DOI: 10.1111/tog.

12740 2021;23:196–205
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Identification and management of fetal anaemia:

a practical guide
James Castleman MA MD MRCOG,a Leo Gurney MD MRCOG,
a
Mark Kilby MD DSc FRCOG FRCPI,
b,c

R Katie Morris PhD MRCOGb,d*

a
Subspecialty Trainee in Maternal and Fetal Medicine, West Midlands Fetal Medicine Centre, Birmingham Women’s and Children’s NHS
Foundation Trust, Birmingham B15 2TG, UK
b
Honorary Consultant in Maternal and Fetal Medicine, West Midlands Fetal Medicine Centre, Birmingham Women’s and Children’s NHS
Foundation Trust, Birmingham B15 2TG, UK
c
Professor of Fetal Medicine, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK
d
Professor of Obstetrics and Maternal Fetal Medicine, Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, UK
*Correspondence: Katie Morris. Email: [email protected]

Accepted on 4 August 2020. Published online 9 June 2021.

Key content Learning objectives

 Fetal anaemia can be caused by alloimmune or infectious red cell  To understand the varied aetiologies and pathophysiology of fetal
destruction, disorders of fetal red cell production, fetal anaemia and to adopt a system for reaching a diagnosis.
haemorrhage and as a complication of monochorionic  To appreciate the different diagnostic tools available, comprising
multifetal pregnancy. ultrasonography, microbiological testing, noninvasive and invasive
 A fetus at risk from maternal alloimmunisation can be detected by tests in fetal medicine units and electronic fetal monitoring in the
maternal serum screening for red cell antibodies and by acute setting.
fetal ultrasonography.
Ethical issues
 Undiagnosed cases may present in routine obstetric practice, so
 Management involves balancing maternal and fetal risks.
awareness of the identification and initial management of fetal
 Research ethics should be considered in relation to experimental
anaemia is important.
 Pregnancies must be triaged depending on clinical urgency, with
treatments and trials in fetal therapy.
input from fetal medicine specialists required. Keywords: alloimmunisation / fetal anaemia / fetomaternal
 Developments in fetal ultrasound assessment and in fetal therapy haemorrhage / in utero transfusion / middle cerebral artery Doppler
have improved outcomes and contemporary research will focus on
improving long term outcomes for neonatal survivors.

Please cite this paper as: Castleman J, Gurney L, Kilby M, Morris RK. Identification and management of fetal anaemia: a practical guide. The Obstetrician &
Gynaecologist 2021;23:196–205. https://doi.org/10.1111/tog.12740

below the mean for gestation, or less than 0.55 multiples of

Introduction
the median.1,2 Reduced tissue perfusion and oxygenation in
Fetal anaemia is an uncommon but potentially dangerous severe anaemia leads to end organ dysfunction, including
complication of pregnancy that can lead to considerable fetal brain injury, high-output cardiac failure and, ultimately,
or neonatal morbidity and mortality if unrecognised and intrauterine fetal death. The ‘hydrops zone’ on the
untreated. Among the multiple causes of fetal anaemia, the nomogram is gestation dependent, ranging from fHb
commonest is antibody-mediated destruction of red blood <40 g/L at 18 weeks of gestation to fHb <80 g/L at term.3
cells via maternal alloimmunisation. Infection (most This article provides an overview of the prospective
frequently with parvovirus B19) is the major nonimmune identification and management of fetal anaemia, along with
aetiology of fetal anaemia. Rarer causes include fetal a tabulated reference guide to key aspects of screening,
haemorrhage (occult or revealed), fetal tumours (for diagnosis and management of the main underlying
example, placental chorioangioma) and complications of aetiologies encountered in obstetric practice. Failure to
monochorionicity in multiple pregnancies. Fetal recognise and appropriately manage suspected fetal
haemoglobin (fHb) values should increase with advancing anaemia can be devastating, thus we present a diagnostic
gestation to a mean of 150 g/L at 40 weeks.1 Well-defined approach to fetal anaemia encompassing core principles of
fHb nomograms define severe anaemia as greater than 70 g/L general obstetric and fetal medicine care, involving

196 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited and is not used for commercial purposes.
 Castleman et al.

ultrasonography, invasive and noninvasive testing and

Table 1. Clinically significant red cell antibodies
multidisciplinary counselling.
Antigen
System Antigen Haemolytic Disease
Red cell alloimmunisation
Rhesus D Frequently severe in fetus and neonate
Haemolytic disease of the fetus and newborn (HDFN) can c Frequently severe in fetus and neonate
develop after a woman is exposed to a mismatch of paternally c+E Severe in combination, in fetus and neonate
derived red blood cell (RBC) antigens from the fetus via, usually, E Infrequently severe, usually in neonate
a sensitising event during pregnancy. This results in maternal C Infrequently severe, usually in neonate
e Infrequently severe, usually in neonate
generation of antibodies capable of placental transfer, which Ce Infrequently severe, usually in neonate
target fetal RBCs containing such antigens for destruction. Kell K (K1) Frequently severe in fetus and neonate
There are over 50 RBC alloantibodies, present in about 1 in 80 (compounded by suppression of
erythropoiesis)
pregnant women, which cause HDFN in 1 in 300–600 live
k (K2) Infrequently severe, usually in neonate
births.4 Sensitising events occurring during pregnancy are the Duffy Fya Infrequently severe, usually in neonate
leading cause of female alloimmunisation, followed by blood Fyb Infrequently severe, usually in neonate
transfusion, so obstetricians have a crucial role in risk reduction MNS S Infrequently severe, usually in neonate
s Infrequently severe, usually in neonate
(see Box 1). The Rhesus (Rh) group of antigens on RBCs are the
U Infrequently severe, usually in neonate
most clinically important in obstetrics; paternally inherited M Infrequently severe, usually in neonate
(autosomal dominant) antigens can trigger alloimmunisation. Kidd Jka Infrequently severe, usually in neonate
Alloimmunisation caused by incompatibility with Rh ‘D’, ‘c’ Jkb Usually mild, in neonate
and ‘E’ antigens can cause severe HDFN. Historically, HDFN Adapted from Moise, 200881 and RCOG, 201412
was most frequently caused by anti-D antibody. Anti-D
immunoprophylaxis was discovered in the 1960s.6 Now,
widespread use of anti-D immunoglobulin prenatally and
immediately postnatally has dropped rates of D- positive.10 The first IgM alloantibody response cannot cross
alloimmunisation to 2%.7 Anti-E is now the most prevalent the placenta. However, on re-exposure to the antigen, the
HDFN-causing alloantibody.4 The rarer ‘K’ and ‘k’ antigens of ‘secondary’ IgG response is more pronounced so the
the Kell group can cause severe, early-onset anaemia at lower antibodies can cross the placenta, potentially causing fetal
levels because they suppress erythropoiesis, as well as causing anaemia. Given that IgG responses are characteristically
red cell destruction.8 Other antibody groups capable of causing mounted over several months, clinically significant
HDFN (more commonly neonatal jaundice) include the Fy, Jk alloimmune effects that may pose a risk to the fetus are
and MNS systems.9 The most clinically important red cell more likely in a subsequent, rather than index, pregnancy.
antigens are listed in Table 1. IgG transport across the placenta is mediated by the neonatal
About 15% of white European and 5% of African and Fc receptor (FcRn).11 In the fetal circulation, IgG
Indian ancestral groups lack the D antigen (Rh-negative) on alloantibodies target RBCs, or their progenitors, for
their RBCs. East Asian women are almost always Rh- destruction. Fetal anaemia results from suppression of
erythropoiesis or by haemolysis.
The Royal College of Obstetricians and Gynaecologists
(RCOG) Green-top guideline on the management of women
Box 1. Sensitising events for Rh D-negative women in pregnancy
with red cell antibodies during pregnancy’12 provides clinicians
 Ectopic pregnancy with evidence-based recommendations for antenatal screening,
 Early miscarriage complicated by pain and/or excessive bleeding diagnosis and management of alloimmunised pregnancies.
 Uterine evacuation (miscarriage, molar pregnancy, termination of Maternal ABO and D blood group and alloantibody status
pregnancy)
 Any pregnancy loss after 12 weeks (miscarriage and intrauterine
should be ascertained at booking and checked again at 28 weeks
death/stillbirth) of gestation. Pregnancies with a high chance of HDFN include
 Invasive fetal tests (amniocentesis, chorionic villus sampling, those in women with a previous history of a fetus or newborn
cordocentesis) affected with haemolytic disease, or who have a critical level of
 Fetal therapy (transfusion, surgery, shunt insertion, laser, fetal
reduction) high-risk alloantibody (Table 2). Such women should receive
 External cephalic version preconceptual counselling and be referred to a fetal
 Abdominal trauma medicine specialist.
 Delivery, regardless of mode
The advent of cell-free fetal DNA (cffDNA) testing from
 Intraoperative cell salvage
Adapted with permission from John Wiley and Sons.5 maternal blood allows noninvasive identification of fetal RBC
antigens, including D, c, C, e, E and Kell.13 The sensitivity

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 197
 Fetal anaemia

Table 2. Identifying pregnancies with increased chance of fetal anaemia and instituting appropriate management

Condition Specific management guidance

Red cell alloimmunisation Ask:

 Previous baby requiring transfusion or known HDFN
Test:
 Maternal blood group and antibody status
 Fetal and paternal genotyping
Refer to fetal medicine specialist:
 Prior HDFN
 Ultrasound evidence of fetal anaemia (MCA-PSV or hydrops)
 Rapid rise in alloantibody or specific thresholds reached:
Anti-D> 4 IU/ml (>15 likely severe)
Anti-c >7.5 IU/ml (>20 likely severe, lower threshold if co-existent anti-E)
Anti-K as soon as detected
Any other alloantibody titre ≥32
Specifics:
 If maternal transfusion likely, need regular crossmatch sample

Fetal infection Ask:

 Current rash or febrile illness, onset
 Unwell contacts and time of exposure (face-to-face or 15 minutes in same room is significant)
Test:
 No routine screening
 Booking sera for IgG to determine seroconversion since
 Current blood sample (for symptomatic or asymptomatic women with contact); retest one month after contact if no
IgG or IgM at initial test
 Consider amniocentesis or fetal blood sample to detect viral DNA
Specifics:
 Serial ultrasound scanning from 4 weeks after symptom onset
 Parvovirus B19: IgM present in maternal blood from first day after rash onset; no IgM means no infection in last
4 weeks; test saved booking blood for viral DNA load or IgG seroconversion or repeat sample for change in IgM
reactivity; scan fetus weekly from 4–10 weeks after confirmed maternal infection; maternal infection after 24 weeks
usually harmless
 CMV: If maternal CMV IgG and IgM are positive, and IgG avidity low, infection is highly likely to have been within 3
months; antiviral drugs may be beneficial in congenital CMV
 Termination of pregnancy may be considered

Genetic and metabolic Ask:

conditions  Family origin questionnaire (screening for haemoglobinopathy)
Test:
 Haemoglobin electrophoresis
 Parental DNA
 Red cell enzyme assays (pyruvate kinase, G6PD)
 Invasive test for genetic diagnosis

Vascular tumours Specifics:

 Regular Doppler assessment to screen for signs of high output state associated with fetal exsanguination
 MRI
 Laser coagulation or radiofrequency ablation of tumour vessels
 Open maternal fetal surgery for resection of SCT in selected, very preterm cases
 Amniodrainage if severe polyhydramnios
 Neonatal team to prepare for microangiopathic haemolytic anaemia and thrombocytopenia

Vasa praevia Specifics:

 Transvaginal colour Doppler ultrasound and rescan to confirm at 32 weeks
 Palpate for pulsating fetal vessels in the membranes on vaginal examination
 Consider inpatient management if preterm labour likely or antenatal bleeding
 Delivery 34–36 weeks after steroids

198 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
 Castleman et al.

Table 2. (Continued)

Condition Specific management guidance

Complications of  Fortnightly scans in local unit from 16 weeks of gestation for all multifetal pregnancies with shared placenta
monochorionicity  Refer monochorionic multifetal pregnancies to a tertiary Fetal medicine centre if:
- Hydrops
- Cardiac dysfunction
- Unexplained polyhydramnios
- Abnormal umbilical artery Doppler velocimetry
- Single twin death
(These fetuses need Doppler assessment of MCA-PSV to detect TAPS)

 Weekly ultrasound surveillance using MCA-PSV after fetoscopic laser ablation for fetofetal transfusion syndrome and in
selective fetal growth restriction (estimated fetal weight discordance ≥25% and an EFW <10th centile)
 Assess neuroanatomy of co-twin survivor(s) with ultrasound and later with MRI
 Fetoscopic laser ablation before 26 weeks, and after 26 weeks IUT for anaemia and exchange transfusion to dilute the
polycythaemic circulation with Hartmann’s solution can be considered32

Abbreviations: CMV = cytomegalovirus; EFW = estimated fetal weight; G6PD = glucose-6-phosphate dehydrogenase; HDFN = haemolytic disease of
the fetus and newborn; IgG = immunoglobulin G; IgM = immunoglobulin M; IU = international unit; IUT = intrauterine transfusion; MCA-PSV =
middle cerebral artery peak systolic velocity; MRI = magnetic resonance imaging; SCT = sacrococcygeal teratoma; TAPS = twin anaemia
polycythaemia sequence

and specificity of cffDNA RhD genotyping is almost 100%, so sufficient to cover 4 ml of fetal RBCs) is confirmed with the
it can be considered a diagnostic test when used in this Kleihauer–Betke test, or with flow cytometry if the sensitising
context.14 Rhesus D, c, C and e are detectable from 16 weeks event occurs after 20 weeks of gestation.7
of gestation and Kell from 20 weeks. Routine cffDNA-based
testing reduces unnecessary anti-D administration and can be
Fetal infection
cost effective.15 Clinicians should be aware of the small risk of
false negative ‘diagnosis’ and, if high-risk alloantibody level Anaemia can be the result of fetal viral infection following
increases, then serial ultrasound surveillance should be vertical transmission from a symptomatic or asymptomatic
considered, as for a sensitised pregnancy.16 Determination woman. The gestational age of infection and previous
of paternal RBC antigen status and zygosity may be infections or exposure should be considered when assessing
considered and, very rarely, invasive testing (chorionic fetal risk. Human parvovirus B19 is probably the most
villus sampling or amniocentesis) remains necessary for common cause for viral-related fetal anaemia in the UK. It is
diagnostic certainty (if the father is heterozygous). a single-stranded DNA virus usually transmitted via
Alloimmunised women require blood tests every 4 weeks up respiratory droplets. In children, viraemia is usually
to 28 weeks of gestation and fortnightly thereafter. Absolute heralded by flu-like illness, then manifests as a rash
levels of alloantibody (see Table 2), or a rapid rise in level spreading from the face (‘slapped cheek syndrome’) to
(doubling over a 14-day period), are important.17 Levels and affect the trunk and limbs – possibly with arthralgia.
titres are less informative in a second at-risk pregnancy, when Infections occurring in adulthood tend to be asymptomatic,
earlier referral is required. With Kell alloimmunisation, there is although more severe disease, including aplastic crises, can
a lower threshold for specialist input because these occur in people who are immunocompromised. More than
alloantibodies can cause severe and unpredictable fetal half of pregnant women will be immune because of infection
anaemia (caused by suppressed erythropoiesis) irrespective before pregnancy, but in those without such immunity, an
of antibody levels and previous pregnancy outcome. Follow-up infection in the first half of pregnancy can cause fetal anaemia
testing for lower risk alloantibodies is individualised. and hydrops secondary to viral destruction of fetal erythroid
Where available, routine use of RhD immune globulin has progenitor cells.18 The risk of fetal loss is estimated to be 13%
reduced the rate of red cell alloimmunisation, with developed with parvovirus B19 infection before 20 weeks of gestation
countries following established protocols for and 0.5% with infection occurring later in pregnancy.19
immunoprophylaxis with anti-D IgG.7 An additional dose of There is no preventive strategy or licensed vaccine available
anti-D is required within 72 hours of a recognised sensitising for parvovirus. Most women infected give a clear history of
event where there is possible fetomaternal haemorrhage exposure to a child with the acute viral illness. Useful
(Box 1). Adequate dosing (500 IU injection of anti-D is guidance is available from Public Health England,20 with

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 199
 Fetal anaemia

pregnant women advised to notify a clinician promptly of haemolytic anaemia, which is commonest in African
any contact with, or development of, rash and to avoid ancestral groups. In G6PD deficiency, red cells are less
exposing other pregnant women.20 tolerant to oxidative stress, which becomes apparent in the
Cytomegalovirus (CMV) is another important maternal context of infection, maternal fava bean ingestion or drug
infection that can cause fetal anaemia. Avidity is an toxicity.26 Pyruvate kinase and glucose phosphate isomerase
important property in testing, with the strength of the IgG deficiencies also cause fetal anaemia.
and antigen complex gradually increasing with time after
primary infection, thus indicating the latency of infection.
Vascular tumours
Low avidity is suggestive of recent infection.21
Approximately 2% of cases are associated with reactivation Any tumour of the fetus or placenta that sequesters red blood
after a previous primary infection. This is helpful to identify cells can cause fetal anaemia. Sacrococcygeal teratoma (SCT)
the timing of the primary infection and to stratify risk to the is the commonest fetal tumour, in which red cells can be
fetus. Rarer infective causes of fetal anaemia include consumed or damaged as they pass through, or there can be
toxoplasmosis, syphilis, malaria, rubella and herpes. Apart bleeding within the tumour leading to fetal anaemia. A large
from fetal hydrops, there may be other ultrasound signs of cohort study27 found that 9.1% of fetuses with SCT
congenital infection, including echogenic bowel, hepatic developed hydrops, although such ultrasound findings with
calcifications, organomegaly, a suspicion of dysplastic tumours may be attributed to high output cardiac failure
kidneys (often with accompanying oligohydramnios), rather than to anaemia. A ‘giant’ placental chorioangioma,
ventriculomegaly and fetal growth restriction. Myocarditis seen on ultrasound with colour Doppler as a ‘mass’
and hepatitis may be important sequelae of vertical protruding into the amniotic cavity from the placenta with
transmission of viral infection. high vascularity, may cause a hyperdynamic circulation with
Detailed descriptions of the investigations and associated polyhydramnios. Fetal anaemia results from
management of viral conditions in pregnancy are outside sequestration and destruction of fetal RBCs within the
the scope of this article, but Table 2 outlines a basic thrombosed vascular mass of the tumour.28 Other tumours,
approach. Further information can be found in the National including haemangiomata (for example, in the fetal liver) and
Institute for Health and Care Excellence (NICE) Clinical arteriovenous malformations can similarly cause
Knowledge Summary (for parvovirus)22 and the RCOG fetal anaemia.
Scientific Impact Paper (for CMV).23
Fetomaternal haemorrhage (transplacental
Disorders of erythropoiesis haemorrhage)
Fetal anaemia can result from problems at any stage of red Any antepartum haemorrhage can cause loss of fetal red
cell production in the bone marrow. It can be secondary to blood cells into the maternal circulation. A woman may
inherited anaemias, metabolic syndromes or bone marrow present without overt clinical signs of bleeding, and reduced
failure. Aplastic anaemia can result from toxicity of drugs or fetal movements may be the only clue. Fetomaternal
radiation, or an underlying genetic problem. Alpha- haemorrhage (FMH) can be detected by the Kleihauer–
thalassaemia, predominantly in couples of Mediterranean Betke test, or by flow cytometry.7 The effect on the fetus
and Asian origin, is the commonest type of inherited depends on gestation (because considerable volume
anaemia, in which the alpha-globin chains in haemoglobin expansion occurs in the fetus and placenta throughout
are reduced or absent. Less normal haemoglobin results in pregnancy) and timescale, with a gradually evolving chronic
less oxygen delivery to fetal tissues. A fetus born to two anaemia being better tolerated. In pregnancies with recurrent
parents with alpha-thalassaemia trait has a one in four chance FMH remote from term, without acute maternal or fetal
of having alpha-thalassaemia major. In this condition, the compromise, supportive care with ultrasound surveillance
complete lack of normal haemoglobin leads to the so-called can be offered; however, the outlook is unpredictable and
Barts hydrops fetalis, which can be ‘mirrored’ by maternal these cases require caution.
pre-eclampsia and is associated with antepartum A sudden large bleed, as in a massive placental abruption
haemorrhage.24 A markedly thickened placenta is a classic or ruptured vasa praevia, will cause fetal hypotension,
sonographic sign. acidaemia and eventually death. Placental abruption is an
Genetic disorders of red cell production include congenital obstetric emergency, usually occurring without warning and
erythropoeitic porphyria, Fanconi anaemia and Diamond– mostly in low-risk pregnancies without modifiable risk
Blackfan anaemia. Transient abnormal myelopoiesis (TAM) factors.29 Other causes of FMH are listed in Box 1.
has a particular association with trisomy 21.25 Glucose-6- Guidance for the management of antepartum haemorrhage
phosphate dehydrogenase (G6PD) deficiency is an X-linked, is provided by the RCOG.29

200 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
 Castleman et al.

this is not routinely screened for in uncomplicated

Vasa praevia
monochorionic twins.38
A diagnosis of vasa praevia may be made following painless
vaginal bleeding coinciding with membrane rupture and
Principles of management of fetal anaemia
fetal compromise. In such cases, there is no time for
diagnostic testing because of associated ‘fetal distress’ Identifying an anaemic fetus
requiring urgent delivery to prevent fetal demise.30 Pregnancies at high risk of fetal anaemia can be identified
Routine antenatal screening does not currently occur in antenatally from the booking history, routine screening to
the UK for this condition, but if discovered in an detect maternal serum antibodies at 12 and 28 weeks of
asymptomatic woman, then RCOG guidelines support gestation, ultrasonographic evidence of hydrops fetalis, or a
delivery by caesarean section at 34–36 weeks of gestation, high-risk fetal condition. Parous women should be asked at
after ultrasound confirmation of persistence and booking about prior transfusion history and previous fetal or
administration of steroids for fetal lung maturity.30 In neonatal transfusion. A history of neonatal jaundice should
situations of anterior placenta praevia, the placenta may be sought. Maternal reporting of relevant infectious exposure
need to be transected during a caesarean section to facilitate or possible fetomaternal haemorrhage is more variable, but
delivery, in which case immediate cord clamping is required should also alert a clinician to evaluate for risk of fetal
to minimise fetal blood loss.31 In any case of major anaemia. High-risk cases should then be evaluated early by a
antepartum haemorrhage, neonatal support should be fetal medicine specialist.
available at delivery. A longer length of cord should be Direct fetal blood sampling is the ‘gold standard’ for the
left attached to the newborn to facilitate umbilical artery diagnosis of fetal anaemia, but carries a procedure-related
catheterisation in case transfusion is required.29 risk of miscarriage or preterm birth of up to 2%.39 Increased
cardiac output and reduced blood viscosity means that
arterial blood flow in the brain of an anaemic fetus is
Complications of monochorionicity in
increased.40 Doppler ultrasound assessment of the fetal
multifetal pregnancies
MCA-PSV is used to screen for fetal anaemia (Figure 1).2,41
Fetal anaemia can be a consequence of vascular anastomoses The ‘action line’ and consideration of fetal blood sampling is
connecting the fetal circulations in multiple pregnancies with a required at 1.5 multiples of the median MCA-PSV for
shared placenta. Specific complications of monochorionicity gestational age. Extramedullary haematopoiesis in a severely
are subacute/chronic fetal anaemia associated with twin anaemic fetus causes hepatosplenomegaly, with subsequent
anaemia polycythaemia sequence (TAPS) and acute anaemia liver congestion and impaired synthetic function, leading to
in the surviving fetus following co-twin demise. TAPS is extracellular fluid accumulation.42 Effusions, ascites, oedema
defined by a significant discordance in haemoglobin levels and polyhydramnios can be detected by ultrasound in
between twins, without substantial differences in amniotic hydrops fetalis, defined as abnormal fetal fluid collections
fluid volume. Prenatal prediction relies on ultrasound Doppler in two or more compartments. Outcomes are worse if
imaging of the middle cerebral artery peak systolic velocity hydrops is present, which makes early detection important.
(MCA-PSV, described in the next section).32 TAPS arises from Ultrasound evidence of cardiac decompensation may include
a chronic transfusion of blood from a donor to recipient fetus cardiomegaly and tricuspid regurgitation. When nonimmune
via miniscule (<1 mm) artery–vein anastomoses. It hydrops is detected on ultrasound scan, maternal wellbeing
spontaneously affects up to 5% of all monochorionic should be assured, including assessment of blood pressure
diamniotic pregnancies.33,34 After fetoscopic laser ablation and dipstick urinalysis to exclude the maternal pre-
for fetofetal transfusion syndrome, TAPS has been reported in eclampsia-like ‘mirror syndrome’.43
up to 16% of monochorionic twins. It is associated with Recently, magnetic resonance imaging (MRI) estimation of
incomplete ablation of placental anastomoses, although the fetal haematocrit has been proposed as a more specific
Solomon technique can reduce the incidence of this imaging technique to identify fetal anaemia (93% versus 88%
complication to 3%.35 for ultrasound MCA-PSV). However, this is a more expensive
Single intrauterine fetal death complicates 1–2% of imaging resource, has not been shown to be cost effective and
monochorionic twin pregnancies. Following this event, an is not readily delivered by the bedside.2,44 While MRI is a less
acute transfusion from the surviving co-twin to the available resource, it may avoid unnecessary intervention at
demised twin can occur, leading to anaemia,36 with the later gestations, or after fetal therapy where MCA-PSV is less
surviving co-twin being at significant risk of subsequent specific.45 MRI can also provide additional information
brain injury and death.37 Complexities surrounding the about the effect of severe anaemia on the fetal brain.46,47
management of such cases mean that input from a tertiary An anaemic fetus may present with an unusual fetal heart
fetal medicine centre is recommended; however, in the UK, rate pattern on cardiotocography.48 A sinusoidal trace may be

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 201
 Fetal anaemia

Figure 1. Middle cerebral artery Doppler assessment. This ultrasound image shows an axial section of the fetal head, with Doppler insonation of
the fetal middle cerebral artery, close to its origin from the internal carotid artery in the Circle of Willis. The peak systolic velocity is measured, using
angle correction and in the absence of fetal breathing movements.

the first objective sign of anaemia or sudden fetomaternal for fetal anaemia after IUT. Therefore, the timing of second and
haemorrhage and should trigger urgent senior review for subsequent IUTs relies on use of MCA-PSV and the calculated
consideration of imminent delivery. fall of fetal Hb with time.58 The use of measured reticulocyte
count in pre-transfusion fetal blood samples may give useful
Intrauterine transfusion information and aid timing of further IUTs. In anaemia caused
The first intrauterine transfusion (IUT) occurred in 1963 and is by RBC antibodies, the fetal reticulocyte count falls with
now performed as an ultrasound-guided percutaneous needle subsequent transfusions and is an indirect marker of
(usually 20–22G) procedure.49,50 Vascular access is commonly suppression of the endogenous erythropoiesis by the
via the umbilical vein (at the placental cord root or intrahepatic presence of a high proportion of donor-packed cells.59 This
vein, the latter with lower complication rates).51,52 Umbilical suppression is evidence that the proportion of circulating fetal
cord ‘free loops’ may be used. In obese women, or at earlier RBCs are predominantly transfused cells and may aid the
gestations (usually <20 weeks) when intravascular transfusion decision to space out the transfusions. In fetuses infected with
is technically challenging, intracardiac transfusion may be human parvovirus B19, the fetal reticulocyte count at initial
performed.53 In modern fetal medicine, intraperitoneal fetal fetal blood sample provides an indication as to whether the
transfusion is used to manage fetal anaemia (in a nonhydropic endogenous erythropoiesis is recovering after infection. A
baby) usually prior to 20 weeks of gestation, often used in reticulocyte count of greater than 10% can suggest recovering
combination with maternal intravenous immunoglobulin endogenous red cell production, thus allowing a more
(IVIg) therapy in severely alloimmunised women.54 The conservative approach to management. Parvovirus B19 is
evidence base most strongly supports in utero transfusion for usually associated with pancytopenia and, if significant
alloimmune anaemia and parvovirus B19 infection, but it can thrombocytopenia is observed, then a platelet transfusion is
also be used in selected cases of inherited anaemias.52 In a case also required. If the fetal haemoglobin is <4 g/L, clinicians
series from the Dutch fetal therapy centre in Leiden,55 must take caution not to over-transfuse the fetus because
alloimmunisation accounted for 86% of IUTs, with the next increases in circulating volume and haematocrit can adversely
commonest indications being parvovirus B19 (9%), TAPS affect fetal haemodynamics, and a significant number of fetuses
(3.6%) and FMH (1.3%). have associated parvovirus myocarditis.60 Fetal and neonatal
More than one in five women (with red cell top-up transfusions are made more likely by additional
alloimmunisation) undergoing IUT form additional antibody formation after transfusion and the suppression of
alloantibodies, which may complicate future pregnancies.56 fetal erythropoiesis, with a recent study showing that 88% of
Precautions to decrease this complication include extended neonates required further intervention.61
phenotype matching (Rhesus, K, Duffy, Kidd and S), use of a The risk of harm to the fetus from IUT is 1–3%; intervention
single, well-matched donor, or serial maternal blood donations at earlier gestations (<20 weeks) is more hazardous because fetal
for IUT.56,57 The presence of adult haemoglobin (from vessels are smaller.62 Intrauterine infection (0.1% per
transfused packed cells) in the fetal circulation affects blood transfusion)52 and ruptured membranes (1.4%)51 may
viscosity and MCA-PSV becomes a less specific screening test complicate transfusions and lead to iatrogenic preterm birth63,

202 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
 Castleman et al.

but procedure-related preterm birth has been reduced to as low

Outcomes of fetal anaemia
as 0.1% per procedure in a high volume centre.52 In the largest
series of 1678 IUTs in 589 fetuses, the procedure-related Red cell alloimmunisation causes over 50 000 stillbirths per
complication rate was 3.3% and the perinatal mortality rate year worldwide.72 Countries with comprehensive antenatal
1.8%.52 An overall 84% survival rate following IUT has been care have reduced the prevalence of HDFN to 2.5/100 000
reported, with greater than 90% survival in the absence live births.72 Many units now prolong affected pregnancies
of hydrops.64,65 until 37 weeks of gestation (if safe) to reduce iatrogenic
Timing of delivery depends on local protocols and the preterm birth and caesarean section rates, with their
cause of anaemia. Fetal therapy is unlikely to be offered after associated morbidity.73 For babies with antenatally
34 weeks of gestation. Term vaginal birth is possible in the diagnosed anaemia, deferred cord clamping at the time of
absence of fetal compromise, with induction of labour likely delivery has been shown to reduce the need for neonatal
to be recommended at 37 weeks of gestation if the pregnancy exchange or top-up transfusion.74 Cord blood of at-risk
continues.12,66 Iatrogenic prematurity and the need for babies is screened for HDFN by performing a direct
neonatal transfusion or prolonged phototherapy must be agglutinin test, with haemoglobin and bilirubin checked
borne in mind. after a positive screen to make the diagnosis.
Maternal antibodies remain in a baby’s circulation for up
Medical treatments to 6 months. Continuing red cell destruction can lead to
Intravenous immunoglobulins (IVIg) given at high doses may chronic unconjugated hyperbilirubinaemia and brain injury
block the transport of alloantibodies across the placenta by (kernicterus). Neonatal jaundice is treated with phototherapy
competitive inhibition.12 IVIg can reduce maternal or exchange transfusion.75 Cholestatic jaundice (conjugated
alloantibody production and delay clinically significant hyperbilirubinaemia) complicates the postnatal course of
anaemia until IUT is more feasible.54,67 The Postponing 13% of HDFN cases and is associated with IUT and
Early intrauterine Transfusion with Intravenous RhD alloimmunisation.76
immunoglobulin Treatment (PETIT) study68 investigated the Early neonatal anaemia in HDFN (within 7 days) is
outcomes of pregnancies in women with prior alloimmunised determined by in utero events and late anaemia is divided
pregnancy complicated by severe fetal anaemia. IVIg therapy into hyporegenerative and haemolytic aetiologies.77 Top-up
(24 women) delayed the onset of clinically significant anaemia transfusions occur in up to four out of five neonates with
compared with the index pregnancy (by 15 days) and HDFN until late postpartum anaemia resolves.75 Multiply
compared with the group not treated with IVIg (28 women, transfused babies are potentially at risk of iron overload. In
by 9 days). This prolongation is insufficient to make a a systematic review of nine single-centre studies of
clinically useful reduction in the risk of invasive fetal outcomes in children born after IUT, the pooled rate of
therapy. Maternal IVIg therapy was associated with cerebral palsy was 2.4% (13/549).78 The LOTUS study
reduction in hydrops and neonatal exchange transfusion, followed up 291 children at a median age of 8.2 years
especially when initiated early. Overall survival was 88%, with following IUT for alloimmune fetal anaemia and found
no difference between groups. neurodevelopmental impairment in 4.8%.79 After TAPS, the
Maternal plasma exchange can clear alloantibodies from the donor twin is at increased risk of neurodevelopmental
maternal circulation. It can be beneficial when a previous impairment (four-fold higher than the recipient) and the
pregnancy has been severely affected by fetal anaemia, or if large incidence of cognitive delay and deafness is increased,
quantities of Rh-positive red blood cells need to be cleared from warranting long term follow-up.80 ABO incompatibility is a
a Rh-negative patient acutely. Potential adverse effects relate to neonatal, rather than fetal, problem; parents can be
maternal morbidity (for example, infection, haematoma reassured that this mild haemolytic anaemia does not get
formation) and altered maternal and fetal haemodynamics, as worse in successive pregnancies.
well as the loss of systemically important proteins.69
Immunomodulatory therapies may prevent
Conclusion
alloimmunisation in high-risk women prior to RBC antigen
exposure, but current evidence is limited to case series, with Fetal anaemia is an important condition, of which clinicians
azathioprine, promethazine and prednisolone amongst the of all levels should be aware. Appropriate antenatal screening
candidate drugs.70 A clinical study of M281 (nipocalimab, and identification of pregnancies at high risk of fetal anaemia
Momenta Pharmaceuticals), a monoclonal antibody that will aid prompt diagnosis. Use of ultrasound and Doppler
blocks transplacental IgG transfer, is investigating whether it investigation of MCA-PSV and referral to fetal medicine
can attenuate the risks of alloimmune fetal anaemia and specialists for assessment and therapy has been shown to
prolong the gestation when IUT may be required.71 improve outcomes.

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 203
 Fetal anaemia

Disclosure of interests 20 Public Health England. Guidance on the investigation, diagnosis and
management of viral illness, or exposure to viral rash illness, in pregnancy.
There are no conflicts of interests. London: Public Health England; 2019.
21 Kilby MD, Ville Y, Acharya G. Screening for cytomegalovirus infection in
Contribution to authorship pregnancy. BMJ 2019;367:l6507.
JC and LG researched and wrote the article. MK reviewed and 22 National Institute for Health and Care Excellence (NICE). Parvovirus B19
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edited the article. RKM instigated and edited the article. All nice.org.uk/parvovirus-b19-infection#!scenario:1].
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24 Liang ST, Wong VC, So WW, Ma HK, Chan V, Todd D. Homozygous alpha-
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