Abstract / Summary
Abstract Background Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality worldwide, yet effective pharmacological preventive strategies remain uncertain. Statins, metformin, and vitamin D, alone or combined with omega-3, have been investigated for potential protective effects, but comparative evidence is limited. Objective To compare the effectiveness of statins, metformin, and vitamin D in preventing preeclampsia and related adverse outcomes among high-risk pregnant women. Methods A systematic review and network meta-analysis of randomized controlled trials was conducted. PubMed, Scopus, Web of Science, Cochrane, and Epistemonikos were searched from September 11, 2020, to September 11, 2025. Eight trials involving 4,078 high-risk pregnant women were included. Participants were randomized to statins, metformin, or vitamin D at different doses versus placebo. The primary outcome was the incidence of preeclampsia. Secondary outcomes included gestational hypertension, preterm birth, low birth weight, neonatal intensive care unit admission, gestational diabetes, respiratory distress syndrome, and perinatal outcomes. Risk ratios with 95% confidence intervals were calculated, and interventions were ranked using the surface under the cumulative ranking probabilities. Results Eight randomized controlled trials were analyzed. Compared with placebo, higher-dose vitamin D supplementation showed associations with lower estimated risks of preeclampsia, particularly vitamin D 4,000 IU/day (risk ratio 0.21, 95% confidence interval 0.06–0.72) and 60,000 IU monthly (risk ratio 0.36, 95% confidence interval 0.19–0.70). These relative effects corresponded to approximate absolute risk differences of 8% and 6%, respectively, based on observed baseline risks, and reflect associations rather than proven causality. Estimates were derived from limited direct evidence within sparse networks. These dose-specific vitamin D regimens had the highest probabilistic ranking for preeclampsia within the network, but these rankings should be interpreted as exploratory rather than definitive. Higher-dose vitamin D was also associated with trends toward lower event rates of preterm births and low-birth-weight infants, although estimates were imprecise. Evidence for statins and metformin was inconsistent, with wide confidence intervals. SUCRA rankings suggested vitamin D as the highest relative ranking probability overall intervention within the network, followed by statins; however, these rankings remain exploratory given the limited network structure. These associations were derived from limited direct evidence within sparse networks and should be interpreted cautiously. Probabilistic rankings and SUCRA values reflect relative positioning within the network rather than comparative effectiveness. Conclusion In high-risk pregnancies, higher-dose vitamin D regimens were associated with lower estimated risks of preeclampsia compared with placebo; however, these findings are based on limited, heterogeneous, and partly indirect evidence from sparse networks. The certainty of evidence is low, and the observed effect sizes should not be interpreted as evidence of clinical effectiveness. These findings are best considered hypothesis-generating and are intended to inform the design of future studies rather than guide clinical practice. Evidence for statins and metformin remains limited and inconsistent. Overall, further large, well-designed randomized trials are required before firm clinical recommendations can be made.