Angiotensin-converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase first-trimester fetal-loss susceptibility

Complications of pregnancy have been found to be related with thrombophilic polymorphisms that explain about 30% of obstetric complications. We evaluated the angiotensin converting enzyme (ACE) and the angiotensin type 1 receptor (AT1R) gene polymorphisms in the renin-angiotensin system (RAS) as possible risk factors for fetal loss. Fifty-nine women with a history of three or more first-trimester fetal losses and 70 healthy women with a history of normal pregnancies were enrolled in this study. Thrombophilic factors, ACE insertion/deletion (I/D) and AT1R A1166C polymorphisms, prothrombin G20210A and factor V Leiden mutations were analyzed. At univariate and multivariate analysis, a significant association between ACE DD and AT1R CC genotype and fetal loss was observed. The effect of the ACE DD genotype on the risk of fetal loss was higher in AT1R C allele carriers. The prevalence of hyperhomocysteinemia (Hcy) (defined as baseline plasma levels higher than the 95% percentile; cut-off, 10.5 micromol/l per l) was significantly higher in women with fetal loss, and an association between Hcy and fetal loss was detected. All patients showed normal antithrombin, protein C, protein S, and plasminogen activator inhibitor-1 (PAI-1) values. The presence of one risk factor not associated with others was found in 33 out of 59 patients (56%); ACE DD genotype was the most prevalent risk factor. Our results identify new possible predictive markers for fetal loss in RAS polymorphisms and Hcy. Large-scale studies are warranted to attribute clinical relevance to these polymorphisms as risk factors for complicated pregnancies.