Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.

BACKGROUND: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels. METHODS: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%). RESULTS: Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity. CONCLUSIONS: Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).

Management of Red Cell Alloimmunization in Pregnancy.

Rhesus immune globulin has resulted in a marked decrease in the prevalence of RhD alloimmunization in pregnancy; however, antibody formation to other red cell antigens continues to occur. Evaluation for the presence of anti-red cell antibodies should be routinely undertaken at the first prenatal visit. If anti-red cell antibodies are detected, consideration of a consultation or referral to a maternal-fetal medicine specialist with experience in the monitoring and treatment of these patients is warranted. Cell-free DNA can be used to determine fetal red cell antigen status to determine whether the pregnancy is at risk of complications from the red cell antibodies. First-time sensitized pregnancies are followed up with serial maternal titers, and, when indicated, serial Doppler assessment of the peak systolic velocity in the middle cerebral artery should be initiated by 16 weeks of gestation. When there is a history of an affected fetus or neonate, maternal titers are less predictive of fetal risk; if the fetus is antigen positive, serial peak systolic velocity in the middle cerebral artery measurements should be initiated by 15 weeks of gestation because intraperitoneal intrauterine blood transfusions can be used at this gestation if needed. The mainstay of fetal therapy involves intrauterine transfusion through ultrasound-directed puncture of the umbilical cord with the direct intravascular injection of red cells. A perinatal survival rate exceeding 95% can be expected at experienced centers. Neonatal phototherapy and "top-up" transfusions attributable to suppressed reticulocytosis often are still required for therapy after delivery.

The use of free DNA for fetal RHD genotyping in the Rh negative pregnant patient - the time has come.

Cell-free DNA (cfDNA) to determine the fetal RHD genotype from the maternal circulation was first described in 1993. High throughput assays using polymerase chain reaction technology were introduced in Europe and gained widespread acceptance in the management of the Rhesus alloimmunized pregnancy. The specificity and sensitivity of these assays approached 99%. As confidence was gained with these results, Scandinavian countries began to employ cfDNA for fetal RHD typing as an integral component of their introduction of antenatal Rhesus immune globulin (RhIG) in non-alloimmunized pregnancies. Since 40% of RhD-negative pregnant women will carry an RhD-negative fetus, doses of RhIG were conserved. Recently two U.S. companies have introduced cfDNA assays for RHD as part of their NIPT assays. Both utilize next generation sequencing and have developed methodologies to detect the aberrant RHD pseudogene and the hybrid RHD-CE-Ds genotype. In addition, excellent correlation studies with either neonatal genotyping or serology have been reported. The manufacturer of RhoGAM® has recently announced a national shortage. . Given the current availability of reliable cfDNA assays for determining the RHD status of the fetus, the time has come to implement this strategy to triage the antenatal use of Rhesus immune globulin in the U.S..

Cell-Free DNA Analysis for the Determination of Fetal Red Blood Cell Antigen Genotype in Individuals With Alloimmunized Pregnancies.

OBJECTIVE: To evaluate the accuracy of next-generation sequencing-based quantitative cell-free DNA analysis for fetal antigen genotyping in individuals with alloimmunized pregnancies undergoing clinical testing in practices across the United States as early as 10 weeks of gestation, with the objective of identifying individuals with pregnancies at risk for hemolytic disease of the fetus and newborn and guiding management. METHODS: This prospective cohort study included patients with alloimmunized pregnancies undergoing clinical fetal antigen cell-free DNA analysis between 10 0/7 and 37 0/7 weeks of gestation at 120 clinical sites. Both the pregnant person with the alloimmunized pregnancy and the neonates resulting from the pregnancies were included. The laboratory issued the cell-free DNA results prospectively as a part of clinical care. After delivery, neonatal buccal swabs collected between 0 and 270 days of life were sent to an outside independent laboratory for antigen genotyping. The outside laboratory was blinded to the fetal cell-free DNA results, and the results were compared. Concordance was reported for the fetal antigen cell-free DNA analysis for antigens to which the pregnant person was alloimmunized and for all antigens for which the pregnant person was genotype negative. RESULTS: A total of 156 pregnant people who received clinically ordered cell-free DNA fetal antigen testing provided neonatal buccal swabs for genotyping after delivery. Overall, 15.4% of participants were Hispanic, 9.0% were non-Hispanic Black, 65.4% were non-Hispanic White, 4.5% were Asian, 1.3% were more than one race or ethnicity, and 4.5% were unknown. The median gestational age at the time of testing was 16.4 weeks with a median fetal fraction of 11.1%. Concordance between cell-free DNA analysis results and neonatal genotype was determined for 465 antigen calls for the following antigens: K1 (n=143), E (124), C (60), Fya (50), c (47), and D(RhD) (41). These 465 calls included 145 in which the fetus was antigen positive and 320 in which the fetus was antigen negative. We observed complete concordance between prenatal fetal antigen cell-free DNA analysis results and neonatal genotypes for the 465 calls, resulting in 100% sensitivity, specificity, and accuracy. CONCLUSION: In a diverse multicenter cohort, cell-free DNA analysis was highly sensitive and specific for determining fetal antigen genotype as early as 10 weeks of gestation in individuals with alloimmunized pregnancies. Taken together with previously published evidence, this study supports the implementation of cell-free DNA testing to manage individuals with alloimmunized pregnancies in the United States.

Hemoglobin Electrophoresis versus Kleihauer-Betke to Determine Bone Marrow Suppression in Fetuses Undergoing Intrauterine Transfusion.

OBJECTIVE: Mainstay therapy for fetuses affected by maternal red cell alloimmunization is serial intrauterine transfusion (IUT). Testing to determine when fetal red cells have been replaced with donor cells historically involves the use of the Kleihauer-Betke (KB) test. Hemoglobin (Hgb) electrophoresis testing may be more rapid with a reduced cost of analysis. We aimed to determine the correlation between fetal Hgb electrophoresis versus the traditional KB test. STUDY DESIGN: This is a retrospective analysis of all alloimmunized singleton pregnancies undergoing IUT between January 1, 2021, and July 1, 2023. Maternal and fetal characteristics were collected along with the indication for IUT. A final fetal blood sample was obtained at the conclusion of each transfusion and sent for KB testing and Hgb electrophoresis. The primary outcome was the assessment of these parameters in their ability to predict the replacement of the fetal circulating red cell population with donor cells. Linear regression analysis and repeated measures analysis of variance were performed, and p-values less than 0.05 were considered significant. RESULTS: A total of 56 IUTs were performed in 16 patients. There were 39 (69.6%) final KB test values collected and compared with 30 (53.6%) final Hgb electrophoresis values. Hgb electrophoresis when compared with the KB test demonstrated a significant correlation (R 2 = 0.93; 95% confidence interval, 0.61-0.76; p < 0.001). This same finding held true when examining the correlation at each individual IUT as well. The final KB test and Hgb electrophoresis values significantly decreased with each transfusion (p = 0.003). A predominance of adult donor blood was noted by the third transfusion for both laboratory indices. CONCLUSION: Fetal Hgb electrophoresis obtained at the time of IUT demonstrates a significant correlation with the traditional KB test. KEY POINTS: · Fetal Hgb electrophoresis following IUT is underexplored. · Hgb electrophoresis is an automated evaluation. · The traditional KB test is a manual evaluation. · These two tests demonstrate significant correlation.

Maternal red blood cell alloimmunization prevalence in the United States.

ABSTRACT: Hemolytic disease of fetus and newborn (HDFN) is a life-threatening disease mediated by maternal alloimmunization to red blood cell (RBC) antigens. Studies of maternal alloimmunization prevalence in the United States lack national data. This study describes prevalence and trends in alloimmunization in pregnancy in the United States. RBC antibodies (abs) were identified in a large, nationwide, commercial laboratory database from 2010 through 2021. The cohort comprised pregnancies for which the year of laboratory collection and patient's state of residence were available. Data were normalized based on US Centers for Disease Control and Prevention estimates of live births and weighted by year and US Census Division. Cochrane-Armitage tests assessed temporal trends of alloimmunization. Of 9 876 196 pregnancies, 147 262 (1.5%) screened positive for RBC abs, corresponding to an estimated prevalence of 1518 of 100 000 pregnancies. Of identified RBC abs, anti-D comprised 64.1% pregnancies (586/100 000). Prevalence of other high-risk RBC abs for HDFN included anti-K (68/100 000) and anti-c (29/100 000). Incidence of all 3 high-risk abs increased from 2010 to 2021 (all P < .001). Among almost 10 million pregnancies in the United States, comprising an estimated 14.4% of all pregnancies, 1.5% screened positive for RBC abs. Almost three-quarters (679/100 000 [74.3%]) of RBC abs identified were high risk for HDFN. Although prevalence of anti-D is difficult to interpret without the ability to distinguish alloimmunization from passive immunity, it remains problematic in HDFN, ranking second only to anti-K in critical titers. Given the sequelae of HDFN, new initiatives are required to reduce the incidence of alloimmunization in patients of reproductive potential.

Receipt of RhD-positive whole blood for life-threatening bleeding in female children: A survey in alloimmunized mothers regarding minimum acceptable survival benefit relative to risk of maternal alloimmunization to anti-D.

BACKGROUND: Low-titer group O whole blood (LTOWB) for treatment of hemorrhagic shock sometimes necessitates transfusion of RhD-positive units due to short supply of RhD-negative LTOWB. Practitioners must choose between using RhD-positive LTOWB when RhD-negative is unavailable against the risk to a female of childbearing potential of becoming RhD-alloimmunized, risking hemolytic disease of the fetus and newborn (HDFN) in future children, or using component therapy with RhD-negative red cells. This survey asked females with a history of red blood cell (RBC) alloimmunization about their risk tolerance of RhD alloimmunization compared to the potential for improved survival following transfusion of RhD-positive blood for an injured RhD negative female child. STUDY DESIGN AND METHODS: A survey was administered to RBC alloimmunized mothers. Respondents were eligible if they were living in the United States with at least one red cell antibody known to cause HDFN and if they had at least one RBC alloimmunized pregnancy. RESULTS: Responses from 107 RBC alloimmmunized females were analyzed. There were 32/107 (30%) with a history of severe HDFN; 12/107 (11%) had a history of fetal or neonatal loss due to HDFN. The median (interquartile range) absolute improvement in survival at which the respondents would accept RhD-positive transfusions for a female child was 4% (1%-14%). This was not different between females with and without a history of severe or fatal HDFN (p = .08 and 0.38, respectively). CONCLUSION: Alloimmunized mothers would accept the risk of D-alloimmunization in a RhD-negative female child for improved survival in cases of life-threatening bleeding.

Erythrokinetic mechanism(s) causing the "late anemia" of hemolytic disease of the fetus and newborn.

A transfusion-requiring "late anemia" can complicate the management of neonates convalescing from hemolytic disease of the fetus and newborn (HDFN). This anemia can occur in any neonate after HDFN but is particularly prominent in those who received intrauterine transfusions and/or double-volume exchange transfusions. Various reports describe this condition as occurring based on ongoing hemolysis, either due to passive transfer of alloantibody through breast milk or persistence of antibody not removed by exchange transfusion. However, other reports describe this condition as the result of inadequate erythrocyte production. Both hypotheses might have merit, because perhaps; (1) some cases are primarily due to continued hemolysis, (2) others are primarily hypoproductive, and (3) yet others result from a mixture of these two mechanisms. We propose prospective collaborative studies that will resolve this issue by serially quantifying end-tidal carbon monoxide. Doing this will better inform the assessment and treatment of neonates recovering from HDFN.

The Special Delivery Unit: A Novel Concept for Mother-Baby Continuity for Major Fetal Abnormalities.

OBJECTIVE: This article describes the experience in the planning and development of a special delivery unit (SDU) at our free-standing children's hospital in Austin, Texas. STUDY DESIGN: Description of various aspects of the development of the SDU. In addition, telephone surveys were obtained from five other institutions regarding the planning and current status of their SDUs. RESULTS: Since the advent of the SDU at Children's Hospital of Philadelphia in 2008, several free-standing children's hospitals have opened similar units at their institutions. Developing an obstetrical unit in a children's hospital can be a daunting task on many fronts. The costs of providing 24-hour obstetrical, nursing, and anesthesiology coverage must be considered. Although most SDUs are associated with a fetal center and fetal surgery/interventions, some units function exclusively for the delivery of pregnancies complicated by major fetal conditions where the neonate will require immediate surgical care or other interventions. CONCLUSION: Research on the cost-effectiveness and the effect of SDUs on clinical outcome, teaching, and patient satisfaction is warranted. KEY POINTS: · Specialized delivery units are becoming more common at free-standing children's hospitals.. · The primary aim of the SDU is to maintain mother-baby continuity in cases of congenital anomalies.. · Developing an obstetrical unit at a pediatric hospital is a daunting task..

Live birth prevalence of hemolytic disease of the fetus and newborn in the United States from 1996 to 2010.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is mediated by maternal alloantibodies, a consequence of immune sensitization during pregnancy with maternal-fetal incompatibility with ABO, Rhesus factor (Rh), and/or other red blood cell antigens. RhD, Kell, and other non-ABO alloantibodies are the primary cause of moderate to severe HDFN, whereas ABO HDFN is typically mild. HDFN live birth prevalence owing to Rh alloimmunization among newborns in the United States was last estimated to be 106 per 100,000 births in 1986. HDFN live birth prevalence owing to all alloantibodies was estimated to be 817 to 840 per 100,000 in Europe. There is a need for updated prevalence estimates in the United States and a better understanding of disease demographics, severity, and treatments. OBJECTIVE: This study aimed to estimate the live birth prevalence of HDFN and the proportion of severe cases of HDFN in the United States, to describe the associated risk factors, and to compare the clinical outcomes and treatments among healthy newborns, newborns with HDFN, and newborns who are sick without HDFN using a nationally representative hospital discharge database. STUDY DESIGN: In this retrospective, observational cohort study, we used data from the 1996 to 2010 National Hospital Discharge Survey to identify live births, defined by inpatient visits with the newborn flag, with and without a diagnosis of HDFN across 200 to 500 sampled hospitals (≥6 beds) per year. Patient and hospital characteristics, alloimmunization status, disease severity, treatment, and clinical outcomes were evaluated. Frequencies and weighted percentages were calculated for all variables. Logistic regression was used to compare the characteristics between newborns with HDFN and other newborns using odds ratios. RESULTS: Of 480,245 live births identified, 9810 HDFN cases were recorded. When weighted to the United States population, this corresponded to a live birth prevalence of 1695 per 100,000 live births. Compared with other newborns, newborns with HDFN were more likely to be female, Black, living in the South (vs the Midwest or West), and treated at larger (>100 beds) and government-owned hospitals. ABO and Rh alloimmunization accounted for 78.1% and 4.3% of newborns with HDFN, respectively, whereas HDFN caused by other antigens, such as Kell and Duffy, accounted for 17.6% of the cases. Among newborns with HDFN, 22% received phototherapy, 1% received simple transfusions, and 0.5% received exchange transfusions or intravenous immunoglobulin. Newborns affected by HDFN caused by Rh alloimmunization were more likely to require medical interventions, including simple or exchange transfusions, and more likely to be delivered by cesarean delivery. Overall, HDFN was associated with a longer hospital length of stay in the neonatal intensive care unit when compared with healthy and other sick newborns, a higher rate of cesarean delivery, and a higher rate of nonroutine discharge than healthy newborns. CONCLUSION: Overall, the live birth prevalence of HDFN was higher than those previously reported, whereas Rh-induced HDFN live birth prevalence was similar to those previously reported. HDFN live birth prevalence owing to Rh alloimmunization decreased over time, likely because of continued Rh immune globulin prophylaxis. Treatment patterns for newborns with HDFN and the comparative clinical outcomes when compared with healthy newborns confirm the continued clinical needs of this population.

Open and endoscopic fetal myelomeningocele surgeries display similar in-hospital safety profiles in a large, multi-institutional database.

BACKGROUND: Open intrauterine fetal myelomeningocele repair has demonstrated decreased ventriculoperitoneal shunting and improved motor outcomes despite maternal and fetal risks. Few data directly compare the safety of open vs endoscopic approaches. OBJECTIVE: This study aimed to analyze in-hospital maternal and fetal outcomes of pregnant patients undergoing open vs endoscopic fetal myelomeningocele repair using a large, multi-center database. STUDY DESIGN: This was a review of the Pediatric Health Information System database from October 1, 2015, to December 31, 2021. All patients who underwent open or endoscopic fetal myelomeningocele repair according to the International Classification of Diseases, Tenth Revision, were identified. Demographics, gestational age, and outcomes were analyzed. Descriptive and univariate statistics were used. RESULTS: A total of 378 pregnant patients underwent fetal myelomeningocele repair. The approach was endoscopic in 143 cases (37.8%) and open in 235 cases (62.2%). Overall postprocedural outcomes included no maternal in-hospital mortalities or intensive care unit admissions, a median length of stay of 4 days (interquartile range, 4-5), 14 cases (3.7%) of surgical and postoperative complications, 6 cases (1.6%) of intrauterine infections, 12 cases (3.2%) of obstetrical complications (including preterm premature rupture of membranes), 3 cases (0.8%) of intrauterine fetal demise, and 16 cases (4.2%) of preterm delivery. Compared with an open approach, the endoscopic approach occurred at a later gestational age (25 weeks [interquartile range, 24-25] vs 24 weeks [interquartile range, 24-25]; P<.001) and had an increased rate of intrauterine infection (6 [4.2%] cases vs 0 [0%] case; P=.002). There was no difference between approaches in the rates of surgical complications, obstetrical complications, intrauterine fetal demise, or preterm deliveries. CONCLUSION: Compared with an open approach, endoscopic fetal myelomeningocele repair displays a comparable rate of fetal complications, including intrauterine fetal demise and preterm delivery, and a similar in-hospital maternal safety profile despite an association with increased intrauterine infection.

Immunomodulation for early-onset haemolytic disease of the fetus/newborn: Can we delay the need for intrauterine transfusions?

When cases of severe fetal anaemia due to maternal red-cell alloimmunization present in the early second trimester, standard treatment with intrauterine transfusion often results in fetal loss. The report by Vlachodimitropoulou et al. offers new insight into the use of maternal intravenous immune globulin to delay the need for intrauterine transfusion. Performing these procedures at a later gestational age increases the likelihood of technical success and subsequent perinatal survival. Commentary on: Vlachodimitropoulou et al. Intravenous immune globulin in the management of severe early onset of red cell alloimmunization. Br J Haematol 2023; 200:97-103.

Congenital myotonic dystrophy: An overlooked diagnosis not amenable to detection by sequencing.

OBJECTIVE: To increase the clinical awareness of the need for genetic evaluation for congenital myotonic dystrophy (CDM1) in cases of fetal akinesia sequence and idiopathic polyhydramnios. METHODS: Retrospective case review. RESULTS: A 27 y.o. G1P0 with no significant family history presented for ultrasound at 25 weeks gestation. Notable findings included lack of extension of the fetal arms and legs with bilateral talipes consistent with fetal akinesia sequence. Polyhydramnios with an amniotic fluid index of 32.2 cm was also present. Amniotic fluid obtained by amniocentesis was sent for chromosomal microarray and a next generation sequencing fetal akinesia panel which both returned normal. The patient underwent serial amnioreductions for recurrent severe polyhydramnios with removal of a total of 9.3 L. Further amniotic fluid testing for CDM1 identified >200 repeats in one copy of the fetal DMPK gene, consistent with a diagnosis of CDM1. The patient was delivered at 35 weeks gestation and neonatal demise occurred on the second day of life. CONCLUSION: Congenital myotonic dystrophy should be a consideration for cases of severe polyhydramnios identified by ultrasound. Myotonic dystrophy is detected using PCR and southern blot and is not typically included on next generation sequencing (NGS) panels that test for similar conditions. Clinicians should consider more specialized genetic testing than microarray and NGS in these cases.

Predicting fetal and neonatal demise after fetoscopy for twin-twin transfusion syndrome using recursive partitioning.

OBJECTIVE: Donor demise after laser surgery for twin-twin transfusion syndrome (TTTS) is well-characterized, but recipient demise is not, nor is neonatal death. This study aims to characterize factors associated with recipient death, donor death, and dual twin death after laser, both before and after birth. METHODS: This is a prospective cohort study of monochorionic twin pairs who underwent laser ablation for TTTS. Risk factors for fetal and neonatal death of both twins were identified using univariable analysis and recursive partitioning, a novel statistical method to quantify contributions of each factor to outcomes. RESULTS: In 413 twin pairs, death of both twins occurred in 9.2% (38/413), donor death in 12.1% (50/413), and recipient death in 2.4% (10/413). Recursive partitioning showed that gestational age at delivery predicts dual twin death (below 23.7 weeks, likely [p < 0.001], above 28.3 weeks, unlikely [p = 0.004]). Abnormal umbilical artery Doppler and weight discordance predict donor demise (p < 0.001 and p = 0.033, respectively). Cervical length under 16 mm predicts neonatal death of both twins (p < 0.001). CONCLUSIONS: Parents can gain individualized information about the survival of each fetus based on variables available from preoperative and delivery variables. Short cervix and premature delivery cause significant mortality in TTTS.

Low Transverse versus Midline Abdominal Skin Incisions for in utero Spina Bifida Repair.

OBJECTIVE: The 2 types of maternal skin incisions for in utero spina bifida repair are low transverse (LT) incision perceived to be cosmetic benefit and midline longitudinal (ML) incision, typically associated with a reduction in surgical time and lower blood loss. Our objective was to compare short- and long-term outcomes associated with these 2 types of skin incisions following in utero spina bifida repair. METHODS: Prospective observational cohort of 72 patients undergoing fetal spina bifida repair at a single institution between September 2011 and August 2018. The decision for the type of incision was at the discretion of the surgeons. The primary outcome was total operative time. Secondary outcomes included an analog scale of wound pain score on postoperative day 3, duration of postoperative stay, and postoperative wound complications within the first 4 weeks. The Patient Scar Assessment Questionnaire, a validated questionnaire, was obtained for all patients (≥6 months from delivery) using 4 categories (appearance, consciousness, satisfaction with appearance and with symptoms), with higher scores reflecting a poorer perception of the scar. RESULTS: There were 43 women (59.7%) in the LT group and 29 (40.3%) in the ML group. In all patients, the same incision was used during cesarean delivery. The total operative time was higher in the LT group by 33 min (p < 0.001), primarily due to abdominal wall incision time (open and closure). No significant differences were found between the groups in pain score, length of postoperative stay, or the rate of wound complications. Fifty-three patients (73.6%) responded to the questionnaire, 36/43 from the LT group and 17/29 from the ML group. There was no difference in the scores of appearance, consciousness, and satisfaction with appearance and symptoms between the groups. CONCLUSION: ML incisions shorten operative times without altering long-term incision-related satisfaction when compared to LT incisions.