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

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).