ILAE Commission on Therapeutic Strategies
– Torbjörn Tomson, Chair

Defining optimal treatment strategies for women with epilepsy who consider pregnancy is one of the greatest challenges in epileptology. The potential adverse effects of antiepileptic drugs (AEDs) on the foetus need to be weighed against the foetal and maternal risks associated with uncontrolled seizures during pregnancy. This task is particularly difficult since our understanding of the possible adverse foetal effects of maternal seizures as well as of the developmental toxicity of AEDs is insufficient. Although intrauterine growth retardation, major birth defects as well as delayed postnatal development have been discussed as possible consequences of exposure to AEDs in utero, the prevailing treatment strategy is based on the assumption that convulsive seizures are more harmful to the mother and to the foetus than are the drugs. The treatment objective is therefore to maintain control of seizures throughout pregnancy by using AEDs in such a way that the risk of adverse effects to the mother and the foetus are minimized.

In order to assist physicians in fulfilling these objectives, the Commission on Genetics, Pregnancy, and the Child of the International League Against Epilepsy (ILAE) has developed guidelines for the care of women with
epilepsy of childbearing age. These were first published in 1989 and in an updated version in 1993 (1). The guidelines provide general recommendations for the treatment of women with epilepsy considering pregnancy: the most effective drug for the patient’s seizure type or syndrome should be used at the lowest effective dosage and if possible as monotherapy and the treatment should be optimised before conception. However, the guidelines offer no advise with respect to which AED is most likely to be effective and has the least probability of causing harm although this is the question of highest priority for the patient as well as her physician. The reason for the vague recommendations in this respect is that conclusive data comparing the teratogenic potential of different AEDs was lacking when the guidelines were published, despite numerous studies on this issue since the 1960s. Unfortunately, the situation has not improved much during the ten years that have followed the publication of the latest ILAE guidelines although several new cohort studies on birth defects associated with use of AEDs during pregnancy have been published (for review see 2). While each such study represents a major effort and provides valuable data, they lack the power to demonstrate differences in teratogenic potential between the various treatments. Given the large number of different drugs and drug combinations, the number of patients on each individual treatment regimen is too small for a meaningful internal comparison. It is therefore not surprising that, although the studies demonstrate an increased risk for birth defects with use of AEDs in general and polytherapy in particular, they have failed to detect differences in birth defect rates among different treatment regimens. Additionally, even the more recent studies are based on pregnancies collected over long periods, sometimes 20-25 years. Consequently, their results do not necessarily reflect outcome with present treatment strategies and in particular these studies include very few pregnancies with exposure to the new generation AEDs.

Hence, we remain in the unfortunate position where a rational approach to the management of women of childbearing potential is hampered by lack of essential, conclusive data, which is largely due to methodological shortcoming, in particular lack of statistical power, in previous studies.

Pregnancy registries have been developed in recent years to facilitate the collection of large numbers of exposures and thus overcome one major problem of previous studies. The registries monitor pregnancies prospectively with standardized methodology for collection of data to assess the occurrence of birth defects associated with different AEDs. The importance of these initiatives was recognised early by the ILAE, and a workshop was organised for the newly established pregnancy registries in conjunction with the International Epilepsy Congress in Prague in 1999 (3). Registries initiated by pharmaceutical companies as well as by independent research groups from North America, Europe, Asia and Australia were present at this event to discuss differences and similarities in methodology and possibilities for future collaboration.

Pregnancy registries set up by pharmaceutical companies to collect information on the company’s own products may be important, but their value is limited by the lack of an internal control, which is best provided by comparison with other AEDs. Non-company based registries include information on all AEDs in use. The North American AED Pregnancy Registry (NAREP) and the United Kingdom Epilepsy and Pregnancy Registry were launched in 1996-7. EURAP is an international pregnancy registry. It was originally launched in Europe in 1999 but partly as a result of the ILAE workshop, registries with similar methodology from Australia and India agreed to share data and collaborate using the same protocol. EURAP now includes collaborators from 40 countries from Europe, Asia, Australia and South America. Using somewhat different methodologies, these registries continue to enrol pregnancies at increasing rates and have each enlisted 3-5000 pregnancies in women with epilepsy. The North American and the UK registries have already published some preliminary observations. NAREP discloses malformation rates associated with specific treatments as soon as they are found to differ significantly from the rate found in the offspring of unexposed women, and thus far a significant elevation in risk has been reported with exposure to phenobarbital (6.5% malformation rate, relative risk 4.2, 1.5-9.4; 95%CI; n=77) (4). There was, however, no significant difference in the rate of malformations among phenobarbital-exposed infants in comparison with those exposed to other AEDs in the same registry. Moreover, a number of previous studies failed to identify a greater teratogenic risk of phenobarbital compared with other AEDs (2), raising the possibility that the elevated risk associated with phenobarbital in the above report might relate to the influence of confounders, such as differences in socio-economic status. NAREP has also published a preliminary report in abstract form indicating a significantly higher malformation rate with exposure to valproate compared with unexposed controls (8.9%, relative risk 6.0, 3.5 - 10.2, n=123) but an internal comparison with other AEDs was not presented (5). At the 25th International Epilepsy Congress in Lisbon, the UK registry reported major malformation rates of 2.3% (1.4-3.7%) for carbamazepine (n=700), 5.9% (4.3-8.2%) for valproate (n=572), and 2.1% (1.0-4.0%) for lamotrigine (n=390), all in monotherapy (6). Hence, this preliminary report from the UK suggests a higher risk for birth defects with valproate compared with carbamazepine and lamotrigine. At this stage, these results should still be interpreted with caution and assessed against the background of a long series of studies that failed to demonstrate differences among AEDs. Nevertheless, it should be pointed out that most of the recent large-scale prospective studies did identify a trend towards a higher teratogenicity of valproate over other commonly used AEDs (2).

Pregnancy registries as well as most previous studies have focused on the risk of major birth defects rather than on potential adverse effects of exposure to AEDs in utero on postnatal psychomotor development. However, there are suggestions from retrospective studies that children exposed to valproate in utero may encounter learning problems at school more often than children exposed to other AEDs such as carbamazepine. These results need to be confirmed in adequately powered prospective investigations. Studies addressing these important issues are underway in the US and the UK, and some pregnancy registries are also considering extending the follow-up of exposed children to allow for assessment of long-term psychomotor development.

A major limitation of all studies reported to date is that none allowed assessing the impact of possible confounders, such as type of epilepsy, seizure frequency, family history of birth defects and exposure to additional risk factors. For obvious reasons, these are all observational studies. In such studies, women are not randomised to different AEDs, and the selection of a particular AED and its dosage will depend on individual variables such as type of epilepsy, seizure frequency and socio-economic status, all of which theoretically could be linked to a higher or lower risk of malformations. This complicates the evaluation of causality in the observed associations between exposure to a drug and adverse pregnancy outcome. Large numbers of pregnancies as well as prospective and reliable recording of critical information are necessary to control for such major confounding variables and thus better allow dissection of the contribution of drug treatment. This is why signals on possible associations between exposure to a specific AED and adverse outcome need to be confirmed in independent studies and analysed in depth taking into account other potential explanations for the observed associations.

Thus, despite the signals discussed above, more data are necessary to permit evidence-based recommendations for selection of AEDs for women with epilepsy of childbearing potential. Although the pregnancy registries all inevitably suffer from the limitations of observational studies, with continued support to these initiatives more solid comparative data on the most frequently used monotherapy regimens will become available within a few years. Data emerging from the registries will hopefully also shed some light on the influence of other potentially important prognostic variables including the use of folic acid. The role of the ILAE in this important effort should be to help enhance patient enrollment by promotion of the existing pregnancy registries, to facilitate collaboration between the registries and to provide a forum for the timely dissemination of their results. An entire scientific session has therefore been dedicated to updates from the major registries at the 26th International Epilepsy Congress in Paris in 2005. The session will highlight the progress that has been made since the Congress in 1999 and hopefully demonstrate that we are beginning to build a foundation for a more rational strategy for the management of women with epilepsy that are of childbearing potential. Based on the data that will be presented in Paris, the ILAE will hopefully be in the position to take the initiative for updated guidelines with more specific, evidence-based recommendations.

References

1. Commission on Genetics, Pregnancy and the Child, International League against Epilepsy. Guidelines for the care of women of childbearing age with epilepsy. Epilepsia 1993;34 (4):588-9.
2. Tomson T, Battino D, Perucca E. Navigating toward fetal and maternal health: the challenge of treating epilepsy in pregnancy. Epilepsia 2004 in press.
3. Beghi E, Annegers JF; Collaborative group for pregnancy registries in epilepsy. Epilepsia 2001;42:1422-5.
4. Holmes LB, Wyszynski DF, Lieberman E. The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Arch Neurol 2004;61:673-678.
5. Holmes L, Wyszynski D, Mittendorf R. Evidence for an increased risk of birth defects in the offspring of women exposed to valproate during pregnancy: Findings from the AED pregnancy registry [Abstract].
   Am J Ob Gyn 2002;187 (suppl):S137.
6. Morrow J. Which antiepileptic drug is safest in pregnancy? [Abstract]. Epilepsia 2003;44 (suppl 8):60.