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

Infertility Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00994812
• Other study ID #: T59108
• Status: Completed
• Phase: Phase 3
• First received: October 9, 2009
• Last updated: February 22, 2010
• Start date: August 2002
• Est. completion date: December 2009

Study information

• Verified date: October 2009
• Source: University of Oulu
• Contact: n/a
• Is FDA regulated: No
• Health authority: Finland: Ethics Committee
• Study type: Interventional

Clinical Trial 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).

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%.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 326
• Est. completion date: December 2009
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Abortion, Spontaneous
• Diabetes, Gestational
• Gestational Diabetes
• Infertility
• Miscarriage
• Polycystic Ovary Syndrome
• Syndrome
• Toxemia

Intervention

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.

Locations

Country	Name	City	State
Finland	University Hospital Of Helsinki	Helsinki
Finland	University Hospital of Kuopio	Kuopio
Finland	University Hopsital of Oulu	Oulu
Finland	University Hospital of Tampere	Tampere
Finland	University Hospital of Turku	Turku

Sponsors (5)

Lead Sponsor	Collaborator
University of Oulu	Helsinki University, University of Eastern Finland, University of Tampere, University of Turku

Country where clinical trial is conducted

Finland, 

References & Publications (7)

Glueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril. 2001 Jan;75(1):46-52. — View Citation

Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002 Mar;77(3):520-5. — View Citation

Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab. 2002 Feb;87(2):524-9. — View Citation

Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod. 2004 Nov;19(11):2474-83. Epub 2004 Sep 9. — View Citation

Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66. — View Citation

Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ. 2006 Jun 24;332(7556):1485. Epub 2006 Jun 12. — View Citation

Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005 Jul;90(7):4068-74. Epub 2005 Apr 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Miscarriage rates		at 7-8 weeks of pregnancy or later if miscarriage happens later	No
Secondary	Effect of metformin versus placebo on the time to be pregnant		3-6 months	Yes
Secondary	Effect of metformin versus placebo on the rates of toxemia during pregnancy		3 months after birth of the child	Yes
Secondary	Effects of metformin versus placebo on the rates of gestational diabetes during pregnancy		3 months after the birth of the child	Yes