Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomesReportar como inadecuado

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BMC Medicine

, 15:95

First Online: 05 May 2017Received: 14 November 2016Accepted: 28 March 2017DOI: 10.1186-s12916-017-0845-1

Cite this article as: Veroniki, A.A., Cogo, E., Rios, P. et al. BMC Med 2017 15: 95. doi:10.1186-s12916-017-0845-1


BackgroundPregnant women with epilepsy frequently experience seizures related to pregnancy complications and are often prescribed anti-epileptic drugs AEDs to manage their symptoms. However, less is known about the comparative safety of AED exposure in utero. We aimed to compare the risk of congenital malformations CMs and prenatal outcomes of AEDs in infants-children who were exposed to AEDs in utero through a systematic review and Bayesian random-effects network meta-analysis.

MethodsMEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to December 15, 2015. Two reviewers independently screened titles-abstracts and full-text papers for experimental and observational studies comparing mono- or poly-therapy AEDs versus control no AED exposure or other AEDs, then abstracted data and appraised the risk of bias. The primary outcome was incidence of major CMs, overall and by specific type cardiac malformations, hypospadias, cleft lip and-or palate, club foot, inguinal hernia, and undescended testes.

ResultsAfter screening 5305 titles and abstracts, 642 potentially relevant full-text articles, and 17 studies from scanning reference lists, 96 studies were eligible n = 58,461 patients. Across all major CMs, many AEDs were associated with higher risk compared to control. For major CMs, ethosuximide OR, 3.04; 95% CrI, 1.23–7.07, valproate OR, 2.93; 95% CrI, 2.36–3.69, topiramate OR, 1.90; 95% CrI, 1.17–2.97, phenobarbital OR, 1.83; 95% CrI, 1.35–2.47, phenytoin OR, 1.67; 95% CrI, 1.30–2.17, carbamazepine OR, 1.37; 95% CrI, 1.10–1.71, and 11 polytherapies were significantly more harmful than control, but lamotrigine OR, 0.96; 95% CrI, 0.72–1.25 and levetiracetam OR, 0.72; 95% CrI, 0.43–1.16 were not.

ConclusionThe newer generation AEDs, lamotrigine and levetiracetam, were not associated with significant increased risks of CMs compared to control, and were significantly less likely to be associated with children experiencing cardiac malformations than control. However, this does not mean that these agents are not harmful to infants-children exposed in utero. Counselling is advised concerning teratogenic risks when the prescription is written for a woman of childbearing age and before women continue with these agents when considering pregnancy, such as switching from polytherapy to monotherapy with evidence of lower risk and avoiding AEDs, such as valproate, that are consistently associated with CMs. These decisions must be balanced against the need for seizure control.

Systematic Review RegistrationPROSPERO CRD42014008925

KeywordsNetwork meta-analysis Systematic review Epilepsy Fetus Pregnancy Adverse effects Antiepileptic drugs Congenital malformations Miscarriage Knowledge synthesis AbbreviationsAEDanti-epileptic drugs

CMcongenital malformations

CrIcredible interval

NMAnetwork meta-analysis

ORodd ratios

RCTrandomized clinical trials

SUCRAsurface under the cumulative ranking curve

Electronic supplementary materialThe online version of this article doi:10.1186-s12916-017-0845-1 contains supplementary material, which is available to authorized users.

Autor: Areti Angeliki Veroniki - Elise Cogo - Patricia Rios - Sharon E. Straus - Yaron Finkelstein - Ryan Kealey - Emily Reynen


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