Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12Marta Ebbing, Kaare Harald Bønaa, Ottar Nygård, Egil Arnesen, Per Magne Ueland, Jan Erik Nordrehaug, Knut Rasmussen, Inger NjølstadHelga Refsum, Dennis W. Nilsen, Aage Tverdal, Klaus Meyer, Stein Emil Vollset. JAMA. 2009;302(19):2119-2126. Context Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. Objective To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. Design, Setting, and Participants Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. Interventions Oral treatment with folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) and vitamin B6 (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B12 (0.4 mg/d) (n = 1703); vitamin B6 alone (40 mg/d) (n = 1705); or placebo (n = 1721). Main Outcome Measures Cancer incidence, cancer mortality, and all-cause mortality. Results During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B12 vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B12 vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B12 vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B12. Vitamin B6 treatment was not associated with any significant effects. Conclusion Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.