Association Between Folate Status and Risk of Cervical Cancer: A Systematic Review, Dose–Response Meta-analysis, and Mendelian Randomization Study

CONTEXT: Cervical cancer (CC) is one of the leading cancers threatening women's health worldwide. Folate is essential for one-carbon metabolism, influencing DNA synthesis and methylation. However, the role of folate status in cervical carcinogenesis is not fully understood. OBJECTIVE: To explore the association between folate deficiency and CC risk in women, and the association between folate supplementation and the regression of cervical intraepithelial neoplasia (CIN). DATA SOURCES: We conducted a comprehensive literature search in PubMed and Ovid databases with no initial restrictions on publication dates initially conducted on June 1, 2023, and updated on January 30, 2025. Mendelian randomization data were obtained from the IEU Open GWAS Project database (https://gwas.mrcieu.ac.uk/). DATA EXTRACTION: Two of the authors independently extracted data using a standardized method and protocol. DATA ANALYSIS: Twenty-five studies with 14 304 participants were included. The lowest quartile of dietary folate intake (odds ratio [OR]: 1.36; 95% CI: 1.18, 1.58), serum folate (OR: 1.54; 95% CI: 1.18, 2.01), and red blood cell (RBC) folate (OR: 1.43; 95% CI: 1.07, 1.93) were associated with a higher CIN and/or CC risk. Dose-response meta-analysis indicated that an additional 240-280.5 μg/day of folate supplementation was associated with a reduction in CIN and/or CC risk by up to 26%. Each 5-nmol/L increase in serum folate and 50-nmol/L increase in RBC folate were associated with 21% and 5% risk reductions, respectively. Folate supplementation showed a significant association with CIN regression (OR: 1.23; 95% CI: 0.88, 1.72). Mendelian randomization supported a reduced CC risk linked to folate intake (OR: 1.000252; 95% CI: 1.000036, 1.000468). CONCLUSION: Our findings suggest that an additional 240-280.5 μg/day of folate supplementation, along with higher serum and RBC folate concentrations, may be associated with reduced CIN and/or CC risk, highlighting the importance of folate in CC prevention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no.: CRD42019123443.