Ultrasound Obstet Gynecol 2017; 50: 145–153
Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.17555
Editorial
Fetal anemia
N. ABBASI1 , J.-A. JOHNSON2
and G. RYAN1*
1 Fetal Medicine Unit, Department of Obstetrics and Gynaecology,
Mount Sinai Hospital, Toronto, Ontario, Canada; 2 Department of
Obstetrics and Gynaecology, University of Calgary, Calgary,
Alberta, Canada
*Correspondence. (Fetal Medicine Unit, Mount Sinai Hospital,
OPG 3-906, 600 University Ave., Toronto, ON M5G 1Z5, Canada
e-mail: greg.ryan@sinaihealthsystem.ca)
Introduction
Fetal anemia is a relatively rare but serious condition.
An immune-related cause is most common, involv-
ing red-blood-cell (RBC) alloimmunization, followed by
non-immune causes, such as parvovirus B19 infection
and, more rarely, hemoglobinopathies, fetomaternal hem-
orrhage (FMH) and monochorionic twin complications,
among others. Several advances have been made in the
diagnosis and treatment of fetal anemia. High-resolution
ultrasound now permits accurate, non-invasive screening
by measurement of the middle cerebral artery peak sys-
tolic velocity (MCA-PSV)1 , replacing serial amniocenteses
for fetal anemia screening2 . Refinement of fetal blood
sampling (FBS) and intrauterine transfusion (IUT) tech-
niques has resulted in close to 90% survival of anemic
fetuses3 , with very good long-term neurodevelopmental
outcomes4 . In this review, we discuss the most common
etiologies of fetal anemia, current screening and diagnos-
tic tools, management of fetal anemia, including FBS/IUT
techniques and associated risks and benefits, as well as
short- and long-term outcomes following IUT.
Definition of fetal anemia (Table 1)
As fetal hemoglobin (Hb) values increase gradually during
pregnancy, anemia may be classified based on the degree
of Hb deviation from the mean for gestational age (GA)5
or on multiples of the median (MoM)1 for GA (Table 1).
Hydrops typically does not develop until the Hb deficit is
> 70 g/L or the absolute Hb value is < 50 g/L6 .
Etiology of fetal anemia (Table 2)
Red-blood-cell (RBC) alloimmunization/hemolytic
disease of the fetus and newborn (HDFN)
Alloimmunization occurs following maternal exposure to
paternally derived RBC antigens on fetal cells, resulting
in maternal antibody formation and secondary fetal
RBC hemolysis, anemia, hydrops and, ultimately, fetal
demise1 . Although over 50 RBC antigens have been
Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
associated with fetal hemolysis, severe fetal anemia
results most commonly from Rhesus (Rh) D, Rhc or Kell
alloimmunization7 .
RBC alloimmunization is the leading cause of fetal
anemia, despite standardized protocols for RhD immune
globulin (RhIG) prophylaxis, most often due to unrec-
ognized FMH events, inadequate dosing or missed pro-
phylaxis for antenatal sensitizing events, poor patient
compliance, absence of prophylaxis for other RBC anti-
gens and omission of Kell typing of blood transfusions for
women of childbearing age7 .
Pregnancies at risk are identified on the basis of a
previous history of hemolytic disease of the fetus and
newborn (HDFN) or when causative antibodies are
identified on routine maternal blood-group screening.
If paternity is certain, initial management involves
determining the paternal RBC antigen status and zygosity.
If the father is heterozygous for a particular RBC
antigen, the fetus has a 50% risk of inheritance and
fetal genotyping can be performed. If the father is
homozygous, all fetuses will inherit that antigen and
genotyping is unnecessary. Traditionally, fetal genotyping
was determined by amniocentesis, with a sensitivity of
98.7% and specificity of 100% for RhD status8 . The
discovery of cell-free DNA in the maternal plasma has
since enabled non-invasive determination of the fetal RhD
genotype9 . Experience with this approach is extensive,
with prediction accuracy and test sensitivity approaching
100%, and very few false-negative results9 . While results
can be obtained as early as 10 gestational weeks,
the International Blood Group Reference Laboratory in
Bristol, UK currently performs genotyping for RhD, Rhc,
RhC and RhE after 16 weeks and for Kell after 20 weeks’
gestation.
In sensitized pregnancies, serial titers are performed,
typically every 4 weeks until 28 weeks’ gestation and every
2 weeks thereafter7 . Historically, once titers reached a
laboratory-specific ‘critical’ level indicative of high risk of
fetal anemia, commonly defined as ≥ 1:32 for anti-RhD
and most other antibodies and ≥ 1:8 for anti-Kell10 , serial
amniocenteses were then performed for bilirubin levels
to estimate the severity of hemolysis. Spectrophotometry
was used to quantify bilirubin level, which was expressed
as the change in optical density (OD) at a wavelength
of 450 nm (OD450 ). These values were plotted on
Liley’s curve11 or Queenan’s curve (< 27 weeks)12 to
predict fetal anemia. MCA-PSV testing has now replaced
serial invasive testing after a randomized control trial
demonstrated that Doppler assessment of the MCA-PSV
had higher sensitivity and accuracy for prediction of severe
fetal anemia compared with amniotic-fluid OD450 in
Rh-alloimmunized pregnancies2 . Once critical titers are
reached, MCA-PSVs are measured weekly to determine
optimal timing of FBS.
EDITORIAL
146 Abbasi et al.

Table 1 Definitions of fetal anemia

Severity
Definition Reference Mild Moderate Severe
5
Hemoglobin deviation from GA mean Nicolaides et al. < 20 g/L 20–70 g/L > 70 g/L
Hemoglobin values expressed as MoM Mari et al.1 ; Goodwin and Breen96 0.84–0.65 0.64–0.55 ≤ 0.54
Hematocrit Moise Jr and Argoti10 < 30%

GA, gestational age; MoM, multiples of the median.

Table 2 Etiology of fetal anemia

Classification Causes

Immune
RBC alloimmunization* Rh blood group (D, c, C, e, E)*, Kell*, Duffy (Fya )*, Kidd (Jka , Jkb )*or any
IgM RBC antibody*
Non-immune
Congenital infection* Parvovirus B19*, CMV, toxoplasmosis, syphilis
Inherited anemias* Hemoglobinopathies (e.g. α-thalassemia major*), RBC membrane or
enzyme disorders (e.g. G6PD deficiency, pyruvate kinase deficiency)
Bone-marrow disorders Fanconi anemia, Diamond–Blackfan anemia
Hematopoietic malignancies Congenital leukemia, transient myeloproliferative disorder
Fetal or placental tumors, vascular malformations, Sacrococcygeal teratoma*, liver hemangioma, hepatoblastoma, diffuse
other placental pathology* neonatal hemangiomatosis, placental chorangioma*, fetal or placental
arteriovenous malformations, placental mesenchymal dysplasia
Fetomaternal hemorrhage* Placental abruption*, trauma*
Rare genetic disorders Lysosomal storage disorders (e.g. Niemann–Pick, Gaucher disease,
mucopolysaccharidosis), neonatal hemochromatosis
Complications of monochorionic placentation* TAPS*, cotwin demise*

*Potential candidates for intrauterine transfusion (IUT). CMV, cytomegalovirus; G6PD, glucose-6 phosphate dehydrogenase; IgM, immuno-
globulin; RBC, red blood cell; Rh, Rhesus; TAPS, twin anemia–polycythemia sequence.

Parvovirus B19 (PB19) and other congenital infections

Nearly 65% of women of childbearing age are immune to

PB19, and 1.5% of susceptible women will seroconvert
during pregnancy13 . Typically, transmission is by respira- P
tory droplets; less commonly, it is transplacental or from
blood products14 . The overall risk of vertical transmission L A
is approximately 17–33%, with the highest risk occurring
prior to the third trimester15,16 .
PB19 is a single-stranded DNA virus with a particular
affinity for erythroid progenitor cells17 , potentially lead-
ing to hemolysis, bone-marrow aplasia and, occasionally,
thrombocytopenia and neutropenia. Erythema infectio-
sum, or fifth disease, represents the typical presentation
in children, with a low-grade fever, malaise and a Figure 1 Ultrasound image (sagittal view) of a fetus with
characteristic ‘slapped-cheek’ facial rash, followed by a non-immune hydrops secondary to parvovirus B19 infection.
maculopapular truncal and extremity rash. Most adults A, ascites; L, liver; P, polyhydramnios.
are asymptomatic, or may experience polyarthralgia.
> 20 weeks, and approximately 3% of affected fetuses
Rare presentations include myocarditis and heart failure,
will develop hydrops14 .
aplastic crisis in the setting of chronic anemia, and
Diagnosis of maternal infection relies on detection
persistent infection and anemia in immunocompromised of PB19-specific immunoglobulin (Ig)M and/or IgG
individuals17 . antibodies14 . Viremia develops approximately 1 week
Fetal infections are mostly asymptomatic without after inoculation. IgM is detectable 7–10 days after infec-
sequelae15 , but may result in miscarriage, severe ane- tion, peaks at 10–14 days, and remains detectable for
mia and non-immune hydrops (NIH) and stillbirth. up to 6 months. Two weeks after infection, IgG becomes
Marked fetal ascites is pathognomonic of PB19 infection detectable and confers lifelong immunity18 . Fetal infection
(Figure 1). The risk of fetal loss is estimated at 13% when is confirmed by polymerase chain reaction for PB19 DNA
infection occurs < 20 weeks and 0.5% when it occurs in amniotic fluid or fetal blood. NIH typically develops

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2017; 50: 145–153.
Editorial
2–6 weeks after seroconversion19 but may occur up to
10–12 weeks later20 . Ultrasound and MCA-PSV measure-
ments should be performed every 1–2 weeks for approx-
imately 10–12 weeks from maternal seroconversion14 ,
with referral to a fetal medicine unit for FBS with or
without IUT if there is evidence of fetal anemia or hydrops.
Rarely, fetal anemia and hydrops can be caused by
other congenital infections, including cytomegalovirus
(CMV)21 , syphilis22 and toxoplasmosis23 . Other ultra-
sonographic features of congenital infections may include
ascites, placentomegaly, hepatosplenomegaly, echogenic
bowel, liver or intracranial calcifications, ventricu-
lomegaly and intrauterine growth restriction (IUGR).
Hemoglobinopathies, hemolytic anemias and bone-
marrow-failure syndromes
Alpha (α)-thalassemia is caused by the defective synthesis
of α-globin chains and is the most common cause of NIH
in Southeast Asia. The α-globin gene cluster consists of
four copies of the α-globin gene (αα/αα). α-thalassemia
can be classified into four types based on the number
of functional α-globin genes: silent carrier state (-α/αα),
α- thalassemia trait (--/αα (cis) or -α/-α (trans)), Hb H
disease (--/-α) and α-thalassemia major (--/--) (Hb Bart’s
or homozygous α-thalassemia). If both parents carry the
cis deletion (--/αα), the inheritance risk for α-thalassemia
major is 25%. Fetuses with homozygous α-thalassemia
cannot produce normal fetal Hb (α2 γ2 ), instead producing
Hb Bart’s (γ4 ). Clinical features include: cardiomegaly,
ascites, hydrops, IUGR, limb defects24 , intrauterine fetal
death (IUFD) and neonatal death (NND)25–27 . Given the
severe impairment in tissue oxygen delivery, the sequelae
of fetal anemia and hydrops may occur at higher Hb
values than seen with RBC alloimmunization, making
MCA-PSV Doppler less predictive of disease severity.
Maternal complications may include ‘mirror’ syndrome
and antepartum hemorrhage25 .
Prenatal diagnosis is established by DNA analysis via
chorionic villus sampling performed after 10 gestational
weeks or amniocentesis after 15 weeks. Alternatively,
serial sonographic evaluation for cardiomegaly and
placental thickness can be used as a screening tool in early
pregnancy. The sensitivity and specificity of placental
thickness for detection of α-thalassemia major were
72% and 97%, respectively, before 12 weeks and 95%
and 97%, respectively, after 12 weeks28 . Using a car-
diothoracic ratio (CTR) ≥ 0.5 to estimate cardiomegaly,
sensitivity and specificity were 100% at 12–13 weeks26 .
When the predictive value of CTR, MCA-PSV and
placental thickness were compared, CTR was found to
be superior, and sensitivity at 12–15 weeks was further
increased by addition of MCA-PSV measurement27 .
Historically, fetal α-thalassemia major was considered
to be a uniformly lethal condition, but, with the advent
of IUT, increasing numbers of live births have been
reported24 . However, in the absence of curative therapy,
prenatal treatment raises ethical dilemmas and requires
detailed counseling from a multidisciplinary team.
Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
147
Congenital leukemia and myeloproliferative disorders
Congenital leukemia and occasionally transient myelo-
proliferative disorder may present prenatally with fetal
anemia, hepatosplenomegaly, polyhydramnios, placen-
tomegaly, hydrops and IUFD29 , most commonly asso-
ciated with trisomy 2129,30 .
Placental/fetal tumors
Placental chorangiomas are the most common benign pla-
cental tumor and can be associated with fetal anemia31,32 ,
secondary to fetal hemorrhage31 or consumption and
destruction of fetal RBCs within the narrow, thrombosed
vasculature of the chorangioma33 . Other complications
include NIH, polyhydramnios, preterm labor, IUGR and
pre-eclampsia, particularly if tumors are > 4 cm32 . Fetal
sacroccygeal tumors can also result in fetal anemia, due
to hemorrhage within the tumor and RBC consumption,
with secondary high-output cardiac failure and NIH34 .
Fetomaternal hemorrhage (FMH)
Traditionally, FMH has been defined as hemorrhage of
≥ 30 mL fetal blood into the maternal circulation, as this
is the volume of Rh-positive whole fetal blood that is
covered by a standard 300-μg dose of RhIG to prevent
alloimmunization35 . Large or massive FMH has been
defined as blood loss of 80–150 mL36 or > 20 mL/kg37 ,
however, there is no fixed volume above which fetal mor-
bidity or mortality will result unequivocally. Although
the majority of FMHs remain unexplained35 , risk
factors include: external cephalic version38 , abdominal
trauma39 , placental abruption, placenta previa, IUFD,
Cesarean section, manual removal of the placenta and
amniocentesis35 .
Massive FMH with fetal hydrops at 26–28 weeks
has been managed with serial IUTs; however, outcomes
are variable, ranging from resolution of hydrops and
live birth40 to IUFD41 . Whether to expedite delivery or
perform an IUT will depend on GA, antenatal test results
and availability of expertise.
Monochorionic complications: twin–twin transfusion
syndrome (TTTS), twin anemia–polycythemia sequence
(TAPS) and cotwin demise
Twin–twin transfusion syndrome (TTTS) and twin
anemia–polycythemia sequence (TAPS) are chronic forms
of fetofetal transfusion42 . TTTS complicates up to 15% of
monochorionic diamniotic (MCDA) twin pregnancies and
pathogenesis is related to unbalanced blood flow through
placental vascular anastomoses43 . A gradual blood-flow
shift develops, resulting in oliguric oligohydramnios in
the donor and polyuric polyhydramnios and volume
overload in the recipient43 , potentially leading to hydrops
secondary to right ventricular dysfunction44 . A large
intertwin hemoglobin difference is not generally seen,
unless there is coexisting TAPS.
TAPS is characterized by a Hb discordance in MCDA
twins in the absence of the oligopolyhydramnios sequence
Ultrasound Obstet Gynecol 2017; 50: 145–153.
148
seen with TTTS, and occurs when there are only a few, tiny
(< 1 mm), unidirectional arteriovenous vascular anasto-
moses, with sparse or absent compensatory arterioarterial
anastomoses45 . TAPS may occur spontaneously in 3–5%
of MCDA twins, usually presenting after 26 weeks’ ges-
tation (Figure 2), or in 2–13% of TTTS cases, following
incomplete laser ablation of placental anastomoses45 .
Cotwin demise may result in an acute hemodynamic
imbalance, due to a massive transfer of blood from the
survivor to the dead twin via the placental anastomoses in
monochorionic placentae, causing anemia, neurological
handicap or death of the remaining twin46 . Although IUT
can correct the anemia, whether or not it impacts on
neonatal or neurodevelopmental outcome is unknown.
Investigation of suspected fetal anemia (Table 3)
Recommended investigations for evaluation of suspected
fetal anemia are listed in Table 3. Referral to a maternal
fetal medicine specialist and a tertiary care center with
expertise in FBS and IUT is indicated.
Ultrasonographic assessment of fetal anemia (Table 4)
The first manifestation of hydrops secondary to fetal
anemia is always ascites, followed by placental thickening
and hepatomegaly; associated pleural or pericardial
effusions are rare47 . Fetal liver length > 90th percentile48 ,
splenomegaly (spleen perimeter > 2SD)49 and Doppler
measurements of mean blood velocity in the fetal aorta50
and splenic artery PSV51 were also found to correlate
with fetal anemia. When Oepkes et al.52 compared
fetal liver length, spleen perimeter, umbilical vein (UV)
diameter, placental thickness and UV and aortic flow
velocities, only Doppler parameters were predictive of
severe anemia in non-hydropic fetuses.
Middle cerebral artery (MCA) Doppler studies and pre-
diction of fetal anemia. Initial studies in fetal lambs,
measuring blood flow in relation to hematocrit (Hct),
demonstrated compensatory increased flow to the brain,
heart and adrenals to maintain stable oxygen deliv-
ery across a range of Hct53 ; this was also replicated
in humans54 . An inverse relationship was also noted
between fetal Hct and MCA-PSV55 . Subsequently, Mari
et al.1 demonstrated that MCA-PSV > 1.50 MoM in
non-hydropic fetuses at risk of RBC alloimmunization
could detect all cases of moderate to severe anemia, with
a false-positive rate of 12%. Oepkes et al.2 thereafter con-
firmed the superiority of MCA-PSV over amniotic-fluid
OD450 , making serial amniocenteses for fetal anemia
screening essentially obsolete.
Obtaining MCA-PSV measurements: technical aspects.
An axial section of the brain, including thalami, cavum
septi pellucidi and greater wing of sphenoid, with the circle
of Willis identified by color Doppler, should be obtained1 .
The MCA closest to the probe is sampled at or near its
origin from the internal carotid artery. The waveform
Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Abbasi et al.
peak is measured, with the angle of insonation as close as
possible to 0◦ , and always < 30◦ (Figure 3). Higher inter-
and intraobserver variability results from angle correction
and sampling of more distal regions of the MCA56 . The
fetus should be quiescent, as heart-rate accelerations and
movement can alter measurements57 . Other factors that
may influence MCA-PSV include: gender, cardiac status,
uterine contractions, fetal behavioral state58 , advanced
GA59 and previous IUTs60 . Elevated MCA-PSVs may also
be seen in abnormal placentation and IUGR, reflecting
cerebral autoregulation in response to hypoxemia and
hypercapnia61 . These factors, in addition to insufficient
B
Twin
A
(b) 100
1.5 MoM
90
80
70
1.0 MoM
MCA-PSV (cm/s)
60
50
40
30
20
10
0
14 18 22 26 30 34 38
Gestational age (weeks)
Figure 2 (a) Placental ultrasound in a case of spontaneous twin
anemia–polycythemia sequence (TAPS) at 27 + 6 weeks’ gestation,
demonstrating discrepant placental echogenicity, with A represent-
ing the more echogenic territory of the anemic, donor twin and B
the relatively echolucent placenta of the polycythemic recipient
twin. (b) TAPS in monochorionic diamniotic twins. Note
progressively discordant middle cerebral artery peak systolic
velocity (MCA-PSV) Doppler readings after c. 25 weeks’ gestation,
with Twin A/donor twin ( ) having MCA-PSV > 1.5 multiples of
the median (MoM) (anemic) and Twin B/recipient twin ( ) having
MCA-PSV < 0.8 MoM (polycythemic) by approximately 28 weeks.
Arrow indicates timing of fetal blood sampling and intrauterine
transfusion for Twin A (hemoglobin (Hb), 5.6 g/L) and partial
exchange transfusion for Twin B (Hb, 21 g/L), which was followed
by almost immediate resolution of MCA-PSV discordance.
Ultrasound Obstet Gynecol 2017; 50: 145–153.
Editorial 149

Table 3 Investigation of fetal anemia

Maternal
Detailed family and pregnancy history (e.g. ethnicity, consanguinity, genetic syndromes, infection exposure and trauma)
CBC, blood group and screen (indirect Coombs titer if antibody screen +)
Kleihauer–Betke, flow cytometry
Hemoglobin electrophoresis
Serologies (PB19 IgG and IgM, CMV IgG and IgM (avidity testing if IgM +), toxoplasmosis IgG and IgM, syphilis testing)
Referral to fetal medicine unit with detailed fetal and placental ultrasound and MCA-PSV Doppler with or without fetal
echocardiogram if hydrops
Fetal
Fetal blood sample (FBS)* should be sent for blood type, CBC, Hb/Hct, platelet count, direct Coombs, reticulocyte count and
total bilirubin, PCR for CMV and PB19 with or without syphilis and toxoplasmosis
Non-stress test for sinusoidal fetal heart rate
Rare causes of fetal anemia
Hematology and genetics consultation
Parental hemoglobin, high performance liquid chromotagraphy and RBC enzyme assays (i.e. pyruvate kinase, G6PD)
Fetal peripheral smear, hemoglobin electrophoresis and chromosome fragility studies (i.e. Fanconi anemia)
If elevated white blood cell count, obtain differential and peripheral smear and consider congenital leukemia or transient
myeloproliferative disorder

*FBS should be considered if sonographic features suggest fetal anemia (see text). CBC, complete blood count; CMV, cytomegalovirus;
G6PD, glucose-6 phosphate dehydrogenase; Hb, hemoglobin; Hct, hematocrit; Ig, immunoglobulin; MCA-PSV, middle cerebral artery peak
systolic velocity; PCR, polymerase chain reaction; PB19, parvovirus B19; RBC, red blood cell.

Table 4 Sonographic features of fetal anemia

Sonographic features

General Evaluate for secondary causes (i.e. fetal or placental) of anemia

Specific clinical conditions
α-thalassemia major
Congenital infections
Complications of MC twins
TAPS
MCA-PSV > 1.5 MoM1
Placentomegaly, hydrops, ascites97 , enlarged fetal liver48 and spleen49
Placental thickness > 2 SD above GA mean28 or > 18 mm at 12–15 weeks98 or > 30 mm at 18–21 weeks99
Cardiomegaly: CTR > 0.5 before 18 weeks or > 0.52 after 18 weeks98
Ascites
Placentomegaly, hepatosplenomegaly, echogenic bowel, liver calcifications, ventriculomegaly, intracranial
calcifications, growth restriction
Discordant MCA-PSV (> 1.5 MoM in donor and < 0.8 MoM in recipient)100
Discordant placental echogenicity101
‘Starry sky’ appearance of liver in recipient102

CTR, cardiothoracic ratio; GA, gestational age; MC, monochorionic; MCA-PSV, middle cerebral artery peak systolic velocity; TAPS, twin
anemia–polycythemia sequence.

attention to proper technique, may in part explain the

false-positive rate of MCA-PSV for prediction of fetal
anemia, described by Mari et al.1 .
MCA
Fetal blood sampling (FBS)62,63 *
We perform FBS only when the MCA-PSV is above
1.5 MoM and trending upwards. Investigations at the
time of FBS are listed in Table 3. Rare causes of anemia
should be evaluated in conjunction with a hematologist.
Administration of corticosteroids for fetal lung maturity
should be considered prior to FBS after viability.

Treatment: intrauterine transfusion (IUT)

The goal of IUT in HDFN is to replace the fetal
blood with Rh-negative donor blood, thus supressing
Figure 3 Axial section of fetal brain with color flow mapping
fetal erythropoiesis. IUT is generally indicated for fetal
showing circle of Willis ( ) with Doppler gate placed within
Hct < 30%10 or Hb < 10 g/L64 . Fresh, CMV-negative, proximal third of middle cerebral artery (MCA) to measure peak
leukoreduced, irradiated, Type-O, RhD-negative donor systolic velocity (in cm/s).
RBCs, cross-matched to a maternal sample and packed

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2017; 50: 145–153.
150
to a Hct of 75–80%, are used64 . Autologous washed
maternal blood can also be used for IUT once the
maternal Hb level is > 120 g/L, which eliminates the
risk of sensitization to new RBC antigens in random
donor blood. Platelets should be available if PB19 or
CMV are suspected, or in the presence of hydrops
or hepatosplenomegaly. Coexistent severe thrombocy-
topenia has been reported in hydropic alloimmunized
pregnancies65 and hydropic fetuses with PB1966 .
When a previous pregnancy has been complicated
by HDFN, titers are less reliable predictors of severe
fetal anemia and MCA-PSV should be followed serially
instead. Intravenous immune globulin (IVIG)67,68 and
plasmapheresis68 have also been used in some cases with
a history of previous early mid-trimester loss due to
RBC alloimmunization or markedly elevated titers, with
a reported reduction in perinatal mortality and delay
of the first IUT by 1.5 weeks67 . In contrast, one small
randomized controlled trial found no additional benefit
of IVIG when combined with IUT, compared with IUT
alone, in cases of severe RhD alloimmunization69 .
IUT approaches and procedure-related (PR) risks
An intravascular approach, via the UV at the placental
cord insertion (PCI), the intrahepatic vein (IHV) or a
free loop of cord, has largely replaced intraperitoneal
transfusion (IPT), first described in 196370 . IPT may
still have a role in very early pregnancy, as higher fetal
loss rates are associated with intravascular transfusion at
GA < 22 weeks71 . Rarely, an intracardiac approach may
be used. In anatomically normal fetuses, the PR loss rate
with IUT is approximately 1%72 ; this rate may vary, how-
ever, with GA71 , indication and operator experience73 .
In the presence of structural abnormalities or hydrops,
loss rates are reportedly 7% and 25%, respectively72 .
PR risks include bleeding from the needle puncture site
and fetal heart-rate decelerations, which are usually
self-limiting and have been reported in up to 20–30%
and 5–10% of procedures, respectively74 . In one series
evaluating outcomes with IUT, performed mostly using
a PCI approach, 3.1% of procedures had complications,
including preterm prelabor rupture of membranes,
infection, emergency Cesarean section, and IUFD or
NND, with an overall loss rate of 1.6% per procedure75 .
Preterm birth < 37 weeks was found to occur in 3.5%
of cases and only in patients requiring multiple (more
than three) IUTs76 . Fetal bradycardia and abandoned
procedures were more common when a free loop of cord
was targeted compared with IHV or PCI approaches76 .
Although IHV and PCI approaches are preferred over
a free loop of cord, superiority of either IHV or PCI has
not been demonstrated consistently75,77,78 . Ultimately, the
choice depends on operator preference and experience.
Advantages of the IHV approach include avoidance of
arterial puncture and secondary vasospasm and cord
tamponade, less FMH and success rates in the region
of 90%3 . Furthermore, if intraperitoneal bleeding occurs,
it is usually self-limiting and functions as an IPT. We
Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Abbasi et al.
perform > 70% of IUTs via the IHV and find this route
particularly useful in multiple pregnancies or at advanced
gestational ages when the placenta is posterior.
Fetal paralytic agents
Fetal paralytic agents, such as rocuronium, atracurium
and vecuronium, are particularly useful if a prolonged or
difficult procedure is anticipated74 . Paralysis may reduce
the risk of cord complications, such as arterial spasm,
hematoma or excessive bleeding, all of which can result
from needle dislodgement with fetal movement75 .
Volume of transfusion
The volume of transfused blood depends on the estimated
fetal weight, donor and fetal pretransfusion and target
Hb/Hct, presence of hydrops and fetoplacental blood
volume79 . Some authors caution against transfusing,
during a single IUT, volumes > 20 mL/kg, corresponding
to approximately 20% of the fetoplacental blood volume,
as this may be associated with increased fetal mortality,
related to circulatory overload80 . In our experience, the
following formulae provide fairly reliable estimates of the
volume of blood needed for IUT:
• intravascular transfusion (IVT) = ((target Hb – fetal Hb)
× fetoplacental blood volume) / (donor Hb – target Hb);
• intraperitoneal transfusion (IPT) = (GA in weeks – 20)
× 10 mL.
To avoid excessive transfusion and polycythemia,
approximately two-thirds of the calculated volume
should be transfused, followed by FBS to determine
the final volume needed for IUT. Our target Hb level
is 17 g/L, in non-hydropic fetuses.
Fetal anemia and hydrops fetalis: special considerations
for IUT
Several studies have demonstrated worse outcomes
following IUT in hydropic compared with non-hydropic
fetuses75,81,82 , possibly due to their reduced cardiac
reserve and increased susceptibility to volume
overload80,81 . In a review of 80 fetuses that were
hydropic secondary to RBC alloimmunization, which
underwent IUT, the survival rate overall was 78% (98%
in mild and 55% in severe hydrops)82 . Reversal of
hydrops occurred in 65% of cases overall, and only 40%
of persistently hydropic fetuses survived. In practice, we
do not raise the Hb/Hct more than four-fold in severely
anemic, hydropic fetuses during a single IUT, as this
has been found to be a predictor of fetal loss81 . Instead,
we will perform a second procedure within 1–2 days if
necessary to reach the target Hb/Hct.
Management after first IUT
There are no clear guidelines regarding fetal monitoring
following IUT; however, weekly assessment of fetal
wellbeing and MCA-PSV Doppler is reasonable.
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Editorial
Serial IUTs
Timing of subsequent IUTs is debatable, particularly since
the use of MCA-PSV to predict fetal anemia becomes less
reliable after several IUTs, with false-positive rates of
14%, 37% and 90% for the detection of 95% of severely
anemic fetuses following the first, second and third IUT,
respectively60 . As the rise in MCA-PSV in anemic fetuses
likely reflects a hyperdynamic circulation due to decreased
blood viscosity83 , the reduced accuracy of MCA-PSV
following IUT may be related to altered properties of fetal
blood, when admixed with adult blood cells, which have
a lower viscosity60 . Furthermore, due to the replacement
of fetal RBCs with adult RBCs following IUT, the
concentration of fetal Hb, which has a higher affinity
for oxygen84 , is reduced, thus lowering the total arterial
oxygen concentration in the fetal circulation85 . Some
authors have reported higher MCA-PSV thresholds for the
diagnosis of severe anemia following IUT, speculating that
this may be explained by a compensatory rise in cerebral
blood flow, related to lower total oxygen carrying capacity
and oxygen tissue delivery of transfused blood and the
lower viscosity of adult RBCs85 . However, established
cut-offs for diagnosis of fetal anemia following serial
IUTs have not yet been defined. Alternatively, the timing
of subsequent IUTs may be based on the anticipated
decline in fetal Hb, using 0.4 g/L/day, 0.3 g/L/day and
0.2 g/L/day Hb decline for the first, second and third IUT
intervals, respectively60 , or a decline of 1%/day in fetal
Hct86,87 . Others have suggested transfusing empirically
at 10 days, 2 weeks and 3 weeks, for second, third and
subsequent IUTs, respectively10 .
Special considerations for management of TAPS
The ideal treatment of TAPS is laser ablation of the
placental vascular anastomoses. However, if this is not
possible, another option is to transfuse the anemic donor
twin. This can result in worsening polycythemia for the
recipient, especially with serial transfusions; this can be
counteracted by hemodilution using partial exchange
transfusions45 .
Timing of delivery
The therapeutic goal in managing RBC-alloimmunized
pregnancies should be to enable delivery, close to term,
of a healthy neonate who requires neither exchange
transfusion nor prolonged phototherapy. In stable
pregnancies that have undergone three or more IUTs, a
final IUT at 34–35 weeks, with delivery 3–4 weeks later,
is reasonable10,79 , unless other indications for delivery
arise prior to this.
Short-term outcome following IUT
Neonatal survival overall, in the era of IUT, is 84%; 70%
in hydropic and 94% in non-hydropic fetuses88 . The
main short-term neonatal complications are related to
Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
151
hyperbilirubinemia requiring phototherapy or exchange
transfusion, as well as thrombocytopenia, anemia and
cholestasis89 . In the LOTUS (LOng-Term follow-up
after intra-Uterine transfusionS) study4 , which evaluated
short- and long-term neurodevelopmental outcome
after IUT for alloimmunization, 17.5% of infants were
delivered < 35 weeks, with most delivering between 32
and 35 weeks. Severe neonatal morbidity included: respi-
ratory distress syndrome (2.4%), necrotizing enterocolitis
(1.0%), sepsis (5.8%), perinatal asphyxia (3.8%) and
severe cerebral injury (1.7%). When outcome of neonates
delivered ≥ 36 weeks was compared between those
treated with and without IUT, phototherapy was required
for shorter periods in those who had been transfused
in utero; however, the exchange transfusion rate was
similar in both groups and was required in nearly 70%
of cases90 .
Late or ‘hyporegenerative’ anemia presenting up to
3 months after birth has been described in association
with HDFN91 , with nearly 30% of these infants requiring
a RBC ‘top-up’ transfusion78 . Reticulocyte count at birth
is inversely related to the number of top-up transfusions
required, suggesting that suppression of erythropoiesis is
the primary underlying mechanism90 .
Long-term outcome following IUT
Nearly 25% of alloimmunized mothers form additional
antibodies following IUT, despite utilization of Rh- and
Kell-matched blood products92 .
Neurodevelopmental outcome following IUT was nor-
mal in 95% of children assessed at a median age of
8.2 years in the LOTUS study4 . Cerebral palsy, severe
developmental delay and bilateral deafness were detected
in 2%, 3% and 1% of children, respectively. Fac-
tors independently associated with neurodevelopmental
impairment included severe hydrops, number of IUTs and
severe neonatal morbidity.
Outcome in hydropic alloimmunized fetuses following
IUT is variable. In the LOTUS study4 , severe fetal hydrops
was present in nearly 30% of children with, vs 6% of
children without, neurodevelopmental impairment. When
Harper et al.93 evaluated long-term neurodevelopmental
outcome in 18 hydropic fetuses, they found that death
or major morbidity occurred in 22%. Of 16 hydropic
survivors, 13 were normal neurodevelopmentally at a
mean age of 10 years, and those with sequelae had other
contributing factors, particularly prematurity. Long-term
outcome in hydropic fetuses secondary to PB19 infection
is less favorable, with a survival rate of 67–84%79 ,
suggesting that the virus may induce neural toxicity
directly94 . Nagel et al.95 evaluated 24 fetuses that were
hydropic due to PB19 and which underwent IUT; of 16
survivors, one third demonstrated delayed psychomotor
development. In another series, evaluating 44 hydropic
fetuses followed for a median of 5 years, survival was
73% and severe neurodevelopmental impairment was
noted in three children94 .
Ultrasound Obstet Gynecol 2017; 50: 145–153.
152
Summary
RBC alloimmunization is the most common cause
of fetal anemia, followed by PB19 infection and,
more rarely, hemoglobinopathies, FMH, fetal and
placental tumors and complications of monochorionic
placentation. The non-invasive prediction of fetal anemia
by Doppler evaluation of MCA-PSV has revolutionized
the management of fetal anemia1 , replacing amniocentesis
for bilirubin OD450 estimation2 and making redundant
other ultrasound predictors of anemia. Referral to a
maternal–fetal medicine specialist with expertise in FBS
and IUT is indicated when MCA-PSV measurements
are ≥ 1.5 MoM. Baseline maternal investigations should
include blood group and screen, testing for infectious
serologies and FMH, and detailed placental and fetal
ultrasound. If fetal blood is sampled, it should be
tested for blood group and screen, Hb/Hct, platelet and
reticulocyte count, hemolysis and viral infections. Rare
causes may be evaluated in conjunction with hematology
and genetics. FBS and IUTs can be performed by an
intravascular, intraperitoneal or intracardiac approach.
The intravascular approach is most common, preferably
via the PCI or IHV, rather than a free loop of cord, in
order to minimize the risk of fetal complications. Since
the introduction of FBS and IUT, fetal survival has been
reported at 85–90%3,88 and is approaching 97% for
RBC alloimmunization in experienced centers103 , with
excellent long-term neurodevelopmental outcome even in
the context of severe fetal hemolytic disease4 .
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