Neurodevelopmental Effects of Antiepileptic Drugs II

Summary

Principal Investigator: K J Meador
Abstract: The proposed investigation is a continuation of the ongoing NEAD study, which addresses an important health care issue for women and their children. The use of antiepileptic drugs (AEDs) in women of childbearing age for epilepsy and for other indications (e.g., pain and psychiatric disorders) is common, but physicians need additional data, which are critical to adequately advise and direct treatment in these women. Animal studies have clearly demonstrated that commonly employed AEDs impair behavioral neurodevelopment. The potential consequences of such cognitive and behavioral deficits in humans are severe in terms of both personal and societal costs. However, controversy exists on the following issue to be addressed by this proposal. Do the most commonly used AEDs have differential effects on neurobehavioral outcomes in children exposed in utero? The primary objective of this study is to differentiate the relative risks/benefits of the four most commonly used AEDs in the treatment of women with epilepsy in terms of their children's neurobehavioral development after in utero exposure to AED monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate). The NEAD study is a prospective, parallel-group, cohort design, multicenter investigation. The major strength of the NEAD study is that it has enrolled a large and unique cohort of 323 mother/child pairs during pregnancy and collected prospective data on factors, which could affect neurobehavioral outcome. The primary outcome variables are IQ scores of the children and other measures of neurobehavioral development at 6 years/old. This grant extension is designed to follow the children to 6 years/old at which time neurobehavioral measures predict school performance and ultimate adult IQ. Samples have and will be collected for future pharmacogenetic investigations. The NEAD study has an invaluable cohort, and the results of this continuation proposal will impact the clinical management of women receiving these medications, and improve the health of their children.
Funding Period: 2000-09-30 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero
    Rebecca L Bromley
    Department of Neurological Science, University of Liverpool, Liverpool, UK
    Curr Opin Neurol 22:162-6. 2009
  2. pmc Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years
    Kimford J Meador
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
    JAMA Pediatr 168:729-36. 2014
  3. pmc Differential effects of antiepileptic drugs on neonatal outcomes
    P B Pennell
    Harvard Medical School, Brigham and Women s Hospital, 75 Francis Street, Brigham and Women s Hospital, Boston, MA 02115, USA
    Epilepsy Behav 24:449-56. 2012
  4. pmc Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study
    Kimford J Meador
    Neurology and Pediatrics, Emory University, Atlanta, GA 30322, USA
    Lancet Neurol 12:244-52. 2013
  5. pmc The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs
    Rebecca Louise Bromley
    Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
    J Neurol Neurosurg Psychiatry 84:637-43. 2013
  6. pmc Teratogenicity of antiepileptic medications
    Benzi M Kluger
    Department of Neurology, University of Florida, Gainesville, Florida 32610, USA
    Semin Neurol 28:328-35. 2008
  7. pmc Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6years
    Morris J Cohen
    Neurology, Georgia Regents University, Augusta, GA, USA Electronic address
    Epilepsy Behav 29:308-15. 2013
  8. pmc Effects of breastfeeding in children of women taking antiepileptic drugs
    K J Meador
    Department of Neurology, Emory University, Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA
    Neurology 75:1954-60. 2010
  9. pmc Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age
    Kimford J Meador
    Department of Neurology, Emory University, Atlanta, GA 30322, USA
    Brain 134:396-404. 2011
  10. pmc Child development following in utero exposure: levetiracetam vs sodium valproate
    R Shallcross
    Division of Neurosciences, University of Liverpool, UK
    Neurology 76:383-9. 2011

Scientific Experts

  • K J Meador
  • Morris J Cohen
  • C L Harden
  • P B Pennell
  • Jill Clayton-Smith
  • Rebekah Shallcross
  • Maria Briggs
  • Rachel Kneen
  • Rebecca L Bromley
  • G A Baker
  • Gus A Baker
  • Alison Gummery
  • Siddharth Banka
  • Gus Baker
  • George Mawer
  • Loretta Kerr
  • Pete Dixon
  • Rebecca Bromley
  • B Gidal
  • R Finnell
  • J A French
  • T Y Ting
  • B Vazquez
  • P W Kaplan
  • C A Hovinga
  • J Hopp
  • L Holmes
  • W A Hauser
  • B S Koppel
  • J N Robinson
  • A Krumholz
  • S Wiebe
  • A N Wilner
  • C Le Guen
  • D Thurman
  • Rebecca Louise Bromley
  • J Clayton-Smith
  • R Shallcross
  • Alan Fryer
  • Mila Kuzmyshcheva
  • Deirdre Cilliers
  • Lynne Wyatt
  • Gilla Veling-Warnke
  • G Mawer
  • Lynne Owen
  • Kate O'Hanlon
  • Joanne Eatock
  • Sam Lucas
  • Usha Kini
  • G S Gronseth
  • Kelly M McVearry
  • Benzi M Kluger
  • Marta Garcia-Finana
  • Sam B Lucas
  • Christopher Cheyne
  • George E Mawer
  • J D Liporace
  • A M Klein
  • N Browning
  • D W Loring
  • T Crawford
  • L A Kalayjian
  • M Privitera
  • Stephen Hunt
  • John Craig
  • Henry Smithson
  • Linda Parsons
  • James Morrow
  • R L Bromley
  • Aline Russell
  • L J Bonnett
  • Patrick Morrison
  • J Morrow
  • Brenda Liggan
  • Norman Delanty
  • Beth Irwin
  • Iain Robertson
  • B Irwin
  • S B Lucas
  • H Coyle
  • Xin Shi
  • Laura Purdy
  • David Chadwick
  • Jenna Love
  • U Kini
  • Xin Sin
  • R Bromley
  • Jennna Love
  • Audrey Smith
  • Helen Coyle

Detail Information

Publications29

  1. pmc Cognitive abilities and behaviour of children exposed to antiepileptic drugs in utero
    Rebecca L Bromley
    Department of Neurological Science, University of Liverpool, Liverpool, UK
    Curr Opin Neurol 22:162-6. 2009
    ..The aim here is to review the literature regarding the possible cognitive and behavioural impact of exposure to antiepileptic drugs in utero...
  2. pmc Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years
    Kimford J Meador
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
    JAMA Pediatr 168:729-36. 2014
    ..We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities...
  3. pmc Differential effects of antiepileptic drugs on neonatal outcomes
    P B Pennell
    Harvard Medical School, Brigham and Women s Hospital, 75 Francis Street, Brigham and Women s Hospital, Boston, MA 02115, USA
    Epilepsy Behav 24:449-56. 2012
    ..Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years...
  4. pmc Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study
    Kimford J Meador
    Neurology and Pediatrics, Emory University, Atlanta, GA 30322, USA
    Lancet Neurol 12:244-52. 2013
    ..We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age...
  5. pmc The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs
    Rebecca Louise Bromley
    Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
    J Neurol Neurosurg Psychiatry 84:637-43. 2013
    ..Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option...
  6. pmc Teratogenicity of antiepileptic medications
    Benzi M Kluger
    Department of Neurology, University of Florida, Gainesville, Florida 32610, USA
    Semin Neurol 28:328-35. 2008
    ..Management of women with epilepsy should include a discussion of these risks, prophylactic treatment with folic acid, and the minimal use of polypharmacy and valproate needed to maintain optimum seizure control...
  7. pmc Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6years
    Morris J Cohen
    Neurology, Georgia Regents University, Augusta, GA, USA Electronic address
    Epilepsy Behav 29:308-15. 2013
    ....
  8. pmc Effects of breastfeeding in children of women taking antiepileptic drugs
    K J Meador
    Department of Neurology, Emory University, Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA
    Neurology 75:1954-60. 2010
    ..Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children...
  9. pmc Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age
    Kimford J Meador
    Department of Neurology, Emory University, Atlanta, GA 30322, USA
    Brain 134:396-404. 2011
    ..Additional research is needed to confirm these findings, extend the study to other drugs, define the risks associated with drug treatment for seizures in the neonates, and understand the underlying mechanisms...
  10. pmc Child development following in utero exposure: levetiracetam vs sodium valproate
    R Shallcross
    Division of Neurosciences, University of Liverpool, UK
    Neurology 76:383-9. 2011
    ....
  11. pmc Relationship of child IQ to parental IQ and education in children with fetal antiepileptic drug exposure
    Kimford J Meador
    Department of Neurology, Emory University, Atlanta, GA 30322, USA
    Epilepsy Behav 21:147-52. 2011
    ....
  12. pmc Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years
    Morris J Cohen
    Neurology, Georgia Health Sciences University, Augusta, GA 30912, USA
    Epilepsy Behav 22:240-6. 2011
    ....
  13. pmc Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years
    K J Meador
    Neurology and Pediatrics, Emory University, Atlanta, GA, USA
    Neurology 78:1207-14. 2012
    ..To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure...
  14. ncbi Early cognitive development in children born to women with epilepsy: a prospective report
    Rebecca L Bromley
    Department Neurological Science, University of Liverpool, United Kingdom
    Epilepsia 51:2058-65. 2010
    ..In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230)...
  15. pmc Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study
    G Mawer
    Department of Genetic Medicine, St Mary s Hospital, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK
    Seizure 19:112-9. 2010
    ..To determine the influence of epilepsy and its treatment on pregnancy and its outcome...
  16. pmc Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Asses
    C L Harden
    University of Miami, Miami, FL, USA
    Neurology 73:142-9. 2009
    ....
  17. pmc Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee
    C L Harden
    University of Miami, Miami, FL, USA
    Neurology 73:133-41. 2009
    ..To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy...
  18. pmc Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology As
    C L Harden
    University of Miami, Miami, FL, USA
    Neurology 73:126-32. 2009
    ....
  19. pmc Antiepileptic drug use in women of childbearing age
    Kimford J Meador
    Department of Neurology, Emory University, Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6000, Mail Stop 1930 001 1AN, Atlanta, GA 30322, USA
    Epilepsy Behav 15:339-43. 2009
    ..Except for the top two AED monotherapies, there were marked differences in other monotherapies and in polytherapies between U.S. and UK centers. Future investigations are needed to examine reasons for drug choice...
  20. pmc Cognitive/behavioral teratogenetic effects of antiepileptic drugs
    Kimford J Meador
    Department of Neurology, University of Florida, Gainesville, FL, USA
    Epilepsy Behav 11:292-302. 2007
    ..The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain...
  21. pmc Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts
    Kimford Meador
    Department of Neurology, University of Florida, Gainesville, FL 32610 0236, USA
    Epilepsy Res 81:1-13. 2008
    ..To conduct a systematic review and meta-analysis to quantify the incidence of congenital malformations (CMs) and other pregnancy outcomes as a function of in utero anti-epileptic drug (AED) exposure...
  22. ncbi Pregnancy registries in epilepsy: a consensus statement on health outcomes
    K J Meador
    Department of Neurology, Emory University, Atlanta, GA 30322, USA
    Neurology 71:1109-17. 2008
    ..There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED...
  23. pmc Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs
    Kimford J Meador
    Department of Neurology, Emory University, Woodruff Memorial Research Bldg, 101 Woodruff Cir, Suite 6000, Atlanta, GA 30322, USA
    N Engl J Med 360:1597-605. 2009
    ....
  24. pmc A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy
    Kelly M McVearry
    Department of Neurology, Georgetown University Medical Center, Washington, DC 20007, USA
    Epilepsy Behav 16:609-16. 2009
    ..To investigate the differential effects of fetal exposure to antiepileptic drugs (AEDs) on cognitive fluency and flexibility in a prospective sample of children...
  25. pmc In utero antiepileptic drug exposure: fetal death and malformations
    K J Meador
    Department of Neurology, University of Florida, Gainesville 32610, USA
    Neurology 67:407-12. 2006
    ..Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach...