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Now published in The Lancet

Metformin Treatment of Pregnant Women with Polycystic Ovary Syndrome: Results of a Nordic Randomized, Clinical Trial

152 Pages Posted: 30 Oct 2018

See all articles by Tone Loevvik

Tone Loevvik

Norwegian University of Science and Technology (NTNU) - Department of Clinical and Molecular Medicine

Sven M. Carlsen

Norwegian University of Science and Technology (NTNU)

Øyvind Salvesen

Norwegian University of Science and Technology (NTNU)

Berglind Steffensen

University Hospital of Iceland

Marie Bixo

University of Umea

Fransisco Gómez-Real

University of Bergen - Haukeland University Hospital

Marianne Lønnebotn

University of Bergen - Haukeland University Hospital

Kristin V. Hestvold

Vestre Viken Hospital Trust

Renata Zabielska

Vestfold Hospital Trust

Angelica Lindén Hirschberg

Karolinska Institutet - Karolinska University Hospital

Anastasia Trouva

Nordlands Hospital Trust

Solveig Thorarinsdottir

Telemark Hospital Trust

Sissel Hjelle

Ålesund Hospital

Ann Hilde Berg

Innlandet Hospital Trust

Frida Andræ

Nordlands Hospital Trust

Inger S Poromaa

Uppsala University

Johanna Molin

University of Umea - Umea University Hospital

Maria Underdal

Norwegian University of Science and Technology (NTNU)

Eszter Vanky

Norwegian University of Science and Technology (NTNU)

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Abstract

Background: Women with polycystic ovary syndrome (PCOS) have increased risk of pregnancy complications. Two previous randomized controlled trials (RCT) showed tendency to lower incidence of late miscarriages and preterm births among women with PCOS who received metformin during pregnancy compared to placebo. We aimed to explore whether metformin prevents late miscarriage and preterm birth in a third large RCT.

Methods: Randomized, double-blinded, multicenter study (14 centers in Norway, Sweden and Iceland) from 2012-2017. Women with PCOS, with a singleton pregnancy signed up for the study in first trimester of pregnancy. They received study-information at the booking visit or on the internet. In all 487 women were found eligible. Study-participants were randomized to metformin (2000mg/day) or placebo from 1st trimester to delivery. Primary endpoint was the composite incidence of late miscarriage and preterm birth. Secondary endpoints were gestational diabetes (GDM), preeclampsia and pregnancy-induced hypertension. We also present pooled data from all three RCTs.

Findings: In all 487 women were randomly assigned to metformin (n=244) or placebo (n=243), all included in the intention-to-treat (ITT) analysis. The composite incidence of late miscarriage and preterm birth was 12 in the metformin group, and 23 in the placebo-group (p=0·08 OR 0·50 (0·22- 1·08)). No difference in the incidence of GDM, preeclampsia or pregnancy induced hypertension was observed. Pooled ITT analyses on 800 women randomized to metformin (n=397) or placebo (n=403), showed 18 vs. 40 late miscarriages and preterm births (p= 0·004 OR 0·43 (0·24- 0·77)). No difference in the incidence of GDM, preeclampsia or pregnancy induced hypertension.

Interpretation: Metformin from 1st trimester to delivery reduces the risk of late miscarriage and preterm birth in women with PCOS. Metformin neither prevents, nor modifies the clinical course of GDM.

Clinical Trial Number: ClinicalTrials.gov number, NCT01587378, EudraCT number, 2011-002203-15.

Funding Statement: The Research Council of Norway, Novo Nordisk Foundation, St. Olavs University Hospital and the Norwegian University of Science and Technology.

Declaration of Interests: No authors report anything to declare.

Ethics Approval Statement: All participants signed an informed consent before inclusion. Ethical approvals were obtained from the Regional Committee for Health Research Ethics of Central Norway (REC number 2011/1434), the Regional Ethical Review Board in Stockholm (Dnmb: 2012/1200-31/2), and the National Bioethics Committee of Iceland (VSNb2012100011/03.10).

Keywords: PCOS, Metformin, Preterm Birth, Miscarriage, Gestational Diabetes, Preeclampsia

Suggested Citation

Loevvik, Tone and Carlsen, Sven M. and Salvesen, Øyvind and Steffensen, Berglind and Bixo, Marie and Gómez-Real, Fransisco and Lønnebotn, Marianne and Hestvold, Kristin V. and Zabielska, Renata and Lindén Hirschberg, Angelica and Trouva, Anastasia and Thorarinsdottir, Solveig and Hjelle, Sissel and Hilde Berg, Ann and Andræ, Frida and Poromaa, Inger S and Molin, Johanna and Underdal, Maria and Vanky, Eszter, Metformin Treatment of Pregnant Women with Polycystic Ovary Syndrome: Results of a Nordic Randomized, Clinical Trial (October 25, 2018). Available at SSRN: https://ssrn.com/abstract=3273167

Tone Loevvik (Contact Author)

Norwegian University of Science and Technology (NTNU) - Department of Clinical and Molecular Medicine ( email )

Trondheim NO-7491n
Norway

Sven M. Carlsen

Norwegian University of Science and Technology (NTNU)

Høgskoleringen
Trondheim NO-7491, 7491
Norway

Øyvind Salvesen

Norwegian University of Science and Technology (NTNU)

Høgskoleringen
Trondheim NO-7491, 7491
Norway

Berglind Steffensen

University Hospital of Iceland

Reykjavik
Iceland

Marie Bixo

University of Umea

Samhallsvetarhuset, Plan 2
Umea University
Umeå, SE 901 87
Sweden

Fransisco Gómez-Real

University of Bergen - Haukeland University Hospital

Bergen, N-5021
Norway

Marianne Lønnebotn

University of Bergen - Haukeland University Hospital

Bergen, N-5021
Norway

Kristin V. Hestvold

Vestre Viken Hospital Trust

Drammen
Norway

Renata Zabielska

Vestfold Hospital Trust

Tönsberg
Norway

Angelica Lindén Hirschberg

Karolinska Institutet - Karolinska University Hospital ( email )

Solna, 17176
Sweden

Anastasia Trouva

Nordlands Hospital Trust

Bodø
Norway

Solveig Thorarinsdottir

Telemark Hospital Trust

Skien
Norway

Sissel Hjelle

Ålesund Hospital

Ålesund
Norway

Ann Hilde Berg

Innlandet Hospital Trust

Lillehammer
Norway

Frida Andræ

Nordlands Hospital Trust

Bodø
Norway

Inger S Poromaa

Uppsala University

Box 513
Uppsala, 751 20
Sweden

Johanna Molin

University of Umea - Umea University Hospital

Samhallsvetarhuset, Plan 2
Umeå, SE 901 87
Sweden

Maria Underdal

Norwegian University of Science and Technology (NTNU)

Høgskoleringen
Trondheim NO-7491, 7491
Norway

Eszter Vanky

Norwegian University of Science and Technology (NTNU)

Høgskoleringen
Trondheim NO-7491, 7491
Norway

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