Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence

Jong Yeob Kim, Min Ji Son, Chei Yun Son, Joaquim Radua, Michael Eisenhut, Florence Gressier, Ai Koyanagi, Andre F. Carvalho, Brendon Stubbs, Marco Solmi, Theodor B. Rais, Keum Hwa Lee, Andreas Kronbichler, Elena Dragioti, Jae Il Shin, Paolo Fusar-Poli

Research output: Contribution to journalArticlepeer-review

129 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)590-600
Number of pages11
JournalThe Lancet Psychiatry
Issue number7
Publication statusPublished - 2019 Jul

Bibliographical note

Funding Information:
BS is supported by a clinical lectureship (ICA-CL-2017-03-001) jointly funded by Health Education England and the National Institute for Health Research (NIHR). BS is part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust. BS is also supported by the Maudsley Charity, King's College London and the NIHR South London Collaboration for Leadership in Applied Health Research and Care funding. This paper presents independent research. The views expressed in this publication are those of the authors and not necessarily those of the acknowledged institutions.

Publisher Copyright:
© 2019 Elsevier Ltd

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Biological Psychiatry


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