Dina Battino

Summary: Purpose: To analyze seizure control, dose adjustments, and other changes of antiepileptic drug (AED) treatment during pregnancy in a large cohort of women with epilepsy entering pregnancy on monotherapy with carbamazepine, lamotrigine, phenobarbital, or valproate.Methods: Seizure control and AED treatment were recorded prospectively in 3,806 pregnancies of 3,451 women with epilepsy taking part in European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), an international AED and pregnancy registry.Key Findings: Of all cases, 66.6% remained seizure‐free throughout pregnancy. Generalized tonic–clonic seizures (GTCS) occurred in 15.2% of the pregnancies. Women with idiopathic generalized epilepsies were more likely to remain seizure‐free (73.6%) than women with localization‐related epilepsy (59.5%; p < 0.0001). Worsening in seizure control from the first to second or third trimesters occurred in 15.8% of pregnancies. The AED dose was increased during pregnancy in 26.0% and a second AED added to the initial monotherapy in 2.6% of all pregnancies. Seizures were more likely to occur in the first trimester in pregnancies with an increased drug load (35%; increased dose and/or addition of another AED) than in pregnancies without an increased drug load (15.3%) (p < 0.0001). Compared with other monotherapies, pregnancies exposed to lamotrigine were less likely to be seizure‐free, 58.2% (p < 0.0001); had more GTCS, 21.1% (p < 0.0001); had a greater likelihood of deterioration in seizure control from first to second or third trimesters, 19.9% (p < 0.01), and were more likely to require an increase in drug load, 47.7% (p < 0.0001). The mean dose increases from the first to third trimesters were 26% for lamotrigine, 5% for carbamazepine, 11% for phenobarbital, and 6% for valproate. There were 21 cases of status epilepticus (10 convulsive): none with maternal mortality and only one with a subsequent stillbirth.Significance: Although the majority of women remain seizure‐free throughout pregnancy, our data suggest that a more proactive approach to adjusting the dose of all AEDs in pregnancy should be considered, in particular for those pregnancies with seizures occurring in the first trimester and those exposed to lamotrigine, to reduce the risk of deterioration in seizure control.

Managing epilepsy during pregnancy is to balance the maternal and fetal risks associated with uncontrolled seizures against the potential teratogenic effects of antiepileptic drugs (AEDs). A rational approach requires knowledge of such risks as well as an understanding of the effects of pregnancy on seizure control and of gestational effects on AED disposition. Uncontrolled tonic-clonic seizures are potentially hazardous to the mother and, although strict evidence is lacking, are generally also assumed to be more harmful to the fetus than are AEDs. However, infants who have been exposed to AEDs in utero run an increased risk of congenital malformations: approximately twice the rate reported in the general population. Earlier literature has largely failed to demonstrate differences in birth defect rates with different treatment regimens, which can be ascribed mainly to insufficient sample sizes. More recent data have indicated higher malformation rates with exposure to valproic acid compared with some other major AEDs. The teratogenic effects of valproic acid appear to be dose dependent, with higher risks at dosage levels >1000 mg/day. Polytherapy involving treatment with more than one AED also seems to be associated with an increased risk of birth defects compared with monotherapy. Recently, a few small-scale studies have investigated the possibility that exposure to AEDs in utero may adversely affect the postnatal cognitive development of the offspring. Some of these studies have suggested that valproic acid poses a higher risk compared with other AEDs in this respect. These signals are important, but must be interpreted with caution because of the methodological shortcomings of the studies and because adequately powered prospective studies are necessary to draw firm conclusions. More reassuring findings have emerged regarding the obstetric outcome of pregnancy and the risk of worsening of epilepsy during pregnancy. In particular, it seems that the risk of obstetric complications is not significantly increased. Furthermore, most of the women with epilepsy have no change in their seizure frequency during pregnancy. The disposition of many AEDs may change during pregnancy, reflected in declining plasma drug concentrations. This seems to be most pronounced for lamotrigine and possibly also for oxcarbazepine, and can result in break-through seizures. The common treatment strategy has been to use the appropriate AED for the woman’s seizure disorder as monotherapy in the lowest effective dosage throughout pregnancy, the objective being to use AEDs in such a way that generalised tonic-clonic seizures are avoided but with minimised risks to the fetus, the newborn and the breast-fed infant. Valproic acid should be avoided if possible. Any major change in the treatment of a woman with epilepsy should ideally be completed before conception. Regular monitoring of drug concentrations is recommended during pregnancy, in particular for lamotrigine and oxcarbazepine.

To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting. Retrospective, case-matched pharmacokinetic evaluation. Seventy children (aged 1-17 years) with epilepsy and 70 adult controls (aged 18-65 years) with epilepsy, matched for sex and comedication. Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney's U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed. In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 +/- 21.0 vs 28.4 +/- 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 +/- 35.1 vs 46.1 +/- 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis. Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.

Summary:  Purpose: To assess the influence of aging on the steady‐state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting. Methods: The database of a large TDM service was used to identify retrospectively steady‐state serum CBZ concentrations in 157 elderly patients with epilepsy (65 years and older) treated with CBZ alone or in combination with phenobarbital (PB). CBZ apparent oral clearance (CL/F) values were calculated and compared with those determined in an equal number of controls aged 20 to 50 years, and matched for gender, body weight, and comedication. Results: Compared with corresponding controls, mean CBZ CL/F values were 23% and 24% lower, respectively, in the groups of elderly patients receiving monotherapy (57.1 ± 20.6 vs. 74.6 ± 28.3 ml/h/kg; p < 0.0001) and PB comedication (74.7 ± 25.5 vs. 98.7 ± 34.9 ml/h/kg; p < 0.01). Within each age group, patients comedicated with PB showed significantly higher CBZ CL/F values than those on monotherapy. A negative correlation between CL/F and age was found both within the monotherapy and the PB comedicated groups. In addition, CL/F values showed a positive relation with the administered daily dosage, which persisted within subgroups homogeneous for age and comedication. The independent influence of age, CBZ dosage, and comedication on CBZ CL/F was confirmed by multiple regression analysis. Conclusions: CBZ CL/F is decreased in an age‐dependent manner in elderly patients compared with younger subjects, presumably because a reduction in the rate of CYP3A4‐mediated drug metabolism. Elderly patients retain their sensitivity to dose‐dependent autoinduction and to heteroinduction by enzyme‐inducing AEDs, but their metabolic rates remain considerably below those observed in matched controls. As a result of this, patients in old age will require lower CBZ dosages to achieve serum concentrations comparable with those found in nonelderly adults.

The interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy.