Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis

OBJECTIVE: To evaluate whether the C677T polymorphism of the methylenetetrahydofolate reductase (MTHFR) gene is consistently associated with hypertension in pregnancy. DESIGN: Meta-analysis of studies comparing women with and without hypertension in pregnancy for the C677T MTHFR polymorphism. METHODS: Studies were identified with MEDLINE and EMBASE searches complemented with perusal of bibliographies of retrieved articles and communication with investigators. Between-study heterogeneity was estimated and data were combined with random effects models. Sensitivity analyses examined the effect of population and disease characteristics. Bias diagnostics evaluated the evolution of the postulated genetic effect over time and the potential for publication bias. RESULTS: Across 23 comparisons (3169 hypertensive women, 3044 controls), having the T allele (TT or CT) increased the odds of hypertensive disease of pregnancy by 1.21-fold (95% confidence interval, 1.01-1.44), but there was large between-study heterogeneity (P = 0.003). The results were similar and heterogeneity persisted when sensitivity analyses were limited to studies of Caucasian populations, or those of patients with significant proteinuria. While patients with diastolic hypertension > or = 110 mmHg showed an odds ratio of 1.41 (95% confidence interval, 1.03-1.73), no association was seen in patients with less severe diastolic hypertension (odds ratio, 1.00; 95% confidence interval, 0.61-1.65). Early published studies tended to show stronger associations than the subsequent studies. CONCLUSIONS: While bias cannot be excluded, the meta-analysis suggests that the T allele may increase the risk of severe diastolic hypertension during pregnancy.