According to the findings of research published in JAMA, treatment with folic acid plus vitamin B12 may be associated with increased cancer outcomes and all-cause mortality in a population where there is no folic acid fortification of foods.

The authors of this research note that concerns have recently been raised about the safety of folic acid, particularly in relation to cancer risk.  The purpose of their study was to combine data from two studies evaluating folic acid (alone or in combination with other B vitamins) and the value of its homocysteine lowering effects in patients with ischaemic heart disease, to explore whether folic acid treatment was associated with cancer outcomes and all-cause mortality after extended follow-up. A non-significant increase in cancer incidence had already been noted during each individual trial.

The Norwegian Vitamin [NORVIT] trial and Western Norway B Vitamin Intervention Trial [WENBIT] enrolled similar patients (total n=6,837), and involved an identical study design and treatment regime.  Participants received randomised, double-blind treatment with one of the following between 1998 and 2005: 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).  The primary endpoints were cancer incidence, cancer mortality, and all-cause mortality through 2007.

After a median 39 months of treatment and an additional 38 months of post-trial observational follow-up (91.6% participated in post-trial follow-up), the main findings were as follows:

• 341 participants (10.0%) who received folic acid plus vitamin B12 versus 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% CI 1.03-1.41; P=0.02).

• 136 (4.0%) versus 100 (2.9%), respectively, died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P=0.01).

• 548 (16.1%) versus 473 (13.8%), respectively, died from any cause (HR 1.18; 95% CI 1.04-1.33; P=0.01).

• Vitamin B6 treatment was not associated with any significant effects.

Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B12.  There were 56 cases of lung cancer in the folic acid groups compared with 36 cases in the non–folic acid groups (HR, 1.59; 99% CI, 0.92-2.75). There were fewer current smokers in the folic acid groups (38%) than in the non–folic acid groups (41%) (P=0.01). After removal of the lung cancer cases, the HR for cancer incidence in folic acid versus non–folic acid groups was 1.16 (95% CI 0.98-1.37).

Of note: Neither of the 2 trials was originally designed to address cancer risk. By pooling the data and extending the follow-up of both trial populations, the study had a statistical power of 61% to detect the observed difference in cancer incidence between the folic acid and non–folic acid groups.

The authors acknowledge several limitations to their study, including lack of information on other risk factors for cancer, use of vitamin B supplements during post-trial follow-up, and the fact that folic acid and vitamin B12 were not studied separately (although the authors note that the observed associations between the primary endpoints and vitamin concentration measured during study treatment were confined to serum folate, suggesting that the adverse effects were mediated by folic acid).

The authors comment that their results “need confirmation in other populations and underline the call for safety monitoring following the widespread consumption of folic acid from dietary supplements and fortified foods.”