In population-based data sets from 3 Nordic countries that collectively included 22 156 people with ASD and studied mean estimated heritability, the variation in ASD traits attributed to genetic factors was 81% (95% CI, 74%-85%). Environmental factors were associated with 14% to 22% of the risk of ASD in the same study. A relatively small number of rare genetic variants in approximately 100 genes (eg, KMT2A , NRXN1 , SHANK3 ) have been identified that were associated with significant risk, whereas a larger number, perhaps thousands, of common variants were associated with smaller risk but, in combination, accounted for the majority of cases. Genetic risk factors for ASD overlap with other diverse developmental and psychiatric disorders. A variety of genetic and environmental factors have been associated with ASD, but none are absolutely specific for the development of ASD.

Many of the autism risk genes affect gene expression regulation, neurogenesis, chromatin modification, and synaptic function. Additional support for the role of genetic factors was reported by Willsey et al. This study used an in vivo Xenopus model and examined 10 genes with the strongest statistical association with ASD that all were expressed in the telencephalon (the forebrain that is primarily composed of the cerebral hemispheres) at time points corresponding to human mid-prenatal prefrontal cortex development. Estrogen mitigates the effects of ASD risk gene disruption, and this may help explain the sex differences in prevalence.

A meta-analysis of studies identified that maternal factors, such as gestational hypertension (odds ratio, 1.4 [95% CI, 1.2-1.5]), overweight before or during pregnancy (relative risk [RR], 1.3 [95% CI, 1.2-1.4]), preeclampsia (RR, 1.3 [95% CI, 1.2-1.5]), and maternal age of 35 years or older (RR, 1.3 [95% CI, 1.2-1.5]) were associated with higher rates of ASD in offspring (absolute rates not provided).

Background: Numerous studies have identified potential risk factors and biomarkers for autism spectrum disorder. We aimed to study the strength and validity of the suggested environmental risk factors or biomarkers of autism spectrum disorder.

Methods: We did an umbrella review and systematically appraised the relevant meta-analyses of observational studies. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for papers published between database inception and Oct 17, 2018, and screened the reference list of relevant articles. We obtained the summary effect, 95% CI, heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We did analyses under credibility ceilings. This review is registered with PROSPERO, number CRD42018091704.

Findings: 46 eligible articles yielded data on 67 environmental risk factors (544 212 cases, 81 708 787 individuals) and 52 biomarkers (15 614 cases, 15 433 controls). Evidence of association was convincing for maternal age of 35 years or over (relative risk [RR] 1·31, 95% CI 1·18-1·45), maternal chronic hypertension (odds ratio [OR] 1·48, 1·29-1·70), maternal gestational hypertension (OR 1·37, 1·21-1·54), maternal overweight before or during pregnancy (RR 1·28, 1·19-1·36), pre-eclampsia (RR 1·32, 1·20-1·45), prepregnancy maternal antidepressant use (RR 1·48, 1·29-1·71), and maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy (OR 1·84, 1·60-2·11). Only two associations, maternal overweight before or during pregnancy and SSRI use during pregnancy, retained their high level of evidence under subset sensitivity analyses. Evidence from biomarkers was scarce, being supported by p values close to the significance threshold and too few cases.

Interpretation: Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome, are associated with risk of autism spectrum disorder. Although SSRI use during pregnancy was also associated with such risk when exposed and non-exposed groups were compared, this association could be affected by other confounding factors, considering that prepregnancy maternal antidepressant use was also convincingly associated with higher risk of autism spectrum disorder. Findings from previous studies suggest that one possible confounding factor is underlying maternal psychiatric disorders.

Funding: None.

Background: The aim of this meta-analysis was to investigate the prenatal, perinatal, and postnatal risk factors for children autism.

Methods: PubMed, Embase, Web of Science were used to search for studies that examined the prenatal, perinatal, and postnatal risk factors for children autism. A fixed-effects model or random-effects model was used to pool the overall effect estimates.

Results: Data from 37,634 autistic children and 12,081,416 nonautistic children enrolled in 17 studies were collated. During the prenatal period, the factors associated with autism risk were maternal and paternal age≥35 years, mother's and father's race: White and Asian, gestational hypertension, gestational diabetes, maternal and paternal education college graduate+, threatened abortion, and antepartum hemorrhage. During perinatal period, the factors associated with autism risk were caesarian delivery, gestational age≤36 weeks, parity≥4, spontaneous labor, induced labor, no labor, breech presentation, preeclampsia, and fetal distress. During the postnatal period, the factors associated with autism risk were low birth weight, postpartum hemorrhage, male gender, and brain anomaly. Parity≥4 and female were associated with a decreased risk of autism. In addition, exposure to cigarette smoking, urinary infection, mother's and father's race: Black and Hispanic, mother's country of birth outside Europe and North America, umbilical cord around neck, premature membrane rupture, 5-minutes Apgar score<7, and respiratory infection were not associated with increased risk of autism.

Conclusion: The present meta-analysis confirmed the relation between some prenatal, perinatal, and postnatal factors with autism. All these factors were examined individually, thus it was still unclear that whether these factors are causal or play a secondary role in the development of autism. Further studies are needed to verify our findings, and investigate the effects of multiple factors on autism, rather than the single factor.

Background: According to recent evidence, up to 40-50% of variance in autism spectrum disorder (ASD) liability might be determined by environmental factors. In the present paper, we conducted a review of systematic reviews and meta-analyses of environmental risk factors for ASD. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD.

Findings: Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD. On the contrary, advanced parental age is associated with higher risk of ASD. Birth complications that are associated with trauma or ischemia and hypoxia have also shown strong links to ASD, whereas other pregnancy-related factors such as maternal obesity, maternal diabetes, and caesarian section have shown a less strong (but significant) association with risk of ASD. The reviews on nutritional elements have been inconclusive about the detrimental effects of deficiency in folic acid and omega 3, but vitamin D seems to be deficient in patients with ASD. The studies on toxic elements have been largely limited by their design, but there is enough evidence for the association between some heavy metals (most important inorganic mercury and lead) and ASD that warrants further investigation. Mechanisms of the association between environmental factors and ASD are debated but might include non-causative association (including confounding), gene-related effect, oxidative stress, inflammation, hypoxia/ischemia, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways.

Conclusions: Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs.

Background: We explored the association of 29 previously reported neonatal, perinatal, and prenatal conditions, and exposures with later diagnosis of autism spectrum disorder (ASD) in a large sample of children followed over multiple years.

Methods: A retrospective case-cohort study was formed using the Military Health System database. Cases were identified by International Classification of Diseases, Ninth Revision codes for ASD between 2000 and 2013, and were matched 3:1 with controls on sex, date of birth, and enrollment time frame. Exposures included 29 conditions previously associated with ASD; 17 prenatal conditions and their pharmaceutical treatment, 5 perinatal conditions, and 6 neonatal conditions.

Results: A total of 8,760 children diagnosed with ASD between the ages of 2 and 18 years were matched with 26,280 controls. ASD is associated with maternal mental illness, epilepsy, obesity, hypertension, diabetes, polycystic ovary syndrome, infection, asthma, assisted fertility, hyperemesis, younger maternal age, labor complications, low birth weight, infant infection, epilepsy, birth asphyxia, and newborn complications. The greatest increased risk was associated with infant epilepsy (odds ratio (OR) 7.57 (5.68-10.07)), maternal mental health (OR 1.80 (1.65-1.96)), and epilepsy (OR 1.60 (1.02-2.50)) medications.

Conclusion: ASD is associated with a range of prenatal, perinatal, and neonatal factors, with the highest magnitude associations with maternal medication use and neonatal seizure.

In 1943, the first description by Kanner of autistic disturbances included speculation about genetic inheritance, but early psychoanalytic hypotheses focused on the early social environment as a cause for autism, including the fallacy of the “refrigerator mother.” In the 1970s, twin studies identified genetics as a major contributor to the risk of autism. Within the heterogeneous spectrum of ASD, data point to both genetic and environmental risk factors that contribute to risk. In the described case, the patient has a genetic diagnosis of 16p11.2 microdeletion and a birth history of prematurity, risk factors that both likely contribute to his presentation and diagnosis of ASD.

Family studies indicate that shared genetic risk factors increase the likelihood of autism. Identical twins have autism concordance rates of 50% to 80% in most studies, indicating strong heritability but also that other factors determine whether ASD develops. Fraternal twins have up to 30% concordance, whereas the overall rate of recurrence between siblings is approximately 25%. Sibling recurrence increases to 50% if there are 2 or more siblings with ASD or if any affected sibling is female.

Common variants (those present in >1% of the population) contribute the majority of ASD risk at a population level, but individual common variants contribute only a small portion of the overall risk, suggesting that they must act in concert. Genome-wide association is a powerful method to link common variation in specific genetic regions to the risk of ASD, but these studies require large sample sizes to reproducibly link risk to specific common variants. Additional research will be needed to understand how multiple common variants interact with each other and with unique environmental exposures to result in an outcome of ASD.

Rapid progress has been made in the discovery of rare genetic variants (present in <1% of the population) that are associated with the risk of ASD (Figure 1). These genetic variants are likely rare owing to detrimental biological effects that affect the carrier’s reproductive fitness. Rare genetic syndromes (eg, fragile X syndrome and tuberous sclerosis) have long been known to contribute to the risk of ASD and can arise spontaneously (de novo) in the germline.

Figure 1:
Caption: Genetic Risk Variants Associated With the Development of ASD
Description: A, Pedigrees of people affected with autism spectrum disorder (ASD) and their families. Left, pedigree of a family demonstrating multiple inherited genetic risk factors in the affected children of 2 nonaffected parents. Right, pedigree of a family showing the development of a new mutation in the offspring that contributed to the development of ASD in that child. B, Large- and small-scale genetic changes associated with increased risk of ASD. The different classes of genetic variants are presented by size, from large-scale alterations (entire chromosomes or large regions missing or duplicated) at the top, to substitutions of just 1 DNA nucleotide at the bottom. Examples of DNA sequence changes in the coding region of the CHD8 gene associated with ASD are presented in the bottom panel. Sequence corresponds to chromosome 14 (hg19), 21 878 138 to 21 878 130 base pairs (left) and 21 870 179 to 21 870 160 base pairs (right). Variants may be inherited from a carrier parent or develop de novo in the person with ASD. Variants that are more damaging to biological function are less likely to be inherited and may interact with other genetic, environmental, and developmental risk factors to yield a clinical diagnosis of ASD. Single-nucleotide polymorphisms (SNPs) (not depicted) are common variants that contribute to ASD risk, but at this time, individual SNPs have not been linked to risk for ASD to justify clinical screening. Whole-genome sequencing detects copy number and nucleotide sequence variants, but it is not yet clinically available for molecular genetic diagnostic testing owing to increased expense and data storage limitations. PCR indicates polymerase chain reaction.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition marked by difficulties in social communication, languages, and repetitive behaviors. Its rising prevalence has made it a critical global public health issue. ASD is believed to arise from a combination of genetic and environmental influences. While some gene mutations associated with ASD have been identified, most cases lack clear genetic explanations. Evidence increasingly points to early-life environmental factors as key contributors to ASD, including advanced parental age, maternal diabetes during pregnancy, infections, hormonal imbalances, certain medications, and exposure to air pollution. Currently, ASD diagnosis relies on behavioral assessments, but the absence of specific molecular biomarkers poses significant obstacles to early detection and targeted therapies. Encouragingly, research has identified potential biomarkers, such as neuroimaging classifiers, electroencephalography patterns, eye-tracking data, digital analytics, gene expression profiles, inflammatory and chemokine markers, proteomic and metabolomic profiles, and gut microbiota characteristics. Potential therapeutical strategies under investigation include digital therapies, non-invasive brain stimulation, antioxidants, oxytocin, AVPR1a antagonists, PPAR agonists, and mTOR inhibitors. This review explores ASD across five areas: epidemiological trends, genetic mechanisms, early-life environmental factors and their potential roles, diagnostic biomarkers, and therapeutic approaches.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.