80: ABO Incompatibility

Isoimmune hemolytic anemia may result when ABO incompatibility occurs between the mother and the newborn infant. This disorder is most common with blood type A or B infants born to type O mothers. The hemolytic process begins in utero and is the result of active placental transport of maternal isoantibody. In type O mothers, isoantibody is predominantly 7S-IgG (immunoglobulin G) and is capable of crossing the placental membranes. Because of its larger size, the mostly 19S-IgM (immunoglobulin M) isoantibody found in type A or type B mothers cannot cross. Symptomatic clinical disease, which usually does not present until after birth, is a compensated mild hemolytic anemia with reticulocytosis, microspherocytosis, and early-onset unconjugated hyperbilirubinemia.

Risk factors for ABO incompatibility are present in 12–15% of pregnancies, but evidence of fetal sensitization (positive direct Coombs test) occurs in only 3–4%. Symptomatic ABO hemolytic disease occurs in <1% of all newborn infants but accounts for approximately two-thirds of observed cases of hemolytic disease in the newborn.

Transplacental transport of maternal isoantibody results in an immune reaction with the A or B antigen on fetal erythrocytes, which produces characteristic microspherocytes. This process eventually results in complete extravascular hemolysis of the end-stage spherocyte. The ongoing hemolysis is balanced by compensatory reticulocytosis and shortening of the cell cycle time, so that there is overall maintenance of the erythrocyte indices within physiologic limits. A paucity of A or B antigenic sites on the fetal (in contrast to the adult) erythrocytes and competitive binding of isoantibody to myriad other antigenic sites in other tissues may explain the often mild hemolytic process that occurs and the usual absence of progressive disease with subsequent pregnancies.

1. A₁ antigen in the infant. Of the major blood group antigens, the A₁ antigen has the greatest antigenicity and is associated with a greater risk of symptomatic disease. However, the hemolytic activity of anti-B antibodies is higher than those of anti-A and may produce a more severe disease in particular among infants of African American descent.

2. Elevated isohemagglutinins. Antepartum intestinal parasitism or third-trimester immunization with tetanus toxoid or pneumococcal vaccine may stimulate isoantibody titer to A or B antigens.

3. Birth order. Birth order is not considered a risk factor. Maternal isoantibody exists naturally and is independent of prior exposure to incompatible fetal blood group antigens. First-born infants have a 40–50% risk for symptomatic disease. Progressive severity of the hemolytic process in succeeding pregnancies is a rare phenomenon.

1. Jaundice. Icterus is often the sole physical manifestation of ABO incompatibility with a clinically significant level of hemolysis. The onset is usually within the first 24 hours of life. The jaundice evolves at a faster rate over the early neonatal period than nonhemolytic physiologic pattern jaundice.

2. Anemia. Because of the effectiveness of compensation by reticulocytosis in response to the ongoing mild hemolytic process, erythrocyte indices are maintained within a physiologic range that is normal for asymptomatic infants of the same gestational age. Additional signs of clinical disease (eg, hepatosplenomegaly or hydrops fetalis) are extremely unusual but may be seen with a more progressive hemolytic process (see Chapter 127). Exaggerated physiologic anemia may occur at 8–12 weeks of age, particularly when treatment during the neonatal period required phototherapy or exchange transfusion.

Obligatory screening for infants with unconjugated hyperbilirubinemia includes the following studies:

1. Blood type and Rh factor in the mother and the infant. These studies establish risk factors for ABO incompatibility.

2. Reticulocyte count. Elevated values after adjustment for gestational age and degree of anemia, if any, support the diagnosis of hemolytic anemia. For term infants, normal values are 4–5%; for preterm infants of 30–36 weeks' gestational age, 6–10%. In ABO hemolytic disease of the newborn, values range from 10 to 30%.

3. Direct Coombs test (direct antiglobulin test). Because there is very little antibody on the red blood cell (RBC), the direct Coombs test is often only weakly positive at birth and may become negative by 2–3 days of age. A strongly positive test is distinctly unusual and would direct attention to other isoimmune or autoimmune hemolytic processes.

4. Blood smear. The blood smear typically demonstrates microspherocytes, polychromasia proportionate to the reticulocyte response, and normoblastosis above the normal values for gestational age. An increased number of nucleated RBCs in the cord blood could be a sign of ABO incompatibility.

5. Bilirubin levels (fractionated or total and direct). Indirect hyperbilirubinemia is mainly present and provides an index of the severity of disease. The rate at which unconjugated bilirubin levels are increasing suggests the required frequency of testing, usually every 4–8 hours until values plateau.

6. Additional laboratory studies. Supportive diagnostic studies may be indicated on an individual basis if the nature of the hemolytic process remains unclear.

   1. Antibody identification (indirect Coombs test). The indirect Coombs test is more sensitive than the direct Coombs test in detecting the presence of maternal isoantibody and identifies antibody specificity. The test is performed on an eluate of neonatal erythrocytes, which is then tested against a panel of type-specific adult cells.

   2. Maternal IgG titer. The absence in the mother of elevated IgG titers against the infant's blood group tends to exclude a diagnosis of ABO incompatibility.

1. Antepartum treatment. Because of the low incidence of moderate to severe ABO hemolytic disease, invasive maneuvers before term is reached (eg, amniocentesis or early delivery) are usually not indicated.

2. Postpartum treatment

   1. General measures. The maintenance of adequate hydration (see Chapter 9) and evaluation for potentially aggravating factors (eg, sepsis, drug exposure, or metabolic disturbance) should be considered.

   2. Phototherapy. Once a diagnosis of ABO incompatibility is established, phototherapy may be initiated before exchange transfusion is given. Because of the usual mild to moderate hemolysis, phototherapy may entirely obviate the need for exchange transfusion or may reduce the number of transfusions required. For guidelines on phototherapy, see Table 100–1 and Figure 100–2.

   3. Exchange transfusion. See Table 100–1 and Figure 100–3 for guidelines on exchange transfusion and Chapter 30 for exchange transfusion procedure.

   4. Tin (Sn) porphyrin. This can decrease the production of bilirubin and reduce the need for exchange transfusion and duration of phototherapy. It is an inhibitor of heme oxygenase, which is the enzyme that allows the production of bilirubin from heme. The dose of Stannsoporfin is 6 μmol/kg intramuscularly as a single dose given within 24 hours of birth with severe hemolytic disease, and it is available via compassionate use protocol.

   5. Intravenous immunoglobulin (IVIG). By blocking neonatal reticuloendothelial Fc receptors and thus decreasing hemolysis of the antibody-coated RBCs, high-dose IVIG (1 g/kg over 4 hours) reduces serum bilirubin levels and the need for blood exchange transfusion with ABO or Rh hemolytic diseases. Caution should be used when considering treatment with IVIG as there are emerging reports of increased incidence of necrotizing enterocolitis in term and late-preterm infants with hemolytic disease of the newborn and isoimmune neonatal thrombocytopenia who were treated with IVIG.

   6. Synthetic blood group trisaccharides. Their use is investigational; studies have shown a decrease in exchange transfusion rates in severe ABO hemolytic disease when A or B trisaccharides were administered.

For infants with ABO incompatibility, the overall prognosis is excellent. Timely recognition and appropriate management of the rare infant with aggressive ABO hemolytic disease may avoid any potential morbidity or severe hemolytic anemia and secondary hyperbilirubinemia and the inherent risks associated with exchange transfusion with the use of blood products.