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
There is ample evidence that taking folic acid before and early in pregnancy dramatically decreases the risk of neural tube defects, and mounting evidence that it also prevents other birth defects (e.g., (7-10)).
Women are advised to take 400 micrograms a day of folic acid when they plan to become pregnant and continue to do so until the 12th week of pregnancy, the birth defects it prevents occur early in pregnancy (11). The women in the 1960s trial taking the largest dose of folic acid took more than 10 times that amount (1).
A daily multivitamin-mineral supplement, containing 100 % of the Daily Value (DV) for folic acid will provide 400 mcg of folic acid/day. Even with a larger than average intake of folic acid from fortified foods, it is unlikely that an individual's daily folic acid intake would regularly exceed the tolerable upper intake level of 1,000 mcg/day established by the Food and Nutrition Board. Carcinogenesis & Folic Acid
The authors featured a recent study indicating that rats fed diets deficient in folate had increased mammary tumorigenesis compared with rats fed diets with sufficient folate, whereas rats fed a high dose folate diet had similar levels of tumorigenesis to deficient rats (1,12). 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(13). Fenech et al. 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(14). Thus, there are biologically plausible mechanisms by which increasing folic acid consumption would lower the risk for breast cancer (6).
References
Charles, D., Ness, A. R., Campbell, D., Davey Smith, G. & Hall, M. H. (2004)
Taking folate in pregnancy and risk of maternal breast cancer.
BMJ 329: 1375-1376.
Shrubsole, M. J., Jin, F., Dai, Q., Shu, X. O., Potter, J. D., Hebert, J. R., Gao, Y. T. & Zheng, W. (2001)
Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study.
Cancer Res 61: 7136-7141.
Zhang, S. M., Willett, W. C., Selhub, J., Hunter, D. J., Giovannucci, E. L., Holmes, M. D., Colditz, G. A. & Hankinson, S. E.
(2003)
Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer.
J Natl Cancer Inst 95: 373-380.
Choi, S. W. & Mason, J. B. (2002) Folate status: effects on pathways of colorectal carcinogenesis.
J Nutr 132: 2413S-2418S.
Voutilainen, S., Rissanen, T. H., Virtanen, J., Lakka, T. A. & Salonen, J. T. (2001)
Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study.
Circulation 103: 2674-2680.
Oakley, G. P. & Mandel, J. S. (2004)
Folic acid fortification remains an urgent health priority.
BMJ 329: 1376-.
Czeizel, A. E., Dudas, I. & Metneki, J. (1994)
Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation. Final report.
Arch Gynecol Obstet 255: 131-139.
Czeizel, A. E. (1995)
Folic acid in the prevention of neural tube defects.
J Pediatr Gastroenterol Nutr 20: 4-16.
Rieder, M. J. (1994)
Prevention of neural tube defects with periconceptional folic acid.
Clin Perinatol 21: 483-503.
Smithells, R. W. (1984)
Rational use of vitamins.
Lancet 1: 1295.
Koletzko, B. & Kries von, R. (1995)
Prevention of neural tube defects folic acid administration in early pregnancy. Joint recommendations of the German Society of Nutrition, Gynecology and Obstetrics, Human Genetics, Pediatrics, Society of Neuropediatrics.
Gynäkol Geburtshilfliche Rundschau 35: 2-5.
Kotsopoulos, J., Sohn, K.-J., Martin, R., Choi, M., Renlund, R., Mckerlie, C., Hwang, S. W., Medline, A. & Kim, Y.-I. J.
(2003)
Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats.
Carcinogenesis 24: 937-944.
Cabelof, D. C., Raffoul, J. J., Nakamura, J., Kapoor, D., Abdalla, H. & Heydari, A. R. (2004) Imbalanced Base Excision
Repair in Response to Folate Deficiency Is Accelerated by Polymerase {beta} Haploinsufficiency.
J. Biol. Chem. 279: 36504-36513.
Wang, X. & Fenech, M. (2003)
A comparison of folic acid and 5-methyltetrahydrofolate for prevention of DNA damage and cell death in human lymphocytes in vitro.
Mutagenesis 18: 81-86.