Miriam Rubinchik-Stern, Miriam Shmuel, Sara Eyal

Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel; 

Aim: Antiepileptic drugs (AEDs) used by pregnant women can impair fetal development. The aim of the current study was to explore a novel mechanism of AEDs effect on the fetus, altered placental transfer of hormones and nutrients. We utilized BeWo cells for studying the effects of AEDs on placental transporters expression and function.

Methods: BeWo cells were incubated with phenytoin (PHT), valproic acid (VPA),  carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG)  or their vehicles (up to 1% solvent in medium) at different concentrations for 2 or 5 days. Western blot analysis, RT-PCR and accumulation studies were utilized to study the effects of AEDs on transporter expression and functional activity.

Results: Among the studied AEDs, the most prominent effects on transporter expression were those of PHT and VPA. These drugs affected the expression of OATP 1A2 and OATP4A1 which are involved in the transplacental transfer of thyroid hormones (THs), as well as that of the breast cancer resistance protein (BCRP) and the reduced folate carrier (RFC) that mediate transplacental delivery of folic acid.

Conclusion: AEDs affect the expression of carriers that are responsible for uptake and efflux of nutrients and hormones essential for fetal growth as well as the elimination of harmful compounds from the fetus. Future studies are aimed to explore the clinical implications of these findings.