A Randomized, Placebo-Controlled Trial in Women of Childbearing Age to Assess the Effect of Folic Acid and Methyl-Tetrahydrofolate on Erythrocyte Folate Levels

Abstract

Objective: To evaluate the efficacy of a multi-vitamin/mineral preparation (MMP) in achieving erythrocyte folate levels (Fol-E) considered preventive of neural tube defects (NTDs). Methods: In this single-center, double-blind, randomized, placebo (PBO)-controlled trial, healthy women of childbearing potential (WCBP) took either an oral MMP containing 400 μg folic acid and 451 μg L-5-methyltetrahydrofolate (MTHF) or PBO once daily for 16 weeks. Primary endpoints were achievement of Fol-E ≥ 906 nmol/L at Week 4 and maintenance of this level once achieved. Secondary efficacy variables were plasma concentrations of folate, homocysteine, and vitamins B2, B6, and B12 at Week 4, 8, 12, and 16. Results: Of the 40 women enrolled, 20 were randomized to each study arm. All but one PBO-subject completed the study as planned. Baseline characteristics in both groups were comparable with mean Fol-E around 500 nmol/L. In contrast to only one PBO-subject, all MMP subjects achieved and maintained the target Fol-E (MMP: 100% vs PBO: 5%, p<0.001), 14 (70%) MMP subjects already by Week 4 (means ± SD: 976 ± 186 vs 629 ± 215 nmol/L, p<0.001). In plasma, the only change under PBO was a 10% decrease of vitamin B12 whereas under MMP folate and vitamin B6 significantly increased and homocysteine significantly decreased. There was no serious and only one severe adverse event (AE); most common AEs were gastrointestinal with greater incidence in the MMP group (30% versus 5%). Conclusion: Supplementation with folic acid and MTHF at equimolar amounts was efficacious in replenishing Fol-E of WCBP within 4 weeks to levels considered protective of NTDs.