Folate intake, markers of folate status and oral clefts: is the evidence converging?

BACKGROUND: The ability of folic acid in the periconceptional period to prevent the occurrence of neural tube defects has stimulated tremendous interest in its effects on other health outcomes. Its possible effect on oral clefts has generated considerable debate. The purpose of this systematic review and meta-analysis was to assemble evidence on the role of folate in the aetiology of cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). METHODS: Medline, PubMed, Embase, Science Citation Index and the HuGE Published Literature Database were searched to February 2007 for articles related to oral clefts and multivitamin use, dietary folate, folic acid fortification, biochemical markers of folate status and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and other genes involved in folate metabolism. Random effects meta-analysis was conducted when appropriate. RESULTS: Maternal multivitamin use was inversely associated with CL/P odds ratio (OR) 0.75, 95% CI 0.65-0.88, based on 5717 cases and 59 784 controls but to a lesser extent CPO (OR 0.88, 95% CI 0.76-1.01, 2586 cases and 59 684 controls). The volume of evidence on dietary folate, fortification and biochemical and genetic measures of folate status is substantially less; in aggregate, the evidence suggests that no association exists but there is substantial heterogeneity between studies. CONCLUSIONS: The evidence is not converging and there is no strong evidence for an association between oral clefts and folic acid intake alone. Multivitamin use in early pregnancy, however, may protect against oral clefts, especially CL/P although this association may be confounded by other lifestyle factors associated with multivitamin use.