Research Article: Preliminary results of identification and quantification of paclitaxel and its metabolites in human meconium from newborns with gestational chemotherapeutic exposure

Date Published: February 20, 2019

Publisher: Public Library of Science

Author(s): Elyce Cardonick, Robert Broadrup, Peining Xu, Mary T. Doan, Helen Jiang, Nathaniel W. Snyder, Eduardo Ortiz-Panozo.

http://doi.org/10.1371/journal.pone.0211821

Abstract

Cancer diagnosis during pregnancy occurs in 1 out of 1000 pregnancies with common malignancies including breast and hematological cancers. Fetal exposure to currently utilized agents is poorly described. We directly assessed fetal exposure by screening meconium from 23 newborns whose mothers had undergone treatment for cancer during pregnancy.

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. We conducted screening of 23 meconium samples for chemotherapeutics and known metabolites of chemotherapeutics by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Putative identification of paclitaxel and/or its metabolites was made in 8 screened samples. In positively screened samples, we quantified paclitaxel, 3’-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel by stable isotope dilution-LC-HRMS.

Mean (standard deviation) levels of paclitaxel in positively screened samples were 399.9 (248.6) pg/mg in meconium samples from newborn born to mothers that underwent chemotherapy during pregnancy. 3’-p-hydroxypaclitaxel and 6α-hydroxypaclitaxel mean levels were 105.2 (54.6) and 113.4 (48.9) pg/mg meconium, respectively.

Intact paclitaxel, 3’-p-hydroxypaclitaxel, and 6α-hydroxypaclitaxel 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 approach for examining the effects of cancer diagnosis during pregnancy on other outcomes by providing a measure of direct fetal exposure.

Partial Text

Cancer diagnosis occurs in 1 in 1000 pregnancies. The most common malignancies complicating pregnancy are breast cancer, Hodgkin’s and Non-Hodgkin’s lymphoma, and melanoma [1]. The most common agents used during pregnancy include doxorubicin, cyclophosphamide, epirubicin, 5-fluouracil and more recently paclitaxel. Studies of effects of chemotherapy exposure during the second and third trimester have been reassuring, where the majority detail the physical appearance at birth and general health during the first year of life [2–6]. A limited number of studies provide longer follow up with developmental and physical evaluation of children exposed in utero to chemotherapy up until the late teen years and young adulthood [7–9]. In all existing studies, study design has used inclusion by maternal chemotherapy during pregnancy correlated with post-natal growth and development of the children without a direct measure of fetal exposure and internalized dose to the fetus.

To our knowledge, this is the first measurement of chemotherapeutics in human meconium. As a preliminary study, there are severe limitations to our findings. First, we were unable to obtain any other maternal or fetal biospecimens to examine circulating maternal chemotherapeutic concentrations. Combined with a lack of dosage information and a complete accounting of covariates (other pharmaceuticals given, comorbidities, body weight, etc.) this prevents informed pharmacokinetic analysis within this study design. Accounting for these factors in larger future studies may explain some of the variability in paclitaxel across meconium samples, especially in the context of modifiers of paclitaxel metabolism and placental transport. Since diagnosis of breast cancer during pregnancy is increasing due to demographic changes, and these changes may alter transplacental exposures, recruitment of larger and better-described cohorts is reasonable. Second, the use of analytical screening before targeted quantification may limit the ability to detect other chemotherapeutics in meconium. However, it takes significant resources to develop and then validate methods in new biological matrices, especially complex ones such as meconium. Future studies could take advantage of the findings here to further this work with more complete data and biosample collection. The benefit of meconium, in terms of ease of sample collection with a low burden on participants and researchers, may make this feasible. However, one drawback of meconium is that collection is more difficult to standardize since the meconium may pass at different times- corresponding to different hospital branches, care-teams, or at home. It is however unlikely that difference in handling between mothers may lead to differential levels of chemotherapeutics in meconium as pre-labeled packaging was provided, paclitaxel would not be a likely exogenous contaminant, and compounds detected in meconium by definition are stable enough to be detectable in stored samples. Additional future work using cord tissue or more invasive samples including amniotic fluid could provide additional information on concentrations of chemotherapeutics in the fetal compartment.

 

Source:

http://doi.org/10.1371/journal.pone.0211821

 

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