Closing the folate gap in reproductive-age women

Adequate maternal folate levels are necessary for preventing neural tube defects (NTDs); however, an insufficient number of women in the United States avail themselves of folic acid supplementation during their childbearing years,¹ and diet rarely supplies sufficient folate despite the recent fortification of many grains with folic acid.

Folate and folic acid

Folates in foods exist in their natural or reduced (hydroxylated) form. Dietary folates are not efficiently used because they are unstable and lose activity during processing, food preparation, and absorption. Although synthetic, folic acid provides 70% more available bioactive folate than can be achieved from an equivalent amount of dietary folate.^3,4 The differences in absorption between dietary folate and synthetic folic acid must be taken into account when calculating the amount of folate received from all sources. The Recommended Daily Allowances (RDAs) for folate set forth by the Institute of Medicine (IOM) are expressed according to the Dietary Folate Equivalent (DFE), a term developed to help account for the differences in absorption between naturally occurring dietary folate and synthetic folic acid.⁵

Folate prevents NTDs

Adequate maternal serum folate levels ensure robust cell division for the embryo and fetus. Normal mean serum folate levels (>7 ng/mL) correlate with the lowest prevalence of NTDs,⁶ which include anencephaly, spina bifida, and encephalocele. Women with diabetes mellitus or obesity and those who are taking seizure medications are at especially high risk for having offspring with NTDs.² NTDs arise as the result of inadequate closure of the neural tube that forms over the developing embryonic brain and spinal cord. Closure of the neural tube is complete by 28 days' embryogenesis (42 days' gestation).² For this reason, adequate maternal folate levels must exist before pregnancy.

That supplementation with folate could prevent NTDs was first shown in 1980 by Smithells and colleagues, who gave a multivitamin containing 360 μg per day of folic acid to women in whom a prior pregnancy had resulted in offspring with NTDs.⁷ This dose of folic acid was used because it was convenient and because folic acid was the only folate-related compound that had been synthesized at the time. (The bioavailable form L-5-methyl-THF, called metafolin, is now available in supplemental form.) Study results by Smithells and colleagues demonstrated reduction in the predicted recurrence for NTDs. Although expected recurrence in offspring was 5%, in the folic acid group recurrence was only 0.6%.⁷

This study was followed by a randomized, controlled trial conducted by the Medical Research Council Vitamin Study Research Group, who found recurrence of NTDs to be reduced by 72% in women receiving 4,000 μg per day folic acid supplements.⁸

The only randomized, controlled trial showing reduced NTD in the offspring of women who never previously had a child affected with NTDs was conducted in Hungary by Czeizel and Dudás.⁹ The frequency of NTDs was 0 in 2,471 women receiving 800 μg per day of folic acid, compared with 6 in 2,391 women not receiving folic acid. Expected NTD cases were 6.9 and 6.7, respectively.

The Hungarian study was followed by a large population-based study in China, in which 400 μg per day of folic acid was given or not given in geographically distinct regions.¹⁰ Folic acid supplementation reduced the occurrence of NTDs by 79% in high-incidence regions (0.65% NTD incidence) and by 41% in low-incidence regions (0.08% NTD incidence). Perhaps 25% of NTD cases are not folate-sensitive, probably more in low-incidence regions. That certain cases remain folate-resistant may explain the failure to show a benefit in some case-control studies.¹¹