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Background  Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the  MTHFR  gene. Several studies have assessed the association between  MTHFR  C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent.    Methods and Findings  Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between  MTHFR  C677T polymorphism and CHDs risk in children with heterogeneity ( P   heterogeneity  = 0.000) and publication bias ( P   egger  = 0.039), but it turned into null after the trim-and-fill method was implemented (OR = 1.12, 95% CI = 0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity ( P   heterogeneity  = 0.150, OR = 1.16, 95% CI = 1.05–1.29) and publication bias ( P   egger  = 0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size.    Conclusions  Both infant and maternal  MTHFR  C677T polymorphisms may contribute to the risk of CHDs.

MTHFR C677T Polymorphism and Risk of Congenital Heart Defects: Evidence from 29 Case-Control and TDT Studies