This chapter should be cited as follows:
Castleman JS, Kilby MD, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.418123

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 16

The prevention and management of Rh disease

Volume Editors: Professor Gerard HA Visser, Department of Obstetrics and Gynaecology, University Hospital of Utrecht, Heidelberglaan 100, Utrecht 3584EA, The Netherlands
Professor Gian Carlo Di Renzo, University of Perugia, Italy

Chapter

Medical Management of Rhesus Disease

First published: November 2022

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ABSTRACT

Fetal red cell destruction by maternal antibodies remains an important cause of fetal and neonatal morbidity and mortality. Intrauterine fetal blood transfusion is the therapy of choice for severe hemolytic disease of the fetus. Invasive fetal therapy carries risk of miscarriage, preterm birth, fetal demise, and further sensitization. Severe, early onset fetal anemia is more hazardous because fetal intravascular needle insertion is more technically challenging due to small vessel size. Non-invasive, medical treatments are important to minimize or avoid procedure-related risks. Intravenous immunoglobin (IVIg) and novel monoclonal antibody (M281, nipocalimab) treatments may attenuate the transplacental passage and fetal effects of IgG antibodies. By delaying the onset of fetal anemia, immunological therapies can defer the need for first transfusion. These medical therapies in early onset hemolytic disease of the fetus and newborn (HDFN) improve fetal survival. Their wider impact on perinatal management, and the longer-term outcomes for survivors of HDFN are important to elucidate.

INTRODUCTION

Prompt recognition and in utero treatment of alloimmune fetal anemia is vital to avoid fetal death and adverse neonatal outcomes.^1,2 In maternal red blood cell (RBC) alloimmunization, IgG class antibodies cross the placenta to destroy fetal erythroid cells expressing the involved antigen. The antigens D, Kell, and c are considered the most high risk^3,4 and alloimmunized pregnancies should be identified and managed according to international evidence-based guidelines as previously described.^5,6,7,8 Women with a previous pregnancy affected by HDFN or a critical level of high-risk alloantibody, require review by a fetal medicine specialist.⁸

In order to understand the mechanism of action of contemporary medical treatments, it is important to appreciate the underlying pathophysiology of HDFN. The fetal/neonatal Fc receptor (FcRn) is a heterodimer, first identified in the neonatal rodent intestine transporting IgG in breast milk.⁹ FcRn is now recognized as an important transmembrane protein at the maternal–fetal interface, involved in IgG and albumin homeostasis¹⁰ (Figure 1). FcRn in vascular endothelial cells recycles the circulating serum IgG pool, which is a key role in immunoglobulin homeostasis. FcRn in the placental syncytiotrophoblast transports maternal IgG subtypes across the placenta, by transcytosis, into the fetal circulation.¹⁰ There are also several subtypes of IgG antibody that have a differing pathogenicity and rate of transplacental passage.¹¹

The movement of IgG across the placenta by FcRn is dependent on several factors, including the amount of antibody in the maternal circulation, the gestational age and placental "integrity". Features of the antibody and antigen are also important, for example the subclass and degree of glycosylation of IgG, and the expression of antigen (those from the thymus being more intense). The physiological role of FcRn is to provide passive immunity to the fetus by transferring IgG across the placenta, and protecting IgG from degradation. In human disease, this mechanism is potentially harmful, such as in HDFN when alloantibodies enter the fetal circulation to target RBCs for destruction. Passage of the IgG1 subclass is most efficient and most readily causes HDFN.¹²

INVASIVE FETAL THERAPY WITH INTRAUTERINE BLOOD TRANSFUSION

Fetal blood transfusion is described elsewhere in this volume. The risks and benefits of invasive fetal therapy must be borne in mind to appreciate the role of medical therapies in attenuating the disease process and deferring the need for intervention. Needle procedures are associated with pregnancy loss, ruptured membranes, and increased alloantibody formation.^13,14 The largest reported retrospective study of 1678 IUTs in 589 fetuses over three decades from Leiden University Medical Center in the Netherlands, reported a procedure-related complication rate of 3.3% with perinatal loss rate of 1.8%.¹⁵ Intravascular transfusion before 22 weeks is associated with higher overall fetal mortality because the small anatomical dimensions of the fetal vasculature make the procedure more technically challenging.^16,17 A series of 30 intrauterine, intravascular transfusions performed before 22 weeks (range 16–22 weeks) in Toronto reported a procedure-related complication rate of 6.7% and an overall perinatal loss rate of 20%.¹⁶ The Leiden group reported a similar number of cases performed prior to 20 weeks (n = 29, range 16–19+6 weeks) with a procedure-related complication rate of 5% and a non-procedure-related complication risk of 11% (per procedure).¹⁷ The perinatal loss rate overall (per fetus) was 24%, with 85% of losses occurring before 20 weeks. Fetal intraperitoneal transfusion is an option prior to 20 weeks, to defer the time of first fetal intravascular transfusion.¹⁸

Pregnancies with early-onset fetal anemia (prior to 22 weeks) are the main beneficiaries of medical treatments, which dampen the alloimmune antibody-mediated red cell destruction, as they have the highest rates of procedure-related fetal loss. For women with a previous pregnancy affected by HDFN, previous early-onset disease or hydropic stillbirth are risk factors for being susceptible to early-onset disease again. The onset of fetal anemia is usually 4–6 weeks earlier in the subsequent affected pregnancy.¹³

There are four potential mechanisms of action for medical management of red cell alloimmunization. Firstly, a drug might reduce the amount of circulating maternal IgG antibody by preventing its production. Secondly, a molecule might eliminate IgG from the maternal or fetal circulation. A third mechanism would be to prevent IgG against red cell antigen from crossing the placenta (via FcRn) into the fetal circulation. Finally, a therapy could target the antibody–antigen complex and alter the interaction between the antibody and target fetal antigen. Apart from mechanism of action, it is important to consider unwanted effects and cost. Maternal (or fetal) immunosuppression can lead to life-threatening infectious morbidity. When considering any fetal therapy the protection of the woman from complications is a key tenet.^19,20 Maternal immune therapies may be expensive, time consuming, and demanding on healthcare resources.

Maternal immunomodulation therapy

Evidence exists from small cohort series for the use of azathioprine, promethazine, and prednisolone to prevent red cell alloimmunization.^21,22 Such immunomodulation is rarely used, if at all, in contemporary practice. Mouse models of “peptide immune therapy” to alter the recognition of the red cell antigens by T-helper cells to induce active tolerance have yielded promising results but there have been no subsequent reports of this potential therapy.²³ Ongoing research is evaluating the prevention of RBC alloantibody formation following antigen exposure, including the humoral immune processes distinguishing responders from non-responders.²⁴ Antigen recognition, clearance and their interaction with alloantibodies are potential future therapeutic targets.²⁴

Plasma exchange

Maternal plasma exchange has historically been used to clear alloantibodies (non-selectively) from the maternal circulation. Plasmapheresis leads to loss of electrolytes and important proteins like coagulation factors and other immunoglobulins as well as alloantibodies. Other concerns with this technique relate to altered maternal hemodynamics and reduced placental perfusion as well as the impact on resources as it requires specialist skills for vascular access and delivery. A rebound increase in antibody levels after therapeutic plasma exchange occurs due to immune activation as autoregulatory factors are removed.^25,26 Serial plasmapheresis can be combined with IVIg infusion to reduce the chance of further antibody formation.²⁷ Immunoadsorption and intravenous IVIg has been used with good outcomes.²⁸ This technique is rarely now practiced in the management of severe maternal red cell alloimmunization.

Intravenous immunoglobulin (IVIg)

High dose immunoglobulins were first used as a treatment for autoimmune disease in the context of pediatric immune thrombocytopenia in the early 1980s.²⁹ This-therapeutic strategy is a "paradox", as IVIg was originally used as an antitoxin to treat infectious disease (before antibiotics were available) and in immunodeficiency as replacement therapy.³⁰

Delaying the natural history of HDFN can defer the need for transfusion until a later, safer gestation.^18,31,32,33 In women with severe alloimmunization in previous pregnancies, the use of maternal IVIg can postpone invasive intrauterine transfusions.^18,34 The main mechanism of action of IVIg is competitive inhibition, blocking the transplacental transfer of alloimmune IgG. It also dilutes alloantibody, increases antibody “turnover”, reduces the woman’s own antibody production and blocks fetal secondary macrophage function.^35,36 IVIg can cause systemic adverse reactions, such as fever, urticarial (type I hypersensitivity) reaction, hemolytic anemia, aseptic meningitis, and thrombosis. Patients receiving IVIG should be advised that headaches are the commonest side effect, occurring in up to 15%.³⁷ As a derived blood product, there is the theoretical risk of transmitting blood borne infection. IVIg is an expensive, scarce resource ($6000/£4800/€5500 per week) requiring careful health economic consideration.³⁸

The "Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment" (PETIT) study was an international collaboration, pooling multicenter, retrospective observational cohort study data. Cases were enrolled with a qualifying pregnancy, which was affected by HDFN prior to 24 weeks. A subsequent pregnancy with an antigen-positive fetus was treated with or without IVIg.³⁹ The “treatment group” comprised 24 women who received IVIg (at a dose of 1 g per kilogram maternal weight per week). A “control” group of 28 women were not treated with IVIg. Each of the 52 women also served as their own control as outcomes in each pregnancy were compared. IVIg therapy delayed the onset of clinically significant anemia compared to the previous pregnancy by 15 days as compared to the group not treated with IVIg where the delay was 9 days. IVIg also appeared to reduce the overall incidence of fetal hydrops (4% vs. 24%, odds ratio (OR) 0.03; 95% confidence interval, 0–0.5; P = 0.011) and the need for neonatal exchange transfusion (9% vs. 37%; OR: 0.1; 95% confidence interval, 00.5; P = 0.009). Overall survival was 88%, with no difference between IVIg or control groups.³⁹ A subgroup analysis indicated that if the IVIg was initiated before 13 weeks of gestation, fetal anemia was delayed by 25 days as compared to the previous pregnancy. Anemia prior to 20 weeks' gestation occurred less often (23%) as compared to the untreated previous pregnancy (54%). A treatment that could make a more clinically useful reduction in the need for invasive transfusion would revolutionize care.

Experimental monoclonal antibody therapy: M281 (nipocalimab)

M281 is a next-generation Fc receptor (FcRn) blocking agent, which binds with high affinity and specificity to the IgG binding site of FcRn. It may be an effective non-surgical intervention for those women with HDFN likely to require IUT during early gestation when the procedure-related risks are relatively high.^40,41 Also known as nipocalimab, M281 is a fully human, recombinant, aglycosylated IgG1 monoclonal antibody formulated for intravenous infusion. M281 has the potential to inhibit IgG transport across the placenta via FcRn from mother to fetus, including the transfer of anti-red cell alloantibodies. FcRn also prevents the degradation of IgG, instead recycling it during normal internalization of circulating proteins into endothelial cells and maintaining its long half life.¹⁰ The blockade of FcRn-IgG binding is expected to decrease IgG half-life and serum concentrations including those of pathogenic IgG.^42,43 Similar mechanisms have also been postulated for IVIg where high concentrations of administered IgG work by competitive inhibition of endogenous IgG for placental transport and recycling as previously discussed. M281 has greater than 1000-fold higher affinity binding to FcRn than IgG and is therefore likely to be more efficient in inhibiting these processes.

In preclinical studies, M281 demonstrated inhibition of placental IgG transfer from maternal to fetal circulation in a human placental perfusion model within 4 to 6 h, suggesting rapid saturation of FcRn and a fast onset of action.⁴⁴ The risk of fetal and neonatal M281 exposure is considered low because transfer from the maternal to fetal circulation is insignificant. In a murine model, anti-FcRn antibody-protected rodent fetuses from thrombocytopenia due to maternal antiplatelet antibodies⁴⁵ and from miscarriage due to maternal antibodies inducing placental damage.⁴⁶

There were no serious or severe adverse events in the first in-human study of M281.⁴⁰ The drug was well tolerated with only mild reactions reported in similar frequency to placebo. As predicted by its mechanism of action and preclinical studies, M281 induced rapid dose-dependent lowering of serum IgG upon administration of single and multiple doses. FcRn has a role in albumin homeostasis⁴² and M281 was shown to lower serum albumin, but this effect was to a lesser extent than IgG. The human volunteers in the study did not have any signs or symptoms of hypoalbuminemia and the effect was not severe. Studies of other anti-FcRn agents in rheumatology patients have also not reported any serious adverse events.⁴² Early concerns regarding increased risk of infection related to the inhibition of FcRn-mediated lowering of IgG serum concentrations have not been confirmed by preliminary data with M281 or other anti-FcRn agents.⁴² Antagonists of FcRn do not affect other antibody classes. There should be no impact on the ability to fight infection as the IgM response to new antigen is preserved.⁴⁷ Clearly maternal, fetal, and neonatal safety of this novel therapy are of paramount importance to the trial teams and clinicians in research and clinical practice. FcRn antagonism is a promising mechanism of action, with translational research confirming proof of concept, tolerability, and clinical utility.

The UNITY (NCT03755128) study is a multicenter, open-label, proof-of-principle (phase II) clinical study sponsored by Momenta Pharmaceuticals Inc. (Cambridge, Massachusetts, USA) (https://clinicaltrials.gov/ct2/show/NCT03842189?term=M281&draw=2&rank=2). UNITY is designed to evaluate the potential of weekly intravenous M281 to delay or prevent the need for IUT in pregnant mothers at risk of early onset HDFN prior to 24 weeks, the same population analyzed in the PETIT study. M281 is initiated upon confirmation of positive fetal antigen status at approximately 14 weeks of gestation. Weekly dosing until 35 weeks aims to block placental IgG transfer of pathogenic alloantibodies for as long as possible. The study will enroll 15 pregnant women affected by early onset HDFN. Primary endpoints in the study are maternal and infant safety and efficacy as determined by the frequency of live births at ≥32 weeks gestational age without the requirement for an IUT throughout pregnancy. The inclusion criteria make the eligibility quite rare, therefore collaboration between international centers is required. Robust safety of data for this experimental therapy, including detailed pharmacodynamic and pharmacokinetic data in pathologic pregnancies, as well as short- and long-term follow up of surviving children is mandatory.

CONCLUSION

HDFN is an alloimmune pathology associated with an increased risk of perinatal mortality and neonatal morbidity, both from prematurity and the direct effects of anemia and hyperbilirubinemia. A small but significant cohort of women with red cell alloimmunization are at risk of developing early-onset fetal anemia and although IUT is possible (prior to 22 weeks), it carries increased risk of procedure-related complications including miscarriage. In these patients, IVIG administered late in the first trimester may postpone the gestational age when an IUT is required to a technically safer time. A novel strategy to inhibit transplacental alloantibody transfer with maternal M281 monoclonal antibody therapy is under evaluation with potential for greatest impact in these alloimmunized pregnancies at risk of early-onset fetal anemia.

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