Emily Oster

8 min Read Emily Oster

Emily Oster

Diabetes Medication and Birth Defects

A new study on metformin use in men

Emily Oster

8 min Read

Too often, when we talk about issues in fertility or pregnancy, the focus is exclusively on the pregnant woman as the source. This is despite the fact that we know the men can be the source of concern, sometimes in ways that are not well understood. An example is a paper I came across the other day showing that the recurrence of hyperemesis gravidarum in later pregnancies is lower with a different father. It isn’t clear why this would be, but it suggests we have more to understand.

One problem with the focus on women is that it leads to blaming women if things go wrong. But a second problem is that by ignoring the role of men, we ignore the possibility that changes in their behavior might have an impact.

It is this second point that led me to be interested in a paper that just came out, arguing that birth defects are more common among the offspring of men who take metformin, a common diabetes drug, in the months before pregnancy. I want to unpack that paper today, to talk about whether its results are compelling and what it means.

Overview and why this is hard

This paper was published in the Annals of Internal Medicine last week, and you can read the abstract here. The basic idea is straightforward: the authors would like to compare the incidence of major birth defects for children born to men who took metformin during the period of sperm development (roughly the three months before pregnancy occurred) to the incidence in those who did not.

There are at least two things that make this hard to implement.

First, severe birth defects are, blessedly, relatively rare. To study them convincingly, you need a lot of people in your analysis. Moreover, to study this particular question you need not only a large sample but detailed information about the individuals. The authors here want to connect the medications that men take in the months before pregnancy to diagnosed birth defects among their children. This is asking a great deal of the data, since it is not very common to see this information linked across families.

Second, even if you have enough good data to run this correlation, there is an underlying concern that there are other differences between men who take metformin and those who do not. One obvious difference is they are more likely to have diabetes. But there may be other things, such as demographics or other illnesses, that could be the proximate cause. Correlation and causality are difficult to separate.

Part of what makes this paper compelling is that the authors are able to make significant progress on both of these problems.

Implementation and solutions

In the paper, they fix the first problem — the data problem — by using comprehensive data from Denmark. Denmark is one of several countries (including Sweden and Finland) where it is possible to get detailed data on health for individuals, linked over time and across families. In this paper, the authors can combine one data set with information on adult prescriptions with another that has information on birth defect diagnoses with yet another that tells them who is related to whom. Even better: they can do this for the entire population of Denmark.

The result is 20 years of comprehensive data, with over 1.1 million births, linked with data on parental prescriptions. This is enough to pick up relatively small increases in birth defects. The fact that the data comes from official registries and medical records and not from (say) self-reports allows them to be both more confident in the data quality and more precise in timing.

The second problem is more fundamental and more difficult to fix. What the authors can do, though, is provide a number of pieces of supporting evidence that make it less likely that the main results they see reflect confounding.

The main result of the paper is that, after adjusting for some basic demographic controls, there is an increase in the risk of a serious birth defect — about a 40% increase — if the father was taking metformin or a sulfonylureas in the three months before conception. There is no increase for fathers who are on insulin (who are more likely to be Type 1 diabetics). The increase for fathers taking metformin is larger and more consistently statistically significant than for those taking sulfonylureas.

Without additional evidence, this result is subject to many of the concerns we typically raise with observational data. Relative to the control group, men who are on metformin are much more likely to be on a variety of other medications, and they’re older, less educated, and poorer. These demographic differences are largely not present for men who are on insulin. There is the simple fundamental issue that men in this group have Type 2 diabetes, and from the basic analysis we are hard-pressed to separate out all of these other factors from the impact of metformin.

However: the authors do three things that I think make this result more compelling.

First, they compare men who fill prescriptions for metformin in the exposure period of three months before conception with those who fill them in the two years before or the two years after. The results are shown in the graph below. The increase in birth defects relative to the control group shows up only for those who fill the prescription in the sperm development period. You can think of the groups that fill prescriptions in these surrounding periods as a better control group.

A second test involves comparing across children within families. In a small number of cases, the researchers observe at least two children in the same family where the father took metformin during sperm development for one child but not the other(s). This includes cases both where the father changed prescriptions between pregnancies and cases where the actual father changed (same mother, different fathers). In both of these comparisons, the authors find that the exposed siblings were more likely to have birth defects than the unexposed siblings.

The final result that makes this more convincing is the analysis by birth defect type. When the authors break this down, they find the most significant increase is in genital birth defects for boys. They also find that men in the metformin group are less likely to have male children, and they point to evidence from animal models suggesting a link between metformin and testicular development and similar outcomes. This indicates a more specific mechanism for the link.

My read of this paper is that the authors have pushed the data about as far as possible in terms of making a compelling causal case. There isn’t a randomized experiment here, and doing one would be effectively impossible given the small risks — you’d need too large an effect size to make it feasible. What they have done here is to be extremely thoughtful about what is possible with observational data.

Please note: the effects are small

The results in this paper make a good case for causality. But I think it’s very important to note that the effect sizes are small in terms of absolute magnitudes. Overall, these severe birth defects occur in about 3.3% of births, and the data suggest about a 1.3 percentage point increase in risk as a result of metformin exposure. When we say there is a 40% increase in risk, this can be hard to really contextualize without knowing the baseline. The increase here is comparable in size to increases in birth defects for women over 45.

Many of the conditions considered are treatable with surgery or other approaches. Which isn’t to understate their severity, just to say that there are things you can do.

What’s the action item?

A natural question following this is what the appropriate reaction is. My sense is that if we found similar results for something more optional — say, Botox — there would be a push against using it. Metformin, however, is a key component of diabetes treatment, and untreated diabetes has its own risks to fathers’ fertility and health. The bottom line is that this becomes a situation with some possible trade-offs. The short period of sperm development may provide some help — a break from metformin during conception might have a positive effect — but that is also complicated.

The paper ends on what seems to me an appropriate note, which is to argue for the need for more attention to this connection. One piece of that is more evidence on whether this link is consistent in other data. As I said above, a randomized trial is not likely to be feasible, but one could run a study like this one in another country (Sweden, Finland, maybe even with some medical records in the U.S.). A similar finding in another location would be meaningful. The second piece is a need to think about whether there are reasonable treatment alternatives for men in this situation.

A final thought

Studying the impact of health interventions provides us with many situations in which a randomized trial just isn’t really possible, and too often I feel that papers in this space do not sufficiently exploit observational data. While it’s true that the “gold standard” randomized controlled trial evidence isn’t possible here, the approaches they take allow us to go well beyond a simple correlation. And that’s of tremendous value.

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Do you brand things a certain way to get your kid to accept it? Like calling carrots “rabbit popsicles”? Or telling them to put on their “super speed socks” in the morning? Share your rebrands in the comments below! You never know who you might be helping out 👇

#emilyoster #funnytweets #relatabletweets #parentingjokes #kidssaythedarndestthings

Do you brand things a certain way to get your kid to accept it? Like calling carrots “rabbit popsicles”? Or telling them to put on their “super speed socks” in the morning? Share your rebrands in the comments below! You never know who you might be helping out 👇

#emilyoster #funnytweets #relatabletweets #parentingjokes #kidssaythedarndestthings
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Have you ever panic-googled a parenting question when everyone else is asleep? If so, you’re not alone. 

Today is the first episode of a new biweekly series on my podcast: Late-Night Panic Google. On these mini-episodes, you’ll hear from some familiar names about the questions keeping them up at night, and how data can help. First up: @claireholt!

Listen and subscribe to ParentData with Emily Oster in your favorite podcast app 🎧

#parentdata #emilyoster #claireholt #parentingstruggles #parentingtips #latenightpanicgoogle

Have you ever panic-googled a parenting question when everyone else is asleep? If so, you’re not alone.

Today is the first episode of a new biweekly series on my podcast: Late-Night Panic Google. On these mini-episodes, you’ll hear from some familiar names about the questions keeping them up at night, and how data can help. First up: @claireholt!

Listen and subscribe to ParentData with Emily Oster in your favorite podcast app 🎧

#parentdata #emilyoster #claireholt #parentingstruggles #parentingtips #latenightpanicgoogle
...

Sun safety is a must for all ages, especially babies! Here are my tips for keeping your littlest ones protected in the sunshine:
☀️ Most importantly, limit their time out in hot weather. (They get hotter than you do!)
☀️ Keep them in the shade as much as possible when you’re out.
☀️ Long-sleeve but lightweight clothing is your friend, especially on the beach, where even in the shade you can get sunlight reflecting off different surfaces.
☀️ If you want to add a little sunscreen on their hands and feet? Go for it! But be mindful as baby skin tends to more prone to irritation.

Comment “Link” for a DM to an article on the data around sun and heat exposure for babies.

#sunsafety #babysunscreen #babyhealth #parentdata #emilyoster

Sun safety is a must for all ages, especially babies! Here are my tips for keeping your littlest ones protected in the sunshine:
☀️ Most importantly, limit their time out in hot weather. (They get hotter than you do!)
☀️ Keep them in the shade as much as possible when you’re out.
☀️ Long-sleeve but lightweight clothing is your friend, especially on the beach, where even in the shade you can get sunlight reflecting off different surfaces.
☀️ If you want to add a little sunscreen on their hands and feet? Go for it! But be mindful as baby skin tends to more prone to irritation.

Comment “Link” for a DM to an article on the data around sun and heat exposure for babies.

#sunsafety #babysunscreen #babyhealth #parentdata #emilyoster
...

I’m calling on you today to share your story. I know that many of you have experienced complications during pregnancy, birth, or postpartum. It’s not something we want to talk about, but it’s important that we do. Not just for awareness, but to help people going through it feel a little less alone.

That’s why I’m asking you to post a story, photo, or reel this week with #MyUnexpectedStory and tag me. I’ll re-share as many as I can to amplify. Let’s fill our feeds with these important stories and lift each other up. Our voices can create change. And your story matters. 💙

#theunexpected #emilyoster #pregnancycomplications #pregnancystory

I’m calling on you today to share your story. I know that many of you have experienced complications during pregnancy, birth, or postpartum. It’s not something we want to talk about, but it’s important that we do. Not just for awareness, but to help people going through it feel a little less alone.

That’s why I’m asking you to post a story, photo, or reel this week with #MyUnexpectedStory and tag me. I’ll re-share as many as I can to amplify. Let’s fill our feeds with these important stories and lift each other up. Our voices can create change. And your story matters. 💙

#theunexpected #emilyoster #pregnancycomplications #pregnancystory
...

OUT NOW: My new book “The Unexpected: Navigating Pregnancy During and After Complications” is available on April 30th. All of my other books came out of my own experiences. I wrote them to answer questions I had, as a pregnant woman and then as a new parent. “The Unexpected” is a book not to answer my own questions but to answer yours. Specifically, to answer the thousands of questions I’ve gotten over the past decade from people whose pregnancies were more complicated than they had expected. This is for you. 💛 Order now at my link in bio!

OUT NOW: My new book “The Unexpected: Navigating Pregnancy During and After Complications” is available on April 30th. All of my other books came out of my own experiences. I wrote them to answer questions I had, as a pregnant woman and then as a new parent. “The Unexpected” is a book not to answer my own questions but to answer yours. Specifically, to answer the thousands of questions I’ve gotten over the past decade from people whose pregnancies were more complicated than they had expected. This is for you. 💛 Order now at my link in bio! ...

OUT NOW: My new book “The Unexpected: Navigating Pregnancy During and After Complications” is available on April 30th. All of my other books came out of my own experiences. I wrote them to answer questions I had, as a pregnant woman and then as a new parent. “The Unexpected” is a book not to answer my own questions but to answer yours. Specifically, to answer the thousands of questions I’ve gotten over the past decade from people whose pregnancies were more complicated than they had expected. This is for you. 💛 Order now at my link in bio!

OUT NOW: My new book “The Unexpected: Navigating Pregnancy During and After Complications” is available on April 30th. All of my other books came out of my own experiences. I wrote them to answer questions I had, as a pregnant woman and then as a new parent. “The Unexpected” is a book not to answer my own questions but to answer yours. Specifically, to answer the thousands of questions I’ve gotten over the past decade from people whose pregnancies were more complicated than they had expected. This is for you. 💛 Order now at my link in bio! ...

OUT NOW: My new book “The Unexpected: Navigating Pregnancy During and After Complications” is available on April 30th. All of my other books came out of my own experiences. I wrote them to answer questions I had, as a pregnant woman and then as a new parent. “The Unexpected” is a book not to answer my own questions but to answer yours. Specifically, to answer the thousands of questions I’ve gotten over the past decade from people whose pregnancies were more complicated than they had expected. This is for you. 💛 Order now at my link in bio!

OUT NOW: My new book “The Unexpected: Navigating Pregnancy During and After Complications” is available on April 30th. All of my other books came out of my own experiences. I wrote them to answer questions I had, as a pregnant woman and then as a new parent. “The Unexpected” is a book not to answer my own questions but to answer yours. Specifically, to answer the thousands of questions I’ve gotten over the past decade from people whose pregnancies were more complicated than they had expected. This is for you. 💛 Order now at my link in bio! ...

Is side sleeping important during pregnancy? Comment “Link” for a DM to an article on whether sleep position affects pregnancy outcomes.

Being pregnant makes you tired, and as time goes by, it gets increasingly hard to get comfortable. You were probably instructed to sleep on your side and not your back, but it turns out that advice is not based on very good data.

We now have much better data on this, and the bulk of the evidence seems to reject the link between sleep position and stillbirth or other negative outcomes. So go ahead and get some sleep however you are most comfortable. 💤

Sources:
📖 #ExpectingBetter pp. 160-163
📈 Robert M. Silver et al., “Prospective Evaluation of Maternal Sleep Position Through 30 Weeks of Gestation and Adverse Pregnancy Outcomes,” Obstetrics and Gynecology 134, no. 4 (2019): 667–76. 

#emilyoster #pregnancy #pregnancytips #sleepingposition #pregnantlife

Is side sleeping important during pregnancy? Comment “Link” for a DM to an article on whether sleep position affects pregnancy outcomes.

Being pregnant makes you tired, and as time goes by, it gets increasingly hard to get comfortable. You were probably instructed to sleep on your side and not your back, but it turns out that advice is not based on very good data.

We now have much better data on this, and the bulk of the evidence seems to reject the link between sleep position and stillbirth or other negative outcomes. So go ahead and get some sleep however you are most comfortable. 💤

Sources:
📖 #ExpectingBetter pp. 160-163
📈 Robert M. Silver et al., “Prospective Evaluation of Maternal Sleep Position Through 30 Weeks of Gestation and Adverse Pregnancy Outcomes,” Obstetrics and Gynecology 134, no. 4 (2019): 667–76.

#emilyoster #pregnancy #pregnancytips #sleepingposition #pregnantlife
...

My new book, “The Unexpected: Navigating Pregnancy During and After Complications” is available for preorder at the link in my bio!

I co-wrote #TheUnexpected with my friend and maternal fetal medicine specialist, Dr. Nathan Fox. The unfortunate reality is that about half of pregnancies include complications such as preeclampsia, miscarriage, preterm birth, and postpartum depression. Because these are things not talked about enough, it can not only be an isolating experience, but it can also make treatment harder to access.

The book lays out the data on recurrence and delves into treatment options shown to lower risk for these conditions in subsequent pregnancies. It also guides you through how to have productive conversations and make shared decisions with your doctor. I hope none of you need this book, but if you do, it’ll be here for you 💛

#pregnancy #pregnancycomplications #pregnancyjourney #preeclampsiaawareness #postpartumjourney #emilyoster

My new book, “The Unexpected: Navigating Pregnancy During and After Complications” is available for preorder at the link in my bio!

I co-wrote #TheUnexpected with my friend and maternal fetal medicine specialist, Dr. Nathan Fox. The unfortunate reality is that about half of pregnancies include complications such as preeclampsia, miscarriage, preterm birth, and postpartum depression. Because these are things not talked about enough, it can not only be an isolating experience, but it can also make treatment harder to access.

The book lays out the data on recurrence and delves into treatment options shown to lower risk for these conditions in subsequent pregnancies. It also guides you through how to have productive conversations and make shared decisions with your doctor. I hope none of you need this book, but if you do, it’ll be here for you 💛

#pregnancy #pregnancycomplications #pregnancyjourney #preeclampsiaawareness #postpartumjourney #emilyoster
...

We are better writers than influencers, I promise. Thanks to our kids for filming our unboxing videos. People make this look way too easy. 

Only two weeks until our book “The Unexpected” is here! Preorder at the link in my bio. 💙

We are better writers than influencers, I promise. Thanks to our kids for filming our unboxing videos. People make this look way too easy.

Only two weeks until our book “The Unexpected” is here! Preorder at the link in my bio. 💙
...

Exciting news! We have new, high-quality data that says it’s safe to take Tylenol during pregnancy and there is no link between Tylenol exposure and neurodevelopmental issues in kids. Comment “Link” for a DM to an article exploring this groundbreaking study.

While doctors have long said Tylenol was safe, confusing studies, panic headlines, and even a lawsuit have continually stoked fears in parents. As a result, many pregnant women have chosen not to take it, even if it would help them.

This is why good data is so important! When we can trust the data, we can trust our choices. And this study shows there is no blame to be placed on pregnant women here. So if you have a migraine or fever, please take your Tylenol.

#tylenol #pregnancy #pregnancyhealth #pregnancytips #parentdata #emilyoster

Exciting news! We have new, high-quality data that says it’s safe to take Tylenol during pregnancy and there is no link between Tylenol exposure and neurodevelopmental issues in kids. Comment “Link” for a DM to an article exploring this groundbreaking study.

While doctors have long said Tylenol was safe, confusing studies, panic headlines, and even a lawsuit have continually stoked fears in parents. As a result, many pregnant women have chosen not to take it, even if it would help them.

This is why good data is so important! When we can trust the data, we can trust our choices. And this study shows there is no blame to be placed on pregnant women here. So if you have a migraine or fever, please take your Tylenol.

#tylenol #pregnancy #pregnancyhealth #pregnancytips #parentdata #emilyoster
...

How many words should kids say — and when? Comment “Link” for a DM to an article about language development!

For this graph, researchers used a standardized measure of vocabulary size. Parents were given a survey and checked off all the words and sentences they have heard their child say.

They found that the average child—the 50th percentile line—at 24 months has about 300 words. A child at the 10th percentile—near the bottom of the distribution—has only about 50 words. On the other end, a child at the 90th percentile has close to 600 words. One main takeaway from these graphs is the explosion of language after fourteen or sixteen months. 

What’s valuable about this data is it can give us something beyond a general guideline about when to consider early intervention, and also provide reassurance that there is a significant range in this distribution at all young ages. 

#cribsheet #emilyoster #parentdata #languagedevelopment #firstwords

How many words should kids say — and when? Comment “Link” for a DM to an article about language development!

For this graph, researchers used a standardized measure of vocabulary size. Parents were given a survey and checked off all the words and sentences they have heard their child say.

They found that the average child—the 50th percentile line—at 24 months has about 300 words. A child at the 10th percentile—near the bottom of the distribution—has only about 50 words. On the other end, a child at the 90th percentile has close to 600 words. One main takeaway from these graphs is the explosion of language after fourteen or sixteen months.

What’s valuable about this data is it can give us something beyond a general guideline about when to consider early intervention, and also provide reassurance that there is a significant range in this distribution at all young ages.

#cribsheet #emilyoster #parentdata #languagedevelopment #firstwords
...