Introduction:There is a lack of published data on the contemporary use and timing of antenatal corticosteroids in the United States. Our primary objective was to address this gap using clinical data from a large US birth cohort. Our secondary objective was to identify factors associated with optimally timed steroids in births <34 weeks' gestation. Methods:This retrospective study included de-identified clinical data from a quality improvement database for births at 24+0-42+6 weeks' gestation between January 1, 2017 and December 31, 2021 at 12 hospitals in the northwest United States. We evaluated the proportion of live births <34 weeks' gestation that received at least a first dose of antenatal steroids within the 7 days preceding birth ("optimally timed" steroids), and the proportion of patients given antenatal steroids who delivered at term. Annual rates of these measures were also evaluated across the study period. Associations between optimal steroid timing in preterm births <34 weeks' gestation and sociodemographic and medical characteristics were explored with a multilevel logistic regression model using hospitals as random effects. Results:Of 105,981 patients included in the analysis, 6.1% (6443) received steroids before 37 weeks' gestation. A total of 83.1% of live births <34 weeks' gestation received antenatal steroids, but only 55.4% received optimally timed steroids. The rate of optimally timed steroids in births <34 weeks' gestation was stable between 2017 and 2021. Over the same period, the proportion of births at 34+0-36+6 weeks' gestation that received steroids increased from 36.6% to 46.6%, and the proportion that received steroids and then delivered at term increased from 15.5% to 22.1% (p < 0.001). After adjusting for confounders, preeclampsia was associated with increased odds for optimally timed steroids in births <34 weeks' gestation (OR 1.46; 95% CI 1.20, 1.79) while ruptured membranes (odds ratio [OR], 0.76; 95% CI, 0.63, 0.91) and placenta previa (OR, 0.28; 95% CI, 0.16, 0.51) were associated with decreased odds. Conclusion:In our study, most patients who delivered at <34 weeks' gestation received at least one dose of antenatal corticosteroids, but this was outside of the optimal 7-day window in approximately half of cases. Quality improvement efforts should focus on timing, as well as the use of antenatal corticosteroids.

PURPOSE:Early actionable metabolic conditions (EAMCs) are disorders that are often severe but have early interventions that can improve clinical outcomes. EAMCs are not universally included on newborn screening panels. We studied the clinical utility of detecting EAMC gene variants prenatally using reproductive carrier screening (RCS). METHODS:We identified EAMCs from the 113 ACMG-recommended carrier panel and a 275-gene carrier panel. The carrier status for these EAMCs was determined in a cohort of women who underwent RCS between 2022 and 2024. Observed carrier frequencies were used to calculate theoretical affected pregnancy rates. RESULTS:110 EAMCs were identified. Among 54,119 individuals, the carrier frequency for any EAMC was 1 in 6, using the 113-gene panel, and 1 in 4, using the 275-gene panel. Assuming random pairing, the theoretical affected pregnancy rates were 0.07% with the 113-gene panel and 0.08% with the 275-gene panel. The most prevalent EAMCs in this cohort were phenylketonuria (MIM:261600, 1 in 41), congenital adrenal hyperplasia (MIM:201910, 1 in 57), Wilson disease (MIM:201910, 1 in 63), Smith-Lemli-Opitz syndrome (MIM:270400, 1 in 75), and medium-chain acyl-CoA dehydrogenase deficiency (MIM:201450, 1 in 80). CONCLUSION:RCS facilitates detection and early intervention, which may reduce associated morbidity for certain metabolic disorders.

Introduction The importance of prenatal determination of chorionicity for the management of twin pregnancies is well recognized. However, research on the contribution of prenatal evaluation of zygosity to the management of twins is limited. We assessed the utility of adding SNP-based cell-free DNA (cfDNA) zygosity testing to ultrasound chorionicity assessment for the clinical management of twin pregnancies.Methods Prospective observational study involving 13 United States practices with proficiency in prenatal ultrasound. Patients diagnosed by ultrasound with twins in the first trimester were assessed with cfDNA screening for zygosity. Ultrasound assessment of chorionicity was performed prior to cfDNA results. Placental pathology was used as the gold standard for chorionicity assessment. Gestational age at delivery and standardized birthweights were compared, based on chorionicity and zygosity.Results 110 twin pregnancies were included. Among 79 dichorionic (DC) cases confirmed by placental pathology, one (1.3%) was misclassified as monochorionic (MC) by ultrasound, but was dizygous (DZ) by cfDNA, consistent with DC. Of 31 monozygotic (MZ) twins by cfDNA, confirmed as MC by pathology, ultrasound misclassified one (3.6%) as DC. Median gestational age at delivery was earlier for MZ twin pregnancies (35.0 weeks) compared to DZ (36.9 weeks, p = 0.02). After adjusting for fetal sex and gestational age at birth, MZDC twins had significantly lower birthweights (p = 0.006) and birthweight percentiles (p = 0.004) than DZDC twins.Conclusions Based on postpartum placental pathology as the reference standard for determining MC versus DC, cfDNA zygosity testing appears to aid in the prenatal assignment of chorionicity. Larger studies are needed to confirm the value of zygosity testing in the management of twin pregnancies.

Introduction Genetic testing for inherited cancer risk syndromes can inform targeted surveillance and intervention, but testing for male patients is inadequately addressed by medical literature and clinical guidelines despite having higher cancer-related mortality and morbidity than women. Here, we evaluate characteristics and hereditary cancer testing practices and outcomes in men compared to women. Methods This retrospective study analyzed hereditary cancer testing data from a commercial laboratory between 06/2020-08/2023. Outcomes assessed included demographics, personal and family cancer histories, ordering clinic type, gene panel size, test results (pathogenic/likely pathogenic, or negative), and the frequency of clinically actionable variants based on National Comprehensive Cancer Network and other guidelines. Comparisons between men and women were analyzed using odds ratios from Fisher's exact test and Wilcoxon rank test. Results Of the 224,041 individuals receiving hereditary cancer testing, only 10,936 (5%) were men. Compared to women, men were significantly older at testing (54 vs. 43 years; p<0.001), had higher odds of personal cancer history (OR, 2.67; 95% CI, 2.55 to 2.79), and had lower odds of family cancer history (OR, 0.50; 95% CI, 0.48 to 0.53). Testing orders for men were more likely to come from primary care or specialty clinics. Men had higher odds of testing positive for a pathogenic or likely pathogenic variant and for actionable gene variants. Discussion Men represented a minority in genetic testing for hereditary cancers but had higher test positivity rates. These findings underscore the need for greater integration of routine screening for hereditary cancer risk factors for men in primary care settings to enhance early detection and preventive measures. Addressing testing barriers and promoting awareness among healthcare providers has the potential to improve cancer outcomes for male patients and their families.

PURPOSE:To evaluate sociodemographic differences in US individuals screened with expanded versus small reproductive carrier panels at a single commercial laboratory. METHODS:A retrospective analysis of genetic and sociodemographic data (1-2020 to 9-2022) from female patients (18-45 years) that received expanded carrier screening (15-274 genes) or small-panel carrier screening (≤14 genes), excluding those from fertility clinics. Panel size and positive carrier result rates among different sociodemographic groups were assessed. RESULTS:Among 726,665 carrier screening tests, 14.7% were orders for expanded carrier screening. After adjustments, expanded carrier screening orders were 30% less likely to be from Black and Hispanic patients versus White patients (P ≤ .001), 28% less likely to be from patients living in distressed communities versus those in prosperous communities, and half as likely to be from patients with Medicaid insurance versus commercially insured (P ≤ .001). Fewer expanded carrier screening panels were received from Black and Hispanic individuals in prosperous communities compared with other racial/ethnic groups (P ≤ .001). Expanded panels identified 2.3 to 4.6 times more heterozygotes than smaller panels. CONCLUSIONS:Significantly fewer expanded carrier screening tests were from Hispanic and Black patients and those in economically distressed communities suggesting disparities in utilization. Accessible educational resources and consistent guideline recommendations for expanded carrier screening may improve equitable access.

Reproductive carrier screening aims to identify individuals at an increased chance of having children affected by genetic conditions. However, testing can also reveal health implications for autosomal or X‐chromosome heterozygotes. One such example is screening for Alport syndrome ( COL4A3‐5 ‐related disease) which is one of the most common causes of inherited chronic kidney disease. Alport syndrome heterozygotes have an increased chance for chronic kidney disease. Monitoring and providing early treatment can slow kidney disease progression and delay the onset of kidney failure. We provide information on Alport syndrome and propose a simple management algorithm for individuals found on carrier screening to have a pathogenic or likely pathogenic variant in one or more of the Alport syndrome genes. We emphasize the importance of genetic counseling, partner screening, and cascade testing to identify at‐risk family members, including existing children. Clinical management includes baseline evaluation for kidney disease, nephrology referral when needed, enhanced pregnancy surveillance for proteinuria and hypertension, and long‐term follow‐up. The proposed management plan serves as an example for other conditions where screening identifies heterozygotes with a variable chance for disease in the individual tested.

Purpose: To review biotinidase gene (BTD) variants identified in a large, diverse, reproductive carrier screening (RCS) cohort and outline management of heterozygotes with pathogenic or likely pathogenic (P/LP) variants. Methods: This retrospective observational study included samples tested from January 2020 to September 2022 in a 274-gene panel. The study involved females aged 18 to 55 years. Screening was performed using next-generation sequencing covering exons and 10 base-pair fl anking introns. The heterozygote frequency was calculated for P/LP variants for the entire population and individual racial/ethnic groups. Results: Of the 91,637 women tested, 5625 (6.1%) had a P/LP variant in BTD. NM_000060.4:c.1330G>C p.(Asp444His) (referred to as D444H or D424H) alone, or in combination with another variant, accounted for 5193 (92.3%) of the positive tests. P/LP heterozygote rates differed between racial and ethnic groups. We ascertained 7 novel P/LP variants not previously recorded in databases. Conclusion: The BTD P/LP variants identified through RCS were substantially compatible with those found through positive newborn screening. Therefore, RCS provides a potential for earlier diagnosis. We observed significant differences in P/LP heterozygote rates for biotinidase defi- ciency among different racial and ethnic groups. Most reported variants can be interpreted without requiring determination of serum biotinidase activity. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Prenatal diagnosis of chorionicity is critical for the management of twin pregnancies. Although ultrasound has been recommended for this, it has not been thoroughly validated. SNP-based cell-free DNA (cfDNA) can determine zygosity from 9 weeks’ gestation. Dizygotic cfDNA infers dichorionicity (DC). Monozygotic (MZ) cfDNA results may require managing the pregnancy as monochorionic (MC), regardless of chorionicity. The purpose of this study was to assess the accuracy of the diagnosis of chorionicity by ultrasound (C-US) prior to knowledge of cfDNA results. Prospective observational registry multi-institutional study (13 sites in the USA). Inclusion criteria were an ongoing twin pregnancy (< 20 weeks’ gestation) with C-US prior to cfDNA. Exclusion criteria were higher order multiples, contraindication for cfDNA, and twin to twin transfusion syndrome prior to enrollment. C-US, cfDNA results, perinatal outcome and placental pathology reports were collected. A total of 137 twin pregnancies were enrolled in the study. After exclusions for undetermined zygosity on cfDNA (1), missing placental pathology (15), incomplete follow-up (11), and unreported chorionicity on ultrasound (4), 106 pregnancies remained. Median gestation at C-US was 11 weeks. Two of 28 (7.1%) pregnancies reported to be MC on pathology were DC on C-US. All were monozygotic on cfDNA. One in 78 pregnancies (1.3%) reported to be DC on pathology was MC on C-US and was dizygotic on cfDNA. Overall, chorionicity was misdiagnosed by C-US in 2.8% (3/106) of twin pregnancies. Of the MZ-cfDNA twins (41.5%, 44/106), 36% were DC and 64% were MC on pathology. All DZ cfDNA twins (62/106, 58.5%) were DC on pathology. Surgical pathology confirmed the cfDNA zygosity diagnosis in all cases. Ultrasound assessment of chorionicity may be inaccurate in approximately 3% of twins. False negative MC diagnosis may preclude timely management of typical MC complications. False positive MC diagnosis may result in unnecessary surveillance or interventions. cfDNA screening for zygosity is essential in the management of twin pregnancies.