Minor Red Cell Antigens and Fetal Hemolytic Anemia
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.
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: firstname.lastname@example.org, 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
********** Notice Regarding Use ************
The Foundation for Exxcellence in Women’s Health, Inc (“Foundation”) is committed to accuracy and will review and validate all Pearls on an ongoing basis to reflect current practice.
This document is designed to aid practitioners in providing appropriate obstetric and gynecologic care. Recommendations are derived from major society guidelines and high quality evidence when available, supplemented by the opinion of the author and editorial board when necessary. It should not be construed as dictating an exclusive course of treatment or procedure to be followed.
Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The Foundation reviews the articles regularly; however, its publications may not reflect the most recent evidence. While we make every effort to present accurate and reliable information, this publication is provided “as is” without any warranty of accuracy, reliability, or otherwise, either express or implied. The Foundation does not guarantee, warrant, or endorse the products or services of any firm, organization, or person. Neither the Foundation, the ABOG, SASGOG nor their respective officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with this publication or reliance on the information presented.
Copyright 2019 The Foundation for Exxcellence in Women's Health, Inc. All rights reserved. No re-print, duplication or posting allowed without prior written consent.Back to Search Results