SARITA MATURU: My name is Sarita Maturu. I'm from Ohio State Western Medical Center. I'm one of the epileptologists, today, and we're going to be talking about managing epilepsy during pregnancy.

And so, first, I want to briefly touch base about the significance of this topic. So there have been a lot of survey studies that have been done over the years showing that there is a gap of knowledge between women's issues in health care and-- or physicians' ability to educate women in this specific topic. So, for instance, in 2004, there was a survey study that came out that showed that women with epilepsy knew that they were able to have healthy children, and they knew that they were not supposed to discontinue antiepileptics during pregnancy, but they did not know that they were able to breastfeed with antiseizure medications.

And then, this gap of knowledge continued into 2006. There was another survey that went out. And, essentially, many women in the survey felt that they were not adequately educated by their physicians about the impact of epilepsy and antiseizure medications on women health issues.

And then, in 2009, about 50% to 60% of women felt that maybe they were more educated, at this point. So about three years later, they felt that they had more education on these topics. But then when a questionnaire went out to discuss what the impact was of epilepsy and antiseizure medications on women health issues, that revealed this large gap.

And even in 2016-- or 2018, a study was done, and many women just felt like their knowledge of these issues were unsatisfactory. Many childbearing women were on valproic acid, and they had no neurology consultation. And so, really, there's this gap of knowledge between what we know and what we're presenting to our patients and how our patients perceive what their knowledge is of this topic.

So epilepsy is one of the most common neurological conditions affecting women of all ages. 50 million individuals worldwide are estimated to have epilepsy, and one out of 28 females are predicted to have a lifetime risk of epilepsy. It's felt that the prevalence of epilepsy is higher in men in comparison to women, except in the 16 to 25-year age group.

And so there are two proposed hypotheses for this. The first hypothesis is that a lot of generalized epilepsies have a hormonal component to them. So during these ages, women are more susceptible to epilepsy and things like that. But then, after menopause, their seizure frequency is decreased. Then the other hypothesis is that there is a big stigma around having epilepsy and being a woman, and so it might just be underreported.

And the stigma faced by these patients really carries over to their reproductive health choices. So, in general, you know, a long time ago, people that were found to have epilepsy were put into epilepsy colonies. They were thought to have epilepsy because of supernatural causes, things like that, and that evolved in time.

But, even, there were laws in the United States, back in the 1900s, that said that if a woman had epilepsy, they had to remain in an epilepsy colony or they weren't allowed to get married, they weren't allowed to have kids. And although those laws have faded in the present time, there's still a huge stigma that women with epilepsy feel.

And even though we understand epilepsy and how it relates to pregnancy much better, many women still receive messages that they should not consider pregnancy. And so what that does is a lot of patients feel like they can't talk to us about it because if they're told not to get pregnant, then they don't really want to talk about the subject at all. And that leads to a lot of unplanned pregnancy, so about 50% of women with epilepsy have an unplanned pregnancy.

Many women are often unfamiliar with the teratogenic risks of antiseizure drugs and their interactions with contraception. So going back to what I just said, 50% of women with epilepsy have unplanned pregnancies. And so this often leads to a confusion of medications. Some people just stop all their medications when they get pregnant. Some people really don't know what to do with their medications if they get pregnant.

And so we just need to discuss what happens if and when a woman gets pregnant that has epilepsy. And it's really important that we discuss contraception and pregnancy early in their visits and we revisit the topics frequently. So it's not just when they get pregnant, but it's every visit prior to getting pregnant that we need to discuss these topics and make sure that we have open communication.

Epilepsy is the most common major neurological complication in pregnancy. So women with epilepsy tend to have babies that are smaller in gestational age. They have preterm labors, in comparison to women without chronic diseases. And most women with epilepsy will need to remain on antiseizure drugs through their pregnancy. The only exception, in this case, of if a woman was off of their medication for a few years. Then they can remain off of their medication during their pregnancy if they are seizure-free.

And there is a risk of seizures to the fetus during pregnancy. So, of course, if a woman is having a generalized tonic-clonic seizure, that can lead to injury to the woman herself, but also to the fetus. It could lead to placental abruption, preterm labor, things like that. But also, if someone is having breakthrough focal seizures during their pregnancy, we think that can lead to fetal hypoxia, and ultimately it can lead to intracranial hemorrhages.

And, of course, there is a risk of seizures to women during pregnancy. So if they were to stop all their medications, and they had many seizures, they're more predisposed to SUDEP, which is Sudden Unexpected Death in Epilepsy Patients.

And, of course, there are risks related to antiseizure drug use, but these risks can be minimized by a prepartum counseling and optimization of medications. And because the majority of pregnancies are unplanned, prepartum counseling should not-- should start no later than the prescription of the first antiseizure drug to a child of-- to a woman of childbearing age. And so, often, at the first visit, we'll get very many women that say that they're really not thinking about getting pregnant anytime soon, but it's still the time that we need to approach the subject so that we're keeping an open conversation.

Real quick, I wanted a touch base on fertility. So there was a recent study that came out that surveyed 197 females. 89 of those females were women with epilepsy, and 108 were the control women. And it was shown that, in both groups, the rate of getting pregnant was about 60%. So just because you epilepsy does not mean that you have less fertility than the average population.

And this is just a slide looking a little bit more at that study.

So pregnancies exposed to antiseizure drugs in the first trimester increased risk for major congenital malformations. Major congenital malformations include structural abnormalities of surgical, functional, or cosmetic significance. And these structural abnormalities typically occur in the first 8 to 10 weeks of a pregnancy, which again highlights the need for all this preconception planning because, oftentime, when someone knows that they're pregnant, they could be well into their first trimester.

And there is data on the rates of major congenital malformations with the use of antiseizure medications. A lot of that data comes to our North American Pregnancy Registry, but there is variability due to all the follow-up periods and the means of assessment.

So it's really important to explain the risk of major congenital malformations to women with epilepsy. So the general population has about a 2% chance of having a kid with a major congenital malformation. And this differs, this rate of major congenital malformation differs between antiseizure medication. There are some medications that predispose you to higher risk of major congenital malformations, like valproic acid. And, also, the pattern of malformation risk appears to be different for different individuals, and we're not sure why.

For several of the antiseizure medications, the risk of major congenital malformations has been shown to be dose-related. So there was a study done in 2011, and it analyzed the data from EURAP epilepsy and the pregnancy registry, and it reported a direct correlation between antiseizure drug dose at the time of conception and the risk of major congenital malformations up to one year.

And it-- so it broke it down to these four medications, which included valproic acid, phenobarbital, carbamazepine, and Lamictal. And you can see, at lower doses, there is about a 2% to 5% chance, depending on what medication you were on, that you would have a kid with a major congenital malformation. But on higher doses, that could increase up to fourfold.

So, for instance, with valproic acid, if they were on less than 750 milligrams per day, there was about a 5% chance. But if they were greater than that, there was about a 24% chance, which is pretty high. And a lot of our epilepsy patients, if they are on valproic acid monotherapy, then they are on higher doses of that medication.

So if you're thinking about a medication to choose for a woman of childbearing age, whether they're thinking about getting pregnant in the immediate future or not, it would be nice to pick a safer medication.

And then in Lancet Neurology, they included more medications, or antiseizure medications, and this was published in April 2018. And so, now, you see the addition of levetiracetam, oxcarbazepine, topiramate, phenytoin. And so, in this study, it showed about a 3% to 10% chance, based on the medication that you were taking, of an increase in major congenital malformation.

With this study, though, they didn't divided out by dose-related medication. So if you were on any dose of a certain medication, then you were included in the study. And so it doesn't really touch on whether you're on higher doses of medication. Does that make you more predisposed to a major congenital malformation?

And then, Vimpat, which is a relatively newer medication, we do see that some of our patients are on monotherapy just with that. So far, in the NAEED registry, 23 women have reported Vimpat monotherapy, and no malformations were identified in these women. Of course, that's a very small sample size.

There have been some case reports of congenital malformation. The biggest one was one with seven pregnancies with exposure to Vimpat, and three of those pregnancies had minor congenital malformations, but they were also on polytherapy with other medications. It's very difficult to say how much of that was Vimpat and how much of that was a different medication.

It's unknown if serum concentration instead of a dose is a stronger prediction for congenital malformation. But in any case, when you are treating a women with epilepsy, you want to try to find the lowest therapeutic dose that can make them seizure-free, but also would have the least effect on their fetus during their pregnancy.

So when you're thinking about polytherapy versus monotherapy, for many years, it was felt that the fetal risk from prenatal exposure to two more antiseizure medications was significantly greater than the risk from exposure to one anticonvulsant. So the first article is actually published in Epilepsia in 1980. It was a pretty large sample size. It was 657 women. They were taking three or more antiseizure medications. And, in that study, it was shown that these women had fetuses that had more major congenital malformations.

But then, in 2011, and newer study came out in JAMA Neurology, and they used the North American Anti-epileptic Drug Registry, and it actually showed the prior data was mostly driven by valproic acid. And so, in general, this patient population tended to have a higher risk of major congenital malformations because they were taking valproic acid.

And so they studied women that were taking other combinations of, maybe, safer antiseizure medications during pregnancy, and it was reported that poly therapy with these medications was similar to monotherapy. And so it was really felt that valproic acid was the limiting factor in the earlier studies.

Regarding cognitive teratogenesis, initially, studies were done on cognitive development and antiseizure drug exposure. These were retrospective studies or case reviews, and they did not really control for the maternal IQ. And the maternal IQ is very critical in estimating a child's IQ.

So then, in 2013 and 2014, two important studies came out. This was the NEAD study and a study from LMNG, and this accounted for the maternal IQ in addition to other important variables. So the NEAD study and the LMNG study were both prospective studies. They recruited mothers antenatally. They followed the children for about six years. The NEAD study did not have a control group, and they included 307 women. The LMNG study recruited 243 women with epilepsy, and they compared it to a control group of 287 women without epilepsy.

In both studies exposure to valproic acid was associated with a decrease in IQ by approximately 10 points. So if someone was exposed to valproic acid, there was definitely a decrease in IQ. But in the NEAD study, IQs at age six were similar between children exposed to Lamictal, Dilantin, or carbamazepine. And then there were similar findings in the LMNG study.

So in terms of cognitive teratogenesis, we don't feel that there is a real difference between kids that are exposed to antiseizure medications and kids that are not exposed to antiseizure medications. The limiting factor, again, would be to valproic acid. In the LMNG study, though, they did see that children that were exposed to carbamazepine did have decreased verbal abilities.

And one theory behind it is that several antiseizure medications have been shown to induce apoptosis in the brains of rats, and this could be one mechanism by which antiseizure drugs induce cognitive changes. So that's specifically with, like, phenobarbital, phenytoin, and valproic acid. And it did also show that a few antiseizure medications do not produce apoptosis when given alone. So that's carbamazepine, lamotrigine, topiramate.

In these studies, it also showed that levetiracetam did not produce apoptosis when given alone, and it did not enhance apoptosis when given with another antiseizure medication.

Valproic acid has also been associated with adverse effects on behavioral development. So there was a study that came out in 2013, and it included fetuses that were exposed to valproic acid. And it showed that they had about a 4.4% chance of developing autism, and that's compared to the general population, which is about a 1.5% chance.

Studies have shown that women with epilepsy are not at an increased risk for miscarriages, so that's really important to talk to your parents about-- or patients about. Women with epilepsy may be at an increased risk for obstetric complications, so gestational hypertension, preeclampsia, postpartum hemorrhage. And, again, as we kind of discussed in the beginning, patients with epilepsy do often have preterm births, intrauterine growth restriction, small-for-gestational-age infants.

And C-sections may also be more common in epilepsy. So although having epilepsy is not an indication to have a C-section, there is more of a predisposition to have a C-section. And we're not really sure why that is.

Antiseizure drug adjustments during pregnancy are an important part of caring for our patients with epilepsy, and they're really driven by antiseizure drug levels. So antiseizure drug levels should be checked monthly for most medications, but especially those with-- those that are taking Lamictal, Keppra, and oxcarbazepine. So it's really ideal to obtain lots of baseline levels for women that are of childbearing age because that's going to be our baseline level for when they're pregnant, and then we're always going to target that same level.

So, typically, I have a baseline level when I see a patient. Once they get pregnant, I get levels right away. And then around the same time every month, I asked them to get levels around the same time. And I compare those levels to the initial levels, and then I adjust medication based on those levels.

And then it's also important to note that when we're increasing medications during their pregnancy, when they're in their postpartum period, the metabolism of their antiseizure medication goes back down to their baseline. So they're very susceptible to getting toxic on some medications. So Lamictal, or lamotrigine, is one of the medications, I think, that people feel the most toxic on in the postpartum period.

And so to avoid toxicity, we need to be giving our patients a plan before delivery so that they know that right after delivery that their medications are going to be decreased back to their baseline, or a little above their baseline, so that they won't have the toxicity effects of Lamictal or other medications that you might increase during their pregnancy. And so, typically, that happens about four weeks before they're about to deliver. You want to bring them in and go through a postpartum care plan.

Some people are left on high-- slightly higher doses than their original baseline dose for the first one to three months postpartum. And this is really just to protect them from the effects of sleep deprivation and stress and things that can lower their seizure threshold in general.

Most women with epilepsy actually don't experience a change in frequency during pregnancy. So about 80% of women that have a certain seizure frequency before pregnancy, that will be their seizure frequency during pregnancy. 10% of women will tend to get better, and those are typically women that have generalized epilepsy. And 10% of women could potentially get worse.

And seizure stability prior to pregnancy is actually one of the strongest predictors of seizure control during pregnancy. So 90% of women who are seizure-free about nine months during they're pregnant will have about a 90% chance of being seizure-free during their pregnancy. So it's a really strong predictor if you're seizure-free right before you get pregnant.

Again, patients with generalized epilepsy seem to have less of a risk of seizures during pregnancy than those that have focal seizures. And just as we talked about a minute ago, there is an increased risk of seizures in the postpartum period, likely due to sleep deprivation and stress. And so that's just something that we need to be talking to our patients about.

So folic acid, you know, the dosing on folic acid is a little bit controversial. I think everyone does it a little bit different. In 2009, a study was published in Neurology with a focus on folic acid. It reviewed many articles. And essentially, from the study, AAN put out recommendations that said that women that are pregnant and with epilepsy need to be on at least 400 micrograms of folic acid. But there was really insufficient data to say that if you were on more folic acid than that, there was a benefit, and there wasn't really much data to say that there was not a benefit.

There was one study that said that if you were on more than 5 milligrams of folic acid, you could have a baby that had some psychomotor developmental delay. And so anything above 400 micrograms, but less than 5 milligrams, is probably a safe zone to be in.

Initially, vitamin K supplementation was recommended in the third trimester if you were taking an enzyme-inducing antiseizure medication-- so those are like oxcarbazepine, carbamazepine, phenytoin, and phenobarbital-- because there was a concern for an increased risk of neonatal hemorrhage associated with these enzyme-inducing antiseizure medications. But, in 2009, an article was published in Neurology. It reviewed 10 articles on this topic, and the current AAN guidelines conclude that there was insufficient evidence to recommend for or against the practice of vitamin K supplementation in the third trimester.

Breastfeeding is also an important topic to talk about while you're counseling your patients while they're pregnant. So the benefits of breastfeeding have been well-established for women and their infants. There is both benefits to the infant, to the mom, and it promotes mother-infant bonding.

A study published in 2013 in JAMA Neurology showed that children exposed to specific antiseizure drugs in breast milk had higher IQs and language scores at six years of age when compared to those children whose mothers were taking antiseizure medications and did not breastfeed. And they specifically looked at patients that were on carbamazepine, lamotrigine, phenytoin, and valproic acid.

And so, in that sense, if the mother wants to do it, it should be promoted, and there is definite benefits for both the mom and the infant. And there are actually no adverse effects that were found on developmental outcomes related to breast milk exposures on these specific studied medications.

The recommendations for breastfeeding with barbiturates and benzodiazepines need to be evaluated a little bit more carefully, just because these medications have had reports of increased sedation and weight loss in the child.

And, lastly, we really want to talk about postpartum safety to our patients. So it's really important to go over seizure safety with our patients and their families. And while we just talked about how breastfeeding was supported, sleep deprivation that can occur when you're trying to feed your baby every two to four hours can lower seizure threshold.

So what I really recommend is the woman trying to get one bigger chunk of sleep per night, so whether that means pumping in the night and having her husband or a family member feed the baby versus changing around the breastfeeding schedule, just to get a solid amount of sleep through the night, could actually make their seizure frequency better.

Again, it's not-- it is important to not have the infant sleep in bed with the parents. And that's in general. You know, those are the recommendations.

And, lastly, women with epilepsy are at an increased risk for postpartum depression. And so, you know, before they do deliver, it's important to touch base on that topic to make sure that there's open lines of communication, that they're either reaching out to you or their OB-GYN if they do feel that they are significantly more depressed after they deliver.

And, you know, because there are a lot of special considerations for this patient population, here at Ohio State Wexner Medical Center, we did start a clinic in which we see specifically epilepsy patients that are pregnant. We've partnered up with the Maternal Fetal Medicine group. And so this just provides more frequent care, and we talk about all of these special considerations that we just went over in this lecture together.

All right, thank you.