Rh Incompatibility

Rh Incompatibility is a topic covered in the 5-Minute Clinical Consult.

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  • Antibody-mediated destruction of red blood cells (RBCs) that bear Rh surface antigens in individuals who lack the antigens and have become isoimmunized (sensitized) to them
  • System(s) affected: hematologic/lymphatic/immunologic
  • Synonym(s): Rh isoimmunization; Rh alloimmunization; Rh sensitization


Predominantly affects fetuses/neonates of isoimmunized, childbearing females; varies by race and ethnicity

Etiology and Pathophysiology

  • Circulating antibodies to Rh antigens (transplacentally transferred antibodies in the case of a fetus/newborn) attach to Rh antigens on RBCs.
  • Immune-mediated destruction of RBCs leads to hemolysis, anemia, and increased bilirubin production.
  • Transplacental fetomaternal hemorrhage (most common etiology) during pregnancy or at delivery
  • Transfusion of Rh-positive blood to Rh-negative recipient; exposure to needles contaminated with Rh-positive blood
  • Most commonly seen in the Rh-positive fetus of an Rh-negative mother

  • Complex autosomal inheritance of polypeptide Rh antigens; three genetic loci with closely related genes carry an assortment of alleles: Dd, Cc, and Ee.
  • Individuals who express the D antigen (also called Rho or Rho[D]) are considered Rh positive. Individuals lacking the D antigen are Rh negative.
  • Variant D alleles (weak D and partial D) are heterogeneous, altered forms of the D antigen. Some D variants are at risk of formation of anti-D antibodies, whereas others are not. With current blood typing procedures, certain D variants likely to produce alloimmunization are typed as D-negative, although this does not include all genetic subtypes at risk of isoimmunization.
  • Another variant D antigen, DEL, has been identified in some individuals (predominantly Asians). Those with partial DEL expression are at risk for alloimmunization and should be considered clinically Rh negative. Women with complete DEL are not likely to be sensitized by exposure to Rh-D antigens through pregnancy or transfusion and should be considered clinically Rh positive and do not need RhD prophylaxis.
  • Antibodies may be produced to C, c, D, E, or e in individuals lacking the specific antigen; only D is strongly immunogenic.
  • Isoimmunization to Rh antigens in susceptible individuals is acquired, not inherited.

Risk Factors

  • ~15% of the white population and smaller fractions of other races are Rh negative and susceptible to sensitization.
  • Any Rh-positive pregnancy in an Rh-negative woman can result in sensitization.
  • Weak D and partial D women are a heterogeneous group. Although previously reported to be Rh positive and treated as such, alloimmunization has been reported and can result in HDFN or fatal hydrops fetalis.
  • Native risk of isoimmunization after Rh-positive pregnancy had been estimated at ≤15% but seems to be decreasing.
  • The risk of isoimmunization antepartum is only 1–2%.
  • The risk of isoimmunization is 1–2% after spontaneous abortion and 4–5% after induced abortion.
  • Use of Rho(D) immunoglobulin prophylaxis has reduced incidence of isoimmunization to <1% of susceptible pregnancies (1).

General Prevention

  • Blood typing (ABO and Rh) on all pregnant women and prior to blood transfusions
  • Antibody screening early in pregnancy
  • Rh immunoglobulin prevents only sensitization to the D antigen.
  • For prophylaxis, Rho(D) immunoglobulin (RhIG, RhoGAM, HyperRHO, Rhophylac) given to unsensitized, Rh-negative women after the following:
    • Spontaneous abortion
    • Induced abortion
    • Ectopic pregnancy
    • Antepartum hemorrhage
    • Trauma to abdomen
    • Amniocentesis
    • Chorionic villus sampling
    • Within 72 hours of delivery of an Rh-positive infant
    • Given routinely at 28 weeks’ gestation
  • Prophylaxis is to prevent sensitization affecting a subsequent pregnancy and has little effect on the current pregnancy.
  • Dose for prophylaxis
    • 50-μg dose for events up to 12 weeks’ gestation
    • 300-μg dose for events after 12 weeks’ gestation
    • Higher doses may be required in the event of a large fetal–maternal hemorrhage (>30 mL of whole blood).

Commonly Associated Conditions

  • Hemolytic disease of newborn
  • Hydrops fetalis
  • Neonatal jaundice
  • Kernicterus
  • See “Erythroblastosis Fetalis” topic.

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