{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:26:16Z","timestamp":1792290376603,"version":"4.4.0"},"reference-count":138,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T00:00:00Z","timestamp":1525737600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ultrasound in Obstet &amp; Gyne"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To summarize evidence from the literature on genetic and non\u2010genetic risk factors associated with pre\u2010eclampsia (PE), assess the presence of statistical bias in the studies and identify risk factors for which there is robust evidence supporting their association with PE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PubMed and ISI Web of Science were searched from inception to October 2016, to identify systematic reviews and meta\u2010analyses of observational studies examining associations between genetic or non\u2010genetic risk  factors and PE. For each meta\u2010analysis, the summary\u2010effect size was estimated using random\u2010effects and fixed\u2010effects models, along with 95% CIs and the 95% prediction interval. Between\u2010study heterogeneity was expressed using the <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup> statistic, and evidence of small\u2010study effects (large studies had significantly more conservative results than smaller studies) and evidence of excess significance bias (too many studies with statistically significant results) were estimated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifty\u2010eight eligible meta\u2010analyses were identified, which included 1466 primary studies and provided data on 130 comparisons of risk factors associated with PE, covering a wide range of comorbid diseases, genetic factors, exposure to environmental agents and biomarkers. Sixty\u2010five (50%) associations had nominally statistically significant findings at <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05, while 16 (12%) were significant at <jats:italic>P<\/jats:italic>\u2009&lt;\u200910<jats:sup>\u20136<\/jats:sup>. Sixty\u2010five (50%) associations had large or very large heterogeneity. Evidence for small\u2010study effects and excess significance bias was found in 10 (8%) and 26 (20%) associations, respectively. The only non\u2010genetic risk factor with convincing evidence for an association with PE was oocyte donation <jats:italic>vs<\/jats:italic> spontaneous conception, which had a summary odds ratio of 4.33 (95% CI, 3.11\u20136.03), was supported by 2712 cases with small heterogeneity (<jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u200926%) and 95% prediction intervals excluding the null value, and without hints of small\u2010study effects (<jats:italic>P<\/jats:italic> for Egger's test &gt;\u20090.10) or excess of significance (<jats:italic>P<\/jats:italic>\u2009&gt;\u20090.05). Of the statistically significant (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) genetic risk factors for PE, only PAI\u20101 4G\/5G (recessive model) polymorphism was supported by strong evidence for a contribution to the pathogenesis of PE. Eleven factors (serum iron level, pregnancy\u2010associated plasma protein\u2010A, chronic kidney disease, polycystic ovary syndrome, mental stress, bacterial and viral infections, cigarette smoking, oocyte donation <jats:italic>vs<\/jats:italic> assisted reproductive technology, obesity <jats:italic>vs<\/jats:italic> normal weight, severe obesity <jats:italic>vs<\/jats:italic> normal weight and primiparity) presented highly suggestive evidence for an association with PE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A large proportion of meta\u2010analyses of genetic and non\u2010genetic risk factors for PE have caveats that threaten their validity. Oocyte donation <jats:italic>vs<\/jats:italic> spontaneous conception and PAI\u20101 4G\/5G polymorphism (recessive model) showed the strongest consistent evidence for an association with risk for PE. Copyright \u00a9 2017 ISUOG. Published by John Wiley &amp; Sons Ltd.<\/jats:p><\/jats:sec>","DOI":"10.1002\/uog.18959","type":"journal-article","created":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T12:46:45Z","timestamp":1510836405000},"page":"720-730","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Genetic and non\u2010genetic risk factors for pre\u2010eclampsia: umbrella review of systematic reviews and meta\u2010analyses of observational studies"],"prefix":"10.1002","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2185-561X","authenticated-orcid":false,"given":"K.","family":"Giannakou","sequence":"first","affiliation":[{"name":"Cyprus International Institute for Environmental &amp; Public Health Cyprus University of Technology  Limassol Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Evangelou","sequence":"additional","affiliation":[{"name":"Department of Hygiene and Epidemiology University of Ioannina Medical School  Ioannina Greece"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. I.","family":"Papatheodorou","sequence":"additional","affiliation":[{"name":"Cyprus International Institute for Environmental &amp; Public Health Cyprus University of Technology  Limassol Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,8]]},"reference":[{"key":"e_1_2_5_2_1","unstructured":"DuleyL. 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