High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth

Randomized interventional study conducted at six craniofacial clinics in Brazil. Participants were women aged 16-45 with nonsyndromic or isolated oral clefts, or women who had at least one natural child with isolated oral clefts, and were at risk for recurrent clefting.

Oral folic acid was given as a single daily pill, either 0.4 mg or 4 mg, manufactured for the study. Supplementation started before conception and continued through the first trimester if pregnancy occurred, or until study completion if the participant did not become pregnant.

High-dose folic acid did not show added benefit over 0.4 mg for preventing isolated oral cleft recurrence. Recurrence was 2.5% in the 4 mg group and 2.9% in the 0.4 mg group (one-sided Fisher exact test p = 0.59), while both groups were below historical recurrence estimates of 6.8% and 6.3%. There were no significant differences in birth weight, gestational age, length, head circumference, Apgar scores, preeclampsia, or adverse events. Serum and red cell folate levels were higher with 4 mg, but the higher biomarker response did not translate into better clinical outcomes.

The trial was underpowered to detect smaller differences in recurrence between 4 mg and 0.4 mg folic acid. Compliance was only about 74% in both groups, which may have diluted treatment effects. Comparisons with historical recurrence rates are indirect, and the outcome subset for some birth measures was smaller than the randomized arm totals.