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Objective: To analyse fetal gene expression at term using umbilical cord blood, in order to provide insights into the effects of maternal obesity on human development.Design: Prospective case-control study.Setting: Academic tertiary care centre.Population: Eight obese (body mass index ≥30 kg/m(2)) and eight lean (body mass index <25 kg/m(2)) pregnant women undergoing prelabour caesarean delivery at term.Methods: Women were matched for gestational age and fetal sex. Cord blood RNA was extracted and hybridised to gene expression arrays. Differentially regulated genes were identified using paired t-tests and the Benjamini-Hochberg correction. Functional analyses were performed using Ingenuity Pathway Analysis, BioGPS and Gene Set Enrichment Analysis with a fetal-specific annotation. Z-scores ≥2.0 or P-values <0.01 were considered significant.Main Outcome Measure: Functions of differentially regulated genes in fetuses of obese women.Results: A total of 701 differentially regulated genes were identified, producing an expression profile implicating neurodegeneration, decreased survival of sensory neurons, and decreased neurogenesis in the fetuses of obese women. Upstream regulators related to inflammatory signalling were significantly activated; those related to insulin receptor signalling, lipid homeostasis, regulation of axonal guidance, and cellular response to oxidative stress were significantly inhibited. Of 26 tissue-specific genes that were differentially regulated in fetuses of obese women, six mapped to the fetal brain.Conclusion: Maternal obesity affects fetal gene expression at term, implicating dysregulated brain development, inflammatory and immune signalling, glucose and lipid homeostasis, and oxidative stress. This may have implications for postnatal neurodevelopment and metabolism. [ABSTRACT FROM AUTHOR]

Context: Noninvasive prenatal determination of fetal sex using cell-free fetal DNA provides an alternative to invasive techniques for some heritable disorders. In some countries this testing has transitioned to clinical care, despite the absence of a formal assessment of performance.Objective: To document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variables that affect performance.Data Sources: Systematic review and meta-analysis with search of PubMed (January 1, 1997-April 17, 2011) to identify English-language human studies reporting primary data. References from review articles were also searched.Study Selection and Data Extraction: Abstracts were read independently to identify studies reporting primary data suitable for analysis. Covariates included publication year, sample type, DNA amplification methodology, Y chromosome sequence, and gestational age. Data were independently extracted by 2 reviewers.Results: From 57 selected studies, 80 data sets (representing 3524 male-bearing pregnancies and 3017 female-bearing pregnancies) were analyzed. Overall performance of the test to detect Y chromosome sequences had the following characteristics: sensitivity, 95.4% (95% confidence interval [CI], 94.7%-96.1%) and specificity, 98.6% (95% CI, 98.1%-99.0%); diagnostic odds ratio (OR), 885; positive predictive value, 98.8%; negative predictive value, 94.8%; area under curve (AUC), 0.993 (95% CI, 0.989-0.995), with significant interstudy heterogeneity. DNA methodology and gestational age had the largest effects on test performance. Methodology test characteristics were AUC, 0.988 (95% CI, 0.979-0.993) for polymerase chain reaction (PCR) and AUC, 0.996 (95% CI, 0.993-0.998) for real-time quantitative PCR (RTQ-PCR) (P = .02). Gestational age test characteristics were AUC, 0.989 (95% CI, 0.965-0.998) (<7 weeks); AUC, 0.994 (95% CI, 0.987-0.997) (7-12 weeks); AUC, 0.992 (95% CI, 0.983-0.996) (13-20 weeks); and AUC, 0.998 (95% CI, 0.990-0.999) (>20 weeks) (P = .02 for comparison of diagnostic ORs across age ranges). RTQ-PCR (sensitivity, 96.0%; specificity, 99.0%) outperformed conventional PCR (sensitivity, 94.0%; specificity, 97.3%). Testing after 20 weeks (sensitivity, 99.0%; specificity, 99.6%) outperformed testing prior to 7 weeks (sensitivity, 74.5%; specificity, 99.1%), testing at 7 through 12 weeks (sensitivity, 94.8%; specificity, 98.9%), and 13 through 20 weeks (sensitivity, 95.5%; specificity, 99.1%).Conclusions: Despite interstudy variability, performance was high using maternal blood. Sensitivity and specificity for detection of Y chromosome sequences was greatest using RTQ-PCR after 20 weeks' gestation. Tests using urine and tests performed before 7 weeks' gestation were unreliable. [ABSTRACT FROM AUTHOR]

Objective: The FASTER trial compared first and second trimester screening methods for aneuploidy. We examined relationships between maternal serum markers and common congenital anomalies in the pediatric outcome data set of 36 837 subjects.Methods: We used nested case-control studies, with cases defined by the most common anomalies in our follow-up database, and up to four controls matched by enrollment site, maternal age and race, enrollment gestational age, and infant gender. Serum markers were dichotomized to > or = 2 or < 0.5 multiples of the median (MoM). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated.Results: Statistically significant (p < 0.05) associations were found between inhibin A > or = 2 MoM with fetal multicystic dysplastic kidney (MCDK) (OR = 27.5, 95% CI: 2.8-267.7) and two-vessel cord (OR = 4.22, 95% CI:1.6-10.9); hCG of > or = 2 MoM with MCDK (OR = 19.56, 95% CI: 1.9-196.2) and hydrocele (OR = 2.48, 95% CI: 1.3-4.6); and PAPP-A > or = 2.0 MoM with hydrocele (OR = 1.88, 95% CI:1.1-3.3).Conclusion: In this large prospective study, significant associations were found between several maternal serum markers and congenital anomalies. This suggests potential additional benefits to screening programs that are primarily designed to detect aneuploidy. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder. However, the consequences of ADPKD on male and female reproductive health are not widely known. Several abnormalities are found in men with ADPKD, including necrospermia, immotile sperm, seminal vesicle cysts, and ejaculatory duct cysts. Female fertility is not affected. Affected women with ADPKD and normal renal function have a high rate of successful uncomplicated pregnancies. Pregnant women with ADPKD with compromised kidney function should be monitored carefully for the development of hypertension and preeclampsia. Their fetuses should be examined sonographically for signs of uteroplacental insufficiency, such as intrauterine growth restriction and oligohydramnios. The diagnosis of ADPKD should always be considered when prenatal sonographic findings of hyperechogenic enlarged kidneys are found. In this setting, a family history and renal sonogram of both parents is indicated. Sequencing of the PKD1 and PKD2 genes is available and can be used for both prenatal and preimplantation genetic diagnosis. We review in detail these topics to familiarize physicians taking care of patients with ADPKD with the reproductive issues that confront affected individuals. [ABSTRACT FROM AUTHOR]

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive Development SM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual's genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Julia L. Zehr reports a relationship with Jazz Pharmaceuticals Inc that includes: equity or stocks. Co-author’s spouse is employed by Jazz Pharmaceuticals, Inc - JLZ If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier Ltd.)

The 17th century was a time of scientific discovery in Europe. Leading academic centers provided the general population with an opportunity to view anatomic dissections of human bodies. Rather than portray idealized versions of individuals, Dutch painters were committed to accurately representing their models. This was true for Johannes Vermeer. The 2023 exhibition of Vermeer's paintings at the Rijksmuseum in Amsterdam provided an unprecedented opportunity to observe 28 of his 37 existing paintings simultaneously in person. Here the authors suggest that in at least eight paintings a visibly pregnant woman is present. Vermeer's wife was pregnant or lactating most of the time during their 22-year marriage. Further, evidence of specific medical findings and congenital anomalies such as polydactyly, ectrodactyly, alopecia, kyphosis, and hyperthyroidism were observed in the paintings. These have not been previously reported in the medical or art history literature., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Down syndrome is associated with several comorbidities, including intellectual disability, growth restriction, and congenital heart defects. The prevalence of Down syndrome-associated comorbidities is highly variable, and intellectual disability, although fully penetrant, ranges from mild to severe. Understanding the basis of this interindividual variability might identify predictive biomarkers of in utero and postnatal outcomes that could be used as endpoints to test the efficacy of future therapeutic interventions., Objective: The main objective of this study was to examine if antenatal interindividual variability exists in mouse models of Down syndrome and whether applying statistical approaches to clinically relevant measurements (ie, the weights of the embryo, placenta, and brain) could define cutoffs that discriminate between subgroups of trisomic embryos., Study Design: Three commonly used mouse models of Down syndrome (Dp(16)1/Yey, Ts65Dn, and Ts1Cje) and a new model (Ts66Yah) were used in this study. Trisomic and euploid littermate embryos were used from each model with total numbers of 102 for Ts66Yah, 118 for Dp(16)1/Yey, 92 for Ts65Dn, and 126 for Ts1Cje. Placental, embryonic, and brain weights and volumes at embryonic day 18.5 were compared between genotypes in each model. K-mean clustering analysis was applied to embryonic and brain weights to identify severity classes in trisomic embryos, and brain and placental volumetric measurements were compared between genotypes and classes for each strain. In addition, Ts66Yah embryos were examined for malformations because embryonic phenotypes have never been examined in this model., Results: Reduced body and brain weights were present in Ts66Yah, Dp(16)1/Yey, and Ts65Dn embyos. Cluster analysis identified 2 severity classes in trisomic embryos-mild and severe-in all 4 models that were distinguishable using a putative embryonic weight cutoff of <0.5 standard deviation below the mean. Ts66Yah trisomic embryos develop congenital anomalies that are also found in humans with Down syndrome, including congenital heart defects and renal pelvis dilation., Conclusion: Statistical approaches applied to clinically relevant measurements revealed 2 classes of phenotypic severity in trisomic mouse models of Down syndrome. Analysis of severely affected trisomic animals may facilitate the identification of biomarkers and endpoints that can be used to prenatally predict outcomes and the efficacy of treatments., (Published by Elsevier Inc.)

Objectives: To assess brain development in living fetuses with Down syndrome (DS) by biometric measurements on fetal brain magnetic resonance images (MRI)., Methods: We scanned 10 MRIs of fetuses with confirmed trisomy 21 at birth and 12 control fetal MRIs without any detected anomalies. Fetal brain MRIs were analyzed using 14 fetal brain and skull biometric parameters. We compared measures between DS and controls in both raw MRIs and motion-corrected and anterior-posterior commissure-aligned images., Results: In the reconstructed images, the measured values of the height of the cerebellar vermis (HV) and anteroposterior diameter of the cerebellar vermis (APDV) were significantly smaller, and the anteroposterior diameter of the fourth ventricle (APDF) was significantly larger in fetuses with DS than controls. In the raw MRIs, the measured values of the right lateral ventricle were significantly larger in fetuses with DS than in controls. Logistic regression analyses revealed that a new parameter, the cerebellar-to-fourth-ventricle ratio (i.e., (APDV * Height of the vermis)/APDF), was significantly smaller in fetuses with DS than controls and was the most predictive to distinguish between fetuses with DS and controls., Conclusions: The study revealed that fetuses with DS have smaller cerebellums and larger fourth ventricles compared to the controls., (© 2023 John Wiley & Sons Ltd.)

Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care. In this review, we discuss advances, challenges, and possibilities toward the goal of providing proactive, personalized prenatal care. The highlighted advances focus mainly on cell-free nucleic acids; however, we also review research that uses signals from metabolomics, proteomics, intact cells, and the microbiome. We discuss ethical challenges in providing care. Finally, we look to future possibilities, including redefining disease taxonomy and moving from biomarker correlation to biological causation.

Objective: To explore patient perspectives after receiving non-invasive prenatal testing (NIPT) results that suggest maternal cancer., Methods: Individuals who received non-reportable or discordant NIPT results during pregnancy and enrolled in a study were interviewed prior to and after receiving the outcome of their clinical evaluation for cancer. Interviews were independently coded by two researchers and analyzed thematically., Results: Forty-nine participants were included. Three themes were identified: 1) limited pre-test awareness of maternal incidental findings caused considerable confusion for participants, whose initial concerns focused on their babies; 2) providers' communication influenced how participants perceived their risk of cancer and the need to be evaluated; and 3) participants perceived value in receiving maternal incidental findings from NIPT despite any stress it caused during their pregnancy., Conclusion: Participants viewed the ability to detect occult malignancy as an added benefit of NIPT and felt strongly that these results should be disclosed. Obstetric providers need to be aware of maternal incidental findings from NIPT, inform pregnant people of the potential to receive these results during pre-test counseling, and provide accurate and objective information during post-test counseling., Clinical Trial Registration: Incidental Detection of Maternal Neoplasia Through Non-Invasive Cell-Free DNA Analysis (IDENTIFY), a Natural History Study, NCT4049604., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome, translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the gold standard. We used the novel Ts66Yah mouse that carries an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-Hsa21 orthologous region., Methods: Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Because male Ts66Yah mice are fertile, parent-of-origin transmission of the extra chromosome was studied., Results: Forty-five protein-coding genes mapped to the Ts65Dn Mmu17 non-Hsa21 orthologous region; 71%-82% are expressed during forebrain development. Several of these genes are uniquely overexpressed in Ts65Dn embryonic forebrain, producing major differences in dysregulated genes and pathways. Despite these differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in commonly dysregulated disomic genes and pathways. Delays in motor development, communication, and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed milder working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved., Conclusions: Our findings suggest that triplication of the non-Hsa21 orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies., (Published by Elsevier Inc.)

Several non-verbal cognitive and behavioral tests have been developed to assess learning deficits in humans with Down syndrome (DS). Here we used rodent touchscreen paradigms in adult male mice to investigate visual discrimination (VD) learning and inhibitory control in the Dp(16)1/Yey (C57BL/6J genetic background), Ts65Dn (mixed B6 X C3H genetic background) and Ts1Cje (C57BL/6J genetic background) mouse models of DS. Dp(16)1/Yey and Ts1Cje models did not exhibit motivation or learning deficits during early pre-training, however, Ts1Cje mice showed a significant learning delay after the introduction of the incorrect stimulus (late pre-training), suggesting prefrontal cortex defects in this model. Dp(16)1/Yey and Ts1Cje mice display learning deficits in VD but these deficits were more pronounced in the Dp(16)1/Yey model. Both models also exhibited compulsive behavior and abnormal cortical inhibitory control during Extinction compared to WT littermates. Finally, Ts65Dn mice outperformed WT littermates in pre-training stages by initiating a significantly higher number of trials due to their hyperactive behavior. Both Ts65Dn and WT littermates showed poor performance during late pre-training and were not tested in VD. These studies demonstrate significant learning deficits and compulsive behavior in the Ts1Cje and Dp(16)1/Yey mouse models of DS. They also demonstrate that the mouse genetic background (C57BL/6J vs. mixed B6 X C3H) and the absence of hyperactive behavior are key determinants of successful learning in touchscreen behavioral testing. These data will be used to select the mouse model that best mimics cognitive deficits in humans with DS and evaluate the effects of future therapeutic interventions., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Competing Interests: We are all funded by the National Institutes of Health, US Department of Health and Human Services, and contributed to the NIH Climate Change and Health Initiative and the NIH Climate Change and Health Strategic Framework discussed here. RPW is the Director of the National Institute of Environmental Health Sciences (NIEHS). DWB is the Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). GHG is the Director of the National Heart, Lung, and Blood Institute (NHLBI). RIG is the Director of the Fogarty International Center (FIC). JAG is the Director of the National Institute of Mental Health (NIMH). EJP-S is the Director of the National Institute on Minority Health and Health Disparities (NIMHD). SNZ is the Director of the National Institute of Nursing Research (NINR). We declare no other competing interests. We thank Lawrence Tabak, who is Performing the Duties of the NIH Director, and Tara Schwetz, Acting Principal Deputy Director, NIH, for their strong and enthusiastic support for the NIH Climate Change and Health Initiative. We thank the NIH Climate Change and Health Working Group, including Aubrey Miller (NIEHS), Joshua Rosenthal (FIC) who are the Co-Chairs, and Gwen Collman (NIEHS) who is the Strategic Advisor, and others on the Steering Committee and Planning and Implementation Team for their work in developing the NIH Climate Change and Health Initiative Strategic Framework. Members of the NIH Climate Change and Health Steering Committee include Regina Bures (NICHD), Lawrence Fine (NHLBI), B F “Lee” Hall (NIAID), Flora Katz (FIC), Megan Kinnane (NIMH), Ivan Navarro (NIMHD), Louise Rosenbaum (NINR), and Claudia Thompson (NIEHS). Members of the NIH Climate Change and Health Planning and Implementation Team include Linda Bass (NIEHS), Abee Boyles (NIEHS), Trisha Castranio (NIEHS), Adriana Costero-Saint Denis (NIAID), Susan Czajkowski (NCI), Curt DellaValle (NCI), Christie Drew (NIEHS), Arielle Gillman (NIMHD), Alfonso Latoni (NIEHS), Ann Liu (NIEHS), Amit Mistry (FIC), Gila Neta (NCI), Shyamal Peddada (NICHD), Liz Perruccio (NINR), Nishadi Rajapakse (NHLBI), Rachel Scheinert (NIMH), Nina Silverberg (NIA), and Kimberly Thigpen Tart (NIEHS). We thank the 140 members from 20 institutes and centres and four offices of the NIH for their formal and continued engagement in the NIH working group on Climate Change and Health. We thank Kimberly Thigpen Tart (NIEHS) and Stasia Widerynski, Mali Velasco, and Betsy Galluzzo (MDB, Inc.) for their coordination and assistance in preparing this Comment.