Epigraph Vol. 24 Issue 2, Spring 2022
Pregnancy and breastfeeding: Dr. Page Pennell
Reported by Dr. Anca Arbune | Edited and produced by Nancy Volkers
Can women with epilepsy get pregnant, give birth to healthy babies, and breastfeed? What are the myths and misconceptions around epilepsy during pregnancy, and what do physicians and women need to know? Dr. Anca Arbune interviews Dr. Page Pennell about the latest research and knowledge.
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Dr. Arbune: Hello – thank you so much for meeting me. Could you please introduce yourself for our listeners and tell us your main research interests?
Dr. Pennell: I’m Page Pennell; I am a professor of neurology and chair of the Department of Neurology at the University of Pittsburgh School of Medicine. I have been working on research in the area of women’s health and epilepsy for the past few decades. Specifically, a lot of my research has focused on how we can manage women with epilepsy going into pregnancy to improve their maternal outcomes, as well as the outcomes for their children.
Dr. Arbune: One of your biggest projects is MONEAD: the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study. Could you clarify how the idea for this study came up, and why was it necessary?
Dr. Pennell: We designed that study, Dr. Kim Meador and myself, as well as several collaborators. We designed it based upon known gaps in our knowledge about how to help manage women with epilepsy during pregnancy. So we took the last set of guidelines in the United States, the American Academy of Neurology guidelines that were published in 2009 and looked at all the areas where they said they didn’t have enough evidence to come up with recommendations. Based on that, we designed the study.
Because it is an observational, prospective, cohort study, we knew we would not have enough pregnancies or power to answer questions about major congenital malformations (birth defects), which is well addressed by excellent pregnancy registries. But the other types of outcomes we were able to incorporate into the design of the study.
Dr. Arbune: Do you think there’s a large proportion of women of childbearing age who need to take antiseizure medications?
Dr. Pennell: Yes – going back to my years of training and when I was shortly after that as faculty, that’s one of the reasons I became so invested in this area, because of the lack of information we had. It was almost tragic, the way women with epilepsy were counseled at that time. They were told the medicines would have teratogenic effects and cause malformations and affect the child’s brain development. They got very mixed messages, even outright recommendations to stop or lower their medications during pregnancy. Now we’re fortunate to have more information about the risk of different medications, to be able to let women know how important it is they adhere to their medication regimen during pregnancy to keep themselves healthy and safe.
Dr. Arbune: One of the results of the study indicated that the general risk for neurodevelopmental effects in women with epilepsy versus those in the general population is not that big of a difference, that there are no major concerns about this and only when higher doses during the third trimester were reported were there small differences in the motor domain and the adaptive domain on the Bailey Scale.
Dr. Pennell: You quoted that very well. That is from the 2-year-old outcomes, the children tested at 2 years old whose mothers were in the MONEAD study. Those were the findings. A lot of the reason why we incorporated this into the study and why long-term neurodevelopment as such an important part of the study was based upon the prior, NEAD [Neurodevelopmental Effects of Antiepileptic Drugs] study, led by Kim Meador, which showed major negative impacts of valproate on the child’s neurodevelopment, with lower IQs and lower verbal ability. Other investigators showed higher rates of autism and autism spectrum disorder. So we designed this study trying to avoid another valproate story and to get ahead of it and see if there were other medications that have those risks.
But in the current study, we aren’t seeing major risks in the medications that are tending to be prescribed at this time. So women were enrolled, it was observational – their management was by their clinician without any changes dictated by the study. The majority were on levetiracetam or lamotrigine, but other medications were represented. Over time, what was nice to see was out of 350 women, only 4 were on valproate. So the number of women on valproate, receiving it as a prescribed medication during pregnancy, has decreased dramatically.
Dr. Arbune: There are still some concerns, and one is about the cumulative effect. Many women state that if I have been taking an antiepileptic drug for many years, it will automatically impact the fetus. Is this true, or is there any evidence to contradict it?
Dr. Pennell: that’s a great question and you are right – many patients bring this up. There’s no cumulative effect of the medication prior to conception. So the risk, whether were talking about major malformations, birth defects, or we’re talking about neurodevelopment or growth of the baby, all of that is just related to exposure during the trimesters, and prior medications that someone has been on in the past has no impact on those outcomes.
Dr. Arbune: This is great news – I hope our listeners will take that message home. Other fascinating results from your studies was about the changes during pregnancy – the efficiency and clearance of specific antiepileptic drugs. As treating physicians, we should take this into account and compensate for these changes. Could you clarify how soon the hormonal influence exerts itself on serum levels?
Dr. Pennell: This is something that’s not well understood, even by many clinicians. We are trying to get the information out that it really isn’t based on the women’s weight, or very little of it is about her weight. We’re trained as practitioners to think about a milligram per kilogram basis, but this change in accelerated clearance of the medication is related to other physiologic processes.
As estrogen goes up, for some of the medications, especially lamotrigine, levels will go down. This begins very early in pregnancy, the first trimester. One small study showed you could see changes by 5 weeks after the last menstrual period, which is really only a week after conception.
Many practitioners may think it’s just lamotrigine, but we see big changes in clearance in other medications. As an example, levetiracetam is cleared by the kidneys, but the kidneys undergo enormous changes early in pregnancy as well – there’s increased water retention and increased renal blood flow very early in pregnancy. So within our practice, we ask women if they do conceive to let us know as soon as they have a positive pregnancy test, so we begin monitoring blood levels right away.
Dr. Arbune: Could you give some guidelines on the serum level monitoring? This is a big problem for clinicians – we know we should have a baseline serum level before pregnancy, but taking into account that more than 50% of pregnancies are unplanned, what should we do if we face a woman with epilepsy who just learned about her pregnancy? Is a serum level taken then useful, and how often should we take serum levels during pregnancy?
Dr. Pennell: I try to make sure there is a level on women of childbearing age where I know their seizures are under good control for them and that would be good going into pregnancy, even if they aren’t planning a pregnancy. Because as you say, more than 50% are unplanned, in the United States at least, and many other parts of the world as well.
But if we don’t have the luxury of that, as soon as we find out she is pregnant we get a level at that time, and also go through the chart for a history to see if she needs high doses for seizure control. Also putting in a plug – if someone has drug-resistant epilepsy, know that what we’re really looking for is stability of their seizure pattern. It’s not realistic to all of a sudden make them free of seizures, and if we take that approach, we run the risk of really overmedicating, using additional medications or higher doses during pregnancy with very little positive impact on seizure control. So we’re trying to establish what her seizure frequency is and what it will take to keep seizures at that level.
Dr. Arbune: In some countries it’s difficult to get a serum level of a specific antiseizure drug. Can we compensate for changes during pregnancy empirically? If we have a breakthrough seizure should we increase, and how much should we take into account to increase the doses. Any advice on this?
Dr. Pennell: it’s a difficult situation. We just published a paper from MONEAD a few weeks ago in JAMA Neurology. In that, you can see the range of changes across the group of women. For zonisamide, lacosamide, lamotrigine, levetiracetam. At least use those as guardrails, saying okay, there’s a change in clearance that begins in the first trimester – with levetiracetam it peaks at about 20 weeks and it’s by this amount, and then make changes based on that.
It does get a little tricky with lamotrigine – we have identified two subpopulations: One doesn’t have as much increase in clearance, but they are probably only about 13% or 10% of the total number of women. So if I were in that situation, I would make dose changes according to what happens in the majority of women. If they are a subpopulation where they’re not having a lot of change in clearance, they will develop symptomatic toxicity with blurry vision or dizziness, and then you know you don’t need to make as many dose changes in that woman in her pregnancy.
Dr. Arbune: Along with so much information on the internet, women with epilepsy have started reading about these teratogenic effects and adverse effects of anti-epileptic drugs. It’s expected they will have some fear toward their treatment. In some cases they refuse treatment altogether when planning a pregnancy or stop treatment when they learn about a pregnancy. Could you tell our listeners what the risks are of this refusal to take treatment? Does it have good or bad impacts on the fetus?
Dr. Pennell: Obviously partnering with patients and education and having a dialogue is incredibly important. Some of our medications we now have enough information to show that they actually do not have an elevated rate of malformations, or elevated rates of neurodevelopmental problems. On the other side of the equation is what happens if they do not take their medication? That’s where we have grave concerns for maternal death. Sudden unexpected death in epilepsy, SUDEP, is something we think about for all of our patients, and it’s a concern. Often the risk is higher if there are uncontrolled seizures and especially convulsions. There are some reports from the United Kingdom because of the maternal death registry – they have a mortality registry that shows that women with epilepsy are at higher risk for death during pregnancy, and when they were able to look at a lot of the cases, many of them were due to SUDEP and many of those had lower medication levels or perhaps were even not taking their medications. And just to say, SUDEP can occur without a seizure as well, but we know keeping seizures controlled is the best way to lower that risk.
Unfortunately I have had this in my practice, and it was absolutely tragic. I met a young woman after she became pregnant, unplanned. I went through everything. I felt like I’d counseled her adequately and she had a good understanding, and about 8 days later she was found to have not made it through the night. It was the loss of two lives. When we looked into it, she’d never gone to the pharmacy to pick up her medication because she was so fearful of the negative effects of the medication on her pregnancy. Whatever we can do to help partner, that communication, to avoid it, we should all try to do.
Dr. Arbune: Thank you. We have a bit of a problem because at least in Romania, my country, carbamazepine and valproic acid are still prescribed to young women. We often have consults when they learn about a pregnancy and come to us to ask for a dose reduction. Is that of any benefit, taking into account that when they come for a consultation, they are already toward the end of the first trimester? Does dose reduction from the second trimester on have any benefit overall, or is it better to keep the doses until the end of pregnancy?
Dr. Pennell: In that case I would keep the doses until the end of the pregnancy. Sometimes if you do have the luxury of adjusting the dose of valproate lower prior to the first trimester, or at least until the end of the first trimester, there is a lower risk of birth defects with lower doses of valproate. But as you pointed out, if they’re not coming until the latter half of the first trimester, there’s not really much benefit. We do know about the risk of valproate on fetal brain development, and there is some dose response there, but there’s not a safe dose that we don’t see the negative impact.
If you had a history and knew their seizures were controlled with a lower level and a lower dose, maybe you could tweak it, but in general probably it’s too late to make fine tuning adjustments.
Dr. Arbune: So I’ve seen many studies with monotherapy but there are few taking into account what happens during polymedication – it’s just listed as a risk factor for neurodevelopmental effects. Do you think we can have an optimal combination that allows women to have a pregnancy even though they need multiple anti-epileptic drugs?
Dr. Pennell: Yes, I do think that as we learn more about almost anything in medicine, we find out it’s not so simple to have a rule that polytherapy is bad. We have found that certain combinations don’t have a really particularly high risk for malformations, birth defects. Because people are avoiding valproate, we are seeing more polytherapy combinations to avoid valproate in the primary idiopathic generalized epilepsies. We had the theory going into MONEAD that polytherapy would have higher risk on the fetal neurodevelopment – that was one of our hypotheses, as we were seeing higher rates of polytherapy. But in fact, at this point, with the 2-year-old data and we’re looking at the 3-year-old data now, we’re not seeing an increased risk for polytherapy, which is great news.
The rule is never that simple so I wouldn’t say all polytherapy, but in MONEAD most polytherapy was lamotrigine and levetiracetam. There will be some polytherapy combinations that will be more problematic, but it gets difficult to sort out all the differences because you need a certain number of women, the proper sample size to show that. But at least for the combo of lamotrigine and levetiracetam, and when we group all the polytherapies together, we’re not seeing differences in the cognitive outcomes of the children at age 2, and now we’re looking at 3. That’s very young, so the 6-year-old outcomes will be particularly reassuring, if that holds up.
Dr. Arbune: Thank you very much for that answer. And if we complicate things with a case – if we have as a patient a woman with epilepsy who’s approaching her 35th birthday and she has controlled seizures on two medications – lamotrigine and levetiracetam. Is it worth waiting a few more years to try for monotherapy, or would it be safe enough to attempt a pregnancy at this point if she’s not having seizures on these two drugs?
Dr. Pennell: I would feel comfortable reassuring her about that combination. It’s always a communication decision with each individual patient and it’s so interesting how different every patient is. If I told her well, we have very clear data on lamotrigine monotherapy and we think that lamotrigine with levetiracetam is going to be okay, it’s possible she may choose, well, I want the most definitive data, so I want to try to go to lamotrigine monotherapy. That’s where I’d go back in her chart and look carefully. If she’d failed lamotrigine monotherapy before, I would advise against trying to go to that. Or if she’d failed levetiracetam monotherapy. But if she’d never tried either one alone, I wouldn’t strongly suggest trying monotherapy but she may decide she wants to try it before pregnancy.
Dr. Arbune: So the best case – Communication with the patient and establishing the best contact possible. Um, as far as you know, is there any clear evidence that fathers’ antiseizure medication has an influence on fetal development or fertility?
Dr. Pennell: Yeah, so there’s no effect on fetal development. We do get that question a lot, especially if the father is on valproate. But there’s nothing carried through the sperm that affects the growth of the embryo or fetus, so there’s no effect on the developing fetus. There’s some indication that fertility can be affected by some of the medications. The ones we call enzyme-inducing anti-seizure medications – they can increase the sex hormone binding globulin and also lower the testosterone/androgen levels, and overall the free level is lower, which can affect sexual function and fertility. The other finding is that valproate can cause changes in the sperm motility, morphology, and number, so it can affect fertility in that way.
Dr. Arbune: Along the same line with fertility, some women with epilepsy experience problems conceiving and resort to in vitro fertilization. Is there any evidence of influence of specific antiepileptic drugs on these treatments, or some antiepileptic drugs that can help in this process?
Dr. Pennell: There has been mixed literature on fertility and women with epilepsy, and when you put it all together, I think the story is that similar to men, if women are on enzyme-inducing antiseizure medications, that affects their hormone levels and can affect their fertility. So if they were to start infertility treatment, it could impact the infertility treatment but not to the point that it wouldn’t be effective.
Then the other thing about infertility treatments which we don’t have enough information on, is that during those treatments there are changes in the hormones, so if a woman is on medication that’s affected by hormones, such as lamotrigine, I mentioned before, but also valproate and oxcarbazepine because they go through glucuronidation, when they are getting the infertility treatments there will be times when their estrogen levels are a lot higher. At this point I’ll check levels, but there’s not a protocol or any kind of guideline about what to do during that time.
Dr. Arbune: You started a new project as a coinvestigator – a physiological based pharmacokinetic approach to determine the extent of drug exposure of antiseizure medications during pregnancy and breastfeeding. Could you let us know, let our listeners know, what the project is about and what are the main goals of this project?
Dr. Pennell: This project is with Dr. Angela Birnbaum at the University of Minnesota, and she’s an expert in pharmacokinetics and metabolism. So the first two aims of the project will be in her lab, using rodents to model in more detail what happens during pregnancy and lactation with regard to how the medications are metabolized differently, as well as being able to look more specifically at the amount of exposure to the fetus and to the newborn through breastfeeding .
The third aim I’ll be doing at the University of Pittsburgh, which is enrolling a new set of women to be incorporated into our MONEAD data and look at data points we weren’t able to obtain through a large multicenter trial. We’ll enroll a small number of women here to get very precise data on time points we didn’t have in MONEAD. Starting preconception, with a planned pregnancy, and getting very frequent monitoring through a home sampling kit of their medication levels early in pregnancy ,which goes back I think to an early question – how early do we start looking at changes in levels? This will provide a lot more information about that.
Then we’ll follow them during pregnancy like we did in MONEAD, and then post-partum we’ll be able to get levels very frequently, every few days, to see what happens after delivery. At the end we hope to be able to come up with an algorithm, a model, to allow practitioners to say, “Okay, a woman’s on this dose going into a pregnancy, this is how I need to change doses during pregnancy” without having to get the levels, and the blood sampling during pregnancy. One day, I see this as an app, something that clinicians can look up and make changes without having to react to blood levels. This will be especially helpful in countries or regions where it’s difficult to get medication levels or get them paid for. That’s our ultimate goal.
Dr. Arbune: This is wonderful news because it would help clinical practice immensely. Still on this subject, how about the effect of the doses on the newborn child, during breastfeeding? Some women opt to breastfeed for longer periods and some women, for fear their medication could affect their child, opt to stop breastfeeding quite early. What’s the general concern about breastfeeding and the length of breastfeeding?
Dr. Pennell: Yeah, so there’s a couple of things we’ve been able to show that are helpful. Going back to the NEAD study, led by Dr. Kim Meador, we looked at outcomes when children were tested at age 6, their outcomes related to whether they were breastfed.
In NEAD, about 43% or 47% were breastfed and the average duration was around 6 months. And what we found was that if children were breastfed, they did better on full scale IQ and specifically on verbal abilities, compared to children who were not breastfed. There were many adjustments for that, such as maternal IQ, socioeconomic status, et cetera. Even after adjusting for all of those things, there was still a benefit to breastfeeding. Really the biggest concern would be those medications, if continued exposure through breastmilk could affect newborn and infant brain development. But we did show a benefit, which is the same as in the general population, there’s a benefit.
And in MONEAD, because we have different types of medications, we’ve been able to look at levels in the breastfeeding infant and they are very, very low. I think that should be reassuring that it is okay to breastfeed and to breastfeed for longer periods of time. We have an abstract coming out at the American Academy of Neurology meeting the first week of April, a presentation looking at the MONEAD children, and we’re showing no harmful effects of breastfeeding on the child’s neurodevelopment at this point, and again, we need to wait until the 6-year-old data is available to know with greater certainty.
Dr. Arbune: As more and more studies have appeared about the levels of antiepileptic drugs in breastmilk without any great concerns for the fetus, this should encourage patients to breastfeed with more confidence and not be afraid of it. The results of your studies have been really fascinating and I thank you for having time to talk to us. Would you like to add anything or send a message to our listeners or prescribing physicians?
Dr. Pennell: Yeah, I mean I hope everyone has as much enthusiasm about the fact that we have been able to get information to help reassure women living with epilepsy that they can get pregnant with relatively good fertility chances, with the exception of the few things we mentioned, and the high likelihood of having a healthy pregnancy, seizures not getting worse, and then having healthy children who have good long-term neurodevelopment.
But I want to take a moment to thank the women with epilepsy who have contributed to these studies. We wouldn’t have any of this information without their participation. These studies really didn’t provide any benefit to them directly, but they all were willing to participate because they want to make things better for the women who come behind them, and who have the same questions, concerns, and fears that they had.
Dr. Arbune: Yes, I also want to thank them because due to their courage, we know that valproic acid is no good for women of childbearing age and we are seeing big changes in clinical practice. This is good news for all of us and we hope their participation in your future studies will clarify future questions. Thank you very much for the interview.
Dr. Pennell: Thank you so much for your attention to this and helping to get the word out. I really appreciate it.
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