Risk Of Autism Spectrum Disorder In Offspring Research Articles

AOP-based framework for predicting the joint action mode of di-(2-ethylhexyl) phthalate and bisphenol A co-exposure on autism spectrum disorder

Autism spectrum disorder (ASD), also known as autism, is a common, highly hereditary and heterogeneous neurodevelopmental disorder. The global prevalence of ASD among children continues to rise significantly, which is partially attributed to environmental pollution. It has been reported that pre- or post-natal exposure to di-(2-ethylhexyl) phthalate (DEHP) or bisphenol A (BPA), two prevalent environmental endocrine disruptors, increases the risk of ASD in offspring. Yet, the joint action mode linking DEHP and BPA with ASD is incompletely understood. This study aims to unravel the joint action mode of DEHP and BPA co-exposure on the development of ASD. An adverse outcome pathway (AOP) framework was employed to integrate data from multiple public database and construct chemical-gene-phenotype-disease networks (CGPDN) for DEHP- and BPA-related ASD. Topological analysis and comprehensive literature exploration of the CGPDN were performed to build the AOP. By analysis of shared key events (KEs) or phenotypes within the AOP or the CGPDN, we uncovered two AOPs, decreased N-methyl-D-aspartate receptor (NMDAR) and estrogen antagonism that were likely linked to ASD, both with moderate confidence. Our analysis further predicted that the joint action mode of DEHP and BPA related ASD was possibly an additive or synergistic action. Thus, we propose that the co-exposure to BPA and DEHP perhaps additively or synergistically increases the risk of ASD.

The Role of Dietary Patterns and Nutritional Supplements in the Management of Mental Disorders in Children and Adolescents: An Umbrella Review of Meta-Analyses: Le rôle des habitudes alimentaires et des suppléments nutritionnels dans la prise en charge des troubles mentaux chez les enfants et les adolescents : une méta-revue de méta-analyses.

In recent years, the relationship between nutrition and mental health has gained considerable interest. We identified, synthesized, and appraised all meta--analyses of randomized controlled trials (RCTs) and observational studies reporting on the efficacy of dietary patterns and nutrient supplements in the prevention and treatment of mental disorders in children and adolescents. Systematic research in MEDLINE, PsycINFO, Scopus, and Cochrane Database of Systematic Reviews was completed on 8 January 2024. Our research found 24 meta-analyses: 14 on RCTs, 8 on observational studies, and 2 combining both. Emerging evidence suggests that omega-3, in particular eicosapentaenoic acid, and Vitamin D may have adjunctive benefits in the treatment of attention deficit hyperactivity disorder (ADHD), while no evidence was found for autism spectrum disorder (ASD). Observational data also indicated that prenatal folic acid supplementation (>400 μg daily) was associated with a reduced risk of ASD in offspring. In terms of dietary habits, several meta-analyses of observational data revealed that healthy dietary patterns (rich in fruits, vegetables, and fibre, low in saturated fats) during the prenatal period, childhood, and adolescence were linked to a significantly reduced risk of internalizing disorders and externalizing disorders. Conversely, unhealthy dietary habits (high in sugars, saturated animal fats, and industrial foods, low in fruits, vegetables, and fibre) are associated with an elevated risk of these mental health issues. However, the number of available studies on dietary interventions for the treatment of depression, ASD, and ADHD was limited, and the results obtained were either nonsignificant or contradictory. Our findings emphasize the need to establish clear causal relationships between dietary habits and the risk of mental illness in children and adolescents. Moreover, further investigation of the benefits observed with some nutrient supplements (such as omega-3 and vitamin D for ADHD) through larger-scale RCTs is imperative to establish more robust conclusions.

Prenatal, perinatal and parental risk factors for autism spectrum disorder in China: a case- control study.

Autism spectrum disorder (ASD) is heritable neurodevelopmental disorders (NDDs), but environmental risk factors have also been suggested to a play a role in its development. Prenatal, perinatal and parental factors have been associated with an increased risk of ASD in children. The aim of the present study was to explore the prenatal, perinatal, and parenting risk factors in children with autism spectrum disorder (ASD) from Beijing, China by comparing them with typically developing (TD) children. A sample of 151 ASD children's parents who from rehabilitation institutions in Beijing were enrolled in this study, and an additional 151 children from kindergartens in Beijing were recruited as a control group (child age: mean = 4.4 years). TD children were matched according to age, sex and maternal education. We explored the maternal AQ (Autism Spectrum Quotient) scores (mean:19.40-19.71, no significant difference between two groups) to referring the genetic baseline. This study evaluated 17 factors with unadjusted and adjusted analyses. Birth asphyxia was associated with a more than a thirteen-fold higher risk of ASD (adjusted odds ratio (AOR) = 13.42). Breastfeeding difficulties were associated with a higher risk of ASD(AOR = 3.46). Parenting influenced the risk of ASD, with low responding (LR) and harsh or neglectful parenting associated with a higher risk of ASD in offspring (AOR = 2.37 for LR, AOR = 3.42 for harsh parenting and AOR = 3.01 for neglectful parenting). Maternal fever during pregnancy was associated with a higher risk of ASD in offspring (AOR = 3.81). Many factors were associated with ASD in offspring. Further assessment is needed to elucidate the role of modifiable environmental factors to inform prevention strategies.

Dietary nutrients that potentially mitigate autism spectrum disorder and dietary recommendations for children and pregnant women

AbstractThe increasing incidence of autism spectrum disorder (ASD) worldwide poses serious social and family problems. Various risk factors for ASD are gradually being recognized, and there are also various options for the treatment of ASD. It is worth noting that dietary interventions have been shown to have a positive effect in terms of mitigating and preventing some psychiatric disorders, such as epilepsy, Parkinson's disease, and ASD, and they are gradually receiving attention as a safe adjuvant treatment. In this review, based on the current understanding of the pathogenic factors and intervention strategies for ASD, different dietary patterns that can be selected for children with ASD are discussed in depth. Moreover, a review was conducted on the use of dietary factors, such as natural products from food sources, prebiotics, and probiotics, as effective supplements to existing dietary patterns. As increasing evidence shows that maternal risk factors, such as obesity, diabetes, and hypertension, are associated with an increased risk of ASD in offspring, dietary suggestions are also made for pregnant woman with ASD‐related risk factors to counteract the impact of these risk factors. With compensation from food‐derived natural products, prebiotics, and probiotics, suitable dietary patterns can further enhance the effectiveness of dietary interventions for ASD. In addition, dietary recommendations for pregnant woman may reduce the potential impact of obesity, diabetes, and hypertension and may help to prevent the occurrence of ASD to the maximum extent possible.

Maternal multivitamin supplementation is associated with symptoms in offspring with autism spectrum disorder: A multi-center study in China

BackgroundWe aimed to investigate the relationship between maternal vitamin D and multivitamin supplementation during pregnancy and the risk of autism spectrum disorder (ASD) and symptoms in offspring with ASD. MethodsThis study enrolled 1321 children with ASD and 1200 typically developing (TD) children under 7 years old in China. Maternal vitamin supplements were classified for vitamin D, multivitamin (with or without vitamin D), and none (no use of vitamin D or multivitamin). For children with ASD, symptoms were assessed with the Autism Behavior Checklist (ABC), Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS), and neurodevelopmental levels were evaluated with the Children Neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016). ResultsMaternal vitamin D and multivitamin supplementation during pregnancy were both significantly associated with a decreased risk of ASD in offspring (P = 0.024 and P < 0.001). The ASD children born to mothers with gestational multivitamin supplementation had lower CARS [β = −1.342 (−2.275, −0.409), P = 0.005] and communication warning behavior [β = −6.631 (−9.899, −3.363), P < 0.001] scores and higher personal-social quotient [β = 3.347 (0.190, 6.504), P = 0.038] than children born to mothers without supplementation. Maternal vitamin D supplementation was not associated with symptoms and development quotients in ASD children (P > 0.05). ConclusionsThis study supports a protective association between maternal vitamin D and multivitamin supplementation during pregnancy and the risk of ASD in offspring. Maternal multivitamin supplementation may potentially moderate the symptoms and personal-social ability in ASD children. Further studies are needed on the role of maternal nutrition in the etiology and autistic symptoms and the underlying molecular mechanisms.

Maternal autoimmune disease and risk of offspring autism spectrum disorder - a nationwide population-based cohort study.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which cause long term social and behavior impairment, and its prevalence is on the rise. Studies about the association between maternal autoimmune diseases and offspring ASD have controversial results. The aim of this study was to investigate whether maternal autoimmune diseases increase the risk of ASD in offspring from a population-based perspective. The data sources were Taiwan's National Health Insurance Research Database (NHIRD) and Taiwan's Maternal and Child Health Database (MCHD), which were integrated and used to identify newborns whose mothers were diagnosed with autoimmune disease. Newborns were matched by maternal age, neonatal gender, and date of birth with controls whose mothers were without autoimmune disease using a ratio of 1:4 between 2004 and 2019. Data on diagnoses of autoimmune disease and autism spectrum disorders were retrieved from NHIRD. Patients who had at least 3 outpatient visits or at least 1 admission with a diagnosis of autoimmune disease and autism spectrum disorders were defined as incidence cases. The risks of ASD in offspring were compared between mothers with or without autoimmune disorders. We identified 20,865 newborns whose mothers had been diagnosed with autoimmune disease before pregnancy and matched them at a ratio of 1:4 with a total of 83,460 newborn whose mothers were without autoimmune disease, by maternal age, neonatal gender, and date of birth. They were randomly selected as the control group. The cumulative incidence rates of autism spectrum disorders (ASD) were significantly higher among the offspring of mothers with autoimmune diseases. After adjusting for cofactors, the risk of ASD remained significantly higher in children whose mother had autoimmune diseases. Regarding to specific maternal autoimmune disease, Sjögren's syndrome and rheumatoid arthritis were both associated with elevated risks of ASD in offspring. Mother with autoimmune disease might be associated with increasing the risk of autism spectrum disorder in offspring.

Association between maternal gestational diabetes mellitus and the risk of autism spectrum disorder in offspring

To explore the association between maternal gestational diabetes mellitus (GDM) exposure and the development of autism spectrum disorder (ASD) in offspring. A case-control study was conducted, recruiting 221 children with ASD and 400 healthy children as controls. Questionnaires and interviews were used to collect information on general characteristics of the children, socio-economic characteristics of the family, maternal pregnancy history, and maternal disease exposure during pregnancy. Multivariate logistic regression analysis was used to investigate the association between maternal GDM exposure and the development of ASD in offspring. The potential interaction between offspring gender and maternal GDM exposure on the development of ASD in offspring was explored. The proportion of maternal GDM was significantly higher in the ASD group compared to the control group (16.3% vs 9.4%, P=0.014). After adjusting for variables such as gender, gestational age, mode of delivery, parity, and maternal education level, maternal GDM exposure was a risk factor for ASD in offspring (OR=2.18, 95%CI: 1.04-4.54, P=0.038). On the basis of adjusting the above variables, after further adjusting the variables including prenatal intake of multivitamins, folic acid intake in the first three months of pregnancy, and assisted reproduction the result trend did not change, but no statistical significance was observed (OR=1.94, 95%CI: 0.74-5.11, P=0.183). There was an interaction between maternal GDM exposure and offspring gender on the development of ASD in offspring (P<0.001). Gender stratified analysis showed that only in male offspring of mothers with GDM, the risk of ASD was significantly increased (OR=3.67, 95%CI: 1.16-11.65, P=0.027). Maternal GDM exposure might increase the risk of ASD in offspring. There is an interaction between GDM exposure and offspring gender in the development of ASD in offspring.

The association between prenatal psychosocial factors and autism spectrum disorder in offspring at 3years: a prospective cohort study.

Few studies of risk factors for autism spectrum disorder (ASD) have been prospective in design or investigated the role of psychosocial factors measured during pregnancy. We aimed to investigate associations between prenatal psychosocial factors and risk of ASD in offspring, as part of a multicenter prospective cohort study of more than 2000 mother-child pairs. Nulliparous women aged 18-35years, living in Pennsylvania, USA, were interviewed during pregnancy and multiple times postpartum over the course of a 3-year period. There were 2388 mothers who completed the Screen for Social Interaction Toddler Version (SSI-T), a measure of risk of ASD, when their child was 3-years old. Multivariable logistic regression models were used to investigate the associations between prenatal psychosocial factors-including total scores on three scales (social-support, stress and depression), trouble paying for basic needs, mental illness diagnosis and use of antidepressants-and risk of ASD in offspring at the age of 3-years, controlling for relevant confounding variables. There were 102 children (4.3%) who were scored as at-risk of ASD at 3-years. Prenatal psychosocial factors that were significantly associated with risk of ASD in the adjusted models were lower social-support (p < 0.001); stress (p = 0.003): depression (< 0.001), trouble paying for basic needs (p = 0.012), mental illness diagnosis (p = 0.016), and use of antidepressants (p < 0.001). These findings suggest that maternal experience of adverse psychosocial factors during pregnancy may be important intrauterine exposures related to the pathogenesis of ASD.

Stem-Skilled Parents and Autism Spectrum Disorder in Offspring: A Case-Control Study

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterised by a range of deficits in two specific domains: social communication and social interaction and repetitive patterns of behaviour. Several studies have explored the link between ASD and STEM (science, technology, engineering and mathematics, or other mathematics-grounded disciplines), but results are still uncertain. Objective of the study was to estimate the potential role of systemising abilities in parents as a risk factor for ASD in the offspring, using the achievement of a degree in STEM disciplines as a proxy characteristic of the exposure. There were 1,316 participants overall. There were 658 incident consecutive cases of definite ASD, diagnosed in a Reference Centre for ASD in Italy, from 2001 to 2020. The main exposure variable was parental education level. The risk of ASD in the offspring associated with the main exposure variable and the exposure covariates (e.g. use of neurotropic drugs during the first trimester of the mother’s pregnancy, perinatal outcomes of participants and/or preterm birth) was studied by using conditional logistic regression analysis. In addition, we carried out a mediation analysis to investigate whether and the extent to which covariates significantly associated with ASD risk mediate the relationship between parental education level and ASD in offspring. A STEM degree in parents was significantly associated with risk of ASD in offspring (OR 1.43, 95% CI 1.03-2.54). Familiarity was weakly associated with the risk of ASD (OR 1.33, 95% CI 1.00-1.66) and is the stronger mediator (PME 28%). Sensitivity analysis did not show deviations related to gender or ASD level. Our study moves in the direction of confirming the risk of occurrence of ASD in the offspring of parents with elevated systemising abilities.

Association between prenatal antibiotic exposure and autism spectrum disorder among term births: A population-based cohort study.

Prenatal antibiotic exposure induces changes in the maternal microbiome, which could influence the development of the infant's microbiome-gut-brain axis. We assessed whether prenatal antibiotic exposure is associated with an increased risk of autism spectrum disorder (ASD) in offspring born at term. This population-based retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada between April 2000 and December 2014. Exposure was defined as filling antibiotic prescriptions during pregnancy. The outcome was an ASD diagnosis from the British Columbia Autism Assessment Network, with a follow-up to December 2016. To examine the association among pregnant individuals treated for the same indication, we studied a sub-cohort diagnosed with urinary tract infections. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios (HR). The analysis was stratified by sex, trimester, cumulative duration of exposure, class of antibiotic, and mode of delivery. We ran a conditional logistic regression of discordant sibling pairs to control for unmeasured environmental and genetic confounding. Of the 569,953 children included in the cohort, 8729 were diagnosed with ASD (1.5%) and 169,922 were exposed to prenatal antibiotics (29.8%). Prenatal antibiotic exposure was associated with an increased risk of ASD (HR 1.10, 95% confidence interval [CI] 1.05, 1.15), particularly for exposure during the first and second trimesters (HR 1.11, 95% CI 1.04, 1.18 and HR 1.09, 95% CI 1.03, 1.16, respectively), and exposure lasting ≥15 days (HR 1.13, 95% CI 1.04, 1.23). No sex differences were observed. The association was attenuated in the sibling analysis (adjusted odds ratio 1.04, 95% CI 0.92, 1.17). Prenatal antibiotic exposure was associated with a small increase in the risk of ASD in offspring. Given the possibility of residual confounding, these results should not influence clinical decisions regarding antibiotic use during pregnancy.

Labor epidural analgesia and risk of autism Spectrum disorders in offspring: A systematic review and meta-analysis.

The effect of labor epidural anesthesia (LEA) on the risk of autism spectrum disorder (ASD) in offspring has been investigated recently, and available results are inconsistent. We searched the PubMed and EMBASE databases for relevant studies and performed a systematic review and meta-analysis of the literature. Subgroup analyses were conducted to assess the sources of heterogeneity. Both fixed and random effects models were used was used to estimate overall relative risk. Our results showed that LEA was associated with an increased risk of ASD in offspring [HR = 1.3, 95% confidence interval (CI): 1.25-1.35; P < 0.001] after combining crude estimates from the included studies. This association was gradually reduced, but still statistically significant, when potential confounding factors were considered (HR 1.13, 95% CI 1.03-1.25, P = 0.014). However, there was no significant association when we combined data of siblings from other pregnancies (HR = 1.07, 95% CI: 0.99-1.16, P = 0.076), implying that the association was due to confounding factors. The statistically significant association between LEA and ASD in the offspring can be partially explained by unmeasured confounding. Identifier CRD42022302892.

Maternal exposure to pesticides and autism or attention-deficit/hyperactivity disorders in offspring: A meta-analysis

ObjectiveTo analyze the association between maternal pesticide exposure and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorders (ADHD) in offspring. MethodFive databases including PubMed, Embase, Web of Science, Medline, as well as PsycINFO were systematically retrieved for the records related to pesticide exposure during pregnancy and ASD and ADHD in offspring before August 30, 2022. The pesticide category, maternal age and window of exposure as the main subgroups were presented. Results949 studies were initially identified, and 19 studies were eventually included. Eleven were on ASD, seven were on ADHD, and one was on both disorders. Maternal pesticide exposure was positively related to ASD (pooled OR = 1.19 (95%CI: 1.04 to 1.36)) and ADHD (pooled OR = 1.20 (95%CI: 1.04 to 1.38)) in offspring. In the subgroup analysis, organophosphorus pesticides (OPs) (pooled OR = 1.14 (95%CI: 1.04 to 1.24)), pyrethroid (pooled OR = 1.40 (95%CI: 1.09 to 1.80)), and maternal age ≥30 years old (pooled OR = 1.24 (95%CI: 1.10 to 1.40)) increased the risk of ASD in offspring. Maternal organochlorine pesticides (OCPs) exposure was a risk factor for ADHD in offspring (pooled OR = 1.22 (95%CI: 1.03 to 1.45)). ConclusionMaternal pesticide exposure increased the risk of ASD and ADHD in offspring. Moreover, OPs, pyrethroid, and maternal age ≥30 years old were found to be risk factors affecting children's ASD. Maternal exposure to OCPs increased the risk of ADHD in offspring. Our findings contribute to our understanding of health risks related to maternal pesticide exposure and indicate that the in utero developmental period is a vulnerable window-of-susceptibility for ASD and ADHD risk in offspring. These findings should guide policies that limit maternal exposure to pesticides, especially for pregnant women living in agricultural areas.

Association between history of miscarriage and autism spectrum disorder.

This case-control study was designed to examine the association between different types of miscarriage history and autism spectrum disorder (ASD), and determine whether the number of miscarriage history affects the risk of ASD. All of 2274 children with ASD and 1086 healthy controls were recruited. Sociodemographic and prenatal, perinatal, and neonatal characteristics were compared between the two groups. Multivariable logistic regression analyses were applied to investigate association between miscarriage history and ASD. Stratified analyses based on sex and types of miscarriages were similarly performed. History of miscarriage was potential risk factors for ASD ([aOR] = 2.919; 95% [CI] = 2.327-3.517). Stratified analyses revealed that induced ([aOR] = 2.763, 95% [CI] = 2.259-3.379) and spontaneous miscarriage history ([aOR] = 3.341, 95% [CI] = 1.939-4.820) were associated with high risk of ASD, respectively. A sex-biased ratio in the risk of ASD was observed between females ([aOR] = 3.049, 95% [CI] = 2.153-4.137) and males ([aOR] = 2.538, 95% [CI] = 1.978-3.251). Stratified analysis of induced miscarriage history revealed that only iatrogenic miscarriage history was associated with an increased risk ASD ([aOR] = 2.843, 95% [CI] = 1.534-4.268). Also, multiple spontaneous miscarriage histories ([aOR] = 1.836, 95% [CI] = 1.252-2.693) were associated with higher autism risk than one spontaneous miscarriages history ([aOR] = 3.016, 95% [CI] = 1.894-4.174). In conclusion, miscarriage history is related to an increased risk for ASD in offspring, which is affected by the types of miscarriage and sex of the fetus.

Study of Parental Occupational Exposures to Solvents and Risk of Autism Spectrum Disorder in Offspring

BACKGROUND AND AIM: Solvents can accumulate in fat and later metabolize during pregnancy. Additionally, these toxicants could lead to germline mutations. We investigated associations between multiple parental occupational solvent exposures and odds of autism spectrum disorder (ASD) diagnosis in offspring. METHODS: Using population-based data from the Danish National Patient Registry, we identified a subset of ASD cases from 1982 to 2016 and 1:100 sex and birth-year matched controls obtained from the Central Population Register. We determined parental occupation history from age 16 years through 6 months post-childbirth from the Danish Pension Fund and estimated cumulative benzene, methylcyclohexane, toluene, trichloroethylene, perchloroethylene, and 1,1,1-trichloroethane exposure for mothers and fathers based on job exposure matrices (JEMs). Conditional logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for exposures one year prior to conception and during pregnancy. RESULTS: In analysis of data from 1898 people with ASD and 141,702 without ASD, there were no observed associations between maternal solvent exposures during pregnancy and risk of ASD in offspring. However, analysis for maternal benzene exposure one year prior to conception revealed higher adjusted odds for those with any exposure (aOR=1.55; 95% CI 1.02, 2.37). Additionally, although there were no significant associations between paternal solvent exposures during pregnancy and ASD risk, there were significantly increased odds of ASD in offspring whose fathers were exposed to benzene (aOR=3.07; 95% CI 1.72, 5.46) and toluene (aOR=1.66; 95% CI 1.05, 2.62) one year before conception. CONCLUSIONS: Although previous studies have suggested parental solvent exposure during pregnancy can contribute to pathogenesis of ASD, our findings suggest that risk may be increased through exposures prior to conception. However, unavoidable non-differential misclassification from the use of JEMs may have masked truly increased risk during pregnancy.

Autism Risk and Perinatal Antibiotic Use.

Antibiotics are commonly administered during labor and delivery, and research has suggested that fetal exposure to antibiotics can increase risk for autism spectrum disorder (ASD). We assessed whether antibiotic exposure during labor and delivery increased the risk of ASD in the offspring. This retrospective cohort study included everyone who delivered a live singleton-term infant in British Columbia, Canada, between April 1, 2000, and December 31, 2014. This cohort included 569 953 deliveries. To examine the association among pregnant individuals being treated for the same indication, we studied a subcohort of those who tested positive for group B Streptococcus. Cox proportional hazards models were used to estimate unadjusted and adjusted hazard ratios in both cohorts. A sensitivity analysis was conducted using length of first stage of labor as a proxy measure for dose to assess for a dose-response relationship. In this population-based study, antibiotic use during labor and delivery was not associated with an increased risk of ASD in offspring. The unadjusted and adjusted hazard ratios were 1.29 (95% confidence interval, 1.24-1.35) and 0.99 (0.94-1.04), respectively; and 1.07 (0.90-1.27) and 0.88 (0.74-1.05), respectively, in the group B Streptococcus-positive cohort. We observed no substantial difference in the association between antibiotic exposure and ASD depending on length of the first stage of labor. Our findings suggest that concern for ASD should not factor into the clinical decision on whether to administer antibiotics during labor and delivery. Future research is needed to examine longer durations of prenatal antibiotic exposure.

Association between paternal age at childbirth and autism spectrum disorder in offspring.

To study the association between paternal age at childbirth and the risk of autism spectrum disorder (ASD) in offspring. In this cross-sectional study, 71 children with ASD who were diagnosed in the Department of Child Healthcare in six hospitals in Guangzhou, Foshan, Beijing, Wuhan, Hangzhou, and Chongqing of China from August 2016 to March 2017 were enrolled as subjects, and 284 typically developing children matched for age, sex, and maternal age at childbirth with the ASD children served as controls. A self-design questionnaire was used to collect the data on social demography, maternal pregnancy, and delivery. The association between paternal age at childbirth and the development of ASD in offspring was evaluated by the logistic regression analysis. After control for demographic factors and pregnancy- and delivery-related factors, the logistic regression analysis showed that a relatively high paternal age at childbirth was significantly associated with the increased risk of ASD in offspring (OR=1.12, 95%CI: 1.02-1.23, P<0.05). After grouping based on the paternal age, the logistic regression analysis showed that paternal age at childbirth of ≥40 years was significantly associated with the risk of ASD in offspring (before adjustment: OR=7.08, 95%CI: 1.77-28.32, P<0.05; after adjustment: OR=8.50, 95%CI: 1.71-42.25, P<0.05). High paternal age at childbirth is significantly associated with the increased risk of ASD in offspring, and paternal age at childbirth ≥40 years may be the high-risk age group for ASD in offspring.

Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells

Cannabis use in the United States is increasing, with highest consumption among men at their peak reproductive years. We previously demonstrated widespread changes in sperm DNA methylation with cannabis exposure in humans and rats, including genes important in neurodevelopment. Here, we use an in vitro human spermatogenesis model to recapitulate chronic cannabis use and assess DNA methylation at imprinted and autism spectrum disorder (ASD) candidate genes in spermatogonial stem cell (SSC)- and spermatid-like cells. Methylation at maternally imprinted genes SGCE and GRB10 was significantly altered in SSC- and spermatid-like cells, respectively, while PEG3 was significantly differentially methylated in spermatid-like cells. Two of ten randomly selected ASD candidate genes, HCN1 and NR4A2, had significantly altered methylation with cannabis exposure in SSC-like cells. These results support our findings in human cohorts and provide a new tool with which to gain mechanistic insights into the association between paternal cannabis use and risk of ASD in offspring.

A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex.

The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.

Exposure to Intrapartum Epidural Analgesia and Risk of Autism Spectrum Disorder in Offspring

There is conflicting evidence on the association between intrapartum epidural analgesia and risk of autism spectrum disorder (ASD) in offspring. To evaluate the association between intrapartum epidural analgesia and the risk of ASD in offspring. This population-based cohort study was conducted in Ontario, Canada, using the health and administrative records of singleton live births by vaginal delivery between April 1, 2006, and March 31, 2014. Neonates with less than 24 weeks' gestation or weighing less than 500 g were excluded. Offspring were followed up from 18 months of age until ASD diagnosis, loss to follow-up, or the end of the study (December 31, 2020), whichever occurred first. Exposure, covariate, and outcome data were obtained using provincial health administrative databases. Any intrapartum exposure to epidural or combined spinal-epidural analgesia. The primary outcome was ASD diagnosis after 18 months of age. Inverse probability of treatment weighting (IPTW) of Cox proportional hazards regression models was used to estimate the hazard ratio (HR) of intrapartum epidural analgesia and ASD in offspring. Offspring head injury was used as a control outcome. Models were adjusted for maternal sociodemographic factors, health behaviors, and medical and obstetrical history as well as labor, delivery, and offspring characteristics. Post hoc analyses included restriction to term neonates, a conditional within-mother analysis, exclusion of records with concomitant intrapartum pain management exposures, a complete case analysis, use of an alternative ASD definition, and estimation of the average treatment effect in the treated group. Among the 650 373 mother-offspring pairs included in the study, 418 761 (64.4%) were exposed to intrapartum epidural analgesia. The mean (SD) maternal age at delivery was 29.7 (5.5) years; the offspring had a mean (SD) gestational age at delivery of 39.1 (1.6) weeks and included 329 808 male newborns (50.7%). The exposed and unexposed groups were similar in all maternal and newborn characteristics after IPTW (standardized difference <0.10). Autism spectrum disorder was diagnosed in 7546 offspring (1.8%) of mothers who received intrapartum epidural analgesia (incidence rate, 18.8 [95% CI, 18.4-19.3] per 10 000 person-years) compared with 3234 offspring (1.4%) who were unexposed (incidence rate, 14.4 [95% CI, 13.9-14.9] per 10 000 person-years). The crude HR for ASD associated with intrapartum epidural analgesia was 1.30 (95% CI, 1.25-1.36), and the IPTW-adjusted HR was 1.14 (95% CI, 1.08-1.21). Results did not qualitatively differ in post hoc analyses. Results of this study showed that intrapartum epidural analgesia was associated with a small increase in risk for ASD in offspring. The biological plausibility of this association, however, remains unclear, and the finding must be interpreted with caution.

Paternal and maternal psychiatric disorders associated with offspring autism spectrum disorders: A case-control study

A family history of psychiatric diseases was suggested as one risk factor for autism spectrum disorders (ASD). Our aim was to assess the association of paternal and maternal diagnosis of psychiatric disorders with the risk of ASD in offspring in Taiwan. We conducted a population-based case-control study. Using several linked national databases, we obtained 1,000,939 singleton birth records born between 2004 and 2008. We followed these children up to 2015 for cases of ASD, using diagnostic codes in the National Health Insurance databases. There were 8,933 ASD cases and each case was matched to ten controls by sex and year of birth. We extracted their parental diagnosis of psychiatric disorders and performed conditional logistic regression models to assess the association of interest. Our sample included 8,933 cases and 89,330 controls. Eighty-six percent of the sample were boys. After adjustment for parental age, family income, and urbanization, we found that parental psychiatric diseases were significantly associated with ASD, including schizophrenic and psychotic disorders, mood, anxiety and personality disorders, with adjusted odds ratios ranging from 1.32 to 2.39. Notably, the effect estimates were all larger for maternal diagnosis than paternal diagnosis when stratified by mothers or fathers. Cases of ASD are more likely to be born to parents with psychiatric disorders than their counterparts. Maternal psychiatric diagnosis seems to have a larger influence than paternal diagnosis. Both genetics and maternal environmental factors may contribute to the association observed between parental psychiatric diseases and child ASD.