Jae Han Kim1, Jong Yeob Kim1, Jinhee Lee2, Gwang Hun Jeong3, Eun Lee4, San Lee4, Keum Hwa Lee5, Andreas Kronbichler6, Brendon Stubbs7, Marco Solmi8, Ai Koyanagi9, Sung Hwi Hong10, Elena Dragioti11, Louis Jacob12, Andre R Brunoni13, Andre F Carvalho14, Joaquim Radua15, Trevor Thompson16, Lee Smith17, Hans Oh18, Lin Yang19, Igor Grabovac20, Felipe Schuch21, Michele Fornaro22, Andrew Stickley23, Theodor B Rais24, Gonzalo Salazar de Pablo25, Jae Il Shin26, Paolo Fusar-Poli27. 1. Yonsei University College of Medicine, Seoul, Republic of Korea. 2. Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea. 3. College of Medicine, Gyeongsang National University, Jinju, Republic of Korea. 4. Department of Psychiatry, Seoul, Republic of Korea. 5. Department of Pediatrics, Seoul, Republic of Korea. 6. Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria. 7. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Department of Physiotherapy, South London and Maudsley NHS Foundation Trust, London, UK; Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK. 8. Early Psychosis: Interventions and Clinical-Detection Lab, Department of Psychosis Studies, King's College London, London, UK; Neurosciences Department, University of Padova, Padova, Italy; Padua Neuroscience Center, University of Padova, Padova, Italy. 9. Parc Sanitari Sant Joan de Deéu, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Universitat de Barcelona, Fundació Sant Joan de Deéu, Sant Boi de Llobregat, Barcelona, Spain. 10. Department of Global Health and Population, Harvard T H Chan School of Public Health, Boston, MA, USA. 11. Pain and Rehabilitation Centre, and Department of Health, Medicine and Caring Sciences, Linkoping University, Linkoping, Sweden. 12. Research and Development Unit, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Universitat de Barcelona, Fundació Sant Joan de Deéu, Sant Boi de Llobregat, Barcelona, Spain; Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France. 13. Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany; Service of Interdisciplinary Neuromodulation, Department of Psychiatry, Laboratory of Neurosciences and National Institute of Biomarkers in Neuropsychiatry, Institute of Psychiatry, Hospital Universitario, Departamento de Clínica Médica, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil. 14. Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. 15. Early Psychosis: Interventions and Clinical-Detection Lab, Department of Psychosis Studies, King's College London, London, UK; Imaging of Mood- and Anxiety-Related Disorders Group, Institut d'Investigacions Biomèdiques Pi i Sunyer, Barcelona, Spain; Mental Health Research Networking Centre (CIBERSAM), Barcelona, Spain; Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 16. Centre for Chronic Illness and Ageing, University of Greenwich, London, UK. 17. The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Chelmsford, UK. 18. School of Social Work, University of Southern California, Los Angeles, CA, USA. 19. Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada; Departments of Oncology and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. 20. Department of Social and Preventive Medicine, Centre for Public Health, Medical University of Vienna, Vienna, Austria. 21. Department of Sports Methods and Techniques, Federal University of Santa Maria, Santa Maria, Brazil. 22. Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University, Naples, Italy. 23. Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, National Centre of Neurology and Psychiatry, Tokyo, Japan; Stockholm Centre for Health and Social Change, Södertörn University, Huddinge, Sweden. 24. Department of Psychiatry, University of Toledo Medical Center, Toledo, OH, USA. 25. Early Psychosis: Interventions and Clinical-Detection Lab, Department of Psychosis Studies, King's College London, London, UK; Department of Child and Adolescent Psychiatry, King's College London, London, UK; Institute of Psychiatry and Mental Health, Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERSAM, Madrid, Spain. 26. Department of Pediatrics, Seoul, Republic of Korea. Electronic address: shinji@yuhs.ac. 27. Early Psychosis: Interventions and Clinical-Detection Lab, Department of Psychosis Studies, King's College London, London, UK; Outreach and Support in South London (OASIS) Service, South London and Maudsley NHS Foundation Trust, London, UK; National Institute of Health Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
Abstract
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 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. 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.
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 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. 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.
Authors: Elena Dragioti; Joaquim Radua; Marco Solmi; Celso Arango; Dominic Oliver; Samuele Cortese; Peter B Jones; Jae Il Shin; Christoph U Correll; Paolo Fusar-Poli Journal: Mol Psychiatry Date: 2022-04-28 Impact factor: 15.992
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