High-dose folic acid and vitamin B12 supplements were associated with an increased incidence of cancer -- particularly lung cancer -- in a post-hoc analysis of two Norwegian trials.
However, other researchers cautioned that the results should not turn women away from normal folic acid supplements that can help prevent birth defects.
Among study participants who received folic acid plus vitamin B12, some 341 (10%) developed cancer compared with 288 (8.4%) of those who did not receive the two vitamins (HR 1.21, 95% CI 1.03 to 1.41, P=0.02), according to Marta Ebbing, MD, of Haukeland University Hospital in Bergen, and colleagues.
In the folic acid group, there were 56 cases of lung cancer compared with 36 cases in those who didn't get the supplements (HR 1.59, 99% CI 0.92 to 2.75), the researchers reported in the Nov. 18 issue of the Journal of the American Medical Association.
"This is yet another study showing that there may be harms in taking high-dose nutritional supplements," said Tim Byers, MD, of the University of Colorado Cancer Center in Denver, who was not involved in the study.
"Effects of essential nutrients at dietary levels seem to be different from those at pill levels," said Byers, who has conducted epidemiologic and clinical studies of nutrients for protection against cancer.
Since 1998, the U.S. and many other countries (but not Norway), have mandated folic acid supplementation of grain products to reduce the incidence of neural tube birth defects.
The Norwegian trials originally sought to determine if homocysteine-lowering treatment with folic acid and vitamin B12 could protect against cardiovascular morbidity and mortality in high-risk patients, but found no benefit.
More recently, concerns have arisen about a potential increased risk of cancer associated with folic acid. Since the Norwegian population had relatively little environmental exposure to these vitamins, Ebbing and colleagues analyzed data from the 6,837 participants to explore the possible link.
Participants in the trials were randomized to one of four regimens: folic acid plus vitamins B12 and B6, folic acid plus vitamin B12, vitamin B6 alone, or placebo.
Folic acid was given in doses of 0.8 mg/day, while vitamin B12 was given in doses of 0.4 mg/day.
Participants' mean age was 62.3 years, and 23.5% were women.
At baseline, 38% of participants in the folic acid groups were current smokers, compared with 41% in the non-folic acid groups (P=0.01).
A total of 629 subjects were diagnosed with new cancers during a median of 39 months in the trials and during an additional 38 months of an observational follow-up period.
Overall, there were 1,021 deaths, with 23.1% being caused by cancer and 31.8% of the cancer deaths being attributed to lung cancer.
Among those who received folic acid and vitamin B12, 136 (4%) died from cancer compared to 100 (2.9%) of those who did not receive the vitamins (HR 1.38, 95% CI 1.07 to 1.79, P=0.01).
A total of 548 participants (16.1%) who received folic acid and vitamin B12 died from any cause, compared with 473 (13.8%) of those who did not receive the vitamins (HR 1.18, 95% CI 1.04 to 1.33, P=0.01).
Of all cases of lung cancer, 64 (69.6%) were in current smokers, 22 (23.9%) were in former smokers, and six (6.5%) were in patients who had never smoked.
More detail on participants' smoking histories would have been helpful, according to Susan T. Mayne, PhD, of Yale School of Public Health in New Haven.
"The paper did not adequately assess this, only looking at crude categories such as ever, never, current smokers," she said.
Mayne also pointed out that the Norwegian researchers used a biomarker that reflects recent exposure to nicotine (cotinine), and this was slightly higher in the folic acid/vitamin B12 groups.
Baseline cotinine levels in current smokers were 27.1 μg/L and 27.6 μg/L in the two folic acid/vitamin B12 groups and 25.7 μg/L and 25.5 μg/L in the non-folate groups.
"So, it is conceivable that, by chance, these two groups had longer duration smokers with greater smoking intensity (greater pack-years of exposure to tobacco)," she said.
Mayne also noted that a study designed specifically to investigate cancer outcomes would likely have focused more closely on tobacco exposure. The study authors themselves acknowledged that their lack of information on family history of cancer and environmental exposure was a limitation.
Mayne also noted that folic acid was never given alone, but always with vitamin B12, and in doses that were two times the U.S. recommended daily allowance. "In contrast, the dose of vitamin B12 was much higher," she said.
The current recommended daily allowance for vitamin B12 in the U.S. is 2.4 μg/day.
"In this study, the daily dose that was given was 400 μg ... so it is really illogical to try to 'blame' the folic acid for the effects observed, when in fact the result could well reflect the high dose of B12 given," she said.
The bottom line for patients, according to Mayne, is that high-dose supplements should not be used for chronic disease prevention.
But the findings do not imply that folic acid is always harmful. "Folic acid clearly reduces risk for birth defects," said Byers.
"Among younger, fertile women, the risk of fueling an occult neoplasm is low in comparison to that benefit," he added.
In an editorial that accompanied the Norwegian study, Bettina F. Drake, PhD, and Graham A. Colditz, MD, of Washington University in St. Louis, agreed saying that the short-term data presented by Ebbing and colleagues "do not nullify the potential long-term benefits that folic acid fortification may have on population health."
Rather, "cessation of cigarette smoking and prevention of smoking in youth and adolescents remains the highest priority for cancer prevention," Drake and Colditz wrote.
