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

February 22, 2010 updated by: University of Oulu

Effects of Metformin on Fertility and Pregnancy in Women With Polycystic Ovary Syndrome: a Randomized, Prospective, Placebo-controlled Multicenter Study

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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%.

Study Type

Interventional

Enrollment (Actual)

326

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Finland
      • Helsinki, Finland
        • University Hospital of Helsinki
      • Kuopio, Finland
        • University Hospital of Kuopio
      • Oulu, Finland, 90029
        • University Hopsital of Oulu
      • Tampere, Finland
        • University Hospital of Tampere
      • Turku, Finland
        • University hospital of Turku

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Miscarriage rates
Time Frame: at 7-8 weeks of pregnancy or later if miscarriage happens later
at 7-8 weeks of pregnancy or later if miscarriage happens later

Secondary Outcome Measures

Outcome Measure
Time Frame
Effect of metformin versus placebo on the time to be pregnant
Time Frame: 3-6 months
3-6 months
Effect of metformin versus placebo on the rates of toxemia during pregnancy
Time Frame: 3 months after birth of the child
3 months after birth of the child
Effects of metformin versus placebo on the rates of gestational diabetes during pregnancy
Time Frame: 3 months after the birth of the child
3 months after the birth of the child

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Oulu

Collaborators

University of Turku
University of Helsinki
Tampere University
University of Eastern Finland

Investigators

  • Principal Investigator: Laure C Morin-Papunen, PhD, University Hospital of Oulu

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2002

Primary Completion (Actual)

December 1, 2009

Study Completion (Actual)

December 1, 2009

Study Registration Dates

First Submitted

October 9, 2009

First Submitted That Met QC Criteria

October 13, 2009

First Posted (Estimate)

October 14, 2009

Study Record Updates

Last Update Posted (Estimate)

February 23, 2010

Last Update Submitted That Met QC Criteria

February 22, 2010

Last Verified

October 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • T59108

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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