ASPARAGINASE

Drugs in Pregnancy and Lactation.

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Name: ASPARAGINASE
Class: Antineoplastic
Risk Factor:    CM

Fetal Risk Summary

The antineoplastic agent asparaginase, which is used in the treatment of certain types of cancers, contains the enzyme, L-asparagine amidohydrolase, type EC-2, derived from Escherichia coli (1). The drug is teratogenic in rabbits, rats, and mice (1,2 and 3). In pregnant rabbits given 50 IU/kg (5% of the human dose), asparaginase crossed the placenta and produced malformations of the lung, kidney, and skeleton; spina bifida; abdominal extrusion; and missing tail (2). Doses of 1000 IU/kg (equal to the human dose) or more in rats and mice produced exencephaly and skeletal anomalies (3). Maternal and fetal growth retardation have also been observed in pregnant rats and mice treated with 1000 IU/kg (1).

The reported use of asparaginase during human pregnancy is limited to six pregnancies, all in the 2nd trimester, resulting in the birth of seven infants (one set of twins) (4,5,6,7,8 and 9). In each case, multiple other chemotherapeutic agents were used with asparaginase for treatment of the acute leukemias. Therapy with asparaginase was initiated between 16.5 and 22 weeks of pregnancy. No congenital abnormalities were observed in any of the newborn infants, although two newborns had transient, drug-induced bone marrow hypoplasia (4,5). One 34-year-old mother, with acute lymphoblastic leukemia, was treated for 18 weeks, commencing at 22 weeks' gestation, with various combinations of asparaginase, daunorubicin, vincristine, cytarabine, cyclophosphamide, mercaptopurine, and methotrexate (9). Asparaginase, 5000 U/m2/day, was administered on days 15–28 of therapy. She gave birth to a normal female infant after 40 weeks' gestation. The newborn had 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 (9).

A number of reports have evaluated the reproductive histories of men and women who were exposed to asparaginase and multiple other antineoplastic agents before conception (10,11,12,13,14 and 15). Of the 13 men described, 9 fathered 15 children (10,11,12 and 13), including 1 who fathered a child while receiving therapy (10). Two congenital anomalies were observed; one infant had a birthmark (13), and one newborn had multiple anomalies (11). In the latter case, the man, who had been off therapy for at least 3.5 years, also fathered a normal child (11). No relationship between these outcomes and the fathers' exposure to either asparaginase or the other chemotherapeutic agents can be inferred from the two cases.

In 57 women treated with asparaginase and other agents 2 months to 15 years before conception, a total of 83 pregnancies occurred, resulting in 5 spontaneous abortions, 5 elective abortions, 2 stillbirths, and 71 liveborn infants (10,12,13,14 and 15). Among the liveborn infants, 4 were delivered prematurely, 1 was growth retarded, and 7 had congenital defects, 4 minor and 3 major. The minor abnormalities were an epidermal nevus (13), dark hair patch (14), ear tag (14), and congenital hip dysplasia (15). Infants with major defects were the offspring of women who had been treated 15–24 months before conception with asparaginase, chlorambucil, mercaptopurine, methotrexate, procarbazine, thioguanine, vinblastine, vincristine, and prednisone (14). The defects were hydrocephalus, tracheomalacia, and pelvic asymmetry. The authors concluded that the latter defect was most likely a deformation, resulting from the mother's scoliosis or from uterine scarring caused by radiation, rather than a mutagenic effect of drug therapy (14). Causes for the other two defects were not proposed, but they were not thought to be the result of germ cell damage.

In summary, on the basis of limited reports in humans, the use of asparaginase, in combination with other antineoplastics, does not seem to pose a major risk to the fetus when used in the 2nd and 3rd trimesters, or when exposure occurs before conception in either women or men. No reports describing the use of only asparaginase in pregnancy have been located. Because of the teratogenicity observed in animals and the lack of human data after 1st trimester exposure, asparaginase should be used cautiously during this period, if at all.

Breast Feeding Summary

No data are available.

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References

  1. Product information. Elspar. Merck Sharpe & Dohme, 1993.
  2. Adamson RH, Fabro S, Hahn MA, Creech CE, Whang-Peng J. Evaluation of the embryotoxic activity of L-asparaginase. Arch Int Pharmacodyn Ther 1970;186:310–20. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:58–9.
  3. Ohguro Y, Imamura S, Koyama K, Hara T, Miyagawa A, Hatano M, Kanda K. Toxicological studies on L-asparaginase. Yamaguchi Igaku 1969;18:271–92. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:58–9.
  4. Okun DB, Groncy PK, Sieger L, Tanaka KR. Acute leukemia in pregnancy: transient neonatal myelosuppression after combination chemotherapy in the mother. Med Pediatr Oncol 1979;7:315–9.
  5. Khurshid M, Saleem M. Acute leukaemia in pregnancy. Lancet 1978;2:534–5.
  6. Karp GI, Von Oeyen P, Valone F, Khetarpal VK, Israel M, Mayer RJ, Frigoletto FD, Garnick MB. Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep 1983;67:773–7.
  7. Awidi AS, Tarawneh MS, Shubair KS, Issa AA, Dajani YF. Acute leukemia in pregnancy: report of five cases treated with a combination which included a low dose of Adriamycin. Eur J Cancer Clin Oncol 1983;19:881–4.
  8. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:435–40.
  9. Schleuning M, Clemm C. Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. N Engl J Med 1987;317:1666–7.
  10. Blatt J, Mulvihill JJ, Ziegler JL, Young RC, Poplack DG. Pregnancy outcome following cancer chemotherapy. Am J Med 1980;69:828–32.
  11. Evenson DP, Arlin Z, Welt S, Claps ML, Melamed MR. Male reproductive capacity may recover following drug treatment with the L-10 protocol for acute lymphocytic leukemia. Cancer 1984;53:30–6.
  12. Green DM, Hall B, Zevon MA. Pregnancy outcome after treatment for acute lymphoblastic leukemia during childhood or adolescence. Cancer 1989;64:2335–9.
  13. Green DM, Zevon MA, Lowrie G, Seigelstein N, Hall B. Congenital anomalies in children of patients who received chemotherapy for cancer in childhood and adolescence. N Engl J Med 1991;325:141–6.
  14. Mulvihill JJ, McKeen EA, Rosner F, Zarrabi MH. Pregnancy outcome in cancer patients: experience in a large cooperative group. Cancer 1987;60:1143–50.
  15. Pajor A, Zimonyi I, Koos R, Lehoczky D, Ambrus C. Pregnancies and offspring in survivors of acute lymphoid leukemia and lymphoma. Eur J Obstet Gynecol Reprod Biol 1991;40:1–5.

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