An International Antiepileptic Drugs and Pregnancy Registry Central Study Coordinator Dr Dina Battino Neurological Institute Carlo Besta Via Celoria 11 20 133 Milano, Italy Tel: + 39 (0)2 239 42 30 Fax: + 39 (0)2 700 42 91 60 E-mail: email@example.com Chairman Central Project Commission Dr Torbjörn Tomson Department of Neurology Karolinska Hospital S-171 76 Stockholm Sweden Tel: + 46 (0)8 51773705 Fax: + 46 (0)8 51773757 E-mail: firstname.lastname@example.org
All old-generation antiepileptic drugs (AEDs) are considered to be teratogenic and AEDs areamong the most common causes of adverse effects to the foetus. The risks associated with thetreatment of epilepsy during pregnancy is therefore of major concern to all women ofchildbearing potential with epilepsy. The information on the comparative teratogenicity ofthese AEDs in humans is, however, conflicting, mainly due to inadequate sample size andother methodological shortcomings of previous studies. The teratogenic potential of newerAEDs is even less known, a situation that prevents a rational approach to AED treatment inwomen of childbearing potential.
To address this problem, it is necessary to compile more information on outcome ofpregnancies following maternal exposure to AEDs. Such information is needed to providepre-pregnancy counselling concerning teratogenic risks, and possibilities for specific prenatalmonitoring, including prenatal diagnosis of foetal disorders associated with specificmedications. Given the current number of available AEDs and combinations, very largenumbers of pregnancies have to be evaluated in order to establish the safety of each regimen. Large denominators are also needed because of the qualitative diversity of the main endpointof outcome, major congenital malformations.
A number of independent groups with experience and interest in maternal and foetal well-being in association with maternal AED use have agreed on a prospective international multi-centre study of pregnancies with AEDs. Data from all participating groups are shared in aCentral Registry of Antiepileptic Drugs and Pregnancy (EURAP). EURAP was established inthe first centres in some European countries and has since then gradually expanded to includemore centres and countries now involving also Asia, Oceania and Latin America.
The primary objective of EURAP is to evaluate and determine the comparative risk of majorfoetal malformations following intake of AEDs (old and new) and their combinations duringpregnancy.
EURAP is a prospective observational study. Women taking AEDs at the time of conception,irrespective of the indication, may be included. To avoid selection bias, only pregnanciesrecorded before foetal outcome is known and within week 16 of gestation are included in theprospective risk assessment. Cases ascertained later in pregnancy are recorded asretrospective cases, as they may provide signals, but are not included in the comparative riskevaluation.
Information on patients’ demographics, type of epilepsy, seizure frequency, family history ofmalformations, drug therapy and of other potential risk factors is obtained, and follow-up dataare collected once at each trimester, at birth and at one year after delivery.
Networks of reporting physicians have been established in countries taking part in thecollaboration. During the course of the pregnancy, and the follow-up time after delivery, theparticipating physician enters data into five Subforms (Subforms A-E) for each patient. Subform A is completed on enrolment of the patient, Subform B after the first trimester,Subform C after the second trimester, Subform D within three months after delivery, andSubform E within 14 months after birth. Immediately after completion, each Subform issubmitted to the national coordinator for review. The national coordinator transfers thereviewed and accepted Subform to the Central EURAP Registry in Milan, Italy.
The physician records descriptively abnormalities observed in the offspring. The finalassessment and classification of the type of malformation is the responsibility of the CentralProject Commission (CPC). In order to facilitate a uniform and objective assessment, reportsof malformations are assessed regularly by an outcome assessment committee, which is keptblinded with respect to the type of exposure.
Outcome in relation to exposure to individual drugs or drug combinations will be assessedonly after sufficient data is available for a meaningful statistical analysis. Determination ofthe sample size needed is complicated by lack of reliable information about the distribution ofindividual drugs and their combinations and about the incidence of the teratogenic event. Applying the general empirical rule that the ratio between the overall number of events(teratogenic events) and the number of explanatory variables (predictors) should be at leastequal to 10, a total sample size of about 5,000 pregnancies would be needed to allow analysisof 25 predictors (different AEDs and other relevant risk factors) assuming an incidence ofmalformations in the order of 5%. For this reason, the present report does not include data onmalformation rates in relation to specific AEDs.
The present report is based on data available in the Central Registry by November 30, 2002. At that time 31 countries had contributed cases to the Central Registry. Countries that hadbeen active are listed in Table 1.
Table 1Countries that have contributed with pregnancies reported to the Central EURAP Registry
AlbaniaArgentinaAustraliaAustriaChileCroatiaCzech RepublicDenmarkFranceGeorgiaGermanyHong KongHungaryIndia
The present report is based on only those pregnancies for which records are complete byNovember 30, 2002, excluding those reported who failed to meet inclusion criteria (n=34),drop-outs (n=18; withdrawal of consent or lost to follow-up) and those with Case ReportForms (CRFs) that need to be completed or corrected. Thus in total 2175 pregnancies areincluded in this report. Of these, 1568 (72%) are prospective, enrolled at the latest during the16th gestational week. The following information will focus on data obtained from theprospective pregnancies.
The classification of the epilepsy among the prospective pregnancies is given in table 2. Epilepsy was the indication for treatment in all but 20 (1%) of the pregnant women.
Table 2. Classification of the epilepsy in 1568 prospective pregnancies
The maternal age among prospective cases was 29.9±5.1 years (mean±SD), ranging 16-41years. The pregnant women were of Caucasian ethnicity in 91% of the prospective cases.
The number of the current pregnancy in the individual woman is presented in Table 3.
Table 3Number of the pregnancy in prospective cases
By the cut-off time for this analysis, 1174 (75%) of the prospective pregnancies had beenfollowed until three months after delivery, (Subform D); whereas 578 (37%) had alsocompleted the report on follow up one year after birth (Subform E). There were 20 stillbirths,ten perinatal deaths, 40 induced and 86 spontaneous abortions reported among the prospectivepregnancies.
Figure 1Outcome of prospective pregnancies
Number of pregnancies
1460 of the prospective pregnancies had advanced to the stage when Subform B, and thusdetailed data on drug exposure had been entered into the Central database. 1123 (77%) of theprospective pregnancies were using a single AED, 287 (20%) were on two AEDs whereas 50(3%) took three AEDs or more. The exposure to the different AEDs in the prospectivepregnancies is summarised in Table 4.
Table 4. Number of prospective pregnancies with exposure to different AEDs in monotherapy and incombinations.
barbesaclone + lamotrigine + phenobarbital
lamotrigine + phenobarbital + valproic acid
carbamazepine + topiramate + valproic acid
barbesaclone + carbamazepine + valproic acid
carbamazepine + lamotrigine + valproic acid
carbamazepine + phenobarbital + topiramate
phenobarbital + topiramate + valproic acid
clobazam + lamotrigine + phenobarbital + valproic acid
clobazam + lamotrigine + topiramate + valproic acid
clobazam + lamotrigine + topiramate + vigabatrin
clonazepam + oxcarbazepine + phenobarbital + topiramate
carbamazepine + clobazam + phenobarbital + primidone + topiramate
clobazam + lamotrigine + phenobarbital + topiramate + valproic acid
A total of 63 cases with major birth defects have been identified in the prospective cohort. This includes eight cases of malformations among those with induced abortions, stillbirth andperinatal death. There are 16 additional cases with potential birth defects but for which furtherdetailed information is necessary before final classification can be made. Sixty-three casesrepresent a malformation rate of 5% of all 1174 prospective pregnancies for which subform D(follow-up at three months after delivery) has been completed. The corresponding rate is 7%if the 16 potential cases were included. It should be emphasized that this is a preliminaryclassification of outcome based mainly on the follow-up three months after birth.
For reasons given above, outcome in relation to exposure to individual drugs or drugcombinations will not be assessed or reported at this stage.
So far, collaborators in 31 countries have contributed with cases to the Central Registry. Approximately 20% of all eligible pregnancies with antiepileptic drug exposure are enrolledin EURAP in Italy and Scandinavia, where the project was implemented first. However, manyof the participating countries are at an early stage of EURAP and the enrolment rate isexpected to increase gradually in these regions. In addition, networks are being established inother countries and several physicians in additional countries have expressed an interest injoining the collaboration. We therefore expect a continued increase in the enrolment rate,which at present is estimated to 120 new pregnancies monthly.
EURAP is a consortium of independent research groups working on a non-profit basis. Theproject is administratively organised by the Central Project Commission (CPC) with membersrepresenting different geographical areas and disciplines. EURAP is established and carriedout under the auspices of the European Epilepsy Academy (Eurepa) and is endorsed by theCommission on Therapeutic Strategies of the International League Against Epilepsy. Theproject is supported by educational grants to the CPC from GlaxoSmithKline, Janssen-Cilag,Pfizer, Sanofi-Synthelabo, UCB Pharma and Novartis. In addition, national and regionalnetworks may receive support from other pharmaceutical companies. Central Project Commission
Dina Battino, MilanoMarc Beaussart, LilleErminio Bonizzoni, PaviaJohn Craig, BelfastDick Lindhout, UtrechtEmilio Perucca, PaviaAnne Sabers, CopenhagenTorbjörn Tomson, Stockholm, (chair)Frank Vajda, Melbourne
Central Study Coordinator Scientific Advisory Board
Bernd Schmidt, FreiburgMartin J Brodie, Glasgow (Eurepa representative)
Outcome Assessment Committee
Richard Finnell, Houston, TexasFrancesca Faravelli, Genoa, Italy
Frank Vajda, AustraliaGerhard Luef, AustriaDick Lindhout, BeneluxDinko Vitezic, CroatiaJana Zarubova and Robert Kuba, Czech RepublicAnne Sabers, DenmarkNoemi Lisanti, EquadorReetta Kälviäinen, FinlandMarc Beaussart, FranceOtar Toidze and Lela Sturua, GeorgiaBettina Schmitz, GermanyPatrick Kwan, Hong KongGábor Barcs, HungarySanjeev V Thomas, IndiaJohn Craig, UK and IrelandMiri Neufeld, IsraelDaniela Mamoli, ItalyMasaki Tanaka, JapanKarl-Otto Nakken, NorwayPiotr Hincz and Joanna Jedrzejczak, PolandAline Russell, ScotlandBostjan Cebular, SloveniaMertixell Martinez Ferri, SpainTorbjörn Tomson, SwedenBarbara Tettenborn and Hartmut Baier, SwitzerlandÇigdem Özkara, TurkeyDragoslav Sokic, Yugoslavia
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