Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 109
Neurodevelopmental Effects
Eija Gaily
Kimford J. Meador
Introduction
The increased risk of major malformations after prenatal exposure to antiepileptic drugs (AEDs) has been established by research extending over three decades (see Chapter 110). The neurodevelopmental effects of in utero exposure to AEDs have not been as extensively investigated as AED-induced somatic abnormalities. This may be because the assessment of functional outcomes is more complicated and time consuming than major malformations that are usually detected at birth and are less affected by confounding factors.
Teratogens interact with genotype to produce both anatomic and behavioral defects. Whether a defect occurs depends on a susceptible genotype and may involve the interaction of multiple-liability genes.30 The mechanism of anatomic and behavioral teratogenesis may well differ since it appears that the highest risk of anatomic defects is from first-trimester AED exposure, while the highest risk of behavioral defects appears to be from exposure during the third trimester, when neuronal migration and synaptic organization occur.76
Animal studies have clearly demonstrated that prenatal AED exposure can produce behavioral as well as anatomic defects. In contrast to somatic malformations in animals, which usually require AED dosages several times above human therapeutic dosages, behavioral impairments can occur at lower dosages and at blood levels similar to human therapeutic levels.31,42
The first report of mental deficiency after prenatal AED exposure in children with typical minor anomalies but no major malformation was published in 1975.18 After that, a number of studies have investigated the relationship between typical minor anomalies and cognitive impairment in AED-exposed children, and several antiepileptic drug syndromes have been proposed. More recent studies have also addressed the question of whether prenatal antiepileptic drug exposure increases the risk of cognitive impairment even in the absence of detectable anatomic teratogenesis.
Animal Data
Behavioral Data for Individual Antiepileptic Drugs
Benzodiazepines
Neonatal benzodiazepine exposure produces widespread apoptotic neuronal cell death in rats (see Mechanism section). Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior.18 For example, diazepam can affect behavior differentially depending on the stage of development at which the exposure occurs. Midgestation exposure causes transient hyperactivity but no learning or retention deficits on a choice discrimination task. Late prenatal exposure caused no hyperactivity but resulted in poor learning and retention. Early postnatal exposure resulted in lasting hyperactivity as well as learning and retention deficits.34
Carbamazepine
Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been published. In utero carbamazepine exposure did not produce hyperexcitability in primates, unlike phenytoin.70 A preliminary report found that neonatal rats dosed with carbamazepine slightly above the ED50 for anticonvulsant action produced widespread neuronal apoptosis similar to several other AEDs49 (see Mechanism section).
Phenobarbital
Perinatal phenobarbital exposure in rats reduces brain weight.21 Phenobarbital causes apoptotic neuronal cell death in neonatal rats (see Mechanism section). Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and catecholamine brain levels.32,57,61,62,103,104 Rats that had seizures induced by kainic acid as neonates exhibited deficits in water maze (a measure of visuospatial memory) and open-field activity when tested subsequently. Rats receiving kainic acid followed by phenobarbital exhibited even greater disturbances in memory, learning, and activity levels.63 In contrast, this effect was not seen with topiramate, as described below.
Phenytoin
Gestational and neonatal exposure to phenytoin reduces brain weight.43,83 Phenytoin alters neuronal membranes in the hippocampus.94 It also alters critical genes and delays neurodevelopment.8 Dose-dependent apoptotic neuronal cell death occurs in neonatal rats (see Mechanism section). Prenatal phenytoin at subteratogenic dosages (100 to 200 mg/kg) in rats produces impaired spatial learning and motor coordination.26,64,77,89,90,91,93,97 A dose-effect relationship was noted at maternal levels (10 to 25 μg/mL) overlapping the human therapeutic range. The adverse behavioral effects do not resolve as the rats grow older.93,94 Prenatal exposure to phe-nytoin in rats results in hyperactivity.91,97 Similarly, primates who have in utero exposure to phenytoin are hyperactive and hyperexcitable, but those exposed to carbamazepine or stiripentol are not.70
Primidone
Gestational primidone can produce behavioral deficits in rats.71 When tested as adults, the rats that had been exposed in utero to primidone were impaired in their performance of an eight-arm radial maze task and had reduced open-field activity.
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Topiramate
Topiramate has been shown to produce adverse cognitive effects in adults. In contrast, the effects of topiramate in neonatal animal models appear to be protective. Topiramate protects against hypoxic-ischemic white matter injury and decreases the subsequent neuromotor deficits when administered posthypoxic insult in neonatal rats.33 Rats that are treated with to-piramate after a series of 25 neonatal seizures performed significantly better in the water maze than rats treated with saline.106 These findings are in contrast to the adverse effects of phenobarbital in the same animal model.
Valproate
An in vitro study using rat hippocampus cultures found that valproate interferes with formation of the pyramidal cell layer.29 In utero valproate can alter neuronal membranes in the hippocampus and cortex of rats.95 Early postnatal exposure to valproate decreased brain weight in mice.85 Exposure of neonatal rats to valproate resulted in widespread neuronal apoptosis (see Mechanism section). Adverse neurobehavioral effects in rats have been seen following in utero exposure at doses of 150 to 200 mg/kg,87,92 although these effects were not as marked as phenytoin in the same animal model.
Antiepileptic Drug Effects on Neurodevelopment: Potential Mechanisms
Folate-related Mechanisms
Folate demands are increased during pregnancy, and women with epilepsy who have lower folate levels are more likely to have abnormal pregnancy outcomes.20 Several AEDs are known to affect folate metabolism. Phenobarbital, phenytoin, and primidone, but not carbamazepine, deplete folate.12,13,15,16 Valproate alters folate metabolism.12
Ischemia/Hypoxia
Phenytoin can affect cardiac function in fetal rats, and animals exposed in utero to ischemia develop defects that resemble phenytoin-induced defects.19
Neuronal Suppression
AEDs suppress neuronal irritability and could reduce neuronal excitation, altering in utero synaptic growth and connectivity and producing long-term behavioral deficits.
Reactive Intermediates
The teratogenesis of AEDs may be mediated by toxic intermediary metabolites rather than the parent compound.98,99 Oxide intermediates (epoxides) are generated during the metabolism of some AEDs and are highly reactive and can bind nucleic acids. However, the theory of the epoxide mechanism has been questioned because the cytochrome P450 enzymes required for conversion of an AED to an epoxide are not expressed in embryonic tissues.53 An alternative theory posits that AEDs may be metabolized to free-radical reactive intermediates by prostaglandin H synthetase or lipoxygenases, which are active in the fetus.98,99 Then, these reactive oxygen species could bind to DNA, protein, or lipids, resulting in teratogenesis.
Antiepileptic Drug–induced Neuronal Apoptosis
The observation that third-trimester gestational ethanol exposure can produce widespread neuronal apoptosis and neurobehavioral deficits led to the hypothesis that the adverse behavioral effects of AED exposure might be due to a similar mechanism.48 The effect of ethanol is mediated by combined N-methyl-D-aspartate (NMDA) glutamate receptor blockade and γ-aminobutyric acid (GABA)A receptor activation,48 which are receptor mechanisms affected by some AEDs. Recently, several AEDs have been tested for similar apoptotic effects in a neonatal rat model. Widespread neuronal apoptosis occurs as a result of neonatal exposure to clonazepam, diazepam, phenobarbital, phenytoin, vigabatrin, or valproate.9,10 The effect appears to be due to reduced expression of neurotrophins and levels of protein kinases, which are important for neuronal growth and survival. Of note, the adverse effects were ameliorated by β estradiol, which has neurotrophic effects.6,10,39 Similar apoptotic effects were not seen at therapeutic dosages for levetiracetam or topiramate.39,56,60 Additional studies are needed to examine the effects of other AEDs in this animal model, extend the studies to gestational animal models, and determine if a similar mechanism occurs in humans.
Human Data from Offspring of Mothers with Epilepsy
Syndromes and Minor Anomalies
The fetal hydantoin syndrome (FHS) was first described by Hanson and Smith42 in five unrelated children whose mothers had epilepsy. Four mothers had taken 100 to 400 mg of phe-nytoin (one monotherapy) and one had been treated with 300 mg of mephenytoin during pregnancy. Four children had also been exposed to barbiturates and one to additional phensuximide. All displayed a characteristic pattern of craniofacial abnormalities (including short nose with low nasal bridge, and hypertelorism) (Fig. 165), hypoplasia of nails and distal phalanges, and postnatal growth deficiency, and four had motor or mental deficiency. In a later cohort study, Hanson et al.41 estimated that 11% of phenytoin-exposed children showed enough unusual features to be clearly classified as having FHS. Patterns of minor anomalies similar to phenytoin combined with developmental delay have been described in association with prenatal carbamazepine52 and primidone66 exposure, but these have never been established as separate syndromes. A different pattern of abnormalities has been described for valproate, as discussed below.
Of the typical FHS features, distal digital hypoplasia (Fig. 2) has been most consistently associated with prenatal phenyt-oin exposure in prospective studies blinded to exposure.4,55,37 Two studies have used anthropometric methodology. Kelly54 made a radiologic diagnosis of distal phalangeal hypoplasia based on measurements from hand radiographs in 15 of 47 phenytoin-exposed and one of ten control children. In a controlled population-based study, prenatal phenytoin exposure was observed to have a significant dose-related negative correlation with distal phalangeal length measured from hand radiographs.36 A radiologic diagnosis of distal phalangeal hypoplasia was made in 8 of 75 (11%) phenytoin-exposed children compared with 1 of 130 children not exposed to phenytoin (p = 0.003).36 In most of these children, distal digital hypoplasia was not obvious on a clinical examination. Growth and intelligence were within the normal range in all.
Controlled prospective and retrospective studies blinded to prenatal AED exposure have consistently shown that the craniofacial minor anomalies considered typical of FHS are increased in children of mothers with epilepsy compared with control children of mothers without epilepsy.37,46,67,101,105 Most studies observed no increased minor anomalies in
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nonexposed children of mothers with epilepsy,46,101,47 while one study found that some of the facial features such as epicanthus were increased not only in the nonexposed children, but also in the mothers with epilepsy.37 Although the results on whether these typical anomalies are associated with impaired cognitive development are controversial,35,45 multiple minor anomalies in general are known to be associated with delayed development81,86 and should alert the clinician to do a systematic developmental evaluation and follow-up.
FIGURE 1. A: Child exposed to phenytoin monotherapy, aged 18 months. Note telecanthus; short nose with flat nasal bridge and anteverted nares; long, shallow philtrum; and thin upper lip. B: Same child aged 15 years and 3 months. Note that the nose has grown to a more normal appearance. The nasal root is prominent. The philtrum remains shallow and the upper lip thin. (Reproduced with permission from Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37[7]:489–497.)
FIGURE 2. A: Severe distal phalangeal hypoplasia in a child with prenatal phenytoin (86 umol/L) and phenobarbital exposure, aged 5 years and 4 months. The child also had mild hypertelorism (not shown). Growth and intelligence were normal. B: Left-hand radiograph of the same child at age 5 years and 4 months, showing aplastic distal phalanges in fingers 2 and 5 and hypoplastic distal phalanges in fingers 1, 3, and 4.
The fetal valproate syndrome (FVS) was first described by DiLiberti et al.,22 later verified by Ardinger et al.5 in 19 valproate-exposed (eight monotherapy) children of 18 mothers with epilepsy, and reviewed by Clayton-Smith and Donnai.17 The characteristic craniofacial features include trigonocephaly, bifrontal narrowing with indentation of the outer orbital ridge, medial deficiency of eyebrows, long shallow philtrum with long and thin upper lip, and broad or flat nasal bridge (Fig. 359). Major malformations may also occur: The most common are neural tube defects, congenital heart defects, oral clefts, genital abnormalities, and limb defects. Developmental delay is observed in most children with this pattern of minor anatomic abnormalities; some also have autistic features.102,73 Pre- and postnatal growth are usually normal.
FIGURE 3. Fetal valproate syndrome. Note especially trigonocephaly, medial deficiency of eyebrows, broad nasal root, anteverted nares, shallow philtrum, and long and thin upper lip. Patients 1–3, 4 and 5, and 6 and 7 are siblings. Patient 2 was also exposed to phenytoin and patient 7 to vigabatrin; others were exposed to valproate monotherapy only. (Reproduced with permission from Malm H, Kajantie E, Kivirikko S, et al. Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology. 2002;59[4]:630–633.)
The incidences of FHS and FVS are unknown. Based on a prospective population-based study, FHS with mental deficiency appears to be quite rare (<1%), at least in the Finnish population.35 There is only one prospective study on minor anomalies in valproate-exposed children, observing significantly increased anomalies in valproate-exposed children compared to controls,51 but there are no prospective data on the incidence on FVS. Case reports describing drug-exposed multiple pregnancies have found different outcomes after similar exposures. Phelan et al.69 described a dizygotic heteropaternal twin pair exposed to 230 mg of phenytoin during pregnancy, with one twin showing all typical symptoms and signs of FHS, while the other twin was healthy. Bustamante and Stumpff11 reported trizygotic triplets, exposed to 300 mg of phenytoin and 450 mg of phenobarbital, who showed very different manifestations of FHS. Malm et al.59 described three families in which all valproate-exposed siblings had FVS, and Kozma58 reported one family with FVS in two siblings. These observations strongly support the hypothesis that genetic susceptibility
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significantly enhances the risk of serious adverse outcome after prenatal phenytoin or valproate exposure.
Intelligence
In addition to the rare AED syndromes, there is a recognized risk that prenatal antiepileptic drug exposure may have effects on cognitive development even without signs of anatomic teratogenesis. Studies looking at long-term postnatal development face many challenges. Enrolling children in the study during the mother’s pregnancy is mandatory to get reliable prospective exposure data, including maternal drug doses, seizures during pregnancy, and other pregnancy complications. Children must then be followed at least until preschool or early school age. Developmental data acquired from questionnaires or from records not designed for investigational purposes may not be reliable; only standard IQ testing provides data that are comparable across different exposure groups and studies. Before the age of 5 years, cognitive tests have limited predictive power40 and it is not possible to document milder cognitive deficits than moderate to severe mental deficiency reliably. This results in long study durations with a high risk for loss of follow-up and increasing effect of confounding effects. Maternal education84 and especially maternal IQ75 are significant predictors of intelligence in the offspring. Psychosocial and socioeconomic disadvantage associated with epilepsy50,44 as well as maternal depression7 may affect postnatal development of children of mothers with epilepsy. Women with epilepsy or a history of epilepsy have lower marriage rates than controls,79 possibly reflecting a limited choice of partners and resulting in an increased risk of inherited cognitive dysfunction from the paternal side.
Table 1 Intelligence Scores in Children of Mothers with Epilepsy and Control Children from a Population-based Prospective Study
IQ score group Number of children Verbal Mean ± SEM Nonverbal Mean ± SEM Full-scale Mean ± SEM
Study group all 182 92.8 ± 1.3 100.3 ± 1.2 96.0 ± 1.2
No drug exposure 45 94.3 ± 2.6 98.6 ± 2.9 95.6 ± 2.8
Monotherapy exposure 107 94.4 ± 1.7 101.9 ± 1.4 98.0 ± 1.6
CBZ monotherapy 86 96.2 ± 1.9 103.1 ± 1.5 99.7 ± 1.8
VPA monotherapy 13 83.5 ± 3.8 96.3 ± 4.8 89.7 ± 3.6
Other monotherapya 8 91.1 + 6.4 96.9 + 4.6 93.6 + 5.0
Polytherapy exposureb 30 84.9 ± 2.5c 97.1 ± 2.9 89.5 ± 2.4
Control group all 141 94.9 ± 1.2 102.4 ± 1.2 97.6 ± 1.4
SEM, standard error of the mean, CBZ, carbamazepine, VPA, valproate.
a Six phenytoin, two clonazepam.
b Seventeen combinations included valproate.
c F = 8.6, p = 0.004 versus controls, and F = 5.2, p = 0.02 versus study children exposed to monotherapy by covariance analysis, with maternal education and test (WPPSI-R or WISC-R) used as covariates.
Reproduced (slightly modified) with permission from Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology. 2004;62(1):28–32.
Possibly the most important confounding factor for prenatal AED effects is maternal epilepsy. Prenatal drug exposure is not random. The choice of treatment prescribed for the mother is determined by maternal epilepsy type or syndrome and the severity of seizures. Several observations suggest that some epilepsy-associated genes may also have an influence on cognitive development. Siblings of children with epilepsy show increased cognitive dysfunction.25 Cognitive deficits may be present already at onset of idiopathic and cryptogenic epilepsies.94 Idiopathic partial epilepsies and developmental cognitive disorders (such as dysphasia) overlap.23 Low socioeconomic status has been found to be a risk factor for epilepsy of unknown etiology.44 As the risk of cognitive impairment and drugs of choice probably covary in different epilepsy syndromes, the child of a mother with epilepsy may show cognitive impairment that appears to be related to a specific drug but is actually based on genetic traits associated with that particular type of epilepsy. This also makes it impossible to have a perfect control group in cognitive studies. In a control group of children of mothers without epilepsy, not only the prenatal drug exposure, but also the epilepsy factor, is missing. If different drug exposures are compared with each other and with nonexposed children with mothers with a history of epilepsy, we may well be comparing different forms of epilepsy and different genetic risks. To control for the epilepsy factor as
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well as possible, carefully determining maternal epilepsy type and etiology as well as obtaining data on maternal intelligence (or at least educational level) are necessary in studies dealing with prenatal AED effects on development.
Carefully conducted prospective clinic-based studies give a good description of what kind of problems may be anticipated in children of mothers with epilepsy and may provide data on the relative risk of different AEDs. The applicability of their results, however, is limited by selection of the study population. Only population-based studies (i.e., studies in which it is possible to reliably estimate what proportion of the population is included in the study) allow a reliable estimation of the magnitude of the risk for cognitive development in children of mothers with epilepsy compared to the general population.
A recent Cochrane review3 assessed all prospective studies reporting cognitive outcome in children of mothers with epilepsy published from 1966 through 2003. Thirty-one reports based on 18 independent cohorts were included in the review. Eleven studies were considered clinic based and four studies population based (not identified in the review), and the others provided insufficient data on recruitment. Most studies had limited quality and a small number of participants; only seven cohorts included more than 50 AED-exposed children. Attempts to control for confounding factors were described in about half of the studies. Assessment of outcome was blinded in nine studies. Comparison groups varied from study to study, with some studies giving their results only in pooled mono- or polytherapy subgroups and others reporting individual drug exposures (carbamazepine, phenytoin, phenobarbitone). The results were largely conflicting, and the authors concluded that there was very little evidence as to which specific drugs would be more harmful to the prenatally exposed child.
Two controlled, prospective, population-based studies including 50% to 60% of the population35,78 (both included in the Cochrane review) provided data on intelligence scores at 478 and 535 years of age in a total of 297 children of mothers with epilepsy. Cognitive assessments were blinded to the prenatal exposures. Two hundred and five children were exposed to phenytoin (81 monotherapy). The most common combination was phenytoin and phenobarbitone. Forty nonexposed children of mothers with epilepsy were also included. Maternal phenytoin levels were measured by Gaily et al.35: All except one were well under the upper limit of the reference range. Both studies reported lower IQ values in children of mothers with epilepsy than controls, but no significant associations were observed to any drug exposure or to exposure to maternal seizures.35
Hanson et al.41 extracted data on 104 children exposed to phenytoin (24 monotherapy) from the same data source as Shapiro et al.78 (i.e., the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke80). These children were matched for maternal socioeconomic status, maternal age, race, and institution of birth with 100 control children of mothers without epilepsy. Eighty-three children in both groups were tested by Wechsler Intelligence Scale for Children (WISC) at 7 years of age. The mean full-scale score was 92 in the phenytoin-exposed children and 97 in controls (p <0.05). In the absence of other exposure groups and nonexposed children of mothers with epilepsy, it is impossible to know how much of the IQ difference was related to prenatal phenytoin exposure and how much to other epilepsy-related factors.
Two recent population-based studies100,38 (the former not included in the Cochrane review) reported cognitive outcome in a total of 248 children of mothers with epilepsy with carbamazepine monotherapy as the most common AED exposure. Both studies included approximately 50% of the population of children born to mothers with epilepsy in their catchment areas. The investigator performing the cognitive testing was blinded to exposure. Wide et al.100 used the Griffiths test at 2 to 8 years and found no difference between 35 carbamazepine-exposed children and 66 control children of mothers without epilepsy. Gaily et al.38 administered the age-appropriate Wechsler scale at 5 to 11 years. The study included 107 monotherapy exposures (86 carbamazepine), 30 polytherapy exposures (17 including valproate), 45 nonexposed children, and 141 control children of mothers without epilepsy. No impairment was found in the children exposed to carbamazepine compared to nonexposed or controls (Table 1). Verbal IQ was significantly reduced in the polytherapy subgroup. No associations of IQ to maternal epilepsy type or maternal generalized tonic–clonic seizures during pregnancy were observed.
So far prospective data on cognitive outcome in children with prenatal valproate monotherapy exposure are available
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only for 26 children from two population-based studies.38,27 In both studies, the mean verbal IQ was 11 to 13 points lower in the valproate monotherapy–exposed group than in children with no AED exposure or exposed to carbamazepine monotherapy. A significant negative correlation between valproate dose of the mother during pregnancy and verbal IQ in the offspring was observed.38 Although attempts to control for maternal epilepsy type, educational level,38 and maternal IQ27 were made, it was impossible to reliably rule out confounding by genetic and environmental factors. Retrospective studies have reported increased educational needs1 and impaired verbal IQ2 in children exposed to valproate monotherapy, even when controlled for maternal IQ. The reduction of verbal IQ in the valproate monotherapy group in the retrospective study2 was in the same order of magnitude (10 points) as in the prospective studies.38,27 The impairment found in the valproate group has been limited to verbal IQ in all studies except one.27 The findings highlight the urgent need for prospective studies with sufficient power and careful documentation of maternal epilepsy characteristics to investigate the possible harmful effect of valproate on cognitive development.
Table 2 Incidence of Mental Deficiency in Children of Mothers with Epilepsy, Based on Pooled Data from Three Prospective Population-based Studiesa
Antiepileptic drug exposure Number with mental deficiency per total exposed (%) Comment
Phenytoin monotherapy 0/60  
Carbamazepine monotherapy 2/105 (1.9) One West syndrome
Valproate monotherapy 3/34 (8.8) One mother of child with mental
Other monotherapy 0/4 deficiency had subnormal IQ
Polytherapyb 1/84 (1.2) Phenytoin, carbamazepine, and alcohol abuse
No drug exposure 2/64 (3.1) One Down syndrome
Total 8/351 (2.3)  
a The Eriksson et al. study provided population-based data for the valproate monotherapy group only. Included were born in 1975 to 1979 (Gaily E, Kantola-Sorsa E, Granstrom ML. Intelligence of children of epileptic mothers. J Pediatr. 1988;113(4):677–684.), 1989 to 1994 (Gaily E, Kantola-Sorsa E, Hiilesmaa V, et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology. 2004;62(1):28–32), and 1989 to 1997 (Eriksson et al. study).
b Twenty-six combinations included valproate.
From Adab N, Jacoby A, Smith D, et al. Additional educational needs in born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2001;70(1):15-21; Eriksson K, Viinikainen K, Mönkkönen A, et al. Children exposed to valproate in utero - population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy Res. 2005;65:189-200; and Jäger-Roman E, Deichl A, Jakob S, et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pediatr. 1986;108(6):997-1004.
Incidence of Mental Deficiency
In the studies reporting intelligence scores, most participating children have performed well within the normal range. As no follow-up data after IQ testing are available from any of the cognitive studies, it is not clear whether the statistically significant group impairments have any clinical significance that would signal an increased risk for learning problems. Mental deficiency, however, has an obvious impact on the child’s educational achievement. Prospective population-based data on the incidence on mental deficiency in children of mothers with epilepsy are available from two Finnish studies.35,38 A third study27 provided population-based data on valproate monotherapy–exposed children only. The children were tested at age 5 to 13 years. All studies defined mental deficiency as both verbal and nonverbal IQ below 70. Based on the pooled data, the incidence of mental deficiency was 8 of 351 (2.3%) in children of mothers with epilepsy and 3 of 246 (1.2%) in control children of mothers without epilepsy (relative risk [RR] 1.9, 95% confidence interval [CI], 0.5 to 7.0). For comparison, the incidence of mental deficiency in a birth cohort of 12,000 children in Northern Finland was found to be 1.2%.72 The breakdown of the data to AED exposures and other relevant etiologic information are shown in Table 2. Based on the pooled data, children exposed to valproate monotherapy had a higher risk of mental deficiency (3 of 34, 8.8%) than other children of mothers with epilepsy (5 of 317, 1.6%) (RR 5.6, 95% CI, 1.4 to 22.4).
Human Data from Subjects with No Maternal Epilepsy
Long-term cognitive effects of prenatal phenobarbital exposure was studied by Reinisch et al.74 based on data from the Danish Perinatal Cohort. This database comprised the offspring of 9,006 deliveries that took place at the largest hospital in Copenhagen between 1959 and 1961. Demographic, socioeconomic, and medical variables (including drug treatment) were recorded prospectively. Phenobarbital exposure was recognized if maternal treatment had lasted for at least 10 days during pregnancy (range 10 days to entire pregnancy). Two separate cohorts of men were later selected from this database with the criteria of phenobarbital exposure and absence of other significant other risk factors (including maternal epilepsy) during pregnancy. Controls were matched for a number of potential confounders, including a maternal complaint score reflecting indication. The study subjects were given either the Wechsler Adult Intelligence Scale (WAIS) (33 subjects, mean age 23 years) or the Danish Military Draft Board Intelligence test (81 subjects, mean age 19 years). Total phenobarbital dosages varied
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from 225 to 22,500 mg. Men exposed to phenobarbital showed approximately 0.5 standard deviation (SD) lower scores than expected. The IQ impairment was most marked after exposure in the third trimester, and the effects were increased in those from low socioeconomic status and unwanted pregnancy.
A randomized placebo-controlled blinded study28 investigated the cognitive late effects of postnatal phenobarbital exposure of toddler-aged children with febrile seizures. Two hundred and seventeen children were randomized to receive either phenobarbital 4 to 5 mg/kg/day or placebo. There was no difference in Bayley scores between the groups at the beginning of the study. At 2 years after the assignment to treatment, the mean IQ was 8.4 points lower in the children assigned to the phenobarbital group compared to placebo (p < 0.01). Six months after offset of the medication, there was still a 5.2-point difference in the mean IQ. Sixty-four percent of these children were later examined at the age of 7 years by the Wide Range Achievement Test (WRAT-R) and the Stanford-Binet Intelligence Scale.82 The children who had been assigned to the phenobarbital group showed significantly impaired performance in WRAT-R reading scores but not on the Stanford-Binet Scale compared to the placebo group. This long-term follow-up study suggests that exposure to phenobarbital during early childhood may have long-term adverse cognitive effects on the skills (especially language) that are actively acquired at that age.
Summary and Conclusions
Neurobehavioral adverse effects have been observed in animal studies after prenatal exposures to benzodiazepines, phenobarbital, phenytoin, primidone, and valproate. Prenatal exposure to carbamazepine in a primate study did not find adverse neurobehavioral effects. Two studies on perinatal topiramate exposure did not find adverse neurobehavioral effects, and to-piramate even appeared protective against ischemia or seizures. Widespread neuronal apoptosis has been found in neonatal rats exposed to benzodiazepines, phenobarbital, phenytoin, valproate, and vigabatrin, but did not occur to therapeutic dosages of levetiracetam or topiramate. Animal data concerning the behavioral effects of in utero AED exposure are, however, incomplete, especially for AED combinations and the newer AEDs. Further, intraspecies differences exist in susceptibility to AED-induced anatomic malformations, and may also exist for behavioral teratogenesis. Although animal data need to be interpreted cautiously and will ultimately require confirmation in humans, investigations in animals can control for a variety of confounding factors and offer insight.
Prenatal exposure to antiepileptic drugs in humans may result in syndromes with mental deficiency and characteristic minor anomalies as the typical features. The incidences of the fetal hydantoin and valproate syndromes are unknown but are probably rare. Case reports from multiple pregnancies and siblings suggest that genetic susceptibility is required for full syndrome expression.
The results of prospective studies investigating IQ at preschool or school age are somewhat controversial. Most studies have observed a mild but statistically significant IQ reduction in children of mothers with epilepsy compared to control children of mothers without epilepsy. There are several important confounding factors, and the contribution of prenatal AED exposure remains unconfirmed. Data from controlled, prospective, population-based studies have provided no evidence that prenatal phenytoin or carbamazepine exposure would impair intelligence. One perinatal cohort study including subjects with no maternal epilepsy and another study including children with febrile convulsions treated in the toddler years suggest that prenatal or early postnatal exposure to phenobarbital may cause permanent mild IQ impairment. The results of retrospective studies suggest that prenatal valproate exposure may reduce verbal IQ, but prospective data on valproate are until now very limited.
The incidence of mental deficiency has been investigated by three population-based studies; the results suggest that the incidence may be slightly increased in children of mothers with epilepsy. Two studies included mainly phenytoin and carbamazepine exposures and established no increased risk in those children. Insufficient data on valproate exposure from two prospective studies raise concern that prenatal valproate may be associated with an increased risk of cognitive impairment, a concern supported by a retrospective study. Further investigation is needed to completely define the cognitive risk of valproate. However, given the increased incidence of major congenital malformations related to in utero valproate exposure,68 it may be prudent to avoid valproate as a drug of first choice in women of childbearing age. There are no data on cognitive outcome after prenatal exposure to other currently used antiepileptic drugs.
Presently our data on cognitive effects of prenatal exposure to antiepileptic drug are almost limited to IQ only. There is a need in the future to look at other aspects of cognition (e.g., memory and attention) beyond IQ.
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