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Original research
Risk of early neurodevelopmental outcomes associated with prenatal exposure to the antiepileptic drugs most commonly used during pregnancy: a French nationwide population-based cohort study
  1. Pierre-Olivier Blotière1,2,
  2. Sara Miranda3,
  3. Alain Weill1,
  4. Yann Mikaeloff4,5,
  5. Hugo Peyre6,7,8,
  6. Franck Ramus6,
  7. Zureik Mahmoud3,9,
  8. Joël Coste1,10,
  9. Rosemary Dray-Spira3
  1. 1Department of Public Health Studies, French National Health Insurance (CNAM), Paris, France
  2. 2Apemac, EA 4360, Université de Lorraine, Université Paris-Descartes, Nancy, France
  3. 3Department of Epidemiology of Health Products, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
  4. 4Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Unité de Rééducation Neurologique Infantile, Bicêtre, France
  5. 5CESP, Faculté de médecine-Université Paris-Sud, Faculté de médecine-UVSQ, INSERM, Université Paris-Saclay, Villejuif, France
  6. 6Laboratoire de Sciences Cognitives et Psycholinguistique, Ecole Normale Supérieure, EHESS, CNRS, PSL University, Paris, France
  7. 7Department of Child and Adolescent Psychiatry, Robert Debré Hospital, APHP, Paris, France
  8. 8INSERM UMR 1141, Paris Diderot University, Paris, France
  9. 9Versailles Saint-Quentin-en-Yvelines University, Versailles, France
  10. 10Biostatistics and Epidemiology Unit, Hôtel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, and Paris Descartes University, Paris, France
  1. Correspondence to Dr Pierre-Olivier Blotière; poblotiere{at}


Objectives To assess the association between prenatal exposure to monotherapy with the antiepileptic drugs (AEDs) most commonly used during pregnancy and the risk of various neurodevelopmental outcomes compared with lamotrigine.

Design Nationwide population-based cohort study.

Setting French national healthcare databases.

Participants Children born alive between 2011 and 2014 and prenatally exposed to AED monotherapy.

Primary and secondary outcome measures Outcomes included neurodevelopmental disorders (NDD), defined by International Classification of Diseases, 10th Revision codes F70-F98—pervasive developmental disorders (PDD, F84) and mental retardation (MR, F70-F79) were studied separately—and visits to speech therapists. The reference group comprised children prenatally exposed to lamotrigine. Children were followed until outcome, loss to follow-up, death or 31 December 2016. We performed inverse probability of treatment weighting analyses using the propensity score, which included maternal and infant characteristics. Hazard ratios (HRs) were calculated using Cox models.

Results The cohort comprised 9034 children, 2916 of which were exposed to lamotrigine, 1627 to pregabalin, 1246 to clonazepam, 991 to valproic acid (VPA), 621 to levetiracetam, 502 to carbamazepine, 477 to topiramate, 378 to gabapentin and 143 to oxcarbazepine. None of these AEDs, except VPA, was associated with an increased risk of any of the four neurodevelopmental outcomes investigated. Exposure to VPA was associated with increased risks of NDDs (HR=2.7, 95% CI (1.8 to 4.0)), PDD (HR=4.4 (2.1 to 9.3)), MR (HR=3.1 (1.5 to 6.2)) and visits to speech therapists (HR=1.5 (1.1 to 1.9)), with a dose-response relationship.

Conclusions No increased risk of any of the neurodevelopmental outcomes investigated in this study was observed with prenatal exposure to levetiracetam, pregabalin, oxcarbazepine, topiramate, gabapentin, clonazepam or carbamazepine, compared with lamotrigine. However, this study corroborates the well-known association between maternal use of VPA during pregnancy and the risk of neurodevelopmental disorders in the offspring. Longer follow-up is necessary to confirm these findings.

  • epilepsy
  • paediatric neurology
  • child & adolescent psychiatry

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  • Presented at Parts of this work have been previously presented at the 34th International Conference on Pharmacoepidemiology and Therapeutic Risk Management in Prague, Czech Republic (August 2018).

  • Contributors P-OB, SM, AW, MZ, JC and RD-S contributed to the conception and design of the study. P-OB and SM contributed to the acquisition of data. P-OB conducted the statistical analyses. P-OB, SM, AW, YM, HP, FR, MZ, JC and RD-S contributed to the interpretation of data. P-OB drafted the manuscript. AW, YM, HP, FR, MZ, JC and RD-S revised the manuscript for important intellectual content. AW, MZ, JC and RD-S coordinated and supervised the study.

  • Funding P-OB and AW are employees of the French National Health Insurance (CNAM). SM, MZ and RD-S are employees of the French National Agency for Medicines and Health Products Safety (ANSM), YM and JC work at Assistance Publique-Hôpitaux de Paris. None of these authors received any funding. All work by HP and FR is supported by Agence Nationale de la Recherche (grants ANR-17-EURE-0017 and ANR-10-IDEX-0001–02).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval This observational cohort study based on the French healthcare databases was approved by the French Data Protection Agency (CNIL, approval ID: DE-2015-165).

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

  • Data availability statement No data are available. Permanent access to the French health care databases is automatically granted to certain government agencies, public institutions and public service authorities. Temporary access for studies and research is possible on request from the National Health Data Institute (INDS).

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