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

This study has been completed.
Sponsor:
Collaborators:
University of Eastern Finland
Helsinki University
University of Tampere
University of Turku
Information provided by:
University of Oulu
ClinicalTrials.gov Identifier:
NCT00994812
First received: October 9, 2009
Last updated: February 22, 2010
Last verified: October 2009
  Purpose

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 Intervention Phase
Polycystic Ovary Syndrome
Miscarriage
Infertility
Toxemia
Gestational Diabetes
Drug: metformin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by University of Oulu:

Primary Outcome Measures:
  • Miscarriage rates [ Time Frame: at 7-8 weeks of pregnancy or later if miscarriage happens later ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Effect of metformin versus placebo on the time to be pregnant [ Time Frame: 3-6 months ] [ Designated as safety issue: Yes ]
  • Effect of metformin versus placebo on the rates of toxemia during pregnancy [ Time Frame: 3 months after birth of the child ] [ Designated as safety issue: Yes ]
  • Effects of metformin versus placebo on the rates of gestational diabetes during pregnancy [ Time Frame: 3 months after the birth of the child ] [ Designated as safety issue: Yes ]

Enrollment: 326
Study Start Date: August 2002
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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%.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00994812

Locations
Finland
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
Helsinki University
University of Tampere
University of Turku
Investigators
Principal Investigator: Laure C Morin-Papunen, PhD University hospital of Oulu
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Laure Morin-Papunen/ Associate Professor, Dept of Obstetrics and Gynecology, University Hospital of Oulu
ClinicalTrials.gov Identifier: NCT00994812     History of Changes
Other Study ID Numbers: T59108
Study First Received: October 9, 2009
Last Updated: February 22, 2010
Health Authority: Finland: Ethics Committee

Keywords provided by University of Oulu:
Polycystic ovary syndrome
PCOS
Metformin
Miscarriage
Infertility
Complications of pregnancy

Additional relevant MeSH terms:
Abortion, Spontaneous
Infertility
Polycystic Ovary Syndrome
Toxemia
Diabetes, Gestational
Pregnancy Complications
Genital Diseases, Male
Genital Diseases, Female
Ovarian Cysts
Cysts
Neoplasms
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Infection
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014