Epigenetic Modifications of Umbilical Cord Blood and Preeclampsia: a Systematic Review and Metanalysis Protocol

Background Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality worldwide, with growing evidence suggesting that in utero exposure to this condition may induce persistent biological alterations in the offspring through epigenetic mechanisms. Umbilical cord blood offers a valuable substrate to investigate the early molecular imprint of preeclampsia and its potential role in developmental programming. Although numerous studies have reported global and gene-specific DNA methylation changes in cord blood, findings are inconsistent, particularly regarding the direction and magnitude of hypo- or hypermethylation. To address these discrepancies, this protocol outlines a rigorous and reproducible framework for a systematic review and meta-analysis aimed at synthesizing evidence on epigenetic modifications in umbilical cord blood associated with preeclampsia and their relationships with maternal and neonatal characteristics. Methods This study, designed in accordance with the PRISMA 2020 guidelines, will assess epigenetic modifications in umbilical cord blood associated with preeclampsia. Observational studies and clinical trials comparing preeclamptic and normotensive pregnancies and analysing DNA methylation or other epigenetic markers will be included. A comprehensive search will be conducted in PubMed, Web of Science, Scopus, and CENTRAL, supplemented by grey literature sources. Study selection, data extraction, and risk of bias assessment (ROB 2, ROBINS-I) will be performed independently by two reviewers. A meta-analysis will be conducted using RevMan according to heterogeneity, with subgroup analyses, assessment of publication bias, and GRADE evaluation of the certainty of evidence. Ethics and dissemination: The studies included in this review are presumed to have obtained the appropriate ethical approvals in accordance with applicable local and international regulations, umbilical cord blood. Conclusion In conclusion, this study will provide a comprehensive and methodologically robust synthesis of the evidence on epigenetic modifications in umbilical cord blood associated with preeclampsia. By clarifying the direction, agnitude, and consistency of reported alterations, and by exploring sources of heterogeneity across studies, this work will strengthen the understanding of the early-life epigenetic imprint of preeclampsia. The findings are expected to inform future mechanistic research, improve risk stratification strategies, and guide the development of preventive and early-life interventions targeting long-term maternal and offspring health. PROSPERO registration number : CRD420261301497