Rhesus Blood Groups and Maternal-Fetal RhD Incompatibility

Posted on Apr 3, 2025 in Biology

Rhesus Blood Groups and RhD Incompatibility

Rhesus Blood Group System

  • Genetically determined by 6 important antigens (among approximately 50 antigens): c-C, d-D, e-E.
  • Presence of antigen D (a strong antigen) on the erythrocyte membrane determines positivity (Rh+). This applies to about 85% of the European population.
    • Possible Genotypes: CDE, CDe, cDe, cDE
  • Rh negativity (Rh-) is determined by the d antigen (a weak antigen).
    • Possible Genotypes: Cde, Cde, cde, cdE
  • Sometimes, the presence of the E antigen shows weak positivity.
  • Antibodies in the Rh system are normally not present.
  • However: D is a strong antigen that can induce the production of antibodies in Rh-negative individuals upon exposure.

Biochemical Structure and Inheritance

  • The proteins carrying Rh antigens are transmembrane proteins, which seem to function as ion channels.
  • The main antigens are encoded by two adjacent gene loci on chromosome 1 (p36-p34):
    • RHD Gene: Expresses the D-antigen. Various alleles exist. The lack of this gene results in Rh negativity (Rh-). Subject to RHD polymorphism.
    • RHCE Gene: Expresses the next four most common antigens: C, c, E, and e.
  • A child will be Rh negative if both parents are Rh negative.

Hemolytic Disease of the Newborn (HDN)

Hemolytic disease of the newborn develops when maternal IgG antibodies, specific for fetal blood group antigens, cross the placenta and destroy fetal red blood cells (RBCs).

It most commonly develops in an Rh-negative (dd) mother carrying an Rh-positive (D) fetus.

Mechanism of Rh Isoimmunization

First Pregnancy
  • An Rh-negative mother is usually not exposed to a sufficient quantity of fetal RBCs during the first pregnancy to activate a significant immune response.
  • At the time of delivery, the separation of the placenta from the uterine walls allows larger amounts of fetal umbilical cord blood to enter the mother’s circulation.
  • These fetal RBCs activate the mother’s Rh(D)-specific B-cells, leading to the production of anti-D antibodies (initially IgM) and the appearance of memory B-cells.
  • Secreted IgM antibodies clear the Rh(D)+ fetal RBCs from the mother’s circulation, but memory B-cells remain, resulting in Rh isoimmunization.
Second Pregnancy (with Rh+ Fetus)
  • If the mother carries another Rh(D)+ fetus, fetal RBCs crossing the placenta activate the memory B-cells established during the first pregnancy.
  • This triggers a rapid secondary immune response, producing large amounts of high-affinity anti-D IgG antibodies.
  • Maternal IgG antibodies cross the placenta and bind to Rh(D) antigens on the fetal RBCs.
  • This binding activates the complement system or leads to phagocytosis, causing the destruction of fetal red blood cells.

Consequences of Fetal RBC Lysis

  • Hemolytic anemia in the fetus/newborn.
  • Erythroblastosis fetalis (a more severe form characterized by the presence of immature red blood cells in the fetal circulation due to compensatory erythropoiesis).

Diagnosis of HDN Risk

Coombs’ Test (Direct Antiglobulin Test)
  • Determines the presence of maternal IgG antibodies attached to the surface of fetal erythrocytes.
  • Procedure: Isolated fetal RBCs (usually from cord blood after birth) are incubated with Coombs’ reagent (antibodies against human IgG).
  • Positive Result: Agglutination (clumping) of the RBCs occurs if maternal IgG is bound to them, indicating sensitization.

Prevention of Rh Isoimmunization

  • All Rh-negative women are typically given an injection of anti-RhD immunoglobulin (e.g., RhoGAM) during pregnancy (around 28 weeks) and within 72 hours after the delivery of an Rh-positive baby, or after any event potentially causing fetal-maternal hemorrhage.
  • This passively administered antibody destroys any fetal RhD-positive RBCs in the mother’s circulation before they can stimulate her immune system to produce her own anti-D antibodies and memory cells.

Therapy for Hemolytic Disease of the Newborn

  • Severe form: Intrauterine blood exchange transfusion may be performed for the fetus, replacing the fetus’s Rh-positive blood with Rh-negative blood. This may be repeated every 10-21 days until delivery.
  • Less severe cases: Transfusion may not be necessary until after birth. Phototherapy (exposure to specific wavelengths of light, often blue light) is used to break down excess bilirubin (a byproduct of RBC destruction) and prevent jaundice and kernicterus (bilirubin-induced brain damage).
  • Maternal treatment during pregnancy: In some severe cases, plasmapheresis may be considered. A machine separates the mother’s blood into cells and plasma. The plasma containing the harmful anti-D antibodies is discarded, and the cells are re-infused into the mother along with a plasma substitute.