Therapeutic Considerations of Antiseizure Medications-Pharmacology of Anti-Seizer Medications and Contraception: What Every Neurologist Needs to Know

Video Transcription

So I'm not going to be speaking. We're going to shift gears to talk about the reproductive considerations amongst persons with epilepsy. My discussion will be on pharmacology  of anti-seizure medications and contraception. This issue with the limited access to abortion, so to speak, it really highlights the importance of contraception, family planning,  and for us as providers, understanding the interactions. Again, these are my disclosures. So our objectives today will be to appreciate the importance of effective contraception,  as well as, I said, understand the interactions. We'll be talking about the importance of the planned pregnancies, contraceptive use. What kinds of contraception are the patients  that we treat using? Are there barriers? Anne already alluded to that. It was some qualitative research in her talk. Commonly prescribed, it's important for us  to understand what types of anti-seizure medications are the people we treat using. And then again, ending by talking about the interactions with hormonal contraception,  as well as intrauterine devices, of which we have some data. So planned pregnancies have better maternal and fetal outcomes. Controlling generalized tonic-clonic seizures  reduces the risk of miscarriage, preterm labor, as well as adverse cognitive outcomes that have been shown in some retrospective studies. Avoiding teratogens, such as viproic acid,  is also important for optimizing those outcomes. And that will be discussed in more detail by our next speaker. Folic acid supplementation pre-pregnancy  can reduce some risks as well. But how do we do this? We do this with effective contraception and family planning. It's very important for the individuals we treat.  There are different methods of contraception. The effectiveness depends on the method itself, as well as on whether the individual is an average user  or a correct and consistent user. The most effective methods include implant, sterilization for women, vasectomy, IUD, and amongst the correct and consistent users,  you can add injectables, pills, and condoms.  So with that in mind, what types of contraception are the individuals we treat using? Anne and I did a study a number of years ago, published in 2008.  It was a cross-sectional study of 148 individuals. 53% of those were at risk of unplanned pregnancies, used methods with typical failure rates of less than 10%.  Sterilization and hormonal contraception amongst those effective methods was the most common. And the use of long-acting reversible contraception,  or LARC, which includes implants or intrauterine devices, was rare. 50% of the reported pregnancies of over 180 pregnancies were unplanned.  This was more common in pro-Hispanic individuals when compared to Caucasians of higher socioeconomic status.  Similar findings have been described by Andy Herzog in the Epilepsy Birth Control Registry. This is a web-based survey, an educational site.  In that survey, at the point of this publication, 796 individuals at risk of unplanned pregnancy were included. Over 30% did not, about 30% did not  use methods considered to be highly effective. Predictors for effective contraceptive use included insurance, race, ethnicity, and age.  And in this cohort, 65% had unintended pregnancies.  The findings from our study, as well as the Birth Control Registry, are supported by data from a nationwide health care claims database.  In this study, there are over 2,800 individuals between age 15 and 44 identified by epilepsy ICD-9 codes. Female sterilization was seen in 2%. Long-acting reversible contraception,  that is implant and IUDs, in 4%. And in this group, 31%, this includes hormonal contraception as well as pills and patches.  Alarmingly, 63% used other, such as condoms or withdrawal, or no method of contraception. This is the highest that was reported amongst all the medical conditions  that were looked at, 21 medical conditions. Epilepsy was higher than any of those other medical conditions. And the other, or none method used, was 61% higher when compared to those  with no medical condition. So these studies tell us that the individuals we treat are not using effective contraception, had higher percentages when compared to individuals  with other medical conditions, or no medical condition. And we have more than 50% reported of unintended pregnancy. Clearly, we are not doing a very,  these individuals are not getting the care they need, or they're not getting access, for whatever reason, to effective contraception, or they're choosing not to do that.  So why is that? Why is that the case?  Well, there are barriers.  The most common form of contraception in the United States, including amongst individuals with epilepsy, is actually hormonal contraception. And very few healthcare professionals  understand the interactions between anti-seizure medications and contraceptive steroids. Individuals with epilepsy are confused, and alluded to that already.  The neurologist tells me one thing, the gynecologist tells me another, and they don't get it. The gynecologist tells me another, and they don't communicate with each other.  Qualitative study report that individuals of childbearing potential reported that neurologists lacked the necessary expertise in contraception,  and OBGYNs lacked adequate knowledge about epilepsy. From this same study, when the individual raised questions about contraception with either the neurologist or the OBGYN,  no one referred to the other provider. Quite alarming.  Another study finds that individuals with epilepsy of childbearing potential are not actually consulting their neurologist. Of over 1,100 individuals,  amongst those, about 87% had a neurologist. Only 25% consulted their neurologist. So clearly, there are barriers.  So now I wanna shift, because the main focus about the barriers, or why that is, is confusion. Confusion on the patient's end, confusion on the practitioner's end.  People don't understand what it is. I'm sure any of you in the audience have seen an individual where they were told, they were on a certain anti-seizure medication,  and told, you cannot go on contraception. So we're not gonna put you on anything because we think there's an interaction, and we're gonna stay away from that.  So what we're gonna do now is segue into trying understanding the interactions. It's very important for us, at this point, to understand what are the most commonly  prescribed anti-seizure medications amongst individuals with epilepsy of childbearing potential. This data comes from the birth control registry,  from the URAP study, MONID, and WEPOD. This slide looks very different than a slide I would have had up here 20 years ago. The most commonly prescribed medications  are lamotrigine and levotiracetam, and you see that across all of the studies. It's important to understand this so that when you're thinking about the individuals  you treat, what medications they're on, and as we discuss in the upcoming slides, what the interactions are.  Cytochrome P450 enzyme-inducing medications have an effect, as many of us know, on hormonal contraception. It's important to understand that. And keep in mind, this is particularly,  this is the CYP3A4, CYP3A4 isoenzyme.  Enzyme-inducing medications enhance the metabolism of steroids. Contraceptive failure is potential.  I've certainly, as I'm sure many of you in the audience, have had individuals treated with these medications who did have contraceptive failure and got pregnant.  As such, you have an increased unintended pregnancy risk. The combined oral contraceptive medication, as I mentioned earlier, the most commonly used form  of hormonal contraception, is the most studied in this arena, and these, when taking a cytochrome P450 enzyme-inducing medication, you have increased estrogen  as well as progesterone metabolism. What about progestone-only OCPs? They have shortened half-life when taken concomitantly with enzyme-inducing medications,  and they're really not a good choice at all. The progesterone in these pills is very low, and so the failure rate is definitely, you are clearly putting that woman at risk,  that individual at risk, if they're taking an enzyme-inducing medication. Now, the patch and ring avoids first past metabolism interactions,  but honestly, we don't really have a lot of data on what they do when taken in combination  with cytochrome P450 enzyme-inducing medications. There are progesterone implants, and there is a potential for failure. Reports in the literature of failure with Norplant  when taken with phenytoin, and Implanon when taken with carbamazepine.  Depo-medroxyprogesterone acetate is the most likely method to retain effectiveness, and no pharmacodynamic evidence is available.  This is data from a study that Anne did at Columbia, published in 2011 in Epilepsia. She took 10 healthy people of child-bearing potential. They were on carbamazepine or placebo,  and throughout the study, they took lower-dose oral contraceptive medication. The ethinoestradiol and levonorgestrel levels substantially decreased with carbamazepine treatment.  They were more likely to have breakthrough bleeding,  which is a marker of contraceptive failure, as well as ovulation. This study, a very nice, well-designed, albeit small study, clearly demonstrates  that carbamazepine, when taken with low-dose hormonal contraception, increases the failure of that contraceptive agent.  This is a list of cytochrome P450 enzyme-inducing medications. They're not all those medications that were here 20 years ago.  On this list is synebomate, clobazem, and eszacarbazepine, so it is important with all the new agents that may be coming available to understand whether they do have an interaction  in the CYP enzyme system, and whether there is a potential effect on contraception.  Lamotrigine, this is where the story gets a little stickier, all right? So there's lamotrigine, and the case, the situation with lamotrigine is very well  demonstrated by a patient of mine in this case. 26-year-old individual of childbearing potential had seizures well-controlled on lamotrigine. She became sexually active.  She spoke to her neurologist. She was concerned, and the neurologist chose to put her on a combined hormonal contraceptive pill. She had a tonic-clonic seizure.  She fell and broke her jaw. What happened in this individual? Well, lamotrigine is eliminated by conjugation with glucuronic acid.  Reaction is catalyzed by the UDP-glucotransferases. Estrogens are metabolized by glucuronidation. So in this individual, without checking  and without any concomitant increase in lamotrigine, her concentration, lamotrigine concentration decreased, putting her at risk, and in this case, she did actually have a seizure.  Importantly, lamotrigine levels do not change when taken in combination with progesterone-only agents. Valproic acid, similarly, has a metabolic pathway via glucuronidation.  Study finds that the estrogen may decrease valproic acid by over 20%.  Tapyramide has an interesting story. It was often lumped with the enzyme inducers, but it's actually got variable effects on estrogen as well as on progesterone.  One study showed it decreased ethanol estradiol by 18% to 30%. And another study did find some minor changes in estradiol. And in neither of those studies was there  an effect on progesterone. So it's highly likely that it's not an effect on progesterone. So it's highly unlikely that a selective reduction in ethanol estradiol would decrease  contraceptive effectiveness without a decrease in progesterone levels.  These next two slides are busy. And they're really out here to summarize when you look at the effects of anti-seizure medications  when taken with a combined oral contraceptive agent, as discussed, lamotrigine. And as you'll see on the next slide, valproic acid. Estrogens and progestins are decreased  by carbamazepine, cenebamate, clobazam, eslacarbazepine, and felbamate, as well as oxacarbazepine, phenobarbital, phenytoin, rifinamide.  And as discussed, there is a selective decrease in estrogen by tapyramide, but not on progesterone, whereas parampamil decreases progestin and not estrogen.  Keep in mind, this is something Anne taught me years ago, that progesterone is the main contraceptive component of the pill. What about IUDs? Well, IUDs are increasingly being used,  although that is not demonstrated in the studies we discussed earlier. The copper IUD, there's no interaction with anti-seizure medications. Anne and I asked the question years ago,  well, what about hormonal IUDs? So we did a study of 20 individuals with well-controlled epilepsy who initiated a progestin-containing IUD, levonorgestrel,  52 milligrams, that was Norplant. And it was a prospective observational study. We followed seizure diaries, whereby seizures were not changed.  We followed anti-seizure medication trough concentrations, and they remained stable. All participants were either somewhat or very satisfied.  And all participants continued the IUD use at six months. So IUDs are actually a very good option as effective contraception for the individuals we treat.  So overall, the impact of what we discussed on clinical care and practice is that planned pregnancies have better maternal and fetal outcomes  in individuals with epilepsy of childbearing potential. Effective contraception is an important and integral part of optimizing those pregnancy outcomes.  There are potential, as we've discussed, bidirectional interactions. We went through how cytochrome P450 enzyme-inducing medications lowers the efficacy of hormonal contraception.  Estrogen-containing hormonal contraception lowers lamotrigine, and to a lesser extent, valproic acid concentrations. And as discussed, IUDs are considered  a safe and effective form of contraception.

Video Summary

The presentation focuses on reproductive considerations for individuals with epilepsy, particularly the pharmacological interactions between anti-seizure medications and contraceptives. It emphasizes the critical role of effective contraception and family planning, given the limited access to abortion. Unplanned pregnancies often lead to poorer maternal and fetal outcomes, which can be mitigated by controlling seizures and avoiding teratogens like valproic acid. The discussion highlights common contraceptive methods used by those with epilepsy, noting that while hormonal contraception is prevalent, there is confusion due to potential interactions with anti-seizure medications. Many healthcare providers lack knowledge about these interactions, leading to ineffective contraceptive use. The presentation reviews studies showing high rates of unintended pregnancies among individuals with epilepsy, partly due to these interactions and a lack of clear guidance from neurologists and OBGYNs. It concludes by advocating for better understanding and communication among healthcare providers to improve contraceptive efficacy for individuals with epilepsy.

Asset Subtitle

Presenter:

Allison Pack, MD, MPH, FAES, is a Professor of Neurology and Epilepsy Division Chief at Columbia University Irving Medical Center / New York Presbyterian Hospital. She has written numerous original publications as well as reviews on topics pertaining to women with epilepsy as well as endocrine issues in epilepsy. She is the Chair of the Professional Advisory Board of National Epilepsy Foundation and serves on the AAN Guidelines Subcommittee. Between 2015-2019 she was chairperson of the AAN Neuroendocrinology section. In 2012, she received the AAN Neuroendocrine Research Award. Between 2002 and 2017 she was the co-director of the EEG/Neurophysiology fellowship program at the Columbia Comprehensive Epilepsy Center and between 2017 and 2020 was the director of the Columbia Epilepsy ACMGE fellowship.

Keywords

epilepsy

anti-seizure medications

contraceptive interactions

unplanned pregnancies

healthcare communication