Seizure medication and planned pregnancy: balancing the risks and outcomes

ABSTRACT

Introduction

The therapeutic management of women with epilepsy (WWE) of childbearing age can be complicated by the need to balance maternal/fetal risks related to seizure occurrence during gestation with the potential teratogenic risks related to the use of anti-seizure medications (ASMs).

Areas covered

The authors review clinical evidence on seizure-related and ASM-related risks during pregnancy. Current regulatory indications are discussed, evaluating their impact on clinical practice, and ethical implications of pharmacological decisions are debated.

Expert opinion

If properly informed about the maternal/fetal risks carried by different pharmacological choices, WWE can become the final decision makers regarding their care in every phase of their life. Over the coming years, analysis of aggregated pregnancy registry data on the structural impact, on the fetus, of low doses of valproate and of newer ASMs, together with analysis of the main population study data on functional (cognitive and behavioral) outcomes, could lead to huge advances, making choosing an ASM a less complex process for the clinician and a less painful decision for the woman. Future objectives should include identification of the potential role of the pharmacogenomic profile of WWE in determining the risk of fetal malformations.

KEYWORDS:

• Women with epilepsy
• pregnancy
• antiseizure medicines
• valproate
• teratogenicity
• neurodevelopmental teratogenicity
• major congenital malformations
• gender medicine
• pharmacogenomics

Article highlights

• The therapeutic management of WWE in pregnancy is a complex issue frequently faced by epileptologists in clinical practice. The main challenge is how best to optimize seizure control during pregnancy while at the same time minimizing exposure of the fetus to the potentially harmful effects of ASMs. The complexity derives from the need to base decisions on an ethical analysis of the situation that takes equal account of all the personal needs and demands of the woman with epilepsy at that particular juncture in her life (that is, her concerns about her physical health, but also about her socio-professional status), while also considering the health of the fetus. The first ASM used to treat female children and girls/women of childbearing age should always be chosen with a view to a possible future pregnancy.

• Recurrence of GTCSs and FBTCs in WWE is associated with increased morbidity and mortality, as well as major negative repercussions in the social/professional sphere. Maternal outcomes linked to seizure recurrence during pregnancy are poorly studied but can be assumed to be similar to those of seizure recurrence in epilepsy patients generally. The literature reports a 10-fold increased risk of maternal mortality in pregnant WWE compared with the general population. Even in the absence of consolidated data, these observations, together with other maternal outcomes, particularly the possible negative socio-professional consequences of seizure recurrence, should be borne in mind when approaching the management of WWE who wish to plan a pregnancy, remembering that a key objective is to keep the woman seizure free during pregnancy. WWE wishing to conceive should be exhaustively informed by the treating physician of the pros and cons of each option. The woman will then give her informed consent in compliance with the patient’s right to an informed choice based on full awareness of the risks and benefits involved.

• Recurrence, in pregnancy, of GTCSs, FBTCs or a status epilepticus constitutes a serious potential threat to the health of the fetus (bradycardia, hypoxia, intrauterine death) and carries the risk of negative neonatal outcomes, such as LBW, SGA and preterm birth; affected children can have a greater lifetime predisposition to negative health outcomes, including, potentially, an increased risk of developing ASDs. These observations underline the importance of keeping women seizure free during pregnancy and, in any case, of informing them fully of the fetal risks associated with seizure recurrence in pregnancy.

• In utero exposure to ASMs carries an increased risk of MCMs. Solid data are available only for CBZ, LTG, VPA, OXC, PHT, PB, LEV and TPM; based on current knowledge of these ASMs, their risk of causing structural malformations is dose dependent, with the possible exception of LEV. VPA is the ASM most likely to display structural teratogenicity, in a dose-dependent fashion. The relative risk of this drug at low doses (400–450 mg/day) is not known. Data on newer drugs (ZNS, LCM, PER, ESL, BRV) are absent or insufficient. The risk associated with polytherapy seems to be greater if VPA is included in the treatment regimen.

• In utero exposure to ASMs carries a risk of cognitive/behavioral impairment. With VPA this risk is significantly increased, and WWE must be fully informed of this. A possible dose dependence has been reported and should be further investigated. LEV and LTG seem to be associated with a better outcome. Data on all the other ASMs are still insufficient.

Ethical publication statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Declaration of interest

A La Neve has received speaker’s or consultancy fees from Eisai, Mylan, Sanofi, Bial, GW, UCB Pharma, Arvelle Therapeutics, Angelini Pharma and Neuraxpharm. G Falcicchio received consultancy fee from Angelini Pharma. M Trojano has served on scientific Advisory Boards for Biogen, Novartis, Roche, Merck, and Genzyme; has received speaker honoraria from Biogen Idec, Merck, Roche, Teva, Sanofi-Genzyme, and Novartis; and has received research grants for her Institution from Biogen Idec, Merck, Roche, and Novartis. G Boero has received speaker’s or consultancy fees from Eisai, Angelini Pharma and UCB Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.