Epidemiology and Screening

Alloimmunization occurs in approximately one to two percent of pregnancies 1, though this estimate includes antibodies which are not clinically significant (see HDFN and the clinical impact of specific antibodies for a list of clinically significant antibodies). A recent retrospective observational study by Sánchez-Durán et al. in a large university setting identified maternal antibodies in 337 pregnancies in a fifteen-year period, of which 259 were clinically significant and known to have the potential to cause mild to severe hemolysis. Of these 259, the fetus was determined to be at risk (i.e., the fetus did inherit or had the potential to inherit the antibody’s target red blood cell antigen) in 194 2. Though RhD immune globulin (RhIG) prophylaxis is standard in developed countries, anti-D remains one of the most frequently identified antibodies (hence the name “Rh Disease”) along with anti-Kell (anti-K) and anti-E.

All pregnant patients should receive blood typing and an antibody screen (indirect Coombs test) during their first prenatal visit. The results of these screens present the following options for clinical management:

  • Rh positive blood type: no RhD immune globulin prophylaxis needed.
  • Rh negative blood type, “weak D” or “partial D” status: patient should receive RhIG prophylaxis between weeks 26 to 28 of pregnancy 3, within 72 hours of any pregnancy bleeding event ≥ 6 weeks (including miscarriage or abortion) 4, or invasive procedure that may cause fetomaternal bleeding, and within 72 hours of birth of an RhD positive fetus.
    • – It should be emphasized that a positive antibody screen for RhD that is thought not to be a result of recent RhIG prophylaxis indicates the patient is already sensitized to the RhD antigen, and therefore RhIG prophylaxis is not necessary.
    • – A patient with a non-D antibody who is also Rh negative should continue to receive RhIG as scheduled above.
  • Negative indirect Coombs test: no further evaluation necessary
  • Positive indirect Coombs test: conduct antibody identification and determine antibody titer.
    • – A positive indirect Coombs test for anti-D = no RhIG needed.
    • – A positive indirect Coombs test for anti-D within 6 months 4 of RhIG administration may be a response related to RhIG and not indicative of true alloimmunization. In this case the titer for anti-D is low (1:2 or 1:4).

Once a patient’s antibody type and titer is established, the following sequence must take place to determine whether the fetus is at risk:

  • Determine whether the mother has had a child affected by HDFN requiring intervention in a previous pregnancy. If this is the case and paternity is assured to be the same as the previous pregnancy, one should expect a similar or more severe course of HDFN 5.
  • Previous history cannot indicate that a fetus will be unaffected. When a mother with a clinically significant antibody presents, she must still be monitored and the fetal antigen status should still be determined unless the paternal testing reveals a homozygous status for the involved antigen.
  • If the mother has not had a previously affected pregnancy, determine whether the antibody has the potential to cause HDFN.
  • If the antibody does not have the potential to cause HDFN, proceed with routine obstetric care.
  • If the antibody does have the potential to cause HDFN and paternity is certain, obtain zygosity testing from the father for the antigen in question. In the case of RhD, genetic testing of the father must be used instead of serology since there is no Rh negative antigen. Serology can be used through most blood banks to determine paternal zygosity through standard serologic testing. Note that while the mother is tested for her antibody and titer, the father is tested for the corresponding antigen (not antibody or titer).
    • – If the father is homozygous for the antigen in question (e.g., an EE genotype in the case of an anti-E pregnancy), the fetus is certain to be at risk.
    • – If the father is heterozygous for the antigen in question (e.g., an Ee genotype in the case of an anti-E pregnancy), or paternity is uncertain, the fetus may be at risk. Options to determine fetal antigen status include:
      • Cell-free DNA testing of maternal blood can determine fetal antigen status for RhD, RhC, Rhc, RhE, and Kell with over 99% accuracy. If cffDNA testing for the antigen in question is not an option in the patient’s country, the patient’s blood can be shipped to a country where testing is available. Read more about cffDNA testing.
      • Amniocentesis (after 15 weeks gestation) can be presented as an option to the mother in order to definitively determine fetal antigen status, though it is used less frequently due the risk of feto-maternal hemorrhage 5. If it is undertaken, a transplacental approach should be avoided at all costs. Chorionic villus sampling (CVS) is CONTRAINDICATED due to the elevated risk for feto-maternal hemorrhage and a resulting increase in the maternal titer.
      • If cffDNA is not available and the patient does not want to proceed with amniocentesis, the pregnancy can be followed with serial middle cerebral artery peak systolic velocity (MCA-PSV) Doppler ultrasound examinations (see description below) However the clinician must be aware that the MCA-PSV is associated with a 10% false positive rate for the detection of fetal anemia – this could lead to unnecessary invasive fetal procedures.
    • If the father is negative for the antigen in question (e.g., an ee genotype in the case of an anti-E pregnancy) and paternity is certain, the fetus is not at risk. No further testing or specialized ultrasound exams are indicated. The issue of certain paternity should be documented in the medical record.

Read more about the necessary and optional laboratory assessments for the mother, father, and fetus.

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