The Alloimmune Disorders of Pregnancy: Optimizing Fetal Outcomes Through Advances in Diagnosis and Treatment 

Introduction

Though uncommon, antibody-mediated fetal diseases remain a significant cause of fetal and neonatal morbidity and mortality for patients with affected pregnancies. The general pathophysiology of these diseases revolves around maternal exposure to foreign antigens, often involving exposure to fetal cells that invariably enter the maternal circulation during pregnancy, with resulting formation of antibodies. High-affinity immunoglobulin G (IgG) antibodies can then cross the placenta and bind to the corresponding fetal antigens to cause destruction of those specific cells. The fetal or neonatal disease depends upon the cells targeted by these antibodies, with such outcomes as fetal/neonatal anemia, thrombocytopenia, congenital heart block, and fetal hepatic injury. To date, management of these diseases has revolved around prevention of fetal disease with maternal immunosuppression via maternally administered intravenous immunoglobulin (IVIG) and/or corticosteroids, direct inutero therapy such as fetal intravascular transfusion to address the downstream effects of the disease, preterm delivery as indicated, and/or treatment of the newborn. A novel form of therapy that targets transplacental transport of IgG to the fetus may revolutionize our management of these diseases by potentially allowing us to avoid the risks of in utero therapy and improving outcomes for affected fetuses and neonates. This review will discuss the current state of the science for the most common alloimmune disorders, namely, hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT) and will examine how novel immune therapy may change the scope of these disorders.

Alloimmune Disorders of Pregnancy

There are at least seven recognized antibody-mediated diseases that may affect the fetus and/or newborn (Table 1). Hemolytic disease of the fetus and newborn and fetal and neonatal alloimmune thrombocytopenia are the most common of these antibody-mediated disorders. The most familiar antibody-mediated disease is HDFN, a condition in which maternal alloantibodies target antigens on fetal red blood cells to cause fetal hemolysis and subsequent anemia.¹ With appropriate monitoring for fetal anemia and treatment as indicated, outcomes are excellent in countries such as the United States, but fetal loss or adverse neurologic sequelae still occur, particularly in low resource settings.

FNAIT occurs in the setting of alloantibodies that target antigens on fetal platelets to cause thrombocytopenia, potentially resulting in fetal intracranial hemorrhage (ICH) and subsequent adverse neurologic sequelae. FNAIT is currently estimated to occur in <1 in 1000 pregnancies.^2,3 However, in the absence of universal anti-platelet antibody screening in obstetric populations, the true incidence is unknown and the disease is usually diagnosed after the fetus or neonate presents with associated severe sequelae such as ICH. Additionally, in contrast to HDFN, FNAIT may occur in a first pregnancy. Contemporary therapy is directed at prevention of recurrent fetal thrombocytopenia in a subsequent pregnancy and includes high-dose, maternally administered IVIG with or without corticosteroids.^4,5

Alloimmune congenital heart block (CHB) occurs due to transplacental passage of antibodies to Ro/SSA and La/SSB intracellular ribonucleotide proteins that bind to the conduction tissues of the fetal heart, leading to congenital heart block (usually third-degree heart block).^6,7 CHB may occur in the setting of a more systemic disease known as neonatal lupus, with additional sequelae including liver damage and cytopenias.⁸ Cardiac damage is irreversible, resulting in lifelong pacemaker dependency.^6,7,9 The global incidence of autoimmune CHB has been estimated in the 1 in 20,000-30,000 range, and the mortality rate of this disease is just shy of 20%.⁹ Fetal echocardiography screening, maternal corticosteroid use, and use of hydroxychloroquine in high-risk pregnancies have shown incomplete results as to ameliorating this fetal and neonatal disease.

Gestational alloimmune liver disease (GALD) results from antibodies that bind to proteins on fetal hepatic cells, causing severe liver cell damage and even liver failure with resulting neonatal death. This disease is very rare, and mortality correlates strongly with the presence of encephalopathy (estimated as 33% in the absence of encephalopathy compared to 66% in the presence of encephalopathy).^10,11 Liver transplantation is necessary in 20-25% of affected individuals.^12,13 As in FNAIT, no universal screen is available thus treatment is directed at prevention of recurrent GALD following an affected pregnancy and is centered on maternal IVIG administration.   Transplacental passage of maternal stimulatory thyrotropin receptor antibodies can result in fetal or neonatal hyperthyroidism. Of the 0.2% of pregnant patients who have Graves’ hyperthyroidism, 1 in 5 infants will be diagnosed with neonatal Graves’ disease.^14,15 Fetal and neonatal sequelae of hyperthyroidism include tachycardia, goiter, advanced bone maturation, fetal growth restriction and development of hydrops fetalis.¹⁵

Neonatal alloimmune glomerulonephropathy (a form of congenital membranous nephropathy) results from the transplacental passage of anti-neutral endopeptidase antibodies which can cause severe renal damage in the fetus, resulting in neonatal renal failure and nephrotic syndrome.^16,17 Supportive therapy, including possible renal replacement therapy, may be necessary, but the disease usually resolves spontaneously in the first few months of life as maternal antibodies are cleared from the baby’s system.¹⁶ Neonates exposed to maternal antibodies that target granulocytes or neutrophils may present with severe neutropenia, and affected babies are at risk for severe, even life-limiting, infectious diseases such pneumonia, cellulitis, and sepsis.¹⁸ Treatment revolves around aggressive use of anti-microbial agents.

The Pathophysiology Underlying Alloimmune Disorders of the Fetus/Newborn: HDFN and FNAIT

In HDFN the underlying pathophysiology occurs with the exposure of fetal red cells to the maternal circulation that expresses dissimilar antigens. The maternal immune system is stimulated, and antigen specific B-lymphocyte lines are established. Immunoglobulin M antibodies are produced, however given their limited transplacental passage, these remain in the circulation for a short duration and exist as pentamers that are too large to cross the placenta to cause fetal sequalae.   Memory B-cell lines are then established, and IgG is then produced and can be detected in maternal serum 5-16 weeks post exposure. The presence of maternal red cell antibodies is termed red cell alloimmunization. Given that most maternal exposure to red cell antigens occurs in the third trimester and the time frame for development of high-affinity IgG is usually longer than the remainder of the pregnancy, the first exposed pregnancy is rarely associated with fetal or neonatal disease. In a subsequent pregnancy, though, repeat exposure to fetal red cell antigens results in the differentiation of B-lymphocytes to plasma cells, producing mature IgG. IgG then is actively transported across the placenta via the neonatal Fc receptor (FcRn) into the fetal circulation. The IgG antibodies bind to fetal antigen positive red blood cells or red blood cell precursors (Kell antigen), and these complexes are sequestered in the fetal spleen where they undergo extravascular hemolysis. With a fetal hemoglobin deficit of >2 g/dL there is a compensatory increase in fetal bone marrow reticulocytes. In the setting of progressive hemolysis to a hemoglobin deficit of >7 g/dL (fetal hematocrit <15% or hemoglobin <5 g/dL), erythroblasts are produced from the fetal liver, increased fetal cardiac output is noted, and immune mediated hydrops fetalis may occur. Hydrops fetalis is associated with lower fetal survival and is the primary predictor of long-term neurodevelopmental impairment associated with HDFN. Despite the introduction of Rh(D) immunoglobulin in the early 1970s, anti-Rh(D) remains the most frequently identified red blood cell antibody in sensitized pregnancies (identified in 586 of 100,000 pregnancies) followed by anti-Rh(E) (prevalence of 110 per 100,000 pregnancies), anti-K (68 per 100,000 pregnancies), and anti-Rh(C) (29 per 100,000 pregnancies).¹⁹ Neonatal discharge data indicates a rate of HDFN secondary to Rh(D) alloimmunization of 44.4 cases per 100,000 pregnancies.²⁰

FNAIT shares similar underlying pathophysiology to HDFN, however alloantibodies are directed to platelet antigens. Platelet membrane glycoprotein (GP) GPIba and GPIIb/IIIa are the two major receptors on the platelet surface that are responsible for platelet activation and adhesion.⁵ GPIba and GPIIb are present on platelets and megakaryocytes while GPIIIa is also present on endothelial progenitor cells and trophoblast cells and may be responsible for angiogenesis and placental development.⁵ Antibodies to platelet membrane GP are associated with maternal diseases such as autoimmune thrombocytopenia in addition to FNAIT. Platelet antibodies develop following maternal exposure to paternally derived fetal platelet antigens that the mother herself lacks. The alloantibodies are identified as human platelet alloantigens (HPA) and denoted by a specific number, eg, HPA-1a. The ‘a’ indicates the higher frequency allele and ‘b’ the lower frequency allele. FNAIT has been associated with more than 30 different HPAs. Anti-HPA-1a and anti-HPA-5a antibodies are the most common FNAIT associated antibodies in a Caucasian population, while anti-HPA-5b and anti-HPA-4b are more commonly associated with FNAIT in Japanese populations.⁵ Maternal exposure to fetal platelet antigens may arise from exposure to trophoblasts as well as fetal platelets. Maternal macrophages clear platelet antigens via attachment to the MHC class II molecules which are then cleared by T helper (Th) cells. The Th cells promote B cell differentiation which produces high-affinity, platelet-specific immunoglobulins. Similar to HDFN, the immunoglobulin binds to the placental/fetal Fc receptor for transportation into the fetal circulation. Antibody bound platelets are then destroyed in the fetal spleen, resulting in severe fetal thrombocytopenia. The most severe sequela of fetal thrombocytopenia, ICH, may be due to a combination of both severe thrombocytopenia as well as impaired angiogenesis in the fetal circulation.²¹ Finally, the presence of the specific maternal MHC class II HLA-DRB3*01:01 has been associated with significantly higher risk of HPA-1a FNAIT as well as with higher levels of HPA-1a antibodies than HLA-DRB3 negative mothers.² It is suggested that antigen presenting cells are more efficient in recruiting Th cells in the setting of the specific HLA DRB3 molecule. Among women that are anti-HPA-1a alloimmunized, >90% are HLA-DRB3 positive.²

Diagnostic Considerations of Alloimmune Disorders of Pregnancy: A Focus on HDFN and FNAIT

Given the availability of Rh(D) immunoglobulin for prevention of alloimmunization, screening and treatment for red cell alloimmunization is part of standard obstetrical care. In routine first trimester prenatal care, maternal indirect Coombs test is used to detect the presence of potentially pathologic maternal red cell antibodies. Fetal risk for HDFN is only present when the antibody titer is above a critical level, usually 16-32 for most red cell antibodies and >2 for Kell, and the fetus is a carrier of the corresponding red cell antigen.¹ Once maternal antibodies are detected, titers are measured every 4 weeks until 24 weeks and then every 2 weeks until critical titer is reached or delivery occurs.¹ Fetal antigen status can be determined by paternal phenotype and genotype assessment, PCR of fetal amniocytes via amniocentesis, or by cell free fetal DNA evaluation from maternal blood, currently available for D, K, C/c, E, and Fya.^1,22 If fetal antigen status is confirmed negative by one of these approaches, the fetus is not at risk for HDFN and routine prenatal care is warranted. If the fetal antigen carrier status is positive or unknown and critical red cell antibody titers are present, assessment for the presence of fetal anemia is determined by serial (every 1-2 weeks) ultrasound assessment of the peak systolic velocity (PSV) in the fetal middle cerebral artery (MCA).^1,23 PSV of the MCA evaluation is started as early as 16 weeks gestational age and is highly reproducible.²³ PSV greater than 1.5 multiples of the median for gestational age is highly sensitive and specific for severe fetal anemia (fetal HCT <30%), with a negative likelihood ratio of 0.02.²³ Future pregnancies are at risk for earlier onset and more severe fetal anemia and antibody titers are not predictive of HDFN in subsequent pregnancies, thus fetal antigen assessment and serial MCA PSV assessment starting at 16-18 weeks gestational age are the mainstays of diagnosis.¹

FNAIT differs from HDFN in that there is currently no universal pregnancy screening for the presence of maternal antiplatelet antibodies and no immunoglobulin prophylaxis. Most cases of FNAIT are thus diagnosed either with clinical diagnosis of fetal ICH by prenatal ultrasound or in the neonatal period with diagnosis of thrombocytopenia (<150,000/mL) within 72 hours of birth.^4,5 When clinically suspected, the diagnosis of FNAIT is made by a comparison of maternal and paternal platelet HPA antigen status as well as assessment of the presence of maternal antiplatelet antibodies. Demonstration of discordant maternal and paternal HPA epitopes, most commonly maternal HPA-1b and paternal HPA-1a phenotypes, and the presence of maternal antiplatelet antibodies, anti-HPA-1a IgG, corresponding to the paternal discordant antigen in the setting of fetal or neonatal thrombocytopenia confirms the diagnosis in the suspected index pregnancy.^4,5 In subsequent pregnancies the only current diagnostic tool for direct assessment of fetal platelet count is percutaneous umbilical cord blood sampling.

Current Therapeutic Approaches to Antibody-Mediated Fetal and Neonatal Conditions: HDFN and FNAIT

With the exception of RhD immunoglobin, which is able to prevent RhD mediated red cell alloimmunization, most therapeutic approaches are based on reduction of maternal alloantibody production and placental transmission to prevent the fetal disease or palliative treatment of the fetal or neonatal disease. As examples, neonatal alloimmune glomerulonephropathy and neonatal alloimmune neutropenia are exceedingly rare conditions without the availability of literature to guide antenatal management, but the mainstay of preventative, in utero therapy for the other antibody mediated diseases includes immunomodulation through IVIG, plasmapheresis, disease-specific medications, and/or corticosteroids. IVIG is perhaps the most useful of these therapies, although the exact mechanism of action remains elusive, the efficacy is far from ideal, and exposed patients are at risk for significant side effects and/or complications. For alloimmune CHB, hydroxychloroquine may reduce the likelihood of disease, but data regarding the use of corticosteroids to prevent progression from first- or second-degree heart block to complete block is inconclusive and therefore routine use is not recommended by the Society for Maternal-Fetal Medicine.^24,25 GALD is not suspected until after delivery, however in subsequent pregnancies, IVIG in the early second trimester has been shown to improve the chance of a healthy child from 30% to 94%.²⁶ Finally, antithyroid drugs such as methimazole and propylthiouracil may prevent fetal hyperthyroidism, but both medications, particularly methimazole, are potentially teratogenic to the developing fetus.¹⁵

Therapeutic interventions for HDFN are more well known, however they are either incompletely effective in preventing fetal anemia or carry significant fetal risk. In the first affected pregnancy, once MCA Doppler PSV assessment suggests the presence of fetal anemia, intrauterine fetal transfusion (IUT) is a very effective intervention in experienced centers. Fetal IUT is performed under ultrasound guidance using donor antigen negative blood, concentrated to hematocrit of 75-80%. Local or neuraxial maternal anesthesia is used and the fetal umbilical vein is accessed percutaneously with a 20-22 g needle. Fetal blood is sampled, allowing immediate determination of the fetal hematocrit.  With the first procedure, Coombs testing and fetal antigen status can also be confirmed. The volume of transfusion is based on the fetal blood volume and starting hematocrit, with a goal of final fetal hematocrit of 40-45%. Repeat assessment of fetal hematocrit during the procedure can ensure appropriate transfusion. In the setting of fetal hydrops, a smaller volume of transfusion is needed to reduce the risk of fetal bradycardia, and thus more frequent transfusions may be indicated until the hydrops hopefully resolves. If the fetal umbilical vein cannot be accessed, intraperitoneal, intrahepatic vein, or direct fetal intra-cardiac transfusions have been reported.¹ Given the normal life span of the RBC and continued hemolysis, fetal transfusions are usually required every 2-3 weeks until term. A final transfusion can then be performed at 34-35 weeks with a subsequent term delivery. While safe within experienced centers, IUT can be associated with intra-operative fetal bradycardia and preterm premature rupture of membranes which can result in preterm delivery, and there is a 1.6% risk of fetal loss attributable to each fetal IUT.²⁷ HDFN is likely to recur with more severe anemia and at an earlier gestational age in subsequent pregnancies. This is clinically impactful because IUT is a more challenging procedure prior to 22-24 weeks with a 10-fold higher risk of pregnancy loss and inability to complete the procedure compared to later gestational ages.²⁸ In patients at risk for severe, early onset disease (with such risk defined by the need for IUT before 24 weeks, or previous pregnancy loss due to HDFN), IVIG and plasmapheresis have been utilized. Plasmapheresis followed by IVIG administration weekly starting at 12-14 weeks gestational age has been shown to delay the need for IUT by 25 days and result in higher live birth rates compared to the patient’s prior pregnancy.^28,29

In the absence of universal screening, the first FNAIT affected pregnancy is usually not identified until the neonatal period. Neonatal care then is supportive with platelet transfusion until maternal IgG is no longer present. FNAIT has a very high risk of recurrence, thus interventions to prevent or treat fetal thrombocytopenia have been applied.^4,5 Traditionally, in suspected pregnancies, serial fetal blood sampling and IUT of platelets to treat fetal thrombocytopenia have been performed. As previously discussed, this approach not only carries procedure related fetal risk but, due to the anti-angiogenic effects of the HPA antibodies, may incompletely prevent ICH.⁵ Fetal platelet transfusions are now limited to being performed to allow a vaginal delivery for patients who are highly motivated to avoid a cesarean delivery in pregnancies at risk for FNAIT, while in most pregnancies at risk for FNAIT, planned cesarean delivery has been proposed to reduce the risk of intrapartum ICH.⁴ Serial transfusions have been replaced by maternal administration of IVIG and prednisone to prevent fetal/neonatal thrombocytopenia and thus ICH, with data suggesting a decrease in ICH from 7-26% without therapy to 2.7% with treatment.³⁰ Dosage of IVIG for prevention of FNAIT ranges 0.5-1.0 g/kg/week to 2.0 g/kg/week based on presence of prior ICH (higher dosing) starting at 12 weeks estimated gestational age, with the addition of prednisone 0.5mg/kg/day starting in the third trimester.⁴

Importantly, while IVIG may play a role in preventing these diseases or improving the outcomes, side effects and complications are not uncommon. Side effects include headaches and influenza-like symptoms such as malaise and body aches, and prophylactic treatment with acetaminophen, diphenhydramine and intravenous hydration may minimize the severity of these concerns. Life-threatening complications such as anaphylaxis, hemolytic anemia, renal impairment, venous thromboembolic disease, and aseptic meningitis can also occur, though, and prescribing physicians must remain vigilant in ensuring early diagnoses and treatments of these conditions. It is also an expensive and time consutling therapy, with a need for weekly IVIG administration and costs of $300,000 in the United States for attempted prevention of FNAIT for each pregnancy.⁵ Long term prednisone in pregnancy has been associated with maternal glucose intolerance, and the duration of the dosing will require a prolonged maternal taper. Finally, despite the cost, need for weekly infusion therapy, and potential maternal risks, FNAIT and ICH may still occur, thus highlighting the need for novel therapies..

Beyond these preventative treatment modalities in HDFN and FNAIT, management of other antibody-mediated conditions is largely reactionary in nature.

The Role of the Neonatal Fc Receptor Pathway as a Therapeutic Approach to Alloimmune Disorders of Pregnancy

The neonatal Fc receptor may provide a unique target for the prevention of fetal disease in alloimmune diseases like HDFN and FNAIT. Although it is called the neonatal Fc receptor, the FcRn (neonatal fragment crystallizable receptor) is expressed throughout the body for the entirety of one’s life.^31,32 Although we are only beginning to understand the myriad biological roles that it plays, one of its primary functions is to promote the salvage of IgG antibodies.^31,33 The FcRn binds IgG within vascular endothelial cells, protecting the antibodies from catabolism and recycling them back into the circulation.^31,32 The end result is a half-life of IgG antibodies that far exceeds that of the other antibodies.^31,33 The FcRn is also a transport receptor.^31,32,34 In pregnancy, it plays a critical role in the transplacental transport of IgG, binding to these antibodies within the placenta to transport them from the maternal to the fetal circulation.^32-34

Given the crucial role it plays throughout the human body, the FcRn has recently been recognized as a potential target for treatment of multiple antibody-mediated diseases.³⁵ Specifically, two possible mechanisms of action have been proposed that may prove beneficial for prevention of antibody-mediated disease in pregnancy. First, antagonist binding to the FcRn receptor can result in blockade of antibody recycling. FcRn receptor sites on vascular endothelium that are bound to a pharmaceutical antagonist are thus not available to bind to IgG antibodies.^31,35 Instead of being salvaged back into the circulation, these unbound antibodies are destroyed within lysosomes.^31,35 Decreasing the half-life of these antibodies could effectively decrease maternal IgG concentrations.^31,35 The second mechanism of action is pregnancy specific. In the placenta, FcRn receptor sites that are bound to a pharmaceutical antagonist are no longer available for IgG binding, thereby blocking the transport of IgG antibodies from the maternal to the fetal circulation.^32,35

Given both its ability to lower maternal IgG concentrations and, perhaps more importantly, its potential to block transport of IgG antibodies from the maternal circulation to the fetus, FcRn blockade via a pharmaceutical agent known as nipocalimab has been proposed as a novel way to prevent antibody-mediated diseases of pregnancy.³⁵ Nipocalimab is a fully human, glycosolated IgG1 monoclonal antibody that binds with high affinity and blocks the FcRn. Nipocalimab received Fast Track designation for HDFN in July 2019 and for FNAIT in March 2024.³⁶

Prior to exposing pregnant humans to this agent, robust pre-clinical studies were performed. Much of this data is beyond the scope of this review, but the following findings should be noted. Nipocalimab rapidly saturates the FcRn ex vivo to lower transplacental IgG transport with little to no transfer of the agent itself. In a primary human villous trophoblast model, nipocalimab was found to saturate the FcRn within 30-60 minutes.³⁷ Accordingly, the transfer rate of adalimumab (a representative IgG molecule) across dually perfused human placental lobules decreased 3-4-fold to a rate that rivals that of IgA (an antibody isotype that is known to transfer extremely poorly across human placentas).³⁷ The transfer rate of nipocalimab itself across the perfused placental lobule was 0.002% (+/-0.002%), a rate that is nearly 100-fold lower than that of adalimumab.³³ Nipocalimab also binds to the FcRn with high affinity to exert its effects. In vitro, nipocalimab binds with high specificity to the FcRn without activating the receptor.³⁷ Nipocalimab rapidly saturates the FcRn and lowers serum IgG concentrations in healthy human volunteers. Nipocalimab resulted in rapid FcRn saturation as measured by receptor occupancy, and serum IgG concentrations were shown to decrease to as much as 85% of baseline in human volunteers.³⁸ Half of volunteers experienced a decrease of IgG concentrations to below 200 mg/dL.³⁸ Nipocalimab was well-tolerated in healthy human volunteers. In a Phase 1 study, 20% of healthy volunteers experienced treatment-emergent adverse events following exposure to nipocalimab that were considered related to the study drug. The most common adverse event was headache followed by nausea with or without emesis, back pain, nasal congestion, and rash of pruritis. No severe side effects, deaths, serious adverse effects, or discontinuations of treatmentwere reported.³⁸ Laboratory studies were notable for a decrease in mean albumin levels, but these levels remained within 10-15% of baseline and returned to normal within 8-15 days after dosing.³⁸ Thus, preclinical trials of nipocalimab demonstrated safety and tolerability as well as proof of concept in reducing IgG levels.

FcRn Receptor Blocker Clinical Trials in Antibody Mediated Fetal Disease, HDFN

The first pregnancy related clinical trial using nipocalimab for the prevention of HDFN is the Unity Trial.³⁹ Unity is an open label, international, single-group, phase 2 study in a population of patients with prior early onset severe HDFN. This population is at particularly high risk of adverse complications in subsequent pregnancies with a near 100% expectation of recurrent early onset severe HDFN, with a risk of pregnancy loss with transfusion prior to 20 weeks gestation of nearly 1 in 5.²⁷ The specific aim of the Unity trial was to study the safety and efficacy of nipocalimab in delaying or reducing the need for IUT in pregnancies with previous early-onset severe HDFN.

The Unity study was conducted at eight high volume fetal centers with experience in management of red cell alloimmunization and fetal transfusion across seven countries. Participants in the Unity trial had a qualifying prior pregnancy complicated by severe fetal anemia at or prior to 24 weeks gestational age, defined as any of 1) fetal hydrops with MCA PSV >1.5 MoM, 2) fetal anemia defined by cordocentesis with hemoglobin <0.55 MoM for gestational age, or 3) fetal loss with fetal or placental pathologic features of HDFN. The study included pregnant persons with maternal anti-Kell or anti-D antibodies with titers ≥4 and ≥32 respectively, and fetal antigen positivitiy for K or D was established based on cell free fetal DNA.

Weekly infusions of nipocalimab were started at 14 weeks EGA and continued until 35 weeks EGA. Dosing of the Nipocalimab was adjusted during the study to ensure complete receptor coverage and to adjust for maternal weight gain across the pregnancy. Dosing started at 30 mg/kg based on baseline weight, subsequently increased to 45 mg/kg for both current and future participants based on baseline weigh by protocol amendment to ensure full FcRn coverage. Thus, 30 mg/kg, 30 mg/kg  switched to 45 mg/kg, and only 45 mg/kg dosing were all evaluated (and adjusted every two weeks). A single maternal dose of 500 mg IVIG was given 48-72 hours prior to planned delivery in those who had completed the course of therapy. Standard of care for evaluation of fetal anemia was performed with weekly MCA Doppler PSV evaluation, cordocentesis for assessment of fetal hemoglobin was performed in the setting of MCA PSV >1.5 MoM for gestational age, and IUT performed for documented fetal severe anemia by cordocentesis.

The primary outcome for the Unity study was live birth at or after 32 weeks EGA without a fetal transfusion. Secondary outcomes included live birth, gestational age at the first transfusion, live birth without transfusion at 24 weeks EGA, number of transfusions, gestational age at delivery, fetal hydrops, need for neonatal phototherapy, and need for exchange transfusion or simple transfusion in the first 12 week of life. The outcomes for the study pregnancy were compared to the outcomes from the qualifying pregnancy. Given the mechanism of action of nipocalimab on reduction in IgG levels, important safety outcomes included infections that led to anti-infective treatment, unexpected or unusual illnesses in the neonate or infant, and decreases of the IgG level in the neonate or infant below age-specified thresholds. As none of the qualifying pregnancies met the primary outcome, a clinically significant a priori primary outcome was defined as 10%.

A total of 13 pregnancies were treated in the Unity Study. The primary outcome (live birth without transfusion after 32 weeks) occurred in 54% (7/13, 95% CI 25 to 81) of the study pregnancies, compared to 0/13 qualifying pregnancies (P < 0.001). The majority of those participants who met the primary outcome received 45 mg/kg nipocalimab dosing. The overall rate of live birth in the study pregnancy was 92% (12/13) compared to 38% (5/13) in the qualifying pregnancy and there were no cases of fetal hydrops in the study pregnancies (54% (7/13) in qualifying pregnancies). The one fetal loss in the study pregnancies occurred at 23 weeks following the first IUT in that pregnancy at 22 weeks gestational age. The median gestational age at the first transfusion and the median gestational age at delivery were significantly later in the study pregnancy and there were fewer IUTs per pregnancy in the study population. These and other selected outcomes from the UNITY Trial³⁹ are shown in Table 2. Of those pregnancies meeting the primary outcome, 6/7 did not require any prenatal or postnatal transfusions.

As anticipated by the mechanism of action of nipocalimab, maternal IgG levels decreased up to 85% from baseline and remained suppressed during treatment. IgG levels returned to baseline 1-2 weeks following cessation of weekly study medication infusion. Similarly, alloantibody titers decreased by 4-32 times baseline during treatment and returned to baseline at 4 weeks postpartum in those who had not received IUT. Neonatal IgG levels were suppressed in 6/10 pregnancies that completed nipocalimab to 35 weeks, even among those receiving maternal IVIG prior to delivery. Cord blood alloantibody titers also reflected nipocalimab dosing with neonatal alloantibody titers less than maternal titers 2-3 weeks after completing treatment at 35 weeks, while titers were significantly higher in cord blood when nipocalimab was stopped more than 7 weeks prior to delivery.

Infectious morbidity was carefully evaluated in both pregnant persons and neonates in this study given the reduction in IgG levels due to nipocalimab. Infectious complications overall were rare and none of unusual types were noted. Infections that required treatment occurred in 38% (5/13) of maternal patients (4 UTIs and one case of mastitis) and 25% (3/12) of neonates (one URI, one oral candida, and one ear infection). The remainder of serious neonatal adverse events were attributable to the alloimmunization condition, treatment of alloimmunization, or prematurity, including the above post-IUT fetal loss, neonatal respiratory distress (2/12), hyperbilirubinemia (5/12), and anemia (5/12).

Given the nature of a phase 2 study, there are some limitations in the Unity trial, including lack of blinding, small sample size and lack of diversity in the participants, potential for the qualifying pregnancy to have variable levels of care during that pregnancy, and the use of the patient as their own historical control. Given these limitations, however, the Unity outcomes are far more favorable than expected in pregnancies complicated by a prior pregnancy with early onset, severe HDFN. Overall, the favorable outcomes in the Unity study compared to standard care of surveillance with IUT or early pregnancy IVIG, without signals of adverse outcomes, support the continued investigation of nipocalimab for the prevention of HDFN in alloimmunized pregnancies.

Future Directions

With the favorable safety and efficacy results from the Unity trial, FcRn therapy is poised for potential broader application to HDFN as well as other fetal antibody mediated diseases. Prevention of HDFN and FNAIT in alloimmunized pregnancies is currently the main obstetric focus for FcRn targeted therapy. An international phase 3 double-blind, randomized, placebo-controlled trial, Azalea (ClinicalTrials.gov NCT05912517), is currently enrolling participants with prior pregnancies complicated by HDFN who required a prior IUT for treatment with nipocalimab compared to placebo. Additionally, FREESIA-1 is underway in Europe and South America (ClinicalTrials.gov NCT06449651). FREESIA-1 is a randomized, placebo-controlled, double-blind trial of nipocalimab for prevention of fetal severe thrombocytopenia and fetal or neonatal bleeding in pregnancies with maternal HPA-1a antibodies and fetal HPA-1a antigen and a prior pregnancy affected with fetal and neonatal alloimmune thrombocytopenia without ICH. Finally, the FREESIA-3 trial is in development, a trial that will randomize patients with a prior pregnancy affected with fetal and neonatal alloimmune thrombocytopenia to nipocalimab and IVIG.

Fc receptor blockade has also demonstrated proof of concept in the management of antibody mediated diseases outside of pregnancy. Most notably, therapeutic blockade of FcRn is being adapted as a treatment of myasthenia gravis (MG). MG often occurs in the setting of anti-acetylcholine receptor auto-antibodies, targeting antigens in the postsynaptic membrane of the neuromuscular junction,⁴⁰ resulting in muscle weakness of potentially debilitating severity. Conventional therapies include acetylcholinesterase agents (ie, pyridostigmine), corticosteroids, other immunosuppressive agents, IVIG and/or plasmapheresis, and thymectomy, all of which have potentially significant side effects or complications.⁴⁰ Blockade of the FcRn has been proposed as an alternative therapy aimed at reducing circulating IgG concentrations, and at least two pharmaceutical agents (efgartigimod and rozanolixizumab) are FDA-approved for this purpose.⁴⁰ At least two other agents nipocalimab (received Priority Review Status for generalized myasthenia gravis in January 2025) and batoclimab, could be available for use within the next few years.⁴⁰ Ongoing research is needed to determine the optimal doses and duration of treatment and to assess the long-term safety and cost-effectiveness, but this targeted form of “medical plasma exchange” could prove highly useful in the management of MG.⁴⁰ FcRn blockade is also being studied as a potential treatment for pemphigus and idiopathic thrombocytopenia, and future targets for study could include other autoimmune conditions, cancer, or infectious processes.³¹

Antibody mediated diseases such as HDFN and FNAIT continue to have significant fetal and neonatal morbidity with less than ideal current therapeutic options. Other antibody mediated fetal diseases, such as CHB and GALD remain without proven therapy.Based on current efficacy and safety studies, FcRn receptor therapy has the potential to very favorably alter the natural history and current therapeutic options for a variety of historically challenging to treat fetal antibody mediated diseases, ushering in a new era for management of HDFN and FNAIT, and other less well known disorders.

TABLES

Table 1. Current Diagnosis and Management of Alloimmune Disorders of Pregnancy

HDFN, hemolytic disease of the fetus and newborn; FNAIT; fetal, neonatal alloimmune thrombocytopenia; GALD, gestational associated liver disease; CHB, congenital heart block; TSI. thyroid stimulating antibodies; PTU, propylthiouracil; MCA, middle cerebral artery; PSV, peak systolic velocity.