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848 Part VI: The Erythrocyte Chapter 55: Alloimmune Hemolytic Disease of the Fetus and Newborn 849

indirect bilirubin peaks by the fourth or fifth day and then declines of life, regardless of severity of HDFN, treatment received, or antibody
slowly. Premature infants may have higher levels of serum bilirubin for a specificity. 32
longer duration because of lower hepatic glucuronyl transferase activity.
Conjugated hyperbilirubinemia at birth is sometimes noted in infants OBSTETRIC HISTORY
who received multiple IUTs. Babies who received IUTs may still have
anemia at birth and may still develop significant hyperbilirubinemia in The course and outcome of prior pregnancies are critically important
the neonatal period. As discussed later in the section “Postnatal Man- in the initial evaluation of an alloimmunized pregnancy. A history of
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agement”, these infants may require intermittent transfusion therapy early fetal deaths or hydrops is ominous. In Rh alloimmunization, the
until 2 to 3 months of age due to persistent anemia. severity of HDFN typically remains the same or worsens in subsequent
affected pregnancies. Hydrops recurs in 90 percent of affected pregnan-
cies, often at an earlier gestation in subsequent pregnancies. Alloimmu-
KERNICTERUS nized women who report previous neonatal deaths, neonatal exchange
An important complication of elevated serum levels of indirect biliru- transfusions, or IUTs should receive very close fetal surveillance. Jaun-
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bin in the neonate is the development of bilirubin encephalopathy. dice as a result of hemolysis often recurs to the same degree of severity
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This disorder, also termed kernicterus, is caused by bilirubin pigment in subsequent affected siblings. The history of prior blood transfusions
deposition in the basal ganglia and brainstem nuclei, leading to neu- may be obtained in women sensitized to antigens other than RhD, espe-
ronal necrosis. Acute bilirubin encephalopathy is initially marked by cially if Kell alloimmunization is detected. Establishment of paternity
lethargy, poor feeding, and hypotonia. With increasing severity, the for each pregnancy is particularly relevant in both Rh and Kell allo-
infant develops a high-pitched cry, fever, hypertonia progressing to immunization, because the fetus is at risk only if the father is positive
frank opisthotonos, and irregular respiration. The infants then develop for the antigen in question. Unlike Rh and other minor alloantibody
any or all of the classic sequelae of kernicterus: choreoathetoid cere- HDFN, ABO HDN may affect the first-born ABO-incompatible infant.
bral palsy, gaze abnormalities, especially in upward gaze, sensorineural Although rare, severe ABO HDN may recur in subsequent ABO-
hearing loss, and cognitive deficits. The clinical presentation of bilirubin incompatible pregnancies. 34
encephalopathy in preterm infants may be less distinctive. Abnormal or
absent brainstem auditory evoked potentials and magnetic resonance DIFFERENTIAL DIAGNOSIS
imaging scans demonstrating the characteristic bilateral lesions of the
globus pallidus help confirm the clinical diagnosis of kernicterus. Hydrops fetalis may be secondary to α-thalassemia (Chap. 49) cardiac
Infants with HDFN are at higher risk for kernicterus than are anomalies or arrhythmias, fetal genetic or metabolic disorders, intra-
other infants with the same bilirubin level from other causes. Heme uterine infections such as syphilis or toxoplasmosis, or any of a mul-
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pigments produced during active hemolysis are hypothesized to inhibit titude of causes that lead to severe derangements in fetal homeostasis.
bilirubin–albumin binding. Alternatively, many conditions that poten- These disorders are classified as nonimmune hydrops and are differen-
tially compromise the blood–brain barrier, such as prematurity, aci- tiated from the etiologies discussed in this chapter by the absence of
dosis, hypoxemia, hypothermia, and hypoglycemia, are present in any clinically significant red cell alloantibodies in the mother’s blood.
severely affected infants, making them more vulnerable to bilirubin Parvovirus B19 infection of the mother at any time during gestation can
encephalopathy. cause nonimmune hydrops, profound fetal anemia, and death.
Neonatal anemia caused by intrinsic red cell defects such as hered-
OTHER CLINICAL FEATURES itary spherocytosis (Chap. 46), red cell enzyme deficiencies (Chap. 47),
and hemoglobinopathies, notably α-thalassemia (Chap. 48) can give a
Extensive extramedullary hemopoiesis in the liver and spleen may cause similar clinical picture to HDN. The absence of maternal red cell allo-
portal and umbilical venous hypertension, leading to ascites, pleu- antibodies, a negative direct antiglobulin test (DAT) result, and detec-
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ral effusions, and consequent pulmonary hypoplasia. Trophoblastic tion of the specific defect determining the disorder clarify the diagnosis.
hypertrophy and placental edema cause impaired placental function. Disorders of bilirubin metabolism can lead to unconjugated hyperbi-
Hypoproteinemia as a result of liver dysfunction leads to generalized lirubinemia; however, they are not associated with anemia. Hepatitis
edema. “Hydrops fetalis,” a state of anasarca, is the end result of a com- or obstructive biliary diseases present with direct hyperbilirubinemia,
bination of anemia, hypoproteinemia, cardiac failure, elevated venous most often after the first week of life.
pressures, increased capillary permeability, and impaired lymphatic
clearance. Hepatosplenomegaly is usually present. Cholestatic liver dis-
ease, previously believed to be associated with iron overload caused by PATHOPHYSIOLOGY
IUTs, has been shown to occur in 13 percent of neonates with HDFN There are three main classes of alloimmune HDFN, based on the anti-
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independent of previous IUT treatment and type of alloimmunization. gen(s) involved: (1) Rh, (2) minor red cell antigens (i.e., Kell, Duffy, Kidd
Hydropic babies may also have respiratory distress as a result of pul- antigens), and (3) ABO. Factors affecting the risk to the fetus or neonate
monary hypoplasia, pleural and/or pericardial effusions, or surfactant not only include the class of antigens involved, but also the titer (i.e.,
deficiency. 4 vs. 32) and class/subclass (i.e., IgM vs. IgG vs. IgG ) of the antibody,
1
4
Although the pathophysiology is not entirely clear, purpura associ- the level of antigen expression on fetal RBCs, and the antibody’s ability
ated with thrombocytopenia is sometimes seen in infants with HDFN. to suppress erythropoiesis (i.e., anti-K). 35,36 Rh HDFN is discussed first
Thrombocytopenia at birth has been occurs in 26 percent of neonates because it is archetypal of this condition; however, ABO incompatibility
with HDFN, independent of other comorbidities, such as lower gesta- is much more common than Rh HDFN. The distinguishing features of
tional age at birth, being small for gestational age (SGA), and previous the three classes of HDFN are highlighted below.
IUTs. Severe fetal thrombocytopenia (platelet count <50 × 10 /L) has
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been reported in 3 percent of all fetal blood samplings and in 23 percent
of severely RhD alloimmunized hydropic fetuses in one center when RHD HEMOLYTIC DISEASE
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fetal platelet counts were measured prior to IUT. In addition, neutro- The standard nomenclature for designation of one’s blood type is ABO
penia is a common feature of HDN and may be prolonged up to a year and Rh-positive or Rh-negative based on the presence or absence of the

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