Cancer During Pregnancy: The Role of Vascular Toxicity in Chemotherapy-Induced Placental Toxicity

Abstract

Breast cancer is diagnosed in ~0.3% of pregnant women. Studies that have addressed gestational and neonatal outcomes of chemotherapy during pregnancy have demonstrated increased gestational complications including preeclampsia and intrauterine growth retardation. We hypothesized that anthracycline-induced gestational complications could be derived from direct toxicity on the placenta vasculature. Pregnant ICR mice (day E12.5) were treated with doxorubicin (DXR; 8 mg/kg) or saline, while their umbilical cord blood flow was imaged by pulse-wave (PW) Doppler. Mice were euthanized on day E18.5, and their embryos and placentae were collected for further analysis. Unlike control mice, the DXR-treated mice presented an acute change in the umbilical cord’s blood flow parameters (velocity time integral and heart rate interval), reduced embryos’ weight, reduced placenta efficiency, and modulation in vascular-related pathways of treated placenta proteomics. Apoptosis and proliferation were also enhanced, as demonstrated by TUNEL and proliferating cell nuclear antigen (PCNA) analysis. We further examined the placentae of patients treated with epirubicin (EPI), who had been diagnosed with breast cancer during pregnancy (weeks 27–35). The immunohistochemistry of the EPI-treated human placentae showed enhanced proliferation and apoptosis as compared with matched chemo-naïve placentae, as well as reduced neovascularization (CD34). Our findings suggest that anthracycline-induced vascular insult promotes placental toxicity, and could point to potential agents designated to offset the damage and to reduce gestational complications in pregnant cancer patients.

Cancer during Pregnancy: A Review of Preclinical and Clinical Transplacental Transfer of Anticancer Agents

“…In humans, a pharmacokinetic study concluded that there is suboptimal exposure to anthracyclines during pregnancy due to gestation-induced changes, and suggested that the dose should be increased by 5.5% and 8% for doxorubicin and epirubicin, respectively [ 109 ]. A recent study on the pathways involved in anthracycline-induced gestational complications (preeclampsia and IUGR) [ 116 ] used both a mouse model and in vitro human placental cells to demonstrate the direct toxicity of doxorubicin on trophoblasts.…”

Update on the Management of Breast Cancer during Pregnancy

“…After administration of doxorubicin to pregnant mice during the second trimester, the authors observed a vascular-derived placental toxicity, with a reduced blood flow, and a lower birth weight. Furthermore, a histological section of the placenta of women exposed to chemotherapy revealed a decreased neovascularization and higher proliferation and apoptosis as compared with gestational age-matched chemo-naïve women [31].…”

“…Thus, chemotherapy can be safely administered in the second and third trimesters, always with a close surveillance of the mother and the fetus [7,16]. The blood placenta barrier limits the fetal exposure to cytotoxic drugs, with a different transplacental capacity for different drugs [30,31].…”

Cancer and Pregnancy: A Comprehensive Review

“…Another in vitro study examining placental tissue explants of 3rd trimester pregnancies, which were exposed to various cytotoxic drugs at therapeutic plasma concentrations (between 1 µM and 100 µM), such as doxorubicin, paclitaxel, cisplatin, carboplatin, crizotinib, gefitinib, imatinib or sunitinib and all cytotoxic drugs but paclitaxel led to reduced cell and tissue viability within 72 h of exposure [ 72 ]. In vivo animal studies showed impaired umbilical cord blood flow parameters and reduced placenta efficiency when mice were treated with doxorubicin during gestation [ 73 ].…”