Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
This synthetic anthracenedione, structurally related to doxorubicin, is an antineoplastic antibiotic used in the treatment of acute nonlymphocytic leukemia, refractory lymphomas, and cancers of the breast, ovary, and liver. Reports describing the use of this agent in five pregnancies, all in the 2nd trimester, have been located. Mitoxantrone is toxic to DNA and has a cytocidal effect on both proliferating and nonproliferating human cells (1).
FETAL RISK SUMMARY
The mean half-life of mitoxantrone is 5.8 days (range 2.3–13.0 days) and may be longer in tissue. Moreover, the drug accumulates after multiple dosing in plasma and tissue (1).
Mitoxantrone administration to pregnant rats at a dose 0.05 times the recommended human dose based on BSA (RHD) caused decreased fetal weight and retarded development of the fetal kidney (1). Although not teratogenic in rabbits, a dose 0.01 times the RHD was associated with an increased incidence of premature delivery (1).
Two case reports, both during the 2nd trimester, have described the use of mitoxantrone in human pregnancy (2,3). A 26-year-old woman at 20 weeks’ gestation presented with acute myeloblastic leukemia and was treated with an induction course of cytarabine and daunorubicin that failed to halt the disease progression (2). At approximately 23 weeks’ gestation, a second induction course was started with mitoxantrone (12 mg/m2, days 1–3) and cytarabine (days 1–4). Complete remission was achieved 60 days from the start of therapy. Weekly ultrasound examinations documented normal fetal growth. Because of the long interval required for remission, treatment was changed to idarubicin and cytarabine for the consolidation phase. Shortly after the start of this therapy, the woman delivered a 2200-g stillborn infant (gestational age not specified). No apparent congenital malformations were observed but permission for an autopsy was refused. The authors speculated that the fetal death was secondary to the use of idarubicin (2).
In the second case, a 28-year-old woman at 24 week’s gestation with acute promyelocytic leukemia was treated with an induction course of behenoyl-cytosine arabinoside (enocitabine; converted in vivo to cytarabine), daunorubicin, and 6-mercaptopurine (3). Following a rapid, complete remission and her first consolidation therapy with cytarabine and mitoxantrone (dose not specified), a cesarean section was performed at 34 weeks’ gestation to deliver a healthy 2960-g female infant who was alive and well at 16 months of age (3).
A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (4). The first cycle of chemotherapy occurred at a mean gestational age of 26 weeks with delivery occurring at a mean 34.7 weeks. A total of 38 cycles were administered during pregnancy with a median of two cycles per woman. None of the women received radiation therapy during pregnancy. The pregnancy outcomes included two spontaneous abortions (both exposed in the 1st trimester), one intrauterine death (exposed in the 2nd trimester), and 17 live births, one of whom died at 8 days of age without apparent cause. The 16 surviving children were developing normally at a mean follow-up of 42.3 months (4). Mitoxantrone, in combination with cyclophosphamide and fluorouracil, was administered to two of the women at a mean dose of 12 mg/m2. The outcomes were two surviving liveborn infants, both exposed in the 2nd trimester. One of the infants was growth restricted (1460 g, born at 33 weeks’ gestation after two cycles of chemotherapy) (4).
In a 2009 case report, a woman with relapse of acute myeloid leukemia at 22 weeks’ gestation was treated with mitoxantrone, fludarabine, cytarabine, idarubicin, and gemtuzumab ozogamicin (5). The fetus developed signs of idarubicin-induced cardiomyopathy, transient cerebral ventriculomegaly, anemia, and intrauterine growth restriction. The newborn, delivered at 33 weeks’ by cesarean section, showed no congenital malformations (5).
Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).
BREASTFEEDING SUMMARY
Mitoxantrone is excreted in breast milk (3). After delivery at 34 weeks’ gestation, a 28-year-old woman with acute promyelocytic leukemia in remission (case described above) was treated with a second consolidation therapy course of cytarabine and mitoxantrone. She maintained milk secretion by pumping her breasts during this and a third consolidation course consisting of mitoxantrone (6 mg/m2, days 1–3), etoposide, and behenoyl-cytosine arabinoside (enocitabine; converted in vivo to cytarabine). The milk concentration of mitoxantrone on the 3rd day of this last course of therapy was 120 ng/mL and was still high (18 ng/mL) 28 days later. Although data on the drug concentration in milk were not yet available, and against the authors’ advisement, the patient voluntarily began to breastfeed her infant 21 days after drug administration. Her infant, exposed to mitoxantrone in utero and during nursing was doing well at 16 months of age (3).
Although no adverse effects were observed in the above infant, the long-term consequences of such exposure are unknown. Mitoxantrone accumulates in the plasma and tissue after multiple doses and is slowly eliminated from the body (1). Because of its long elimination time and the uncertainty over the potential toxicity, women who have been treated with this agent should not breastfeed. The American Academy of Pediatrics classifies doxorubicin, an antineoplastic agent structurally related to mitoxantrone, as contraindicated during breastfeeding (see Doxorubicin).
References
1.Product information. Novantrone. Immunex, 2000.
2.Reynoso EE, Huerta F. Acute leukemia and pregnancy—fatal fetal outcome after exposure to idarubicin during the second trimester. Acta Oncologica 1994;33:703–16.
3.Azuno Y, Kaku K, Fujita N, Okubo M, Kaneko T, Matsumoto N. Mitoxantrone and etoposide in breast milk. Am J Hematol 1995;48:131–2.
4.Giacalone PL, Laffargue F, Benos P. Chemotherapy for breast carcinoma during pregnancy. Cancer 1999;86:2266–72.
5.Baumgartner AK, Oberhoffer R, Jacobs VR, Ostermayer E, Menzel H, Voigt M, Schneider KT, Pildner von Steinburg S. Reversible foetal cerebral ventriculomegaly and cardiomyopathy under chemotherapy for maternal AML. Onkologie 2009;32:40–3.