Rh Incompatibility – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- 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
Predominant age and sex: Affects fetuses/neonates of isoimmunized child-bearing females
- 15% of white population and smaller fractions of other races are Rh-negative and susceptible to sensitization (1).
- Any Rh-positive pregnancy in an Rh-negative woman can result in sensitization.
- Native risk of isoimmunization after Rh-positive pregnancy had been estimated to be ≤15%, but seems to be decreasing.
- Risk of isoimmunization antepartum is only 1–2%.
- Risk of isoimmunization is 1–2% after spontaneous abortion and 4–5% after induced abortion (2).
- Use of Rho(D) immune globulin prophylaxis has reduced incidence of isoimmunization to <1% of susceptible pregnancies.
- Complex autosomal inheritance of polypeptide Rh antigens; 3 genetic loci with closely related genes carry an assortment of alleles: Dd, Cc, and Ee (3).
- Individuals who express the D antigen (also called Rho or Rho[D]) or its weak D (Du) variant are considered Rh-positive. Individuals lacking the D antigen are Rh-negative. (There is no antigen identified with the d allele.)
- Antibodies may be produced to C, c, D, E, or e in individuals lacking the specific antigen; only D is strongly immunogenic (4).
- Isoimmunization to Rh antigens in susceptible individuals is acquired, not inherited.
- Blood typing (ABO and Rh) on all pregnant women and prior to blood transfusions
- Antibody screening early in pregnancy
- Rh immune globulin prevents only sensitization to the D antigen.
- For prophylaxis, Rho(D) immune globulin (RhIG, RhoGAM, HyperRHO, RHOphylac) given to unsensitized, Rh-negative women after the following:
- Spontaneous abortion
- Induced abortion
- Ectopic pregnancy
- Antepartum hemorrhage
- Trauma to abdomen
- Chorionic villus sampling
- Routinely at 28 weeks’ gestation
- Within 72 h of delivery of an Rh-positive infant
- Dose for prophylaxis:
- 50-µg (50 microgram) dose for events up to 12 weeks’ gestation
- 300-µg (300 microgram) 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).
- 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.
- Transfusion of Rh-positive blood to Rh-negative recipient
- Maternal exposure to fetal Rh antigens, either antepartum or intrapartum
- Most commonly seen in the Rh-positive fetus or infant of an Rh-negative mother
Commonly Associated Conditions
- Hemolytic disease of newborn
- Hydrops fetalis
- Neonatal jaundice
- See related topic: Erythroblastosis Fetalis
- Jaundice of newborn
- Fetal hydrops or fetal death in utero if severe (see related topic Erythroblastosis Fetalis)
Diagnostic Tests & Interpretation
Initial lab tests
- Positive indirect Coombs test (antibody screen) during pregnancy
- Paternal blood type
- Kleihauer-Betke (fetal hemoglobin acid elution, Hb F slide elution) test to quantify an acute fetal–maternal bleed
- Congenital or fetal anemia
- Blood type, direct Coombs test in newborn
Follow-Up & Special Considerations
Prior administration of D immune globulin may lead to weakly (false-) positive indirect Coombs test in mother and direct Coombs test in infant.
- ABO incompatibility
- Other blood group (non-Rh) isoimmunization
- Nonimmune fetal hydrops
- Hereditary spherocytosis
- RBC enzyme defects
- Depending on severity of involvement, treatment of fetus may include:
- Intrauterine transfusion
- Early delivery
- Treatment of newborn may include:
- Exchange transfusion
- Transfusion after delivery
- Diuretics and digoxin for hydrops
- Immunoglobulin infusion has reduced the need for exchange transfusion in a few studies (5)[C].
Issues for Referral
Because of the specialized, somewhat hazardous treatment measures involved, pregnancies in Rh-sensitized women are usually managed at tertiary-care level.
Initial monitoring of newborn is inpatient, in special care nursery if treatment interventions are needed.
- In most cases, outpatient ambulatory management is appropriate during the antepartum period.
- Antibody titer measured at 20 weeks and every 4 weeks thereafter during pregnancy; a titer of ≥1:16 indicates the need for further testing (3).
- If the patient had a previously affected infant, an Rh-positive fetus in the current pregnancy should be considered at risk regardless of antibody titers (6):
- Fetal heart rate testing/ultrasonography to assess fetal status
- Doppler ultrasonography measurement of cerebral blood flow is now a suitable alternative to invasive tests (amniocentesis, cordocentesis) for diagnosing fetal anemia (6).
- Umbilical blood sampling (cordocentesis) for fetal blood type, hematocrit, reticulocyte count, and presence of erythroblasts (3)
- Amniocentesis for amniotic fluid bilirubin levels (3)
- Amniocentesis for fetal lung maturity if early delivery is a treatment option (3)
- With appropriate monitoring and treatment, infants born of severely affected pregnancies have a survival rate of >80% (3).
- Fetuses with hydrops have a higher mortality rate.
- Even with severe disease, the neurologic outcome of survivors is generally good.
- Disease is likely to be more severe in affected subsequent pregnancies.
- Pregnancy loss from umbilical blood sampling
- Pregnancy loss from intrauterine transfusion
- Fetal distress requiring emergent delivery (3)
1. Bianchi DW, Avent ND, Costa JM, et al. Noninvasive prenatal diagnosis of fetal Rhesus D: ready for Prime(r) Time. Obstet Gynecol. 2005;106:841–4.
2. Bowman J. Thirty-five years of Rh prophylaxis. Transfusion. 2003;43:1661–6.
3. Management of alloimmunization during pregnancy. ACOG Practice Bulletin 75. Aug 2006, reaffirmed 2008.
4. Agre P, Cartron JP. Molecular biology of the Rh antigens. Blood. 1991;78:551–63.
5. Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev. 2006;Issue 1.
6. Moise KJ. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol. 2008;112:164–76.
Prevention of Rh D alloimmunization. ACOG Practice Bulletin 4. May 1999, reaffirmed 2009.
See Also (Topic, Algorithm, Electronic Media Element)
Anemia, Autoimmune Hemolytic; Erythroblastosis Fetalis; Jaundice
- 656.11 Rhesus isoimmunization, affecting management of mother, delivered
- 656.13 Rhesus isoimmunization, affecting management of mother, antepartum condition
- 773.0 Hemolytic disease of fetus or newborn due to Rh isoimmunization
- V28.5 Antenatal screening for isoimmunization
- 88924008 Rh incompatibility reaction (disorder)
- 44795003 Rhesus isoimmunization affecting pregnancy (disorder)
- 169673001 antenatal RhD antibody screening (procedure)
- If paternity is certain, determining that the father does not carry the Rh(D) blood group antigen eliminates the need to give RhIG prophylaxis during pregnancy or the need for special fetal surveillance if the mother is already sensitized.
- Attempts have been made to determine the fetal blood type noninvasively by detecting fetal DNA in the maternal blood. Because Rh antigens are polymorphic among racial groups, this technique has both false-positive and false-negative results and should be considered experimental.
- The weak D antigen, formerly called Du, is a weakly reacting variant of the D antigen. A “weak D–positive” mother or infant should be managed as any other D-positive mother or infant, respectively.
- The dose of RhIG for prophylaxis is affected by gestational age. The fetal blood volume is only a few milliliters at 12 weeks’ gestation. Therefore, a 50-µg (50 microgram) dose of RhIG may be used for threatened, spontaneous, or induced abortions up to 12 weeks’ gestation instead of the standard 300-µg (300 microgram) dose.