Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Busulfan is a human teratogen when used during organogenesis.
FETAL RISK SUMMARY
Busulfan is an alkylating antineoplastic agent. Reproductive studies in pregnant rats revealed that the drug produced sterility in both male and female offspring due to the absence of germinal cells in testes and ovaries (1).
The use of busulfan has been reported in at least 49 human pregnancies, of which 31 were treated in the 1st trimester (2–10). One of these references reviewed eight earlier cases that are included in the above totals (9). Malformations in six infants were: unspecified malformations, aborted at 20 weeks; anomalous deviation of left lobe liver, bilobar spleen, pulmonary atelectasis; pyloric stenosis; cleft palate, microphthalmia, cytomegaly, hypoplasia of ovaries and thyroid gland, corneal opacity, intrauterine growth restriction (IUGR); myeloschisis, aborted at 6 weeks; IUGR, left hydronephrosis and hydroureter, absent right kidney and ureter, hepatic subcapsular calcifications (2,4–6).
Data from one review indicated that 40% of the infants exposed to anticancer drugs were of low birth weight (2). This finding was not related to the timing of the exposure. One mother with chronic granulocytic leukemia was treated with busulfan and allopurinol beginning at 20 weeks’ gestation (8). A growth-restricted infant was delivered at 39 weeks with absence of the right kidney, hydronephrosis of the left kidney, and hepatic subcapsular calcifications. The kidney and liver defects predated the onset of drug therapy, but their cause was unknown. The growth restriction, however, was thought to be caused by busulfan.
Long-term studies of growth and mental development in offspring exposed to busulfan during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (11). However, a few infants have been studied for periods of up to 10 years without evidence of adverse outcome (3,9,10). Moreover, a 1994 review concluded that although there were insufficient data to assess the fetal risk from busulfan, use after the 1st trimester would reduce the risk of birth defects (12).
Chromosomal damage has been associated with busulfan therapy, but the clinical significance of this to the fetus is unknown (13). Irregular menses and amenorrhea, with the latter at times permanent, have been reported in women receiving busulfan (14,15). Reversible ovarian failure with delivery of a normal infant has also been reported after busulfan therapy (16).
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 studies describing the use of busulfan during human lactation or measuring the amount, if any, excreted into milk have been located. Because of the potential for serious toxicity in a nursing infant, the use of the drug during lactation should be considered contraindicated.
References
1.Product information. Myleran. Glaxo Wellcome Oncology/HIV, 1997.
2.Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 1968;75:307–12.
3.Lee RA, Johnson CE, Hanlon DG. Leukemia during pregnancy. Am J Obstet Gynecol 1962;84:455–8.
4.Diamond I, Anderson MM, McCreadie SR. Transplacental transmission of busulfan (Myleran) in a mother with leukemia: production of fetal malformation and cytomegaly. Pediatrics 1960;25:85–90.
5.Abramovici A, Shaklai M, Pinkhas J. Myeloschisis in a six weeks embryo of a leukemic woman treated by busulfan. Teratology 1978;18:241–6.
6.Gililland J, Weinstein L. The effects of cancer chemotherapeutic agents on the developing fetus. Obstet Gynecol Surv 1983;38:6–13.
7.Ozumba BC, Obi GO. Successful pregnancy in a patient with chronic myeloid leukemia following therapy with cytotoxic drugs. Int J Gynecol Obstet 1992;38:49–53.
8.Boros SJ, Reynolds JW. Intrauterine growth retardation following third-trimester exposure to busulfan. Am J Obstet Gynecol 1977;129:111–2.
9.Dugdale M, Fort AT. Busulfan treatment of leukemia during pregnancy. JAMA 1967;199:131–3.
10.Zuazu J, Julia A, Sierra J, Valentin MG, Coma A, Sanz MA, Batlle J, Flores A. Pregnancy outcome in hematologic malignancies. Cancer 1991;67:703–9.
11.Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:1155.
12.Wiebe VJ, Sipila PEH. Pharmacology of antineoplastic agents in pregnancy. Crit Rev Oncol Hematol 1994;16:75–112.
13.Gebhart E, Schwanitz G, Hartwich G. Chromosomal aberrations during busulphan therapy. Dtsch Med Wochenschr 1974;99:52–6.
14.Galton DAG, Till M, Wiltshaw E. Busulfan: summary of clinical results. Ann NY Acad Sci 1958;68:967–73.
15.Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:109–14.
16.Shalev O, Rahav G, Milwidsky A. Reversible busulfan-induced ovarian failure. Eur J Obstet Gynecol Reprod Biol 1987;26:239–42.