AIMS: Metformin is used to treat type 2 diabetes, polycystic ovary syndrome associated infertility, and gestational diabetes. This study aims to evaluate the safety of metformin in early pregnancy. METHOD: We evaluated the risk of major birth defects and pregnancy losses in a cohort of pregnant women exposed to metformin during the first trimester for different indications relative to a matched unexposed reference group. RESULTS: The risk of major birth defects was 5.1% (20/392) in pregnancies exposed to metformin during the first trimester and 2.1% (9/431) in the reference group [adjusted odds ratio (OR) 1.70; 95% CI 0.70-4.38]. Among metformin users, this risk was 7.8% (17/219) in patients with pre-gestational diabetes and 1.7% (3/173) in those without this diagnosis. Compared to the unexposed reference, the OR for metformin user with diabetes was 3.95 (95% CI 1.77-9.41) and for metformin with other indications it was 0.83 (95% CI 0.18-2.81). The risk of pregnancy losses (spontaneous abortions and stillbirths) was 20.8% in women on metformin during the first trimester and 10.8% in the reference group [adjusted hazard ratio (HR) 1.57; 95% CI 0.90-2.74]. The risks for women on metformin with and without pre-gestational diabetes were 24.0% and 16.8% respectively, with adjusted HR of 2.51 (95% CI 1.44-4.36) and 1.38 (95% CI 0.74-2.59) when compared to the reference. CONCLUSION: Pregnant women with pre-gestational diabetes on metformin are at a higher risk for adverse pregnancy outcomes than the general population. This appears to be due to the underlying diabetes since women on metformin for other indications do not present meaningfully increased risks.

BELTIS Rabin Medical Center and NICU Schneider Children's Medical Center of Israel Petach Tikva Israel and Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Centro di Riferimento Regionale di Tossicologia Perinatale SODc Tossicologia Medica Azienda Ospedaliero Universitaria Careggi Firenze Italy

CZTIS 3rd Faculty of Medicine Charles University Prague Czech Republic

Department of Epidemiology Harvard School of Public Health Boston Massachusetts USA

Faculty of Medicine Department of Pharmacology Karadeniz Technical University Trabzon Turkey

Faculty of Medicine Department of Pharmacology Teratology Information Service Izmir Katip Celebi University Izmir Turkey

Institute of Social and Preventive Medicine Centre Hospitalier Universitaire Vaudois Lausanne Switzerland

Materno Fetal and Obstetrics Research Unit Departement Femme Mere Enfant University Hospital Lausanne Switzerland

Pharmacovigilance Center of Dijon CHU Dijon France

Pharmacovigilance Center of Lyon Hospices Civils de Lyon France

Pharmacovigilance Center of Tours CHRU Tours France

Poison Control Center Bergamo Italy

Registre des Malformations en Rhone Alpes Faculté Laennec Lyon France

School of Pharmaceutical Sciences University of Geneva and Lausanne Geneva Switzerland

Swiss Teratogen Information Service and Service of Clinical Pharmacology University Hospital Lausanne Switzerland

Telefono Rosso Teratology Information Service Department of Obstetrics and Gynecology Catholic University of Sacred Heart Rome Italy

Teratology Information Service Clinical Genetics Unit Department of Women's and Children's Health University of Padova Padova Italy

Teratology Information Service Netherlands Pharmacovigilance Centre Lareb The Netherlands

UKTIS Regional Drug and Therapeutics Centre Newcastle upon Tyne UK

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