View larger version (17K): [in this window] [in a new window]   Figure 2. The chemical structure of folic acid. (Reprinted with permission of Ed Uthman, M.D., from Uthman.4)

The causes of about 60 percent of all birth defects are still largely unknown. But each day, 411 babies are born with some type of birth defect.⁸ The effects of many are multifaceted and lifelong. From an economic standpoint, the treatment of a child with Down syndrome over his or her entire lifetime costs nearly half a million dollars.⁹

Strong evidence of folic acid’s benefit appeared in 1991, with the publication of the results of a prevention trial involving more than 1,800 women.¹⁰ All had had previous pregnancies affected by NTDs, which increased the risk of a subsequent affected pregnancy. The study—conducted at 33 medical centers in seven countries—found that 4,000 micrograms of folic acid taken supplementally provided a 72 percent protective effect and no demonstrable harm.¹¹

The next year, a Hungarian study found that supplementation with 800 µg of folic acid also reduced the risk of NTDs in women who were not at increased risk of experiencing such a pregnancy—they had either never been pregnant before or had normal previous pregnancies. Of the babies born to the more than 2,000 women in the study who received folic acid, none had an NTD; in babies born to women in the control group, six NTDs were identified.¹¹

Based on this evidence, as well as on intervention clinical trial studies of folate supplementation that related NTDs to folate intake and folate concentrations, the U.S. Public Health Service, or PHS, recommended that all women in the United States who might become pregnant should consume 400 µg of folic acid daily to reduce the risk of NTDs in their offspring.¹² Other public and private agencies and organizations—including the U.S. Food and Drug Administration, or FDA; the Teratology Society; and the Spina Bifida Association of America—recommend daily intake of folic acid.

If the take-home message is that folic acid is for pregnant women, the message is incomplete. Because NTDs develop in the first 28 days after conception, by the time a woman knows she is pregnant, it’s too late for folic acid to help. And because half of the pregnancies in this country are unplanned, folic acid recommendations are for all women—not only those planning a pregnancy.¹³

To make it easier for women to increase their folic acid intake, in 1996 the FDA issued regulations requiring the addition of 140 µg of folic acid per 100 grams of grain to cereals, breads, pastas and other foods labeled "enriched." However, most women will not be able to rely on enriched foods alone; it is estimated that this additional amount of folic acid will prevent only 5 to 20 percent of the NTDs that folic acid can affect.¹⁴

It may be difficult enough to persuade people to alter their lifestyles by quitting tobacco use or adjusting to a low-fat diet. But even recommendations to take a vitamin supplement containing folic acid—begun in the early 1990s—all too often have not been heard. Although approximately 25 percent of the U.S. population takes vitamin supplements,⁵ not all of that 25 percent are women, and not all of those supplements contain folic acid. Since the publication of those landmark studies tying folic acid supplements to a reduction in NTDs, public education efforts have attempted to let women know about the incredible benefits of taking a multivitamin containing folic acid. However, according to the March of Dimes, the proportion of women taking a multivitamin containing folic acid has not increased.¹⁵ The organization reports that only 18 percent of nonpregnant women aged 18 to 24 years, 30 percent aged 25 to 34 years and 33 percent aged 35 to 44 years are taking folic acid. Percentages were even lower among women with less education and smaller household incomes.¹⁵

However, more women now know about folic acid; from 1995 to 1998, the percentage of women who had heard of the vitamin increased from 52 percent to 68 percent. But only 32 percent were taking folic acid in 1998 (a weak increase from 28 percent in 1995), and only 13 percent knew that folic acid could prevent birth defects.¹⁵ Among Canadian women aged 16 to 40 years who completed a questionnaire while visiting their family physicians in 1996, only 22.5 percent knew that NTDs were preventable, and less than 2 percent knew that folic acid supplements taken before conception could reduce the risk of NTDs.¹⁶

In the United Kingdom, peri-conception folate supplementation also has been encouraged since the early 1990s, and the U.K. Department of Health recommends that all women of childbearing age take 400 µg of folic acid daily.¹⁷ However, no concurrent decline in NTDs has been observed by regional congenital anomaly registers.¹⁸

Ironically, serum folate levels in women in the United States do seem to be increasing, possibly because of food fortification. From 1994 to 1998, median serum folate values in clinical specimens increased, and the percentage of low values decreased.¹⁹ This raises a key difficulty in this, and many other, research areas: how do we measure folate and determine its availability and actual use, and which measurements are important? Most research uses either serum folate or red blood cell folate as a measure of folate status, but these methods can differ by as much as a factor of nine.²⁰ A standardization program is needed to ensure the comparability of data and help further research on folic acid fortification and supplementation.

Still, the benefits of daily folic acid supplementation for women of childbearing age far exceed the risks. If all women received the recommended folic acid supplements, the incidence of NTDs could be reduced by as much as 70 percent.²¹ For women who already have had a pregnancy affected by an NTD, the PHS recommends consulting with a health professional about taking a much larger dose, as much as 4,000 µg (4 milligrams). In the past, there was a concern that high doses of folic acid could mask the symptoms of vitamin B₁₂ deficiency, a sign of pernicious anemia. But this condition is rare in young and middle-aged people, and there now are other tests to check for a B₁₂ deficiency that will reveal it, even if large amounts of folic acid are present.²² Folic acid supplementation shows a cost:benefit ratio that would make any economist’s mouth water. The lifetime health care costs of one child with spina bifida average nearly $300,000⁹; a bottle of 100 folic acid–enriched vitamins costs less than $8. Imagine if every woman received a gift of a one-year supply of multivitamins supplemented with folic acid at a cost of less than $30.

Educational efforts must persist, particularly those targeted at women younger than 25 years of age. Although only 18 percent of these women take supplemental folic acid, this age group accounts for nearly 40 percent of all births in the United States.²³ As health care professionals, we should capitalize on a situation in which a simple preventive strategy can have a profound effect. What would make a more original and health-promoting wedding gift (or birthday gift, going-away present, holiday office gift) than a supply of vitamins, enriched with folic acid?

I could end this month’s column here and still have illustrated a powerful health-promotion strategy. But there’s more. Besides NTDs, folic acid supplementation has been associated with a reduction in orofacial clefts, congenital heart defects, obstructive urinary tract anomalies, limb deficiencies and congenital hypertrophic pyloric stenosis, as well as reductions in placenta-related diseases, preterm deliveries and intrauterine growth retardation. Adequate folic acid intake in adults has been associated with a reduction in cardiovascular disease and some cancers,^24,25 and folate mouthwash may reduce the severity of gingivitis.^26,27

How does folic acid work its magic? The answer is still incomplete, but evidence is mounting that for some people, folic acid supplements may help overcome difficulties in folate metabolism brought about by genetic polymorphisms. As many as one in seven people may carry a genotype that causes them to have a deficiency in folic acid, even if they are consuming a diet containing the recommended amount of folate. These people have difficulty in folate metabolism, resulting in lower folic acid levels in the blood.¹⁴

Research has pinpointed a specific genetic mutation in a gene called methylenetetrahy-drofolate reductase, or MTHFR, that is involved in folate metabolism. The mutation is small—one nucleotide has been changed from cytosine to thymine. Women with this genetic polymorphism in the MTHFR gene are 2.5 times more likely to have a child with Down syndrome.²⁸ This same mutation also is associated with inflammatory bowel disease, colon cancer, oral clefting and higher levels of homocysteine.^29-32

Precisely how folic acid protects against NTDs is not known, but supplementation may overcome the metabolic roadblock of certain MTHFR polymorphisms, rather than counteract a deficiency.^33,34 In an interesting twist to the story, taking supplemental folic acid and eating fortified foods seem to be a better strategy than simply increasing the amount of foods containing natural folate. In a three-month intervention study in the United Kingdom, only the first two of these measures increased folate concentrations.¹⁷ Although these results make sense—folic acid is easier for the body to metabolize than is folate—the usual mantra in nutrition is for people to use supplements only when absolutely necessary, and to rely on dietary changes as a first line of defense.

In the case of folic acid, supplements and fortified foods are that first line. Unfortunately, not all supplements are created equal. In a 1997 study of a variety of brand-name and generic multivitamin products, only one-third met United States Pharmacopeial Convention standards for folic acid release. Most of the products missed the cutoff levels by a wide margin; folic acid availability from two of the products was less than 25 percent.³⁵

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In the end, then, it’s never just as easy as taking a pill. Educational efforts and better communication by health care providers must be combined with stricter pharmacological and pharmaco-genetic standards. All women—and most critically, those women who have had a pregnancy affected by an NTD—should consider the benefits of taking a multivitamin supplement that contains folic acid. It’s an excellent gift for any woman, and the first gift a mother can give her child.