The Effects of Metformin on Pregnancy and Miscarriage Rates in Polycystic Ovary Syndrome (PCOS)
Condition: Polycystic Ovary Syndrome; Miscarriage; Infertility; Toxemia; Gestational Diabetes
MeSH terms: Toxemia; Polycystic Ovary Syndrome; Infertility; Diabetes, Gestational; Abortion, Spontaneous; Syndrome
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of this study is to determine whether metformin may improve pregnancy rates, and
      decrease miscarriage rates and complications of pregnancy, such as toxemia and gestational
      diabetes, in women with polycystic ovary syndrome (PCOS).
    

Detailed description: 
      Women with PCOS represent about 5-10% of the general female population and one third of the
      women treated for infertility. Thus, the development of new therapies to improve the
      efficiency of ovulation induction treatments and the outcome of pregnancy, and to reduce the
      long-term risks of the syndrome would bring important health benefits.

      The central role played by insulin resistance and hyperinsulinemia in PCOS - causing
      hyperandrogenism, premature follicular atresia, anovulation, oligo-amenorrhea and anovulatory
      infertility - has led to the use of insulin-lowering drugs for the treatment of this
      syndrome. The most studied agent is metformin, a biguanide antihyperglycemic drug used to
      treat Type 2 diabetes mellitus. It has been shown to improve significantly hyperinsulinemia
      and insulin resistance, to decrease androgen levels, and to improve menstrual pattern and,
      alone or in addition to clomiphene citrate, to induce ovulation and improve pregnancy rates
      in women with PCOS in some studies (1,2). Metformin may also decrease risks of early
      spontaneous miscarriage and gestational diabetes in PCOS (3-6). Two recent RCTs, however,
      have shown no beneficial effect of metformin compared to placebo as regards rates of
      pregnancy, miscarriage or life births in women with PCOS (7,8).

      Our hypothesis is that metformin may improve pregnancy rates and decrease miscarriage
      occurrence and complications of pregnancy, such as toxemia and gestational diabetes, in women
      with PCOS. This multicenter randomized placebo-controlled study is conducted in all five
      University Hospitals of Finland (Oulu, Kuopio, Helsinki, Tampere and Turku). Blood samples
      are drawn and the oral glucose tolerance test (OGTT) done before and at 3 months of
      treatment, after which the treatment with placebo/metformin is continued another 6 months'
      period together with the appropriate infertility treatment. If pregnancy occurs, the OGTT is
      done at 7-8 weeks of pregnancy and the placebo/metformin treatment is continued until 12
      weeks of pregnancy. The study has already started and is estimated to continue at least until
      the end of 2009. Power analysis indicated that a minimum of 60 pregnant patients are needed
      in each group to decrease the risk of miscarriage from 44% to the normal 15%.
    

Intervention name(s): metformin
Intervention type(s): Drug
Intervention description(s): The obese women will be randomized either to metformin (2g/day) or to placebo, and the non-obese either to metformin (1.5g/day) or to placebo. All subjects will be evaluated 1 to 7 days after spontaneous menstruation (oligomenorrheic patients), or at any other convenient time (amenorrheic subjects). After the treatment of 3 months with metformin/placebo alone, another appropriate infertility treatment will be combined with metformin/placebo (clomiphene, ovulation induction, insemination or in vitro fertilization) if no pregnancy has occurred. This treatment will be continued another 6 months' period. If pregnancy occurs, subjects will be re-examined at 7-8 weeks of gestation.
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Polycystic ovary syndrome; PCOS; Metformin; Miscarriage; Infertility; Complications of pregnancy