Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
There is limited human pregnancy experience with ifosfamide. The drug is carcinogenic and mutagenic in experimental studies. In addition, it is teratogenic and embryotoxic in three animal species at doses far less than the recommended human dose. Because of the close relationship of ifosfamide to cyclophosphamide, a known human teratogen, ifosfamide should be considered an agent with a high potential for human teratogenicity and embryo–fetal toxicity.
FETAL RISK SUMMARY
Ifosfamide is chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide (see also Cyclophosphamide). Ifosfamide is a prodrug that requires metabolic activation by microsomal liver enzymes to produce biologically active metabolites. It is indicated for the treatment of germ cell testicular cancer. Combination with a prophylactic agent such as mesna is recommended to prevent hemorrhagic cystitis (1).
Ifosfamide was carcinogenic in rats (including a significant incidence of leiomyosarcomas and mammary fibroadenomas in female rats) and mutagenic in several assays (1). Reproduction studies have been conducted in pregnant mice, rats, and rabbits. In mice, a single dose of 30 mg/m2 (1/40 the daily recommended human dose of 1200 mg/m2) administered on gestational day 11 caused an increase in the incidence of resorptions and anomalies (not specified). Evidence of embryolethality was observed in rats given 54-mg/m2 doses on gestational days 6–15. Embryotoxic effects (not specified) were observed when a smaller dose (18 mg/m2) was administered over the same period. Embryotoxicity and teratogenicity were observed in rabbits given 88 mg/m2/day on gestational days 6–18 (1). Maternal toxicity was not mentioned in any of the above studies.
A 1973 study described the teratogenic and embryotoxic effects of various single intraperitoneal doses (5, 10, and 20 mg/kg) of ifosfamide given to mice on gestational day 11 (2). Only the 20-mg/kg dose was embryolethal (significantly increased resorption rates), but significant fetal toxicity (decreased body weight and/or crown–rump length) was observed with the 10- and 20-mg/kg doses. A number of anomalies were observed in the highest dose group: open eyes, internal and external hydrocephalus, microphakia, micromelia, adactyly, syndactyly, microcaudate, kinky tails, kidney ectopia, and hydronephrosis. Both 10- and 20-mg/kg doses increased the number of skeletal defects and the 5-mg/kg dose was associated with a significant increase in supernumerary ribs. Finally, a single SC dose of 45 mg/kg administered to 1-day-old mice resulted in reduced body weight and altered development (2).
In sexually mature male rabbits, single IV doses of ifosfamide (0, 60, 90, 120, or 240 mg/kg) caused transient and dose-dependent depression of spermatocytogenesis, spermiogenesis, and sperm maturation in comparison to controls (3). In the second part of this study, using the same methods, the investigators combined ifosfamide with mesna (an uroprotectant agent) (4). Three groups of male rabbits were given different doses of the combination (ifosfamide 30, 45, or 60 mg/kg plus mesna 6, 9, or 12 mg/kg, followed by a second equal dose of mesna 4 hours later). Each group received 10 weekly treatments. Controls were given either mesna alone (three groups) or saline (one group). Dose-related ifosfamide–mesna suppression of spermatogenesis and epididymal sperm maturation was observed. In addition, the investigators noted incomplete recovery of the germinal epithelium (4).
A 1997 review stated that ifosfamide is less toxic for stem cell spermatogonia (type A spermatogonia) than is cyclophosphamide (5). In 15 of 16 patients who received 15–30 g/m2 of ifosfamide, the median follicle-stimulating hormone levels returned to normal. In addition, there was no evidence of an increased risk of malformations or malignancies in offspring fathered by patients with germ cell cancer after chemotherapy (5). However, a 2003 study confirmed that ifosfamide exposure is a potential cause of male infertility (6). A significant (p = 0.005) dose-dependent relationship was observed between increasing doses of ifosfamide and infertility in patients treated for osteosarcoma.
It is not known if ifosfamide or its active metabolites cross the placenta to the fetus. The low molecular weight of the parent prodrug (about 261) suggests that it reaches the fetal circulation.
A 20-year-old woman at 23 weeks’ gestation was treated with ifosfamide (5 g/day on days 1 and 2), vincristine (2 mg/day on days 1 and 14), and dactinomycin (1 mg/day on days 1 and 2) for advanced rhabdomyosarcoma of the face (7). In addition to the antineoplastics, the patient also received mesna and urate oxidase (used for the treatment of hyperuricemia). A second course of therapy was given 4 weeks later. At initiation of the chemotherapy, the fetal weight was estimated to be at the 20th percentile with normal amniotic fluid volume and active movements. At the time of the second course of chemotherapy, ultrasound revealed a complete absence of amniotic fluid, an empty fetal bladder, cessation of fetal growth, and absence of fetal movements. An emergency cesarean section was performed 2 weeks later after evidence of continued anhydramnios, intrauterine growth arrest, and acute fetal hypoxia. A 720-g female was delivered with Apgar scores of 3, 7, and 7 at 1, 5, and 10 minutes, respectively. An ultrasound of the neonate revealed bilateral intraventricular hemorrhage and left occipital meningeal hematomas. Anuria persisted, and the girl died at age 7 days. Autopsy noted extensive cerebral lesions associated with prematurity but no renal lesions or chromosome abnormalities. The placenta had large areas of ischemic necrosis without evidence of chorioamnionitis. No cancer cells were found in the fetus or placenta. The authors speculated that the lack of renal lesions suggested that causes in addition to ifosfamide-induced toxicity should be considered to explain the anuria in the fetus and newborn (7).
In contrast to the above study, a 21-year-old woman was treated with three courses of ifosfamide/mesna (each 5 g/m2 three times weekly) and doxorubicin (50 mg/m2 three times weekly) for Ewing’s sarcoma of the pelvis (8). The three courses were given in the 27th, 30th, and 33rd week of pregnancy. Mild intrauterine growth restriction was detected by ultrasound. A cesarean section at the beginning of the 36th gestational week delivered a 42-cm-long, 1300-g female infant. No adverse effects were noted in the infant, who was doing well at 2 years of age (8).
In a 2004 case report, a 17-year-old woman at 22 weeks’ gestation was diagnosed with an extraskeletal Ewing’s sarcoma (9). 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 (9).
A 2006 case report described the pregnancy outcome of a 21-year-old woman with Burkitt’s lymphoma who was treated with intensive chemotherapy (10). 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 (10).
BREASTFEEDING SUMMARY
No reports describing the use of ifosfamide during lactation have been located. Ifosfamide is excreted into breast milk (1). This is consistent with its low molecular weight (about 261). Although the amount of ifosfamide in milk was not stated, severe toxicity in a nursing infant is a potential concern (e.g., bone marrow depression, urinary system, and CNS toxicity). Therefore, women receiving ifosfamide should not breastfeed.
References
1.Product information. Ifex. Bristol-Myers Squibb, 2000.
2.Bus JS, Gibson JE. Teratogenicity and neonatal toxicity of Ifosfamide in mice. Proc Soc Exp Biol Med 1973;143:965–70.
3.Ypsilantis P, Papaioannou N, Psalla D, Politou M, Simopoulos C. Effects of single-dose administration of ifosfamide on testes and semen characteristics in the rabbit. Reprod Toxicol 2003;17:237–45.
4.Ypsilantis P, Papaioannou N, Psalla D, Politou M, Pitiakoudis M, Simopoulos C. Effects of subchronic ifosfamide-mesna treatment on testes and semen characteristics in the rabbit. Reprod Toxicol 2003;17:699–708.
5.Pont J, Albrecht W. Fertility after chemotherapy for testicular germ cell cancer. Fert Steril 1997;68:1–5.
6.Longhi A, Macchiagodena M, Vitali G, Bacci G. Fertility in male patients treated with neoadjuvant chemotherapy for osteosarcoma. J Pediatr Hematol Oncol 2003;25:292–6.
7.Fernandez H, Diallo A, Baume D, Papiernik E. Anhydramnios and cessation of fetal growth in a pregnant mother with polychemotherapy during the second trimester. Prenat Diag 1989;9:681–2.
8.Merimsky O, Chevalier TL, Missenard G, Lepechoux C, Cojean-Zelek I, Mesurolle B, Le Cesne A. Management of cancer in pregnancy: a case of Ewing’s sarcoma of the pelvis in the third trimester. Ann Oncol 1999;10:345–50.
9.Nakajima W, Ishida A, Takahashi M, Hirayama M, Washino N, Ogawa M, Takahashi S, Okada K. Good outcome for infant of mother treated with chemotherapy for Ewing sarcoma at 25–30 weeks’ gestation. J Pediatr Hematol Oncol 2004;26:308–11.
10.Lam MSH. Treatment of Burkitt’s lymphoma during pregnancy. Ann Pharmacother 2006;40:2048–52.