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.
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To cite: Wien TN, Pike E, Wisløff T, et al. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open 2012;2:e000653. doi:10.1136/bmjopen-2011-000653
Funding This work was supported by the Norwegian Knowledge Centre for the Health Services.
Competing interests All authors have completed the Unified Competing Interest form, http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author), and declare no competing interests for the submitted work.
Ethics approval This is a systematic review not requiring approval.
Contributors All authors contributed to the design of the systematic review, analysis and interpretation of the data. All authors had full access to all the data and take responsibility for the integrity of the data and the accuracy of the analysis. TNW, EP and TW extracted the data from the included studies. TNW drafted the manuscript, and the other authors critically reviewed the manuscript.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement An extended version of this report in Norwegian is available at the web pages of the Norwegian Knowledge Centre for the Health Services www.nokc.no. Appendices to the extended report including search strategy, tables of included and excluded studies, data analyses on crude and adjusted data and GRADE files are available in English.
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