MERCAPTOPURINE

Fetal Risk Summary

Mercaptopurine (6-MP) is an antimetabolite antineoplastic agent. References citing the use of mercaptopurine in 79 human pregnancies have been located, including 34 cases in which the drug was used in the 1st trimester (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20 and 21). Excluding those pregnancies that ended in abortion or stillbirths, congenital abnormalities were observed in only one infant (10). Defects noted in the infant were cleft palate, microphthalmia, hypoplasia of the ovaries and thyroid gland, corneal opacity, cytomegaly, and intrauterine growth retardation. The anomalies were attributed to busulfan.

Neonatal toxicity as a result of combination chemotherapy has been observed in three infants: pancytopenia (6), microangiopathic hemolytic anemia (9), and transient severe bone marrow hypoplasia (12). In the latter case, administration of mercaptopurine was stopped 3.5 weeks before delivery because of severe maternal myelosuppression. No chemotherapy was given during this period, and her peripheral blood counts were normal during the final 2 weeks of her pregnancy (12).

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 (14). Mercaptopurine was administered throughout the 3rd trimester. 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 since 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 (14).

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 exposure. In addition, except in a few cases, long-term studies of growth and mental development in infants exposed to mercaptopurine during the 2nd trimester, the period of neuroblast multiplication, have not been conducted (22). However, growth and development were normal in 13 infants (one set of twins) examined for 6 months to 10 years (12,15,16,18,19,20 and 21).

Severe oligospermia has been described in a 22-year-old male receiving sequential chemotherapy of cyclophosphamide, methotrexate, and mercaptopurine for leukemia (23). After treatment was stopped, the sperm count returned to normal and the patient fathered a healthy female child. Others have also observed reversible testicular dysfunction (24).

Ovarian function in females exposed to mercaptopurine does not seem to be affected adversely (25,26,27,28 and 29). An investigator noted in 1980 that long-term analysis of human reproduction following mercaptopurine therapy had not been reported (30). However, a brief 1979 correspondence described the reproductive performance of 314 women after treatment of gestational trophoblastic tumors, 159 of whom had conceived with a total of 218 pregnancies (28). Excluding the 17 women still pregnant at the time of the report, 38 (79%) of 48 women exposed to mercaptopurine as part of their therapy delivered live, term infants. A more detailed report of these and additional patients was published in 1984 (31). This latter study, and another published in 1988 (32), both involving women treated for gestational trophoblastic neoplasms, are discussed below.

In 436 long-term survivors treated with chemotherapy between 1958 and 1978, 95 (22%) received mercaptopurine as part of their treatment regimens (31). Of the 95 women, 33 (35%) had at least one live birth (numbers given in parentheses refer to mean/maximum mercaptopurine dose in grams) (5.9/30.0), 3 (3%) conceived but had no live births (5.3/14.0), 3 (3%) failed to conceive (1.3/2.0), and 56 (59%) did not try to conceive (5.4/30.0). Additional details, including congenital anomalies observed, are described in the monograph for methotrexate (see Methotrexate).

A 1988 report described the reproductive results of 265 women who had been treated from 1959 to 1980 for gestational trophoblastic disease (32). Single-agent chemotherapy was administered to 91 women, including 26 cases in which mercaptopurine was the only agent used, whereas sequential (single-agent) and combination therapy was administered to 67 and 107 women, respectively. Of the total group, 241 were exposed to pregnancy and 205 (85%) of these women conceived, with a total of 355 pregnancies. The time interval between recovery and pregnancy was 1 year or less (8.5%), 1–2 years (32.1%), 2–4 years (32.4%), 4–6 years (15.5%), 6–8 years (7.3%), 8–10 years (1.4%), and more than 10 years (2.8%). A total of 303 (4 sets of twins) liveborn infants resulted from the 355 pregnancies, 3 of whom had congenital malformations: anencephaly, hydrocephalus, and congenital heart disease (1 in each case). No gross developmental abnormalities were observed in the dead fetuses. Cytogenetic studies were conducted on the peripheral lymphocytes of 94 children and no significant chromosomal abnormalities were noted. Moreover, follow-up of the children, with more than 80% of the group older than 5 years of age (the oldest was 25 years), revealed normal development. The reproductive histories and pregnancy outcomes of the treated women were comparable to those of the normal population (32).

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 mercaptopurine during lactation have been located. Because of the relatively low molecular weight (about 170), transfer into milk should be expected. Because of the potential for severe toxicity in the nursing infant, women receiving this antineoplastic agent should not breast feed.

References

1. Moloney WC. Management of leukemia in pregnancy. Ann NY Acad Sci 1964;114:857–67.
2. Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases. J Obstet Gynaecol Br Commonw 1968;75:307–12.
3. Gililland J, Weinstein L. The effects of cancer chemotherapeutic agents on the developing fetus. Obstet Gynecol Surv 1983;38:6–13.
4. Wegelius R. Successful pregnancy in acute leukaemia, Lancet 1975;2:1301.
5. Nicholson HO. Leukaemia and pregnancy: a report of five cases and discussion of management. J Obstet Gynaecol Br Commonw 1968;75:517–20.
6. Pizzuto J, Aviles A, Noriega L, Niz J, Morales M, Romero F. Treatment of acute leukemia during pregnancy: presentation of nine cases. Cancer Treat Rep 1980;64:679–83.
7. Burnier AM. Discussion. In Plows CW. Acute myelomonocytic leukemia in pregnancy: report of a case. Am J Obstet Gynecol 1982;143:41–3.
8. Dara P, Slater LM, Armentrout SA. Successful pregnancy during chemotherapy for acute leukemia. Cancer 1981;47:845–6.
9. McConnell JF, Bhoola R. A neonatal complication of maternal leukemia treated with 6-mercaptopurine. Postgrad Med J 1973;49:211–3.
10. Diamond J, 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.
11. Khurshid M, Saleem M. Acute leukaemia in pregnancy. Lancet 1978;2:534–5.
12. 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.
13. Doney KC, Kraemer KG, Shepard TH. Combination chemotherapy for acute myelocytic leukemia during pregnancy: three case reports. Cancer Treat Rep 1979;63:369–71.
14. Schleuning M, Clemm C. Chromosomal aberrations in a newborn whose mother received cytotoxic treatment during pregnancy. N Engl J Med 1987;317:1666–7.
15. Turchi JJ, Villasis C. Anthracyclines in the treatment of malignancy in pregnancy. Cancer 1988;61:435–40.
16. Feliu J, Juarez S, Ordonez A, Garcia-Paredes ML, Gonzalez-Baron M, Montero JM. Acute leukemia and pregnancy. Cancer 1988;61:580–4.
17. Haerr RW, Pratt AT. Multiagent chemotherapy for sarcoma diagnosed during pregnancy. Cancer 1985;56:1028–33.
18. Frenkel EP, Meyers MC. Acute leukemia and pregnancy. Ann Intern Med 1960;53:656–71.
19. Loyd HO. Acute leukemia complicated by pregnancy. JAMA 1961;178:1140–3.
20. Lee RA, Johnson CE, Hanlon DG. Leukemia during pregnancy. Am J Obstet Gynecol 1962;84:455–8.
21. Coopland AT, Friesen WJ, Galbraith PA. Acute leukemia in pregnancy. Am J Obstet Gynecol 1969;105:1288–9.
22. Dobbing J. Pregnancy and leukaemia. Lancet 1977;1:1155.
23. Hinkes E, Plotkin D. Reversible drug-induced sterility in a patient with acute leukemia. JAMA 1973;223:1490–1.
24. Lendon M, Palmer MK, Hann IM, Shalet SM, Jones PHM. Testicular histology after combination chemotherapy in childhood for acute lymphoblastic leukaemia. Lancet 1978;2:439–41.
25. Schilsky RL, Lewis BJ, Sherins RJ, Young RC. Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 1980;93:109–14.
26. Gasser C. Long-term survival (cures) in childhood acute leukemia. Paediatrician 1980;9:344–57.
27. Bacon C, Kernahan J. Successful pregnancy in acute leukaemia. Lancet 1975;2:515.
28. Walden PAM, Bagshawe KD. Pregnancies after chemotherapy for gestational trophoblastic tumours. Lancet 1979;2:1241.
29. Sanz MH, Rafecas FJ. Successful pregnancy during chemotherapy for acute promyelocytic leukemia. N Engl J Med 1982;306:939.
30. Steckman ML. Treatment of Crohn's disease with 6-mercaptopurine: what effects on fertility? N Engl J Med 1980;303:817.
31. Rustin GJS, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 1984;288:103–6.
32. Song H, Wu P, Wang Y, Yang X, Dong S. Pregnancy outcomes after successful chemotherapy for choriocarcinoma and invasive mole: long-term follow-up. Am J Obstet Gynecol 1988;158:538–45.