Folate and vitamin B12 linked to cancer

vitaminsTreating people who have pre-existing heart conditions with folic acid and vitamin B12 could increase their risk of cancer and death from any cause, according to a new study in the Journal of American Medical Association.

The study was conducted in Norway, which does not have folic acid fortification of its foods and hence was felt to be a good study population, and looked at patients with ischemic heart disease.

The research found a statistically significant increase in cancer diagnosis and later death amongst those patients who had been treated with vitamin B12 and folic acid, with lung cancer patients particularly affected.  The authors caution, however, that more research needs to be conducted in other populations, and that close monitoring should occur in populations where folic acid fortification is mandatory.

The SMC went to experts to get their views on the paper, which can also be accessed through the SMC Resource Library.

Dr Murray Skeaff, Professor of Human Nutrition at the University of Otago comments:

“The best way to judge if the results reported by Ebbing et al are convincing and reproducible, is to compare them with the evidence from all other clinical trials of folic acid supplementation.

“Fortunately, there are about ten other large clinical trials of folic acid supplementation that have been completed and whose results are being combined in an impressive international collaborative effort, an effort which includes the researchers who conducted the Norwegian studies and includes their study results. The scientific and public health communities eagerly await the final results of the combined “pooled analysis”.

“Reassuringly, the preliminary results presented earlier this year at a Scientific Meeting in Prague, and in a report of the European Food Safety Authority, show no evidence that folic acid increases overall risk of cancer.”

Dr Elaine Rush, Professor of Nutrition at Auckland University of Technology, comments:

“Pushing the boundaries of application to “normal, real  life” and the question of folic acid fortification is not strong because all who received folic acid received vitamin B12. The dose of vitamin B12 was 150 times higher (i.e. 400 mcg vs 2.4mcg) than that normally obtained from foods by a person who eats red meat – an excellent source of vitamin B12. (Vitamin B12 is an exclusive vitamin because it only comes from animal products).

“The adminstration of B12 is further complicated by the fact that vitamin B12 is stored in the body for more than a year.  Folic acid dose was close to the recommendation and the study group did have low folate to start.  Folate, vitamin B12 and vitamin B6 work together in a metabolic pathway that has a profound influence on how body cells divide but the way cells divide can be influenced by too much or too little of these nutrients.  Supplements are not good nutrition in a pill – more is not necessarily better.  We have evolved to function best when a variety of whole, unprocessed foods are consumed.

“The message is: eat a variety of whole foods every day, not too much and not too little and keep active.

Dr Welma Stonehouse, Associate Professor in Human Nutrition at the Institute of Food, Nutrition and Human Health at Massey University, comments:

“The findings from the extensive randomised double-blind placebo controlled clinical trial on large dosage of B vitamins and cancer risk by Ebbing et al is very relevant, especially in the light of the recent debate in New Zealand regarding the mandatory fortification of bread and concerns about folic acid in relation to cancer risk.

“There is no doubt that the trial had an excellent study design to investigate the causal relationship between the B vitamins and cancer risk. Other strong points of the trial was that it was conducted in a population where there is no folic acid fortification of food; the study included a large sample size (6837 patients with heart disease) and the trial had a long follow-up period from 1998 – 2005 and a post-trial follow-up to December 2007. In short, they reported an increased cancer incidence, cancer mortality and all-cause mortality in the folic-acid treated groups compared to the non-folic acid treated groups.

“It is important to note that none of the groups consumed folic acid alone, but in combination with other B vitamins (folic acid + vitamin B12 + vitamin B6 OR folic acid + vitamin B12 OR vitamin B6 alone or placebo).  It is also important to note that the increased incidence of cancer was mainly driven by increased lung cancer incidence which could have been explained by the high percentage of former and current smokers. This confirms what has been shown by other studies with folic acid and anti-oxidant vitamin supplementation that the risk for cancer increases in populations that already has a higher risk for cancer, like smokers. The supplementation may promote the progression of already existing undiagnosed lesions. Also, of note is that no association was found between folic acid treatment and colorectal cancer, which were previously implicated to be associated with intakes of high dosages of folic acid.

“It is important to realise that the high dosages of folic acid consumed by the participants in this study were six times higher than the proposed dosage for the mandatory fortification of bread in New Zealand. The participants in this study who had the lowest cancer incidence, cancer mortality and all-cause mortality were the group who had serum folate concentrations ranging from 8.63-23.92 nmol/L. These concentrations are probably more likely to be achieved with mandatory fortification. Thus, the results of this study cannot be extrapolated to what may be expected with mandatory fortification. What is needed is a similar trial using fortified foods that provides dosages used in mandatory fortification programmes.

“The results of Ebbing et al does, however, emphasise the importance of monitoring fortification programmes for those small groups of people who might consume high levels of folic acid due to supplement use combined with fortified foods.”

Dr Paul Brent, Chief Scientist at Food Standards Australia New Zealand, comments:

“Food Standards Australia New Zealand (FSANZ) is aware of this Norwegian study.  This  is a combined analysis of two intervention trials conducted from 1998 to 2005 to examine the effect of three B vitamins on heart disease (Ebbing et al., 2009). The two trials allocated 6837 ischemic heart disease patients to receive either folic acid, vitamin B12 and vitamin B6; folic acid and vitamin B12; vitamin B6 or a placebo.  The trials had a mean duration of 3 years, finished in 2004-5 and the authors followed-up the subjects until the end of 2007 – three years after they had stopped taking the vitamins.   Approximately 70% of subjects were current or ex-smokers.

“Approximately forty months after the trials stopped, cancer outcomes and all deaths were investigated. Around 9% of patients were diagnosed with cancer and 3% had died from cancer (often lung cancer).  These results are similar to the original trial findings.  The authors report cancer incidence and mortality was higher in the groups receiving folic acid and vitamin B12 treatment.

“These are only two of the trials that are investigating folic acid in people with prior cardiovascular disease.  There are several other trials, including the VITATOPS trial based in Perth (lead by Prof Graeme Hankey).  Overall, these trials have about 30,000 subjects and have lasted for up to 7 years and used doses of folic acid up to 40mg/day.  These trials are being conducted to test the hypothesis that reducing homocysteine levels using folic acid will decrease the incidence of cardiovascular disease.  Some of these trials have published some of their data and they do not concur with the increase in mortality seen in the two Norwegian trials.  The cancer outcome data is less frequently reported.

“The large cardiovascular trials, including these two Norwegian trials, are part of a pooled analysis in which the original data is being combined and re-analysed to assess both the impact on cardiovascular disease and other outcomes such as cancer and cognitive function. This work is being lead by Prof Robert Clarke at Oxford University.  The results are not available yet, but the report from the European Food Safety Authority (EFSA) meeting held in Uppsala in January 2009 alludes to the result as the ‘meta-analysis showed no evidence of any significant effect of folic acid supplementation on overall risk of cancer’ (see paragraph 54 of the report).  Therefore the results of just two of the trials going into the larger meta/pooled-analysis should not be regarded as a summary of all the available information.

“FSANZ has concluded that, based on the totality of evidence, the levels of folic acid being added to bread are safe for the entire population.”


Prior reports of the Norwegian trials:

· Bønaa KH, Njølstad I, Ueland PM et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354:1578-88.

· Ebbing M, Bleie Ø, Ueland PM et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008;300:795-804.

Description of the Oxford pooled analysis:

· Clarke R, Lewington S, Sherliker P, Armitage J. Effects of B-vitamins on plasma homocysteine concentrations and on risk of cardiovascular disease and dementia. Curr Opin Clin Nutr Mebab Care 2007;10:32-9.

Report from Uppsala meeting:

· Appendix 2 of