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Environmental risk/protective factors and peripheral biomarkers for attention-deficit/hyperactivity disorder: an umbrella review

Environmental risk/protective factors and peripheral biomarkers for attention-deficit/hyperactivity disorder: an umbrella review

Kim, Jae Han, Yeob Kim, Jong, Lee, Jinhee, Jeong, Gwang Hun, Lee, Eun, Kronbichler, Andreas, Stubbs, Brendon, Solmi, Marco, Koyanagi, Ai, Dragioti, Elena, Jacob, Louis, Carvalho, Andre F., Thompson, Trevor ORCID: 0000-0001-9880-782X, Smith, Lee, Oh, Hans, Shin, Jae Il and Fusar-Poli, Paolo (2020) Environmental risk/protective factors and peripheral biomarkers for attention-deficit/hyperactivity disorder: an umbrella review. Lancet Psychiatry, 7 (11). pp. 955-970. ISSN 2215-0366 (Print), 2215-0374 (Online) (doi:

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Many potential environmental risk and protective factors, and peripheral biomarkers for ADHD have been investigated, but their consistency and magnitude are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD.

We did an umbrella review of meta-analyses. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews providing meta-analyses of observational studies that examined associations of potential environmental risk factors, protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta- analyses using categorical ADHD diagnosis criteria according to DSM, or hyperkinetic disorder according to ICD, and accepted less rigorous criteria such as self-reports. We excluded articles that did not examine environmental risk factors, protective factors, or peripheral biomarkers of ADHD; articles that did not include a meta-analysis; and articles that did not present enough data for re-analysis. We excluded non-human studies, primary studies, genetic studies, and conference abstracts. We calculated the summary effect estimates (odds ratio [OR], relative risk [RR], and weighted mean difference [WMD]), 95% CI, heterogeneity I2 statistic, 95% prediction interval, small study effects, and excess significance biases. We did analyses under credibility ceilings, and assessed the quality of the meta- analyses with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). This study is registered with PROSPERO, number CRD42019145032.

We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median control 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49–1·77), childhood eczema (1·31, 1·20–1·44), hypertensive disorders during pregnancy (1·29, 1·22–1·36), preeclampsia (1·28, 1·21–1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17–1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45–1·76), childhood asthma (1·51, 1·4–1·63), maternal pre- pregnancy overweight (1·28, 1·21–1·35), and serum vitamin D (WMD −6·93, 95% CI −9·34 to −4·51).

Maternal obesity, overweight, preeclampsia, and hypertension; maternal acetaminophen exposure or smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD in offspring. Previous familial studies suggest that pre-pregnancy obesity, overweight, and maternal smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality.

Item Type: Article
Additional Information: Note this has a large team of authors, but my contribution was a substantial one; a large author team is needed for Umbrella reviews and reflects the sheer scope of the work (we reviewed 63 meta-analyses and 1839 individual studies).
Uncontrolled Keywords: ADHD; biomarkers; meta-research; umbrella review
Subjects: B Philosophy. Psychology. Religion > BF Psychology
G Geography. Anthropology. Recreation > GE Environmental Sciences
Faculty / Department / Research Group: Faculty of Education, Health & Human Sciences
Faculty of Education, Health & Human Sciences > Department of Psychology, Social Work & Counselling
Last Modified: 01 May 2021 01:38
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
Selected for REF2021: None

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