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Background: An infant's presentation at delivery may be an early indicator of developmental differences. Non-vertex presentation (malpresentation) complicates delivery and often leads to caesarean section, which has been associated with neurodevelopmental delays, including autism spectrum disorder (ASD). However, malpresentation could be an early sign of an existing developmental problem that is also an upstream factor from caesarean delivery. Little research has been done to investigate the association between malpresentation and ASD., Objectives: We examine the association between malpresentation at delivery and ASD and whether this association differs by gestational age., Methods: We used data from the Study to Explore Early Development (SEED), a multi-site, case-control study of children with ASD compared to population controls. The foetal presentation was determined using medical records, birth records and maternal interviews. We defined malpresentation as a non-vertex presentation at delivery, then further categorised into breech and other malpresentation. We used multivariable logistic regression to estimate the adjusted odds ratio (aOR) for the association between malpresentation and ASD., Results: We included 4047 SEED participants, 1873 children with ASD and 2174 controls. At delivery, most infants presented vertex (n = 3760, 92.9%). Malpresentation was associated with higher odds of ASD (aOR 1.31, 95% confidence interval [CI] 1.02, 1.68) after adjustment for maternal age, poverty level, hypertensive disorder and smoking. The association was similar for breech and other types of malpresentation (aOR 1.28, 95% CI 0.97, 1.70 and aOR 1.40, 95% CI 0.87, 2.26, respectively) and did not differ markedly by gestational age., Conclusions: Malpresentation at delivery was modestly associated with ASD. Early monitoring of the neurodevelopment of children born with malpresentation could identify children with ASD sooner and enhance opportunities to provide support to optimise developmental outcomes., (© 2024 John Wiley & Sons Ltd.)

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., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Children with autism spectrum disorder (ASD) have a greater prevalence of gastrointestinal (GI) symptoms than children without ASD. We tested whether polygenic scores for each of three GI disorders (ulcerative colitis, inflammatory bowel disease, and Crohn's disease) were related to GI symptoms in children with and without ASD. Using genotyping data (564 ASD cases and 715 controls) and external genome-wide association study summary statistics, we computed GI polygenic scores for ulcerative colitis (UC-PGS), inflammatory bowel disease (IDB-PGS), and Crohn's disease (CD-PGS). Multivariable logistic regression models, adjusted for genetic ancestry, were used to estimate associations between each GI-PGS and (1) ASD case-control status, and (2) specific GI symptoms in neurotypical children and separately in ASD children. In children without ASD, polygenic scores for ulcerative colitis were significantly associated with experiencing any GI symptom (adjusted odds ratio (aOR) = 1.36, 95% confidence interval (CI) = 1.03-1.81, p = 0.03) and diarrhea specifically (aOR = 5.35, 95% CI = 1.77-26.20, p = 0.01). Among children without ASD, IBD-PGS, and Crohn's PGS were significantly associated with diarrhea (aOR = 3.55, 95% CI = 1.25-12.34, p = 0.02) and loose stools alternating with constipation (aOR = 2.57, 95% CI = 1.13-6.55, p = 0.03), respectively. However, the three PGS were not associated with GI symptoms in the ASD case group. Furthermore, polygenic scores for ulcerative colitis significantly interacted with ASD status on presentation of any GI symptom within a European ancestry subset (aOR = 0.42, 95% CI = 0.19-0.88, p = 0.02). Genetic risk factors for some GI symptoms differ between children with and without ASD. Furthermore, our finding that increased genetic risks for GI inflammatory disorders are associated with GI symptoms in children without ASD informs future work on the early detection of GI disorders., (© 2023 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

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., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022 John Wiley & Sons Ltd.)

Increasing evidence exists for an association between early life fine particulate matter (PM 2.5 ) exposure and several neurodevelopmental outcomes, including autism spectrum disorder (ASD); however, the association between PM 2.5 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 PM 2.5 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. PM 2.5 exposure was associated with poorer VABS scores for several domains, including daily living skills and socialization. Associations were present between prenatal PM 2.5 and lower MSEL scores for all groups combined; results were most prominent for population controls in stratified analyses. These data suggest that early life PM 2.5 exposure is associated with specific aspects of cognitive and adaptive functioning in children with and without ASD.

Gastrointestinal symptoms (GIS) are commonly reported in children with autism spectrum disorder (ASD). This multi-site study evaluated the prevalence of GIS in preschool-aged children with ASD/(n = 672), with other developmental delays (DD)/(n = 938), and children in the general population (POP)/(n = 851). After adjusting for covariates, children in the ASD group were over 3 times more likely to have parent-reported GIS than the POP group, and almost 2 times more likely than the DD group. Children with GIS from all groups had more behavioral and sleep problems. Within the ASD group, children with developmental regression had more GIS than those without; however, there were no differences in autism severity scores between children with and without GIS. These findings have implications for clinical management., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2021 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: This study aims to clarify relationships of maternal psychiatric conditions and selective serotonin reuptake inhibitor (SSRI) use during preconception and pregnancy with risk of neurodevelopmental disorders in offspring., Methods: We used data from the Study to Explore Early Development, a multisite case-control study conducted in the United States among children born between 2003 and 2011. Final study group classifications of autism spectrum disorder (ASD) (n = 1367), developmental delays or disorders (DDs) (n = 1750), and general population controls (n = 1671) were determined by an in-person standardized developmental assessment. Maternal psychiatric conditions and SSRI use during pregnancy were ascertained from both self-report and medical records. We used logistic regression to evaluate associations of ASD and DDs (vs. population controls) with maternal psychiatric conditions and SSRI treatment in pregnancy. To reduce confounding by indication, we also examined SSRI associations in analyses restricted to mothers with psychiatric conditions during pregnancy., Results: Psychiatric conditions and SSRI use during pregnancy were significantly more common among mothers of children with either ASD or DDs than among population controls. Odds of ASD were similarly elevated among mothers with psychiatric conditions who did not use SSRIs during pregnancy (adjusted odds ratio 1.81, 95% confidence interval 1.44-2.27) as in mothers who did use SSRIs (adjusted odds ratio 2.05, 95% confidence interval 1.50-2.80). Among mothers with psychiatric conditions, SSRI use was not significantly associated with ASD in offspring (adjusted odds ratio 1.14, 95% confidence interval 0.80-1.62). Primary findings for DDs exhibited similar relationships to those observed with ASD., Conclusions: Maternal psychiatric conditions but not use of SSRIs during pregnancy were associated with increased risk of neurodevelopmental disorders in offspring., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Background: Pica, the repeated ingestion of nonfood items, can result in gastrointestinal (GI) outcomes. Children with autism spectrum disorder (ASD) and other developmental disabilities (DDs) are disproportionately affected by both pica and GI symptoms. Study of the inter-relationship between pica, GI symptoms, and ASD/DD is limited., Objective/hypothesis: We assessed associations between pica and GI symptoms in preschool-aged children with and without ASD and other (non-ASD) DDs in the Study to Explore Early Development., Methods: Our sample included children with ASD (n = 1244), other DDs (n = 1593), and population (POP) controls (n = 1487). Data to define final case-control status, pica, and GI symptoms were from standardized developmental assessments/questionnaires. Prevalence ratios, adjusted for sociodemographic factors (aPRs), and 95% confidence intervals were derived from modified Poisson regression., Results: Within each group (ASD, DD, POP) and for the total sample, pica was associated with vomiting (aPR for total sample 2.6 [1.7, 4.0]), diarrhea (1.8 [1.4, 2.2]), and loose stools (1.8 [1.4, 2.2]). In the DD group, pica was associated with constipation (1.4 [1.03, 1.9]) and pain on stooling (1.8 [1.2, 2.6]). In analyses of the subgroup without pica, increases in GI symptoms were still evident in the ASD and DD groups compared to POP group., Conclusion: These findings highlight an important adverse effect of pica, GI symptoms, in children with and without ASD and DDs; nonetheless, pica does not fully explain the increased risk for GI symptoms among children with ASD and DDs. These findings inform the specialized healthcare needs of children with ASD and other DDs., Competing Interests: Declaration of competing interest The authors have no financial relationships and no conflicts of interest relevant to this article to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: Pica, the repeated ingestion of nonfood items, can be life-threatening. Although case reports describe pica in children with autism spectrum disorder (ASD) or intellectual disability (ID), there has been little systematic study of pica prevalence. We assessed pica in children 30 to 68 months of age (median = 55.4 months) with and without ASD., Methods: Our sample from the Study to Explore Early Development, a multisite case-control study, included children with ASD ( n = 1426), children with other developmental disabilities (DDs) ( n = 1735), and general population-based controls (POPs) ( n = 1578). We subdivided the ASD group according to whether children had ID and the DD group according to whether they had ID and/or some ASD characteristics. Standardized developmental assessments and/or questionnaires were used to define final study groups, subgroups, and pica. We examined pica prevalence in each group and compared ASD and DD groups and subgroups to the POP group using prevalence ratios adjusted for sociodemographic factors., Results: Compared with the prevalence of pica among POPs (3.5%), pica was higher in children with ASD (23.2%) and DD (8.4%), and in the following subgroups: ASD with ID (28.1%), ASD without ID (14.0%), DD with ID (9.7%), DD with ASD characteristics (12.0%), and DD with both ID and ASD characteristics (26.3%); however, pica prevalence was not elevated in children with DD with neither ID nor ASD characteristics (3.2%). Between-group differences remained after adjustment (adjusted prevalence ratio range 1.9-8.0, all P <.05)., Conclusions: Pica may be common in young children with ASD, ASD characteristics, and ID. These findings inform the specialized health care needs of these children., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Previous studies investigating the association between dysmorphology and cognitive, behavioral, and developmental outcomes among individuals with autism spectrum disorder (ASD) have been limited by the binary classification of dysmorphology and lack of comparison groups. We assessed the association using a continuous measure of dysmorphology severity (DS) in preschool children aged 2-5 years (322 with ASD and intellectual disability [ID], 188 with ASD without ID, and 371 without ASD from the general population [POP]). In bivariate analyses, an inverse association between DS and expressive language, receptive language, fine motor, and visual reception skills was observed in children with ASD and ID. An inverse association of DS with fine motor and visual reception skills, but not expressive language and receptive language, was found in children with ASD without ID. No associations were observed in POP children. These results persisted after exclusion of children with known genetic syndromes or major morphologic anomalies. Quantile regression models showed that the inverse relationships remained significant after adjustment for sex, race/ethnicity, maternal education, family income, study site, and preterm birth. DS was not associated with autistic traits or autism symptom severity, behaviors, or regression among children with ASD with or without ID. Thus, DS was associated with a global impairment of cognitive functioning in children with ASD and ID, but only with fine motor and visual reception deficits in children with ASD without ID. A better understanding is needed for mechanisms that explain the association between DS and cognitive impairment in children with different disorders. Autism Res 2020, 13: 1227-1238. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined whether having more dysmorphic features (DFs) was related to developmental problems among children with autism spectrum disorder (ASD) with or without intellectual disability (ID), and children without ASD from the general population (POP). Children with ASD and ID had more language, movement, and learning issues as the number of DFs increased. Children with ASD without ID had more movement and learning issues as the number of DFs increased. These relationships were not observed in the POP group. Implications are discussed., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)

Objective: To examine the association between neonatal jaundice and autism spectrum disorder (ASD) and non-ASD developmental disorder (DD)., Study Design: We analyzed data from the Study to Explore Early Development, a US multisite, case-control study conducted from 2007 to 2011. Developmental assessment classified children aged 2-5 years into: ASD (n = 636), DD (n = 777), or controls (POP; n = 926). Neonatal jaundice (n = 1054) was identified from medical records and maternal interviews. We examined associations between neonatal jaundice and ASD and DD using regression models to obtain adjusted odds ratios (aOR)., Results: Our results showed interaction between gestational age and neonatal jaundice. Neonatal jaundice was associated with ASD at 35-37 weeks (aOR = 1.83, 95%CI 1.05, 3.19), but not ≥38 weeks gestation (aOR = 0.97, 95%CI 0.76, 1.24). Similar results were observed with DD., Conclusions: Further exploration of timing and severity of neonatal jaundice and ASD/DD is warranted.

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.

Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res 2019, 12: 1551-1561. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

Previous studies have shown complications of pregnancy, often examined in aggregate, to be associated with autism spectrum disorder (ASD). Results for specific complications, such as maternal diabetes and hypertension, have not been uniformly consistent and should be investigated independently in relation to ASD in a large community-based sample. The Study to Explore Early Development (SEED), a US multisite case-control study, enrolled children born in 2003-2006 at 2-5 years of age. Children were classified into three groups based on confirmation of ASD (n = 698), non-ASD developmental delay (DD; n = 887), or controls drawn from the general population (POP; n = 979). Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records and maternal self-report. Logistic regression models estimated adjusted odds ratios (aOR) and confidence intervals (CI) adjusting for maternal age, race/ethnicity, education, smoking during pregnancy, and study site. Models for hypertension were additionally adjusted for parity and plurality. Among 2,564 mothers, we identified 246 (9.6%) with any diabetes and 386 (15.1%) with any hypertension in pregnancy. After adjustment for covariates, any diabetes during pregnancy was not associated with ASD (aOR = 1.10 [95% CI 0.77, 1.56]), but any hypertension was associated with ASD (aOR = 1.69 [95% CI 1.26, 2.26]). Results were similar for DD, and any diabetes (aOR = 1.29 [95% CI 0.94, 1.78]) or any hypertension (aOR = 1.71 [95% CI 1.30, 2.25]). Some pregnancy complications, such as hypertension, may play a role in autism etiology and can possibly serve as a prompt for more vigilant ASD screening efforts. Autism Res 2019, 12: 967-975. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied if common complications in pregnancy are associated with autism spectrum disorder (ASD) in a large sample of mothers and children. Our results show an association between conditions marked by high blood pressure and ASD, but no association with conditions marked by high blood sugar and ASD. Associations were similar for children who had a developmental disorder that was not ASD, suggesting that this relationship may not be specific to ASD., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

We examined associations between child body mass index at 2-5 years and maternal pre-pregnancy body mass index, gestational weight gain, and rapid weight gain during infancy in children with autism spectrum disorder, developmental delays, or population controls. The Study to Explore Early Development is a multi-site case-control study of children, aged 2-5 years, classified as autism spectrum disorder ( n = 668), developmental delays ( n = 914), or population controls ( n = 884). Maternal gestational weight gain was compared to the Institute of Medicine recommendations. Rapid weight gain was a change in weight-for-age z-scores from birth to 6 months > 0.67 standard deviations. After adjusting for case status, mothers with pre-pregnancy overweight/obesity were 2.38 times (95% confidence interval: 1.96-2.90) more likely, and mothers who exceeded gestational weight gain recommendations were 1.48 times (95% confidence interval: 1.17-1.87) more likely, to have an overweight/obese child than other mothers ( P < 0.001). Children with autism spectrum disorder showed the highest frequency of rapid weight gain (44%) and were 3.47 times (95% confidence interval: 1.85-6.51) more likely to be overweight/obese as children with autism spectrum disorder without rapid weight gain ( P < 0.001). Helping mothers achieve a healthy pre-pregnancy body mass index and gestational weight gain represent important targets for all children. Healthy infant growth patterns carry special importance for children at increased risk for an autism spectrum disorder diagnosis.

Studies report inconsistent findings on the relationship between ASD and breastfeeding. We explored associations between ASD and breastfeeding initiation (yes/no) and duration (months categorized in tertiles) in the Study to Explore Early Development, a community-based case-control study in six sites in the Unites States. We adjusted for various child and mother demographic and pregnancy factors. Breastfeeding initiation was reported in 85.7% of mothers of children with ASD and 90.6% of mothers of controls. After adjustment, we found no significant difference in breastfeeding initiation (adjusted odds-ratio [aOR]: 0.88 and 95% confidence interval (CI) 0.60-1.28). However, mothers of children with ASD were less likely to report duration of breastfeeding in the high (≥12 months) versus low tertile (<6 months) (aOR and 95% CI: 0.61 [0.45-0.84]) or the middle (6-<12 months) versus low tertile (0.72: 0.54-0.98). The association of ASD and breastfeeding duration was slightly attenuated when the presence of the broader autism phenotype (BAP) in the mother was accounted for, but still remained for the highest tertile. This association does not appear to be totally explained by maternal BAP. We were unable to distinguish whether the difference in duration was due to difficulties breastfeeding children who later develop ASD, other factors not adjusted in our study, or greater ASD risk resulting from shorter breastfeeding duration. Longitudinal studies that compare reasons why mothers stop breastfeeding between ASD and controls and establish a temporal relation between ASD and breastfeeding are needed. Future studies should also evaluate interactions between ASD risk genes and breastfeeding. Autism Research 2019, 12: 816-829. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, we compared breastfeeding practices between mothers of children with and without autism spectrum disorder (ASD). We found that the percentage of mothers who started breastfeeding was similar between the two groups, but mothers of children with ASD breastfed for a shorter amount of time compared to mothers of children without ASD. Future studies are needed to evaluate the reasons why the duration of breastfeeding was shorter for mothers of children with ASD compared to those without ASD., (© 2019 International Society for Autism Research, Wiley Periodicals, Inc.)

The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD.

This study explored whether ASD phenotypes in the child were associated with a history of anxiety or depression in the mother. We hypothesized that an ASD profile in children characterized by mild delays and increased rates of dysregulation would be associated with preexisting maternal anxiety or depression. Participants were 672 preschool children with ASD and their mothers. Children were classified as ASD after a comprehensive developmental evaluation. Mothers reported whether a healthcare provider ever diagnosed them with anxiety or depression before the birth of their child. Four child ASD phenotypes were derived from latent class analysis: Mild Language Delay with Cognitive Rigidity (Type 1), Significant Developmental Delay with Repetitive Motor Behaviors (Type 2), General Developmental Delay (Type 3), and Mild Language and Motor Delay with Dysregulation (i.e., aggression, anxiety, depression, emotional reactivity, inattention, somatic complaints, and sleep problems) (Type 4). Type 2 ASD served as the referent category in statistical analyses. Results showed that 22.6% of mothers reported a diagnosis of anxiety or depression before the birth of their child. Maternal anxiety or depression was associated with 2.7 times the odds (95% confidence interval: 1.4, 5.3) of Type 4 or Dysregulated ASD in the child; maternal anxiety and depression was associated with 4.4 times the odds (95% confidence interval: 1.4, 14.0) of Type 4 or Dysregulated ASD in the child. Our findings suggest an association between Dysregulated ASD in the child and anxiety and depression in the mother. These findings can enhance screening methods and inform future research efforts.

: media-1vid110.1542/5984243260001PEDS-VA&#95;2018-0492 Video Abstract BACKGROUND: Sleep problems can impact daytime behavior, quality of life, and overall health. We compared sleep habits in young children with autism spectrum disorder (ASD) and other developmental delays and disorders and in children from the general population (POP)., Methods: We included 2- to 5-year-old children whose parent completed all items on the Children's Sleep Habits Questionnaire (CSHQ) in a multisite case-control study: 522 children with ASD; 228 children with other developmental delays and disorders with autism spectrum disorder characteristics (DD w/ASD); 534 children with other developmental delays and disorders without autism spectrum disorder characteristics (DD w/o ASD); and 703 POP. Multivariable analysis of variance compared CSHQ mean total score (TS) and subscale scores between groups. Logistic regression analysis examined group differences by using TS cutoffs of 41 and 48. Analyses were adjusted for covariates., Results: Mean CSHQ TS for children in each group: ASD (48.5); DD w/ASD (50.4); DD w/o ASD (44.4); and POP (43.3). Differences between children with ASD and both children with DD w/o ASD and POP were statistically significant. Using a TS cutoff of 48, the proportion of children with sleep problems was significantly higher in children in the ASD group versus DD w/o ASD and POP groups (adjusted odds ratios [95% confidence intervals]: 2.12 [1.57 to 2.87] and 2.37 [1.75 to 3.22], respectively)., Conclusions: Sleep problems are more than twice as common in young children with ASD and DD w/ASD. Screening for sleep problems is important in young children to facilitate provision of appropriate interventions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Reynolds has participated in clinical trials with Roche Pharmaceuticals and Ovid Therapeutics; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

The autism spectrum disorder phenotype varies by social and communication ability and co-occurring developmental, behavioral, and medical conditions. Etiology is also diverse, with myriad potential genetic origins and environmental risk factors. Examining the influence of parental broader autism phenotype-a set of sub-clinical characteristics of autism spectrum disorder-on child autism spectrum disorder phenotypes may help reduce heterogeneity in potential genetic predisposition for autism spectrum disorder. We assessed the associations between parental broader autism phenotype and child phenotype among children of age 30-68 months enrolled in the Study to Explore Early Development (N = 707). Child autism spectrum disorder phenotype was defined by a replication of latent classes derived from multiple developmental and behavioral measures: Mild Language Delay with Cognitive Rigidity, Mild Language and Motor Delay with Dysregulation (e.g. anxiety/depression), General Developmental Delay, and Significant Developmental Delay with Repetitive Motor Behaviors. Scores on the Social Responsiveness Scale-Adult measured parent broader autism phenotype. Broader autism phenotype in at least one parent was associated with a child having increased odds of being classified as mild language and motor delay with dysregulation compared to significant developmental delay with repetitive motor behaviors (odds ratio: 2.44; 95% confidence interval: 1.16, 5.09). Children of parents with broader autism phenotype were more likely to have a phenotype qualitatively similar to broader autism phenotype presentation; this may have implications for etiologic research.

Most prior studies examining maternal pre-pregnancy body mass index (BMI) in relation to offspring autism spectrum disorders (ASD) have reported an association, though findings are not uniform and few have also examined gestational weight gain (GWG). Therefore, we examined both in the Study to Explore Early Development, a multi-site case-control study of children born in 2003-2006. Children identified from clinics, schools, and birth certificates were enrolled at ages 2-5 year and using standardized developmental evaluations, classified as: ASD, other developmental delays (DD), or population-based controls. Maternal height, weight, and GWG were self-reported during the telephone interview. Three primary weight risk factors were examined: (a) Pre-pregnancy BMI, classified as underweight to obese, (b) GWG continuous and categorized as quintiles, and (c) Institute of Medicine clinical weight-gain recommendations. Odds ratios adjusted (AOR) for sociodemographic and prenatal factors were calculated among term singletons, comparing the ASD (n = 540) or DD (n = 720) groups to the control group (n = 776). The AOR of ASD and maternal obesity was 1.37 (95%CI 0.98-1.92). Associations with higher GWG were stronger (Quintile5 vs. Quintile3 AOR = 1.58, 95%CI 1.08-2.31), and particularly so among overweight/obese women (AOR = 1.90, 95%CI 0.98-3.68). DD was associated with maternal overweight and obesity (obesity AOR = 1.48, 95%CI 1.08-2.02), but not with total GWG or clinical recommendations. High maternal BMI and GWG are risk factors for other pregnancy and child outcomes, and our results suggest they may also represent modifiable risk factors for neurodevelopmental outcomes. Autism Res 2019, 12: 316-327 © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In a large, national study, we found that children with autism were more likely than unaffected children to have mothers with higher weight gain during pregnancy; risk of autism may be even stronger if mothers were also overweight before pregnancy. Children with other developmental delays were more likely to have mothers who were overweight or obese before pregnancy, but not who gained more weight during pregnancy. Overweight and weight gain may represent factors that could be modified., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Objective: To assess contributing factors to increased obesity risk, by comparing children with autism spectrum disorder (ASD), developmental delays/disorders, and general population controls in weight status, and to examine associations between weight status and presence of co-occurring medical, behavioral, developmental, or psychiatric conditions across groups and ASD severity among children with ASD., Study Design: The Study to Explore Early Development is a multisite cross-sectional study of children, 2-5 years of age, classified as children with ASD (n = 668), children with developmental delays/disorders (n = 914), or general population controls (n = 884). Using an observational cohort design, we compared the 3 groups. Children's heights and weights were measured during a clinical visit. Co-occurring conditions (medical, behavioral, developmental/psychiatric) were derived from medical records, interviews, and questionnaires. ASD severity was measured by the Ohio State University Global Severity Scale for Autism., Results: The odds of overweight/obesity were 1.57 times (95% CI 1.24-2.00) higher in children with ASD than general population controls and 1.38 times (95% CI 1.10-1.72) higher in children with developmental delays/disorders than general population controls. The aORs were elevated for children with ASD after controlling for child co-occurring conditions (ASD vs general population controls: aOR = 1.51; 95% CI 1.14-2.00). Among children with ASD, those with severe ASD symptoms were 1.7 times (95% CI 1.1-2.8) more likely to be classified as overweight/obese compared with children with mild ASD symptoms., Conclusions: Prevention of excess weight gain in children with ASD, especially those with severe symptoms, and in children with developmental delays/disorders represents an important target for intervention., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Research 2019, 12: 123-135. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Immune system abnormalities have been widely reported among children with autism spectrum disorder (ASD), which may increase the risk of childhood infections. The Study to Explore Early Development (SEED) is a multisite case-control study of children aged 30-69 months, born in 2003-2006. Cases are children previously diagnosed and newly identified with ASD enrolled from education and clinical settings. Children with a previously diagnosed non-ASD developmental condition were included in the developmental delay/disorder (DD) control group. The population (POP) control group included children randomly sampled from birth certificates. Clinical illness from infection during the first 28 days ("neonatal," from medical records) and first three years of life (caregiver report) in cases was compared to DD and POP controls; and between cases with and without regression. Children with ASD had greater odds of neonatal (OR = 1.8; 95%CI: 1.1, 2.9) and early childhood infection (OR = 1.7; 95%CI: 1.5, 1.9) compared to POP children, and greater odds of neonatal infection (OR = 1.5; 95%CI: 1.1, 2.0) compared to DD children. Cases with regression had 1.6 times the odds (95%CI: 1.1, 2.3) of caregiver-reported infection during the first year of life compared to cases without regression, but neonatal infection risk and overall early childhood infection risk did not differ. Our results support the hypothesis that children with ASD are more likely to have infection early in life compared to the general population and to children with other developmental conditions. Future studies should examine the contributions of different causes, timing, frequency, and severity of infection to ASD risk. Autism Research 2019, 12: 136-146. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at infections during early childhood in relation to autism spectrum disorder (ASD). We found that children with ASD were more likely to have an infection in the first 28 days of life and before age three compared to children with typical development. Children with ASD were also more likely than children with other developmental delays or disorders to have an infection in the first 28 days of life., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

: media-1vid110.1542/5839990273001PEDS-VA&#95;2017-4161 Video Abstract OBJECTIVES: To estimate the national prevalence of parent-reported autism spectrum disorder (ASD) diagnosis among US children aged 3 to 17 years as well as their treatment and health care experiences using the 2016 National Survey of Children's Health (NSCH)., Methods: The 2016 NSCH is a nationally representative survey of 50 212 children focused on the health and well-being of children aged 0 to 17 years. The NSCH collected parent-reported information on whether children ever received an ASD diagnosis by a care provider, current ASD status, health care use, access and challenges, and methods of treatment. We calculated weighted prevalence estimates of ASD, compared health care experiences of children with ASD to other children, and examined factors associated with increased likelihood of medication and behavioral treatment., Results: Parents of an estimated 1.5 million US children aged 3 to 17 years (2.50%) reported that their child had ever received an ASD diagnosis and currently had the condition. Children with parent-reported ASD diagnosis were more likely to have greater health care needs and difficulties accessing health care than children with other emotional or behavioral disorders (attention-deficit/hyperactivity disorder, anxiety, behavioral or conduct problems, depression, developmental delay, Down syndrome, intellectual disability, learning disability, Tourette syndrome) and children without these conditions. Of children with current ASD, 27% were taking medication for ASD-related symptoms, whereas 64% received behavioral treatments in the last 12 months, with variations by sociodemographic characteristics and co-occurring conditions., Conclusions: The estimated prevalence of US children with a parent-reported ASD diagnosis is now 1 in 40, with rates of ASD-specific treatment usage varying by children's sociodemographic and co-occurring conditions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Objective: Mothers of advanced maternal age (AMA) at childbirth (age ≥35 years) may have different perceptions of autism spectrum disorder (ASD) risk, independent of sociodemographic factors, that may affect ASD identification. We aimed to estimate associations between AMA and both age of a child's first evaluation noting developmental concerns and time from first evaluation to first ASD diagnosis., Methods: We used data for 8-year-olds identified with ASD in the 2008 to 2012 Autism and Developmental Disabilities Monitoring Network. We estimated differences in age at first evaluation noting developmental concerns and time to first ASD diagnosis by AMA using quantile and Cox regression., Results: Of 10,358 children with ASD, 19.7% had mothers of AMA. AMA was associated with higher educational attainment and previous live births compared with younger mothers. In unadjusted analyses, AMA was associated with earlier first evaluation noting developmental concerns (median 37 vs 40 mo) and patterns in time to first evaluation (hazard ratio: 1.12, 95% confidence interval: 1.06-1.18). Associations between AMA and evaluation timing diminished and were no longer significant after adjustment for socioeconomic and demographic characteristics. Children's intellectual disability did not modify associations between AMA and timing of evaluations., Conclusion: Advanced maternal age is a sociodemographic factor associated with younger age of first evaluation noting developmental concerns in children with ASD, but AMA was not independently associated likely, because it is a consequence or cofactor of maternal education and other sociodemographic characteristics. AMA may be a demographic factor to consider when aiming to screen and evaluate children at risk for ASD.

We compared the prevalence of various medical and behavioral co-occurring conditions/symptoms between 4- and 8-year-olds with autism spectrum disorder (ASD) from five sites in the Autism and Developmental Disabilities Monitoring Network during the 2010 survey year, accounting for sociodemographic differences. Over 95% of children had at least one co-occurring condition/symptom. Overall, the prevalence was higher in 8- than 4-year-olds for 67% of co-occurring conditions/symptoms examined. Further, our data suggested that co-occurring conditions/symptoms increased or decreased the age at which children were first evaluated for ASD. Similarly, among the 8-year-olds, the prevalence of most co-occurring conditions/symptoms was higher in children with a previous ASD diagnosis documented in their records. These findings are informative for understanding and screening co-occurring conditions/symptoms in ASD.

The ratio of the index (2nd) finger to ring (4th) finger lengths (2D:4D) is a proxy for fetal testosterone and estradiol. Studies suggesting 2D:4D is inversely associated with autism spectrum disorder (ASD) in males were limited by lack of confounder and subgroup assessments. Studies of females are sparse. We examined associations between ASD and 2D:4D among children in the Study to Explore Early Development; we considered case subgroups and numerous potential demographic and maternal-perinatal health confounders. We observed a modest inverse association between ASD and right-hand 2D:4D in males; subgroup analyses indicated associations were limited to ASD cases with birth defects/genetic syndromes or dysmorphic features. We observed a positive association between ASD and left-hand 2D:4D in females, overall and within most case subgroups.

Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies., Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample., Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p  < 1.12 × 10 - 7 . Seven CpGs showed differences at p  < 1 × 10 - 5 and 48 at 1 × 10 - 4 . Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance ( r  = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds., Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD., Competing Interests: This study was approved by the institutional review boards at each SEED site: SEED 1 recruitment was approved by the IRBs of each recruitment site: Institutional Review Board (IRB)-C, CDC Human Research Protection Office; Kaiser Foundation Research Institute (KFRI) Kaiser Permanente Northern California IRB, Colorado Multiple IRB, Emory University IRB, Georgia Department of Public Health IRB, Maryland Department of Health and Mental Hygiene IRB, Johns Hopkins Bloomberg School of Public Health Review Board, University of North Carolina IRB and Office of Human Research Ethics, IRB of The Children’s Hospital of Philadelphia, and IRB of the University of Pennsylvania. All enrolled families provided written consent for participation. This methylation substudy was approved as an amendment of the Johns Hopkins Institutional Review Board (IRB) approval. For participants from the Simons simplex collection, parents consented and children assented as required by each local institutional review board, which included a coalition of clinics located at Michigan, Yale, Emory, Columbia, Vanderbilt, McGill Washington, and Harvard Universities (Children’s Hospital of Boston), and at the Universities of Washington, Illinois (Chicago), Missouri, UCLA, and the Baylor College of Medicine. To protect the privacy of participants, Global Unique Identifiers (GUIDs) were constructed from personal information using an algorithm devised in collaboration with scientists at the NIH [66]. Each clinic retained personal identifiers on site and transmitted de-identified GUIDs to a central database, as described previously [37].Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This study examined the effect of demographic factors on Social Communication Questionnaire (SCQ) scores in children aged 30-68 months. Diagnoses of ASD were made after a gold standard evaluation that included the Autism Diagnostic Observation Schedule (ADOS), and the Autism Diagnostic Interview Revised (ADI-R). The relationship of demographic variables to SCQ scores was compared in two source populations: (a) children recruited from clinical and educational sources serving children who have ASD or other developmental disorders (CE) and (b) children recruited from birth certificates to represent the general population (BC). The impact of the demographic variables-child sex, child age, maternal language, maternal ethnicity, maternal education, maternal race, and household income-on total SCQ score were studied to examine their impact on the SCQ's performance. Demographic factors predicting the SCQ total score were used to generate ROCs. Factors that had a significant influence on SCQ performance were identified by examining the area under the ROCs. Optimal SCQ cut-points were generated for significant factors using the Youden's Index. Overall male sex, lower household income, lower maternal education and Black race predicted higher SCQ scores. In this sample, the most common optimum value for the SCQ cut-point across the different sociodemographic groups was 11. Autism Res 2018, 11: 695-706. © 2018 International Society for Autism Research, Wiley Periodicals, Inc., Lay Summary: Screeners are used to help identify children who are more likely to have ASD than their peers. Ideally screeners should be accurate for different groups of children and families. This study examined how well the Social Communication Questionnaire (SCQ) predicts ASD. We found that male sex, lower household income, lower maternal education and Black race were associated with higher SCQ scores. In this study an SCQ cut-point of 11 worked best across the different sociodemographic groups in our sample., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

Autism spectrum disorder (ASD) is a prevalent developmental disorder. Studies indicate that while ASD etiology has a genetic component, the risk is polygenic, with gene-environment interactions being likely. The prenatal period is a critical exposure window for nongenetic risk factors. Previous studies have found positive associations between congenital malformations (all types) and ASD; a few also found specific associations between genitourinary system malformations and ASD; and one study found an association between hypospadias and ASD. In the accompanying article, Rotem et al. (Am J Epidemiol. 2018;187(4):656-663) describe how they conducted a comprehensive analysis focusing on the shared risk of ASD with hypospadias or cryptorchidism, using existing data from a large Israeli health services system, which afforded several advantages because of the large sample size and low attrition of the patient population. The authors conducted a careful analysis, including sensitivity analyses, to account for risk factor and case misclassifications that might have occurred had they relied solely on preexisting diagnostic codes to define exposures and outcome. They observed positive associations between both hypospadias and cryptorchidism and ASD that were independent of numerous sociodemographic and pregnancy health factors. This study advances our understanding of ASD etiology and illustrates how existing data might be used to assess some ASD risk factors.

This study examined caregiver-reported medically-attended injuries among 30-68 month old children with autism spectrum disorder (ASD) compared to general population (POP) and non-ASD developmental disorders (DD) controls in the Study to Explore Early Development. Injuries were common in ASD cases (32.3%) as well as POP (30.2%) and DD (27.8%) controls; most resulted in an emergency visit or hospitalization. After accounting for sociodemographic, health, IQ and behavior differences, odds of injury in ASD cases were significantly higher than DD controls but similar to POP controls. Attention problems mediated the relationships. Clinicians caring for children with both ASD and attention problems should consider providing targeted safety advice. Differences in injury risk between children with ASD vs. other developmental disorders need further study.

Objective: Although data on publicly available special education are informative and offer a glimpse of trends in autism spectrum disorder (ASD) and use of educational services, using these data for population-based public health monitoring has drawbacks. Our objective was to evaluate trends in special education eligibility among 8-year-old children with ASD identified in the Autism and Developmental Disabilities Monitoring Network., Methods: We used data from 5 Autism and Developmental Disabilities Monitoring Network sites (Arizona, Colorado, Georgia, Maryland, and North Carolina) during 4 surveillance years (2002, 2006, 2008, and 2010) and compared trends in 12 categories of special education eligibility by sex and race/ethnicity. We used multivariable linear risk regressions to evaluate how the proportion of children with a given eligibility changed over time., Results: Of 6010 children with ASD, more than 36% did not receive an autism eligibility in special education in each surveillance year. From surveillance year 2002 to surveillance year 2010, autism eligibility increased by 3.6 percentage points ( P = .09), and intellectual disability eligibility decreased by 4.6 percentage points ( P < .001). A greater proportion of boys than girls had an autism eligibility in 2002 (56.3% vs 48.8%). Compared with other racial/ethnic groups, Hispanic children had the largest increase in proportion with autism eligibility from 2002 to 2010 (15.4%, P = .005) and the largest decrease in proportion with intellectual disability (-14.3%, P = .004)., Conclusion: Although most children with ASD had autism eligibility, many received special education services under other categories, and racial/ethnic disparities persisted. To monitor trends in ASD prevalence, public health officials need access to comprehensive data collected systematically, not just special education eligibility.

Previous studies of autism spectrum disorder (ASD) and birth spacing had limitations; few examined phenotypic case subtypes or explored underlying mechanisms for associations and none assessed whether other (non-ASD) developmental disabilities (DDs) were associated with birth spacing. We assessed associations between inter-pregnancy interval (IPI) and both ASD and other DDs using data from the Study to Explore Early Development, a multi-site case-control study with rigorous case-finding and case-classification methods and detailed data collection on maternal reproductive history. Our sample included 356 ASD cases, 627 DD cases, and 524 population (POP) controls born in second or later births. ASD and DD cases were further sub-divided according to whether the child had intellectual disability (ID). ASD cases were also sub-divided by ASD symptom severity, and DD cases were subdivided by presence of some ASD symptoms (indicated on an autism screener). Odds ratios, adjusted for maternal-child sociodemographic factors, (aORs) and 95% confidence intervals were derived from logistic regression models. Among term births, ASD was associated with both IPI <18 months (aOR 1.5 [1.1-2.2]) and ≥60 months (1.5 [0.99-2.4]). Both short and long IPI associations were stronger among ASD cases with high severity scores (aORs 2.0 [1.3-3.3] and 1.8 [0.99-3.2], respectively). Associations were unchanged after adding several factors potentially related to the causal pathway to regression models. DD was not associated with either short or long IPI-overall, among term births, or in any subgroup examined. These findings extend those from previous studies and further inform recommendations on optimal pregnancy spacing. Autism Res 2018, 11: 81-94. © 2017 International Society for Autism Research, Wiley Periodicals, Inc., Lay Summary: We investigated whether the amount of time between pregnancies was associated autism spectrum disorder (ASD) or other developmental disabilities (DD) in children. ASD was increased in second and later-born children who were conceived less than 18 months or 60 or more months after the mother's previous birth. Other DDs were not associated with birth spacing., (© 2017 International Society for Autism Research, Wiley Periodicals, Inc.)

Previous studies of associations between ASD and conception using assisted reproductive technology (ART) are inconsistent and few studies have examined associations with other infertility treatments or infertility disorders. We examined associations between ASD and maternal/paternal infertility disorders and numerous maternal treatments among 1538 mother-child pairs in the Study to Explore Early Development, a population-based case-control study. ASD was associated with any female infertility diagnosis and several specific diagnoses: blocked tubes, endometriosis, uterine-factor infertility, and polycystic ovarian syndrome. Stratified analyses suggested associations were limited to/much stronger among second or later births. The findings were not explained by sociodemographic factors such as maternal age or education or multiple or preterm birth. ASD was not associated with ART or non-ART infertility treatments.

Background: Prenatal alcohol exposure can affect neurodevelopment, but few studies have examined associations with autism spectrum disorder (ASD)., Methods: We assessed the association between maternal alcohol use and ASD in the Study to Explore Early Development, a multi-site case-control study of children born between September 2003 and August 2006 in the US Regression analyses included 684 children with research clinician-confirmed ASD, 869 children with non-ASD developmental delays or disorders (DDs), and 962 controls ascertained from the general population (POP). Maternal alcohol exposure during each month from 3 months prior to conception until delivery was assessed by self-report., Results: Mothers of POP children were more likely to report any prenatal alcohol use than mothers of children with ASD or DD. In trimester one, 21.2% of mothers of POP children reported alcohol use compared with 18.1% and 18.2% of mothers of children with ASD or DD, respectively (adjusted OR for ASD vs. POP 0.8, 95% confidence interval 0.6, 1.1). During preconception and the first month of pregnancy, one to two drinks on average per week was inversely associated with ASD risk., Conclusions: These results do not support an adverse association between low-level alcohol exposure and ASD, although these findings were based on retrospective self-reported alcohol use. Unmeasured confounding or exposure misclassification may explain inverse associations with one to two drinks per week. Pregnant or potentially pregnant women should continue to follow recommendations to avoid alcohol use because of other known effects on infant health and neurodevelopment., (© 2017 John Wiley & Sons Ltd.)

Objectives: To describe the association between indicators of socioeconomic status (SES) and the prevalence of autism spectrum disorder (ASD) in the United States during the period 2002 to 2010, when overall ASD prevalence among children more than doubled, and to determine whether SES disparities account for ongoing racial and ethnic disparities in ASD prevalence., Methods: We computed ASD prevalence and 95% confidence intervals (CIs) from population-based surveillance, census, and survey data. We defined SES categories by using area-level education, income, and poverty indicators. We ascertained ASD in 13 396 of 1 308 641 8-year-old children under surveillance., Results: The prevalence of ASD increased with increasing SES during each surveillance year among White, Black, and Hispanic children. The prevalence difference between high- and low-SES groups was relatively constant over time (3.9/1000 [95% CI = 3.3, 4.5] in 2002 and 4.1/1000 [95% CI = 3.6, 4.6] in the period 2006-2010). Significant racial/ethnic differences in ASD prevalence remained after stratification by SES., Conclusions: A positive SES gradient in ASD prevalence according to US surveillance data prevailed between 2002 and 2010, and racial and ethnic disparities in prevalence persisted during this time among low-SES children.

Autism spectrum disorder (ASD) diagnosis relies on parent-reported and clinician-observed instruments. Sometimes, results between these instruments disagree. The broader autism phenotype (BAP) in parent-reporters may be associated with discordance. Study to Explore Early Development data (N = 712) were used to address whether mothers with BAP and children with ASD or non-ASD developmental disabilities were more likely than mothers without BAP to 'over-' or 'under-report' child ASD on ASD screeners or interviews compared with clinician observation or overall impression. Maternal BAP was associated with a child meeting thresholds on a maternal-reported screener or maternal interview when clinician ASD instruments or impressions did not (risk ratios: 1.30 to 2.85). Evidence suggests acknowledging and accounting for reporting discordances may be important when diagnosing ASD.

We compared early-diagnosed autism spectrum disorder (ASD) (defined as diagnosis by age 4 years) between the 2002 and 2006 birth cohorts, in five sites of the Autism and Developmental Disabilities Monitoring Network. In the 2002 cohort, the prevalence/1000 of early-diagnosed ASD was half the 8-year-old prevalence (7.2 vs. 14.7, prevalence ratio [PR] 0.5 [0.4-0.6]). Overall, the prevalence of early-diagnosed ASD did not differ between birth cohorts (PR 1.1 [0.9-1.3]). However, in three sites with complete case ascertainment, the prevalence of early-diagnosed ASD was higher for those born in 2006 versus 2002 (PR 1.3 [1.1-1.5]), suggesting possible improvement in early identification. The lack of change in two sites may reflect less complete case ascertainment. Studies in more recent cohorts are needed.

The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts population-based surveillance of autism spectrum disorder (ASD) among 8-year old children in multiple US sites. To classify ASD, trained clinicians review developmental evaluations collected from multiple health and education sources to determine whether the child meets the ASD surveillance case criteria. The number of evaluations collected has dramatically increased since the year 2000, challenging the resources and timeliness of the surveillance system. We developed and evaluated a machine learning approach to classify case status in ADDM using words and phrases contained in children's developmental evaluations. We trained a random forest classifier using data from the 2008 Georgia ADDM site which included 1,162 children with 5,396 evaluations (601 children met ADDM ASD criteria using standard ADDM methods). The classifier used the words and phrases from the evaluations to predict ASD case status. We evaluated its performance on the 2010 Georgia ADDM surveillance data (1,450 children with 9,811 evaluations; 754 children met ADDM ASD criteria). We also estimated ASD prevalence using predictions from the classification algorithm. Overall, the machine learning approach predicted ASD case statuses that were 86.5% concordant with the clinician-determined case statuses (84.0% sensitivity, 89.4% predictive value positive). The area under the resulting receiver-operating characteristic curve was 0.932. Algorithm-derived ASD "prevalence" was 1.46% compared to the published (clinician-determined) estimate of 1.55%. Using only the text contained in developmental evaluations, a machine learning algorithm was able to discriminate between children that do and do not meet ASD surveillance criteria at one surveillance site., Competing Interests: The authors have declared that no competing interests exist.

Background: The Study to Explore Early Development (SEED) is designed to enhance knowledge of autism spectrum disorder characteristics and etiologies., Objective: This paper describes the demographic profile of enrolled families and examines sociodemographic differences between children with autism spectrum disorder and children with other developmental problems or who are typically developing., Methods: This multi-site case-control study used health, education, and birth certificate records to identify and enroll children aged 2-5 years into one of three groups: 1) cases (children with autism spectrum disorder), 2) developmental delay or disorder controls, or 3) general population controls. Study group classification was based on sampling source, prior diagnoses, and study screening tests and developmental evaluations. The child's primary caregiver provided demographic characteristics through a telephone (or occasionally face-to-face) interview. Groups were compared using ANOVA, chi-squared test, or multinomial logistic regression as appropriate., Results: Of 2768 study children, sizeable proportions were born to mothers of non-White race (31.7%), Hispanic ethnicity (11.4%), and foreign birth (17.6%); 33.0% of households had incomes below the US median. The autism spectrum disorder and population control groups differed significantly on nearly all sociodemographic parameters. In contrast, the autism spectrum disorder and developmental delay or disorder groups had generally similar sociodemographic characteristics., Conclusions: SEED enrolled a sociodemographically diverse sample, which will allow further, in-depth exploration of sociodemographic differences between study groups and provide novel opportunities to explore sociodemographic influences on etiologic risk factor associations with autism spectrum disorder and phenotypic subtypes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To characterize wandering, or elopement, among children with autism spectrum disorder (ASD) and intellectual disability., Study Design: Questions on wandering in the previous year were asked of parents of children with ASD with and without intellectual disability and children with intellectual disability without ASD as part of the 2011 Survey of Pathways to Diagnosis and Services. The Pathways study sample was drawn from the much larger National Survey of Children with Special Health Care Needs conducted in 2009-2010., Results: For children with special healthcare needs diagnosed with either ASD, intellectual disability, or both, wandering or becoming lost during the previous year was reported for more than 1 in 4 children. Wandering was highest among children with ASD with intellectual disability (37.7%) followed by children with ASD without intellectual disability (32.7%), and then children with intellectual disability without ASD (23.7%), though the differences between these groups were not statistically significant., Conclusions: This study affirms that wandering among children with ASD, regardless of intellectual disability status, is relatively common. However, wandering or becoming lost in the past year was also reported for many children with intellectual disability, indicating the need to broaden our understanding of this safety issue to other developmental disabilities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

While studies report associations between perinatal outcomes and both autism spectrum disorder (ASD) and intellectual disability (ID), there has been little study of ASD with versus without co-occurring ID. We compared perinatal risk factors among 7547 children in the 2006-2010 Autism and Developmental Disability Monitoring Network classified as having ASD + ID, ASD only, and ID only. Children in all three groups had higher rates of preterm birth (PTB), low birth weight, small-for-gestational-age, and low Apgar score than expected based on the US birth cohort adjusted for key socio-demographic factors. Associations with most factors, especially PTB, were stronger for children with ID only than children with ASD + ID or ASD only. Associations were similar for children with ASD + ID and ASD only.

We examined prevalence of diagnosed autism spectrum disorder (ASD) and age at diagnosis according to child's race/ethnicity and primary household language. From the 2009-2010 National Survey of Children with Special Health Care Needs, we identified 2729 3-17-year-old US children whose parent reported a current ASD diagnosis. We compared ASD prevalence, mean diagnosis age, and percentage with later diagnoses (≥5 years) across racial/ethnic/primary household language groups: non-Hispanic-white, any language (NHW); non-Hispanic-black, any language (NHB); Hispanic-any-race, English (Hispanic-English); and Hispanic-any-race, other language (Hispanic-Other). We assessed findings by parent-reported ASD severity level and adjusted for family sociodemographics. ASD prevalence estimates were 15.3 (NHW), 10.4 (NHB), 14.1 (Hispanic-English), and 5.2 (Hispanic-Other) per 1000 children. Mean diagnosis age was comparable across racial/ethnic/language groups for 3-4-year-olds. For 5-17-year-olds, diagnosis age varied by race/ethnicity/language and also by ASD severity. In this group, NHW children with mild/moderate ASD had a significantly higher proportion (50.8 %) of later diagnoses than NHB (33.5 %) or Hispanic-Other children (18.0 %). However, NHW children with severe ASD had a comparable or lower (albeit non-significant) proportion (16.4 %) of later diagnoses than NHB (37.8 %), Hispanic-English (30.8 %), and Hispanic-Other children (12.0 %). While NHW children have comparable ASD prevalence and diagnosis age distributions as Hispanic-English children, they have both higher prevalence and proportion of later diagnoses than NHB and Hispanic-Other children. The diagnosis age findings were limited to mild/moderate cases only. Thus, the prevalence disparity might be primarily driven by under-representation (potentially under-identification) of older children with mild/moderate ASD in the two minority groups.