We assessed whether hypofibrinolytic plasminogen activator inhibitor (PAI-Fx) was independently associated with first-trimester miscarriage in 430 women with polycystic ovary syndrome (PCOS) who had previous pregnancies. We hypothesized that Glucophage optimizes live births in women with PCOS by lowering PAI-Fx before conception and further lowering PAI-Fx in the first trimester of pregnancy. We also assessed whether PAI-Fx levels were independently related to PAI-1 genotype and to modifiable risk factors, BMI, insulin, and triglyceride (TG). By stepwise logistic regression with the dependent variable being previous pregnancy outcomes at 3 levels (live birth pregnancies only [n = 208], both one or more 1 live births and $ one or more first-trimester miscarriages [n = 111] or first-trimester miscarriages only [n = 71]), and explanatory variables PAI-1 genotype, PAI-Fx, insulin, HOMA IR, BMI, and TG, PAI-Fx was positively associated with first-trimester miscarriage, p = .004. For each 5 IU/mL increment in PAI-Fx, the risk being in an adverse first-trimester miscarriage category increased, odds ratio 1.12, 95% CI 1.04 to 1.20. Prospectively, from pretreatment to the last preconception visit on Glucophage, in 30 women who subsequently had live births, PAI-Fx fell 44% but rose 19% in 23 women with first-trimester miscarriage, p = .03. In the 30 women with live birth pregnancies, median PAI-Fx fell continuously from pretreatment through the first trimester (from 16.8 to 6.7 IU/mL), while PAI-Fx was either unchanged or rose in women with first-trimester miscarriage. Of the 921 PCOS women who had 4G5G data, 718 (78%) had 4G4G-4G5G genotypes vs 87/126 (69%) normal female controls (x2 = 4.95, p = .026). The 4G-allele frequency was 53% in PCOS women vs 46% in controls (x2 = 4.3, p = .04). By stepwise regression, positive independent determinants of PAI-Fx included BMI (partial R 2 = 10.6%, p < .0001), insulin (partial R2 = 2.8%, p < .0001), TG (partial R2 = 1.1%, p = .0009), and PAI-genotype (partial R 2 = 1%, p = .0011). The PAI-1 gene 4G polymorphism is more common in PCOS than normal women, and, in concert with obesity, hyperinsulinemia and hypertriglyceridemia, contributes to treatable, hypofibrinolytic, miscarriage-promoting, high PAI-Fx. Preconception and first-trimester decrements in PAI-Fx on Glucophage are associated with live births, whereas increments or no change in PAI-Fx despite Glucophage appear to be associated with first-trimester miscarriage.
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