Antineoplastic
PREGNANCY RECOMMENDATION: Human Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The limited human pregnancy experience and the use of combination therapy prevent a complete assessment of the embryo–fetal risk. In addition to the potential for structural anomalies, cytarabine may cause fetal bone marrow suppression.
FETAL RISK SUMMARY
Cytarabine is an antineoplastic agent used in the treatment of various types of leukemia. It is classified as an antimetabolite in the subclass of pyrimidine analogs. Other antineoplastic agents in the subclass are capecitabine, floxuridine, fluorouracil, and gemcitabine.
The drug is teratogenic in the hamster and rat (1). Cytarabine is classified as an antimetabolite in the subclass of pyrimidine analogs. Other antineoplastic agents in the subclass are capecitabine, floxuridine, and gemcitabine.
Normal infants have resulted following in utero exposure to cytarabine during all stages of gestation (2–27). Follow-up of seven infants exposed in utero during the 2nd trimester to cytarabine revealed normal infants at 4–60 months (20,22–26). Two cases of intrauterine fetal death after cytarabine combination treatment have been located (20,23). In one case, maternal treatment for 5 weeks starting at the 15th week of gestation ended in intrauterine death at 20 weeks’ gestation of a fetus without abnormalities or leukemic infiltration (20). The second case also involved a woman treated from the 15th week who developed severe pregnancy-induced hypertension at 29 weeks’ gestation (23). An apparently normal fetus died 1 week later, most likely as a consequence of the preeclampsia.
Use during the 1st and 2nd trimesters has been associated with congenital and chromosomal abnormalities (21,28–30). One leukemic patient treated during the 2nd trimester elected to have an abortion at 24 weeks’ gestation (21). The fetus had trisomy for group C autosomes without mosaicism. A second pregnancy in the same patient with identical therapy ended normally. In another case, a 34-year-old woman with acute lymphoblastic leukemia was treated with multiple antineoplastic agents from 22 weeks’ gestation until delivery of a healthy female infant 18 weeks later (28). Cytarabine was administered only during the 27th week of gestation. Chromosomal analysis of the newborn revealed a normal karyotype (46,XX) but with gaps and a ring chromosome. The clinical significance of these findings is unknown, but because these abnormalities may persist for several years, the potential existed for an increased risk of cancer as well as for a risk of genetic damage in the next generation (28). Two women, one treated during the 1st trimester and the other treated throughout pregnancy, delivered infants with the following multiple anomalies:
Bilateral microtia and atresia of external auditory canals, right hand lobster claw with three digits, bilateral lower limb defects (29)
Two medial digits of both feet missing, distal phalanges of both thumbs missing with hypoplastic remnant of the right thumb (30)
Congenital anomalies have also been observed after paternal use of cytarabine plus other antineoplastics prior to conception (31). The investigators suggested that the antineoplastic agents may have damaged the sperm without producing infertility in the two fathers. The relationship between use of the chemotherapy in these men and the defects observed is doubtful due to the lack of experimental evidence and confirming reports. The results of these pregnancies were as follows: tetralogy of Fallot, syndactyly of first and second digits of right foot, and a stillborn with anencephaly. Cytarabine may produce reversible azoospermia (32,33). However, male fertility has been demonstrated during maintenance therapy with cytarabine (34).
Pancytopenia was observed in a 1000-g male infant exposed to cytarabine and five other antineoplastic agents during the 3rd trimester (12).
Data from one review indicated that 40% of the mothers exposed to antineoplastic drugs during pregnancy delivered low-birth-weight infants (35). This finding was not related to the timing of exposure. Except for the few cases noted above, long-term studies of growth and mental development in offspring exposed to cytarabine during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (36).
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
No reports describing the use of cytarabine during lactation have been located. Because of the potential for serious adverse effects in nursing infants, women receiving this drug should not breastfeed.
References
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