Practice guideline on outcomes after in utero exposure to anti-seizure medications: Dr. Alison Pack

A recent practice guideline provides updated evidence-based conclusions and recommendations regarding in utero effects of anti-seizure medications and folic acid supplementation on the prevalence of major congenital malformations, adverse perinatal outcomes, and neurodevelopmental outcomes. Dr. Parthvi Ravat interviewed Dr. Alison Pack about the guideline, which was produced by the American Academy of Neurology, American Epilepsy Society, and Society for Maternal-Fetal Medicine.

Review the practice guideline: Teratogenesis, perinatal, and neurodevelopmental outcomes after in utero exposure to antiseizure medication (Neurology, May 2024)

Other studies mentioned in the episode:
Risk of major congenital malformations and exposure to antiseizure medication monotherapy (JAMA Neurology, March 2024)

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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Transcript

For links to studies mentioned in this episode, please see the episode's show notes.

[00:00:00] Dr. Parthvi Ravat: Good morning, everyone. Welcome to the Sharp Waves podcast. I'm Parthvi Ravat and today's topic is the recent guidelines released by the collaborative efforts of AAN, AES, and SMFM about people with epilepsy of childbearing potential regarding teratogenesis, perinatal, and neurodevelopmental outcomes after in utero exposure to anti seizure medications.

These guidelines were led by Dr. Alison Pack from New York, who is with us today, and we welcome her to the show today. Dr. Pack, would you like to introduce yourself? Thank you. 

[00:00:33] Dr. Alison Pack: Thank you for having me. Yes, I'm Dr. Alison Pack. As stated, I'm the lead person for this guideline that we'll be discussing, and I'm a professor of neurology at Columbia University in New York.

[00:00:48] Dr. Parthvi Ravat: We are very happy to have you on the show today. Let us start with the first recommendation which concerns joint decision making. The guidelines emphasize joint decision making in people with epilepsy of childbearing potential. I'm So, how important is it when we select an ASM, dose their ASM, and what should we consider before making those decisions?

[00:01:09] Dr. Alison Pack: Joint decision making is critical to the care of the individual, as well as the relationship between the provider and the individual. When choosing an anti-seizure medication for a person with epilepsy of childbearing potential, you need to factor in multiple components. 

Seizure control, notably, control of convulsive seizures. Whether it be generalized tonic-clonic seizures or focal to bilateral tonic-clonic seizures, they are associated with potential risks for the mother as well as the developing fetus. Side effect profiles and long-term implications of treatment are also factors that one needs to consider when choosing and dosing an anti-seizure medication. It's very important to, as I said, to engage in shared decision making to not only address all of the above but also help the person with epilepsy of childbearing potential understand the implications of anti-seizure medication selection and dosing on reproductive outcomes, which was the focus of this guideline.

[00:02:17] Dr. Parthvi Ravat: So then, before getting pregnant, what should we counsel as clinicians to our patients regarding major congenital malformations and intrauterine death? 

[00:02:26] Dr. Alison Pack: Well, let's start talking about major congenital malformations. Before we get into this topic, I do think it's important to highlight the most persons with epilepsy of childbearing potential will have normal, healthy babies, with a low risk of major congenital malformations. I think that's a very important message to relay to the individuals that we treat. 

Among anti-seizure medications with available data, we found the following. Lamotrigine, levetiracetam, and oxcarbazepine were associated with the lowest risk of major congenital malformations overall. I would like to draw your attention to the recent publication of EURAP major congenital malformation outcomes that was published in JAMA in March of this year. Findings in this study support our conclusions. And these are the highest numbers from a single registry when looking at different anti-seizure medication exposures in pregnancy. Valproic acid is associated with the highest risk overall. We found no clear increased risk in our analysis. when comparing polytherapy to monotherapy.

 Valproic acid is associated with the highest risk of neural tube defects at 1.4 percent when compared to other anti-seizure medications. Phenobarbital had the highest risk of cardiac malformations at 4.4 percent when compared to other anti-seizure medications. Phenobarbital and topiramate, the highest unadjusted risk of oral and cleft palate at 2.2 percent and 1.4 percent respectively. And valproic acid associated with the highest risk of neurogenital malformations at 1.2 percent and renal malformations at 1.4 percent. When looking at intrauterine death, the prevalence of intrauterine death did not differ across anti-seizure medications.

[00:04:35] Dr. Parthvi Ravat: You've spoken about a lot of individual drugs. One of the longstanding drugs which we've been using a lot is valproate. And recent guidelines from Europe and the UK have specifically stated that valproate should not be used in patients of both males and females less than 55 years of age unless two independent clinicians independently assess and document that there is no other effective, tolerated treatment for those people. So what are your thoughts about this? And how is it different from what you have suggested in your guidelines? 

[00:05:10] Dr. Alison Pack: Well, in general, we agree with the idea that valproic acid should be avoided in persons with epilepsy of childbearing potential.

The EMA and UK governing bodies have taken a different approach than we have in the AAN/AES/SMFM guideline. Let's start off by discussing females or persons with epilepsy of childbearing potential who are the focus of this guideline. 

In our recommendations, we state that clinicians must avoid the use of valproic acid in persons with epilepsy of childbearing potential to minimize the risk of major congenital malformations or neural tube defects, if clinically feasible. Clinicians must counsel persons with epilepsy of childbearing potential when considering or starting valproic acid that the risk of any major congenital malformation is highest with valproic acid when compared to other standard studied anti-seizure medications.

And that's not something we've specifically discussed, but we did find an increased risk of [negative] neurodevelopmental outcomes in association with valproic acid. So in order to reduce this risk, including autistic spectrum disorder and lower IQ to children born to persons with epilepsy or childbearing potential, clinicians must avoid valproic acid. These are all the highest level of recommendations. That is level A recommendations. 

We also state that you should avoid valproic acid to minimize the risk of small for gestational age and to minimize the risk of urogenital and renal outcomes. These are level B recommendations.

Throughout these recommendations, we state “if clinically feasible”—why did we include this? We included this because for some individuals, valproic acid is the treatment of choice in order to control convulsive seizures, particularly in persons with drug-resistant idiopathic generalized epilepsy. We all have those individuals in our practices whereby valproic acid is the only medication that controls the convulsive seizures.

I'm concerned that the EMA and UK restrictions may be putting some individuals at risk of having seizures. In addition, when you step back and think about it, the EMA and UK restrictions view that all females or persons with epilepsy of child bearing potential will have children. Essentially it considers those people only from the perspective of their having a uterus and potential to get pregnant. They do not factor in or consider other factors or life choices. 

In this guideline, we do not specifically address males as the focus was females or persons with childbearing potential. 

[00:08:16] Dr. Parthvi Ravat: Well, that's really a fresh perspective and a lot of food for thought that these guidelines might not be inclusive to everybody around us. 

So then now coming to when, once you get pregnant, one of the recommendations says priorities during pregnancy. So once pregnant, what should be the main focus about how to avoid convulsive seizures during pregnancy?

[00:08:39] Dr. Alison Pack: So it is important to maintain seizure control, notably convulsive seizure control. How does one accomplish this? Well, you follow concentrations if available. I recognize that not all regions of the world have access to anti-seizure medication at drug level monitoring. And as such, one needs to consider adjusting doses. The AAN, AES, and SMFM are currently putting together a protocol to address this issue in particular, that a protocol to create a guideline, and this will be done under the leadership of Dr. Mark Keezer in Montreal. 

[00:09:23] Dr. Parthvi Ravat: Right. 

We look forward to those guidelines, which should be a good roadmap. For clinicians all across the globe, what screening and intervention measures are recommended for pregnant females during the nine months of pregnancy and thereafter for various defects related to ASMs. 

[00:09:43] Dr. Alison Pack:  I recognize as we discuss this that there are variable international practices regarding this, but let me go through what we specifically recommended in the guideline. We recommended detailed anatomic ultrasound, if available. As this ultrasound will detect most major congenital malformations. These ultrasounds are typically done between 16 and 20 weeks gestational age.

For persons taking phenobarbital, we recommend screening cardiac investigations. As discussed, we find increased risk of cardiac malformations in association with phenobarbital use in pregnancy. Typically this is done with fetal echocardiography. For persons treated with valproic acid or topiramate, we recommend screening of fetal growth.

This can be done crudely with maternal weight, measurement of the height of the uterine fundus, ultrasound and combination Doppler studies. All of these can be used to monitor the fetal growth. We also recommend age-appropriate developmental screening for all anti-seizure medications. The testing will vary depending on age and other international variables.

These screening mechanisms are important because as for any child who potentially has developmental delays, it is important to screen and get early intervention. So these are the recommendations one should consider as you state during pregnancy and when following the child in those early years. 

[00:11:38] Dr. Parthvi Ravat: And then talking about neurodevelopmental outcomes, a question always comes to mind. We already know that neural tube defects occur during the initial phase of pregnancy, but is there any data on the occurrence of poor neurodevelopmental outcomes and the timing of intake of anti-seizure medications?

[00:11:58] Dr. Alison Pack: That's a really good question. We don't know specific mechanisms, but we do know that brain development occurs throughout the entire pregnancy. When thinking about major congenital malformations, we really focus those in the early part of the pregnancy, whereas brain development occurs throughout pregnancy and in our analysis, we find that folic acid supplementation in the periconceptional period, as well as throughout pregnancy is associated with a lower risk of adverse neurodevelopmental outcomes, such as autistic spectrum disorder and IQ and therefore it is important to take folic acid supplementation throughout the entire pregnancy. 

[00:12:56] Dr. Parthvi Ravat: So you're clear about the timings, but there is a lot of controversy regarding the dose of folic acid and some benefits versus risks related to cancer and folic acid. What are your thoughts about it?

[00:13:09] Dr. Alison Pack: You know, the folic acid question was one that people really had a lot of interest in and I think it was one of the most eagerly anticipated outcomes of the guideline.

You know, what is the optimal timing? What is the optimal dosing? So let's just step back a little bit and address the findings for folic acid overall. 

The evidence does not support a reduced risk of major congenital malformations in children of persons with epilepsy of childbearing potential exposed to anti-seizure medications. So why is that? Why do we not see that? Folic acid has been supplemented in over 60 countries throughout the world in grains and cereals. In the United States. it's been supplemented since 1998. And when you step back and look at the overall risk of major congenital malformations in the general population, and neural tube defects in particular, you find that the risk has reduced.

And therefore, for the individuals we treat, they are likely getting enough in their diet and that overrides, so to speak, any potential benefit in reducing the risk when looking specifically at major congenital malformations. As I mentioned earlier, though, the evidence does support that folic acid supplements reduce the risk of adverse neurodevelopmental outcomes. Specifically, it reduces the risk of autistic traits and is associated with a higher global IQ. So given that, what is the optimal dose? Well, we had hoped to clarify the optimal dose. Unfortunately, the data does not support a recommendation beyond at least 0.4 milligrams per day. Some of the most rigorous studies evaluating the effect of folic acid grouped individuals by whether they were taking a folic acid or not, and we're not able to provide data on the specific dose. 

One study, a Scandinavian study, does support a reduced risk of autistic traits if given in the pre conceptional period. We have not been able to define the optimal dose, but it's very unclear if high dose is necessary.

And when you look around the world, there are variable practices, you know, in the United States, for example, we tend to give less folic acid than they do in countries in Europe. And there was a study that was published, it was an analysis from Scandinavia of over 27, 000 children born to people with epilepsy. And what they found was that exposure of greater than 1 mg per day was associated with a 0.9 percent absolute risk of childhood cancer, notably CNS cancers before the age of 20, resulting in a hazard ratio of 2.7. 

I will say when you look at that analysis in more detail, that risk was skewed more towards the higher end. And certainly the findings from this study need to be reproduced, and I know many individuals have had some concerns with this, so I'm not here to support that, but I do think the findings from this study raises the question that too much folic acid may not be beneficial to the developing fetus.

[00:17:02] Dr. Parthvi Ravat: So then what are the critical areas of research in the management of epilepsy in people of childbearing potential? 

[00:17:09] Dr. Alison Pack: I think the one thing that we just talked about is we really do need better clarification of the optimal timing and dose of folic acid supplementation. That is one thing that we need to address better.

We need better understanding of the understudied anti-seizure medications. We were not able to draw any conclusions in our guideline on lacosamide, and increasingly people are using cenobamate, of which we have no information.

We need better understanding of the polytherapy impact. As I mentioned earlier, we did not find an independent risk of polytherapy, but polytherapy is complex; it depends on the specific agents used and the specific dosing may also be a factor.

And we need to, we touched upon developmental or some screening. Well, we need to understand the impact of screening on fetal anomalies, major congenital malformations and fetal outcomes, such as neurodevelopmental outcomes. So we need to have better understanding of that. 

[00:18:19] Dr. Parthvi Ravat: Before finishing off, do you have some personal anecdotes from your practice where you faced a challenge and then some challenges, some successes in managing patients with epilepsy? 

[00:18:30] Dr. Alison Pack: Let's touch upon the valproic acid question, and you know, I did allude to the fact that some individuals need to, that valproic acid is the only medication, so to speak, that controls their convulsive seizures.

So I do have certain people in my practice whereby that is the case. And in those individuals what I had chosen to do is have them on valproic acid at the lowest dose possible. And then I'll use other medications. 

I saw one woman recently. She's on valproic acid and her level is around 40 and that's actually dropped during pregnancy. She takes in combination with that lamotrigine as well as levetiracetam. And she's in the third trimester. The baby has no major congenital malformations. And we are obviously going to be following or the pediatrician will be following that child closely for any neurodevelopmental outcomes.

And she, her husband and I had a very long conversation about that the other day. So that is a tricky case whereby I have to factor in seizure control as well as potential effects on the developing fetus. 

As we talked about, most individuals will have normal, healthy babies. And I can think of two particular cases that show each end of the spectrum. I had one woman that I took care of in my practice on relatively low-dose lamotrigine. And in the first trimester, it was found through screening that her baby had a major congenital malformation that was incompatible with life.

So, we had a long conversation about that and in terms of future pregnancies. She'd done well on lamotrigine and we had a discussion about, well, does that mean it was the lamotrigine? And the answer to that is likely not. I mean, as we've discussed, lamotrigine is associated with the lowest risk of major congenital malformation when compared to other anti-seizure medications.

And therefore, in treating her and taking care of her through Future pregnancies, I'm happy to say that she went on to have had two children, two successful pregnancies, and was on lamotrigine. 

Another thing to think about is you know, I had another patient that I can think of who was not interested in getting pregnant and that was not at risk of getting pregnant, and then came into my office pregnant. And she was on multiple anti-seizure medications. She had been on folic acid. I've taken care of her through adolescence and had I always had her on folic acid supplementation. And I am happy to say that despite being on multiple anti-seizure medications, including a relatively high dose of topiramate, she also had a normal, healthy baby.

We want to work together with the individual to reduce the risk of major congenital malformations. But please keep in mind that most people do have normal, healthy babies. 

And as stated, I do believe very strongly in avoiding valproic acid. I don't want anyone to get the idea that I think it's okay to use that. I strongly avoid using valproic acid and do everything I can. It is not a first, second, or third-line agent in my practice for persons with epilepsy of childbearing potential. And I do everything I can to either not start it, or remove it if they're already on it.

[00:22:26] Dr. Parthvi Ravat: 

A wonderful few cases you discussed very quickly. And so good luck to that polytherapy patient of yours, the first one you discussed, for her pregnancy. And thank you so much for this wonderful conversation. It was a very good brush up of the entire guidelines and we could go through all the guidelines in one way or the other.

So thank you so much. 

[00:22:47] Dr. Alison Pack: Thank you, Parthvi. Thank you for having me today. It was my pleasure.