Previous findings on relationships between infertility, infertility therapies, and autism spectrum disorders (ASD) have been inconsistent. The goals of this study are first, to briefly review this evidence and second, to examine infertility and its treatments in association with having a child with ASD in newly analyzed data. In review, we identified 14 studies published as of May 2013 investigating infertility and/or its treatments and ASD. Overall, prior results showed little support for a strong association, though some increases in risk with specific treatments were found; many limitations were noted. In new analyses of the CHildhood Autism Risk from Genetics and the Environment (CHARGE) population-based study, cases with autism spectrum disorder (ASD, n = 513) and controls confirmed to have typical development (n = 388) were compared with regard to frequencies of infertility diagnoses and treatments overall and by type. Infertility diagnoses and treatments were also grouped to explore potential underlying pathways. Logistic regression was used to obtain crude and adjusted odds ratios overall and, in secondary analyses, stratified by maternal age (≥35 years) and diagnostic subgroups. No differences in infertility, infertility treatments, or hypothesized underlying pathways were found between cases and controls in crude or adjusted analyses. Numbers were small for rarer therapies and in subgroup analyses; thus the potential for modest associations in specific subsets cannot be ruled out. However, converging evidence from this and other studies suggests that assisted reproductive technology is not a strong independent risk factor for ASD. Recommendations for future studies of this topic are provided.

The effects of hyperthyroidism or hypothyroidism, alone or in combination with the tricyclic antidepressant desmethylimipramine (DMI), on brain beta-adrenergic and serotonin (5HT2) receptors were studied in adult male Sprague-Dawley rats. Intraperitoneal administration of T3 or T4 for 7 days increased the number of cortical beta-adrenergic and 5HT2 receptors. These increases were significant at levels of 250 micrograms/kg or above for both hormones. Neither thyroidectomy nor "reverse" T3 (rT3) (500 micrograms/kg) produced an effect on either receptor type. The down-regulation of beta-adrenergic receptors produced by daily subcutaneous injections of 20 mg/kg of DMI for 7 days was partially offset by concurrent administration of T4, whereas the down-regulation of 5HT2 receptors produced by the drug was not affected by concurrent administration of either T3 or T4. Hypothyroidism (thyroidectomy) did not significantly affect the adaptation of these receptor populations to DMI. As regards brain regions other than cortex, T4 (250 micrograms/kg) produced the same changes in hippocampus as in cortex, while thyroidectomy decreased beta-adrenergic receptors only in the cerebellum. Thyroxine also elevated 5HT2 receptors in the hippocampus; thyroidectomy caused a significant decrease in 5HT2 receptors in the striatum.

To assess validity of maternally-reported diabetes and hypertensive disorders, and reliability of BMI measurements during periconception and pregnancy compared with medical records when mothers are interviewed 2-5 years after delivery. To investigate whether reporting accuracy differed by child's case status (autism, delays, typical development). Participants were mothers of 2-5 year old children with and without neurodevelopmental disorders from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) Study who had both prenatal/delivery records and telephone interviews. Sensitivity and specificity of self-report in telephone interview was assessed by comparison with medical records; agreement was evaluated by kappa statistics. Deviations in reported BMI were evaluated with Bland-Altman plots and concordance correlation coefficient (CCC). Mothers of children with neurodevelopmental disorders (autism or developmental delay) reported metabolic conditions slightly more accurately than control mothers. For diabetes, sensitivity ranged from 73 to 87% and specificity was ≥98% across groups. For hypertensive disorders, sensitivity ranged from 57 to 77% and specificity from 93 to 98%. Reliability of BMI was high (CCC = 0.930); when grouped into BMI categories, a higher proportion of mothers of delayed children were correctly classified (κ(wt) = 0.93) compared with the autism group and controls (κ(wt) = 0.85 and κ(wt) = 0.84, respectively; P = 0.05). Multiparity was associated with higher discrepancies in BMI and misreporting of hypertensive disorders. For purposes of etiologic studies, self-reported diabetes and hypertensive disorders during periconception and pregnancy show high validity among mothers irrespective of child's case status. Recall of pre-pregnancy BMI is reliable compared with self-reported values in medical records.

Approximately 23% of mothers of children with autism spectrum disorder (ASD) produce specific patterns of autoantibodies to fetal brain proteins that have been detected in only 1% of mothers of typically developing children. The biological mechanisms underlying the development of ASD-specific maternal autoantibodies are poorly understood. We sought to determine whether ASD-specific maternal autoantibodies identified postnatally were associated with metabolic conditions (MCs) during gestation. Participants were 227 mothers of 2-5 year old children with confirmed ASD, enrolled in CHARGE (Childhood Autism Risk from Genetics and the Environment) between January 2003 and April 2008, and from whom blood samples were collected and analyzed for anti-fetal brain autoantibodies (Ab+). MCs included diabetes, hypertensive disorders, and prepregnancy obesity or overweight, ascertained from medical records or structured telephone interviews. Log-linear regression models were performed to estimate prevalence ratios and 95% confidence intervals (CI) based on robust standard errors. Fifty-six (25%) mothers were Ab+. Ab+ prevalence was higher among mothers with diabetes, hypertensive disorders, or overweight compared to healthy mothers, but differences were not statistically significant. In a subset of 145 mothers whose children exhibited severe ASD (31 Ab+), those diagnosed with type 2 or gestational diabetes were 2.7-fold more likely to be Ab+ (95% CI 1.1, 6.6), controlling for delivery payer and smoking. Gestational diabetes specifically was associated with a 3.2-fold increased Ab+ prevalence (95% CI 1.2, 8.6). In this exploratory study, mothers whose children had severe ASD and who experienced diabetes were more likely to have anti-fetal brain autoantibodies 2-5 years later. Autism Res 2017, 10: 89-98. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Studies of the effects of thyroid hormones on the uptake of neurotransmitters by homogenates of rat cerebral cortex have revealed a significant competitive inhibition of neuronal uptake of [3H]GABA by thyroid hormones (T3 greater than T4 greater than rT3). The IC50 for inhibition of GABA uptake by T3 was estimated at 4 microM and that of T4 at 11 microns. GABA uptake in homogenates of cerebral cortex from hypothyroid rats was significantly enhanced over that of controls; however, uptake in tissues from hyperthyroid rats was not significantly diminished.

Importance

Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal, and fetal physiologic mechanisms.

Objective

To determine whether preeclampsia is associated with ASD and/or DD.

Design, setting, and participants

The Childhood Autism Risks from Genetics and the Environment (CHARGE) study is a population-based, case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24 to 60 months at the time of recruitment and living in catchment areas with a biological parent fluent in English or Spanish were enrolled from January 29, 2003, through April 7, 2011. Children with ASD (n = 517) and DD (n = 194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, and referrals. Controls with typical development (TD) (n = 350) were randomly selected from birth records and frequency matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status.

Exposures

Preeclampsia and placental insufficiency were self-reported and abstracted from medical records.

Main outcomes and measures

The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection.

Results

Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend, P = .02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64).

Conclusions and relevance

Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation, and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise.

Growing evidence identifies maternal adiposity as a potentially modifiable risk factor for adverse neurodevelopment. This retrospective cohort analysis examined whether maternal prepregnancy adiposity and gestational weight gain were associated with behavioral outcomes in 173 rhesus macaque infants at the California National Primate Research Center. Dams conceived indoors, had uncomplicated pregnancies, delivered vaginally, and reared infants indoors. Infants underwent standardized biobehavioral analysis at 90-120 days of age from 3/2001-5/2015. Offspring of mothers with greater baseline adiposity or gestational weight gain exhibited a pattern of poor adaptability characterized by greater emotionality as the assessments proceeded, blunted affective response to a human intruder challenge, and reduced interest in novel stimuli which is associated with poorer social functioning later in life. They also had lower cortisol levels following dexamethasone suppression, perhaps a response to cortisol excess during gestation. These results amplify growing public health concerns implicating maternal adiposity in impaired fetal neurobehavioral programming.

Background

Excess gestational weight gain (EGWG) is associated with multiple pregnancy complications and health risks for birthing people and their infants. Likewise, postpartum weight retention (PPWR), or not losing all pregnancy weight, has long-term health consequences. EGWG among people who enter pregnancy with overweight or obesity have worse obstetric outcomes and increased PPWR compared to women who gain within Institute of Medicine guidelines.

Methods

This study protocol describes the details of a blinded, randomized clinical trial of GROWell: Goals for Reaching Optimal Wellness, a mHealth tool designed to improve diet quality among people who enter pregnancy with overweight or obese BMIs to help them achieve appropriate GWG and safe postpartum pregnancy weight loss. Individuals with overweight and obesity will be randomly assigned to an attention control or intervention arm. The intervention group will receive personalized, goal-oriented text messages regarding dietary choices, while the attention control group will receive text messages about healthy pregnancy, labor, delivery, and early infancy. Both groups will complete online surveys at baseline, follow up, 3 and 6 months postpartum.

Results and discussion

Currently, 162 subjects have been enrolled. Outcomes associated with GWG and pregnancy are expected in late 2023, while outcomes on postpartum weight retention GROWell adherence are expected in late 2024. The results of this trial will support the use of an evidence-based mHealth tool to be integrated into clinical practice to reduce EGWG and PPWR among pregnant people with overweight and obese BMIs, a resource that is currently lacking.

Trial registration

ClinicalTrials.gov identifier: NCT04449432. Registered on June 26, 2020.

Prenatal exposure to phthalates, a family of endocrine-disrupting plasticizers, is associated with disruption of maternal metabolism and impaired neurodevelopment. We investigated associations between prenatal phthalate exposure and alterations of both the maternal third trimester serum metabolome and the placental metabolome at birth, and associations of these with child neurodevelopmental outcomes using data and samples from the Markers of Autism Risk in Babies Learning Early Signs (MARBLES) cohort. The third trimester serum (n = 106) and placental (n = 132) metabolomes were investigated using ¹H nuclear magnetic resonance spectroscopy. Children were assessed clinically for autism spectrum disorder (ASD) and cognitive development. Although none of the urinary phthalate metabolite concentrations were associated with maternal serum metabolites after adjustment for covariates, mixture analysis using quantile g-computation revealed alterations in placental metabolites with increasing concentrations of phthalate metabolites that included reduced concentrations of 2-hydoxybutyrate, carnitine, O-acetylcarnitine, glucitol, and N-acetylneuraminate. Child neurodevelopmental outcome was not associated with the third trimester serum metabolome, but it was correlated with the placental metabolome in male children only. Maternal phthalate exposure during pregnancy is associated with differences in the placental metabolome at delivery, and the placental metabolome is associated with neurodevelopmental outcomes in males in a cohort with high familial ASD risk.

Human placenta is a fetal-derived tissue that offers a unique sample of epigenetic and environmental exposures present in utero. In the MARBLES prospective pregnancy study of high-risk younger siblings of children with autism spectrum disorder (ASD), pregnancy and environmental factors collected by maternal interviews were examined as predictors of placental DNA methylation, including partially methylated domains (PMDs), an embryonic feature of the placental methylome. DNA methylation data from MethylC-seq analysis of 47 placentas of children clinically diagnosed at 3 years with ASD or typical development using standardized assessments were examined in relation to: child's gestational age, birth-weight, and diagnosis; maternal pre-pregnancy body mass index, smoking, education, parity, height, prenatal vitamin and folate intake; home ownership; pesticides professionally applied to lawns or gardens or inside homes, pet flea/tick pouches, collars, or soaps/shampoos used in the 3 months prior to or during pregnancy. Sequencing run, order, and coverage, and child race and sex were considered as potential confounders. Akaike information criterion was used to select the most parsimonious among candidate models. Final prediction models used sandwich estimators to produce homoscadisticity-robust estimates of the 95% confidence interval (CI) and P-values controlled the false discovery rate at 5%. The strongest, most robust associations were between pesticides professionally applied outside the home and higher average methylation over PMDs [0.45 (95% CI 0.17, 0.72), P = 0.03] and a reduced proportion of the genome in PMDs [-0.42 (95% CI - 0.67 to -0.17), P = 0.03]. Pesticide exposures could alter placental DNA methylation more than other factors.