Metformin Treatment of Pregnant Women With Polycystic Ovary Syndrome: a Pilot Study (pilPregMet)

• ClinicalTrials.gov Identifier: NCT03259919
• Recruitment Status: Completed
• First Posted: August 24, 2017
• Last Update Posted: October 18, 2018
• Sponsor: Norwegian University of Science and Technology
• Collaborator: St. Olavs Hospital
• Information provided by (Responsible Party): Norwegian University of Science and Technology

Study Description

Brief Summary:

To investigate the effect of metformin on pregnancy complications and pregnancy outcome in the II. and III. trimester of pregnancy in women with polycystic ovary syndrome.

Condition or disease	Intervention/treatment	Phase
Polycystic Ovary Syndrome	Drug: Metformin; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Metformin Treatment of Pregnant Women With Polycystic Ovary Syndrome: a Pilot Study
• Actual Study Start Date: October 2000
• Actual Primary Completion Date: March 2003
• Actual Study Completion Date: March 2003

Arms and Interventions

Arm	Intervention/treatment
Experimental: Metformin; Metformin 850 mg x 2 daily	Drug: Metformin; Metformin 850 mg x 1 per day for the first week, and 850 mg x 2 per day for the rest of the study period.. Orally. From inclusion (before gestational week 8) to delivery. Verbal and written diet and lifestyle advices at inclusion to the study. In addition 1 mg tablet of folate and one daily multivitamin tablet.; Other Name: metformin from Weifa 425 mg / tablet
Placebo Comparator: placebo; Placebo 1 tablet x 2 daily	Drug: Placebo; Placebo, 2 tablets x 1 daily for the first week, and 2 tablets x 2 for the rest of the study period.Orally. From inclusion (that is before gestational week 12) to delivery. Verbal and written diet and lifestyle advices at inclusion to the study. In addition 1 mg tablet of folate and one daily multivitamin tablet.; Other Name: Placebo from Weifa

Outcome Measures

Primary Outcome Measures :

1. Dehydroepiandrosterone sulfate (DHEAS) [ Time Frame: up to delivery ]
   (µmol/l) Analysed in serum, from venous blood samples from the mother and venous and arterial umbilical cord blood (separately) collected within 1 h of birth. Measured using a competitive immunoassay on an Immulite 2000 analyser using the reagents and calibrators supplied by the manufacturer (Diagnostic Products Corp., USA)
2. Androstenedione [ Time Frame: up to delivery ]
   Analysed in serum, from venous blood samples from the mother and venous and arterial umbilical cord blood (separately) collected within 1 h of birth. measured by a double antibody technique on an Elecsys 2010 analyser (Roche Diagnostics GmbH, Germany) using reagents and calibrators supplied by the manufacturer
3. Testosterone [ Time Frame: up to delivery ]
   Analysed in serum, from venous blood samples from the mother and venous and arterial umbilical cord blood (separately) collected within 1 h of birth. measured by a double antibody technique on an Elecsys 2010 analyser (Roche Diagnostics GmbH, Germany) using reagents and calibrators supplied by the manufacturer
4. Sex hormone binding globulin (SHBG) [ Time Frame: up to delivery ]
   (nmol/l) Analysed in serum, from venous blood samples from the mother and venous and arterial umbilical cord blood (separately) collected within 1 h of birth. Measured using a competitive immunoassay on an Immulite 2000 analyser using the reagents and calibrators supplied by the manufacturer (Diagnostic Products Corp., USA)
5. Free testosterone index [ Time Frame: up to delivery ]
   Calculated as total testosterone divided by SHBG and multiplied by a factor of 100. SHBG measured using a competitive immunoassay on an Immulite 2000 analyser using the reagents and calibrators supplied by the manufacturer (Diagnostic Products Corp., USA)

Secondary Outcome Measures :

1. Occurence of pregnancy complications [ Time Frame: up to 6 weeks post partum ]
   Gestational diabetes (GDM) defined according to World Health Organization (1998) criteria, i.e. 2 h plasma glucose values ≥7.8 mmol/l during an Oral Glucose Tolerance Test (OGTT) with 75 g. Uncomplicated GDM treated with dietary advice only was not ranked among the complications in this study. Pre-eclampsia defined as a blood pressure ≥140/90mmHg with concomitant albuminuria ≥0.3 g/24 h measured on two separate occasions after gestational week 20. Premature delivery was defined as delivery before gestational week 37 + 0 according to an estimated date of delivery, based on mid-trimester ultrasound scan
2. Pregnancy outcome - gestational age [ Time Frame: after delivery ]
   Gestational age at birth (days)
3. Pregnancy outcome - gestational length [ Time Frame: after delivery ]
   Gestational length (cm) measured at birth
4. Pregnancy outcome - head circumference [ Time Frame: after delivery ]
   Head circumference (cm) measured at birth.
5. Pregnancy outcome - birthweight [ Time Frame: after delivery ]
   Birthweight (g) measured at birth
6. Pregnancy outcome - placental weight [ Time Frame: after delivery ]
   Placental weight (g) measured at birth
7. Pregnancy outcome - Agpar score at 5 minutes [ Time Frame: after delivery ]
   Apgar score at 5 minutes
8. Pregnancy outcome - Agpar score at 10 minutes [ Time Frame: after delivery ]
   Apgar score at 10 minutes
9. Pregnancy outcome - umbilical artery pH [ Time Frame: after delivery ]
   Umbilical artery pH measured in umbilical artery blood, immediately after delivery on a Rapidlab 248pH/Blood Gas Analyzer, using reagents and calibrators supplied by the manufacturer (Bayer Corp., USA)

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• diagnosis polycystic ovary syndrome (PCOS ) before pregnancy
• BMI 27-40 kg/m2
• Human chorionic gonadotropin, beta subunit (HCG-beta) verified pregnancy week 5-8
• At least one of the following criteria: (1) serum testosteron > 2,5 nmol/L; (2) Sex hormone binding globulin (SHBG) < 30 nmol; (3) Fasting C-peptid > 1,0 nmol/L; (4) Menstrual disturbances: oligo-/amenorrhea or metrorrhagia; (5) Hirsutism

Exclusion Criteria:

• known liver disease or ALAT > 60 IU/L
• S-creatinin > 130 micromol/L
• diabetes mellitus
• alcohol or drug abuse
• peroral steroid treatment (except inhalation steroids)
• use of cimetidine, anticoagulant, erythromycin or other macrolides
• not suitable for other reasons

Contacts and Locations

Locations

Norway

Departments of Obstetrics and Gynecology and Endocrinology, St. Olav's Hospital

Trondheim, Norway

Sponsors and Collaborators

Norwegian University of Science and Technology

St. Olavs Hospital

Investigators

• Study Director: Sven M Carlsen, MD, PhD; Norwegian University of Science and Technology

More Information

Publications of Results:

Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod. 2004 Aug;19(8):1734-40. doi: 10.1093/humrep/deh347. Epub 2004 Jun 3.

Hanem LGE, Stridsklev S, Juliusson PB, Salvesen O, Roelants M, Carlsen SM, Odegard R, Vanky E. Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1612-1621. doi: 10.1210/jc.2017-02419.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Trouva A, Alvarsson M, Calissendorff J, Asvold BO, Vanky E, Hirschberg AL. Thyroid Status During Pregnancy in Women With Polycystic Ovary Syndrome and the Effect of Metformin. Front Endocrinol (Lausanne). 2022 Feb 21;13:772801. doi: 10.3389/fendo.2022.772801. eCollection 2022.

Underdal MO, Salvesen O, Henriksen AH, Andersen M, Vanky E. Impaired Respiratory Function in Women With PCOS Compared With Matched Controls From a Population-Based Study. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz053. doi: 10.1210/clinem/dgz053.

Underdal MO, Stridsklev S, Oppen IH, Hogetveit K, Andersen MS, Vanky E. Does Metformin Treatment During Pregnancy Modify the Future Metabolic Profile in Women With PCOS? J Clin Endocrinol Metab. 2018 Jun 1;103(6):2408-2413. doi: 10.1210/jc.2018-00485.

• Responsible Party: Norwegian University of Science and Technology
• ClinicalTrials.gov Identifier: NCT03259919
• Other Study ID Numbers: 220800
• First Posted: August 24, 2017
• Last Update Posted: October 18, 2018
• Last Verified: October 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Norwegian University of Science and Technology:

Metformin; Pregnancy outcome; Androgens

Additional relevant MeSH terms:

Polycystic Ovary Syndrome; Syndrome; Disease; Pathologic Processes; Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs