Congenital heart defects and maternal genetic, metabolic, and lifestyle factors

BACKGROUND: The purpose of this study was to identify metabolic, genetic, and lifestyle factors that discriminate between women who have pregnancies affected by congenital heart defects (CHDs) from those who have unaffected pregnancies. METHODS: We analyzed the concentrations of 13 serum biomarkers, 3 functional genetic variants, and 4 lifestyle factors among 417 women with CHD-affected pregnancies and 250 controls. To identify risk factors that discriminated between cases and controls, we used logistic regression followed by recursive partitioning to identify non-linear interactions. A receiver operating characteristic (ROC) curve was constructed to evaluate the discriminatory accuracy of the final model. RESULTS: A combination of risk factors discriminated women who had pregnancies affected by CHDs from those who had unaffected pregnancies. Among 21 possible determinants, serum concentrations of homocysteine and methionine, and reduced:oxidized glutathione ratios (GSH:GSSG) had the greatest discriminatory power. Recursive partition modeling resulted in five terminal nodes each illustrating the interplay of these three biomarkers. Women with elevated homocysteine and low GSH:GSSG had the highest risk of having CHD-affected pregnancy, whereas women with low homocysteine, high methionine, and high GSH:GSSG had the lowest risk. The corresponding area under the ROC curve was 81.6% (95% confidence interval [CI], 78.1-85.2%), indicating high ability to discriminate between cases and controls. CONCLUSION: High homocysteine, low methionine, and a reduced GSH:GSSG ratio were the strongest discriminating factors between cases and controls. Measurement of total homocysteine, methionine, and total and reduced glutathione in reproductive aged women may play a role in primary prevention strategies targeted at CHDs.