1 Unité dOncologie Médicale, Service de Médecine Interne, Paris; 2 Maternité Port Royal, Groupe Hospitalier Cochin, AP-HP, Paris, France
Received 7 April 2003; revised 18 July 2003; accepted 13 August 2003
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ABSTRACT |
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Anthracyclines are essential for the treatment of malignancies observed in pregnant patients. Knowledge of the potential side-effects of chemotherapy on the developing fetus is essential for patient counseling.
Patients and methods:
We collected information concerning patients treated with anthracyclines during pregnancy from a review of literature between 1976 and 2001 and our experience. The events analyzed were malformations, fetal death and spontaneous abortion. A 2 test with a Yates correction was used to compare the distribution of severe events.
Results:
A total of 160 patient pregnancies were analyzed. The fetal outcome was frequently normal (73%). Abnormalities included malformations (3%), fetal death (9%), spontaneous abortion (3%), fetal complications (8%) and prematurity (6%). Fetal death was often directly consecutive to maternal death (40%). Unfavorable fetal outcome was significantly more frequent in leukemia patients (P = 0.001). In patients with solid tumors, the first trimester was significantly associated with more complications (P = 0.029). The risk of severe fetal toxicity was increased 30-fold when the dose of doxorubicin per cycle exceeded 70 mg/m2 (P = 0.037).
Conclusions:
Anthracyclines may induce embryofetal toxicity. Nevertheless the risk seems low, especially after the first trimester and using doses of doxorubicin below 70 mg/m2.
Key words: anthracyclines, fetal outcome, pregnancy, transplacental passage
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Introduction |
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Anthracyclines damage DNA through different mechanisms, including topoisomerase II poisoning [7]. Anthracyclines are mutagenic and carcinogenic in vitro and in animals [8]. Since topoisomerase II is overexpressed in rapidly growing tissues [9], poisoning topoisomerase II is a potential source of major damage for the embryo, or to a lesser extent to the fetus. On the other hand, only low concentrations of anthracyclines have been detected in fetal tissues, and their cytotoxic potential remains unknown [1013 and present article].
We retrospectively analyzed the data available in the literature and in our institution concerning pregnancy and fetal outcomes following chemotherapy with an anthracycline-containing regimen in pregnant cancer patients. In this database of 160 patients, we were able to identify parameters suitable to help the physician in this specific setting.
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Patients and methods |
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Results |
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The outcomes of the pregnancies are reported in Table 4. Amongst 15 fetal deaths, six were associated with maternal death (40%). The median time to fetal death was 2 weeks after the first anthracycline infusion. Fetal death was more frequent after daunorubicin (73%) and in patients with acute leukemia (87%). Administrations during the second and third trimesters could be associated with any of the anthracycline-induced toxicities. Cardiac toxicity was seen in two cases (two cases of myocardial distress; one lethal, one with recovery and one reversible intermittent sinusoidal fetal heart). The lethal cardiac toxicity was consecutive to the injection of 8 mg/kg daunorubicin during the third trimester. The most frequent pathological conditions in preterm newborns were respiratory distress (73%), ventricular hemorrhage (18%) and enterocolitis (9%).
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Discussion |
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Progressive maternal disease was the first cause of fetal death. This may account for the significantly higher frequency of unfavorable fetal outcomes in patients with acute leukemia.
A total of five malformations (3%) were reported: three in the first trimester (80%), the period of organogenesis, and two following chemotherapy during the second trimester, one Downs syndrome unrelated to chemotherapy [17], one eye malformation (congenital adherence of the iris to the cornea, without consequence) [18]. In rats, doxorubicin exposure in utero induced fetal esophageal atresia, tracheaesophageal fistula, and axial alterations [19]. These findings were not reported in pregnant patients. The combination chemotherapy regimens resulting in malformations included ara-C or cyclophosphamide, two agents able to easily cross the placenta [20, 21]. In contrast to other anticancer agents, which may rapidly cross the placenta and have a complete transfer, anthracyclines cross the placenta incompletely for the following reasons: (i) The molecular weights of doxorubicin and daunorubicin are 580 and 564 Da, respectively. Drugs with molecular weights >500 Da have an incomplete transfer across the human placenta [22]. (ii) Anthracyclines are substrates of the P-gp [23], a placental drug-transporting glycoprotein of great importance in vivo in limiting the fetal penetration of potentially harmful compounds [24]. (iii) Placental transfer of relatively hydrophilic molecules is slow, especially for doxorubicin, where a single maternal dose is concerned [22]. (iv) The transplacental transfer of doxorubicin and 4'epi-iadriamycine ex vivo is very low (2.96 ± 0.75% and 3.66 ± 1.07%, respectively) [25, 26]. (v) After intravenous injection of anthracyclines, only barely detectable concentrations can be found in the fetus (Table 2). These concentrations are 100- to 1000-fold below those found in adult tissues or in the tumor in similar conditions [27]. (vi) Fetal uptake of anticancer agents can be profoundly altered by the changes in both uterine and umbilical blood flows observed in various pathophysiological conditions [28]. Placental transfer diminishes under conditions that decrease the surface area or increase the thickness of the placenta. All the changes related to evolutive malignancy are able to affect this parameter, influencing drug penetration.
The risks associated with chemotherapy depend on the date of administration. Both the level of fetal exposure to anthracyclines and the susceptibility to anthracyclines are likely to vary during pregnancy. In patients with solid tumors, chemotherapy during the first trimester, as expected, was significantly associated with more damage than during other trimesters. While the toxicity of anthracyclines during the first trimester is not fully demonstrated, their toxicity during the second and third trimesters is clearly documented. Cardiotoxicity is a specific feature of anthracycline toxicity, and was observed in several cases of late administration.
When exposure to anthracyclines during pregnancy cannot be avoided, we suggest using standard doses. We exclude both dose reduction or the use of very high doses (>70 mg/m2 doxorubicin) in pregnant patients. Bolus or short infusion should be preferred to continuous infusion. Another anthracycline, 4'epi-iadriamycine should be alternatively used in pregnant cancer patients with breast cancer [29] or lymphoma [30] to reduce the risk of fetal myocardiopathy. In leukemia patients, the main risk for the fetus is maternal disease progression and chemotherapy should not be postponed. In other malignancies, whenever possible, anthracyclines should be administered in a therapeutic window which starts with the second trimester (to prevent malformations) until 2 weeks before the delivery (to prevent neonatal infection or neutropenia).
The collection of more information concerning the effects of anticancer agents during pregnancy is an important issue, and the implementation of registries such as ours is useful to generate new information and improve the guidelines.
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Acknowledgements |
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FOOTNOTES |
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