Publications by authors named "Lisa A Croen"

149 Publications

COVID-19 prevalence, symptoms, and sociodemographic disparities in infection among insured pregnant women in Northern California.

PLoS One 2021 3;16(9):e0256891. Epub 2021 Sep 3.

Division of Research Kaiser Permanente Northern California, Oakland, CA, United States of America.

Background: Research on COVID-19 during pregnancy has mainly focused on women hospitalized for COVID-19 or other reasons during their pregnancy. Little is known about COVID-19 in the general population of pregnant women.

Objective: To describe the prevalence of COVID-19, symptoms, consequent healthcare use, and possible sources of COVID-19 exposure among a population-based sample of pregnant women residing in Northern California.

Methods: We analyzed data from 19,458 members of Kaiser Permanente Northern California who were pregnant between January 2020 and April 2021 and responded to an online survey about COVID-19 testing, diagnosis, symptoms, and their experiences during the COVID-19 pandemic. Medical diagnosis of COVID-19 during pregnancy was defined separately by self-report and by documentation in electronic health records (EHR). We examined relationships of COVID-19 with sociodemographic factors, underlying comorbidities, and survey measures of COVID-19-like symptoms, consequent healthcare utilization, and possible COVID-19 exposures.

Results: Among 19,458 respondents, the crude prevalence of COVID-19 was 2.5% (n = 494) according to self-report and 1.4% (n = 276) according to EHR. After adjustment, the prevalence of self-reported COVID-19 was higher among women aged <25 years compared with women aged ≥35 years (prevalence ratio [PR], 1.75, 95% CI: 1.23, 2.49) and among Hispanic women compared with White women (PR, 1.91, 95% CI: 1.53, 2.37). Prevalence of self-reported COVID-19 was higher among women affected by personal or partner job loss during the pandemic (PR, 1.23, 95% CI: 1.02, 1.47) and among women living in areas of high vs. low neighborhood deprivation (PR, 1.74, 95% CI: 1.33, 2.27). We did not observe differences in self-reported COVID-19 between women with and without underlying comorbidities. Results were similar for EHR-documented COVID-19. Loss of smell or taste was a unique and common symptom reported among women with COVID-19 (42.3% in self-reported; 54.0% in EHR-documented). Among women with symptomatic COVID-19, approximately 2% were hospitalized, 71% had a telehealth visit, and 75% quarantined at home. Over a third of women with COVID-19 reported no known exposure to someone with COVID-19.

Conclusions: Observed COVID-19 prevalence differences by sociodemographic and socioeconomic factors underscore social and health inequities among reproductive-aged women. Women with COVID-19 reported unique symptoms and low frequency of hospitalization. Many were not aware of an exposure to someone with COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256891PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415576PMC
September 2021

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

Obesity (Silver Spring) 2021 09 4;29(9):1554-1564. Epub 2021 Aug 4.

Environmental Health Investigation Branch, California Department of Public Health, Richmond, California, USA.

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.
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http://dx.doi.org/10.1002/oby.23228DOI Listing
September 2021

Maternal Psychiatric Conditions, Treatment With Selective Serotonin Reuptake Inhibitors, and Neurodevelopmental Disorders.

Biol Psychiatry 2021 08 14;90(4):253-262. Epub 2021 Apr 14.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

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.
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http://dx.doi.org/10.1016/j.biopsych.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504533PMC
August 2021

The Association of Prenatal Vitamins and Folic Acid Supplement Intake with Odds of Autism Spectrum Disorder in a High-Risk Sibling Cohort, the Early Autism Risk Longitudinal Investigation (EARLI).

J Autism Dev Disord 2021 Jun 10. Epub 2021 Jun 10.

Department of Public Health Sciences and The MIND Institute, School of Medicine, University of California-Davis, UC Davis School of Medicine - Medical Sciences 1C, Suite 123, Davis, CA, 95616, USA.

We examined maternal prenatal vitamin use or supplemental folic acid intake during month one of pregnancy for association with autism spectrum disorder (ASD) in the Early Autism Risk Longitudinal Investigation, an enriched-risk pregnancy cohort. Total folic acid intake was calculated from monthly prenatal vitamins, multivitamins, and other supplement reports. Clinical assessments through age 3 years classified children as ASD (n = 38) or non-ASD (n = 153). In pregnancy month one, prenatal vitamin use (59.7%) was not significantly associated with odds of ASD (OR = 0.70, 95%CI 0.32, 1.53). Sample size was limited and residual confounding was possible. Given the estimated effect sizes in this and previous work, prenatal vitamin intake during early pregnancy could be a clinically useful preventative measure for ASD.
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http://dx.doi.org/10.1007/s10803-021-05110-9DOI Listing
June 2021

Maternal blood metal concentrations and whole blood DNA methylation during pregnancy in the Early Autism Risk Longitudinal Investigation (EARLI).

Epigenetics 2021 Apr 2:1-16. Epub 2021 Apr 2.

Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins University, Baltimore, USA.

The maternal epigenome may be responsive to prenatal metals exposures. We tested whether metals are associated with concurrent differential maternal whole blood DNA methylation. In the Early Autism Risk Longitudinal Investigation cohort, we measured first or second trimester maternal blood metals concentrations (cadmium, lead, mercury, manganese, and selenium) using inductively coupled plasma mass spectrometry. DNA methylation in maternal whole blood was measured on the Illumina 450 K array. A subset sample of 97 women had both measures available for analysis, all of whom did not report smoking during pregnancy. Linear regression was used to test for site-specific associations between individual metals and DNA methylation, adjusting for cell type composition and confounding variables. Discovery gene ontology analysis was conducted on the top 1,000 sites associated with each metal. We observed hypermethylation at 11 DNA methylation sites associated with lead (FDR False Discovery Rate -value <0.1), near the genes , and . Lead-associated sites were enriched (FDR -value <0.1) for the pathways cell adhesion, nervous system development, and calcium ion binding. Manganese was associated with hypermethylation at four DNA methylation sites (FDR -value <0.1), one of which was near the gene . Manganese-associated sites were enriched for cellular metabolism pathways (FDR -value<0.1). Effect estimates for DNA methylation sites associated ( < 0.05) with cadmium, lead, and manganese were highly correlated (Pearson ρ > 0.86). DNA methylation sites associated with lead and manganese may be potential biomarkers of exposure or implicate downstream gene pathways.
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http://dx.doi.org/10.1080/15592294.2021.1897059DOI Listing
April 2021

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

Mol Autism 2021 03 18;12(1):24. Epub 2021 Mar 18.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

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.
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http://dx.doi.org/10.1186/s13229-021-00429-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977191PMC
March 2021

Gestational Exposure to Phthalates and Social Responsiveness Scores in Children Using Quantile Regression: The EARLI and HOME Studies.

Int J Environ Res Public Health 2021 01 30;18(3). Epub 2021 Jan 30.

Department of Epidemiology, Brown University, Providence, RI 02903, USA.

Linear regression is often used to estimate associations between chemical exposures and neurodevelopment at the mean of the outcome. However, the potential effect of chemicals may be greater among individuals at the 'tails' of outcome distributions. Here, we investigated distributional effects on the associations between gestational phthalate exposure and child Autism Spectrum Disorder (ASD)-related behaviors using quantile regression. We harmonized data from the Early Autism Risk Longitudinal Investigation (EARLI) ( = 140) Study, an enriched-risk cohort of mothers who had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study ( = 276), a general population cohort. We measured concentrations of 9 phthalate metabolites in urine samples collected twice during pregnancy. Caregivers reported children's ASD-related behaviors using the Social Responsiveness Scale (SRS) at age 3-8 years; higher scores indicate more ASD-related behaviors. In EARLI, associations between phthalate concentrations and SRS scores were predominately inverse or null across SRS score quantiles. In HOME, positive associations of mono-n-butyl phthalate, monobenzyl phthalate, mono-isobutyl phthalate, and di-2-ethylhexyl phthalate concentrations with SRS scores increased in strength from the median to 95th percentile of SRS scores. These results suggest associations between phthalate concentrations and SRS scores may be stronger in individuals with higher SRS scores.
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http://dx.doi.org/10.3390/ijerph18031254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908417PMC
January 2021

Association between self-reported caffeine intake during pregnancy and social responsiveness scores in childhood: The EARLI and HOME studies.

PLoS One 2021 15;16(1):e0245079. Epub 2021 Jan 15.

Department of Epidemiology, Brown University, Providence, Rhode Island, United States of America.

Maternal nutrition during gestation has been investigated for its role in child neurodevelopment. However, little is known about the potential impact of gestational caffeine exposure on child autistic behaviors. Here, we assess the relation between maternal caffeine intake during pregnancy and children's behavioral traits related to Autism Spectrum Disorder (ASD). We harmonized data from two pregnancy cohorts, Early Autism Risk Longitudinal Investigation (EARLI) (n = 120), an enriched-risk cohort of mothers who previously had a child with ASD, from Pennsylvania, Maryland, and Northern California (2009-2012), and the Health Outcomes and Measures of the Environment (HOME) Study (n = 269), a general population cohort from Cincinnati, Ohio (2003-2006). Mothers self-reported caffeine intake twice during pregnancy. Caregivers reported child behavioral traits related to ASD using the Social Responsiveness Scale (SRS) when children were aged 3-8 years. Higher scores indicate more ASD-related behaviors. We estimated covariate-adjusted differences in continuous SRS T-scores per interquartile range increase in caffeine intake. Self-reported caffeine intake during pregnancy was positively associated with SRS T-scores among children in EARLI (β: 2.0; 95% CI -0.1, 4.0), but to a lesser extent in HOME (β: 0.6; 95% CI -0.5, 1.6). In HOME, pre-pregnancy body mass index (BMI) modified the association between caffeine intake and SRS T-scores, where more positive associations were observed among women with higher BMIs. Our findings suggest gestational caffeine intake may represent a marker of vulnerability to childhood ASD-related behaviors. Additional studies are warranted to extend these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245079PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810310PMC
May 2021

Gastrointestinal Symptoms in 2- to 5-Year-Old Children in the Study to Explore Early Development.

J Autism Dev Disord 2021 Nov 4;51(11):3806-3817. Epub 2021 Jan 4.

The Children's Hospital of Philadelphia, 2716 South Street, Philadelphia, PA, 19146, USA.

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.
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http://dx.doi.org/10.1007/s10803-020-04786-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375271PMC
November 2021

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

J Neurodev Disord 2020 12 16;12(1):42. Epub 2020 Dec 16.

Division of Research, Kaiser Permanente of Northern California, Oakland, CA, USA.

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.
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http://dx.doi.org/10.1186/s11689-020-09343-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745402PMC
December 2020

Prenatal Multivitamin Use and Genotype Are Associated with Newborn Cord Blood DNA Methylation.

Int J Environ Res Public Health 2020 12 9;17(24). Epub 2020 Dec 9.

Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

Background: Fetal development involves cellular differentiation and epigenetic changes-complex processes that are sensitive to environmental factors. Maternal nutrient levels during pregnancy affect development, and methylene tetrahydrofolate reductase () is important for processing the nutrient folate.

Hypothesis: We hypothesize that supplement intake before pregnancy and maternal genotype are associated with DNA methylation in newborns.

Methods: In the pregnancy cohort, Early Autism Risk Longitudinal Investigation (EARLI), health history, and genotype information was obtained (n = 249 families). Cord blood DNA methylation (n = 130) was measured using the Illumina HumanMethylation450k array and global DNA methylation levels were computed over 455,698 sites. Supplement use preconception and during pregnancy were surveyed at visits during pregnancy. We evaluated associations between maternal preconception supplement intake and global DNA methylation or DNA methylation density distributions of newborn cord blood, stratified by the presence of a variant maternal C677T allele.

Results: Maternal preconceptional multivitamin intake was associated with cord blood methylation, dependent on maternal genotype (interaction term = 0.013). For mothers without the variant allele, multivitamin intake was associated with 0.96% (95% CI: 0.09, 1.83) higher global cord blood methylation ( = 0.04) and was also associated with the cumulative density distribution of methylation ( = 0.03). For mothers with at least one variant allele, multivitamin intake had a null -0.06% (95% CI: -0.45, 0.33) association with global cord blood DNA methylation, and was not associated with the cumulative density distribution ( = 0.37).

Conclusions: We observed that cord blood DNA methylation was associated with maternal supplement exposure preconception and maternal genotype. Genetic context should be considered when assessing DNA methylation effects of modifiable risk factors around the time of pregnancy.
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http://dx.doi.org/10.3390/ijerph17249190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764679PMC
December 2020

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort.

Mol Autism 2020 11 23;11(1):93. Epub 2020 Nov 23.

AJ Drexel Autism Institute, Drexel University, 3020 Market St, Suite 560, Philadelphia, PA, 19104, USA.

Background: Prenatal exposure to increased androgens has been suggested as a risk factor for autism spectrum disorder (ASD). This hypothesis has been examined by measurement of steroids in amniotic fluid, cord blood, saliva, and blood with mixed results.

Methods: To provide an orthogonal measure of fetal exposure, this study used meconium, the first stool of a newborn, to measure prenatal androgen exposure from infants in the Early Autism Risk Longitudinal Investigation (EARLI). EARLI is a familial-enriched risk cohort that enrolled pregnant mothers who already had a child with an ASD diagnosis. In the younger child, we investigated the association between meconium unconjugated (u) and total (t) concentrations of major androgens testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4), and ASD-related traits at 12 and 36 months of age. Traits were measured at 12 months with Autism Observation Scale for Infants (AOSI) and at 36 months with total score on the Social Responsiveness Scale (SRS). One hundred and seventy children had meconium and AOSI, 140 had meconium and SRS, and 137 had meconium and both AOSI and SRS.

Results: Separate robust linear regressions between each of the log-transformed androgens and log-transformed SRS scores revealed three-way interaction between sex of the child, sex of the proband, and testosterone concentration. In the adjusted analyses, t-T, u-A4, and u-DHEA (P ≤ 0.01) were positively associated with AOSI scores, while u-T (P = 0.004) and u-DHEA (P = 0.007) were positively associated with SRS total score among females with female probands (n = 10). Additionally, higher concentrations of u-T (P = 0.01) and t-T (P = 0.01) predicted higher SRS total score in males with male probands (n = 63). Limitations Since we explored three-way interactions, this resulted in a limited sample size for some analyses. This study was from an enriched-risk cohort which may limit generalizability, and this study used ASD-assessment scales as outcomes instead of diagnostic categories. Additionally, the novel use of meconium in this study limits the ability to compare the results in this cohort to others due to the paucity of research on meconium.

Conclusions: This study supports the utility of meconium for studies of endogenous fetal metabolism and suggests the sex of older siblings with autism should be considered as a biological variable in relevant studies.
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http://dx.doi.org/10.1186/s13229-020-00395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686740PMC
November 2020

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.

Autism Res 2020 12 2;13(12):2216-2229. Epub 2020 Nov 2.

Kaiser Permanente Division of Research, Oakland, California, USA.

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.
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http://dx.doi.org/10.1002/aur.2424DOI Listing
December 2020

Psychometric testing of a set of patient-reported instruments to assess healthcare interventions for autistic adults.

Autism 2021 04 25;25(3):786-799. Epub 2020 Oct 25.

Portland State University (PSU), USA.

Lay Abstract: Interventions to improve healthcare for autistic adults are greatly needed. To evaluate such interventions, researchers often use surveys to collect data from autistic adults (or sometimes, their supporters), but few survey measures have been tested for use with autistic adults. Our objective was to create and test a set of patient- or proxy-reported survey measures for use in studies that evaluate healthcare interventions. We used a community-based participatory research (CBPR) approach, in partnership with autistic adults, healthcare providers, and supporters. We worked together to create or adapt survey measures. Three survey measures focus on things that interventions may try to change directly: (1) how prepared patients are for visits; (2) how confident they feel in managing their health and healthcare; and (3) how well the healthcare system is making the accommodations patients feel they need. The other measures focus on the outcomes that interventions may hope to achieve: (4) improved patient-provider communication; (5) reduced barriers to care; and (6) reduced unmet healthcare needs. We then tested these measures in a survey of 244 autistic adults recruited from 12 primary care clinics in Oregon and California, USA (with 194 participating directly and 50 participating via a proxy reporter). Community partners made sure items were easy to understand and captured what was important about the underlying idea. We found the survey measures worked well in this sample. These measures may help researchers evaluate new healthcare interventions. Future research needs to assess whether interventions improve healthcare outcomes in autistic adults.
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http://dx.doi.org/10.1177/1362361320967178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068734PMC
April 2021

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

Environ Res 2021 05 22;196:110320. Epub 2020 Oct 22.

Department of Environmental Medicine and Public Health, And Pediatrics, Institute for Exposomics Research, Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Air pollution exposure is ubiquitous with demonstrated effects on morbidity and mortality. A growing literature suggests that prenatal air pollution exposure impacts neurodevelopment. We posit that the Environmental influences on Child Health Outcomes (ECHO) program will provide unique opportunities to fill critical knowledge gaps given the wide spatial and temporal variability of ECHO participants.

Objectives: We briefly describe current methods for air pollution exposure assessment, summarize existing studies of air pollution and neurodevelopment, and synthesize this information as a basis for recommendations, or a blueprint, for evaluating air pollution effects on neurodevelopmental outcomes in ECHO.

Methods: We review peer-reviewed literature on prenatal air pollution exposure and neurodevelopmental outcomes, including autism spectrum disorder, attention deficit hyperactivity disorder, intelligence, general cognition, mood, and imaging measures. ECHO meta-data were compiled and evaluated to assess frequency of neurodevelopmental assessments and prenatal and infancy residential address locations. Cohort recruitment locations and enrollment years were summarized to examine potential spatial and temporal variation present in ECHO.

Discussion: While the literature provides compelling evidence that prenatal air pollution affects neurodevelopment, limitations in spatial and temporal exposure variation exist for current published studies. As >90% of the ECHO cohorts have collected a prenatal or infancy address, application of advanced geographic information systems-based models for common air pollutant exposures may be ideal to address limitations of published research.

Conclusions: In ECHO we have the opportunity to pioneer unifying exposure assessment and evaluate effects across multiple periods of development and neurodevelopmental outcomes, setting the standard for evaluation of prenatal air pollution exposures with the goal of improving children's health.
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http://dx.doi.org/10.1016/j.envres.2020.110320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060371PMC
May 2021

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes.

Genome Med 2020 10 14;12(1):88. Epub 2020 Oct 14.

Department of Medical Microbiology and Immunology, Genome Center, and MIND Institute, University of California, Davis, CA, USA.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. The neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development and influence future health outcomes.

Methods: We performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth. Samples were split into discovery and replication sets and stratified by sex, and their DNA methylation profiles were tested for differentially methylated regions (DMRs) between ASD and typically developing control cord blood samples. DMRs were mapped to genes and assessed for enrichment in gene function, tissue expression, chromosome location, and overlap with prior ASD studies. DMR coordinates were tested for enrichment in chromatin states and transcription factor binding motifs. Results were compared between discovery and replication sets and between males and females.

Results: We identified DMRs stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development.

Conclusions: At birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD and provides novel insights for early diagnosis and therapy.
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http://dx.doi.org/10.1186/s13073-020-00785-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559201PMC
October 2020

Distributional Properties and Criterion Validity of a Shortened Version of the Social Responsiveness Scale: Results from the ECHO Program and Implications for Social Communication Research.

J Autism Dev Disord 2021 Jul;51(7):2241-2253

A.J. Drexel Autism Institute, Drexel University, 3020 Market St, Philadelphia, PA, 19104, USA.

Prior work proposed a shortened version of the Social Responsiveness Scale (SRS), a commonly used quantitative measure of social communication traits. We used data from 3031 participants (including 190 ASD cases) from the Environmental Influences on Child Health Outcomes (ECHO) Program to compare distributional properties and criterion validity of 16-item "short" to 65-item "full" SRS scores. Results demonstrated highly overlapping distributions of short and full scores. Both scores separated case from non-case individuals by approximately two standard deviations. ASD prediction was nearly identical for short and full scores (area under the curve values of 0.87, 0.86 respectively). Findings support comparability of shortened and full scores, suggesting opportunities to increase efficiency. Future work should confirm additional psychometric properties of short scores.
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http://dx.doi.org/10.1007/s10803-020-04667-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965796PMC
July 2021

Development and psychometric testing of the AASPIRE Adult Autism Healthcare Provider Self-Efficacy Scale.

Autism 2021 04 28;25(3):767-773. Epub 2020 Aug 28.

Academic Autism Spectrum Partnership in Research and Education, USA.

Lay Abstract: The adult healthcare system is ill-prepared to provide high-quality care to autistic adults. Lack of provider training may contribute to the problem, but there are few previously tested survey instruments to guide provider training efforts. Our objective was to develop and test a measure of healthcare providers' confidence (or "self-efficacy") in providing healthcare to autistic adults and to use it to better understand their training needs. We used a community-based participatory research (CBPR) approach, in partnership with academic researchers, autistic adults, supporters, and healthcare providers, throughout the project. We developed a one-page questionnaire and surveyed 143 primary care providers from eight primary care clinics in Oregon and California, United States. Preliminary testing of the AASPIRE Adult Autism Healthcare Provider Self-Efficacy Scale suggests that the measure is reliable and valid. Using this scale, we found only a minority of providers reported high confidence in communicating with patients (25%); performing physical exams or procedures (43%); accurately diagnosing and treating other medical issues (40%); helping patients stay calm and comfortable during visits (38%); identifying accommodation needs (14%); and making necessary accommodations (16%). While providers need training across all aspects of care related to autism in adulthood, interventions should pay particular attention to helping providers communicate with patients, and identify and make necessary accommodations. Future research is needed to further validate this scale and to understand how to meet providers' training needs most effectively.
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http://dx.doi.org/10.1177/1362361320949734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204689PMC
April 2021

Factors Influencing Participation in Biospecimen Research among Parents of Youth with Mental Health Conditions.

Public Health Genomics 2020 22;23(3-4):122-132. Epub 2020 Jul 22.

Kaiser Permanente Northern California, Division of Research, Oakland, California, USA.

Introduction: Biospecimens are tools that have the potential to improve early identification and treatment for autism spectrum disorders (ASD) and bipolar disorders (BPD). Unfortunately, most biobanks lack racial/ethnic diversity. One challenge to including a diverse sample of youth is recruiting and engaging families.

Objective: We sought to better understand facilitators and barriers to participation in biospecimen research among a diverse group of parents of youth with ASD and BPD.

Methods: The current study involved 3 Mental Health Research Network sites. At each site, parents participated in an interview that explored attitudes and beliefs about genetic research. Interviews were audio-recorded, and audio files were transcribed and coded using content analysis.

Results: A total of 58 interviews were conducted. Four challenges emerged: (1) contacting and engaging potential research participants, (2) motivating potential participants to read recruitment and consent materials, (3) motivating participation in research, in general, and (4) motivating participation in research involving biospecimen donation, specifically.

Conclusions: Participants were eager to participate as long as the research process involved trust, clarity, and flexibility. Future research involving youth with mental health conditions would benefit from implementing multimodal strategies for recruitment and data collection and sharing knowledge gained by the research with study participants.
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http://dx.doi.org/10.1159/000509120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592921PMC
February 2021

Healthcare service utilization and cost among transition-age youth with autism spectrum disorder and other special healthcare needs.

Autism 2021 04 25;25(3):705-718. Epub 2020 Jun 25.

Kaiser Permanente Division of Research, USA.

Lay Abstract: Youth with autism spectrum disorder often have complex medical needs. Disruptions of healthcare during the transition from pediatric to adult healthcare may put youth with autism spectrum disorder at higher risk of medical emergencies and high medical costs. To understand healthcare utilization during the transition years, we conducted a study among transition-age youth (14-25 years old) receiving healthcare at Kaiser Permanente Northern California during 2014-2015. We examined differences in healthcare utilization and costs among youth with autism spectrum disorder ( = 4123), attention deficit and hyperactivity disorder ( = 20,6015), diabetes mellitus ( = 2156), and general population controls ( = 20,615). Analyses were also stratified by age and sex. Youth with autism spectrum disorder had the highest utilization of outpatient primary care, mental health, and psychotropic medications and the lowest utilization of obstetrics/gynecology and urgent care. Costs for youth with autism spectrum disorder were higher than those for attention deficit and hyperactivity disorder and general population peers and lower than for diabetes mellitus. Healthcare utilization patterns varied by age. Transition-age youth with autism spectrum disorder generally used healthcare at higher rates relative to attention deficit and hyperactivity disorder and general population peers but at similar or lower rates than diabetes mellitus peers, indicating this group's complex combination of psychiatric and medical healthcare needs. The relatively high utilization of psychiatric services and low utilization of women's health services in transition-age youth with autism spectrum disorder may have implications for long-term health and warrants additional research.
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http://dx.doi.org/10.1177/1362361320931268DOI Listing
April 2021

Transitioning youth with autism spectrum disorders and other special health care needs into adult primary care: A provider survey.

Autism 2021 04 18;25(3):731-743. Epub 2020 Jun 18.

Kaiser Permanente Division of Research, Oakland CA, USA.

Lay Abstract: The transition from pediatric to adult care is a critical inflection point for the long-term health of youth with autism spectrum disorders and other special health care needs. However, for many patients, their caregivers, and providers, the transition lacks coordination. This survey study demonstrates that pediatric and adult providers struggle to implement many components of transition best practices for youth with autism and other chronic conditions, highlighting the urgent need for enhanced medical coordination and additional transition training and resources.
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http://dx.doi.org/10.1177/1362361320926318DOI Listing
April 2021

The Association Between Maternal Prenatal Fish Intake and Child Autism-Related Traits in the EARLI and HOME Studies.

J Autism Dev Disord 2021 Feb;51(2):487-500

Dornsife School of Public Health, Department of Epidemiology and Biostatistics, Drexel University, Philadelphia, PA, USA.

We examined the association between prenatal fish intake and child autism-related traits according to Social Responsiveness Scale (SRS) and cognitive development scores in two US prospective pregnancy cohorts. In adjusted linear regression analyses, higher maternal fish intake in the second half of pregnancy was associated with increased child autism traits (higher raw SRS scores; ß = 5.60, 95%CI 1.76, 12.97). Differences by fish type were suggested; shellfish and large fish species were associated with increases, and salmon with decreases, in child SRS scores. Clear patterns with cognitive scores in the two cohorts were not observed. Future work should further evaluate potential critical windows of prenatal fish intake, and the role of different fish types in association with child autism-related outcomes.
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http://dx.doi.org/10.1007/s10803-020-04546-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725860PMC
February 2021

Air pollution, neighborhood deprivation, and autism spectrum disorder in the Study to Explore Early Development.

Environ Epidemiol 2019 Oct;3(5)

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: To examine whether neighborhood deprivation modifies the association between early life air pollution exposure and autism spectrum disorder (ASD), we used resources from a multisite case-control study, the Study to Explore Early Development.

Methods: Cases were 674 children with confirmed ASD born in 2003-2006; controls were 855 randomly sampled children born during the same time period and residents of the same geographic areas as cases. Air pollution was assessed by roadway proximity and particulate matter <2.5 μm (PM) exposure during pregnancy and first year of life. To characterize neighborhood deprivation, an index was created based on eight census tract-level socioeconomic status-related parameters. The continuous index was categorized into tertiles, representing low, moderate, and high deprivation. Logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs).

Results: Neighborhood deprivation modified ( = 0.08) the association between PM exposure during the first year of life and ASD, with a stronger association for those living in high (OR = 2.42, 95% CI = 1.20, 4.86) rather than moderate (OR=1.21, 95% CI = 0.67, 2.17) or low (OR=1.46, 95% CI = 0.80, 2.65) deprivation neighborhoods. Departure from additivity or multiplicativity was not observed for roadway proximity or exposures during pregnancy.

Conclusion: These results provide suggestive evidence of interaction between neighborhood deprivation and PM exposure during the first year of life in association with ASD.
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http://dx.doi.org/10.1097/ee9.0000000000000067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260884PMC
October 2019

The Association Between Parental Age and Autism-Related Outcomes in Children at High Familial Risk for Autism.

Autism Res 2020 06 21;13(6):998-1010. Epub 2020 Apr 21.

Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

Advanced parental age is a well-replicated risk factor for autism spectrum disorder (ASD), a neurodevelopmental condition with a complex and not well-defined etiology. We sought to determine parental age associations with ASD-related outcomes in subjects at high familial risk for ASD. A total of 397 younger siblings of a child with ASD, drawn from existing prospective high familial risk cohorts, were included in these analyses. Overall, we did not observe significant associations of advanced parental age with clinical ASD diagnosis, Social Responsiveness Scale, or Vineland Adaptive Behavior Scales scores. Instead, increased odds of ASD were found with paternal age < 30 years (adjusted odds ratio [AOR] = 2.83 and 95% confidence intervals [CI] = 1.14-7.02). Likewise, younger age (<30 years) for both parents was associated with decreases in Mullen Scales of Early Learning early learning composite (MSEL-ELC) scores (adjusted β = -9.62, 95% CI = -17.1 to -2.15). We also found significant increases in cognitive functioning based on MSEL-ELC scores with increasing paternal age (adjusted β associated with a 10-year increase in paternal age = 5.51, 95% CI = 0.70-10.3). Results suggest the potential for a different relationship between parental age and ASD-related outcomes in families with elevated ASD risk than has been observed in general population samples. Autism Res 2020, 13: 998-1010. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Previous work suggests that older parents have a greater likelihood of having a child with autism. We investigated this relationship in the younger siblings of families who already had a child with autism. In this setting, we found a higher likelihood of autism, as well as poorer cognitive scores, in the siblings with younger fathers, and higher cognitive scores in the siblings with older parents. These results suggest that parental age associations may differ based on children's familial risk for autism.
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http://dx.doi.org/10.1002/aur.2303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396152PMC
June 2020

Genetic Contributions to Maternal and Neonatal Vitamin D Levels.

Genetics 2020 04 11;214(4):1091-1102. Epub 2020 Feb 11.

Department of Psychiatry, Institute for Human Genetics, University of California, San Francisco, California 94143.

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 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 and We found no interactions with ASD. However, when including a set of cases with intellectual disability but not ASD ( = 179), we observed a suggestive interaction between decreased levels of neonatal vitamin D and a specific maternal genotype near the 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.
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http://dx.doi.org/10.1534/genetics.119.302792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153928PMC
April 2020

Neonatal Thyroid Stimulating Hormone and Subsequent Diagnosis of Autism Spectrum Disorders and Intellectual Disability.

Autism Res 2020 03 10;13(3):444-455. Epub 2019 Dec 10.

Kaiser Permanente Division of Research, Oakland, California.

Hypothyroid conditions in early life, if left untreated, are associated with adverse neurodevelopmental outcomes, including intellectual disability (ID). However, evidence addressing the role of neonatal thyroid hormone insufficiencies in the altered neurobiology underlying autism spectrum disorders (ASD), particularly among its subphenotypes, is limited. We conducted a population-based, case-control study among a sample of children born during 2000-2003 in Southern California. We examined neonatal thyroid-stimulating hormone (TSH) measured during routine newborn screening among children later diagnosed with ASD (n = 518) or ID (n = 145) and general population (GP) controls (n = 399). TSH was further analyzed in relation to ASD subgroups of intellectual ability and onset type (early-onset ASD vs. ASD with regression) ascertained by expert review of developmental services records. Odds ratios (ORs) of the differences in TSH between groups were obtained from multivariate logistic regression. We examined neonatal TSH as continuous (ln-transformed) and as quartiles. We found no association between continuous neonatal TSH levels and ASD (adj-OR: 1.00, 95% CI: 0.79-1.26) nor ID (adj-OR = 1.01, 95% CI: 0.73-1.40). Among ASD subphenotypes, we observed a suggestive inverse trend between ASD with regression and TSH, though the association only reached statistical significance in the highest TSH quartile (adj-OR: 0.50, 95% CI: 0.26-0.98). While there was little evidence that neonatal TSH is related to overall ASD risk, more work is needed to understand the influence of thyroid hormones on ASD subphenotypes. Autism Res 2020, 13: 444-455. © 2019 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Low levels of thyroid hormone at birth can negatively impact brain development. We studied whether newborn levels of thyroid stimulating hormone (TSH) were associated with autism spectrum disorder (ASD) and its subtypes in a sample of children born in California. Newborn TSH was not related to the overall risk of ASD or intellectual disability. However, the relationships of thyroid hormone levels at birth and specific subtypes of ASD, particularly ASD with developmental regression, may need more research.
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http://dx.doi.org/10.1002/aur.2247DOI Listing
March 2020

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood.

Mol Autism 2019 24;10:36. Epub 2019 Oct 24.

4Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD USA.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children.

Methods: Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis.

Results: While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log(fold change) > 0.1,  < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR  < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions.

Limitations: ASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder.

Conclusions: This is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.
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http://dx.doi.org/10.1186/s13229-019-0287-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814108PMC
June 2020

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

Epidemiology 2020 01;31(1):103-114

From the Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.

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.
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http://dx.doi.org/10.1097/EDE.0000000000001109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888962PMC
January 2020

Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities.

Pediatrics 2019 09;144(3)

Brown Center for the Study of Children at Risk and Departments of Psychiatry and Human Behavior and Pediatrics, Alpert Medical School, Brown University, Providence, Rhode Island.

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.
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http://dx.doi.org/10.1542/peds.2019-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759228PMC
September 2019

Neonatal jaundice in association with autism spectrum disorder and developmental disorder.

J Perinatol 2020 02 6;40(2):219-225. Epub 2019 Aug 6.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

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.
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http://dx.doi.org/10.1038/s41372-019-0452-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031756PMC
February 2020
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