Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review
Open accessAbstract
Background Many potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD have been investigated, but the consistency and magnitude of their effects are unclear. We aimed to systematically appraise the published evidence of association between potential risk factors, protective factors, or peripheral biomarkers, and ADHD.Methods In this umbrella review of meta-analyses, we searched PubMed including MEDLINE, Embase, and the Cochrane Database of Systematic Reviews, from database inception to Oct 31, 2019, and screened the references of relevant articles. We included systematic reviews that provided meta-analyses of observational studies that examined associations of potential environmental risk factors, environmental protective factors, or peripheral biomarkers with diagnosis of ADHD. We included meta-analyses that used categorical ADHD diagnosis criteria according to DSM, hyperkinetic disorder according to ICD, or criteria that were less rigorous than DSM or ICD, such as self-report. We excluded articles that did not examine environmental risk factors, environmental 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 summary effect estimates (odds ratio [OR], relative risk [RR], weighted mean difference [WMD], Cohen's d, and Hedges' g), 95% CI, heterogeneity I 2 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.Findings We identified 1839 articles, of which 35 were eligible for inclusion. These 35 articles yielded 63 meta-analyses encompassing 40 environmental risk factors and environmental protective factors (median cases 16 850, median population 91 954) and 23 peripheral biomarkers (median cases 175, median controls 187). Evidence of association was convincing (class I) for maternal pre-pregnancy obesity (OR 1·63, 95% CI 1·49 to 1·77), childhood eczema (1·31, 1·20 to 1·44), hypertensive disorders during pregnancy (1·29, 1·22 to 1·36), pre-eclampsia (1·28, 1·21 to 1·35), and maternal acetaminophen exposure during pregnancy (RR 1·25, 95% CI 1·17 to 1·34). Evidence of association was highly suggestive (class II) for maternal smoking during pregnancy (OR 1·6, 95% CI 1·45 to 1·76), childhood asthma (1·51, 1·4 to 1·63), maternal pre-pregnancy overweight (1·28, 1·21 to 1·35), and serum vitamin D (WMD -6·93, 95% CI -9·34 to -4·51).Interpretation Maternal pre-pregnancy obesity and overweight; pre-eclampsia, hypertension, acetaminophen exposure, and smoking during pregnancy; and childhood atopic diseases were strongly associated with ADHD. Previous familial studies suggest that maternal pre-pregnancy obesity, overweight, and smoking during pregnancy are confounded by familial or genetic factors, and further high-quality studies are therefore required to establish causality.Funding None.
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Recent umbrella reviews have shown that most meta-analyses claiming significant associations for putative biomarkers for ASD and ADHD were likely inflated by high risk of bias, including excess of significance bias.
“Recent umbrella reviews have shown that, in the case of many putative biomarkers for ASD and ADHD, most meta-analyses claiming significant associations were likely inflated by high risk of bias, including excess of significance bias 15-17”
From Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review (2023) · cites this paper as [16]
The Database results (page unavailable) report limited robustness for ADHD peripheral-biomarker associations, and the Quality assessment finds seven of nine biomarker meta-analysis articles low or critically low quality. But 11 of the 14 statistically significant biomarker associations had neither detected small-study effects nor excess-significance bias. This source therefore does not establish that most significant associations were inflated by those biases; it also does not assess ASD. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome persons with ADHD/ASD are often from socioeconomically disadvantaged groups/areas and are more likely to be exposed to environmental risk factors (eg, substance misuse, violence) than other populations.
“However, some persons with ADHD/ASD are often from socioeconomically disadvantaged groups/areas and are more likely to be exposed to environmental risk factors (eg, substance misuse, violence) than other populations.61,62,63”
From Mortality in Persons With Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis (2022) · cites this paper as [63]
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- Authors
- Kim, J. H., Kim, J. Y., Lee, J., Jeong, G. H., Lee, E., Lee, S., Lee, K. H., Kronbichler, A., Stubbs, B., Solmi, M., Koyanagi, A., Hong, S. H., Dragioti, E., Jacob, L., Brunoni, A. R., Carvalho, A. F., Radua, J., Thompson, T., Smith, L., Oh, H., Yang, L., Grabovac, I., Schuch, F., Fornaro, M., Stickley, A., Rais, T. B., Salazar de Pablo, G., Shin, J. I., & Fusar-Poli, P.
- Affiliations
- Yonsei University (KR)
- Gyeongsang National University (KR)
- Innsbruck Medical University (AT)
- King's College London (GB)
- University of Padua (IT)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- Harvard University (US)
- Linköping University (SE)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Centre for Addiction and Mental Health (CA)
- University of Greenwich (GB)
- Anglia Ruskin University (GB)
- University of Southern California (US)
- Alberta Health Services (CA)
- Medical University of Vienna (AT)
- Universidade Federal de Santa Maria (BR)
- University of Naples Federico II (IT)
- Södertörn University (SE)
- University of Toledo Medical Center (US)
- Yonsei University Health System (KR)
- Corresponding author
- Shin, Jae Il
- ORCID
- Venue
- The Lancet Psychiatry
- Publisher
- Elsevier BV
- Published
- 2020-11
- Volume
- 7
- Issue
- 11
- Pages
- 955-970
- ISSN
- 2215-0366 (ISSN-L)
- OpenAlex
- W3093088760
- Cited by
- 258
- References
- 110
- Citations by year
- 2026: 30 · 2025: 65 · 2024: 64 · 2023: 45 · 2022: 35 · 2021: 17 · 2020: 2
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Locations
- The Lancet Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Greenwich Academic Literature Archive (University of Greenwich) (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- HAL (submittedVersion)
- Anglia Ruskin Research Online (Anglia Ruskin University) (submittedVersion)
- Figshare (submittedVersion, cc-by-nc-nd)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Keywords
- attention deficit hyperactivity disorder, environmental risk factors, peripheral biomarkers, pediatric atopic dermatitis, hypertensive disorders of pregnancy, maternal smoking
- MeSH terms
- Acetaminophen, Attention Deficit Disorder with Hyperactivity, Female, Humans, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Risk Factors, Biomarkers, Protective Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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