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

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.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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 Names: Placebo from Weifa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dehydroepiandrosterone sulfate (DHEAS)	(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)	up to delivery
Androstenedione	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	up to delivery
Testosterone	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	up to delivery
Sex hormone binding globulin (SHBG)	(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)	up to delivery
Free testosterone index	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)	up to delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of pregnancy complications	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	up to 6 weeks post partum
Pregnancy outcome - gestational age	Gestational age at birth (days)	after delivery
Pregnancy outcome - gestational length	Gestational length (cm) measured at birth	after delivery
Pregnancy outcome - head circumference	Head circumference (cm) measured at birth.	after delivery
Pregnancy outcome - birthweight	Birthweight (g) measured at birth	after delivery
Pregnancy outcome - placental weight	Placental weight (g) measured at birth	after delivery
Pregnancy outcome - Agpar score at 5 minutes	Apgar score at 5 minutes	after delivery
Pregnancy outcome - Agpar score at 10 minutes	Apgar score at 10 minutes	after delivery
Pregnancy outcome - umbilical artery pH	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)	after delivery

Collaborators and Investigators

• Sponsor: Norwegian University of Science and Technology
• Collaborators: St. Olavs Hospital
• Investigators: Study Director: Sven M Carlsen, MD, PhD, Norwegian University of Science and Technology

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2000
• Primary Completion (Actual): March 1, 2003
• Study Completion (Actual): March 1, 2003

Study Registration Dates

• First Submitted: August 17, 2017
• First Submitted That Met QC Criteria: August 21, 2017
• First Posted (Actual): August 24, 2017

Study Record Updates

• Last Update Posted (Actual): October 18, 2018
• Last Update Submitted That Met QC Criteria: October 16, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Metformin; Androgens; Pregnancy outcome
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 220800

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No