The IVS1-401 T-Allele of the Estrogen Receptor (ER)-α Is an Independent Predictor of Late Fetal Loss.

Estrogens are involved in the regulation of placental function and fetal development through their interaction with estrogen receptor a (ER-α). Sequence variants in the gene encoding for ER-a could disturb estrogen-dependent mechanisms in pregnancy maintenance, probably leading to fetal loss. We determined the IVS1-401C/T polymorphism of the human ER-α, the G1691A mutation of the factor V gene (factor V Leiden), the G20210A mutation of the prothrombin gene, and the C677T polymorphism of the methylenetetrahydrofolate-reductase (MTHFR) gene in 104 women with fetal loss and 277 normal women. Inclusion criteria for the women with fetal loss<were either recurrent early fetal loss (three or more consecutive fetal losses at < 12 weeks gestation and no late fetal loss) or at least one late fetal loss (≥ 12 weeks gestation). Only women with post-embryonic loss after ultrasonic disappearance of fetal pulse from the intrauterine fetal pole were included in the study. Documented first trimester preclinical and blighted ovum abortions as well as fetal losses that were the result of documented fetal malformation or the result of an infectious complication were excluded. The women enrolled with recurrent fetal loss had no previous history of venous or arterial thromboembolic disease, diabetes mellitus, chronic hypertension, thyroid dysfunction, systemic lupus erythematosus, intrauterine growth retardation, pregnancy-induced hypertension, or preeclampsia. They all had a detailed investigation which was negative for potential causes of fetal demise including fasting glucose, basal FSH, LH and estradiol levels on day 3 of a natural cycle, TSH and prolactin levels and antinuclear factor. In addition, transvaginal scanning was performed in all patients included to verify ovarian morphology. Women with three or more first trimester or one or more second or third trimester pregnancy losses underwent a hypersalpingography and/or hysteroscopy to confirm uterine cavity normalcy, and both partners were also investigated for chromosomal aberrations. The 277 normal women had at least one previous pregnancy and no previous fetal loss or late pregnancy complications, and no history of previous arterial or venous thromboembolism In a subgroup analysis of women with recurrent early fetal loss (n=34), the prevalence of the genetic markers did not differ significantly between women with early fetal loss and normal women. In contrast, in the subgroup analysis of women with at least one late miscarriage (n=70), the prevalences of the ER-α IVS1-401 T-allele (TT vs. CC, odds ratio 2.85, p=0.018, TT+CT vs. CC, odds ratio 2.28, p=0.043) and of heterozygous factor V Leiden (odds ratio 3.2, p=0.002) were significantly higher among women with late fetal loss than among normal women. Carriers of both risk determinants have an at least additive increase in risk for late abortions (odds ratio 7.0, p=0.0004). The fraction of all late abortions that would be attributable to the genetic variants (population attributable risk) was 13.9 percent for factor V Leiden and 49.2 percent for the ER-α IVS1-401 T-allele. Women with the IVS1-401 T-allele of the ER-α and/or factor V Leiden are at increased risk of late fetal loss.