Ultrasound Obstet Gynecol 2017; 50: 145–153

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.17555

Editorial

Fetal anemia associated with fetal hemolysis, severe fetal anemia

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

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. 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 147

2–6 weeks after seroconversion19 but may occur up to Congenital leukemia and myeloproliferative disorders
10–12 weeks later20 . Ultrasound and MCA-PSV measure-
Congenital leukemia and occasionally transient myelo-
ments should be performed every 1–2 weeks for approx-
proliferative disorder may present prenatally with fetal
imately 10–12 weeks from maternal seroconversion14 ,
anemia, hepatosplenomegaly, polyhydramnios, placen-
with referral to a fetal medicine unit for FBS with or
tomegaly, hydrops and IUFD29 , most commonly asso-
without IUT if there is evidence of fetal anemia or hydrops.
ciated with trisomy 2129,30 .
Rarely, fetal anemia and hydrops can be caused by
other congenital infections, including cytomegalovirus
Placental/fetal tumors
(CMV)21 , syphilis22 and toxoplasmosis23 . Other ultra-
sonographic features of congenital infections may include Placental chorangiomas are the most common benign pla-
ascites, placentomegaly, hepatosplenomegaly, echogenic cental tumor and can be associated with fetal anemia31,32 ,
bowel, liver or intracranial calcifications, ventricu- secondary to fetal hemorrhage31 or consumption and
lomegaly and intrauterine growth restriction (IUGR). destruction of fetal RBCs within the narrow, thrombosed
vasculature of the chorangioma33 . Other complications
include NIH, polyhydramnios, preterm labor, IUGR and
Hemoglobinopathies, hemolytic anemias and bone-
pre-eclampsia, particularly if tumors are > 4 cm32 . Fetal
marrow-failure syndromes
sacroccygeal tumors can also result in fetal anemia, due
Alpha (α)-thalassemia is caused by the defective synthesis to hemorrhage within the tumor and RBC consumption,
of α-globin chains and is the most common cause of NIH with secondary high-output cardiac failure and NIH34 .
in Southeast Asia. The α-globin gene cluster consists of
four copies of the α-globin gene (αα/αα). α-thalassemia Fetomaternal hemorrhage (FMH)
can be classified into four types based on the number
of functional α-globin genes: silent carrier state (-α/αα), Traditionally, FMH has been defined as hemorrhage of
α- thalassemia trait (--/αα (cis) or -α/-α (trans)), Hb H ≥ 30 mL fetal blood into the maternal circulation, as this
disease (--/-α) and α-thalassemia major (--/--) (Hb Bart’s is the volume of Rh-positive whole fetal blood that is
or homozygous α-thalassemia). If both parents carry the covered by a standard 300-μg dose of RhIG to prevent
cis deletion (--/αα), the inheritance risk for α-thalassemia alloimmunization35 . Large or massive FMH has been
major is 25%. Fetuses with homozygous α-thalassemia defined as blood loss of 80–150 mL36 or > 20 mL/kg37 ,
cannot produce normal fetal Hb (α2 γ2 ), instead producing however, there is no fixed volume above which fetal mor-
Hb Bart’s (γ4 ). Clinical features include: cardiomegaly, bidity or mortality will result unequivocally. Although
ascites, hydrops, IUGR, limb defects24 , intrauterine fetal the majority of FMHs remain unexplained35 , risk
death (IUFD) and neonatal death (NND)25–27 . Given the factors include: external cephalic version38 , abdominal
severe impairment in tissue oxygen delivery, the sequelae trauma39 , placental abruption, placenta previa, IUFD,
of fetal anemia and hydrops may occur at higher Hb Cesarean section, manual removal of the placenta and
values than seen with RBC alloimmunization, making amniocentesis35 .
MCA-PSV Doppler less predictive of disease severity. Massive FMH with fetal hydrops at 26–28 weeks
Maternal complications may include ‘mirror’ syndrome has been managed with serial IUTs; however, outcomes
and antepartum hemorrhage25 . are variable, ranging from resolution of hydrops and
Prenatal diagnosis is established by DNA analysis via live birth40 to IUFD41 . Whether to expedite delivery or
chorionic villus sampling performed after 10 gestational perform an IUT will depend on GA, antenatal test results
weeks or amniocentesis after 15 weeks. Alternatively, and availability of expertise.
serial sonographic evaluation for cardiomegaly and
Monochorionic complications: twin–twin transfusion
placental thickness can be used as a screening tool in early
syndrome (TTTS), twin anemia–polycythemia sequence
pregnancy. The sensitivity and specificity of placental
(TAPS) and cotwin demise
thickness for detection of α-thalassemia major were
72% and 97%, respectively, before 12 weeks and 95% Twin–twin transfusion syndrome (TTTS) and twin
and 97%, respectively, after 12 weeks28 . Using a car- anemia–polycythemia sequence (TAPS) are chronic forms
diothoracic ratio (CTR) ≥ 0.5 to estimate cardiomegaly, of fetofetal transfusion42 . TTTS complicates up to 15% of
sensitivity and specificity were 100% at 12–13 weeks26 . monochorionic diamniotic (MCDA) twin pregnancies and
When the predictive value of CTR, MCA-PSV and pathogenesis is related to unbalanced blood flow through
placental thickness were compared, CTR was found to placental vascular anastomoses43 . A gradual blood-flow
be superior, and sensitivity at 12–15 weeks was further shift develops, resulting in oliguric oligohydramnios in
increased by addition of MCA-PSV measurement27 . the donor and polyuric polyhydramnios and volume
Historically, fetal α-thalassemia major was considered overload in the recipient43 , potentially leading to hydrops
to be a uniformly lethal condition, but, with the advent secondary to right ventricular dysfunction44 . A large
of IUT, increasing numbers of live births have been intertwin hemoglobin difference is not generally seen,
reported24 . However, in the absence of curative therapy, unless there is coexisting TAPS.
prenatal treatment raises ethical dilemmas and requires TAPS is characterized by a Hb discordance in MCDA
detailed counseling from a multidisciplinary team. twins in the absence of the oligopolyhydramnios sequence

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2017; 50: 145–153.
148 Abbasi et al.

seen with TTTS, and occurs when there are only a few, tiny peak is measured, with the angle of insonation as close as
(< 1 mm), unidirectional arteriovenous vascular anasto- possible to 0◦ , and always < 30◦ (Figure 3). Higher inter-
moses, with sparse or absent compensatory arterioarterial and intraobserver variability results from angle correction
anastomoses45 . TAPS may occur spontaneously in 3–5% and sampling of more distal regions of the MCA56 . The
of MCDA twins, usually presenting after 26 weeks’ ges- fetus should be quiescent, as heart-rate accelerations and
tation (Figure 2), or in 2–13% of TTTS cases, following movement can alter measurements57 . Other factors that
incomplete laser ablation of placental anastomoses45 . may influence MCA-PSV include: gender, cardiac status,
Cotwin demise may result in an acute hemodynamic uterine contractions, fetal behavioral state58 , advanced
imbalance, due to a massive transfer of blood from the GA59 and previous IUTs60 . Elevated MCA-PSVs may also
survivor to the dead twin via the placental anastomoses in be seen in abnormal placentation and IUGR, reflecting
monochorionic placentae, causing anemia, neurological cerebral autoregulation in response to hypoxemia and
handicap or death of the remaining twin46 . Although IUT hypercapnia61 . These factors, in addition to insufficient
can correct the anemia, whether or not it impacts on
neonatal or neurodevelopmental outcome is unknown.

Investigation of suspected fetal anemia (Table 3)

B
Twin
Recommended investigations for evaluation of suspected
fetal anemia are listed in Table 3. Referral to a maternal
A
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 , (b) 100
1.5 MoM
splenomegaly (spleen perimeter > 2SD)49 and Doppler
measurements of mean blood velocity in the fetal aorta50 90
and splenic artery PSV51 were also found to correlate 80
with fetal anemia. When Oepkes et al.52 compared
fetal liver length, spleen perimeter, umbilical vein (UV) 70
diameter, placental thickness and UV and aortic flow 1.0 MoM
MCA-PSV (cm/s)

velocities, only Doppler parameters were predictive of 60

severe anemia in non-hydropic fetuses. 50

40
Middle cerebral artery (MCA) Doppler studies and pre-
diction of fetal anemia. Initial studies in fetal lambs, 30
measuring blood flow in relation to hematocrit (Hct),
demonstrated compensatory increased flow to the brain, 20
heart and adrenals to maintain stable oxygen deliv-
10
ery across a range of Hct53 ; this was also replicated
in humans54 . An inverse relationship was also noted 0
between fetal Hct and MCA-PSV55 . Subsequently, Mari 14 18 22 26 30 34 38
et al.1 demonstrated that MCA-PSV > 1.50 MoM in Gestational age (weeks)
non-hydropic fetuses at risk of RBC alloimmunization
could detect all cases of moderate to severe anemia, with Figure 2 (a) Placental ultrasound in a case of spontaneous twin
anemia–polycythemia sequence (TAPS) at 27 + 6 weeks’ gestation,
a false-positive rate of 12%. Oepkes et al.2 thereafter con- demonstrating discrepant placental echogenicity, with A represent-
firmed the superiority of MCA-PSV over amniotic-fluid ing the more echogenic territory of the anemic, donor twin and B
OD450 , making serial amniocenteses for fetal anemia the relatively echolucent placenta of the polycythemic recipient
screening essentially obsolete. 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,
Obtaining MCA-PSV measurements: technical aspects. with Twin A/donor twin ( ) having MCA-PSV > 1.5 multiples of
An axial section of the brain, including thalami, cavum the median (MoM) (anemic) and Twin B/recipient twin ( ) having
septi pellucidi and greater wing of sphenoid, with the circle MCA-PSV < 0.8 MoM (polycythemic) by approximately 28 weeks.
Arrow indicates timing of fetal blood sampling and intrauterine
of Willis identified by color Doppler, should be obtained1 . transfusion for Twin A (hemoglobin (Hb), 5.6 g/L) and partial
The MCA closest to the probe is sampled at or near its exchange transfusion for Twin B (Hb, 21 g/L), which was followed
origin from the internal carotid artery. The waveform by almost immediate resolution of MCA-PSV discordance.

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. 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

MCA-PSV > 1.5 MoM1
Placentomegaly, hydrops, ascites97 , enlarged fetal liver48 and spleen49
Specific clinical conditions
α-thalassemia major 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
Congenital infections Placentomegaly, hepatosplenomegaly, echogenic bowel, liver calcifications, ventriculomegaly, intracranial
calcifications, growth restriction
Complications of MC twins
TAPS 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

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150 Abbasi et al.

to a Hct of 75–80%, are used64 . Autologous washed perform > 70% of IUTs via the IHV and find this route
maternal blood can also be used for IUT once the particularly useful in multiple pregnancies or at advanced
maternal Hb level is > 120 g/L, which eliminates the gestational ages when the placenta is posterior.
risk of sensitization to new RBC antigens in random
donor blood. Platelets should be available if PB19 or Fetal paralytic agents
CMV are suspected, or in the presence of hydrops
Fetal paralytic agents, such as rocuronium, atracurium
or hepatosplenomegaly. Coexistent severe thrombocy-
and vecuronium, are particularly useful if a prolonged or
topenia has been reported in hydropic alloimmunized
difficult procedure is anticipated74 . Paralysis may reduce
pregnancies65 and hydropic fetuses with PB1966 .
the risk of cord complications, such as arterial spasm,
When a previous pregnancy has been complicated
hematoma or excessive bleeding, all of which can result
by HDFN, titers are less reliable predictors of severe
from needle dislodgement with fetal movement75 .
fetal anemia and MCA-PSV should be followed serially
instead. Intravenous immune globulin (IVIG)67,68 and
Volume of transfusion
plasmapheresis68 have also been used in some cases with
a history of previous early mid-trimester loss due to The volume of transfused blood depends on the estimated
RBC alloimmunization or markedly elevated titers, with fetal weight, donor and fetal pretransfusion and target
a reported reduction in perinatal mortality and delay Hb/Hct, presence of hydrops and fetoplacental blood
of the first IUT by 1.5 weeks67 . In contrast, one small volume79 . Some authors caution against transfusing,
randomized controlled trial found no additional benefit during a single IUT, volumes > 20 mL/kg, corresponding
of IVIG when combined with IUT, compared with IUT to approximately 20% of the fetoplacental blood volume,
alone, in cases of severe RhD alloimmunization69 . as this may be associated with increased fetal mortality,
related to circulatory overload80 . In our experience, the
IUT approaches and procedure-related (PR) risks following formulae provide fairly reliable estimates of the
volume of blood needed for IUT:
An intravascular approach, via the UV at the placental
cord insertion (PCI), the intrahepatic vein (IHV) or a • intravascular transfusion (IVT) = ((target Hb – fetal Hb)
free loop of cord, has largely replaced intraperitoneal × fetoplacental blood volume) / (donor Hb – target Hb);
transfusion (IPT), first described in 196370 . IPT may • intraperitoneal transfusion (IPT) = (GA in weeks – 20)
still have a role in very early pregnancy, as higher fetal × 10 mL.
loss rates are associated with intravascular transfusion at
GA < 22 weeks71 . Rarely, an intracardiac approach may To avoid excessive transfusion and polycythemia,
be used. In anatomically normal fetuses, the PR loss rate approximately two-thirds of the calculated volume
with IUT is approximately 1%72 ; this rate may vary, how- should be transfused, followed by FBS to determine
ever, with GA71 , indication and operator experience73 . the final volume needed for IUT. Our target Hb level
In the presence of structural abnormalities or hydrops, is 17 g/L, in non-hydropic fetuses.
loss rates are reportedly 7% and 25%, respectively72 .
PR risks include bleeding from the needle puncture site Fetal anemia and hydrops fetalis: special considerations
and fetal heart-rate decelerations, which are usually for IUT
self-limiting and have been reported in up to 20–30% Several studies have demonstrated worse outcomes
and 5–10% of procedures, respectively74 . In one series following IUT in hydropic compared with non-hydropic
evaluating outcomes with IUT, performed mostly using fetuses75,81,82 , possibly due to their reduced cardiac
a PCI approach, 3.1% of procedures had complications, reserve and increased susceptibility to volume
including preterm prelabor rupture of membranes, overload80,81 . In a review of 80 fetuses that were
infection, emergency Cesarean section, and IUFD or hydropic secondary to RBC alloimmunization, which
NND, with an overall loss rate of 1.6% per procedure75 . underwent IUT, the survival rate overall was 78% (98%
Preterm birth < 37 weeks was found to occur in 3.5% in mild and 55% in severe hydrops)82 . Reversal of
of cases and only in patients requiring multiple (more hydrops occurred in 65% of cases overall, and only 40%
than three) IUTs76 . Fetal bradycardia and abandoned of persistently hydropic fetuses survived. In practice, we
procedures were more common when a free loop of cord do not raise the Hb/Hct more than four-fold in severely
was targeted compared with IHV or PCI approaches76 . anemic, hydropic fetuses during a single IUT, as this
Although IHV and PCI approaches are preferred over has been found to be a predictor of fetal loss81 . Instead,
a free loop of cord, superiority of either IHV or PCI has we will perform a second procedure within 1–2 days if
not been demonstrated consistently75,77,78 . Ultimately, the necessary to reach the target Hb/Hct.
choice depends on operator preference and experience.
Advantages of the IHV approach include avoidance of Management after first IUT
arterial puncture and secondary vasospasm and cord
tamponade, less FMH and success rates in the region There are no clear guidelines regarding fetal monitoring
of 90%3 . Furthermore, if intraperitoneal bleeding occurs, following IUT; however, weekly assessment of fetal
it is usually self-limiting and functions as an IPT. We wellbeing and MCA-PSV Doppler is reasonable.

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2017; 50: 145–153.
Editorial 151

Serial IUTs hyperbilirubinemia requiring phototherapy or exchange

transfusion, as well as thrombocytopenia, anemia and
Timing of subsequent IUTs is debatable, particularly since cholestasis89 . In the LOTUS (LOng-Term follow-up
the use of MCA-PSV to predict fetal anemia becomes less after intra-Uterine transfusionS) study4 , which evaluated
reliable after several IUTs, with false-positive rates of short- and long-term neurodevelopmental outcome
14%, 37% and 90% for the detection of 95% of severely after IUT for alloimmunization, 17.5% of infants were
anemic fetuses following the first, second and third IUT, delivered < 35 weeks, with most delivering between 32
respectively60 . As the rise in MCA-PSV in anemic fetuses and 35 weeks. Severe neonatal morbidity included: respi-
likely reflects a hyperdynamic circulation due to decreased
ratory distress syndrome (2.4%), necrotizing enterocolitis
blood viscosity83 , the reduced accuracy of MCA-PSV
(1.0%), sepsis (5.8%), perinatal asphyxia (3.8%) and
following IUT may be related to altered properties of fetal
severe cerebral injury (1.7%). When outcome of neonates
blood, when admixed with adult blood cells, which have
delivered ≥ 36 weeks was compared between those
a lower viscosity60 . Furthermore, due to the replacement
treated with and without IUT, phototherapy was required
of fetal RBCs with adult RBCs following IUT, the
for shorter periods in those who had been transfused
concentration of fetal Hb, which has a higher affinity
in utero; however, the exchange transfusion rate was
for oxygen84 , is reduced, thus lowering the total arterial
similar in both groups and was required in nearly 70%
oxygen concentration in the fetal circulation85 . Some
of cases90 .
authors have reported higher MCA-PSV thresholds for the
Late or ‘hyporegenerative’ anemia presenting up to
diagnosis of severe anemia following IUT, speculating that
3 months after birth has been described in association
this may be explained by a compensatory rise in cerebral
with HDFN91 , with nearly 30% of these infants requiring
blood flow, related to lower total oxygen carrying capacity
a RBC ‘top-up’ transfusion78 . Reticulocyte count at birth
and oxygen tissue delivery of transfused blood and the
is inversely related to the number of top-up transfusions
lower viscosity of adult RBCs85 . However, established
required, suggesting that suppression of erythropoiesis is
cut-offs for diagnosis of fetal anemia following serial
the primary underlying mechanism90 .
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
Long-term outcome following IUT
0.2 g/L/day Hb decline for the first, second and third IUT
intervals, respectively60 , or a decline of 1%/day in fetal Nearly 25% of alloimmunized mothers form additional
Hct86,87 . Others have suggested transfusing empirically antibodies following IUT, despite utilization of Rh- and
at 10 days, 2 weeks and 3 weeks, for second, third and Kell-matched blood products92 .
subsequent IUTs, respectively10 . Neurodevelopmental outcome following IUT was nor-
mal in 95% of children assessed at a median age of
Special considerations for management of TAPS 8.2 years in the LOTUS study4 . Cerebral palsy, severe
developmental delay and bilateral deafness were detected
The ideal treatment of TAPS is laser ablation of the in 2%, 3% and 1% of children, respectively. Fac-
placental vascular anastomoses. However, if this is not tors independently associated with neurodevelopmental
possible, another option is to transfuse the anemic donor impairment included severe hydrops, number of IUTs and
twin. This can result in worsening polycythemia for the severe neonatal morbidity.
recipient, especially with serial transfusions; this can be Outcome in hydropic alloimmunized fetuses following
counteracted by hemodilution using partial exchange IUT is variable. In the LOTUS study4 , severe fetal hydrops
transfusions45 . was present in nearly 30% of children with, vs 6% of
children without, neurodevelopmental impairment. When
Timing of delivery Harper et al.93 evaluated long-term neurodevelopmental
outcome in 18 hydropic fetuses, they found that death
The therapeutic goal in managing RBC-alloimmunized or major morbidity occurred in 22%. Of 16 hydropic
pregnancies should be to enable delivery, close to term, survivors, 13 were normal neurodevelopmentally at a
of a healthy neonate who requires neither exchange mean age of 10 years, and those with sequelae had other
transfusion nor prolonged phototherapy. In stable contributing factors, particularly prematurity. Long-term
pregnancies that have undergone three or more IUTs, a outcome in hydropic fetuses secondary to PB19 infection
final IUT at 34–35 weeks, with delivery 3–4 weeks later, is less favorable, with a survival rate of 67–84%79 ,
is reasonable10,79 , unless other indications for delivery suggesting that the virus may induce neural toxicity
arise prior to this. directly94 . Nagel et al.95 evaluated 24 fetuses that were
hydropic due to PB19 and which underwent IUT; of 16
Short-term outcome following IUT survivors, one third demonstrated delayed psychomotor
development. In another series, evaluating 44 hydropic
Neonatal survival overall, in the era of IUT, is 84%; 70% fetuses followed for a median of 5 years, survival was
in hydropic and 94% in non-hydropic fetuses88 . The 73% and severe neurodevelopmental impairment was
main short-term neonatal complications are related to noted in three children94 .

Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2017; 50: 145–153.
152 Abbasi et al.

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