American Diabetes Association
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Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes – A Nordic Register-Based Cohort Study

posted on 2023-06-21, 22:08 authored by Lars J Kjerpeseth, Carolyn E Cesta, Kari Furu, Anders Engeland, Mika Gissler, Hanne L Gulseth, Øystein Karlstad, Maarit K Leinonen, Laura Pazzagli, Helga Zoega, Jacqueline M Cohen


Objective: Assess risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes.

Research Design and Methods: Cohort study using four Nordic countries’ nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome and fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratio (RR) and 95% CI was estimated for any and cardiac malformations.

Results: Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in first trimester, and 4023 singleton infants included. A malformation was diagnosed in 147 (4.7%) of 3145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46 to 1.54). Among 2852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin, respectively 127 (4.4%) and 20 (6.8%) had a malformation. The adjusted risk was not increased for neither metformin alone (0.83, 0.44 to 1.58) nor both metformin and insulin (0.98, 0.56 to 1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55 to 1.84) for any metformin, 0.92 (0.47 to 1.81) for metformin alone and 1.72 (0.76 to 3.91) for both metformin and insulin.

Conclusions: No evidence of an increased malformation risk with metformin versus insulin in first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.


This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS, project no. 83539), and by the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS, project no. 273366), and partly by the Research Council of Norway through its Centers of Excellence funding scheme (project no. 262700). H.Z. was supported by a UNSW Scientia Program Award during the conduct of the study. C.E.C. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 844728. L.P. received and was supported by a grant from FORTE Swedish Research Council for Health, Working Life and Welfare while the study was conducted (project no. 2021-01080). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript.