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.).

The Role of cfDNA Biomarkers and Patient Data in the Early Prediction of Preeclampsia: Artificial Intelligence Model.

OBJECTIVE: Accurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12-16 weeks' gestation when there is evidence for its effectiveness, as well as guiding appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks' gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA (cfDNA) screening. Secondary outcomes were prediction of early onset preeclampsia (<34 weeks' gestation) and term preeclampsia (≥37 weeks' gestation). METHODS: This secondary analysis of a prospective, multicenter, observational prenatal cfDNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and two characteristics of cfDNA, total cfDNA and fetal fraction (FF), were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the 'reference' classifier was a shallow logistic regression (LR) model. We also explored several feedforward (non-linear) neural network (NN) architectures with one or more hidden layers and compared their performance with the LR model. We selected a simple NN model built with one hidden layer and made up of 15 units. RESULTS: Of 17,520 participants included in the final analysis, 72 (0.4%) developed early onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cfDNA measurement was 12.6 weeks and 2,155 (12.3%) had their cfDNA measurement at 16 weeks' gestation or greater. Preeclampsia was associated with higher total cfDNA (median 362.3 versus 339.0 copies/ml cfDNA; p<0.001) and lower FF (median 7.5% versus 9.4%; p<0.001). The expected, cross-validated area under the curve (AUC) scores for early onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively for the LR model, and 0.797, 0.800, and 0.713, respectively for the NN model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% CI 0.569, 0.599) for the LR model and 59.3% (95% CI 0.578, 0.608) for the NN model.The contribution of both total cfDNA and FF to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cfDNA and FF features from the NN model was associated with a 6.9% decrease in sensitivity at a 15% screen positive rate, from 54.9% (95% CI 52.9-56.9) to 48.0% (95% CI 45.0-51.0). CONCLUSION: Routinely available patient characteristics and cfDNA markers can be used to predict preeclampsia with performance comparable to other patient characteristic models for the prediction of preterm preeclampsia. Both LR and NN models showed similar performance.

Trends in Reporting of Nuchal Translucency Measurements After the Clinical Introduction of Cell-Free DNA Screening.

Nuchal translucency (NT) measurement in conjunction with serum analytes has been used for first-trimester aneuploidy screening in the United States since 2005. We sought to analyze the trends in reporting of NT measurements to the Nuchal Translucency Quality Review program in all pregnancies beginning after the clinical introduction of cell-free DNA (cfDNA) screening for fetal aneuploidy in 2011. Overall, reported NT measurements decreased 74.3% from 2012 to 2022. A similar decline was noted among individuals with pregnancies at increased risk for aneuploidy based on patient age and twin gestations. The decrease in reporting aligns temporally with the availability of cfDNA screening and the coronavirus disease 2019 (COVID-19) pandemic.

Genetic ancestry and diagnostic yield of exome sequencing in a diverse population.

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.

Pregnancy Outcomes of Nifedipine Compared With Labetalol for Oral Treatment of Mild Chronic Hypertension.

OBJECTIVE: To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. METHODS: We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding. RESULTS: Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine. CONCLUSION: No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.

Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Optimal Timing of Delivery for Pregnant Individuals With Mild Chronic Hypertension.

OBJECTIVE: To investigate the optimal gestational age to deliver pregnant people with chronic hypertension to improve perinatal outcomes. METHODS: We conducted a planned secondary analysis of a randomized controlled trial of chronic hypertension treatment to different blood pressure goals. Participants with term, singleton gestations were included. Those with fetal anomalies and those with a diagnosis of preeclampsia before 37 weeks of gestation were excluded. The primary maternal composite outcome included death, serious morbidity (heart failure, stroke, encephalopathy, myocardial infarction, pulmonary edema, intensive care unit admission, intubation, renal failure), preeclampsia with severe features, hemorrhage requiring blood transfusion, or abruption. The primary neonatal outcome included fetal or neonatal death, respiratory support beyond oxygen mask, Apgar score less than 3 at 5 minutes, neonatal seizures, or suspected sepsis. Secondary outcomes included intrapartum cesarean birth, length of stay, neonatal intensive care unit admission, respiratory distress syndrome (RDS), transient tachypnea of the newborn, and hypoglycemia. Those with a planned delivery were compared with those expectantly managed at each gestational week. Adjusted odds ratios (aORs) with 95% CIs are reported. RESULTS: We included 1,417 participants with mild chronic hypertension; 305 (21.5%) with a new diagnosis in pregnancy and 1,112 (78.5%) with known preexisting hypertension. Groups differed by body mass index (BMI) and preexisting diabetes. In adjusted models, there was no association between planned delivery and the primary maternal or neonatal composite outcome in any gestational age week compared with expectant management. Planned delivery at 37 weeks of gestation was associated with RDS (7.9% vs 3.0%, aOR 2.70, 95% CI, 1.40-5.22), and planned delivery at 37 and 38 weeks was associated with neonatal hypoglycemia (19.4% vs 10.7%, aOR 1.97, 95% CI, 1.27-3.08 in week 37; 14.4% vs 7.7%, aOR 1.82, 95% CI, 1.06-3.10 in week 38). CONCLUSION: Planned delivery in the early-term period compared with expectant management was not associated with a reduction in adverse maternal outcomes. However, it was associated with increased odds of some neonatal complications. Delivery timing for individuals with mild chronic hypertension should weigh maternal and neonatal outcomes in each gestational week but may be optimized by delivery at 39 weeks.