Management of epilepsy during pregnancy

Fondazione I R C C S Istituto Neurologico Carlo Besta, Milan, Italy.
Drugs (Impact Factor: 4.13). 01/2007; 67(18):2727-46. DOI: 10.2165/00003495-200767180-00007
Source: PubMed

ABSTRACT 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.

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    • "In addition, its clinical use is limited because of two severe side effects: teratogenicity and hepatotoxicity [5] [6]. Consequently, there is a substantial need for the development of new second-generation drugs to VPA that preserve its broad-spectrum efficacy at lower doses and lack hepatotoxicity and teratogenicity [5] [6] [7] [8] [9] [10] [11] [12]. Both teratogenicity and hepatotoxicity are related to structure, although, unlike teratogenicity, hepatotoxicity results from a minor metabolite(s) of VPA with a terminal double bond (e.g., 4-ene-VPA) [13]. "
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    ABSTRACT: A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maximal electroshock, subcutaneous metrazol, and 6-Hz (32-mA) seizure tests. In mice, the ED(50) values of N-methoxy-VCD were 142 mg/kg (maximal electroshock test), 70 mg/kg (subcutaneous metrazol test), and 35 mg/kg (6-Hz test), and its neurotoxicity TD(50) was 118 mg/kg. In rats, the ED(50) of N-methoxy-VCD in the subcutaneous metrazol test was 36 mg/kg and its protective index (PI=TD(50)/ED(50)) was >5.5. In the rat pilocarpine-induced status epilepticus model, N-methoxy-VCD demonstrated full protection at 200mg/kg, without any neurotoxicity. N-Methoxy-VCD was tested for its ability to induce teratogenicity in a mouse strain susceptible to VPA-induced teratogenicity and was found to be nonteratogenic, although it caused some resorptions. Nevertheless, a safety margin was still maintained between the ED(50) values of N-methoxy-VCD in the mouse subcutaneous metrazol test and the doses that caused the resorptions. On the basis of these results, N-methoxy-VCD is a good candidate for further evaluation as a new anticonvulsant and central nervous system drug.
    Epilepsy & Behavior 09/2011; 22(3):461-8. DOI:10.1016/j.yebeh.2011.08.026
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    • "nonepileptic CNS disorders, and consequently is the most prescribed AED (Perucca, 2002; Nalivaeva et al., 2009). The clinical utilization of VPA is limited by different side effects, with the most serious of those being teratogenicity (Kaneko et al., 1999; Battino & Tomson, 2007) and hepatotoxicity (Chang & Abbott, 2006; Koenig et al., 2006), which restrict its utilization in women of child-bearing age and in children. To overcome the severe side effects associated with use of VPA and to retain its beneficial antiepileptic and CNS activity, numerous VPA analogs and derivatives have been designed and evaluated, and some of these second-generation VPA compounds have been found to possess favorable pharmacodynamic properties (Bialer & Yagen, 2007). "
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    ABSTRACT: α-Fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide (α-F-TMCD) and α-Cl-TMCD, are α-halo derivatives of TMCD, the corresponding amide of a cyclopropane analog of valproic acid (VPA). This study aimed to comparatively evaluate the pharmacodynamics and pharmacokinetics of α-F-TMCD and α-Cl-TMCD in rodent models of epilepsy and for antiepileptic drug (AED)-induced teratogenicity. The potential of α-F-TMCD as an antiallodynic and antinociceptive compound was also evaluated. α-F-TMCD and α-Cl-TMCD were synthesized. α-Cl-TMCD anticonvulsant activity was evaluated in comparison to VPA in the mouse maximal-electroshock-seizure (MES), Metrazol (scMet), and 6-Hz psychomotor-seizure tests. Neurotoxicity was assessed by the Rotorod-ataxia test. Induction of neural tube defects (NTDs) by α-Cl-TMCD and α-F-TMCD was evaluated after intraperitoneal administration to a mouse strain highly susceptible to VPA-induced teratogenicity. The ability of α-F-TMCD to reduce pain was evaluated in the rat spinal nerve ligation (SNL) model for neuropathic pain and in the formalin test. α-F-TMCD and α-Cl-TMCD pharmacokinetics was evaluated following intraperitoneal (40 mg/kg) and oral (60 mg/kg) administration to rats. α-F-TMCD and α-Cl-TMCD had similar potencies in the 6-Hz test and were more potent than VPA in this model and in the scMet test. Neither induced NTDs, and both exhibited wide safety margins. α-F-TMCD was active in the two pain models, and was found to be equipotent to gabapentin in the SNL model (ED(50) = 37 and 32 mg/kg, respectively). Comparative pharmacokinetic analysis showed that α-Cl-TMCD is less susceptible to liver first-pass effect than α-F-TMCD because of lower total (metabolic) clearance and liver extraction ratio. Based on their potent anticonvulsant activity and lack of teratogenicity, α-F-TMCD and α-Cl-TMCD have the potential for development as new antiepileptics and central nervous system (CNS) drugs.
    Epilepsia 10/2010; 51(10):1944-53. DOI:10.1111/j.1528-1167.2010.02684.x
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    • "Pregnancy of a woman with epilepsy is a high-risk pregnancy due to a more frequent occurrence of complications and a higher risk for congenital fetal malformations and postnatal developmental anomalies than observed in the general population [7] [8] [9] [10] [11]. There is a direct association between the treatment for epilepsy with the use of AEDs and the onset of congenital developmental anomalies ([4] [8] [12]; De Santis et al. [19]). Pippenger suggests that every drug from the group of AEDs introduced on the market before 1990 ('older generation AEDs') taken by pregnant women with epilepsy was related to a certain degree with the onset of congenital developmental anomalies. "
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    ABSTRACT: Epidemiological data indicate that pregnancies of epileptic women constitute about 1% of all pregnancies. Newborns of mothers exposed to anti-epileptic drugs (AEDs) are at increased risk for major congenital malformations, cognitive impairment and fetal death. Cord-blood lymphocytes of the newborns whose mothers received long-term AEDs therapy during pregnancy were used in this study. There were 37 newborns (Group A), divided into two subgroups, i.e. from mothers receiving mono-therapy (A1) and from those receiving poly-therapy (A2). The major drugs given to the pregnant women with epilepsy in mono-therapy were valproic acid (VPA) and carbamazepine (CBZ) analogues. In poly-therapy, besides VPA and CBZ derivatives also phenyltriazine, sulphanamide, benzodiazepines and gamma-aminobutyric acid (GABA) derivatives were administered. Three kinds of in vitro cytogenetic test were applied: the chromosome aberration (CA) assay, the sister chromatid exchange (SCE) assay, and the cytokinesis-block micronucleus assay (CBMN). In addition, the mitotic index (MI), the replication index (RI) and the nuclear division index (NDI) were determined. The mean number of CA/cell (excluding gaps) for group A did not differ statistically significantly from the negative controls (p>0.1), nor did the mean MI value (p>0.1). In group A, the mean number of SCE/cell was statistically significantly higher compared with the negative control (p<0.05). The mean RI value for group A did not demonstrate statistically significant differences (p>0.1). The mean MN number for group A was higher than in the negative control, but this difference was on the border of statistical significance (p=0.07). The value of NDI for group A did not differ significantly from the value in the negative control (p>0.1). The anti-epileptic drugs given to epileptic women in mono- and poly-therapy during pregnancy evoked potentially clastogenic and genotoxic effects in cord-blood lymphocytes. These drugs did not exert a cytotoxic effect, neither did they inhibit the cell-division kinetics of cord-blood lymphocytes.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 05/2010; 701(2):111-7. DOI:10.1016/j.mrgentox.2010.05.003
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