Chapter 18. Fetal Disorders
BS. Nguyễn Hồng Anh
Fetal disorders may be acquired—such as alloimmunization;
may be genetic—congenital adrenal hyperplasia; or may be
sporadic—like many structural malormations. Tis chapter
reviews etal anemia and thrombocytopenia and immune and
nonimmune etal hydrops. Hydrops is perhaps the quintessential etal disorder, as it can be a maniestation o severe illness
rom a wide variety o etiologies. Fetal structural malormations
are reviewed in Chapter 15, genetic abnormalities in Chapters
16 and 17, and conditions amenable to medical or surgical etal
therapy in Chapter 19. Because congenital inections arise as a
result o maternal inection or colonization, they are discussed
in Chapters 67 and 68.
FETAL ANEMIA
Anemia may result rom alloimmunization, inection, genetic
disorders, or etomaternal hemorrhage. Red cell alloimmunization results rom transplacental passage o maternal antibodies
that destroy etal red cells. Alloimmunization leads to overproduction o immature etal and neonatal red cells—erythroblastosis
etalis—a condition now reerred to as hemolytic disease o the
etus and newborn (HDFN). Congenital inections are also associated with etal anemia, particularly parvovirus B19, discussed
in Chapter 67 (p. 1191). In Southeast Asian populations,
α0-thalassemia is a common cause o severe anemia and nonimmune hydrops. Rare genetic causes o anemia include red cell
production disorders—such as Diamond-Blackan anemia and
Fanconi anemia; red cell enzymopathies—glucose-6-phosphate
dehydrogenase deciency and pyruvate kinase deciency; red
cell structural abnormalities—hereditary spherocytosis and
elliptocytosis; lysosomal storage diseases—Gaucher disease,
Niemann-Pick, and mucopolysaccharidosis VII; and myeloprolierative disorders—leukemias. Fetomaternal hemorrhage
is discussed on page 357. Fetal anemia is typically identied
through Doppler evaluation o the etal middle cerebral artery
(MCA) peak systolic velocity (p. 355).
Progressive etal anemia rom any cause leads to heart ailure,
hydrops etalis, and ultimately death. reatment with intrauterine transusions can be liesaving. Severely anemic etuses
transused in utero have survival rates exceeding 90 percent,
and even in cases o hydrops etalis, survival rates approach 80
percent (Lindenberg, 2013; Mizuuchi, 2021; Zwiers, 2017).
■ Red Cell Alloimmunization
Currently, 36 dierent blood group systems and 360 erythrocyte antigens are recognized by the International Society
o Blood ransusion (Storry, 2019). Blood banks routinely
screen or erythrocyte antigens. Some are immunologically and
genetically important, but many are rare and o little clinical signicance. An individual who lacks a specic erythrocyte
antigen may produce antibodies against it when exposed to
that antigen. Such antibodies can prove harmul i an individual receives an incompatible blood transusion. During
pregnancy, these antibodies may cross the placenta and lyse
etal red cells that contain the associated antigens, resulting
in anemia.
Te etus typically inherits at least one erythrocyte antigen
rom the ather that is lacking in the mother. Te pregnant
woman may become sensitized i enough etal red cells reach
her circulation to elicit an immune response. Importantly,
alloimmunization is uncommon or the ollowing reasons:
(1) low prevalence o incompatible erythrocyte antigens; (2)
insucient transplacental passage o etal antigens and maternal antibodies; (3) maternal-etal ABO incompatibility, which
leads to rapid clearance o etal erythrocytes beore they elicit
an immune response; (4) variable antigenicity; and (5) variable
maternal immune response to the antigen.
Te prevalence o red cell alloimmunization in pregnancy
approximates 1 percent (Bollason, 2017; Koelewijn, 2008).
Most cases o severe etal anemia requiring antenatal transusion are attributable to anti-D, anti-Kell, anti-c, or anti-E alloimmunization (de Haas, 2015).
Maternal blood type and antibody screen are routinely
assessed at the rst prenatal visit. Unbound antibodies in maternal serum are detected with an indirect Coombs test (Chap. 10,
p. 178). I the result is positive, the specic antibodies are
identied; their immunoglobulin subtype is determined as
either immunoglobulin G (IgG) or M (IgM); and the titer is
quantied. Only IgG antibodies are concerning, because IgM
antibodies do not cross the placenta. Selected antibodies and
their potential to cause etal hemolytic anemia are listed in
Table 18-1. Te critical titer is the level at which signicant
etal anemia may develop. It may vary according to antibody
and laboratory but is usually between 1:8 and 1:32. I the laboratory’s critical titer threshold or anti-D antibodies is 1:16, a
titer ≥1:16 indicates the possibility o severe hemolytic disease.
An important exception is Kell sensitization, which is discussed
on page 354.
CDE (Rh) Blood Group Incompatibility
Te CDE system includes ve erythrocyte antigens: C, c, D,
E, and e. Tere is no “d” antigen, and D-negativity is dened
as the absence o the D antigen. Although most people are D
positive or negative, more than 200 D antigen variants exist
(Daniels, 2013). Te CDE group was ormerly termed Rh or
rhesus, due to a misconception that red cells rom rhesus monkeys expressed these human antigens. In transusion medicine,
“rhesus” is no longer used (Sandler, 2017).
CDE antigens are clinically important. D-negative individuals may become sensitized ater a single exposure to as little as
0.1 mL o etal erythrocytes (Bowman, 1988). Te two responsible genes—RHD and RHCE—are located on the short arm o
chromosome 1 and are inherited together, independent o other
blood group genes. Antigen positivity varies according to race
and ethnicity. Nearly 85 percent o non-Hispanic white Americans are D-positive, as are approximately 90 percent o Native
Americans, 93 percent o Arican Americans and Hispanic
Americans, and 99 percent o Asian Americans (Garratty, 2004).
TABLE 18-1. Selected Red Cell Antigens and Their Relationship to Fetal
Hemolytic Disease
Blood Group
System Antigens Fetal Hemolysis Potential
CDE (Rh) D, c Severe disease risk
E, Bea, Ce, Cw, Cx, ce,
Dw, Evans, e, G, Goa7,
Hr, Hro, JAL, HOFM,
LOCR, Riv, Rh29, Rh32,
Rh42, Rh46, STEM, Tar
Severe disease infrequent, mild disease risk
Kell K Severe disease risk
k, Kpa, Kpb, K11, K22
Ku, Jsa, Jsb, Ula
Severe disease infrequent, mild disease risk
Duffy Fya Severe disease infrequent, mild disease risk
Fyb Not associated with fetal hemolytic disease
Kidd Jka Severe disease infrequent, mild disease risk
Jkb, Jk3 Mild disease possible
MNS M, N, S, s, U, Mta, Ena,
Far, Hil, Hut, Mia, Mit,
Mut, Mur, Mv, sD, Vw
Severe disease infrequent, mild disease risk
Colton Coa, Co3 Severe disease infrequent, mild disease risk
Diego Dia, Dib, Wra, Wrb Severe disease infrequent, mild disease risk
Dombrock Doa, Gya, Hy, Joa Mild disease possible
Gerbich Ge2, Ge3, Ge4, Lsa Mild disease possible
Scianna Sc2 Mild disease possible
I I, i Not associated with fetal hemolytic disease
Lewis Lea, Leb Not associated with fetal hemolytic disease
Data from de Haas, 2015; Moise, 2008; Weinstein, 1982.354 The Fetal Patient
Section 6
Te prevalence o D alloimmunization complicating pregnancy ranges rom 0.5 to 0.9 percent (Koelewijn, 2008; Martin, 2005). Without anti-D immune globulin prophylaxis, a D-negative woman delivered o a D-positive, ABO-compatible newborn has a 16-percent likelihood o developing alloimmunization. wo percent will become sensitized by the time o delivery, 7 percent by 6 months postpartum, and the remaining 7 percent will be “sensibilized”—producing detectable antibodies only in a subsequent pregnancy (Bowman, 1985). I there is ABO incompatibility, the D alloimmunization risk decreases to 2 percent because erythrocyte destruction o incompatible cells limits sensitization (Bowman, 2006). D sensitization may also occur ollowing rst-trimester pregnancy complications, prenatal diagnostic procedures, and maternal trauma (Table 18-2).
Te C, c, E, and e antigens have lower immunogenicity than the D antigen but can cause hemolytic disease. Sensitization to E, c, and C antigens complicates approximately 0.3 percent o pregnancies in screening studies and accounts or about 30 percent o red cell alloimmunization cases (Howard, 1998; Koelewijn, 2008). Anti-E alloimmunization is the most common, but the need or etal or neonatal transusions is greater with anti-c alloimmunization than with anti-E or anti-C (de Haas, 2015; Hackney, 2004; Koelewijn, 2008).
The Grandmother Effect. In virtually all pregnancies, small amounts o maternal blood enter the etal circulation. Polymerase
chain reaction (PCR) has identied maternal D-positive DNA
in peripheral blood rom preterm and ull-term D-negative newborns (Lazar, 2006). Tus, a D-negative emale etus exposed
to maternal D-positive red cells might develop sensitization,
and later might produce anti-D antibodies beore or during
pregnancy. Tis mechanism is called the grandmother efect
because the etus in the current pregnancy is jeopardized by
maternal antibodies that were initially provoked by his or her
grandmother’s erythrocytes.
Alloimmunization to Minor Antigens
Because routine administration o anti-D immune globulin prevents anti-D alloimmunization, proportionately more cases o
hemolytic disease are caused by red cell antigens other than D
(American College o Obstetricians and Gynecologists, 2019a;
Koelewijn, 2008). Tese are also known as minor antigens.
Kell antigens are among the most requent. Other antigens
with potential to cause severe alloimmunization include Duy
group A—Fya, MNS, and Kidd—Jka (de Hass, 2015; Moise,
2008). In most cases, sensitization to a minor antigen results
rom an incompatible blood transusion. However, i an IgG
red cell antibody is detected and there is any doubt as to its
signicance, the pregnancy should be evaluated or hemolytic
disease.
Only a ew blood group antigens pose no etal risk. Lewis
antibodies—Lea and Leb—are cold agglutinins, as are I antibodies. Tey are predominantly IgM and are not expressed on
etal red cells (American College o Obstetricians and Gynecologists, 2019a). Another antibody that does not cause etal
hemolysis is Duy group B—Fyb.
Kell Alloimmunization. Approximately 90 percent o nonHispanic white Americans and up to 98 percent o Arican
Americans are Kell antigen negative. Kell type is not routinely
determined. ransusion history is important, as nearly 90
percent o Kell sensitization cases result rom transusion with
Kell-positive blood.
Kell sensitization may develop more rapidly and may be
more severe than with sensitization to D and other blood group
antigens. Tis is because Kell antibodies attach to erythrocyte
precursors in the etal bone marrow and thereby impair the
normal hemopoietic response to anemia. With ewer erythrocytes produced, there is less hemolysis, and thus severe anemia
may not be predicted by the maternal Kell antibody titer.
Slootweg and colleagues (2018) reviewed 93 pregnancies
with Kell alloimmunization in which the etus was conrmed
to be Kell-positive. Tey ound that a titer o 1:4 had 100
percent sensitivity, 27 percent specicity, and 60 percent positive predictive value or transusion requirement in the etal or
neonatal period. More than 50 percent o Kell antigen–positive etuses ultimately needed transusions. Given the potential
or severe anemia, the American College o Obstetricians and
Gynecologists (2019a) has recommended that antibody titers
not be used to monitor Kell-sensitized pregnancies.
ABO Blood Group Incompatibility
Incompatibility or the major blood group antigens A and B
is the most common cause o hemolytic disease in newborns,
but it does not cause appreciable hemolysis in the etus. Tis is
because most anti-A and anti-B antibodies are IgM types and
do not cross the placenta. Also, etal red cells have ewer A and
B antigenic sites than adult cells and are thus less immunogenic. Approximately 20 percent o newborns have ABO blood
TABLE 18-2. Causes of Fetomaternal Hemorrhage
group incompatibility, although only 5 percent are aected
clinically. In such cases, the resulting anemia is typically mild.
Te condition diers rom CDE incompatibility in several
respects. First, ABO incompatibility is oten seen in rstborn
neonates, unlike sensitization to other blood group antigens.
Tis is because most group O women have developed anti-A
and anti-B isoagglutinins beore pregnancy rom exposure to
bacteria displaying similar antigens. Additionally, ABO alloimmunization rarely becomes more severe in successive pregnancies. Fetal surveillance and early delivery are not indicated in
pregnancies with prior ABO incompatibility. Postnatally however, neonates are evaluated or hyperbilirubinemia, which may
require treatment with phototherapy or occasionally transusion (Chap. 33, p. 606).
■ Management of the Alloimmunized
Pregnancy
O etuses rom D-alloimmunized pregnancies, 25 to 30 percent will have mild to moderate hemolytic anemia, and up to
25 percent have anemia severe enough to cause hydrops (annirandorn, 1990). I alloimmunization is detected and the titer
is below the critical value, the titer is generally repeated every
4 weeks or the duration o the pregnancy (American College
o Obstetricians and Gynecologists, 2019a). In any pregnancy
in which the antibody titer has reached a critical value, there is
no benet to repeating the titer. Te pregnancy is at risk even
i the titer drops, and urther evaluation is required. Similarly,
i a prior pregnancy was complicated by alloimmunization, the
pregnancy is considered at risk regardless o titer.
Fetal Risk Assessment
Te presence o anti-D antibodies refects maternal sensitization but does not indicate whether the etus is D-positive or
D-negative. Up to 40 percent o D-negative pregnant women
carry a D-negative etus. I a woman is sensitized rom a prior
pregnancy, her antibody titer may rise during the current pregnancy even i the current etus is D-negative because o an
amnestic response. In a non-Hispanic white couple in which the
woman is D-negative, there is an 85-percent chance that the
man is D-positive. However, there is a 60-percent likelihood
that he is heterozygous at the D-locus, and only hal o his
children will be at risk or hemolytic disease.
Initial evaluation o alloimmunization begins with determining the paternal erythrocyte antigen status. Provided that
paternity is certain, i the ather is negative or the red cell antigen to which the mother is sensitized, the pregnancy is not at
risk. A prior blood transusion may be the cause o alloimmunization to a red cell antigen other than D. In a D-alloimmunized
pregnancy in which the ather is D-positive, it is helpul to
determine paternal zygosity or the D antigen using DNAbased analysis. I the ather is heterozygous—or i paternity is
not known—the woman should be oered assessment o etal
genotype. raditionally, this was done with amniocentesis and
PCR testing o uncultured amniocytes, which has a positive
predictive value o 100 percent and negative predictive value o
approximately 97 percent (Van den Veyver, 1996). Fetal testing or other antigens—such as E/e, C/c, Duy, Kell, Kidd,
and M/N—also is available with this method. Chorionic villus sampling is not recommended because o greater risk or
etomaternal hemorrhage and subsequent worsening o alloimmunization (American College o Obstetricians and Gynecologists, 2019a).
Noninvasive etal D genotyping has been perormed using
cell-ree DNA (cDNA) rom maternal plasma (Chap. 17, p.
335). Te reported sensitivity exceeds 99 percent, the speci-
city exceeds 95 percent, and positive or negative predictive
values are similarly very high (Johnson, 2017; Moise, 2016;
Pazourkova, 2021). Fetal D genotyping with cDNA is routinely used in parts o Europe but is not yet a widely used
clinical tool in the United States (American College o Obstetricians and Gynecologists, 2019a). wo potential indications
or cDNA use in D-negative pregnant women are: (1) in the
setting o D alloimmunization, testing can identiy etuses who
are also D-negative and do not require anemia surveillance, and
(2) in women without D alloimmunization, anti-D immune
globulin might be withheld i the etus is D negative. In the
case o the latter, the American College o Obstetricians and
Gynecologists (2019b) does not recommend routine cDNA
screening in D-negative pregnancies until it has been demonstrated to be cost-eective.
Management o the alloimmunized pregnancy typically consists o maternal antibody titer surveillance ollowed by ultrasound monitoring o the etal MCA peak systolic velocity i
a critical antibody titer is reached. As noted earlier (p. 354),
pregnancies with Kell alloimmunization oten receive ultrasound
surveillance regardless o titer. Fetal blood sampling is generally
perormed i the MCA peak systolic velocity exceeds the threshold or severe anemia, with plan or concurrent intrauterine
transusion as needed. Spectrophotometric analysis o amnionic
fuid bilirubin, also known as the ΔOD450 test, is no longer recommended (Society or Maternal-Fetal Medicine, 2015a).
Recent eorts have ocused on use o maternal intravenous
immunoglobulin (IVIG) therapy to postpone the initial intrauterine transusion to beyond 20 weeks in severely aected
pregnancies (Maisonneuve, 2021). Its mechanism o action is
unclear, but IVIG therapy has been reported to delay need or
transusion by an average o 3 weeks and to lower the risk or
hydrops (Zwiers, 2018).
Middle Cerebral Artery Doppler Velocimetry. Serial measurement o the peak systolic velocity o the etal MCA is the recommended test to detect etal anemia (Society or Maternal–Fetal
Medicine, 2015a). Te anemic etus shunts blood preerentially
to the brain to maintain adequate oxygenation. Te velocity rises
because o increased cardiac output and decreased blood viscosity. Measurement technique is discussed in Chapter 14 (p. 262).
In a landmark study, Mari and coworkers (2000) measured
the MCA peak systolic velocity serially in 111 etuses at risk
or anemia and in 265 normal control etuses. Te threshold
value o 1.5 multiples o the median (MoM) or gestational age
correctly identied all etuses with moderate or severe anemia.
Tis provided a sensitivity o 100 percent, with a alse-positive
rate o 12 percent.
MCA peak systolic velocity is ollowed serially, and values are plotted on a curve like the one shown in Figure 18-1.
I the velocity is between 1.0 and 1.5 MoM and the slope is
rising—such that the value is approaching 1.5 MoM—MCA
Doppler surveillance is generally perormed at least weekly.
Te alse-positive rate o MCA peak systolic velocity increases
signicantly beyond 34 weeks’ gestation and stems rom the
normal rise in cardiac output that develops at this gestational
age (Moise, 2008; Zimmerman, 2002). At Parkland Hospital,
MCA peak systolic velocity is not measured beyond 35 weeks,
but ultrasound evaluation or hydrops is perormed as needed.
Fetal Blood Transfusion
I the MCA peak systolic velocity exceeds 1.5 MoM or i
hydrops develops and anemia is the leading etiology, etal blood
sampling and intrauterine transusion should be considered.
Fetal transusion is typically perormed prior to 34 to 35 weeks’
gestation (Society or Maternal-Fetal Medicine, 2015a). Later
in gestation, the benets o transusion may be outweighed by
the risks o delaying delivery. ransusion is most commonly
intravascular. However, the umbilical vein may be too narrow
in the early second trimester to readily permit needle entry, and
severe hemolysis may necessitate intraperitoneal etal transusion. In the setting o hydrops, peritoneal absorption may be
impaired, and some preer to transuse into both the etal peritoneal cavity and umbilical vein.
ransusion is generally recommended only i the etal
hematocrit is <30 percent (Society or Maternal-Fetal Medicine, 2015a). I hydrops has developed, the hematocrit is usually 15 percent or lower. Te red cells transused are type O,
D-negative, cytomegalovirus-negative, packed to a hematocrit
o approximately 80 percent to prevent volume overload, irradiated to prevent etal grat-versus-host reaction, and leukocytepoor. Te etal–placental volume allows rapid inusion o a
relatively large quantity o blood. Beore transusion, a paralytic
agent such as vecuronium may be given to the etus to minimize movement. In a nonhydropic etus, the target hematocrit
is 40 to 50 percent. Te volume transused may be estimated
by multiplying the estimated etal weight in grams by 0.02 or
each 10-percent rise in hematocrit needed (Giannina, 1998). In
the severely anemic etus at 18 to 24 weeks’ gestation, a smaller
volume is transused initially, and another transusion may be
planned or approximately 2 days later. Subsequent transusions
take place every 2 to 4 weeks, depending on the hematocrit.
Te MCA peak systolic velocity threshold or severe anemia
is higher ollowing an initial transusion—1.70 MoM rather
than 1.50 MoM (Society or Maternal-Fetal Medicine, 2015a).
It is hypothesized that the change in threshold compensates
or the contribution o donor cells in the initial transusion,
because the donor cells are rom adults and have a smaller mean
corpuscular volume. Following transusion, the etal hematocrit
drops by approximately 1 percent per day. Te initial decline
may be more rapid i hydrops has developed.
Outcomes. Te overall survival rate approximates 95 percent
(Zwiers, 2017; Mizuuchi, 2021). Complications include etal
death in 2 percent, need or emergent cesarean delivery in 1 percent, and inection and preterm rupture o membranes in 0.3
percent each, respectively. Te stillbirth rate exceeds 15 percent
i transusion is required beore 20 weeks (Lindenberg, 2013;
Zwiers, 2017). For hydropic etuses, the neonatal survival rate
is about 80 percent (Emiroglu, 2020; Van Kamp, 2001). In
one series, 95 percent o neonates survived i hydrops resolved
ollowing intrauterine transusion compared with ewer than
40 percent i hydrops persisted (Van Kamp, 2001).
Lindenberg (2012) reviewed long-term outcomes ollowing intrauterine transusion in a cohort o more than 450
alloimmunized pregnancies. Alloimmunization was secondary
to anti-D in 80 percent, anti-Kell in 12 percent, and anti-c
in 5 percent. Approximately a ourth o aected etuses had
hydrops, and more than hal also required exchange transusion
in the neonatal period. Among nearly 300 children aged 2 to
17 years who participated in neurodevelopmental testing, ewer
than 5 percent had severe impairments.
■ Prevention of AntiD Alloimmunization
Anti-D immune globulin has been used or more than ve
decades to prevent D alloimmunization. Unortunately, 50
percent o women around the world who would benet rom
anti-D immune globulin do not receive it (Pegoraro, 2020).
In countries without access, up to 10 percent o D-negative
pregnancies are complicated by hemolytic disease o the etus
and newborn (Zipursky, 2015). With immunoprophylaxis,
however, the alloimmunization risk may be reduced to <0.2
percent. Despite long-standing and widespread use, its mechanism o action is not completely understood.
Fetomaternal hemorrhage at delivery accounts or as many
as 90 percent o alloimmunization cases. Routine postpartum
administration o anti-D immune globulin to at-risk pregnancies within 72 hours o delivery lowers the alloimmunization
rate by 90 percent (Bowman, 1985). Additionally, provision
o anti-D immune globulin at 28 weeks’ gestation reduces
the third-trimester alloimmunization rate rom approximately
2 percent to 0.1 percent (Bowman, 1988). Whenever there is
doubt whether to give anti-D immune globulin, it should be given.
I not needed, it will not cause harm, but ailure to provide it
when needed may have severe consequences.
0 16 18 20 22 24 26
Gestational age (week)
Peak systolic velocity in the
middle cerebral artery (cm/sec)
28 30 32 34 36 38 40
Fetus with severe anemia
Fetus without anemia or with mild anemia
120
100
80
60
40
20
0
140
FIGURE 18-1 Doppler measurements of the peak systolic velocity in the middle cerebral artery (MCA) in 165 fetuses at risk for severe anemia. The blue line indicates the median peak systolic velocity in normal pregnancies, and the red line shows 1.5 multiples of the median. (Reproduced with permission from Oepkes D, Seaward PG, Vandenbussche et al: Doppler ultrasonography versus amniocentesis to predict fetal anemia, N Engl J Med. 2006 Jul 13;355(2):156–164.)
Anti-D immune globulin is derived rom human plasma donated by individuals with high-titer anti-D immunoglobulin D antibodies. Formulations prepared by cold ethanol ractionation and ultraltration must be administered intramuscularly because they contain plasma proteins that could result in anaphylaxis i given intravenously. Formulations prepared using ion exchange chromatography may be administered either intramuscularly or intravenously, which is relevant when treating signicant etomaternal hemorrhage. Both preparation methods eectively remove viral particles, including hepatitis and human immunodeciency viruses. Depending on the preparation, the hal-lie o anti-D immune globulin ranges
rom 16 to 24 days, which is why it is given both in the third trimester and ollowing delivery. Te standard intramuscular dose o anti-D immune globulin—300 μg or 1500 IU—will protect the average-sized mother rom a etal hemorrhage o up to 30 mL o etal whole blood or 15 mL o etal red cells.
In the United States, anti-D immune globulin is given prophylactically to all D-negative, unsensitized women at approximately 28 weeks’ gestation, and a second dose is given ater delivery i the newborn is D-positive (American College o Obstetricians and Gynecologists, 2019b). Beore the 28-week dose o anti-D immune globulin, repeat antibody screening is recommended to identiy individuals who have become alloimmunized (American Academy o Pediatrics, 2017). Following delivery, anti-D immune globulin should be given within 72 hours. Recognizing that 40 percent o neonates born to
D-negative women are also D negative, administration o immune globulin is recommended only ater the newborn is conrmed to be D positive (American College o Obstetricians and Gynecologists, 2019b). I immune globulin is inadvertently not administered ollowing delivery, it should be given as soon as the omission is recognized, because there may be some protection up to 28 days postpartum (Bowman, 2006). Anti-D immune globulin is also administered ater pregnancy-related events that could result in sensitization (see able 18-2). In the rst trimester, smaller doses o 50 or 120 µg may be suitable, as discussed in Chapters 11 and 12 (p. 203 and 221).
Anti-D immune globulin may produce a weakly positive—1:1 to 1:4—indirect Coombs titer in the mother. Tis is harmless and should not be conused with development o alloimmunization. Additionally, as the body mass index increases above 27 to 40 kg/m2, serum antibody levels decrease by 30 to 60 percent and may be less protective (MacKenzie, 2006; Woeler, 2004).
D-negative women who receive other types o blood products— including platelet transusions and plasmapheresis—also are at risk o becoming sensitized, and this can be prevented with antiD immune globulin. Rarely, a small amount o antibody crosses the placenta and results in a weakly positive direct Coombs test in cord and inant blood. Despite this, passive immunization does not cause signicant etal or neonatal hemolysis. In 2 to 3 per 1000 pregnancies, the volume o etomaternal hemorrhage may exceed 30 mL o whole blood (American College o Obstetricians and Gynecologists, 2019b). A single dose o anti-D immune globulin would be insucient in such situations. I additional anti-D immune globulin is considered only
or women with risk actors such as those shown in able 18-2, hal o those who require additional immune globulin may be missed. For this reason, all D-negative women should be screened at delivery, typically with a rosette test, ollowed by quantitative testing i indicated (American College o Obstetricians and Gynecologists, 2019b).
Te rosette test is a qualitative test that identies whether etal D-positive cells are present in the circulation o a D-negative woman. A sample o maternal blood is mixed with anti-D antibodies that coat any D-positive etal cells present in the sample. Indicator red cells bearing the D-antigen are then added, and rosettes orm around the etal cells as the indicator cells attach to them by the antibodies. Tus, i rosettes are visualized, there are etal D-positive cells in that sample. In the setting o D incompatibility, or any time a large etomaternal hemorrhage is suspected—regardless o antigen status, a Kleihauer-Betke test or fow cytometry test are used. Tese are discussed on page 358.
Te dosage o anti-D immune globulin is calculated rom the estimated volume o the etal-to-maternal hemorrhage, as described on page 358. One 300-μg dose is given or each
15 mL o etal red cells or 30 mL o etal whole blood to be
neutralized. I using an intramuscular preparation o anti-D
immune globulin, no more than ve doses may be given in
a 24-hour period. I using an intravenous preparation, two
ampules—totaling 600 μg—may be given every 8 hours. A
positive indirect Coombs test or the presence o circulating etal
cells on a rosette test demonstrate that the dose was sucient.
Serological Weak D Phenotypes
Formerly called Du, these are the most common antigenic D
variants in the United States and Europe (American College
o Obstetricians and Gynecologists, 2019a). Serological weak
D phenotypes have been urther rened into two general categories using molecular analysis to complete RHD genotyping.
Molecular weak D phenotypes carry reduced numbers o intact
D antigens on the red cell surace. Partial D types have protein
deletions associated with abnormal D antigens that lack epitopes (Sandler, 2017).
Many individuals who test positive or weak D have weak D
phenotypes 1, 2, or 3. Tese phenotypes may be managed as i
D-positive. Te pregnancy is not considered at risk or alloimmunization, and thus anti-D immune globulin is not needed
(Sandler 2015, 2017). In contrast, individuals with partial
D antigens may be at risk or D-sensitization and do require
immune globulin. Molecular RHD genotyping has been suggested or pregnant women with weak D phenotype, but costbenet analysis o this strategy is presently lacking (American
College o Obstetricians and Gynecologists, 2019b). I molecular genetic testing has not been perormed in those with serologic
weak D phenotype, D immunoprophylaxis should be administered.
FETOMATERNAL HEMORRHAGE
A small amount o etomaternal bleeding likely occurs in all
pregnancies and may be sucient to provoke an antigen-antibody reaction in two thirds. As shown in Figure 18-2, the incidence increases with advancing gestation and with the volume
o etal blood in the maternal circulation (Choavaratana, 1997).358 The Fetal Patient
Section 6
Te prevalence o etomaternal bleeding o at least 30 mL is
estimated to be 3 events per 1000 pregnancies (Wylie, 2010).
Fortunately, rank hemorrhage is rare. In one series o more
than 30,000 pregnancies, etomaternal hemorrhage ≥150 mL
complicated 1 in 2800 births (de Almeida, 1994).
Selected causes o etomaternal hemorrhage are shown in
able 18-2. With signicant hemorrhage, the most common
presenting complaint is decreased etal movement (Bellussi,
2017; Wylie, 2010). A sinusoidal etal heart rate pattern is
inrequently seen but warrants immediate evaluation (Chap.
24, p. 451). Sonography may demonstrate elevated MCA peak
systolic velocity, and indeed this is reported to be the most
accurate predictor (Bellusi, 2017; Wylie, 2010). Hydrops is an
ominous nding. I the MCA peak systolic velocity is elevated
or hydrops is identied, urgent etal transusion or delivery
should be considered. In more than 80 percent o cases, no
etiology o the etomaternal hemorrhage is identied.
One limitation o quantitative tests or etal cells in the
maternal circulation is that they do not provide inormation
regarding the timing or chronicity o hemorrhage (Wylie,
2010). Anemia that develops gradually, as with alloimmunization, is generally better tolerated by the etus than acute anemia.
Chronic anemia may not produce etal heart rate abnormalities
until the etus is moribund. In contrast, signicant acute hemorrhage may result in proound etal neurological impairment
rom cerebral hypoperusion, ischemia, and inarction. In some
cases, etomaternal hemorrhage is identied during stillbirth
evaluation (Chap. 35, p. 325).
■ Hemorrhage Quantification
Estimating the volume o etomaternal hemorrhage is needed
to calculate the appropriate dose o anti-D immune globulin i
the woman is D-negative, and it may also infuence obstetrical
management. Te most commonly used quantitative test or
etal red cells in the maternal circulation is the acid elution or
Kleihauer-Betke (KB) test (Kleihauer, 1957). Fetal erythrocytes
contain hemoglobin F, which is more resistant to acid elution
than hemoglobin A. Following exposure to acid, only etal
hemoglobin remains. Tereore, ater staining, the etal erythrocytes appear red and adult erythrocytes appear as “ghosts”
(Fig. 18-3). Te etal cells are then counted and expressed as
a percentage o adult cells. Te etal blood volume involved in
the etomaternal hemorrhage may be calculated using the ollowing ormula:
MBV × maternal Hct × % etal cells in KB test
Fetal blood volume =
newborn Hct
For a pregnant woman o normal size who is normotensive
and has reached ull-term, the maternal blood volume (MBV)
may be estimated as 5000 mL. Tus, in a woman with a hematocrit o 35 percent and whose etus has a hematocrit o 50
percent, the calculation or a KB test demonstrating staining o
1.7 percent o sample cells is:
5000 × 0.35 × 0.017
Fetal blood volume = = 60 mL
0.5
Te etal-placental blood volume at term approximates
125 mL/kg. For a 3000-g etus, that would equate to 375 mL.
Tus, this etus lost approximately 15 percent (60 ÷ 375 mL)
o the etal-placental volume. Assuming the hematocrit is
50 percent in a term etus, this 60 mL o whole blood represents
30 mL o red cells lost into the maternal circulation. A loss o
this magnitude should be well tolerated hemodynamically but
would require two 300-μg doses o anti-D immune globulin to
prevent alloimmunization. A more precise method to estimate
the maternal blood volume includes a calculation based on the
maternal height, weight, and anticipated physiological maternal blood volume accrual (able 42-1, p. 732).
Te KB test is labor intensive. Tere are also two scenarios
in which the KB may be inaccurate: (1) maternal hemoglobinopathies in which the etal hemoglobin level is elevated, such
First
40
50
Incidence (percent)
60
70
80
0.07 mL
0.08 mL
0.13 mL
0.19 mL
Second
Trimester
Third Delivery
FIGURE 18-2 Incidence of fetomaternal hemorrhage during pregnancy. The numbers at each data point represent total volume of fetal blood estimated to have been transferred into the maternal circulation.
FIGURE 18-3 Kleihauer-Betke test demonstrating massive fetomaternal hemorrhage. After acid-elution treatment, fetal red cells rich in hemoglobin F stain darkly, whereas maternal red cells with only very small amounts of hemoglobin F stain lightly.
as β-thalassemia, and (2) at or near term, because the etus
may already be producing hemoglobin A.
Another method o quantiying etomaternal hemorrhage
is with fow cytometry, which uses monoclonal antibodies
to hemoglobin F or to the D antigen and then measures the
degree o fuorescence (Chambers, 2012; Welsh, 2016). Flow
cytometry is an automated test that can analyze a greater number o cells than the KB test. It is also unaected by maternal
levels o etal hemoglobin and by etal levels o hemoglobin
A. Flow cytometry has been reported to be more sensitive and
accurate than the KB test, however, it uses specialized technology not routinely available in many hospitals (Chambers, 2012; Corcoran, 2014; Fernandes, 2007).
FETAL THROMBOCYTOPENIA
■ Alloimmune Thrombocytopenia
Tis is also reerred to as etal and neonatal alloimmune thrombocytopenia (FNAIT). Alloimmune thrombocytopenia (AI)
is the most common cause o severe thrombocytopenia
among term newborns, with a requency o 1 to 2 cases per
1000 births (Kamphuis, 2010; Pacheco, 2013; Risson, 2012).
FNAI is caused by maternal alloimmunization to paternally
inherited etal platelet antigens. Maternal antiplatelet antibodies cross the placenta in a manner similar to red cell alloimmunization (p. 352). Unlike immune thrombocytopenia, the
maternal platelet count is normal with FNAI. And, unlike
anti-D alloimmunization, severe sequelae may aect the initial
at-risk pregnancy.
Maternal platelet alloimmunization against human platelet
antigen-1a (HPA-1a) accounts or 80 to 90 percent o cases
and is associated with the greatest severity (Bussel, 1997;
Knight, 2011; iller, 2013). Tis is ollowed in order o requency by alloimmunization against HPA-5b, HPA-1b, and
HPA-3a. Alloimmunization to other antigens accounts or
only 1 percent o reported cases.
Approximately 85 percent o non-Hispanic white individuals
are HPA-1a positive. wo percent are homozygous or HPA-
1b and at risk or alloimmunization. However, only 10 percent
o these women produce antiplatelet antibodies when carrying
an HPA-1a etus. Approximately a third o aected etuses or
neonates will develop severe thrombocytopenia, and 10 to 20
percent with severe thrombocytopenia sustain an intracranial
hemorrhage (ICH) (Kamphuis, 2010). As a result, populationbased screening studies have identied one case o FNAI-associated ICH per 25,000 to 60,000 pregnancies (Kamphuis, 2010;
Knight, 2011).
FNAI has a spectrum o presentation. Neonatal thrombocytopenia may be an incidental nding, the newborn may
maniest petechiae, or the etus or neonate may develop devastating ICH. O 600 pregnancies with FNAI identied
through a large international registry, etal or neonatal ICH
complicated just 7 percent o cases (iller, 2013). Hemorrhage
aected the rst-born child in 60 percent and occurred beore
28 weeks’ gestation in hal. A third o aected children died
soon ater birth, and 50 percent o survivors had severe neurological disabilities.
Bussel and coworkers (1997) evaluated etal platelet counts
beore therapy in 107 etuses with FNAI. Trombocytopenia severity was predicted by a prior sibling with perinatal
ICH. Fity percent had an initial platelet count <20,000/μL.
And, among those in whom the initial platelet count was
>80,000/μL, it dropped by at least 10,000/μL per week in the
absence o therapy.
Diagnosis and Management
AI is typically diagnosed ollowing delivery o a neonate with
severe and unexplained thrombocytopenia to a woman whose
platelet count is normal. Rarely, the diagnosis is ascertained
ater identiying etal ICH. Te condition recurs in 70 to 90
percent o subsequent pregnancies, is oten severe, and usually
develops earlier with each successive pregnancy. raditionally,
etal blood sampling was perormed to detect etal thrombocytopenia and to tailor therapy. Platelets were transused i the
etal platelet count was <50,000/μL. Te reported rate o procedure-related complications exceeds 10 percent (Winkelhorst,
2017). For this reason, most avor empirical treatment with
IVIG instead (Berkowitz, 2006; Pacheco, 2011).
Terapy may be stratied according to whether a prior
aected pregnancy was complicated by perinatal ICH, and
i so, at what gestational age (Table 18-3) (Pacheco, 2011).
Pioneering work by Bussel (1996) and Berkowitz (2006) and
their colleagues demonstrated the ecacy o such treatment. In
one series o 50 pregnancies with etal thrombocytopenia secondary to FNAI, IVIG raised the platelet count by approximately 50,000/μL, and no etus developed ICH (Bussel, 1996).
Among pregnancies at particularly high risk, which was based
on a platelet count <20,000/μL or a sibling with FNAI-associated ICH, the addition o corticosteroids to IVIG therapy
was associated with a rise in platelet count in 80 percent o cases
(Berkowitz, 2006). However, a systematic review identied no
consistent benet o corticosteroid treatment compared with
IVIG therapy alone (Winkelhorst, 2017). Tus, corticosteroid
therapy is somewhat controversial. Cesarean delivery is generally recommended at or near term.
■ Immune Thrombocytopenia
Also known as immune or idiopathic thrombocytopenic purpura (IP), this autoimmune disorder is characterized by antiplatelet IgG antibodies that attack platelet glycoproteins. Te
antibodies may cross the placenta and cause etal thrombocytopenia. Maternal IP is discussed in Chapter 59 (p. 1059).
Fetal thrombocytopenia rom maternal IP is usually mild.
However, neonatal platelet levels may all rapidly ater birth
and nadir at 48 to 72 hours o lie. Neither the maternal platelet count, identication o antiplatelet antibodies, nor treatment with corticosteroids eectively predicts etal or neonatal
platelet counts (Hachisuga, 2014). Importantly, etal platelet
counts are usually adequate to allow vaginal delivery without
an increased risk o ICH. In a review o more than 400 pregnancies with IP, there was no case o etal or neonatal ICH
and no inant with any central nervous system abnormality
(Wyszynski, 2016). Fetal blood sampling is not recommended
TABLE 18-3. Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT) Treatment Recommendations
Risk
Group Criteria Suggested Management
1 Prior fetus or newborn with ICH, but no
maternal anti-HPA antibody identified
Maternal anti-HPA antibody screening and cross-matching with
paternal platelets at 12, 24, and 32 weeks’ gestation; no treatment
for negative test results
2 Prior fetus or newborn with
thrombocytopenia and maternal
anti-HPA antibody, but no ICH
Beginning at 20 wks: IVIG 1g/kg/wk and prednisone 0.5 mg/kg/d or
IVIG 2 g/kg/wk
Beginning at 32 wks: IVIG 2 g/kg/wk and prednisone 0.5 mg/kg/d
Continue until delivery
3 Prior fetus with 3rd-trimester ICH or prior
newborn with ICH, and maternal antiHPA antibody
Beginning at 12 wks: IVIG 1 g/kg/wk
Beginning at 20 wks: either increase IVIG to 2 g/kg/wk or add
prednisone 0.5 mg/kg/d
Beginning at 28 wks: IVIG 2 g/kg/wk and prednisone 0.5 mg/kg/d
Continue until delivery
4 Prior fetus with ICH before the 3rd
trimester and maternal anti-HPA
antibody
Beginning at 12 wks: IVIG 2 g/kg/wk
Beginning at 20 wks: add prednisone 1 mg/kg/d
Continue both until delivery
HPA = human platelet antigen; ICH = intracerebral hemorrhage; IVIG = intravenous immunoglobulin G.
(Neunert, 2011). Mode o delivery is based on standard obstetrical indications.
HYDROPS FETALIS
Tis phrase has its origins in Middle English, Latin, and Greek.
Te condition was described by Ballantyne in 1892 as general
dropsy, that is, edema, o the etus (Kaiser, 1971). Hydrops
can be a maniestation o severe illness rom a wide variety o
etiologies (Table 18-4) (Bellini, 2015).
Hydrops is diagnosed by identiying two or more etal
eusions—pleural, pericardial, or ascites—or one eusion plus
anasarca (Fig. 18-4). Sonographically measured skin thickness
o >5 mm constitutes edema or anasarca. Placentomegaly is
dened as placental thickness ≥4 cm in the second trimester or
≥6 cm in the third trimester (Bellini, 2009; Society or Maternal–Fetal Medicine, 2015b). As hydrops progresses in severity,
anasarca is an invariable eature and is usually accompanied by
placentomegaly and hydramnios.
I ound in association with red cell alloimmunization,
hydrops is termed immune, otherwise, it is nonimmune.
Immune and nonimmune hydrops are postulated to share
several physiological abnormalities. Te precise pathogenesis
remains unknown but is likely multiactorial. As shown in
Figure 18-5, these include decreased colloid oncotic pressure,
increased hydrostatic or central venous pressure, and enhanced
vascular permeability.
■ Immune Hydrops
Tis condition results rom transplacental passage o maternal
antibodies that destroy etal red cells. Te resultant anemia
stimulates marrow erythroid hyperplasia and extramedullary
hematopoiesis in the spleen and liver (see Fig. 18-5). Te latter
likely causes portal hypertension and impaired hepatic protein
synthesis, which lowers plasma oncotic pressure (Nicolaides,
1985). Fetal anemia may also raise central venous pressure
(Weiner, 1989). issue hypoxia rom anemia may increase capillary permeability, such that fuid collects in the etal thorax,
abdominal cavity, and/or subcutaneous tissue.
Te incidence o immune hydrops has decreased dramatically with the advent o anti-D immune globulin and with use
o MCA Doppler to aid anemia detection. Only severe anemia results in immune hydrops. Mari and colleagues (2000)
reviewed 70 pregnancies with etal anemia rom red cell alloimmunization and ound that all with immune hydrops had
hemoglobin values <5 g/dL. As discussed on page 356, immediate etal blood transusion may be liesaving.
■ Nonimmune Hydrops
At least 90 percent o cases o hydrops are nonimmune (Bellini,
2012). Te prevalence approximates 1 case per 1500 secondtrimester pregnancies (Heinonen, 2000). Te number o specic disorders that can lead to nonimmune hydrops is extensive.
Etiologies and the proportion o births within each hydrops
category rom a review o more than 6700 aected pregnancies
are summarized in able 18-4 (Bellini, 2015).
A cause is identied in approximately 60 percent prenatally
and in up to 80 percent postnatally (Bellini, 2009, 2015; Santo,
2011). O prenatally diagnosed cases, aneuploidy accounts or
approximately 20 percent, cardiovascular abnormalities or 15
percent, and inections or 14 percent—the most common o
which is parvovirus B19 (Santo, 2011; Sileo, 2020; Sparks,
2019). In multietal gestations, twin-twin transusion syndrome is the most requent cause (Yeom, 2015). Fetal deaths
and stillbirths are common with nonimmune hydrops. Overall, only 40 percent o aected pregnancies result in a livebornFetal Disorders 361
CHAPTER 18
TABLE 18-4. Categories and Etiologies of Nonimmune Hydrops Fetalis
Category Percenta
Cardiovascular
Structural defects: Ebstein anomaly, tetralogy of Fallot with absent pulmonary valve,
hypoplastic left or right heart, premature closure of ductus arteriosus, arteriovenous
malformation (vein of Galen aneurysm)
Cardiomyopathies
Tachyarrhythmias
Bradycardia, as may occur in heterotaxy syndrome with endocardial cushion defect or
with anti-Ro/La antibodies
21
Chromosomal
Turner syndrome (45,X), triploidy, trisomies 21, 18, and 13
13
Hematological
Hemoglobinopathies, such as α4-thalassemia
Erythrocyte enzyme and membrane disorders
Erythrocyte aplasia/dyserythropoiesis
Decreased erythrocyte production (myeloproliferative disorders)
Fetomaternal hemorrhage
10
Lymphatic Abnormalities
Cystic hygroma, systemic lymphangiectasis, pulmonary lymphangiectasis
8
Infections
Parvovirus B19, syphilis, cytomegalovirus, toxoplasmosis, rubella, enterovirus, varicella,
herpes simplex, coxsackievirus, listeriosis, leptospirosis, Chagas disease, Lyme disease
7
Syndromic
Arthrogryposis multiplex congenita, lethal multiple pterygium, congenital
lymphedema, myotonic dystrophy type I, Neu-Laxova, Noonan, and Pena-Shokeir
syndromes
5
Thoracic Abnormalities
Cystic adenomatoid malformation
Pulmonary sequestration
Diaphragmatic hernia
Hydro/chylothorax
Congenital high airway obstruction sequence (CHAOS)
Mediastinal tumors
Skeletal dysplasia with very small thorax
5
Gastrointestinal
Meconium peritonitis, gastrointestinal tract obstruction
1
Kidney and Urinary Tract
Kidney malformations
Bladder outlet obstructions
Congenital (Finnish) nephrosis, Bartter syndrome, mesoblastic nephroma
2
Placental, Twin, and Cord Abnormalities
Placental chorioangioma, twin-twin transfusion syndrome, twin reversed arterial
perfusion sequence, twin anemia polycythemia sequence, cord vessel thrombosis
5
Other Rare Disorders
Inborn errors of metabolism: Gaucher disease, galactosialidosis, GM1 gangliosidosis,
sialidosis, mucopolysaccharidoses, mucolipidoses
Tumors: sacrococcygeal teratoma, hemangioendothelioma with Kasabach-Merritt
syndrome
5
Idiopathic 18
aPercentages reflect the proportion within each category from a systematic review of 6775 pregnancies with nonimmune hydrops.362 The Fetal Patient
Section 6
30 percent had a pathogenic genetic variant. Te most common
etiology was RASopathies, and many such cases resulted in Noonan
syndrome. It is anticipated that as experience with whole exome
sequencing accrues, the diagnostic yield will continue to increase.
Although the prognosis o nonimmune hydrops is guarded,
it depends heavily on etiology. In a large series rom Tailand
and Southern China, α0-thalassemia is the main cause o nonimmune hydrops. It accounts or 30 to 50 percent o cases and con-
ers an extremely poor prognosis (Liao, 2007; Ratanasiri, 2009;
Suwanrath-Kengpol, 2005). In contrast, treatable etiologies such
as parvovirus inection, chylothorax, and tachyarrhythmias, which
each constituting approximately 10 percent o cases, can result in
survival in two thirds o cases with etal therapy (Sohan, 2001).
Diagnostic Evaluation
Hydrops is readily detected with prenatal sonography (see
Fig. 18-5). Imaging and laboratory evaluation may identiy
neonate, and o these, the neonatal survival rate is just 50 percent (Nassr, 2018; Yeom, 2015).
Importantly, the etiology o nonimmune hydrops varies
according to the gestational age at diagnosis. In a review o 63
pregnancies undergoing genetic testing or hydrops in the rst
trimester, aneuploidy was the cause in 70 percent (Sileo, 2020).
O cases diagnosed rom 14 through 24 weeks, aneuploidy and
congenital inection each accounted or 20 percent. When nonimmune hydrops presents beore 24 weeks’ gestation, the most
requent aneuploidy is 45,X—Turner syndrome, and in such
cases, the survival rate is <5 percent (Sohan, 2001).
Recent advances in genetic testing have improved the understanding o hydrops cases that were previously considered
idiopathic. In a review rom the University o Caliornia FetalMaternal Consortium, whole exome sequencing was studied in
127 cases o unexplained nonimmune hydrops in which traditional genetic testing was uninormative (Sparks, 2020). Nearly
A B
C D
FIGURE 18-4 Sonographic findings that define hydrops. A. This profile of a 23-week fetus with nonimmune hydrops secondary to B19
parvovirus infection depicts scalp edema (arrowheads) and ascites (*). B. This 34-week fetus had hydrops secondary to an arteriovenous
malformation in the brain, known as a vein of Galen aneurysm. In this coronal image, prominent pleural effusions (*) outline the lungs (L).
Fetal ascites is also present (arrows), as is anasarca. C. This axial (transverse) image depicts a pericardial effusion (arrows) in a 23-week fetus
with hydrops from B19 parvovirus infection. The degree of cardiomegaly is impressive, and the ventricular hypertrophy raises concern for
myocarditis, which can accompany parvovirus infection. D. This axial (transverse) image depicts fetal ascites (*) in a 15-week fetus with
hydrops secondary to large cystic hygromas. Anasarca is also seen (bracket).
etal structural abnormalities, arrhythmias, anemia, aneuploidy,
placental abnormalities, and complications o monochorionic
twinning. Depending on the circumstances, initial evaluation
includes the ollowing:
1. Indirect Coombs test to identiy alloimmunization
2. Detailed ultrasound examination o the etus and placenta
that includes:
• A detailed anatomical survey to assess for the structural
abnormalities listed in able 18-4
• Fetal echocardiography to further evaluate cardiac structure and unction
• MCA Doppler peak systolic velocity to assess for fetal
anemia
3. Amniocentesis to obtain samples or chromosomal microarray analysis or karyotyping and or parvovirus B19, cytomegalovirus, and toxoplasmosis testing, as discussed in
Chapter 67
4. Kleihauer-Betke test to detect etomaternal hemorrhage i
anemia is suspected, depending on ndings and test results
5. Consideration o testing or alpha-thalassemia and/or inborn
errors o metabolism.
Whole exome sequencing has signicant potential to identiy
a genetic etiology i the aorementioned evaluation is not inormative (Sparks, 2020). Counseling should include anticipated
turnaround times, costs, and variants o uncertain signicance.
It is not recommended or routine use (American College o
Obstetricians and Gynecologists, 2020). In addition, because
sequencing is generally perormed on the etus and parents, a
parent may be identied or suspected to have an unrelated but
medically actionable nding, such as a cancer predisposition.
Isolated Effusion or Edema. Te initial presentation o hydrops
may be as a single eusion or anasarca. Although neither is
diagnostic o hydrops, the above evaluation should be considered, and requent surveillance may be prudent. A pericardial
eusion may precede development o hydrops in etal parvovirus B19 inection (Chap. 67, p. 1191). Similarly, isolated ascites may be the initial nding in etal parvovirus B19 inection
or may result rom a gastrointestinal abnormality such as meconium peritonitis. An isolated pleural eusion may represent
a chylothorax, which is amenable to prenatal diagnosis, and
or which etal therapy may be liesaving i hydrops develops
(Chap. 19, p. 376). Last, isolated edema, particularly involving
Metabolic disorders
Infection
Red cell alloimmunization
Fetomaternal hemorrhage
Hematological disorder
Infection
Anemia
Extramedullary
hematopoiesis
Increased
hydrostatic pressure
Tissue
hypoxia
Lymphatic
abnormality
Selected fetal anomalies
Placental abnormality
Volume overload or
Impaired venous return
? Heart failure
Hepatic dysfunction,
impaired protein synthesis
Decreased
lymphatic flow
Decreased plasma
oncotic pressure
Increased
capillary permeability
Increased
interstitial fluid
Hydrops fetalis
FIGURE 18-5 Proposed pathogenesis of immune and nonimmune hydrops fetalis. (Data from Bellini, 2009; Lockwood, 2009.)364 The Fetal Patient
Section 6
the upper torso or the dorsum o the hands and eet, may be
ound in urner or Noonan syndrome or may represent congenital lymphedema syndrome (Chap. 16, p. 314).
■ Mirror Syndrome
Te association between etal hydrops and the development o
maternal edema, in which the mother mirrors the etus, is attributed to Ballantyne. He called the condition triple edema because
the etus, mother, and placenta all became edematous. Mirror
syndrome has been reported to complicate at least 20 percent o
hydrops cases (Chen, 2021). Te etiology o the hydrops is not
related to development o mirror syndrome. It has been associated with hydrops rom D alloimmunization, twin-twin transusion syndrome, placental chorioangioma, etal cystic hygroma,
Ebstein anomaly, sacrococcygeal teratoma, chylothorax, bladder
outlet obstruction, supraventricular tachycardia, vein o Galen
aneurysm, and various congenital inections (Braun, 2010).
In a review o more than 50 cases o mirror syndrome,
Braun (2010) ound that approximately 90 percent o women
had edema, 60 percent had hypertension, 40 percent had proteinuria, 20 percent had liver enzyme elevation, and nearly 15
percent had headache and visual disturbances. Based on these
ndings, it is reasonable to consider mirror syndrome a orm
o severe preeclampsia (Espinoza, 2006; Midgley, 2000). Others, however, have suggested that it is a separate disease process
with hemodilution rather than hemoconcentration (Carbillon,
1997; Livingston, 2007).
Some reports describe the same imbalance o angiogenic and
antiangiogenic actors that is observed with preeclampsia, and
this suggests a common pathophysiology (Goa, 2013; Hobson,
2020; Llurba, 2012). Tese ndings, which include elevated
concentrations o soluble ms-like tyrosine kinase 1 (sFlt-1),
decreased placental growth actor (PlGF) levels, and elevation o soluble vascular endothelial growth actor receptor 1
(sVEGFR-1) concentrations, are discussed urther in Chapter 40
(p. 694).
In most cases with mirror syndrome, prompt delivery is
indicated and ollowed by resolution o maternal edema and
other ndings (Braun, 2010). However, in isolated cases o etal
anemia, supraventricular tachycardia, hydrothorax, or bladder
outlet obstruction, successul etal treatment has resulted in
resolution o both etal hydrops and maternal mirror syndrome
(Goa, 2013; Livingston, 2007; Llurba, 2012; Midgley, 2000).
Normalization o the angiogenic imbalance has also been
described ollowing etal transusion or parvovirus B19 inection. Fetal therapy or these conditions is reviewed in Chapter
19. Given the parallels to severe preeclampsia, delaying delivery
to eect etal therapy should be considered only with caution. I
the maternal condition deteriorates, delivery is recommended
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