Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population-based case-control study of women meeting the folic acid recommendations

Abstract

Background: Neural tube defects (NTDs) still occur among some women who consume 400 μg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs.

Objectives: To investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations.

Methods: Data were from the National Birth Defects Prevention Study (United States population-based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 μg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center.

Results: NTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake.

Conclusions: Our findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

Keywords: betaine; choline; folic acid; methionine; methylation; neural tube defects; one-carbon metabolism; vitamin B complex; zinc.

FIGURE 1

Associations between a number of methyl donors and other micronutrients involved in one-carbon metabolism with higher intake and neural tube defects. Data were from the National Birth Defects Prevention Study (1999–2011). To categorize each micronutrient intake (higher or lower intake), we used a combination of information from diet and supplements. Excluding supplementers, we regressed case-control status on the energy-adjusted dietary estimate of a given methyl donor, using restricted cubic splines with ≤5 knots controlling for estimated dietary folate equivalents as a model covariate, and identified a cut point where the OR comparing higher compared with lower intake was maximized. Subsequently, we grouped the supplementers into the respective higher intake category if the typical content of the supplement was expected to be greater than the identified dietary cutoff (refer to Table 1). ORs and 95% CIs were estimated using unconditional logistic regression with Firth’s penalized likelihood adjusted for age, race/ethnicity, education, and study center. The y-axis is on the log scale. The reference group for all comparisons is intake in the higher range for none or only 1 of the micronutrients of interest. Ref, reference.

FIGURE 2

Associations between specific groups with concurrent higher intakes of methyl donors and other micronutrients involved in one-carbon metabolism and neural tube defects. Data were from the National Birth Defects Prevention Study (1999–2011). To categorize each micronutrient intake (higher or lower intake), we used a combination of information from diet and supplements. Excluding supplementers, we regressed case-control status on the energy-adjusted dietary estimate of a given methyl donor, using restricted cubic splines with ≤5 knots controlling for estimated dietary folate equivalents as a model covariate, and identified a cut point where the OR comparing higher compared with lower intake was maximized. Subsequently, we grouped the supplementers into the respective higher intake category if the typical content of the supplement was expected to be greater than the identified dietary cutoff (refer to Table 1). ORs and 95% CIs were estimated using unconditional logistic regression with Firth’s penalized likelihood adjusted for age, race/ethnicity, education, and study center. The y-axis is on the log scale. The reference group for all comparisons is intake in the higher range for none or only 1 of the micronutrients of interest. Ref, reference.