Pregnancy Planning and its Association with Autism Spectrum Disorder: Findings from the Study to Explore Early Development.

OBJECTIVES: To examine associations between pregnancy planning and autism spectrum disorder (ASD) in offspring. METHODS: The Study to Explore Early Development (SEED), a multi-site case-control study, enrolled preschool-aged children with ASD, other DDs, and from the general population (POP). Some children with DDs had ASD symptoms but did not meet the ASD case definition. We examined associations between mother's report of trying to get pregnant (pregnancy planning) and (1) ASD and (2) ASD symptomatology (ASD group, plus DD with ASD symptoms group combined) (each vs. POP group). We computed odds ratios adjusted for demographic, maternal, health, and perinatal health factors (aORs) via logistic regression. Due to differential associations by race-ethnicity, final analyses were stratified by race-ethnicity. RESULTS: Pregnancy planning was reported by 66.4%, 64.8%, and 76.6% of non-Hispanic White (NHW) mothers in the ASD, ASD symptomatology, and POP groups, respectively. Among NHW mother-child pairs, pregnancy planning was inversely associated with ASD (aOR = 0.71 [95% confidence interval 0.56-0.91]) and ASD symptomatology (aOR = 0.67 [0.54-0.84]). Pregnancy planning was much less common among non-Hispanic Black mothers (28-32% depending on study group) and Hispanic mothers (49-56%) and was not associated with ASD or ASD symptomatology in these two race-ethnicity groups. CONCLUSION: Pregnancy planning was inversely associated with ASD and ASD symptomatology in NHW mother-child pairs. The findings were not explained by several adverse maternal or perinatal health factors. The associations observed in NHW mother-child pairs did not extend to other race-ethnicity groups, for whom pregnancy planning was lower overall.

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.

Exposure to Perfluoroalkyl Substances and Associations with Pubertal Onset and Serum Reproductive Hormones in a Longitudinal Study of Young Girls in Greater Cincinnati and the San Francisco Bay Area.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), endocrine disrupting chemicals with worldwide exposure, cause changes in mammary gland development in rodents. A few human studies report delay in pubertal events with increasing perfluorooctanoic acid (PFOA) exposure, but to our knowledge none have examined reproductive hormone levels at thelarche. METHODS: In a cohort of Greater Cincinnati (GC) and San Francisco Bay Area (SFBA) girls recruited at 6-8 years of age, clinical examinations were conducted annually or semiannually with sequential Tanner staging. PFAS concentrations were measured in the first serum sample of 704 girls. In 304 GC girls, estradiol (E2), estrone (E1), testosterone (T), and dihydroepiandrosterone sulfate (DHEAS) were measured in serum at four time points around puberty. Relationships between PFAS and age at thelarche, pubarche, and menarche were analyzed using survival and structural equation models. The association between PFAS and reproductive hormones was assessed using linear regression models. RESULTS: Median PFOA serum concentrations in GC (N=353, 7.3 ng/mL) and the SFBA (N=351, 5.8 ng/mL) were higher than in the U.S. POPULATION: In multivariable Cox proportional hazard models [adjusted for race, body mass index (BMI)], increasing serum log-transformed PFOA was associated with a delay in pubarche [hazard ratio (HR)=0.83; 95% CI: 0.70, 0.99] and menarche (HR=0.04; 95% CI: 0.01, 0.25). Structural equation models indicated a triangular relationship between PFOA, BMI percentile, and the age at the pubertal milestone. Increased PFOA had a statistically significant direct effect of delay on all three milestones, as did BMI. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDeA), and 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (Me-PFOSA-AcOH) also were associated with later thelarche, and Me-PFOSA-AcOH also with later pubarche. PFOA was inversely associated with DHEAS (p<0.01), E1 (p=0.04), and T (p=0.03) concentrations at 6 months prior to puberty. CONCLUSIONS: PFAS may delay pubertal onset through the intervening effects on BMI and reproductive hormones. The decreases in DHEAS and E1 associated with PFOA represent biological biomarkers of effect consistent with the delay in onset of puberty. https://doi.org/10.1289/EHP11811.

Prenatal ultrasound use and risk of autism spectrum disorder: Findings from the case-control Study to Explore Early Development.

BACKGROUND: Studies evaluating the association between prenatal ultrasounds and autism spectrum disorder (ASD) have largely produced negative results. Concern remains due to the rising identification of children with ASD and ultrasound use. OBJECTIVE: To evaluate the association between prenatal ultrasound use and ASD. METHODS: We used data from the Study to Explore Early Development, a multisite case-control study of preschool-aged children with ASD implemented during 2007-2012. We recruited cases from children receiving developmental disability services and randomly selected population controls from birth records. ASD case status was based on in-person standardised assessments. We stratified analyses by pre-existing maternal medical conditions and pregnancy complications associated with increased ultrasound use (ultrasound indications) and used logistic regression to model case status by increasing ultrasound counts. For pregnancies with medical record data on ultrasound timing, we conducted supplementary tests to model associations by trimester of exposure. RESULTS: Among 1524 singleton pregnancies, ultrasound indications were more common for ASD cases than controls; respectively, for each group, no indications were reported for 45.1% and 54.2% of pregnancies, while ≥2 indications were reported for 26.1% and 18.4% of pregnancies. The percentage of pregnancies with multiple ultrasounds varied by case status and the presence of ultrasound indications. However, stratified regression models showed no association between increasing ultrasound counts and case status, either for pregnancies without (aOR 1.01, 95% CI 0.92, 1.11) or with ultrasound indications (aOR 1.01, 95% CI 0.95, 1.08). Trimester-specific analyses using medical record data showed no association in any individual trimester. CONCLUSIONS: We found no evidence that prenatal ultrasound use increases ASD risk. Study strengths included gold-standard assessments for ASD case classification, comparison of cases with controls, and a stratified sample to account for conditions associated both with increased prenatal ultrasound use and ASD.

Migraine and its association with pubertal maturation and behavioral traits among adolescent girls.

OBJECTIVE: To determine if the ages at pubertal milestones are associated with the prevalence of adolescent migraine. BACKGROUND: Migraine headaches are a common disease in adolescent girls. Past studies have evaluated the relationship between age of onset of menarche and migraine headache, but none have studied earlier pubertal milestones such as thelarche and pubarche. METHODS: In this cross-sectional study, a previously validated questionnaire was administered to girls (15-18 years) in Breast Cancer and the Environment Research Program puberty cohort to ascertain if they met criteria for migraine over the past year. Ages of pubertal development were ascertained by serial examinations beginning at 6-8 years of age and ending in late puberty. Logistic regression analyses determined if age of onset of each pubertal milestone (thelarche, pubarche, menarche separately) was associated with adolescent migraine after adjusting for other risk factors. RESULTS: Of 761girls, 222 (29.2%) met the criteria for migraine. Later thelarche was associated with a lower odds of adolescent migraine (OR 0.83; 95% CI 0.72-0.97, p = 0.019). In models further adjusted for BASC-2 internalizing problems (n = 490), both later thelarche (OR 0.78; 95% CI 0.64-0.96, p = 0.016) and later menarche (OR 0.81; 95%CI 0.67-0.98, p = 0.026) were associated with a lower migraine prevalence. Internalizing problems (OR 1.05; 95% CI 1.03-1.07) externalizing problems (OR 1.05; 95% CI 1.02-1.07) and behavioral symptoms (OR 1.05; 95% CI 1.03-1.08) were associated with increased prevalence of migraine in separate models. CONCLUSIONS: Age of onset of thelarche and menarche, and internalizing, externalizing, and behavioral symptoms were all associated with adolescent migraine.

Pre- and Postnatal Fine Particulate Matter Exposure and Childhood Cognitive and Adaptive Function.

Increasing evidence exists for an association between early life fine particulate matter (PM2.5) exposure and several neurodevelopmental outcomes, including autism spectrum disorder (ASD); however, the association between PM2.5 and adaptive and cognitive function remains poorly understood. Participants included 658 children with ASD, 771 with a non-ASD developmental disorder, and 849 population controls from the Study to Explore Early Development. Adaptive functioning was assessed in ASD cases using the Vineland Adaptive Behavior Scales (VABS); cognitive functioning was assessed in all groups using the Mullen Scales of Early Learning (MSEL). A satellite-based model was used to assign PM2.5 exposure averages during pregnancy, each trimester, and the first year of life. Linear regression was used to estimate beta coefficients and 95% confidence intervals, adjusting for maternal age, education, prenatal tobacco use, race-ethnicity, study site, and season of birth. PM2.5 exposure was associated with poorer VABS scores for several domains, including daily living skills and socialization. Associations were present between prenatal PM2.5 and lower MSEL scores for all groups combined; results were most prominent for population controls in stratified analyses. These data suggest that early life PM2.5 exposure is associated with specific aspects of cognitive and adaptive functioning in children with and without ASD.

Reasons for participation in a child development study: Are cases with developmental diagnoses different from controls?

BACKGROUND: Current knowledge about parental reasons for allowing child participation in research comes mainly from clinical trials. Fewer data exist on parents' motivations to enrol children in observational studies. OBJECTIVES: Describe reasons parents of preschoolers gave for participating in the Study to Explore Early Development (SEED), a US multi-site study of autism spectrum disorder (ASD) and other developmental delays or disorders (DD), and explore reasons given by child diagnostic and behavioural characteristics at enrolment. METHODS: We included families of children, age 2-5 years, participating in SEED (n = 5696) during 2007-2016. We assigned children to groups based on characteristics at enrolment: previously diagnosed ASD; suspected ASD; non-ASD DD; and population controls (POP). During a study interview, we asked parents their reasons for participating. Two coders independently coded responses and resolved discrepancies via consensus. We fit binary mixed-effects models to evaluate associations of each reason with group and demographics, using POP as reference. RESULTS: Participants gave 1-5 reasons for participation (mean = 1.7, SD = 0.7). Altruism (48.3%), ASD research interest (47.4%) and perceived personal benefit (26.9%) were most common. Two novel reasons were knowing someone outside the household with the study conditions (peripheral relationship; 14.1%) and desire to contribute to a specified result (1.4%). Odds of reporting interest in ASD research were higher among diagnosed ASD participants (odds ratio [OR] 2.89, 95% confidence interval [CI] 2.49-3.35). Perceived personal benefit had higher odds among diagnosed (OR 1.92, 95% CI 1.61-2.29) or suspected ASD (OR 3.67, 95% CI 2.99-4.50) and non-ASD DD (OR 1.80, 95% CI 1.50-2.16) participants. Peripheral relationship with ASD/DD had lower odds among all case groups. CONCLUSIONS: We identified meaningful differences between groups in parent-reported reasons for participation. Differences demonstrate an opportunity for future studies to tailor recruitment materials and increase the perceived benefit for specific prospective participants.

Peri-Pregnancy Cannabis Use and Autism Spectrum Disorder in the Offspring: Findings from the Study to Explore Early Development.

The association of autism spectrum disorder (ASD) with self-reported maternal cannabis use from 3 months pre-conception to delivery ("peri-pregnancy") was assessed in children aged 30-68 months, born 2003 to 2011. Children with ASD (N = 1428) were compared to children with other developmental delays/disorders (DD, N = 1198) and population controls (POP, N = 1628). Peri-pregnancy cannabis use was reported for 5.2% of ASD, 3.2% of DD and 4.4% of POP children. Adjusted odds of peri-pregnancy cannabis use did not differ significantly between ASD cases and DD or POP controls. Results were similar for any use during pregnancy. However, given potential risks suggested by underlying neurobiology and animal models, further studies in more recent cohorts, in which cannabis use and perception may have changed, are needed.

Maternal prepregnancy weight and gestational weight gain in association with autism and developmental disorders in offspring.

OBJECTIVE: Maternal prepregnancy BMI and gestational weight gain (GWG) are examined in relation to autism spectrum disorder (ASD) and other developmental disorders (DD) in offspring in a multisite case-control study. METHODS: Maternal prepregnancy BMI, obtained from medical records or self-report, was categorized as underweight, normal weight, overweight, obesity Class 1, or obesity Class 2/3. GWG was standardized for gestational age (GWG z score), and the rate (pounds/week) was categorized per adherence with clinical recommendations. Logistic regression models, adjusting for demographic factors, were used to assess associations with ASD (n = 1,159) and DD (n = 1,617), versus control children (n = 1,633). RESULTS: Maternal obesity Class 2/3 was associated with ASD (adjusted odds ratio [AOR] = 1.87, 95% CI: 1.40-2.51) and DD (AOR = 1.61, 95% CI: 1.22-2.13). GWG z score was not associated with DD (AOR = 1.14, 95% CI: 0.95-1.36), but the GWG z score highest tertile was associated with higher odds of ASD, particularly among male children (AOR = 1.47, 95% CI: 1.15-1.88). CONCLUSIONS: Results indicate that maternal prepregnancy severe obesity increases risk of ASD and DD in children and suggest high gestational-age-adjusted GWG is a risk factor for ASD in male children. Because maternal BMI and GWG are routinely measured and potentially modifiable, these findings could inform early interventions for high-risk mother-child dyads.

Childhood Socioeconomic Status and Menarche: A Prospective Study.

PURPOSE: The relationship between socioeconomic status (SES) and menarche has implications for understanding social level influences on early life development and adult disease, including breast cancer, but remains ill defined. We report here results from the Breast Cancer and the Environment Research Program, which permitted a longitudinal study of age at menarche in relationship to childhood SES in a diverse cohort of 1,069 girls across three urban areas of the United States. METHODS: We assessed the association of SES index quintiles with age at pubertal onset with breast budding and subsequent tempo to the age at menarche between 2004 and 2015 using multiple-event Cox regression models to estimate hazard ratios and 95% confidence intervals. RESULTS: In an unadjusted model, lower SES was predictive of both earlier pubertal onset and tempo and thus earlier age at menarche in trends across quintiles. After adjusting for the potentially mediating effects of body mass index, SES trends remained significant for both outcomes. After adjusting for both body mass index and race/ethnicity, the association with SES remained substantial for pubertal onset but was much diminished and nonsignificant for tempo and thus age at menarche. CONCLUSIONS: These results suggest that a lower SES environment and social adversity affect the age at menarche primarily by hastening pubertal onset rather than by shortening tempo.

A profile and review of findings from the Early Markers for Autism study: unique contributions from a population-based case-control study in California.

BACKGROUND: The Early Markers for Autism (EMA) study is a population-based case-control study designed to learn more about early biologic processes involved in ASD. METHODS: Participants were drawn from Southern California births from 2000 to 2003 with archived prenatal and neonatal screening specimens. Across two phases, children with ASD (n = 629) and intellectual disability without ASD (ID, n = 230) were ascertained from the California Department of Developmental Services (DDS), with diagnoses confirmed according to DSM-IV-TR criteria based on expert clinical review of abstracted records. General population controls (GP, n = 599) were randomly sampled from birth certificate files and matched to ASD cases by sex, birth month and year after excluding individuals with DDS records. EMA has published over 20 papers examining immune markers, endogenous hormones, environmental chemicals, and genetic factors in association with ASD and ID. This review summarizes the results across these studies, as well as the EMA study design and future directions. RESULTS: EMA enabled several key contributions to the literature, including the examination of biomarker levels in biospecimens prospectively collected during critical windows of neurodevelopment. Key findings from EMA include demonstration of elevated cytokine and chemokine levels in maternal mid-pregnancy serum samples in association with ASD, as well as aberrations in other immune marker levels; suggestions of increased odds of ASD with prenatal exposure to certain endocrine disrupting chemicals, though not in mixture analyses; and demonstration of maternal and fetal genetic influence on prenatal chemical, and maternal and neonatal immune marker and vitamin D levels. We also observed an overall lack of association with ASD and measured maternal and neonatal vitamin D, mercury, and brain-derived neurotrophic factor (BDNF) levels. LIMITATIONS: Covariate and outcome data were limited to information in Vital Statistics and DDS records. As a study based in Southern California, generalizability for certain environmental exposures may be reduced. CONCLUSIONS: Results across EMA studies support the importance of the prenatal and neonatal periods in ASD etiology, and provide evidence for the role of the maternal immune response during pregnancy. Future directions for EMA, and the field of ASD in general, include interrogation of mechanistic pathways and examination of combined effects of exposures.

Girls' Pubertal Timing and Tempo and Mental Health: A Longitudinal Examination in an Ethnically Diverse Sample.

PURPOSE: Earlier timing and faster tempo of puberty have been linked to adolescents' poor mental health. Previous research rarely adjusted for childhood mental health, did not use physical examination to assess puberty, and excluded Latinas and Asian Americans. This study addressed these limitations. METHODS: We followed 822 girls, recruited at ages 6-8, for 8 years. Breast and pubic hair development and anxiety and depressive symptoms were assessed prospectively and repeatedly. Structural equation models tested whether pubertal timing and tempo were associated with adolescent mental health symptoms and whether associations varied by ethnicity. Models were adjusted for childhood mental health symptoms, body mass index, and family income. RESULTS: Earlier breast development was associated with higher depressive symptoms among whites (ß = -.19; p < .01) and higher anxiety symptoms among Latinas (ß = -.26; p < .05), but lower depressive symptoms among Asians (ß = .24, p < .05). Later pubic hair development (b = .24; p < .05) and faster pubic hair tempo (ß = .26; p < .01) were associated with higher anxiety symptoms among Latinas. Faster pubic hair tempo was associated with lower depressive symptoms among Asians (ß = -.34; p < .05). Tempo of breast development showed no associations. CONCLUSIONS: Findings confirmed that earlier breast development was associated with higher mental health symptoms for Latina and white girls but was protective among Asians. Results for pubic hair and pubertal tempo were inconsistent, requiring future examination. While targeted interventions to prevent mental health problems among early-maturing girls are critical, there is variability among who might benefit most.

Association Between Midpregnancy Polyunsaturated Fatty Acid Levels and Offspring Autism Spectrum Disorder in a California Population-Based Case-Control Study.

Polyunsaturated fatty acids (PUFAs) are critical for brain development and have been linked with neurodevelopmental outcomes. We conducted a population-based case-control study in California to examine the association between PUFAs measured in midpregnancy serum samples and autism spectrum disorder (ASD) in offspring. ASD cases (n = 499) were identified through the California Department of Developmental Services and matched to live-birth population controls (n = 502) on birth month, year (2010 or 2011), and sex. Logistic regression models were used to examine crude and adjusted associations. In secondary analyses, we examined ASD with and without co-occurring intellectual disability (ID; n = 67 and n = 432, respectively) and effect modification by sex and ethnicity. No clear patterns emerged, though there was a modest inverse association with the top quartile of linoleic acid level (highest quartile vs. lowest: adjusted odds ratio = 0.74, 95% confidence interval: 0.49, 1.11; P for trend = 0.10). Lower levels of total and ω-3 PUFAs were associated with ASD with ID (lowest decile of total PUFAs vs. deciles 4-7: adjusted odds ratio = 2.78, 95% confidence interval: 1.13, 6.82) but not ASD without ID. We did not observe evidence of effect modification by the factors examined. These findings do not suggest a strong association between midpregnancy PUFA levels and ASD. In further work, researchers should consider associations with ASD with ID and in other time windows.

Coccidioidomycosis outbreak among inmate wildland firefighters: California, 2017.

BACKGROUND: In California, state prison inmates are employed to fight wildfires, which involves performing soil-disrupting work. Wildfires have become more common, including areas where Coccidioides, the soil-dwelling fungus that causes coccidioidomycosis, proliferates. However, work practices that place wildland firefighters at risk for coccidioidomycosis have not been investigated. METHODS: On August 17, 2017, the California Department of Public Health was notified of a cluster of coccidioidomycosis cases among Wildfire A inmate wildland firefighters. We collected data through medical record abstraction from suspected case-patients and mailed a survey assessing potential job task risk factors to Wildfire A inmate firefighters. We described respondent characteristics and conducted a retrospective case-control investigation to assess coccidioidomycosis risk factors. RESULTS: Among 198 inmate firefighters who worked on Wildfire A, 112 (57%) completed the survey. Of 10 case-patients (four clinical and six laboratory-confirmed), two were hospitalized. In the case-control analysis of 71 inmate firefighters, frequently cutting fire lines with a McLeod tool (odds ratio [OR]: 5.5; 95% confidence interval [CI]: 1.1-37.2) and being in a dust cloud or storm (OR: 4.3; 95% CI: 1.1-17.4) were associated with illness. Two of 112 inmate firefighters reported receiving coccidioidomycosis training; none reported wearing respiratory protection on this wildfire. CONCLUSIONS: Wildland firefighters who use hand tools and work in dusty conditions where Coccidioides proliferates are at risk for coccidioidomycosis. Agencies that employ them should provide training about coccidioidomycosis and risk reduction, limit dust exposure, and implement respiratory protection programs that specify where respirator use is feasible and appropriate.

Maternal immune response and air pollution exposure during pregnancy: insights from the Early Markers for Autism (EMA) study.

BACKGROUND: Perinatal exposure to air pollution and immune system dysregulation are two factors consistently associated with autism spectrum disorders (ASD) and other neurodevelopmental outcomes. However, little is known about how air pollution may influence maternal immune function during pregnancy. OBJECTIVES: To assess the relationship between mid-gestational circulating levels of maternal cytokines/chemokines and previous month air pollution exposure across neurodevelopmental groups, and to assess whether cytokines/chemokines mediate the relationship between air pollution exposures and risk of ASD and/or intellectual disability (ID) in the Early Markers for Autism (EMA) study. METHODS: EMA is a population-based, nested case-control study which linked archived maternal serum samples collected during weeks 15-19 of gestation for routine prenatal screening, birth records, and Department of Developmental Services (DDS) records. Children receiving DDS services for ASD without intellectual disability (ASD without ID; n = 199), ASD with ID (ASD with ID; n = 180), ID without ASD (ID; n = 164), and children from the general population (GP; n = 414) with no DDS services were included in this analysis. Serum samples were quantified for 22 cytokines/chemokines using Luminex multiplex analysis technology. Air pollution exposure for the month prior to maternal serum collection was assigned based on the Environmental Protection Agency's Air Quality System data using the maternal residential address reported during the prenatal screening visit. RESULTS: Previous month air pollution exposure and mid-gestational maternal cytokine and chemokine levels were significantly correlated, though weak in magnitude (ranging from - 0.16 to 0.13). Ten pairs of mid-pregnancy immune markers and previous month air pollutants were significantly associated within one of the child neurodevelopmental groups, adjusted for covariates (p < 0.001). Mid-pregnancy air pollution was not associated with any neurodevelopmental outcome. IL-6 remained associated with ASD with ID even after adjusting for air pollution exposure. CONCLUSION: This study suggests that maternal immune activation is associated with risk for neurodevelopmental disorders. Furthermore, that prenatal air pollution exposure is associated with small, but perhaps biologically relevant, effects on maternal immune system function during pregnancy. Additional studies are needed to better evaluate how prenatal exposure to air pollution affects the trajectory of maternal immune activation during pregnancy, if windows of heightened susceptibility can be identified, and how these factors influence neurodevelopment of the offspring.

Maternal Vitamin D Levels During Pregnancy in Association With Autism Spectrum Disorders (ASD) or Intellectual Disability (ID) in Offspring; Exploring Non-linear Patterns and Demographic Sub-groups.

Increasing vitamin D deficiency and evidence for vitamin D's role in brain and immune function have recently led to studies of neurodevelopment; however, few are specific to autism spectrum disorder (ASD) and vitamin D in pregnancy, a likely susceptibility period. We examined this in a case-control study of 2000-2003 Southern Californian births; ASD and intellectual disability (ID) were identified through the Department of Developmental Services and controls from birth certificates (N = 534, 181, and 421, respectively, in this analysis). Total 25-Hydroxyvitamin D (25(OH)D) was measured in mid-pregnancy serum, categorized as deficient (<50 nmol/L), insufficient (50-74 nmol/L), or sufficient (≥75 nmol/L, referent category), and examined continuously (per 25 nmol/L). Crude and adjusted odds ratios (AORs) and 95% confidence intervals (95% CI) were calculated. Non-linearity was examined with cubic splines. AORs (95% CI) for ASD were 0.79 (0.49-1.3) for maternal deficiency (9.5%), 0.93 (0.68-1.3) for insufficiency (25.6%), and 0.95 (0.86, 1.05) for linear continuous 25(OH)D. Results were similarly null for ASD with or without ID, and ID only. Interactions were observed; non-Hispanic whites (NHW) (AOR = 0.82, 95% CI = 0.69-0.98) and males (AOR = 0.89, 95% CI = 0.80-0.99) had protective associations for ASD with continuous 25(OH)D. A positive association with ASD was observed in females (AOR = 1.40, 95% CI = 1.06-1.85). With splines, a non-linear inverted j-shaped pattern was seen overall (P = 0.009 for non-linearity), with the peak around 100 nmol/L; a non-linear pattern was not observed among NHW, females, nor for ID. Our findings from a large study of ASD and prenatal vitamin D levels indicate that further research is needed to investigate non-linear patterns and potentially vulnerable sub-groups. LAY SUMMARY: We studied whether mothers' vitamin D levels during pregnancy were related to their children having autism (or low IQ) later. Low vitamin D levels were not related to greater risk of autism or low IQ in children overall. With higher levels of mothers' vitamin D, risk of autism went down in boys, but went up in girls. Risk of autism also went down in children of non-Hispanic white mothers with higher vitamin D levels, but we did not find a relation in other race/ethnic groups.

Polyunsaturated Fatty Acids in Newborn Bloodspots: Associations With Autism Spectrum Disorder and Correlation With Maternal Serum Levels.

We conducted a population-based case-control study to examine newborn polyunsaturated fatty acid (PUFA) levels in association with autism spectrum disorder (ASD) and assess PUFA correlation across two time points. ASD cases (n = 200) were identified through the Department of Developmental Services and matched to live-birth population controls (n = 200) on birth month, year (2010-2011), and sex. Nonesterified PUFAs were measured by isotope dilution liquid chromatography-high resolution mass spectrometry from archived newborn dried blood spots and maternal mid-pregnancy serum samples. Crude and adjusted conditional logistic regression models were used to examine the association between neonatal PUFA levels, categorized in quartiles and according to distributional extremes, and ASD. Cubic splines were utilized to examine nonlinear relationships between continuous neonatal PUFAs and ASD. The correlation between neonatal and maternal levels was examined using Pearson correlation coefficients. In adjusted analyses of neonatal PUFA levels, no clear trends emerged, though there was an elevated odds ratio of ASD for the third quartile of linoleic acid, relative to the first (adjusted odds ratio = 2.49, 95% confidence interval: 1.31, 4.70). Cubic spline analysis suggested a nonlinear association between linoleic acid and ASD, though this was not robust to sensitivity analyses. While individual PUFAs were significantly correlated with one another within a given time point, aside from docohexaseanoic acid, PUFAs were not correlated across maternal and neonatal samples. Overall, our findings do not support an association between neonatal PUFA levels and ASD. Future work should confirm and expand these findings by examining associations with phenotypic subgroups and considering PUFAs in other time points. LAY SUMMARY: In this study, we examined whether levels of fats known as polyunsaturated fatty acids, measured in newborns, were related to later child diagnosis of autism spectrum disorder (ASD). Overall, we did not find strong evidence for hypothesized reduction in risk of ASD based on newborn levels of these fats. Future studies in larger samples and considering other time points may be useful to explain whether these fats are important in brain development related to ASD. Autism Res 2020, 13: 1601-1613. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Urinary polycyclic aromatic hydrocarbons in relation to anthropometric measures and pubertal development in a cohort of Northern California girls.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous, environmental chemicals that may have endocrine disrupting capabilities. We investigated whether childhood exposure to PAHs was associated with adiposity and pubertal timing in a longitudinal study of 404 girls enrolled in the Northern California site of the Breast Cancer and the Environment Research Program cohort. METHODS: Baseline urinary samples from girls aged 6-8-years-old were assayed for 2-naphthol, fluorene metabolites, phenanthrene metabolites, 1-hydroxypyrene, and sum of PAH metabolites. Mixed-effects linear models were used to estimate how concentrations of PAH metabolites were related to changes in girl's body mass index (BMI) and waist-to-height ratio from age 7 through 16 years old. Accelerated failure time models were used to estimate age of pubertal onset (Tanner stages 2 or higher for breast and pubic hair development). RESULTS: Higher adiposity measurements among high tertiles of baseline PAH metabolites were evident at age 7 years old and increased thereafter (i.e., BMI for all PAH metabolites, waist-to-height ratio for fluorene and phenanthrene metabolites) or leveled off (i.e., waist-to-height ratio for 2-naphthol, 1-hydroxypyrene, sum of PAHs). Among girls overweight/obese at baseline, median age of breast development onset for high tertiles was 9.1-9.4 years old compared with 10-10.2 years old for low tertiles for all PAH metabolites; in contrast, found no association or slightly later onset of breast development for girls with normal weight at baseline. DISCUSSION: These results suggest that exposure to specific PAHs during childhood may influence adiposity throughout adolescence and effect pubertal timing.

Genetic Contributions to Maternal and Neonatal Vitamin D Levels.

Vitamin D is essential for several physiological functions and biological processes. Increasing levels of maternal vitamin D are required throughout pregnancy as a unique source of vitamin D for the fetus, and consequently maternal vitamin D deficiency may result in several adverse outcomes in newborns. However, the genetic regulation of vitamin D in pregnancy and at birth is not yet well understood. We performed genome-wide association studies of maternal midgestational serum-derived and neonatal blood-spot-derived total 25-hydroxyvitamin D from a case-control study of autism spectrum disorder (ASD). We identified one fetal locus (rs4588) significantly associated with neonatal vitamin D levels in the GC gene, encoding the binding protein for the transport and function of vitamin D. We also found suggestive cross-associated loci for neonatal and maternal vitamin D near immune genes, such as CXCL6-IL8 and ACKR1 We found no interactions with ASD. However, when including a set of cases with intellectual disability but not ASD (N = 179), we observed a suggestive interaction between decreased levels of neonatal vitamin D and a specific maternal genotype near the PKN2 gene. Our results suggest that genetic variation influences total vitamin D levels during pregnancy and at birth via proteins in the vitamin D pathway, but also potentially via distinct mechanisms involving loci with known roles in immune function that might be involved in vitamin D pathophysiology in pregnancy.

Early Life Exposure to Air Pollution and Autism Spectrum Disorder: Findings from a Multisite Case-Control Study.

BACKGROUND: Epidemiologic studies have reported associations between prenatal and early postnatal air pollution exposure and autism spectrum disorder (ASD); however, findings differ by pollutant and developmental window. OBJECTIVES: We examined associations between early life exposure to particulate matter ≤2.5 µm in diameter (PM2.5) and ozone in association with ASD across multiple US regions. METHODS: Our study participants included 674 children with confirmed ASD and 855 population controls from the Study to Explore Early Development, a multi-site case-control study of children born from 2003 to 2006 in the United States. We used a satellite-based model to assign air pollutant exposure averages during several critical periods of neurodevelopment: 3 months before pregnancy; each trimester of pregnancy; the entire pregnancy; and the first year of life. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for study site, maternal age, maternal education, maternal race/ethnicity, maternal smoking, and month and year of birth. RESULTS: The air pollution-ASD associations appeared to vary by exposure time period. Ozone exposure during the third trimester was associated with ASD, with an OR of 1.2 (95% CI: 1.1, 1.4) per 6.6 ppb increase in ozone. We additionally observed a positive association with PM2.5 exposure during the first year of life (OR = 1.3 [95% CI: 1.0, 1.6] per 1.6 µg/m increase in PM2.5). CONCLUSIONS: Our study corroborates previous findings of a positive association between early life air pollution exposure and ASD, and identifies a potential critical window of exposure during the late prenatal and early postnatal periods.