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CHAPTER 55 The resulting hemolysis or suppression of erythropoiesis may cause
fetal and/or neonatal anemia and significant neonatal jaundice. There
ALLOIMMUNE HEMOLYTIC are three main classes of alloimmune HDFN, based on the antigen(s)
involved: Rh (rhesus), minor red cell antigens (i.e., Kell, Duffy, Kidd
DISEASE OF THE FETUS antigens) and ABO.
Prior to the development of medical interventions in the 1950s,
almost half of all newborn infants with Rh HDFN died or were severely
AND NEWBORN handicapped. Although the clinical condition was described in new-
born infants as early as the 1600s, it was only in the 1930s and 1940s that
the pathophysiology of Rh HDFN was uncovered. In 1932, Diamond
1
and colleagues recognized that the clinical syndromes of stillbirth with
Ross M. Fasano, Jeanne E. Hendrickson, and Naomi L. C. Luban unusual erythroblastic activity in the extramedullary sites and blood,
fetal hydrops, anemia in the newborn, and “icterus gravis neonatorum”
were closely related and likely had the same pathophysiology in the
hematopoietic system. In 1938, Ruth Darrow, a pathologist who lost a
SUMMARY baby to kernicterus, postulated that hemolysis of fetal RBCs was a result
of maternal antibody produced in response to fetal hemoglobin. The
2
Alloimmune hemolytic disease of the fetus and newborn is caused by the discovery of the Rh factor by Landsteiner and Weiner led to elucidation
action of transplacentally transmitted maternal immunoglobulin (Ig) G anti- of Rh HDFN by Levine and colleagues who established that erythrob-
bodies on paternally inherited antigens present on fetal red cells but absent lastosis fetalis was caused by immunization of an Rh-negative mother
on the maternal red cells. Maternal IgG antibodies bind to fetal red cells, caus- by the red cells from an Rh-positive fetus. Antibodies produced by the
3
ing hemolysis or suppression of erythropoiesis. As a consequence, anemia, sensitized mother crossed the placenta in the next pregnancy and coated
extramedullary hematopoiesis, and neonatal hyperbilirubinemia may result, the fetal Rh-positive cells, leading to hemolysis, anemia, hydrops, and
with severe cases resulting in fetal loss or neonatal death or disability. Col- severe neonatal jaundice.
laboration among maternal–fetal medicine specialists, hematologists, trans- Neonatal mortality from Rh HDFN decreased considerably with
fusion medicine physicians, radiologists, and neonatologists has substantially the development of exchange transfusion techniques for correction
of severe anemia and hyperbilirubinemia. However, severely affected
4
reduced perinatal mortality and morbidity resulting from hemolytic disease of fetuses continued to die in utero before 34 weeks’ gestation. In 1961,
the fetus and newborn. Antenatal diagnostic methods identify at risk fetuses, Liley demonstrated the prognostic value of amniotic fluid spectropho-
and assess disease severity in affected fetuses. After birth, phototherapy and tometry in identifying fetuses at risk and then showed that intrauter-
exchange transfusions prevent serum bilirubin from rising to levels that could ine transfusions (IUTs) could prevent fetal deaths. The most dramatic
5
produce bilirubin encephalopathy and resultant brain damage (kernicterus), reduction in the incidence of Rh HDFN was achieved in the 1960s and
remove maternal antibody, and replace circulating fetal red blood cells with 1970s with the development of postpartum and antepartum anti-D pro-
those negative for the implicated antigen(s). RhIg has successfully prevented phylaxis to prevent maternal Rh sensitization. 6
alloimmune hemolytic disease resulting from rhesus D sensitization in many Despite these advances, Rh HDFN has not disappeared, and cases
at risk infants, but no prophylactic therapy exists as of this writing to pre- of hemolytic disease of the newborn resulting from red cell antibod-
vent alloimmune hemolytic disease resulting from other red cell antibodies. ies directed toward antigens other than the Rh blood group system are
7–11
Advances in immunohematology and molecular biology may offer new ave- being increasingly recognized. Furthermore, maternal Rh isoimmu-
nization and Rh hemolytic disease still occur, particularly in develop-
nues for prevention and treatment in the future.
ing countries where anti-RhD prophylaxis is not widely available or in
infants born outside of medical facilities. 12

Alloimmune hemolytic disease of the fetus and newborn (HDFN) is EPIDEMIOLOGY
a disorder in which the life span of fetal and/or neonatal red cells is
shortened as a result of binding of transplacentally transferred mater- The epidemiology of HDFN varies in different ethnic and racial groups;
nal immunoglobulin (Ig) G antibodies on fetal red blood cell (RBC) the frequency of specific blood group alleles in a given population
antigens foreign to the mother, inherited by the fetus from the father. determines the probability of blood group incompatibility and maternal
alloimmunization. Antigen-negative women may have naturally occur-
ring antibodies to certain red cell antigens (anti-A or anti-B) or may
develop antibodies as a result of exposure to foreign red cell antigens
Acronyms and Abbreviations: AAP, American Academy of Pediatrics; anti-D, through blood transfusion or by silent fetomaternal hemorrhage during
antibody against D antigen; ccff-DNA, circulating cell-free fetal DNA; DAT, direct pregnancy or at delivery. More than 50 different RBC antigens are asso-
antiglobulin test; ΔOD , change in optical density at 450 nm; FFP, fresh-frozen ciated with maternal alloimmunization 7–11,13 and with HDFN of varying
450
plasma; FMH, fetomaternal hemorrhage; HDFN, hemolytic disease of the fetus and severity; however, the vast majority of clinically significant maternal
newborn; HDN, hemolytic disease of the newborn; IAT, indirect antiglobulin test; Ig, alloantibodies are within the Rh (D, CE), Kell, Duffy, MNS, and Kidd
immunoglobulin; IUT, intrauterine transfusion; IVIG, intravenous immunoglobulin systems (Table 55–1).
G; QT-PCR, quantitative polymerase chain reaction; RBC, red blood cell; Rh, rhesus; Antenatal screening programs detect antibodies to clinically
rHuEPO, recombinant human erythropoietin; RhIg, Rho(D) immunoglobulin; SGA, significant Rh or other minor RBC antigens in 0.01 to 0.4 percent of
small for gestational age; TBV, total blood volume; TSB, total serum bilirubin; WB, pregnant women, 7–11,13 although these numbers vary by country. Approx-
whole blood. imately 15 percent of Americans of European descent are RhD-negative,
compared to 7 percent of Americans of African descent and Hispanics,

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