March 28, 2022

expert reaction to study of birth defects and diabetic men using metformin during sperm development

A study published in Annals of Internal Medicine looks at preconception antidiabetic drugs in men and birth defects in offspring.

Prof Kevin McConway, Emeritus Professor of Applied Statistics at The Open University, said:

“This is a competent piece of research, in statistical terms. But, wisely, the researchers don’t go beyond recommending that more research should be done to see whether the patterns that they found also occur in other populations. Particularly they recommend that this further research should do more to rule out other possible interpretations of their findings, to clarify what the patterns of cause and effect actually are.

“The reason that the researchers can’t go further in their recommendations is that a study of this kind can’t pin down closely enough what causes what. The results are consistent with a lot of different possible explanations, only one of which is that taking metformin by future fathers, at the time when their sperm is developing, may lead to a higher risk of birth defects in their children – but the results are consistent with other possible explanations too.

“These potential doubts arise mainly because the study is observational, but also to some extent because of the data source that the researchers used. The data come from nationwide registers of health information in Denmark. Among other things, these record the characteristics of pregnancies and births, including some diagnoses (but not be GPs or the equivalent), and including some details of birth defects. They also record prescriptions. Using this data source, the researchers recorded whether the fathers of babies had or had not been prescribed drugs to treat diabetes during the time when their bodies would have been developing the sperm that produced their children. They then recorded whether or not the babies had a serious birth defect, and they found that the risk of a birth defect was higher in fathers who had a metformin prescription at the relevant time.

“The snag is that there were differences between the fathers who were prescribed metformin and the fathers who didn’t, apart from whether they took metformin. For instance, the data in the research report show that fathers who were prescribed metformin were, on average, older and had lower incomes than those who were prescribed no diabetes drug, and that they were considerably more likely also to have been prescribed drugs that work on the heart or blood circulation (that is, on the cardiovascular system, such as drugs to reduce high blood pressure or high cholesterol levels). So the observed higher risk of birth defects in babies whose fathers were prescribed metformin could, in part or even in whole, be caused by some of these other factors and not by the metformin prescriptions at all. The researchers made several statistical adjustments to allow for some of these other differences – so-called ‘potential confounders’ – and the association between metformin prescriptions and birth defects was still present. They also carried out additional statistical analyses, which included making more adjustments for being prescribed cardiovascular drugs, and the association was still there.

“But these adjustments and other statistical analyses can’t deal with everything – in particular, you can’t adjust for factors on which you have no data. One important such factor is mentioned explicitly by the researchers. They had little data on the nature of the diabetes in men who had had prescriptions of diabetes drugs, or indeed in men who had not had such a prescription, because it wasn’t available on the registry data they were using. Perhaps the nature of the diabetes, and the reasons for why certain men were prescribed certain diabetes drugs and others weren’t, could have had something to do with the patterns of cause and effect, rather than the drugs themselves. Some of the statistical analyses that were done, comparing men who took the drugs at different times in relation to pregnancy, make this look less likely than it would otherwise be, but on its own, this can’t get rid of the doubt about cause and effect. That’s one reason why I say the data remain consistent with other possibilities than metformin causing an increased risk of birth defects, and that’s why it’s sensible that the authors call for more (and more detailed) research.”

Dr Sarah Martins Da Silva, Senior Lecturer in Reproductive Medicine at the University of Dundee, said:

“This study is important, not least because it highlights how little we know about how sperm are made, the things that might affect sperm, including prescribed medication, as well as the impact of sperm quality on offspring.  The study raises the possibility that metformin, a drug commonly used to treat diabetes, might be of specific concern. However, as the authors state, there is no detail about medication compliance or diabetic control. This is important because poor compliance and/or poor sugar control could be alternative explanations for the higher number of abnormalities seen in children whose fathers were prescribed metformin. 

“I would not suggest that anyone taking metformin should stop their medication without consulting their specialist, but men trying to conceive should check with their pharmacist or GP that any medication they are taking is pregnancy-safe. Further studies that include detail of men’s diabetic control and tablet taking behaviour are required to truly understand whether metformin is an issue and should be avoided when trying to conceive.”

Dr Channa Jayasena, Consultant & Head of Andrology, Imperial College Healthcare NHS Trust & Imperial College London, said:

“Diabetes has well established, bad effects on the male reproductive system, and may be treated with metformin or insulin. This study surprises us by suggesting that metformin, but not insulin, in dads might increase risks of deformed genitalia in future newborn sons. Insulin is a stronger medication than metformin, so the authors cannot exclude that men on metformin had worse control of their diabetes. So, the results are thought-provoking but inconclusive. Men with diabetes should not be dissuaded from taking metformin, but this is worth looking at more closely.”

Prof Allan Pacey, Professor of Andrology at The University of Sheffield, said:

“This is a very interesting and elegant study which has found an association between a father’s use of metformin (to control Type 2 diabetes) during the period of sperm development and a small but increased risk of birth defects in any sons born with those sperm.

“The observation is based on the analysis of registry data in Denmark, the likes of which we could only dream of in the UK. The authors successfully linked the register containing the father’s medical prescriptions, with the birth register of babies born, and the register of any birth defects found within the first year of life. Genius!

“It is compelling that the authors only found an increased risk of birth defects when metformin was taken by the father in the three months prior to conception, compared to when he took it at other times, or when other medication (e.g. Insulin) was used, or in siblings where no diabetes medication was being taken.  Three months is the critical time window because this is roughly how long the sperm production process takes.

“However, although a relationship between metformin use and the birth defects of any sons born is credibly highlighted in this paper, we cannot be completely sure that the effect is down to the metformin drug itself.  To clarify that, we would need to see the study repeated in other populations and it would also be necessary to find out more precise details about the diabetic control and reproductive physiology of men who were given a metformin prescription.

“Since metformin is a commonly used drug in men of reproductive age, this study does raise questions about whether men who are taking metformin (and are planning to start a family in the near future), should be concerned.  This should be discussed with their family doctor or the diabetes specialist who is looking after them.

“Thankfully other drugs and interventions are available to help control type 2 diabetes, but since we know that diabetes itself can affect male fertility it is important that men take some form of medication rather than stop their metformin altogether. Also, if they stop taking any medication at all they would be putting their own health at risk by having uncontrolled diabetes for a period of time.  This would not be a good thing to do.”

Prof Sheena Lewis, Honorary Professor of Reproductive Medicine, Queen’s University Belfast, said:

“Can medicines taken by dads around conception affect their children’s health?  The evidence from this large well-designed population based Danish study concludes that the antidiabetic drug Metformin can.  

“The researchers studied over one million babies born to fathers with diabetes who were taking Metformin; a medicine used to lower blood sugar in men with type 2 diabetes. Mothers with diabetes were excluded so the relationship between birth defects and diabetes is linked exclusively to the father.  The increase is small but significant with the babies from fathers on Metformin at the time of conception being more likely (3%) to have a major birth defect.   

“One factor missing from the study is how well these men were regulating their diabetes and we already know that the disease itself can damage sperm quality.  As couples wait until older before starting families, their chances of being on medication for other chronic illnesses increases. The take home message is that men who are trying to have children should discuss all other medications with their family doctors to ensure these have no known adverse effects on male fertility.”

‘Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring’ by Maarten J. Wensink et al. was published in Annals of Internal Medicine at 10pm UK time on Monday 28 March.

DOI: 10.7326/M21-4389

Declared interests

Prof Sheena Lewis: “SEM Lewis is CEO of Examenlab Ltd, a university molecular diagnostics company specialising in male reproductive health.”

Prof Allan Pacey: “Chairman of the advisory committee of the UK National External Quality Assurance Schemes in Andrology, Editor in Chief of Human Fertility, Trustee of the Progress Educational Trust (Charity Number: 1139856) and Trustee of the British Fertility Society (Charity Number:1075661) (all unpaid).”

Dr Channa Jayasena: “No conflicts of interest relevant to this work.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”