title: IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.
abstract: OBJECTIVE
  To delineate the risk to child IQ associated with frequently 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 6 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% confidence interval [CI] -4.9 to -14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, 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, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85.
  
  
  CONCLUSIONS
  Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Gus A
authors.initials: GA
authors.lastname: Baker
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA. rebecca.bromley@manchester.ac.uk.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Bromley
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Maria
authors.initials: M
authors.lastname: Briggs
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cheyne
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Cohen
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Marta
authors.initials: M
authors.lastname: García-Fiñana
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Alison
authors.initials: A
authors.lastname: Gummery
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kneen
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: David W
authors.initials: DW
authors.lastname: Loring
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: George
authors.initials: G
authors.lastname: Mawer
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Kimford J
authors.initials: KJ
authors.lastname: Meador
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Shallcross
authors.affiliation: From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects*; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002657:Child Development / Q000187:drug effects*; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007360:Intelligence / Q000187:drug effects*; D000077213:Lamotrigine; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D011446:Prospective Studies; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects*; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D000077213:Lamotrigine