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Rh Incompatibility
Kirsten A. Winnie, MD
Jennifer G. Chang, MD
image 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
Predominant age and sex: affects fetuses/neonates of isoimmunized, childbearing females
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.
  • 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
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 heterogenous, 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 (1).
  • Another variant D antigen, DEL, has been identified in some individuals (predominantly Asians) who are classified as Rh-negative by the usual assays. Although testing Rh-negative, these individuals are not likely to be sensitized by exposure to Rh-D antigens through pregnancy or transfusion and should be considered clinically Rh-positive (2).
  • Antibodies may be produced to C, c, D, E, or e in individuals lacking the specific antigen; only D is strongly immunogenic (3).
  • 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 (4).
  • Any Rh-positive pregnancy in an Rh-negative woman can result in sensitization.
  • Weak D and partial D women are a heterogenous 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 (5).
  • 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 (6).
  • Use of Rho(D) immunoglobulin prophylaxis has reduced incidence of isoimmunization to <1% of susceptible pregnancies (7)[A].
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, Rho-GAM, 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-&mgr;g dose for events up to 12 weeks’ gestation
    • 300-&mgr;g 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.
image DIAGNOSIS
PHYSICAL EXAM
  • Jaundice of newborn
  • Kernicterus
  • Fetal hydrops or fetal death in utero if severe (see “Erythroblastosis Fetalis” topic)
DIFFERENTIAL DIAGNOSIS
  • ABO incompatibility
  • Other blood group (non-Rh) isoimmunization
  • Nonimmune fetal hydrops
  • Hereditary spherocytosis
  • RBC enzyme defects
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • 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
  • Flow cytometry using antibody to hemoglobin F is emerging as an alternative to the Kleihauer-Betke test to detect or quantify fetal-maternal bleed (8).
  • Congenital or fetal anemia
  • Blood type, direct Coombs test in newborn
  • Cell-free fetal DNA (Cff DNA) test (see “Clinical Pearls”)
Follow-Up Tests & Special Considerations
Prior administration of Rho(D) may lead to weakly (false-) positive indirect Coombs test in mother and direct Coombs test in infant.
image TREATMENT
GENERAL MEASURES
  • Depending on severity of involvement, treatment of fetus may include the following:
    • Intrauterine transfusion (9)[C]
    • Early delivery
  • Treatment of newborn may include the following:
    • Exchange transfusion
    • Transfusion after delivery
    • Phototherapy
  • Inconclusive evidence on efficacy of IVIG to reduce need for exchange transfusion (10)[A]
P.919

ISSUES FOR REFERRAL
Because of the specialized, somewhat hazardous treatment measures involved, pregnancies in Rhsensitized women are usually managed at tertiarycare facilities with maternal fetal medicine specialists.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Initial monitoring of the newborn is inpatient or in special care nursery if treatment interventions are needed.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • 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 (5).
  • 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 (11).
    • Fetal heart rate testing/US to assess fetal status
    • Doppler US measurement of cerebral blood flow is now a suitable alternative to invasive tests (amniocentesis, cordocentesis) for diagnosing fetal anemia (11).
    • Umbilical blood sampling (cordocentesis) for fetal blood type, hematocrit, reticulocyte count, and presence of erythroblasts (5)
    • Amniocentesis for amniotic fluid bilirubin levels (5)
    • Amniocentesis for fetal lung maturity if early delivery is a treatment option (5).
PROGNOSIS
  • With appropriate monitoring and treatment, infants born of severely affected pregnancies have a survival rate of >80% (11).
  • Even with severe disease, the neurologic outcome of survivors is generally good (8)[C].
  • Fetuses with hydrops have a higher mortality rate and higher risk of neurologic impairment (8)[C].
  • Disease is likely to be more severe in affected subsequent pregnancies.
REFERENCES
1. Flegel WA. Molecular genetics and clinical applications for RH. Transfus Apher Sci. 2011;44(1):81-91.
2. Shao CP, Xu H, Xu Q, et al. Antenatal Rh prophylaxis is unnecessary for “Asia type” DEL women. Transfus Clin Biol. 2010;17(4):260-264.
3. Agre P, Cartron JP. Molecular biology of the Rh antigens. Blood. 1991;78(3):551-563.
4. Bianchi DW, Avent ND, Costa JM, et al. Noninvasive prenatal diagnosis of fetal Rhesus D: ready for Prime(r) Time. Obstet Gynecol. 2005;106(4):841-844.
5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 75: management of alloimmunization during pregnancy. Obstet Gynecol. 2006;108(2):457-464.
6. Bowman J. Thirty-five years of Rh prophylaxis. Transfusion. 2003;43(12):1661-1666.
7. Crowther CA, Middleton P, McBain RD. Anti-D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database Syst Rev. 2013;(2):CD000020.
8. Kim YA, Makar RS. Detection of fetomaternal hemorrhage. Am J Hematol. 2012;87(4):417-423.
9. Lindenburg IT, Smits-Wintjens VE, van Klink JM, et al. Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study. Am J Obstet Gynecol. 2012;206(2):141.e1-141.e8.
10. Louis D, More K, Oberoi S, et al. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2014;99(4):F325-F331.
11. Moise KJ Jr, Argoti PS. Management and prevention of red cell alloimmunization in pregnancy: a systematic review. Obstet Gynecol. 2012;120(5):1132-1139.
12. Elalfy MS, Elbarbary NS, Abaza HW. Early intravenous immunoglobulin (two-dose regimen) in the management of severe Rh hemolytic disease of newborn—a prospective randomized controlled trial. Eur J Pediatr. 2011;170(4):461-467.
13. Tiblad E, Tuane Wikman A, Ajne G, et al. Targeted routine antenatal anti-D prophylaxis in the prevention of RhD immunization—outcome of a new antenatal screening and prevention program. PloS One. 2013;8(8):e70984.
14. Hawk AF, Chang EY, Shields SM, et al. Costs and clinical outcomes of noninvasive fetal RhD typing for targeted prophylaxis. Obstet Gynecol. 2013;122(3):579-585.
Additional Reading
&NA;
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 4: prevention of Rh D alloimmunization. Int J Gynaecol Obstet. 1999;66(1): 63-70.
See Also
&NA;
Anemia, Autoimmune Hemolytic; Erythroblastosis Fetalis; Jaundice
Codes
&NA;
ICD10
  • P55.0 Rh isoimmunization of newborn
  • O36.0990 Maternal care for other rhesus isoimmunization, unspecified trimester, not applicable or unspecified
  • T80.40XA Rh incompat react due to tranfs of bld/bld prod, unsp, init
Clinical Pearls
&NA;
  • 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.
  • Cell-free fetal DNA (Cff DNA) testing has evolved as the standard practice in many European countries; it is available in the United States but is not a widely covered benefit. It allows detection of fetal Rh genotype with accuracy of 97.1%, sensitivity of 97.2%, and specificity of 96.8% (11).
  • 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 (13). Currently, routine administration of Rh immune globulin is more cost effective than use of Cff DNA testing in the United States (14).
  • 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-&mgr;g dose of RhIG may be used for threatened, spontaneous, or induced abortions up to 12 weeks’ gestation, instead of the standard 300-&mgr;g dose.