Hemolytic Disease of the Newborn

Rhesus (Rh) hemolytic disease of the newborn (HDN) is a serious, often fatal disease caused by incompatibility between an Rh-negative mother and her Rh-positive fetus.^1-3 If prophylaxis were not available today—as was the situation prior to the introduction of RhoGAM^® Brand in 1968—then the following statistics^1,2,4,5 would be true:

• 13% to 14% of Rh-negative expectant mothers could become alloimmunized during an Rh-incompatible pregnancy
• 25% of fetuses would need immediate treatment to avoid kernicterus (a form of brain damage caused by excessive jaundice and associated symptoms)
• 25% of fetuses would develop hydrops fetalis and die
• Only 50% of fetuses would be mildly affected and not require treatment

PATHOGENESIS¹

Alloimmunization

• An Rh-negative woman may become alloimmunized to the D antigen present on fetal red blood cells (RBCs) during the first Rh-incompatible pregnancy.
• Alloimmunization can occur during a number of situations, including fetal-maternal hemorrhage, bleeding that occurs during normal delivery, ectopic pregnancies, spontaneous or induced abortions, and abdominal trauma.
• The first pregnancy is rarely affected because the number of Rh antibodies produced by the mother during primary immunization is low and the antibodies are usually IgM in nature.

Rh Hemolytic Disease of the Newborn (HDN): Pathogenesis¹

Anamnestic response

• When the mother is exposed to D-positive fetal RBCs during a subsequent Rh-incompatible pregnancy, the mother mounts an anamnestic, or secondary, immune response to the fetus’ RBCs. A large number of IgG-class Rh antibodies are produced.
• The IgG antibodies cross the placenta and make fetal red cells susceptible to destruction. The fetal RBCs are then destroyed by the fetal immune system.
• Anemia develops in the fetus with a concomitant increase in unconjugated bilirubin.
• The anemia and unconjugated bilirubin levels can lead to a number of conditions.

CLINICAL MANIFESTATIONS

The clinical manifestations of Rh HDN can range from very mild to death in utero or shortly after delivery.^1,2,4,5

Examples include:

• The fetal liver and spleen enlarge as they attempt to produce more fetal RBCs in response to hemolysis. Nucleated RBCs can be observed in the fetal blood due to the release of immature erythyrocytes (this gave rise to the name, erythroblastosis fetalis).
• In the worst cases, severe anemia leads to hydrops fetalis, which is characterized by severe edema that develops sometime after 18 weeks’ gestation. Hydrops fetalis develops secondary to congestive heart failure and liver failure due to extreme hepatosplenomegaly (enlargement of the liver and spleen) and portal hypertension.
• After delivery, jaundice may occur due to an increase in RBCs. The infant lacks sufficient amounts of glucuronidase and albumin to process the bilirubin, which was metabolized by the placenta and the mother before birth.
• Kernicterus or bilirubin encephalopathy can occur as levels of unconjugated bilirubin increase. The bilirubin can accumulate in neuronal tissues resulting in central nervous system damage and developmental problems that can include:
  • dental enamel dysplasia
  • high-frequency nerve deafness
  • athetoid cerebral palsy
  • mental retardation, pulmonary hemorrhage
  • death

References:

1. Rubin E, Farber JL. Development and genetic diseases. In: Pathology. 2nd ed. Philadelphia, Pa: JB Lippincott Company;1994:256.
2. Prasad AS. Acquired hemolytic anemias. In: Bick RL, ed. Hematology: Clinical and Laboratory Practice. Vol 1. St. Louis, Mo: Mosby-Yearbook, Inc.;1993:391-396.
3. Turgeon ML. Hemoyltic disease of the newborn. In: Turgeon ML, ed. Fundamentals of Immunohematology: Theory and Technique. Philadelphia,PA: Lea & Febiger;1989:321-343.
4. Bowman JM. Antenatal suppression of Rh alloimmunization. Clin Obstet Gynecol. 1991;34:296-303.
5. Freda VJ, Gorman JG, Pollack W, et al. Prevention of Rh hemolytic disease—ten years’ clinical experience with Rh immune globulin. N Engl J Med. 1975;292:1014-1016.