The Association Between the Risk of Hypertensive Disorders of Pregnancy and Folic Acid: A Systematic Review and Meta-Analysis

Although folic acid (FA) supplementation has been shown to reduce general cardiovascular risks, its impact on hypertensive disorders of pregnancy (HDP) is unclear. We performed a systematic review and meta-analysis to clarify the association between FA and the risk of HDP (pre-eclampsia (PE) and gestational hypertension (GH)). PubMed, EmBase, and Cochrane Library were searched up to June 18, 2020, stratified by type of disease, initiation time of FA, form of FA and pre-conception Body Mass Index (BMI). The quality assessment of included studies was evaluated using Newcastle-Ottawa Scale (NOS) for cohort studies and Cochrane Collaboration's Risk of Bias Assessment Tool for randomized controlled trials (RCTs). Between-study heterogeneity was quantified using Cochran's Q-statistic and I2 statistics. Sensitivity analysis was performed by excluding the studies one by one, and publication bias was analyzed using funnel plots. Twenty studies with 359041 patients were identified for inclusion in the meta-analysis which included 3 RCTs and 17 cohort studies. Pooled estimates showed RR of 0.83 (95%CI 0.74-0.93, P=0.0008) for association between low dose FA (LD-FA) and the risk of PE, but LD-FA was not associated with GH (RR 1.05, 95% CI 0.97-1.13, P=0.20). In addition, the results of subgroup analysis showed that post-conception LD-FA had a 31% decreased risk of PE (RR 0.69, 95% CI 0.59-0.80, P