With this protocol of systematic review and meta-analysis, we wish to identify the association of the polymorphisms C677T and A1298C of the MTHFR gene with the maternal risk for DS, as well as to perform subgroup analyses to investigate the effect of ethnic differences in allele frequencies, combined genotypes, circulating folate levels, maternal age at conception and type of meiotic error in modulating the maternal risk for DS resulting from these polymorphisms, and investigate their role as risk factors for CHD in DS newborns. This evidence concerns the gene MTHFR and coronary artery disorder.