Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial

Randomized controlled trial in women aged 20 to 45 years with three or more idiopathic recurrent abortions recruited from recurrent abortion clinics in Tehran, Iran. The active intervention arms included 110 participants per group, and MTHFR C677T and A1298C polymorphisms were assessed.

Women received either folic acid 1 mg daily or 5-methyltetrahydrofolate (5-MTHF) 1 mg daily. Supplements were given from at least 8 weeks before conception through the 20th week of pregnancy and were dispensed every 4 weeks.

5-MTHF improved serum folate more than folic acid, but it did not improve clinical pregnancy outcomes. Ongoing pregnancy at 20 weeks was 27 of 66 in the folic acid group versus 36 of 69 in the 5-MTHF group, and the difference was not significant. Plasma homocysteine decreased in both groups over time, but the between-group difference was not significant (value = 0.01, p = 0.147). The authors concluded that, aside from higher serum folate levels, 5-MTHF did not provide additional benefit over folic acid for recurrent abortion across MTHFR polymorphisms.

Clinical interpretation is limited by a modest sample size and reduced analyzable numbers for the pregnancy endpoint (66 and 69). The trial was single-center, follow-up was relatively short, and route of administration was not stated. No meaningful clinical advantage was demonstrated despite a biochemical difference in serum folate.