Elevated maternal iron biomarkers and risk of pre-eclampsia in pregnancy: protocol for a systematic review and meta-analysis of observational studies

Background Pre-eclampsia remains a significant contributor to maternal and perinatal morbidity and mortality worldwide. Altered maternal iron metabolism during pregnancy, including, but not limited to, elevated iron biomarkers and dysregulated iron handling, has been implicated in the pathophysiology of pre-eclampsia, through mechanisms involving oxidative stress, endothelial injury, inflammatory activation, and placental dysfunction. However, evidence linking maternal iron biomarkers to pre-eclampsia remains inconclusive, partly because markers like ferritin may reflect both iron status and inflammation. Objectives The systematic review and meta-analysis will synthesise evidence on the association between maternal iron biomarkers and pre-eclampsia in pregnancy. The primary objective is to determine whether elevated maternal iron biomarkers are associated with pre-eclampsia compared with normotensive pregnancies. Secondary objectives are to examine associations by biomarker type and to explore whether gestational timing of biomarker assessment, study design, diagnostic criteria, and adjustment for inflammation or other confounders contribute to heterogeneity. Methods This protocol was developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines, and the completed review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. A systematic search will be conducted in PubMed/MEDLINE, Scopus, Web of Science, Embase, DOAJ, ProQuest Dissertations & Theses and the Cochrane Library for observational studies published from database inception to the final search date. Eligible studies will include pregnant women with measured maternal iron biomarkers and reported pre-eclampsia outcomes. Two reviewers will independently screen studies, extract data, and assess risk-of-bias using an appropriate tool for observational studies. Where appropriate, pooled effect estimates will be calculated using a random-effects model. The certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. Discussion This review will synthesise evidence on the association between maternal iron biomarkers and pre-eclampsia and identify gaps and sources of heterogeneity in the literature. Findings may improve understanding of the role of maternal iron dysregulation in pre-eclampsia and inform future research. Strengths include duplicate screening and formal risk-of-bias assessment, while anticipated limitations include reliance on observational evidence and variability in biomarker measurement. Systematic review registration PROSPERO CRD420261399815 .