Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 1
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Mula, M. and Cock, H. R. 2015. More than seizures: improving the lives of people with refractory epilepsy. European Journal of Neurology, Vol. 22, Issue. 1, p. 24.


Risks of neurobehavioral teratogenicity associated with prenatal exposure to valproate monotherapy: a systematic review with regulatory repercussions

  • Salvatore Gentile (a1)
  • DOI:
  • Published online: 26 February 2014

Beyond its formal indications (epilepsy, bipolar disorder, and migraine), valproate sodium (VPA) is widely used in a number of other clinical conditions. Recently, however, the U.S. Food and Drug Administration (FDA) issued a warning regarding a decrease in IQ scores in children prenatally exposed to the drug. For patients with migraine, the pregnancy labeling of VPA will be changed from Category “D” to “X.” VPA products will remain in pregnancy category “D” for treating epilepsy and manic episodes associated with bipolar disorder. Thus, this article aims to assess (through a computerized Medline/PubMed search) the neurobehavioral teratogenicity of valproate monotherapy, in order to evaluate alternative regulatory decisions. Reviewed information suggests a detrimental impact of antenatal valproate exposure on the global child neurodevelopment. Affected areas include not just reduced IQ scores, but also behavioral problems and a potential increase in the risk for a future diagnosis of attention-deficit/hyperactivity disorder. An increased risk of developing autism-spectrum disorders has also been reported. Thus, in my opinion, VPA should be assigned definitively to the Category “X,” independent of any considerations about its clinical indications, and should be strictly avoided during pregnancy, due to the demonstrated risk of both neurobehavioral and neurocognitive teratogenicity.

Corresponding author
*Address for correspondence: Salvatore Gentile, Department of Mental Health, ASL Salerno, Mental Health Centre n. 63 Cava de' Tirreni - Vietri Sul Mare, Piazza Galdi, 841013 Cava de’ Tirreni, Salerno, Italy. (Email:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1.C Johannessen Landmark , PG Larsson , E Rytter , SI Johannessen . Antiepileptic drugs in epilepsy and other disorders--a population-based study of prescriptions. Epilepsy Res. 2009; 87(1): 3139.

2.J Hayes , P Prah , I Nazareth , etal. Prescribing trends in bipolar disorder: cohort study in the United Kingdom THIN primary care database 1995–2009. PLoS One. 2011; 6(12): e28725.

4.DA Adedinsewo , DJ Thurman , YH Luo , etal. Valproate prescriptions for nonepilepsy disorders in reproductive-age women. Birth Defects Res A Clin Mol Teratol. 2013; 97(6): 403408.

5.S Gentile . Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers. Bipolar Disord. 2006; 8(3): 207220.

6.S Gentile . Bipolar disorder and pregnancy: to treat or not to treat? BMJ. 2012; 345: e7367.

7.FJ Vajda , TJ O'Brien , JE Graham , CM Lander , MJ Eadie . Dose dependence of fetal malformations associated with valproate. Neurology. 2013; 81(11): 9991003.

8.KJ Meador . Comment: valproate dose effects differ across congenital malformations. Neurology. 2013; 81(11): 1002.

9.PB Pennell , AM Klein , N Browning , etal. Differential effects of antiepileptic drugs on neonatal outcomes. Epilepsy Behav. 2012; 24(4): 449456.

11.S Koch , K Titze , RB Zimmermann , etal. Long-term epilepsy and neuropsychological consequences of maternal anticonvulsant treatment during pregnancy for school-age children and adolescents. Epilepsia. 1999; 40(9): 12371243.

13.HC Steinhausen , G Losche , S Koch , H Helge . The psychological development of children of epileptic parents. I. Study design and comparative findings. Acta Paediatr. 1994; 83(9): 955960.

14.G Losche , HC Steinhausen , S Koch , H Helge . The psychological development of children of epileptic parents. II. The differential impact of intrauterine exposure to anticonvulsant drugs and further influential factors. Acta Paediatr. 1994; 83(9): 961966.

16.N Adab , D Jacoby , D Smith , D Chadwick . Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2001; 70(1): 1521.

17.CS Dean , H Hailey , SJ Moore , etal. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet. 2002; 39(4): 251259.

19.K Eriksson , K Viinikainen , A Monkkonen , etal. Children exposed to valproate in utero—population based evaluation of risks and confounding factors for long-term neurocognitive development. Epilepsy Res. 2005; 65(3): 189200.

20.K Viinikainen , K Eriksson , A Monkkonen , etal. The effects of valproate exposure in utero on behavior and the need for educational support in school-aged children. Epilepsy Behav. 2006; 9(4): 636640.

21.SV Thomas , B Ajaykumar , K Sindhu , etal. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy Behav. 2008; 13(1): 229236.

22.KJ Meador , GA Baker , N Browning , etal. for the NEAD Study Group. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009; 360(16): 15971605.

23.KM McVearry , WD Gaillard , J VanMeter , KJ Meador . A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy. Epilepsy Behav. 2009; 16(4): 609616.

24.MJ Cohen , KJ Meador , N Browning , etal. Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral/functioning at age 3 years. Epilepsy Behav. 2011; 22(2): 240246.

25.KJ Meador , GA Baker , N Browning , etal. for the NEAD Study Group. Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years. Neurology. 2012; 78(16): 12071214.

26.KJ Meador , GA Baker , N Browning , etal. for the NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013; 12(3): 244252.

27.MJ Cohen , KJ Meador , N Browning , etal, for the NEAD study group. Fetal antiepileptic drug exposure: adaptive and emotional/behavioral functioning at age 6 years. Epilepsy Behav. 2013; 29(2): 308315.

28.KJ Meador , GA Baker , N Browning , etal, for the NEAD Study Group. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age. Brain. 2011; 134(Pt 2): 396404.

29.N Adab , U Kini , J Vinten , etal. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2004; 75(11): 15751583.

30.J Vinten , N Adab , U Kini , etal, for the Liverpool and Manchester Neurodevelopment Study Group. Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology. 2005; 64(6): 949954.

31.J Vinten , RL Bromley , J Taylor , etal, on behalf of the Liverpool and Manchester Neurodevelopment Group. The behavioral consequences of exposure to antiepileptic drugs in utero. Epilepsy Behav. 2009; 14(1): 197201.

32.RL Bromley , G Mawer , J Love , etal, on behalf of the Liverpool and Manchester Neurodevelopment Group. Early cognitive development in children born to women with epilepsy: a prospective report. Epilepsia. 2010; 51(10): 20582065.

33.R Shallcross , RL Bromley , B Irwin , etal, on behalf of the Liverpool/Manchester Neurodevelopment Group and the UK Epilepsy and Pregnancy Register. Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology. 2011; 76(4): 383389.

34.RL Bromley , G Mawer , J Clayton-Smith , GA Baker , on behalf of the Liverpool and Manchester Neurodevelopment Group. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology. 2008; 71(28): 19231924.

35.RL Bromley , GE Mawer , M Briggs , etal, on Behalf of the Liverpool and Manchester Neurodevelopment Group.. The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs. J Neurol Neurosurg Psychiatry. 2013; 84(6): 637643.

36.CP Johnson , SM Myers . American Academy of Pediatrics Council on Children with Disabilities. Identification and evaluation of children with autistic spectrum disorders. Pediatrics. 2007; 120(5): 11831215.

38.C Nadebaum , V Anderson , F Vajda , etal. Language skills of school-aged children prenatally exposed to antiepileptic drugs. Neurology. 2011; 76(8): 719726.

39.C Cummings , M Stewart , M Stevenson , J Morrow , J Nelson . Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine. Arch Dis Child. 2011; 96(7): 643647.

40.E Kantola-Sorsa , E Gaily , M Isoaho , M Korkman . Neuropsychological outcomes in children of mothers with epilepsy. J Int Neuropsychol Soc. 2007; 13(4): 642652.

41.J Christensen , TK Grønborg , MJ Sørensen , etal. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013; 309(16): 16961703.

42.G Veiby , AK Daltvei , S Schjølberg , etal. Exposure to antiepileptic drugs in utero and child development: a prospective population-based study. Epilepsia. 2013; 54(8): 14621472.

44.G Veiby , BA Engelsen , NE Gilhus . Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. JAMA Neurol. 2013; 70(11): 13671374.

45.JM Thomas , AL Benham , M Gean , etal. Practice parameters for the psychiatric assessment of infant and toddlers (0-36 months). American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry. 1997; 36(10 Suppl): S21S36.

47.S Gentile . SSRIs in pregnancy and lactation with emphasis on neurodevelopmental outcome. CNS Drugs. 2005; 19(7): 623633.

48.A Thapar , T Fowler , F Rice , etal. Maternal smoking during pregnancy and attention deficit hyperactivity disorder symptoms in offspring. Am J Psychiatry. 2003; 160(11): 19851989.

49.HJ Larsson , WW Eaton , KK Madsen . Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Am J Epidemiol. 2005; 161(10): 916925.

50.CM Hultman , P Sparén , S Cnattingius . Perinatal risk factors for infantile autism. Epidemiology. 2002; 13(4): 417423.

51.PJ Easterbrook , JA Berlin , R Gopalan , DR Matthews . Publication bias in clinical research. Lancet. 1991; 337(8746): 867872.

54.AW Fox , ML Diamond , EL Spiering . Migraine during pregnancy: options for therapy. CNS Drugs. 2005; 19(6): 465481.

56.LB Holmes , S Hernandez-Diaz . Newer anticonvulsants: lamotrigine, topiramate and gabapentin. Birth Defects Res A Clin Mol Teratol. 2012; 94(8): 599606.

58.E Campbell , F Kennedy , B Irwin , etal. Malformation risks of antiepileptic drug monotherapies in pregnancy. J Neurol Neurosurg Psychiatry. 2013; Nov; 84(11): e2.

59.S Gentile . Lithium in pregnancy: the need to treat, the duty to ensure safety. Exp Opin Drug Saf. 2012; 11(3): 425437.

60.FJ Vajda , J Graham , A Roten , etal. Teratogenicity of the newer antiepileptic drugs—the Australian experience. J Clin Neurosci. 2012; 19(1): 5759.

61.S Gentile . Antipsychotic therapy during early and late pregnancy: a systematic review. Schizophr Bull. 2010; 36(3): 518544.

62.D Kjaer , J Christensen , BH Becha , etal. Preschool behavioral problems in children prenatally exposed to antiepileptic drugs—a follow-up study. Epilepsy Behav. 2013; 29(2): 407411.

63.R Boden , M Lundgren , L Brandt , etal. Risks of adverse pregnancy and birth outcomes in women treated or not treated with mood stabilisers for bipolar disorder: population based cohort study. BMJ. 2012; 345: e7085.

66.G Wright , M Patel . Focal migraine and pregnancy. BMJ. 1986; 293(6561): 15571558.

67.EA MacGregor . Headache in pregnancy. Neurol Clin. 2012; 30(3): 835866.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *