Vasa previa is a rare but potentially catastrophic obstetric condition characterized by unprotected fetal blood vessels over or adjacent to the internal cervical os. Although advances in prenatal ultrasound have dramatically improved neonatal survival through planned cesarean delivery, many aspects of vasa previa remain poorly understood. Existing studies are limited by small sample sizes, single-center designs, heterogeneous diagnostic criteria, and inconsistent reporting of clinical outcomes, highlighting the need for large, systematically collected multicenter datasets. Here we describe, to our knowledge, the first United States multicenter registry of pregnancies complicated by vasa previa without concurrent placenta previa, the U.S. Vasa Previa Registry (US-VPR). This report outlines the rationale, design, and implementation of a large, multicenter, retrospective registry developed to characterize patient demographics, risk factors, placental pathology, natural history, antenatal management, maternal outcomes, neonatal outcomes, and healthcare utilization associated with vasa previa. The US-VPR includes contributions from 15 tertiary referral centers and represents the largest multicenter cohort of pregnancies complicated by vasa previa without concurrent placenta previa reported to date. By leveraging multicenter collaboration and standardized data collection, the registry provides a unique opportunity to characterize variation in clinical practice and outcomes across referral centers, strengthen the evidence base for this rare condition, and inform future prospective studies and evidence-based patient counseling.

OBJECTIVE:Exome sequencing (ES) detects a monogenic disorder in approximately 30% of pregnancies with unexplained nonimmune hydrops fetalis spectrum (NIHFS), defined as the presence of one or more pathologic fetal fluid collection. Since genome sequencing (GS) can identify additional genetic variants not detectable by ES, we sought to determine the proportion of cases with new reportable findings on GS following nondiagnostic standard of care testing, including ES, for NIHFS. STUDY DESIGN:Cohort study of pregnancies with NIHFS that had nondiagnostic results of karyotype and/or chromosomal microarray analysis (CMA) and ES. Eligible fetal fluid collections included at least one of: ascites, pleural or pericardial effusions, skin edema, cystic hygroma, and/or nuchal translucency ≥3.5 mm. Pregnancies with NIHFS that did not receive a clear diagnosis with prior testing underwent additional testing with GS. ES and GS were performed in a Clinical Laboratory Improvement Amendments-approved laboratory, and genetic variants were classified according to the American College of Medical Genetics and Genomics guidelines. Primary outcome was the proportion of new reportable pathogenic or likely pathogenic (P/LP) variants identified on GS and resulting in a new diagnosis. Secondary outcome was the incremental yield of GS for detecting new secondary findings and variants of uncertain significance (VUSs). RESULTS:Overall, 118 fetal samples underwent GS following negative (n=102) or inconclusive (n=16) ES. GS identified four P/LP copy number variants previously not detected by karyotype, CMA, or ES that led to a new genetic diagnosis in three pregnancies, providing a new positive finding yield of 2.5% (3/118). Additionally, one secondary finding and four VUSs were identified by GS in four different pregnancies. In contrast to the primary outcome, these additional findings were largely the result of updated analytical tools and literature rather than GS-specific technology. CONCLUSION:GS has a small but clinically relevant increased diagnostic yield over chromosome studies and ES for NIHFS, particularly for identifying copy number variants. As interpretation of noncoding regions and complex genomic variations improves, the incremental positive finding yield of GS is expected to further increase.

Cystic fibrosis (CF) is a multisystem genetic disease caused by pathogenic variants in the cystic fibrosis transmembrane receptor ( CFTR ) gene, leading to abnormal function in the lungs, pancreas, intestines, and other organs. CFTR modulators (CFTRm), small molecule therapies for CF, have significantly improved disease prognosis. As a result, more patients with CF can conceive, and pregnancy has become more common. While data surrounding CFTRm use during pregnancy are limited, the significant risk of untreated CF on maternal and pregnancy outcomes means that many patients opt to continue CFTRm during gestation. In addition, CF begins to manifest before birth, with potential in-utero complications like pancreatic injury and meconium ileus. This review article summarizes pregnancy safety data, animal studies, and emerging case reports with prenatal CFTRm therapy for fetuses affected by CF. Available data are generally reassuring for patients with CF who continue CFTRm during pregnancy. Continuation has been associated with preserved maternal lung function, while discontinuation has been linked in some cases to clinical decline that resolves when therapy is restarted. These medications can cross the placenta, with fetal levels equal to or higher than maternal levels, and are present at low levels in breastmilk. Some safety concerns remain, including rare hepatotoxicity, and complications seen in animal models include development of cataracts and drug accumulation in the fetal brain. However, in a CF ferret model, in utero ivacaftor prevented intestinal disease, preserved exocrine pancreatic function, and preserved the vas deferens in male offspring. This supports the possibility that treatment before birth could protect against some fetal CF manifestations. Human data on CFTRm during pregnancy remain limited but suggest possible fetal benefits. Twenty published cases describe prenatal CFTRm use in unaffected pregnant carriers whose fetuses were diagnosed with CF. Most received standard adult dosing of elexacaftor/tezacaftor/ivacaftor (Trikafta or triple therapy) after invasive prenatal diagnosis. Among 15 fetuses with meconium ileus who were treated through maternal CFTRm during pregnancy, ultrasound findings resolved before delivery in 10 cases. Findings were less likely to resolve when treatment began later or when complications such as volvulus, meconium peritonitis, or meconium pseudocyst were already present. Among published cases, the mean gestational age at diagnosis of meconium ileus was 23.8 weeks, while treatment began at a mean of 30.4 weeks, reflecting delays in diagnosis and access to therapy. Several reports also described preserved or borderline pancreatic function and lower-than-expected sweat chloride levels. Because prenatal treatment can reduce biochemical signs of pancreatic injury, newborn screening may be falsely negative, so infants with known prenatal CF diagnoses still need postnatal diagnostic evaluation. Prenatal CFTRm therapy is promising but remains investigational. Standardized guidelines for treatment have not been created, and care should include multidisciplinary counseling, genetic confirmation of fetal CF, maternal liver function monitoring, fetal ultrasound surveillance, and postnatal follow-up. Significant unanswered questions include the optimal timing of treatment, minimum effective dose, neurodevelopmental safety, and whether treatment should continue after birth to avoid withdrawal effects. Access is also a major ethical issue because therapy is expensive and insurance delays can push treatment later into gestation. Overall, the review suggests that prenatal CFTRm may prevent or improve fetal manifestations of CF, particularly meconium ileus, but prospective studies are needed before this approach can become routine care. (Summarized from Zaretsky MV, Blumenfeld YJ, Szentpetery SS, et al Translating emerging data for fetal treatment of cystic fibrosis. Prenat Diagn. 2026;46:417-423. doi:10.1002/pd.70098)

OBJECTIVE:Exome sequencing (ES) and gene panels can be considered for fetal anomalies. Whether ES offers substantial benefit over targeted panels is not clear. METHODS:Secondary analysis of a prospective cohort study of pregnancies with fetal anomalies undergoing ES. We included cases with isolated or multisystem skeletal dysplasias, CNS anomalies, and/or cardiac anomalies. Participants underwent ES, and pathogenic (P) and likely pathogenic (LP) variants were reported. The primary outcome was the percentage of P/LP variants found on ES that would have been identified on panels available prenatally in the United States. RESULTS:109 cases with relevant anomalies were included in the primary analysis. Of these, 20 (18%) had P/LP variant(s) identified on ES-4 multisystem, 4 isolated CNS, 6 isolated cardiac, and 6 isolated skeletal dysplasia. Gene panels would have detected 50 (88%) of the variants identified by ES. Yield was highest for isolated skeletal anomalies (100%) compared to CNS and cardiac malformations (75% and 67%, p = 0.02). Yield was higher for isolated anomalies than multisystem anomalies (median 91.5% vs. 50%, p < 0.01). CONCLUSIONS:In cases of fetal anomalies with genetic etiologies identified on ES, commercial gene panels had variable diagnostic yields. Panels performed worst for multisystem anomalies.

Abstract Skeletal dysplasias are a group of Mendelian disorders that variably alter the development of the musculoskeletal system and phenotypically range from mild short stature syndromes to severe perinatal or neonatal morbidity. Prenatal diagnosis of these conditions can be challenging due to the lack of precision with ultrasound imaging compared to postnatal radiographs as well as the known allelic heterogeneity and phenotypic variability underlying these conditions. Historically, the sonographic approach for phenotyping these conditions lacked genotypic specificity and counseling focused on predicting perinatal lethality. However, recent advances in genomic medicine and prenatal ultrasound resolution have enabled more precise diagnosis and individualized counseling. The following review provides a comprehensive overview of best practices for prenatal ultrasonography and molecular work‐up for skeletal dysplasias and provides a standardized evidence‐based framework for evaluation.

Clinicians use virtual gene panels to analyze regions of patients’ genomes for variants associated with disease. With the increasing availability of this technology, 2 perinatal screening tests have become more common: genetic reproductive carrier screening (RCS) and genomic newborn screening (gNBS). RCS identifies couples at higher risk of conceiving a child with a genetic disease to support reproductive decision-making, while gNBS typically screens newborns for treatable childhood-onset diseases to improve clinical outcomes. Despite overlapping goals, the specific genes included in these tests, both between test categories and across different platforms, vary significantly. The authors of this commentary argue that the independent development of these testing approaches, without coordination, has the potential to influence and complicate patient counseling. To examine how RCS and gNBS platforms intersect and differ, the authors use an Australian RCS study (Mackenzie’s Mission) and a gNBS study (BabyScreen+) as models. The 1300 genes included in the RCS model target X-linked or autosomal recessive conditions with onset before 18 years of age and limited or burdensome treatment options. The 604 genes analyzed in the gNBS model focus on genetic disorders associated with early childhood disease (before 5 years of age), substantial morbidity or mortality, and time-sensitive effective treatment. A total of 318 genes are shared between the two panels, largely representing severe, early-onset conditions with some available treatment. BabyScreen+ includes 286 unique genes, 73 of which are dominant conditions with less intensive treatments and variable expressivity, potentially leading to diagnosis in a carrier parent. In contrast, Mackenzie’s Mission includes 982 genes not assessed by gNBS that are typically untreatable or emerge later in childhood. As perinatal genetic testing evolves, clinicians will face greater challenges in counseling patients about available options and interpreting results. Variation in genes analyzed between testing platforms could contribute to confusion among providers and patients and introduce inequities in care. The authors urge collaboration among genetic counselors and other health professionals to enable families to make informed decisions that align with their values as the list of gene-disease associations continues to expand.(Summarized from Downie L, Lunke S, Stark Z, et al. The intersection between genetic reproductive carrier screening and genomic newborn screening: Implications for clinical practice. Prenat Diagn. 2025 Sep;45(10):1277-1280. doi: https://doi.org/10.1002/pd.6771)

Exome and genome sequencing are increasingly used for rare disease diagnosis even among asymptomatic individuals, though their utility for predicting future disease risk remains uncertain. This is largely due to an incomplete understanding of penetrance, or the probability that a pathogenic genotype results in symptoms, which varies widely across many variables and is difficult to estimate. Population-scale biobanks that link genomic and electronic health record data have enabled “genotype-first” studies, which suggest that many presumed pathogenic variants show low rates of actual disease expression. However, these estimates may be influenced by incomplete phenotyping and differences in diagnostic criteria. In this study, the authors evaluated disease expression among individuals with predicted loss-of-function (pLOF) variants in genes associated with haploinsufficient disorders using large biobank data sets, and investigated factors contributing to low penetrance. This study used exome and genome sequencing data linked to electronic health records from the UK Biobank and All of Us cohorts to assess disease expression among individuals with pLOF variants in genes associated with haploinsufficient disorders. The authors identified 91 autosomal or pseudoautosomal-dominant diseases linked to 117 genes and identified heterozygous carriers of rare variants after quality control and annotation. Disease expression was evaluated using a complex aggregate of diagnostic codes, phenotype risk scores, and a symptom-based probabilistic model based on structured health record data, with noncarrier cohorts for comparison. Additional analyses assessed the impact of incomplete clinical data as a possible explanation for seemingly low penetrance and evaluated for associations between specific types of variants and disease expression using machine-learning models. The study identified over 6000 unique pLOF variants between the two biobanks. Analyses found that 3% to 4.5% of individuals carried at least one variant, which strongly challenges the presumption that each of these variants results in phenotypically expressed disease. While pLOF carriers had a greater risk of symptoms and disease than the reference cohorts, overall disease expression remained low at <10%. After accounting for annotation artifacts, missed diagnoses, and incomplete electronic health record coverage, estimates for disease expression modestly increased, but the discrepancy was not resolved. Machine-learning models that incorporated the genomic features present in each type of pLOF successfully stratified variants by expression risk and outperformed standard pathogenicity filters, suggesting that some variants retain partial function and have intrinsically reduced penetrance. Predicted loss-of-function variants in haploinsufficient disease genes showed consistently low disease expression rates, even after accounting for likely confounders such as annotation errors and incomplete medical records. Standard pathogenicity annotations, including ClinVar, were poorly predictive of disease expression, whereas models incorporating variant-specific genomic features more effectively identified higher-risk variants. These findings suggest that many pLOF variants retain partial function or are rescued through other mechanisms, which results in reduced penetrance and limited predictive value of genomic screening. Although data limitations may lead to underestimation, the results highlight fundamental challenges in prognostic genetic testing and emphasize the importance of cautious interpretation of genomic data in asymptomatic individuals. (Summarized from Blair DR, Risch N. Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks. Am J Hum Genet . 2025;112:2922–2942. doi:10.1016/j.ajhg.2025.11.002)

Abstract Non‐immune hydrops fetalis (NIHF) can result from a multitude of underlying causes, such as fetal genetic diseases, congenital anomalies, infections, fetal arrhythmias, placental tumors, monochorionic twin complications, and other disorders. Management is complex and rooted in the preferences of the pregnant individual and the known or suspected etiology of NIHF. In this Consult, we review general considerations and a contemporary approach to the diagnosis, evaluation, and management of NIHF, providing recommendations based on the available evidence. The following are the Society for Maternal‐Fetal Medicine's recommendations: (1) we recommend fetal diagnostic testing for all pregnancies when one or more fetal effusions are detected; this testing should include chromosomal microarray analysis (CMA) with or without karyotype. When infectious etiologies are in the differential diagnosis, polymerase chain reaction studies should also be performed (grading of recommendations assessment, development, and evaluation [GRADE] 1C); (2) we recommend that exome or genome sequencing be offered in pregnancies with NIHF or NIHF spectrum following CMA or karyotype that does not yield a diagnosis and in the absence of another suspected etiology. If the risk of aneuploidy is low or a single‐gene disorder is strongly suspected, offering exome or genome sequencing concurrently with CMA is reasonable (GRADE 1C); (3) we recommend that all patients who develop mirror syndrome in the setting of NIHF receive individualized counseling about delivery or abortion care; expectant management should be reserved only for rare circumstances, after counseling about the maternal risks and shared decision‐making (GRADE 1C); (4) given the associated maternal risks, we recommend that all patients with pregnancies complicated by NIHF receive individualized counseling and be offered all management options, including abortion care (GRADE 1C); (5) we recommend that timing of delivery be individualized for each pregnancy with NIHF and that preterm delivery be reserved for obstetrical indications such as preeclampsia or mirror syndrome, preterm labor or premature rupture of membranes, new or worsening NIHF, or when the overall maternal or fetal risks of continued management are expected to outweigh those of delivery (GRADE 1C); (6) we recommend antenatal corticosteroids for continuing pregnancies with NIHF when preterm delivery is anticipated within 7 days, if neonatal resuscitation is desired and would be offered (GRADE 1C); (7) we recommend that cesarean delivery be performed for standard obstetrical indications in the setting of NIHF when postnatal resuscitation and life‐supporting care are planned for the neonate (GRADE 1C). This Consult replaces Society for Maternal‐Fetal Medicine Clinical Guideline #7: Non‐immune hydrops fetalis.

Hemolytic disease of the fetus and newborn (HDFN) occurs when maternal alloantibodies target fetal red blood cell antigens and is associated with neonatal morbidity and mortality. While anti-D prophylaxis to prevent maternal sensitization has nearly eliminated RhD-related cases, alloimmunization to other antigen variants remains unaddressed. Accurate and early determination of fetal antigen status helps guide decisions surrounding surveillance, management, and resource utilization. Previously, this has required invasive testing with amniocentesis, which has procedural risks and is limited to pregnancies past 15 weeks. Advances in cell-free DNA (cfDNA) analysis now allow for noninvasive fetal antigen genotyping from maternal plasma as early as 10 weeks’ gestation. This study assesses the diagnostic accuracy of cfDNA for detecting fetal red blood cell antigen status across different antigens and laboratory methods. This systematic review and meta-analysis conducted in 2024 employed a comprehensive literature search of MEDLINE, Embase, and the Cochrane Library to identify studies evaluating cfDNA for fetal red blood cell antigen genotype. Eligible studies included pregnant individuals undergoing cfDNA testing for fetal antigen status, with neonatal genotype or serology as the reference standard. Both observational and interventional studies were included, while case reports and reviews were excluded. Data were independently extracted and evaluated for diagnostic accuracy by comparing cfDNA results with confirmed neonatal antigen status. The included studies used several laboratory techniques, including quantitative, multiplex, and digital PCR, next-generation sequencing, and MALDI-TOF. Overall test performance was summarized by calculating pooled sensitivity, specificity, and diagnostic odds ratios. Study quality and bias risk were assessed using QUADAS-2. After the search and review, a total of 84 studies with a cumulative 77,187 fetal antigen assessments met the inclusion criteria. Most studies were prospective and predominantly evaluated RhD-negative pregnancies, although some included alloimmunized cohorts and additional antigens such as RhC, Rhc, RhE, Kell, and Fy a . PCR was the most commonly used method, with fewer studies using next-generation sequencing or MALDI-TOF (matrix-assisted laser desorption/ionization-time of flight). Across all laboratory techniques, cfDNA demonstrated pooled sensitivity and specificity of approximately 99% (95% CI: 99-100). For PCR, the sensitivities for RhD, C, c, E, and Kell were 99% to 100%; for next-generation sequencing, the sensitivities for RhD, C, c, E and Kell were all 100%; and for MALDI-TOF, the sensitivity for RhD was 99%. The Fy a antigen was only assessed with NGS, and sensitivity was 100%. Study quality was found to be high, with low risk of bias and minimal variability in diagnostic performance between studies. The results support cfDNA testing as a highly accurate and reliable method for determining fetal red blood cell antigen status in alloimmunized and RhD-negative pregnancies, offering a safe and effective alternative to invasive procedures. In addition, cfDNA can be assessed earlier in pregnancy, thereby improving risk stratification, reducing unnecessary monitoring, and allowing for more conservative use of anti-D immunoglobulin, which is particularly relevant given current supply shortages. Strengths of this study include the large pooled sample size, high overall study quality, and consistent diagnostic performance across laboratory methods and populations, while limitations include variability in study design, differences in laboratory techniques, and limited validation for less common antigens. These findings support broader implementation of cfDNA testing to improve the management and safety of pregnancies at risk for HDFN. (Summarized from Mustafa HJ, Najjariasl P, Aghajani F. Diagnostic accuracy of cell- free DNA for the determination of fetal red blood cell antigen genotype: a systematic review and meta-analysis. Am J Obstet Gynecol . 2025;233:428–445.e16. doi: 10.1016/j.ajog.2025.05.004)

This article is a report of a 2‐day workshop titled “Developing an Optimal Maternal‐Fetal Medicine Ultrasound Practice,” held during the Society for Maternal‐Fetal Medicine's 2023 Annual Pregnancy Meeting. Participants’ fields of expertise included obstetrics and gynecology, sonography, maternal‐fetal medicine, genetics, and genetic counseling. The American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Registry for Diagnostic Medical Sonography, International Society of Ultrasound in Obstetrics and Gynecology, Gottesfeld‐Hohler Memorial Foundation, and Perinatal Quality Foundation cosponsored the workshop. The workshop included presentations and small group discussions, and its goals were to accomplish the following: Review best practices and emerging technologies for designing and running an efficient obstetrical ultrasound unit Discuss strategies for quality assurance in the setting of obstetrical ultrasound at the individual provider and unit level Identify needs and opportunities for ongoing education and training in ultrasound imaging and ultrasound‐guided procedures for maternal‐fetal medicine fellows, physicians, and sonographers Review current and emerging approaches to managing the pregnant patient with obstetrical ultrasound abnormalities

Introduction:Hydrops fetalis carries high risks of morbidity and mortality for the fetus, as well as obstetric risks such as hypertensive disorders, or mirror syndrome, for the pregnant person. We aimed to characterize the prevalence and types of hypertensive disorders diagnosed in pregnancies with non-immune hydrops fetalis and single effusions, as well as to investigate fetal risk factors for the development of hypertension. Methods:This was a secondary analysis of a prospectively enrolled cohort. We included pregnancies with non-immune hydrops fetalis that demonstrated ≥2 fetal effusions (ascites, pleural effusion, pericardial effusion, and/or skin edema), as well as pregnancies with only one of these effusions. We excluded pregnancies that did not continue beyond 20 weeks gestation as most hypertensive disorders of pregnancy develop after this. Primary outcomes were the prevalence and types of hypertensive disorders diagnosed during pregnancy or within 6 weeks postpartum. Secondary outcomes were the prevalence of hypertensive disorders by number of fetal effusions and presence of an underlying fetal genetic disease. Results:Among 116 pregnancies with fetal effusions, 22 (19%) developed hypertensive disorders of pregnancy, with 22% (19/85) and 10% (3/31) of pregnancies with non-immune hydrops fetalis and single effusions affected, respectively (p = 0.12). Of those with hypertensive disorders, 8 (36%) developed preeclampsia with severe features, 4 (18%) preeclampsia without severe features, 2 (9%) atypical preeclampsia, and 8 (36%) gestational hypertension; 82% of these diagnoses were made antepartum. The presence of a fetal genetic disease did not result in statistically significant increased risk of hypertensive disorders. Conclusions:In this contemporary cohort that continued beyond 20 weeks gestation, 22% with non-immune hydrops fetalis and 10% with single effusions developed a range of hypertensive disorders of pregnancy, with most arising in the antepartum period. These data allow clinicians to provide more evidence-based counseling, anticipate obstetric risks, and consider close surveillance strategies for the development of hypertensive disorders in pregnancies with fetal effusions.

OBJECTIVES:Nonimmune hydrops fetalis is well understood to be heterogenous and the common endpoint of many genetic diseases. However, less is known about the prevalence and presenting features of genetic diseases that underlie other types of fetal effusions such as single effusions, leaving uncertainty in clinical practice about optimal approaches to testing and counseling for these pregnancies. We aimed to determine the diagnostic yield of exome sequencing by type of fetal effusion and presence of concurrent structural abnormalities and to identify the unique presenting features of underlying genetic diseases. STUDY DESIGN:We conducted a prospective cohort study of pregnancies with nonimmune hydrops fetalis and other fetal effusions, with participants enrolled from across the United States. Inclusion criteria were nondiagnostic results of chromosomal microarray and/or karyotype and the presence of at least 1 fetal effusion, including nuchal translucency ≥3.5 mm, cystic hygroma, pleural effusion, pericardial effusion, ascites, and/or skin edema. Exome sequencing was performed by our institution's Clinical Laboratory Improvement Amendments-approved laboratory and results were returned to participants and their providers. Detailed fetal phenotypic data were ascertained and used to inform genetic variant interpretation, including fetal imaging findings (ultrasound, magnetic resonance imaging, and echocardiogram), pathology reports, and laboratory reports. Pregnancies with a variant or variants classified as pathogenic or likely pathogenic were considered diagnostic or positive. The primary outcome was the diagnostic yield of exome sequencing by the type of fetal effusion, with and without concurrent structural abnormalities. Secondary outcomes were the types of fetal effusions observed by category of genetic disease. RESULTS:In all, 118 pregnancies with nonimmune hydrops fetalis and other effusions underwent exome sequencing and 23% (27/118) had positive (diagnostic) findings. Pregnancies with nonimmune hydrops fetalis with and without concurrent structural abnormalities had diagnostic yields of 21% (9/42) and 40% (6/15), respectively (P=.15). Single effusions such as pleural effusion with and without concurrent structural abnormalities had diagnostic yields of 23% (6/26) and 17% (1/6), respectively (P=.61). The diagnostic yield for increased nuchal translucency or cystic hygroma was significantly greater for pregnancies with concurrent structural abnormalities (42%, 5/12) compared to those without (0%, 0/17, P<.01). We further observed numerous patterns in terms of how genetic diseases present in utero, such as RASopathies and musculoskeletal disorders demonstrating all types of effusions, while other disorders marked by neurodevelopmental delays after birth demonstrated all types of effusions except for nonimmune hydrops fetalis. CONCLUSION:The diagnostic yield of exome sequencing was high across all types of effusions including single effusions with and without concurrent structural abnormalities, with the exception of isolated increased nuchal translucency or cystic hygroma. Furthermore, we observed numerous patterns in terms of how genetic diseases present in utero with fetal effusions. These findings contribute important information for counseling and clinical management, highlight the utility of exome sequencing for fetal effusions beyond nonimmune hydrops fetalis, and inform accurate results of phenotype-driven tests such as exome sequencing.

OBJECTIVE:Current technical standards for chromosomal microarray (CMA) interpretation are not prescriptive for reporting variants of uncertain significance (VUS) identified prenatally. We sought to compare prenatal CMA reporting among cytogenetic labs and identify potential drivers of practice variation. METHODS:We conducted an electronic cross-sectional survey of cytogeneticists in the United States and Canada from July-December 2023. Participants were identified through the American Cytogenetics Forum List. RESULTS:Labs reported differences in their size threshold used when reporting CNVs lacking OMIM annotated genes as a VUS, variable use of clinical data such as ultrasound or family history when deciding to report a VUS, and differences in opinion regarding the underlying pathogenicity of certain CNVs. Many cytogeneticists reported concerns about legal liability related to prenatal CMA reporting, and many shared concerns that a patient may terminate a pregnancy based on a VUS. CONCLUSION:Reporting criteria for prenatally identified variants of uncertain significance differs among cytogenetic laboratories in North America. Many possible drivers of this practice variation were identified, including a lack of national guidelines that comprehensively address the unique considerations for prenatal CMA reporting.

BACKGROUND AND PURPOSE:Schizencephaly is a rare brain anomaly that is increasingly detected in utero. There are limited data on the etiology and outcomes in fetal schizencephaly to guide work-up and counseling. We aimed to determine the associated imaging findings, etiology, and outcomes in schizencephaly detected in utero. MATERIALS AND METHODS:This retrospective cohort study included 22 fetuses with a total of 34 schizencephaly defects identified by keyword search of fetal MRI reports from 1996 to 2022 followed by image review. Follow-up fetal and postnatal imaging, when available, was reviewed. Data on demographics, etiology, and outcomes were extracted from the electronic medical record. RESULTS:The schizencephaly defect was open in 28/34, most common in the MCA territory (23/34), and commonly involved the frontal lobe (16/34). Additional intracranial abnormalities were seen in all fetuses, including other cortical malformations (13/22), abnormal posterior fossa (12/22), abnormal corpus callosum (10/20), and intraparenchymal hemorrhage (9/22). The cause of schizencephaly was classified as secondary (as evidenced by intraparenchymal hemorrhage at schizencephaly, monochorionic twin gestation, infection, or maternal/placental risk factor) in 64% (14/22), potentially genetic in 9% (2/22), and unknown in 27% (6/22). Among those liveborn (n = 8), we observed the following outcomes: postnatal death (1/8), tube feeding (1/7), shunted hydrocephalus (1/7), and epilepsy (4/7). Among those older than 1 year of age, cerebral palsy (4/5) and speech delay or intellectual disability (3/5) were common. Cortical malformations remote from schizencephaly were associated with epilepsy (P = .03). On postnatal imaging, open defects were often involuted (8/11), and there were high rates of new/additional findings (4/6). CONCLUSIONS:In this cohort, fetal schizencephaly was always associated with additional intracranial abnormalities. In most cases, there was evidence that schizencephaly was likely secondary to prior injury. Imaging characteristics may provide clues regarding neurodevelopmental outcome. Postnatal imaging is crucial in assessing the evolution as well as detection of additional abnormalities.

OBJECTIVE:To estimate the association between third-trimester maternal low blood pressure (BP) and delivery of a neonate with small-for-gestational-age (SGA) birth weight in patients treated for mild chronic hypertension. METHODS:This is a secondary analysis of the CHAP (Chronic Hypertension and Pregnancy) study, which randomized pregnant participants with mild chronic hypertension to treatment to achieve goal BP below 140/90 mm Hg compared with usual care. We calculated mean systolic and diastolic BPs between 28 and 34 weeks of gestation and excluded those with systolic BP of 140 mm Hg or higher or diastolic BP of 90 mm Hg or higher. We defined low BP as mean systolic BP below 110 and mean diastolic BP below 70 mm Hg or mean arterial pressure below 80 mm Hg and compared those individuals with participants with mean systolic BP of 110-139 mm Hg or mean diastolic BP of 71-89 mm Hg or both or mean arterial pressure of 80 mm Hg or higher. Our primary outcome was delivery of a neonate with SGA birth weight (birth weight below the 5th percentile). Logistic regression estimated the association between low BP and SGA birth weight, and adjusted odds ratios (aORs) and 95% CIs were reported. RESULTS:Of 2,408 CHAP participants, 1,205 (50.0%) met analysis criteria. Of those 1,205, 31 (2.6%) had low BP and 1,174 (97.4%) had mean BP 110/70-139/89 mm Hg; 33 (2.7%) had mean arterial pressure below 80 mm Hg, and 1,172 (97.3%) had mean arterial pressure of 80 mm Hg or higher. Having a neonate with SGA birth weight below the 5th percentile occurred in 62 participants (5.1%): 1 of the 31 (3.2%) with BP below 110/70 mm Hg and 1 of the 33 (3.0%) with mean arterial pressure below 80 mm Hg. There was no significant association between delivery of a neonate with SGA birth weight less than the 5th percentile and low BP by either mean systolic BP and mean diastolic BP (aOR 0.46, 95% CI, 0.06-3.58) or mean arterial pressure (aOR 0.53, 95% CI, 0.07-4.01). We found a nonlinear relationship between mean arterial pressure and delivery of a neonate with SGA birth weight less than the 5th percentile, and, as mean arterial pressure decreased, there was lower probability of having a neonate with SGA birth weight ( P =.02). CONCLUSION:Pharmacologic treatment of mild chronic hypertension infrequently results in low BP and does not appear to be associated with delivery of a neonate with SGA birth weight less than the 5th percentile for birth weight.

Malformations of cortical development (MCDs) are a heterogeneous family of congenital brain malformations that originate from disturbed development of the cerebral cortex. MCDs can arise from primary genetic disorders that lead to dysfunction of the molecular processes controlling neuronal proliferation, neuronal migration, cortical folding or cortical organization. MCDs can also result from secondary, disruptive causes, such as congenital infection or other in utero brain injuries. Sequelae of MCDs can include epilepsy, intellectual disability and cerebral palsy, among other symptoms, with a high burden of paediatric morbidity. Advances in antenatal genetic testing and imaging have improved the ability to diagnose MCDs, yet limited literature exists to aid clinicians in prognostication of outcomes and perinatal management. These clinical realities can make it challenging for clinicians caring for fetal neurological conditions to counsel families and make recommendations for interdisciplinary care. We aim to review the literature on fetal MCDs and present practice guidelines for clinicians regarding the pre- and postnatal management of MCDs.

To evaluate the association of longitudinal systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in early pregnancy with later development of superimposed preeclampsia with severe features in pregnancies complicated by mild chronic hypertension. This secondary analysis used data from the CHAP (Chronic Hypertension and Pregnancy) trial, a multicenter randomized controlled trial that involved pregnant individuals with chronic hypertension. Participants were categorized based on the development of superimposed preeclampsia with severe features. Longitudinal blood pressure measurements from enrollment to the development of superimposed preeclampsia with severe features or delivery were assessed using regression models. Separate models were created for SBP, DBP, and MAP to evaluate their associations with the primary outcome. Predictive performance was assessed using area under the curve (AUC) values, the integrated calibration index, and a Brier score. Of 2,316 individuals with chronic hypertension, 600 (25.9%) developed superimposed preeclampsia with severe features. Higher SBP, DBP, and MAP all were associated with superimposed preeclampsia with severe features, with MAP demonstrating the strongest association. Adjusted hazard ratios (HR) indicated that increased MAP, SBP, and DBP were significantly associated with the risk of superimposed preeclampsia with severe features (eg, adjusted HR 1.1556 [95% credible interval: 1.1332–1.1784] per mm Hg increase in MAP). Although MAP showed slightly better predictive metrics compared with SBP and DBP, overall predictive precision remained moderate. The lowest Brier score and highest AUC values were observed for MAP models, though differences among blood pressure metrics were minimal. In pregnancies complicated by chronic hypertension, longitudinal MAP trends provide a stronger association with superimposed preeclampsia with severe features compared with SBP or DBP. Although predictive performance was only moderate, these findings support the consideration of MAP as an important component of vital sign monitoring in prenatal care. Further research is warranted to refine risk prediction models through the integration of additional clinical and biomarker data. ClinicalTrials.gov, NCT02299414.

Objective Analysis of exome sequencing (ES) relies on correlation with phenotypic features, but fetal phenotyping is often incomplete. The additional yield of postnatal follow-up in cases with negative or inconclusive prenatal ES has not been demonstrated. Our objective was to assess the incremental diagnostic yield of ES reanalysis after initially negative prenatal ES for congenital anomalies incorporating features identified postnatally.Methods This was a secondary analysis of two prospective cohort studies of ES for fetal anomalies. We included cases in which initial ES utilizing the prenatal phenotype was not diagnostic. The primary outcome was incremental diagnostic yield of ES when incorporating postnatal findings.Results Eighty-seven cases with negative or inconclusive prenatal ES and postnatal follow-up available were included. Of those, 56 (64%) had new findings postnatally. There was an incremental yield of 2% in the entire cohort, and 7% in those with new postnatal findings. In two additional cases, postnatal evaluation suggested a specific genetic diagnosis that was not detectable with ES.Conclusion Among pregnancies with fetal anomalies and no clear diagnosis identified by prenatal ES, postnatal follow-up is recommended. Reanalysis of ES results can result in a genetic diagnosis in 7% of cases with new findings.

This exploratory empirical study documents how prenatal genetic counseling practice was evolving one year after the 2022 Supreme Court decision overturning the constitutional right to abortion in Dobbs v. Jackson Women’s Health Organization. This study captures a moment when prenatal genetic counselors, clinicians who provide education and counseling about genetic and other fetal health issues before and during pregnancy, were navigating new state abortion restrictions. Qualitative interviews were conducted with 27 genetic counselors in 15 states representing a range of abortion regulations. Thematic analysis identified five key findings: 1) Genetic counselors in restrictive states adapted their practices in response to the evolving legal landscape and institutional context by continuing to discuss abortion but shifting their counseling approach and limiting medical record documentation; 2) Variable institutional guidance and interpretation of laws resulted in inconsistent support as counselors navigated restrictions; 3) Genetic counselors responded to patient questions and concerns emerging from the legal context; 4) Legal and medical ambiguity about lethal fetal anomalies led to varied medical and institutional approaches to patient care; 5) Abortion restrictions complicated provider relationships and expectations. Our data show that legal restrictions, uncertainty and a climate of fear resulted in logistical challenges, challenges to professional practice standards, and moral distress. Our findings contribute to a greater understanding of how healthcare for pregnancies with fetal anomalies is evolving post-Dobbs, and how reproductive healthcare providers beyond physicians are affected by state laws restricting abortion.