Evolving Strategies in the Diagnosis and Management of Hemolytic Disease of the Fetus and Newborn
Since its introduction in the mid-1960s, IUT of compatible red cells to the anemic fetus has proven to be the most effective fetal therapy to date. In the mid-1980s, improvements in ultrasound technology allowed for direct access to the fetal circulation through a puncture of the umbilical vein at either the cord insertion into the placenta or as the vein courses through the fetal liver. Survival rates have improved to more than 95% in experienced centers, with reports of complications in 1.2% of procedures.9 The widespread adoption of the MCA-PSV to detect fetal anemia earlier in gestation before the onset of hydrops fetalis has probably been the major factor in improved outcomes.10 However, a growing concern is that the decreasing incidence of disease due to the implementation of antenatal and postpartum prophylaxis for RhD alloimmunization will lead to fewer training opportunities to maintain the availability of skilled fetal interventionists. A recent study found that between 30 and 50 IUT procedures were required for a physician in training to achieve an optimal perinatal outcome.11 An annual case rate of 10 procedures was required to maintain that expertise.
Early-onset severe HDFN (EOS-HDFN) presents a greater challenge to even the most experienced fetal medicine specialist. In these cases, technical issues with the puncture of small-diameter fetal vessels and a fragile fetal cardiovascular physiology contribute to a higher rate of perinatal mortality. Prior to 22 weeks’ gestation, fetal loss can complicate up to 20% of procedures.12 Should a perinatal loss occur, the management of a subsequent pregnancy is even more difficult, because fetal anemia typically occurs earlier in gestation. In such cases characterized by EOS-HDFN, nonspecific immunomodulation has been used in the form of intravenous immunoglobulin (IVIG) with or without the use of serial plasmapheresis to lower the maternal titer.13 Proposed mechanisms of action of IVIG include suppression of the maternal titer, partial placental blockade through competition for transport sites, and transplacental passage with suppression of the fetal reticuloendothelial system to decrease the phagocytosis of sensitized fetal red cells. In the PETIT retrospective study of 52 pregnancies affected with EOS-HDFN, standard treatment resulted in the onset of fetal anemia at the same gestational age or several weeks earlier than the antecedent pregnancy. In those patients treated with IVIG before 13 weeks’ gestation, a 25-day delay in the gestational age at first IUT was noted compared with the previous pregnancy.14
IVIG therapy is costly and associated with significant maternal adverse effects and complications including headaches, aseptic meningitis, and hemolysis. Other reproductive options for women with a history of EOS-HDFN include surrogate pregnancy, donor sperm from an individual who is RhD negative, and adoption. Pre-implantation genetic testing (PGTM) has been reported with a heterozygous paternal RhD genotype and is also an option for couples in which the male partner is heterozygous for RhD.15
Given the complexity and increased risk for adverse outcomes in such cases, a more targeted immunologic approach to HDFN is needed that will minimize or negate the risks associated with IUT. The offending maternal immunoglobulin G (IgG) in red cell alloimmunization is actively transported across the placenta through binding at the neonatal Fc receptor (FcRn). FcRn is also found on adult endothelial cells and is responsible for maintaining the circulating pool of IgG by preventing intracellular catabolism. Recently, several monoclonal antibodies have been developed that target this receptor in an effort to treat adult immunologic-based diseases such as myasthenia gravis. Such monoclonal therapy for red cell alloimmunization in pregnancy would have 2 beneficial actions: a decrease in the circulating maternal anti-red cell antibody titer and, more importantly, a blockade at the level of the placenta to protect the fetus. One such monoclonal antibody, nipocalimab (M281), is currently in a phase 2 clinical trial to evaluate its use in the treatment of EOS-HDFN (https://clinicaltrials.gov/ct2/show/nct03842189).
We await the results of this exciting trial, which may well complete the mission I once proposed for red cell alloimmunization in pregnancy—the time has come to put the needles away.16
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.
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- 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.
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- 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.
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- 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.