DNA methylation signatures of prenatal socioeconomic position associated with 36-month language outcomes.

BACKGROUND: Socioeconomic position (SEP), which reflects one's position in society and access to resources, is strongly tied to neurodevelopment and is associated with epigenetic changes. AIM: This study examined whether DNA methylation signatures of prenatal SEP, measured in birth samples, are associated with child neurodevelopmental outcomes at 36 months of age. METHODS: Prenatal SEP DNA methylation scores were derived using 97 placenta and 127 cord blood biospecimens in the Early Autism Risk Longitudinal Investigation cohort. Participants completed the Mullen Scales of Early Learning (MSEL) and Vineland Adaptive Behavior Scales (VABS) at 36 months of age. Generalized regression analyses, adjusting for maternal age and race, were performed to test the association between SEP methylation score, for each birth biospecimen type, and MSEL and VABS scores. RESULTS: Significant associations were observed between placenta SEP methylation score and MSEL Expressive Language outcomes (beta = -2.7, p = 0.046, 95 % CI [- 5.43, -0.05]) and Receptive Language outcomes (beta = -2.5, p = 0.037, 95 % CI [-4.82, -0.16]). In cord blood, methylation-SEP scores were significantly associated with Receptive Language outcomes (beta = -2.0, p = 0.037, 95 % CI [-3.85, -0.12]). No significant associations were observed with VABS scores. CONCLUSION: Our results confirm associations between prenatal SEP and early childhood language development using a novel empiric DNA methylation measure of exposure.

Do small effects matter more in vulnerable populations? an investigation using Environmental influences on Child Health Outcomes (ECHO) cohorts.

BACKGROUND: A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. METHODS: Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight < 2500g). We computed mean birthweight in unexposed/exposed groups by sociodemographic categories (maternal education, health insurance, race, ethnicity) using a range of hypothetical exposure effect sizes. We compared the difference in mean birthweight and the percentage LBW, calculated using a distributional approach. RESULTS: When the hypothetical mean exposure effect was fixed (at 50, 125, 167 or 250g), the absolute difference in % LBW (risk difference) was not constant but varied by socioeconomic categories. The risk differences were greater in sub-populations with the highest baseline percentages LBW: ranging from 3.1-5.3 percentage points for exposure effect of 125g. Similar patterns were seen for other mean exposure sizes simulated. CONCLUSIONS: Vulnerable sub-populations with greater baseline percentages at high risk fare worse when exposed to a small insult compared to the general population. This illustrates another facet of health disparity in vulnerable individuals.

Psychiatric comorbidities in epilepsy: population co-occurrence, genetic correlations and causal effects.

Background: Psychiatric comorbidities are common in patients with epilepsy. Reasons for the co-occurrence of psychiatric conditions and epilepsy remain poorly understood. Aim: We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these conditions. Methods: Using nationwide Swedish health registries, we quantified the lifetime prevalence of psychiatric disorders in patients with epilepsy. We then used summary data from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score regression. Finally, we assessed the potential bidirectional relationships using two-sample Mendelian randomisation. Results: In a cohort of 7 628 495 individuals, we found that almost half of the 94 435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime (adjusted lifetime prevalence, 44.09%; 95% confidence interval (CI) 43.78% to 44.39%). We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric conditions. For example, we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder (rg=0.18, 95% CI 0.09 to 0.27, p<0.001)-a correlation that was more pronounced in focal epilepsy (rg=0.23, 95% CI 0.09 to 0.36, p<0.001). Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric conditions. Conclusions: Psychiatric comorbidities are common in patients with epilepsy. Genetic correlations may partially explain some comorbidities; however, there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric conditions. These findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psychiatric comorbidities in epilepsy.

Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder.

BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits.

Characterizing self-reported physical activity before and during a subsequent pregnancy among parents in a familial autism cohort.

LAY ABSTRACT: Parents of autistic children may have limited time and resources to participate in physical activity, a key aspect of health. Previous studies have been small and included mostly mothers, rather than fathers. No studies have examined physical activity in these parents during another pregnancy, when physical activity is especially important for maternal and fetal health. We aimed to fill this gap by examining physical activity levels among mothers and fathers caring for an autistic child before and during a subsequent pregnancy. We used data from a study which followed pregnant individuals who already had a child with autism. We asked mothers and fathers to report their levels of moderate and vigorous physical activity. We found that mothers and fathers of autistic children reported lower physical activity levels than the national average and were unlikely to meet Physical Activity Guidelines for Americans. Pregnant mothers were the least likely to participate in physical activity, particularly if their autistic child scored highly on a measure of autistic traits. Given that parental physical activity has benefits for parents and children, family-based interventions may be needed to help support parents' physical activity levels.

Association of maternal fish consumption and ω-3 supplement use during pregnancy with child autism-related outcomes: results from a cohort consortium analysis.

BACKGROUND: Prenatal fish intake is a key source of omega-3 (ω-3) polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking. OBJECTIVE: This study aimed to examine associations of prenatal fish intake and ω-3 supplement use with both autism diagnosis and broader autism-related traits. METHODS: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and ω-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-second edition (n = 3939 and v3609 for fish intake analyses, respectively; n = 4537 and n = 3925 for supplement intake analyses, respectively). RESULTS: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (odds ratio: 0.84; 95% confidence interval [CI]: 0.77, 0.92), and a modest reduction in raw total SRS scores (ß: -1.69; 95% CI: -3.3, -0.08). Estimates were similar across categories of fish consumption from "any" or "less than once per week" to "more than twice per week." For ω-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (ß: 1.98; 95% CI: 0.33, 3.64). CONCLUSIONS: These results extend previous work by suggesting that prenatal fish intake, but not ω-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low-fish intake in the United States general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals.

Prenatal air pollution and children's autism traits score: Examination of joint associations with maternal intake of vitamin D, methyl donors, and polyunsaturated fatty acids using mixture methods.

Background: Maternal nutrient intake may moderate associations between environmental exposures and children's neurodevelopmental outcomes, but few studies have assessed joint effects. We aimed to evaluate whether prenatal nutrient intake influences the association between air pollutants and autism-related trait scores. Methods: We included 126 participants from the EARLI (Early Autism Risk Longitudinal Investigation, 2009-2012) cohort, which followed US pregnant mothers who previously had a child with autism. Bayesian kernel machine regression and traditional regression models were used to examine joint associations of prenatal nutrient intake (vitamins D, B12, and B6; folate, choline, and betaine; and total omega 3 and 6 polyunsaturated fatty acids, reported via food frequency questionnaire), air pollutant exposure (particulate matter <2.5 µm [PM2.5], nitrogen dioxide [NO2], and ozone [O3], estimated at the address level), and children's autism-related traits (measured by the Social Responsiveness Scale [SRS] at 36 months). Results: Most participants had nutrient intakes and air pollutant exposures that met US standards. Bayesian kernel machine regression mixture models and traditional regression models provided little evidence of individual or joint associations of nutrients and air pollutants with SRS scores or of an association between the overall mixture and SRS scores. Conclusion: In this cohort with a high familial likelihood of autism, we did not observe evidence of joint associations between air pollution exposures and nutrient intake with autism-related traits. Future work should examine the use of these methods in larger, more diverse samples, as our results may have been influenced by familial liability and/or relatively high nutrient intakes and low air pollutant exposures.

Reproducibility between preschool and school-age Social Responsiveness Scale forms in the Environmental influences on Child Health Outcomes program.

Evidence suggests core autism trait consistency in older children, but development of these traits is variable in early childhood. The Social Responsiveness Scale (SRS) measures autism-related traits and broader autism phenotype, with two age-dependent forms in childhood (preschool, 2.5-4.5 years; school age, 4-18 years). Score consistency has been observed within forms, though reliability across forms has not been evaluated. Using data from the Environmental Influences on Child Health Outcomes (ECHO) program (n = 853), preschool, and school-age SRS scores were collected via maternal report when children were an average of 3.0 and 5.8 years, respectively. We compared reproducibility of SRS total scores (T-scores) and agreement above a clinically meaningful cutoff (T-scores ≥ 60) and examined predictors of discordance in cutoff scores across forms. Participant scores across forms were similar (mean difference: 3.3 points; standard deviation: 7), though preschool scores were on average lower than school-age scores. Most children (88%) were classified below the cutoff on both forms, and overall concordance was high (92%). However, discordance was higher in cohorts following younger siblings of autistic children (16%). Proportions of children with an autism diagnoses were also higher among those with discordant scores (27%) than among those with concordant scores (4%). Our findings indicate SRS scores are broadly reproducible across preschool and school-age forms, particularly for capturing broader, nonclinical traits, but also suggest that greater variability of autism-related traits in preschool-age children may reduce reliability with later school-age scores for those in the clinical range.

The association between prenatal oxidative stress levels measured by isoprostanes and offspring neurodevelopmental outcomes at 36 months.

Oxidative stress during pregnancy has been a mechanistic pathway implicated in autism development, yet few studies have examined this association directly. Here, we examined the association of prenatal levels of 8-iso-PGF2α, a widely used measure of oxidative stress, and several neurodevelopmental outcomes related to autism in children. Participants included 169 mother-child pairs from the Early Autism Risk Longitudinal Investigation (EARLI), which enrolled mothers who had an autistic child from a previous pregnancy and followed them through a subsequent pregnancy and until that child reached age 3 years. Maternal urine samples were collected during the second trimester of pregnancy and were later measured for levels of isoprostanes. Child neurodevelopmental assessments included the Mullen Scales of Early Learning (MSEL), the Social Responsiveness Scale (SRS), and the Vineland Adaptive Behavior Scale (VABS), and were conducted around 36 months of age. Primary analyses examined associations between interquartile range (IQR) increases in 8-iso-PGF2α levels, and total composite scores from each assessment using quantile regression. In adjusted analyses, we did not observe statistically significant associations, though estimates suggested modestly lower cognitive scores (ß for MSEL = -3.68, 95% CI: -10.09, 2.70), and minor increases in autism-related trait scores (ß for SRS T score = 1.68, 95% CI: -0.24, 3.60) with increasing 8-iso-PGF2α. These suggestive associations between decreased cognitive scores and increased autism-related traits with increasing prenatal oxidative stress point to the need for continued investigation in larger samples of the role of oxidative stress as a mechanistic pathway in autism and related neurodevelopmental outcomes.

First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study.

BACKGROUND: Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage. METHODS: We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995-2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications. RESULTS: ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20). CONCLUSION: We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.

Food, nutrition, and autism: from soil to fork.

Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD.

Multigenerational association between smoking and autism spectrum disorder: findings from a nationwide prospective cohort study.

Animal studies have shown that exposure to cigarette smoke during pregnancy can induce neurobehavioral anomalies in multiple subsequent generations. However, little work has examined such effects in humans. We examined the risk of grandchild autism spectrum disorder (ASD) in association with grandmother's smoking during pregnancy, using data from 53 562 mothers and grandmothers and 120 267 grandchildren in Nurses' Health Study II. In 1999, Nurses' Health Study II participants with children reported on their mothers' smoking. Grandchildren's ASD diagnoses were reported by the mothers in 2005 and 2009. Among grandmothers, 13 383 (25.0%) smoked during pregnancy, and 509 (0.4%) grandchildren were diagnosed with ASD. The adjusted odds ratio for ASD for grandmother smoking during pregnancy was 1.52 (95% CI, 1.06-2.20). Results were similar with direct grandmother reporting in 2001 of her smoking during pregnancy from the Nurses' Mothers Cohort Study subgroup (n = 22 167 grandmothers, n = 49 917 grandchildren) and were stronger among grandmothers who smoked ≥15 cigarettes per day during pregnancy (adjusted odds ratio = 1.93 [95% CI, 1.10-3.40]; n = 1895 grandmothers, n = 4212 grandchildren). Results were similar when we adjusted for mother's smoking during pregnancy. There was no association with grandfather's smoking as reported by the grandmother. Our results suggest a potential persistent impact of gestational exposure to environmental insults across 3 generations.

Birth outcomes in relation to neighborhood food access and individual food insecurity during pregnancy in the Environmental Influences on Child Health Outcomes (ECHO)-wide cohort study.

BACKGROUND: Limited access to healthy foods, resulting from residence in neighborhoods with low-food access or from household food insecurity, is a public health concern. Contributions of these measures during pregnancy to birth outcomes remain understudied. OBJECTIVES: We examined associations between neighborhood food access and individual food insecurity during pregnancy with birth outcomes. METHODS: We used data from 53 cohorts participating in the nationwide Environmental Influences on Child Health Outcomes-Wide Cohort Study. Participant inclusion required a geocoded residential address or response to a food insecurity question during pregnancy and information on birth outcomes. Exposures include low-income-low-food-access (LILA, where the nearest supermarket is >0.5 miles for urban or >10 miles for rural areas) or low-income-low-vehicle-access (LILV, where few households have a vehicle and >0.5 miles from the nearest supermarket) neighborhoods and individual food insecurity. Mixed-effects models estimated associations with birth outcomes, adjusting for socioeconomic and pregnancy characteristics. RESULTS: Among 22,206 pregnant participants (mean age 30.4 y) with neighborhood food access data, 24.1% resided in LILA neighborhoods and 13.6% in LILV neighborhoods. Of 1630 pregnant participants with individual-level food insecurity data (mean age 29.7 y), 8.0% experienced food insecurity. Residence in LILA (compared with non-LILA) neighborhoods was associated with lower birth weight [ß -44.3 g; 95% confidence interval (CI): -62.9, -25.6], lower birth weight-for-gestational-age z-score (-0.09 SD units; -0.12, -0.05), higher odds of small-for-gestational-age [odds ratio (OR) 1.15; 95% CI: 1.00, 1.33], and lower odds of large-for-gestational-age (0.85; 95% CI: 0.77, 0.94). Similar findings were observed for residence in LILV neighborhoods. No associations of individual food insecurity with birth outcomes were observed. CONCLUSIONS: Residence in LILA or LILV neighborhoods during pregnancy is associated with adverse birth outcomes. These findings highlight the need for future studies examining whether investing in neighborhood resources to improve food access during pregnancy would promote equitable birth outcomes.

Gestational thyroid hormones and autism-related traits in the EARLI and HOME studies.

Thyroid hormones are essential for neurodevelopment. Few studies have considered associations with quantitatively measured autism spectrum disorder (ASD)-related traits, which may help elucidate associations for a broader population. Participants were drawn from two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI), enrolling pregnant women who already had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study, following pregnant women from the greater Cincinnati, OH area. Gestational thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured in mid-pregnancy 16 (±3) weeks gestation serum samples. ASD-related traits were measured using the Social Responsiveness Scale (SRS) at ages 3-8 years. The association was examined using quantile regression, adjusting for maternal and sociodemographic factors. 278 participants (132 from EARLI, 146 from HOME) were included. TSH distributions were similar across cohorts, while FT4 levels were higher in EARLI compared to HOME. In pooled analyses, particularly for those in the highest SRS quantile (95th percentile), higher FT4 levels were associated with increasing SRS scores (ß = 5.21, 95% CI = 0.93, 9.48), and higher TSH levels were associated with decreasing SRS scores (ß = -6.94, 95% CI = -11.04, -2.83). The association between TSH and SRS remained significant in HOME for the 95% percentile of SRS scores (ß = -6.48, 95% CI = -12.16, -0.80), but not EARLI. Results for FT4 were attenuated when examined in the individual cohorts. Our results add to evidence that gestational thyroid hormones may be associated with ASD-related outcomes by suggesting that relationships may differ across the distribution of ASD-related traits and by familial likelihood of ASD.

Demographic and health characteristics associated with fish and n-3 fatty acid supplement intake during pregnancy: results from pregnancy cohorts in the ECHO programme.

OBJECTIVE: n-3 fatty acid consumption during pregnancy is recommended for optimal pregnancy outcomes and offspring health. We examined characteristics associated with self-reported fish or n-3 supplement intake. DESIGN: Pooled pregnancy cohort studies. SETTING: Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. PARTICIPANTS: A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. RESULTS: Overall, 24·6 % reported consuming fish never or less than once per month, 40·1 % less than once a week, 22·1 % 1-2 times per week and 13·2 % more than twice per week. The relative risk (RR) of ever (v. never) consuming fish was higher in participants who were older (1·14, 95 % CI 1·10, 1·18 for 35-40 v. <29 years), were other than non-Hispanic White (1·13, 95 % CI 1·08, 1·18 for non-Hispanic Black; 1·05, 95 % CI 1·01, 1·10 for non-Hispanic Asian; 1·06, 95 % CI 1·02, 1·10 for Hispanic) or used tobacco (1·04, 95 % CI 1·01, 1·08). The RR was lower in those with overweight v. healthy weight (0·97, 95 % CI 0·95, 1·0). Only 16·2 % reported n-3 supplement use, which was more common among individuals with a higher age and education, a lower BMI, and fish consumption (RR 1·5, 95 % CI 1·23, 1·82 for twice-weekly v. never). CONCLUSIONS: One-quarter of participants in this large nationwide dataset rarely or never consumed fish during pregnancy, and n-3 supplement use was uncommon, even among those who did not consume fish.

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study.

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics.

Mixture of air pollution, brominated flame retardants, polychlorinated biphenyls, per- and polyfluoroalkyl substances, and organochlorine pesticides in relation to vitamin D concentrations in pregnancy.

Over two-thirds of pregnant women in the U.S. have insufficient 25(OH)D (Vitamin D) concentrations, which can adversely impact fetal health. Several pollutants have been associated with 25(OH)D, but have not been considered in the context of chemical co-exposures. We aimed to determine associations between a broad mixture of prenatal environmental chemical exposures and 25(OH)D concentrations in mid-pregnancy. Stored mid-pregnancy serum samples were assayed from 421 women delivering live births in Southern California in 2000-2003. 25(OH)D, six BFRs, eleven polychlorinated biphenyls (PCBs), six per- and polyfluoroalkyl substances, and two organochlorine pesticides were detected in ≥60% of specimens. Gestational exposures to airborne particulate matter ≤ 10 µm (PM10) and ≤ 2.5 µm (PM2.5), nitrogen monoxide (NO), nitrogen dioxide (NO2), and ozone concentrations were derived from monitoring station data. Bayesian Hierarchical Modeling (BHM) and Bayesian Kernel Machine Regression (BKMR) analyses estimated overall mixture and individual chemical associations accounting for co-exposures and covariates with mean 25(OH)D levels, and BHM was used to estimate associations with insufficient (<75 nMol/L) 25(OH)D levels. Non-mixture associations for each chemical were estimated with linear and logistic models. PM10 [BHM estimate: -0.133 nmol/l 95% Credible Interval (-0.240, -0.026)] was associated with lower 25(OH)D in BHM and BKMR. Higher quantiles of combined exposures were associated with lower 25(OH)D, though with wide credible intervals. In non-mixture models, PM10, PM2.5, NO, and NO2 were associated with lower concentrations, while O3 and PBDE153 were associated with higher 25(OH)D and/or lower insufficiency. While some chemicals were associated with increased and others with decreased 25(OH)D concentrations, the overall mixture was associated with lower concentrations. Mixture analyses differed from non-mixture regressions, highlighting the importance of mixtures approaches for estimating real-world associations.

A Mixture of Urinary Phthalate Metabolite Concentrations During Pregnancy and Offspring Social Responsiveness Scale Scores.

BACKGROUND: Phthalates are a group of chemicals with ubiquitous exposure worldwide. Exposures to phthalates during pregnancy may play a role in autism spectrum disorder (ASD) etiology by disrupting hormone levels or directly impacting fetal neurodevelopment. However, there is little research quantifying the aggregate effect of phthalates on child ASD-related behaviors. METHODS: We used data from two prospective pregnancy and birth cohorts-the Health Outcomes and Measures of the Environment (HOME) and the Early Autism Risk Longitudinal Investigation (EARLI). HOME is a general population cohort while participants in EARLI were at higher familial risk for ASD. Using quantile g-computation and linear regression models, we assessed the joint and individual associations of a mixture of six phthalate metabolites during pregnancy with child ASD-related traits measured by Social Responsiveness Scale (SRS) scores at ages 3-8 years. RESULTS: Our analyses included 271 participants from HOME and 166 participants from EARLI. There were imprecise associations between the phthalate mixture and SRS total raw scores in HOME (difference in SRS scores per decile increase in every phthalate = 1.3; 95% confidence interval [CI] = -0.2, 2.8) and EARLI (difference in SRS scores per decile increase in every phthalate = -0.9; 95% CI = -3.5, 1.7). CONCLUSIONS: The cohort-specific effect sizes of the pthalates-SRS associations were small and CIs were imprecise. These results suggest that if there are associations between phthalate metabolites during pregnancy and child SRS scores, they may differ across populations with different familial liabilities. Further studies with larger sample sizes are warranted.

Association of maternal education, neighborhood deprivation, and racial segregation with gestational age at birth by maternal race/ethnicity and United States Census region in the ECHO cohorts.

Background: In the United States, disparities in gestational age at birth by maternal race, ethnicity, and geography are theorized to be related, in part, to differences in individual- and neighborhood-level socioeconomic status (SES). Yet, few studies have examined their combined effects or whether associations vary by maternal race and ethnicity and United States Census region. Methods: We assembled data from 34 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program representing 10,304 participants who delivered a liveborn, singleton infant from 2000 through 2019. We investigated the combined associations of maternal education level, neighborhood deprivation index (NDI), and Index of Concentration at the Extremes for racial residential segregation (ICERace) on gestational weeks at birth using linear regression and on gestational age at birth categories (preterm, early term, post-late term relative to full term) using multinomial logistic regression. Results: After adjustment for NDI and ICERace, gestational weeks at birth was significantly lower among those with a high school diploma or less (-0.31 weeks, 95% CI: -0.44, -0.18), and some college (-0.30 weeks, 95% CI: -0.42, -0.18) relative to a master's degree or higher. Those with a high school diploma or less also had an increased odds of preterm (aOR 1.59, 95% CI: 1.20, 2.10) and early term birth (aOR 1.26, 95% CI: 1.05, 1.51). In adjusted models, NDI quartile and ICERace quartile were not associated with gestational weeks at birth. However, higher NDI quartile (most deprived) associated with an increased odds of early term and late term birth, and lower ICERace quartile (least racially privileged) associated with a decreased odds of late or post-term birth. When stratifying by region, gestational weeks at birth was lower among those with a high school education or less and some college only among those living in the Northeast or Midwest. When stratifying by race and ethnicity, gestational weeks at birth was lower among those with a high school education or less only for the non-Hispanic White category. Conclusion: In this study, maternal education was consistently associated with shorter duration of pregnancy and increased odds of preterm birth, including in models adjusted for NDI and ICERace.

Opportunities for Examining Child Health Impacts of Early-Life Nutrition in the ECHO Program: Maternal and Child Dietary Intake Data from Pregnancy to Adolescence.

Background: Longitudinal measures of diet spanning pregnancy through adolescence are needed from a large, diverse sample to advance research on the effect of early-life nutrition on child health. The Environmental influences on Child Health Outcomes (ECHO) Program, which includes 69 cohorts, >33,000 pregnancies, and >31,000 children in its first 7-y cycle, provides such data, now publicly available. Objectives: This study aimed to describe dietary intake data available in the ECHO Program as of 31 August, 2022 (end of year 6 of Cycle 1) from pregnancy through adolescence, including estimated sample sizes, and to highlight the potential for future analyses of nutrition and child health. Methods: We identified and categorized ECHO Program dietary intake data, by assessment method, participant (pregnant person or child), and life stage of data collection. We calculated the number of maternal-child dyads with dietary data and the number of participants with repeated measures. We identified diet-related variables derived from raw dietary intake data and nutrient biomarkers measured from biospecimens. Results: Overall, 66 cohorts (26,941 pregnancies, 27,103 children, including 22,712 dyads) across 34 US states/territories provided dietary intake data. Dietary intake assessments included 24-h recalls (1548 pregnancies and 1457 children), food frequency questionnaires (4902 and 4117), dietary screeners (8816 and 23,626), and dietary supplement use questionnaires (24,798 and 26,513). Repeated measures were available for ∼70%, ∼30%, and ∼15% of participants with 24-h recalls, food frequency questionnaires, and dietary screeners, respectively. The available diet-related variables describe nutrient and food intake, diet patterns, and breastfeeding practices. Overall, 17% of participants with dietary intake data had measured nutrient biomarkers. Conclusions: ECHO cohorts have collected longitudinal dietary intake data spanning pregnancy through adolescence from a geographically, socioeconomically, and ethnically diverse US sample. As data collection continues in Cycle 2, these data present an opportunity to advance the field of nutrition and child health.