The ups and downs of folic acid fortification

During our reproductive years, extra folic acid is essential. After that, it may be too much.

Folic acid is a synthetic form of folate, a B vitamin found naturally in various fruits, vegetables, and legumes. We need folate to produce and maintain new cells (in particular, red blood cells) and to keep nerve cells functioning properly. It also helps prevent DNA changes that may lead to cancer. In the body, folic acid and naturally occurring folate are identical in their actions, but the bioavailability of folic acid is somewhat higher than that of folate.

There's abundant evidence that women who take folic acid supplements during the periconceptual period (just before conception and throughout the first trimester) can prevent neural tube defects such as spina bifida in their babies. That explains the drive for folic acid fortification of grain and cereal products, which became mandatory in the United States and Canada in 1998. (Voluntary fortification was well under way before then.) Around the same time, health officials boosted the recommended daily adult intake of folic acid to 400 micrograms (mcg). And women of childbearing age were advised to get at least 400 mcg of folic acid per day as part of a healthy diet including foods naturally high in folate and fortified foods. At the time, it was estimated that fortification would contribute about 100 mcg of folic acid per day to the average diet.

Although the main reason for adding folic acid to the food supply was to prevent neural tube defects, health experts thought there might be benefits for others besides pregnant women and their children. Folic acid and vitamins B₆ and B₁₂ help keep homocysteine in check. Homocysteine is an amino acid that has been associated with heart disease, stroke, dementia, and Alzheimer's disease when found in the blood at high levels. The hope was that increased folic acid intake would help reduce homocysteine levels and possibly the risk of cardiovascular disease. Epidemiological and animal studies suggested that it might also help prevent certain forms of cancer, particularly colorectal cancer. In Harvard's long-term Nurses' Health Study, for example, women who got adequate folic acid were less likely to develop colon cancer and, among those who drank alcohol, breast cancer.

Effects of folic acid fortification

In countries that require folic acid fortification, including the United States and Canada, the rate of neural tube defects has fallen by 25% to 50%. Other factors have probably contributed to this effect, such as increased use of prenatal multivitamins, ultrasound screening, and public health programs, but fortification has clearly played an important role. Preliminary research suggests that extra folic acid may also protect against certain childhood cancers and lower the risk of cleft palate and congenital heart disease in newborns.

But when it comes to the secondary benefits of adding folic acid to the food supply, the picture is distinctly mixed. Since fortification was mandated, the average level of folate in the blood of Americans has risen and the average level of homocysteine has fallen. The question is, to what effect? On the plus side, a study published in the journal Circulation (March 14, 2006) found that the rate of stroke deaths fell dramatically in the United States and Canada during the first four years of fortification, compared with the seven preceding years. There was no such improvement (and no fall in the rate of neural tube defects) in England and Wales, where fortification is not mandatory. Stroke mortality has gradually declined since 1990, probably because of wider use of statins, aspirin, and other medications, as well as lifestyle changes. But the authors of the study believe the sharp drop between 1998 and 2002 is probably due to fortification.

However, about the time that fortification was mandated, there was also an uptick in colorectal cancer. Researchers at Tufts University, working with large population-based cancer registries, studied trends in colorectal cancer from 1986 to 2002 in the United States and Canada. The results, published in the July 2007 issue of Cancer Epidemiology Biomarkers and Prevention, showed a 15-year decline that was suddenly reversed in the early fortification years, when average blood levels of folate doubled. As a result, an extra four to six cases of colorectal cancer per 100,000 people per year — a total of 16,500 extra cases — were estimated to have occurred.

Although the chronological link between increased colorectal cancer cases and higher blood levels of folate isn't proof of cause and effect, the Tufts researchers think there are biological reasons why extra folic acid may be to blame. Folic acid and folate play complex roles in the body. There's compelling evidence that high dietary intake of folate may protect healthy cells against colorectal and other cancers. But there's equally strong laboratory and clinical evidence that — under certain circumstances — folic acid can stimulate the growth of cancer cells.

This may also help explain the disappointing results of the Aspirin/Folate Polyp Prevention Study, published in the June 6, 2007, Journal of the American Medical Association. That trial took place between 1994 and 2004 and involved 1,021 men and women who had all had procedures to remove adenomatous polyps (the kind most likely to turn into cancer). To find out if folic acid would prevent more polyps from developing, researchers assigned subjects to receive either 1,000 mcg of folic acid per day or a placebo. Colonoscopies performed after three years and again three to five years later found little difference in the incidence of adenomas. But at the second follow-up, the subjects taking folic acid had nearly double the rate of advanced adenomas and were more than twice as likely to have three or more precancerous polyps. This study doesn't tell us whether folic acid supplements prevent or promote the development of polyps in the first place. But it raises concerns about the effects of excessive folic acid from both supplements and fortification, especially on people ages 50 and over, who are more likely to already have polyps.

Now what?

There's a lot we don't know. Although blood levels of folate have increased in the population as a whole and homocysteine levels have come down, only long-term monitoring can tell us whether fortifying foods with folic acid is a safe or effective public health strategy — and clarify who is more (or less) likely to benefit.

Until recently, experts hoped that lowering homocysteine with folic acid and vitamin B₆ and B₁₂ supplements would lead to fewer heart attacks and cardiovascular events. But several large trials have been disappointing. However, those trials involved only people who already had heart disease, so we don't know yet whether such supplements have any effect on the development of heart disease. Also, most of the study participants did not have the kind of high homocysteine levels that are linked to heart disease. For now, the American Heart Association doesn't recommend folic acid and B vitamin supplements to reduce the risk of heart attack or stroke.

The bottom line? Unless you're pregnant or lactating or have a recognized folate deficiency, the recommended daily intake of folic acid is 400 mcg per day — the amount found in a typical multivitamin. According to Dr. Walter Willett, Chairman of the Department of Nutrition at the Harvard School of Public Health, "the added folic acid from food fortification is on average 100 to 200 mcg per day, but this varies widely, depending on food choice." The tolerable upper intake level (UL) — the maximum safe amount — of folic acid from fortified foods and supplements is 1,000 mcg per day. With all the fortified foods on the market, you may exceed that limit, especially if you're already taking a daily multivitamin containing 400 mcg of folic acid. So it's a good idea to check the nutrition labels of cereal and grain products to find out how much you're getting from fortified foods. (For some examples of fortified foods and their folic acid content, see the table above.)

There's no known health risk from foods naturally high in folate, nor is there a UL for naturally occurring folate in foods, so try to get as much of your daily requirement from a healthy diet that includes fruits, vegetables, and legumes, which also have many other important nutrients. (For some folate-rich foods, see "Food servings with 100 micrograms of naturally occurring folate.") If you need more, take a multivitamin. Make sure it contains adequate vitamin B₁₂ (2.4 mcg/day), because high folic acid intake can mask a vitamin B₁₂ deficiency, which can cause anemia and neurological damage. Don't take folic acid as a single supplement unless a clinician recommends it.