Non-genetic risk factors for preeclampsia: an updated umbrella review

Abstract Background Preeclampsia (PE) is a common pregnancy disorder with complex mechanisms, and multiple risk factors may contribute to its development. Our objective is to update our literature search from our previous umbrella review, summarizing recent evidence on non-genetic risk factors associated with PE and assessing their credibility to identify those supported by robust epidemiological evidence. Methods We searched PubMed, EMBASE, Scopus, and ISI Web of Science up to June 2023. For each meta-analysis, we computed summary effect estimates, 95% confidence intervals, 95% prediction intervals, and assessed heterogeneity using I², while also examining small-study effects and excess significance bias. Quality assessment was conducted using the AMSTAR-2 tool. Results 89 meta-analyses were identified, providing data on 219 associations. Of these, 151 (69%) showed statistically significant findings at P < 0.05, with 52 (24%) remaining significant at P < 10-6. Large or very large heterogeneity was observed in 121 (55%) associations. Evidence for small-study effects and excess significance bias was found in 27 (12%) and 29 (13%) associations, respectively. Only 16 (7%) presented convincing evidence: Polycystic Ovary Syndrome (PCOS), PCOS (adjusted), Obstructive Sleep Apnea (OSA), Obesity (adjusted), Chronic Kidney Disease (CKD), Pregnancy Intrahepatic Cholestasis, SARS-CoV-2 infection (adjusted), Oocyte donation (OD) vs. In vitro fertilization (IVF), Fresh embryo transfer vs. spontaneous conception (SC) (singleton), Frozen embryo transfer vs. SC, OD vs. SC (singleton), IVF-OD vs. IVF-AO, IVF-OD fresh ET vs. IVF-AO fresh ET, NC frozen embryo transfer vs. AC frozen embryo transfer, Fetal sex (term), and Smoking. Conclusions Maternal health conditions like PCOS, along with reproductive interventions such as OD and IVF, as well as lifestyle factors like obesity and smoking, showed convincing associations with PE. Key messages • Maternal health conditions, reproductive interventions, and lifestyle factors showed compelling evidence of association with preeclampsia. • Our findings emphasize the multifactorial nature of preeclampsia and suggest potential avenues for further research and clinical intervention.