Newborn Dried Blood Spot Folate in Relation to Maternal Self-reported Folic Acid Intake, Autism Spectrum Disorder, and Developmental Delay.

BACKGROUND: Maternal folic acid intake has been associated with decreased risk for neurodevelopmental disorders including autism spectrum disorder (ASD). Genetic differences in folate metabolism could explain some inconsistencies. To our knowledge, newborn folate concentrations remain unexamined. METHODS: We measured folate in archived newborn dried blood spots of children from the CHARGE (Childhood Autism Risks from Genetics and the Environment) case-control study who were clinically confirmed at 24-60 months to have ASD (n = 380), developmental delay (n = 128), or typical development (n = 247). We quantified monthly folic acid intake from maternally-reported supplements and cereals consumed during pregnancy and 3 months prior. We assessed associations of newborn folate with maternal folic acid intake and with ASD or developmental delay using regression. We stratified estimates across maternal and child MTHFR genotypes. RESULTS: Among typically developing children, maternal folic acid intake in prepregnancy and each pregnancy month and prepregnancy prenatal vitamin intake were positively associated with newborn folate. Among children with ASD, prenatal vitamin intake in pregnancy months 2-9 was positively associated with newborn folate. Among children with developmental delay, maternal folic acid and prenatal vitamins during the first pregnancy month were positively associated with neonatal folate. Associations differed by MTHFR genotype. Overall, neonatal folate was not associated with ASD or developmental delay, though we observed associations with ASD in children with the MTHFR 677 TT genotype (odds ratio: 1.76, 95% CI = 1.19, 2.62; P for interaction = 0.08). CONCLUSION: Maternal prenatal folic acid intake was associated with neonatal folate at different times across neurodevelopmental groups. Neonatal folate was not associated with reduced ASD risk. MTHFR genotypes modulated these relationships.

Epigenetic changes in sperm are associated with paternal and child quantitative autistic traits in an autism-enriched cohort.

There is a need to consider paternal contributions to autism spectrum disorder (ASD) more strongly. Autism etiology is complex, and heritability is not explained by genetics alone. Understanding paternal gametic epigenetic contributions to autism could help fill this knowledge gap. In the present study, we explored whether paternal autistic traits, and the sperm epigenome, were associated with autistic traits in children at 36 months enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is a pregnancy cohort that recruited and enrolled pregnant women in the first half of pregnancy who already had a child with ASD. After maternal enrollment, EARLI fathers were approached and asked to provide a semen specimen. Participants were included in the present study if they had genotyping, sperm methylation data, and Social Responsiveness Scale (SRS) score data available. Using the CHARM array, we performed genome-scale methylation analyses on DNA from semen samples contributed by EARLI fathers. The SRS-a 65-item questionnaire measuring social communication deficits on a quantitative scale-was used to evaluate autistic traits in EARLI fathers (n = 45) and children (n = 31). We identified 94 significant child SRS-associated differentially methylated regions (DMRs), and 14 significant paternal SRS-associated DMRs (fwer p < 0.05). Many child SRS-associated DMRs were annotated to genes implicated in ASD and neurodevelopment. Six DMRs overlapped across the two outcomes (fwer p < 0.1), and, 16 DMRs overlapped with previous child autistic trait findings at 12 months of age (fwer p < 0.05). Child SRS-associated DMRs contained CpG sites independently found to be differentially methylated in postmortem brains of individuals with and without autism. These findings suggest paternal germline methylation is associated with autistic traits in 3-year-old offspring. These prospective results for autism-associated traits, in a cohort with a family history of ASD, highlight the potential importance of sperm epigenetic mechanisms in autism.

Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized. METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts. RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD. CONCLUSION: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study.

BACKGROUND: Literature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. OBJECTIVE: To evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. METHODS: Maternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. RESULTS: Higher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (ß = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p'-DDE was associated with lower social deficits (ß = -8.34, 95% CI: -15.32, -1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (ß = 5.68, 95% CI: 0.18, 11.17; ß = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p'-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. CONCLUSIONS: We observed independent effects of PCB180, PCB187, PBDE47, and p,p' DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

Cardiometabolic Pregnancy Complications in Association With Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO.

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (ß = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (ß = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

The association of unconventional natural gas development with diagnosis and treatment of internalizing disorders among adolescents in Pennsylvania using electronic health records.

BACKGROUND: Unconventional natural gas development (UNGD) introduces physical and psychosocial hazards into communities, which could contribute to psychosocial stress in adolescents and an increased risk of internalizing disorders, common and impactful health outcomes. OBJECTIVES: To evaluate associations between a 180-day composite UNGD activity metric and new onset of internalizing disorders, overall and separately for anxiety and depressive disorders, and effect modification by sex. METHODS: We used a nested case-control design from 2008 to 2016 in 38 Pennsylvania counties using electronic health records from adolescent Geisinger subjects. Cases were defined by at least two diagnoses or medication orders indicating new onset of an internalizing disorder, and controls frequency-matched 4:1 on age, sex, and year. To evaluate associations, we used generalized estimating equations, with logit link, robust standard errors, and an exchangeable correlation structure within community. RESULTS: We identified 7,974 adolescents (65.9% female, mean age 15.0 years) with new onset internalizing disorders. There were no associations when we used data from the entire study period. When restricted to years with higher UNGD activity (2010-2016), comparing the highest to lowest quartile, UNGD activity was associated (odds ratio [95% confidence level]) with new onset internalizing disorders (1.15 [1.06, 1.25]). Associations were slightly stronger for depressive disorders. Associations were only present in females (p = 0.009). DISCUSSION: This is the first epidemiologic study of UNGD in relation to adolescent mental health, an important health outcome in a potentially susceptible group to the environmental and community impacts of UNGD. UNGD activity was associated with new onset internalizing disorders in females in this large sample in an area of active UNGD.

Placental morphology in association with autism-related traits in the EARLI study.

BACKGROUND: In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. METHODS: Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). RESULTS: In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. CONCLUSIONS: Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

Prenatal air pollution exposure and neurodevelopment: A review and blueprint for a harmonized approach within ECHO.

BACKGROUND: Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants. OBJECTIVES: We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO. METHODS: We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO. DISCUSSION: While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research. CONCLUSIONS: In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.

A framework for assessing the impact of chemical exposures on neurodevelopment in ECHO: Opportunities and challenges.

The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward.

Measuring Anhedonia in Adolescents: A Psychometric Analysis.

Anhedonia-the reduced capacity to experience pleasure-is a trait implicated in mental and physical health. Yet, psychometric data on anhedonia measures in adolescents are absent. We conducted an in-depth psychometric analysis of the Snaith-Hamilton Pleasure Scale (SHAPS; Snaith et al., 1995 )-a self-report measure of anticipated pleasure response to 14 pleasant experiences-in adolescents. Adolescents (N = 585, M age = 14.5) completed the SHAPS and other paper-and-pencil surveys. Item response theory models were used to evaluate the psychometric performance of each SHAPS item. Correlations of the SHAPS with other personality and psychopathology measures were calculated to evaluate construct validity. Results showed that (a) certain items (e.g., reported pleasure from basic experiences like "seeing smiling faces" or "smelling flowers") provided more information about latent anhedonia than others; and (b) SHAPS scales exhibited construct-consistent convergent and discriminant validity (i.e., stronger correlations with low positive affect constructs, weaker correlations with negative affect). Reporting diminished pleasure from basic pleasant experiences accurately indicates adolescent anhedonia, which is important for future scale development and understanding the phenomenology of anhedonia in teens. These data support using the SHAPS for assessing anhedonia in epidemiological research and school-based universal prevention programming in general adolescent populations.

Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene.

BACKGROUND: Independent studies report association of autism spectrum disorder with air pollution exposure and a functional promoter variant (rs1858830) in the MET receptor tyrosine kinase (MET) gene. Toxicological data find altered brain Met expression in mice after prenatal exposure to a model air pollutant. Our objective was to investigate whether air pollution exposure and MET rs1858830 genotype interact to alter the risk of autism spectrum disorder. METHODS: We studied 252 cases of autism spectrum disorder and 156 typically developing controls from the Childhood Autism Risk from Genetics and the Environment Study. Air pollution exposure was assigned for local traffic-related sources and regional sources (particulate matter, nitrogen dioxide, and ozone). MET genotype was determined by direct resequencing. RESULTS: Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower air pollutant exposures. There was evidence of multiplicative interaction between NO2 and MET CC genotype (P= 0.03). CONCLUSIONS: MET rs1858830 CC genotype and air pollutant exposure may interact to increase the risk of autism spectrum disorder.

Association of Time in Bed, Social Jetlag, and Sleep Disturbances With Cognitive Performance in Children With ADHD.

OBJECTIVES: Children with ADHD commonly exhibit sleep disturbances, but there is limited knowledge about how sleep and sleep timing are associated with cognitive dysfunction in children with ADHD. METHODS: Participants were 350 children aged 5 to 12 years diagnosed with ADHD. Three sleep-related constructs-time in bed, social jetlag (i.e., discrepancy in sleep timing pattern between school nights and weekend nights), and sleep disturbances were measured using a caregiver-report questionnaire. Linear regression models assessed the associations between sleep-related constructs and cognitive performance. RESULTS: After adjustment for sociodemographic variables, there were few associations between time in bed or sleep disturbances and cognitive performance, however, greater social jetlag was negatively associated with processing speed (ß = -.20, 95% CI [-0.35, -0.06]), visually-based reasoning (ß = -.13, 95% CI [-0.27, 0.00]), and language-based reasoning (ß = -.22, 95% CI [-0.36, -0.08]); all p < .05). CONCLUSION: Social jetlag, but not time in bed or disturbances, was associated with lower cognitive performance among children with ADHD.

Exposure to air pollution is associated with DNA methylation changes in sperm.

Exposure to air pollutants has been associated with adverse health outcomes in adults and children who were prenatally exposed. In addition to reducing exposure to air pollutants, it is important to identify their biologic targets in order to mitigate the health consequences of exposure. One molecular change associated with prenatal exposure to air pollutants is DNA methylation (DNAm), which has been associated with changes in placenta and cord blood tissues at birth. However, little is known about how air pollution exposure impacts the sperm epigenome, which could provide important insights into the mechanism of transmission to offspring. In the present study, we explored whether exposure to particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, nitrogen dioxide (NO2), or ozone (O3) was associated with DNAm in sperm contributed by participants in the Early Autism Risk Longitudinal Investigation prospective pregnancy cohort. Air pollution exposure measurements were calculated as the average exposure for each pollutant measured within 4 weeks prior to the date of sample collection. Using array-based genome-scale methylation analyses, we identified 80, 96, 35, and 67 differentially methylated regions (DMRs) significantly associated with particulate matter less than 2.5 microns in diameter, particulate matter less than 10 microns in diameter, NO2, and O3, respectively. While no DMRs were associated with exposure to all four pollutants, we found that genes overlapping exposure-related DMRs had a shared enrichment for gene ontology biological processes related to neurodevelopment. Together, these data provide compelling support for the hypothesis that paternal exposure to air pollution impacts DNAm in sperm, particularly in regions implicated in neurodevelopment.

Associations of a toenail metal mixture with attention and memory in the Gulf long-term follow-up (GuLF) study.

BACKGROUND: Research on metal-associated neurodegeneration has largely focused on single metals. Since metal exposures typically co-occur as combinations of both toxic and essential elements, a mixtures framework is important for identifying risk and protective factors. This study examined associations between toenail levels of an eight-metal mixture and attention and memory in men living in US Gulf states. METHODS: We measured toenail concentrations of toxic (arsenic, chromium, lead, and mercury) and essential (copper, manganese, selenium, and zinc) metals in 413 non-smoking men (23-69 years, 46 % Black) from the Gulf Long-Term Follow-Up (GuLF) Study. Sustained attention and working memory were assessed at the time of toenail sample collection using the continuous performance test (CPT) and digit span test (DST), respectively. Associations between toenail metal concentrations and performance on neurobehavioral tests were characterized using co-pollutant adjusted general linear models and Bayesian Kernel Machine Regression. RESULTS: Adjusting for other metals, one interquartile range (IQR) increase in toenail chromium was associated with a 0.19 (95 % CI: -0.31, -0.07) point reduction in CPT D Prime score (poorer ability to discriminate test signals from noise). One IQR increase in toenail manganese was associated with a 0.20 (95 % CI, -0.41, 0.01) point reduction on the DST Reverse Count (fewer numbers recalled). Attention deficits were greater among Black participants compared to White participants for the same increase in toenail chromium concentrations. No evidence of synergistic interaction between metals or adverse effect of the overall metal mixture was observed for either outcome. CONCLUSIONS: Our findings support existing studies of manganese-related memory deficits and are some of the first to show chromium related attention deficits in adults. Longitudinal study of cognitive decline is needed to verify chromium findings. Research into social and chemical co-exposures is also needed to explain racial differences in metal-associated neurobehavioral deficits observed in this study.

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.

Prenatal Metal Exposures and Child Social Responsiveness Scale Scores in 2 Prospective Studies.

Background: Prenatal exposure to metals is hypothesized to be associated with child autism. We aim to investigate the joint and individual effects of prenatal exposure to urine metals including lead (Pb), mercury (Hg), manganese (Mn), and selenium (Se) on child Social Responsiveness Scale (SRS) scores. Methods: We used data from 2 cohorts enriched for likelihood of autism spectrum disorder (ASD): Early Autism Risk Longitudinal Investigation (EARLI) and the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) studies. Metal concentrations were measured in urine collected during pregnancy. We used Bayesian Kernel Machine Regression and linear regression models to investigate both joint and independent associations of metals with SRS Z-scores in each cohort. We adjusted for maternal age at delivery, interpregnancy interval, maternal education, child race/ethnicity, child sex, and/or study site. Results: The final analytic sample consisted of 251 mother-child pairs. When Pb, Hg, Se, and Mn were at their 75th percentiles, there was a 0.03 increase (95% credible interval [CI]: -0.11, 0.17) in EARLI and 0.07 decrease (95% CI: -0.29, 0.15) in MARBLES in childhood SRS Z-scores, compared to when all 4 metals were at their 50th percentiles. In both cohorts, increasing concentrations of Pb were associated with increasing values of SRS Z-scores, fixing the other metals to their 50th percentiles. However, all the 95% credible intervals contained the null. Conclusions: There were no clear monotonic associations between the overall prenatal metal mixture in pregnancy and childhood SRS Z-scores at 36 months. There were also no clear associations between individual metals within this mixture and childhood SRS Z-scores at 36 months. The overall effects of the metal mixture and the individual effects of each metal within this mixture on offspring SRS Z-scores might be heterogeneous across child sex and cohort. Further studies with larger sample sizes are warranted.

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.

Associations of Organophosphate Ester Flame Retardant Exposures during Pregnancy with Gestational Duration and Fetal Growth: The Environmental influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Widespread exposure to organophosphate ester (OPE) flame retardants with potential reproductive toxicity raises concern regarding the impacts of gestational exposure on birth outcomes. Previous studies of prenatal OPE exposure and birth outcomes had limited sample sizes, with inconclusive results. OBJECTIVES: We conducted a collaborative analysis of associations between gestational OPE exposures and adverse birth outcomes and tested whether associations were modified by sex. METHODS: We included 6,646 pregnant participants from 16 cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program. Nine OPE biomarkers were quantified in maternal urine samples collected primarily during the second and third trimester and modeled as log2-transformed continuous, categorized (high/low/nondetect), or dichotomous (detect/nondetect) variables depending on detection frequency. We used covariate-adjusted linear, logistic, and multinomial regression with generalized estimating equations, accounting for cohort-level clustering, to estimate associations of OPE biomarkers with gestational length and birth weight outcomes. Secondarily, we assessed effect modification by sex. RESULTS: Three OPE biomarkers [diphenyl phosphate (DPHP), a composite of dibutyl phosphate and di-isobutyl phosphate (DBUP/DIBP), and bis(1,3-dichloro-2-propyl) phosphate] were detected in >85% of participants. In adjusted models, DBUP/DIBP [odds ratio (OR) per doubling=1.07; 95% confidence interval (CI): 1.02, 1.12] and bis(butoxyethyl) phosphate (OR for high vs. nondetect=1.25; 95% CI: 1.06, 1.46), but not other OPE biomarkers, were associated with higher odds of preterm birth. We observed effect modification by sex for associations of DPHP and high bis(2-chloroethyl) phosphate with completed gestational weeks and odds of preterm birth, with adverse associations among females. In addition, newborns of mothers with detectable bis(1-chloro-2-propyl) phosphate, bis(2-methylphenyl) phosphate, and dipropyl phosphate had higher birth weight-for-gestational-age z-scores (ß for detect vs. nondetect=0.04-0.07); other chemicals showed null associations. DISCUSSION: In the largest study to date, we find gestational exposures to several OPEs are associated with earlier timing of birth, especially among female neonates, or with greater fetal growth. https://doi.org/10.1289/EHP13182.

The Coronavirus Impact Scale: Construction, Validation, and Comparisons in Diverse Clinical Samples.

Objective: This report is of the construction and initial psychometric properties of the Coronavirus Impact Scale in multiple large and diverse samples of families with children and adolescents. The scale was established to capture the impact of the coronavirus pandemic during its first wave. Differences in impact between samples and internal structure within samples were assessed. Method: A total of 572 caregivers of children and adolescents or expecting mothers in diverse clinical and research settings completed the Coronavirus Impact Scale. Samples differed in regard to developmental stage, background, inpatient/outpatient status, and primary research or clinical setting. Model free methods were used to measure the scale's internal structure and to determine a scoring method. Differences between samples in specific item responses were measured by multivariate ordinal regression. Results: The Coronavirus Impact Scale demonstrated good internal consistency in a variety of clinical and research populations. Across the groups studied, single, immigrant, predominantly Latinx mothers of young children reported the greatest impact of the pandemic, with noteworthy effects on food access and finances reported. Individuals receiving outpatient or inpatient care reported greater impacts on health care access. Elevated scores on the Coronavirus Impact Scale were positively associated with measures of caregiver anxiety and both caregiver- and child-reported stress at a moderate effect size. Conclusion: The Coronavirus Impact Scale is a publicly available scale with adequate psychometric properties for use in measuring the impact of the coronavirus pandemic in diverse populations.

Accelerated epigenetic age at birth and child emotional and behavioura development in early childhood: a meta-analysis of four prospective cohort studies in ECHO.

Background: 'Epigenetic clocks' have been developed to accurately predict chronologic gestational age and have been associated with child health outcomes in prior work.Methods: We meta-analysed results from four prospective U.S cohorts investigating the association between epigenetic age acceleration estimated using blood DNA methylation collected at birth and preschool age Childhood Behavior Checklist (CBCL) scores.Results: Epigenetic ageing was not significantly associated with CBCL total problem scores (ß = 0.33, 95% CI: -0.95, 0.28) and DSM-oriented pervasive development problem scores (ß = -0.23, 95% CI: -0.61, 0.15). No associations were observed for other DSM-oriented subscales.Conclusions: The meta-analysis results suggest that epigenetic gestational age acceleration is not associated with child emotional and behavioural functioning for preschool age group. These findings may relate to our study population, which includes two cohorts enriched for ASD and one preterm birth cohort.; future work should address the role of epigenetic age in child health in other study populations.Abbreviations: DNAm: DNA methylation; CBCL: Child Behavioral Checklist; ECHO: Environmental Influences on Child Health Outcomes; EARLI: Early Autism Risk Longitudinal Investigation; MARBLES: Markers of Autism Risk in Babies - Learning Early Signs; ELGAN: Extremely Low Gestational Age Newborns; ASD: autism spectrum disorder; BMI: body mass index; DSM: Diagnostic and Statistical Manual of Mental Disorders.