Abstracts

Rationale: The use of antiepileptic drugs (AEDs) during pregnancy represents a clinical dilemma that necessitates balancing the effects of the AED versus maternal illness on fetal health. Placental passage of each of the AEDs can be determined at the time of delivery by the ratio of umbilical cord /maternal plasma concentration [U/M]. Previously reported findings vary between low ratios for carbamazepine (CBZ) (0.7) suggesting incomplete placental transfer, to very high ratios for gabapentin (GBP) (1.7) and valproic acid (VPA) (1.7), suggesting excessive transfer. This analysis was performed to expand the current knowledge of placental passage for 8 AEDs, including their active metabolites, and total and free measurements for the AEDs that are >50% protein-bound. Methods: Pregnant women who chose to continue treatment with AEDs (CBZ, GPB, VPA, lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), phenytoin (PHT), and topiramate (TPM)) for epilepsy or bipolar disorder were followed prospectively in an observational study examining the pharmacokinetic properties of AEDs during pregnancy and delivery. Umbilical cord blood and maternal plasma were collected at delivery, coded and stored at -80’C until assay. All assays were completed blind to maternal dose using HPLC. Active metabolites measured included CBZ-10,11-epoxide and the monohydroxy-derivative of OXC [MHD]. Total and free concentrations were measured for all compounds except LEV, TPM, and GBP. Placental passage [U/M] and newborn outcomes were determined. Results: After providing informed consent, 124 women on AEDs during pregnancy enrolled and completed this prospective observational study. Umbilical cord and maternal blood samples were obtained at the time of delivery and have been analyzed for 79 mother-child pairs. 77.2% of the women had a primary diagnosis of epilepsy, 15.2% bipolar disorder, and 7.6% another psychiatric illnesses. Placental passage [U/M] of each AED and active metabolites are reported in the Table. Placental passage [U/M] ranged from 0.87 for total CBZ to 1.47 for total VPA, although the [U/M] for the free components were in the opposite directions. The ratios for the AED metabolites were also close to unity. Newborn outcomes included 8.5% preterm deliveries, 7.4% low birth weight infants, and 13.3% of infants were admitted to a special care nursery or neonatal intensive care unit. None of the newborns had 5- minute APGAR scores of <7, and 83.3% had 5-minute APGAR scores of ≥9. Conclusions: These data confirm that fetal exposure to AEDs is substantial and the [U/M] for the total, free, and active metabolites of these 8 AEDs approach unity, most consistent with complete transfer. Pharmacogenetic variations in placental transporter proteins could still modify transfer, however. Further consideration of exposure throughout the entire pregnancy with modeling of serial maternal plasma concentrations could also add to the prediction of fetal outcomes. Acknowledgments: Supported in part by the National Institutes of Health P50 MH-68036 and MH-71531.