Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study
Kimford J. Meador,Gus A. Baker,Nancy Browning,Morris J. Cohen,Rebecca Bromley,Jill Clayton-Smith,Laura A. Kalayjian,Andres M. Kanner,Joyce Liporace,Page B. Pennell,Michael Privitera,David W. Loring +11 more
TLDR
In this paper, the effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age were assessed with linear regression adjusted for maternal IQ and periconceptional folate.Abstract:
Summary Background Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. Methods In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. Findings We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94–101) than to carbamazepine (105, 102–108; p=0·0015), lamotrigine (108, 105–110; p=0·0003), or phenytoin (108, 104–112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ ( r =–0·56, p r =–0·40, p=0·0045), non-verbal ability ( r =–0·42, p=0·0028), memory ( r =–0·30, p=0·0434), and executive function ( r =–0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106–111) than they were in unexposed children (101, 98–104; p=0·0009). Interpretation Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal ( vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies. Funding US National Institutes of Health, UK Epilepsy Research Foundation.read more
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Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism.
Jakob Christensen,Therese Koops Grønborg,Merete Juul Sørensen,Diana Schendel,Erik T. Parner,Lars Pedersen,Mogens Vestergaard +6 more
TL;DR: Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy.
Journal ArticleDOI
Epilepsy: new advances
TL;DR: The lives of most people with epilepsy continue to be adversely affected by gaps in knowledge, diagnosis, treatment, advocacy, education, legislation, and research and Concerted actions to address these challenges are urgently needed.
Journal ArticleDOI
Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period
TL;DR: The evidence regarding the epidemiology, risk factors, and treatment of severe mental illness in relation to childbirth, focusing on bipolar disorder, affective psychosis, and schizophrenia is summarised.
Journal ArticleDOI
Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry
Torbjörn Tomson,Torbjörn Tomson,Dina Battino,Erminio Bonizzoni,John Craig,Dick Lindhout,Emilio Perucca,Anne Sabers,Sanjeev V Thomas,Frank J.E. Vajda,Francesca Faravelli,Chiara Pantaleoni,Elisabeth Robert-Gnansia,Leonor Cabral-Lim,Boštjan Čebular,Alejandro De Marinis,Reetta Kälviäinen,Ketevan Khomeriki,Gordana Kiteva-Trencevska,Silvia Kochen,Martin Kurthen,Gerhard Luef,Meritxell Martinez Ferri,Maja Milovanovic,Karl O. Nakken,Miri Neufeld,Hideyuki Ohtani,Aline Russell,Vladimír Safcák,Bettina Schmitz,Luigi Maria Specchio,Barbara Tettenborn,Eugène van Puijenbroek,Hsiang-Yu Yu,Jana Zárubová,Claus Albretsen,Silje Alvestad,Noémi Becser Andersen,Luisa Antonini,Jens Arentsen,Dag Aurlien,Ismael Barzinji,Juan Luis Becerra Cuñat,Natalia Bohorquez Morera,Martin J. Brodie,Eylert Brodtkorb,Laura Broglio,Elsebeth Bruun Christensen,Petr Bušek,Claudia Cagnetti,Maria Paola Canevini,Astrid Carius,Maria Dolores Castro Vilanova,Michela Cecconi,T.-Y. Chang,Jakob Christensen,Giovanni De Maria,Dieter Dennig,Brenda Diputado,Janne Marit Ertresvåg,Toni Escartin,Dominique Flügel,Birgitte Forsom Sondal,Nicoletta Foschi,Albertina Franza,Katsuyuki Fukushima,Antonio Gambardella,Iñigo Garamendi Ruiz,Helena Gauffin,Pia Gellert,Leif Gjerstad,Lisa Gordon,Katrine Haggag,Imad Halawa,Terttu Heikinheimo-Connell,Tim Hendgen,Zarouhi Hertz,Odo Hildenhagen,Stephanie Hödl,Ineke Hogenesch,Anette Huuse Farmen,Yushi Inoue,Stefan Juhl,Masaaki Kato,Germaine Kenou Van Rijckevorssel,E. Kluck,Hana Krijtová,Eva Kumlien,Angelo Labate,Theresa Lasch,Hans Lindsten,Renata Listonova,Rasmus Lossius,Anders Lundgren,Kristina Malmgren,Iva Marečková,Daniela Marino,Peter Mattsson,Aileen McGonigal,Katarzyna Miesczanleh,Masahiro Mizobuchi,Barbara Mostacci,Birgit Müffelmann,Uden Navn,Anders Nilsson,Bernhard Oehl,Andrea Ortenzi,Judith Osseforth,Aldo Paggi,Eliana Pastor,Birthe Pedersen,Vaiva Petrenaite,Pietro Pignatta,Isabel Pires,Alessandra Pistelli,Jesús Antonio Riuz Gimenez,Raffaele Rocchi,Lone Rodam,Reina Roivainen,Gisela Rytířová,Christian Samsonsen,Gemma Sansa Fayos,Anna Maija Saukkonen,Alma Sikiric,David Sopelana Garay,Bernhard J. Steinhoff,Maria Strandberg,Torleiv Svendsen,Erik Tauboll,Kiyohito Terada,Marina Trivisano,Katherine Turner,Mogens Worm,Elias Zakharia,Elena Zambrelli,Morteza Zarifi-Oskoie +135 more
TL;DR: Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs, and rational selection of these drugs is facilitated.
Journal ArticleDOI
Drug treatment of epilepsy in adults
TL;DR: The development of antiepileptic drugs urgently needs to be revitalized so that the authors can discover more effective antiseizure drugs for the treatment of drug resistant epilepsy, including catastrophic forms.
References
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Book
Statistical Analysis with Missing Data
TL;DR: This work states that maximum Likelihood for General Patterns of Missing Data: Introduction and Theory with Ignorable Nonresponse and large-Sample Inference Based on Maximum Likelihood Estimates is likely to be high.
Reference EntryDOI
NEPSY: A Developmental Neuropsychological Assessment
Ron Dumont,John O. Willis +1 more