Pregnancy and Epilepsy

Abstract

Purpose of Review

This review encompasses issues regarding the management of women with epilepsy and pregnancy, including preconception planning, antiepileptic drug (AED) effects on the exposed offspring, and consequences of seizures during pregnancy, with an emphasis on counseling points and risk management.

Recent Findings

In utero valproate exposure continues to show the highest risk of congenital malformations and of adverse cognitive outcomes, including autism, compared to other AEDs. In utero topiramate exposure is associated with facial clefts. In utero exposure to lamotrigine, carbamazepine, phenytoin, and levetiracetam has been evaluated in large numbers of offspring, and all of these AEDs have a low risk of major congenital malformations, near 2.5%. The risk of major congenital malformations due to in utero AED exposure is dose associated. Folic acid taken at the time of conception decreases the risk of adverse cognitive outcomes. AED polytherapy may adversely affect fertility, and in utero exposure of AED polytherapy is associated with infants who are small for their gestational age. Seizure freedom before pregnancy is a good predictor of remaining seizure free during pregnancy.

Summary

Counseling points are complex for managing women with epilepsy contemplating pregnancy, including evaluation of AED choice and dose. The physician must have knowledge of the issues to enable an honest discussion and appropriate decision making in partnership with the patient.

INTRODUCTION

The majority of people with epilepsy experience prolonged seizure remission, usually while taking antiepileptic drugs (AEDs). It follows, then, that many women with epilepsy who in general feel little affected by their illness on a day-to-day basis have a similar outlook toward family planning as do women without chronic illness, and therefore hope to bear children. The medical community must provide informed guidance for these patients. In the conversation with the patient, discussion points should address (1) whether it is reasonable and safe to become pregnant based on the individual’s epilepsy severity and current treatment and (2) what the most appropriate AED choices are based on risk to the offspring and expectations of seizure control. Because about half of pregnancies are unplanned, this discussion should be initiated by the clinician and touched upon at every office visit with women with epilepsy of childbearing potential, so that the patient’s therapy is optimized for pregnancy during childbearing years.

The decision about bearing children is very personal, emotional, and fundamental to family life. The multiple risks to women with epilepsy around pregnancy vary in their severity and timing, as well as in whether the patient or the baby is at greater risk. This review will discuss risks to women with epilepsy and their offspring during pregnancy and delivery and conclude with a summary of these considerations.

INFERTILITY IN EPILEPSY

Birth rates to women with epilepsy have been estimated using large population-based registries. However, birth rates do not directly assess infertility, which is defined as lack of conception after 1 year of frequent sexual activity without the use of birth control. Birth rate statistics cannot be directly translated to fertility since they do not account for the many patients and couples who simply choose not to have children because of the risks of epilepsy and AEDs. For example, in a study using national insurance data in Finland, the birth rates to women with epilepsy were 17% lower than the general population of women.1 However, approximately 15% to 18% of women with epilepsy in this population had severe comorbidity and therefore were unlikely to choose to bear children; this could, in great part, account for the difference between groups.1 The Kerala Registry of Epilepsy and Pregnancy from southern India provides some nuance to the question of fertility in epilepsy. The investigators evaluated factors associated with not achieving pregnancy in their cohort of 375 women with epilepsy prospectively followed as they actively tried to conceive.2 The follow-up period was at least 1 year, with a mean of 3 years. While 61% did become pregnant, an important factor associated with not conceiving was using more than one AED (P=.001; odds ratio [OR] 1.33, 95% confidence interval [CI] 1.11 to 1.60). While taking one AED did not increase the risk of not conceiving compared to the small group of women with epilepsy not taking AEDs (n = 14), a significant trend was found for an increase in risk correlating with the number of AEDs used, with taking three or more AEDs imparting a 20-fold risk of not conceiving. However, this data set also implies an important nonbiological impact on birth rates as well, in that less than 10 years of education was associated with a doubled risk of not conceiving.2

Psychosocial factors certainly contribute to these outcomes, but reasonable biological hypotheses exist for reproductive endocrine disruption in women with epilepsy. For example, AEDs alter the endogenous hormonal profile and thereby affect menstrual cycle length and ovulation rates. Additionally, seizures and epilepsy themselves may produce a central reproductive hormonal dysregulation and cause pituitary-mediated anovulation.3

TAKING ANTIEPILEPTIC DRUGS DURING PREGNANCY: A COMPLEX DECISION

Ideally, women should not take medications during pregnancy. Epilepsy, however, is a rather unforgiving illness in that physically dangerous seizures can occur without provocation for many people with epilepsy, and AEDs decrease the chance of seizure occurrence. This seizure risk, however low in many patients with epilepsy, becomes of even greater concern when the patient is a pregnant woman with epilepsy. Hence, the physician faces the dilemma of balancing the risks of seizures to the mother and developing fetus versus the risks of in utero AED exposure to the developing fetus. The mother is the patient and arguably the physician’s primary responsibility in this risk assessment. She, on the other hand, may feel a greater responsibility to the fetal well-being than to herself. It is imperative for maintaining a therapeutic alliance that her concerns and opinions be addressed and that she participate in this often emotional discussion. An informed, acceptable consensus must be reached that incorporates medically informed decisions regarding taking AEDs altogether and decision points for increasing AED doses based on clinical factors and blood levels during pregnancy. Since many women with epilepsy will be taking AEDs during pregnancy, a discussion of the risks associated with in utero AED exposure follows.

RECENT INFORMATION REGARDING RISKS OF MAJOR CONGENITAL MALFORMATIONS IN ANTIEPILEPTIC DRUG USE

Contribution of the American Academy of Neurology Evidence-Based Practice Parameters

The American Academy of Neurology (AAN) evidence-based practice parameters on management of women with epilepsy regarding pregnancy synthesized the available evidence at the time of publication in 2009.4,5,6 The methodology involves stratifying the risk of bias in the studies to find the strongest scientific evidence to determine whether a causal relationship exists between AED in utero exposure and adverse outcomes in the offspring. The information in these documents appears to have stood the test of time thus far, but major additions to the field have occurred since then that can help guide management. Important factors used in the practice parameters for determining unbiased studies for AED-associated teratogenesis are put forth in Table 3-1. 5 Key considerations are that major congenital malformations were considered objective outcomes, and studies were therefore not required to have investigators be blinded to the AED exposure in order to be considered strong, high-level studies. Major congenital malformations are defined as life-threatening malformations or those that need surgical treatment. This was not the case for the more subtle outcome of cognitive impairment, in which the high-level studies required the investigators evaluating the children to be blinded to the specific AED exposure. Further, maternal IQ must have been accounted for in the cognitive assessment of the offspring, since this factor is highly associated with the child’s IQ.

Table 3-1.

Criteria for Unbiased Studies Used in 2009 Women With Epilepsy Practice Guidelines^a

The practical essence of the AAN practice parameters regarding AED teratogenesis are summarized in Table 3-2. The absolute rate of teratogenesis with valproate is 6% to 9%, which is approximately threefold the risk of untreated women with epilepsy and those treated with lamotrigine or carbamazepine. Spina bifida is specifically associated with valproate use. A small but increased risk exists with polytherapy versus monotherapy exposure; this risk is increased when valproate is part of the polytherapy. Valproate is associated with a risk of neurocognitive deficits, specifically a lower-than-expected verbal IQ.5

Table 3-2.

Major Points Regarding Teratogenesis From AAN Practice Parameters^a

Teratogenic Risks of Specific Antiepileptic Drugs

Valproate. Valproate is well recognized to be associated with a higher risk of major congenital malformations and adverse cognitive outcomes than other AEDs. Its use should be avoided if possible in women with epilepsy of childbearing potential. While some major congenital malformations appear to be a class effect of AEDs in general, such as spinal bifida,7 valproate has a higher risk of spina bifida than the other AEDs and is also specifically associated with hypospadias.8 The relative risk of major congenital malformations with in utero first trimester valproate exposure compared to other AEDs is approximately threefold, and the absolute risk is 6% to 9% of pregnancies exposed. The high risk of major congenital malformations with valproate has been recognized since 19848 and is confirmed in several large pregnancy registries.9,10,11 A dose-associated risk clearly exists, with the risk below 700 mg of valproate per day being around 4%, similar to the rate of lamotrigine at more than 300 mg/d and carbamazepine at more than 400 mg/d in this study.12 The escalation of risk with first trimester use of valproate at greater than approximately 700 mg/d has been observed by other investigators,13 and both of these reports show rates of major congenital malformations at greater than 20% when the dose is 1500 mg/d or more.12,13 This dose information is useful for those women whose epilepsy absolutely cannot be controlled on other AEDs; lower daily doses of valproate in these women may optimize risk management.

The recent publication from the North American Antiepileptic Drug Pregnancy Registry (NAAEDPR) provides a snapshot of the risks of major congenital malformations associated with each AED as first trimester monotherapy exposure (Figure 3-1).14 These data are consistent with worldwide experience. They also show the important new finding that phenobarbital also has a significantly increased risk of major congenital malformations, most often cardiac malformations. Phenobarbital should also be avoided for women of childbearing potential who have epilepsy. While it is not widely used in developed countries, it is a mainstay of therapy in many areas of the world, with continuing impact on pregnancy outcomes.

Figure 3-1.

North American AED Pregnancy Registry between 1997 and 2011. Percent of major congenital malformations and 95% confidence interval with monotherapy in first trimester exposure. CBZ = carbamazepine; VPA = valproate; LTG = lamotrigine; PHT = phenytoin; OXC = oxcarbazepine; GBP = gabapentin; PB = phenobarbital; ZNS = zonisamide; TPM = topiramate; CZP = clonazepam; LVT = levetiracetam. Data from Hernández-Díaz S, et al, Neurology.14 www.neurology.org/content/78/21/1692.abstract?sid=4a54bb28-bec2-496a-8fcb-e348d3da2b98.

The point estimates of the percentage of major congenital malformations with valproate and phenobarbital exposure are greater than with the other AEDs. Further, the CIs with valproate do not overlap with most of the other AEDs (specifically, carbamazepine, lamotrigine, phenytoin, oxcarbazepine, gabapentin, zonisamide, and levetiracetam), which indicates that valproate carries a significant increase in risk compared to these AEDs. These results are reliable estimates for carbamazepine, lamotrigine, phenytoin, and levetiracetam. While there were not enough exposures to oxcarbazepine, gabapentin, zonisamide, and clonazepam in the large NAAEDPR study to determine precise estimates, the upper limits of the 95% CIs for three of these agents (gabapentin, oxcarbazepine, and zonisamide) are still low. With these four widely used AEDs for which the data are most precise (carbamazepine, lamotrigine, phenytoin, and levetiracetam), the major congenital malformation rates all cluster closely around 2% to 2.5%. This study also showed that, compared to the risk with lamotrigine, the risk ratio was fivefold with valproate, threefold with phenobarbital, and twofold with topiramate.14

Topiramate. One of the most important findings since the publication of the AAN practice parameters in 2009 is the association of topiramate first trimester exposure with an increased risk of facial clefts. The association prompted the US Food and Drug Administration (FDA) to issue a report changing the pregnancy risk category from C to D in March 2011, meaning that topiramate is a known teratogen in humans. This has important implications for both epilepsy and headache treatment.

The FDA categories provide a common language for understanding teratogenic risks (see Appendix A); however, the clinical decision-making pathway for AED use usually incorporates additional factors based on emerging evidence, such as dose effects and family history of major congenital malformations.

The association of facial clefts with in utero topiramate exposure has been reported from several populations. The rate of oral clefts with topiramate first trimester exposure was 1.4% in NAAEDPR, which is an approximately 10-fold increase compared to the local control population prevalence of 0.11%.14 In this report, oral cleft prevalence was 0.5% with lamotrigine, carbamazepine, and phenytoin; 1.2% with valproate; and 4% with phenobarbital. The UK AED Pregnancy Register reported a 2.2% rate of facial clefts with first trimester topiramate exposure.15 Compared to the general UK population prevalence of 0.2%, topiramate increased the risk of facial clefts at a similar magnitude as the NAAEDPR study. This increased risk was also found in two large birth defect registries using a different method. Two large registries located in the United States, the Slone Epidemiology Center Birth Defects Study and the National Birth Defects Prevention Study, were analyzed from 1997 to 2007 for the association of cleft lip with or without cleft palate in offspring exposed in utero to topiramate compared to no AED use. The OR from pooled data for periconceptional topiramate use and cleft lip with or without cleft palate in these registries was 5.4 (1.5–20.1).16 Emerging findings also suggest an association with topiramate use and hypospadias in exposed offspring.8,17

Carbamazepine. Although spina bifida has been strongly associated with in utero valproate exposure, new evidence confirms that carbamazepine exposure is also associated with spina bifida.7,18 In a 2010 study using the European Surveillance of Congenital Anomalies (EUROCAT) Antiepileptic Study database and incorporating other published reports, Jentink and colleagues found an association between spina bifida and in utero carbamazepine exposure compared to no exposure (OR 2.6, 95% CI 1.2 to 5.3).7 Notably, the risk with carbamazepine was approximately 80% less than with valproate, but was not different from the risk of exposure to other AEDs, specifically lamotrigine, levetiracetam, phenobarbital, and clonazepam. The EUROCAT database found no evidence of an association between lamotrigine exposure and orofacial clefts.19

Levetiracetam. Information on the teratogenic risk of one of the most widely used AEDs, levetiracetam, is emerging, and the information thus far is reassuring. In a recent report from the UK pregnancy registry of 671 levetiracetam first trimester–exposed pregnancies, 304 were monotherapy exposures. Of these, two major congenital malformations occurred (0.70% of the total; 95% CI 0.19% to 2.51%).20 The specific malformations were an inguinal hernia with maternal use of 4000 mg/d and reflux requiring surgery with maternal use of 2000 mg/d. These results also hint at a dose effect; the mean daily dose for pregnancies with normal outcomes was 1680 mg. The NAAEDPR also confirms a low risk of major congenital malformations with levetiracetam at 2.4% (95% CI 1.2 to 4.3) with 450 exposures.14

Risk of Repeated Major Congenital Malformations

Vajda and colleagues recently reported on the outcomes of second pregnancies in women with epilepsy after the occurrence of a major congenital malformation in the first pregnancy while taking the same AED for both pregnancies.21 The risk of a major congenital malformation in the second pregnancy was 35.7% if the first pregnancy showed a major congenital malformation versus 3.1% if the first pregnancy was normal (OR 17.6, 95% CI 4.5–68.7). This effect was most marked with valproate, with which the second pregnancy had a major congenital malformation rate of 57% if the first pregnancy also showed a MCM. The authors suggest that a maternal genetic influence predisposes to teratogenicity and compounds the AED risk. Interestingly, the types of malformations varied within families.21

Antiepileptic Drug Teratogenic Dose Effects

The clearest evidence for dose-associated risk of major congenital malformations is from the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) study.12 In this study, dose effects were present for four widely used AEDs for which large sample sizes were available for first trimester monotherapy exposures: phenobarbital, valproate, carbamazepine, and lamotrigine. The rates of major congenital malformations were the lowest with less than 300 mg/d of lamotrigine (at 1.7%) and with less than 400 mg/d of carbamazepine (at 2%). Although the major congenital malformation rates were higher with phenobarbital and valproate at all doses, each AED showed a significant dose effect. For carbamazepine at or above 1000 mg/d, the rate of major congenital malformations was 7.7%, and for lamotrigine at or above 300 mg/d it was 3.6%.12 Although these dose effects have been debated in the literature, the large sample sizes in this prospective international study are convincing, especially in light of the biological plausibility. Family history of major congenital malformations was also a significant factor in the occurrence of major congenital malformations in exposed offspring (Table 3-3).12

Table 3-3.

Author’s Stratification of Risk for Antiepileptic Drugs Structural Teratogenesis (Occurrence of Major Congenital Malformations)

COGNITIVE TERATOGENESIS WITH ANTIEPILEPTIC DRUGS

Developmental delays associated with in utero AED exposure were initially described as part of the fetal antiepileptic drug syndrome. This syndrome is characterized by a variable set of malformations but always includes “minor” congenital malformations. The minor malformations are cosmetic rather than life-threatening. Their existence should be determined by careful measurement using comparisons to population normative values, because it has been demonstrated that relying on observation alone is not a sensitive method.22 These malformations include craniofacial dysmorphic features, such as a flat nasal bridge, epicanthic folds, a prominent upper lip over wide mouth, and hypertelorism. Fingernail and distal phalanx hypoplasia may be present. Microcephaly and facial clefts (a major malformation) are also described in association with the fetal AED syndrome, as well as developmental delay.23

While the initial reports of minor congenital malformations in babies exposed in utero to AEDs are from the 1970s, more recent reports confirm that minor congenital abnormalities are highly correlated with the occurrence of decreased verbal IQ, performance IQ, and full-scale IQ.22,24 From a 2005 study of 76 children whose mothers took AEDs in pregnancy, the investigators concluded that either midface hypoplasia or digital hypoplasia in a neonate exposed to AEDs in utero should prompt a developmental evaluation.24

Another influential study in this field was put forth by Reinisch and colleagues in 1995.25 The investigators evaluated adult men exposed to phenobarbital in utero and an unexposed, age-matched control group, and found that phenobarbital exposure during gestation was associated with a seven-point reduction in verbal IQ compared to controls. Notably, the mothers of the study subjects did not have epilepsy and used phenobarbital during pregnancy for other conditions, such as blood pressure control and anxiety treatment.25 The investigators’ important findings include the specific vulnerability of verbal IQ compared to other cognitive domains, which has been borne out in subsequent studies with other AED exposures. Further, they found that third trimester exposure imparted greater risk than first trimester exposure.25 This report also led to the appreciation that subtle but clinically important cognitive teratogenesis occurs in the absence of any dysmorphism. Conversely, major congenital malformations have not been shown to be associated with lower verbal IQ.26

Two subsequent retrospective studies showed a risk of significantly lower verbal IQ in children exposed in utero to valproate as compared to other AED exposures or to nonexposed children.27,28 In the study by Vinten and colleagues in 2005, 249 children between the ages of 6 and 16 years with in utero AED exposures were evaluated. Valproate-exposed children were more likely to have a verbal IQ lower than 69. Importantly, maternal IQ was controlled for in this study, indicating that the adverse effect occurred independently of the influence of maternal IQ.27 The 2004 study by Gaily and colleagues was performed with the investigators masked to the exact AED exposure; they evaluated 182 school-aged children whose mothers were treated for epilepsy.28 Again, verbal IQ was significantly lower than expected in children with a history of valproate exposure as either polytherapy or monotherapy. The average verbal IQ in these groups was 82 and 85, respectively, while carbamazepine-exposed children had an average verbal IQ of 95—not different from a control group, which implied no risk with carbamazepine exposure.28 Doses and serum AED levels were evaluated in this study; notably, the median valproate dose was 950 mg/d, which is thought to be a relatively safe dose for structural teratogenesis.

The need for prospective, well-controlled studies to evaluate the effects of AEDs on cognitive outcomes in offspring exposed to AEDs in utero was recognized and funded by the National Institute of Neurological Disorders and Stroke (NINDS). The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is an ongoing, prospective, observational, nonrandomized but assessor-masked, multicenter study performed at 25 sites in the United States and United Kingdom. The offspring of women with epilepsy taking one of four monotherapy AEDs (phenytoin, lamotrigine, valproate, and carbamazepine) during pregnancy were evaluated. Three reports on the outcomes of this study are available, tracking the cognitive development of 224 enrolled children at 3 years,29 4.5 years,30 and 6 years of age.31 Findings in this study have been consistent as the children have grown, with an overall trend of improvement in cognitive abilities in all groups across the evaluation period.31 In all NEAD reports, valproate exposure was associated with adverse cognitive outcomes. This finding emerged at the earliest interim analysis point, where maternal IQ was highly associated with the children’s IQ for all exposures except valproate, for which there was a clear dissociation with the children’s IQ falling below the predicted range based on the maternal IQ.29

The primary outcome of the NEAD study was IQ at age 6 years. After a multivariate analysis, the finding is that children exposed in utero to valproate had a significantly lower IQ (mean 97, 95% CI 94 to 101) than those exposed to carbamazepine (mean 105, 95% CI 102 to 108; P=.0015), lamotrigine (mean 108, 95% CI 105 to 110; P=.0003) or phenytoin (mean 108, 95% CI 104 to 112; P=.0006). A dose effect, with worse cognitive scores associated with higher maternal medication doses, was present for valproate but not for the other AEDs. The valproate dose effect was found across all cognitive domains including IQ, verbal ability, nonverbal ability, memory and executive function.31

The vulnerability of verbal IQ development to in utero AED exposure was supported by the NEAD study findings. Although the study had no unexposed control group to provide comparison, verbal abilities were lower than nonverbal abilities for all AED exposures. Left-handedness was more frequent in the overall study group and was most markedly increased in the valproate- and lamotrigine-exposed groups compared to expected rates. These interesting findings prompted the investigators to speculate that AED exposure may alter the development of cerebral lateralization.31

Determining a preventive effect of folate supplementation on AED-associated major congenital malformations has been elusive,12 but this was not the case for cognitive teratogenesis according to the NEAD study findings. The mean IQs were higher in children exposed to periconceptional folate (mean 108, 95% CI 106 to 111) than they were in unexposed children for all AEDs (mean 101, 95% CI 98 to 104; P=.0009).31

Levetiracetam is one of the most widely used AEDs, including in women of childbearing potential who have epilepsy. This is appropriate because emerging evidence indicates a low risk for structural teratogenesis. Regarding the evidence for risk of cognitive teratogenesis with levetiracetam, a recent report suggests that levetiracetam exposure also carries less risk of developmental delay than valproate and no risk increase over unexposed controls.32 These data should be considered preliminary; the AED groups were small, consisting of 51 levetiracetam-exposed and 44 valproate-exposed children each, and the children were tested at less than 2 years of age using a developmental scale, since IQ tests cannot be used at this early age.32 The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study33 follows on the findings of the NEAD study and will include a levetiracetam-exposed group of offspring, which will augment these findings (Table 3-4).

Table 3-4.

Summary of Risk Management for Cognitive Teratogenesis

Autism and In Utero Valproate Exposure

One of the most convincing initial reports on the association between in utero valproate exposure and autism spectrum disorder was by Bromley and colleagues in 2008.34 In this prospective study of the offspring of women with epilepsy and an untreated nonepileptic control group, 6.3% of valproate-exposed children had autism spectrum disorder or key symptoms of this disorder (language impairment, reduced attention, social difficulties) compared to 0.9% of the control children, a sevenfold increase in occurrence.34 In the NEAD study, behavioral problems were also found in the valproate-exposed children; parents of these children reported a decline in social skills and the presence of hyperactive behaviors, suggesting a risk for the development of attention deficit hyperactivity disorder.35 The autism and valproate association was confirmed in a recent population-based retrospective study using Danish national medical registers.36 In this population, children exposed to valproate and other AEDs in utero, as well as unexposed children, were identified for occurrence of autism. In valproate-exposed children, the absolute risk of autism spectrum disorder was 4.42% and of childhood autism was 2.95%. By comparison, in the overall population, the absolute risk of autism spectrum disorder was 1.53% and of childhood autism was 0.48%. No increased risk was evident with other AED exposures, and no significant increase in risk was imparted by maternal epilepsy itself.36 These two studies34,36—the Bromley and colleagues report and the Danish study performed using national medical registries—performed by differing methods show similar absolute and relative risks of autism spectrum disorder and autism in children exposed to valproate in utero. Further, as with other teratogenic outcomes, an increased risk with valproate compared to other AEDs is present (Table 3-5).

Table 3-5.

Autism and Valproate: Autism Spectrum Disorder Risk

RISKS OF SEIZURES DURING PREGNANCY

The immediate risk of a seizure to the developing fetus is difficult to quantify. Certainly, a generalized seizure could cause trauma that would put the pregnancy at risk. However, prevention of trauma, injury, drowning, and sudden unexpected death due to seizures is important for the nonpregnant as well as the pregnant epilepsy population and is in great part the motivation for treatment. Case reports have been published of fetal heart rate decelerations in association with focal seizures.37,38 However, systematic evaluations of this issue must be extrapolated from the obstetric literature, in which fetal heart rate changes following eclamptic convulsions are well described.39 These include fetal bradycardia, transient late decelerations, decreased beat-to-beat variability, and compensatory tachycardia. These changes are thought to be caused by maternal hypoxia and reverse within 3 to 10 minutes after the convulsion terminates.39

The EURAP study enrolled patients from Europe, India, and Australia and reported on 1956 pregnancies in women with epilepsy who were followed prospectively. Status epilepticus occurred in 36 pregnancies (1.8%) and was convulsive in 12. It resulted in one stillbirth and no miscarriages or maternal deaths.40

It is not the case, however, that seizures during pregnancy are without adverse consequences. One intriguing study showed that 5 or more convulsive seizures during pregnancy was independently associated with lower verbal IQ in the offspring; children were tested at age 6 years and older. Verbal IQ was approximately seven points below that of offspring of mothers without seizures during pregnancy.26 The mechanism for this effect is not known.

Another important study from the Taiwanese birth certificate registry showed that, for women with epilepsy, seizures during pregnancy were associated with an increased risk of offspring who were small for gestational age compared with women with epilepsy who did not have seizures during pregnancy (OR 1.34; 95% CI 1.01 to 1.84).41 This study is remarkable because none of the women with epilepsy in this study took AEDs41; therefore, a major confounder for the occurrence of small-for-gestational-age offspring42 was not present.

The pregnancies in women with epilepsy are also at risk simply due to the fact that women with epilepsy appear to have a much higher rate of death either during pregnancy or within 42 days of pregnancy termination, according to data from the UK Confidential Inquiry Into Maternal Deaths.26 The rate of maternal deaths for women with epilepsy is estimated to be 10 times higher than expected in the general population. Available details of some cases point to the cessation of medication, poor compliance, and seizures as possible causes. These sobering findings point up the importance of seizure prevention with effective treatments in women with epilepsy. They also underscore the need for an open understanding between the patient and the provider that the patient will discuss any AED changes before undertaking them on her own, especially in the case of an unexpected pregnancy.

SEIZURE CONTROL DURING PREGNANCY

Using retrospective studies, with patients as their own control, the AAN practice parameters reported that 80% to 90% of women with epilepsy who were seizure free for 9 to 12 months before pregnancy were likely to remain so during pregnancy.4 These findings are reassuring and suggest that the physiologic changes of pregnancy do not in general adversely affect seizure threshold. Similar results were reported from the EURAP study, in which data were prospectively obtained, using the first trimester seizure frequency as a comparison for the second and third trimesters.40 These investigators did report small proportions of either seizure frequency increase (17.3%) or decrease (15.9%) during pregnancy, consistent with previous information.4 In the EURAP study, use of oxcarbazepine as monotherapy was associated with seizure occurrence.40 Further, AED dose increases occurred more frequently in the oxcarbazepine- and lamotrigine-treated subjects, probably reflecting the need for treatment of ongoing seizures with use of these AEDs.

In another recent publication during which seizure frequency in women with epilepsy was documented before pregnancy as well as during pregnancy, the prepregnancy seizure occurrence was highly predictive of the course of seizure activity during pregnancy.43 Seizure relapse was most likely during the second and third months and again in the sixth month.43 The investigators found that oxcarbazepine and other AEDs used as monotherapy were associated with an increased risk of seizure occurrence, but that valproate was associated with a lower risk of seizure occurrence. Overall, polytherapy was associated with the risk of seizures during pregnancy, consistent with a more severe underlying seizure disorder.43 Both of these studies showed that seizures occurring around the time of delivery were highly associated with prior seizure occurrence.40,43 Seizures during labor occurred in 3.5% of subjects in the EURAP study.40 Seizures during the month before conception was associated with a 3.7-fold increase in the risk of seizures in the peripartum period in the second study.43

MANAGEMENT OF ANTIEPILEPTIC DRUG LEVELS DURING PREGNANCY

It is important that patients who are pregnant or planning pregnancy understand and anticipate that serum AED levels should be checked during pregnancy, when levels of AEDs generally tend to decrease.6 Ideally, an individual therapeutic level at which the patient is doing well is documented, thereby providing a target level to maintain during pregnancy. Induction of AED metabolism by the high hormone levels of pregnancy is the main cause of decreased levels, and this will affect both total and unbound compartments of the circulating AEDs.44 Glucuronidation is markedly induced by pregnancy, which is the main metabolic avenue for lamotrigine and oxcarbazepine. This probably explains the increased risk of seizures reported with use of these AEDs during pregnancy and also indicates that frequent monitoring and dose adjustment should be undertaken when women are using these AEDs. Carbamazepine levels remain little changed during pregnancy.6,44 Topiramate and valproate also decline less than other AEDs during pregnancy, from 10% to 30%. Other AEDs for which there is information regarding a decline in levels during pregnancy from 40% to 70% include levetiracetam, phenytoin, phenobarbital, and zonisamide.44

These changes during pregnancy have much interindividual variability. Within-individual changes may be morepredictable as a result of genetically imparted metabolic capacity. Therefore, a simple AED monitoring recommendation is to monitor AED levels monthly (or every 2 weeks at the beginning of pregnancy for oxcarbazepine and lamotrigine), aiming to maintain the predetermined therapeutic level. Ongoing monitoring can be based on this initial information; however, obtaining levels monthly throughout pregnancy is reasonable, keeping in mind that the maximum period of metabolic induction is in the third trimester.44 Allowing the level to drift below the therapeutic target level may be risky, since many women with epilepsy are titrated to the lowest effective level before pregnancy.44

At this time, changes in levels during pregnancy have not been studied for pregabalin, lacosamide, and retigabine.

FOLIC ACID USE DURING PREGNANCY

Folic acid supplementation during pregnancy has been associated with a risk reduction in the occurrence of congenital malformations, including neural tube defects, of approximately 50%.45 The importance of folic acid supplementation is a widely accepted general health measure. Since 1998, by US federal mandate, folic acid has been added to cold cereals, flour, breads, pasta, bakery items, cookies, and crackers. The American College of Obstetricians and Gynecologists (ACOG) advocates that women with epilepsy take a folic acid dose of 4 mg/d,46 although the effectiveness of this dose versus lower doses in the absence of a family history of neural tube defects has not been established. Two important studies have not shown a benefit of folic acid supplementation in reducing the risk of major congenital malformations.12,47 These findings imply that the mechanism of AED-associated major congenital malformations does not primarily involve folate mechanism. However, the NEAD study showed a clear benefit in reduction of cognitive teratogenesis with folic acid supplementation. In another recent publication using a subset of the EURAP population, folic acid supplementation before pregnancy reduced the risk of spontaneous abortion in women with epilepsy.48 Folic acid supplementation is recommended for women of childbearing potential who have epilepsy, and in keeping with ACOG guidelines, 4 mg/d is often used during preconception and pregnancy.

OBSTETRIC RISKS

The evidence cited in the AAN and American Epilepsy Society practice parameters showed that for women with epilepsy taking AEDs, there was probably no substantially increased risk (meaning that the risk was not more than twice the expected risk) of cesarean delivery or late-pregnancy bleeding, and probably no moderately increased risk (meaning that the risk was not more than 1.5 times the expected risk) of premature contractions or premature labor and delivery.4 However, in a population-based study published subsequent to the AAN report,49 women with epilepsy who took AEDs had an increased risk of mild preeclampsia (OR 1.8, 95% CI 1.3 to 2.4), gestational hypertension (OR 1.5, 95% CI 1.0 to 2.2), vaginal bleeding late in pregnancy (OR 1.9, 95% CI 1.1 to 3.2), and delivery before 34 weeks of gestation (OR 1.5, 95% CI 1.1 to 2.0) compared to women with epilepsy not taking AEDs, who in turn did not differ from the general population.49 Although these analyses do not greatly differ in that the obstetric risks are still relatively low, the strength of evidence imparted by large, population-based studies is likely to tip the scales toward an increase in obstetric risks. These findings support a recommendation that women with epilepsy taking AEDs who are contemplating pregnancy should be counseled that they are at increased risk for pregnancy complications, including premature delivery.

Recent evidence from the NEAD study also indicates a risk for offspring who are small for gestational age with in utero valproate exposure42 compared to the other AED exposures. A study using the Finnish national health register also indicates an association between AED use in women with epilepsy and increased neonatal risks, including a low 5-minute Apgar score and the need for transfer to a neonatal intensive care unit.50

ADVISING A PATIENT WHO IS CONTEMPLATING PREGNANCY

Several clear tenets serve to assist in answering the question of how best to provide care for a patient contemplating pregnancy. First, the patient’s seizures should be well controlled, particularly generalized convulsions. An individualized therapeutic level should be established with at least two serum values before pregnancy. Secondly, the AED used should not be valproate or phenobarbital, if possible. If valproate or phenobarbital must be used because of failure or intolerability of other meds, the lowest effective dose should be used (ideally below 750 mg/d for valproate) and folic acid supplementation should be given. In general, to decrease risk, the lowest dose of the most streamlined regimen should be achieved, with monotherapy if possible. Thirdly, the physician and patient should have a clear understanding of the risks given the individual circumstances, and a plan for how to manage them. A plan for monitoring AED levels and what to do in the setting of declining levels should be discussed. Some women with epilepsy may not be taking AEDs, and discussion of how to manage seizure recurrence should be discussed. Women with epilepsy should hear that no health care provider can guarantee that the pregnancy will result in a healthy baby, since many factors, including genetic influences, are outside the scope of medical management. They should also hear that in almost 2% of pregnancies in the general population, in women not taking medications, babies are born with a major congenital malformation. If the patient is taking topiramate, she should understand the small but increased risk of facial cleft, and discuss whether the AED should be changed before conception, based on factors such as response to topiramate treatment, family history, and previous AEDs used. Both the patient and the caregiver need to have a certain amount of confidence in the available data to navigate the decisions and to accept the risks and a willingness to work hard together for a most worthy outcome, a child. The management paradigm is presented in Table 3-6.

Table 3-6.

Management of Epilepsy During Pregnancy^a

Case 3-1 demonstrates management strategies and pitfalls for a woman with primary generalized epilepsy.

Case 3-2 demonstrates the challenges of managing seizures that have not been well controlled early in pregnancy.

Case 3-1

A 27-year-old right-handed woman with a history of juvenile myoclonic epilepsy since 17 years of age was considering becoming pregnant. She was in a long-term relationship and had been using condoms for birth control. She took low-dose valproate at 750 mg/d and had no seizures for 2 years and rare myoclonus premenstrually. Her previous generalized tonic-clonic seizures only occurred when she missed her medication or was sleep deprived. Although extremely reluctant to consider changing medications, she was gradually cross-tapered to levetiracetam because of teratogenic concerns. She tolerated levetiracetam at a dose of 1500 mg twice per day but had another generalized tonic-clonic seizure. She was then restarted on valproate, and lamotrigine was added to her regimen. She gradually tapered off valproate and was maintained on lamotrigine at 500 mg/d with levels of 6 μg/mL to 7 μg/mL. She had no seizures and generally felt well.

She continued on lamotrigine monotherapy, became pregnant after stopping use of condoms, and did well during the first two trimesters of pregnancy, with an increase in her dose of lamotrigine from 500 mg/d to 800 mg/d. However, she had several generalized tonic-clonic seizures in 1 day at 26 weeks when her lamotrigine level had decreased to 5 μg/mL. She was also tired and stressed during pregnancy. Her lamotrigine dose was gradually increased to 1000 mg/d based on levels checked twice per month. On this dose, at 34 weeks, her level had increased to 12 μg/mL. She began to experience dizziness and mild discoordination, thought to be adverse effects of lamotrigine. She had several more generalized tonic-clonic seizures at 35 weeks, and levetiracetam was added to her regimen at 500 mg twice per day, while lamotrigine was decreased to 800 mg/d. She had no further seizures and delivered a healthy baby at 39 weeks.

Comment. This case illustrates that with primary generalized epilepsy, such as juvenile myoclonic epilepsy, for which valproate is often a very effective medication, the patient can be successfully transitioned to a less teratogenic antiepileptic drug. With careful monitoring of her lamotrigine levels, she did well during most of the pregnancy.

However, this case also illustrates the pitfalls of lamotrigine use during pregnancy, as well as the susceptibility of some women to seizures late in pregnancy. Her lamotrigine levels were monitored frequently and followed by dose adjustment, but the usual proportional dose-to-level relationship became unpredictable, as might be expected with the complex influence of pregnancy reproductive hormones on lamotrigine metabolism. She began to have seizures again, even with increased lamotrigine levels to the point of mild toxicity. With the addition of levetiracetam, a medication she had previously tolerated, she safely continued the pregnancy.

Case 3-2

A 24-year-old right-handed woman presented after having her first generalized tonic-clonic seizure during the daytime. Further history revealed that she had been having abnormal nocturnal behavior for the previous 6 months. Her video-EEG showed left frontal low-amplitude fast activity progressing to hemispheral rhythmic slowing during the nocturnal events. Her behavior consisted of raising her right arm and striking it against the pillow, as well as flexor posturing of the left arm. The patient smiled during the events but did not vocalize and did not always remember them, although in general she could count how many spells had occurred in the night. The events occurred out of sleep without warning. Her brain MRI was normal. She was recently married and using condoms for birth control.

She had difficulty accepting the diagnosis of epilepsy and reluctantly took oxcarbazepine at a dose of 1200 mg/d. Because of inadequate seizure control, levetiracetam was briefly added to her regimen but caused severe sedation. Lamotrigine was added at 25 mg twice per day with a plan to escalate the dose.

She was not planning pregnancy but, on the day of a scheduled positron emission tomography (PET) scan as part of a presurgical evaluation, discovered that she was 5 weeks pregnant. Her seizures had increased from two to three per night to six to seven per night at this point. The lamotrigine was stopped and oxcarbazepine increased to 1500 mg/d in an attempt to control the seizures on monotherapy, but her seizure frequency remained unchanged. At 9 weeks gestation, she had another secondarily generalized tonic-clonic seizure and was hospitalized. She was having 10 nocturnal seizures per day on video-EEG monitoring. Phenytoin was added to her regimen with a 1000 mg oral loading dose in divided doses. The seizures decreased to two per night, and a maintenance dose of 200 mg phenytoin twice daily was started, with a phenytoin level of 15 μg/mL. Since she was responding to the phenytoin, an attempt was made to decrease the oxcarbazepine, but the seizures again increased to 8 per night. She was then maintained on oxcarbazepine at 600 mg twice per day and phenytoin 200 mg twice per day, with levels of phenytoin at 17 μg/mL to 18 μg/mL and free levels of 1.8 μg/mL. She remained seizure free on this regimen and delivered a healthy baby girl at 39 weeks gestation.

Comment. This case illustrates the challenges of poorly controlled seizures before pregnancy and the risk of worsening seizures at the beginning of pregnancy, likely due to a decrease in the level of oxcarbazepine caused by pharmacokinetic effects of reproductive hormones. While phenytoin is a well-known antiepileptic drug used readily when seizures are escalating in the nonpregnant patient, this case prompts a review of existing data on the teratogenic effects of phenytoin. The recent data from pregnancy registries and cognitive outcome studies are reassuring regarding phenytoin. Further, one of the main issues for using phenytoin during pregnancy, which is management of levels, are stable for this patient.

KEY POINTS

• Low birth rates are not the same as infertility.

• Psychosocial factors play a role in lower birth rates to women with epilepsy.

• Medical factors contributing to lower birth rates to women with epilepsy include severe neurologic disability and antiepileptic drug polytherapy.

• The assessment of structural teratogenesis is much different than the assessment for cognitive teratogenesis.

• Structural teratogenesis is due to first trimester exposure, while cognitive teratogenesis is a likely risk with exposure throughout pregnancy.

• Dose-related risks are likely to be present with most antiepileptic drug intrauterine exposure.

• The most clearly demonstrated dose-related risk is a marked increase in risk with maternal use of valproate at more than 700 mg/d.

• For antiepileptic drugs with large numbers of exposures, such as carbamazepine, lamotrigine, phenytoin, and levetiracetam, the estimates of risks for major congenital malformations is precise. For less frequently used or newer antiepileptic drugs, such as zonisamide, oxcarbazepine, clonazepam, topiramate, and phenobarbital, the estimates are less precise, and larger numbers of exposure must be evaluated in order to determine the actual risk.

• Little information regarding lacosamide is available at this time.

• The risk of midline defects, such as facial clefts, spina bifida, and hypospadias, may be increased with in utero exposure to several antiepileptic drugs. However, the risk of these defects is much greater with valproate exposure.

• In the Neurodevelopmental Effects of Antiepileptic Drugs study, in utero valproate exposure was associated with impaired cognitive development; IQ at 6 years of age was lower after exposure to valproate than to carbamazepine, lamotrigine, or phenytoin.

• Adverse effects of seizures in pregnancy include (1) maternal death from seizures when antiepileptic drugs are abruptly stopped; (2) infants who are small for their gestational age; (3) decreased verbal IQ in offspring when five or more convulsive seizures occur during pregnancy; and (4) fetal heart rate alterations during convulsive seizures.

• Women with epilepsy should be advised that folic acid use does not eliminate the risk of major congenital malformations associated with antiepileptic drug use.

• Folic acid use during preconception and pregnancy in women with epilepsy decreases the risk of lowered verbal IQ caused by antiepileptic drug exposure. It also decreases the risk of spontaneous miscarriage.