Review
Effect of anti-epileptic drug therapy on the unborn child

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Abstract

Antiepileptic drugs have been shown to be teratogenic, affect children’s physical development and have neurodevelopmental effects. These drug-related effects are part of the major burden of epilepsy. Individual drugs need to be assessed via prospective studies, possible only by using pregnancy registers complying with ethical guidelines. Monotherapy data indicate valproate to be the most teratogenic drug, although it is the most effective drug and its teratogenicity is dose-related. To the author’s knowledge no specific malformations have clearly been proven to be attributable to a specific drug with the exception of valproate. Other antiepileptic drugs appear to be mildly teratogenic and newer drugs are possibly safer. A balance must be achieved between efficacy and teratogenicity. An outline is given of the problems of seizure control, polytherapy issues and lack of specific malformations ascribed to any individual drugs, and a brief reference to cognitive changes is presented.

Section snippets

Background

Antiepileptic drugs (AED) in pregnancy are associated with an increased risk of foetal malformations (FM). This has been documented by studies dating from the 1970s related to the traditional AED and more recently from prospective studies [1].

Due to lack of prospective data and adequate numbers, not enough is known of the new AED but it appears that they are no more teratogenic than the traditional ones. A significant period of time, perhaps a decade, needs to elapse before any long-term

The burden of epilepsy

Patients with epilepsy are concerned about the risk of seizures and resultant injuries, restrictions on driving and alcohol, and employment discrimination, but the greatest concern for a pregnant woman with epilepsy is the unborn child.

Three questions are often posed. Will the baby inherit epilepsy? Will the baby be physically normal? And will the baby be normal in terms of mental and emotional development? The third question is particularly complex. Answers to the first two questions may

Pregnancy registers

Registers were established in the late 1990s in order to undertake observational studies, based on Ethics Committee approval, informed consent and voluntary participation. Their ethical basis has been soundly affirmed by Sevulescu [20]. Registers comprise the North American, European International Registry of Antiepileptic Drugs and Pregnancy (EURAP), Danish, British and Australian registers, which collaborate closely. Their similarities and differences have been published [21], [22], [23], [24]

Polytherapy considerations and folate supplementation

In spite of conservative teaching on the merits of monotherapy in the treatment of epilepsy, about 25% of patients report exposure to more than one AED. As the number of possible AED combinations is high, the exploration of the teratogenicity of AED combinations has been infrequently undertaken [6], although it remains a fertile field for study.

The concept that polytherapy is inherently more teratogenic than monotherapy has been challenged in recent reports, suggesting that it is the content of

Teratogenicity of individual AED

Individual AED and FM were the subject of an excellent review by Eadie [1].

New or second generation AED

All new AED were initially designed to treat partial epilepsy. Effective and specific drugs for the treatment of genetic generalised epilepsy are sadly lacking. Over time, the approvals for lamotrigine (LTG), topiramate (TPM) and levetiracetam were extended to include genetic generalised epilepsy.

Data accrued for use in monotherapy are less robust for these drugs than for traditional drugs, as they were used as add-on treatments in many countries.

Among live-born infants in Denmark, first

Cognitive developmental defects and AED exposure

The collaborative NEAD study represents a major landmark initiative, reporting prospective results and extensive investigations of children exposed to AED in pregnancy [55]. There are several excellent reports arising out of this project. Its key findings are very important because of the implication that neurodevelopmental dysfunction may be even more devastating than many of the physical malformations resulting from AED exposure in utero. The findings of this study cause concern and are

Overview and conclusions

Prospective studies are needed to obtain valid data on questions related to foetal exposure to AED. Pregnancy registers can be used to study aspects besides teratogenicity of AED. All AED are teratogenic to a variable degree when compared to untreated WWE.

Dose issues are important particularly for VPA, as high doses are responsible for both physical FM and cognitive defects, affecting IQ and language [56], [57], [58].

A suggested upper VPA dose limit is 400 to 700 mg per day in divided doses, but

Conflicts of Interest/Disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgments

I wish to thank my colleagues, M.J. Eadie, T.J. O’Brien, C.M. Lander, A. Wood, and the Coordinator of the Australian Pregnancy Register, J. Graham. Thanks also to T. Tomson and the EURAP Central Project Commission, D. Battino, E. Bonizzoni, J. Craig, D. Lindhout, E. Perucca and A. Sabers.

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