Cancer risk with folic acid supplements: a systematic review and meta-analysis
What this study found
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…
- Study & population
- Systematic review and meta-analysis of randomized controlled trials and controlled observational studies in adults taking folic acid supplements.
- Intervention
- Oral folic acid supplementation, generally as tablets, at doses of at least 0.4 mg/day across the included trials.
- Key limitation
- Evidence came largely from highly selected trial populations, limiting generalizability to broader groups such as women of childbearing age.
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Open PDFOriginal abstract
Objective To explore if there is an increased cancer risk associated with folic acid supplements given orally. Design Systematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer incidence and/or cancer mortality. Studies on folic acid fortification of foods were not included. Data sources Cochrane Library, Medline, Embase and Centre of Reviews and Dissemination, clinical trial registries and hand-searching of key journals. Results From 4104 potential references, 19 studies contributed data to our meta-analyses, including 12 randomised controlled trials (RCTs). Meta-analysis of the 10 RCTs reporting overall cancer incidence (N=38 233) gave an RR of developing cancer in patients randomised to folic acid supplements of 1.07 (95% CI 1.00 to 1.14) compared to controls. Overall cancer incidence was not reported in the seven observational studies. Meta-analyses of six RCTs reporting prostate cancer incidence showed an RR of prostate cancer of 1.24 (95% CI 1.03 to 1.49) for the men receiving folic acid compared to controls. No significant difference in cancer incidence was shown between groups receiving folic acid and placebo/control group, for any other cancer type. Total cancer mortality was reported in six RCTs, and a meta-analysis of these did not show any significant difference in cancer mortality in folic acid supplemented groups compared to controls (RR 1.09, 95% CI 0.90 to 1.30). None of the observational studies addressed mortality. Conclusions A meta-analysis of 10 RCTs showed a borderline significant increase in frequency of overall cancer in the folic acid group compared to controls. Overall cancer incidence was not reported in the seven observational studies. Prostate cancer was the only cancer type found to be increased after folic acid supplementation (meta-analyses of six RCTs). Prospective studies of cancer development in populations where food is fortified with folic acid could indicate whether fortification similar to supplementation moderately increases prostate cancer risk.