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.

The Impact of Preconceptional Multiple-Micronutrient Supplementation on Female Fertility

“…Available safety data from the use of vitamins and/or minerals during preconceptional use indicate that supplementation is well tolerated, 54–56 although gastrointestinal adverse events have been reported with MMN supplementation. 54…”

“…46 It should be noted that none of the MMN supplements used in women trying to conceive contained vitamins or minerals in doses higher than those recommended for use during pregnancy. Available safety data from the use of vitamins and/or minerals during preconceptional use indicate that supplementation is well tolerated, 54–56 although gastrointestinal adverse events have been reported with MMN supplementation. 54…”