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20 PLASMINOGEN ACTIVATOR INHIBITOR ACTIVITY, 4G5G POLYMORPHISM OF THE PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1) GENE, AND FIRST-TRIMESTER MISCARRIAGE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME.
  1. C. J. Glueck,
  2. L. Sieve,
  3. B. Zhu,
  4. P. Wang
  1. Cholesterol Center, Jewish Hospital, MDL Laboratories, Cincinnati, OH

Abstract

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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