Clinical StudyTeratogenicity of the newer antiepileptic drugs – the Australian experience
Introduction
In the last decade of the 20th century, more than 10 new antiepileptic drugs (AED) were introduced, often known as the second generation, in contrast to the traditional agents, some of which have been available since the 1940s. These new AED possess some novel characteristics, fueling expectations that they may be more suitable for managing difficult-to-treat epilepsy syndromes, more easily tolerable than the older agents, and undergo fewer interactions. Their favorable pharmacokinetic profiles may render them suitable for use in polytherapy and in special situations such as in pregnant women with epilepsy (WWE).1, 2, 3 However, there are also the important issues of the possible teratogenic effects of these newer AED when taken in pregnancy, how they compare with the older generation of AED in this regard, and whether such effects may extend to both the physical and the cognitive development of the infant.
Recent action by the US Food and Drug Administration (FDA) in issuing a warning of an increased risk of harelip and facial cleft abnormalities associated with use of topiramate in pregnancy, and that this AED is increasingly used as a migraine prophylactic as well as an antiepileptic agent and so may be taken by growing numbers of women early in pregnancy, has prompted an analysis of the data in the Australian Register of Antiepileptic Drugs in Pregnancy to try to assess the degree of foetal hazard associated with exposure to this, and the other newer, AED.4
Section snippets
Register methodology
The Australian Register – The Australian Pregnancy Register (APR) – was established in 1999 as an observational database, employing prospective data collection, with full Ethics Committee approval and informed consent. The purpose of the APR is to study the efficacy and teratogenicity of AED and to provide data that may be used clinically to help achieve optimal management of pregnancy for WWE. This is clearly a womens’ and societal health issue of major importance. Enrolment in the APR is
Results
As of November 2010, the APR contained details of 1317 pregnancies whose outcome at the time of birth were known. In the great majority, the outcome 12 months post-partum also was known, and that parameter has been used in the data analysis. Table 1 shows the number of pregnancies exposed to the various AED in monotherapy, with the associated numbers and rates of FM, and the corresponding numbers for all pregnancies involving each drug. A pregnancy leading to a malformed offspring may appear
Discussion
The dose-related teratogenicity of the new AED has not, until recently, been examined systematically in any of the international registers set up to study the comparative effects of AED on FM. The recent paper by EURAP addressed this issue, and showed that, in monotherapy, there were statistically significant associations between FM risk and drug dosage for CBZ, VPA, LTG and phenobarbitone.7 In the Australian health system, it is only when older drugs have proved unsatisfactory in a given
Conclusions
There was no statistically significant evidence of an increased risk of teratogenesis or of dose-related teratogenicity for LTG. Although the numbers of monotherapy-exposed pregnancies was relatively small, there was also no evidence of dose-related teratogenesis for TPM or LEV compared with the risk in AED-untreated women.
Acknowledgments
We thank our colleagues, the Advisory Board, the Ethics Committees, participating women, and our sponsors: the Epilepsy Society of Australia, Sanofi, UCB Pharma, Janssen, Pfizer, Novartis, National Health and Medical Research Council for a linkage grant, and the Royal Melbourne Hospital Neuroscience Foundation.
References (14)
Efficacy and tolerability of the new antiepileptic drugs: a comparison of two recent guidelines
Lancet Neurol
(2004)- et al.
Dose-dependent risk of malformations with antiepileptic drugs: analysis of data from the EURAP epilepsy and pregnancy registry
Lancet Neurol
(2011) Pharmacokinetic profile of levetiracetam: toward ideal characteristics
Pharmacol Ther
(2000)- et al.
Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register
Seizure
(2010) - et al.
Teratogenic effects of antiepileptic medications
Neurol Clin
(2009) Drug selection for the newly diagnosed patient: when is the new generation antiepileptic drug indicated?
J Neurol
(2004)The clinical pharmacology and therapeutic use of the new antiepileptic drugs
Fundam Clin Pharmacol
(2001)
Cited by (73)
Teratogenic potential of third-generation antiepileptic drugs: Current status and research needs
2019, Pharmacological ReportsCitation Excerpt :Despite the improved efficacy of SGAEDs, these agents were not devoid of congenital malformations and associated with sporadic incidences of congenital malformations (major or minor) in clinical and experimental regimes. In the majority of clinical studies, the rate of fetal malformations was slightly higher in SGAEDs exposed children than non-exposed subjects with SGAEDs or general pregnant population [21,25,33–36]; whereas some studies have demonstrated that rate of congenital malformations caused by SGAEDs was lower than FGAEDs [20]. It concluded that there was no strong association with an increased risk of major birth defects with SGAEDs than traditional drugs used as monotherapy.
Neurologic Disorders in Pregnancy
2016, Obstetrics: Normal and Problem PregnanciesMonotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child
2023, Cochrane Database of Systematic ReviewsStudy on the Safety of Antiepileptic Drugs during Pregnancy
2019, Chinese Journal of Modern Applied Pharmacy