Elsevier

The Lancet Neurology

Volume 17, Issue 6, June 2018, Pages 530-538
The Lancet Neurology

Articles
Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

https://doi.org/10.1016/S1474-4422(18)30107-8Get rights and content

Summary

Background

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy.

Methods

We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors.

Findings

Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250–4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30–4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250–4000 mg/day (OR 2·41, 95% CI 1·33–4·38; p=0·0055) and oxcarbazepine at doses of 75–4500 mg/day (2·37, 1·17–4·80; p=0·0169).

Interpretation

Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study.

Funding

Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Introduction

The teratogenic risks associated with antiepileptic drugs are a concern for prescribers from many disciplines because epilepsy is often managed by primary care physicians and there has been an increasing use of these drugs for indications other than epilepsy. Evidence suggests that infants exposed to antiepileptic drugs are at higher risk for major congenital malformations than are infants of untreated mothers with epilepsy.1 Observational studies have reported that valproate has a higher teratogenic risk than other antiepileptic drugs,2, 3, 4, 5, 6, 7 that this risk is dose dependent,2, 3, 5, 7 and that offspring exposed prenatally to valproate are also at higher risk for impaired postnatal cognitive development8, 9, 10 and, possibly, autism spectrum disorders.11 On the basis of these observations, the US Food and Drug Administration12 and the European Medicines Agency13 issued restrictions on the use of valproate in women of childbearing age and, in the case of the European Medicines Agency, also in girls.

Research in context

Evidence before this study

Although the use of antiepileptic drugs during pregnancy has been known for more than 50 years to be associated with increased risks of major congenital malformations in the offspring, it is not until more recent years, with emerging data from prospective pregnancy registries, that the teratogenic potential of different antiepileptic drugs had begun to be delineated. We refer to two recently published systematic reviews and meta-analyses. One review focused on newer antiepileptic drugs and searched, on Nov 12, 2014, PubMed and Embase for all newer antiepileptic drugs, congenital anomalies, and pregnancy. The second systematic review searched MEDLINE, Embase, and the Cochrane Central Register of Controlled trials from inception to Dec 15, 2015. We did a separate PubMed search for articles published from Dec 16, 2015, to Dec 15, 2017, using the search terms “anticonvulsants”, “antiepileptic drugs”, “teratogenicity”, and “birth defects”. Our search was limited to studies in English and we did not set any criteria for assessment of quality.

Although meta-analyses increase the statistical power, they combine data from heterogeneous studies sometimes with different outcome criteria, and do not provide direct within-study comparisons between antiepileptic drug treatments. Such internal comparisons have been made in individual reports from independent prospective antiepileptic drug and pregnancy registries but so far only between the most frequently used antiepileptic drugs. Taken together, these studies have consistently reported increased risk of major congenital malformations associated with valproate and phenobarbital compared with pregnancies unexposed to antiepileptic drugs, as well as compared with pregnancies exposed to other antiepileptic drugs such as carbamazepine and lamotrigine. Findings also suggest increased risks associated with topiramate. Pregnancy registries have also reported that the risks associated with some drugs, in particular valproate, might be dose dependent.

Added value of this study

On the basis of the largest published prospective cohort of pregnancies in women with epilepsy so far, we provide the prevalence of major congenital malformations at 1 year after birth following exposure to the eight most frequently used antiepileptic drugs in monotherapy. Where a dose dependency relationship was apparent, risks are reported at different doses used at conception. In a multivariable analysis, we report 36 direct comparisons of risks between different treatment modalities.

Implications of all the available evidence

With epilepsy often managed by primary care physicians, and an increasing use of antiepileptic drugs for other indications, the risk of major congenital malformations is a concern for prescribers from many disciplines. Epilepsy, as well as some psychiatric conditions, might have serious consequences and require continuation of treatment during pregnancy. Treatment modalities should be reviewed regularly in all women of childbearing potential to assess risks and benefits of treatment alternatives and enable any appropriate modifications before pregnancy. Current evidence has made clear that, whenever possible, valproate should be avoided in the treatment of women of childbearing potential, but risks differ also between other treatments. Our comprehensive study, with comparisons of risks between a multitude of antiepileptic drug treatments and dosages, provides physicians with vital information when they consider alternatives for women of childbearing potential.

The use of valproate for the treatment of epilepsy in pregnancy14 and in women of childbearing age has recently declined.15 By contrast, the use of valproate for other indications has increased,15 in particular for psychiatric conditions,14 which might reflect a gap in awareness among those outside the field of neurology.14 Prescription patterns, however, might also reflect the shortage of appropriate treatment alternatives and insufficient data for the teratogenicity of other antiepileptic drugs,16 particularly newer generation antiepileptic drugs, the use of which has increased substantially in pregnancy.14, 17

Information about comparative risks of major congenital malformations with different antiepileptic drugs comes primarily from prospective registries.2, 3, 4, 5, 18 However, because of power limitations, so far only the most frequently used antiepileptic drugs have been assessed. Meta-analyses might increase statistical power, but are limited by methodological heterogeneity across included studies and fail to assess important variables such as the influence of the dose used.1, 19 Therefore to overcome these limitations, we aimed to compare the risks of major congenital malformations for eight major antiepileptic drugs, including the risks associated with different doses of the most commonly used agents to provide physicians with novel tools for rational selection of these drugs.

Section snippets

Study design and participants

We did a longitudinal prospective, cohort study based on EURAP, an international registry collecting data for the assessment of risks of antiepileptic drugs during pregnancy. EURAP was established in 1999 and has since involved 42 countries with more than 1500 collaborators (appendix).

We included data for pregnant women for prospective assessment if they were exposed to antiepileptic drugs at conception, enrolled in EURAP within gestation week 16 (based on the date of the last menstrual

Results

Of the 21 875 pregnancies registered in the database from June 20, 1999, to May 20, 2016, 9089 pregnancies were identified prospectively in women who had been exposed to antiepileptic drug monotherapy and had complete follow-up data up to 1 year. Of these pregnancies, 7555 met eligibility criteria (figure). 237 (3%) of the 7555 pregnancies were enrolled through the UK and Ireland Epilepsy and Pregnancy Register, 419 (6%) from the Australian Pregnancy Register, and 226 (3%) from the Kerala

Discussion

In this large cohort study, we ascertained the comparative risk of major congenital malformations for eight commonly used antiepileptic drugs. We did multivariable analysis of 36 direct comparisons between treatment modalities by using, as a measure of exposure, the dose taken at time of conception, which is the dose that physicians can best relate to for treatment decisions before planned pregnancies. We are aware that dose at conception is only an approximate measure of exposure, not least

References (31)

  • GA Baker et al.

    IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study

    Neurology

    (2015)
  • KJ Meador et al.

    Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs

    N Engl J Med

    (2009)
  • J Christensen et al.

    Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism

    JAMA

    (2013)
  • FDA drug safety communication: valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children

  • Assessment report: procedure under article 31 of directive 2001/83/EC resulting from pharmacovigilance data

  • Cited by (0)

    *

    Contributed equally

    The appendix shows the complete list of collaborators

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