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The Effects of Metformin on Pregnancy and Miscarriage Rates in Polycystic Ovary Syndrome (PCOS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00994812
Recruitment Status : Completed
First Posted : October 14, 2009
Last Update Posted : February 23, 2010
University of Eastern Finland
University of Helsinki
Tampere University
University of Turku
Information provided by:
University of Oulu

Brief 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).

Condition or disease Intervention/treatment Phase
Polycystic Ovary Syndrome Miscarriage Infertility Toxemia Gestational Diabetes Drug: metformin Phase 3

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%.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 326 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Metformin on Fertility and Pregnancy in Women With Polycystic Ovary Syndrome: a Randomized, Prospective, Placebo-controlled Multicenter Study
Study Start Date : August 2002
Actual Primary Completion Date : December 2009
Actual Study Completion Date : December 2009

Arm Intervention/treatment
Experimental: Metformin Drug: metformin
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.

Primary Outcome Measures :
  1. Miscarriage rates [ Time Frame: at 7-8 weeks of pregnancy or later if miscarriage happens later ]

Secondary Outcome Measures :
  1. Effect of metformin versus placebo on the time to be pregnant [ Time Frame: 3-6 months ]
  2. Effect of metformin versus placebo on the rates of toxemia during pregnancy [ Time Frame: 3 months after birth of the child ]
  3. Effects of metformin versus placebo on the rates of gestational diabetes during pregnancy [ Time Frame: 3 months after the birth of the child ]

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. age < 40 years at entry
  2. BMI > 19 kg/m2
  3. Infertility lasting > 1 year
  4. Criteria for PCOS are as defined by ESHRE/ASRM: at least two of the following findings:

    • polycystic ovaries shown by vaginal ultrasonography (more than 12 subcapsular follicles of 3-8 mm diameter in one plane of the ovary)
    • oligomenorrhea or amenorrhea
    • clinical manifestations of hyperandrogenism such as a hirsutism score of > 7 according to Ferriman and Gallwey (Ferriman & Gallwey 1961)and/or an elevated serum testosterone level (> 2.7 nmol/l).

Exclusion Criteria:

  1. diabetic subjects
  2. alcohol users
  3. active liver disease (ALAT > +2 SD the upper normal value i.e.> 100IU/l)
  4. hormonal drugs
  5. past or present cardiac failure (NYHA I-IV)
  6. liver or renal failure (S-Creatinine above the normal value ie.124 umol/l)
  7. pregnancy or lactation
  8. hypersensitivity to metformin

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00994812

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University Hospital Of Helsinki
Helsinki, Finland
University Hospital of Kuopio
Kuopio, Finland
University Hopsital of Oulu
Oulu, Finland, 90029
University Hospital of Tampere
Tampere, Finland
University Hospital of Turku
Turku, Finland
Sponsors and Collaborators
University of Oulu
University of Eastern Finland
University of Helsinki
Tampere University
University of Turku
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Principal Investigator: Laure C Morin-Papunen, PhD University hospital of Oulu

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Laure Morin-Papunen/ Associate Professor, Dept of Obstetrics and Gynecology, University Hospital of Oulu Identifier: NCT00994812    
Other Study ID Numbers: T59108
First Posted: October 14, 2009    Key Record Dates
Last Update Posted: February 23, 2010
Last Verified: October 2009
Keywords provided by University of Oulu:
Polycystic ovary syndrome
Complications of pregnancy
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Diabetes, Gestational
Abortion, Spontaneous
Pathologic Processes
Ovarian Cysts
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Pregnancy Complications
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Hypoglycemic Agents
Physiological Effects of Drugs