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Background: Numerous potential environmental risk/protective factors and biomarkers for attention deficit/hyperactivity disorder (ADHD) have been investigated, but their consistency and magnitude are unclear. Methods: We conducted an umbrella review (registered in PROSPERO, registration: CRD42019145032) to systematically appraise the evidence of association between risk/protective factors or biomarkers and ADHD. We searched PubMed/MEDLINE, Embase, and Cochrane Database of Systematic Reviews from inception to Oct 31 st , 2019 and screened the references of relevant articles. We calculated the summary effect estimates (e.g. odds ratio [OR], relative risk [RR], and weighted mean difference [WMD]), 95% confidence interval, heterogeneity I 2 statistic, 95% prediction interval, small study effects and excess significance biases. Analyses under credibility ceilings were conducted. We assessed the quality of the meta-analyses with AMSTAR 2. Findings: The 37 eligible articles yielded 67 meta-analyses encompassing 43 environmental risk/protective factors (ADHD cases= 728 899, population=37 898 120) and 24 biomarkers (cases=13 784, population=37 629). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR=1·63, 1·49-1·77), childhood eczema (OR=1·31, 1·20-1‧44), preeclampsia (OR=1·31, 1·23-1‧40), hypertensive disorders during pregnancy (OR=1·29, 1·22-1·36), and maternal acetaminophen exposure during pregnancy (RR=1·25, 95% CI=1·17-1·34), and highly suggestive (class II) for maternal smoking during pregnancy (OR=1·56, 1·41-1·73), childhood asthma (OR=1·51, 1·4-1·63), childhood unhealthy dietary pattern (OR=1·41, 1·25-1·58), maternal pre-pregnancy overweight (OR=1·28, 1·21-1·35), and low serum vitamin D (WMD=−6·93, −9·34-−4·51). Interpretation: Pre-pregnancy obesity, overweight, and acetaminophen in pregnancy are strongly associated with ADHD. However, these associations are not necessarily causative and further high-quality studies to confirm these findings would be required. Funding Statement: None. Declaration of Interests: The authors declare no competing interests in relation to the current manuscript. Ethics Approval Statement: PROSPERO: CRD42019145032 |
