- Deborah Charles, research assistant1,
- Andy R Ness (), senior lecturer in epidemiology2,
- Doris Campbell, reader in obstetrics and gynaecology1,
- George Davey Smith, professor of clinical epidemiology3,
- Marion H Hall, emeritus professor1
- 1 Dugald Baird Centre For Research on Women's Health, Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Aberdeen AB25 2ZL
- 2 Unit of Paediatric and Perinatal Epidemiology, Division of Child Health, Bristol BS8 1TQ
- 3 Department of Social Medicine, University of Bristol, Bristol B58 2PR
- Correspondence to: A R Ness
- Accepted 7 October 2004
Taking folate before conception and then for the first three months of pregnancy reduces the risk of recurrence of neural tube defects,1 and fortification of food has been proposed. The effects of long term exposure to high concentrations of supplemental folate are unknown, and antimetabolite effects are theoretically possible.2 Data on the long term effects of increased folate intake in pregnancy are limited. We followed up a large trial of folate supplementation in pregnancy from the 1960s.3 4 We examined the association between folate status and death, and we also analysed the effects of folate supplementation.
Participants, methods, and results
From June 1966 to June 1967, 3187 women were identified as potentially eligible for a trial of folate supplementation.3 4 At her booking visit, the mother's age, gestation, parity, weight, and blood pressure were recorded, and blood was taken to measure serum folate concentrations. Tablets were supplied in six colours, two of which contained folate in 0.2 mg and 5 mg daily doses. The tablets were kept in numbered drawers and distributed in sequence. The trial was double blind. The husband or partner's occupation at the time of delivery was used to determine social class. Linking the trial data to the Aberdeen maternity and neonatal databank added information on maternal smoking and maternal height. No women withdrew from the trial. Compliance was assessed by self report and by measurement of folate status.
The records were linked with those held by the National Health Service Central Registry in Edinburgh and the cause of death ascertained. In all, 3037 women were recruited to the study, and 2928 were randomised. In the placebo group, 1.9% reported that they had not taken their tablets regularly compared with 1.7% in the group taking 0.2 mg folate and 3.2% in the group taking 5 mg. Initial folate concentrations were similar in the three groups. For later folate measurements there was a dose-response relation between dose of folate and folate status. Baseline characteristics of the women in the three treatment groups were comparable.
By the end of September 2002, 210 women had died; 40 deaths were attributable to cardiovascular disease, 112 to cancer, and 31 to breast cancer (table).
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. This increased risk in deaths attributable to breast cancer is unlikely to be due to competing causes as the number of deaths was small and all cause mortality appeared to be greater. 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 we had no prespecified hypothesis that taking folate supplements in pregnancy would increase the risk of cancer. As this randomised trial was of high quality, bias and confounding are unlikely explanations for our findings. A recent study indicated that rats fed diets deficient in folate had increased mammary tumorigenesis compared with rats fed diets with sufficient folate,5 whereas rats fed a high dose folate diet had similar levels of tumorigenesis to deficient rats.5 Our data are preliminary and these findings require confirmation.
What this paper suggests
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
What research is needed now
This may be a chance finding, so further studies should examine the association between folate supplementation in pregnancy and risk of breast cancer
Contributors DC did the fieldwork and the analysis. AN wrote the first draft. All the authors commented on this and subsequent drafts. AN is guarantor.
Funding The original study had a project grant from the board of management for the Aberdeen Special Hospitals. Glaxo supplied the tablets. A project grant from the British Heart Foundation supported the reanalysis and follow up.
Competing interests None declared.
Ethical approval Multi-Centre Research Ethics Committee and the local Grampian Research Ethics Committee.