Accepted Baker et al IQ at 6 years following in utero exposure to antiepileptic drugs

Baker et al IQ at years following in utero exposure to antiepileptic drugs: a controlled cohort study Gus A Baker PhD1, Rebecca L Bromley PhD2,3, Maria Briggs RGN3, Christopher P Cheyne PhD4, Morris J Cohen EdD5, Marta García-Fiđana PhD4, Alison Gummery BSc5, Rachel Kneen, MD6, David W Loring PhD7, George Mawer PhD FRCP3, Kimford J Meador MD8, Rebekah Shallcross PhD9, Jill Clayton-Smith MD2,3, On behalf of the Liverpool and Manchester Neurodevelopment Group* Department of Molecular and Clinical Pharmacology, University of Liverpool, L9 7LJ, UK Institute of Human Development, University of Manchester, UK 3Manchester Academic Health Sciences Centre, Central Manchester University Hospitals Foundation Trust, Manchester, UK Department of Biostatistics, University of Liverpool, UK 5Department of Neurology, Georgia Regents University, Augusta, GA, USA 5Institute of Infection and Global Health, University of Liverpool, UK 6Alder Hey Children’s Hospital & Institute of Infection & Global Health, University of Liverpool, UK 7Department of Neurology & Pediatrics, Emory University, Atlanta, USA 8Department of Neurology & Neurological Sciences, Stanford University, Stanford, USA 9Department of Clinical Psychology, University of Liverpool, UK Corresponding author: Dr Rebecca Bromley University of Manchester, Institute of Human Development, 6th Floor St Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK rebecca.bromley@manchester.ac.uk +44 161 701 4514 Title Character Count: 92, Abstract Word Count: 250, Word Count: 2996 Key Words: [61] antiepileptic drugs, [199] neuropsychology/behaviour, [204] intelligence, [228] developmental disorders, pregnancy Baker et al Author Contributions Professor Baker contributed to acquisition of funding, conception and design of the study, analysis and interpretation of data, drafting the article, and final approval Professor Baker accepts full responsibility for the finished article, had access to any data, and controlled the decision to publish Dr Bromley contributed to the conception and design of the study, data collection, study coordination, analysis and interpretation of data, drafting the article, and final approval Ms Briggs contributed to data collection, interpretation of data, drafting of the article, and final approval Dr Cheyne conducted the data analysis and contributed to the interpretation of data, drafting the article and final approval Dr Cohen contributed to the design of the study, interpretation of data, drafting of the article and final approval Dr García-Fiđana supervised the data analysis and contributed to the interpretation of results, drafting of the article and final approval Ms Gummery contributed to data collection, interpretation of data, drafting of the article, and final approval Dr Kneen contributed to data collection, interpretation of data, drafting of the article, and final approval Professor Loring contributed to the design of the study, interpretation of data, drafting of the article and final approval Professor Meador contributed to the acquisition of funding, to the design of the study, interpretation of data, drafting of the article and final approval Dr Shallcross contributed to data collection, interpretation of data, drafting of the article, and final approval Professor Mawer contributed to the conception and design of the study, study coordination, data collection, analysis and interpretation of data, drafting of the article, and final approval Professor Clayton-Smith contributed the acquisition of funding, to the conception and design of the study, data collection, study coordination, analysis and interpretation of data, drafting the article, and final approval Study Funding Epilepsy Research UK (RB219738), Sanofi Aventis and US National Institutes of Health for the NEAD Study (2R01 NS038455) UK National Institute of Health Research funding through the Manchester Baker et al Biomedical Research Centre The funder played no role in the design, execution, and analysis or in the decision to publish Disclosure G Baker has received educational grants from Sanofi Aventis to support this research directly; he has received educational grants from UCB Pharma and lecture speaker fees from Sanofi Aventis, UCB Pharma and GSK Dr Baker has given expert testimony on fetal anticonvulsant Syndrome R Bromley has received lecture fees from Sanofi Aventis (two occasions); received conference travel support from UCB Pharma and provided expert testimony pertaining to fetal anticonvulsant syndrome Professors Mawer and Clayton-Smith have given expert testimony pertaining to fetal anticonvulsant syndrome M Briggs reports no disclosures relevant to the manuscript C Cheyne reports no disclosures relevant to the manuscript M Cohen has received research support from NIH and is author of the Children’s Memory Scale M García-Fiđana reports no disclosure relevant to the manuscript A Gummery reports no disclosure relevant to the manuscript R Kneen reports no disclosure relevant to the manuscript D Loring reports receiving consulting fees from NeuroPace and grant support from UCB and Pfizer G Mawer reports no disclosure relevant to the manuscript K Meador reports active grants included NIH/NINDS 2U01-NS038455-11A1, NIH R01 NS07666501A1, PC0RI 527 and a UCB Pharma grant; other grants include money from: NIH Epilepsy Foundation, Cybertronics, GSK, Eisai, Marius, Myriad, Neuropace, Pfizer, SAM Technology, Schwartz Bioscience (UCB Pharma) and UCB Pharma; consultancies: Epilepsy Study Consortium which received money from multiple pharmaceutical companies: Eisai, Neuropace, Novartis, Supernus, Upsher Smith Laboratories, UCB Pharma and Vivus Pharmaceuticals; funds from consulting were paid Baker et al to his university; travel support from Sanofi Aventis to a lecture in 2010; clinical income from EEG procedures and care of neurological patients R Shallcross has attended conferences with the support of UCB Pharma and has received honorarium for lectures J Clayton-Smith reports no disclosure relevant to the manuscript Baker et al Abstract Objective To delineate the risk to child IQ associated with commonly prescribed antiepileptic drugs Methods Children born to women with epilepsy (n=243) and women without epilepsy (n=287) were recruited during pregnancy and followed prospectively Of these, 408 were blindly assessed at six years of age Maternal and child demographics were collected and entered into statistical models Results The adjusted mean IQ was 9.7 points lower (95% CI -4·9 to -14·6; P800mg daily) valproate , with a similar significant effect observed for the verbal, non-verbal and spatial subscales Children exposed to high dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8·0; 2·5 to 19·7; P