9/1/2016
Minor Red Cell Antigens and Fetal Hemolytic Anemia
Registered users can also download a PDF or listen to a podcast of this Pearl.
Log in now, or create a free account to access bonus Pearls features.
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.
********** Notice Regarding Use ************
The Society for Academic Specialists in General Obstetrics and Gynecology, Inc. (“SASGOG”) 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. SASGOG 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. SASGOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or person. Neither SASGOG nor its 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 2024 The Society for Academic Specialists in General Obstetrics and Gynecology, Inc. All rights reserved. No re-print, duplication or posting allowed without prior written consent.
Back to Search Results