Medley 2018

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Cochrane Database of Systematic Reviews

Interventions during pregnancy to prevent preterm birth: an
overview of Cochrane systematic reviews (Review)
Medley N, Vogel JP, Care A, Alfirevic Z
Medley N, Vogel JP, Care A, Alfirevic Z.

Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews.
Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD012505.
DOI: 10.1002/14651858.CD012505.pub2.
www.cochranelibrary.com

Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews (Review)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 3
BACKGROUND.............................................................................................................................................................................................. 5
OBJECTIVES.................................................................................................................................................................................................. 5
METHODS..................................................................................................................................................................................................... 5
RESULTS........................................................................................................................................................................................................ 7
Figure 1.................................................................................................................................................................................................. 9
Figure 2.................................................................................................................................................................................................. 12
Figure 3.................................................................................................................................................................................................. 13
Figure 4.................................................................................................................................................................................................. 14
Figure 5.................................................................................................................................................................................................. 15
Figure 6.................................................................................................................................................................................................. 16
Figure 7.................................................................................................................................................................................................. 17
Figure 8.................................................................................................................................................................................................. 18
Figure 9.................................................................................................................................................................................................. 18
Figure 10................................................................................................................................................................................................ 19
Figure 11................................................................................................................................................................................................ 21
Figure 12................................................................................................................................................................................................ 22
Figure 13................................................................................................................................................................................................ 23
Figure 14................................................................................................................................................................................................ 24
Figure 15................................................................................................................................................................................................ 25
Figure 16................................................................................................................................................................................................ 26
Figure 17................................................................................................................................................................................................ 26
Figure 18................................................................................................................................................................................................ 27
Figure 19................................................................................................................................................................................................ 28
DISCUSSION.................................................................................................................................................................................................. 29
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 31
ACKNOWLEDGEMENTS................................................................................................................................................................................ 31
REFERENCES................................................................................................................................................................................................ 32
ADDITIONAL TABLES.................................................................................................................................................................................... 40
APPENDICES................................................................................................................................................................................................. 59
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 64
DECLARATIONS OF INTEREST..................................................................................................................................................................... 64
SOURCES OF SUPPORT............................................................................................................................................................................... 65
INDEX TERMS............................................................................................................................................................................................... 65
Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews (Review) i
Informed decisions.

[Overview of Reviews]
Interventions during pregnancy to prevent preterm birth: an overview

of Cochrane systematic reviews
Nancy Medley1, Joshua P Vogel2, Angharad Care3, Zarko Alfirevic3
1Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, The University of Liverpool, Liverpool, UK.
2Maternal and Child Health, Burnet Institute, Melbourne, Australia. 3Department of Women's and Children's Health, The University of
Liverpool, Liverpool, UK
Contact address: Nancy Medley, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, The University
of Liverpool, First Floor, Liverpool Women's NHS Foundation Trust, Crown Street, Liverpool, L8 7SS, UK. [email protected].
Editorial group: Cochrane Pregnancy and Childbirth Group

Publication status and date: New, published in Issue 11, 2018.
Citation: Medley N, Vogel JP, Care A, Alfirevic Z. Interventions during pregnancy to prevent preterm birth: an overview of Cochrane
systematic reviews. Cochrane Database of Systematic Reviews 2018, Issue 11. Art. No.: CD012505. DOI: 10.1002/14651858.CD012505.pub2.
ABSTRACT
Background
Preterm birth (PTB) is a major factor contributing to global rates of neonatal death and to longer-term health problems for surviving infants.
Both the World Health Organization and the United Nations consider prevention of PTB as central to improving health care for pregnant
women and newborn babies. Current preventative clinical strategies show varied efficacy in different populations of pregnant women,
frustrating women and health providers alike, while researchers call for better understanding of the underlying mechanisms that lead to
PTB.
Objectives
We aimed to summarise all evidence for interventions relevant to the prevention of PTB as reported in Cochrane systematic reviews (SRs).
We intended to highlight promising interventions and to identify SRs in need of an update.
Methods
We searched the Cochrane Database of Systematic Reviews (2 November 2017) with key words to capture any Cochrane SR that prespec-
ified or reported a PTB outcome. Inclusion criteria focused on pregnant women without signs of preterm labour or ruptured amniotic
membranes. We included reviews of interventions for pregnant women irrespective of their risk status. We followed standard Cochrane
methods.
We applied GRADE criteria to evaluate the quality of SR evidence. We assigned graphic icons to classify the effectiveness of interventions as:
clear evidence of benefit; clear evidence of harm; clear evidence of no effect or equivalence; possible benefit; possible harm; or unknown
benefit or harm. We defined clear evidence of benefit and clear evidence of harm to be GRADE moderate- or high-quality evidence with a
confidence interval (CI) that does not cross the line of no effect. Clear evidence of no effect or equivalence is GRADE moderate- or high-
quality evidence with a narrow CI crossing the line of no effect. Possible benefit and possible harm refer to GRADE low-quality evidence
with a clear effect (CI does not cross the line of no effect) or GRADE moderate- or high-quality evidence with a wide CI. Unknown harm or
benefit refers to GRADE low- or very low-quality evidence with a wide CI.
Main results
We included 83 SRs; 70 had outcome data. Below we highlight key results from a subset of 36 SRs of interventions intended to prevent PTB.
Outcome: preterm birth
Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews (Review) 1
Informed decisions.

Clear evidence of benefit
Four SRs reported clear evidence of benefit to prevent specific populations of pregnant women from giving birth early, including mid-
wife-led continuity models of care versus other models of care for all women; screening for lower genital tract infections for pregnant
women less than 37 weeks' gestation and without signs of labour, bleeding or infection; and zinc supplementation for pregnant women
without systemic illness. Cervical cerclage showed clear benefit for women with singleton pregnancy and high risk of PTB only.
Clear evidence of harm
No included SR reported clear evidence of harm.
No effect or equivalence
For pregnant women at high risk of PTB, bedrest for women with singleton pregnancy and antibiotic prophylaxis during the second and
third trimester were of no effect or equivalent to a comparator.
Possible benefit
Four SRs found possible benefit in: group antenatal care for all pregnant women; antibiotics for pregnant women with asymptomatic
bacteriuria; pharmacological interventions for smoking cessation for pregnant women who smoke; and vitamin D supplements alone for
women without pre-existing conditions such as diabetes.
Possible harm
One SR reported possible harm (increased risk of PTB) with intramuscular progesterone, but this finding is only relevant to women with
multiple pregnancy and high risk of PTB. Another review found possible harm with vitamin D, calcium and other minerals for pregnant
women without pre-existing conditions.
Outcome: perinatal death
Two SRs reported clear evidence of benefit to reduce pregnant women's risk of perinatal death: midwife-led continuity models of care for
all pregnant women; and fetal and umbilical Doppler for high-risk pregnant women.
No included SR reported clear evidence of harm.
No effect or equivalence
For pregnant women at high risk of PTB, antibiotic prophylaxis during the second and third trimester was of no effect or equivalent to a
comparator.
Possible benefit
One SR reported possible benefit with cervical cerclage for women with singleton pregnancy and high risk of PTB.
Possible harm
One SR reported possible harm associated with a reduced schedule of antenatal visits for pregnant women at low risk of pregnancy com-
plications; importantly, these women already received antenatal care in settings with limited resources.
Outcomes: preterm birth and perinatal death
Unknown benefit or harm
For pregnant women at high risk of PTB for any reason including multiple pregnancy, home uterine monitoring was of unknown benefit
or harm. For pregnant women at high risk due to multiple pregnancy: bedrest, prophylactic oral betamimetics, vaginal progesterone and
cervical cerclage were all of unknown benefit or harm.
Authors' conclusions
Implications for practice
The overview serves as a map and guide to all current evidence relevant to PTB prevention published in the Cochrane Library. Of 70 SRs
with outcome data, we identified 36 reviews of interventions with the aim of preventing PTB. Just four of these SRs had evidence of clear
Informed decisions.

benefit to women, with an additional four SRs reporting possible benefit. No SR reported clear harm, which is an important finding for
women and health providers alike.
The overview summarises no evidence for the clinically important interventions of cervical pessary, cervical length assessment and vaginal
progesterone because these Cochrane Reviews were not current. These are active areas for PTB research.
The graphic icons we assigned to SR effect estimates do not constitute clinical guidance or an endorsement of specific interventions for
pregnant women. It remains critical for pregnant women and their healthcare providers to carefully consider whether specific strategies
to prevent PTB will be of benefit for individual women, or for specific populations of women.
Implications for research
Formal consensus work is needed to establish standard language for overviews of reviews and to define the limits of their interpretation.
Clinicians, researchers and funders must address the lack of evidence for interventions relevant to women at high risk of PTB due to mul-
tiple pregnancy.
PLAIN LANGUAGE SUMMARY
Ways to help pregnant women avoid preterm birth
What is the issue?
Preterm birth, or being born before 37 weeks of pregnancy, is a major reason why newborns die and may also mean long-term disability
for surviving infants. There are many ways healthcare providers try to prevent women from having their babies too early. Pregnant women
may be encouraged to take vitamins, reduce smoking, take medicines for infections or attend regular healthcare visits. Our overview looks
at different ways (or interventions) to prevent preterm birth. We searched for relevant papers in the Cochrane Library on 2 November, 2017.
Why is this important?
Preterm birth is devastating and costly for women, families and health systems. We aimed to summarise relevant information for pregnant
women, healthcare workers and researchers.
What evidence did we find?
We included 83 systematic reviews with evidence about whether or not the intervention was able to reduce pregnant women's chance of
having a preterm birth or a baby death. Seventy of these reviews had information about preterm birth. We categorised the evidence we
found as: clear benefit or harm; no effect; possible benefit or harm; or unknown effect.
Outcome: preterm birth
Clear benefit
We were confident that the following interventions were able to help specific populations of pregnant women avoid giving birth early:
midwife-led continuity models of care versus other models of care for all women; screening for lower genital tract infections; and zinc
supplementation for pregnant women without systemic illness. Cervical stitch (cerclage) was of benefit only for women at high risk of
preterm birth and with singleton pregnancy.
Clear harm
We found no treatment that increased women’s chance of giving birth preterm.
Possible benefit
The following interventions may have helped some groups of pregnant women avoid preterm birth, but we have less confidence in these
results: group antenatal care for all pregnant women; antibiotics for pregnant women with asymptomatic bacteriuria; pharmacological
interventions for smoking cessation; and vitamin D supplements alone for women without health problems.
Possible harm
We found two interventions that may have made things worse for some pregnant women: intramuscular progesterone for women at high
risk of preterm birth with multiple pregnancy; and taking vitamin D supplements, calcium and other minerals for pregnant women without
health problems.
Outcome: perinatal death
Clear benefit
Informed decisions.

We were confident in evidence for midwife-led continuity models of care for all pregnant women; and for fetal and umbilical Doppler for
high-risk pregnant women; these interventions appeared to reduce women's chance of experiencing baby death.
Clear harm
We found no intervention that increased women’s risk of baby death.
Possible benefit
We found a possible benefit with cervical stitch (cerclage) for women with singleton pregnancy and high risk of preterm birth.
Possible harm
One review reported possible harm associated with having fewer antenatal visits, even for pregnant women at low risk of pregnancy
problems. The pregnant women in this review already received limited antenatal care.
Outcomes: preterm birth and perinatal death
Unknown benefit or harm
For pregnant women at high risk of preterm birth for any reason including multiple pregnancy, home uterine monitoring was of unknown
benefit or harm. For high-risk pregnant women with multiple pregnancy: bedrest, prophylactic oral betamimetics, vaginal progesterone
and cervical cerclage were all of unknown benefit or harm.
What does this mean?
There is valuable information in the Cochrane Library relevant to women, doctors, midwives and researchers interested in preventing early
birth. We have summarised the results of systematic reviews to describe how well different strategies work to prevent early birth and baby
death. We organised our information in clear figures with graphic icons to represent how confident we were in the results and to point
readers toward promising treatments for specific groups of pregnant women.
Our overview found no up-to-date information in the Cochrane Library for the important treatments of cervical pessary, vaginal proges-
terone or cervical assessment with ultrasound. We found no high-quality evidence relevant to women at high risk of preterm birth due
to multiple pregnancy. It remains important for pregnant women and their healthcare providers to carefully consider whether specific
strategies to prevent preterm birth will be of benefit for individual women, or for specific populations of women.
Informed decisions.

BACKGROUND Description of the interventions

Preterm birth (PTB) places a substantial burden on economies, Many interventions to prevent PTB target all pregnant women;
health systems and families worldwide. PTB contributes dispropor- these may begin before or during pregnancy, such as folate supple-
tionately to global rates of neonatal death, and infants who survive mentation or improved access to antenatal care (Iams 2008). Other
early birth may suffer serious complications and long-term disabil- interventions target specific populations of pregnant women con-
ity (Blencowe 2013; Liu 2015). PTB cost the UK economy £2.9 billion sidered to be at higher risk of PTB, such as women with multiple
in a single year (Mangham 2009), while affected families suffered pregnancy or women who smoke. This overview will include all in-
equally profound financial, social and psychological consequences terventions that could be applied during pregnancy to prevent PTB,
(Carson 2015; Hodek 2011; Vigod 2010). regardless of women's risk factors. In this overview, we included in-
terventions for women with co-morbid conditions such as diabetes
The World Health Organization (WHO) identified PTB as a "top ten" or hypertension, for women with recognised risk factors such as
research priority to 2025 (Yoshida 2016). The United Nations has al- short cervix or multiple pregnancy, and for pregnant women with-
so positioned PTB research as central to achieving a reduction in out any known risk.
newborn deaths and the Sustainable Development Goals to 2030
(Lawn 2016). Though the PTB rate in countries such as the USA has How the intervention might work
fallen, early birth contributes to high mortality in low- and mid- We do not fully understand the pathways leading to PTB, which lim-
dle-income countries (Blencowe 2012; Gyamfi-Bannerman 2014). its implementation of appropriate clinical and public health pre-
The March of Dimes and the International Federation of Gynecolo- vention strategies. Interventions may reduce PTB via diverse path-
gy and Obstetrics Working Group urge researchers to think beyond ways. Nutritional supplements may modify low body mass index
current clinical and preventive strategies and to expand basic re- (BMI) to reduce risk, while screening for asymptomatic bacteriuria
search to develop new interventions for PTB (Ferrero 2016; Martin may reduce the risk of infection-related PTB. We included SRs of in-
2017). terventions regardless of whether the mechanism of action on PTB
was known.
Description of the condition
PTB is usually defined as birth before 37 weeks + 0 days' gesta- Why it is important to do this overview
tion (or 259 days) (Anonymous 1977). The Global Alliance to Pre- We aim to improve the care of pregnant women. There is a wealth
vent Prematurity and Stillbirth (GAPPS) defined 'provider-initiated' of information in the Cochrane Library relevant to PTB preven-
PTB as early births related to: severe maternal, fetal or placental tion. Initial searches returned over 800 SRs, and yet there is no
conditions, maternal request, breech presentation, cephalopelvic efficient way for researchers, funding organisations, clinicians or
disproportion, or previous caesarean section. In contrast, 'spon- pregnant women themselves to quickly access this evidence. This
taneous' preterm births (sPTB) were not related to severe clinical overview extends previous efforts to catalogue SRs of PTB interven-
conditions (Villar 2012). When applied to 60,000+ births, the GAP- tions (Iams 2008; Piso 2014) and applies the agreed core outcome
PS classification system found 22% of all early births to occur spon- set for PTB (van't Hooft 2016).
taneously and without association to any severe condition (Barros
2015). OBJECTIVES
This overview is concerned with sPTB rather than provider-initiated We aimed to summarise all evidence for interventions relevant
PTB, but in practice the early births reported in included SRs may be to the prevention of PTB as reported in Cochrane systematic re-
a mix of the two. The United States Vital Statistics and the Office of views (SRs). We intended to highlight promising interventions and
National Statistics in the UK do not distinguish spontaneous from to identify SRs in need of an update.
provider-initiated PTB when reporting national rates. A recent US
study makes the distinction, but the PTB Core Outcome Set does METHODS
not (Gyamfi-Bannerman 2014; van't Hooft 2016).
Criteria for considering reviews for inclusion
We applied the inclusion and exclusion criteria below when assess-
ing SRs for this overview.

Eligibility Inclusion Exclusion
Participant Population Pregnant women including those with risk factors or Pregnant women with acute signs of
level co-morbidities preterm labour
Pregnant women with singleton or multiple pregnan- Pregnant women with a previous episode
cy of preterm labour in current pregnancy
Healthcare providers Pregnant women with preterm prelabour

ruptured membranes (PPROM)
Pregnant women with major fetal anom-

alies
Informed decisions.

Pregnant women undergoing induction of

labour
Review level Review Cochrane systematic reviews published from 2014 We listed reviews with a relevant popu-
lation and intervention published before
2014 or with a search date prior to 2014
Trial design Randomised clinical trials (including cluster- or qua- Non-randomised study designs
si-randomised trials)
Any setting, language or year
Intervention Behavioural, clinical or health systems interventions Interventions for preconception only
Interventions to prevent or treat miscar-

riage
Interventions comprising fertility treat-

ment
Comparison One main comparison (designated as such by review Additional review comparisons do not con-
authors) tribute to data summaries
Alternative intervention or no intervention (including

placebo)
Outcome Preterm birth outcome (any gestational age (GA) val- Preterm birth outcome (any GA value) not
ue) specified or reported (prespecified or post-hoc) specified or reported

The inclusion and exclusion criteria define a pregnant population whether the population and intervention met our inclusion criteria
without signs of preterm labour. We excluded SRs of interventions and to confirm that the review included randomised trial evidence.
for women with PPROM because these women receive individu- We list characteristics of reviews excluded at full-text assessment.
alised management with interventions with a short timeframe to
delivery and, often, the goal of improving neonatal outcomes (e.g. Data extraction and management
magnesium sulphate for neuro protection). We excluded reviews of For each included SR one overview author (NM) independently ex-
interventions targeting the neonate. tracted data; a second overview author checked the data for accu-
racy. We resolved disagreements by discussion. We extracted the
Search methods for identification of reviews following characteristics from each included SR.
Only Cochrane systematic reviews were eligible for inclusion in this
overview. We searched the Cochrane Database of Systematic Re- 1. Search date
views (2 November 2017) with a broad strategy using all possible 2. Number of trials included in the review
keywords to capture reviews relevant to preterm birth (see Appen- 3. Number of participants included in the review
dix 1). 4. Overview outcomes with data
5. Authors' conclusions
Data collection and analysis
We followed standard methods for overviews of reviews as de- Two overview authors piloted the data synthesis tables to improve
scribed below. the content and presentation of SR results. When the final format
was agreed amongst all overview authors, one overview author cre-
Selection of reviews ated figures to present outcome data and a second overview author
checked the figures.
We conducted eligibility in duplicate with all conflicts resolved
through discussion with a third overview author. Assessment of methodological quality of included reviews
We staged eligibility assessment. First, two overview authors as- Methodological quality of included systematic reviews
sessed titles and abstracts to ensure that SRs targeted appropri-
Several recent publications have explored problems with the AMS-
ate populations of pregnant women and summarised relevant in-
TAR tool for assessing systematic review (SR) quality (Burda 2016;
terventions. Second, we set aside all relevant Cochrane protocols;
Faggion 2015; Pollock 2017; Shea 2007; Wegewitz 2016). Because of
we will check the status of these in future updates of this overview.
the identified shortcomings of AMSTAR, we decided against using it
We set aside potentially relevant titles published before 2014. Final-
and explored using the Risk of Bias in Systematic Reviews (ROBIS)
ly, we assessed the full text of remaining reviews to explore further
quality checklist instead.
Informed decisions.

ROBIS users first establish the relevance of the systematic review We separated SRs of interventions to prevent PTB from SRs of inter-
(SR) by checking that the population, intervention, comparator ventions targeting other problems during pregnancy. We then or-
and outcomes align between the review and overview. Next, re- ganised SR outcome data in figures according to type of interven-
searchers use ROBIS to consider review methods: study eligibility tion: device, health systems, lifestyle, medicines, multiple interven-
criteria; identification and selection of studies; data collection and tions, nutrition, screening, psychosocial, and surgical. The catego-
study appraisal; and synthesis and findings. Key questions within ry of 'multiple' interventions includes SRs where different types of
each of these four domains sum to an overall risk of bias for the re- interventions were tested for a particular problem; for example, the
view. Throughout, the tool prompts assessors to flag specific con- SR of interventions to prevent nausea in pregnancy included both
cerns. Finally, ROBIS requires the assessors to weigh their concerns drug and acupressure interventions.
with SR methods alongside SR conclusions for a judgement of low,
high or unclear risk of bias (Whiting 2016). To assign a graphic icon we first considered the pooled summary
statistic and confidence interval, any GRADE judgements made by
Quality of trial evidence included in reviews the review author team and the amount of information present:-
the number of trials, women and events contributing to the meta-
We did not reassess the risks of bias for the individual trials includ-
analysis. GRADE criteria include: study design limitations in trials
ed in eligible SRs. 'Risk of bias' assessment is a component of all
contributing data; imprecision of effects (wide confidence inter-
Cochrane Reviews; review authors consider aspects of trial conduct
vals, sparse data or both); inconsistency (unexplained heterogene-
and reporting and note whether bias may have impacted the trial's
ity as measured by the I2 statistic); indirectness (when trials test a
reported effect estimates (Higgins 2011a). Further, when we eval-
different population, intervention, comparison or outcome than is
uated pooled outcome data from a particular SR, we made use of
specified in the review); and publication bias. All randomised trial
the review authors’ GRADE assessments. GRADE incorporates the
evidence begins as of high certainty but may be downgraded by one
review authors' 'Risk of bias' judgements for individual trials com-
for a ‘serious’ problem or by two for 'very serious' problem with any
prising pooled estimates. Where review authors did not undertake
of these criteria. The GRADEpro Guideline Development Tool sums
GRADE, we ourselves reviewed pooled summary statistics and tri-
downgrading decisions into a quality rating of high, moderate, low,
als' risks of bias according to criteria described in the GRADE Hand-
or very low (Schünemann 2013).
book (Schünemann 2013).
There is a large literature on conducting, interpreting and com-
Data synthesis
municating GRADE assessment (Guyatt 2011a; Santesso 2015a;
Types of outcomes Santesso 2015b). Researchers continue to explore ways to ex-
press SR effect estimates and to delineate the scope of their inter-
We included Cochrane systematic reviews that specified or re-
pretation (Hultcrantz 2017). Our graphic icons communicate the
ported preterm birth (PTB) as one of the outcome measures. We
GRADE quality assessment found in SR 'Summary of findings' ta-
planned to include all core outcome set domains for effective-
bles. Where SR authors did not GRADE relevant trial evidence for
ness, safety, maternal satisfaction and economic costs (van't Hooft
PTB or PD, two overview authors independently applied GRADE
2016). Due to variation in outcome definition and reporting, and
criteria and resolved disagreement through discussion (GRADE as-
to the large number of included SRs, we present outcome data for
sessments not shown).
PTB (any gestational age (GA) value) and perinatal death (PD), on-
ly (PD includes stillbirth and neonatal death). Formal consensus For all included SRs, two overview authors independently assessed
work with diverse stakeholders (including parents, midwives and data for the outcomes of PD and PTB to assign a graphic icon. We
other health professionals) confirmed GA at delivery and offspring resolved disagreements through discussion or by consultation with
mortality as the top two clinical outcomes for evaluating interven- a third overview author.
tions to prevent preterm birth (van't Hooft 2016). Updates of this
overview will explore adding additional outcome domains and/ Limitations of the overview and bias in the review process
or specific outcome measures. As stated above, we expect most
One limitation of our overview is its restriction to Cochrane system-
SR reporting of PTB outcomes may include both spontaneous and
atic reviews. Including all relevant, published SRs may have cap-
provider-initiated early births.
tured more current evidence on important topics. Cochrane Re-
Data synthesis and presentation views are also all published in the English language. Finally, our
search strategy did not include unpublished, industry and govern-
We planned to structure data synthesis as in other Cochrane mental SRs.
overviews (Farquhar 2018; Jones 2012; Lassi 2015; Welsh 2015). Due
to the large number of included SRs, we instead created figures to To minimise bias in the overview process, we followed standard re-
present review data visually. We assigned graphic icons to commu- view methods including duplication of effort. Where an overview
nicate the direction of review effect estimates and our confidence author was also an author of a relevant SR, they were excluded from
in the available data. The graphic icons indicate mutually exclusive eligibility assessment and data synthesis for that SR.
assessment categories: clear evidence of benefit; clear evidence of
harm; clear evidence of no effect or equivalence; possible benefit; RESULTS
possible harm; or unknown benefit or harm. Our presentation of
data is modelled on graphics produced by the WHO to describe dif- Search results
ferent types of workers and their roles in maternal and newborn We searched the Cochrane Database of Systematic Reviews (2 No-
care (http://optimizemnh.org/optimizing-health-worker-roles-ma- vember 2017) with a list of key words to capture all systematic re-
ternal-newborn-health/). views (SRs) specifying or reporting any preterm birth (PTB) out-
come (See Appendix 1 for the search strategy). We documented as-
Informed decisions.

sessment of titles and full-text reviews in a study flow diagram (See teria. We resolved discrepancies between overview authors by dis-
Figure 1). We used Covidence software to manage eligibility assess- cussion with a third author. No overview author assessed his or her
ment for 898 titles. Two overview authors independently assessed own SR (several eligible reviews were authored by members of the
titles and full texts against prespecified inclusion and exclusion cri- overview team).

Informed decisions.

Figure 1. Study flow diagram. Search date 2 November 2017

Informed decisions.

Figure 1. (Continued)
Informed decisions.

We included 83 SRs; their characteristics appear in Table 1; 70 in- Methodological quality of included reviews
cluded reviews reported relevant outcome data. We documented
reasons for exclusion of 24 reviews at full-text assessment in Table As noted above, researchers identified problems with the AMSTAR
2. We identified 33 protocols for SRs potentially relevant to future tool to assess SR quality (Burda 2016; Pollock 2017). We decid-
versions of this overview; these titles will be assessed for future ver- ed not to use AMSTAR and explored using the ROBIS tool instead.
sions of the overview. We decided against using ROBIS as well, because all SRs includ-
ed in this overview followed standard methodology recommended
Out-of-date systematic reviews in the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011b). For more recent SR updates, review authors also
Our protocol stated that we would apply a decision tree to poten- followed methods set out by the Cochrane Editorial Unit (i.e. MECIR
tially eligible but out-of-date reviews - SRs published before 2014 standards Higgins 2016). We are confident that all included SRs are
or with a search date before 2014. We found 96 reviews in this cat- of low risk of methods bias.
egory. It was not feasible to conduct new searches for all of these
reviews. Some reviews in this category are currently in the editorial Effect of interventions
process, while other reviews may summarise evidence for interven-
tions no longer in use. We regret that we were unable to complete Notes for Interpreting Graphic Icons
further assessment of these SR titles. As one peer reviewer pointed Graphic Icons
out - there may be interventions associated with harm in the list of
out-of-date reviews, because authors would be less likely to com- We summarised systematic review (SR) evidence for the outcomes
plete new trials or to update reviews of interventions where there of PTB and PD by assigning one of six graphic icons to indicate our
was known evidence of harm. We listed the titles in Appendix 2. confidence in and interpretation of the available evidence. Figure
2 shows the icons and explains the mutually exclusive assessment
Description of included reviews categories. The first three categories represent GRADE moderate-
or high-quality evidence for which we found either clear benefit,
We documented key characteristics of 83 included studies in Table clear harm or clear evidence of no effect (i.e. equivalence with a
1, including the search date, number of trials, number of women comparator). These categories are identified by a green tick, a red-
and the authors' conclusions about the effectiveness of the inter- cross and a green equal-sign icon, respectively. For 'clear' benefit
ventions. The language of authors' conclusions is directly quoted or harm, the confidence interval associated with the effect size did
from the original Cochrane published reviews. Of 83 included SRs, not cross the line of no effect. For 'clear evidence of no effect or
seven had no randomised trials (i.e. these are 'empty reviews'). Six equivalence' we considered a confidence interval within the range
further SRs reported no trial data for either overview outcome of of risk ratio (RR) 0.75 to 1.25 as sufficiently narrow to indicate a min-
PTB or perinatal death (PD). All remaining 70 SRs contributed effect imal effect relative to the comparator; these are thresholds recom-
estimates for at least one overview outcome. mended by GRADE (Guyatt 2011b). The overview author team indi-
vidually discussed the handful of cases where an SR reported the
odds ratio rather than relative risk.

Informed decisions.

Figure 2. All icons by Freepik at www.flaticon.com.

Continuing down Figure 2, two yellow icons represent evidence for Evidence 'Quality' or 'Certainty'?
which we had less confidence due to risks of bias in trials, impre-
Our categories of assessment follow GRADE ratings of high, mod-
cision or other GRADE criteria for downgrading evidence quality
erate, low or very low to indicate the quality of evidence rather
(Schünemann 2013). The yellow icons indicate possible benefit (the
than its certainty. Though evidence quality and certainty are of-
plus sign) or possible harm (the minus sign). Yellow icons represent
ten used interchangeably, 'certainty' represents newer language
GRADE moderate- or high-quality evidence when the confidence
that extends GRADE methods to the development of formal clini-
interval crossed the line of no effect. Yellow icons also represent
cal guidance (Hultcrantz 2017). This overview does not constitute
GRADE low-quality evidence when the finding was of clear bene-
formal clinical guidance. The SR evidence summarised here would
fit or harm (i.e. the confidence interval did not cross RR 1.0). We
be considered "non-contextualised" rather than "contextualised"
must emphasise the reduced confidence and caution we intended
in the newer GRADE framework that aims to situate evidence in clin-
to communicate when assigning the yellow graphic icons.
ical, economic and geographic contexts.
Finally, we assigned a blue question mark icon to indicate 'un-
SRs included in this overview applied GRADE criteria to a single out-
known harm or benefit' associated with the relative effect of an in-
come independently rather than to a set of critical outcomes val-
tervention versus a comparator. The blue question-mark icon indi-
ued together, as guideline developers might. SRs did not pre-spec-
cates GRADE low-quality evidence with a confidence interval cross-
ify thresholds for interpreting effect size or confidence intervals,
ing the line of no effect as well as all GRADE very low-quality evi-
and, though most SRs identified trial countries in their 'Summary
dence.
of findings' tables, none reported this geographic information per
outcome. No SR calculated a minimum information size required
for meta-analysis. Most SRs did not incorporate formal analyses of
the economic cost or of the acceptability of interventions to preg-
Informed decisions.

nant women. Finally, included Cochrane SRs do not make clinical The figures of graphic icons are not intended to replace close in-
recommendations (see Higgins 2011b, section 12.7.4 "Common er- spection of individual SRs and the often complicated results found
rors in reaching conclusions"). there. Rather, our overview intends to assess the quality of evi-
dence for the key outcomes of preterm birth and perinatal death
Therefore, a GRADE of moderate or high quality in this overview and to signpost readers interested in specific effect estimates to
reflects our confidence that the pooled estimate is correct (i.e. its full SRs. Individual SRs report complete details of the relevant clin-
'quality') rather than an endorsement of the intervention's use in a ical populations and geographic settings, trials' risks of bias, and
specific clinical setting or population of pregnant women. Follow- forest plots indicating the relative contribution of individual trials
ing this, the overview graphic icons do not represent clinical rec- to a pooled estimate. The Characteristics of included studies table
ommendations for the use of interventions. The graphic icons rep- (Table 1) may be read in tandem with the figures of graphic icons;
resent the quality of the evidence found in reviews and direct read- this table includes information on the review search date, the num-
ers to the full text of SRs for further scrutiny. ber of clinical trials and pregnant women included in the review,
overview outcome measures reported and review authors' conclu-
Presentation of results
sions.
Due to the large number of reviews we wanted to included in this
overview, and because we wanted to avoid presenting 50 pages of Not all included SRs reported on both overview outcomes of
data tables, we took decisions to limit the information presented in preterm birth and perinatal death. For some SRs, our figures sum-
tables and figures. Figures 3 to 19 summarise evidence from the 83 marise effect estimates for more than one comparison. No SR re-
included reviews. ported spontaneous PTB as distinct from PTB, and we expect most
results below represent a mix of spontaneous and provider-initiat-
We grouped SRs specifically targeting preterm birth prevention ed PTB.
(Figures 3 to 10) and SRs targeting either diabetes or other prob-
lems women might face during pregnancy (Figures 11 to 19). Inter- We report results for preterm birth and perinatal death separate-
ventions targeting PTB had this indication stated in the SR title or ly. For preterm birth, we summarised any outcome measure of
had PTB as a primary review outcome. We also grouped SRs ac- preterm birth (any gestational age (GA) value) and followed individ-
cording to intervention type: device, health systems, lifestyle, med- ual SR decisions to prioritise specific time points (e.g. if we found
icines, multiple interventions, nutrition, screening, psychosocial, PTB < 34 weeks' gestation in the 'Summary of findings' table and
and surgical. In all figures below 'Not reported' means that no trial other time points in the text, we took the measure used in the 'Sum-
included in the SR reported data for that particular outcome. 'Not mary of findings' table). We note that perinatal death as reported
a review outcome' means that the SR did not search eligible trials in SRs refers to stillbirths and neonatal deaths counted together.
for that outcome because the outcome was not a review priority.
Results from reviews of interventions targeting PTB prevention
Finally, 'No trials' indicates an empty SR.
Thirty-six SRs summarised evidence for interventions with the aim
Results from all SRs of preterm birth prevention. The following figures present graph-
We included 83 SRs; seven of these were empty reviews (i.e. includ- ic icons assigned to SR evidence for the outcomes of preterm birth
ed no randomised trials), and a further six SRs had no trial data and perinatal death: Figure 3 Device; Figure 4 Health systems; Fig-
for either of the overview outcomes of PD or PTB. We categorised ure 5 Lifestyle; Figure 6 Medicines; Figure 7 Nutrition; Figure 8
available outcome effect estimates as of clear benefit, clear harm, Psychosocial; Figure 9 Screening; and Figure 10 Surgical. Because
clear evidence of no effect or equivalence, possible benefit, possi- these interventions were intended as preterm birth prevention, we
ble harm or unknown benefit or harm as explained in Figure 2. include details of any preterm birth-related risk factors in the target
populations.

Figure 3.

Informed decisions.

Figure 4.

Informed decisions.

Figure 5.

Informed decisions.

Figure 6.

Informed decisions.

Figure 7.

Informed decisions.

Figure 8.

Figure 9.
Informed decisions.


Figure 10.

Systematic reviews with no included trials Clear evidence of harm
The following SRs targeted preterm birth prevention but included Clear evidence of harm refers to evidence of GRADE moderate or
no randomised clinical trials: nutritional advice in multiple preg- high quality with a confidence interval that does not cross the line
nancy (Bricker 2015b); risk-scoring systems for predicting preterm of no effect. No included SR reported clear evidence of harm asso-
birth (Davey 2015); screening for genital Chlamydia (Low 2016); and ciated with an intervention; that is, we found no intervention that
reduction in the number of fetuses in multiple pregnancy (Dodd increased women’s chances of giving birth preterm.
2015a).
Clear evidence of no effect or equivalence
Impact on preterm birth rates
The following SRs reported evidence of GRADE moderate or high
Clear evidence of preterm birth reduction quality with a narrow confidence interval crossing the line of no ef-
Clear evidence of benefit signals evidence of GRADE moderate or fect. These interventions we categorised to be of clear evidence of
high quality with a confidence interval that does not cross the line no effect or equivalence with a comparator: alternative versus stan-
of no effect. We found four SRs reporting clear evidence of benefit to dard packages of antenatal care for women at low risk of develop-
prevent specific populations of pregnant women from giving birth ing pregnancy complications (Dowswell 2015); bed rest for women
early. These reviews were: midwife-led continuity models of care with high risk of preterm birth and singleton pregnancy (Sosa 2015);
versus other models of care for all women (Sandall 2016); cervical antibiotic prophylaxis during the second and third trimester for all
cerclage for women at high risk of preterm birth and with single- women or for women with high risk of PTB (Thinkhamrop 2015);
ton pregnancy (Alfirevic 2017a); zinc supplementation for pregnant calcium supplementation (other than for hypertension) for all preg-
women without systemic illness (Ota 2015a); and antenatal lower nant women (Buppasiri 2015); daily oral iron supplementation for
genital tract infection screening for pregnant women less than 37 all pregnant women (Peña-Rosas 2015a); vitamin C supplementa-
weeks' gestation and without signs of labour, bleeding or infection tion for all pregnant women (Rumbold 2015a); vitamin E supple-
(Sangkomkamhang 2015). mentation for all pregnant women (Rumbold 2015b); routine ultra-
sound in later pregnancy for women in unselected or low-risk pop-
ulations (Bricker 2015a); and screening and subsequent manage-
ment for thyroid dysfunction for women before or during pregnan-
cy without pre-existing thyroid problems (Spencer 2015).
Informed decisions.

Possible benefit Clear evidence of harm
Possible benefit refers to GRADE low-quality evidence with clear No SR reported clear evidence of harm associated with the inter-
benefit (the confidence interval does not cross the line of no effect) vention; no intervention summarised here increased a woman’s
or GRADE moderate- or high-quality evidence with wide confidence chance of PD.
intervals crossing the line of no effect. We found evidence of pos-
sible benefit to specific populations of women reported in the fol- Clear evidence of no effect or equivalence
lowing SRs: group antenatal care for all pregnant women (Catling The following SRs reported GRADE moderate- or high-quality ev-
2015); antibiotics for pregnant women with asymptomatic bacteri- idence with narrow confidence intervals crossing the line of no
uria (Smaill 2015); pharmacological interventions for smoking ces- effect, suggesting the intervention had no effect or equivalence
sation for pregnant women who smoke (Coleman 2015); and vita- to a comparator: antibiotic prophylaxis during the second and
min D supplements alone for women without pre-existing condi- third trimester for all pregnant women and women at high risk
tions such as diabetes (De-Regil 2016). of PTB (Thinkhamrop 2015); calcium supplementation (other than
for preventing or treating hypertension) for all pregnant women
Possible harm
(Buppasiri 2015); vitamin C for all pregnant women (Rumbold
Possible harm refers to GRADE low-quality evidence with clear 2015a); vitamin E supplementation for all pregnant women (Rum-
harm (the confidence interval does not cross the line of no effect) bold 2015b); routine ultrasound in late pregnancy (after 24 weeks'
or GRADE moderate- or high-quality evidence with wide confidence gestation) for unselected pregnant women and women of low risk
intervals crossing the line of no effect. One SR reported possible (Bricker 2015a); and screening and subsequent management for
harm for the effects of intramuscular progesterone for women at thyroid dysfunction before or during pregnancy, for women with-
high risk of preterm birth with multiple pregnancy (Dodd 2017). An- out pre-existing thyroid disorders (Spencer 2015).
other review found possible harm with vitamin D supplements, cal-
cium and other minerals for pregnant women without pre-existing Possible benefit
conditions (De-Regil 2016). Possible benefit refers to GRADE low-quality evidence with clear
benefit (the confidence interval does not cross the line of no effect)
Unknown harm or benefit
or GRADE moderate- or high-quality evidence with wide confidence
Ten SRs reported evidence for the outcome of PTB that we cat- intervals crossing the line of no effect. One SR reported possible
egorised to be of unknown harm or benefit due to effect esti- benefit of cervical stitch (cerclage) for women with singleton preg-
mates with wide confidence intervals and evidence of GRADE low nancy and high risk of preterm birth (Alfirevic 2017a).
or very low quality: home uterine monitoring for high-risk preg-
nant women (Urquhart 2017); bed rest for women with multiple Possible harm
pregnancy (da Silva Lopes 2017); restricted caffeine intake for all Possible harm refers to GRADE low-quality evidence with clear
women (Jahanfar 2015); duration of treatment for women with harm (the confidence interval does not cross the line of no effect)
asymptomatic bacteriuria (Widmer 2015); treating genital Chlamy- or GRADE moderate- or high-quality evidence with wide confidence
dia trachomatis infection in pregnancy (Cluver 2017); vaginal prog- intervals crossing the line of no effect. One SR reported possible
esterone for women with multiple pregnancy (Dodd 2017); prophy- harm associated with a reduced schedule of antenatal visits for
lactic oral betamimetics for women with multiple pregnancy (Ya- pregnant women at low risk of pregnancy complications; these
masmit 2015); intermittent oral iron supplementation for women pregnant women already received antenatal care in settings with
without tuberculosis or HIV (Peña-Rosas 2015a); iodine supplemen- limited resources (Dowswell 2015).
tation for pregnant women without thyroid disorders, tuberculosis
or HIV (Harding 2017); and multiple micronutrient supplements for Unknown harm or benefit
pregnant women without HIV (Haider 2017). Evidence summarised in the following SRs was of GRADE low or
Systematic reviews not reporting data for a preterm birth outcome very low quality with a wide confidence interval crossing the line of
no effect: home uterine monitoring for high-risk pregnant women
The following SRs included trials that did not report data for (Urquhart 2017); group versus conventional antenatal care for all
any preterm birth outcome measure: increasing prenatal care pregnant women (Catling 2015); specialised antenatal clinics for
use (Till 2015); specialised antenatal clinics for multiple pregnan- women with multiple pregnancy (Dodd 2015b); bedrest for women
cy (Dodd 2015b); and pyridoxine (vitamin B6) supplementation with multiple pregnancy (da Silva Lopes 2017); treating genital
(Salam 2015c). Chlamydia trachomatis infection in pregnancy (Cluver 2017); intra-
muscular progesterone for women with multiple pregnancy (Dodd
Impact on perinatal death in preterm birth prevention reviews
2017); vaginal progesterone for women with multiple pregnancy
Clear evidence of reduction in perinatal deaths (Dodd 2017); prophylactic oral beta mimetics for women with mul-
Two SRs reported evidence of GRADE moderate or high quality with tiple pregnancy (Yamasmit 2015); daily oral iron supplementation
clear evidence of benefit (the confidence interval does not cross for all pregnant women (Peña-Rosas 2015a); intermittent oral iron
the line of no effect): midwife-led continuity models of care for all supplements for women without tuberculosis or HIV (Peña-Rosas
pregnant women (Sandall 2016); and fetal and umbilical Doppler 2015b); iodine supplementation for pregnant women without thy-
for pregnant women at high risk (Alfirevic 2017b). roid disorders, tuberculosis or HIV (Harding 2017); multiple mi-
cronutrient supplements for pregnant women without HIV (Haider
2017); vitamin D supplementation for pregnant women without
pre-existing conditions such as diabetes (De-Regil 2016); zinc sup-
plementation for pregnant women without systemic illness (Ota
Informed decisions.

2015a); Cervical stitch (cerclage) for women with multiple pregnan- Results from reviews of interventions targeting diabetes or
cy (Rafael 2014); and Treating periodontal disease (Iheozor-Ejiofor other problems during pregnancy
2017).
Forty-seven SRs summarised relevant evidence for interventions
Systematic reviews not reporting data for the outcome perinatal targeting diabetes or other problems women might face during
death pregnancy. All reviews were included in this overview because they
included an eligible population of pregnant women and prespec-
The following SRs included trials that did not report the outcome ified or reported data for an overview priority outcome (perina-
of perinatal death: incentives for increasing prenatal care for all tal death or any measure of preterm birth). The following figures
pregnant women (Till 2015); bed rest for women with singleton present the graphic icons assigned to SR evidence for these out-
pregnancy and high risk of PTB (Sosa 2015); restricted caffeine comes: Figure 11 Health systems; Figure 12 Lifestyle; Figure 13 Med-
for all pregnant women (Jahanfar 2015); antibiotics for asympto- icines targeting diabetes; Figure 14 Medicines targeting other preg-
matic bacteriuria (Smaill 2015); duration of treatment for asympto- nancy conditions; Figure 15 Multiple interventions; Figure 16 Nutri-
matic bacteriuria (Widmer 2015); and antenatal lower genital tract tion; Figure 17 Psychosocial; Figure 18 Screening; Figure 19 Surgi-
infection screening for women without signs of preterm labour cal. We found no SRs of Device interventions, so there is no figure
(Sangkomkamhang 2015). for this category.

Figure 11.

Informed decisions.

Figure 12.

Informed decisions.

Figure 13.

Informed decisions.

Figure 14.

Informed decisions.

Figure 15.

Informed decisions.

Figure 16.

Figure 17.

Informed decisions.

Figure 18.

Informed decisions.

Figure 19.

For the sake of brevity, below we do not summarise individual SRs Possible benefit
with evidence of unknown harm or benefit for overview outcomes Possible benefit refers to GRADE low-quality evidence with clear
as symbolised by the blue question mark graphic - this task would benefit (the confidence interval does not cross the line of no effect)
reiterate what is already apparent in the figures - i.e. there are many or GRADE moderate- or high-quality evidence with wide confidence
interventions for which we have little trial evidence summarised in intervals crossing the line of no effect. Three SRs reported such
SRs. Neither do we list the SRs that did not report outcome data - evidence for: diet and exercise interventions for preventing gesta-
this information may also be found directly in the figures. As above, tional diabetes mellitus (Bain 2015); antenatal dietary education
we direct readers to consider evidence presented in the figures to- and supplementation to increase energy and protein intake (Ota
gether with the 'Characteristics of included systematic reviews' ta- 2015b); and pharmacological interventions for promoting smoking
ble (Figure 1). cessation during pregnancy (Coleman 2015).
Systematic reviews with no included trials
Possible harm
The following SRs targeted diabetes or other problems during preg- Possible harm refers to GRADE low-quality evidence with clear
nancy and prespecified an overview priority outcome but included harm (the confidence interval does not cross the line of no effect)
no randomised clinical trials: customised versus population-based or GRADE moderate- or high-quality evidence with wide confidence
growth charts as a screening tool for detecting small for gestation- intervals crossing the line of no effect. One SR reported such evi-
al age babies (Carberry 2014); routine blood cultures for the man- dence for the effects of external cephalic version for breech presen-
agement of pyelonephritis in pregnancy (Gomi 2015); and directed tation before term (Hutton 2015).
preconception health programs and interventions for women who
are overweight or obese (Opray 2015). Unknown harm or benefit
Impact on preterm birth Evidence summarised in many SRs was of GRADE low or very low
quality with a wide confidence interval crossing the line of no effect
(see Figures 11 to 19).
One SR reported evidence of GRADE moderate or high quality with
clear evidence of benefit (the confidence interval does not cross the Impact on perinatal death
line of no effect): lifestyle interventions for the treatment of women Clear evidence of benefit
with gestational diabetes (Brown 2017a).
Two SRs reported evidence of GRADE moderate- or high-quality
Clear evidence of harm with clear evidence of benefit (the confidence interval does not
cross the line of no effect): combined health systems interven-
No SR reported clear evidence of harm associated with the inter- tions to improve antenatal care uptake (Mbuagbaw 2015); and fetal
vention; no intervention summarised here increased a woman’s and umbilical Doppler ultrasound in high-risk pregnancy (Alfirevic
chance of PTB. 2017b).
Clear evidence of no effect or equivalence
The following SRs reported GRADE moderate- or high-quality evi- No SR reported clear evidence of harm associated with the inter-
dence with narrow confidence intervals crossing the line of no ef- vention; no intervention summarised here increased a woman’s
fect, suggesting the intervention had no effect or equivalence to chance of PD.
a comparator: combined health systems interventions to improve
antenatal care uptake (Mbuagbaw 2015); diet or exercise or both for Clear evidence of no effect or equivalence
preventing excessive weight gain in pregnancy (Muktabhant 2015);
vitamin A supplementation (McCauley 2015); antihelminthics dur- The following SRs reported GRADE moderate- or high-quality ev-
ing pregnancy (Salam 2015a); psychosocial interventions to stop idence with narrow confidence intervals crossing the line of no
smoking in pregnancy (Chamberlain 2017); and fetal and umbilical effect, suggesting the intervention had no effect or equivalence
Doppler ultrasound in normal pregnancy (Alfirevic 2015). to a comparator: combined health systems interventions to im-
prove antenatal care uptake (Mbuagbaw 2015); vitamin A supple-
Informed decisions.

mentation (McCauley 2015); and antihelminthics during pregnancy 2015). Cervical cerclage was the only surgical intervention found to
(Salam 2015a). be of benefit, and is relevant only for women with high risk of PTB
and singleton pregnancy (Alfirevic 2017a).
Possible benefit
Possible benefit refers to GRADE low-quality evidence with clear It is worth noting that only midwife-led continuity models of care
benefit (the confidence interval does not cross the line of no effect) for all pregnant women (Sandall 2016) showed both reduction in
or GRADE moderate- or high-quality evidence with wide confidence PTB and improvement in perinatal survival. The review authors
intervals crossing the line of no effect. One SR reported such evi- called for further investigation into how a model of care might pre-
dence for computerised cardiotocography in the SR Antenatal car- vent PTB. They stressed that this is a complex intervention that re-
diotocography for fetal assessment (Grivell 2015). quires theoretical modelling of the relationships between process-
es and outcomes in the trial. Authors cautioned against general-
Possible harm ising results to a population with health complications and noted
that no included trial took place in a resource-constrained setting.
Possible harm refers to GRADE low-quality evidence with clear
harm (the confidence interval does not cross the line of no effect) Authors of the zinc supplementation review qualified their finding
or GRADE moderate- or high-quality evidence with wide confidence of benefit to say that most women in included trials were of low
intervals crossing the line of no effect. No SR reported such evi- income and may have had poor nutrition (Ota 2015a). Infection
dence. screening programs were relevant to a general population of preg-
nant women (Sangkomkamhang 2015), whilst the benefit of cervi-
Unknown harm or benefit
cal cerclage was only relevant to women at high risk of PTB and sin-
Evidence summarised in many SRs was of GRADE low or very low gleton pregnancy (Alfirevic 2017a).
quality with a wide confidence interval crossing the line of no effect
(see Figures 11 to 19). No included reviews reported clear evidence of harm, which is very
reassuring.
Network meta-analysis
Reviews targeting diabetes or other pregnancy conditions
We found no eligible Cochrane Reviews with network meta-analy-
ses (NMA) for inclusion in this overview. If in future updates of the Forty-seven included reviews described various interventions tar-
overview we identify relevant reviews, we will apply the method- geting diabetes and other conditions in pregnancy. Each speci-
ologies outlined in our protocol to pilot GRADE for important net- fied or reported a PTB outcome, but PTB prevention was not their
work comparisons and outcomes and to present key network re- primary focus. The review by Brown 2017a reported clear bene-
sults visually. fit of lifestyle interventions for women with gestational diabetes;
lifestyle interventions usually involved healthy eating, exercise and
Interactive 'Summary of findings' tables self-monitoring of glucose concentrations. Review authors cau-
We did not pilot an interactive 'Summary of findings' table for this tioned against generalising this result to women in low- or mid-
version of the overview, but we aim to pilot ideas for presenting lay- dle-income countries.
ered data tables in online versions of the overview for the next up-
No review targeting diabetes or other health problems during preg-
date.
nancy reported benefit for both PTB and perinatal death outcomes.
DISCUSSION Combined community and health systems interventions to im-
There is little consensus or guidance on the appropriate rationale, prove antenatal care coverage reduced pregnant women’s chances
methodology or outputs for overviews of systematic reviews (SRs of experiencing perinatal death but had no clear impact on PTB
(Ballard 2017; Pieper 2012; Pollock 2016). We have summarised the rates (Mbuagbaw 2015). However, this review finding is from a sin-
evidence from relevant Cochrane Reviews using graphic icons to gle trial investigating augmented care for African-American women
communicate both our confidence in, and the relative effective- with multiple pregnancy risks (Klerman 2001).
ness of diverse interventions with possible impact on preterm birth Fetal and umbilical Doppler for high-risk pregnant women also
(PTB). We stress that preterm birth rates reported in included SRs showed a reduction in perinatal death but no clear impact on PTB
are likely to be a mix of provider-initiated and spontaneous PTB. rates (Alfirevic 2017b). As most trials did not have a clearly-defined
Perinatal deaths include both stillbirth and neonatal deaths. management protocol that followed abnormal Doppler test, it is
difficult to be certain which aspect of subsequent care is the most
Summary of main results
important – the obvious candidates are better timing of delivery,
We found 36 SRs evaluating interventions with PTB prevention as more appropriate mode of labour (vaginal versus caesarean), and
the main focus. Most reviews evaluated interventions related to better targeting of antenatal corticosteroids.
health systems or screening, or tested the impact of medicines and
vitamin supplements. Reassuringly, no included reviews reported clear evidence of harm.
Four reviews reported clear evidence of benefit, with three relevant Overall completeness and applicability of evidence
to a general pregnant population: midwife-led continuity models One of our main aims was to highlight strategies to prevent sponta-
of care versus other models of care for all women (Sandall 2016); neous preterm birth (sPTB), but none of the included Cochrane Re-
zinc supplementation for pregnant women without systemic ill- views reported sPTB as an outcome distinct from provider-initiated
ness (Ota 2015a); and antenatal lower genital tract infection screen- PTB. Despite their focus on PTB prevention, none of the 36 relevant
ing for women without signs of preterm labour (Sangkomkamhang
Informed decisions.

Cochrane Reviews referenced the Global Alliance to Prevent Pre- We also question how far an overview should attempt to inter-
maturity and Stillbirth (GAPPS) classification system for PTB (Villar pret SR results in terms of practice recommendations. If individual
2012). We would encourage researchers to try to apply these dis- SRs should not make clinical recommendations (see Higgins 2011b,
tinctions to enable more nuanced analysis of PTB-related interven- section 12.7.4 "Common errors in reaching conclusions"), then nei-
tions. ther should overviews of reviews, unless overview authors have
embarked upon a formal process to vet all available evidence and
What is missing from the overview? produce fully-contextualised clinical guidance.
We identified 96 SRs that may have been eligible during title assess- An example of an evidence synthesis project that can endorse spe-
ment but were out-of-date (these are listed in Appendix 2). We re- cific interventions for clinical practice is a SR of relevant guidelines.
gret that we were unable to look further into these SRs. Medley 2018 reviewed recommendations in 49 clinical guidelines
to identify international consensus for specific interventions to pre-
Our peer reviewers noted that the overview misses out three wide-
vent or manage PTB.
ly-used interventions to prevent PTB in high-risk pregnant women:
cervical pessary, cervical length screening and vaginal proges- We draw attention to a lack of a good evidence base for women
terone. Certainly there are other interventions that are absent be- with multiple pregnancy. We classified all evidence relevant to mul-
cause they we not the subject of a Cochrane Review. For these three tiple pregnancy to be of unknown harm or benefit, and of low- or
specific interventions, we direct readers to several other SRs. Sac- very-low quality, with the exception of intramuscular progesterone
cone 2017a and Saccone 2017b reviewed trials of cervical pessary (which may be harmful for women, see Dodd 2017 and Figure 6). We
for women with singleton and multiple pregnancy and short cervix; currently have no credible options to offer this population, and this
pessary did not reduce the rate of sPTB or improve outcomes for situation must change. Clinicians, researchers and funders must
the neonate. Berghella 2017 found that cervical length screening address the lack of high-quality evidence for interventions relevant
reduced women’s risk of preterm before 37 weeks' gestation, but to women at high risk of preterm birth due to multiple pregnancy.
led to no improvements in other outcomes for women or neonates.
Romero 2018 reported that vaginal progesterone reduced risk of Potential biases in the overview process
preterm births < 33 weeks' gestation for women with singleton
pregnancy and a short cervix mid-trimester; progesterone also im- We followed standard methods to minimise bias. Two overview au-
proved outcomes for the neonate. We also look forward to the EPP- thors independently conducted eligibility assessment and data ex-
PIC collaboration’s individual participant data (IPD) meta-analy- traction, with resolution of conflicts through consultation with a
sis of progestogens (Stewart 2017), and to an updated Cochrane third overview author. None of the overview authors appraised his
Review on progestogens for singleton pregnancy (Dodd and col- or her own SR for inclusion; likewise, overview authors did not as-
leagues, forthcoming). A network meta-analysis comparing prog- sess outcome data or assign graphic icons to pooled effect esti-
esterone, cerclage and cervical pessary was also relevant; Jarde mates from their own SRs.
2017a found that progesterone (natural and 17-OHPC were both in-
We changed our methods from those presented in our protocol to
cluded here) was the most effective for preventing PTB in single-
accommodate the large number of included SRs and to communi-
ton pregnancy. No intervention was effective to prevent PTB in twin
cate the evidence we found. Such deviation from protocol may be
pregnancy (Jarde 2017b).
considered a source of bias.
Quality of the evidence Agreements and disagreements with other studies or
We did not conduct formal evaluation of the risks of bias in included reviews
SRs with either the AMSTAR or ROBIS tool, due to our confidence in
We found three other publications that assessed SRs relevant to
Cochrane Review methodology. All Cochrane Review authors must
PTB prevention. We found no study that summarised randomised
conduct exhaustive searches for published and unpublished stud-
trial evidence for interventions according to a classification scheme
ies; an Information Specialist checks review search results, and ed-
similar to ours.
itorial topic experts check review authors’ eligibility decisions. All
review authors apply Cochrane's 'Risk of bias' tool to included tri- Piso 2014 summarised 56 Cochrane Reviews of interventions to
als and report transparent results in tables (Higgins 2011a). From reduce PTB at less than 37 weeks' gestation. Authors found
2016, all Cochrane review authors also assess the quality of review three interventions that increased preterm birth: metronidazole
effect estimates using GRADE criteria and report results in 'Sum- for pregnant women with asymptomatic trichomoniasis (Gülme-
mary of findings' tables (Higgins 2018). Cochrane Review method- zoglu 2011); oestrogen supplementation to prevent miscarriage;
ology alerts readers to potential bias in pooled effect estimates. and vitamin C (Bamigboye 2003). The metronidazole and oestro-
Our overview further classified review effect estimates to assign a gen Cochrane Reviews are out of date and are not included in this
graphic icon and communicate evidence quality (see Figure 2). overview. The result for vitamin C in an updated review included
here no longer shows harm but rather shows equivalence of vita-
To ensure the credible interpretation of SR estimates researchers
min C with the comparator (Rumbold 2015a, see also Figure 7). Piso
should consider whether meta-analyses have adequate statistical
cites 12 additional reviews reporting benefit to women, including
power (e.g. Schünemann 2013). GRADE criteria consider the impre-
interventions such as smoking cessation programs and antenatal
cision of a pooled estimate, which is related to power, but no SR
genital tract infection screening. Our overview does not included
included in this overview formally reported whether a meta-analy-
the same set of Cochrane Reviews as Piso because some of these
sis had adequate data to draw meaningful conclusions. Overview
Cochrane Reviews are now out-of-date.
authors may provide such context to improve interpretation of SR
evidence.
Informed decisions.

Nijman 2016 reviewed interventions to diagnose and treat threat- be an excuse today when access to some form of social media is
ened PTB. The authors found that cervical length measurement almost universal. The overview summarises no evidence for cervi-
combined with fetal fibronectin was the most effective way to iden- cal pessary, cervical length assessment and vaginal progesterone
tify women who may labour within seven days; corticosteroids in singleton pregnancy because these Cochrane Reviews were not
improved neonatal outcome; tocolytic therapy should be restrict- current. Readers should be aware that these are active areas for
ed to 48 hours’ use; maintenance tocolysis did not work; mag- PTB research.
nesium sulphate improved neurological outcomes for the baby;
and erythromycin improved neonatal outcomes when women had The graphic icons assigned to systematic review effect estimates
preterm prelabour rupture of membranes. do not constitute clinical guidance or an endorsement of specif-
ic interventions for pregnant women. Readers should refer to full
Lucaroni 2018 summarised SRs of biomarkers to predict sponta- systematic reviews for important details on clinical efficacy, tar-
neous PTB and concluded that cervical fetal fibronectin, alpha fe- get populations, and the geographic setting of clinical trials. Preg-
toprotein, C-reactive protein and interleukin 6 each had good diag- nant women and their healthcare providers must carefully consid-
nostic accuracy to identify women at risk of spontaneous PTB. er whether specific strategies to prevent PTB will be of benefit for
individual women, or for specific populations of women.
One of the important challenges we faced was the appropriate use
of user-friendly language bearing in mind that a significant pro- Implications for research
portion of the readership may not have English as their first lan-
guage. Jones 2012 categorised interventions for pain during labour The difficulty of maintaining timeliness of live systematic reviews in
with “What works”; “What may work”; and “Insufficient evidence.” such an active research field as PTB prevention cannot be overstat-
For Ciapponi 2017, an “effective” intervention had GRADE moder- ed. Researchers associated with Cochrane have proposed strate-
ate- or high-certainty evidence showing benefit for a key outcome gies to streamline review production in a series of papers (Elliott
and no negative effects via other outcomes; similarly, for Shep- 2017). Limiting meta-analyses to priority outcome domains and
herd 2017, “effective” meant GRADE high-quality evidence. Far- measures may also make regular updates more feasible and facili-
quhar 2018 classified interventions as effective, promising, ineffec- tate easier and more accurate data pooling (van't Hooft 2016). Fu-
tive, and possibly ineffective or no conclusions, possible due to lack ture updates of Cochrane Reviews should apply the Global Alliance
of evidence. to Prevent Prematurity and Stillbirth (GAPPS) classification system
or another to enable more nuanced reporting and analysis of PTB
We aimed to create a similarly straight-forward classification (Villar 2012).
scheme able to communicate both review conclusions about an
interventions and GRADE criteria and decision-making. We also Formal consensus work is needed to establish standardised lan-
wanted readers to be able to consider multiple reviews together guage for overviews and to draw limits for their interpretation of
in the same figure, without encouraging the direct comparison of review evidence and its (un)certainty for benefit or harm.
relative risk estimates across different SRs. To this end, we creat-
For effective interventions, the underlying mechanism of action on
ed the graphic icons to communicate the effects of interventions
PTB or perinatal death was not always clear. Whilst this should not
and our confidence in the estimates. To improve the usefulness of
be an excuse for not implementing interventions demonstrating
overviews, researchers should agree standard language and inves-
clear benefit, researchers must be encouraged to find the links that
tigate new ways to communicate complex SR evidence via graphic
would enable further improvements and open other areas of scien-
or interactive media.
tific enquiry.
AUTHORS' CONCLUSIONS ACKNOWLEDGEMENTS
Implications for practice As part of the prepublication editorial process, four peers (an editor
No clear evidence of harm from any of the included intervention is and three referees who are external to the editorial team), a mem-
reassuring, but the possibility that as many as four may be harm- ber of Cochrane Pregnancy and Childbirth's international panel of
ful to women and neonates is a concern. For anyone contemplating consumers and the Cochrane Pregnancy and Childbirth's Statisti-
their implementation, a careful risk/benefit assessment should be cal Adviser commented on the protocol draft. We are grateful for
made depending on the setting and available alternative. Reduced the carefully-considered and helpful comments made during peer
antenatal visits may have increased women’s risk of perinatal death review and especially thank Prof. David Haas. The named overview
in settings where pregnant women already received limited ante- authors alone are responsible for the final content and conclusions
natal care (Dowswell 2015). Likewise, women’s risk of preterm birth of the overview.
(PTB) may have increased with the administration of: intramuscu-
This project is supported by the University of Liverpool's Har-
lar progesterone for women with multiple pregnancy (Dodd 2017);
ris-Wellbeing of Women Preterm Birth Centre research award (Sum-
vitamin D, calcium and other supplements for women without pre-
mer 2015).
existing conditions (De-Regil 2016); and external cephalic version
for women with breech presentation before term (Hutton 2015). This project is supported by the National Institute for Health Re-
search (NIHR), via Cochrane Infrastructure funding to Cochrane
For health systems where the four effective interventions listed in
Pregnancy and Childbirth. The views and opinions expressed there-
the discussion are not part of clinical care, a rationale for their ex-
in are those of the overview authors and do not necessarily reflect
clusion should be made available to users. The forums in which
those of the Systematic Reviews Programme, the NIHR, the NHS or
such decisions can be justified may not exist, but this can hardly
the UK Department of Health.
Informed decisions.

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ADDITIONAL TABLES

Table 1. Characteristics of included systematic reviews
Review ID and title Search No. in- No. in- Overview Review authors' conclusions
date (CPC cluded cluded outcomes
register) trials partic- reported (quoted directly from published Cochrane Review)
Informed decisions.

Table 1. Characteristics of included systematic reviews (Continued)

ipants
(women)
Alfirevic 2015 28 Febru- 5 14,185 1. Perina- Existing evidence does not provide conclusive evidence
ary 2015 tal that the use of routine umbilical artery Doppler ultra-
Fetal and umbilical death sound, or combination of umbilical and uterine artery
Doppler ultrasound with Doppler ultrasound in low-risk or unselected popula-
in normal pregnan- anom- tions benefits either mother or baby. Future studies
cy. alies should be designed to address small changes in peri-
2. Any natal outcome, and should focus on potentially pre-
death ventable deaths.
after
ran-
domi-
sation
3. Neona-
tal
death
(to 28
days)
4. Still-
birth
5. Poten-
tially
pre-
ventable
perina-
tal
death
6. Preterm
birth <
37
weeks
7. Gesta-
tional
age at
birth
Alfirevic 2017a 30 June 15 3490 1. Perina- Cervical cerclage reduces the risk of preterm birth in
2016 tal women at high risk of preterm birth and probably re-
Cervical stitch (cer- death duces risk of perinatal deaths. There was no evidence
clage) for prevent- 2. Still- of any differential effect of cerclage based on previ-
ing preterm birth in birth ous obstetric history or short cervix indications, but da-
singleton pregnan- ta were limited for all clinical groups. The question of
3. Neona-
cy. whether cerclage is more or less effective than other
tal
death preventative treatments, particularly vaginal proges-
terone, remains unanswered.
4. Preterm
birth <
37, <
34 and
< 28
weeks
Alfirevic 2017b 31 March 19 10,667 1. Perina- Current evidence suggests that the use of Doppler ul-
2017 tal trasound on the umbilical artery in high-risk pregnan-
Fetal and umbilical death cies reduces the risk of perinatal deaths and may result
Doppler ultrasound 2. Preterm in fewer obstetric interventions. The results should be
in high-risk preg- labour interpreted with caution, as the evidence is not of high
nancies quality. Serial monitoring of Doppler changes in duc-
Informed decisions.


< 37 tus venosus may be beneficial, but more studies of high
weeks quality with follow-up including neurological develop-
ment are needed for evidence to be conclusive.
Bain 2014 2 June 8 1181 1. Perina- Based on eight included trials, of moderate quality
2014 tal overall, no firm conclusions about optimal interven-
Interventions for death tions for managing asthma in pregnancy can be made.
managing asthma 2. Still- Five trials assessing pharmacological interventions did
in pregnancy. birth not provide clear evidence of benefits or harms to sup-
3. Neona- port or refute current practice.
tal
death
4. Preterm
birth
5. Gesta-
tional
age at
birth
Bain 2015 11 Febru- 13 4983 1. Perina- Based on the data currently available, conclusive evi-
ary 2014 tal dence is not available to guide practice.
Diet and exercise death
interventions for 2. Still-
preventing gesta- birth
tional diabetes mel-
3. Neona-
litus.
tal
This review was up- death
dated as 4. Preterm
birth
5. Gesta-
tional
age at
birth
Boelig 2016 20 Decem- 25 2052 1. Still- On the basis of this review, there is little high-quality
ber 2015 across 18 birth and consistent evidence supporting any one interven-
Interventions for compar- and tion, which should be taken into account when making
treating hypereme- isons neona- management decisions.
sis gravidarum. tal
death
2. Preterm
birth
Bricker 2015a 31 May 13 34,980 1. Perina- Based on existing evidence, routine late pregnancy ul-
2015 tal trasound in low-risk or unselected populations does
Routine ultrasound death not confer benefit on mother or baby. There was no dif-
in late pregnancy 2. Still- ference in the primary outcomes of perinatal mortal-
(after 24 weeks' birth ity, preterm birth less than 37 weeks, caesarean sec-
gestation). tion rates, and induction of labour rates if ultrasound in
3. Neona-
tal late pregnancy was performed routinely versus not per-
death formed routinely.
4. Preterm
birth
5. Gesta-
tional
age at
birth
Informed decisions.


Bricker 2015b 15 June 0 0 None There is no robust evidence from randomised trials to
2015 indicate whether specialised diets or nutritional advice
Nutritional advice for women with multiple pregnancies do more good
for improving out- than harm. There is a clear need to undertake a ran-
comes in multiple domised controlled trial.
pregnancies.
Brown 2016 7 April 2 142 1. Preterm There are insufficient data to evaluate the effect of
2016 birth myo-inositol for the treatment of gestational diabetes,
Dietary supplemen- with no data to examine the majority of outcomes in
tation with myo- this review. There do not appear to be any benefits for
inositol in women the infant associated with exposure to myo-inositol
during pregnancy
for treating gesta-
tional diabetes.
Brown 2017a 14 May 15 4501 1. Perina- Lifestyle interventions are the primary therapeu-
2016 tal tic strategy for women with GDM. Women receiving
Lifestyle interven- death lifestyle interventions were less likely to have postna-
tions for the treat- 2. Preterm tal depression and were more likely to achieve postpar-
ment of women birth < tum weight goals. Exposure to lifestyle interventions
with gestational di- 37 and was associated with a decreased risk of the baby being
abetes. < 32 born LGA and decreased neonatal adiposity. Long-term
weeks maternal and childhood/adulthood outcomes were
poorly reported. The value of lifestyle interventions in
low- and middle-income countries or for different eth-
nicities remains unclear. The longer-term benefits or
harms of lifestyle interventions remains unclear due to
limited reporting.
Brown 2017b 27 August 11 638 1. Perina- Short- and long-term outcomes of interest for this re-
2016 tal view were poorly reported. Current evidence is con-
Exercise for preg- death founded by the large variety of exercise interventions.
nant women with 2. Preterm There was insufficient high-quality evidence to be able
gestational dia- birth < to determine any differences between exercise and
betes for improving 37 and control groups for our outcomes of interest.
maternal and fetal < 32
outcomes. weeks
Brown 2017c 14 May 11 1487 None There were insufficient data comparing oral anti-dia-
2016 betic pharmacological therapies with placebo/stan-
Oral anti-diabet- dard care (lifestyle advice) to inform clinical practice.
ic pharmacolog- There was insufficient high-quality evidence to be able
ical therapies for to draw any meaningful conclusions as to the benefits
the treatment of of one oral anti-diabetic pharmacological therapy over
women with gesta- another due to limited reporting of data for the prima-
tional diabetes. ry and secondary outcomes in this review. Short- and
long-term clinical outcomes for this review were inade-
quately reported or not reported. Current choice of oral
anti-diabetic pharmacological therapy appears to be
based on clinical preference, availability and national
clinical practice guidelines.
Buppasiri 2015 30th 25 18587 1. Perina- This review indicates that there are no clear additional
Septem- tal benefits to calcium supplementation in prevention of
Calcium supple- ber 2014 death preterm birth or low infant birthweight.
mentation (other 2. Still-
than for preventing birth or
or treating hyper-
tension) for improv-
Informed decisions.


ing pregnancy and fetal
infant outcomes. death
3. Preterm
birth
Carberry 2014 12 March 0 0 None There is no randomised trial evidence currently avail-
2014 able. Further randomised trials are required to accu-
Customised versus rately assess whether the improvement in detection
population-based shown is secondary to customised charts alone or an
growth charts as a effect of the policy change.
screening tool for
detecting small for
gestational age in-
fants in low-risk
pregnant women.
Catling 2015 31 Octo- 4 2350 1. Perina- Available evidence suggests that group antenatal care
ber 2014 tal is acceptable to women and is associated with no ad-
Group versus con- death verse outcomes for them or for their babies. No differ-
ventional antenatal 2. Preterm ences in the rate of preterm birth were reported when
care for women. birth women received group antenatal care. This review is
3. Gesta- limited because of the small numbers of studies and
tional women, and because one study contributed 42% of
age at the women. Most of the analyses are based on a sin-
birth gle study. Additional research is required to determine
whether group antenatal care is associated with signifi-
cant benefit in terms of preterm birth or birthweight.
Chamberlain 2017 13 No- 102 28,000 1. Perina- Psychosocial interventions to support women to stop
vember tal smoking in pregnancy can increase the proportion of
Psychosocial inter- 2015 death women who stop smoking in late pregnancy and the
ventions for sup- 2. Preterm proportion of infants born low birthweight.
porting women to birth <
stop smoking in 37
pregnancy. weeks
Cluver 2017 26 June 15 1754 1. Perina- Treatment with antibacterial agents achieves microbi-
2017 tal ological cure from C. trachomatis infection during preg-
Interventions for death nancy. There was no apparent difference between as-
treating genital 2. Preterm sessed agents (amoxicillin, erythromycin, clindamycin,
Chlamydia tra- birth azithromycin) in terms of efficacy (microbiological cure
chomatis infection and repeat infection) and pregnancy complications
in pregnancy. (preterm birth, preterm rupture of membranes, low
birthweight). Azithromycin and clindamycin appear to
result in fewer side effects than erythromycin.
Coleman 2015 11 July 9 2210 1. Still- There is no evidence that NRT used for smoking ces-
2015 birth sation in pregnancy has either positive or negative im-
Pharmacological 2. Neona- pacts on birth outcomes.
interventions for tal
promoting smok- death
ing cessation dur-
3. Preterm
ing pregnancy.
birth
da Silva Lopes 2017 30 May 6 636 1. Preterm The evidence to date is insufficient to inform a policy of
2016 birth routine bed rest in hospital or at home for women with
Bed rest with and a multiple pregnancy.
without hospitali-
sation in multiple
pregnancy for im-
Informed decisions.


proving perinatal
outcomes.
Davey 2015 30 June 0 0 None The role of risk-scoring systems in the prevention of
2015 preterm birth is unknown.
Risk-scoring sys-
tems for predicting
preterm birth with
the aim of reducing
associated adverse
outcomes.
De-Regil 2015 31 August 5 7391 1. Still- Folic acid, alone or in combination with vitamins and
2015 birth minerals, prevents neural tube defects, but does not
Effects and safety 2. Neona- have a clear effect on other birth defects.
of periconception- tal
al oral folate sup- death
plementation for
3. Preterm
preventing birth de-
birth
fects.
De-Regil 2016 23 Febru- 15 2388 1. Still- New studies have provided more evidence on the ef-
ary 2015 birth fects of supplementing pregnant women with vitamin
Vitamin D sup- 2. Neona- D alone or with calcium on pregnancy outcomes. Sup-
plementation for tal plementing pregnant women with vitamin D in a single
women during death or continued dose increases serum 25-hydroxyvitamin
pregnancy. D at term and may reduce the risk of pre-eclampsia,
3. Preterm
birth low birthweight and preterm birth. However, when vit-
amin D and calcium are combined, the risk of preterm
birth is increased. The clinical significance of the in-
creased serum 25-hydroxyvitamin D concentrations is
still unclear. In light of this, these results need to be in-
terpreted with caution. Data on adverse effects were
lacking in all studies.
Dodd 2015a 31 July 0 0 None We found no available data from randomised trials
2015 to inform the risks and benefits of pregnancy reduc-
Reduction of the tion procedures for women with a multiple pregnan-
number of fetuses cy. While randomised controlled trials will provide the
for women with a most reliable evidence about the risks and benefits of
multiple pregnan- fetal reduction procedures, reduction in the number of
cy. fetuses by selective termination may not be acceptable
to women, particularly couples with a past history of
infertility. The acceptability of this option, and willing-
ness to undergo randomisation will depend on the cou-
ple's social background and beliefs, and consequently,
recruitment to such a trial may prove exceptionally dif-
ficult.
Dodd 2015b 31 May 1 162 1. Perina- There is currently limited information available from
2015 tal randomised controlled trials to assess the role of 'spe-
Specialised ante- death cialised' antenatal clinics for women with a multiple
natal clinics for 2. Still- pregnancy compared with 'standard' antenatal care in
women with a mul- birth improving maternal and infant health outcomes.
tiple pregnancy for
3. Neona-
improving mater-
tal
nal and infant out-
death
comes.
Informed decisions.


Dodd 2017 1 Novem- 17 4773 1. Perina- Overall, for women with a multiple pregnancy, treat-
ber 2016 tal ment with progesterone (either intramuscular or
Prenatal adminis- death vaginal) does not appear to reduce the likelihood of
tration of progesto- 2. Preterm preterm birth or improve outcomes for babies.
gens for prevent- birth <
ing spontaneous 37, <
preterm birth in 34 and
women with a mul- < 28
tiple pregnancy. weeks
Dowswell 2015 23 March 7 60,000+ 1. Perina- In settings with limited resources where the number
2015 tal of visits is already low, reduced visits programmes of
Alternative versus death antenatal care are associated with an increase in peri-
standard packages 2. Preterm natal mortality compared to standard care, although
of antenatal care birth admission to neonatal intensive care may be reduced.
for low-risk preg- Women prefer the standard visits schedule. Where the
nancy. standard number of visits is low, visits should not be re-
duced without close monitoring of fetal and neonatal
outcome.
Farrar 2016 31 March 5 153 1. Perina- There is no evidence to support the use of one partic-
2016 tal ular form of insulin administration over another for
Continuous subcu- death pregnant women with diabetes. There are only a small
taneous insulin in- 2. Gesta- number of trials appropriate for meta-analysis, a small
fusion versus multi- tional number of women included and questionable general-
ple daily injections age at isability of the trial population.
of insulin for preg- birth
nant women with
3. Preterm
diabetes.
birth
Farrar 2017 9 January 7 1420 1. Gesta- There is insufficient evidence to suggest which strategy
2017 tional is best for diagnosing GDM.
Different strategies age at
for diagnosing ges- birth
tational diabetes to
improve maternal
and infant health.
Gomi 2015 31 Decem- 0 0 None There are no large-scale randomised controlled trials to
ber 2014 assess outcomes in the management of pyelonephritis
Routine blood in pregnancy with or without blood cultures.
cultures in the
management of
pyelonephritis in
pregnancy for im-
proving outcomes.
Grivell 2015 26 June 6 2105 1. Perina- There is no clear evidence that antenatal CTG improves
2015 tal perinatal outcome, but further studies focusing on the
Antenatal car- death use of computerised CTG in specific populations of
diotocography for 2. Any po- women with increased risk of complications are war-
fetal assessment. tential- ranted.
ly pre-
ventable
perina-
tal
death
Informed decisions.


3. GA at
birth
Haider 2017 11 March 19 138,538 1. Perina- Our findings support the effect of MMN supplements
2015 tal with iron and folic acid in improving some birth out-
Multiple-micronu- death comes. Overall, pregnant women who received MMN
trient supplementa- 2. Preterm supplementation had fewer low birthweight babies
tion for women dur- birth and small-for-gestational-age babies. The findings,
ing pregnancy. consistently observed in several systematic evaluations
of evidence, provide a basis to guide the replacement
of iron and folic acid with MMN supplements contain-
ing iron and folic acid for pregnant women in low and
middle-income countries where MMN deficiencies are
common among women of reproductive age. Efforts
could focus on the integration of this intervention in
maternal nutrition and antenatal care programs in low-
and middle-income countries.
Han 2017 8 March 19 1398 1. Perina- Evidence from 19 trials assessing different types of di-
2016 tal etary advice for women with GDM suggests no clear
Different types of death differences for primary outcomes and secondary out-
dietary advice for 2. Preterm comes assessed using GRADE, except for a possible re-
women with gesta- birth duction in caesarean section for women receiving a
tional diabetes. DASH diet compared with a control diet. Few differ-
ences were observed for secondary outcomes.
Harding 2017 14 No- 11 2700 1. Perina- There were insufficient data to reach any meaningful
vember tal conclusions on the benefits and harms of routine io-
Iodine supplemen- 2016 death dine supplementation in women before, during or after
tation for women 2. Preterm pregnancy.
during the precon- birth
ception, pregnancy
and postpartum pe-
riod
Heazell 2015 31 July 3 740 1. Perina- There is insufficient evidence to support the use of bio-
2015 tal chemical tests of placental function to reduce perina-
Use of biochemi- death tal mortality or increase identification of small-for-ges-
cal tests of placen- (still- tational-age infants. However, we were only able to in-
tal function for im- birth or clude data from two studies that measured oestrogens
proving pregnancy neona- and hPL. The quality of the evidence was low or very
outcome. tal low.
death
togeth-
er)
2. Still-
birth
3. Neona-
tal
death
4. Preterm
birth
Hofmeyr 2016 6 July 1 34 None There is insufficient evidence to fully evaluate the ef-
2016 fectiveness of using transcervical amnioinfusion for
Amnioinfusion for chorioamnionitis and to assess the safety of this inter-
chorioamnionitis. vention or women’s satisfaction. We did not identify
any trials that used transabdominal amnioinfusion.
Informed decisions.


Hofmeyr 2017 10 August 1 60 1. Perina- Calcium supplementation (≥ 1 g/day) is associated with
2017 tal a significant reduction in the risk of pre-eclampsia, par-
Calcium supple- death ticularly for women with low-calcium diets. The treat-
mentation com- 2. Preterm ment effect may be overestimated due to small-study
mencing before or birth effects or publication bias. It also reduces preterm birth
early in pregnancy, and the occurrence of the composite outcome 'mater-
or food fortification nal death or serious morbidity'. We considered these
with calcium, for benefits to outweigh the increased risk of HELLP syn-
preventing hyper- drome, which was small in absolute numbers. The
tensive disorders of World Health Organization recommends calcium 1.5 g
pregnancy. to 2 g daily for pregnant women with low dietary calci-
um intake.
Hutton 2015 31 March 5 2187 1. Perina- Compared with no ECV attempt, ECV commenced be-
2015 tal fore term reduces non-cephalic presentation at birth.
External cephalic death Compared with ECV at term, beginning ECV at between
version for breech 2. Still- 34 to 35 weeks may have some benefit in terms of de-
presentation before birth creasing the rate of non-cephalic presentation, and
term. risk of vaginal breech birth. However, early ECV may in-
3. Preterm
labour crease risk of late preterm birth, and it is important that
any future research reports infant morbidity outcomes.
4. Still-
Results of the review suggest that there is a need for
birth or
careful discussion with women about the timing of the
neona-
ECV procedure so that they can make informed deci-
tal
sions.
death <
7 days
Iheozor-Ejiofor 7 October 15 7161 1. Perina- It is not clear if periodontal treatment during pregnan-
2017 2016 tal cy has an impact on preterm birth (low-quality evi-
death dence). There is low-quality evidence that periodontal
Treating periodon- 2. Preterm treatment may reduce low birth weight (< 2500 g), how-
tal disease for pre- birth < ever, our confidence in the effect estimate is limited
venting adverse 37
birth outcomes in weeks
pregnant women
Jahanfar 2014 31 July 10 3417 1. Preterm There is insufficient evidence to assess the effective-
2014 birth ness of interventions for domestic violence on preg-
Interventions for nancy outcomes. There is a need for high-quality, RCTs
preventing or re- with adequate statistical power to determine whether
ducing domestic intervention programs prevent or reduce domestic vi-
violence against olence episodes during pregnancy, or have any effect
pregnant women. on maternal and neonatal mortality and morbidity out-
comes.
Jahanfar 2015 16 Janu- 1 1197 1. Preterm There is insufficient evidence to confirm or refute the
ary 2016 birth effectiveness of caffeine avoidance on birthweight or
Effects of restrict- other pregnancy outcomes. There is a need to con-
ed caffeine intake duct high-quality, double-blinded RCTs to determine
by mother on fetal, whether caffeine has any effect on pregnancy outcome.
neonatal and preg-
nancy outcomes.
Low 2016 14 Febru- 6 359,078 None. No There is an absence of RCT evidence about the effects
ary 2016 included of chlamydia screening in pregnancy. Future RCTs of
Screening for geni- RCT mea- chlamydia screening interventions should determine
tal chlamydia infec- sured the the effects of chlamydia screening in pregnancy, of re-
tion. effects of peated rounds of screening on the incidence of chlamy-
screen-
Informed decisions.


ing in dia-associated PID and chlamydia reinfection in gener-
pregnant al and high-risk populations.
women
Martis 2016 31 Janu- 1 180 1. Gesta- There is insufficient evidence to guide clinical prac-
ary 2016 tional tice for targets for glycaemic control for women with
Different intensi- age at GDM to minimise adverse effects on maternal and fe-
ties of glycaemic birth tal health. Glycaemic target recommendations from
control for women international professional organisations for maternal
with gestational di- glycaemic control vary widely and are reliant on con-
abetes mellitus. sensus given the lack of high-quality evidence. Further
high-quality trials are needed, and these should com-
pare different glycaemic targets for guiding treatment
of women with GDM, assess both short-term and long-
term health outcomes for women and their babies, in-
clude women's experiences and assess health services
costs. Four studies are ongoing.
Matthews 2015 19 Janu- 41 5449 1. Spon- Given the high prevalence of nausea and vomiting in
ary 2015 ta- early pregnancy, women and health professionals need
Interventions for neous clear guidance about effective and safe interventions,
nausea and vom- abor- based on systematically reviewed evidence. There is a
iting in early preg- tion lack of high-quality evidence to support any particular
nancy. 2. Still- intervention.
birth
3. Perina-
tal
death
4. Preterm
birth
Mbuagbaw 2015 7 June 34 400,000 1. Perina- Single interventions may improve ANC coverage (at
2015 tal least one visit and four or more visits) and deliveries
Health system and death in health facilities. Combined interventions may im-
community level in- 2. Preterm prove ANC coverage (at least one visit), reduce perina-
terventions for im- labour tal mortality and reduce the occurrence of low birth-
proving antenatal weight. The effects of the interventions are unrelated
care coverage and to whether they are community or health system inter-
health outcomes. ventions.
McCauley 2015 30 March 19 310,000 1. Perina- The pooled results of three large trials in Nepal, Ghana
2015 tal and Bangladesh (with over 153,500 women) do not cur-
Vitamin A supple- death rently suggest a role for antenatal vitamin A supple-
mentation during 2. Still- mentation to reduce maternal or perinatal mortality.
pregnancy for ma- birth However, the populations studied were probably differ-
ternal and newborn ent with regard to baseline vitamin A status and there
3. Neona-
outcomes. were problems with follow-up of women. There is good
tal
mortal- evidence that antenatal vitamin A supplementation re-
ity duces maternal night blindness, maternal anaemia for
women who live in areas where vitamin A deficiency is
4. Preterm
common or who are HIV-positive. In addition, the avail-
birth
able evidence suggests a reduction in maternal infec-
tion, but these data are not of a high quality.
Middleton 2016 31 Janu- 3 223 1. Perina- In a very limited body of evidence, few differences in
ary 2016 tal outcomes were seen between very tight and tight-mod-
Different intensities death erate glycaemic control targets in pregnant women
of glycaemic con- 2. Gesta- with pre-existing type 1 diabetes, including actual gly-
trol for pregnant tional caemic control achieved. There is evidence of harm (in-
Informed decisions.


women with pre-ex- age at creased pre-eclampsia, caesareans and birthweights
isting diabetes. birth greater than 90th centile) for 'loose' control (FBG above
7 mmol/L). Future trials comparing interventions,
rather than glycaemic control targets, may be more
feasible. Trials in pregnant women with pre-existing
type 2 diabetes are required.
Moy 2017 30 No- 10 538 1. Perina- This review found no evidence that any glucose mon-
vember tal itoring technique is superior to any other technique
Techniques of mon- 2016 death among pregnant women with pre-existing type 1 or
itoring blood glu- 2. Preterm type 2 diabetes. The evidence base for the effectiveness
cose during preg- birth of monitoring techniques is weak and additional evi-
nancy for women dence from large well-designed randomised trials is re-
with pre-existing di- quired to inform choices of glucose monitoring tech-
abetes. niques.
Muktabhant 2015 5 Novem- 65 (49 11,444 1. Preterm High-quality evidence indicates that diet or exercise,
ber 2014 with data) birth or both, during pregnancy can reduce the risk of exces-
Diet or exercise, or sive GWG. Other benefits may include a lower risk of
both, for preventing caesarean delivery, macrosomia, and neonatal respi-
excessive weight ratory morbidity, particularly for high-risk women re-
gain in pregnancy. ceiving combined diet and exercise interventions. Ma-
ternal hypertension may also be reduced. Exercise ap-
pears to be an important part of controlling weight gain
in pregnancy and more research is needed to establish
safe guidelines. Most included studies were carried out
in developed countries and it is not clear whether these
results are widely applicable to lower-income settings.
O'Neill 2017 17 Octo- 5 554 1. Preterm With limited evidence and no meta-analyses, as each
ber 2016 birth trial looked at a different comparison, no firm conclu-
Different insulin sions could be made about different insulin types and
types and regi- regimens in pregnant women with pre-existing type 1
mens for pregnant or 2 diabetes. Further research is warranted to deter-
women with pre-ex- mine who has an increased risk of adverse pregnan-
isting diabetes. cy outcome. This would include larger trials, incorpo-
rating adequate randomisation and blinding, and key
outcomes that include macrosomia, pregnancy loss,
pre-eclampsia, caesarean section, fetal anomalies, and
birth trauma.
Opray 2015 31 Decem- 0 0 None We found no randomised controlled trials that as-
ber 2014 sessed the effect of preconception health programs
Directed precon- and interventions in overweight and obese women
ception health with the aim of improving pregnancy outcomes. Un-
programs and in- til the effectiveness of preconception health programs
terventions for and interventions can be established, no practice rec-
improving preg- ommendations can be made. Further research is re-
nancy outcomes quired in this area.
for women who
are overweight or
obese.
Ota 2015a 31 Octo- 21 17,000 1. Preterm The evidence for a 14% relative reduction in preterm
ber 2014 birth birth for zinc compared with placebo was primarily rep-
Zinc supplementa- 2. Still- resented by trials involving women of low income and
tion for improving birth or this has some relevance in areas of high-perinatal mor-
pregnancy and in- neona- tality. There was no convincing evidence that zinc sup-
fant outcome. tal plementation during pregnancy results in other use-
death ful and important benefits. Since the preterm associa-
Informed decisions.


(re- tion could well reflect poor nutrition, studies to address
ported ways of improving the overall nutritional status of pop-
as a ulations in impoverished areas, rather than focusing on
single micronutrient and or zinc supplementation in isolation,
out- should be an urgent priority.
come)
3. Gesta-
tional
age at
birth
Ota 2015b 31 Janu- 17 9030 1. Still- This review provides encouraging evidence that an-
ary 2015 birth tenatal nutritional education with the aim of increas-
Antenatal dietary 2. Neona- ing energy and protein intake in the general obstetric
education and sup- tal population appears to be effective in reducing the risk
plementation to in- death of preterm birth, low birthweight, increasing head cir-
crease energy and cumference at birth, increasing birthweight among un-
3. Preterm
protein intake. dernourished women, and increasing protein intake.
birth
There was no evidence of benefit or adverse effect for
any other outcome reported.
Peña-Rosas 2015a 10 Janu- 61 (44 43,274 1. Neona- Supplementation reduces the risk of maternal anaemia
ary 2015 with data) tal and iron deficiency in pregnancy but the positive effect
Daily oral iron sup- death on other maternal and infant outcomes is less clear.
plementation dur- 2. Preterm Implementation of iron supplementation recommen-
ing pregnancy. birth dations may produce heterogeneous results depend-
ing on the populations' background risk for low birth-
weight and anaemia, as well as the level of adherence
to the intervention.
Peña-Rosas 2015b 31 July 27 (21 5490 1. Neona- This review is the most comprehensive summary of
2015 with data) tal the evidence assessing the benefits and harms of in-
Intermittent oral death termittent iron supplementation in pregnant women
iron supplementa- 2. Preterm on haematological and pregnancy outcomes. Findings
tion during preg- birth suggest that intermittent regimens produced similar
nancy. maternal and infant outcomes as daily supplementa-
tion but were associated with fewer side effects and re-
duced the risk of high levels of Hb in mid and late preg-
nancy, although the risk of mild anaemia near term was
increased. While the quality of the evidence was as-
sessed as low or very low, intermittent may be a feasi-
ble alternative to daily iron supplementation among
those pregnant women who are not anaemic and have
adequate antenatal care.
Phupong 2015 30 June 9 725 None Further RCTs are needed to fully evaluate the effective-
2015 ness of interventions for heartburn in pregnancy. Fu-
Interventions for ture research should also address other medications
heartburn in preg- such as histamine 2-receptor antagonists, promotility
nancy. drugs, proton pump inhibitors, and a raft-forming al-
ginate reflux suppressant in treatment of heartburn in
pregnancy. More research is needed on acupuncture
and other complimentary therapies as treatments for
heartburn in pregnancy. Future research should also
evaluate any adverse outcomes, maternal satisfaction
with treatment and measure pregnant women's quality
of life in relation to the intervention.
Radeva-Petrova 1 June 17 14,481 1. Still- Routine chemoprevention to prevent malaria and its
2014 2014 birth consequences has been extensively tested in RCTs,
Informed decisions.


Drugs for prevent- 2. Perina- with clinically important benefits on anaemia and para-
ing malaria in preg- tal sitaemia in the mother, and on birthweight in infants.
nant women in en- death
demic areas: any 3. Neona-
drug regimen ver- tal and
sus placebo or No Infant
treatment. death
4. Preterm
birth
Rafael 2014 30 June 5 1577 1. Perina- This review is based on limited data from five small
2014 tal studies of average to above average quality. For multi-
Cervical stitch (cer- death ple gestations, there is no evidence that cerclage is an
clage) for prevent- 2. Still- effective intervention for preventing preterm births and
ing preterm birth in birth reducing perinatal deaths or neonatal morbidity.
multiple pregnan-
3. Neona-
cy.
tal
death
4. Preterm
birth
5. Gesta-
tional
age at
birth
Raman 2017 30 11 1272 1. Perina- Evidence from 11 RCTs assessing different methods or
Septem- tal settings for glucose monitoring for GDM suggests no
Different methods ber 2016 death clear differences for the primary outcomes or other
and settings for glu- 2. Preterm secondary outcomes assessed in this review.
cose monitoring birth
for gestational dia-
betes during preg-
nancy.
Rumbold 2015a 31 March 21 22,192 1. Perina- The data do not support routine vitamin C supplemen-
2015 tal tation alone or in combination with other supplements
Vitamin C supple- death for the prevention of fetal or neonatal death, poor fe-
mentation in preg- 2. Still- tal growth, preterm birth or pre-eclampsia. Further re-
nancy. birth search is required to elucidate the possible role of vi-
3. Neona- tamin C in the prevention of placental abruption and
tal prelabour rupture of membranes. There was no con-
death vincing evidence that vitamin C supplementation alone
or in combination with other supplements results in
4. Preterm
other important benefits or harms.
birth
5. Gesta-
tional
age at
birth
Rumbold 2015b 31 March 29 24,300 1. Still- The data do not support routine vitamin E supplemen-
2015 birth tation in combination with other supplements for the
Vitamin E supple- 2. Neona- prevention of stillbirth, neonatal death, preterm birth,
mentation in preg- tal pre-eclampsia, preterm or term PROM or poor fetal
nancy. death growth. Further research is required to elucidate the
3. Perina- possible role of vitamin E in the prevention of placental
tal abruption. There was no convincing evidence that vita-
death min E supplementation in combination with other sup-
plements results in other important benefits or harms.
Informed decisions.


4. Preterm
birth
5. Gesta-
tional
age at
birth
Salam 2015a 31 Janu- 4 4265 1. Perina- The evidence to date is insufficient to recommend use
ary 2015 tal of antihelminthic for pregnant women after the first
Effect of admin- death trimester of pregnancy. More well-designed, large-scale
istration of anti- 2. Preterm randomised controlled trials are needed to establish
helminthics for birth the benefit of antihelminthic treatment during preg-
soil-transmitted nancy.
helminths during
pregnancy.
Salam 2015b 29 Janu- 2 2262 1. Perina- There is limited evidence (from one small trial at a high
ary 2015 tal risk of bias) on the effectiveness on Hib during preg-
Impact of death nancy for improving maternal, neonatal and infant
Haemophilus in- 2. Infant health outcomes. Evidence from one large high-qual-
fluenzae type B death ity trial on the effectiveness of viral influenza vaccine
(Hib) and viral in- during pregnancy suggests reduced RT-PCR confirmed
3. Preterm
fluenza vaccina- influenza among women and their babies, suggesting
birth
tions in pregnan- the potential of this strategy for scale up but further ev-
cy for improving idence from varying contexts is required. Further trials
maternal, neonatal for both Hib and viral influenza vaccines with appropri-
and infant health ate study designs and suitable comparison groups are
outcomes. required.
Salam 2015c 31 March 4 1646 None There were few trials, reporting few clinical outcomes
2015 and mostly with unclear trial methodology and inade-
Pyridoxine (vitamin quate follow-up. There is not enough evidence to de-
B6) supplementa- tect clinical benefits of vitamin B6 supplementation
tion during preg- in pregnancy and/or labour other than one trial sug-
nancy or labour gesting protection against dental decay. Future trials
for maternal and assessing this and other outcomes such as orofacial
neonatal outcomes. clefts, cardiovascular malformations, neurological de-
velopment, preterm birth, pre-eclampsia and adverse
events are required.
Sandall 2016 31 May 15 17,674 1. Overall This review suggests that women who received mid-
2015 fetal wife-led continuity models of care were less likely to
Midwife-led conti- loss experience intervention and more likely to be satisfied
nuity models ver- and with their care with at least comparable adverse out-
sus other models of neona- comes for women or their infants than women who re-
care for childbear- tal ceived other models of care.
ing women. death
2. Preterm Further research is needed to explore findings of few-
birth er preterm births and fewer fetal deaths less than 24
weeks, and all fetal loss/neonatal death associated
with midwife-led continuity models of care.
Sangkomkamhang 30 No- 1 4155 1. Neona- There is evidence from one trial that infection screen-
2015 vember tal ing and treatment programs for pregnant women be-
2014 death fore 20 weeks' gestation reduce preterm birth and
Antenatal lower 2. Preterm preterm low birthweight. Infection screening and treat-
genital tract in- birth ment programs are associated with cost savings when
fection screening used for the prevention of preterm birth. Future trials
and treatment pro- should evaluate the effects of different types of infec-
grams for prevent- tion screening programs.
Informed decisions.


ing preterm deliv-
ery.
Schneeberger 2015 20 May 1 200 1. Miscar- A daily dose of nitrofurantoin and close surveillance
2015 riage has not been shown to prevent RUTI compared with
Interventions for 2. Preterm close surveillance alone. A significant reduction of ASB
preventing recur- birth was found in women with a high clinic attendance rate
rent urinary tract and who received nitrofurantoin and close surveil-
infection during lance. There was limited reporting of both primary and
pregnancy. secondary outcomes for both women and infants. No
conclusions can be drawn regarding the optimal inter-
vention to prevent RUTI in women who are pregnant.
Randomised controlled trials comparing different phar-
macological and non-pharmacological interventions
are necessary to investigate potentially effective inter-
ventions to prevent RUTI in women who are pregnant.
Smaill 2015 19 March 14 2000 1. Preterm While antibiotic treatment is effective in reducing the
2015 birth risk of pyelonephritis in pregnancy, the estimate of the
Antibiotics for effect is very uncertain because of the very low qual-
asymptomatic bac- ity of the evidence. The reduction in low birthweight
teriuria in pregnan- and preterm birth with antibiotic treatment is consis-
cy. tent with theories about the role of infection in adverse
pregnancy outcomes, but this association should be in-
terpreted with caution given the very poor quality of
the included studies.
Smyth 2015 31 May 7 326 None There is moderate-quality evidence to suggest that ru-
2015 tosides appear to help relieve the symptoms of vari-
Interventions for cose veins in late pregnancy. However, this finding
varicose veins and is based on one study (69 women) and there are not
leg oedema in preg- enough data presented in the study to assess its safety
nancy. in pregnancy. Reflexology or water immersion appears
to help improve symptoms for women with leg oede-
ma, but again this is based on two small studies (43 and
32 women, respectively).
Sosa 2015 18 Decem- 2 1266 1. Preterm There is no evidence, either supporting or refuting
ber 2014 birth the use of bed rest at home or in hospital, to prevent
Bed rest in single- preterm birth. Although bed rest in hospital or at home
ton pregnancies for is widely used as the first step of treatment, there is no
preventing preterm evidence that this practice could be beneficial. Due to
birth. the potential adverse effects that bed rest could have
on women and their families, and the increased costs
for the healthcare system, clinicians should discuss the
pros and cons of bed rest to prevent preterm birth. Po-
tential benefits and harms should be discussed with
women facing an increased risk of preterm birth. Ap-
propriate research is mandatory. Future trials should
evaluate both the effectiveness of bed rest, and the ef-
fectiveness of the prescription of bed rest, to prevent
preterm birth.
Spencer 2015 14 July 2 26,408 1. Fetal Based on the existing evidence, though universal
2015 and screening for thyroid dysfunction in pregnancy increas-
Screening and sub- neona- es the number of women diagnosed with hypothy-
sequent manage- tal roidism who can be subsequently treated, it does not
ment for thyroid death clearly impact (benefit or harm) maternal and infant
dysfunction pre- (re- outcomes. More evidence is needed to assess the bene-
pregnancy and dur- ported fits or harms of different screening methods for thyroid
Informed decisions.


ing pregnancy for as a dysfunction in pregnancy, on maternal, infant and child
improving maternal single health outcomes. Future trials should assess impacts
and infant health. out- on use of health services and costs, and be adequate-
come) ly powered to evaluate the effects on short- and long-
2. Miscar- term outcomes.
riage
3. Preterm
birth
4. Preterm
labour
Suchdev 2015 31 Janu- 2 1172 None Limited evidence suggests that micronutrient powders
ary 2015 for point-of-use fortification of foods have no clear dif-
Multiple micronu- ference as multiple micronutrient supplements on ma-
trient powders for ternal anaemia (very low-quality evidence) and Hb at
home (point-of- or near term. There is limited evidence to suggest that
use) fortification of women were more likely to adhere to taking tablets
foods in pregnant than using micronutrient powders.
women.
Terplan 2015 January 14 1298 1. Preterm The present evidence suggests that there is no differ-
2015 birth ence in treatment outcomes to address drug use in
Psychosocial inter- pregnant women with use of psychosocial interven-
ventions for preg- tions, when taken in the presence of other comprehen-
nant women in sive care options. However, few studies evaluated ob-
outpatient illicit stetrical or neonatal outcomes and rarely did so in a
drug treatment pro- systematic way, making it difficult to assess the effect
grams compared to of psychosocial interventions on these clinically im-
other interventions. portant outcomes. It is important to develop a better
evidence base to evaluate psychosocial modalities of
treatment in this important population.
Thinkhamrop 2015 31 July 7 2100 1. Perina- Antibiotic prophylaxis did not reduce the risk of
2014 tal preterm prelabour rupture of membranes or preterm
Antibiotic prophy- death delivery (apart from in the subgroup of women with a
laxis during the 2. Preterm previous preterm birth who had bacterial vaginosis).
second and third birth Antibiotic prophylaxis given during the second or third
trimester to reduce trimester of pregnancy reduced the risk of postpartum
3. Gesta-
adverse pregnancy endometritis, term pregnancy with prelabour rupture
tional
outcomes and mor- of membranes and gonococcal infection when given
age at
bidity. routinely to all pregnant women. Substantial bias pos-
birth
sibly exists in the review's results because of a high rate
of loss to follow-up and the small numbers of studies
included in each of our analyses. There is also insuffi-
cient evidence on possible harmful effects on the ba-
by. Therefore, we conclude that there is not enough
evidence to support the use of routine antibiotics dur-
ing pregnancy to prevent infectious adverse effects on
pregnancy outcomes.
Tieu 2017a 7 April 0 0 None The role of interconception care for women with a his-
2017 tory of GDM remains unclear. Randomised controlled
Interconception trials are required evaluating different forms and pro-
care for women tocols of interconception care for these women on peri-
with a history of natal and long-term maternal and infant health out-
gestational dia- comes, acceptability of such interventions and cost-ef-
betes for improving fectiveness.
maternal and infant
outcomes.
Informed decisions.


Tieu 2017b 3 January 11 2786 1. Perina- Very low-quality evidence from five trials suggests a
2016 tal possible reduction in GDM risk for women receiving
Dietary advice in- death dietary advice versus standard care, and low-quality
terventions in preg- 2. Gesta- evidence from four trials suggests no clear difference
nancy for prevent- tional for women receiving low- versus moderate- to high-GI
ing gestational dia- age at dietary advice. A possible reduction in pregnancy-in-
betes. birth duced hypertension for women receiving dietary ad-
vice was observed and no clear differences were seen
for other reported primary outcomes. There were few
outcome data for secondary outcomes. More high-
quality evidence is needed to determine the effects of
dietary advice interventions in pregnancy.
Tieu 2017c 31 Octo- 3 241 1. Perina- There are insufficient RCT data to evaluate the use of
ber 2016 tal oral anti-diabetic agents in women with established
Oral anti-diabetic death diabetes, impaired glucose tolerance or previous ges-
agents for women 2. Preterm tational diabetes who are planning a pregnancy, or in
with established di- birth < pregnant women with pre-existing diabetes.
abetes/impaired 37 and
glucose tolerance < 32
or previous ges- weeks
tational diabetes
planning pregnan-
cy, or pregnant
women with pre-ex-
isting diabetes .
Tieu 2017d 31 Janu- 2 4523 1. Perina- Further, high-quality randomised controlled trials are
ary 2017 tal needed to assess the value of screening for GDM, which
Screening for gesta- death may compare different protocols, guidelines or pro-
tional diabetes mel- 2. Preterm grammes for screening (based on different risk profiles
litus based on dif- birth and settings), with the absence of screening, or with
ferent risk profiles other protocols, guidelines or programmes. There is a
and settings for im- need for future trials to be sufficiently powered to de-
proving maternal tect important differences in short- and long-term ma-
and infant health. ternal and infant outcomes, such as those important
outcomes pre-specified in this review. As only a propor-
tion of women will be diagnosed with GDM in these tri-
als, large sample sizes may be required.
Till 2015 31 Janu- 5 11,935 None The included studies did not report on this review's
ary 2015 main outcomes: preterm birth, small-for-gestational
Incentives for in- age, or perinatal death. There is limited evidence that
creasing prenatal incentives may increase utilisation and quality of pre-
care use by women natal care, but may also increase caesarean rate. Over-
in order to im- all, there is insufficient evidence to fully evaluate the
prove maternal and impact of incentives on prenatal care initiation. There
neonatal outcomes. is a need for high-quality RCTs to determine whether
incentive program increase prenatal care use and im-
prove maternal and neonatal outcomes. Incentive pro-
grams, in particular cash-based programs, as suggest-
ed in this review and in several observational studies
may improve the frequency and ensure adequate qual-
ity of prenatal care.
Urquhart 2017 30 June 15 6008 1. Perina- Home uterine monitoring may result in fewer admis-
2016 tal sions to a neonatal intensive care unit, but in more un-
Home uterine mon- death scheduled antenatal visits and tocolytic treatment; the
itoring for detecting 2. Preterm level of evidence is generally low to moderate. Impor-
preterm labour. birth tant group differences were not evident when we un-
Informed decisions.


dertook sensitivity analysis using only trials at low risk
of bias. There is no impact on maternal and perinatal
outcomes such as perinatal mortality or incidence of
preterm birth.
Widmer 2015 31 August 13 1622 1. Preterm A single-dose regimen of antibiotics may be less effec-
2015 birth tive than a short course (four- to seven-day) regimen,
Duration of treat- but more evidence is needed from large trials measur-
ment for asympto- ing important outcomes, such as cure rate. Women
matic bacteriuria with asymptomatic bacteriuria in pregnancy should
during pregnancy. be treated by the standard regimen of antibiotics un-
til more data become available testing seven-day treat-
ment compared with shorter courses of three- or five-
day regimens.
Wiysonge 2017 7 Septem- 5 7298 1. Preterm Antepartum or postpartum vitamin A supplementation,

ber 2017 birth or both, probably has little or no effect on mother-to-
Vitamin A supple- child transmission of HIV in women living with HIV in-
ments for reducing fection and not on antiretroviral drugs. The interven-
mother-to-child HIV tion has largely been superseded by ART which is wide-
transmission. ly available and effective in preventing vertical trans-
mission.
Yamasmit 2015 21 6 374 1. Neona- There is insufficient evidence to support or refute the
Septem- tal use of prophylactic oral betamimetics for preventing
Prophylactic oral ber 2015 death preterm birth in women with a twin pregnancy.
betamimetics for 2. Preterm
reducing preterm labour
birth in women
3. Preterm
with a twin preg-
birth
nancy.
Zhou 2015 31 March 6 390 None It is unclear from the evidence reviewed whether any of
2015 the interventions (oral magnesium, oral calcium, oral
Interventions for vitamin B or oral vitamin C) provide an effective treat-
leg cramps in preg- ment for leg cramps. This is primarily due to outcomes
nancy. being measured and reported in different, incompa-
rable ways, and design limitations compromising the
quality of the evidence (the level of evidence was grad-
ed low or very low). This was mainly due to poor study
design and trials being too small to address the ques-
tion satisfactorily.
ANC: antenatal care

ART: antiretroviral therapy
ASB: asymptomatic bacteriuria
CTG: cardiotocography
DASH: Dietary Approaches to Stop Hypertension
ECV: external cephalic version
FBG: fasting blood glucose
GA: gestational age
GDM: gestational diabetes mellitus
GWG: gestational weight gain
Hb: haemoglobin
HELLP: haemolysis, elevated liver enzymes, low platelets
hpl: human placental lactogen
LGA: large-for-gestational age
MMN: multiple-micronutrient
NRT: nicotine replacement therapy
Informed decisions.

PROM: prelabour rupture of membranes

RCT: randomised controlled trial
RT-PCR: reverse-transcriptase–polymerase-chain-reaction
RUTI: recurrent urinary tract infections
UTI: urinary tract infection

Table 2. Excluded systematic reviews
Review ID Review title Reason for exclusion
Amaya-Guio 2016 Antibiotic treatment for the sexual partners of The review does not report results for pregnant women; the
women with bacterial vaginosis. intervention does not target health providers.
Balogun 2016a Vitamin supplementation for preventing miscar- Reviews targets miscarriage in early pregnancy.
riage.
Balogun 2016b Interventions for initiation of breastfeeding. Overview outcomes of preterm birth and perinatal death
are not specified as review outcomes. Review concerned
with post-pregnancy outcomes.
Chi 2015 Safety of topical corticosteroids in pregnancy. All evidence is from cohort studies
Demicheli 2015 Vaccines for women for preventing neonatal The intervention targets the neonate.
tetanus.
Dickinson 2014 Creatine for women in pregnancy for neuropro- The intervention targets the neonate.
tection of the fetus.
Frazer 2016 Legislative smoking bans for reducing harms Evidence for the effectiveness of smoking bans to impact
from secondhand smoke exposure, smoking preterm birth comes from non-randomised study designs.
prevalence and tobacco consumption.
Grivell 2014 Prenatal versus postnatal repair procedures for Intervention targets pregnant women with major fetal ab-
spina bifida for improving infant and maternal normality.
outcomes.
Hemmingsen 2017 Dipeptidyl-peptidase (DPP)-4 inhibitors and Pregnant women are excluded from many of the trials in-
glucagon-like peptide (GLP)-1 analogues for cluded in this review.
prevention or delay of type 2 diabetes mellitus
and its associated complications in people at in-
creased risk for the development of type 2 dia-
betes mellitus.
Heslop 2016 Interventions for men and women with their first Data are not reported for pregnant women. Pregnancy was
episode of genital herpes. an exclusion criteria for several included clinical trials. The
intervention does not target healthcare providers.
Jahanfar 2017 Ultrasound for diagnosis of birthweight discor- This is a DTA review and no outcome data relevant to the
dance in twin pregnancies (Protocol). overview are planned.
Karanth 2015 Desmopressin acetate (DDAVP) for preventing Preterm birth is not a review outcome.
and treating acute bleeds during pregnancy in
women with congenital bleeding.
Khattri 2017 Adjunctive systemic antimicrobials for the non- Pregnant women are excluded from this review protocol.
surgical treatment of chronic and aggressive pe-
riodontitis (Protocol).
Informed decisions.

Table 2. Excluded systematic reviews (Continued)

Li 2014 Periodontal therapy for the management of car- Pregnant women were not eligible for this review. The in-
diovascular disease in patients with chronic pe- tervention does not target healthcare providers.
riodontitis.
Li 2016 Chinese herbal medicines for unexplained recur- This review is concerned with recurrent miscarriage in early
rent miscarriage. pregnancy.
Liddle 2015 Interventions for preventing and treating low- Preterm birth and perinatal death are not specified as re-
back and pelvic pain during pregnancy. view outcomes.
Martineau 2016 Vitamin D for the management of asthma. This review included children and adults. There is no indi-
cation that pregnant women were included or excluded
from the review.
O'Doherty 2015 Screening women for intimate partner violence This review is not specific to a pregnant population and no
in healthcare settings. pregnancy outcomes are specified.
Okusanya 2016 Prophylactic versus selective blood transfusion Preterm birth mentioned in the text; only non-randomised
for sickle cell disease in pregnancy. data presented in the discussion.
Stock 2016 Immediate versus deferred delivery of the Pregnant women included in this review were expected to
preterm baby with suspected fetal compromise deliver preterm.
for improving outcomes.
Tieu 2017f Preconception care for diabetic women for im- Intervention limited to the preconception period and tar-
proving maternal and infant health. geted women who were not pregnant. PTB is a review out-
come.
Weston 2016 Monotherapy treatment of epilepsy in pregnan- This review is concerned with outcomes for the neonate
cy: congenital malformation outcomes in the and child.
child.
Whitworth 2015 Ultrasound for fetal assessment in early preg- This review does not cover the use of ultrasound to identify
nancy. women at risk of preterm birth; that topic is covered in an-
other review.
Wilkinson 2016 Melatonin for women in pregnancy for neuro- The intervention in this review targets the health of the
protection of the fetus. neonate.
DTA: diagnostic test accuracy

PTB: preterm birth

APPENDICES
Appendix 1. Search strategy

Date Run: 02/11/17 15:23:15.642
#1 preterm near birth* 2798
#2 preterm near lab*r 1164
#3 preterm near delivery 1213
#4 pre-term near birth* 161
#5 pre-term near delivery 89
Informed decisions.

#6 premature near birth* 2067
#7 pre-term near lab*r 55
#8 premature near delivery 319
#9 premature near lab*r 2029
#10 MeSH descriptor: [Premature Birth] explode all trees 582
#11 MeSH descriptor: [Obstetric Labor, Premature] explode all trees 1329
#12 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 5913
Limit to Cochrane reviews and protocols
898 Cochrane reviews or protocols
Appendix 2. Eligible but out of date systematic reviews

1. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database
of Systematic Reviews 2014, Issue 2. [DOI: 10.1002/14651858.CD002252.pub3]
2. Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary for preventing preterm birth. Cochrane Database of Systematic Reviews
2013, Issue 5. [DOI: 10.1002/14651858.CD007873.pub3]
3. Alexander S, Boulvain M, Ceysens G, Haelterman E, Zhang W-H. Repeat digital cervical assessment in pregnancy for identifying women
at risk of preterm labour. Cochrane Database of Systematic Reviews 2010, Issue 6. [DOI: 10.1002/14651858.CD005940.pub2]
4. Barrett HL, Dekker NM, Conwell LS, Callaway LK. Probiotics for preventing gestational diabetes. Cochrane Database of Systematic Re-
views 2014, Issue 2. [DOI: 10.1002/14651858.CD009951.pub2]
5. Bergamaschi DP, Mariath AB, Abbade JF, Grillo LP, Diniz CS, Hinnig PF. Selenium supplementation during pregnancy for improving ma-
ternal and newborn outcomes. Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI: 10.1002/14651858.CD009673]
6. Berghella V, Baxter JK, Hendrix NW. Cervical assessment by ultrasound for preventing preterm delivery. Cochrane Database of Systematic
Reviews 2013, Issue 1. [DOI: 1002/14651858.CD007235.pub3]
7. Berghella V, Hayes E, Visintine J, Baxter JK. Fetal fibronectin testing for reducing the risk of preterm birth. Cochrane Database of Sys-
tematic Reviews 2008, Issue 4. [DOI: 1002/14651858.CD006843.pub2]
8. Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database of Systematic
Reviews 2013, Issue 1. [DOI: 10.1002/14651858.CD000262.pub4]
9. Carlin AJ, Alfirevic Z, Gyte GM. Interventions for treating peripartum cardiomyopathy to improve outcomes for women and babies.
10. Churchill D, Beevers GD, Meher S, Rhodes C. Diuretics for preventing pre-eclampsia. Cochrane Database of Systematic Reviews 2007,
Issue 1. [DOI: 10.1002/14651858.CD004451.pub2]
11. Churchill D, Duley L, Thornton JG, Jones L. Interventionist versus expectant care for severe pre-eclampsia between 24 and 34 weeks'
gestation. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 1002/14651858.CD003106.pub2]
12. Dennis C-L, Dowswell T. Interventions (other than pharmacological, psychosocial or psychological) for treating antenatal depression.
13. Dennis C-L, Ross LE, Grigoriadis S. Psychosocial and psychological interventions for treating antenatal depression. Cochrane Database
of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD006309.pub2]
14. Dodd JM, McLeod A, Windrim RC, Kingdom J. Antithrombotic therapy for improving maternal or infant health outcomes in women con-
sidered at risk of placental dysfunction. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD006780.pub3]
15. Dowswell T, Middleton P, Weeks A. Antenatal day care units versus hospital admission for women with complicated pregnancy.
16. Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia.
Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 1002/14651858.CD000025.pub2]
Informed decisions.

17. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database of Systematic Reviews
2010, Issue 10. [DOI: 1002/14651858.CD000128.pub2]
18. Duley L, Henderson-Smart DJ, Meher S. Altered dietary salt for preventing pre-eclampsia, and its complications. Cochrane Database
of Systematic Reviews 2005, Issue 4. [DOI: 1002/14651858.CD005548]
19. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane
Database of Systematic Reviews 2007, Issue 2. [DOI: 1002/14651858.CD004659.pub2]
20. Duley L, Henderson-Smart DJ, Walker GJ, Chou D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database of System-
atic Reviews 2010, Issue 12. [DOI: 1002/14651858.CD000127.pub2]
21. Duley L, Matar HE, Almerie MQ, Hall DR. Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia.
22. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database of Systematic Reviews
2013, Issue 7. [DOI: 1002/14651858.CD001449.pub3]
23. Duley L, Williams J, Henderson-Smart DJ. Plasma volume expansion for treatment of pre-eclampsia. Cochrane Database of Systematic
Reviews 1999, Issue 4. [DOI: 1002/14651858.CD001805]
24. Eames AJ, Grivell RM, Deussen AR, Hague W, Dodd JM. Metformin for women who are obese during pregnancy for improving maternal
and infant outcomes. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 1002/14651858.CD010564]
25. Earl R, Crowther CA, Middleton P. Interventions for hyperthyroidism pre-pregnancy and during pregnancy. Cochrane Database of Sys-
26. Furber CM, McGowan L, Bower P, Kontopantelis E, Quenby S, Lavender T. Antenatal interventions for reducing weight in obese women
for improving pregnancy outcome. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 1002/14651858.CD009334.pub2]
27. Gagnon AJ, Sandall J. Individual or group antenatal education for childbirth or parenthood, or both. Cochrane Database of Systematic
28. Gamble CL, Ekwaru JP, ter KFO. Insecticide-treated nets for preventing malaria in pregnancy. Cochrane Database of Systematic Reviews
2006, Issue 2. [DOI: 1002/14651858.CD003755.pub2]
29. Grivell RM, Wong L, Bhatia V. Regimens of fetal surveillance for impaired fetal growth. Cochrane Database of Systematic Reviews 2012,
Issue 6. [DOI: 1002/14651858.CD007113.pub3]
30. Guinto VT, De Guia B, Festin MR, Dowswell T. Different antibiotic regimens for treating asymptomatic bacteriuria in pregnancy. Cochrane
31. Gülmezoglu AM, Azhar M. Interventions for trichomoniasis in pregnancy. Cochrane Database of Systematic Reviews 2011, Issue 5. [DOI:
1002/14651858.CD000220.pub2]
32. Gurung V, Stokes M, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for treating cholestasis in pregnancy. Cochrane Data-
base of Systematic Reviews 2013, Issue 6. [DOI: 1002/14651858.CD000493.pub2]
33. Han S, Crowther CA, Middleton P. Interventions for pregnant women with hyperglycaemia not meeting gestational diabetes and type
2 diabetes diagnostic criteria. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 1002/14651858.CD009037.pub2]
34. Han S, Middleton P, Crowther CA. Exercise for pregnant women for preventing gestational diabetes mellitus. Cochrane Database of
Systematic Reviews 2012, Issue 7. [DOI: 1002/14651858.CD009021.pub2]
35. Henriquez DD, Roos-Hesselink JW, Schalij MJ, Klautz RJ, Helmerhorst FM, de Groot CJ. Treatment of valvular heart disease
during pregnancy for improving maternal and neonatal outcome. Cochrane Database of Systematic Reviews 2011, Issue 5. [DOI:
1002/14651858.CD008128.pub2]
36. Hodnett ED, Fredericks S, Weston J. Support during pregnancy for women at increased risk of low birthweight babies. Cochrane Data-
base of Systematic Reviews 2010, Issue 6. [DOI: 1002/14651858.CD000198.pub2]
37. Jefferys AE, Siassakos D, Draycott T, Akande VA, Fox R. Deflation of gastric band balloon in pregnancy for improving outcomes. Cochrane
38. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database of Systematic Reviews 2012,
Issue 10. [DOI: 1002/14651858.CD001321.pub5]
Informed decisions.

39. Khanprakob T, Laopaiboon M, Lumbiganon P, Sangkomkamhang US. Cyclo-oxygenase (COX) inhibitors for preventing preterm labour.
40. Khianman B, Pattanittum P, Thinkhamrop J, Lumbiganon P. Relaxation therapy for preventing and treating preterm labour. Cochrane
41. Khunpradit S, Tavender E, Lumbiganon P, Laopaiboon M, Wasiak J, Gruen RL. Non-clinical interventions for reducing unnecessary
caesarean section. Cochrane Database of Systematic Reviews 2011, Issue 6. [DOI: 1002/14651858.CD005528.pub2]
42. Kramer MS, McDonald SW. Aerobic exercise for women during pregnancy. Cochrane Database of Systematic Reviews 2006, Issue 3.
[DOI: 1002/14651858.CD000180.pub2]
43. Lalor JG, Fawole B, Alfirevic Z, Devane D. Biophysical profile for fetal assessment in high risk pregnancies. Cochrane Database of Sys-
44. Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes.
45. Lavender T, Richens Y, Milan SJ, Smyth RM, Dowswell T. Telephone support for women during pregnancy and the first six weeks post-
partum. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 1002/14651858.CD009338.pub2]
46. Lewin S, Munabi-Babigumira S, Glenton C, Daniels K, Bosch-Capblanch X, van WBE, et al. Lay health workers in primary and community
health care for maternal and child health and the management of infectious diseases. Cochrane Database of Systematic Reviews 2010,
Issue 3. [DOI: 1002/14651858.CD004015.pub3]
47. Lim DC, Cheng LN, Zahid S, Wong FW. Prostaglandin A for treating pre-eclampsia. Cochrane Database of Systematic Reviews 2012, Issue
2. [DOI: 1002/14651858.CD009657]
48. Lindegren ML, Kennedy CE, Bain-Brickley D, Azman H, Creanga AA, Butler LM, et al. Integration of HIV/AIDS services with mater-
nal, neonatal and child health, nutrition, and family planning services. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI:
1002/14651858.CD010119]
49. Lui S, Terplan M, Smith EJ. Psychosocial interventions for women enrolled in alcohol treatment during pregnancy. Cochrane Database
of Systematic Reviews 2008, Issue 3. [DOI: 1002/14651858.CD006753.pub2]
50. Macdonald G, Bennett C, Higgins JP, Dennis JA. Home visiting for socially disadvantaged mothers. Cochrane Database of Systematic
51. Magee L, Duley L. Oral beta-blockers for mild to moderate hypertension during pregnancy. Cochrane Database of Systematic Reviews
2003, Issue 3. [DOI: 1002/14651858.CD002863]
52. Makrides M, Crosby DD, Bain E, Crowther CA. Magnesium supplementation in pregnancy. Cochrane Database of Systematic Reviews
2014, Issue 4. [DOI: 1002/14651858.CD000937.pub2]
53. Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncom-
plicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI:
1002/14651858.CD003402.pub2]
54. Marc I, Toureche N, Ernst E, Hodnett ED, Blanchet C, Dodin S, et al. Mind-body interventions during pregnancy for preventing or treating
women's anxiety. Cochrane Database of Systematic Reviews 2011, Issue 7. [DOI: 1002/14651858.CD007559.pub2]
55. Martí-Carvajal AJ, Peña-Martí GE, Comunián-Carrasco G, Martí-Peña AJ. Interventions for treating painful sickle cell crisis during preg-
nancy. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 1002/14651858.CD006786.pub2]
56. Mathanga DP, Uthman OA, Chinkhumba J. Intermittent preventive treatment regimens for malaria in HIV-positive pregnant women.
57. Meher S, Abalos E, Carroli G. Bed rest with or without hospitalisation for hypertension during pregnancy. Cochrane Database of Sys-
58. Meher S, Duley L. Progesterone for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2006,
Issue 4. [DOI: 1002/14651858.CD006175]
59. Meher S, Duley L. Rest during pregnancy for preventing pre-eclampsia and its complications in women with normal blood pressure.
Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 1002/14651858.CD005939]
Informed decisions.

60. Meher S, Duley L. Exercise or other physical activity for preventing pre-eclampsia and its complications. Cochrane Database of System-
atic Reviews 2006, Issue 2. [DOI: 1002/14651858.CD005942]
61. Meher S, Duley L. Garlic for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2006, Issue 3.
[DOI: 1002/14651858.CD006065]
62. Meher S, Duley L. Nitric oxide for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2007,
Issue 2. [DOI: 1002/14651858.CD006490]
63. Miller BJ, Murray L, Beckmann MM, Kent T, Macfarlane B. Dietary supplements for preventing postnatal depression. Cochrane Database
64. Minozzi S, Amato L, Bellisario C, Ferri M, Davoli M. Maintenance agonist treatments for opiate-dependent pregnant women. Cochrane
65. Mujezinovic F, Alfirevic Z. Technique modifications for reducing the risks from amniocentesis or chorionic villus sampling. Cochrane
66. Nabhan AF, Elsedawy MM. Tight control of mild-moderate pre-existing or non-proteinuric gestational hypertension. Cochrane Database
67. Neilson JP. Interventions for suspected placenta praevia. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI:
1002/14651858.CD001998]
68. Orton LC, Omari AA. Drugs for treating uncomplicated malaria in pregnant women. Cochrane Database of Systematic Reviews 2008,
Issue 4. DOI: 10.1002/14651858.CD004912.pub3]
69. Othman M, Alfirevic Z, Neilson JP. Probiotics for preventing preterm labour. Cochrane Database of Systematic Reviews 2007, Issue 1.
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CONTRIBUTIONS OF AUTHORS
ZA, JV, NM and AC designed the study and wrote the protocol. All authors contributed to eligibility assessment, creation of data tables and
writing the text for the overview.
DECLARATIONS OF INTEREST
NM: Nancy Medley's work was financially supported by the University of Liverpool's Harris-Wellbeing of Women Preterm Birth Centre
research award. NM was an author on a Cochrane systematic review included in the overview. Assessments for this review was made by
another member of the overview team.
JV: none known.
AC: none known.
ZA: Zarko Alfirevic was an author on a Cochrane systematic review included in the overview and also an author on a clinical trial included
in an eligible Cochrane systematic review. Assessments for these were made by another member of the overview team. My employer
(University of Liverpool) has received grants from UK National Institute of Health Research, Wellbeing of Women charity and Perkin Elmer
to support my research group's work related to preterm birth prevention and my Cochrane editorial work.
Informed decisions.

SOURCES OF SUPPORT
Internal sources
• University of Liverpool, UK.
External sources
• Harris-Wellbeing of Women Preterm Birth Centre, UK.
INDEX TERMS
Medical Subject Headings (MeSH)

*Systematic Reviews as Topic; Anti-Bacterial Agents [therapeutic use]; Bed Rest; Premature Birth [*prevention & control]; Smoking
Cessation; Vitamin D [administration & dosage]; Vitamins [administration & dosage]
MeSH check words

Female; Humans; Pregnancy

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Medley N, Vogel JP, Care A, Alfirevic Z

Medley N, Vogel JP, Care A, Alfirevic Z.

Interventions during pregnancy to prevent preterm birth: an overview

Nancy Medley1, Joshua P Vogel2, Angharad Care3, Zarko Alfirevic3

Editorial group: Cochrane Pregnancy and Childbirth Group

Outcome: preterm birth

Clear evidence of benefit

Clear evidence of harm

No included SR reported clear evidence of harm.

Outcome: perinatal death

Clear evidence of benefit

Clear evidence of harm

No included SR reported clear evidence of harm.

Outcomes: preterm birth and perinatal death

Unknown benefit or harm

Implications for research

Ways to help pregnant women avoid preterm birth

What is the issue?

Why is this important?

What evidence did we find?

Outcome: preterm birth

We found no treatment that increased women’s chance of giving birth preterm.

Outcome: perinatal death

We found no intervention that increased women’s risk of baby death.

Outcomes: preterm birth and perinatal death

Unknown benefit or harm

What does this mean?

BACKGROUND Description of the interventions

Healthcare providers Pregnant women with preterm prelabour

Pregnant women with major fetal anom-

Pregnant women undergoing induction of

Any setting, language or year

Interventions to prevent or treat miscar-

Interventions comprising fertility treat-

Alternative intervention or no intervention (including

Figure 1. Study flow diagram. Search date 2 November 2017

Figure 2. All icons by Freepik at www.flaticon.com.

Possible benefit Clear evidence of harm

da Silva Lopes 2017 Farrar 2017

Dowswell 2015 Hofmeyr 2017

Farrar 2016 Hutton 2015

Iheozor-Ejiofor 2017 Muktabhant 2015

Jahanfar 2014 O'Neill 2017

Middleton 2016 Radeva-Petrova 2014

Raman 2017 Smyth 2015

Salam 2015a Suchdev 2015

Salam 2015b Terplan 2015

Salam 2015c Thinkhamrop 2015

Tieu 2017d Balogun 2016b

Yamasmit 2015 Grivell 2014

during pregnancy in women with congenital bleeding disorders. Weston 2016

implications. Lancet 2012;379(9832):2162-72. [DOI: 10.1016/ Guyatt 2011a

Iams 2008 Mangham 2009

Jarde 2017a Martin 2017

Saccone 2017a van't Hooft 2016

Schünemann 2013 Welsh 2015

Table 1. Characteristics of included systematic reviews (Continued)

Table 1. Characteristics of included systematic reviews (Continued)

Table 1. Characteristics of included systematic reviews (Continued)

Table 1. Characteristics of included systematic reviews (Continued)