IUT is processed to order as it only has 24 hours shelf life after processing and normally
requires a minimum of 1 working days notice, unless an emergency.22,23 As with neonatal exchange
blood, if maternal antibodies other than anti-D, -c, -C, -E or -K are present, advance warning should
be given where possible to ensure that suitable blood, negative for all relevant antigens, is available.
Evidence
level 4
7.1.3 Blood for neonatal exchange

anti-A or -B antibodies present), RhD negative (or RhD identical with neonate), K negative, negative for
the corresponding antigen to which the woman has an antibody and cross-match compatible with the
womans blood sample.
Blood should be less than 5 days old (to ensure low supernatant potassium levels), CMV negative and
irradiated unless the risk to the baby of delaying exchange transfusion while obtaining irradiated blood
outweighs this. It should be plasma reduced (rather than in saline-adenine-glucose-mannitol [SAGM]
additive solution), with a haematocrit of 0.500.60.
If maternal antibodies other than anti-D, -c, -C, -E or -K are present, units negative for those antigens
may require a search of other centres. Ideally, in view of the 5-day shelf life, staff should discuss such
cases with the blood transfusion laboratory in advance of delivery to ensure that appropriate blood
is available. Once irradiated, exchange blood has a shelf life of 24 hours.22
Blood should be CMV negative, to minimise the risk of CMV infection in the neonate and irradiated
to prevent transfusion-associated graft-versus-host disease, due to the large volume of blood
transfused to a neonate. Plasma-reduced blood is preferable as blood suspended in SAGM contains
glucose, which can result in rebound hypoglycaemia, and mannitol with potential diuretic and
intracerebral pressure effects. The recommended haematocrit allows for sufficient correction of
anaemia after exchange, but without an unacceptably high haematocrit, with its associated risks to
the neonate.22
Evidence
level 4
Blood for exchange transfusion is normally obtained from a regional blood centre, which routinely stocks
groups O negative and O positive (c negative and K negative) exchange units on the shelf. Blood transport
time and time for cross-match should also be taken into account.
15 of 26
7.1.4 Blood for neonatal small volume (top-up) transfusion

anti-A or -B antibodies present), RhD negative (or RhD identical with neonate), K negative and negative
for the corresponding antigen to which the woman has an antibody and cross-match compatible with
the womans blood sample.
Blood should be CMV negative but does not need to be irradiated unless the neonate has had a previous
IUT and blood can be stored in SAGM (rather than plasma reduced) and be up to 35 days old (as a topup transfusion is a much smaller volume than an exchange transfusion).
Clinicians considering transfusion in a neonate must check if the baby has had an IUT, as if so, blood
must be irradiated to prevent transfusion-associated graft-versus-host disease.
While blood for IUT should be irradiated because of the physiological immune incompetence of
the fetus allowing transfusion-induced tolerance or immunosuppression, for top-up (small volume)
neonatal transfusions, in the absence of any preceding IUT, irradiation is not required.22
Evidence
level 4
In view of the less restrictive shelf life of blood required, blood compatible for maternal antibodies other than
anti-D, -c, -C, -E or -K may be more readily available in the regional blood centre than blood for exchange or
IUT, but advance warning should be given to transfusion labs wherever possible.
7.2 What blood or blood components can be administered in the emergency situation to a woman known to
have red cell antibodies?
The decision to use ABO-, RhD- and K-compatible blood that is not matched for other antibodies (or O
negative, where the womans ABO and RhD groups are unknown) should be made on the balance of risks
(severe haemorrhage versus a haemolytic transfusion reaction).
Transfusion should not be delayed in the event of life-threatening haemorrhage. Close liaison with the
transfusion laboratory is essential.
P
P
Obstetric, haematology and transfusion laboratory staff should discuss when to give alternative blood, when
sufficient compatible blood is not readily available, based on the balance of clinical risks (severe haemorrhage
versus a haemolytic transfusion reaction with associated complications, including renal failure).
If ABO-, RhD- and K-compatible blood that is not matched for other antibodies is used for
resuscitation in the event of life-threatening haemorrhage, consider giving intravenous
methylprednisolone 1 g and monitor the woman closely.27 If a severe transfusion reaction develops,
full resuscitative measures, including the use of adrenaline, may be required.28 The presence of
maternal red cell antibodies has no implications for other blood components such as platelets, fresh
frozen plasma, cryoprecipitate or fractionated products.
8.
Evidence
level 4
Birth
8.1 What is the optimum mode, place and timing of birth?

Timing of delivery for women with red cell antibodies that can cause fetal anaemia will depend on the
antibody levels/titres, rate of rise as well as if any fetal therapy has been required. The mode, timing
and place of delivery are otherwise dependent on standard obstetric grounds.
16 of 26
If a woman is at risk of requiring significant amounts of transfused blood either antenatally, intrapartum
or postnatally, consideration should be given to transferring her care to a centre capable of processing
cross-match samples and providing appropriate compatible blood rapidly.
As these are high-risk pregnancies, continuous electronic fetal heart monitoring is advised during labour.
P
P
In general, for red cell antibodies that could cause fetal anaemia but which have been stable throughout
pregnancy, delivery should take place between 37 and 38 weeks of gestation. If an IUT has not been required
but antibody levels are rising then consideration for earlier delivery may be necessary. If an IUT has been
required, delivery will need to be timed to ensure that the fetus is not significantly anaemic at birth. This will
depend on the gestation that the last IUT was performed as well as the estimated rate of drop of fetal
haemoglobin/haematocrit. Decisions about the timing of delivery are most appropriately made by the fetal
medicine team managing these pregnancies. Prior IUT is not in itself an indication for elective caesarean section.
The neonatal team should be advised of the timing of delivery in the event that further neonatal care is required.
As not all obstetric units will have the haematological expertise and resources to deal with cases of massive
obstetric haemorrhage against the background of difficulties in obtaining blood safe for transfusion,
consideration should be given to transferring these more complex cases to a centre where such facilities
are available.
Although the National Institute for Health and Care Excellence (NICE) guideline on intrapartum care contains
no specific recommendation for fetal monitoring in pregnancies complicated by red cell antibodies,29 these
pregnancies are generally considered to be high risk and intrapartum continuous electronic fetal heart
monitoring is therefore advised.
9.
Cord blood investigations
9.1 What cord blood investigations should be performed?

If a woman has clinically significant antibodies (Appendix 1) then cord samples should be taken for a
direct antiglobulin test (DAT), haemoglobin and bilirubin levels.
Cord blood investigations (DAT, haemoglobin and bilirubin levels) should be undertaken in addition to ABO
and RhD typing where the mother is known to have immune red cell antibodies. A positive DAT indicates
that the infants red cells are coated with antibody but in itself cannot predict severity of haemolysis. Notably
the DAT may be negative in ABO HDFN. It is therefore essential to also determine haemoglobin and bilirubin
levels to ascertain the degree of anaemia and haemolysis at birth and this helps guide management as below.
10. Management
10.1 How should the neonate be managed?

This depends on the risk of haemolysis or anaemia conferred by the relevant red cell antibody. The
neonate should have regular clinical assessment of its neurobehavioural state and be observed for the
development of jaundice and/or anaemia.
Regular assessment of bilirubin and haemoglobin levels should be made and early discharge is not
advisable.
The mother should be encouraged to feed the baby regularly to guard against dehydration, since
dehydration can increase the severity of jaundice.
17 of 26
Clinicians should be aware that if bilirubin levels rise rapidly or above the interventional threshold,
phototherapy and/or exchange transfusion may be required.
Pregnancies complicated by red cell alloimmunisation with a minimal or no risk of fetal or neonatal
anaemia require no specific treatment.
Guidance from NICE30 summarises the approach to the management of neonatal jaundice including
bilirubin and haemoglobin monitoring, indications for phototherapy, intravenous immunoglobulin
use and exchange transfusion. Exchange transfusion may be used to manage severe anaemia at birth
and to treat severe hyperbilirubinaemia. Such a transfusion is undertaken with the aims of removing
both the antibody-coated red cells and the excess bilirubin.22
11.
P
Evidence
level
2+/2++
Future risks
11.1 What is the risk of recurrence in a future pregnancy?

A woman with a history of a pregnancy or infant affected by HDFN should be referred for early
assessment to a fetal medicine specialist in all further pregnancies.
The risk of recurrence of HDFN depends on the type of antibody, the paternal genotype as well as the severity
and gestational onset of the fetal anaemia.
12. Long-term consequences of red cell antibodies to women and their offspring
12.1 What are the long-term health consequences for the woman?
Women can be advised that there are no long-term adverse health consequences associated with the
presence of red cell antibodies.
There are no long-term health consequences for the woman, but an antibody card should be carried
in case transfusion is required.31
P
Evidence
level 2
12.2 What are the long-term health concerns for the children of women with red cell antibodies during
pregnancy?
Clinicians should be aware that some infants may experience anaemia persisting for a few weeks
following birth.
Clinicians should be aware that some infants may develop late anaemia which is usually due to
hyporegenerative anaemia.
Anaemia persisting for a few weeks after birth is usually the result of passively acquired maternal
antibodies causing continued haemolysis.32
Evidence
level 2+
Late anaemia may develop due to a transient suppression of neonatal erythropoiesis, itself due to
transfusion. Babies who have required several IUTs are at particular risk.32
Affected infants have suppression of erythropoiesis with low numbers of reticulocytes despite a low packed
cell volume and normal erythropoietin values. Top-up transfusions are required only if the infant is
symptomatic. There is some evidence that the need and frequency of top-up transfusions may be decreased
if recombinant erythropoietin is used.3335
18 of 26
The risk of long-term neurodevelopmental delay is no different in the antenatally treated cohort compared
with unaffected pregnancies, with normal outcome expected in more than 90% of cases.36 With appropriate
management, kernicterus is seen rarely. Sensorineural hearing loss is more common in infants affected by
haemolytic disease of the newborn because of the toxic effect of prolonged exposure of bilirubin on the
developing eighth cranial nerve.

Studies37,38 using maternally administered intravenous immunoglobulin have demonstrated some benefit in
severe cases of RhD incompatibility but the precise mechanism of action is not established. This treatment
modality is appropriate only in selected cases and it may prolong the time interval before the first intrauterine
treatment is required. Further studies are required.
The use of intravenous immunoglobulin administered to the infant to reduce the severity of
hyperbilirubinaemia and the number of exchange transfusions also needs further validation in larger studies.
Pregnancy outcomes of women referred for antenatal fetal therapy for fetal anaemia.
Proportion of women referred to a fetal medicine specialist once their antibody level/titre has reached
an interventional threshold.
Outcomes of women with rare/unusual antibodies requiring blood or blood components during
pregnancy or in the puerperium.
Outcomes of neonates requiring phototherapy or transfusion (exchange or top-up) because of
haemolysis secondary to red cell alloimmunisation.
Confirmation of the accuracy of free fetal DNA tests as basic quality assurance for laboratories
undertaking such tests.
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Bonsel GJ. Risk factors for the presence of non-rhesus D red
blood cell antibodies in pregnancy. BJOG 2009;116:65564.
British Committee for Standards in Haematology, Blood
Transfusion Task Force. Guidelines for blood grouping and red
cell antibody testing during pregnancy. Transfus Med
1996;6:714.
Goodrick MJ, Hadley AG, Poole G. Haemolytic disease of the
fetus and newborn due to anti-Fy(a) and the potential clinical
value of Duffy genotyping in pregnancies at risk. Transfus Med
1997;7:3014.
Moise KJ Jr. Non-anti-D antibodies in red-cell alloimmunization.
Moran P, Robson SC, Reid MM. Anti-E in pregnancy. BJOG
2000;107:14368.
Daniels G, Poole J, de Silva M, Callaghan T, MacLennan S, Smith
N.The clinical significance of blood group antibodies. Transfus
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10. Schumacher B, Moise KJ Jr. Fetal transfusion for red blood cell
alloimmunization in pregnancy. Obstet Gynecol
1996;88:13750.
11. Daniels G. Hadley A, Green CA. Causes of fetal anemia in
hemolytic disease due to anti-K [letter]. Transfusion
2003;43:1156.
12. Ahaded A, Brossard Y, Debbia M, Lambin P. Quantitative
determination of anti-K (KEL1) IgG and IgG subclasses in the
serum of severely alloimmunized pregnant women by ELISA.
13. Lo YM. Fetal DNA in maternal plasma: application to noninvasive blood group genotyping of the fetus. Transfus Clin
Biol 2001;8:30610.
14. Geifman-Holtzman O, Grotegut CA, Gaughan JP, Holtzman EJ,
Floro C, Hernandez E. Noninvasive fetal RhCE genotyping from
maternal blood. BJOG 2009;116:14451.
15. Scheffer PG, van der Schoot CE, Page-Christiaens GC, de Haas
M. Noninvasive fetal blood group genotyping of rhesus D, c, E
and of K in alloimmunised pregnant women: evaluation of a 7year clinical experience. BJOG 2011;118:13408.
16. Royal College of Obstetricians and Gynaecologists. The Use of
Anti-D Immunoglobulin for Rhesus D Prophylaxis. Green-top
17. Nicolaides KH, Rodeck CH. Maternal serum anti-D antibody
concentration and assessment of rhesus isoimmunisation. BMJ
1992;304:11556.
18. Kozlowski CL, Lee D, Shwe KH, Love EM. Quantification of antic in haemolytic disease of the newborn. Transfus Med
1995;5:3742.
19 of 26
19. Bowman JM, Pollock JM, Manning FA, Harman CR, Menticoglou
S. Maternal Kell blood group alloimmunization. Obstet Gynecol
1992;79:23944.
20. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R,
Moise KJ Jr, et al.; Collaborative Group for Doppler Assessment
of the Blood Velocity in Anemic Fetuses. Noninvasive diagnosis
by Doppler ultrasonography of fetal anemia due to maternal
red-cell alloimmunization. N Engl J Med 2000;342:914.
21. Bhide A, Acharya G, Bilardo CM, Brezinka C, Cafici D,
Hernandez-Andrade E, et al. ISUOG practice guidelines: use of
Doppler ultrasonography in obstetrics. Ultrasound Obstet
Gynecol 2013;41:2339.
22. British Committee for Standards in Haematology Transfusion
Task Force.Transfusion guidelines for neonates and older
children. Br J Haematol 2004;124:43353.
23. Transfusion Task Force. Amendments and corrections to the
'Transfusion Guidelines for neonates and older children'
(BCSH, 2004a); and to the 'Guidelines for the use of fresh
frozen plasma, cryoprecipitate and cryosupernatant' (BCSH,
2004b). Br J Haematol 2007;136:5146.
24. British Committee for Standards in Haematology. Guidelines for
pre-transfusion compatibility procedures in blood transfusion
laboratories. London: BCSH; 2012
[www.bcshguidelines.com/documents/Compat_Guideline_for
_submission_to_TTF_011012.pdf].
25. Advisory Committee on the Safety of Blood,Tissues and Organs
(SaBTO). Cytomegalovirus tested blood components: position
statement. London: Department of Health; 2012
[www.dh.gov.uk/en/Publicationsandstatistics/Publications/Publ
icationsPolicyAndGuidance/DH_132965].
26. Pilgrim H, Lloyd-Jones M, Rees A. Routine antenatal anti-D
prophylaxis for RhD-negative women: a systematic review and
economic evaluation. Health Technol Assess 2009;13(10).
27. Woodcock BE,Walker S,Adams K. Haemolytic transfusion
reactionsuccessful attenuation with methylprednisolone and
high dose immunoglobulin. Clin Lab Haematol 1993;15:5961.
28. Tinegate H, Birchall J, Gray A, Haggas R, Massey E, Norfolk D, et
al.; BCSH Blood Transfusion Task Force. Guideline on the
investigation and management of acute transfusion reactions.
Prepared by the BCSH Blood Transfusion Task Force. Br J
Haematol 2012;159:14353.
Intrapartum care: Care of healthy women and their babies
during childbirth. NICE clinical guideline 55. Manchester:
NICE; 2007.
30. National Institute for Health and Care Excellence. Neonatal
jaundice. NICE clinical guideline 98. Manchester: NICE; 2010.
31. Working Party of British Committee for Standards in
Haematology Blood Transfusion Task Force. Guidelines for
compatibility procedures in blood transfusion laboratories.
Transfus Med 2004;14:5973.
32. Millard DD, Gidding SS, Socol ML, MacGregor SN, Dooley SL,
Ney JA, et al. Effects of intravascular, intrauterine transfusion on
prenatal and postnatal hemolysis and erythropoiesis in severe
fetal isoimmunization. J Pediatr 1990;117:44754.
33. Zuppa AA, Alighieri G, Calabrese V, Visintini F, Cota F, Carducci
C, et al. Recombinant human erythropoietin in the prevention
of late anemia in intrauterine transfused neonates with Rhisoimmunization. J Pediatr Hematol Oncol 2010;32:e95e101.
34. Erduran E, Bahadir A.The effectiveness of recombinant human
erythropoietin (EPO) treatment in a neonate with
hyporegenerative anemia following Rh isoimmunization in
spite of normal serum Epo level [letter]. Pediatr Hematol
Oncol 2011;28:7212.
35. Zuppa AA, Alighieri G, Fracchiolla A, Catenazzi P, D'Antuono A,
Riccardi R, et al. Comparison between two treatment protocols
with recombinant human erythropoietin (rHuEpo) in the
treatment of late anemia in neonates with Rh-isoimmunization.
Pediatr Med Chir 2012;34:18691.
36. Hudon L, Moise KJ Jr, Hegemier SE, Hill RM, Moise AA, Smith
EO, et al. Long-term neurodevelopmental outcome after
intrauterine transfusion for the treatment of fetal hemolytic
disease. Am J Obstet Gynecol 1998;179:85863.
37. Ruma MS, Moise KJ Jr, Kim E, Murtha AP, Prutsman WJ, Hassan
SS, et al. Combined plasmapheresis and intravenous immune
globulin for the treatment of severe maternal red cell
alloimmunization. Am J Obstet Gynecol 2007;196:138.e16.
38. Novak DJ,Tyler LN, Reddy RL, Barsoom MJ. Plasmapheresis and
intravenous immune globulin for the treatment of D
alloimmunization in pregnancy. J Clin Apher 2008;23:1835.
39. Joy SD, Rossi KQ, Krugh D, O'Shaughnessy RW. Management of
pregnancies complicated by anti-E alloimmunization. Obstet
Gynecol 2005;105:248.
40. Chao AS, Chao A, Ho SY, Chang YL, Lien R. Anti-E
alloimmunization: a rare cause of severe fetal hemolytic disease
resulting in pregnancy loss. Case Report Med
2009;2009:471623.
41. Wikman A, Edner A, Gryfelt G, Jonsson B, Henter JI. Fetal
hemolytic anemia and intrauterine death caused by anti-M
immunization. Transfusion 2007;47:9117.
42. Bowman JM, Harman FA, Manning CR, Pollock JM.
Erythroblastosis fetalis produced by anti-k. Vox Sang
1989;56:1879.
20 of 26
Appendix I: Red cell antibodies showing published clinical significance

Antibody
HDFN
Haemolytic transfusion reaction
Severe in fetus and neonate
Severe
Severe
Severe
c+E
Severe in fetus and neonate*
Severe
Yes in neonate*
Yes
Yes in neonate*
Yes
Yes in neonate
Yes
39,40
Ce
Yes in neonate
Fy
Yes in neonate*
Yes
Fy
Yes in neonate
Yes
Fy
No
Yes
Jk
Yes in neonate*
Yes
Jkb
No
Yes
Yes in neonate
Yes
Yes in neonate
Yes
Yes in neonate*
Yes (occasionally)*
Yes (if active at 37C)
Mild (1 case)
Yes
H (Bombay)
Yes in neonate*
Yes
Yes in neonate
Yes
Yes in neonate*
Yes
Kp
Yes (in neonate occasionally)
No
Yes (in neonate occasionally)
No
Vel
No
Yes
Yes
6
Yes
41
42
Anti-D, -c and -K are the three main antibodies that have been reported to cause severe anaemia, jaundice or death in the fetus or neonate.
Many other antibodies (*) can cause anaemia or jaundice predominantly in the neonatal period but there have also been occasional case
reports of the fetus being severely affected.
The antibodies listed in the table above are the most common, clinically significant antibodies. Other rarer
antibodies can cause HDFN and haemolytic transfusion reactions occasionally. For further advice, discussion
with the transfusion laboratory and/or consultant haematologist would be beneficial.
21 of 26
Appendix II: Timing and frequency of antibody screening in pregnancy
At booking
All pregnant women
ABO + RhD* typing
Antibody screen
Clinically significant antibody screen

positive (see 6.2)
Anti-D, -c or-K
antibodies**
Test monthly until
28 weeks
See Appendix 3
From 28 weeks:
Test 2 weekly until
delivery
See Appendix 3
No clinically significant
antibodies
All other clinically

significant antibodies
(see 6.2)
Consider paternal/fetal
genotyping for
corresponding antigen(s)
(see 6.4)
Repeat testing at
28 weeks
Repeat antibody screen

at 28 weeks
Cord blood for:

DAT, Hb, bilirubin
No antibodies
No further action
Clinically significant
antibodies
* If RhD-negative mother with no immune anti-D antibodies then advise anti-D prophylaxis for any potentially
sensitising events in pregnancy and give routine antenatal anti-D prophylaxis either RAADP single dose or
two doses (see RCOG anti-D guidelines); after delivery check cord sample for RhD type and maternal sample
for fetomaternal haemorrhage (e.g. Kleihauer) testing to check if further anti-D needed in addition to the
standard dose which should be given in the first instance after delivery.
** Pregnancies with immune anti-D, -K or -c are at particular risk of severe fetal HDFN so further early assessment
and referral to fetal medicine specialist is indicated (see 6.7).
Legend
DAT direct antiglobulin test; Hb haemoglobin; RAADP routine antenatal anti-D prophylaxis
22 of 26
23 of 26
Legend
Ab antibody
Bili bilirubin
DAT direct antiglobulin test
ffDNA free fetal DNA
Hb haemoglobin
HDFN haemolytic disease of the fetus and newborn
IUT intrauterine transfusion
MCA Doppler middle cerebral artery Doppler
Mod moderate
Pos/Neg positive/negative
US ultrasound
Cord blood Hb, Bili, DAT
Deliver at 37 weeks
Refer to specialist unit

Fetus US, MCA Doppler
IUT if needed
FETUS AT RISK OF HDFN
D Pos
K Neg
K Pos
Homozygous
D Pos
Test father
D Neg
Heterozygous
D Pos
ffDNA
Homozygous
Heterozygous
K Neg
Non-invasive prenatal diagnosis
Or
Anti-D antibodies
Quantitate Ab level
415 iu/ml mod risk HDFN
> 15 iu/ml severe risk HDFN
ffDNA
K Pos
Test father
K Pos
Or
Anti-K antibodies
Titre Ab
D Neg
c Pos
ffDNA
Homozygous
c Pos
Test father
c Neg
Heterozygous
c Pos
Or
Anti-c antibodies
Quantitate Ab level
7.520 iu/ml mod risk HDFN
> 20 iu/ml severe risk HDFN
Appendix III: Management algorithm for pregnancies complicated with anti-D, anti-K or anti-c alloimmunisation
c Neg
Appendix IV: List of abbreviations

ART
BCSH
CMV
CPD
DAT
FBS
ffDNA
HDFN
HTR
IAT
IgG
IUT
MCA PSV
MoM
NICE
PCV
RAADP
RhD
SAGM
assisted reproductive techniques

British Committee for Standards in Haematology
cytomegalovirus
citrate phosphate dextrose
direct antiglobulin test
fetal blood sampling
free fetal DNA
haemolytic disease of the fetus and newborn
haemolytic transfusion reaction
indirect antiglobulin test
immunoglobulin G
intrauterine transfusion
middle cerebral artery peak systolic velocities
multiples of the median
National Institute for Health and Care Excellence
packed cell volume
routine antenatal anti-D prophylaxis
rhesus D
saline-adenine-glucose-mannitol
24 of 26

at http://www.rcog.org.uk/files/rcog-corp/CGA1dConsensusMethods.pdf). These recommendations are
not intended to dictate an exclusive course of management or treatment. They must be evaluated with
reference to individual patient needs, resources and limitations unique to the institution and variations
in local populations. It is hoped that this process of local ownership will help to incorporate these
guidelines into routine practice.Attention is drawn to areas of clinical uncertainty where further research
may be indicated. The evidence used in this guideline was graded using the scheme below and the
recommendations formulated in a similar fashion with a standardised grading scheme.

1+

low risk of bias

risk of bias

2+



case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
25 of 26

development group
This guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and Gynaecologists by:
Professor SK Surendran FRCOG, Brisbane, Australia; Dr S Allard MD FRCP FRCPath, Barts and the London NHS Trust
and NHS Blood and Transplant, London; and Dr F Regan FRCP FRCPath, Imperial College Healthcare NHS Trust and
NHS Blood and Transplant, London
and peer-reviewed by:
Mr SA Abdel-Fattah FRCOG, Bristol; Dr ACG Breeze MRCOG, Kingston upon Thames; Dr JE Brennand FRCOG, Glasgow;
The British Committee for Standards in Haematology (BCSH); British Maternal and Fetal Medicine Society (BMFMS);
Dr HM Cameron FRCOG, Sunderland; Mrs AHD Diyaf MRCOG, Barnstaple; Dr NJ Engineer MRCOG, Coventry;
Mr OS Eskandar FRCOG, Barnstaple; NHS Blood and Transplant (NHSBT); Northern Ireland Blood Transfusion Service;
Dr AOS Olawo MRCOG, Rotherham; Mr TG Overton FRCOG, Bristol; Dr KP Rege, Peterborough City Hospital, Peterborough;
RCOG Womens Network; Scottish Clinical Transfusion Advisory Committee (SCTAC) Group; Dr N Singh MRCOG, Bolton;
Mrs P Sinha FRCOG, St Leonards-on-Sea; UK National Screening Committee; Watch Tower Bible and Tract Society of Britain;
Ms A Wijemanne MRCOG, London.
Committee lead reviewers were: Dr P Owen FRCOG, Glasgow, Scotland; Ms J Elson FRCOG, Leicester; and
Dr M Gupta MRCOG, London.
Conflicts of interest: None declared.
DISCLAIMER
health services.
26 of 26
Management of Beta Thalassaemia

in Pregnancy
March 2014
Management of Beta Thalassaemia in Pregnancy

1.
Purpose and scope
The purpose of this guideline is to produce evidence-based guidance on the management of women with
beta () thalassaemia major and intermedia in pregnancy. In this guideline, thalassaemia major women are
those who require more than seven transfusion episodes per year and thalassaemia intermedia women are
those needing seven or fewer transfusion episodes per year or those who are not transfused.Women who are
thalassaemia carriers do not require transfusion. It will include preconceptual, antenatal, intrapartum and
postnatal management and contraception in both primary and secondary care settings. It will not cover
screening as the British Committee for Standards in Haematology has published guidelines for screening and
diagnosis of thalassaemias.1
2.
Haemoglobinopathies are one of the most common inherited disorders. More than 70 000 babies are born
with thalassaemia worldwide each year2 and there are 100 million individuals who are asymptomatic
thalassaemia carriers. The basic defect in the thalassaemia syndromes is reduced globin chain synthesis with
the resultant red cells having inadequate haemoglobin content. The pathophysiology of thalassaemia
syndromes is characterised by extravascular haemolysis due to the release into the peripheral circulation of
damaged red blood cells and erythroid precursors because of a high degree of ineffective erythropoiesis.3
Thalassaemia major (homozygous thalassaemia) results from the inheritance of a defective globin gene
from each parent. This results in a severe transfusion-dependent anaemia. The heterozygous state,
thalassaemia trait (thalassaemia minor) causes mild to moderate microcytic anaemia with no significant
detrimental effect on overall health.
Thalassaemia intermedia is defined as a group of patients with thalassaemia whose disease severity varies.
At the severe end of the clinical spectrum of thalassaemia intermedia, patients are usually diagnosed between
the ages of two and six years and, although they survive without regular blood transfusions, growth and
development are impaired. At the other end of the spectrum, there are patients who are completely
asymptomatic until adulthood, when they present with mild anaemia and splenomegaly often found by
chance during haematological examinations or family studies. The diagnosis is dependent on the patient
maintaining a satisfactory haemoglobin (Hb) level at the time of diagnosis without the need for regular blood
transfusions. Patients with severe forms of thalassaemia intermedia and those patients with thalassaemia
major who had poor access to blood were previously offered splenectomy to help reduce transfusion
requirements. Splenectomy is no longer the mainstay of treatment for these conditions but a considerable
number of both thalassaemia major and intermedia patients have undergone splenectomy.2,4
The cornerstones of modern treatment in thalassaemia are blood transfusion and iron chelation therapy.5
Multiple transfusions cause iron overload resulting in hepatic, cardiac and endocrine dysfunction.The anterior
pituitary is very sensitive to iron overload and evidence of dysfunction is common.6 Puberty is often delayed
and incomplete, resulting in low bone mass.7 Most of these women are subfertile due to hypogonadotrophic
hypogonadism and therefore require ovulation induction therapy with gonadotrophins to achieve a
pregnancy.810 Cardiac failure is the primary cause of death in over 50% of cases.11 Improved transfusion
techniques and effective chelation protocols have improved the quality of life and survival of individuals with
thalassaemia.12,13 The mortality from cardiac iron overload has reduced significantly since the development of
magnetic resonance imaging (MRI) methods for monitoring cardiac (cardiac T2*) and hepatic iron overload
(liver T2*) and FerriScan liver iron assessment (FerriScan, Resonance Health, Australia).These methods are
now available in most large centres looking after patients with haemoglobinopathies.
2 of 17
There are approximately 1000 individuals affected by thalassaemia major or intermedia syndromes in the UK.
The absolute number of affected individuals is unclear and is currently being assessed nationally as part of the
National Haemoglobinopathy Registry. Previously, the community affected was principally from Cyprus and the
Mediterranean. However, currently the Asian communities of India, Pakistan and Bangladesh account for 79% of
thalassaemia births with only 7% occurring in the Cypriot population who have taken advantage of the
availability of prenatal diagnosis.14 High incidence areas include Greater London, Birmingham and Manchester.
The NHS Sickle Cell and Thalassaemia Screening Programme in England during 2009/10 identified
approximately 16 000 women as carriers of a haemoglobinopathy and partner testing was offered. 59% of
screen positive women had partner testing and 1006 couples were identified as being at high risk of having a
child with a clinically significant haemoglobinopathy (sickle cell disease or thalassaemia). 396 couples accepted
the offer of prenatal diagnosis, which revealed 23 pregnancies affected by thalassaemia and 46 fetuses that were
carriers of thalassaemia.The majority of pregnancies affected by thalassaemia major were terminated.15
3.
Guidelines. Databases searched included the Cochrane Database of Systematic Reviews, DARE, EMBASE,TRIP,
Medline and PubMed. Search terms included:beta thalassaemia,Cooley's anaemia,Mediterranean anaemia,
hypogonadotrophic hypogonadism, ovulation induction, assisted reproduction, iron burden, serum
ferritin, penicillin prophylaxis, iron chelation, fetal growth and measurement and ultrasonography. The
search was limited to humans and the English language and from 1980 to July 2013. Exclusions were alpha
thalassaemia or beta thalassaemia minor.There are no systematic reviews in this area and only small numbers
of randomised controlled trials looking at particular interventions.The National Guideline Clearinghouse was
also searched for relevant guidelines and reviews. Where possible, recommendations are based on available
evidence. Areas lacking evidence are highlighted and annotated as Good Practice Points.
4.
Preconception care
4.1 What are the additional risks to the woman and baby?
Thalassaemia is associated with an increased risk to both mother and baby. In particular, there are the issues
surrounding cardiomyopathy in the mother due to iron overload and the increased risk of fetal growth
restriction (FGR). In addition, with around 9 months of little or no chelation, women with thalassaemia major
may develop new endocrinopathies: in particular, diabetes mellitus, hypothyroidism and hypoparathyroidism
due to the increasing iron burden.7,16
4.2 What is the optimum preconceptual care for women with thalassaemia?
At each visit with the thalassaemia team, there should be a discussion and documentation of intentions
regarding pregnancy. This should include screening for end-organ damage and optimisation of
complications prior to embarking on any pregnancy.
Each Specialist Haemoglobinopathy Centre should have a guideline for the management of pregnant
women with thalassaemia.
Women should be advised to use contraception despite the reduced fertility associated with
thalassaemia.
Fertility may be reduced in transfusion-dependent individuals where chelation has been suboptimal
and iron overload has occurred resulting in damage to the anterior pituitary.8,10,17 They may require
ovulation induction using injectable gonadotrophins to conceive.
3 of 17
Evidence
level 2+
There is no contraindication to the use of hormonal methods of contraception such as the

combined oral contraceptive pill, the progestogen-only pill, the Nexplanon implant (Merck Sharp
& Dohme Limited, Hoddesdon, Herts, UK) and the Mirena intrauterine system (Bayer plc,
Newbury, Berks, UK) in women with thalassaemia.18
Evidence
level 4
Women with thalassaemia are best cared for in a multidisciplinary team setting, including an obstetrician with
expertise in managing high-risk pregnancies and a haematologist. This team should provide prepregnancy
counselling so that the woman is fully informed about how thalassaemia affects pregnancy and vice versa.The
preconception evaluation involves a review of transfusion requirements, compliance with chelation therapy
and assessment of the body iron burden. The assessment should include optimisation of management and
screening for end-organ damage.
At both local and specialist centres, the womans aspirations regarding pregnancy and contraception should be
explored in consultation and discussion with the haemoglobinopathy team so that the decision making is
shared. This should be done well in advance of the proposed pregnancy because a prolonged period of iron
chelation therapy may be required to control iron overload prior to both induction of ovulation and pregnancy.
4.3 Are there any interventions which are beneficial at the preconceptual stage?
Aggressive chelation in the preconception stage can reduce and optimise body iron burden and reduce
end-organ damage.
There is evidence from clinical trials that optimising body iron reduces end-organ damage and can
reverse cardiac iron loading. Longitudinal studies show that patients who have been optimally
chelated are less likely to suffer from endocrinopathies or cardiac problems.1923
Evidence
level 1+
Due to lack of safety data, all chelation therapy should be regarded as potentially teratogenic in the
first trimester. Desferrioxamine is the only chelation agent with a body of evidence for use in the
second and third trimester.2426 The optimisation of iron burden is therefore critical as the ongoing
iron accumulation from transfusion in the absence of chelation may expose the pregnant woman to
a high risk of new complications related to iron overload, particularly diabetes and cardiomyopathy.
Evidence
level 1-
4.3.1 Pancreas
Diabetes is common in women with thalassaemia. Women with diabetes should be referred to a
diabetologist. Good glycaemic control is essential prepregnancy.
Women with established diabetes mellitus should ideally have serum fructosamine concentrations
< 300 nmol/l for at least 3 months prior to conception. This is equivalent to an HbA1c of 43 mmol/mol.
Diabetes mellitus is common in adults with thalassaemia. Diabetes is multifactorial, due to insulin
resistance, iron-induced islet cell insufficiency, genetic factors and autoimmunity.27 Similar to
women with diabetes without thalassaemia, an HbA1c of less than 43 mmol/mol is associated with
a reduced risk of congenital abnormalities.28 HbA1c is not a reliable marker of glycaemic control as
this is diluted by transfused blood and results in underestimation, so serum fructosamine is
preferred for monitoring.29
Evidence
level 3
4.3.2 Thyroid
Thyroid function should be determined. The woman should be euthyroid prepregnancy.
Hypothyroidism is frequently found in patients with thalassaemia. Untreated hypothyroidism can

result in maternal morbidity, as well as perinatal morbidity and mortality. Patients should be
4 of 17
B
Evidence
level 2++
assessed for thyroid function as part of the preconceptual planning and, if known to be
hypothyroid, treatment initiated to ensure that they are clinically euthyroid.30
Evidence
level 2++
4.3.3 Heart
All women should be assessed by a cardiologist with expertise in thalassaemia and/or iron overload
prior to embarking on a pregnancy.
An echocardiogram and an electrocardiogram (ECG) should be performed as well as T2* cardiac MRI.
It is important to determine how well the cardiac status of the woman will support a pregnancy as well as
the severity of any iron-related cardiomyopathy. Cardiac arrhythmias are more likely in older patients who
have previously had severe myocardial iron overload and are now clear of cardiac iron.
The aim is for no cardiac iron, but this can take years to achieve so care should be individualised to
the woman. Otherwise, aim for cardiac T2* > 20 ms wherever possible as this reflects minimal iron
in the heart. However, pregnancies with successful maternal and fetal outcomes have occurred with
lower cardiac T2* values. A T2* < 10 ms is associated with an increased risk of cardiac failure.31 A
reduced ejection fraction is a relative contraindication to pregnancy and the management should be
the subject of multidisciplinary discussions involving a cardiologist with experience of cardiac
pathology in pregnancy, a maternal medicine specialist, a haematologist and an obstetric anaesthetist.
Evidence
level 4
4.3.4 Liver
Women should be assessed for liver iron concentration using a FerriScan or liver T2*. Ideally the liver
iron should be < 7 mg/g (dry weight) (dw).
Liver and gall bladder (and spleen if present) ultrasound should be used to detect cholelithiasis and
evidence of liver cirrhosis due to iron overload or transfusion-related viral hepatitis.
A target liver iron of less than 7 mg/g (dw) is recommended because iron chelation is discontinued during
pregnancy and therefore transfusional iron burden and the risk of iron overload-related complications
increases. Anecdotally, ovulation induction is more likely to be successful when iron burden is well controlled.
If liver iron exceeds the target range, a period of intensive preconception chelation is required to optimise
liver iron burden.
If liver iron exceeds 15 mg/g (dw) prior to conception, the risk of myocardial iron loading increases
so iron chelation with low-dose desferrioxamine should be commenced between 20 and 28 weeks
under guidance from the haemoglobinopathy team.32
Evidence
level 3
Cholelithiasis is common in women with thalassaemia due to the underlying haemolytic anaemia and they
may develop cholecystitis in pregnancy. Liver cirrhosis and active hepatitis C (HCV) may run a more complex
clinical course during pregnancy. Women who are HCV RNA-positive should be reviewed by their
hepatologist preconceptually. Women who have any evidence of cirrhosis, either due to previous hepatitis or
as a consequence of severe hepatic iron loading, should be reviewed by a hepatologist.
4.3.5 Bone density scan
All women should be offered a bone density scan to document pre-existing osteoporosis.
Serum vitamin D concentrations should be optimised with supplements if necessary.
5 of 17
Osteoporosis is a common finding in adults with thalassaemia.33 The pathology is complex, but
thought to be due to a variety of factors including underlying thalassaemic bone disease, chelation
of calcium by chelation drugs, hypogonadism and vitamin D deficiency.34
Evidence
level 4
Most women with thalassaemia syndromes are vitamin D deficient and often osteoporotic as well.
All women should have vitamin D levels optimised before pregnancy and thereafter maintained in
the normal range.34
4.3.6 Red cell antibodies
ABO and full blood group genotype and antibody titres should be measured.
35
Alloimmunity occurs in 16.5% of individuals with thalassaemia. Red cell antibodies may indicate
a risk of haemolytic disease of the fetus and newborn.36 If antibodies are present there may be
challenges in obtaining suitable blood for transfusion.37
Evidence
level 4
4.4 What medications should be reviewed preconceptually?

Iron chelators should be reviewed and deferasirox and deferiprone ideally discontinued 3 months
before conception.
Women with thalassaemia are often on a range of drugs, some of which may be teratogenic, e.g.
deferiprone. Animal studies with deferasirox did not show teratogenicity.38 However, there is only
limited safety data on its use in pregnancy. Deferasirox and deferiprone should ideally be
discontinued 3 months before conception and women converted to desferrioxamine iron chelation.
Evidence
level 4
Desferrioxamine has a short half-life and is safe for infusion during ovulation induction therapy.
Desferrioxamine should be avoided in the first trimester owing to lack of safety data. It has been
used safely after 20 weeks of gestation at low doses.26
Evidence
level 3
All bisphosphonates are contraindicated in pregnancy and should ideally be discontinued 3 months prior to
conception in accordance with the product safety information sheet.
4.5 What is the importance of genetic screening and what procedure(s) are involved for women with
thalassaemia?
If the partner is a carrier of a haemoglobinopathy that may adversely interact with the womans
genotype then genetic counselling should be offered.
In vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) with a pre-implantation genetic

diagnosis (PGD) should be considered in the presence of haemoglobinopathies in both partners so that
a homozygous or compound heterozygous pregnancy can be avoided.
Egg and sperm donors considering IVF should be screened for haemoglobinopathies.
Preconception counselling for women with thalassaemia includes partner screening and genetic
counselling (Table 1) as well as the methods and risks of prenatal diagnosis and termination of
pregnancy.39 In high-risk couples PGD is an option. If the partner is unavailable, an offer of prenatal
testing is appropriate. Due to the risk of a haemoglobinopathy, potential egg and sperm donors are
screened for haemoglobinopathies.
6 of 17
Evidence
level 4
Table 1: Conditions requiring counselling where the mother is affected by thalassaemia

Carrier or sufferer condition in partner
Affected offspring
Beta thalassaemia
HbS
HbE
Delta beta thalassaemia
Hb Lepore
HbO Arab
Hb Constant Spring
Risk of serious haemoglobinopathy applies to all
HbC
Other variant haemoglobin
Risk of a mild to moderate disorder
4.6 What is the importance of immunisation and antibiotic prophylaxis in women who are at risk of
transfusion-related viral infections or have had a previous splenectomy?
Hepatitis B vaccination is recommended in HBsAg negative women who are transfused or may be
transfused.
Hepatitis C status should be determined.
All women who have undergone a splenectomy should take penicillin prophylaxis or equivalent.
All women who have undergone a splenectomy should be vaccinated for pneumococcus and
Haemophilus influenzae type b if this has not been done before.
Women who are transfused regularly or intermittently are at risk of transfusion-transmitted

infections. It is therefore important to ascertain infectivity and manage the common transfusionrelated viral infections appropriately.40
Evidence
level 4
The majority of women with thalassaemia major will have been immunised against hepatitis B but some
women with thalassaemia intermedia may not.
Hepatitis C is a common and often asymptomatic virus, so all women who are transfused require hepatitis C
antibody testing. If a woman has a positive hepatitis C test, RNA titres should be determined with referral to
a hepatologist.
Women who have undergone splenectomy are at risk of infection from encapsulated bacteria such
as Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type b. UK
guidance is that daily penicillin prophylaxis is given to all high-risk splenectomised patients.41
Women who are allergic to penicillin should be recommended erythromycin.
Evidence
level 4
In addition, women should be given Haemophilus influenzae type b and the conjugated
meningococcal C vaccine as a single dose if they have not received it as part of primary
vaccination. The pneumococcal vaccine (such as PneumovaxII, Sanofi Pasteur MSD Limited,
Maidenhead, UK) should be given every 5 years.41
Evidence
level 2+
4.7 What vitamin supplements should be recommended?

Folic acid (5 mg) is recommended preconceptually to all women to prevent neural tube defects.
Women with thalassaemia have a much higher demand for folic acid so high-dose supplementation
is needed. Folic acid 5 mg daily should be commenced 3 months prior to conception.42,43
7 of 17
A
Evidence
level 1++
5. Antenatal care
5.1 How is specialist input delivered for women with thalassaemia?

Women with thalassaemia should be reviewed monthly until 28 weeks of gestation and fortnightly
thereafter. The multidisciplinary team should provide routine as well as specialist antenatal care.
Women with both thalassaemia and diabetes should have monthly assessment of serum fructosamine
concentrations and review in the specialist diabetic pregnancy clinic.
All women with thalassaemia major should undergo specialist cardiac assessment at 28 weeks of
gestation and thereafter as appropriate.
Thyroid function should be monitored during pregnancy in hypothyroid patients.
The multidisciplinary team should include an obstetrician, a midwife with experience of high-risk antenatal
care and a haematologist with an interest in thalassaemia. A diabetologist and cardiologist may also provide
additional specialist input.
The pattern of care should be individualised depending on the degree of end-organ damage and women with
diabetes or cardiac dysfunction may be reviewed more frequently.
Cardiac assessment is important to determine cardiac function and possible further iron chelation as well as
planning for labour.
Thyroid function should be determined periodically throughout pregnancy and if hypothyroid the dose of
thyroxine altered.
5.2 What is the recommended schedule of ultrasound scanning during pregnancy?

Women should be offered an early scan at 79 weeks of gestation.
In addition to the routine first trimester scan (1114 weeks of gestation) and a detailed anomaly scan at
1820+6 weeks of gestation, women should be offered serial fetal biometry scans every 4 weeks from 24
weeks of gestation.
Women with both thalassaemia and diabetes have a higher risk of early pregnancy loss. Fertility treatment
with ovulation induction is often required to achieve pregnancy so an early scan is indicated to determine
viability as well as the presence of a multiple pregnancy.
Severe maternal anaemia predisposes to FGR in women with thalassaemia.4446 Chronic anaemia
affects placental transfer of nutrients and can therefore adversely affect fetal growth.
Evidence
level 3
5.3 How should the transfusion regimen be managed during pregnancy in women with thalassaemia major?
All women with thalassaemia major should be receiving blood transfusions on a regular basis aiming
for a pretransfusion haemoglobin of 100 g/l.
Women with thalassaemia major will already be established on transfusion regimens which generally remain
stable during pregnancy. In cases where lower pretransfusion thresholds have been used preconceptually, the
aim is to achieve a pretransfusion haemoglobin of 100 g/l.
5.4 How should the transfusion regimen be managed during pregnancy in women with thalassaemia
intermedia?
8 of 17
If there is worsening maternal anaemia or evidence of FGR, regular transfusions should be considered.
If a woman with thalassaemia intermedia starts transfusion, haemoglobin targets are managed as for
thalassaemia major.
Women with thalassaemia intermedia who are asymptomatic with normal fetal growth and low
haemoglobin should have a formal plan outlined in the notes with regard to blood transfusion in late
pregnancy.
The decision to initiate a transfusion regimen is a clinical one based on the womans symptoms and fetal
growth. If there is worsening maternal anaemia or evidence of FGR, regular transfusions should be started
aiming for maintenance of pretransfusion haemoglobin concentration above 100 g/l. Initially a 23 unit
transfusion should be administered with additional top-up transfusion if necessary the following week until
the haemoglobin reaches 120 g/l.
The haemoglobin should be monitored after 2 to 3 weeks and a 2-unit transfusion administered if the
haemoglobin has fallen below 100 g/l. Each womans haemoglobin falls at different rates after transfusion so
close surveillance of pretransfusion haemoglobin concentrations is required.
Generally, in nontransfused patients, if the haemoglobin is above 80 g/l at 36 weeks of gestation, transfusion
can be avoided prior to delivery. Postnatal transfusion can be provided as necessary.
If the haemoglobin is less than 80 g/l then aim for a top-up transfusion of 2 units at 3738 weeks of gestation.
5.5 What antenatal thromboprophylaxis is recommended?

Women with thalassaemia who have undergone splenectomy or have a platelet count greater than
600 x 109/l should commence or continue taking low-dose aspirin (75 mg/day).
Women with thalassaemia who have undergone splenectomy and have a platelet count above
600 x 109/l should be offered low-molecular-weight heparin thromboprophylaxis as well as low-dose
aspirin (75 mg/day).
Women with thalassaemia who are not already using prophylactic low-molecular-weight heparin
should be advised to use it during antenatal hospital admissions.
Women with thalassaemia major or intermedia have a prothrombotic tendency due to the presence of
abnormal red cell fragments, especially if they have undergone splenectomy. These red cell fragments
combined with a high platelet count significantly increase the risk of venous thromboembolism. This
risk is highest in splenectomised women with thalassaemia intermedia who are not receiving
transfusions since a good transfusion regimen suppresses endogenous erythropoiesis.47,48
Evidence
level 4
5.6 What is the optimum antenatal management of iron chelation therapy?

Iron chelation therapy is complex and should be tailored to the needs of the individual woman.
The chelation should be managed by a haematologist with experience in iron chelation therapy particularly
during pregnancy.
5.6.1 Management of women with myocardial iron
Women with myocardial iron loading should undergo regular cardiology review with careful monitoring
of ejection fraction during the pregnancy as signs of cardiac decompensation are the primary indications
for intervention with chelation therapy.
9 of 17
Those women at highest risk of cardiac decompensation should commence low-dose subcutaneous
desferrioxamine (20 mg/kg/day) on a minimum of 45 days a week under joint haematology and
cardiology guidance from 2024 weeks of gestation.
Cardiac MRI is safe in pregnancy and should be undertaken in women who have not received
preconceptual assessment or where there is concern about cardiac function. As the cardiac T2*
value falls below 20 ms there is an increasing risk of cardiac decompensation. Those women at
highest risk are those where the value is below 10 ms.31
Evidence
level 2+
Women with myocardial iron loading and T2* > 20 ms do not require desferrioxamine chelation during
pregnancy unless there is severe hepatic iron overload.
Women with thalassaemia major and myocardial iron loading with T2* of < 10 ms are at high risk of cardiac
decompensation which may present as increasing breathlessness, paroxysmal nocturnal dyspnoea,
orthopnoea, syncope, palpitations or peripheral oedema. Presentation in the first trimester is associated with
adverse clinical outcome.
If a woman describes symptoms of palpitations then a cardiac assessment is appropriate. A falling
ejection fraction or increasing ventricular volumes on echocardiography will suggest increasing
risk of developing heart failure. If the woman complains of palpitations then a detailed history, ECG
and 24 hour ECG monitor assessment are needed to confirm a pathological cause. In either
circumstance desferrioxamine infusions may be indicated if there are concerns.22,49,50
Evidence
level 2+
5.6.2 Management of women with liver iron

Women with severe hepatic iron loading should be carefully reviewed and consideration given to lowdose desferrioxamine iron chelation from 20 weeks.
High concentrations of liver iron (liver iron > 15 mg/g dw as measured by MRI) are associated with an
increased risk of myocardial iron and in all women with thalassaemia major the therapeutic aim is to
achieve a liver iron concentration below 15 mg/g dw to reduce the risk of myocardial iron overload.32
P
Evidence
level 2
6. Intrapartum care
6.1 What is the best intrapartum management for women with thalassaemia major or intermedia?
Timing of delivery should be in line with national guidance.
Senior midwifery, obstetric, anaesthetic and haematology staff should be informed as soon as the
woman is admitted to the delivery suite.
In the presence of red cell antibodies, blood should be cross-matched for delivery since this may delay
the availability of blood. Otherwise a group and save will suffice.
In women with thalassaemia major intravenous desferrioxamine 2 g over 24 hours should be administered
for the duration of labour.
Continuous intrapartum electronic fetal monitoring should be instituted.
Thalassaemia in itself is not an indication for caesarean section.
10 of 17
There is no specific evidence regarding the timing or mode of delivery for women with thalassaemia.
The timing of delivery should be based on national guidelines dependent on any issues identified in
the pregnancy (e.g. diabetes or FGR) but if otherwise uncomplicated the delivery can be planned
according to local guidelines.51
Evidence
level 4
If there are medical complications such as cardiomyopathy, a detailed management plan formulated during
the pregnancy should be in the womans notes.
Depending on the timing of the last blood transfusion, the woman may well have a low haemoglobin. If the
haemoglobin is less than 100 g/l, cross-match 2 units on admission to the labour ward.
Women who are transfusion-dependent and not on a chelating agent will have high serum concentrations of a toxic
iron species known as non-transferrin bound iron. These may cause free radical damage and cardiac dysrhythmia
when the woman is subjected to the stress of labour.52 Peripartum chelation therapy is therefore recommended.
Continuous electronic fetal monitoring is recommended as women with thalassaemia are considered to be at
an increased risk of operative delivery due to possible fetal hypoxia.53
Women with thalassaemia may have a low haemoglobin at the time of delivery and there is
randomised controlled trial evidence that the active management of labour reduces blood loss.37,54
Evidence
level 1++
6.2 Postpartum care

6.2.1 What should be the optimum care post delivery?
Women with thalassaemia should be considered at high risk for venous thromboembolism.
Breastfeeding is safe and should be encouraged.
There is a high risk of venous thromboembolism due to the presence of abnormal red cells in the
circulation. Women should receive low-molecular-weight heparin prophylaxis while in hospital.47,55,56
Evidence
level 4
In addition, low-molecular-weight heparin should be administered for 7 days post discharge

following vaginal delivery or for 6 weeks following caesarean section.56
Women with thalassaemia major who plan to breastfeed should restart desferrioxamine as soon as the initial
24-hour infusion of intravenous desferrioxamine finishes after delivery. Desferrioxamine is secreted in breast
milk but is not orally absorbed and therefore not harmful to the newborn. There is minimal safety data on
other iron chelators.
If a woman decides not to breastfeed, intravenous or subcutaneous desferrioxamine infusions are continued
until discharge from hospital or until resumption of her previous iron chelation regimen under haematology
supervision, whichever is sooner.
7. Auditable topics
Pregnancies in women with thalassaemias are relatively few in number. Audit should be approximately every
3 years and should address the following:
preconceptual compliance with targets for liver iron, cardiac iron and fructosamine
thalassaemia intermedia pregnancy outcomes, especially indications for transfusion, management of maternal
anaemia in nontransfused patients and FGR
compliance with prophylaxis against venous thromboembolic disease in women who have undergone
splenectomy.
11 of 17
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27. de Assis RA, Ribeiro AA, Kay FU, Rosemberg LA, Nomura CH,
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Appendix I: Booking appointment

Offer information, advice and support in relation to optimising general health.
Discuss information, education and advice about how thalassaemia will affect pregnancy.
Primary care or hospital appointment offer partner testing if not already done, review partner results if available and discuss prenatal
diagnosis (chorionic villus sampling, amniocentesis or cell-free fetal DNA) if appropriate.
Take a clinical history to establish the extent of thalassaemia complications. Women with diabetes to be referred to joint diabetes pregnancy
clinic with haematology input.
Review medications e.g. chelators such as deferiprone or deferasirox.
Women should be taking 5 mg folic acid.
Women who have had a splenectomy should receive antibiotic prophylaxis.
Discuss vaccinations with those women who have had a splenectomy.
Offer MRI heart and liver (T2* and FerriScan) if these have not been performed in the previous year for thalassaemia major patients only.
Determine presence of any red cell antibodies.
Document blood pressure.
Send midstream specimen of urine for culture.
Confirm viability with ultrasound.
14 of 17
Appendix II: Schedule of antenatal appointments

1114 weeks
Midwife with high-risk obstetric experience. Review partner results and discuss prenatal diagnosis if appropriate. Confirm that all actions from
first visit are complete. Continue folic acid 5 mg.
16 weeks
Midwife and multidisciplinary review (haematologist, obstetrician and diabetologist if diabetic).
20 weeks
Midwife and multidisciplinary review.
2024 weeks
Women assessed with risks of cardiac decompensation should start on low-dose subcutaneous desferrioxamine (20 mg/kg/day) on a
minimum of 4 to 5 days a week under guidance of a haematologist with experience in iron chelation.
Women with T2* > 10 but < 20 ms should be assessed for risks and consideration given to starting desferrioxamine infusions if there are
concerns.
Women with T2* > 20 ms (optimal preconception result) should not be given any desferrioxamine chelation during pregnancy unless there is
severe hepatic iron overload.
24 weeks
Ultrasound for fetal biometry.
28 weeks
Midwife and multidisciplinary review. Ultrasound for fetal biometry.
Specialist cardiology review and formulation of delivery plan based on cardiac function.
30 weeks
Midwife for routine assessment.
32 weeks
Ultrasound for biometry.
34 weeks
36 weeks
Midwife and multidisciplinary review. A care plan regarding the delivery should be formulated by the team and documented in the notes.
Ultrasound for fetal biometry.
Offer information and advice about:
Timing, mode and management of the birth
Analgesia and anaesthesia; arrange anaesthetic assessment if cardiac dysfunction
Care of baby after birth.
38 weeks
Midwife and obstetrician for routine assessment.
Offer induction of labour if the woman has diabetes.
39 weeks
40 weeks
Obstetrician for routine assessment.
41 weeks
Obstetrician for routine assessment.
For a nondiabetic woman with normal fetal growth and no complications, offer induction of labour in accordance with the NICE guideline for
induction of labour.
15 of 17
APPENDIX III: Explanation of guidelines and evidence levels


1+

low risk of bias

risk of bias

2+



case series
Expert opinion


1++ or 1+

results; or
2++
Good practice point
16 of 17

development group
Miss AAA Kyei-Mensah FRCOG, London; Mr B Davis FRCP FRCPath MD, London; Dr M Gupta MRCOG, London;
Mr G Lieberman MRCOG, London; Ms H Morgan FRCOG, London; and Dr FT Shah FRCP FRCPath MD, London
and peer-reviewed by:
Dr C Bagot, Consultant Haematologist, Glasgow; Mrs A Diyaf MRCOG, Barnstaple; Mr DI Fraser FRCOG, Norwich;
Professor R Hussain FRCOG, Karachi, Pakistan, on behalf of the Pakistan Representative Committee;
Dr S Pavord, Leicester Royal Infirmary, Leicester; RCOG Womens Network; Royal College of General Practitioners;
Royal College of Midwives; Ms SM Tuck FRCOG, London; UK National Screening Committee; and UK Thalassaemia Society.
Committee lead reviewers were: Dr P Owen FRCOG, Glasgow and Mr M Griffiths FRCOG, Luton.
Conflicts of interest: None declared.
DISCLAIMER
health services.
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GREEN TOP

Tocolysis for Women in

Tocolysis for Women in Preterm Labour

Purpose and scope

Identification and assessment of evidence

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

Uses of tocolysis for women in preterm labour.

4.1 Does tocolysis prevent preterm birth?

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

When should tocolytic drugs be used?

Tocolysis should not be used where there is a contraindication to prolonging pregnancy.

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

Cyclo-oxygenase (COX) enzymes contribute to production of prostaglandins, which are

Royal College of Obstetricians and Gynaecologists

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

10. What is the cost effectiveness of tocolysis for preterm labour?

Should tocolysis by used in multiple pregnancy?

12. Is maintenance tocolytic therapy worthwhile?

A systematic review of any maintenance tocolytic therapy compared with placebo or no

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

14. Auditable standards

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

Saigal S, Doyle LW. An overview of mortality and sequelae of

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

Well-conducted meta-analyses, systematic

Meta-analyses, systematic reviews of

2++ High-quality systematic reviews of case

Well-conducted casecontrol or cohort

Non-analytical studies, e.g. case reports,

RCOG Green-top Guideline No. 1b

At least one meta-analysis, systematic review or

A body of evidence including studies rated as

A body of evidence including studies rated as

Good practice point

Recommended best practice based on the

Royal College of Obstetricians and Gynaecologists

RCOG Green-top Guideline No. 1b

Royal College of Obstetricians and Gynaecologists

Antenatal Corticosteroids to Reduce

Antenatal Corticosteroids to Reduce Neonatal Morbidity and

Purpose and scope

Identification and assessment of evidence

What are the benefits of antenatal corticosteroids?

Antenatal corticosteroids have no known benefits for the mother.

RCOG Green-top Guideline No. 7

Royal College of Obstetricians and Gynaecologists