THIOGUANINE

Fetal Risk Summary

Thioguanine is a purine analogue that interferes with nucleic acid biosynthesis. The drug is potentially mutagenic, carcinogenic, and teratogenic (1).

Reproduction studies in rats at a dose 5 times the human dose caused resorptions and malformed or stunted offspring (1). Malformations observed included generalized edema, cranial defects, general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and limb defects (1).

The use of thioguanine in pregnancy has been reported in 26 patients, four during the 1st trimester (2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18 and 19). An elective abortion, resulting in a normal fetus, was performed at 21 weeks' gestation in one pregnancy after 4 weeks of chemotherapy (17). Use in the 1st and 2nd trimesters has been associated with chromosomal abnormalities in one infant (relationship to antineoplastic therapy unknown), trisomy group C autosomes with mosaicism (2), and congenital malformations in another, two medial digits of both feet missing and distal phalanges of both thumbs missing with hypoplastic remnant of right thumb (3). In a third case, a fetus, who was not exposed to antineoplastic agents until the 23rd week, long after development of the affected extremity, was delivered at 42 weeks' gestation with polydactyly (six toes on the right foot), a condition that had occurred previously in this family (18).

Two cases of intrauterine fetal death have occurred after antineoplastic therapy with thioguanine and other agents (15,18). In one case, a mother, whose antileukemic chemotherapy was initiated at 15 weeks' gestation, developed severe pregnancy-induced hypertension in the 29th week of pregnancy (15). Before this time, fetal well-being had been continuously documented. One week after onset of the preeclampsia, intrauterine fetal death was confirmed by ultrasound. In the second case, a woman, with a history of two previous 1st-trimester spontaneous abortions, was treated for acute myeloblastic leukemia and ulcerative colitis beginning at 15 weeks' gestation (18). Intrauterine fetal death occurred at 20 weeks. No congenital abnormalities were found at autopsy in either of the fetuses.

Data from one review indicated that 40% of the infants exposed to anticancer drugs were of low birth weight (20). This finding was not related to the timing of exposure. Long-term studies of growth and mental development in offspring exposed to thioguanine during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (21). However, individual children have been followed for periods ranging from a few months to 5 years and, in each case, normal development was documented (14,15,17,18).

Although abnormal chromosomal changes were observed in one aborted fetus, the clinical significance of this observation and the relationship to antineoplastic therapy are unknown. In two other newborns, karyotyping of cultured cells did not show anomalies (2,5). Paternal use of thioguanine with other antineoplastic agents before conception has been suggested as a cause of congenital defects observed in three infants: anencephalic stillborn (22), tetralogy of Fallot with syndactyly of the first and second toes (22), and multiple anomalies (23). However, confirmation of these data has not been forthcoming, and any such relationship is probably tenuous at best. Exposed men have also fathered normal children (23,24).

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).

Breast Feeding Summary

No reports describing the use of thioguanine during lactation have been located. It is not known if the drug is excreted into breast milk. Because of the potential for severe toxicity, including tumors, in a nursing infant, women receiving thioguanine should not breast feed.

References

1. Product information. Thioguanine. Glaxo Wellcome, 2000.
2. Maurer LH, Forcier RJ, McIntyre OR, Benirschke K. Fetal group C trisomy after cytosine arabinoside and thioguanine. Ann Intern Med 1971;75:809–10.
3. Schafer AI. Teratogenic effects of antileukemic chemotherapy. Arch Intern Med 1981;141:514–5.
4. Au-Yong R, Collins P, Young JA. Acute myeloblastic leukaemia during pregnancy. Br Med J 1972;4:493–4.
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8. Moreno H, Castleberry RP, McCann WP. Cytosine arabinoside and 6-thioguanine in the treatment of childhood acute myeloblastic leukemia. Cancer 1977;40:998–1004.
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13. Plows CW. Acute myelomonocytic leukemia in pregnancy: report of a case. Am J Obstet Gynecol 1982;143:41–3.
14. Lowenthal RM, Marsden KA, Newman NM, Baikie MJ, Campbell SN. Normal infant after treatment of acute myeloid leukaemia in pregnancy with daunorubicin. Aust NZ J Med 1978;8:431–2.
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17. Doney KC, Kraemer KG, Shepard TH. Combination chemotherapy for acute myelocytic leukemia during pregnancy: three case reports. Cancer Treat Rep 1979;63:369–71.
18. Volkenandt M, Buchner T, Hiddemann W, Van De Loo J. Acute leukaemia during pregnancy. Lancet 1987;2:1521–2.
19. Feliu J, Juarez S, Ordonez A, Garcia-Paredes ML, Gonzalez-Baron M, Montero JM. Acute leukemia and pregnancy. Cancer 1988;61:580–4.
20. Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 1968;75:307–12.
21. Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:1155.
22. Russell JA, Powles RL, Oliver RTD. Conception and congenital abnormalities after chemotherapy of acute myelogenous leukaemia in two men. Br Med J 1976;1:1508.
23. 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.
24. Matthews JH, Wood JK. Male fertility during chemotherapy for acute leukemia. N Engl J Med 1980;303:1235.