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Comparative safety of antiepileptic drugs for neurological development in children exposed during pregnancy and breast feeding: a systematic review and network meta-analysis
  1. Areti Angeliki Veroniki1,
  2. Patricia Rios1,
  3. Elise Cogo1,
  4. Sharon E Straus1,2,
  5. Yaron Finkelstein3,4,5,
  6. Ryan Kealey1,
  7. Emily Reynen1,
  8. Charlene Soobiah1,6,
  9. Kednapa Thavorn7,8,9,
  10. Brian Hutton7,10,
  11. Brenda R Hemmelgarn11,
  12. Fatemeh Yazdi1,
  13. Jennifer D'Souza1,
  14. Heather MacDonald1,
  15. Andrea C Tricco1,12
  1. 1 Li Ka Shing Knowledge Institute,St. Michael’s Hospital, Toronto, Canada
  2. 2 Department of Medicine, University of Toronto, 27 King’s College Circle, Toronto, Canada
  3. 3 The Hospital for Sick Children,555 University Avenue, Toronto, Canada
  4. 4 Department of Paediatrics, University of Toronto, Toronto, Canada
  5. 5 Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Toronto, Canada
  6. 6 Institute for Health Policy Management & Evaluation,University of Toronto, Toronto, Canada
  7. 7 School of Epidemiology,Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada
  8. 8 Clinical Epidemiology Program,Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Canada
  9. 9 Institute of Clinical and Evaluative Sciences (ICES uOttawa), Ottawa, Canada
  10. 10 Ottawa Hospital Research Institute,Center for Practice Changing Research, Ottawa, Canada
  11. 11 Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Canada
  12. 12 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
  1. Correspondence to Dr Andrea C Tricco; triccoa{at}


Objectives Compare the safety of antiepileptic drugs (AEDs) on neurodevelopment of infants/children exposed in utero or during breast feeding.

Design and setting Systematic review and Bayesian random-effects network meta-analysis (NMA). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched until 27 April 2017. Screening, data abstraction and quality appraisal were completed in duplicate by independent reviewers.

Participants 29 cohort studies including 5100 infants/children.

Interventions Monotherapy and polytherapy AEDs including first-generation (carbamazepine, clobazam, clonazepam, ethosuximide, phenobarbital, phenytoin, primidone, valproate) and newer-generation (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, vigabatrin) AEDs. Epileptic women who did not receive AEDs during pregnancy or breast feeding served as the control group.

Primary and secondary outcome measures Cognitive developmental delay and autism/dyspraxia were primary outcomes. Attention-deficit hyperactivity disorder, language delay, neonatal seizures, psychomotor developmental delay and social impairment were secondary outcomes.

Results The NMA on cognitive developmental delay (11 cohort studies, 933 children, 18 treatments) suggested that among all AEDs only valproate was statistically significantly associated with more children experiencing cognitive developmental delay compared with control (OR=7.40, 95% credible interval (CrI) 3.00 to 18.46). The NMA on autism (5 cohort studies, 2551 children, 12 treatments) suggested that oxcarbazepine (OR 13.51, CrI 1.28 to 221.40), valproate (OR 17.29, 95% CrI 2.40 to 217.60), lamotrigine (OR 8.88, CrI 1.28 to 112.00) and lamotrigine+valproate (OR 132.70, CrI 7.41 to 3851.00) were associated with significantly greater odds of developing autism compared with control. The NMA on psychomotor developmental delay (11 cohort studies, 1145 children, 18 treatments) found that valproate (OR 4.16, CrI 2.04 to 8.75) and carbamazepine+phenobarbital+valproate (OR 19.12, CrI 1.49 to 337.50) were associated with significantly greater odds of psychomotor delay compared with control.

Conclusions Valproate alone or combined with another AED is associated with the greatest odds of adverse neurodevelopmental outcomes compared with control. Oxcarbazepine and lamotrigine were associated with increased occurrence of autism. Counselling is advised for women considering pregnancy to tailor the safest regimen.

Trial registration number PROSPERO database (CRD42014008925).

  • multiple treatment meta-analysis
  • knowledge synthesis
  • epilepsy
  • pregnancy
  • infants
  • developmental delay

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

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  • Contributors AAV analysed the data, interpreted the results and drafted the manuscript. ACT and SES conceived and designed the study, helped obtain funding, interpreted the results and helped write sections of the manuscript. PR and EC coordinated the review, screened citations and full-text articles, abstracted data, appraised quality, resolved discrepancies, contacted authors and edited the manuscript. CS provided methodological support and screened citations and full-text articles and edited the manuscript. RK, ER, FY, JDS, KT and HM screened citations and full-text articles, abstracted data and/or appraised quality. BH, BRH and YF helped conceive the study and edited the manuscript. All authors read and approved the final manuscript.

  • Funding This systematic review was funded by the Canadian Institutes for Health Research/Drug Safety and Effectiveness Network (CIHR/DSEN).

  • Disclaimer The funder had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.

  • Competing interests AAV is funded by the Banting Postdoctoral Fellowship Program from the CIHR. SES is funded by a Tier 1 Canada Research Chair in Knowledge Translation. BH is funded by a CIHR/DSEN New Investigator Award in Knowledge Synthesis. BRH receives funding from the Alberta Heritage Foundation for Medical Research. ACT is funded by a Tier 2 Canada Research Chair in Knowledge Synthesis.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data sets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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