Rh Incompatibility

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

To view the entire topic, please or .

Medicine Central™ is a quick-consult mobile and web resource that includes diagnosis, treatment, medications, and follow-up information on over 700 diseases and disorders, providing fast answers—anytime, anywhere. Explore these free sample topics:

-- The first section of this topic is shown below --

Basics

Description

  • 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

Epidemiology

Incidence
  • Predominantly affects fetuses/neonates of isoimmunized, childbearing females; varies by race and ethnicity
  • ~15% of the white population and smaller fractions of other races are Rh-negative and susceptible to sensitization.

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 during pregnancy or, more commonly, at delivery
  • Most cases of alloimmunization involve small volume fetomaternal hemorrhage (0.1 mL or less) and occur with uncomplicated vaginal 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 (~10% of all pregnancies)

Genetics
  • 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

  • Any Rh-positive fetus in an Rh-negative pregnant 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. It is unclear what the risk is with early medication-induced abortion but is likely very low due to the small volume of embryonic red cells.
  • Cesarean delivery, multifetal gestation, placenta previa or abruption, manual removal of the placenta may increase volume of fetomaternal hemorrhage.
  • Use of Rho(D) immunoglobulin prophylaxis has reduced incidence of isoimmunization to <1% in susceptible pregnancies (1)[C].

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.
  • Cell-free fetal (Cff) DNA testing with selective administration of Rh immunoglobulin when the fetus tests Rh positive has been shown to be as effective at preventing new Rh sensitization when compared to routine administration of Rh immunoglobulin to all Rh-negative women. Such an approach avoids unnecessary use of Rh immunoglobulin (2)[B].
  • Currently, routine administration of Rh immune globulin is more cost-effective than use of Cff DNA testing in the United States (1)[C].
  • For prophylaxis, Rho(D) immunoglobulin (RhIG, RhoGAM, HyperRHO, Rhophylac) given to unsensitized, Rh-negative women after the following:
    • Threatened miscarriage or miscarriage (controversial before 12 weeks’ gestation)
    • Therapeutic pregnancy termination (no evidence for or against prophylaxis before 6–7 weeks in medication-induced abortion)
    • Ectopic pregnancy
    • Evacuation of molar pregnancy
    • Intrauterine fetal death
    • Antepartum hemorrhage
    • Trauma to abdomen
    • Amniocentesis or cordocentesis
    • Chorionic villus sampling
    • External cephalic version
    • Within 72 hours of delivery of an Rh-positive infant
    • Given routinely at 28 weeks’ gestation
  • Prophylaxis prevents sensitization that could affect a subsequent pregnancy and has little effect on the current pregnancy.
  • Dose for prophylaxis
    • 50-μg (up to 120-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

  • Neonatal jaundice (common)
  • Hemolytic disease of newborn (less common)
  • Hydrops fetalis (rare)
  • Kernicterus (rare)
  • See “Erythroblastosis Fetalis” topic.

-- To view the remaining sections of this topic, please or --

Basics

Description

  • 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

Epidemiology

Incidence
  • Predominantly affects fetuses/neonates of isoimmunized, childbearing females; varies by race and ethnicity
  • ~15% of the white population and smaller fractions of other races are Rh-negative and susceptible to sensitization.

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 during pregnancy or, more commonly, at delivery
  • Most cases of alloimmunization involve small volume fetomaternal hemorrhage (0.1 mL or less) and occur with uncomplicated vaginal 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 (~10% of all pregnancies)

Genetics
  • 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

  • Any Rh-positive fetus in an Rh-negative pregnant 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. It is unclear what the risk is with early medication-induced abortion but is likely very low due to the small volume of embryonic red cells.
  • Cesarean delivery, multifetal gestation, placenta previa or abruption, manual removal of the placenta may increase volume of fetomaternal hemorrhage.
  • Use of Rho(D) immunoglobulin prophylaxis has reduced incidence of isoimmunization to <1% in susceptible pregnancies (1)[C].

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.
  • Cell-free fetal (Cff) DNA testing with selective administration of Rh immunoglobulin when the fetus tests Rh positive has been shown to be as effective at preventing new Rh sensitization when compared to routine administration of Rh immunoglobulin to all Rh-negative women. Such an approach avoids unnecessary use of Rh immunoglobulin (2)[B].
  • Currently, routine administration of Rh immune globulin is more cost-effective than use of Cff DNA testing in the United States (1)[C].
  • For prophylaxis, Rho(D) immunoglobulin (RhIG, RhoGAM, HyperRHO, Rhophylac) given to unsensitized, Rh-negative women after the following:
    • Threatened miscarriage or miscarriage (controversial before 12 weeks’ gestation)
    • Therapeutic pregnancy termination (no evidence for or against prophylaxis before 6–7 weeks in medication-induced abortion)
    • Ectopic pregnancy
    • Evacuation of molar pregnancy
    • Intrauterine fetal death
    • Antepartum hemorrhage
    • Trauma to abdomen
    • Amniocentesis or cordocentesis
    • Chorionic villus sampling
    • External cephalic version
    • Within 72 hours of delivery of an Rh-positive infant
    • Given routinely at 28 weeks’ gestation
  • Prophylaxis prevents sensitization that could affect a subsequent pregnancy and has little effect on the current pregnancy.
  • Dose for prophylaxis
    • 50-μg (up to 120-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

  • Neonatal jaundice (common)
  • Hemolytic disease of newborn (less common)
  • Hydrops fetalis (rare)
  • Kernicterus (rare)
  • See “Erythroblastosis Fetalis” topic.

There's more to see -- the rest of this entry is available only to subscribers.