Seizure 24 (2015) 143–144
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Invited Commentary The dilemma of treating young women with generalized epilepsy with sodium valproate and how to get out of it
1. The dilemma Despite the introduction of modern antiepileptic drugs (AEDs) such as lamotrigine or topiramate, sodium valproate (VPA) is seen by many as the most effective medication for seizure control in idiopathic generalized epilepsy (IGE). The case vignettes and the great review by Mole et al.1 in this issue dramatically illustrate the ill effects of withholding VPA for seizure control and the therapeutic benefits of VPA. That is however only one side of the coin. The other side of the coin is that we have learnt in the last 30 years that VPA is the most teratogenic epilepsy drug on the market with an overall risk of 11% for major congenital malformations.2 VPA monotherapy is associated with significantly increased risks for six specific malformations including spina bifida 12.7-fold increased risk for spina bifida.3 Although alarming, this is not new. Preliminary case reports were published as early in the mid-1980s.4 In addition, Meador and colleagues5 have convincingly shown in recent years that exposure to VPA during early pregnancy causes long-lasting intelligence deficits in the offspring.5 The effect was dose dependent, and the impact of the effect appeared greater in verbal than in nonverbal abilities.5 Given these risks, physicians are justifiably reluctant to recommend VPA in young women with generalized epilepsy unless contraceptive measures are taken. Yet, the merit of the opinion piece by Mole et al.,1 is that it they reminded us that indiscriminately withholding VPA in young women with generalized epilepsy may not be the best solution, either. How can we get out of this dilemma? 2. Ways out of the dilemma There is general agreement that, if possible, VPA should be avoided in the first trimester of pregnancy due to the risks.6 If this is not possible, when, for example, prior attempts to lower the dose or to stop VPA altogether have been unsuccessful, women should be warned that stopping or lowering the dose of VPA should not be done without consultation with her physician. Once it has been determined that VPA needs to be continued during pregnancy, the patient must be informed of the relative risks including the general side-effect profile of VPA, particularly weight gain, and counseled appropriately. Counseling about the teratogenic risks of major congenital malformations should
include the important information that the vast majority of children will be unaffected. If VPA is needed, it should preferably be given prior to or during pregnancy at daily doses not exceeding 1000 mg. This recommendation is based on evidence suggesting that the teratogenic risk of VPA seems to be higher at daily doses beyond 1000 mg.7 If 800–1000 mg/day of VPA do not achieve seizure-freedom, it is better to find this out prior to than during pregnancy, if possible. It is reassuring in that respect that pregnancy itself does not seem to substantially affect seizure control.8 Whether absence or myoclonic seizures and self-limiting, brief tonic-clonic-seizures affect the health and the development of the child in utero, is not well known. However, prolonged seizures and status epilepticus are thought to be a serious threat to both mother and fetus according to a case report.9 Most physicians seem to prefer to add another suitable AED, if needed for seizure control, and shy away from removing VPA during pregnancy (as any other AED). As a caveat, it should be noted that the best evidence for the usefulness of any of these treatment options during pregnancy is largely anecdotal as in any patient with refractory generalized epilepsy. Folate supplementation (at least 0.4 mg folic acid/day) is generally recommended during conception and pregnancy although the proper dose and the treatment effect, if any, is not well known.6 In summary, navigating VPA treatment in women with generalized epilepsy who need it, by protecting from teratogenic risks and yet maintaining or achieving seizure control requires an individualized balance. Mole and colleagues1 are commended to have reminded us that a one-sided approach to ban sodium valproate from the treatment of women with generalized epilepsy may not always be in the best interest of the patient.
References 1. Mole TB, Marson A, Appleton R. Withholding the choice of sodium valproate to young women with generalised epilepsy: are we causing more harm than good? Seizure 2015;24:127–30. 2. Meador KJ, Reynolds RW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 2008;81:1–13. 3. Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, et al. EUROCAT Antiepileptic Study Working Group. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 2010;362:2185–93. 4. Lindhout D, Schmidt D. In-utero exposure to valproate and neural tube defects. Lancet 1986:1392–3. 5. Meador KJ, Baker GA, Browning N, Cohen MJ, Clayton-Smith J, Kalayjian LA, et al. NEAD Study Group. Foetal antiepileptic drug exposure and verbal versus nonverbal abilities at three years of age. Brain 2011;134:396–404. 6. Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA. Practice parameter update: management issues for women with epilepsy – focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:133–41.
http://dx.doi.org/10.1016/j.seizure.2014.10.004 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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Invited Commentary / Seizure 24 (2015) 143–144
7. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. EURAP Study Group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;7:609–17. 8. Schmidt D. The effect of pregnancy on the natural history of epilepsy: review of the literature. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, and the child. New York: Raven Press; 1982 . p. 3–14.
9. Hiilesman V. Effects of maternal seizures on the fetus. In: Tomson T, Gram L, Sillanpa¨a¨ M, Johannesen S, editors. Epilepsy and pregnancy. Peterfield, UK/Bristol, PA, USA: Wrightson Biomedical Publishing Ltd.; 1996. p. 135–41.
Dieter Schmidt Epilepsy Research Group, Berlin, Germany E-mail address: [email protected] (D. Schmidt).
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Invited Commentary The dilemma of treating young women with generalized epilepsy with sodium valproate and how to get out of it
1. The dilemma Despite the introduction of modern antiepileptic drugs (AEDs) such as lamotrigine or topiramate, sodium valproate (VPA) is seen by many as the most effective medication for seizure control in idiopathic generalized epilepsy (IGE). The case vignettes and the great review by Mole et al.1 in this issue dramatically illustrate the ill effects of withholding VPA for seizure control and the therapeutic benefits of VPA. That is however only one side of the coin. The other side of the coin is that we have learnt in the last 30 years that VPA is the most teratogenic epilepsy drug on the market with an overall risk of 11% for major congenital malformations.2 VPA monotherapy is associated with significantly increased risks for six specific malformations including spina bifida 12.7-fold increased risk for spina bifida.3 Although alarming, this is not new. Preliminary case reports were published as early in the mid-1980s.4 In addition, Meador and colleagues5 have convincingly shown in recent years that exposure to VPA during early pregnancy causes long-lasting intelligence deficits in the offspring.5 The effect was dose dependent, and the impact of the effect appeared greater in verbal than in nonverbal abilities.5 Given these risks, physicians are justifiably reluctant to recommend VPA in young women with generalized epilepsy unless contraceptive measures are taken. Yet, the merit of the opinion piece by Mole et al.,1 is that it they reminded us that indiscriminately withholding VPA in young women with generalized epilepsy may not be the best solution, either. How can we get out of this dilemma? 2. Ways out of the dilemma There is general agreement that, if possible, VPA should be avoided in the first trimester of pregnancy due to the risks.6 If this is not possible, when, for example, prior attempts to lower the dose or to stop VPA altogether have been unsuccessful, women should be warned that stopping or lowering the dose of VPA should not be done without consultation with her physician. Once it has been determined that VPA needs to be continued during pregnancy, the patient must be informed of the relative risks including the general side-effect profile of VPA, particularly weight gain, and counseled appropriately. Counseling about the teratogenic risks of major congenital malformations should
include the important information that the vast majority of children will be unaffected. If VPA is needed, it should preferably be given prior to or during pregnancy at daily doses not exceeding 1000 mg. This recommendation is based on evidence suggesting that the teratogenic risk of VPA seems to be higher at daily doses beyond 1000 mg.7 If 800–1000 mg/day of VPA do not achieve seizure-freedom, it is better to find this out prior to than during pregnancy, if possible. It is reassuring in that respect that pregnancy itself does not seem to substantially affect seizure control.8 Whether absence or myoclonic seizures and self-limiting, brief tonic-clonic-seizures affect the health and the development of the child in utero, is not well known. However, prolonged seizures and status epilepticus are thought to be a serious threat to both mother and fetus according to a case report.9 Most physicians seem to prefer to add another suitable AED, if needed for seizure control, and shy away from removing VPA during pregnancy (as any other AED). As a caveat, it should be noted that the best evidence for the usefulness of any of these treatment options during pregnancy is largely anecdotal as in any patient with refractory generalized epilepsy. Folate supplementation (at least 0.4 mg folic acid/day) is generally recommended during conception and pregnancy although the proper dose and the treatment effect, if any, is not well known.6 In summary, navigating VPA treatment in women with generalized epilepsy who need it, by protecting from teratogenic risks and yet maintaining or achieving seizure control requires an individualized balance. Mole and colleagues1 are commended to have reminded us that a one-sided approach to ban sodium valproate from the treatment of women with generalized epilepsy may not always be in the best interest of the patient.
References 1. Mole TB, Marson A, Appleton R. Withholding the choice of sodium valproate to young women with generalised epilepsy: are we causing more harm than good? Seizure 2015;24:127–30. 2. Meador KJ, Reynolds RW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res 2008;81:1–13. 3. Jentink J, Loane MA, Dolk H, Barisic I, Garne E, Morris JK, et al. EUROCAT Antiepileptic Study Working Group. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 2010;362:2185–93. 4. Lindhout D, Schmidt D. In-utero exposure to valproate and neural tube defects. Lancet 1986:1392–3. 5. Meador KJ, Baker GA, Browning N, Cohen MJ, Clayton-Smith J, Kalayjian LA, et al. NEAD Study Group. Foetal antiepileptic drug exposure and verbal versus nonverbal abilities at three years of age. Brain 2011;134:396–404. 6. Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA. Practice parameter update: management issues for women with epilepsy – focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes. Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:133–41.
http://dx.doi.org/10.1016/j.seizure.2014.10.004 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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Invited Commentary / Seizure 24 (2015) 143–144
7. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. EURAP Study Group. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;7:609–17. 8. Schmidt D. The effect of pregnancy on the natural history of epilepsy: review of the literature. In: Janz D, Bossi L, Dam M, Helge H, Richens A, Schmidt D, editors. Epilepsy, pregnancy, and the child. New York: Raven Press; 1982 . p. 3–14.
9. Hiilesman V. Effects of maternal seizures on the fetus. In: Tomson T, Gram L, Sillanpa¨a¨ M, Johannesen S, editors. Epilepsy and pregnancy. Peterfield, UK/Bristol, PA, USA: Wrightson Biomedical Publishing Ltd.; 1996. p. 135–41.
Dieter Schmidt Epilepsy Research Group, Berlin, Germany E-mail address: [email protected] (D. Schmidt).
