In utero antiepileptic drug exposure: fetal death and malformations.
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.
Meador
K J
KJ
Department of Neurology, University of Florida, Gainesville 32610, USA. kimford.meador@neurology.ufl.edu
Baker
G A
GA
Finnell
R H
RH
Kalayjian
L A
LA
Liporace
J D
JD
Loring
D W
DW
Mawer
G
G
Pennell
P B
PB
Smith
J C
JC
Wolff
M C
MC
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects*; D002220:Carbamazepine / Q000009:adverse effects; D003071:Cognition / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D006801:Humans; D000077213:Lamotrigine; D010672:Phenytoin / Q000009:adverse effects; D011247:Pregnancy; D011248:Pregnancy Complications / Q000139:chemically induced*; D011256:Pregnancy Outcome; D011446:Prospective Studies; D014227:Triazines / Q000009:adverse effects; D014599:Uterus / Q000187:drug effects; D014635:Valproic Acid / Q000009:adverse effects
D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D000077213:Lamotrigine