Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Doxorubicin caused structural anomalies and death in two animal species, and has been associated with similar outcomes in humans after exposure during organogenesis. Exposure during the 1st trimester should be avoided. [See Rituximab for additional data.]
FETAL RISK SUMMARY
Doxorubicin is an antineoplastic agent used for the treatment of various types of cancer. It is in the same antineoplastic subclass of anthracyclines as daunorubicin, epirubicin, idarubicin, and valrubicin. The drug is embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits (1).
Several reports have described the use of doxorubicin in pregnancy, including three during the 1st trimester (2–21). One of the fetuses exposed during the 1st trimester to doxorubicin, cyclophosphamide, and unshielded radiation was born with an imperforate anus and rectovaginal fistula (15). At about 3 months of age, the infant was small with a head circumference of 46 cm (<5th percentile) but was doing well after two corrective surgeries (15). A 1983 report described the use of doxorubicin and other antineoplastic agents in two pregnancies, one of which ended in fetal death 36 hours after treatment had begun (18). Other than maceration, no other fetal abnormalities were observed. The investigators could not determine the exact cause of the outcome but concluded that the chemotherapy was probably not responsible. The only other complication observed in exposed infants was transient polycythemia and hyperbilirubinemia in one subject. Infants who have been evaluated have shown normal growth and development.
A 1999 report from France described the outcomes of pregnancies in 20 women with breast cancer who were treated with antineoplastic agents (18). 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 (18). Doxorubicin (D), in combination with cyclophosphamide (C), fluorouracil (F), or vincristine (V), was administered to four of the women at a mean dose of 68.7 mg/m2(range 50–100 mg/m2). The outcomes were four surviving liveborn infants (two exposed to DCF and one each to DF and DV in the 2nd or 3rd trimesters).
Three studies have investigated the placental passage of doxorubicin (2,19,20). In one, the drug was not detected in the amniotic fluid at 20 weeks’ gestation, which suggested that the drug was not transferred in measurable amounts to the fetus (2). Placental transfer was demonstrated in a 17-week-old aborted fetus, however, using high-performance liquid chromatography (HPLC) (20). High concentrations were found in fetal liver, kidney, and lung. The drug was not detected in amniotic fluid (<1.66 ng/mL), brain, intestine, or gastrocnemius muscle. A third study examined the placental passage of doxorubicin in two pregnancies, one resulting in the birth of a healthy infant at 34 weeks’ gestation and one ending with a stillborn fetus at 31 weeks’ gestation (19). Using HPLC, doxorubicin was demonstrated in the first case, 48 hours after a 45-mg/m2 dose (total cumulative dose, 214 mg/m2), on both sides of the placenta and in the umbilical cord but not in cord blood plasma. In the stillborn, doxorubicin was not detected in any fetal tissue, 36 hours after a single dose of 45 mg/m2. However, a substance was detected in all fetal tissues analyzed that the investigators concluded may have represented an unknown doxorubicin metabolite (19).
In a 2004 case report, a 17-year-old woman at 22 weeks’ gestation was diagnosed with an extraskeletal Ewing’s sarcoma (21). She was treated with doxorubicin 50 mg/m2 by 48-hour continuous infusion and ifosfamide 2 g/m2 as a single injection, both given at 25, 28, and 30 weeks’. Mild fetal growth restriction was noted from the 29th week of gestation. An elective cesarean section delivered a 1.245-kg male infant with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. Based on weight and length (38 cm), the infant was small for gestational age. The infant had no congenital anomalies and no respiratory distress syndrome, but did have mild hyperbilirubinemia. He was growing well at 8 months of age (21).
A 2006 case report described the pregnancy outcome of a 21-year-old woman with Burkitt’s lymphoma who was treated with intensive chemotherapy (22). Beginning at 26 weeks’, she was treated with two cycles of chemotherapy that included ifosfamide, cyclophosphamide, vincristine, doxorubicin, cytarabine, etoposide, cytarabine, and mesna. At 32 weeks’, a cesarean section delivered a 1.731-kg male infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. His weight, length, and head circumference were within normal limits for gestational age. No anomalies were noted but respiratory distress was evident. At 9 months of age, his weight was 6.36 kg. He had mild delayed motor skills that were thought to result from his premature birth. Otherwise he was healthy (22).
Long-term studies of growth and mental development of offspring exposed to doxorubicin and other antineoplastic agents in the 2nd trimester, the period of neuroblast multiplication, have not been conducted (23).
Doxorubicin may cause reversible testicular dysfunction (24,25). Similarly, normal pregnancies have occurred in women treated before conception with doxorubicin (26). In 436 long-term survivors treated with chemotherapy for gestational trophoblastic tumors between 1958 and 1978, 33 (8%) received doxorubicin as part of their treatment regimens (26). Of the 33 women, five (15%) had at least one live birth (data given in parentheses refer to mean/maximum doxorubicin dose in milligrams) (100/100), two (6%) had no live births (150/200), one (3%) failed to conceive (100/100), and 25 (76%) did not try to conceive (140/400). Additional details, including congenital anomalies observed, are described in the monograph for methotrexate (see Methotrexate).
The long-term effects of combination chemotherapy on menstrual and reproductive function have been described in a 1988 report (27). Only one of the 40 women treated for malignant ovarian germ cell tumors received doxorubicin. The results of this study are discussed in the monograph for cyclophosphamide (see Cyclophosphamide).
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, including doxorubicin, are presented in the monograph for cyclophosphamide (see Cyclophosphamide).
BREASTFEEDING SUMMARY
Doxorubicin is excreted into human milk. A 31-year-old woman, 7 months postpartum, was given doxorubicin (70 mg/m2), infused over 15 minutes, for the treatment of ovarian cancer (28). Both doxorubicin and the metabolite, doxorubicinol, were detected in the plasma and the milk. Peak concentrations of the two substances in the plasma occurred at the first sampling time (0.5 hour) and were 805 and 82 ng/mL, respectively. In the milk, the peak concentrations occurred at 24 hours with levels of 128 and 111 ng/mL, respectively. The AUC of the parent compound and metabolite in the plasma were 8.3 and 1.7 µmol/L × hours, respectively, while the AUC in the milk were 9.9 and 16.5 µmol/L × hours, respectively. The highest milk:plasma ratio, 4.43, was measured at 24 hours. Although milk concentrations often exceeded those in the plasma, the total amount of active drug available in the milk was only 0.24 mcg/mL (28). If the infant consumed 150 mL/kg/day, the estimated dose would be 0.036 mg/kg/day
Although the above amounts might be considered negligible, the American Academy of Pediatrics classifies doxorubicin as a drug that may interfere with the cellular metabolism of the nursing infant (29).
References
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