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. 2024 Oct 16:387:e080127.
doi: 10.1136/bmj-2024-080127.

Paternal metformin use and risk of congenital malformations in offspring in Norway and Taiwan: population based, cross national cohort study

Lin-Chieh Meng  1 , Marleen M H J van Gelder  2 , Hui-Min Chuang  1 , Liang-Kung Chen  3   4   5 , Fei-Yuan Hsiao  6   7   8 , Hedvig M E Nordeng  2   9
Affiliations

Paternal metformin use and risk of congenital malformations in offspring in Norway and Taiwan: population based, cross national cohort study

Lin-Chieh Meng et al. BMJ. .

Abstract

Objective: To evaluate the association between paternal metformin use and risk of congenital malformations in offspring.

Design: Population based, cross national cohort study.

Setting: Norway and Taiwan.

Participants: 619 389 offspring with paternal data during the period of sperm development (three months before pregnancy) in the Norwegian cohort during 2010-21 and 2 563 812 in the Taiwanese cohort during 2004-18.

Main outcome measures: The primary outcome was any congenital malformation, and the secondary outcome was organ specific malformations, classified according to the European surveillance of congenital anomalies guidelines. Relative risks were estimated with an unadjusted analysis and with analyses restricted to the cohort of men with type 2 diabetes mellitus and those using overlap propensity score weighting to control for severity of diabetes and other potential confounders. Sibling matched comparisons were conducted to account for genetic and lifestyle factors. Relative risk estimates for Norwegian and Taiwanese data were pooled using a random effects meta-analytical approach.

Results: Paternal data on metformin use during the period of sperm development was available for 2075 (0.3%) offspring in Norway and 15 276 (0.6%) offspring in Taiwan. Among these offspring, 104 (5.0%) in Norway and 512 (3.4%) in Taiwan had congenital malformations. Increased risks of any congenital malformation associated with paternal metformin use were observed in the unadjusted analysis and attenuated with increasing control of confounding. The relative risks of any malformations with paternal metformin use were 1.29 (95% confidence interval 1.07 to 1.55) in Norway and 1.08 (0.99 to 1.17) in Taiwan in the unadjusted analysis and 1.20 (0.94 to 1.53) and 0.93 (0.80 to 1.07), respectively, in the analysis restricted to fathers with type 2 diabetes mellitus. In the overlap propensity score weighting analysis restricted to fathers with type 2 diabetes mellitus, the relative risks were 0.98 (0.72 to 1.33) in Norway and 0.87 (0.74 to 1.02) in Taiwan, resulting in a pooled estimate of 0.89 (0.77 to 1.03). No associations were observed between paternal metformin use and any organ specific malformations. These findings were consistent in sibling matched comparisons and sensitivity analyses.

Conclusions: The findings suggest that paternal use of metformin during the period of sperm development is not associated with congenital malformations in offspring, including organ specific malformations. Metformin can therefore continue to be considered a suitable initial oral agent for managing glucose levels in men with type 2 diabetes mellitus who plan on having children.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: this work was supported by the Norwegian Research Council and by the National Science and Technology Council of Taiwan; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. The authors had full access to all the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Figures

Fig 1
Fig 1
Baseline characteristic of pregnancies with and without paternal metformin use during the period of sperm development by paternal characteristics. Standardised differences illustrate the balance in baseline characteristics across the overall cohort and the cohort restricted to fathers with type 2 diabetes mellitus before and after adjustment for overlap propensity score weight. *As availability of diagnostic codes differed between the data sources in Norway and Taiwan, the aDCSI and comorbidities are not directly comparable. SD=standard deviation; aDCSI=adaptive diabetes complications severity index; RAAS=renin-angiotensin-aldosterone system
Fig 2
Fig 2
Baseline characteristic of pregnancies with and without paternal metformin use during the period of sperm development by maternal characteristics during pregnancy. Standardised differences illustrate the balance in baseline characteristics across the overall cohort and the cohort restricted to fathers with type 2 diabetes mellitus before and after adjustment for overlap propensity score weight. *As availability of diagnostic codes differed between the data sources in Norway and Taiwan, the aDCSI and comorbidities are not directly comparable. SD=standard deviation; aDCSI=adaptive diabetes complications severity index
Fig 3
Fig 3
Associations between paternal metformin use during the period of sperm development and risk of any congenital malformation. CI=confidence interval; PS=propensity score; T2DM=type 2 diabetes mellitus
Fig 4
Fig 4
Associations between paternal metformin use and risk of specific congenital malformations in cohort restricted to fathers with type 2 diabetes mellitus and overlap propensity score weighting. Only categories with enough numbers were reported. CI=confidence interval
Fig 5
Fig 5
Associations between paternal metformin use before pregnancy and risk of any congenital malformation after type 2 diabetes mellitus restricted with overlap propensity score weighting: sensitivity analyses. CI=confidence interval
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