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.

Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts?

Abnormalities in folate and/or homocysteine metabolism may adversely influence embryonic development, leading to the birth of infants with a variety of congenital malformations, including neural tube defects (NTDs) and craniofacial abnormalities. Based upon suggestive evidence that periconceptional folic acid supplementation is effective in preventing a significant proportion of the aforementioned birth defects, genetic variation in the folate biosynthetic pathways may influence the infant's susceptibility to these birth defects. The goal of our study was to investigate sequence variations in the betaine-homocysteine methyltransferase (BHMT) and betaine-homocysteine methyltransferase (BHMT2) genes as modifiers of risk of spina bifida, cleft palate, and cleft lip and palate. The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida. Genotype frequencies for the BHMT2 rs626105 polymorphism also did not reveal any elevated risks for spina bifida, and only a modest, imprecise elevation of risk for orofacial clefts. The results of these experiments suggest that variants of the BHMT/BHMT2 genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population.