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  1. Definition. Isoimmune hemolytic anemia of variable severity may result when Rh incompatibility develops between an Rh-negative mother previously sensitized to the Rh (D) antigen and her Rh-positive fetus. The onset of clinical disease begins in utero as the result of active placental transfer of maternal IgG-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.

  2. 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 ~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. 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. This cannot be prevented by the use of D antigen–specific Rh immunoglobulin.

  3. 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, results in anemia in the newborn infant and a risk of multiple systemic complications.

  4. Risk factors

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

      1. Fetomaternal hemorrhage. The volume of fetal erythrocytes entering the maternal circulation correlates with the risk of sensitization. The risk is ~8% with each pregnancy but ranges from 3–65%, depending on the volume of fetal blood (3% with 0.1 mL compared with 22% with >0.1 mL) that passes into the maternal circulation.

      1. ABO incompatibility. Coexistent incompatibility for either the A or B blood group antigen reduces the risk of maternal Rh sensitization to 1.5–3.0%. Rapid immune clearance of these fetal erythrocytes after their entry into the maternal circulation exerts a partial protective effect. It confers no protection once sensitization has occurred.

      1. Obstetric factors. Cesarean delivery or trauma to the placental bed during the third stage of labor increases the risk of significant fetomaternal transfusion and subsequent maternal sensitization.

      1. Gender. Male infants are reported to have an increased risk of more severe disease than females, although the basis for this ...

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