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Minor Red Cell Antigens and Fetal Hemolytic Anemia

Author: Patricia A. Smith, MD

Mentor: Nancy D. Gaba, MD
Editor: Sangini Sheth, MD, MHP, FACOG

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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 and are poorly expressed on fetal and newborn erythrocytes.  In addition, these antigens are poorly expressed on fetal and newborn erythrocytes.

Some of the more than 50 minor antigens can cause severe fetal disease. The most common are:   anti-Kell (K1), anti-Rh c, anti-Rh E, anti-Duffy and anti-Kidd antibodies.  

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.  In cases of certain paternity, Management can begin with 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.    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, c, E, and Kell antigens.

For at-risk pregnancies i.e. positive paternal testing or uncertain paternity), titer levels should be followed monthly unless a critical titer is reached:  at most centers between 1:8 and 1:32.  At this point, middle cerebral artery peak Doppler velocimetry should be initiated. Serial titer monitoring is inadequate for mothers who are Kell-sensitized or have previously had an affected fetus or neonate.  Kell antibodies do not correlate with fetal status.

The use of delta optical density 450 (ΔOD450) to detect fetal anemia is primarily of historic interest and used only 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) 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; Major Revision January 2021; Reaffirmed July 2022; Minor Revision May 2024.


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