The prevalence of major neural tube defects in the United States is estimated to be one per 1,000 births, equivalent to approximately 2,500 affected infants annually. International studies investigating the dramatic differences between the occurrence of neural tube defects in different populations concluded that the folic acid intake of mothers immediately before conception was a critical factor. Locksmith and Duff reviewed recent evidence to make recommendations regarding the optimal intake of supplemental folic acid to prevent neural tube defects.
The authors conducted a MEDLINE search using the terms “folic acid” and “neural tube defects” to identify 55 articles published between 1990 and 1997, including reviews, official recommendations, theoretical papers and studies of several different designs. Evidence that folic acid can prevent neural tube defects comes from results of large trials in countries where there is a high prevalence of neural tube defects. A British study of women who had previously given birth to children with neural tube defects demonstrated a 72 percent reduction in recurrence using 4 mg folic acid supplementation beginning four weeks before conception and continuing through the first trimester. In a Hungarian study of unselected women, there were no cases of neural tube defects in 2,104 infants born to mothers receiving 0.8 mg of folic acid, compared with six infants born with the defect in 2,052 mothers receiving a placebo.
Although the mechanism of action of folic acid in preventing neural tube defects is not well understood, it is believed to relate to homocysteine metabolism. With inadequate metabolism of folic acid, teratogenic levels of homocysteine could accumulate. Another theory suggests that folic acid acts by inducing the spontaneous abortion of fetuses with neural tube defects.
Folic acid is present in a variety of foods such as leafy green vegetables, legumes, liver, citrus fruits and whole wheat bread, but it is estimated that only 8 percent of adult women consume at least 0.4 mg of folic acid daily. Food sources must be converted in the upper small intestine for absorption; synthetic folic acid supplements actually offer better bio-availability than natural forms. The authors concur with official recommendations that women who may potentially become pregnant should consume at least 0.4 mg of folic acid daily. This may be achieved by taking a daily multivitamin supplement. It is recommended that women with previous offspring affected by neural tube defect take 4 mg of folic acid beginning at least one month before conception and continuing for the first three months of pregnancy. However, prenatal vitamins should not be the source for such a large dosage of folic acid because the number of tablets required would contain potentially dangerous levels of other components, especially vitamin A. Although they are at higher risk of having infants with neural tube defects, it is not recommended that women who are taking valproic acid or carbamazepine, or who have type 1 diabetes or a family history of neural tube defects take the higher dosage because the mechanism of their increased risk is unclear.
Since many pregnancies are unplanned and only one third of women consume multivitamins containing folic acid, fortification of flour has been considered as a way of preventing neural tube defects. Whether to expose the entire population to an intervention that would benefit relatively few women is an important consideration.
The authors conclude that women who plan to become pregnant should take folic acid supplements to reduce their risk of having infants with neural tube defects; however, the optimal dosage, timing and vehicle have yet to be established. For most women, a daily multivitamin with 0.4 to 0.8 mg of folic acid, beginning at least one month before conception and continuing through the first trimester, would be well advised.