Annals of Internal Medicine
Summary for Patients: Preconception Antidiabetic Drugs in
From: Wensink MJ, Lu Y,
Tian L, et al. Preconception
antidiabetic drugs in men
and birth defects in offspring.
A nationwide cohort study.
Ann Intern Med. 29 March
2022. [Epub ahead of print].
doi:10.7326/M21-4389
This article was published at
Annals.org on 29 March
2022.
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SUMMARIES FOR PATIENTS
Men and Birth Defects in Offspring
What is the problem and what is known about it so far?
Poorly controlled diabetes can reduce sperm quality. However, the effects of diabetes
medications on sperm quality are uncertain. Information is lacking about the risk for
birth defects in babies born to fathers with diabetes. If birth defects were more common
with some diabetes medications, birth outcomes could potentially be improved if men
with diabetes switched to other diabetes medications when trying to father a child.
Why did the researchers do this particular study?
The researchers wanted to estimate the risk for birth defects in babies born to fathers
with diabetes and see if the risks were different depending on the diabetes medications
a man took during the 3 months before the baby was conceived, the time period during
which the sperm responsible for the pregnancy were developing.
Who was studied?
The researchers studied 1 116 779 babies born in Denmark from 1996 to 2017 to mothers
who did not have diabetes or high blood pressure.
How was the study done?
The researchers used health databases in Denmark. Babies were considered exposed
to a diabetes drug if their father filled at least 1 prescription during the 3 months when
the fertilizing sperm were developing. The researchers then compared birth defects in
the babies across diabetes drugs and the timing of taking the drug relative to develop-
ment of fertilizing sperm in unexposed siblings of the babies. The study only looked at
3 types of diabetes drugs: insulin, metformin, and sulfonylureas.
What did the researchers find?
Of the 1 116 779 babies studied, 3.3% had a major birth defect overall. Babies whose
fathers took insulin had no increased risk for a birth defect compared with the general
group. Babies whose fathers took metformin had an increased risk for birth defects.
There were too few babies whose fathers took sulfonylureas to determine risks for birth
defects with any certainty. The researchers did not find an increased risk for birth defects
in babies whose fathers took metformin before or after but not during the period of sperm
development. Siblings who were not exposed to metformin did not have increased risk for
birth defects.
What were the limitations of the study?
There are newer drug classes used to treat type 2 diabetes that were not studied. The study
did not account for how well a father's diabetes was controlled during sperm development.
The researchers were unable to determine whether fathers taking insulin had type 1 or type
2 diabetes. Metformin and sulfonylureas are only used to treat type 2 diabetes, so it is
reasonable to assume that the fathers receiving these drugs had type 2 diabetes.
What are the implications of the study?
Metformin taken during the period of sperm development seems to increase the risk for
birth defects in babies fathered during this time. Further studies are needed to confirm and
better understand this association. However, men with diabetes who are taking metformin
should talk to their doctors about whether they should switch to another treatment when
trying to conceive a child. Because diabetes control also affects sperm quality, discontinuing
metformin treatment could also affect birth outcomes.
Ann Intern Med. doi:10.7326/P22-0003
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