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418123 08/10/2023
This chapter should be cited as follows:
Castleman JS, Kilby MD, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.418123
Chapter
AUTHORS
James S Castleman
West Midlands Fetal Medicine Centre, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
Mark D Kilby
West Midlands Fetal Medicine Centre, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham; Institute of
Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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 e ects of IgG antibodies. By delaying the onset of fetal anemia, immunological therapies can defer the
need for rst 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
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The Continuous Textbook of Women's Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.418123 08/10/2023
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 risk3,4 and
alloimmunized pregnancies should be identi ed and managed according to international evidence-based guidelines as
previously described.5,6,7,8 Women with a previous pregnancy a ected 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, rst identi ed 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 di ering pathogenicity and rate of
transplacental passage.11
Figure 1 Schematic diagram of FcRn function and M281 blockade. Adapted from Roopenian & Akilesh Nat Rev Immunol
2007;7(9):715–25. doi:10.1038/nri2155, © Momenta Pharmaceuticals Inc. All rights reserved.
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 e cient and most readily causes HDFN.12
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The Continuous Textbook of Women's Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.418123 08/10/2023
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.
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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 immunode ciency 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 e ect, 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 a ected 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 signi cant 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% con dence interval, 0–0.5; P = 0.011) and the need for neonatal exchange transfusion (9% vs.
37%; OR: 0.1; 95% con dence interval, 00.5; P = 0.009). Overall survival was 88%, with no di erence 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.
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 a nity binding
to FcRn than IgG and is therefore likely to be more e cient 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
insigni cant. 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 rst in-human study of M281. 40 The drug was well tolerated with
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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 e ect was to a lesser
extent than IgG. The human volunteers in the study did not have any signs or symptoms of hypoalbuminemia and the
e ect 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 con rmed by preliminary data with M281 or other anti-FcRn agents.42
Antagonists of FcRn do not a ect other antibody classes. There should be no impact on the ability to ght 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 con rming 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 con rmation 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 a ected by early onset HDFN. Primary endpoints in the
study are maternal and infant safety and e cacy 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 e ects of anemia and hyperbilirubinemia. A small but signi cant 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 rst 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.
PRACTICE RECOMMENDATIONS
• Maternal red cell alloimmunization carries increased fetal risk of perinatal morbidity and mortality and
requires antenatal monitoring.
• The most sensitive and specific, non-invasive screening for fetal anemia is by serial middle cerebral artery
Doppler peak systolic velocity.
• In utero transfusion of the fetus is the "gold standard" therapy but carries increased risks at early gestation
(<20 weeks).
• Maternal therapy, such as serial intravenous immunoglobulin (IVIG) infusions may prolong the gestation of
first in utero transfusion in this high-risk group.
• The use of IVIG or more contemporary immunological therapies may attenuate transplacental IgG transfer,
reducing the need for in utero transfusion and requires more research assessment before introduction into
clinical practice.
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CONFLICTS OF INTEREST
Professor Kilby receives no direct funding from Momenta Pharmaceuticals. Birmingham Women’s and Children’s Research
Development/University of Birmingham, UK receives funding from Momenta for the ongoing phase II clinical trial.
There is no original data presented in this review article. Data from published studies are referenced.
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