Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study
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Visual Abstract. Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring.
Diabetes reduces semen quality and increasingly occurs during reproductive years. Whether diabetes medications have glucose-independent effects on the male reproductive system is uncertain. This study examined whether the risk for birth defects in offspring varies with preconception pharmacologic treatment of fathers with diabetes.
Abstract
Background:
Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.
Objective:
To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes.
Design:
Nationwide prospective registry-based cohort study.
Setting:
Denmark from 1997 to 2016.
Participants:
All liveborn singletons from mothers without histories of diabetes or essential hypertension.
Measurements:
Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings.
Results:
Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073).
Limitation:
Information on underlying disease status was limited.
Conclusion:
Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation.
Primary Funding Source:
National Institutes of Health.
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Published In
Annals of Internal Medicine
Volume 175 • Number 5 • May 2022
Pages: 665 - 673
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Published online: 29 March 2022
Published in issue: May 2022
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© 2022 American College of Physicians.
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Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study. Ann Intern Med.2022;175:665-673. [Epub 29 March 2022]. doi:10.7326/M21-4389
Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study. Ann Intern Med.2022;175:665-673. [Epub 29 March 2022]. doi:10.7326/M21-4389
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A comment on Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring
We read with interest the article by Wensink et al1 that described an excess of birth defects in neonates fathered by men who took metformin during the 3-month period of spermatogenesis before conception (SDev). This is an important contribution. Nevertheless, we would place its findings into a broader clinical context.
It is known that hyperglycaemia, increasing age and obesity are risk factors for foetal malformations or other outcomes.2-4 The type 1 diabetes (T1D) patients, 84% of the insulin (control) cohort, likely had been on insulin for years. We do not know how many of the metformin and sulfonylurea (SU) cohorts (type 2 diabetes [T2D], presumably) were diagnosed/treated during or shortly before SDev. It typically takes weeks-to-months of metformin titration to control glycaemia. Thus, the severity of hyperglycaemia during SDev may have differed between the metformin and insulin groups.
Also, the metformin and SU cohorts were ~7 years older on average vs. insulin. The metformin and SU cohorts had about 2–5-fold higher use of cardiovascular drugs than the insulin cohort, consistent with a likely higher prevalence of metabolic syndrome and therefore obesity. These factors may have introduced a bias, beyond the multivariate adjustment for age. We note that the excess risk was similar for metformin and SU, although confidence intervals for SU were wider: a similar bias might apply to each and maybe both represent the risk with this age, obesity diabetes type and glycemia.
The background rate of genital malformations in Denmark is 3.3–4.8/1000 births.5 The rate in the absence of metformin (2.4/1000 births) was lower than this. Had the control group and metformin groups been the same size (n=1,451), there would have been <10 excess genital malformations for metformin, and a chance finding cannot be excluded.
Overall, the insulin and antidiabetes-drug treated groups may have differed in important ways in the aetiology and management of their diabetes. Further analyses, perhaps restricting the analysis to type 2 diabetes, and involving subjects who took metformin for at least the year before conception may help clarify these effects.
Metformin is a foundation treatment for type 2 diabetes, and there has been no previous suggestion of paternal toxicity from preclinical or clinical studies. We believe that this study alone is insufficient to prompt a change in the clinical use of metformin for type 2 diabetes and look forward to more data on this topic.
References
Disclosures:
PR has received consultancy and/or speaking fees (to Steno Diabetes Center Copenhagen) from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Merck, MSD, Mundipharma, Novo Nordisk, Vifor, and Sanofi Aventis, and research grants from AstraZeneca and Novo Nordisk. MG has provided editorial consultancy services to Merck Healthcare KGaA, Darmstadt, Germany.
Author Response to Rossing and Gwilt
We thank Rossing and Gwilt for their interest in our work (1).
Metformin-treated diabetes is associated with age. However, in agreement with the references in the Rossing-Gwilt comment, paternal age was not a risk factor for birth defects in our cohort, i.e. all liveborn singletons in Denmark 1997-2016. This is interpreted along with adjustment for maternal age in the same model, which increases the birth defect frequency for ages exceeding 35 years. Our analyses were based on generalized additive models with cross-validation on the entire population, which all but excludes residual confounding by age.
Metformin is the first line drug for all persons with type 2 diabetes irrespective of obesity. We compared offspring of fathers filling a metformin prescription during sperm development (SDev) to offspring of fathers redeeming a prescription for a different diabetes drug during SDev, to offspring of fathers redeeming a metformin prescription at a different moment relative to SDev, and to unexposed siblings. These comparisons, robust to many confounders, all gave odds ratios around 1.5.
The severity of hyperglycemia may differ between the metformin and insulin group. However, the observation of the background birth defect frequency in the insulin group casts doubt on glycaemic control as a pathway. It is indeed a limitation that diagnoses of type 2 diabetes given by general practitioners are not in the registries. Studies accounting for these variables are needed.
The source that Rossing and Gwilt refer to for “the background rate of genital malformations” ascertained birth defects differently: it 1) allowed five years follow-up instead of one and 2) included stillbirths and multiple births (2). Both these factors increase the birth defect rate. While the number of offspring with genital defects was limited, ten additional cases compared to three expected cases is substantive, as expressed in the confidence interval. Importantly, the background rate represents the entire population.
Metformin is used for treating polycystic ovarian syndrome in women, where it reduces testosterone levels. The effect on the development of the male reproductive system is less well studied, yet animal data demonstrate an effect. For example, male fish exposed to metformin can become intersex (3).
We agree with Rossing and Gwilt that our findings need to be confirmed in another cohort before metformin is contraindicated in reproductive aged men (1). Until such confirmation, providers may want to inform men endeavoring to conceive of the potential risks identified in this study associated with metformin.
References
Disclosures:
Since writing the original article, M. Wensink has become gainfully employed at Novo Nordisk A/S. M. Wensink writes this comment/reply in their personal capacity.