INTRODUCTION — Women with epilepsy were once counseled to avoid pregnancy, but epilepsy is no longer considered a contraindication to pregnancy. Over 90 percent of women with epilepsy will have good outcomes [1].
There are several important issues to be addressed by the care team when a woman with seizures becomes pregnant. Successful management of these pregnancies therefore ideally involves prepregnancy consultation and close collaboration between the obstetric and neurology providers as a multidisciplinary team.
This topic will discuss the management of epilepsy during pregnancy, delivery, and the postpartum period. The risks associated with epilepsy and the risks of antiseizure medication (ASM) treatment during pregnancy are discussed separately. (See "Risks associated with epilepsy during pregnancy and postpartum period".)
RISK CONSIDERATIONS — Historically, considerations of the effects of epilepsy on pregnancy have focused on the structural and neurodevelopmental teratogenic effects of antiseizure medications (ASMs). While these considerations are important, they overlook the risks associated with nonteratogenic outcomes of pregnancy. These issues are reviewed briefly here and discussed in greater detail elsewhere. (See "Risks associated with epilepsy during pregnancy and postpartum period".)
●What effect do maternal epilepsy and seizures have on the course of pregnancy? Women with epilepsy are at increased risk for a range of perinatal complications compared with the general population, including preeclampsia, premature delivery, hemorrhage, fetal growth restriction, stillbirth, and a dramatically increased risk of maternal mortality. Cesarean delivery is also more common among women with epilepsy. While observation of these risks has been consistent across multiple populations, the underlying reasons for these increases are not well understood. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Perinatal morbidity and mortality'.)
●What effect does pregnancy have on seizure risk? At least half of women with epilepsy will have no alteration of their seizure pattern during pregnancy, but some women experience seizure worsening compared with their baseline. Possible risk factors for increased seizures during pregnancy include baseline seizure frequency before pregnancy, underlying localization-related (focal) epilepsy, ASM polytherapy, patient adherence, and altered pharmacokinetics of ASMs during pregnancy. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of pregnancy on seizures'.)
●What effect do ASMs have on the fetus? Major congenital malformations are more common in fetuses exposed to ASMs in utero compared with offspring of untreated women with epilepsy and women without epilepsy. Across all studies, valproate carries the highest risk for major malformations. Phenytoin, phenobarbital, and topiramate have also been associated with relatively high baseline rates of major malformations. Many ASM polytherapy regimens also increase the risk. In utero exposure to some ASMs is associated with impaired cognitive and neurologic development. The spectrum of structural and neurodevelopmental teratogenic risks for different ASM monotherapies is depicted in the figure (figure 1). (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of ASMs on the fetus and neonate' and "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Neurodevelopmental risks of ASMs'.)
PRECONCEPTION MANAGEMENT — A broad overview of the management of women with epilepsy, beginning before conception, is provided in the table (table 1) [2].
Counseling — Counseling all women of childbearing age about potential future pregnancies is important because approximately one-half of pregnancies are unplanned and the risks of complications can be minimized by interventions before and early on in pregnancy [3]. In addition, many women with epilepsy report limited knowledge about key issues regarding pregnancy and childbirth [4]. Therefore, clinicians should discuss the importance of planning a pregnancy for women with epilepsy who are of childbearing potential at each visit [2]. Such counseling should include information about birth control, the potential of antiseizure medications (ASMs) to cause contraceptive failure, contraceptive efficacy considering the ASM prescribed, the risks of ASMs on pregnancy outcomes, possible changes needed to optimize the ASM regimen, and the importance of folic acid supplementation to prevent neural tube defects [5].
Additionally, as many states in the US have legalized the use of recreational marijuana, its use in pregnancy is increasing [6]. However, the American College of Obstetricians and Gynecologists warns against marijuana use during pregnancy or lactation [7]. Patients should be instructed not to use marijuana for seizure control or as an adjunctive treatment for seizure control during pregnancy. In particular, effects on the developing fetal brain are likely and have not yet been characterized.
Birth control — Ideally, pregnancies for women on ASMs should be planned. This allows the clinical team and the patient to choose the best treatment regimen for disease control that has an acceptably low structural and neurodevelopmental teratogenic risk profile. For women taking hormonal contraceptives, the use of enzyme-inducing ASMs is associated with an elevated risk of unplanned pregnancies [8]. Thus, for women on these ASMs, it is ideal to use one of the long-acting reversible contraceptives (LARC), such as an intrauterine device (IUD) or intramuscular depot medroxyprogesterone acetate (DMPA).
●Enzyme-inducing ASMs – The degree to which ASMs induce hepatic enzymes that accelerate the metabolism of hormonal contraceptive agents can be categorized as follows [9]:
•Strong inducers:
•Weak inducers:
•Non-inducers:
-Clonazepam
Hepatic enzyme induction accelerates metabolism and alters protein binding of exogenous estrogen and progesterone, which may decrease the efficacy of coadministered estrogen-progestin contraceptives and progestin-only contraceptives other than levonorgestrel-releasing IUDs, including progestin-only pills and progestin implants [10-12]. Lower levels of ethinyl estradiol have also been reported in volunteers taking vigabatrin, which is not an enzyme inducer [13]. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Drug interactions' and "Etonogestrel contraceptive implant", section on 'Drug interactions'.)
The clearest evidence of the effects of enzyme-inducing ASMs on hormonal contraceptives comes from studies of carbamazepine. One report demonstrated that carbamazepine decreased levels of contraceptive steroids, increased breakthrough bleeding, and permitted ovulation during use of a low-dose oral contraceptive [14]. Another study in women using a contraceptive implant demonstrated that carbamazepine lowered etonogestrel concentrations below the threshold of ovulatory suppression [12]. Conversely, one report demonstrated good safety and acceptability of use of a progestin intrauterine device in 20 women with epilepsy [15].
Contraceptive failure in women taking enzyme-inducing ASMs during use of hormonal pill, patch, or ring contraceptives as well as progestin implants has been described in multiple reports [10,14,16]. While contraceptive failure rates have not been estimated in large studies of women with epilepsy, one older small cohort study found that the expected failure rate of 0.7 per 100 person-years using oral contraceptives was increased to 3.1 per 100 person-years in women who were concomitantly taking enzyme-inducing ASMs [16]. Efficacy rates of various contraceptive options in the general population are reviewed separately. (See "Contraception: Counseling and selection", section on 'Discuss method characteristics'.)
A cross-sectional questionnaire study at an academic medical center showed that among women on an enzyme-inducing ASM, 65 percent were unaware of the decreased efficacy of oral contraceptives [17].
●Method of contraception – As noted above, ASMs that are strong enzyme inducers lower the efficacy of hormonal contraceptives (eg, oral contraceptive pills, vaginal ring, etonogestrel implant). Thus, for patients on these ASMs, we suggest choosing a long-acting reversible contraceptive (LARC) (ie, an intrauterine device or intramuscular depot medroxyprogesterone acetate). Alternatively, a higher-dose combined oral contraceptive pill may be effective if one of the LARC options is not used, although precise studies are lacking.
The World Health Organization (WHO) suggests that women taking enzyme-inducing ASMs, including lamotrigine, use a method of contraception other than combined hormonal pill, patch, ring, or injectable contraceptives, or a progestin-only pill. Recommendations from the United States Centers for Disease Control and Prevention (CDC) are generally similar. Copper or levonorgestrel IUDs are highly effective alternatives that carry no potential for drug-drug interactions, depending on the method [18-20]. In addition, the contraceptive efficacy of DMPA does not appear to be attenuated by the use of enzyme-inducing ASMs. More information can be found in the Centers for Disease Control and Prevention United States Medical Eligibility Criteria for Contraceptive Use and the World Health Organization Medical Eligibility Criteria for Contraceptive Use. (See "Contraception: Counseling and selection", section on 'Special populations' and "Intrauterine contraception: Candidates and device selection" and "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Beneficial effects on comorbid conditions'.)
While as yet unconfirmed in systematic studies, the increased failure rate with oral contraceptives may be ameliorated by increasing the dose and using extended cycle regimens with shorter pill-free intervals [10,18,21]. For women taking enzyme-inducing ASMs who have no alternative to oral contraceptives, clinicians often recommend a preparation with at least 50 mcg of the estrogen component [10,18]. It is expected that both the efficacy and the incidence of adverse effects associated with a higher dose of hormones used in conjunction with enzyme-inducing ASMs should be comparable with standard doses when not combined with ASMs [18]. However, this is unproven. (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Dosing regimens'.)
The efficacy of the "morning after pill" may be similarly affected by enzyme-inducing antiseizure drugs. Two doses of levonorgestrel 1.5 mg separated by 12 hours is recommended in these circumstances [18,22]. (See "Emergency contraception".)
In addition to the effect of ASMs on oral contraceptive metabolism, oral estrogen-progestin contraceptives can increase the metabolism of lamotrigine, thereby reducing the plasma drug concentration, typically by approximately 50 percent. Lamotrigine levels can rise significantly upon discontinuation of an oral contraceptive, even during the seven-day pill-free interval, and therefore continuous dosing may be preferred in this setting. Pregnancy has a similar effect on many other antiseizure drugs. (See 'Antiseizure medication monitoring and dose adjustment' below and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Lamotrigine'.)
Necessity for antiseizure medications — There are two issues that must be considered concerning the administration of ASMs in any woman with a seizure disorder who wants to become pregnant:
●Is the diagnosis of epilepsy well established? In some patients, routine electroencephalography (EEG) recordings or continuous video/EEG monitoring may be warranted to confirm the diagnosis. Psychogenic nonepileptic seizures (PNES) are commonly mistaken for epilepsy seizures. Other mimics include syncope and movement disorders. Re-evaluation of the diagnosis and treatments prescribed should occur prior to a planned pregnancy or early in all pregnancies if not performed recently, so that the clinicians know what they are treating and how to best balance the risk versus benefit of ASMs.
●Does the patient require ASMs, and, if so, is she on the most appropriate medication(s) and at the minimum dose to maintain seizure control? If a woman has been seizure free for a satisfactory period and she meets the general criteria for consideration of discontinuing medications, we suggest doing so at least 6 to 12 months prior to becoming pregnant, as the risk of seizure recurrence after withdrawal is highest during this period. (See "Overview of the management of epilepsy in adults", section on 'Discontinuing antiseizure medication therapy'.)
Choice of antiseizure medication — For women with epilepsy of childbearing age who are planning pregnancy, lamotrigine or levetiracetam monotherapy are preferred as first line treatment options because they have the most abundant and consistent data for low structural and neurodevelopmental teratogenic risk during pregnancy. However, the clinician should weigh many factors when choosing which ASM(s) to prescribe to provide the best balance between maternal seizure control and minimal side effects versus risks to the developing fetus. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of ASMs on the fetus and neonate'.)
Key considerations are prior medication failures (if any), epilepsy syndrome and seizure types, seizure severity, adverse effects, and comorbidities. Medication decision-making should be considered in this context and in partnership with the informed patient after counselling. Although it is especially difficult to change from an ASM regimen that is working, some women will choose to change medications to an ASM that has proven low fetal risks (figure 1) while others will choose to stay on their current regimen.
Valproate should be avoided in all situations, with the rare exception that it may be used as a last resort when other ASMs have been tried and have failed to provide adequate control of seizures [23,24]. If valproate is used, it should be prescribed at the lowest effective dose. If possible, aim for doses of 500 to 600 mg/day [23] and for lower plasma levels (<70 mcg/mL) unless absolutely necessary to control seizures [25]. There are abundant, consistent data verifying that valproate carries a substantially increased risk for major congenital malformations, adverse neurodevelopmental consequences, and autism/autism spectrum disorder. These data are reviewed in detail separately. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Major congenital malformations and their risk factors' and "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Risks with specific ASMs' and "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Valproate' and "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Neurodevelopmental risks of ASMs'.)
Differential risks between other ASMs have emerged with increasing data from the pregnancy registries and population-based studies (figure 1). Some ASMs have moderately elevated risk for malformations, intrauterine growth retardation, and/or adverse neurodevelopmental effects (phenytoin, phenobarbital, topiramate); others have modestly elevated risk (carbamazepine, oxcarbazepine, zonisamide); while some ASMs have minimal or no elevated risk (lamotrigine, levetiracetam) for malformations and are associated with outcomes approximating those in the general population. For many ASMs, however, information is not available to even begin to categorize the level of risk during pregnancy to the developing fetus. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of ASMs on the fetus and neonate'.)
ASM polytherapy should also be simplified, particularly if the regimen involves valproate, phenobarbital, and topiramate. It has been our practice to simplify medication regimes prior to pregnancy when possible.
Antiseizure medication dosing at conception — ASMs should be administered at the lowest effective dose to control seizures to the optimal level for each individual woman. It is important to establish the ideal target concentration for each woman prior to entering pregnancy, as this target concentration will be an important goal during pregnancy and the associated dramatic pharmacokinetic changes [2,26]. (See 'Antiseizure medication monitoring and dose adjustment' below.)
Data from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) show that the risk for major congenital malformations varies not only according to which ASM is prescribed, but also by the daily dose at conception (see "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Major congenital malformations and their risk factors'). The risk for major malformations increases with higher-dose ranges with valproic acid, phenobarbital, carbamazepine, and lamotrigine monotherapy (figure 2).
Folic acid supplementation — Preconceptional folic acid supplementation for women of reproductive age in the general population is universally agreed upon as effective in lowering the risk for neural tube defects.
●Dose of folic acid supplementation – The standard folic acid supplementation dose is 0.4 to 0.8 mg daily (see "Folic acid supplementation in pregnancy", section on 'Folic acid supplementation for prevention of neural tube defects'). It is not known, however, if this dose is sufficient for women on ASMs, or if higher doses offer greater protective benefits [26,27].
•Given that the higher doses of folic acid have not been associated with adverse effects, we suggest folic acid, at least 1 mg daily, for all women of childbearing potential who are taking ASMs, beginning prior to conception and continued through pregnancy.
•For women taking carbamazepine or valproate, or those with a previous pregnancy affected by a neural tube defect or with a neural tube defect affecting either parent, we suggest a higher folic acid dose of 4 mg daily.
Guidelines differ; the American College of Obstetricians and Gynecologists (ACOG) recommends folic acid 4 mg daily for women at high risk of having offspring with neural tube defects [28], but does not recommend doses above 0.4 mg daily for women taking ASMs [29]; nor do 2009 guidelines from the AAN [26]. A 2019 report from the ILAE concludes that women of childbearing potential taking ASMs should take at least 0.4 mg daily of folate [2].
●Risk with low serum folate levels – Low serum folate levels in women with epilepsy are independently associated with an increased risk of major fetal malformations [30]. It has not been conclusively determined if folic acid supplementation lowers the risk of neural tube defects in women receiving ASMs. However, animal studies have shown that valproate and phenytoin decrease the concentration of certain forms of folate and are associated with neural tube defects [31,32]. A limited number of observational studies in women with epilepsy have failed to demonstrate a reduction in the risk of neural tube defects with preconception use of folic acid compared with folic acid supplementation beginning later in pregnancy [33,34].
●Benefit of folic acid supplementation – The benefit of supplemental folic acid during the periconceptional interval and during pregnancy has been demonstrated in cognitive and behavioral studies of children born to women with epilepsy on ASMs.
In the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, mean Intelligence quotients (IQs) were higher in the six-year-old children of mothers who took periconceptional folic acid versus children of mothers who did not take periconceptional folic acid and only began folic acid later in pregnancy [35,36]. After entry into the study, virtually all women were prescribed folic acid. A population-based, prospective study, the Norwegian Mother and Child Cohort Study, found that the risk for autistic traits was significantly higher at 18 months of age (adjusted odds ratio [OR] 5.9, 95% CI 2.2-15.8) and 36 months of age (adjusted OR 7.9, 95% CI 2.5-24.9) in the children of mothers who had not taken supplemental folic acid compared with children of mothers who had taken folic acid [37]. Additionally, the degree of autistic traits was inversely associated with folic acid doses. These findings were most marked for the pattern of folic acid use prior to pregnancy and during the first trimester.
This key evidence of a beneficial effect of supplemental folic acid taken prior to and early in pregnancy (in addition to later in pregnancy) in women on ASMs supports the recommendation that all women with epilepsy of child-bearing age should be encouraged to take supplemental folic acid, especially given the high unplanned pregnancy rate.
MANAGEMENT DURING PREGNANCY — During pregnancy and the intrapartum period, women are more likely to be exposed to potential seizure triggers and may have an increase in seizure occurrence. Common triggers include sleep deprivation and increased emotional stress, as well as nausea and vomiting affecting medication levels. The risk of worsened seizures is increased in patients with higher baseline seizure frequency before pregnancy and with focal epilepsy. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Effect of pregnancy on seizures'.)
Adequate counseling about trying to reduce seizure triggers and emphasizing medication adherence during pregnancy can mitigate these potential risks [3]. Counseling should emphasize the continued need for ASM therapy, given that any potential risk to the fetus related to ASM exposure must be weighed against the risk of injury to the fetus and the mother caused by increased seizures in the absence of effective ASM therapy [2].
Further, although the mechanisms are not yet clear, there appears to be a significant increase in the risk of maternal mortality around the time of delivery in women with epilepsy, along with a more modest increase in the risk of a range of obstetric complications. This highlights the importance of close intrapartum care and the need for a better understanding of the mechanisms underlying these risks, so that preventive interventions can be devised. (See "Risks associated with epilepsy during pregnancy and postpartum period", section on 'Perinatal morbidity and mortality' and "Labor and delivery: Management of the normal first stage".)
A broad overview of the management of women with epilepsy, beginning before conception, is provided in the table (table 1).
Continued folic acid supplementation — Preconceptional doses of folic acid should be continued throughout pregnancy. (See 'Folic acid supplementation' above.)
Antiseizure medication monitoring and dose adjustment — Given the changes in volume of distribution and the increased renal clearance and hepatic metabolism of antiseizure medications (ASMs) associated with pregnancy (see 'Increased antiseizure medication clearance' below), blood levels of ASMs should be followed at regular intervals. Free (unbound) drug levels for the highly protein-bound ASMs (eg, phenytoin, phenobarbital, valproate, carbamazepine) are more reliable during pregnancy. The optimal frequency of testing is unknown. We suggest testing ASM levels in the following fashion, and adjusting dosages as needed to maintain the patient's individualized target serum concentration:
●Routinely at four-week intervals throughout pregnancy, and beginning when pregnancy is reported
●Once at the six-week postpartum visit
●Immediately if the patient reports or presents with increased seizure activity or worsened seizure severity
●Immediately if the patient experiences dizziness, blurred vision, or other common complaints associated with ASM medication toxicity
When ASM blood levels are not available, a 2019 report from the International League Against Epilepsy (ILAE) notes that it is reasonable to increase the ASM dose after the first trimester for women with epilepsy when the following conditions apply [2]:
●The treatment involves ASMs that are prone to marked changes in clearance (lamotrigine, levetiracetam, and oxcarbazepine) with pregnancy
●The seizures include focal to bilateral or generalized tonic-clonic seizures
●The seizure control was sensitive to changes in ASM levels before pregnancy
●The patient entered pregnancy on the lowest effective ASM dose
Increased antiseizure medication clearance — Pregnancy is accompanied by many alterations in drug metabolism, including increased hepatic metabolism, renal clearance, and volume of distribution, as well as decreased gastrointestinal absorption and plasma protein binding [38-41]. As an example, for ASMs that are highly protein bound (eg, phenytoin, phenobarbital, valproate, carbamazepine), the total plasma drug level may decrease with impaired protein binding, but the physiologically important free or unbound drug concentration may not change as much.
A 2019 report from the International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy concluded that the most pronounced increases in ASM clearance (with corresponding decreases in serum levels) during pregnancy are seen with lamotrigine, levetiracetam, and oxcarbazepine, but a clinically important increase in clearance also occurs with phenobarbital, phenytoin, topiramate, and zonisamide [2]. Considerations for specific ASMs vary (table 2):
●Lamotrigine – Several studies found a substantial increase in lamotrigine clearance between prepregnancy baseline and the second and third trimesters [42-44], beginning as early as the fifth gestational week [45]. A prospective study demonstrated that lamotrigine clearance was increased during all three trimesters, with peak increases of 94 (total) and 89 (free) percent in the third trimester [44]. Seizure frequency significantly increased when the lamotrigine level decreased to <65 percent of the preconceptional individualized target lamotrigine concentration. A meta-analysis, with data from six observational studies, suggested that monitoring of lamotrigine levels in pregnancy reduces seizure deterioration [46].
There appears to be substantial interindividual variability in the magnitude of the enhanced lamotrigine clearance during pregnancy [44]. A pharmacokinetic analysis utilizing a population-based model demonstrated two subpopulations [47]. Most women (77 percent) displayed a marked increase in lamotrigine clearance from baseline, whereas a minority (23 percent) had a minimal increase. The large difference in lamotrigine clearance between these two subpopulations argues for therapeutic drug monitoring during pregnancy.
●Levetiracetam – Small studies demonstrate that levetiracetam levels decrease by 40 to 62 percent during the second and third trimesters [48-51]. A more detailed analysis of 12 pregnancies demonstrated an even greater change in clearance of levetiracetam from nonpregnant baseline to the third trimester, with an increase of 242 percent [48]. However, the effects on seizure control are less clear from these studies. A prospective study of 18 pregnancies in women on levetiracetam revealed that the increased clearance is maximal in the first trimester, reaching 1.7 times baseline, and that seizure worsening occurs when the individual's serum concentration decreases to 65 percent or less of the non-pregnant baseline concentration [52].
●Oxcarbazepine – In data from the EURAP study, oxcarbazepine monotherapy was associated with an increased risk of seizure, suggesting the possibility that it is affected by pharmacokinetic changes in pregnancy and requires more frequent monitoring [53]. However, oxcarbazepine serum levels were not obtained in the EURAP study. In another study of 12 women monitored in pregnancy, the concentration of 10-monohydroxy derivative, an active oxcarbazepine metabolite, decreased significantly in gestation and increased after delivery [53-55]. These and other reports support close clinical monitoring of women taking oxcarbazepine during pregnancy [56].
●Topiramate – A study describing 12 women on topiramate therapy during pregnancy reported that serum concentrations declined by approximately 30 percent [57]. Increased seizure frequency in pregnancy was also observed in this series.
●Carbamazepine – One exceptional finding in several studies was that the women on carbamazepine had very low rates of worsened seizure control (0 to 15 percent) and were less likely to have dose adjustments during pregnancy [58,59]. A prospective study that followed 15 pregnancies (in 12 women) found no significant changes in the clearance of total and free carbamazepine or carbamazepine-epoxide (CBZ-EPO) throughout the pregnancy compared with nonpregnant baseline [60]. The free fraction of carbamazepine increased from 0.23 at baseline to a maximum of 0.32 in the third trimester, thus potentially providing additional seizure protection. In the women on carbamazepine monotherapy, seizure worsening did not correspond to a ratio to baseline concentration of less than 0.65 for total or free carbamazepine or CBZ-EPO.
Given these findings, carbamazepine may be a particularly good choice for women with focal-onset seizures when monitoring for ASM blood levels during pregnancy is not readily available; additional favorable features of carbamazepine include its relatively low structural teratogenic risk [61,62] and the normal neurocognitive profiles of children following prenatal exposure [36].
Many other ASMs undergo substantial clearance changes during pregnancy, but data are sparse about the clinical consequences.
The 2019 ILAE report concluded that a decrease of more than 35 percent in the ASM serum level (ie, a fall to less than 65 percent of the optimal prepregnancy serum level) is associated with an increased risk of worsening seizure control [2]. One group of researchers investigated if the "65 percent rule," as first determined with lamotrigine [44], held true with other ASMs [58]. In other words, when the ASM serum concentration fell to less than 65 percent of preconception baseline (ie, a 35 percent or greater decline), did seizures worsen? Using a retrospective analysis of clinic patients at a single epilepsy center with 115 pregnancies in 95 women, they reported that significant changes in clearance occurred with lamotrigine and levetiracetam, with average peak clearance increases of 191 and 207 percent, respectively, above nonpregnant baseline [58]. Despite increasing doses across most ASMs, seizures still increased in 38 percent of women during pregnancy, and seizure deterioration was significantly more likely in patients during the second trimester when the ASM concentration fell to <65 percent of preconception baseline. Other factors associated with seizure deterioration during pregnancy were the presence of seizures in the 12 months prior to conception and focal seizure types, similar to reports from the EURAP study [59]. Additionally, the women on levetiracetam monotherapy or ASM polytherapy had the highest rates of seizure deterioration.
These studies highlight the importance of therapeutic ASM monitoring during pregnancy to help prevent seizure deterioration in women on a variety of ASMs, and support recommendations by several experts to adjust ASM dosing during pregnancy [26,40,63]. Gestational-induced pharmacokinetic data are lacking for many of the newer ASMs (eg, pregabalin, lacosamide, eslicarbazepine acetate, rufinamide, clobazam), in part because prescriptions in pregnant women are often delayed until some teratogenic safety data are available.
Changing antiseizure medications during pregnancy — With few exceptions, we do not alter ASMs during an established pregnancy solely for the purpose of reducing the risk of ASM-related fetal malformations. Doing so is likely ineffective as a means of structural teratogen avoidance, while potentially risky with regard to seizure occurrence. However, there is evidence that prescribing patterns for women of childbearing age with epilepsy are changing toward ASMs with more favorable teratogenic profiles [64,65]. These selections are most often made prior to conception, which underscores the importance of selecting ASMs based on the potential for an unplanned as well as planned pregnancy. If the ASM is changed, the switch should be accomplished with adequate time to determine the effectiveness and tolerance of the new regimen well before conception [2].
As heightened vulnerability to any potential teratogen exists primarily in the first nine weeks after the last menstrual period, significant exposure has likely already occurred by the time of missed menstruation (4 to 5 weeks) or presentation to prenatal care (8 to 12 weeks). Therefore, it is usually unwise to alter ASMs during an established pregnancy purely out of a concern for minimization of teratogenic risk. Furthermore, altering an ASM regime often involves the synchronous overlapping of medications, with the potential for the interaction of effects associated with the individual agents described above. Finally, patients undergoing medication transitions are at increased risk of seizure occurrence [1].
There are a few exceptions. If a woman with an unplanned pregnancy is on multiple ASMs, and it is felt that seizure control would not be compromised significantly, it may be reasonable to remove one or more ASM(s) to lower fetal exposure to ASMs with an unfavorable or unknown risk profile. Another possible exception would be a woman on valproate whose seizures have not proven to be refractory to other ASMs; in such a case, transition off valproate at any point during pregnancy (the sooner the better) may lower the risk for neurodevelopmental delay and autism.
Screening for malformations — Epilepsy does not alter a woman's risk of chromosomal aneuploidy. Optional screening for aneuploidy is based on maternal age. (See "Prenatal screening for common aneuploidies using cell-free DNA".)
Ultrasound screening for morphologic anomalies in the fetus can be definitively undertaken at 17 to 20 weeks gestation (see "Neural tube defects: Prenatal sonographic diagnosis"). The finding of normal posterior fossa and fetal spine will typically adequately exclude the presence of a neural tube defect. If additional reassurance is desired, measurement of the serum alpha-fetoprotein (AFP) concentration or amniocentesis for amniotic fluid AFP levels should be performed between at or after 16 weeks, especially in women treated with valproate and carbamazepine [66-68]. It is not our practice to recemented fetal echocardiography unless abnormalities are noted on the screening ultrasound. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Alpha-fetoprotein'.)
The suspected presence of an anomaly should prompt an immediate referral to a qualified tertiary fetal imaging center. Timely diagnosis of morphologic anomaly in the fetus will allow the patient to prepare for the care of an affected child or consider potentially terminating the pregnancy. We acknowledge that these are both highly personal and individualized considerations and should be conducted by qualified maternal-fetal medical and neonatal personnel who can appropriately discuss the risk of continuing a pregnancy and the care needs of the neonate and child.
APPROACH TO A FIRST SEIZURE IN PREGNANCY — Occasionally, a woman presents with a first seizure in pregnancy. With a few exceptions, the approach to diagnosis and management of a first seizure is the same as in a nonpregnant individual. (See "Evaluation and management of the first seizure in adults" and "Initial treatment of epilepsy in adults".)
Additional considerations in a pregnant woman include:
●Diagnostic considerations for new seizures must include exclusion of possible pregnancy-associated conditions, such as eclampsia and cerebral venous thrombosis. (See "Eclampsia" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)
●Depending on the stage of pregnancy, there may be safety concerns regarding the use of neuroimaging procedures. Concern about the possible fetal effects of ionizing radiation should not prevent medically indicated diagnostic procedures using the best available modality for the clinical situation. Magnetic resonance imaging can be performed at any stage of pregnancy when the information requested from the study cannot be acquired by other nonionizing procedures, and the data are needed to care for the patient or fetus during the pregnancy. Gadolinium should generally be avoided in the pregnant patient unless its use significantly improves diagnostic performance and is likely to improve patient outcome. Gadolinium-based contrast agents are present at very low levels in human milk and not absorbed well by the infant gut; no adverse effects have been reported in infants exposed through lactation. (See "Diagnostic imaging in pregnant and nursing patients", section on 'Fetal risks from magnetic resonance imaging'.)
●The choice of antiseizure medication (ASM) treatment is complicated by concerns of fetal safety. The evidence linking valproate to fetal malformations and neurodevelopmental disorders is sufficiently convincing to recommend avoiding its initiation in pregnancy. Although lamotrigine is a favorable choice during preconceptional planning, it is not a good choice for initiation during pregnancy; lamotrigine cannot be started quickly due to the higher risk of rash with accelerated titration , and it is difficult to get to a therapeutic concentration due to the enhanced clearance during pregnancy (see "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Lamotrigine'). Levetiracetam is a medication with a favorable reproductive safety profile, which can be started at a therapeutic dose immediately, and which has a broad spectrum of action across multiple seizure types. If seizures are focal and begin after the first trimester, carbamazepine is another option given the data supporting normal neurodevelopmental profiles after in utero exposure [36,69]. (See "Risks associated with epilepsy during pregnancy and postpartum period".)
Other management issues follow those of women with established epilepsy in pregnancy.
MANAGEMENT AT DELIVERY — Most women with epilepsy have a normal vaginal delivery [2,70-72] and the mode of delivery should be dictated by obstetric indications. However, peripartum is a time of increased seizure risk. Antiseizure medication (ASM) doses must not be missed during the period of labor. The Kerala registry of epilepsy and pregnancy reported that seizure relapse was the highest during the three peripartum days, which they counted as the day prior to delivery, day of delivery, and day after delivery [73]. It is therefore essential to maintain the individualized ASM target concentration known to protect the woman against seizures during the third trimester and during delivery.
The labor and delivery room environment should be optimized for the woman with epilepsy; attention to pain management is particularly important. Consultation with anesthesia should be undertaken early in labor, if not prior to admission for delivery. We actively encourage our patients with epilepsy to receive neuroaxial analgesia while in labor. With an appropriately dosed epidural, many women can nap or sleep during the first stage of labor and thereby minimize the potential consequences of sleep deprivation as well as minimize pain-associated stress. Well-meaning visitors and family should be encouraged to allow the laboring mother to rest and minimize external stimulation. Lighting can be lowered to encourage sleep at appropriate intervals. It has not been our practice to pad the bed railing during labor, but standard nursing practices regarding raising bed rails should nonetheless be observed.
●Managing seizures during labor and delivery – Convulsive seizures, if they occur during labor and delivery, should be treated promptly with intravenous (IV) benzodiazepines; lorazepam is considered the drug of choice (see "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis"). To avoid pharmacy-associated delays, it is our practice to have rescue IV lorazepam at the bedside or at least on the delivery floor for all women with epilepsy during labor. We generally recommend 1 mg IV for nonconvulsive seizures and 2 mg IV for a generalized tonic-clonic convulsion.
The occurrence of a seizure during labor should not alter the intended mode of delivery so long as the seizure can be treated and prophylactic medications administered. Continuous fetal monitoring should be applied as soon as possible after a seizure is diagnosed. The fetal heart tracing will be temporarily depressed by a maternal seizure but should return to an appropriate category within five minutes.
Given the underlying risk of placental abruption associated with maternal seizure, the progressive deterioration of the fetal heart rate strip or its failure to return to a reassuring status is an indication for an expedited delivery. Magnesium sulfate is not an appropriate treatment for epileptic seizures. However, when seizures first present during the third trimester of pregnancy or the early postpartum period, it may be difficult to distinguish eclampsia from a new onset or late relapse of epilepsy. Immediate consultation with maternal-fetal medical personnel is warranted in this circumstance. Treatment of eclampsia and evaluation of other etiologies for the seizure is warranted. The treating team should simultaneously evaluate for a recurrent epileptic seizure and check ASM levels while excluding potential precipitants. Both diagnoses (eclampsia and new onset or late relapse of epilepsy) can be pursued and treated in parallel until one can be safely excluded. (See "Eclampsia".)
●Antiseizure medications and neonatal sedation – After delivery, phenobarbital, primidone, and benzodiazepines remain in neonatal plasma for several days. These medications can cause sedation and hyporesponsiveness in the newborn, and evaluation and resuscitation should be undertaken by qualified neonatology personnel [74]. There are very few reports of neonatal sedation with the other ASMs in monotherapy. However, ASM polytherapy and a high drug burden may be associated with a higher risk for neonatal sedation, decreased responsiveness, and poor feeding, and the newborn may develop features similar to the neonatal abstinence syndrome over the first few days of life.
MANAGEMENT IN THE POSTPARTUM PERIOD — There are several basic principles of management for women with epilepsy during the postpartum period [9,20]. These address antiseizure medication (ASM) tapering, possible worsening of seizures due to sleep deprivation, safety precautions with the newborn, and breastfeeding. A broad overview of the management of women with epilepsy at all stages of pregnancy, including the postpartum period, is provided in the table (table 1).
Postpartum antiseizure drug tapering — The rate of taper of ASMs back to prepregnancy dose or slightly above depends mainly on the primary route of elimination for each individual ASM [2]. The physiologic changes to renal and some hepatic enzymatic function (eg, glucuronidation) associated with pregnancy will rapidly resolve over the first two to three weeks postpartum, while other hepatic enzymes (many of the cytochrome P450 enzymes) may take one to two months to return to baseline clearance rates.
It is our practice to hold at the delivery dose until postpartum day 3, and then taper over the appropriate interval for the ASM.
●We decrease lamotrigine and levetiracetam over two to three weeks postpartum, and do the same for other medications that are cleared via hepatic glucuronidation or renal excretion (eg, eslicarbazepine, gabapentin, lacosamide, oxcarbazepine, pregabalin, rufinamide, topiramate, valproic acid, vigabatrin).
●For medications metabolized by the cytochrome P450 enzymes (eg, carbamazepine, clobazam, ethosuximide, felbamate, perampanel, phenobarbital, phenytoin, primidone, tiagabine, zonisamide), we tend to taper more slowly, over approximately six weeks, although there is even less evidence to direct these tapers.
Postpartum ASM tapers need to occur empirically, as a steady-state level is not obtainable with the rapid changes in clearance, and it often takes a few days to get the results for most of the second- and third-generation ASMs at most clinical centers.
Lamotrigine is the only ASM that has been formally studied in the early postpartum period. Lamotrigine clearance decreases quickly in the first few weeks postpartum, and dose adjustments should be made relatively quickly. In one case series, adherence to a postpartum taper schedule of lamotrigine over 10 days reduced the likelihood of maternal lamotrigine toxicity [42]. The dose was incrementally reduced at postpartum days 3, 7, and 10, with return to preconception dose or preconception dose plus 50 mg to help counteract the effects of sleep deprivation. A later formal pharmacokinetic modeling study of lamotrigine clearance postpartum suggested that it could take up to 19 days after delivery for return to baseline clearance [47], so we now aim for reaching our target dose at approximately two weeks postpartum.
Avoiding sleep deprivation — The risk of seizures may be increased in the postpartum period, sometimes for several months, due to sleep deprivation [9]. Families and caregivers should be counseled, ideally as a function of prenatal care, to make arrangements to allow adequate sleep while caring for a newborn. Typically, most families and caregivers adopt a "shift" approach so the mother can reliably obtain uninterrupted and regular nightly sleep, and many couples enlist the help of other relatives. Additionally, even if the mother has been seizure free for a long time, she should take a more conservative safety approach until she is getting regular sleep again, given that sleep deprivation is a strong provoker of many seizure types [9].
Safety precautions — Common sense safety considerations must be discussed; these include not driving, not having the mother bathe the baby alone, and not co-sleeping with the baby. If the mother is at risk of myoclonic seizures, then a baby carrier (sling or harness) should be used when walking around with the baby. The mother should also be discouraged in the early postpartum period from taking a bath herself behind a closed, locked door or when no other adult is around.
Breastfeeding — Given the benefits to breastfeeding with regard to both short- and long-term neonatal health, taking ASMs does not contraindicate breastfeeding [1]. However, we acknowledge that new mothers with epilepsy are less likely to breastfeed [75,76]. Therefore, clinicians should reinforce the benefits. In agreement with a 2019 report from International League Against Epilepsy (ILAE) Task Force on Women and Pregnancy [2], we encourage women to consider breastfeeding, but with adaptation according to how sensitive their seizures are to sleep deprivation, based upon their history and their epilepsy syndrome. Many women choose to breastfeed but will introduce the bottle in the hospital. This allows another adult to give at least one feeding via bottled formula or pumped breastmilk, permitting the mother to obtain at least one four-hour stretch of uninterrupted sleep per 24 hours. We recommend this and another two hours of sleep through naps to achieve a minimum of six hours of sleep per 24 hours to reduce the risk of seizures. However, there are no high-quality studies evaluating the risk of seizures in the postpartum period relative to specific sleep patterns.
All of the ASMs are measurable in breast milk, but levels in breast milk are variable [77-79]. The reported percentage of maternal plasma levels in breast milk varies from 5 to 10 percent with valproate [80], to 41 percent with lamotrigine [81], to 90 percent with ethosuximide [82], to 100 percent with levetiracetam [83]. However, the ASM levels in the nursing infant's serum are often much lower [84], and are always substantially lower than the umbilical cord blood ASM concentration at delivery, which is close to unity to the maternal serum concentration [85]. In a prospective study of 139 mother-infant pairs exposed to a variety of ASMs, almost 50 percent of ASM concentrations in the nursing infants were less than the lower limit of detection; the median percentage of infant-to-mother concentrations ranged from ranged from 0.3 to 44.2 percent [84]. Small studies of lamotrigine reported that infant plasma concentrations were 18 to 30 percent of maternal plasma concentrations [81,86]. Small studies of levetiracetam, topiramate, and gabapentin have found that, while present in breast milk in concentrations similar to maternal plasma, the concentrations in infant plasma were low, suggesting rapid elimination [83,87,88].
There is little evidence to support that ASM exposure from breast milk has clinical effects on the newborn [26]. Anecdotal reports suggest that problems tend to occur only with the highly sedating drugs, such as phenobarbital, primidone, or benzodiazepines. Nursing newborns may become irritable, fall asleep shortly after beginning to nurse, or fail to thrive. If this occurs, breastfeeding may need to be discontinued. However, for the vast majority of ASMs, especially those used first line in contemporary neurology practice, adverse effects on nursing infants are lacking.
Moreover, neurodevelopmental studies in children of women with epilepsy on ASMs demonstrate benefits to nursing. Neurodevelopmental outcomes were examined in 181 children exposed to either carbamazepine, lamotrigine, phenytoin, or valproate in utero; 42.9 percent of these children were breastfed a mean of 7.2 months. Intelligence quotients (IQs) for breastfed children were four points higher than the non-breastfed group after adjusting for potential confounding through propensity score matching, and in specific cognitive domains, verbal abilities were higher [89]. No adverse effects of ASM exposure via breastmilk were observed. Another study that included 223 children exposed to ASMs in utero found that prenatal exposure was associated with adverse developmental outcomes regardless of breastfeeding status during the first year of life, but that infants who were breastfed continuously for more than six months had slightly better outcomes than those who were not breastfed [90].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Epilepsy and pregnancy (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Risk considerations with epilepsy – Risks associated with epilepsy during pregnancy include the potential for perinatal complications, seizure worsening, and adverse effects of antiseizure medications (ASMs) on the fetus and later development. These risks may be minimized by interventions before and during pregnancy. (See 'Risk considerations' above.)
●Preconception management – A broad overview of the management of women with epilepsy, beginning before conception, is provided in the table (table 1).
•Counseling – Epilepsy is not a contraindication to pregnancy. Women of childbearing potential should be counseled regarding the interactions between ASMs and hormonal contraceptive therapy, the potential risks associated with epilepsy and pregnancy, and the importance of folic acid supplementation starting before conception to prevent neural tube defects. Preconception counseling should include providing options for other forms of effective contraception, especially for patients on an enzyme-inducing ASM. (See 'Counseling' above.)
•Folic acid – For all women of child-bearing potential who are taking ASMs, we recommend supplementation with folic acid, and we suggest folic acid 1 mg daily rather than a lower dose (Grade 2C), regardless of pregnancy planning, given that approximately half of pregnancies are unplanned and that periconceptional folic acid is associated with improved cognitive and behavioral outcomes of children born to women on ASMs. This should continue throughout the entire pregnancy. For women taking carbamazepine or valproate, or those with a previous pregnancy affected by a neural tube defect or with a neural tube defect affecting either parent, we suggest folic acid 4 mg daily (Grade 2C). Some experts advise folic acid 4 mg daily for all women of childbearing potential taking any ASM, beginning prior to conception and continuing throughout pregnancy. (See 'Folic acid supplementation' above.)
•Reassess need for antiseizure medication – The diagnosis of epilepsy and the need for ongoing ASM therapy should be assessed before conception. A small minority of women who have been seizure free for a prolonged period may be eligible to discontinue ASM therapy prior to conception. The risk of recurrent seizures varies based on the specific epilepsy syndrome and other factors, and the decision should be individualized. (See 'Necessity for antiseizure medications' above.)
•Choice of antiseizure medication – Pregnancy registry and population-based studies demonstrate that there are differential levels of teratogenic risk between ASMs (figure 1 and figure 2). Among ASMs appropriate for an individual woman's seizure type, the goal is to choose the ASM with the lowest proven risk for major congenital malformations and adverse neurodevelopmental consequences, and administer the drug at the lowest effective dose prior to conception. Valproate should be avoided and only prescribed if no other ASM is effective for that particular patient. Overall, monotherapy is preferred if possible. (See 'Choice of antiseizure medication' above.)
●Management during pregnancy – A broad overview of the management of women with epilepsy is provided in the table (table 1).
•Antiseizure medication monitoring – Increased ASM clearance during pregnancy (table 2) can lead to seizure deterioration (increased frequency or severity) if target blood levels are not maintained. We suggest monitoring ASM levels during pregnancy. Our preferred schedule is to test levels every four weeks, and more often if seizures increase or side effects worsen. (See 'Antiseizure medication monitoring and dose adjustment' above.)
•First seizure in pregnancy – With a few exceptions, the approach to the diagnosis and management of a first seizure in pregnancy is the same as in a nonpregnant individual. Additional diagnostic considerations include pregnancy-associated conditions such as eclampsia and cerebral venous thrombosis. The choice of ASM treatment is complicated by concerns of fetal safety; levetiracetam has a favorable reproductive safety profile, can be started at a therapeutic dose immediately, and has a broad spectrum of action across multiple seizure types. If seizures are focal and begin after the first trimester, carbamazepine is another option. (See 'Approach to a first seizure in pregnancy' above.)
•Delivery – The mode of delivery should be dictated by obstetric indications; most women with epilepsy have a normal vaginal delivery. However, peripartum is a time of increased seizure risk. ASM doses must not be missed during the period of labor. Convulsive seizures, if they occur during labor and delivery, should be treated promptly with intravenous benzodiazepines; lorazepam is considered the drug of choice. (See 'Management at delivery' above.)
●Postpartum management – During the postpartum period, the rate of ASM dose tapering depends mainly on the primary route of elimination for each individual ASM. Arrangements should be made to avoid sleep deprivation, which increases the risk of seizures. ASM therapy is generally not considered a contraindication to breastfeeding. (See 'Management in the postpartum period' above.)
35 : Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.
46 : Effects of monitoring strategies on seizures in pregnant women on lamotrigine: a meta-analysis.
