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

BMJ Open

Jan 2012

DOI: 10.1136/bmjopen-2011-000653

Citations:197

Influential Citations:7

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

Systematic review and meta-analysis of randomized controlled trials and controlled observational studies investigating cancer incidence and mortality in adults taking folic acid supplements; populations included adults with cardiovascular disease or high cardiovascular risk, history of colorectal adenoma, atrophic gastritis, and one trial in pregnant women; study designs encompassed RCTs and observational studies.

Intervention

Oral folic acid supplements (tablets); dosage ranged from 0.4 mg/day to 5 mg/day (pregnant women studied at 5 mg/day); duration varied from several months to about 40 months of active treatment, with some trials including ~38 months of post-trial follow-up; sometimes coadministered with other B vitamins or aspirin.

Results

Folic acid supplementation showed a borderline significant increase in overall cancer incidence in RCTs (RR ~1.07; 95% CI around 1.00–1.14). Prostate cancer incidence was higher in RCTs (RR ~1.24; 95% CI 1.03–1.49). No clear increase in incidence for other cancer types. Cancer mortality did not show a significant overall increase (RR ~1.09; 95% CI 0.92–1.30), though a subgroup with high smoking prevalence showed higher mortality (RR ~1.38; 95% CI 1.10–1.72). Conclusions: There is a very modest but statistically significant signal of increased cancer risk with folic acid supplementation, particularly for prostate cancer, though results mainly come from selected populations; benefits for neural tube defect prevention remain for periconceptional use, but applicability to the general population is uncertain.

Limitations

Short follow-up in many trials; highly selected populations (mostly cardiovascular patients) limit generalizability; variation in dose and co-interventions; incomplete reporting of cancer outcomes in some studies; potential confounding factors such as smoking; relatively few cancer mortality events; heterogeneity across studies.

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. show less