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.
| Discipline Area | Score |
|---|---|
| Internal Medicine |  |
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Endocrine |  |
| Obstetrics | |
Rather unique study on a topic that is rarely is studied: paternal use of medications and their effect on offspring. Unfortunately, without randomization there will always be a risk of residual confounding.
The results of this large population-based cohort study demystify the uncertainty related to using metformin in males of reproductive age with type 2 diabetes (T2D) as there were signals for an association of increased fetal malformations from previous studies. Considering the large sample sizes from 2 entirely unmatched ethnic cohorts, the current study results are quite encouraging regarding the safety of metformin, a time-tested antidiabetic agent used over the past 5 decades globally. Even after the discovery of many disease modifying agents for T2D, metformin remains the first-line agent for the disease and will likely have the same position in T2D management in the years to come. Moreover, the other beneficial effects of metformin including cancer prevention should help clinicians use this drug even in prediabetic patients for its prevention of T2D incidence by about 30%.
Important information as the incidence of diabetes type 2 continues to increase worldwide and metformin is a commonly used preparation. The findings were as expected, but it's important to have data.
