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

The trial demonstrated high acceptability in both supplementation arms.

• Acceptability was 86% in arm A (5-MTHF) and 94% in arm B (folic acid).
• 22 reproductive dyads were randomized across the two arms.
• The trial was conducted in Australia as a double-blind RCT feasibility study.

Adherence rates for supplement use exceeded 78% in each arm.

• Adherence was over 78% in each arm throughout the trial period.
• Participants adhered to dietary restrictions and abstained from conception for two cycles.
• Participants completed regular assessments as part of the protocol.

Unmetabolized folic acid concentration decreased in the 5-MTHF group but rose significantly in the folic acid group.

• The divergence in unmetabolized folic acid levels between the two arms was a preliminary efficacy finding.
• Rising unmetabolized folic acid in the FA group is consistent with known metabolic saturation effects of synthetic folic acid supplementation.
• This finding was based on biochemical marker assessment as a primary outcome measure.

Degradation of 5-MTHF was observed in retained samples, identifying formulation instability as a confounder.

• This was described as a 'critical finding' in the study.
• The instability of 5-MTHF in retained samples represents a methodological concern for future trials.
• The authors recommend that future trials address formulation stability as a priority.

A fully online RCT comparing 5-MTHF and FA in couples with recurrent pregnancy loss is feasible.

• The study was designed as a feasibility trial with primary outcomes including feasibility, adherence, acceptability, and preliminary efficacy.
• 22 reproductive dyads were successfully randomized and completed the protocol.
• The authors conclude that future trials should expand sample size to evaluate clinical efficacy and personalized folate strategies.

Pregnancy loss affects up to 15% of pregnancies, with over half of cases remaining unexplained.

• Emerging evidence suggests folate metabolism may influence reproductive outcomes.
• Methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C variants may be particularly relevant.
• This provided the rationale for comparing 5-MTHF versus folic acid supplementation in this population.