Should folic acid fortification be mandatory? YesBMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39232.493252.47 (Published 14 June 2007) Cite this as: BMJ 2007;334:1252
- 1Wolfson Institute of Preventive Medicine, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ
- 2Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
- Correspondence to: N J Wald
- Accepted 30 May 2007
Delay in fortifying flour with folic acid is unjustified. In many countries this public health measure has increased blood folate levels and reduced neural tube defects. When the effect of folic acid on neural tube defects was shown in 1991, prevention was attempted through diet and supplements.1 But supplements must be taken before pregnancy is confirmed, and most pregnancies remain unprotected.
Voluntary fortification has proved inadequate. Expert advisory committees considering mandatory fortification with folic acid have concluded that it is necessary, effective, and safe; about 40 countries, including the United States, have adopted this policy.
It is important to reach people who are less well off—they have most to gain from fortification. In Chile, where fortification has achieved a relatively high folic acid intake, neural tube defects were reduced by 43%; in the United States, with a lower fortification level, the reduction was about 20%.2 With fortification on a global basis, each year about 250 000 children could be saved from spina bifida or anencephaly and the devastating consequences.3 This public health opportunity should not be lost.
Evidence indicates other benefits from folic acid fortification: a modest but important protection against cardiovascular disease and a suggested reduction in the evidence of a cleft lip and in the rate of cognitive decline with age.4 5 6 We consider the scientific validity of four concerns that are raised against fortification.
“Folic acid may cause cancer”
If judgment were to be made, it would be that folic acid prevented cancer, not that it caused it. The US nurses' health study followed 88 756 women prospectively, and indicated that long term use of folic acid may substantially reduce the risk of colon cancer.7 After 15 years, the relative risk was 0.25 (95% confidence interval 0.13 to 0.51), representing 15 instead of 68 new colon cancers per 10 000 women aged 55 to 69. A meta-analysis of seven cohort and nine case-control studies of colorectal cancer found an overall reduction in risk with folic acid intake.8 Smaller cohort studies have been cited to show that low folate may protect against colorectal cancer,9 but this interpretation arises from a data subset analysis, is probably due to chance, and is unsupported by the overall results of the trial.
The aspirin-folate prevention trial concluded that folic acid did not result in a significant decrease in large bowel adenomas,10 but absence of benefit is not equivalent to the presence of harm. An observed increase of borderline significance was not considered a real effect. Random differences between groups are common in small trials; for example, there were half the number of deaths from all causes in the folic acid group compared with the control group in this trial, which does not mean that folic acid protects against all deaths. A meta-analysis showing a relative risk of 0.99 (0.98 to 1.01) for breast cancer and folate indicates that folic acid neither increases nor decreases the risk of breast cancer.11 It is important not to overinterpret marginally significant associations from individual studies (such as one on breast cancer12); such associations can arise by chance, confounding, or both. The evidence on folic acid and cancer is that there is no harm, and there may be a long term benefit on colorectal cancer.
“Randomised trials have shown no benefit in cardiovascular disease”
The case for fortification is sufficiently made on preventing neural tube defects, irrespective of cardiovascular disease prevention. Until recently, the randomised trials of folic acid and cardiovascular disease lacked the statistical power to show that lowering homocysteine by folic acid has a preventive effect, though the HOPE-2 study showed a significant reduction in strokes.13 A meta-analysis has now confirmed this.14 The genetic polymorphism studies also indicate that homocysteine is a cause of cardiovascular disease.4
“Folic acid may make B-12 deficiency worse”
The assertion that folic acid exacerbates B-12 deficiency is without scientific foundation. It is based on reports published more than 50 years ago, when patients with B-12 deficiency had unknowingly been incorrectly treated with folic acid instead of B-12, so the neurological consequences of untreated B-12 deficiency progressed while the macrocytic anaemia (indistinguishable from that due to folate deficiency) improved because high dose folic acid can reverse the arrest of DNA synthesis that causes a B-12 macrocytosis deficiency. The doses of folic acid used in fortification are below those which resolve the anaemia associated with B-12 deficiency.15 Moreover, these concerns are unwarranted, because the clinical consequences of B-12 deficiency can be avoided by awareness of the neurological nature of B-12 deficiency , the application of the appropriate biochemical tests, and treatment with B-12.
“Folic acid is a form of folate that does not occur in nature”
Synthetic folic acid is ideal for fortification: it is more bio-available than natural folate and, unlike natural folate, is stable in food, even during cooking. It is readily absorbed into the bloodstream—an advantage, as folic acid must pass from the mother's blood to the fetus to be effective. Millions of people have consumed folic acid as supplements for decades before fortification and as a result have had free folic acid in their blood with no credible evidence of any adverse health effects.
Folic acid fortification shows clear benefit in preventing spina bifida and anencephaly, with substantial evidence on safety, and no valid indication of harm. Public health authorities have a responsibility to take action, recognising that failure to fortify has serious health consequences; withholding a benefit causes harm.
Competing interests: GPO is a co-inventor (while at CDC, compensation, if any, will be under the regulations of CDC) of a patent that covers adding folic acid to contraceptive pills and has been a paid consultant to Ortho McNeil on the matter of folate. NJW is a co-inventor of a combination pill for the prevention of cardiovascular disease, which optionally may include folic acid.