A recent U.S. randomized controlled trial reports that prenatal multivitamins formulated with 5-methyltetrahydrofolate (5-MTHF) can maintain maternal and fetal folate levels comparable to those with folic acid, while leading to lower levels of unmetabolized folic acid (UMFA), a circulating form that reflects folic acid intake that has not been fully processed by the body.
A growing number of prenatal multivitamin (MVI) products use 5-MTHF in place of the synthetic folic acid (FA), because FA must be reduced to 5-MTHF for use in cellular methylation reactions and excess FA consumption can increase unmetabolized FA (UMFA) concentrations in circulation, the researchers wrote.
The results come as prenatal supplement brands, including Perelel, Thorne and the study’s funder Ritual, bring 5-MTHF-based formulations to market, while federal recommendations for early pregnancy continue to focus on folic acid.
Comparable folate status despite lower dose
The 24-week trial followed 80 pregnant participants who took prenatal multivitamins containing either 5-MTHF or folic acid from the second trimester. By week 24, folate levels in maternal blood, cord blood and placental tissue were comparable between the two groups.
“Supplementation with a prenatal MVI containing 6S-5-MTHF, as compared to FA, resulted in reduced concentrations of UMFA in both the maternal and placental compartments while having no significant difference in total folate status,” the researchers wrote.
Notably, the folic acid formulation delivered a higher total folate dose, without translating into higher measured folate status.
“The folate content in the FA-MVI was about 30% higher than that in the MTHF-MVI, yet there was no difference in 5-MTHF and total folate status across maternal blood, placenta, and fetal blood between the two groups,” the researchers reported.
Differences appear in unmetabolized folic acid
The difference between groups was most evident in circulating UMFA. “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,” the researchers reported.
Similar differences were observed in placental tissue.
“Supplementation with a 5-MTHF-containing MVI significantly reduced UMFA concentrations in maternal blood and placenta, although it did not completely eliminate UMFA detection,” the researchers wrote.
Fortification context influences total exposure
In the United States, mandatory folic acid fortification is considered when baseline intake is established before supplementation. Mandatory fortification of enriched cereal grain products with folic acid was authorized by the U.S. Food and Drug Administration in 1996 and fully implemented by industry in 1998.
Against that backdrop, supplementation adds to existing intake.
In the trial, residual UMFA in the 5-MTHF group was linked, at least in part, to background intake from fortified foods. As noted by researchers, formulation differences translated into differences in total exposure.
“Consistent with prior findings, the present study demonstrates that nearly one-third of participants in the FA-MVI group exceeded the current UL by the end of the intervention,” the researchers reported.
Fewer participants in the 5-MTHF group reached or exceeded the upper intake level.
Clinical significance of UMFA remains unclear
The data add to the ongoing discussion around UMFA, which is widely detected but not yet clearly linked to health outcomes. “The clinical implications of UMFA elevation in humans remain unclear,” the researchers wrote.
At the same time, the research indicates that formulation choices can influence circulating levels. “Further studies that investigate the association between UMFA and the health of the mother-fetus dyad are needed,” researchers reported.
Early pregnancy remains outside the evidence base
Folic acid remains the recommended form of folate for women who are pregnant or may become pregnant, due to its established role in reducing neural tube defects early in gestation. “It should be noted, however, that human studies investigating whether other forms of folate could be as effective as FA for NTD risk reduction are lacking,” the researchers wrote.
The current trial did not assess supplementation during early pregnancy; instead, it focused on the second and third trimesters. The absence of data in early pregnancy and on longer-term outcomes leaves key questions open for regulators and industry alike.
Researchers concluded that “prenatal MVIs containing 6S-5-MTHF may offer an efficacious alternative to those containing FA in the latter two trimesters of pregnancy, as they reduce concentrations of UMFA in maternal and fetal tissues, without compromising total folate status.”
Source: Frontiers in Nutrition 2026 doi: 10.3389/fnut.2026.1679067 “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.” Authors: F. Draicchio et al.