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I. DEFINITION

Rh incompatibility is a condition that occurs during pregnancy when a mother with Rh-negative blood [who is previously sensitized to the Rh(D) antigen] is exposed to her fetus who is Rh-positive leading to the development of Rh antibodies and resulting in fetal isoimmune hemolytic anemia of variable severity. The onset of clinical disease begins in utero as the result of active placental transfer of maternal immunoglobulin (Ig)G-Rh antibody. It is manifested as a partially compensated, moderate to severe hemolytic anemia at birth, with unconjugated hyperbilirubinemia developing in the early neonatal period.

II. INCIDENCE

Historically, Rh hemolytic disease of the newborn accounted for up to a third of symptomatic cases seen and was associated with detectable antibody in approximately 15% of Rh-incompatible mothers. The use of Rh immunoglobulin (RhoGAM) prophylaxis has reduced the incidence of Rh sensitization to <1% of Rh-incompatible pregnancies. In developing countries without prophylaxis, stillbirth still occurs in 14% of affected pregnancies, and 50% of pregnancies survivors either die in the neonatal period or develop cerebral injury. Other alloimmune antibodies have become relatively more important as a cause of hemolysis. Anti-c, Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), MNS (M, N, S, and s), and less commonly anti-C and anti-E may cause severe hemolytic disease of the newborn.

III. PATHOPHYSIOLOGY

Initial exposure of the mother to the Rh antigen occurs most often during parturition, miscarriage, abortion, and ectopic pregnancy. Invasive investigative procedures such as amniocentesis, chorionic villus sampling, and fetal blood sampling also increase the risk of fetal transplacental hemorrhage and alloimmunization. Recognition of the antigen by the immune system ensues after initial exposure, and reexposure to the Rh antigen induces a maternal anamnestic response and elevation of specific IgG-Rh antibody. Active placental transport of this antibody and immune attachment to the Rh-antigenic sites on the fetal erythrocyte are followed by extravascular hemolysis of erythrocytes within the fetal liver and spleen. The rate of the hemolytic process is proportionate in part to the levels of the maternal antibody titer but is more accurately reflected in the antepartum period by elevation of the amniotic fluid bilirubin concentration and in the postpartum period by the rate of rise of unconjugated bilirubin. In contrast to ABO incompatibility, the greater antigenicity and density of the Rh-antigen loci on the fetal erythrocyte facilitates progressive, rapid clearance of fetal erythrocytes from the circulation. A demonstrable phase of spherocytosis will be absent. Compensatory reticulocytosis and shortening of the erythrocyte generation time, if unable to match the often high rate of hemolysis in utero, result in anemia in the newborn infant and a risk of multiple systemic complications.

IV. RISK FACTORS

  1. Birth order. The first-born infant is at minimum risk (<1%) unless sensitization has occurred previously. Once sensitization has occurred, subsequent pregnancies are at a progressive increased risk for fetal disease.

  2. Fetomaternal hemorrhage. The volume of fetal erythrocytes entering the maternal circulation correlates with the risk of sensitization. The risk is approximately 8% with each pregnancy but ...

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