Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses.
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.


RESULTS
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.
Department of Psychiatry and Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, USA.
Amirhossein
A
Modabbernia
Department of Psychiatry and Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, USA.|Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.
Eva
E
Velthorst
Department of Psychiatry and Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, USA.|Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.|Friedman Brain Institute, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.|Seaver Autism Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA.
Abraham
A
Reichenberg
D000067877:Autism Spectrum Disorder / Q000209:etiology*; D036861:Delivery, Obstetric / Q000009:adverse effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D006801:Humans; D015201:Meta-Analysis as Topic; D019216:Metals, Heavy / Q000633:toxicity*; D010290:Parents; D011247:Pregnancy; D011446:Prospective Studies; D012307:Risk Factors; D000078202:Systematic Reviews as Topic
D019216:Metals, Heavy
Autism spectrum disorders; Environment; Epigenetics; Gene-environment interaction; Metals; Nutrition; Pregnancy prenatal; Toxin; Vaccine