Environmental Risk Factors and Biomarkers for Autism Spectrum Disorder: An Umbrella Review of the Evidence

Abstract

Background: Numerous studies have identified the potential risk factors and biomarkers for autism spectrum disorder (ASD). We aim to study the strength and validity of the suggested environmental risk factors or biomarkers of ASD. Methods: We conducted an umbrella review and systematically appraised the relevant meta-analyses of observational studies (PROSPERO registration: CRD42014010715). We searched PubMed from inception to 10/17/2018 and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval (CI), heterogeneity, and 95% prediction intervals. We examined small study effects and excess significance. We performed analyses under credibility ceilings. Findings: A total of 46 eligible articles yielded data on 67 environmental risk factors (cases=544212, population=81708787) and 52 biomarkers (cases=15614, controls=15417). Evidence of association was convincing for greater maternal age (RR=1·31, 95% CI=1·18 to 1·45), maternal chronic hypertension (OR=1·48, 95% CI=1·29 to 1·70), maternal gestational hypertension (OR=1·37, 95% CI=1·21 to 1·54), maternal overweight (RR=1·28, 95% CI=1·19 to 1·36), preeclampsia (RR=1·32, 95% CI=1·20 to 1·45), pre-pregnancy maternal antidepressant exposure (RR=1·48, 95% CI=1·29 to 1·71), and selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy (OR=1·84, 95% CI=1·60 to 2·11). Only two associations, maternal overweight and SSRI during pregnancy, retained high level of evidence under subgroup sensitivity analyses. Evidence from biomarkers was limited. Interpretation: Convincing evidence suggests that maternal factors, such as age and features of metabolic syndrome are associated with risk of ASD. SSRI use during pregnancy was also convincingly associated with risk of ASD, but confounding from underlying maternal psychiatric disorders is possible. Funding: None. Declaration of Interest: We declare no competing interests. Ethical Approval: PROSPERO registration: CRD42014010715