Evolving Strategies in the Diagnosis and Management of Hemolytic Disease of the Fetus and Newborn
Once a significant cause of perinatal loss, alloimmunization to red cell antigens is infrequently encountered in obstetrical practice today. Although maternal alloimmunization to the rhesus blood group D (RhD) antigen remains the leading cause of fetal anemia, more than 50 different red cell antigens have been associated with hemolytic disease of the fetus and newborn (HDFN). Sensitization to any one of these antigens occurs in approximately 1% of pregnancies.1 Most of these anti-red cell antibodies result in the need for only phototherapy or simple transfusions after birth. However, after anti-RhD, only a few red cell antibodies are associated with profound HDFN necessitating fetal therapy. A review of one large series of intrauterine transfusions (IUTs) from a national referral center indicated that 10% of IUTs were secondary to Kell disease, and 3.5% of IUTs were secondary to anti-c alloimmunization.2 In another large series of IUTs, antiE, anti-e, and anti-Fya were reported to require IUT in single cases.3 Significant advances in diagnostic tools for the management of red cell alloimmunization have occurred with the addition of genetic testing of the parents and fetus and the use of Doppler ultrasonography for the detection of fetal anemia.
Pregnant women routinely undergo red cell typing and an antibody screen at their first prenatal visit. Identification of an antibody associated with HDFN should result in a reflex determination of the maternal titer. Until recently, titers were performed manually by laboratory technicians using an indirect Coombs test on serial dilutions of the patient’s serum combined with indicator red cells. Gel technology now allows for automation of the process of performing antibody screens and determining antibody titers. Gel titers typically provide results 2 to 3 dilutions higher than conventional tube titers (eg, 1:8 is found to be 1:64 with gel), making the threshold for a critical titer more difficult to determine.4 Obstetricians and maternalfetal medicine specialists should discuss the results of a titer with their local blood bank to better understand the methodology and to decide if further fetal surveillance is warranted.
Paternal antigen and subsequent zygosity testing is an important next step in the evaluation process. An RhD-negative paternal blood type indicates the fetus is not at risk for HDFN as long as paternity is assured. DNA technology is now the preferred approach to determine if 1 or 2 copies of the paternal RhD gene are present.5 A heterozygous result (only one RhD gene present) indicates a 50% chance of an affected fetus. For other cases of red cell alloimmunization, paternal testing through serologic methods can still be used to determine zygosity. For example, a Kell-positive partner can have his red cells tested with anti-K and anti-k reagents. A reaction to anti-K indicates the individual is Kell positive. If the anti-k serology test is also positive, the individual is heterozygous for Kell, which is true for the majority of individuals. If the anti-k reaction is negative, the individual is homozygous for Kell, which is a rare phenotype. Direct DNA testing can also determine paternal zygosity in these cases.
Another advance in the field is the ability to determine the fetal antigen status through free fetal DNA. Often employed in clinical practice for determining the risk for chromosomal abnormalities, free fetal DNA after approximately 12 weeks’ gestation can be used to determine the fetal RhD status when the patient’s partner is heterozygous or paternity is unknown.6 European reference labs have expanded this technology to determine the fetal antigen status for other important red cell antigens associated with severe HDFN, namely Kell, RhC, and RhE7; however, these tests are currently unavailable in the United States.
Kenneth J. Moise, Jr., MD
Department of Obstetrics, Gynecology and
McGovern School of Medicine – UT Health
The Fetal Center
Children’s Memorial Hermann Hospital
To receive CME credit, please read the articles and go to www.omniaeducation.com/HDFN to access the posttest and evaluation.
Hemolytic disease of the fetus and newborn (HDFN) is a rare condition with an estimated 3 to 80 cases per 100,000 persons annually in the United States. Nonetheless, the complexity and increased risk for adverse outcomes in such cases requires more targeted approaches to HDFN that minimize or negate the risks associated with intrauterine transfusion.
This article focuses on the pathophysiology underlying fetal/newborn allo- and autoimmune diseases, especially HDFN and the current/evolving diagnostic and treatment regimens for HDFN.
- Sean T. Barrett has nothing to disclose.
- Barry A. Fiedel, PhD has nothing to disclose.
- Amanda Hilferty has nothing to disclose.
- Kenneth J. Moise, Jr., MD receives royalties from Up-To-Date, Inc. and has contracted research with Momenta Pharmaceuticals Inc.
- Robert Schneider, MSW, has nothing to disclose.
- Lee Philip Shulman, MD, FACOG, FACMG, receives consulting fees from Biogix, Celula, Cooper Surgical, Natera, and Vermillion Aspira, is a speaker for Bayer, Lupin Pharmaceuticals, Inc., and Myriad.
After participating in this educational activity, participants should be better able to:
- Explain the pathophysiology underlying fetal/newborn allo- and autoimmune diseases, with a focus on HDFN.
- Identify current diagnostic and treatment regimens for HDFN.
- Explain the role of the neonatal Fc receptor pathway as a therapeutic means to address HDFN.
ACCREDITATION AND CREDIT DESIGNATION STATEMENTS:
Global Learning Collaborative is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Global Learning Collaborative designates this enduring material for a maximum of .25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This activity is supported by an independent educational grant from Momenta Pharmaceuticals.
- Smith HM, Shirey RS, Thoman SK, Jackson JB. Prevalence of clinically significant red blood cell alloantibodies in pregnant women at a large tertiary-care facility. Immunohematology. 2013;29(4):127-130.
- Van Kamp IL, Klumper FJ, Oepkes D, et al. Complications of intrauterine intravascular transfusion for fetal anemia due to maternal red-cell alloimmunization. Am J Obstet Gynecol. 2005;192(1):171-177.
- Tiblad E, Kublickas M, Ajne G, et al. Procedure-related complications and perinatal outcome after intrauterine transfusions in red cell alloimmunization in Stockholm. Fetal Diagn Ther. 2011;30(4):266-273.
- Novaretti MC, Jens E, Pagliarini T, Bonifacio SL, DorlhiacLlacer PE, Chamone DA. Comparison of conventional tube test with diamed gel microcolumn assay for anti-D titration. Clin Lab Haematol. 2003;25(5):311-315.
- Chiu RW, Murphy MF, Fidler C, Zee BC, Wainscoat JS, Lo YM. Determination of RhD zygosity: comparison of a double amplification refractory mutation system approach and a multiplex real-time quantitative PCR approach. Clin Chem. 2001;47(4):667-672.
- Moise KJ Jr, Boring NH, O’Shaughnessy R, et al. Circulating cell-free fetal DNA for the detection of RHD status and sex using reflex fetal identifiers. Prenat Diagn. 2013;33(1):95-101.
- Finning K, Martin P, Summers J, Daniels G. Fetal genotyping for the K (Kell) and Rh C, c, and E blood groups on cell-free fetal DNA in maternal plasma. Transfusion. 2007;47(11):2126-2133.
- Mari G, Deter RL, Carpenter RL, et al; Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. N Engl J Med. 2000;342(1):9-14.
- Zwiers C, Lindenburg ITM, Klumper FJ, de Haas M, Oepkes D, Van Kamp IL. Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures. Ultrasound Obstet Gynecol. 2017;50(2):180-186.
- Zwiers C, Oepkes D, Lopriore E, Klumper FJ, de Haas M, van Kamp IL. The near disappearance of fetal hydrops in relation to current state-of-the-art management of red cell alloimmunization. Prenat Diagn. 2018;38(12):943-950.
- Lindenburg IT, Wolterbeek R, Oepkes D, Klumper FJ, Vandenbussche FP, van Kamp IL. Quality control for intravascular intrauterine transfusion using cumulative sum (CUSUM) analysis for the monitoring of individual performance. Fetal Diagn Ther. 2011;29(4):307-314.
- Yinon Y, Visser J, Kelly EN, et al. Early intrauterine transfusion in severe red blood cell alloimmunization. Ultrasound Obstet Gynecol. 2010;36(5):601-606.
- Ruma MS, Moise KJ Jr, Kim E, et al. Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization. Am J Obstet Gynecol. 2007;196(2):138.e1-e6.
- Zwiers C, van der Bom JG, van Kamp IL, et al. Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn. Am J Obstet Gynecol. 2018;219(3):291.e1- e9.
- Seeho SK, Burton G, Leigh D, Marshall JT, Persson JW, Morris JM. The role of preimplantation genetic diagnosis in the management of severe rhesus alloimmunization: first unaffected pregnancy: case report. Hum Reprod. 2005;20(3):697-701.
- Moise KJ Jr. Diagnosing hemolytic disease of the fetus—time to put the needles away? N Engl J Med. 2006;355(2):192-194.