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Cancer in Pregnancy: Cytarabine
Cytarabine is an antimetabolite used in the treatment of acute leukemia and occasionally in lymphomas. It is a nucleoside analogue, which inhibits DNA synthesis.
|Animal studies *||Mice and rats||2 to 67 times the human dose||Increased frequency of limb defects, particularly ectrodactyly and digital anomalies. 1-4 These effects were time and dose dependent.|
|10 to 93 times the human dose, late pregnancy||Increased incidence of brain and kidney defects 5-8|
|Chicks, rats, mice, hamsters||Increased incidence of skeletal defects 9-12, cleft palate 3,10,11, cerebellar hypoplasia 5,13 and retinal dysplasia 5.|
|Human studies||Case reports||1st trim exposure||Many case reports of normal babies after 1st trimester exposure were found 14-16. Two malformed infants were reported after 1st trimester exposure to cytarabine:|
|Combination with thioguanine||A male baby
born to a mother who received cytarabine and thioguanine during the
whole pregnancy. He was born at 38 weeks of pregnancy, with low birth
weight (2,232g). The following anomalies were found: absence of the
medial two toes of both feet, absence of the distal phalange of the
left thumb and of the distal and proximal phalange of the right thumb.
Otherwise he was normal. Karyotype showed no abnormalities.
The same mother got pregnant again one year later with the same chemotherapy and gave birth to a female baby without anomalies. Karyotype was normal 17
|Cytarabine only||A male baby born to a mother who received ARA-C as a single agent during all pregnancy. The baby showed the following anomalies: bilateral microtia with atresia of the external auditory canals; right hand with lobster claw deformity and only three digits; lower limb anomalies. Karyotype was normal 18|
|2nd and 3rd trim exposures||Chromosomal abnormalities were described in two cases after 2nd trimester exposure to ARA-C:|
|A patient treated from 20th
week of pregnancy with thioguanine and cytarabine. A therapeutic
abortion was performed at 24 weeks. No congenital abnormalities were
found at autopsy but the karyotype from chorionic tissue showed a group
C trisomy mosaicism 19.
A healthy girl born to a woman who received combination therapy including ARA-C for acute lymphoblastic leukemia, from 22nd week to term. Karyotype analysis showed 46 chromosomes with the presence of gaps and a ring chromosome. The clinical significance of this finding is still unknown but it may represent an risk of cancer as well as a risk of genetic damage in the next generation 20
Three cases of intrauterine death after combination therapy were reported, two in the second trimester 21,22 and one in the third 23. One baby exposed during the second trimester was born with bruising and petechia over multipleareas. The mother was treated with doxorubicin, cytarabine and thioguanine 21.
A case of severe myelosupression in an infant exposed to combined therapy during 1st, 2nd and 3rd trim 24, details below Two other cases of neutropenia and thrombocytopenia were reported 25,26
There are many case reports of normal babies born after cytarabine exposure during the second and/or third trimester 21,27-29.
epidemiological studies of congenital anomalies among infants of women
that were treated with ARA-C during pregnancy were identified. The
following case series were found:
1. No congenital anomalies were observed in one series among 9 children born to women treated during pregnancy with cancer chemotherapeutic regimens that included ARA-C. Five of these women were treated during the first trimester 28. Their growth, intellectual development and cytogenetic analysis were normal in ages rangingfrom 3 - 19 years at the time of the follow-up.
2. In a series of 9 patients with acute leukemia during pregnancy, 4 of them with the use of cytarabine during the first trimester, no one was born with congenital malformation24, but 2 had a subnormal birth weight. One of them had severe pancytopenia and low birth weight. The mother of this patient received combination chemotherapy (cytosine arabinoside, prednisone, 6-mercaptorurine, methotrexate andvincristine) during 1st, 2nd and 3rd trimesters.
3. In a case series of 7 pregnant patients with acute leukemia, 4 of them with combination therapy including ARA-C during the 2nd or 3rd trimester, there were 4 live births without major malformations, but 2 of them were of low birth weight. One had a mild perinatal thrombocytopenia. Their long-term follow-up (1 to 11 years) did not show any developmental abnormality 29.
- Ritter EJ, Scot WJ, Wilson JG. Teratogenesis and Inhibition of DNA synthesis induced in rat embryos by cytosine arabinoside. Teratology.4: 7-14, 1971.
- Rooze M. Correlations between necrotic patterns and limb skeletal defects induced by antimitotic drugs in the mouse. Prog Clin Biol Res.110 (Pt A): 365-375, 1983.
- Ortega A, Puig M. Domingo JL. Maternal and developmental toxicity of low doses of cytosine arabinoside in mice. Teratology. 44: 379-384,1991.
- Ishikawa H, Omoe K, Endo A. Growth and differentiation schedule of mouse embryos obtained from delayed matings. Teratology. 45(6): 655-659,1992.
- Percy DH. Teratogenic effects of the pyrimidine analogues 5-iododeoxyuridine and cytosine arabinoside in late fetal mice and rats. Teratology. 11: 103-118, 1975.
- Shimada M, Abe Y, Yamano T, et al. The pathogenesis of abnormal cytoarchitecture in the cerebral cortex and hippocampus of the mouse treated transplacentally with cytosine arabinoside. ActaNeuropathol. 58: 159-167, 1982.
- Matsutani T, Tamaru M, Hayakawa Y, et al. A neurochemical study of developmental impairment of the brain caused by the administration of cytosine arabinoside during the fetal or neonatal period of rats. Neurochem Res. 8(10): 1295-1306, 1983.
- Ohno M. Neuroanatomical study of somatomotor cortexin microcephalic mice induced by cytosine arabinoside. Brain Dev.6(6): 528-538, 1984.
- Karnofsky DA, Lacon CR. The effects of 1-beta-d-arabinofuransyl-cytosine on the developing chick embryo. Biochem Pharmacol. 15: 1435-1442,1966.
- Chaube S, Murphy ML. Teratogenic effects of cytosine arabinoside (CA)in the rat fetus. Proc Am Assoc Cancer Res. 6:11, 1965.
- Chaube S, Murphy ML. Teratogenic effects of the recent drugs active in cancer chemotherapy, in Woollam (ed): Advances inTeratology, Vol 3, NY. Academic Press, 1968 pp 204-5.
- Goto T, Endo A. Dose and stage related sex difference in the incidence of cytosine arabinoside induced digit anomalies in the mouse fetus. Teratology. 35: 35-40, 1987.
- Fisher DS, Jones AM. Cerebellar hypoplasia resulting from cytosine arabinoside treatment in the neonatal hamster. Clin Res. 13: 540,1965.
- Schardein JL. Chemically induced birth defects, Marcel Dekker, New Yorkand Basel 1993, p 480.
- Schafer AI.Teratogenic effects of antileukemic chemotherapy. ArchIntern Med. 141: 514-5, 1981.
- Wagner VW, et al. Congenital anomalies in a baby born to cytarabine treated mother. Lancet. 2: 98-100, 1980.
- Maurer LH, et al. Fetal group C trisomy after cytosine arabinoside and thioguanine. Ann Intern Med. 75: 809-10, 1971.
- Schleuning & Clemm: Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. New Engl J Med 317: 1666-7, 1987.
- Zemlickis D, Lishner M, Degendorfer P, et al. Fetal outcome after in utero exposure to cancer chemotherapy. Arch InternMed. 152: 573-576, 1992.
- Volkenandt M, Buchner T, Hiddemann W, van de Loo J. Acute leukaemia during pregnancy. Lancet. 2: 1521-1522, 1987.
- O'Donnell R, Costigan C, O'Connell LG. Two cases of acute leukaemia in pregnancy. Acta Haemat. 61: 298-300, 1979.
- Pizzuto J, Aviles A, Noriega L, et al. Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat Rep.64(4-5): 679-683, 1980.
- Colbert N, Najman A, Gorin NC, et al. Acute leukaemia during pregnancy: favourable course of pregnancy in two patients treated with cytosine arabinoside and anthracyclines. Nouv Press Med.9: 175-178, 1980.
- Taylor G, Blom J. Acute leukemia during pregnancy.South Med J. 73(10): 1314-1315, 1980.
- Gililland J, Weinstein L. The effects of cancer chemotherapeutic agents on the developing fetus. Obstet Gynecol Surv. 38(1): 6-12, 1983.
- Caligiuri MA, Mayer RJ. Pregnancy and leukemia. Semin Oncol.16(5): 388-396, 1989.
- Plows CW. Acute myelomonocytic leukemia in pregnancy: Report of a case. Am J Obstet Gynecol. 143(1): 41-43, 1982.
- Aviles A, Diaz-Maqueo JC, Talavera A, et al. Growth and development of children of mothers treated with chemotherapy during pregnancy. Current status of 43 children. Am J Hematol. 36: 243-248,1991.
- Reynoso et al: Acute Leukemia during pregnancy: the Toronto Leukemia Study group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol5:1098-1106, 1987.