Supplementation with (6S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada

Abstract

Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF] is available in some commercial prenatal vitamins an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomized 60 pregnant individuals at 8-21 weeks’ gestation to 0.6 mg/day folic acid or (6S)-5-MTHF x 16-weeks. Fasting blood specimens were collected at baseline and after 16-weeks (endline). Red blood cell (RBC) and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolized folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake, and gestational weeks. At endline (n=54), the mean ± SD (or median, IQR) RBC folate, serum folate, and plasma UMFA (nmol/L) in those supplemented with (6S)-5-MTHF versus folic acid, respectively, was: 1826 ± 471 and 1998 ± 421; 70 ± 13 and 78 ± 17; 0.5 (0.4, 0.8) and 1.3 (0.9, 2.1). In regression analyses, RBC and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0.6 nmol/L higher (95% CI: 0.2-1.1) in those supplementing with folic acid as compared to (6S)-5-MTHF. In conclusion, supplementation with (6S)-5-MTHF may reduce plasma UMFA by ∼50% as compared to supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined.