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. 2022 Jan;10(1):e002363.
doi: 10.1136/bmjdrc-2021-002363.

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

Kerstin M G Brand  1 , Laura Saarelainen  2 , Jaak Sonajalg  3 , Emmanuelle Boutmy  4 , Caroline Foch  4 , Marja Vääräsmäki  5   6 , Laure Morin-Papunen  5   6 , Judith Schlachter  4 ; CLUE Study Group; Katja M Hakkarainen  7 , Pasi Korhonen  2
Collaborators, Affiliations

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

Kerstin M G Brand et al. BMJ Open Diabetes Res Care. 2022 Jan.

Abstract

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.

Keywords: diabetes; gestational; metformin; pregnancy.

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Conflict of interest statement

Competing interests: KMGB, CF, EB, and JuS are employees of Merck Healthcare KGaA, Darmstadt, Germany, the metformin originator and sponsor of this study, and participated in the authoring/revision of the manuscript. IQVIA performs commissioned pharmacoepidemiological studies, including this one, for several pharmaceutical companies. LS, JaS, MV, RT and KMH are employees of IQVIA, which performs commissioned pharmacoepidemiological studies for several pharmaceutical companies. HS is an employee of IQVIA and has received consulting fees from Celgene, outside the submitted work. PK was at the time of conducting the study an employee of IQVIA.

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