Global survey of guidelines for the management of epilepsy in pregnancy: A report from the international league against epilepsy task force on women and pregnancy

The ILAE Task Force on Women and Pregnancy conducted a survey among ILAE Chapters of their use of guidelines or recommendations for the management of women with epilepsy during pregnancy. A web-based questionnaire including 10 questions was sent to the 118 ILAE Chapters in December 2017 with repeated reminders until the end of February 2018. In total, 77 chapters (65%) responded, although not to all questions. Out of those responding, 68% reported having guidelines or recommendations, 34% of which were from 2014 or earlier. At least 20% of the guidelines did not include information on possible risk to cognitive development, information regarding specific risks with specific antiepileptic drugs, nor recommendations regarding selection of antiepileptic drugs. Among those responding to the question, 91% reported that recommendations were made regarding folate supplementation, but the recommended dose ranged from 0.4 mg/d to 4 mg/d or more; 34% did not include recommendations regarding drug level monitoring during pregnancy, and 19% did not include guidelines on breastfeeding. Our survey demonstrates that there is a need for the development of up-to-date, globally applicable recommendations for the management of epilepsy during pregnancy.Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Karolinska University Hospital. Department of Neurology; SueciaFil: Battino, Dina. Fondazione IRCCS Istituto Neurologico Carlo Besta. Department of Neurophysiology and Experimental Epileptology. Epilepsy Center; ItaliaFil: Bromley, Rebecca. Central Manchester University Hospitals NHS Foundation Trust; Reino Unido. University of Manchester; Reino UnidoFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Meador, Kimford J.. University of Stanford; Estados UnidosFil: Pennell, Page B.. Brigham and Women's Hospital. Harvard Medical School. Department of Neurology. Divisions of Epilepsy and Women's Health; Estados UnidosFil: Thomas, Sanjeev V.. Sree Chitra Tirunal Institute of Medical Sciences and Technology. Department of Neurology; Indi

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250?4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30?4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250?4000 mg/day (OR 2·41, 95% CI 1·33?4·38; p=0·0055) and oxcarbazepine at doses of 75?4500 mg/day (2·37, 1·17?4·80; p=0·0169). Interpretation: Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Funding: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Battino, Dina. Foundation Irccs Neurological Institute "c. Besta"; ItaliaFil: Bonizzoni, Erminio. Università degli Studi di Milano; ItaliaFil: Craig, John. Belfast Health And Social Care Trust; Reino UnidoFil: Lindhout, Dick. Stichting Epilepsie Instellingen Nederland; Países BajosFil: Perucca, Emilio. Universita Degli Studi Di Pavia; ItaliaFil: Sabers, Anne. Rigshospitalet; DinamarcaFil: Thomas, Sanjeev V. Sree Chitra Tirunal Institute For Medical Sciences And Technology; IndiaFil: Vajda, Frank. University of Melbourne; AustraliaFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Bohorquez Morera, Natalia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentin

Gender issues in antiepileptic drug treatment

The purpose of this review is to discuss gender-related aspects in the, pharmacokinetics, effects, selection and use of antiepileptic drugs (AED). In general, there are few known gender related differences in pharmacokinetics or efficacy of AEDs. Conversely, gender has a significant influence on the susceptibility to certain adverse effects, not the least those involving alterations in sex hormone metabolism. Particularly relevant are the teratogenic effects of AEDs, with important differences among AEDs in their potential to cause adverse effects on the fetus when used during pregnancy. Pregnancy can also markedly affect the pharmacokinetics of several AEDs, and dose adjustments are often needed during pregnancy to maintain seizure control. Some treatments that are used only by women, such as contraceptive steroids and hormone replacement therapy, can also interact with AEDs to an extent that may affect the utilization of both the AEDs and the other drug

Valproic acid after five decades of use in epilepsy: Time to reconsider the indications of a time-honoured drug

Since the serendipitous discovery of its anticonvulsant properties more than 50 years ago, valproic acid has become established as an effective broad-spectrum antiepileptic drug that is particularly useful for the management of generalised epilepsies, for which treatment alternatives are few. However, during the past few years increasing evidence has accumulated that intake of valproic acid during pregnancy is associated with a significant risk of dose-dependent teratogenic effects and impaired postnatal cognitive development in children. Because of these risks, valproic acid should not be used as a first-line drug in women of childbearing potential whenever equally or more effective alternative drugs are available-as in the case of focal epilepsy. In some generalised epilepsy syndromes, such as juvenile myoclonic epilepsy, valproic acid has better documented efficacy than alternative drugs and drug selection should be a shared decision between the clinician and the informed patient based on careful risk-benefit assessment

The remarkable story of valproic acid

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Management of epilepsy in pregnancy:a report from the International League Against Epilepsy Task Force on Women and Pregnancy

The risks associated with use of antiepileptic drugs during pregnancy are a major concern for all women with epilepsy with childbearing potential. These risks have to be balanced against foetal and maternal risks associated with uncontrolled seizures. This report from the International League Against Epilepsy Task Force on Women and Pregnancy aims to provide a summary of relevant data on these risks as a basis for expert opinion recommendations for the management of epilepsy in pregnancy. The report reviews data on maternal and foetal risks associated with seizures as well as teratogenic risks associated with antiepileptic drug exposure, including effects on intrauterine growth, major congenital malformations, and developmental and behavioural outcomes. The impact of pregnancy on seizure control and on the pharmacokinetics of antiepileptic drugs are also discussed. This information is used to discuss how treatment may be optimized before conception and further managed during pregnancy.Fil: Tomson, Torbjörn. Karolinska University Hospital; SueciaFil: Battino, Dina. No especifíca;Fil: Bromley, Rebecca. University of Manchester; Reino UnidoFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Meador, Kimford. University of Stanford; Estados UnidosFil: Pennell, Page. Brigham And Women's Hospital; Estados UnidosFil: Thomas, Sanjeev V.. Sree Chitra Tirunal Institute For Medical Sciences And Technology; Indi

Breastfeeding while on treatment with antiseizure medications:a systematic review from the ILAE Women Task Force

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Battino, Dina. Instituto Neurologico Carlo Besta; ItaliaFil: Bromley, Rebecca. University of Manchester; Reino Unido. Royal Manchester Children's Hospital; Reino UnidoFil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; ArgentinaFil: Meador, Kimford J.. University of Stanford; Estados UnidosFil: Pennell, Page B.. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Thomas, Sanjeev V.. Institute For Communicative And Cognitive Neurosciences; Indi

Withdrawal of valproic acid treatment during pregnancy and seizure outcome: Observations from EURAP

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a causeeffect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study