Gesellschaft für angewandte Vitaminforschung (GVF)

GVF-Statement zur aktuellen Folsäure-Diskussion (engl.)

Charles, D., Ness, A. R., Campbell, D., Davey Smith, G. & Hall, M. H.
Taking folate in pregnancy and risk of maternal breast cancer (November 2004).
BMJ 329: 1375-1376.

Objective The Aberdeen Folate Supplementation Trial in pregnancy from the 1960s was followed up to enrich the incomplete data on the long term effects of increased folate intake in pregnancy. The association between folate status and death was examined.

Methodology 2,928 pregnant women were followed up enrolled in the Aberdeen Folate Supplementation Trial. The women were randomly assigned to receive a daily dose of 0.2 mg of folate, 5 mg of folate or a placebo. Factors such as age, weight, blood pressure, and smoking habits were also taken into account.

The trial data was linked to the Aberdeen maternity and neonatal databank added information on maternal smoking and maternal height. Furthermore, the records were linked with those held by the National Health Service Central Registry in Edinburgh and the cause of death ascertained. Results By the end of September 2002, 210 women (7.2%) had died; 40 (1.4%) deaths were attributable to cardiovascular disease, 112 (3.8%) to cancer, and 31 (1%) to breast cancer. In women randomised to high doses of supplemental folate, all cause mortality was about a fifth greater, and the risk of deaths attributable to breast cancer was twice as great.

Conclusions Women taking high doses of folate throughout pregnancy may be more likely to die from breast cancer in later life than women taking no folate. However, the increase in mortality and in death from breast cancer with high doses of folate could be a chance finding. The number of deaths was small, the confidence intervals were wide, and there was no pre-specified hypothesis that taking folate supplements in pregnancy would increase the risk of cancer. The data are preliminary and require further research.

Comment

Statistics
 • This report presents a non-statistically significant association between short term prenatal consumption of folic acid and  breast cancer.
• Only 31 breast cancer deaths were found, and the confidence intervals were wide and include one.
• The Hazard Ratio (HR) of 2.02 is based on only 8 cases in the group of women who took tablets of 5 mg folate. Controlling for so many variables (maternal age, smoking height, weight, social class, systolic blood pressure, parity and gestational age) when only 8 cases are considered could produce spurious association even if such does not exist.
• It is very likely that this finding is by chance only, as the authors concluded by it self.
• The finding that the current study outcome is a chance one is supported by the existing literature indicating that increased chronic consumption of folate and higher blood folate concentrations lower the risk of breast cancer, especially among women who consume one or more drinks of alcohol a day. Shrubsole and colleagues found, in a population based study of 1321 cases and 1382 controls, that dietary folate is inversely associated with breast cancer (2). In a prospective follow up cohort, Zhang and colleagues did a nested case-control study, which included 712 breast cancer cases and 712 controls. Comparing women in the upper quintile for blood folate with those in the lowest quintile, they reported a protective relative risk of 0.73. Among women consuming more than 15 g of alcohol a day, they found a highly protective relative risk of 0.11 (3). Folic acid supplementation was not only found to be protective against breast cancer, but also for colorectal cancer (4) and heart disease (5).
• The randomised controlled trial sought to evaluate the effect of antenatal folate consumption and pregnancy outcomes, not breast cancer. General Issues with the Study
• The trial carried out in the 1960s does not meet current standards, and the technical terms used in the paper such as "double blind" and "randomised" should mean what it is agreed that they mean, not something else. The experimental set-up led to the conclusion that this is not the case. Misleading by the Press
• Although, the results of the study are not significant, it is widely communicated in the international press. This could mislead the public and discourage future mothers that there is really risk of taking folic acid over the pregnancy.
• It is preferable such reports that attracts the attention of the media to be based on sound methodology and valid conclusions. This was not the case with this report.
• The authors did qualify their findings with several notes of caution (1) and the findings were balanced by the commentary (6), however, the title of the article and the main media message presented were misleading and unhelpful.
• As the findings are so inconclusive, reporting of this article in the media should have been accompanied by a message reiterating that currently the evidence supported the use of folate in preventing neural tube defects is far stronger and better established than these chance findings. Current Recommendation for Folic Acid