AZATHIOPRINE

Fetal Risk Summary

Azathioprine is used primarily in patients with organ transplants or in those with inflammatory bowel disease as an immunosuppressant. Prednisone is commonly combined with azathioprine in these patients. The drug readily crosses the placenta, and trace amounts of its active metabolite, 6-mercaptopurine, have been found in fetal blood (see also Mercaptopurine) (1).

Azathioprine is teratogenic in rabbits, producing limb reduction defects after small doses, but not in mice and rats (2). The manufacturer, however, has reproduction data on file indicating that azathioprine, in doses equivalent to the human dose (5 mg/kg/day), was teratogenic in both mice and rabbits (3). Malformations included skeletal defects and visceral anomalies.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 7 newborns had been exposed to azathioprine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (14.3%) major birth defect was observed (none expected), but information on the type of malformation is not available. No cases were observed in six defect categories, including cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias.

Most investigators have found azathioprine to be relatively safe in pregnancy (4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24 and 25). Several References have described the use of azathioprine during pregnancy in women who have received renal transplants (22,25,26,27,28 and 29), liver transplants (30,31 and 32), or a heart transplant (33). The drug has not been associated with congenital defects in these reports.

Sporadic anomalies have been reported but these are not believed to be related to the drug therapy (22,26). Defects observed include pulmonary valvular stenosis (34), preaxial polydactyly (thumb polydactyly type) (35), hypothyroidism and atrial septal defect (azathioprine therapy started in 2nd trimester) (36), hypospadias (mother also had severe diabetes mellitus) (19), plagiocephaly with neurologic damage (13), congenital heart disease (mild mitral regurgitation) (13), bilateral pes equinovarus (13), cerebral palsy (frontal hemangioma) and cerebral hemorrhage (died at 2 days of age) in twins (13), hypospadias (13), and congenital cytomegalovirus infection (13). The latter infection has also been reported in another infant whose mother was taking azathioprine (10). Chromosomal aberrations were noted in three infants after in utero exposure to the drug, but the relationship to azathioprine and the clinical significance of the findings are questionable (13,37).

Immunosuppression of the newborn was observed in one infant whose mother received 150 mg of azathioprine and 30 mg of prednisone daily throughout pregnancy (10). The suppression was characterized by lymphopenia, decreased survival of lymphocytes in culture, absence of immunoglobulin M, and reduced levels of immunoglobulin G. Recovery occurred at about 15 weeks of age. An infant exposed to 125 mg of azathioprine plus 12.5 mg of prednisone daily during pregnancy was born with pancytopenia and severe combined immune deficiency (38). The infant died at 28 days of complications brought on by irreversible bone marrow and lymphoid hypoplasia. To avoid neonatal leukopenia and thrombocytopenia, maternal doses of azathioprine were reduced during the 3rd trimester in a 1985 study (39). The investigators found a significant correlation between maternal leukocyte counts at 32 weeks' gestation and at delivery and cord blood leukocyte count. If the mother's count was at or below 1 SD for normal pregnancy, her dose of azathioprine was halved. Before this technique was used, several newborns had leukopenia and thrombocytopenia, but no low levels were measured after institution of the new procedure.

Intrauterine growth retardation may be related to the use of azathioprine in pregnancy. Based on animal experiments and analysis of human exposures, one investigator concluded that growth retardation was associated with the drug (40). More recent reports have also supported this association (41). The incidence of small-for-gestational age infants from women who have undergone renal transplants and who are maintained on azathioprine and corticosteroids is approximately 20% (20, 22), but some centers have rates as high as 40% (41). However, the effects of the underlying disease, including hypertension, vascular disease, and renal impairment, as well as the use of multiple medications other than azathioprine, cannot be excluded as major or sole contributors to the growth retardation.

Azathioprine has been reported to interfere with the effectiveness of intrauterine contraceptive devices (IUDs) (22,42). Two renal transplant patients, maintained on azathioprine and prednisone, received a copper IUD (Cu7) and both became pregnant with the IUD in place (42). At another institution, 6 of 20 renal transplant patients have become pregnant with IUD devices in place (22). Because of these failures, additional or other methods of contraception should be considered in sexually active women receiving azathioprine and prednisone.

Breast Feeding Summary

No data are available.

References

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2. Tuchmann–Duplessis H, Mercier-Parot L. Foetopathes therapeutiques: production experimentale de malformations des membres. Union Med Can 1968;97:283–8. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:63.
3. Product information. Imuran. FARO Pharmaceuticals, 2000.
4. Gillibrand PN. Systemic lupus erythematosus in pregnancy treated with azathioprine. Proc R Soc Med 1966;59:834.
5. Board JA, Lee HM, Draper DA, Hume DM. Pregnancy following kidney homotransplantation from a non–twin: report of a case with concurrent administration of azathioprine and prednisone. Obstet Gynecol 1967;29:318–23.
6. Kaufmann JJ, Dignam W, Goodwin WE, Martin DC, Goldman R, Maxwell MH. Successful, normal childbirth after kidney homotransplantation. JAMA 1967;200:338–41.
7. Anonymous. Eleventh annual report of human renal transplant registry. JAMA 1973;216:1197.
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27. Cararach V, Carmona F, Monleón FJ, Andreu J. Pregnancy after renal transplantation: 25 years experience in Spain. Br J Obstet Gynaecol 1993;100:122–5.
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29. Sturgiss SN, Davison JM. Effect of pregnancy on long-term function of renal allografts. Am J Kidney Dis 1992;19:167–72.
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32. Ville Y, Fernandez H, Samuel D, Bismuth H, Frydman R. Pregnancy in liver transplant recipients: course and outcome in 19 cases. Am J Obstet Gynecol 1993;168:896–902.
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37. Leb DE, Weisskopf B, Kanovitz BS. Chromosome aberrations in the child of a kidney transplant recipient. Arch Intern Med 1971;128:441–4.
38. DeWitte DB, Buick MK, Cyran SE, Maisels MJ. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr 1984;105:625–8.
39. Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol 1985;92:233–9.
40. Scott JR. Fetal growth retardation associated with maternal administration of immunosuppressive drugs. Am J Obstet Gynecol 1977;128:668–76.
41. Pirson Y, Van Lierde M, Ghysen J, Squifflet JP, Alexandre GPJ, van Ypersele De Strihou C. Retardation of fetal growth in patients receiving immunosuppressive therapy. N Engl J Med 1985;313: 328.
42. Zerner J, Doil KL, Drewry J, Leeber DA. Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med 1981;26:99–102.