Folic Acid for the Prevention of Neural Tube Defects

WOMEN WITH NO HISTORY OF A PREVIOUS NTD-AFFECTED PREGNANCY

Of children with an NTD, 95% are born to couples with no family history of these defects. Evidence to date suggests that supplementation with a multivitamin containing 400 (0.4 mg) μg of folic acid prevents the occurrence of >50% of NTDs when it is taken before conception and continued throughout the first trimester of pregnancy.⁵ The USPHS recommends that all women of childbearing age who are capable of becoming pregnant take 400 μg of folic acid daily.⁵ Implementing this recommendation may provide the opportunity for primary prevention of 50% or more of these serious disabling birth defects. Regular and ongoing ingestion of folic acid by women of childbearing age is necessary because approximately half of the pregnancies in the United States are unplanned,⁶ and neural tube closure occurs during the first 4 weeks of gestation.⁷ Despite the publication of the USPHS recommendation in September 1992, a 1998 poll showed that 70% of women aged 18 to 45 years still are not following the USPHS recommendation.⁸

WOMEN WHO HAVE HAD A PREVIOUS NTD-AFFECTED PREGNANCY

Among US couples who have had a child with an NTD, the recurrence risk is 2% to 3% in subsequent pregnancies.⁹ In 1991, the Medical Research Council (MRC) Vitamin Study Group reported the results of a well-designed, prospective, randomized trial of folic acid supplementation for the prevention of NTDs in pregnancies of women who had a previous child with an NTD, and the CDC published its recommendations for consumption of 4000 (4 mg) μg of folic acid.⁴ The results of the MRC study conclusively demonstrated that a daily dosage of 4000 μg of folic acid, in addition to folate in the diet, before and during early pregnancy resulted in a 71% reduction of recurrence of NTDs. The addition of other vitamins to the dosage of folic acid did not reduce the risk further. Use of multivitamins without folic acid did not result in a reduced risk for NTDs. The MRC study did not explore the possible benefit of a dosage lower than 4000 μg of folic acid. However, an earlier nonrandomized study conducted in the United Kingdom suggested that a lower dosage, 360 μg daily, resulted in a comparable reduction of recurrence of NTDs.¹⁰ Although adverse maternal or fetal effects of a daily 4000 μg dosage of folic acid were not detected by the MRC study, the small size of the study groups precluded detection of uncommon adverse effects.

FOLATE AND FOLIC ACID

Folic acid, also known as pteroylmonoglutamic acid, is a synthetic compound used in dietary supplements and fortified foods. The term folate includes all compounds that have the vitamin properties of folic acid—including folic acid and naturally occurring compounds in food.¹¹ The average diet in the United States contains 200 μg of naturally occurring food folate, which is less bioavailable than folic acid.¹² Additional intake of foods rich in folate could raise the average intake, but it has not been demonstrated that increased consumption of food folate would prevent NTDs as effectively as a daily vitamin supplement containing 400 μg of folic acid. A small comparison study suggests that blood folate concentrations are increased much more by folic acid supplementation than by naturally occurring food folate in the diet.¹³Economic and social circumstances may make an adequate increase in dietary folate difficult or unlikely, and the behavioral change required among a large fraction of women may take years to achieve.

Folic acid is a water-soluble vitamin that has no known toxicity. However, higher doses of folic acid can correct the anemia of vitamin B₁₂ deficiency (pernicious anemia), which might be an important clue to the presence of vitamin B₁₂ deficiency in some instances. Folic acid does not prevent the neurologic consequences of vitamin B₁₂ deficiency, and, for this reason, the USPHS recommendation cautioned that intake of folate should be not >1000 μg per day. However, the Institute of Medicine (IOM) Food and Nutrition Board recently set the tolerable upper intake limit of synthetic folic acid at 1000 μg, thus eliminating food folate from the calculation.¹⁴ Because pernicious anemia rarely occurs before the age of 50 years, it is likely to be rare among women consuming folic acid during the reproductive years. Folic acid has been consumed by about a quarter of all women for many years and extensively during later pregnancy without apparent adverse effects; however, studies that definitively address the question of maternal and fetal safety of folic acid are not available.

The IOM Food and Nutrition Board's recommended dietary allowance (RDA) for folate is 400 μg for adults and 600 μg for pregnant women.¹⁴ To reduce the risk for NTDs, the IOM recommended that women capable of becoming pregnant consume 400 μg of folic acid daily from fortified foods, vitamin supplements, or a combination of the two. This is in addition to the naturally occurring folate obtained from a varied diet.¹⁴ The majority of multivitamin preparations contain 400 μg of folic acid. These preparations are available over the counter and are already being taken by about 30% of nonpregnant women aged 18 to 45 years in the United States.⁸ Tablets containing folic acid alone are available over the counter in dosages up to 800 μg but the availability is very limited when compared with multivitamin preparations. Folic acid tablets in a 1000 μg dose are available by prescription only. This preparation is most frequently utilized by women who are taking 4000 μg because of a previous NTD-affected pregnancy.

In March 1996, the Food and Drug Administration mandated that enriched cereal-grain products be fortified with 140 μg of folic acid per 100 g of flour.¹⁵ This measure increases the proportion of women who consume the USPHS-recommended daily dosage of 400 μg of folic acid only an additional 3%, because this fortification level will provide the average woman only an additional 100 μg of folic acid per day (unpublished data, 1992).