Gene Mutation Associated With Miscarriage, Found More Common in PCOS


WASHINGTON — The hypofibrinolytic plasminogen activator inhibitor was an independent predictor of miscarriage in a cohort of 441 women with polycystic ovary syndrome who had previous pregnancies, Charles J. Glueck, M.D., reported at the Clinical Research 2005 meeting.

PAI-Fx is highly correlated with fasting serum insulin resistance, and Glucophage (metformin) (2.25–2.5 g/day) sharply lowers both insulin and PAI-Fx levels, significantly improving the odds of live births for women with PCOS, said Dr. Glueck, director of the Jewish Hospital Cholesterol Center in Cincinnati.

The 441 women were part of a larger cohort of 968 women with PCOS. Of these 441 women, 206 had only live births, 118 had at least one live birth and one miscarriage, and 75 had only miscarriages.

In addition, of 926 women with PCOS for whom genetic data were available, 727 (79%) had the 4G5G or 4G4G genotype vs. 87 of 126 (69%) healthy female controls.

This PAI-1 genetic mutation was significantly associated with miscarriage, in part through its gene product, PAI-Fx, and appears to be more common in women with PCOS than in healthy women, Dr. Glueck said at the meeting, sponsored by the American Federation for Medical Research.

The overall frequency of the 4G allele was 53% among PCOS women, compared with 46% of the controls.

Dr. Glueck and his associates also evaluated 30 women who took metformin during pregnancy and had live births and 23 women who took it and had first-trimester miscarriages. The PAI-Fx level fell by approximately 44% among the women who had live births, but it rose approximately 19% among the women who had early miscarriages. Among the women who had live births, PAI-Fx fell consistently from pre-pregnancy treatment through the first trimester, from 16.8 to 6.7 units/mL.

Left untreated, approximately 50% of pregnant women with PCOS experience first-trimester miscarriages; treatment with metformin, combined with dietary changes, reduces this figure to approximately 15% (the national average in the United States).

PCOS-associated obesity, hyperinsulinemia, and hypertriglyceridemia can contribute to the high PAI-Fx levels that promote miscarriage in women with PCOS, Dr. Glueck noted.

Physicians can optimize pregnancy outcomes by prescribing metformin and diet, which has been shown to reduce obesity, hyperinsulinemia, hypertriglyceridemia, and PAI-Fx levels.

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