Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes
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Published version
Author(s)
Type
Journal Article
Abstract
Background Pregnant 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. Methods MEDLINE, 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). Results After 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. Conclusion The 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.
Date Issued
2017-05-05
Online Publication Date
2017-05-05
2018-07-05T08:54:22Z
Date Acceptance
2017-03-28
ISSN
1741-7015
Publisher
BioMed Central
Journal / Book Title
BMC Medicine
Volume
15
Issue
1
Copyright Statement
© 2017 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000400551800001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Network meta-analysis
Systematic review
Epilepsy
Fetus
Pregnancy
Adverse effects
Antiepileptic drugs
Congenital malformations
Miscarriage
Knowledge synthesis
MANAGEMENT ISSUES
EPILEPSY
WOMEN
INCONSISTENCY
INTERVENTIONS
MODEL
TERATOGENICITY
CONSISTENCY
MULTIARM
TRIALS
Abnormalities, Drug-Induced
Adult
Anticonvulsants
Bayes Theorem
Child
Female
Humans
Infant
Network Meta-Analysis
Pregnancy Complications
Pregnancy Outcome
Young Adult
11 Medical And Health Sciences
Publication Status
Published
Article Number
95
Date Publish Online
2017-05-05