Recent findings from a randomized controlled trial in the United States highlight the potential benefits of prenatal multivitamins containing 5-methyltetrahydrofolate (5-MTHF). These supplements can effectively maintain folate levels in both mothers and fetuses similarly to those achieved with folic acid, yet lead to significantly lower levels of unmetabolized folic acid (UMFA), which indicates the presence of folic acid not fully utilized by the body.
An increasing number of prenatal multivitamin products are now incorporating 5-MTHF as an alternative to synthetic folic acid (FA). This shift is due to the fact that FA must be converted into 5-MTHF to be utilized in cellular processes. Excessive intake of FA can lead to increased levels of unmetabolized forms in circulation, as noted by researchers.
The findings come at a time when various prenatal supplement brands, including Perelel, Thorne, and the trial’s sponsor Ritual, are introducing formulations based on 5-MTHF, even as federal guidelines remain focused on folic acid for early pregnancy.
Comparable Folate Status with Lower Doses
The 24-week study involved 80 pregnant participants who were administered prenatal multivitamins containing either 5-MTHF or folic acid starting from their second trimester. By the trial’s conclusion at 24 weeks, results indicated that folate levels in maternal blood, cord blood, and placental tissues were statistically similar across both groups.
“Supplementation with a prenatal multivitamin containing 6S-5-MTHF resulted in lower UMFA levels in both maternal and placental blood, without a significant change in overall folate status,” the researchers observed.
Interestingly, while the folic acid formulation provided a higher total dose of folate, this did not translate into improved folate status. “The folate content in the FA multivitamin was nearly 30% higher than in the MTHF multivitamin, yet there was no measurable difference in total folate levels across the maternal blood, placenta, and fetal blood between the two groups,” they reported.
Unmetabolized Folic Acid Levels
The contrast between the groups was most striking regarding circulating UMFA levels. “Fewer participants in the 5-MTHF group displayed detectable UMFA (7% versus 31%), and those in this group exhibited lower average UMFA levels in their maternal blood,” the researchers reported.
Similar patterns were noted in placental tissues. “While using a multivitamin with 5-MTHF significantly reduced UMFA in maternal blood and the placenta, it did not completely eliminate UMFA detection,” they stated.
Influence of Fortification on Total Exposure
In the U.S., mandatory folic acid fortification is implemented based on baseline intake levels prior to supplementation. The Food and Drug Administration authorized this mandatory fortification of enriched cereal grains in 1996, with implementation completed by 1998.
Given this context, supplementation can lead to increased total folate intake. In the current study, the residual UMFA within the 5-MTHF group was partly linked to dietary intake from fortified foods. The researchers noted that formulation differences substantially affect overall exposure.
“Consistent with previous findings, our study shows that nearly one-third of participants in the FA group exceeded the current upper limit by the end of the intervention,” they stated. Notably, fewer in the 5-MTHF group reached or surpassed this upper intake level.
Uncertainty Surrounding Clinical Implications of UMFA
These findings contribute to the ongoing discourse regarding UMFA, which, while commonly detected, lacks well-established links to specific health outcomes. “The clinical significance of elevated UMFA levels in humans remains unclear,” the researchers remarked.
Furthermore, the research indicates that the choice of supplement formulation plays a critical role in influencing circulating levels. “Further studies are necessary to explore the relationship between UMFA levels and the health of both mother and fetus,” the researchers concluded.
Lack of Evidence in Early Pregnancy
Folic acid continues to be the recommended form of folate during pregnancy due to its proven effectiveness in minimizing the risk of neural tube defects in early pregnancy. However, it’s important to note that there is a lack of studies examining the efficacy of other folate forms for reducing NTD risk.
The current trial did not investigate supplementation in the early stages of pregnancy; it focused solely on the second and third trimesters. The absence of research in early pregnancy as well as long-term outcomes presents unresolved questions for both regulators and the industry.
In conclusion, the researchers stated that “prenatal multivitamins containing 6S-5-MTHF may represent an effective alternative to those with folic acid during the latter stages of pregnancy, as they decrease UMFA levels in maternal and fetal tissues without compromising overall 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.
