Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Comparison of outcomes between intracytoplasmic sperm injection and in vitro fertilization inseminations with preimplantation genetic testing for aneuploidy, analysis of Society for Assisted Reproductive Technology Clinic Outcome Reporting System data.

OBJECTIVE: To evaluate whether insemination via intracytoplasmic sperm injection (ICSI) provides any benefit over in vitro fertilization (IVF) insemination for nonmale factor infertility with respect to preimplantation genetic testing (PGT) results and pregnancy outcome. DESIGN: Retrospective cohort study of the Society for Assisted Reproductive Technology database. SETTINGS: US-based fertility clinics reporting to the Society for Assisted Reprodcutive Technology. PATIENTS: Patients undergoing IVF or ICSI inseminations in nonmale factor PGT for aneuploidy cycles. INTERVENTION: In vitro fertilization vs. ICSI inseminations. MAIN OUTCOME MEASURES: Primary outcomes were the percentage of embryos suitable for transfer and live birth rates (LBRs). Secondary outcomes included subgroup analysis for embryos suitable for transfer on cycles from patients ≥35-year-old vs. <35-year-old, ≤6 oocytes retrieved vs. >6 oocytes retrieved, and unexplained infertility. Additionally, gestational age at delivery and birth weight between IVF and ICSI inseminations were evaluated. RESULTS: A total of 30,446 nonmale factor PGT diagnoses for aneuploidy cycles were evaluated, of which 4,867 were IVF inseminations and 25,579 were ICSI inseminations. Following exclusion criteria and adjustment for any necessary confounding variables, no significant differences existed in embryos suitable for transfer between IVF and ICSI treatment cycles, 41.6% (40.6%, 42.6%) vs. 42.5% (42.0%, 42.9%), respectively, or in LBRs, 50.1% (37.8, 62.4%) vs. 50.8% (38.5%, 62.9%), respectively. CONCLUSION: There were no significant differences in the rates of embryos suitable for transfer and LBRs between IVF and ICSI inseminations in nonmale factor cycles undergoing PGT for aneuploidy.

Serum Gonadotropin Levels Predict Post-Trigger Luteinizing Hormone Response in Antagonist Controlled Ovarian Hyperstimulation Cycles.

The objective of this study was to investigate the utility of using serum gonadotropin levels to predict optimal luteinizing hormone (LH) response to gonadotropin releasing hormone agonist (GnRHa) trigger. A retrospective cohort study was performed of all GnRH-antagonist controlled ovarian hyperstimulation (COH) cycles at an academic fertility center from 2017-2020. Cycles that utilized GnRHa alone or in combination with human chorionic gonadotropin (hCG) for trigger were included. Patient and cycle characteristics were collected from the electronic medical record. Optimal LH response was defined as a serum LH ≥ 40 mIU/mL on the morning after trigger. Total sample size was 3865 antagonist COH cycles, of which 91% had an optimal response to GnRHa trigger. Baseline FSH (B-FSH) and earliest in-cycle LH (EIC-LH) were significantly higher in those with optimal response. Multivariable logistic regression affirmed association of optimal response with EIC-LH, total gonadotropin dosage, age, BMI and Asian race. There was no difference in the number of oocytes retrieved (p = 0.14), maturity rate (p = 0.40) or fertilization rates (p = 0.49) based on LH response. There was no difference in LH response based on use of combination vs. GnRHa alone trigger (p = 0.21) or GnRHa trigger dose (p = 0.46). The EIC-LH was more predictive of LH trigger response than B-FSH (p < 0.005).The optimal B-FSH and EIC-LH values to yield an optimal LH response was ≥ 5.5 mIU/mL and ≥ 1.62 mIU/mL, respectively. In an era of personalized medicine, utilizing cycle and patient characteristics, such as early gonadotropin levels, may improve cycle outcomes and provide further individualized care.

Universal SARS-CoV-2 polymerase chain reaction screening and assisted reproductive technology in a coronavirus disease 2019 pandemic epicenter: screening and cycle outcomes from a New York City fertility center.

OBJECTIVE: To evaluate the prevalence of coronavirus disease 2019 (COVID-19) and efficacy of a universal screening program in patients undergoing controlled ovarian stimulation (COS). DESIGN: Single-center retrospective cohort study. SETTING: Academic fertility center in an epicenter of the COVID-19 pandemic. PATIENT(S): All patients undergoing COS from June 17, 2019, to February 28, 2021. INTERVENTION(S): Universal COVID-19 screening starting June 17, 2020, with SARS-CoV-2 polymerase chain reaction testing within 5 days of oocyte retrieval, patient-reported symptom screening, and temperature monitoring. MAIN OUTCOMES MEASURE(S): The primary outcome was the number of positive COVID-19 cases in patients undergoing COS cycles. The secondary outcomes were cycle outcomes compared with before COVID-19 COS cycles, adverse outcomes in COVID-canceled cycles, and center-specific COVID-19 detection rates compared with New York City cases. RESULT(S): From June 17, 2020, to February 28, 2021, 1,696 COS cycles were initiated with only seven positive COVID-19 cases for an overall positivity rate of 0.4%. When compared with before COVID cycles from June 17, 2019, to February 28, 2020, the volume of COS cycles were higher, while the overall cycle cancelation rate was lower during COVID-19. Cycle outcomes including oocyte yield and blast utilization rates were unchanged from pre-COVID cycles. Cases of COVID-19, while very low, occurred more frequently during surges in New York City rates. CONCLUSION(S): Assisted reproductive technology can be performed during the COVID-19 pandemic utilizing frequent universal screening and safe practices with low SARS-CoV-2 positivity, low cycle cancelation rates, and positive patient outcomes.

Application of telemedicine video visits in a maternal-fetal medicine practice at the epicenter of the COVID-19 pandemic.

BACKGROUND: Telemedicine in obstetrics has mostly been described in the rural areas that have limited access to subspecialties. During the COVID-19 pandemic, health systems rapidly expanded telemedicine services for urgent and nonurgent healthcare delivery, even in urban settings. The New York University health system implemented a prompt systemwide expansion of video-enabled telemedicine visits, increasing telemedicine to >8000 visits daily within 6 weeks of the beginning of the pandemic. There are limited studies that explore patient and provider satisfaction of telemedicine visits in obstetrical patients during the COVID-19 epidemic, particularly in the United States. OBJECTIVE: This study aimed to evaluate both the patients' and the providers' satisfaction with the administration of maternal-fetal medicine services through telemedicine and to identify the factors that drive the patients' desire for future obstetrical telemedicine services. STUDY DESIGN: A cross-sectional survey was administered to patients who completed a telemedicine video visit with the Division of Maternal-Fetal Medicine at the New York University Langone Hospital-Long Island from March 19, 2020, to May 26, 2020. A 10-question survey assessing the patients' digital experience and desire for future use was either administered by telephone or self-administered by the patients via a link after obtaining verbal consent. The survey responses were scored from 1-strongly disagree to 5-strongly agree. We analyzed the demographics and survey responses of the patients who agreed to vs those who answered neutral or disagree to the question "I would like telehealth to be an option for future obstetric visits." The providers also answered a similar 10-question survey. The median scores were compared using appropriate tests. A P value of <.05 was considered significant. RESULTS: A total of 253 patients participated in 433 telemedicine visits, and 165 patients completed the survey, resulting in a 65% survey response rate. Overall, there were high rates of patient satisfaction in all areas assessed. Those who desired future telemedicine had significantly greater agreeability that they were able to see and hear their provider easily (5 [4.5, 5] vs 5 [4, 5]; P=.014) and that the lack of physical activity was not an issue (5 [4, 5] vs 5 [4, 5]; P=.032). They were also more likely to agree that the telemedicine visits were as good as in-person visits (4 [3, 5] vs 3 [2, 3]; P<.001) and that telehealth made it easier for them to see doctors or specialists (5 [4, 5] vs 3 [2, 3]; P<.001). The patients seeking consults for poor obstetrical history were more likely to desire future telemedicine compared with other visit types (19 (90%) vs 2 (10%); P=.05). Provider survey responses also demonstrated high levels of satisfaction, with 83% agreeing that they would like telemedicine to be an option for future obstetrical visits. CONCLUSION: We demonstrated that maternal-fetal medicine obstetrical patients and providers were highly satisfied with the implementation of telemedicine during the initial wave of the COVID-19 pandemic and a majority of them desire telemedicine as an option for future visits. A patient's desire for future telemedicine visits was significantly affected by their digital experience, the perception of a lack of need for physical contact, perceived time saved on travel, and access to healthcare providers. Health systems need to continue to improve healthcare delivery and invest in innovative solutions to conduct physical examinations remotely.

Prenatal Hyperglycemia Exposure and Cellular Stress, a Sugar-Coated View of Early Programming of Metabolic Diseases.

Worldwide, the number of people with diabetes has quadrupled since 1980 reaching 422 million in 2014 (World Health Organization). This distressing rise in diabetes also affects pregnant women and thus, in regard to early programming of adult diseases, creates a vicious cycle of metabolic dysfunction passed from one generation to another. Metabolic diseases are complex and caused by the interplay between genetic and environmental factors. High-glucose exposure during in utero development, as observed with gestational diabetes mellitus (GDM), is an established risk factor for metabolic diseases. Despite intense efforts to better understand this phenomenon of early memory little is known about the molecular mechanisms associating early exposure to long-term diseases risk. However, evidence promotes glucose associated oxidative stress as one of the molecular mechanisms able to influence susceptibility to metabolic diseases. Thus, we decided here to further explore the relationship between early glucose exposure and cellular stress in the context of early development, and focus on the concept of glycemic memory, its consequences, and sexual dimorphic and epigenetic aspects.

Intrauterine Hyperglycemia Is Associated with an Impaired Postnatal Response to Oxidative Damage.

Hyperglycemia and other adverse exposures early in life that reprogram stem cells may lead to long-lasting phenotypic influences over the lifetime of an individual. Hyperglycemia and oxidative stress cause DNA damage when they exceed the protective capabilities of the cell, in turn affecting cellular function. DNA damage in response to hyperglycemia and oxidative stress was studied in human umbilical cord mesenchymal stem cells (hUC-MSCs) from large-for-gestational-age (LGA) infants of mothers with gestational diabetes mellitus (LGA-GDM) and control subjects. We tested the response of these cells to hyperglycemia and oxidative stress, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activities. We find that hUC-MSCs from LGA-GDM infants have increased DNA damage when exposed to oxidative stress. With the addition of hyperglycemic conditions, these cells have an increase in ROS and a decrease in antioxidant glutathione peroxidase (GPx) activity, indicating a mechanism for the increased ROS and DNA damage. This study demonstrates that a memory of in utero hyperglycemia, mediated through downregulation of GPx activity, leads to an increased susceptibility to oxidative stress. The alteration of GPx function in self-renewing stem cells, can mediate the effect of intrauterine hyperglycemia to be propagated into adulthood and contribute to disease susceptibility.

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition.

Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals. HELP-tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease.

A polycomb-mediated epigenetic field defect precedes invasive cervical carcinoma.

Human papillomavirus (HPV)-associated cervical carcinoma is preceded by stages of cervical intra-epithelial neoplasia (CIN) that can variably progress to malignancy. Understanding the different molecular processes involved in the progression of pre-malignant CIN is critical to the development of improved predictive and interventional capabilities. We tested the role of regulators of transcription in both the development and the progression of HPV-associated CIN, performing the most comprehensive genomic survey to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. While the loss of DNA methylation occurs mostly at intergenic regions, acquisition of DNA methylation is at sites involved in transcriptional regulation, with strong enrichment for targets of polycomb repression. Using an independent cohort from The Cancer Genome Atlas, we validated the loci with increased DNA methylation and found that these regulatory changes were associated with locally decreased gene expression. Secondary validation using immunohistochemistry showed that the progression of neoplasia was associated with increasing polycomb protein expression specifically in the cervical epithelium. We find that perturbations of genomic regulatory processes occur early and persist in cervical carcinoma. The results indicate a polycomb-mediated epigenetic field defect in cervical neoplasia that may represent a target for early, topical interventions using polycomb inhibitors.

Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.

Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.