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Minor Red Cell Antigens and Fetal Hemolytic Anemia

Author: Patricia A. Smith, MD

Mentor: Nancy D. Gaba, MD
Editor: Julie DeCesare, MD

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There are more than 300 recognized blood-group antigens, of which the Rhesus (Rh) blood-group system is the most common cause of maternal alloimmunization. It is comprised of the c, C, D, e and E antigens.  Anti-Rh D antibody was the major cause of hemolytic disease of the fetus and newborn (HDFN) until the 1970s, when widespread use of antenatal and postpartum Rh immune globulin resulted in a major reduction in the incidence of Rh D alloimmunization in pregnancy.

Non-Rh D antigens expressed on erythrocytes are often referred to as minor or atypical antigens.     Since no prophylactic immune globulins are available to prevent the formation of non-Rh D antibodies, maternal alloimmunization to non-Rh D red cell antigens is becoming a more frequent cause of HDFN. Overall, antibodies to minor antigens occur in 1.5–2.5% of obstetric patients.

The most frequently encountered atypical antibodies are Lewis and I antibodies. Lewis and I antigens do not result in antibodies that cause HDFN because they predominantly consist of immunoglobulin M, which does not cross the placenta.  In addition, these antigens are poorly expressed on fetal and newborn erythrocytes.

Among the more than 50 minor antigens, only three are commonly associated with antibodies that cause severe fetal disease. They are anti-Kell (K1), anti-Rh c and anti Rh E.  Duffy and Kidd antibodies are a less common cause of HDFN among the atypical antigens.

The incidence of the Kell (anti-K1) antibody has been increasing in the United States. Kell has surpassed anti-RhD as the leading antibody associated with HDFN in many countries where anti-D immunoglobulin is routinely used. Kell alloimmunization is often caused by prior transfusion because Kell compatibility was not considered during cross-matching blood.

Once a maternal antibody associated with HDFN is detected, an indirect Coombs titer should be obtained. Care of patients with sensitization to atypical antigens that are known to cause HDFN should be the same as that for patients with D alloimmunization.  Similar titer levels should be used to guide care except in in mothers who have previously had an affected fetus or neonate and in Kell-sensitized patients because Kell antibodies do not correlate with fetal status.

Management also includes determination of paternal erythrocyte antigen status.  If the biologic father is negative for the antigen and there is no question of paternity, no further testing is warranted as the fetus will not be at risk for HDFN.  If paternal testing returns positive, zygosity testing should be requested from the blood bank as a heterozygous state can be detected through serologic testing.  Cell-free fetal DNA testing is only clinically available for Rh (D) in the United States, while in Europe assays are available for c, E, and Kell antigens.

Fetal ultrasound evaluation of the middle cerebral artery peak systolic velocity (MCA-PSV) should be the primary method of diagnosis and management of fetal anemia. The use of delta optical density 450 (ΔOD450) to detect fetal anemia is primarily of historic interest and no longer routinely used except in rare circumstances.

Further reading:

American College of Obstetricians and Gynecologists, ACOG Practice Bulletin No. 192: Management of Alloimmunization During Pregnancy. Obstet Gynecol. 2018 Mar;131(3):e82-e90. doi: 10.1097/AOG.0000000000002528.

Society for Maternal-Fetal Medicine (SMFM). Electronic address:, Mari G, Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: the fetus at risk for anemia--diagnosis and management. Am J Obstet Gynecol. 2015 Jun;212(6):697-710. doi: 10.1016/j.ajog.2015.01.059. Epub 2015 Mar 27.

Initial Approval May 2016, Published September 2016, Revised November 2017, Reaffirmed May 2019


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