Charles and colleagues report a non-statistically significant association between short term prenatal consumption of folic acid and breast cancer.1 As the authors note, even though these data are from a randomised controlled trial, they had no prespecified hypothesis. The randomised controlled trial sought to evaluate the effect of antenatal folate consumption and pregnancy outcomes, not breast cancer. Only 31 breast cancer deaths were found, and the confidence intervals were wide and include one. We believe that the most likely explanation for the reported association is chance.

In contrast to the results reported by Charles and colleagues, the existing literature indicates 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 (odds ratio 0.71; 95% confidence interval 0.56 to 0.92).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 (95% confidence interval 0.50 to 1.07). Among women consuming more than 15 g of alcohol a day, they found a highly protective relative risk of 0.11 (0.02 to 0.59).3

Mutagenic mechanisms by which folate deficiency might induce cancer have also been sought. The current search is focused on DNA that is damaged by imbalanced base excision repair of DNA that had uracil incorporated because there was not enough folate to provide sufficient thymine.4 Fenech and colleagues have looked at in vitro human cell systems and found an inverse dose-response effect between mutagenic end points and concentrations of folic acid in the culture.5 Thus, there are biologically plausible mechanisms by which increasing folic acid consumption would lower the risk for breast cancer.

Our argument that Charles' and colleagues' finding is a chance one is buttressed by these epidemiological and mutation studies, which indicate that more folic acid is likely to prevent breast cancer rather than to cause it. Charles' report should not deter mandatory folic acid fortification of wheat and corn flour around the world. Mandatory fortification should be immediately implemented for the known benefits of preventing birth defects and anemia. Folic acid fortification in the United States was followed each year with a reduction in deaths from strokes and heart attacks that is greater than the annual deaths from vehicular crashes, indicating another important public health improvement from fortification. Inertia on mandatory folic acid fortification continues to be bad policy.