Clinical Study
The internal control group in a register of antiepileptic drug use in pregnancy

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Abstract

The aim of this study was to determine how valid 68 first-trimester pregnancies of untreated epileptic women would prove as an internal control group for investigating foetal malformation rates in 709 simultaneously collected antiepileptic drug-exposed pregnancies in an Australian register of pregnancies in epileptic women. We carried out comparisons of values for parameters relating to personal details, obstetric aspects, and epilepsies prior to and during pregnancy in the drug-exposed and drug-unexposed pregnancies, with observations on subpopulations within the drug-unexposed group. Statistically significant (p < 0.05) differences existed for only seven of more than 50 parameters compared. None of these seven parameters had a statistically significant influence on foetal malformation rates in the whole dataset. In 23 of the 65 epileptic pregnancies unexposed to antiepileptic drugs, therapy had been ceased shortly prior to pregnancy and was often resumed after the first trimester. In the remaining 42, therapy had been ceased earlier, often despite continuing seizures. Planned withdrawal of therapy did not appear to produce additional hazards for mothers and foetuses in the former subgroup. In the data collection studied, there did not appear to be evidence of statistically significant differences between untreated pregnancies and treated epileptic pregnancies that would be likely to invalidate the former group as an internal control for the latter, at least when assessing foetal malformation rates.

Introduction

A number of studies since the 1970s have demonstrated an association between the intake of antiepileptic drugs (AEDs) during pregnancy and the occurrence of malformed offspring. Many of these studies have been population-based. The earlier studies, summarised by Janz,1 were often retrospective ones. The more recent studies have usually been based on relatively large prospective data collections. These studies have utilised various comparison populations against which the malformation rate in the offspring of antiepileptic drug-treated mothers has been assessed. In some studies, relatively little attention appears to have been paid to the suitability of the comparison population employed. The malformation rate in the general population has sometimes been used for this purpose, as in the early studies reviewed by Janz2. In this case the data from the two populations compared may not have been collected in identical ways, because the general population data would have probably been obtained retrospectively. Also, the general population may differ from the population of women with antiepileptic drug-treated epilepsy in respects that may be important to the risk of foetal malformations, such as socioeconomic status, nutrition, smoking habit and alcohol exposure. Occasionally, previous antiepileptic drug-treated pregnancies in the same women have been employed as the comparison group. This again involves comparing retrospectively and prospectively collected data; furthermore, the size of the control population is likely to be relatively small, and the control population will be younger.

For studying the relationship between antiepileptic drug exposure in pregnancy and foetal malformations, the best practicable comparator would be a group of simultaneously studied untreated pregnant women with epilepsy. Approximations to such an internal control group have been employed in a number of studies of antiepileptic drug-associated teratogenesis.[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14] However, the question then arises as to why such untreated epileptic populations should have existed when antiepileptic drugs are effective in preventing epileptic seizures. Might the untreated epileptic women also have differed in some other important way from the treated epileptic women, and could this difference have invalidated the comparison between the two groups? It has been stated in the literature that differences do exist between populations of treated and untreated pregnant epileptic women.[9], [15], [16], [17] However, there have been relatively few studies published that actually examined any differences that were present and assessed their implications for foetal malformation rates.[6], [7], [12]

The Australian Register of Antiepileptic Drug Use in Pregnancy has accumulated sufficient data to now permit an analysis of its potential internal comparison group of pregnant, mainly epileptic, women who had not taken antiepileptic drugs, at least in the first trimester of their pregnancies, to assess how valid the pregnancies of these women might be as a comparator group.

Section snippets

Materials and methods

In 1999 an Australia-wide register was set up to collect data on pregnancies and their foetal outcomes in epileptic women or in non-epileptic women who were taking, or who had previously been taking, antiepileptic drugs. The existence of the register was advertised within the Australian medical community, and by epilepsy associations and other relevant lay bodies. The register was based at the Raoul Wallenberg Centre for Clinical Neuropharmacology, commencing in 1999 at St. Vincent’s Hospital

Results

Of the 68 pregnancies for which the women involved were not treated with antiepileptic drugs in the first trimester of pregnancy, 65 were in women with epilepsy, as were 695 of the 709 drug-treated pregnancies (95.6% and 98.0%, respectively). Two of the 68 antiepileptic drug-untreated pregnancies were lost to follow up between 7 months of pregnancy and term, and in a further five antiepileptic drug therapy was resumed between the 13th and the 18th weeks of pregnancy. There were thus 61

Discussion

If foetal malformation data are collected for a particular population, for example antiepileptic drug-treated mothers, and no reasonably matched comparative data are available, it is impossible to know whether the malformation rate found differs from that in the normal population, although useful internal comparisons within the population studied will still be possible. As a possible comparator for the malformation rate found in the Australian Register of Antiepileptic Drug Use in Pregnancy

Acknowledgement

We wish to thank our colleagues, both medical and paramedical, for their referrals, and our Advisory Board, the Epilepsy Society of Australia, and lay bodies for their support. We wish to thank the following pharmaceutical companies for their unrestricted grants for this research: Sanofi-Aventis, UCB Pharma, Janssen Cilag, Novartis, Pfizer, Mayne Pharma, Biogen, and GSK. Our thanks are due to the Ethical Research Committees of St. Vincent’s Hospital and Monash University and Medical Centre.

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