Identification and Quantification of Paclitaxel and its Metabolites in Human Meconium from Newborns with Gestational Chemotherapeutic Exposure

Abstract

Objective.Cancer diagnosis during pregnancy occurs in 1 out of 1000 pregnancies with common malignancies including breast and hematological cancers. The pharmacology of chemotherapeutics, especially the transplacental disposition of currently utilized agents, is poorly described. This impedes the selection of agents for optimal therapy. We directly assessed fetal exposure by screening meconium from 23 newborns whose mothers had undergone treatment for cancer during pregnancy. Study Design.Meconium was collected from newborns whose mothers were diagnosed with cancer during pregnancy and underwent chemotherapy in the second or third trimester as part of the Cancer and Pregnancy Registry.Screening of 23 meconium samples for chemotherapeutics and known metabolites of chemotherapeutics was conducted by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Putative identification of paclitaxel and/or its metabolites was made in 8 screened samples. Identification was confirmed by quantification of paclitaxel, 3'-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel by stable isotope dilution-LC-HRMS. Results.Paclitaxel was detected at 399.9 pg/mg in meconium samples from newborn born to mothers that underwent chemotherapy during pregnancy. 3'-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel were detected at 105.2 and 113.4 pg/mg meconium, respectively. Conclusion.3 Intact paclitaxel, and at least two of its major metabolites were detected in meconium, providing unambiguous confirmation of human fetal exposure. Variability in meconium levels between individuals may indicate a potential for reducing fetal exposure based on timing, dosing, and individual characteristics. This preliminary study may provide an efficient approach for examining the effects of cancer diagnosis during pregnancy on other outcomes by providing a measure of direct fetal exposure.