University of Oulu

Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diabetes Research and Care 2022;10:e002363. doi: 10.1136/bmjdrc-2021-002363

Metformin in pregnancy and risk of adverse long-term outcomes : a register-based cohort study

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Author: Brand, Kerstin M G1; Saarelainen, Laura2; Sonajalg, Jaak3;
Organizations: 1Merck KGaA, Darmstadt, Germany
2Global Database Studies, IQVIA, Espoo, Finland
3Global Database Studies, IQVIA, Tartu, Estonia
4PEDEGO Research Unit, Medical Research Centre Oulu, Oulu University Hospital, Oulu, Finland
5University of Oulu, Oulu, Finland
6Global Database Studies, IQVIA, Solna, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.3 MB)
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Language: English
Published: BMJ, 2022
Publish Date: 2022-07-07


Introduction: This study aimed to investigate if maternal pregnancy exposure to metformin is associated with increased risk of long-term and short-term adverse outcomes in the child.

Research design and methods: This register-based cohort study from Finland included singleton children born 2004–2016 with maternal pregnancy exposure to metformin or insulin (excluding maternal type 1 diabetes): metformin only (n=3967), insulin only (n=5273) and combination treatment (metformin and insulin; n=889). The primary outcomes were long-term offspring obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and challenges in motor–social development. In a sensitivity analysis, the primary outcomes were investigated only among children with maternal gestational diabetes. Secondary outcomes were adverse outcomes at birth. Analyses were conducted using inverse- probability of treatment weighting (IPTW), with insulin as reference.

Results: Exposure to metformin or combination treatment versus insulin was not associated with increased risk of long-term outcomes in the main or sensitivity analyses. Among the secondary outcomes, increased risk of small for gestational age (SGA) was observed for metformin (IPTW-weighted OR 1.65, 95% CI 1.16 to 2.34); increased risk of large for gestational age, preterm birth and hypoglycemia was observed for combination treatment. No increased risk was observed for neonatal mortality, hyperglycemia, or major congenital anomalies.

Conclusions: This study found no increased long-term risk associated with pregnancy exposure to metformin (alone or in combination with insulin), compared with insulin. The increased risk of SGA associated with metformin versus insulin suggests caution in pregnancies with at-risk fetal undernutrition. The increased risks of adverse outcomes at birth associated with combination treatment may reflect confounding by indication or severity.

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CLUE Study Group

Members of the CLUE Study Group are Minna Vehkala (Global Database Studies, IQVIA), Robyn Thorén (Global Database Studies, IQVIA), Henrik Svanström (Global Database Studies, IQVIA).

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Series: BMJ open diabetes research & care
ISSN: 2052-4897
ISSN-E: 2052-4897
ISSN-L: 2052-4897
Volume: 10
Issue: 1
Article number: e002363
DOI: 10.1136/bmjdrc-2021-002363
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was funded by Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).
Copyright information: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.