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Changing Australian prescribing patterns for antiepileptic drugs in pregnancy and their possible consequences

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Abstract

We report progress in the accumulation of data by the Australian Pregnancy Register over 64 months, confirming the rise in enrolment and the predominantly epileptic indication for taking antiepileptic drugs. Eighty percent of the enrolment was prospective. The focus of the current report is the observation that as a possible result of education and dissemination of information about the risks of exposure to high-dose valproate, there has been a decline in the drug’s doses prescribed in Australia, as well as a decline in the proportion of patients prescribed this drug in pregnancy. The risk of teratogenicity associated with valproate in doses in excess of 1100 mg/day was confirmed, and the incidence of lamotrigine-related malformations was comparable to that associated with exposure to phenytoin and carbamazepine. Reporting of data for this paper took into account the 12 months follow-up period for each pregnancy outcome, thus in effect making the evaluation period 21 months for each pregnancy and its outcome.

Introduction

In previous communications we have reported the results of a series of analyses based on data acquired from the Australian Pregnancy Register over a period of 52 months.[1], [2], [3] Sodium valproate (VPA), at doses greater than 1100 mg/day, was associated with a statistically significant higher incidence of fetal malformations (FM) than that which applied for other commonly prescribed anti-epileptic drugs (AEDs), or for women with epilepsy not taking AEDs. We also noted the relative freedom from FMs in pregnancies associated with exposure to lamotrigine monotherapy. Compared to unexposed fetuses of epileptic mothers with epilepsy, those exposed in utero to carbamazepine (CBZ) and phenytoin in the absence of VPA did not appear to have a statistically significant higher incidence of FMs than fetuses not exposed to AEDs.

We reported also that, although not based on a randomised controlled trial protocol, the use of VPA appeared more effective in offering protection from seizures to expectant mothers than lamotrigine, while CBZ was comparable to VPA in this regard. Too few patients were enrolled on other AEDs to make any definitive comment on their safety and efficacy against seizures in pregnancy.

It was suggested that although isolated seizures did not appear to cause damage to the fetus, repeated severe convulsions or status epilepticus might contribute to fetal loss.4

The purpose of this current paper was to analyse the outcomes of pregnancy in the Australian Pregnancy Register of AEDs at the completion of 64 months of data collection, particularly with respect to any changes in prescribing patterns over this time. We hypothesised that, in view of the dissemination of information concerning the teratogenicity of VPA, there would be a fall in the doses of VPA employed in pregnant women in Australia, and that this may be associated with a decrease in the rate of AED-associated birth defects, but also potentially with an increase in seizures during pregnancy.

Section snippets

Patients and methods

The methodology of the Register has been reported previously.[1], [2], [3], [4] It is based on observational data collected with ethical approval and informed consent. All participants routinely underwent four telephone interviews, in the first trimester or on enrolment, at 7 months of pregnancy, at delivery, and 1 year thereafter. Fetal outcomes were expressed in relation to the number of products of pregnancies, rather than to numbers of mothers, or pregnancies, because of the numerical

Enrolment figures at 64 months

Because some women had more than one pregnancy included in the Register, enrolments are expressed in terms of pregnancies rather than pregnant women (Table 1). The table indicates that the majority of pregnancies of women with epilepsy participating in the Registry are prospective (86.3%). ‘Prospective’ refers to pregnancies in which the presence of any fetal malformation is unknown at the time of inclusion in the Register (‘truly prospective’ enrolment refers to pregnancies enrolled prior to

Discussion and conclusions

It has been a practice of the Australian Pregnancy Register to report its progressive results on at least an annual basis. This contrasts with the policy of other Registers, such as the North American Register, which involves releasing results only when they attain statistical significance. The rationale for our approach has been to allow prescribers, and the wider epilepsy community, access to the most recent data on which to make informed choices. It has the potential to influence prescribing

Acknowledgement

We thank our medical colleagues, and members of epilepsy-related lay bodies for their support, the Medical and Scientific Advisory Board, The Epilepsy Society of Australia, and its President, John Dunne, The Scientific Advisory Committee of the Registry, Epilepsy Australia, The Epilepsy Association, and our sponsors, Sanofi Aventis, Glaxo Smith Kline , UCB Pharma, Cilag Janssen, Novartis, Pfizer, and the Ethics Comittees of St. Vincent’s Hospital, Monash Medical Centre, and Mercy Hospital,

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