Results of small study: metformin betters pregnancy outcomes in PCOS

OB/GYN News, July 1, 2004 by Kate Johnson

MONTREAL -- Despite ongoing debate about the safety of metformin use during pregnancy, patients with polycystic ovarian syndrome do better with the therapy than without it, Dr. Sonia Malik said at the 18th World Congress on Fertility and Sterility.

"Metformin lowered bleeding and pregnancy loss in my PCOS patients, even if it was given for a short time," said Dr. Malik, an ob.gyn. at Holy Angels Hospital in Vasant Vihar, New Delhi.

Dr. Malik stated that concerns have been raised about metformin's safety during pregnancy because there are no randomized controlled trials to support its use.

A recent Australian review by Dr. R.J. Norman and associates suggests that "the use of metformin in early pregnancy for reducing the risk of miscarriage should be avoided outside of the context of properly designed prospective randomized trials" (Curr. Opin. Obstet. Gynecol. 16[3]:245-50, 2004). The article also states that "there is some reason for use of metformin in midpregnancy for gestational diabetes but better evidence from randomized controlled trials is urgently needed."

In the absence of randomized controlled trials, however, Dr. Malik said that metformin, an insulin sensitizer, has proven benefits. In her retrospective study, which she presented at the meeting, she found that even 3 months of metformin treatment in pregnant patients with PCOS significantly reduced bleeding and pregnancy loss.

Her study included 30 pregnant patients with PCOS who returned to her hospital after spontaneously conceiving a second child. In all cases, the first pregnancy was achieved with metformin therapy, which was continued throughout the pregnancy.

Ten of the patients took 500 mg of metformin three times a day for the first 3 months of their second pregnancy (either because they had started the therapy on their own when they discovered they were pregnant, or because they were prescribed the therapy because of a high risk of spontaneous abortion), while the remaining 20 patients did not take metformin.

Bleeding occurred in 10% of patients who had 3 months of metformin therapy, compared with 27% of patients who did not take metformin.

Similarly, there was no pregnancy loss in patients receiving metformin, while 20% of those who were not receiving metformin experienced pregnancy loss, she said at the meeting, sponsored by the International Federation of Fertility Societies.

Both groups had a high level of complications (only 14% had uneventful pregnancies, while no complications had been reported in their previous metformin-supported pregnancies).

However, those receiving metformin had a lower rate of complications (80%), compared with those not receiving metformin (86%).

Although metformin is commonly used to treat gestational diabetes (GD), both groups in the study had high rates of GD (40% overall), compared with no GD in their first metformin-supported pregnancies. Additionally, 67% of the fetuses had macrosomia, which was strongly associated with a cumulative weight gain (over both pregnancies) of more than 16 kg.

"For some of these patients, the second pregnancy was conceived very quickly after the birth of their first child, and they didn't have time to lose weight. I wonder whether if they had returned to their previous weight maybe they wouldn't have shown up with all these problems," Dr. Malik said in an interview. She further speculated that the absence of or limited exposure to metformin in the second pregnancy--which had kept the patients' weight under control in the first pregnancy--may have caused them to put on lots of weight.

Dr. Malik says she has started measuring plasminogen activator inhibitor to better determine which PCOS patients will benefit most from receiving metformin therapy.

"This is a marker of fibrinolytic activity, which indicates microthrombi formation that happens in insulin resistance. When I find these levels are normal I don't put [patients] on metformin, and they do not bleed during pregnancy," she said.

Despite concerns about the potential teratogenicity of metformin in pregnancy, Dr. Malik says there have been no reports of adverse outcomes.

In fact, a new prospective analysis by Dr. C.J. Glueck and associates of 126 live births to women with PCOS who were treated with metformin (1.5-2.55 g/day through pregnancy) concludes that "metformin reduced the development of GD, was not teratogenic, and did not adversely affect birth length and weight, growth, or motor-social development of children in the first 18 months of life" (Hum. Reprod. 19[6]:1323-30, 2004).

BY KATE JOHNSON

Contributing Writer