Prenatal antidepressant exposure and child development

This episode explores the critical intersection of maternal mental health and child development, focusing on the implications of antidepressant use during pregnancy. Dr. Tim Oberlander discusses his extensive research on the effects of prenatal antidepressant exposure, the importance of managing maternal mental health, and the resilience of children despite various risk factors.

This conversation emphasizes the need for a balanced approach to treatment, considering both pharmacological and non-pharmacological strategies, while addressing common misconceptions surrounding antidepressants and their effects on child development.

Learn more about the topics discussed in this episode:

Potential risks and benefits of prenatal selective serotonin reuptake inhibitor medications for maternal mental health and child development, Nature Mental Health

An article that references the above work: Prenatal SSRI risks and benefits: Maternal, child impact, Scienmag

CANMAT’s clinical practice guidelines for the management of perinatal mood, anxiety, and related disorders: Canadian Network for Mood and Anxiety Treatments 2024 Clinical Practice Guideline for the Management of Perinatal Mood, Anxiety, and Related Disorders, The Canadian Journal of Psychiatry

All episodes written and produced by the Research Communications team at BC Children's Hospital Research Institute.

Theme music: "Life Is Beautiful" by Anastasia Kir

Transcript

Kristen Hovet (00:00)
My name is Kristen Hovet and I'm the Interim Research Communications Manager for BC Children's Hospital Research Institute. Joining me today is Dr. Tim Oberlander, a developmental pediatrician at BC Children's Hospital and an investigator here at BCCHR. We'll be discussing how treating maternal depression and anxiety during pregnancy shapes a child's development, including what we know about the safety of antidepressants like SSRIs and what's truly at risk when maternal mental health goes untreated.

Tim Oberlander (00:33)
I'm Tim Oberlander. I'm a developmental pediatrician and I'm also the medical lead with the Complex Pain Service here at BC Children's Hospital. I also have a research program and for the last 25 years or so I've been studying the developmental impact of prenatal antidepressant exposure in both fetuses and now we followed our birth cohort up to 18 years of age.

Kristen Hovet (00:55)
Thank you, and also thank you so much for being here. Before we get into the science, I'd love to know what drew you to this area of research. What inspired you to focus on maternal mental health specifically, and then medication like SSRIs and child development?

Tim Oberlander (01:13)
To answer that question, have to go back to my developmental origins as a newly minted developmental pediatrician in 1993 when I was recruited to our division, which was at the time at Sunny Hill on Slocan Street. I was recruited to do a job that I was never trained to do.

But I needed a job. I had a young family and I wanted to move back to Vancouver. And so I was hired to look after an inpatient ward of eight babies whose mothers had been using methadone, cocaine, heroin, and a variety of other psychotropic drugs during pregnancy. And my task was to safely withdraw them and ensure healthy adaptation.

Then I was also looking after a very large outpatient clinic of babies who had been in the same position and had grown up and were now in their three and four and five year age range. Within the first six months or so, I became aware that many of the infants and young children were actually developing in healthy and typical ways. And I thought, wow, that is so interesting, which took me back to sort of my interest in health in medical school, because I thought I'd become a wellness doctor, thinking I would see patients when they were well and figure out how to keep them well and what sustained their wellness. And so I was really intrigued by how healthy many of these children were under what at the time seemed like adverse circumstances. Resiliency, pretty interesting question. 

That led to three formative questions which formed my entire career. And the first question was, I was thinking, well, maybe it had something to do with the mother's capacity to metabolize the drug and that it somehow limited or prevented fetal drug exposure, transplacental exposure to whatever drug it was. And maybe it was something about a genotype or a particular capacity of a metabolic enzyme to reduce drug exposure. I thought that was really interesting. So then I got interested in the question of whether there was some exposure to a particular drug at a very specific time during pregnancy that might have made a difference to promoting resiliency.

And I thought maybe we should look at timing genes. But my attention then focused on what was really the core underlying question and that for a lot of women, self-medication of poor mental health, depression in particular, and anxiety was really the underlying question of medication, drug use, and other substances. And I think that that really is the core question was how well was mother's mental health managed?

And I began to see patterns, and this was just  empiric observation in the clinic, that many children did very well when mother's mental health was well managed. I began to think about how was mental health predicting good outcomes or beneficial outcomes or positive outcomes in this setting. And that sort of got me thinking about the relationship between mental health and infant development. Now turns out that around that time, in 1993, the first paper emerged which reported on neonatal adaptation or neonatal behaviour following prenatal antidepressant exposure. And so at that time, there was really only one drug, fluoxetine, that was being studied. And there were case reports of babies who were having very difficult times with post-natal adaptation. So in the first few days of life, their ability to sleep, feed, and have relaxed muscle tone was affected by the... what we thought at the time was prenatal exposure to that antidepressant. And my wife went to a fascinating talk by Shaila Misri, who was head of reproductive mental health at the time, and she came back home and said, you know what, you've got to take a look at this antidepressant infant behaviour question, because it is super interesting and it's very much aligned with the sort of questions you're asking about cocaine and methadone and heroin.

And this could be a really interesting story. And she knew at the time that I was very interested in this neurotransmitter called serotonin, which is really one of those targets of SSRIs, as its name implies, serotonin reuptake inhibitors.

Kristen Hovet (05:20)
How common was that at the time, like you said, was that like a really new question to be looking at maternal mental health and their mental health medications?

Tim Oberlander (05:29)
So we've known for generations and probably well back into antiquity that mother's stress and depression and anxiety, which are really two sides of the same coin, stress-related disorders, have had a negative impact on fetal and neonatal well-being and probably has been associated with decrease in language and cognitive and behavioural outcomes across the early lifespan. So there's been awareness of that. But the question of how does antidepressant exposure add to that or manage that or reduce that was a relatively new question at the time. In 1993, the first case report of fluoxetine exposure and neonatal outcomes appeared. And so by 1996, which is when I wrote my first grant to investigate this question in a systematic way, this was a relatively new field. Although there were increasing reports of these neonatal adaptation questions, there really wasn't a systematic examination of how do antidepressants affect newborn outcomes in presumably infant and child development.

Kristen Hovet (06:30)
Depression and anxiety during pregnancy are perhaps more common than many people realize. Can you give us a sense of what's at stake when these conditions go untreated for both mothers and babies?

Tim Oberlander (06:43)
The incidence can be as high as 20 % of all pregnancies where mothers experience symptomatic depression and anxiety to the point of where medical intervention is necessary, whether it's pharmacologic or non-pharmacologic. Some studies, it's less. Also, probably, certainly from our data, the use of antidepressants in pregnancy ranges from 3 to 5%. And in some studies, it's as high as 8 % of pregnancies. So these are not uncommon phenomena. 

Untreated depression, from the perspective of a pediatrician, we would see reduced birth weight, shortened gestational age, behaviours that could look like poor neonatal adaptation, which is what you'd get with drug withdrawal. But you also might see, in the course of early lifespan, delayed language or disordered language development, anxiety, depression, and maybe difficulty with adaptation to early school age behaviour.

Now whether that's associated with depression during pregnancy or ongoing exposure in the home is sometimes very difficult to tease apart. So we really need to look at the effects of maternal depression across the early lifespan, which really should probably include preconception, pregnancy, and post-natal. But it would be incomplete just to stop the story there because the determinants of child development are really more than just biologic or maternal influences.

You have to include a partner, a father, and of course the environment in which the child grows up. And so to ascribe all of the outcomes, if they're adverse, to one particular exposure, would probably be inaccurate and incomplete. And over time, we've also come to understand that child development is also a function of the physical environment. And so increasingly we're now aware that green space, air pollution, and arguably, the links to climate change should also be included when we're trying to understand the fullness of why a child develops the way they do, both for better and worse.

Kristen Hovet (08:50)
Thank you. That's really interesting. And I guess the next question kind of loops into that, which is expecting parents sometimes face a tough decision of whether to take antidepressants during pregnancy. From your perspective, how do the potential risks of antidepressants compare with the risks of leaving maternal mood disorders like depression untreated?

Tim Oberlander (09:13)
Yeah, this is a very difficult question, which doesn't lend itself well to overgeneralizations, hand-waving, and incomplete science. What we're talking about here is a significant mental health question that should be of public health concern, and that, while there are public and scientific questions, at the end of the day, it's intensely personal and it should be a private conversation that is ultimately decided on between mothers, their partners, and their clinicians. 

Non-treatment is not an option. The real question is when to introduce antidepressants and I think that the guiding principles that were published in the Canadian Journal of Psychiatry in early '25 is well worth looking at and essentially the view of this group that has reviewed the literature to date suggests that the risks are minimal and that these are not risks that should prevent the appropriate use of antidepressants in pregnancy. Now, let's talk about what would be an appropriate context. Typically, non-pharmacologic management is the first step, and that would include management of sleep, exercise, stress, and all the other non-pharmacologic things that we know work well. Then, for moderate to severe depression that does not respond to non-pharmacologic approaches, that's when antidepressants are best considered.

Kristen Hovet (10:40)
I guess I wanted to make it clear what treatment could be. Like you said, it could be therapy, sleep, other life changes.

Tim Oberlander (10:47)
The considered opinion is that you'd want to maximize management of those essential bio-rhythms, sleeping, eating, exercise, stress reduction, in whatever way is possible. And for some women this may be quite appropriate. Light therapy and CBT and other non-pharmacologic psychological approaches could be quite effective. Now, granted that they're not available to many women, both for money and for distance, geography, and all those other social determinants that we know make a difference to access to non-pharmacologic approaches. But I think overall we need to consider that antidepressants have an effective place for moderate to severe depression that typically doesn't respond to those non-pharmacologic options.

Kristen Hovet (11:34)
My next question, I think it's probably more of an obvious question about SSRIs leading to definite benefits. But I guess I wanted to ask this because I remember when I was pregnant and reading the literature out there and the parenting books, there's a lot said out there about, oh, don't take medication if you can avoid it. What do we know about how SSRIs can support maternal mental health during pregnancy and also after birth?

Tim Oberlander (12:05)
So that is an extremely important question, which I'll break into two parts. First of all, I think we have to understand that maternal mental health during pregnancy is a reflection of mental health across the lifespan. And that while the reproductive period of life may have unique characteristics to it, what we're now beginning to understand is that, for many women, depression and anxiety is a chronic condition, and that for many women it precedes conception, coexists with pregnancy, and it goes on long after the birth of their child. 

So if we're going to look at where's the impact the greatest or where should we intervene to make the biggest difference, I would say across the lifespan. So the lesson certainly that I'm learning, over a 30 plus year career in this area, is that we have to think about anxiety and depression as a public health issue that we address early and often and continuously across the lifespan. Second is that there's no free lunch. And I don't know if you know that expression, but it's, it's there's no, there's no risk-free option out there. The real question is how to reduce the risk, how to stack the deck in favour of optimal outcomes, both for the child and for his or her mother and father. There are options. 

Medications may be one of those options. What we do know is that SSRI antidepressants, which work by changing levels of critical neurotransmitters, serotonin in particular, probably have a greater impact earlier in life, but then a lot of life course things intervene along the way: mother's depression and anxiety during childhood, father's mental health, and of course the genes the child has inherited, as well as the environment in which they're growing up. And so to think about antidepressant effects having an impact across the lifespan, that's a difficult question to answer, but I think we have to think about the effects of prenatal exposure and antidepressants in the context of all these other factors: what's happening at home, what's happening in mother's mood after pregnancy, and what's happening in the child's own life as they get older, they go to school, they grow up. Early on, our lab became very focused on trying to understand the emergence of anxiety in children whose mothers had been treated with an antidepressant during pregnancy. 

And a lot of my thinking in the early 2000s was shaped by a series of papers that appeared which showed in animal models that, paradoxically, and it's kind of an unusual finding, that rodents who were exposed to antidepressants in what was our third trimester, they were more anxious and depressed as adolescents or adults. 

So that was kind of an... an interesting finding which actually paralleled what we were seeing in our three-year-olds. And we've now followed up our cohort to 18 years. And in the next year or so, we'll report on the 18-year outcome. But at 12 years, and at six years, and at three years, we were also finding our children in our cohort were more anxious, as reported by their parents, by their mother in particular, when the mother had been treated with an antidepressant during pregnancy. But what was important was that mother's mood during pregnancy was also having an enduring effect and increasingly over time, mother's mood at the time of the follow-up, at three years, at six years, at 12 years, was having an increasing and probably even more important sustained effect. And in fact, the antidepressant exposure part of the story actually diminished over time. So while children were showing more anxiety when their mothers had been treated with an antidepressant, it didn't look like the antidepressant was the thing that was contributing to their mood, their behaviour in childhood and early adolescence. And that got me thinking about this really intriguing question about what was it that connected SSRI exposure, prenatal exposure, with anxiety. If you looked at it with a lens of I'm going to replicate what was shown in animal models, then you'd say, okay, it looks like there was an association between prenatal exposure and behavioural outcome during childhood and early adolescence. But actually that's not the whole story because really what we were showing was that mother's mood, which was closely tied to SSRI exposure because after all you wouldn't be prescribed an SSRI if you weren't depressed, which actually turns out to be what I think is going to probably be the main finding which is that it's a mother's mood question. How well is mother's mood treated? And if she's well treated, her children actually turned out to be doing quite well.

And so it's not just an SSRI exposure story. It's really about mother's depression. And then it raises the question if it's just depression or mostly depression, maybe it has something to do with a genetic inheritance that was conferred upon the child because the mother was depressed and it was because of her genetics that maybe she got depressed and that's why she took an SSRI. And it wasn't really the SSRI. It was really this underlying genetic risk of becoming anxious, depressed as a child.

And so I think it's probably, in the end, really a question of how do we manage depression and anxiety during pregnancy? How do we manage child anxiety and depression? And if SSRIs are necessary, because we know that promoting good mental health during pregnancy has benefits to the mother and her offspring by extension, then we're working in the right direction. But if we were to say, SSRIs are associated with some adverse outcome and therefore we shouldn't use them, That would be both limiting mother's treatment options, preventing her from having arguably a beneficial treatment and it would be ignoring what is probably underlying all of this which is a question of mental health and genetic inheritance. So the real issue that I think we have to face, what are we doing to optimize mother's mental health and, by extension, what are we doing to optimize child developmental outcomes? And if medications help, great. If they don't help, then let's move on to something else.

Kristen Hovet (18:31)
This isn't a question that I had for you originally, but it came to my mind. So I have a podcast called The Other Autism, and I explore the latest in autism research and I also look at late diagnosed autism. The topic has come up of just how common mental health conditions are for those of us. I'm autistic. So overlapping depression, overlapping anxiety, that's very, very common. But because we're late diagnosed, it's not connected to the fact that we're autistic or have other neurodevelopmental differences. So like when I had my son, it wasn't yet known that I was autistic.  I just wonder how common it is that someone presenting with depression and anxiety would also have neurodevelopmental conditions that are maybe not diagnosed yet or recognized yet. And so I guess that goes into your genetic risk comment as well of like, we're passing this genetic risk on and it's looking like it could be something we're taking, some environmental factor when it's actually just, we're passing this neurodevelopmental difference on to our offspring.

Tim Oberlander (19:43)
So you raise a really important point that I want to take an opportunity to comment on. We need to be very careful not to think that two things that are associated, so antidepressant exposure has been reported to be associated with increased risk for autism, for example, which it's not, and I want to emphasize that, or anxiety as an outcome in childhood. These are associations. They're not causally related.

We can't do causal studies of medication in pregnancy. I want to be really clear about this. Randomized control trials are fine for high blood pressure medications in older men, but it is not an appropriate research design for studying psychotropic drugs in pregnancy. We cannot randomize to a placebo group for both ethical, I would argue legal, and medical reasons. That's just not an appropriate way to sort this out.

One of the problems we, of course, have as scientists is can we tease apart the effects of the drug from the medication itself? This is a problem that we've turned confounding by indication. The very reason that the antidepressant is being used is because of depression. So teasing these apart becomes both methodologically, scientifically challenging. I would argue that it's important to do that and we have methods of doing that and we've done that with big data here in BC.

We've done that with small data. But ultimately, we need to probably agree that as good as our techniques are of separating out antidepressant effects from depression effects, it may not actually be that necessary. Because at the end of the day, it's the child that matters. It's the mother's mood that matters. How well are they doing? How well are they functioning? Are we supporting them the best way we can at home, at school, in the playground? What's dinnertime like?

In that sense, we need to take an exposure-agnostic approach and say, let's take a look at how well the child's functioning, not in respect to their prenatal exposure to something, but can we do something to support their everyday life? Which takes me to address this next question, which I think you raised, which is around SSRI exposure and a reported risk for autism. This started in 2011 with a very important paper.

And over time, a series of other papers have reported outcomes both at an individual level and at a population level. I think that it would be fair to summarize the findings at this point, which are the association between SSRIs and autism does not exist. When you carefully control for genetics, using sibling matches, or controlling for mother's mental health and many other related confounders, that association between SSRI exposure and autism disappears. It was an important 10 or 12 years of discovery that has helped both methodologically address that question, but also conceptually address that question about is there an association? And it has not been proven and we need to move on to looking at other sources of where autism comes from. It is not associated with SSRI exposure.

Kristen Hovet (23:09)
So for expecting parents listening right now, what would you most like them to know when it comes to making decisions about SSRIs with their healthcare providers?

Tim Oberlander (23:19)
I'm going to answer that question as a developmental pediatrician seeing children after pregnancy. But if the question really is about what should parents expect or what should they be concerned about in their yet unborn child, it would be that the focus on managing maternal anxiety and depression during pregnancy should be job one. That should be using approaches that include both pharmacologic and non-pharmacological strategies. If we think about the place for antidepressants, then there is a place for it. I would also say that if there is any doubt or concern about mother's well-being, eating, sleeping, self-harm, inter-partner violence, these all need to be addressed right up front. So to think about antidepressants as being a single strategy in the absence of holistic care, that would not be appropriate and I'm not saying that's what goes on but one just needs to keep that in mind. So expecting parents should be aware that there are many other issues that need to be addressed in addition to the question of whether antidepressants are an appropriate strategy. The healthiest possible pregnancy, the healthiest possible mental health, both for mothers, their partners and their living conditions needs to be the most important question you address. The question of long-term health of the child and growing up will become clear as birth, labour, delivery, and early infancy unfolds. And that can be managed as well by attention to mother's and family mental health, living conditions, nutrition, infant behaviour, and all of those other things that we know are core ingredients to optimizing early infancy and  later childhood development.

Kristen Hovet (25:08)
As research continues, what makes you feel hopeful about the future of caring for maternal mental health in ways that support both mothers and children?

Tim Oberlander (25:18)
I'm hopeful because the last 30 years has allowed us to move away from just thinking about antidepressants as the treatment of choice. We've come to understand risk, both for mothers and their offspring, and we've figured out that there are non-pharmacologic approaches that do make a difference. Now granted, not everybody has access to it for both financial, socio-cultural, and geographic reasons, but there are effective strategies that are available that are both virtual internet related and in person. So we do have strategies that let us move away from thinking about one size fits all. 

The second is that I think as a society we've now come to understand the role that mental health during pregnancy plays and the importance that it should play at a public health level. And I think that's true of British Columbia and many jurisdictions in Canada. 

And the third is that my work and many others as well in the field highlight that many children are resilient, that even in the face of some risk exposure, their outcomes are actually pretty good. And that maps onto what I was seeing 30 years ago when I started at Sunny Hill, that many children, even under adverse circumstances, are developmentally very healthy. And our task is really to figure out how to keep them on a healthy course, how to get them there, how to keep them on this course, and one moment in time does not predict the next moment. So to say that  the outcomes because of  risk exposure are all going to be adverse is really, it's both scientifically wrong and it's unfair to the child and family.

Kristen Hovet (27:02)
This next question we're asking everyone, it's sort of related to our title of our podcast. How does your research help children live their best lives?

Tim Oberlander (27:13)
Developmental health comes from many different sources. Some of them are biologic, some of them we have no control over. We can't go choose our grandparents. We also can't choose our parents. But within the context of our families and communities, there are many ways in which healthy childhood can unfold. And some of it has to do with our postal code, where we live. Now that's not something an individual family can do much about, but certainly our public health officials and government can play a role in ensuring adequate and safe environments for growing up, access to services. Health and social and education services do make a difference. 

I think my research has pointed to the importance of understanding both biologic factors, which includes both genes and the drug exposure, do have an impact, but not for all children. And they really... address this question of why some but not all children develop the way they do and increasingly we're showing that it's not just the main effect of a particular exposure in pregnancy, but it's the interaction between factors. So that, for example, growing up in a chaotic environment can make a difference, when the chaos is substantial, to children of mothers who were depressed during pregnancy and treated with an antidepressant. 

But at low levels of household chaos, the outcomes are just fine. And therefore, we can't think about drug exposure as affecting all children in all circumstances all the time. Similarly, genes do matter. And we've looked at a particular gene that influences the reuptake of that very interesting neurochemical called serotonin. And with some alleles, some variations that regulate the amount of serotonin that's present in that space between two nerves, we found that, in the context of a depressed mother, children actually think and  appear to learn in similar ways to children who had no exposure and had a different genetic combination. So it's really, the core answer to your question really has to do with life circumstances in which children grow up in that include understanding biologic risk in the context of everyday life.

So it's not just where we start from, but it's where we end up that makes a difference.