Using 6S-5-methyltetrahydrofolate instead of folic acid in prenatal multivitamin reduces unmetabolized folic acid concentrations in the mother-fetus dyad: a 24-week randomized controlled trial

A growing number of prenatal multivitamin (MVI) products use 5-methyltetrahydrofolate (5-MTHF) in place of the synthetic folic acid (FA), because FA needs to be reduced to 5-MTHF for use in cellular methylation reactions and excess FA consumption can increase unmetabolized FA (UMFA) concentrations in circulation. However, the efficacy of 5-MTHF supplementation on maintaining maternal and fetal folate status in comparison to FA has not been sufficiently investigated. This study examined whether using 6S-5-MTHF instead of FA in a prenatal MVI affected total folate and UMFA status in maternal and fetal tissues. Eighty first-trimester pregnant participants were randomized to receive either a prenatal MVI containing 1,000 μg DFE of 6S-5-MTHF (MTHF-MVI group) or 1,330 μg DFE of FA (FA-MVI group) for 24 weeks ( n = 40/group) beginning at their second trimester. Fasting blood samples were collected at week 0, 12, and 24 of the study whereas cord blood and placental samples were collected at delivery. Thirty-one participants in each group completed the study. By week 24 of the study, 5-MTHF and total folate concentrations in maternal and cord serum and the placenta did not differ between groups. There were significantly fewer participants (7% vs. 31%) with detectable UMFA and lower average UMFA concentrations in maternal blood of the MTHF-MVI group vs. the FA-MVI group ( p < 0.01). UMFA concentrations in the placenta were lower in the MTHF-MVI group than the FA-MVI group ( p < 0.01). Few cord blood samples ( n = 2) contained detectable UMFA and both were from the FA-MVI group. In conclusion, during the second and third trimesters of pregnancy, prenatal MVIs providing 6S-5-MTHF may be an efficacious alternative to FA to maintain total folate status while reducing UMFA concentrations in maternal and fetal compartments. More research is needed to delineate the influence of different folate forms on fetal health and developmental outcomes. Clinical trial registration ClinicalTrials.gov , identifier: NCT05673070.