Amniocentesis in pregnancies at or beyond 24 weeks: an international multicenter study.

BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVE: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved 9 referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and postprocedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within 2 weeks postprocedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24 and 28 weeks and those between 28 and 32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSION: Late amniocentesis, at or after 24 weeks of gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.

Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta-analysis.

OBJECTIVES: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. METHODS: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. RESULTS: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. CONCLUSIONS: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.

The utility of gene sequencing in identifying an underlying genetic disorder in prenatally suspected lower urinary tract obstruction.

OBJECTIVE: Fetal megacystis generally presents as suspected lower urinary tract obstruction (LUTO), which is associated with severe perinatal morbidity. Genetic etiologies underlying LUTO or a LUTO-like initial presentation are poorly understood. Our objectives are to describe single gene etiologies in fetuses initially ascertained to have suspected LUTO and to elucidate genotype-phenotype correlations. METHODS: A retrospective case series of suspected fetal LUTO positive for a molecular diagnosis was collected from five centers in the Fetal Sequencing Consortium. Demographics, sonograms, genetic testing including variant classification, and delivery outcomes were abstracted. RESULTS: Seven cases of initially prenatally suspected LUTO-positive for a molecular diagnosis were identified. In no case was the final diagnosis established as urethral obstruction that is, LUTO. All variants were classified as likely pathogenic or pathogenic. Smooth muscle deficiencies involving the bladder wall and interfering with bladder emptying were identified in five cases: MYOCD (2), ACTG2 (2), and MYH11 (1). Other genitourinary and/or non-genitourinary malformations were seen in two cases involving KMT2D (1) and BBS10 (1). CONCLUSION: Our series illustrates the value of molecular diagnostics in the workup of fetuses who present with prenatally suspected LUTO but who may have a non-LUTO explanation for their prenatal ultrasound findings.

Trust in prenatal exome sequencing for expectant families facing unexplained fetal anomalies.

OBJECTIVE: Despite exome sequencing (ES) becoming increasingly incorporated into the prenatal setting, few studies have elucidated motivations for and trust in ES and genomic research among a diverse cohort of patients and their partners. METHODS: This is a qualitative study that involved semi-structured interviews with pregnant or recently pregnant individuals and their partners, interviewed separately, in the setting of ES performed through research for a fetal structural anomaly. All interview transcripts were coded thematically and developed by a multidisciplinary team. RESULTS: Thirty-five individuals participated, the majority of whom (66%) self-identified as a racial or ethnic group underrepresented in genomic research. Many patients and their partners expressed trust in the healthcare system and research process and appreciated the extensive testing for information and closure. There were nonetheless concerns about data privacy and protection for individuals, including those underrepresented, who participated in genomic testing and studies. CONCLUSION: Our findings illustrate important elements of motivation, trust and concern related to prenatal ES performed in the research setting, taking into account the perspectives not only of diverse and underrepresented study participants but also partners of pregnant individuals.

The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease.

BACKGROUND: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions. METHODS: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology. FINDINGS: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases. CONCLUSIONS: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO). FUNDING: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04.

Optimal timing of delivery for growth restricted fetuses with gastroschisis: A decision analysis.

OBJECTIVE: Our objective was to determine the optimal timing of delivery of growth restricted fetuses with gastroschisis in the setting of normal umbilical artery (UA) Dopplers. METHODS: We designed a decision analytic model using TreeAge software for a hypothetical cohort of 2000 fetuses with isolated gastroschisis, fetal growth restriction (FGR), and normal UA Dopplers across 34-39 weeks of gestation. This model accounted for costs and quality adjusted life years (QALYs) for the pregnant individual and the neonate. Model outcomes included stillbirth, respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), short gut syndrome (SGS), neonatal sepsis, neonatal death, and neurodevelopmental disability (NDD). RESULTS: We found 38 weeks to be the optimal timing of delivery for minimizing overall perinatal mortality and leading to the highest total QALYs. Compared to 37 weeks, delivery at 38 weeks resulted in 367.98 more QALYs, 2.22 more cases of stillbirth, 2.41 fewer cases of RDS, 0.02 fewer cases of NEC, 1.65 fewer cases of IVH, 0.5 fewer cases of SGS, 2.04 fewer cases of sepsis, 11.8 fewer neonatal deaths and 3.37 fewer cases of NDD. However, 39 weeks were the most cost-effective strategy with a savings of $1,053,471 compared to 38 weeks. Monte Carlo analysis demonstrated that 38 weeks was the optimal gestational age for delivery 51.70% of the time, 39 weeks were optimal 47.40% of the time, and 37 weeks was optimal 0.90% of the time. CONCLUSION: Taking into consideration a range of adverse perinatal outcomes and cost effectiveness, 38-39 weeks gestation is ideal for the delivery of fetuses with gastroschisis, FGR, and normal UA Dopplers. However, there are unique details to consider for each case, and the timing of delivery should be individualized using shared multidisciplinary decision making.

Access to prenatal exome sequencing for fetal malformations: A qualitative landscape analysis in the US.

OBJECTIVE: There is increasing evidence supporting the clinical utility of next generation sequencing for identifying fetal genetic disorders. However, there are limited data on the demand for and accessibility of these tests, as well as payer coverage in the prenatal context. We sought to identify clinician perspectives on the utility of prenatal exome sequencing (ES) and on equitable access to genomic technologies for the care of pregnancies complicated by fetal structural anomalies. METHOD: We conducted two focus group discussions and six interviews with a total of 13 clinicians (11 genetic counselors; 2 Maternal Fetal Medicine/Geneticists) from U.S. academic centers and community clinics. RESULTS: Participants strongly supported ES for prenatal diagnostic testing in pregnancies with fetal structural anomalies. Participants emphasized the value of prenatal ES as an opportunity for a continuum of care before, during, and after a pregnancy, not solely as informing decisions about abortions. Cost and coverage of the test was the main access barrier, and research was the main pathway to access ES in academic centers. CONCLUSION: Further integrating the perspectives of additional key stakeholders are important for understanding clinical utility, developing policies and practices to address access barriers, and assuring equitable provision of prenatal diagnostic testing.

The Medical Action Ontology: A Tool for Annotating and Analyzing Treatments and Clinical Management of Human Disease.

Navigating the vast landscape of clinical literature to find optimal treatments and management strategies can be a challenging task, especially for rare diseases. To address this task, we introduce the Medical Action Ontology (MAxO), the first ontology specifically designed to organize medical procedures, therapies, and interventions in a structured way. Currently, MAxO contains 1757 medical action terms added through a combination of manual and semi-automated processes. MAxO was developed with logical structures that make it compatible with several other ontologies within the Open Biological and Biomedical Ontologies (OBO) Foundry. These cover a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. We have created a database of over 16000 annotations that describe diagnostic modalities for specific phenotypic abnormalities as defined by the Human Phenotype Ontology (HPO). Additionally, 413 annotations are provided for medical actions for 189 rare diseases. We have developed a web application called POET (https://poet.jax.org/) for the community to use to contribute MAxO annotations. MAxO provides a computational representation of treatments and other actions taken for the clinical management of patients. The development of MAxO is closely coupled to the Mondo Disease Ontology (Mondo) and the Human Phenotype Ontology (HPO) and expands the scope of our computational modeling of diseases and phenotypic features to include diagnostics and therapeutic actions. MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).

Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population.

The diagnostic yield of exome sequencing (ES) has primarily been evaluated in individuals of European ancestry, with less focus on underrepresented minority (URM) and underserved (US) patients. We evaluated the diagnostic yield of ES in a cohort of predominantly US and URM pediatric and prenatal patients suspected to have a genetic disorder. Eligible pediatric patients had multiple congenital anomalies and/or neurocognitive disabilities and prenatal patients had one or more structural anomalies, disorders of fetal growth, or fetal effusions. URM and US patients were prioritized for enrollment and underwent ES at a single academic center. We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P = 0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status. Our results demonstrate a similar diagnostic yield of ES between prenatal and pediatric URM/US patients and non-URM/US patients for positive and inconclusive results. These data support the use of ES to identify clinically relevant variants in patients from diverse populations.

Understanding Preterm Birth in Pregnancies Complicated by Nonimmune Hydrops Fetalis.

OBJECTIVE: Nonimmune hydrops fetalis (NIHF) is associated with poor perinatal outcomes including preterm birth (PTB). However, the frequency and causes of PTB in this population are not well understood. We hypothesized that NIHF frequently results in PTB due to medically indicated delivery for fetal distress. STUDY DESIGN: This was a secondary analysis of a prospectively enrolled cohort of pregnancies with NIHF that underwent exome sequencing if standard testing was nondiagnostic. The primary outcome was frequency of PTB at <37 weeks' gestation. Secondary outcomes were reasons for PTB, fetal predictors of PTB, and frequency of neonatal death following PTB. RESULTS: Fifty-six cases were included, with a median gestational age at delivery of 32.8 weeks (interquartile range [IQR]: 30.3-35.0). Overall, 86% (48/56) were delivered preterm. Among 48 PTBs, 18 (38%) were spontaneous, 9 (19%) were medically indicated for maternal indications (primarily preeclampsia), and 21 (44%) were medically indicated for fetal indications (nonreassuring antenatal testing or worsening effusions). Neither fetal genetic diagnosis nor polyhydramnios was associated with PTB. CONCLUSION: More than four-fifths of pregnancies with NIHF result in PTB, often due to nonreassuring fetal status. These data are informative for counseling patients and for developing strategies to reduce PTB in pregnancies with NIHF. KEY POINTS: · Pregnancies complicated by nonimmune hydrops fetalis often result in preterm birth.. · Preterm birth in these cases is most often medically indicated for fetal benefit.. · Fetal genetic conditions and polyhydramnios may be associated with preterm birth in cases of NIHF..

A systematic review and meta-analysis of cell-free DNA testing for detection of fetal sex chromosome aneuploidy.

OBJECTIVES: The aim was to determine the accuracy of cell-free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies. METHODS: A systematic review and meta-analysis was performed to assess cfDNA accuracy for prenatal detection of 45,X, 47,XXY, 47,XXX and 47,XYY. Inclusion was restricted to studies published between January 2010 and December 2021 reporting both cfDNA and confirmatory diagnostic test results. RESULTS: For 45,X, the sensitivity was 98.8% (95%CI 94.6%-100%), specificity 99.4% (95%CI 98.7%-99.9%) and positive predictive value (PPV) 14.5% (95%CI 7.0%-43.8%). For 47,XXY, the sensitivity was 100% (95%CI 99.6%-100%), specificity 100% (95%CI 99.9%-100%) and PPV 97.7% (95%CI 78.6%-100%). For 47,XXX, the sensitivity was 100% (95%CI 96.9%-100%), specificity 99.9% (95%CI 99.7%-100%) and PPV 61.6% (95%CI 37.6%-95.4%). For 47,XYY, the sensitivity was 100% (95%CI 91.3%-100%), specificity 100% (95% CI 100%-100%) and PPV 100% (95%CI 76.5%-100%). All four SCAs had estimated negative predictive values (NPV) exceeding 99.99%, though false negatives were reported. CONCLUSIONS: This analysis suggests that cfDNA is a reliable screening test for SCA, though both false negatives and false positives were reported. These estimates of test performance are derived from pregnancies at high pretest risk for aneuploidy, limiting the generalisability to average risk pregnancies.

How to choose a test for prenatal genetic diagnosis: a practical overview.

Establishing the diagnosis of a fetal genetic disease in utero expands decision-making opportunities for individuals during pregnancy and enables providers to tailor prenatal care and surveillance to disease-specific risks. The selection of prenatal genetic tests is guided by key details from fetal imaging, family and obstetrical history, suspected diagnoses and mechanisms of disease, an accurate understanding of what abnormalities each test is designed to detect, and, at times, the gestational age at which testing is initiated. Pre- and posttest counseling, by or in conjunction with providers trained in genetics, ensure an accurate understanding of genetic tests, their potential results and limitations, estimated turnaround time for results, and the clinical implications of their findings. As prenatal diagnosis and testing options continue to expand rapidly, it is increasingly important for obstetrical providers to understand how to choose appropriate genetic testing and contextualize the clinical implications of their results.

Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation.

We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.

Prenatal phenotype of 47, XXY (Klinefelter syndrome).

OBJECTIVE: There is a paucity of knowledge regarding the prenatal presentation of Klinefelter syndrome, or 47, XXY. Accurate prenatal counseling is critical and in utero diagnosis is currently limited by a poor understanding of the prenatal phenotype of this condition. METHODS: This is a case series of fetuses with cytogenetically confirmed 47, XXY in the prenatal period or up to age 5 years, with prenatal records available for review from four academic institutions between 2006 and 2019. Ultrasound reports were reviewed in detail to assess for increased nuchal translucency and structural abnormalities. Additionally, we reviewed results of cell-free DNA and serum analyte testing when performed to inform our understanding of the detection of fetal 47, XXY through standard genetic screening tests. RESULTS: Forty-one cases with confirmed cytogenetic diagnosis of 47, XXY and prenatal records available for review were identified: 37 had a prenatal diagnosis and 4 had a postnatal diagnosis. Nuchal translucency was increased ≥3.0 mm in 23.1% (6/26) of cases with a documented measurement. In 29.2% (7/24) of cases with a second trimester anatomical ultrasound available for review, a fetal abnormality was identified (3 brain anomalies, 1 cardiac abnormality, 1 echogenic bowel, and 2 limb abnormalities). Among those who had cell-free DNA and serum analytes performed, 92.6% (25/27) and 36.3% (4/11) had an abnormal result respectively. CONCLUSION: This case series expands our knowledge of the prenatal presentation of 47, XXY by identifying first and second trimester fetal sonographic abnormalities. Prenatal identification of this condition enables accurate counseling, focused prenatal management, and early postnatal interventions to ameliorate some of the known complications.

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series.

OBJECTIVE: Tubulinopathies refer to conditions caused by genetic variants in isotypes of tubulin resulting in defective neuronal migration. Historically, diagnosis was primarily via postnatal imaging. Our objective was to establish the prenatal phenotype/genotype correlations of tubulinopathies identified by fetal imaging. METHODS: A large, multicenter retrospective case series was performed across nine institutions in the Fetal Sequencing Consortium. Demographics, fetal imaging reports, genetic screening and diagnostic testing results, delivery reports, and neonatal imaging reports were extracted for pregnancies with a confirmed molecular diagnosis of a tubulinopathy. RESULTS: Nineteen pregnancies with a fetal tubulinopathy were identified. The most common prenatal imaging findings were cerebral ventriculomegaly (15/19), cerebellar hypoplasia (13/19), absence of the cavum septum pellucidum (6/19), abnormalities of the corpus callosum (6/19), and microcephaly (3/19). Fetal MRI identified additional central nervous system features that were not appreciated on neurosonogram in eight cases. Single gene variants were reported in TUBA1A (13), TUBB (1), TUBB2A (1), TUBB2B (2), and TUBB3 (2). CONCLUSION: The presence of ventriculomegaly with cerebellar abnormalities in conjunction with additional prenatal neurosonographic findings warrants additional evaluation for a tubulinopathy. Conclusive diagnosis can be achieved by molecular sequencing, which may assist in coordination, prognostication, and reproductive planning.

Prenatal Somatic Cell Gene Therapies: Charting a Path Toward Clinical Applications (Proceedings of the CERSI-FDA Meeting).

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

Cost-Effectiveness of Exome Sequencing versus Targeted Gene Panels for Prenatal Diagnosis of Fetal Effusions and Non-Immune Hydrops Fetalis.

BACKGROUND: Although exome sequencing has a greater overall diagnostic yield than targeted gene panels in the evaluation of nonimmune hydrops fetalis and fetal effusions, the cost-effectiveness of this approach is not known. OBJECTIVE: This study aimed to evaluate the costs and outcomes of targeted gene panels vs exome sequencing for prenatally diagnosed nonimmune hydrops fetalis and fetal effusions when next-generation sequencing is pursued following nondiagnostic standard nonimmune hydrops fetalis evaluations, including karyotype or chromosomal microarray. STUDY DESIGN: A decision-analytical model was designed using TreeAge Pro to compare 10 genetic testing strategies, including a single test only (RASopathy, metabolic, or nonimmune hydrops fetalis-targeted gene panel or exome sequencing), sequential testing (RASopathy panel followed by nonimmune hydrops fetalis panel, metabolic panel followed by nonimmune hydrops fetalis panel, RASopathy panel followed by exome sequencing, metabolic panel followed by exome sequencing, and nonimmune hydrops fetalis panel followed by exome sequencing), and no additional genetic testing. Our theoretical cohort included cases with normal karyotype and/or microarray and excluded cases of alloimmunization and congenital viral infections. As nonimmune hydrops fetalis and fetal effusions can present throughout gestation, whereas pregnancy management options vary depending on gestational age, outcomes were calculated for 3 time intervals: 10 to 18, 18 to 22, and >22 weeks of gestation. The primary outcome was incremental cost per quality-adjusted life year. Additional outcomes included termination of pregnancy, stillbirth, neonatal death, and neonates born with mild, moderate, and severe or profound disease phenotypes. The cost-effectiveness threshold was $100,000 per quality-adjusted life year. RESULTS: Among women <18 weeks of gestation, exome sequencing alone was the dominant strategy associated with the lowest costs ($221 million) and the highest quality-adjusted life years (10,288). Strategies with exome sequencing alone or as a sequential test resulted in more terminations but fewer stillbirths, neonatal deaths (NNDs), and affected infants than strategies without exome sequencing. Among women between 18 and 22 weeks of gestation, exome sequencing alone was also associated with the lowest costs ($188 million) and the highest quality-adjusted life years (8734), and similar trends were observed in pregnancy outcomes. Among patients >22 weeks of gestations, when termination was not available, exome sequencing was associated with lower costs ($300 million) and the highest quality-adjusted life years (8492). Exome sequencing was cost-effective up to a cost per test of $50,451 at <18 weeks of gestation, $50,423 at 18 to 22 weeks of gestation, and $9530 at >22 weeks of gestation. Targeted genetic panels and exome sequencing were cost-effective strategies compared with no additional genetic testing. CONCLUSION: For cases of nonimmune hydrops fetalis and fetal effusions with nondiagnostic karyotype or microarray, next-generation sequencing was cost-effective compared with a strategy without additional genetic testing. For those that undergo next-generation sequencing, exome sequencing was the cost-effective strategy compared with all other testing strategies using targeted gene panels, leading to lower costs and fewer adverse perinatal outcomes. Exome sequencing was cost-effective in a setting without the option for pregnancy termination. These data supported the routine use of exome sequencing when next-generation sequencing is pursued for establishing a genetic diagnosis underlying otherwise unexplained nonimmune hydrops fetalis and fetal effusions.

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

"Let's Just Wait Until She's Born": Temporal Factors That Shape Decision-Making for Prenatal Genomic Sequencing Amongst Families Underrepresented in Genomic Research.

Genomic sequencing has been increasingly utilized for prenatal diagnosis in recent years and this trend is likely to continue. However, decision-making for parents in the prenatal period is particularly fraught, and prenatal sequencing would significantly expand the complexity of managing health risk information, reproductive options, and healthcare access. This qualitative study investigates decision-making processes amongst parents who enrolled or declined to enroll in the prenatal arm of the California-based Program in Prenatal and Pediatric Genome Sequencing (P3EGS), a study in the Clinical Sequencing Evidence-Generating Research (CSER) consortium that offered whole exome sequencing for fetal anomalies with a focus on underrepresented groups in genomic research. Drawing on the views of 18 prenatal families who agreed to be interviewed after enrolling (n = 15) or declining to enroll (n = 3) in P3EGS, we observed that the timing of sequencing, coupled with unique considerations around experiences of time during pregnancy and prenatal testing, intersect with structural supports beyond the clinic to produce preferences for and against prenatal sequencing and to contain the threat of unwelcome, uncertain knowledge. Particularly for those without structural supports, finding out consequential information may be more palatable after the birth, when the first stage of the uncertain future has been revealed. Future research should examine the role of temporality in decision-making around prenatal genomic sequencing across diverse population cohorts, in order to observe more precisely the role that structural barriers play in patient preferences.