MTHFR A1298C polymorphism and risk of pregnancy-induced hypertension: a systematic review and meta-analysis

The association between the methylenetetrahydrofolate reductase ( MTHFR ) A1298C polymorphism and susceptibility to pregnancy-induced hypertension (PIH) has been widely investigated, but the results remain inconsistent. This meta-analysis aimed to systematically evaluate the relationship between the MTHFR A1298C polymorphism and PIH risk. This meta-analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies were identified through a comprehensive search of databases including PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Chinese Science and Technology Journal Full-text, and China Biomedical Literature (CBM), up to November 2025. Relevant data were extracted independently by two investigators. Pooled odds ratios ( OR s) with 95% confidence intervals ( CI s) were calculated to assess the association between the MTHFR A1298C polymorphism and PIH under six genetic models. The false discovery rate (FDR) was applied across the six genetic models and subgroup analyses. Subgroup analyses were performed to explore sources of heterogeneity, and publication bias was assessed using Begg’s and Egger’s tests. A total of 31 studies involving 3,816 PIH patients and 17,303 controls were included. After adjusting for multiple comparisons using the FDR method, no statistically significant association was observed between the MTHFR A1298C polymorphism and PIH risk under any of the six genetic models, including the dominant model, allele, recessive, homozygous, heterozygous, or overdominant models. This meta-analysis indicates no statistically significant association between the MTHFR A1298C polymorphism and PIH susceptibility after adjusting for multiple comparisons. The findings suggest that this variant may not be a major genetic risk factor for PIH. Given the limitations of current evidence, further large-scale, high-quality studies across diverse populations are required to provide a more definitive conclusion.