Could a vitamin with proven benefits in one group cause harm to another? That’s the growing concern with folic acid, the vitamin that dramatically reduces the risk of neural tube birth defects such a spina bifida. Studies designed to explore the possible benefits of folic acid for heart disease, stroke and cancer are giving out some worrying signs: At best, folic acid is ineffective, and at worst it may be increasing the risks of some cancers. So what does this say about routine supplementation for the typical healthy individual, and its overall risk and benefit?

Folate (vitamin B9) is an essential nutrient found green, leafy vegetables, broccoli, peas, corn, oranges, grains, cereals, and meats. Folate has important roles in the synthesis of DNA, and consequently cell division. Significant folate deficiency can lead to macrocytic anemia. Folic acid, a synthetic form of folate, is used in multivitamins supplements because it is better absorbed.

Folic acid’s benefits in pregnancy are well documented. Supplementation before conception, and in the first few weeks of pregnancy, significantly and substantially lower the risk of several different birth defects, including neural tube defects (NTDs). The neural tube is the embryonic precursor to the brain and spinal column. NTDs include very serious defects like spinal bifida and anencephaly, birth without part of the brain.

The stakes are high, and because the neural tube forms so early in pregnancy (day 26 to 28), deficiencies must be corrected before a woman knows she is pregnant. This has led to public health strategies that mandate supplementation in food products: In both the United States and Canada, folic acid has been added to white flour since the late 1990’s, where it finds its way into baked goods like bread. Following food fortification, neural tube defects have subsequently dropped.

In addition to food fortification, women that could become pregnant are generally advised to take a multivitamin containing at least 0.4mg of folic acid daily. Women at high risk of NTDs may be advised to take higher doses. But as higher doses of folic acid can mask the symptoms of Vitamin B12 deficiency, higher doses warrant medical advice and supervision.

Even with fortification, it’s clear there are still opportunities to improve folic acid consumption in pregnancy. A Canadian population study showed that 20% of women of childbearing age failed to have appropriate folic acid levels in their blood. And while virtually no-one was dangerously deficient, over 40% had levels that would be considered high.

Beyond pregnancy

Observational trials have correlated a diet rich in fruits and vegetables with a lower risk of diseases like colorectal cancer. Based on this epidemiologic evidence, several randomized controlled trials were initiated investigating the effect of the B vitamins (including folic acid) on cancer risk. Folic acid held particular promise because of its proven effects preventing neural tube birth defects.

But the effects were not as expected.

The Warning Signals

That folic acid may interfere with cancer has been known since the 1940’s. The chemotherapy drug methotrexate is an antifolate agent that blocks the metabolism of folic acid, developed after it was noted that a diet deficient in folic acid helped patients with leukemia.

Studies of folic acid supplementation are raising flags about the potential risks of therapy, possibly as a result of excessive consumption. One of the most startling was a study that looked at folic acid supplementation in patients with colorectal adenomas, which are cancer precursors. Participants were randomized to folic acid 1mg or placebo for up to six years. While it was hypothesized that folic acid would provide a protective effect, the results were disappointing. Not only did folic acid have no effect on adenoma incidence (even in those with low folate status),  there was a significant increase in the risk of non-colorectal cancers (10.5% vs. 6.3%), due mainly to an excess of prostate cancers.

Futher worrying evidence emerged in 2009, when a Norwegian study of heart failure patients was published. Researchers randomized almost 7000 patients to folic acid and vitamin B12 versus other vitamins or placebo. The vitamins significantly raised the risks of both cancer and all-cause mortality, driven mainly by more cases of lung cancer. On balance, looking at heart disease, folic acid supplementation don’t seem to have any persuasive effects, either. In combination with other B-vitamins to lower homocysteine levels it hasn’t been shown to have meaningful effects on cardiovascular disease prevention, either.

The same worrying cancer signal has appeared with breast cancer in postmenopausal women, even while dietary folate seems to be beneficial. And in studies looking at prostate cancer, when folic acid is combined with other vitamins, the data are unclear.

So could fortification be causing harm? While correlations have been drawn between food fortification and population studies of colorectal cancer, causality hasn’t been established. Screening rates or other factors could be contributing. Still, the idea is troubling, even though the harms (if real) are slight compared to the demonstrable and significant benefits fortification has played  in reducing NTDs.

Conclusion

In women of childbearing age, folic acid supplementation has a demonstrable and meaningful benefit, reducing the incidence of NTDs. Its use in this population is evidence-based and demonstrably effective. And for treatments for conditions like end-stage kidney disease, folic acid may be of benefit. But when we look at the use of folic acid for primary prevention, the data are less clear. In children, men, and women beyond their childbearing years, supplementation in the absence of deficiency has no demonstrated health benefits, and there are worrying signals that it may raise cancer risks, possibly by “feeding” existing cancers.

Is fortification of our food supply harming and hurting? The benefits on NTD incidence have been demonstrated, while the harms haven’t been proven yet. Still, folic acid’s evolving story may become a cautionary tale about the consequences of fortification and supplementation with the hope of improved health outcomes. If we’re not in our childbearing years, we may be better off relying only on food sources for folate. So pass the spinach, and hold the multivitamins with folic acid.