Article

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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    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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    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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