Pregnancy in women who have epilepsy Page B. Pennell, MD

Neurol Clin 22 (2004) 799–820

Emory Epilepsy Program, Department of Neurology, Emory University School of Medicine, 101 Woodruff Circle, Suite 6000 Atlanta, GA 30322, USA

More than one million women who have epilepsy in the United States are in their active reproductive years and give birth to more than 24,000 infants each year. It is estimated, however, that the total number of children in the United States exposed in utero to antiepileptic drugs (AEDs) is nearly two times that amount with the emergence of AED use for other illnesses, including headache, chronic pain, and mood disorders [1], and AEDs are one of the most frequent teratogen exposures for all pregnancies [2,3]. Many of the principles about AED use during pregnancy outlined in this article can be extrapolated to women who have any disorder treated with these agents.

Although the majority of women who have epilepsy have a normal pregnancy with favorable outcomes, they do have increased maternal and fetal risks compared with the general population. Careful planning and management of any pregnancy in a woman who has epilepsy is essential to minimize these risks. The reduction of these risks begins with preconcep- tional planning. The initial visit between the physician and a woman of childbearing age who has epilepsy should include a discussion about family planning. Topics should include effective birth control, the importance of planned pregnancies with AED optimization and folate supplementation before conception, obstetric complications, and teratogenicity of AEDs versus the risks for seizures during pregnancy. The goal is effective control of maternal seizures with the least risk to the fetus.

Funding supported by a Specialized Center of Research grant P50 MH68036 from the National Institutes of Health.

Dr. Pennell has received speaking honoraria from GlaxoSmithKline (Durham, NC); UCB Pharma (Smyrna, GA); Novartis (Morristown, NJ); and Pfizer (Cambridge, MA); Dr. Pennell has received consulting fees from Ortho-McNeill (Raritan, NJ); Novartis, GlaxoSmithKline, and Elan Pharmaceuticals (San Diego, CA). Dr. Pennell has received re- search support from GlaxoSmithKline and Pfizer.

E-mail address: page_pennell@emoryhealthcare.org

0733-8619/04/$ – see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2004.07.004

800 P.B. Pennell / Neurol Clin 22 (2004) 799–820 Birth control for women taking antiepileptic drugs

Careful planning requires effective birth control. Many of the AEDs induce the hepatic cytochrome P-450 system, which also is the primary metabolic pathway of the sex steroid hormones. The resulting increased enzymatic activity can lead to rapid clearance of steroid hormones and allow ovulation in women taking oral contraceptives or other hormonal forms of birth control [4,5]. In 1998, the recommendation in the guidelines by the American Academy of Neurology was to use an estradiol dose of 50 lg or its equivalent for 21 days of each cycle when using oral contraceptive agents with the enzyme-inducing AEDs [6]. More recently, however, it is re- cognized that this still is inadequate protection against pregnancy, and a backup barrier method is recommended. Patients need to be warned that midcycle bleeding indicates possible birth control failure, but its absence does not indicate adequate birth control efficacy. Table 1 lists effects of the individual AEDs on hormonal contraceptive agents [5,7,8]. Subdermal levonorgestrel (Norplant) and the newer transdermal patch formulation have a higher failure rate with these AEDs [9]. Intramuscular medrox- yprogesterone provides higher dosages of progestin but still may require dosing at 8- to 10-week intervals rather than 12-week intervals. This has not been evaluated fully for women taking AEDs.

The fetal anticonvulsant syndrome

Offspring of women who have epilepsy are at an increased risk for intrauterine growth retardation, minor anomalies, major congenital malformations, cognitive dysfunction, microcephaly, and infant mortality [10,11]. The term, ‘‘fetal anticonvulsant syndrome,’’ is used to include various combinations of these findings and has been described with virtually all the AEDs [12,13].

Intrauterine growth retardation results in low birth weight (less than 2500 g) in 7% to 10% of infants born to women who have epilepsy [10,11] and is even more prevalent in infants exposed to polytherapy [14].

Table 1

Antiepileptic drug effects on hormonal contraceptive agents

Lowers hormone levels

Phenobarbital Phenytoin Carbamazepine Primidone Topiramate Oxcarbazepine

No significant effects

Ethosuximide Valproate Gabapentin Lamotrigine Tiagabine Levetiracetam Zonisamide

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Minor anomalies

Minor anomalies are defined as structural deviations from the norm that do not constitute a threat to health. Minor anomalies affect 6% to 20% of infants born to women who have epilepsy, an approximately 2.5-fold increased rate compared with that of the general population [15]. Minor anomalies seen in infants of mothers taking AEDs include distal digital and nail hypoplasia and the midline craniofacial anomalies, including broad nasal bridge, ocular hypertelorism, epicanthal folds, short upturned nose, altered lips, and low hairline [15,16]. Many of the craniofacial anomalies are outgrown by age 5, but the digital and nail hypoplasias are more likely to persist.

Major malformations

Major malformations are defined as abnormalities of an essential anatomic structure present at birth that interfere significantly with function or require major intervention. Major malformations occur in 2% to 3% of the general population births; reported rates in offspring of women who have epilepsy range from 1.25% to 11.5%, with the combined estimates yielding a rate of 4% to 7% [6,17–19].

Major malformations (Table 2) most commonly associated with AED exposure include congenital heart disease, cleft lip/palate, urogenital defects, and neural tube defects (NTDs) [15,16]. The congenital heart defects include atrial septal defect, ventricular septal defect, patent ductus arteriosus, pulmonary stenosis, coarctation of the aorta, and tetralogy of Fallot. Urogenital defects commonly involve glandular hypospadias.

NTDs are malformations of the central nervous system and its membranes because of faulty neuralation or abnormal development of the neural tube. The NTDs associated with AEDs usually are lower defects but tend to be severe open defects frequently complicated by hydrocephaly and other midline defects [20]. Some studies identify spina bifida aperta, which is an open defect with failure of the neural tube to close over the spinal cord, as the NTD most commonly associated with valproic acid (VPA) or carbamazepine (CBZ) exposure. Other types of NTDs associated with AED exposure include myelomeningocele and, rarely, anencephaly. The abnor- mal neural tube closure usually occurs between the third and fourth weeks

Table 2

Major malformations in infants of women who have epilepsy

Congenital heart Cleft lip/palate Neural tube defect

Urogenital defects

General population

0.5% 0.15% 0.06%

0.7%

Infants of women who have epilepsy

1.5%–2%

1.4%

1%–3.8% (VPA) 0.5%–1% (CBZ) 1.7%

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of gestation. By the time most women realize they are pregnant, it is too late

to make medication adjustments to avoid malformations (Table 3). Antiepileptic drug polytherapy during pregnancy

The risk for major malformations is consistently higher across studies for women on AED polytherapy regimens compared with women on AED monotherapy regimens [13,21–28]. In one study, the rate of major malformations increased to 25% for those women taking four or more AEDs [29]. Another study in Japan of 172 deliveries reports that the infants exposed to AED monotherapy had a malformation rate of 6.5%, whereas the infants exposed to polytherapy had a malformation rate of 15.6% (P=0.01) [23]. Comparison of two cohorts of patients from different intervals at the same Canadian institution found that the prevalence of major malformations was significantly different between groups (24.1% versus 8.8%; P \ 0.01), and the decreased prevalence correlated with the proportion of patients receiving AED monotherapy and a smaller mean number of drugs [30]. A prospective study in southeast France also reports that the rate of malformations was higher in infants exposed to polytherapy (15%) than in those exposed to monotherapy (5%) (P \ 0.01) [22]. These consistent results have led to the recommendation that AED monotherapy is preferred to polytherapy during pregnancy and should be achieved during the preconception planning phase [13,15].

Antiepileptic drug monotherapies during pregnancy

Features of the fetal anticonvulsant syndrome are described in association with virtually all the AEDs, but there are some differences in the likelihood of specific malformations with the different AEDs [13,31].

In a comparison between two cohorts [25], representing different prescribing practices, the older cohort (1972–1979) had more women taking phenobarbital (PB), primidone (PRM), and phenytoin (PHT) than the later cohort. The features of this cohort were congenital heart defects, facial clefts, developmental retardation, and minor anomalies. The newer cohort (1981–1985) represented more monotherapy with VPA or CBZ, and the

Table 3

Relative timing and developmental pathology of certain malformations

Tissues

Central nervous system Heart

Face

Malformations

Neural tube defect Ventricular septal defect Cleft lip

Cleft maxillary palate

Postconceptional age

28 days

42 days

36 days 47–70 days

From Moore K. The developing human: clinically oriented embryology. 4th edition. Philadelphia: WB Saunders; 1988.

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malformations identified most frequently were NTDs and glandular hypospadias.

Arpino et al [12] report findings from an international database for surveillance of infants who have malformations. Of the 299 cases of major malformations with first-trimester AED exposure, associations were found for spina bifida with VPA; for oral clefts with PB and methylphenobarbital (MPB); for cardiac malformations with PB, MPB, VPA, and CBZ; and for hypospadias with VPA.

In a recent study [32], the frequencies of most of the embryopathy findings were increased in the 87 infants exposed to PHT monotherapy compared with control infants. One congenital anomaly reported commonly in infants exposed to PHT, with or without PB, is marked hypoplasia of the nails and stiff joints [33,34].

In a prospective study of 970 pregnancies of women from 1980 to 1998 who had epilepsy, major malformations were detected in 3.8% of the fetuses exposed to AEDs during the first trimester and in 0.8% of fetuses born to women who had a history of epilepsy but were not taking AEDs (P = 0.02). [19]. After logistic regression analysis, the occurrence of major malforma- tions was associated independently with the use of CBZ (adjusted odds ratio [OR] 2.5; 95% confidence interval [CI], 1.0 to 6.0), use of VPA (adjusted OR 4.1; CI, 1.5 to 11), low serum folate concentrations (adjusted OR 5.8; CI, 1.3 to 27), and low maternal level of education. They included polytherapy and monotherapy together, however, when analyzing each medicine.

In the analysis by Samre ́ n et al [27] of the European prospective studies, the relative risk (RR) for a major malformation in children exposed to CBZ monotherapy was 4.9 (95% CI, 1.3 to 18.0). In the study by Holmes et al [32], the frequency of major malformations, microcephaly, and growth re- tardation, but not of facial or digit hypoplasia, was higher in the 58 infants exposed to CBZ monotherapy. For NTDs, Rosa [35] reports that 1% of CBZ- exposed infants had spina bifida. Data from an ongoing case-control study in the United States and Canada compares data on 1242 infants who have NTDs with data from a control group of infants who have malformations not related to vitamin supplementation. They report that the adjusted OR of NTDs related to exposure to CBZ is 6.9 (95% CI ,1.9 to 25.7) [36].

A recent review pooled data from prospective studies and analyzed 1255 cases of exposure to CBZ [37]. Among 1255 CBZ-exposed children, 85 (6.7%) were described as having major congenital anomalies compared with 88 (2.34%) of 3756 control children (P \ 0.05; OR 3.02; 95% CI, 2.56 to 4.56). The major malformations reported most commonly were NTDs, cardiovascular and urinary tract anomalies, and cleft palate. The risk for major congenital anomalies was highest when CBZ was used in polytherapy combinations, with a rate of 18.8% (n = 99) versus 5.28% for those exposed to CBZ monotherapy. CBZ also seemed to reduce gestational age at delivery.

The RR for NTDs with valproate is at least 20 times that in the general population [38]. One analysis pooling data from five prospective studies

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suggests that the absolute risk with valproate monotherapy may be as high as 3.8% for NTDs, and that offspring of women receiving more than 1000 mg/d of valproate are at an especially increased risk [27]. Other collaborative studies support the significant dose-response relationship for valproate, with higher risks associated with doses above 1000 mg/d or with levels above 70 lg/ml [18,28,39–42].

A recent study directly compares the teratogenic effects of VPA and CBZ in monotherapy and finds that exposure to VPA monotherapy compared with CBZ monotherapy has an OR of 2.51 (95% CI, 1.43 to 4.68) for a diagnosis of malformations [43].

Currently ongoing prospective pregnancy registries hope to provide better information about the RRs of each AED. Recent prospective data from the North American AED Pregnancy Registry is available for PB and VPA. Of 77 women receiving PB monotherapy, five of the infants had confirmed major malformations (6.5%; 95% CI, 2.1% to 14.5%). Major malformations in exposed infants included one cleft lip and palate and four heart defects. When compared with the background rate for major malformations in this hospital-based pregnancy registry (1.62%), the RR is 4.2, with a 95% CI of 1.5 to 9.4 [44]. In first-trimester VPA monotherapy exposures (n=125), major birth defects occurred in 8.9% of infants compared with 2.8% in infants exposed to other AED monotherapies and 1.6% in external control infants (RR 5.43; 95% CI, 3.09 to 9.55). Birth defects were cardiac anomalies (n = 4), NTDs (n = 2), hypospadias (n = 1), polydactyly (n = 1), bilateral inguinal hernia (n = 1), dysplastic kidney (n = 1), and equinovarus club foot (n = 1) [45].

The most recent results from the lamotrigine (LTG) pregnancy registry are based on 395 monotherapy exposures during the first trimester resulting in a live birth [46]. The major malformation rate was 2.8% (95% CI, 1.4% to 5.2%). Although this still is an insufficient sample size for reaching definitive conclusions about the possible teratogenic risk of LTG, the results are encouraging for LTG monotherapy.

Results of a multicenter prospective study in Denmark of pregnant women who had epilepsy also suggest differences between AEDs. The majority of the 147 women were on monotherapy (74%) and supplemental folic acid (80%). The overall rate of major malformations was 3.1%. Of the infants of women taking LTG, the rate of major malformations was 2.0%, and of the infants of women treated with VPA, the major malformation rate was 6.7% [47]. Overall, the number of patients is too small to make statistically valid conclusions, but a consistent pattern is emerging among several of these studies.

The newest generation of AEDs consists of a large number of structurally diverse compounds, most of which demonstrate teratogenic effects in preclinical animal experiments. With the possible exception of LTG, none have sufficient human pregnancy experience to assess their safety or teratogenicity. Human birth defects are reported with oxcarbazepine

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(OXC), topiramate (TPM), gabapentin (GBP), tiagabine, levetiracetam (LEV), and zonisamide (ZNS), but accurate denominators are not available to calculate rates. Preliminary reports of experience with these agents during pregnancy are discussed later, but prospective population-based studies in postmarketing evaluation with larger numbers of outcomes are essential to establish safety in human pregnancies.

A recent series of GBP exposures during pregnancy evaluates prospective and retrospective outcomes for 51 fetuses of women who had epilepsy and other disorders, with 44 live births. No malformations were seen in the 11 patients taking GBP monotherapy. Two newborns had major malforma- tions with polytherapy exposure (VPA and PB) and one had minor anomalies (LTG) [48]. The number of outcomes is too small, however, to make any definitive conclusions.

A small case series of three women who had epilepsy and were taking LEV monotherapy (750 to 3000 mg/d) during pregnancy demonstrates no congenital malformations or developmental delays [49].

A case series from Argentina included 35 women on OXC monotherapy and all infants were healthy; of the 20 infants exposed to polytherapy with OXC, one had a cardiac malformation [50]. A prospective study from Denmark [47] included 37 women taking OXC, and two (5%) had infants with major malformations, both ventricular septal defects. One of the mothers was on OXC monotherapy and one was taking OXC with low-dose LTG. Another small series of nine infants exposed to OXC monotherapy reports one major malformation [19].

One case series reports 26 pregnancies with ZNS exposure [51]. Two of the 26 fetuses (7.7%) had major malformations, although one of these was exposed to PHT also and the other to PHT and VPA.

Preliminary results from a TPM pregnancy registry examine reports to Johnson and Johnson companies worldwide. Nineteen prospective TPM monotherapy cases show no malformations. Craniofacial/skeletal and urogenital defects are reported in four retrospective monotherapy cases, and these women tended to be on higher daily dosages (mean 850 􏰀 SD 532 mg) compared with the group that did not have malformations (mean 240 􏰀 SD 120 mg). In the prospective cases of multidrug exposure, 8 of 33 (24.2%), subjects demonstrated malformations, including craniofacial, cardiovascular, gastrointestinal, urogenital, or NTDs. These numbers are too small to make any conclusions about TPM use during pregnancy [52].

Prenatal screening

Women taking AEDs during pregnancy should be encouraged to undergo adequate prenatal screening to detect any fetal major malforma- tions. Although only a fraction of women may consider therapeutic abortions, the prenatal diagnosis of a cardiac malformation or NTD allows the appropriate specialist to establish any special plans for labor, delivery,

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and neonatal care. Surgical interventions often are indicated immediately after birth and prenatal interventions are becoming more plausible for some of the cardiac defects.

Transvaginal ultrasonography can be performed early to detect the most severe defects. NTDs should be screened for with a combination of maternal serum a-fetoprotein at 15 to 22 weeks and expert, targeted level II (structural) ultrasound at 16 to 20 weeks [6]. Ideally, the latter should be performed by a perinatologist. These tests can identify more than 95% of fetuses that have open NTDs [53,54]. Amniocentesis (with measurements of amniotic fluid a- fetoprotein and acetylcholinesterase) is not performed routinely but should be offered if these tests are equivocal, increasing the sensitivity for detection of NTDs to greater than 99%. Detailed sonographic imaging of the fetal heart can be performed at 18 to 20 weeks’ gestation and may be followed by fetal echocardiography if visualization is suboptimal. This approach can detect up to 85% of prenatally diagnosable cardiac abnormalities [54]. Careful imaging of the fetal face for cleft lip and palate can be performed at 18 to 20 weeks’ gestational age, but the sensitivity often is greater if repeated at 24 to 28 weeks. The accuracy of prenatal diagnosis is less established [54]. If the patient’s weight gain and fundal growth do not seem appropriate, serial sonography should be performed to assess fetal size and amniotic fluid [55].

Neurodevelopmental outcome

The majority of studies investigating cognitive outcome in children of women who have epilepsy report an increased risk for mental deficiency, affecting 1.4% to 6% of children of women who have epilepsy, compared with 1% of control subjects [10,56,57]. Verbal scores of neuropsychometric measures may be selectively more involved [1,21,58]. Various factors contribute to the cognitive problems of children of mothers who have epilepsy, but AEDs seem to play a role [1]. For example, children of mothers who have epilepsy have an increased risk for developmental delay but not children of fathers who have epilepsy [1,59,60]. Furthermore, children of women who have epilepsy but who take no AEDs during pregnancy have no behavioral deficits compare with matched control subjects [61].

Studies of particular AEDs report that a child’s level of IQ is correlated negatively with in utero exposure to PRM [58], PB [62], PHT [21,63], CBZ [21,37,64], VPA [21,65], and polytherapy [21,58,65]. Exposure during the last trimester may be the most detrimental [62].

A recent retrospective survey suggests an especially high risk with VPA for the neurodevelopment of children exposed in utero [65]. Compared with children of women who have epilepsy but take no AEDs, the ORs for additional educational needs were 1.49 for all children exposed to AEDs in utero and 3.4 for children exposed to VPA monotherapy. A recent study tested 182 preschool and school-age children who had prenatal exposure to AEDs and compared them to 141 control children. Eighty-six children were

P.B. Pennell / Neurol Clin 22 (2004) 799–820 807

exposed to CBZ monotherapy and 13 to VPA. Significantly reduced verbal IQ scores were found in the polytherapy group and in the VPA monotherapy group, although the latter group was confounded by low maternal education [66]. In this study, the CBZ group demonstrated no differences from control subjects in their mean verbal and nonverbal IQ scores.

Some, but not all, studies support an increased risk for poor cognitive outcome with AED polytherapy exposure in utero. A recent systematic review of prospective cohort-controlled studies of children exposed in utero to AEDs reports that four of seven studies demonstrate a poorer develop- mental outcome in children exposed to polytherapy in utero compared with monotherapy regimens [67].

Factors other than specific AED use are associated with cognitive impairment, including seizures [68], a high number of minor anomalies, major malformations, decreased maternal education, impaired maternal- child relations, and maternal partial seizure disorder [69]. It is possible that these risk factors not only are additive but also potentially synergistic.

Microcephaly is associated with in utero AED exposure [10,11]. One multicenter, prospective study finds that the risk for small head circumfer- ence is increased for polytherapy, PB, and PRM [70].

The risk for epilepsy in children of women who have epilepsy is higher (RR 3.2) compared with control children [71]. Children of fathers who have epilepsy do not demonstrate this same degree of increased risk. This may be related to the finding that the occurrence of maternal seizures during pregnancy, but not AED use, confers an increased risk for seizures in the offspring (RR 2.4) [72].

Mortality

Fetal death (fetal loss at later than 20 weeks’ gestational age) is another increased risk in women who have epilepsy. Reported stillbirth rates vary from 1.3% to 14.0% compared with rates of 1.2% to 7.8% for women who do not have epilepsy [10]. Perinatal death rates also are up to twofold higher in women who have epilepsy (1.3% to 7.8%) compared with control subjects (1.0% to 3.9%) [10]. Spontaneous abortions (before 20 weeks’ gestational age) also may occur more frequently, although figures from different studies vary considerably [6,73,74].

Potential mechanisms

The causes of the anticonvulsant embryopathy likely are multifactorial. Recent studies, however, support that anticonvulsant drugs are the most significant offending factor, more so than actual traits carried by mothers who have epilepsy, environmental factors, or possibly seizures during pregnancy [32,39,61]. A recent research group reports that infants whose mothers have a history of epilepsy but took no AEDs during pregnancy do

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not have a higher frequency of these abnormalities compared with control infants [32], including abnormalities of cognitive function [61].

Teratogenecity by AEDs likely is mediated by several mechanisms, including antifolate effects and reactive intermediates of AEDs. PHT, CBZ, PB, and PRM are associated with folate deficiency, and VPA and LTG interfere with folate metabolism [17,75,76]. The beneficial effects of folic acid supplementation are clear for lowering the risk for NTDs in women who do not have epilepsy [77,78], and it may reduce the risks for other major malformations [79]. The maximal benefit of folate is achieved, however, only with folate supplementation beginning before and continuing after conception. Because of this and the high rates of unplanned pregnancies and of late contact with a physician, all women who have epilepsy and have childbearing potential should be placed on folate supplementation of at least 0.4 mg/d [6]. In a recent study of pregnant women taking AEDs, however, a daily multivitamin supplement that included folic acid at 0.4 mg/d did not reduce the incidence of major malformations [80]. Investigators from The North American AED Pregnancy Registry recently report similar findings. Among the 505 infants born to the study participants, 34 (6.7%) had a major malformation; maternal use of folic acid at the time of conception was not associated with a statistically significant reduction in risk for having an infant who had a major malformation. The study does not speak to dosage of folic acid, and perhaps folic acid supplementation at higher dosages is more preventive in this special population of women who have epilepsy and are taking AEDs. These and other investigators recommend as much as 5 mg/d supplemental folate [80,81]. The American College of Obstetricians and Gynecologists recommends that women who have epilepsy and are treated with VPA or CBZ receive at least 4 mg/d folic acid [82].

Reactive intermediates of AEDs include free radicals (via peroxidation reactions) and oxidative metabolites, both of which may contribute to AED teratogenesis [83]. AED polytherapy especially may promote epoxide production and inhibit epoxide metabolism via epoxide hydrolase. Fetuses may benefit from AEDs, which lack epoxide intermediates (such as OXC or GBP), and avoidance of polytherapy. Selenium supplementation at 200 lg/d [84] also may be important, especially for minimizing free radical- mediated damage.

Seizures during pregnancy

The effect of pregnancy on seizure frequency is variable and unpredict- able among patients. According to recent studies, approximately 20% to 33% of patients have an increase in their seizures, 7% to 25% a decrease in seizures, and 50% to 83% no significant change [85–88]. Pregnancy is associated with physiologic and psychologic changes that can alter seizure frequency, including changes in sex hormone concentrations, changes in AED metabolism, sleep deprivation, and new stresses. One study

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demonstrates that sleep deprivation or noncompliance plays a clear role in up to 70% of women who have an increase in seizures during pregnancy [89], so it is important to inquire about sleep patterns and compliance in pregnant patients who have epilepsy. Sleep deprivation can result from physical discomforts, movements of the fetus, and nocturia. Marital and financial stress and personal doubts and concerns can contribute to sleep deprivation or cause a more direct increase in likelihood of seizure occurrence. Noncompliance with medications is common during pregnancy and is in large part the result of the strong message that any drugs during pregnancy are harmful to the fetus. Teratogenic effects of AEDs are well described, but risks to the fetus often are exaggerated or misrepresented. Proper education about the risks of AEDs versus the risks for seizures can be helpful in assuring compliance during pregnancy.

During pregnancy, the risk for seizures to the fetus is important and should be discussed thoroughly with the patient and other family members. Generalized tonic-clonic seizures (GTCSs) can cause maternal and fetal hypoxia and acidosis [10,90]. After a single GTCS, fetal intracranial hemorrhages [91], miscarriages, and stillbirths are reported [17]. A single brief tonic-clonic seizure has been shown to cause depression of fetal heart rate for more than 20 minutes [92], and longer or repetitive tonic-clonic seizures are incrementally more hazardous to the fetus and the mother. Status epilepticus is an uncommon complication of pregnancy, but when it does occur, it carries a high maternal and fetal mortality rate. One series of 29 cases reports 9 maternal deaths and 14 infant deaths [93].

It is not as clear what the effects of nonconvulsive seizures are on the developing fetus. One case report describes that during labor, a complex partial seizure was associated with a strong, prolonged uterine contraction with fetal heart rate deceleration for 3.5 minutes [94]. Many types of seizures can cause trauma, which can result in ruptured fetal membranes with an increased risk for infection, premature labor, and even fetal death [16]. Abruptio placenta occurs after 1% to 5% of minor and 20% to 50% of major blunt injuries [95]. Restrictions from driving and climbing heights should be reinforced with each patient, with special emphasis on the risk to the fetus of what otherwise seems to be a trivial injury.

In addition to the potential risks for seizures to the developing fetus, reemergence of seizures in a woman who previously experienced seizure control can be devastating. In addition to the immediate risk to herself and the fetus, the loss of the ability to drive legally can have remarkable psychosocial effects.

Antiepileptic drug management

Management of AEDs during pregnancy can be complex. Clearance of virtually all of the AEDs increases during pregnancy, resulting in a decrease in serum concentrations (Table 4) [88,96,97]. Clearance of most of the AEDs

810 P.B. Pennell / Neurol Clin 22 (2004) 799–820

Table 4

Alterations of antiepileptic drug clearance or concentrations during pregnancy

Antiepileptic drug

LTG

PHT

CBZ

PB

PRM Derived PB VPA

ESX

Reported increases in clearance

65%–230% 20%–100% 0%–20% —

— 35%–183% —

Reported decreases in total concentrations

— 55%–61% 0%–42% 55%

55%

70%

50% Inconsistent

decreases

Reported decreases in free concentrations

— 18%–31% 0%–28% 50%

— (25%–30%)a —

a Free concentrations of VPA decrease during the first two trimesters but normalize or increase by delivery.

Adapted from Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 2003;61(6 Suppl 2):S35–42, with permission.

normalizes gradually during the first 2 to 3 postpartum months. LTG metabolism, however, undergoes an exaggerated increase throughout pregnancy and quickly converts back to baseline clearance within the first few weeks post partum [98–100].

Several physiologic factors contribute to the decline in AED levels during pregnancy (Table 5) [96]. Important mechanisms include decreased albumin concentration and induction of the hepatic microsomal enzymes by the increased sex steroid hormones. The greater extent of increased LTG clearance during pregnancy probably reflects its distinctive metabolic pathway of glucuronidation. Approximately 50% of VPA elimination also is via glucuronidation and probably also accounts for its relatively higher increased clearance during pregnancy. VPA metabolism is complicated further by saturable protein binding, causing unpredictable changes in free concentrations as pregnancy progresses [101,102].

Table 5

Physiologic changes during pregnancy: effects on drug disposition

Parameter

” Total body water, extracellular fluid

” Fat stores

” Cardiac output

” Renal blood flow and glomerular flow rate Altered cytochrome P-450 activity

# Maternal albumin

Consequences

Altered drug distribution

# Elimination of lipid soluble drugs

” Hepatic blood flow leading to ” elimination ” Renal clearance of unchanged drug Altered systemic absorption and hepatic

elimination

Altered free fraction; increased availability of

drug for hepatic extraction

Adapted from Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 2003;61(6 Suppl 2):S35–42, with permission.

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The changes in AED levels during pregnancy vary widely and are not predictable for the individual based on reported group changes or total levels only for moderately to highly protein-bound AEDs. Although the ratio of free to bound drug increases during pregnancy, the amount of free AED still usually declines [96,102]. The optimal approach to monitoring AED levels during pregnancy is one that measures free levels of any AED that is highly or moderately protein bound [6]. Total levels are sufficient for AEDs that are minimally protein bound. The ideal AED (free) level needs to be established for each individual patient before conception and should be the level at which seizure control is the best possible for that patient without debilitating side effects. Levels should be obtained, at least at baseline, before conception and repeated at the beginning of each trimester and again in the last 4 weeks of pregnancy [6]. Some investigators recommend monthly monitoring, given the possibility of rapid and unpredictable decreases in AED levels in an individual patient [96,103]. The frequency of monitoring levels needs to be tailored to each situation, including increased monitoring for worsening seizure control, adverse effects, and compliance issues.

Obstetric complications

Women who have epilepsy have an increased risk for certain obstetric complications. There is an approximately twofold increased risk for vaginal bleeding, hyperemesis gravidarum, anemia, eclampsia, abruptio placentae, preterm delivery, and the need for induced labor, interventions during labor, or cesarean section [10,104]. Weak uterine contractions are described in women taking AEDs, which may account for the twofold increase in use of interventions during labor and delivery, including induction, mechanical rupture of membranes, forceps or vacuum assistance, and cesarean sections.

Neonatal vitamin K deficiency

Many of the AEDs can inhibit vitamin K transport across the placenta [105–107]. AEDs reported to induce a vitamin K deficiency in the fetus include CBZ, PHT, PB, ethosuximide (ESX), vigabatrin, PRM, diazepam, mephobarbital, and amobarbital [10,108]. Other AEDs may be involved but have not yet been studied. One report of 25 women taking AEDs found that maternal vitamin K concentrations were lower and the presence of detectable protein induced by vitamin K absence of factor II (PIVKA-II) in cord samples was higher in the AED group compared with control subjects [109]. These abnormalities reversed with the oral administration of 10 mg/day of vitamin K1 to the mothers beginning at 36 weeks’ gestational age [110]. Infant mortality from this hemorrhagic disorder is high, greater than 30%, and usually is the result of bleeding in the abdominal and pleural cavities, which leads to shock. Therefore, although the incidence of neonatal

812 P.B. Pennell / Neurol Clin 22 (2004) 799–820

hemorrhage is low, guidelines recommend prophylactic treatment with vitamin K1 administered orally as 10 mg to the mother during the last month of pregnancy and 1 mg administered intramuscularly or intrave- nously to the newborn at birth [6]. If the woman has not received supplemental vitamin K1 before labor onset, then she should receive parenteral vitamin K1. If two of the neonate’s coagulation factors fall below 5% of the normal values, intraveneous fresh frozen plasma needs to be administered [107].

Labor and delivery

The majority of women who have epilepsy have a safe vaginal delivery without seizure occurrence. One research group reports that in their epilepsy population only 1% to 2% of women had GTCSs during labor, and an additional 1% to 2% had seizures during the first 24 hours after delivery [111]. Seizures during labor and delivery, however, may be more likely to occur in women who have primary generalized epilepsy; one study reports an occurrence rate in 12.5% compared with 0% of women who had partial epilepsy [112]. Sleep deprivation may provoke seizures, and obstetric anesthesia may be used to allow for rest before delivery if sleep deprivation has been prolonged. The specific analgesic meperidine should be avoided because of its potential to lower seizure threshold.

During a prolonged labor, oral absorption of AEDs may be erratic and any emesis confounds the problem. PB, (fos)PHT, and VPA can be given intravenously at the same maintenance dosage. Convulsive seizures and repeated seizures during labor should be treated promptly with parenteral lorazepam or diazepam [111]. Benzodiazepines can cause neonatal re- spiratory depression, decreased heart rate, and maternal apnea if given in large doses, and these potential side effects need to be monitored closely. Administration of another, longer-acting AED is controversial because of the inhibitory effects on myometrial contractions [111].

GTCSs need to be treated aggressively because of the high risk for the mother and fetus, especially if they progress to status epilepticus. Oxygen should be administered to the patient and she should be placed on her left side to increase uterine blood flow and decrease the risk for maternal aspiration [55]. Prompt cesarean section should be performed when repeated GTCSs cannot be controlled during labor or when the mother is unable to cooperate during labor because of impaired awareness during repetitive absence or complex partial seizures [111].

Postpartum care

Most of the AED levels gradually increase after delivery and plateau by 10 weeks post partum. AED levels should be followed closely during this

Antiepileptic drug

CBZ PHT PB ESX PRM VPA LTG TPM ZNS LEV

Breast milk/maternal concentration

0.4–0.6 0.18–0.4 0.36–0.6 0.8–0.9 0.7–0.9 0.01–0.10 0.6 0.69–0.86 0.41–0.93 3.09

Adult half-life

8–25 12–50 75–126 32–60 4–12 6–18 —

— 63 —

Neonate half-life

8–28 15–105 45–500 32–40 7–60 30–60 —

— 61–109 —

P.B. Pennell / Neurol Clin 22 (2004) 799–820 813

postpartum period [6]. LTG levels, however, increase immediately and plateau within 2 to 3 weeks post partum. Adjustments in LTG doses may be needed on an anticipatory basis beginning within the first few days after delivery [99].

Perinatal lethargy, irritability, and feeding difficulties are attributed to intrauterine exposure to benzodiazepines and barbiturates, and breastfeed- ing while taking these medications may prolong sedation and feeding problems. Most infants of women who have epilepsy can breastfeed successfully without complications. The concentrations of the different AEDs in breast milk are considerably less than those in maternal serum (Table 6). The infant’s serum concentration is determined by this factor and the AED elimination half-life in neonates, which usually is more prolonged than that in adults [74,96,113]. The benefits of breastfeeding are believed to outweigh the small risk for adverse effects of AEDs [6,53]. Parents should be advised to watch for signs of increased lethargy to a degree that interferes with normal growth and development.

The puerperium and its inevitable sleep disruption often is a time of seizure worsening and may provoke seizure recurrence in women who have had previously controlled seizures. Extra precautions should be taken during this time [114]. Appropriate individualized safety issues must take into account the mother’s ictal semiology. If she is likely to drop objects she is holding but remain upright, such as happens during myoclonic seizures or many complex partial seizures, then she should use a harness when carrying the baby. If she is likely to fall, then a stroller within the house is a better option. Changing diapers and clothes are performed best on the floor rather than on an elevated changing table. Bathing never should be performed alone, as a brief lapse in attention can result in a fatal drowning. The important role that sleep deprivation plays in exacerbation of seizures needs to be emphasized. Especially if the mother is breastfeeding, sleep deprivation may be unavoidable. The possibility of other adults sharing the burden of

Table 6

Antiepileptic drug exposure through breast milk

Adapted from Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 2003;61(6 Suppl 2):S35–42, with permission.

814 P.B. Pennell / Neurol Clin 22 (2004) 799–820

nighttime feedings through the use of formula or harvested breast milk should be considered, and the mother should attempt to make up any missed sleep during the infant’s daytime naps.

Summary

Ideal, comprehensive care of women who have epilepsy during the reproductive years must include effective preconceptional counseling and preparation. The importance of planned pregnancies with effective birth control should be emphasized, with consideration of the effects of the enzyme-inducing AEDs on lowering efficacy of hormonal contraceptive medications and the need for back-up barrier methods.

Before pregnancy occurs, the patient’s diagnosis and treatment regimen should be reassessed. Once the diagnosis of epilepsy is confirmed, it is important to verify if the individual patient continues to need medications and if she is taking the most appropriate AED to balance control of her seizures with teratogenic risks. For most women who have epilepsy, withdrawal of all AEDs before pregnancy is not a realistic option. A decision to undergo a trial while not taking AEDs before a planned pregnancy should be based on the same principles used for AED withdrawal in any person who has epilepsy [115,116]. The taper should be completed at least 6 months before planned conception to provide some reassurance that seizures are not going to recur [6].

If a woman who has epilepsy is in the more prevalent category of needing AEDs for seizure control, then monotherapy at the lowest effective dosage should be used. If large daily doses are needed, then frequent smaller doses or extended-release formulations may be helpful to avoid high peak levels. Some of the newest information about differential risks between AEDs also should be considered. The woman’s AED regimen should be optimized and folate supplementation should begin before pregnancy. Given that 50% of pregnancies are unplanned in the United States, folate supplementa- tion should be encouraged in all women of childbearing age who are taking any AED for any indication. Dosing recommendations vary from 0.4 mg/d to 5 mg/d.

It is not uncommon for a physician to consider changing AED regimens when the patient first reports that she is pregnant. In many cases, she already is in or past the critical period of organogenesis (Table 3). If a woman who has epilepsy presents after conception and is taking a single AED that is effective, her medication usually should not be changed. Exposing the fetus to a second agent during a crossover period of AEDs only increases the teratogenic risk, and seizures are more likely to occur with any abrupt medication changes. If a woman is on polytherapy, it may be possible to switch to monotherapy safely.

Seizure control remains an important goal during pregnancy. In particular, convulsive seizures place the mother and fetus at risk.

P.B. Pennell / Neurol Clin 22 (2004) 799–820 815

Nonconvulsive seizures also may be harmful, especially if they involve falling or other forms of trauma. Monitoring serum AED levels during pregnancy can be helpful in optimizing seizure control.

Prenatal screening can detect major malformations in the first and second trimesters. Vitamin K1 is given 10 mg/d orally during the last month of pregnancy followed by 1 mg intramuscularly or intravenously to the new- born [6].

Although women who have epilepsy and women who are taking AEDs for other indications do have increased risks for maternal and fetal complications, these risks can be reduced considerably with effective preconceptional planning and careful management during pregnancy and the postpartum period.

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