Behavioural outcomes following in utero exposure to anti-seizure medication: protocol for a systematic review

Introduction Prenatal exposure to certain antiseizure medications (ASMs) has been associated with increased risk of adverse neurodevelopmental outcomes in offspring. While the cognitive and intellectual outcomes of ASM-exposed offspring have been well-described, the long-term behavioural and functional sequalae in these children have received less attention. This systematic review aims to synthesise evidence on the relationship between prenatal ASM exposure and postnatal adverse neurodevelopmental outcomes, focusing on non-cognitive and intellectual domains of neurodevelopment including reduced social, emotional, behavioural, and adaptive functioning, as well as the frequency of neurodevelopmental and psychiatric disorders. This will have meaningful clinical implications for how we counsel women taking ASMs in pregnancy. Methods and analysis Studies reporting predefined neurodevelopmental outcomes will be identified by electronic searches of MEDLINE, PsychINFO, EMBASE, as well as additional manual and grey literature searches. Eligible studies will report outcomes of offspring exposed to ASMs in utero either prospectively or retrospectively from 1990 to present, with screening performed in duplicate. We will use the Newcastle-Ottawa Scale to conduct methodological quality assessments of included observational studies. A narrative synthesis will be used to report on the review findings. Meta-analysis is not anticipated. Ethics and dissemination Ethics clearance is not required for the current study. The systematic review will be prepared as a journal article and published in a peer-reviewed journal upon completion. PROSPERO registration number PROSPERO CRD42021281919 Article Summary Strengths and limitations of this study ### Competing Interest Statement None to declare. P.P has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma. He is an Associate Editor for Epilepsia Open. F.J.E Vajda has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, National Health and Medical Research Council, Royal Melbourne Hospital Neuroscience Foundation, Epilepsy Action Australia, Sanofi-Aventis, UCB Pharma, Janssen-Cilag, and Sci-Gen. T.J. O'Brien has received research support from the Epilepsy Society of Australia, National Health and Medical Research Council, Royal Melbourne Hospital Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, Janssen-Cilag, Novartis, and Sci-Gen. ### Funding Statement This work forms part of E.H.'s PhD studies. E.H. and E.C. are supported by an Australian Government Research Training Program Scholarship. P.P. is supported by an Early Career Fellowship from the National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, the Royal Australasian College of Physicians, The University of Melbourne, Monash University, the Weary Dunlop Medical Research Foundation, Brain Australia, and the Norman Beischer Medical Research Foundation. G.R. is supported by an Investigator Grant from the National Health and Medical Research Council (APP2008737) and funding from the Australian Epilepsy Research Fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: N/A I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The systematic review will be written into a journal article and published in a peer-reviewed journal, with raw data available upon request.