Paternal exposure to antidiabetic medications during reproductive period and adverse birth outcomes: A meta-analysis and systematic review

Background

Diabetes affected approximately 6% of all adults globally in 2021, and the use of antidiabetic medications is expected to increase among men of reproductive age. The impact of paternal exposure to these medications during spermatogenesis on offspring is still unclear.

Objective

To review the association between paternal use of antidiabetic medications during spermatogenesis and adverse birth outcomes.

Data sources: On 27 January 2025, a systematic search of Medline, Embase and Cochrane libraries was conducted without restriction on publication year, supplemented by a manual search.

Study selection and synthesis: Population-based studies examining paternal preconception exposure to antidiabetic medications compared with non-exposed fathers were included. Study quality and validity were assessed using the MOOSE guidelines, and synthesis used fixed- and random-effects models. The Oxford Centre for Evidence-Based Medicine and risk-of-bias tools were also used.

Main outcome: Congenital malformations.

Results

Of 2859 studies identified, four met the inclusion criteria. Two studies (2,435,462 births analysed) linked metformin to congenital malformations [adjusted odds ratio (aOR) 1.40, 95 % confidence interval (CI) 1.08–1.82; p = 0.012; adjusted hazard ratio 1.4, 95 % CI 1.11–1.76]. The common-effect model for metformin and congenital malformations was non-significant (aOR 1.05, 95 % CI 0.95–1.17) with high heterogeneity (I² = 76.9 %) (p = 0.0017).

Conclusion and relevance.

Paternal use of metformin during spermatogenesis was not consistently associated with congenital malformations based on low-certainty evidence. Further studies should investigate polytherapy and poorly controlled diabetes as risk factors for adverse birth outcomes.