(Bower and Stanley, 1992b; Mulinare et al., 1988; Shaw et al., 1995c; Werler et al., 1993) (Table 8-7). The optimal timing for supplementation seems to be during the 4 weeks before and after conception (Mulinare et al., 1988).

In the United States the risk reduction achieved with a daily supplement of 400 µg of folate, the most usual dose in multivitamins, was 70 percent (relative risk 0.3; 95 percent confidence interval [CI], 0.2 to 0.6) in New England (Werler et al., 1993) and 35 percent (relative risk 0.65; 95 percent CI, 0.45 to 0.94) in California (Shaw et al., 1995c) in unselected populations with average daily dietary folate intake of about 300 µg. The intake values assume a high level of compliance with supplementation, and the points represent values adjusted for bioavailability because they are given in dietary folate equivalents. It is not clear whether supplements at doses lower than 400 µg/day of folic acid provide the same level of protection as 400 µg/day or whether higher doses are associated with increased risk reduction.

The Medical Research Council Trial (Wald et al., 1991) (Table 8-8), which addressed reduction of the recurrence of NTD, used a factorial design to investigate folate in a dose of 4.0 mg/day and a mixture of other vitamins (A, thiamin, riboflavin, B₆, C, D, and nicotinamide). This study found a 71 percent decreased NTD incidence in offspring of women taking the folate supplement relative to those on no supplements but no reduction with the other vitamins. In a nonrandomized trial on the risk of NTD recurrence conducted in the United Kingdom, a daily supplement of 360 µg in addition to normal diet was apparently protective (Smithells et al., 1981).

Because NTDs represent a heterogeneous group of congenital malformations both etiologically and pathogenetically, it is probable that there are cases not preventable even by large doses of folate, as was the case in the Medical Research Council Vitamin Study (Wald et al., 1991). More studies are needed to evaluate whether fortification of foods is similarly associated with reduced risk or with a valid proxy for NTD risk.

NTD Risk According to Maternal Folate Status. The erythrocyte folate concentration is a marker of long-term folate status. Studies looking for an association of erythrocyte folate with NTD risk based on estimating erythrocyte folate levels in blood samples taken early in pregnancy are preferred because maternal folate status is likely to change during pregnancy and postpartum. In four studies with blood specimens taken during pregnancy, erythrocyte folate values