Peter S. Bernstein, MD, MPH, FACOG and Esther Schmuel, MD

Disclosures

November 03, 2005

Question

A 31-year-old woman with polycystic ovarian syndrome and metabolic syndrome has been treated with metformin 500 mg twice daily until now; she is in the 8th week of her first pregnancy. Would it be recommended that she continue taking metformin throughout pregnancy or discontinue? What is the risk of the fetal damage caused by metformin? What is the risk of pregnancy loss caused by insulin resistance?

Branislav Sepesi, MD

Response from Peter S. Bernstein, MD, MPH, FACOG and Esther Schmuel, MD

Polycystic ovarian syndrome (PCOS) occurs in 5% to 7% of reproductive-age women and is diagnosed if at least 2 of the following criteria are present: (1) oligo-ovulation or anovulation (often appearing as oligomenorrhea or amenorrhea), (2) elevated levels of androgens (total or free testosterone, androstendione), (3) clinical manifestations of hyperandrogenism (acne, hirsutism, male-pattern baldness), and (4) polycystic appearance of ovaries on ultrasound. Approximately 30% to 40% of women with PCOS have impaired glucose tolerance, and as many as 10% will develop diabetes by the fourth decade. Women with PCOS are also more insulin resistant than similar age- and weight-matched controls.[1,2]

Metformin is an oral biguanide that is approved for the treatment of non-insulin-dependent diabetes. Metformin acts primarily by decreasing hepatic glucose production, as well as by decreasing intestinal absorption of glucose and increasing peripheral uptake and utilization of glucose. In patients with PCOS, it reduces fasting insulin, basal and stimulated luteinizing hormone (LH) levels, and free testosterone concentrations.[3]

The role of metformin in ovulation induction is well established, and several studies have demonstrated that women with PCOS are more likely to ovulate with metformin than with placebo alone.[2,4] Therefore, women with PCOS often conceive while on metformin, and exposure during organogenesis is common. At present, metformin is classified as Class B in pregnancy, with no evidence of animal or fetal toxicity or teratogenicity. 5] Reproduction studies in rats and rabbits show no teratogenicity with dosages up to 600 mg/kg per day, approximately twice the recommended human dosage.[6]Additionally, there are numerous reports using metformin for the treatment of gestational diabetes mellitus (GDM), without evidence of fetal harm.[7,8,9] Although metformin does cross the placenta, a partial placental barrier likely exists, as maternal and fetal concentrations are different.[5,6,10]

Several studies have reported an increased risk of spontaneous abortion in women with PCOS, perhaps 20% to 40% higher than in the general obstetric population.[3] This increased risk may be due to hyperinsulinemia, which adversely affects endometrial function and environment.[3,4] The use of metformin to decrease this risk in women with PCOS was reported in 2 small, observational studies, with a reduction in miscarriage from 58% to 11%.[3,4] However, it must be emphasized that there is a paucity of evidence to support the use of metformin for this indication, and further study using prospective, randomized trials is warranted.[5]

Women with PCOS who are insulin resistant are at high risk for the development of diabetes in pregnancy, and a possible role for metformin therapy may be the prevention of GDM. In a cohort of 33 women with PCOS taking metformin until delivery, GDM occurred in 3% compared with 23% in 39 women taking no medication.[4,6] However, given the lack of data from well-designed, prospective clinical trials, metformin is currently not indicated for the prevention of GDM. Therefore, in a patient who has conceived on metformin, the current recommendation would be to discontinue the medication once pregnancy is confirmed.

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