Current safety concerns about the use of antiseizure medications in pregnancy

ABSTRACT

Introduction

Given the high prevalence of epilepsy in women of childbearing potential (15 million out of 50 million people worldwide), antiseizure medication (ASM) use in pregnancy is common. Identifying the safest and most effective ASM to use during pregnancy is often difficult, but also crucially important. The challenge is to balance two needs: maintaining seizure control while minimizing teratogenicity.

Areas covered

This review looks at seizure- and treatment-related risks to mother and fetus during pregnancy, existing healthcare information programmes, strengths and pitfalls of the main pregnancy registries, known and supposed pharmacokinetic changes during gestation, the utility of therapeutic drug monitoring, and safety concerns. Articles and related content were screened on available publications after January 2000.

Expert opinion

The use of newer ASMs during pregnancy is still limited, as shown by the paucity of data collected by different pregnancy registries. Choosing these medications can be challenging, partly due to unknown pharmacokinetic modifications in pregnancy, an aspect that serum drug monitoring might help to clarify. The safest treatment is chosen also taking into account the woman’s needs, concerns and wishes, but adequate pre-pregnancy counseling is necessary to properly inform her about personal and fetal risks related both to seizures and to medications.

KEYWORDS:

• Antiseizure medications
• pregnancy registries
• teratogenicity
• therapeutic drug monitoring
• women with epilepsy
• valproate

Article highlights

• In people with epilepsy, especially pregnant women, effective treatment is needed in order to prevent seizure-related physical (craniocerebral traumas and soft tissue injuries) and social consequences (isolation and stigma) for the woman and potential negative foetal outcomes (small for gestational age, pre-term birth).

• Pregnant women with epilepsy, being classified as a ‘vulnerable’ category, are excluded from clinical studies and research trials, even though they might benefit from the study interventions under investigation. In clinical practice, neurologists often prescribe medications with limited or absent evidence of efficacy and safety in pregnancy.

• The pharmacokinetics of antiseizure medications changes during gestation due to physiological pregnancy-related changes in the mother’s body (increased volume of distribution, elevated renal clearance, and induction of hepatic metabolism). While information on older antiseizure medications is available, little is known about the newer ones. Therapeutic drug monitoring could therefore be helpful, allowing clinicians to make the most appropriate therapeutic choices.

• Therapeutic drug monitoring is required with certain antiseizure medications known to show serum level changes during pregnancy. Lamotrigine is the main example. A pre-pregnancy reference serum level is recommended and should be maintained throughout gestation.

• Data on the safety of antiseizure medications during pregnancy can be obtained thanks to a new drug labelling schema proposed by the Food and Drug Administration. However, these data may not be constantly or promptly updated. Spontaneous reporting, case reports/case series, and pregnancy registries are extensively used for evaluating medication safety in pregnancy.

• Evidence of the association between major congenital malformations and specific medications (e.g. valproate) has led to a radical change in prescribing practice, with clinicians now choosing less teratogenic agents (lamotrigine and levetiracetam) over other ones.

• The rate of unplanned pregnancies in women with epilepsy is high. Pre-pregnancy counselling needs to be provided at the first clinical assessment and over subsequent clinical appointments to properly inform the woman with epilepsy about teratogenic risks and the usefulness of optimising therapy before conception in the event of a pregnancy.

• Even though rigid restrictions on prescribing valproate in girls and women of reproductive age have been in place since 2018, in clinical practice there are certain critical situations in which it is difficult to radically change or avoid its use, especially in patients who have achieved long-lasting seizure control.

• Expert Italian epileptologists have proposed a therapeutic algorithm for application in idiopathic generalised epilepsy when the use of valproate is contraindicated.

This box summarizes key points contained in the article.

Declaration of interests

G Falcicchio has received consultancy fees from Angelini Pharma. E Russo has received speaker fees or funding from, and has participated in advisory boards for, Arvelle Therapeutics, Angelini Pharma, Eisai, Pfizer, GW Pharmaceuticals, JAZZ pharmaceuticals, UCB and Lundbeck. 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. AL Neve has received speaker’s or consultancy fees from Eisai, Mylan, Sanofi, Bial, GW, UCB Pharma, Arvelle Therapeutics, Angelini Pharma and Neuraxpharma. G Boero has received speaker’s or consultancy fees from Eisai, Angelini Pharma and UCB Pharma. All other authors have nothing to declare. 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.

Author contribution

E Russo and AL Neve organised the structure of the article. G Falcicchio, A Fabiano, M Scalese, G Boero searched the literature for all the relevant articles to be used in the review. G Falcicchio, G Boero, M Trojano, MD Tommaso reviewed the articles selected and obtained the final list to be used. G Falcicchio, A Fabiano, M Scalese wrote the first draft. G Boero, M Trojano, MD Tommaso, AL Neve corrected the first draft. E Russo and AL Neve finalized the first final draft. All Authors approved the final version and contributed to the corrections indicated by the reviewers.

Additional information

Funding

This paper was not funded.