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Project
Cancer treatment during pregnancy: preclinical and clinical assessment of fetal cardiotoxicity
Cancer is diagnosed in 1 in 1000-2000 pregnancies and this number is even likely to increase seen the delay in childbearing till higher maternal ages in developed countries. To treat these cancers, surgery is feasible during the three trimesters. Chemotherapy is contraindicated during the first trimester because of high risk of miscarriage and teratogenicity but is possible during the second and third trimester of pregnancy. Radiotherapy of the upper part of the body is only possible during the first and second trimester since during the third trimester the growing fetus comes to close to the field of irradiation. Anthracyclines combined with other chemotherapeutic agents are commonly used for treating breast and hematological cancers. These agents are known to be associated with both acute and chronic cardiotoxicity in children and in adults. Acute cardiotoxicity is characterized by an acute and mostly transient decrease in cardiac function. Chronic cardiotoxicity can occur years after chemotherapy treatment and leads to ventricular dysfunction, heart failure, cardiomyopathy and death. Radiotherapy also induces cardiotoxicity and affects the pericardium, the myocardium, the valves, the vessels but also the conduction.
Data on how chemotherapy (and especially anthracyclines) and radiotherapy affect the heart are limited. The mechanisms involved in the anthracyclines cardiotoxicity are still controversial butseem mainly related to the oxidative damage, inflammation, apoptosis, depletion of cardiac stem cells. Radiotherapy induces vascular,myocardial, pericardial, valvular diseases and conduction abnormalities. The risk depends on the cumulative dose of radiotherapy and use of concomitant chemotherapy (anthracyclines) but also on other factors including diabetes, hypertension, obesity, dyslipidaemia. Scarce data exist regarding the possible effect of chemotherapy and radiotherapy on the fetal heart. Maternal-fetal transfer of anthracyclines is estimated at 2.2-4.8% in in vitro and animal studies but we did not know the possible fetal cardiac impact of this administration and passage during pregnancy. Therefore we decided to explore this in a preclinical and clinical setting. In this doctoral thesis we firstly focused on the incidence of pregnant cancer patients by a registration of french speaking patients. Subsequently, we analyzed the preclinical and clinical impact of anthracyclines and radiotherapy on the fetal heart.
About one third ofEuropean centres register their pregnant patients with cancer diagnosis. In Belgium, the national and international registration of pregnant patients with cancer diagnosis was initiated in 2005. This registration ismandatory to have a good overview on the incidence, cancer epidemiologyand a basis to study the short and long-term follow-up of children exposed to chemotherapy and radiotherapy in utero. Contact with gynecologists and oncologists from Walloon province, Brussels, Luxembourg has been established and the database completed. Comparison between the French andthe Dutch patients was performed. We found no difference in the tumor type, obstetrical and neonatal outcome. The only difference was the higherrate of patients exposed to radiotherapy and surgery in the Dutch part.This can be explained by the trend to use primary radiotherapy for breast cancers treatment and also by higher number of patients registered. More than 70 % of patients have been treated by anthracyclines but the acute and chronic impact on the fetal heart was not yet documented.
To study the acute cardiac impact of chemotherapy agents and theirpossible mechanisms, pregnant rats have been exposed to anthracyclines.To evaluate the cardiotoxicity maternal and fetal cardiac biopsies, maternal echocardiography and fetal Doppler were performed. Acute maternal cardiotoxicity is characterized by loss of body weight, moderately deteriorated left ventricular function, apoptosis induction and decrease of cell proliferation. Despite lower fetal body weight and elevated plasmatic BNP concentrations following doxorubicin administration, fetal hearts had intact microstructure, unaltered number of apoptotic cells and cell proliferation and normal Doppler compared to controls. This first study on fetal cardiac impact of chemotherapy during pregnancy reveals fetal cardiac protection probably thanks to low transplacental passage and highcardiomyocytes turnover. This study is reassuring for our patients and fetuses exposed to anthracyclines.
The third part was devoted to the clinical study. Short and long-term follow-up of children exposed to chemotherapy and radiotherapy is the key point for patients counselling.
A pilot study was conducted to evaluate short term maternal and fetal cardiac function by two-dimensional echocardiography. In this study we prospectively evaluated maternal and fetal cardiac function by two-dimensional echocardiography including systolic and diastolic parameters. The data obtained in 10 pregnancies are consistent and show no significant effect of maternal chemotherapy on both maternal and fetal cardiac function. The short term follow-up seems to be reassuring.
A European multicenter initiative collecting long-term prospective data on cardiovascular outcome of children exposed to fetal chemotherapy has also been created. The cardiac performance of a pediatric populationwith in utero exposure to chemotherapy has been evaluated. The results showed no significant difference in echocardiography between those patients and the control group. Interestingly a significantly smaller shortening fraction, ejection fraction and interventricular septum thickness were noticed but remain in the normal ranges. Wall stress and strain, early parameters for cardiotoxicity were also normal after anthracycline exposure.
Children and adults exposed to radiotherapy in utero were followed by echocardiography. Irradiation was performed during the second and third trimester of pregnancy. No difference between this group and the control group wasassessed using echocardiography, Tissue Doppler Imaging and strain. The patients number is nevertheless low and larger studies are needed to confirm these conclusions.
In conclusion, the preclinical and clinical studies and results on chemotherapy and radiotherapy on the fetal heart seem to be reassuring. No cardiac dysfunction in fetal life or in children has been diagnosed. Nevertheless we have shown differences in cardiac function parameters of these children albeit still within normal ranges. It is important to enlargeour groups to substantiate and clarify these first results. We continuethe long-term study to expand the number of collaborating centers in order to collect data from more children, resulting in more solid data.
Data on how chemotherapy (and especially anthracyclines) and radiotherapy affect the heart are limited. The mechanisms involved in the anthracyclines cardiotoxicity are still controversial butseem mainly related to the oxidative damage, inflammation, apoptosis, depletion of cardiac stem cells. Radiotherapy induces vascular,myocardial, pericardial, valvular diseases and conduction abnormalities. The risk depends on the cumulative dose of radiotherapy and use of concomitant chemotherapy (anthracyclines) but also on other factors including diabetes, hypertension, obesity, dyslipidaemia. Scarce data exist regarding the possible effect of chemotherapy and radiotherapy on the fetal heart. Maternal-fetal transfer of anthracyclines is estimated at 2.2-4.8% in in vitro and animal studies but we did not know the possible fetal cardiac impact of this administration and passage during pregnancy. Therefore we decided to explore this in a preclinical and clinical setting. In this doctoral thesis we firstly focused on the incidence of pregnant cancer patients by a registration of french speaking patients. Subsequently, we analyzed the preclinical and clinical impact of anthracyclines and radiotherapy on the fetal heart.
About one third ofEuropean centres register their pregnant patients with cancer diagnosis. In Belgium, the national and international registration of pregnant patients with cancer diagnosis was initiated in 2005. This registration ismandatory to have a good overview on the incidence, cancer epidemiologyand a basis to study the short and long-term follow-up of children exposed to chemotherapy and radiotherapy in utero. Contact with gynecologists and oncologists from Walloon province, Brussels, Luxembourg has been established and the database completed. Comparison between the French andthe Dutch patients was performed. We found no difference in the tumor type, obstetrical and neonatal outcome. The only difference was the higherrate of patients exposed to radiotherapy and surgery in the Dutch part.This can be explained by the trend to use primary radiotherapy for breast cancers treatment and also by higher number of patients registered. More than 70 % of patients have been treated by anthracyclines but the acute and chronic impact on the fetal heart was not yet documented.
To study the acute cardiac impact of chemotherapy agents and theirpossible mechanisms, pregnant rats have been exposed to anthracyclines.To evaluate the cardiotoxicity maternal and fetal cardiac biopsies, maternal echocardiography and fetal Doppler were performed. Acute maternal cardiotoxicity is characterized by loss of body weight, moderately deteriorated left ventricular function, apoptosis induction and decrease of cell proliferation. Despite lower fetal body weight and elevated plasmatic BNP concentrations following doxorubicin administration, fetal hearts had intact microstructure, unaltered number of apoptotic cells and cell proliferation and normal Doppler compared to controls. This first study on fetal cardiac impact of chemotherapy during pregnancy reveals fetal cardiac protection probably thanks to low transplacental passage and highcardiomyocytes turnover. This study is reassuring for our patients and fetuses exposed to anthracyclines.
The third part was devoted to the clinical study. Short and long-term follow-up of children exposed to chemotherapy and radiotherapy is the key point for patients counselling.
A pilot study was conducted to evaluate short term maternal and fetal cardiac function by two-dimensional echocardiography. In this study we prospectively evaluated maternal and fetal cardiac function by two-dimensional echocardiography including systolic and diastolic parameters. The data obtained in 10 pregnancies are consistent and show no significant effect of maternal chemotherapy on both maternal and fetal cardiac function. The short term follow-up seems to be reassuring.
A European multicenter initiative collecting long-term prospective data on cardiovascular outcome of children exposed to fetal chemotherapy has also been created. The cardiac performance of a pediatric populationwith in utero exposure to chemotherapy has been evaluated. The results showed no significant difference in echocardiography between those patients and the control group. Interestingly a significantly smaller shortening fraction, ejection fraction and interventricular septum thickness were noticed but remain in the normal ranges. Wall stress and strain, early parameters for cardiotoxicity were also normal after anthracycline exposure.
Children and adults exposed to radiotherapy in utero were followed by echocardiography. Irradiation was performed during the second and third trimester of pregnancy. No difference between this group and the control group wasassessed using echocardiography, Tissue Doppler Imaging and strain. The patients number is nevertheless low and larger studies are needed to confirm these conclusions.
In conclusion, the preclinical and clinical studies and results on chemotherapy and radiotherapy on the fetal heart seem to be reassuring. No cardiac dysfunction in fetal life or in children has been diagnosed. Nevertheless we have shown differences in cardiac function parameters of these children albeit still within normal ranges. It is important to enlargeour groups to substantiate and clarify these first results. We continuethe long-term study to expand the number of collaborating centers in order to collect data from more children, resulting in more solid data.
Date:1 Oct 2009 → 27 Jun 2013
Keywords:Pregnancy, Cancer
Disciplines:Endocrinology and metabolic diseases, Gynaecology and obstetrics, Nursing
Project type:PhD project