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The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs

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The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs Drugs - Real World Outcomes (2016) 3:131–143 DOI 10.1007/s40801-016-0078-1 REVIEW ARTICLE The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs: A Literature Review 1 2 1 Josta de Jong • Ester Garne • Lolkje T. W. de Jong-van den Berg • Hao Wang1 Published online: 24 May 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract found. The signals for associations between topiramate and Background More information is needed about possible cleft lip with/without cleft palate and hypospadias were associations between the newer anti-epileptic drugs considered strong. Associations between lamotrigine and (AEDs) in the first trimester of pregnancy and specific anencephaly and transposition of great vessels were found congenital anomalies of the fetus. within one study and were not supported by other studies. Objectives We performed a literature review to find sig- No signals were found for the other newer AEDs, or the nals for potential associations between newer AEDs information was too limited to provide such a signal. (lamotrigine, topiramate, levetiracetam, gabapentin, Conclusion In terms of associations between monotherapy oxcarbazepine, eslicarbazepine, felbamate, lacosamide, with a newer AED in the first trimester of pregnancy and a pregabalin, retigabine, rufinamide, stiripentol, tiagabine, specific congenital anomaly, the signals for topiramate and vigabatrin, and zonisamide) and specific congenital cleft lip with/without cleft palate and hypospadias should anomalies. be investigated further. Methods We searched PubMed and EMBASE to find observational studies with pregnancies exposed to newer AEDs and detailed information on congenital anomalies. Key Points The congenital anomalies in the studies were classified according to the congenital anomaly subgroups of Euro- Information was found on specific congenital pean Surveillance of Congenital Anomalies (EUROCAT). anomalies in fetuses exposed to lamotrigine, We compared the prevalence of specific congenital topiramate, levetiracetam, gabapentin, and anomalies in fetuses exposed to individual AEDs in the oxcarbazepine monotherapy in the first trimester. combined studies with that of the general population in a reference database. A significantly higher prevalence based The possible association between cleft lip and on three or more fetuses with anomalies was considered a hypospadias and the use of topiramate in pregnancy signal. should be investigated further. Results Topiramate showed a higher rate of congenital anomalies than the other newer AEDs. Four signals were 1 Introduction & Josta de Jong [email protected] Users of anti-epileptic drugs (AEDs) regularly include women of childbearing age. During pregnancy, the treat- 1 Department of Pharmacoepidemiology and Pharmacoeconomics, University of Groningen, ment of epilepsy often needs to be continued, and—if A. Deusinglaan 1, 9713AV Groningen, The Netherlands possible—a pregnant woman with epilepsy should be free 2 Paediatric Department, Hospital Lillebaelt, Kolding, of seizures, because a seizure could harm both mother and Denmark fetus [1]. On the other hand, harm to the fetus from the use 132 J. de Jong et al. of medication in pregnancy should also be minimized. A We searched EMBASE for all newer AEDs separately balance must be found between benefits and risks for using the following search strategy: mother and child through agreement between the pregnant ‘lamotrigine (or other drug) AND congenital malfor- woman and the physician [2, 3]. Objective scientific mation AND pregnancy NOT review’. information on the risks of AEDs to the fetus is essential The search was conducted on 12 November 2014. for these discussions and decisions. AEDs are classified in two groups: older AEDs and 2.2 Selection newer AEDs, the latter being introduced during the last two decades. Since the late 1990s, the use of newer The articles were selected using the following inclusion AEDs has increased, especially for indications other than criteria: epilepsy such as neuropathic pain, mood disorders, – original randomized controlled trials or observational migraine, and depression [4–6]. Lamotrigine, topiramate, studies. gabapentin, and pregabalin are the most commonly used – exposure to a newer AED as monotherapy in the first newer AEDs [4]. Women in particular seem to use more trimester (B12 weeks of gestation). newer AEDs than do men, probably in an effort to avoid – information on congenital anomalies. the use of valproate during childbearing years [7, 8]. – the most recent update of studies based on the same About 0.5 % of pregnant women in Europe use AEDs, long-term databases or pregnancy registries. most often carbamazepine, valproic acid, or lamotrigine; – enrolment of the pregnant women before the outcome the most frequently used AEDs differ between countries of the pregnancy was known in the cohort and [9]. observational studies. More information is needed on the risk of congenital anomalies in exposed pregnancies for the newer AEDs. The articles from PubMed were selected based on the These newer AEDs might have an increased risk for title and abstract. They were classified into two groups specific congenital malformations. We performed an (studies including one AED and studies including more extensive literature search to find signals of higher risks of than one AED) and were read carefully, including the specific congenital anomalies in relation to the use of appendices. The articles were selected based on the newer AEDs in pregnancy. inclusion criteria and categorised per AED; thus, the arti- cles with more than one AED were categorised more than once. Additional articles found in EMBASE or the refer- 2 Methods ences that met the inclusion criteria were added (Fig. 1). 2.1 Search Strategy 2.3 Data Extraction The newer AEDs included in this review were lamotrigine, We reclassified the selected studies into five types based on topiramate, levetiracetam, gabapentin, oxcarbazepine, the study design, which could differ from the design indi- eslicarbazepine, felbamate, lacosamide, pregabalin, reti- cated by the authors: gabine, rufinamide, stiripentol, tiagabine, vigabatrin, and 1a. prospective cohort studies (with reference group). zonisamide. 1b. retrospective cohort studies (with reference group). We searched PubMed for original articles using the 2a. prospective exposed groups (without reference group). following search strategy: 2b. retrospective exposed groups (without reference group). 1. congenital abnormalities [medical subject heading; 3. case–control studies. MeSH] OR pregnancy complications/drug therapy OR We analysed studies that included stillbirths, fetal pregnancy complications/drug effects OR pregnancy deaths, and pregnancy terminations (‘all births’) and outcome [MeSH] studies describing only live births both separately and in AND combination. 2. (felbamate OR gabapentin OR lacosamide OR lamot- rigine OR levetiracetam OR pregabalin OR topiramate 2.4 Data Analysis OR vigabatrin OR eslicarbazepine OR oxcarbazepine OR rufinamide OR stiripentol OR zonisamide OR Two authors (JJ and EG) reclassified all specific congenital tiagabine OR retigabine OR pheneturide) NOT (mod- anomalies into the congenital anomaly subgroups of the els, animal [MeSH] OR animal experimentation European Surveillance of Congenital Anomalies (EURO- [MeSH]). CAT) [10]. Only major anomalies were included in the Newer Antiepileptic Drugs and Congenital Anomalies 133 Fig. 1 Selection process for articles included in the review 134 J. de Jong et al. analysis. When no information was provided on specific 3 Results congenital anomalies, we followed the definition of major congenital anomalies in the article. 3.1 General Results We calculated the overall major anomaly rate for every AED, for which cohort studies or studies with exposed We selected 341 articles from PubMed. In addition, six groups (1a, 1b, 2a, and 2b) were selected, using the articles from EMBASE and references were added (Fig. 1; number of fetuses as the denominator. If the analysis in grey background). The 30 selected studies were catego- an article was based on pregnancies, and the exact num- rized per AED and study design, as shown in Table 1.We ber of fetuses was unknown, we used the number of found no randomized controlled trials. pregnancies, assuming that multiple pregnancies are rare Table 2 shows an overview of the cohort- and exposed and that this difference would not greatly influence the group studies found, with the numbers of fetuses or preg- results. nancies exposed to lamotrigine, topiramate, levetiracetam, We calculated the prevalence of any specific congenital gabapentin, or oxcarbazepine and the percentage of major anomaly subgroup from studies with sufficiently detailed congenital anomalies. Vajda et al. [14] provided no infor- information. mation on whether the congenital anomalies were major or The prevalence of specific anomalies was compared minor, so we counted the total number of congenital with the prevalence of the anomaly subgroup in the anomalies. One study [15] included only live births. EUROCAT AED database, which covers 10,061,059 births Two studies were based on international pregnancy from 21 regions in Europe (1995–2011) and has been registries and were analysed separately: Cunnington et al. described previously [11, 12]. We excluded registrations [16] used the International Lamotrigine Pregnancy Reg- from this database with maternal AED exposure, maternal istry, with information on specific congenital anomalies of epilepsy,
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