Feasibility of a randomized clinical trial comparing 5-methyltetrahydrofolate and folic acid prenatal multivitamins in couples with recurrent pregnancy loss

To assess the feasibility of a randomized controlled trial (RCT) comparing 5-methyltetrahydrofolate (5-MTHF) and folic acid (FA) in couples with recurrent pregnancy loss. Pregnancy loss affects up to 15% of pregnancies, with over half of cases remaining unexplained. Emerging evidence suggests that folate metabolism, particularly in individuals carrying methylenetetrahydrofolate reductase polymorphisms such as C677T and A1298C variants, may influence reproductive outcomes. A double-blind, RCT feasibility trial was conducted in Australia with 22 reproductive dyads randomized to receive either 5-MTHF or FA prenatal multivitamins. Participants adhered to dietary restrictions, abstained from conception for two cycles, and completed regular assessments. Primary outcomes included feasibility, adherence, acceptability, and preliminary efficacy based on biochemical markers and pregnancy outcomes. The trial demonstrated high acceptability (86% in arm A [MTHF-A] and 94% in arm B [FA-B]) and adherence rates for supplement use over 78% in each arm. Unmetabolized FA concentration decreased in the 5-MTHF group but rose significantly in the FA group. A critical finding was the degradation of 5-MTHF in retained samples, highlighting formulation instability as a confounder. A fully online RCT comparing 5-MTHF and FA is feasible. Future trials should address formulation stability and expand sample size to evaluate clinical efficacy and personalized folate strategies.