Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis

There is equivocal evidence in the published literature that folic acid supplementation during pregnancy may protect against the common congenital anomalies cleft lip with or without cleft palate (CLP) and cleft palate alone (CP). We undertook this meta-analysis to test the hypothesis that nonsyndromic oral cleft birth prevalences are different for those whose mothers took folic acid-containing supplements and for those whose mothers did not.

Human studies published in English were identified through MEDLINE, bibliography reviews, and contacting experts in the field. Within strata of prospective and case-control studies, CLP, CP, and all clefts, respectively, were analyzed using either a fixed or random effects model, as appropriate. We assessed for publication bias using Begg and Mazumdar's rank correlation and Egger's regression-based tests.

Five prospective studies were analyzed, yielding combined relative risks of 0.51 (95% CI: 0.32, 0.95) for CLP, 1.19 (95% CI: 0.43, 3.28) for CP, and 0.55 (95% CI: 0.32, 0.95) for all clefts. Twelve case-control studies were assessed, which resulted in combined relative risks of 0.77 (95% CI: 0.65, 0.90) for CLP, 0.80 (95% CI: 0.69, 0.93) for CP, and 0.78 (95% CI: 0.71, 0.85) for all clefts.

In aggregate, our results support the hypothesis of a protective effect of folic acid-containing supplement intake during pregnancy on the risk for oral clefts, although this conclusion is tempered by the potential for bias and uncontrolled confounding.