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From the Department of Neurology (K.J.M., D.W.L.), University of Florida, Gainesville; University of Liverpool (G.A.B.), UK; Texas A&M University Health Science Center (R.H.F.), Houston; Department of Neurology (L.A.K.), University of Southern California, Los Angeles; Department of Neurology (J.D.L.), Riddle Health Care, Media, PA; Department of Neurology (P.B.P.), Emory University, Atlanta, GA; St. Mary’s Hospital (G.M., J.C.S.), Manchester, UK; and EMMES Corp. (M.C.W.), Rockville, MD.
Address correspondence and reprint requests to Dr Meador, McKnight Brain Institute, Department of Neurology, University of Florida, PO Box 100236, University of Florida, Gainesville, FL 32610; e-mail: kimford.meador{at}neurology.ufl.edu
Background: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach.
Objective: To determine if fetal outcomes vary as a function of different in utero AED exposures.
Methods: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69).
Results: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect.
Conclusions: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.
*See the appendix for a complete list of Group members.
Supported by grants 2 RO1 NS038455 from the NIH/NINDS, 1 R01050659 from the NIH/NINDS, and RB219738 from the UK Epilepsy Research Foundation.
Disclosure: Drs. Clayton Smith, Finnell, and Mawer have given expert testimony on fetal anticonvulsant syndrome. Additional disclosure information is available online at www.neurology.org.
Received July 14, 2005. Accepted in final form March 31, 2006.
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