Effects of In Utero Antiepileptic Drug = Exposure

Abstract

Recent studies = demonstrate an=20 increased teratogenic risk for valproate and a probable increased = risk for=20 phenobarbital. Carbamazepine and lamotrigine appear relatively = safe;=20 however, results are inconclusive concerning a specific risk for = cleft=20 lip/palate for both drugs as well as a dose-dependent effect for=20 malformations associated with lamotrigine. Data regarding = teratogenic=20 risks for other antiepileptic drugs are inadequate. Additional = studies are=20 needed to delineate further the risks for all antiepileptic drugs = and=20 determine the underlying mechanisms.

Although the majority = of children=20 born to women with epilepsy are normal, they are at increased risk = for=20 malformations as well as for poor neuropsychological outcomes (1,2). Antiepileptic drugs (AEDs) have the potential = to affect=20 fetal development throughout pregnancy. In the United States = alone, at=20 least 45,000 children are exposed to AEDs during pregnancies of = mothers=20 with epilepsy (2). Given that less than half of AEDs are = prescribed for=20 epilepsy and that the majority are prescribed for psychiatric and = pain=20 indications, the total number of children exposed to this category = of=20 drugs is substantially higher. The risk of in utero exposure has = to be=20 measured against the risk of the underlying disease. For most = women with=20 epilepsy, the risks imposed by seizures affecting both the mother = and=20 child usually outweigh the risks of drug exposure. Women should = not=20 discontinue AEDs without discussion with their physicians, as = trauma is=20 the leading cause of nonobstetrical death in pregnant women with = epilepsy=20 (3). In a UK survey, the death rate during pregnancy = for women=20 with epilepsy was increased tenfold compared to the general = population,=20 primarily as a result of seizures (4). Thus, understanding the magnitude and = differential=20 effects of AEDs on teratogenesis is = important.

Anatomical Teratogenesis

AEDs had been used for a = 100 years when=20 the thalidomide tragedy in the mid-20th century raised concerns = about the=20 potential teratogenic effects of all drugs. Shortly thereafter, = the first=20 report of AED-induced birth defects was published (5). Within a decade, estimates were that AED = exposure raised=20 the risk of malformation two- to threefold (6). Subsequently, this risk has been confirmed in = human and=20 animal studies (7=E2=80=939). The risk increases with higher AED dosages, = higher AED=20 serum levels, or polytherapy. For example, a recent study found = major=20 malformations in 4.5% of children exposed to AED monotherapy but = in 8.6%=20 of children exposed to AED polytherapy (10). This study also suggested that the risk of = malformation=20 is similar for children whose mothers did not have epilepsy yet = took AEDs=20 for other indications. The most common major malformations = associated with=20 AED exposure include cardiac (e.g., ventricular septal defect), = orofacial=20 (e.g., cleft lip with or without cleft palate), urological (e.g.,=20 hypospadias), skeletal (e.g., radial ray defects, phalangeal = hypoplasia),=20 and neural tube defects (e.g., spina bifida) (1,7). In addition to the risk of major malformations, = in utero=20 AED exposure may impact long-term intellectual development (2,9). Many questions remain unanswered; however, = recently there=20 has been an increase in information concerning the teratogenic = effects of=20 AEDs, which is due in large part to the establishment of multiple=20 pregnancy registries.

The most striking new information = arising from=20 these registries is that valproate poses a greater risk for major=20 congenital malformations compared with other AEDs. As outlined in = Table=20 1, the Australian Pregnancy Registry (11), Finnish National Medical Birth Registry (12), International Lamotrigine Pregnancy Registry = (13), Neurodevelopmental Effects of Antiepileptic = Drugs=20 (NEAD) Study (14), North American Pregnancy Registry (15), Swedish Medical Birth Registry (16), and United Kingdom Pregnancy Registry (17) have all reported that valproate exposure is = associated=20 with an increased risk for malformations. Although a risk for = spina bifida=20 (~1.5%) has been known for years, the defects associated with = valproate=20 identified in these recent studies were seen across multiple body = systems.=20 In most of the registry studies, the adverse effects of valproate = were=20 dose dependent (see Table=20 2). A recent meta-analysis found that the risk of major = malformations=20 in children exposed to valproate was 10.73% (95% CIs: 8.16, = 13.29), which=20 is statistically higher than the risk associated with several = other AEDs=20 or the risk for children in the general population (18) (see Table=20 3).

TABLE=20 1

Rates for = Major=20 Congenital Malformations across Recent=20 Studies

TABLE=20 2

Valproate = Dose=20 Effects across Recent=20 Studies

TABLE=20 3

Monotherapy Results=20 of a Recent=20 Meta-Analysis

For some women, valproate may be the = only AED=20 that can control their seizures. Thus, a balance of the risks has = to be=20 considered on an individual patient basis. Valproate is especially = effective for generalized epilepsies, but which women will respond = only to=20 valproate cannot be predicted. Similarly, which children will = suffer=20 valproate-induced teratogenesis cannot be predicted; however, it = is more=20 likely to occur at higher doses (>~1,000 mg/day; see Table=20 2) and blood levels (>~40 mcg/mL) (19). Since there are numerous alternative = effective AEDs, it=20 would seem prudent to try others before prescribing valproate for = women of=20 childbearing potential.

The North American Registry = also has=20 reported an increased risk of malformations for phenobarbital = (6.5%) (20). Another study from the same registry found no = increased=20 risk of malformations overall for lamotrigine, but a specific = increased=20 risk for cleft lip/palate (0.73%) was noted (21). In contrast, the European Surveillance of = Congenital=20 Anomalies (EUROCAT) study found no evidence of increased isolated=20 orofacial clefts relative to other malformations for lamotrigine = (22). The UK Registry reported a dose-dependent = effect for=20 malformations overall with lamotrigine use, yet the pattern was = not seen=20 in the North American Registry or the International Lamotrigine = Registry=20 (13,17,21). It is now known that lamotrigine clearance = increases=20 during the second and third trimesters of pregnancy (which occurs = with=20 other AEDs, although to a lesser degree); regardless, it is = unlikely that=20 lamotrigine clearance would be a major factor in malformations, as = they=20 occur in the first trimester. A report from the North American = Registry=20 has cited an increased risk for cleft lip/palate (0.023%) and = neural tube=20 defect (0.014%) associated with carbamazepine (23). A preliminary study with levetiracetam did = not show=20 increased risk (24), and preliminary studies with topiramate have = had=20 conflicting results (25,26). However, the sample sizes in these studies = are too=20 small to permit confidence in the results (24=E2=80=9326).

Behavioral Teratogenesis

Animal studies have = demonstrated=20 that AEDs can produce cognitive deficits at dosages less than = those=20 required for anatomical teratogenesis (8). Several human studies also have raised concerns = over AED=20 behavioral teratogenesis (see Table=20 4). A retrospective Danish study examined two separate cohorts = of=20 adult men exposed to phenobarbital during their mothers' = pregnancies; each=20 cohort was administered a different cognitive measure. Regardless = of the=20 cognitive measure used, data indicated that in utero phenobarbital = exposure was associated with reduced IQ (27). Retrospective studies from a center in the UK = found=20 that children exposed in utero to valproate had increased = developmental=20 delays among a cohort of children =E2=89=A46 years old, increased = special=20 education needs in a cohort of =E2=89=A56 year olds, and reduced = verbal IQ in a=20 cohort of children =E2=89=A56 years old (4,28). A prospective Finnish study demonstrated = reduced verbal=20 IQ for valproate but not for carbamazepine, although the = monotherapy=20 valproate sample was small (29). Preliminary results from the prospective NEAD = Study in=20 the USA and UK have demonstrated a dose-dependent (see Table=20 2) developmental delay in children exposed in utero to = valproate (19).

TABLE=20 4

Cognitive = Effects=20 of In Utero Antiepileptic Drugs in Recent=20 Studies

Possible Mechanisms of AED=20 Teratogenesis

Anatomical and = behavioral=20 teratogenesis likely differ in mechanisms since first trimester = AED=20 exposure poses the highest risk for anatomical malformations, = while third=20 trimester exposure appears to be associated with the highest risk = for=20 adverse behavioral effects (7,9). Various mechanisms have been proposed for the=20 teratogenicity of AEDs, including folate-related actions, = ischemia,=20 neuronal suppression, reactive intermediates (e.g., free = radicals), and=20 AED-induced neuronal apoptosis (30). All of these mechanisms remain hypothetical. = For=20 example, there is not any evidence that folate supplementation can = reduce=20 the risk of AED-induced malformations. In regard to anatomical=20 teratogenesis, reactive intermediates may be the most likely = candidate.=20 These agents bind to DNA, proteins, and lipids, affecting cell=20 development. Regarding behavioral teratogenesis, several AEDs = (i.e.,=20 clonazepam, diazepam, phenobarbital, phenytoin, vigabatrin, and = valproate)=20 have been shown to induce widespread neuronal apoptosis in = immature animal=20 brains, in a manner similar to ethanol (31=E2=80=9333). Of note, valproate-induced apoptosis occurs = at=20 relatively lower therapeutic concentrations compared with other = AEDs.=20 Similar apoptotic effects were not seen for carbamazepine, = levetiracetam,=20 lamotrigine, or topiramate monotherapy, although all of these = AEDs, except=20 levetiracetam, are capable of enhancing phenytoin-induced = apoptosis in=20 polytherapy (34=E2=80=9337). Considerable variability exists in both = anatomical and=20 behavioral outcomes for individual children exposed in utero to a = specific=20 AED, even when similar dosages are employed during pregnancy. = Teratogens=20 interact with susceptible genotypes (7), which may explain the individual variance. = Additional=20 research is needed to demonstrate the risks for all AEDs, = determine the=20 underlying mechanisms, and delineate reasons for individual = variance in=20 outcomes.

Conclusions

Human studies of AED = teratogenesis=20 are not double-blind randomized trials; consequently, the most = definitive=20 findings are those that are replicated across numerous = investigations.=20 Over recent years, the combined results of multiple anatomical and = behavioral studies of AED teratogenesis provide compelling = evidence that=20 valproate poses a special risk to the unborn child. The = occurrences of=20 various different malformations and of impaired cognitive function = are=20 increased by valproate in a dose-dependent manner. Although less = data are=20 available, phenobarbital also appears to pose a risk for both = anatomical=20 and behavioral impairments. The overall risks for carbamazepine = and=20 lamotrigine appear relatively low; but, as discussed, one registry = reported a dose-dependent effect for lamotrigine, and another = registry=20 reported a specific risk of cleft lip/palate for both = carbamazepine and=20 lamotrigine. However, evidence from other registries is = contradictory or=20 completely absent, which leaves the validity of these observations = in=20 doubt. Information on other AEDs is inadequate. Although many = questions=20 remain unanswered, the recent increase in information is helpful = to=20 physicians and patients in making informed treatment decisions. = Further=20 studies are critical to delineating the risks for specific = deficits=20 associated with individual AEDs. An understanding the mechanisms=20 underlying these defects may help explain the considerable = individual=20 variance in outcomes for children exposed to the same AED. More=20 importantly, this knowledge could lead to preventative=20 measures.