Paternal use of metformin and risk of major congenital malformations: A meta-analysis of 4 studies

Per Damkier; Marleen M H J van Gelder; Krista F Huybrechts; Lin-Chieh Meng; Sonia Hernandez-Diaz; Jan Nielsen; Bente M Nørgård; Hedvig Nordeng

doi:10.1002/bcp.70547

Paternal use of metformin and risk of major congenital malformations: A meta-analysis of 4 studies

Br J Clin Pharmacol. 2026 Apr 5. doi: 10.1002/bcp.70547. Online ahead of print.

Authors

Per Damkier^{1

2}, Marleen M H J van Gelder³, Krista F Huybrechts^{4

5}, Lin-Chieh Meng^{6

7}, Sonia Hernandez-Diaz⁴, Jan Nielsen^{8

9}, Bente M Nørgård^{8

9}, Hedvig Nordeng³

Affiliations

¹ Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark.
² Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
³ Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, Oslo, Norway.
⁴ Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
⁵ Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁶ Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.
⁹ Research Unit of Clinical Epidemiology, Department of Clinical Research, University of Southern Denmark, Odense C, Denmark.

PMID: 41937475
DOI: 10.1002/bcp.70547

Abstract

Metformin is the first-line drug for the treatment of Type 2 diabetes. In 2022, a Danish registry-based study reported a 40% increased risk of major congenital malformations following paternal exposure during spermatogenesis. This raised widespread concern about the use of metformin in males of reproductive age. Three subsequent studies were unable to replicate this finding. We performed a meta-analysis of four observational studies with data from five countries covering more than 11 000 live-born children whose fathers used metformin during spermatogenesis. The pooled risk ratio from an inverse variance-weighted random effects model was 1.03 (95% CI 0.88-1.21). We conclude that paternal exposure to metformin does not confer a meaningfully increased risk of major congenital malformations.

Keywords: congenitalmalformations; metformin; paternal use.