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Comparative Study
. 2012 Apr 17;78(16):1207-14.
doi: 10.1212/WNL.0b013e318250d824. Epub 2012 Apr 4.

Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years

K J Meador  1 , G A Baker, N Browning, M J Cohen, R L Bromley, J Clayton-Smith, L A Kalayjian, A Kanner, J D Liporace, P B Pennell, M Privitera, D W Loring; NEAD Study Group
Collaborators, Affiliations
Comparative Study

Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years

K J Meador et al. Neurology. .

Erratum in

  • Neurology. 2012 May 15;78(20):1622

Abstract

Objective: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure.

Methods: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5).

Results: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills.

Conclusions: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

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Figures

Figure 1
Figure 1. Scatterplots of age 4.5 IQ vs standardized dose for each antiepileptic drug during pregnancy
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See this image and copyright information in PMC

References

    1. Fisher JE, Vorhees CV. Developmental toxicity of antiepileptic drugs: relationship to postnatal dysfunction. Pharmacol Res 1992;26:207–221 - PubMed
    1. Gaily E, Meador KJ. Neurodevelopmental effects. In: Engel J, Pedley TA. eds. Epilepsy: A Comprehensive Textbook, 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2007: 1225–1233
    1. Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597–1605 - PMC - PubMed
    1. FDA Drug Safety Communication. Children born to mothers who took Valproate products while pregnant may have impaired cognitive development (6/30/2011). [Accessed March 1, 2012.]. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm261543.htm.
    1. Kluger BM, Meador KJ. Teratogenicity of antiepileptic medications. Semin Neurol 2008;28:328–335 - PMC - PubMed

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