Abstracts

Ideal treatment of women on AEDs during pregnancy involves achieving a balance between minimizing fetal exposure to medications while maintaining seizure control. Previous studies demonstrated marked increases in total LTG clearances during pregnancy ([gt]330% of baseline), often necessitating dosage increases for seizure control. Free LTG concentrations are the more relevant measures for effects on maternal brain as well as for fetal exposure. This study extends previous findings by looking at alterations in free LTG clearance (Cl) during the course of pregnancy, and examines fetal exposure by measuring umbilical cord free LTG concentrations at birth. Nine pregnant women (7 epilepsy, 2 bipolar disorder) treated with LTG were followed in a prospective observational study. After obtaining informed consent, serum samples were obtained monthly during pregnancy and up to 4 months postpartum (n= 51 samples). Maternal and umbilical cord samples were also obtained in 6 mother-child pairs at delivery. Samples were stored at [ndash]80[deg] C until assay. Free LTG was separated from bound using Centifree cartridges from Millipore Corp, and measured by an HPLC-UV assay from Chromsystems, Munich, Germany. Cl was calculated as LTG daily dose (mg)/ body weight (kg) / free LTG concentration (mg/L). Comparisons were made across perinatal stages using an ANOVA with unbalanced repeated measures design. Umbilical cord/maternal free LTG concentration ratios were calculated and evaluated by regression analysis. Clearance data within each perinatal stage are reported in Table 1. ANOVA revealed a significant main effect of perinatal stage upon free LTG Cl (p[lt].01). Cl values peaked in the third trimester to 205% of baseline postpartum values. Umbilical cord/maternal free LTG concentrations demonstrated a mean placental passage of 1.20 ([plusmn] 0.29). Regression analysis showed a strong correlation (r² =0.962). Outcomes for all pregnancies were devoid of major malformations. [table1] Free LTG Cl progressively increases during pregnancy, but to a lesser degree than that described for total LTG. Free LTG is the more pertinent compound for seizure control and for fetal risk. Substantial [italic]in utero[/italic] exposure occurs with complete placental passage of LTG at all maternal concentrations studied. Therapeutic drug monitoring of free LTG may be warranted throughout pregnancy to optimize maternal and fetal outcomes. (Supported by a Specialized Center of Research P50 MH 68036)