Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias.
OBJECTIVE
The management of epilepsy during pregnancy entails a number of concerns. While seizures may affect adversely maternal and fetal outcome, antiepileptic drugs (AEDs) may increase the incidence of congenital abnormalities and possibly affect postnatal cognitive development in the offspring. Experimental animal studies can aid in assessing teratogenic features associated with individual AEDs and/or with seizures, and to identify the mechanisms involved. The purpose of this study was to investigate the consequences of prenatal exposure to (a) different AEDs and (b) maternal seizures on brain maturational processes in rats.


METHODS
Pregnant rats received from embryonic days 14 to 19 intraperitoneal injections of carbamazepine (20 mg/kg/day), vigabatrin (200 mgkg/day), and valproate (100 mg/kg/day) at doses not widely different from those used clinically. Pups exposed to AEDs in utero were analyzed postnatally. Animals born to "kindled" pregnant animals that had experienced one generalized convulsive seizure per day during the same gestational period were analyzed in parallel.


RESULTS
Prenatal exposure to vigabatrin and valproate, which act on GABA signaling, induced hippocampal and cortical dysplasias, which were likely to result from a neuronal migration defect and neuronal death. By contrast, offspring of rats exposed to carbamazepine (which at the dose used produced low plasma concentrations) or to generalized convulsive seizures showed no clear-cut evidence of dysplasias.


CONCLUSIONS
We suggest that AEDs that increase the extracellular concentration of GABA might induce severe neuronal migration disorders. Drugs acting through other molecular targets would also perturb cortical maturation. The potential clinical relevance of these results should be a subject of future research.
Manent
Jean-Bernard
JB
INMED, INSERM U29, Université de la Méditerranée, Campus de Luminy, Marseille, France.
Jorquera
Isabel
I
Mazzucchelli
Iolanda
I
Depaulis
Antoine
A
Perucca
Emilio
E
Ben-Ari
Yehezkel
Y
Represa
Alfonso
A
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D002220:Carbamazepine / Q000494:pharmacology / Q000633:toxicity; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000187:drug effects* / Q000196:embryology; D005260:Female; D005333:Fetus / Q000187:drug effects; D018682:GABA Agents / Q000494:pharmacology* / Q000633:toxicity; D006624:Hippocampus / Q000002:abnormalities* / Q000187:drug effects* / Q000196:embryology; D007696:Kindling, Neurologic / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D051381:Rats; D012640:Seizures / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology / Q000633:toxicity; D020888:Vigabatrin / Q000494:pharmacology / Q000633:toxicity; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000633:toxicity
D000927:Anticonvulsants; D018682:GABA Agents; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D020888:Vigabatrin