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850 Part VI: The Erythrocyte Chapter 55: Alloimmune Hemolytic Disease of the Fetus and Newborn 851

RhD antigen. However, the Rh blood system consists of numerous other flat or smooth baseline fetal heart rate); however, it also may be clini-
antigens, the most common clinically significant include C, c, E, and e, cally silent, with no clinical signs differentiating such deliveries from
which are encoded on the paired RHCE gene. RhD-positive individuals those with minimal fetomaternal hemorrhage. 43,44 Fetomaternal trans-
may have one or two copies of RHD gene (heterozygous or homozygous fusion can also result from obstetric procedures such as chorionic villus
RhD-positive, respectively). More than 150 alleles have been defined for sampling, amniocentesis, funipuncture, therapeutic abortion, external
RHD and more are likely to be revealed as population studies expand. cephalic version, cesarean section, and manual removal of the placenta,
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In whites, RhD-negative individuals are homozygous for deletion of the and from pathologic conditions such as abdominal trauma, spontane-
RHD gene, which encompasses the whole of RHD and part of each of ous abortion, or ectopic pregnancy. 42,45–47
the flanking Rh boxes. The resultant RhD-negative phenotype is char- The presence of RhD-positive red cells in an RhD-negative mother
acterized by the absence of the whole RhD protein from the red cell initially provokes a weak and slow primary immune response, which
membrane; however the RHCE-encoded antigens are present. Only develops over 4 weeks and consists of transient elevation of IgM anti-
18 percent of RhD-negative Americans of African Descent are homozy- bodies. Subsequently, approximately 5 to 15 weeks after exposure to the
gous for RHD deletion. The majority (66 percent) of RhD-negative RhD-positive red cells, anti-D IgG antibodies capable of crossing the
Americans of African descent have an inactive RHD gene (RHψ), while placenta are produced. The RhD antigen is the most immunogenic of
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15 percent have a hybrid RHD-CE-D gene, neither of which produces the Rh antigens and, indeed, of all red cell antigens (after ABO). The
epitopes of RhD antigen. RhD protein is processed by antigen-processing cells in the spleen and
A number of RHD alleles responsible for RhD protein variants lymphoid tissue of D-negative individuals into multiple short allogeneic
with altered RhD antigen expression have been classified according linear peptides, which stimulate helper T cells, which then activate B
to their phenotype and molecular variation as partial D, weak D, and cells to produce IgM and later IgG antibodies. Memory T and B cells
DEL. Amino acid substitutions located in extracellular domains result that are generated following the initial immune response are long lived,
in different forms of partial D phenotype. Women with partial D phe- and exposure to the antigen, even years later, results in an accelerated
notypes may develop antibodies against D epitopes absent on their cell antibody response as a result of rapid proliferation of antigen-specific
membranes but present on the fetal RBCs. Amino acid substitutions clones. Repeated exposure to RhD-positive fetal RBCs, as in a second
located in the transmembrane or intracellular segments of the RhD RhD-positive pregnancy in a sensitized RhD-negative woman, produces
protein result in a weak D phenotype. The expressed RhD antigen is a brisk secondary immune response marked by rapid production of large
reduced quantitatively but not qualitatively, so carriers are usually not amounts of anti-D IgG antibody by maternal memory B lymphocytes.
susceptible to anti-D immunization. However, some types of weak D In the absence of Rho(D) immunoglobulin (RhIg) prophylaxis,
(weak D type 15, weak D type 4.2 or DAR, and weak D type 7) may sensitization occurs in 7 to 16 percent of RhD-negative women at risk,
produce anti-D. DEL is a very weakly expressed D antigen found in within 6 months after delivery of the first RhD-positive ABO-compat-
30 percent of RhD-“negative” blood donors in East Asia. Anti-D anti- ible fetus. The relatively low rate of 16 percent of primary alloimmuni-
body molecules recognize the epitopes on the external loops of RhD zation in Rh-negative women at risk may be a result of the low volume
protein (Chap. 136). 37–39 of fetomaternal hemorrhage (FMH) in most women. In fact, as little
There currently are no requirements in the United States for blood as 0.03 mL of RhD-positive RBCs has been shown to be sufficient to
banks to test for variant RhD on RhD-negative pregnant mothers. How- immunize some RhD-negative individuals. 49
ever, monoclonal RhD typing sera most commonly used for RhD typing The potential for immunization of the mother is not only deter-
do not detect weak D or partial D phenotypes, which results in report- mined by the extent of FMH and the presence of fetomaternal blood
ing patients with variant RhD phenotypes as RhD-negative. Therefore, group incompatibility, but also by other factors, such as the frequency
pregnant women with variant RhD phenotypes are usually treated with of fetomaternal transfusion and whether the mother and fetus are ABO
anti-D immunoglobulin prophylaxis. compatible. As an example, repetitive exposure to minuscule amounts of
RhD-negative pregnant women who appear to have both anti-D RhD-positive red cells in RhD-negative women who abuse intravenous
and anti-C, especially if at a similar strengths of reactivity serologically, drugs and share needles with RhD-positive partners has been reported
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require special consideration. In this instance, if the pregnant woman is to lead to severe Rh sensitization. Fetomaternal ABO incompatibil-
lacking both RhD and RhC antigens, she is also lacking the RhG anti- ity offers some protection against primary Rh immunization because
gen, a combination antigen in the Rh Blood Group System found on incompatible fetal red cells are destroyed rapidly by maternal anti-A
RBCs containing either RhD or RhC antigens. In these situations, the and anti-B antibodies, reducing maternal exposure to RhD antigenic
laboratory must determine whether the antibodies are truly anti-D/ sites. Primary Rh immunization occurs in 2 to 4 percent of women at
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anti-C rather than an anti-G because a patient who develops anti-C and/ risk after delivery of an ABO-incompatible fetus. ABO incompatibil-
or anti-G antibodies but no anti-D should receive anti-D immunoglob- ity confers no protection against the secondary immune response once
ulin prophylaxis. 40 sensitization has occurred. 52
Binding of transplacentally transferred maternal anti-D IgG anti-
Fetomaternal Hemorrhage and Anti-D Alloimmunization bodies to D-antigen sites on the fetal red cell membrane is followed by
Asymptomatic transplacental passage of fetal red cells occurs in 75 adherence of the coated red cells to the Fcγ receptors of macrophages
percent of pregnant women at some time during pregnancy or during with rosette formation, leading to extravascular noncomplement-medi-
labor and delivery. The incidence of fetomaternal transfusion increases ated phagocytosis and lysis, predominantly in the spleen. Although Rh
41
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with advancing gestation—from 3 percent (first trimester) to 12 percent antigens are found on fetal RBCs as early as week 6 of gestation, active
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(second trimester) to 45 percent (third trimester) and to 64 percent at transport of IgG across the placenta is slow until 20 to 24 weeks of ges-
delivery. The average volume of fetal blood in the maternal circulation tation. The severity of fetal anemia is influenced primarily by the anti-D
after delivery is approximately 0.1 mL in most women and less than 1 IgG concentration, but is also by other factors including: the IgG sub-
mL in 96 percent of women. Intrapartum fetomaternal hemorrhage of class, the rate of transplacental transfer of maternal IgG, the functional
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more than 30 mL may occur in up to 1 percent of deliveries. Massive maturity of the fetal mononuclear phagocyte system, and the presence
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fetomaternal hemorrhage may present with decreased fetal movement of maternal human leukocyte antigen (HLA) antibodies and or mater-
and sinusoidal heart rhythm (undulating wave form alternating with a nal–fetal ABO incompatibility. Although IgG anti-D consists mainly
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