Comparative Bioavailability of 5-Methyltetrahydrofolate and Folic Acid in Pregnant Women: A Randomized Controlled...

Folate supplementation is critical for preventing neural tube defects, while 5-methyltetrahydrofolate (5-MTHF), the predominant circulating form of folate, may offer a pharmacokinetic advantage. However, comparative data in this populations remain limited.

This double-blind randomized controlled trial enrolled 110 pregnant women (9-14 weeks gestation). Participants were randomized 1:1 to receive either 600 μg folic acid (equivalent to 1.36 μmol folate) [FA group] or 1100 μg 5-MTHF glucosamine salt (equivalent to 1.35 μmol folate) [5-MTHF group] to precise equimolar dosage for 12 weeks. Primary outcomes included changes in red blood cell (RBC) folate and secondary outcomes were changes in plasma 5-MTHF, plasma homocysteine, and unmetabolized folic acid (UMFA). Subgroup analyses evaluated the impact of maternal body mass index (BMI).

Ninety-six participants completed the trial (48 per group). Both interventions significantly increased RBC folate (FA: +262.00 ng/mL [IQR: 245.50]; 5-MTHF: +244.50 ng/mL [IQR: 233.50]; p = 0.714) and reduced plasma homocysteine with no significant differences between groups. However, 5-MTHF supplementation resulted in a greater increase in plasma 5-MTHF compared to the FA group (Median change: +5.67 ng/mL [IQR: 5.93] vs. +3.12 ng/mL [IQR: 6.47]; unadjusted p = 0.027; baseline-adjusted p = 0.055), a difference of borderline statistical significance. Median UMFA accumulation was approximately twice as high in the FA group, but the difference failed to reach significance due to non-normal distribution. The bioavailability of 5-MTHF was comparable to folic acid across different BMI categories, with a stronger trend toward higher bioavailability among normal-weight women (p = 0.182) than overweight women (p = 0.304).

Both supplements effectively improve long-term folate status and reduce homocysteine. 5-MTHF was associated with a greater plasma 5-MTHF response (adjusted p=0.055) and more modest UMFA accumulation, a pattern most pronounced in normal-weight women, supporting its use as a highly effective prenatal supplementation alternative CLINICALTRIALS REGISTRATION NO: NCT06935630.