The use of anticonvulsant drugs during pregnancy may be associated with an increased risk of birth defects and, possibly, effects on the IQ and behavior of the child. Balancing these risks against the possible consequences to the fetus of maternal seizures is often faced by neurologists in clinical practice.
What if you are referred a woman with newly diagnosed partial epilepsy, not yet started on medication, who tells you that she plans to start a family in the next few months? We asked two experts for their opinions: Page Pennell, MD, from Emory University and Andre Lagrange, MD, PhD, from Vanderbilt University.
COMMENTS OF EXPERTS
Page Pennell, MD, is Director of The Emory Epilepsy Program and Associate Professor, Department of Neurology, Emory University School. She completed her medical school and Internal Medicine Internship at the University of Florida Health Sciences Center and her Neurology Residency and epilepsy/clinical neurophysiology fellowship at the University of Michigan Medical Center, Ann Arbor. Dr. Pennell holds professional memberships with numerous organizations including the American Academy of Neurology, the American Epilepsy Society, and the American Clinical Neurophysiology Society. Dr. Pennell's area of particular interest and expertise is women's health and epilepsy. She is the recipient of numerous academic and professional honors, and has frequently been published in peer-reviewed journals.
Andre Lagrange, MD, PhD, is Assistant Professor of Neurology at Vanderbilt University. He studied Physiology/Pharmacology, Neuroscience at Oregon Health Sciences University, Portland, Oregon and attended the University of Michigan, Ann Arbor for both his residency in neurology and his fellowship in clinical neurphysiology. He holds board certifications with the American Board of Psychiatry and Neurology with an added qualification in neurophysiology, and the American Board of Clinical Neurophysiology. Currently a member of the Society for Neuroscience, the American Academy of Neurology and the American Epilepsy Society among others, he regularly contributes to peer-reviewed publications in addition to writing chapters for books, reviewing publications and writing abstracts in his area of expertise.
How do the available findings from pregnancy registries influence your decision?
Page Pennell: I use the information from pregnancy registries to identify which medications have enough data to provide us a reasonable idea about the differential risks of that particular AED compared to other AEDs. I consider whether the fetal risk for that particular AED is clearly higher than other medication choices. Given the findings in several registries, I now avoid the use of valproic acid in women of childbearing age, unless they have failed other treatment options or have an extremely low chance of becoming pregnant (sexually inactive, have an IUD, or have had tubal ligation or hysterectomy). In addition to a higher risk for birth defects, valproic acid has also been shown to carry a higher risk for neurodevelopmental delays in the children exposed to valproic acid in utero. I try to choose a medication for which we have substantial information that its risk is not particularly high compared to other medication choices.
Andre Lagrange: With more than 10,000 patients enrolled from nearly 50 countries, the ongoing pregnancy registries have provided invaluable information for the treatment of women with epilepsy.
The first question I would ask is whether this patient needs an antiepileptic medication (AED). This can be a complex decision, which may be further compounded by the reproductive repercussions of these medications. While the pregnancy registries have confirmed the teratogenic potential of the older AEDs, we now have a better understanding of the magnitude of those risks, thereby allowing us to make more well-informed choices in considering the risk-to-benefit ratio of instituting AEDs. Moreover, if medical treatment is instituted, we now also have a better sense for which AEDs are relatively safe in pregnancy.
Prospective parents are often worried that epilepsy will hamper their ability to raise a healthy baby. Thanks to the pregnancy registries, we can now allay some of those fears by telling the parents that having epilepsy per se does not seem to increase the risk of birth defects over the general population.
These studies have also helped improve the care of pregnant women. While most women have no change in their seizure frequency during pregnancy, approximately 20% have increased seizure frequency, especially if they are taking one of the newer AEDs. The registries have helped cast a spotlight on the effects of hormones on AED pharmacokinetics. Armed with this information, we can use frequent blood levels and appropriate dose adjustments to help minimize seizures in our patients during their pregnancies.
Do you discuss all of the available medications with the patient that are appropriate for her seizure type?
Page Pennell: Yes, but part of that discussion is based upon what information we have on specific risks during pregnancy. However, there must also be a decision regarding the need for medication. Most women with epilepsy will need medication during pregnancy, but there will be a small minority of women who can forego starting medication or taper existing medication prior to conception. Since you posed the question – as to “treating a woman with newly diagnosed partial epilepsy, not yet started on medication” – I would presume that she has had a recent seizure. If her seizures have been very rare, isolated events, or if they are only simple partial seizures, then there may be an opportunity to hold off on starting medication. Although the risk for birth defects is only in the first trimester, we also consider medication exposure throughout the entire pregnancy and particularly the third trimester for possible neurodevelopmental consequences.
Andre Lagrange: With the number of AEDs currently available, it is not practical to discuss every type of medication. I usually mention valproate as a particularly problematic AED. I also mention that the older AEDs, while much less expensive, do pose a small risk to the infant. However, I tend to focus on the newer AEDs that seem to be safer in pregnancy.
Among the newer medications, lamotrigine and oxcarbazepine seem to have the lowest risk of birth defects. However, the discussion should be tempered by some of the possible problems associated with these medications. For example, in patients with some forms of idiopathic generalized epilepsy, lamotrigine may not be as effective as valproate and I generally avoid oxcarbazepine altogether. Secondly, while these drugs may be safer for the developing baby, increased metabolism can lead to subtherapeutic blood levels that put the patient at increased risk for breakthrough seizures.
In fact, there is some concern that the apparent safety of lamotrigine and oxcarbazepine in pregnancy may actually be due to subtherapeutic drug levels during pregnancy; an idea that was supported by recent data from the UK registry that showed an increased fetal risk in pregnant women with epilepsy taking > 200 mg per day of lamotrigine monotherapy. However, the other registries have not replicated that finding.
How do you discuss the risks and benefits of AEDs with the patient?
Page Pennell: With all available medications, we need to look at seizure types. Although we can not perform randomized trials of women treated with AEDs versus women not treated and allowed to have seizures during pregnancy, there is general consensus that generalized tonic-clonic seizures should be avoided to the best extent possible. I have concerns about convulsive seizures during pregnancy because of maternal and fetal hypoxia and risk of trauma with the fall. Although rare, I do discuss the possibility of fetal death. Another consideration is the risk for status epilepticus in some patients.
For women who have any type of seizure that impairs awareness, there are additional risks of accidents including motor vehicle accidents, blunt trauma, and drowning. I discuss tub baths in particular, as pregnancy and postpartum is often a time that women will take baths. This will affect many aspects of their daily lives including the ability to drive. They may rely on driving for work or for caring for other children. Although there are risks of AEDs, using them will often outweigh the risk of continued seizures, which can negatively impact maternal medical and social well-being.
Andre Lagrange: The decision of whether to institute AED therapy entails a frank discussion weighing the risks of medication against the potential adverse outcomes of not treating the patient. It is important to remind patients that convulsions can result in premature labor, as well as trauma to the mother and baby. Furthermore, complex partial seizures can lead to self-injury and even partial seizures may be associated with autonomic changes that alter uterine blood flow.
Most patients have already heard of the potential teratogenicity of AEDs. It helps to put things into perspective by telling patients that the absolute risk of birth defects in the general population is as high as 2-4%. The older AEDs, especially valproate, may increase this risk to about 5-15%. However, even with valproate, women with epilepsy have an 85-90% chance of having a perfectly normal baby. Lamotrigine and oxcarbazepine do not consistently raise the risk of birth defects.
What AED would you prescribe and why?
Page Pennell: Since we are discussing partial epilepsy in this case, we have information that the relative risk is fairly low with lamotrigine and carbamazepine. Carbamazepine is the only AED that has evidence for a statistically significant lower risk than valproic acid for both birth defects and for neurodevelopmental consequences.
And we are quickly gathering information on levetiracetam and oxcarbazepine – but we do not have the number of monotherapy cases reported in the literature yet to have a clear idea of the level of risk for each of these medications. I believe that we will have this information in the near future. Other newer medications have even less information from prospective studies, and thus I do not use them as first-line treatment in a woman who states that she is planning a pregnancy in the near future, or in a woman who is at high risk of unplanned pregnancy, perhaps due to inconsistent use of birth control. The newer medications that lack adequate information at this time include topiramate, zonisamide, tiagabine, and pregabalin.
If pregnancy is very unlikely to occur in the next three years, then I will more readily consider these medications and counsel the patient about the need for planned pregnancy and with repeat preconception counseling in the future. It is likely we will have information on these other medications before she actively pursues conception.
Andre Lagrange: The older AEDs increase the risk of major malformations two-fold to three-fold, while the risk is even higher with valproate. In contrast, among the newer AEDs, lamotrigine and oxcarbazepine do not seem to increase the risk of birth defects. Preliminary data from the UK registry suggests that levetiracetam may be safe as well, but the jury is still out. I tend toward recommending lamotrigine and oxcarbazepine, although it is important to discuss the fact that frequent blood tests will probably need to be drawn and there may be small increased risk of breakthrough seizures during pregnancy.
Since our hypothetical patient has partial seizures, I would tend to favor oxcarbazepine because of the rapid titration. In women with idiopathic generalized epilepsy (IGE), I use lamotrigine with the explanation that this drug may be less effective for myoclonic seizures.
Valproate is the AED with the strongest association with birth defects and impaired childhood cognitive development, so I generally avoid this drug in women who may become pregnant. This is not to say that valproate should never be used in women with epilepsy. With our hypothetical patient who has partial seizures, the recently published SANDAT trial and years of experience with valproate indicates that this drug can be very effective in patients with IGE; it is possibly the most effective drug available.
While somewhat safer, the other older AEDs (phenytoin, carbamazepine, and phenobarbital) also have an increased risk of birth defects, along with the same problems affecting all patients with epilepsy, such as drug interactions and long-term side effects. I generally avoid starting patients on these medications, unless these are all that the patient can afford. When patients are on these drugs, it is important to aim for monotherapy, since polytherapy can greatly increase the risk of congenital malformation.
How do you select the daily dose?
Page Pennell: I use two principles. One is that we want to use the lowest dose that will control seizures. We don’t have clear evidence-based information for all medications, but we do have information about a dose-related risk for valproate and possibly for lamotrigine. I still apply this principle to all medications used during pregnancy.
The other principle is to avoid high peak levels of the medication. I use an extended formulation of the medication when available, and I try to spread out the doses, when possible, into 2 or 3 times per day depending upon the medication.
Andre Lagrange: The dose-dependent teratogenicity of valproate has been well-documented in a number of studies and the risk to the fetus may be reduced by using lower doses (< 1100-1500 mg per day). One registry suggested that high doses of lamotrigine may also increase the risk of malformations. While this association has not be found by the other registries, it is still probably prudent to use the lowest effective dose when prescribing AEDs to women with epilepsy.
While determining the dose is based mostly on seizure control, this is one situation in which I rely more heavily on blood levels. Since levels can decline during pregnancy, I generally aim for blood levels in the low therapeutic range and then adjust the dose during the pregnancy to maintain this level.
How do you monitor for seizures and medication dosages through the course of the pregnancy?
Page Pennell: I perform monthly measurements of the AED level and make changes according to that particular woman’s individual target concentration. In a recent study we did see a substantial difference when we took a therapeutic drug monitoring approach to the use of lamotrigine, with only a small portion of women experiencing seizure worsening in comparison to previous studies of seizure frequency in women on lamotrigine. Although a lot has been written about lamotrigine recently, it is important to remember that almost all AEDs decrease in concentration during pregnancy and often in an unpredictable way for each patient.
The individual target concentration for any AED varies between patients according to seizure type, epilepsy syndrome and other personal factors. I try to establish this prior to conception and make sure they have a measurement within the year prior to conception. I then try to maintain that concentration during pregnancy. I think the bigger disservice we can do to our patients, once they decide to use AEDs during their pregnancy, is to inadequately treat their epilepsy, and cause fetal exposure to both antiepileptic drugs and maternal seizures.
Andre Lagrange: If the patient was seizure-free prior to pregnancy, I aim to keep drug concentrations around the pre-pregnancy level. Since pregnancy may alter the volume of distribution and protein binding of some drugs, it is best to follow free levels, when available. Given the variability among laboratories, using the same one throughout the pregnancy is probably a good idea. Depending on the patient, I generally check levels every four to six weeks in patients taking lamotrigine, oxcarbazepine or levetiracetam. For other AEDs, an interval of every 2-3 months is probably sufficient.
In addition to medication therapy is there something else that you would recommend before and during the pregnancy?
Page Pennell: I do recommend the benefits of folic acid as a way to mitigate the possibility of neural tube defects, oral clefts, and possibly other birth defects. Although the benefits of folic acid in women with epilepsy are not clear, the benefits in both the general population and in other groups at high risk are clearly proven. I recommend one milligram of folic acid daily and sometimes will increase the daily folate dose to 4 milligrams, especially if the woman in on carbamazepine or valproate. I also reinforce that they take a prenatal vitamin prior to and during pregnancy, as various theories relate insufficient vitamin intake to AED-induced teratogenicity. It is also important that we establish close contact with her obstetrician and recommend that she gets an ultrasound by a perinatologist at 18 to 22 weeks gestational age.
Andre Lagrange: Folate has clearly been shown to reduce the risk of neural tube defects in the general population. Neural tube defects are one of the more common birth defects in women taking valproate or carbamazepine. Furthermore, AEDs can negatively impact folate metabolism. Given the low cost and risk of folate supplementation, it is reasonable to add 2-5 mg folate to the regimen of women taking AEDs. Having said that, the optimum folate dose is unknown and none of the registries have shown that folate supplementation actually reduces the risk of birth defects in children of women taking AEDs during pregnancy.
Hemorrhagic disease of the newborn is a potentially neurologically devastating condition in which previously normal neonates suffer spontaneous intracerebral hemorrhages. The risk of this condition is increased in the children of mothers taking enzyme-inducing AEDs, especially phenytoin. The increased risk is thought to involve AED-induced changes in Vitamin K metabolism, and the American Academy of Neurology recommends supplementing 10 mg daily of Vitamin K in the last trimester of pregnancy in women taking phenytoin. However, as with folate in pregnancy, there is no study that actually shows that supplementation reduces the risk in these babies.
While most women with epilepsy have normal, vaginal deliveries, I recommend that my patients are followed by a high-risk pregnancy service. As part of their obstetric care, it is also recommended that these women undergo more rigorous prenatal testing. This testing should also be offered to women who would never consider terminating a pregnancy, in that identifying congenital anomalies will allow planning appropriate post-natal care, if any is needed.
Finally, many obstetricians are unfamiliar with the sudden changes in AED metabolism that occur after parturition. When a patient has substantially increased her dose of lamotrigine or oxcarbazepine during the pregnancy, I let both the patient and their physicians know that the dose should be decreased halfway back to their pre-pregnancy dose at the time of delivery. Depending on the patient, I usually titrate the AED back to the pre-pregnancy dose over the next two to three weeks, followed by checking blood levels.
What most concerns you when prescribing medication to a woman who has seizures and who also wishes to start a family?
Page Pennell: I am most concerned about the health of the mother and child. Although there are risks, we can do several things to reduce these risks to a level that is not much higher than the risks of any pregnancy. Guiding principles include use of monotherapy with an AED that has substantial safety information during pregnancy, avoidance of valproate in monotherapy or polytherapy, supplemental folic acid and a prenatal vitamin, and maintaining adequate AED dosages to prevent seizure worsening or at least convulsive seizures or status epilepticus. I provide both counseling at the visit and written materials to assure that the patient and her spouse or partner understand the latest information available, so she can actively participate in making an informed decision about use of AEDs during her pregnancy.
Andre Lagrange: I try to remind patients that the vast majority of women with epilepsy deliver perfectly normal infants and that all of this preceding discussion is simply helping her to further optimize her chances. For most women, adequately treating her epilepsy needs to be the primary goal. Unfortunately, it is all too common for a woman to discontinue her AED upon discovering that she is pregnant, in the mistaken belief that this will be good for her developing baby.
I try to remind each woman about the risks that subsequent seizures pose her and her baby. Furthermore, organogenesis is largely complete before women even are aware of the pregnancy. Since nearly 50% of all pregnancies in the U.S. are unplanned, it is important to have this discussion early. I generally bring it up during the first visit.