Cancer risk with folic acid supplements: a systematic review and meta-analysis

Systematic review and meta-analysis of randomized controlled trials and controlled observational studies in adults taking folic acid supplements. Included populations were highly selected, such as people with cardiovascular disease or high cardiovascular risk, individuals with prior colorectal adenoma, people with atrophic gastritis, and pregnant women, along with observational cohorts from the general population.

Oral folic acid supplementation, generally as tablets, at doses of at least 0.4 mg/day across the included trials. Active-arm doses ranged from 0.5 mg/day to 40 mg/day, with trial durations varying from short-term treatment to long follow-up; some arms compared folic acid with placebo or control and some included folic acid within broader B-vitamin regimens.

Overall, folic acid supplementation showed a borderline increase in cancer incidence in randomized trials and no clear reduction in cancer risk. Total cancer incidence was RR 1.07 (95% CI 1.00 to 1.14) across 10 RCTs, and prostate cancer incidence was significantly higher at RR 1.24 (1.03 to 1.49) across 6 RCTs. Cancer mortality was not significantly increased overall: RR 1.09 (0.92 to 1.30) across 6 RCTs. Observational studies did not show an overall difference in cancer incidence, but subgroup sensitivity analyses suggested higher mortality in studies with >30% smokers, higher folic acid doses, or longer follow-up.

Evidence came largely from highly selected trial populations, limiting generalizability to broader groups such as women of childbearing age. Several arms and covariates were incompletely or inconsistently reported in the source packet, and follow-up may have been insufficient to capture long-latency cancer effects. Results also showed heterogeneity by subgroup, including signals that differed by smoking prevalence, dose, and duration.