Safety of Azathioprine in Pregnancy in Inflammatory Bowel Disease E. M. ALSTEAD, J. K. RITCHIE, J. E. LENNARD-JONES, M.J.G. FARTHING, and M. L. CLARK Departmentsof Gastroenterology,St. Bartholomew’sand St. Mark’sHospitals,London, England

Although azathioprine has been reported to be safe during pregnancy in renal transplant recipients and patients with systemic lupus erythematosus, opinions vary whether it should be continued in pregnancy in inflammatory bowel disease. A retrospective analysis of the outcome of 16 pregnancies in 14 women receiving azathioprine for inflammatory bowel disease was performed. There was one infective complication of pregnancy (hepatitis B virus infection), but there were no congenital abnormalities or subsequent health problems in the children. This preliminary study suggests that azathioprine is safe in pregnancy in inflammatory bowel disease patients and that termination of pregnancy is not mandatory for those who conceive while taking the drug.

lthough azathioprine in clinically used doses has no effect on human interstitial cell function or gametogenesis in either sex (1,2), its possible teratogenie effects are of concern. There has never been any definite demonstration of teratogenicity in humans, although at high doses of the drug, there is some evidence of this in animals (3,4). Women receiving azathioprine have generally been advised against pregnancy, but there have been many normal pregnancies while on the drug (5-15). Although azathioprine has been reported to be safe during pregnancy in renal transplant recipients and patients with systemic lupus erythematosus, opinions vary whether it should be continued during pregnancy in inflammatory bowel disease (IBD). Because of a paucity of data, most clinicians recommend that the azathioprine or 6-mercaptopurine should be discontinued or even that the pregnancy should be terminated (11,12,14). This study aimed to conduct a retrospective analysis of the outcome of 16 pregnancies in 14 women receiving azathioprine for IBD.

A

Materials and Methods Retrospective review of case records from St. Bartholomew’s and St. Mark’s hospitals showed that there were 16 pregnancies in 14 women on azathioprine during the period 1972-1969. Details were obtained from medical records, and, wherever possible, patients were interviewed using a structured questionnaire. Details about disease and drug treatment before and during pregnancy as well as details of the pregnancy, delivery, and health of the children were recorded. Results There were 16 pregnancies in 14 women with median age 28 years [range, 25-34 years). At the time of pregnancy, the mean duration of illness was 4.4 years (range, l-8 years). Fourteen women had Crohn’s disease and two had extensive ulcerative colitis [Table 11.The duration of treatment with azathioprine before pregnancy was 0.5-5 years. Twelve women were receiving prednisolone in addition to azathioprine, six sulfasalazine, and one mesalazine [Table 2). Eight patients had surgery before pregnancy, usually right hemicolectomy, and one woman with colonic Crohn’s disease had had a total colectomy and ileostomy. Seven women continued taking azathioprine throughout pregnancy, but five (in seven pregnancies) stopped the drug before 16 weeks’ gestation. Two women stopped azathioprine on medical advice, and three of their own volition. Two other patients conceived on azathioprine, but the pregnancies were terminated, one following medical advice regarding the drug and the other for psychosocial reasons. The only medical complication encountered during

Abbreviation used in this paper: IBD, Mammatory bowel disease. 0 1990 by the American Gastroenterological Association 001~5085/90/$3.00

444 ALSTEAD ET AL.

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Table 1.

Patient Details

Patient

Age at delivery (yrl

1 2 3 4 5 6 7 a 9 IO 11 12 13 14

27 29 27 30 28 30 28 32 28 25 25 25 30 27 34 33

Diagnosis

Disease extent

Previous surgery

5

+

0

-

C, AR

2 5

_

J, 1

2 4

+

J, 1,C

4 4 4 7

+ + + -

4 4

+ _

CD CD CD CD

Q

CD CD CD CD UC CD CD CD CD UC

Disease duration [yr)

1, C 1, C, A, R C C

IC IC I AR

7

+

1

_

7

-

C

1

_

CD, Crohn’s disease; UC, ulcerative colitis; D, duodenal: J, Jejunal; I, ileal; C, colonic; AR, anorectal.

pregnancy was hepatitis B virus infection in one woman. One patient had a long previous history of infertility with three spontaneous abortions and a neonatal death before the onset of ulcerative colitis; however, she had an uncomplicated pregnancy with normal delivery of healthy twins at 35 weeks. There was one premature birth at 32 weeks following an elective cesarean section for placenta previa. Five of the babies were delivered by cesarean section and the others were normal, uncomplicated deliveries (Table 31. The neonates at term were all above 2.5 kg in weight. There were no congenital abnormalities

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present, and no perinatal problems were experienced. One child was cyanosed shortly after birth but rapidly recovered with no adverse sequelae. The 15 children, 6 girls and 9 boys (current age 6 months to 16 years) are all alive and well. There was no increase in neonatal or childhood infections; also, the children’s growth and development have been normal. No childhood malignancies have occurred in these children.

Discussion Azathioprine has a number of possible adverse effects on the fetus, including teratogenicity, chromosomal effects, immunological and hematological depression, low birth weight, and abortion. Azathioprine has been shown to be teratogenic in rabbit (3) and in some mice studies (4) but not in rats (16). The reasons for species and strain differences are unclear and may be caused by differing patterns of drug metabolism, variations in tissue sensitivity to azathioprine and its metabolites, or dose-related effects. Azathioprine crosses the placenta in humans (17,181; the lack of clear demonstration of teratogenicity in such circumstances suggests that the human fetus is not very sensitive to the drug. Cytogenetic analysis of renal transplant recipients on prednisolone and azathioprine showed an increase in sister-chromatid exchanges both before and after transplantation, thus making the increase unlikely to be directly related to the drugs (18). Chromatid and iso-locus breaks were frequent but did not persist after withdrawing azathioprine. Chromatid and chromosomal exchanges are less common and not clearly

Table 2. Drug Treatment Azathioprine Duration before pregnancy [Yrl

Duration during pregnancy (wk)

Dose (mg/kgl

Term

2 2 2

5 6

5 1 2 3.5 2 3 1 4

7 8 9 10 11 12 13

2 0.5 2 4 6 0.5 1.5

Term

14

0.5

Term

Patient 1 2 3 4

“Elective termination of pregnancy.

7 6 6 15 13

(1

15

Term Term Term

Term

0 14

Prednisolone

+ + +

2 1 2 2 2 2

+

Other drugs

Sulfasalazine

Sulfasalazine Sulfasalazine Mesalazine & codeine phosphate Sulfasalazine Sulfasalazine -

Sulfasalazine

AZATHIOPRINE

August 1990

Table 3. Obstetric Patient 1

2 3 4

5 6 7 8 9 10 11 12 13 14

IN PREGNANCY

IN IBD

445

Details Postnatal complications

Gestation Wl

Delivery

None HBV infection in first pregnancy

Term Term Term Term Term Term

Normal Normal Cesarean Cesarean Normal Normal

None None None None Children HBsAg negative and vaccinated

None None None None None Placenta previa

Term Term Term Term Term 32

Normal Cesarean Normal Cesarean Normal Cesarean

None None Cyanosed at birth None None None

None Twins

Term 35

Normal Normal

None None Normal twins

Antenatal complications None None

HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus. “Elective termination of pregnancy.

to azathioprine (191. There is no present evidence of permanent genomal or gonadal damagethey become manifest later in life in these children (26). There may also be effects of immunosuppressive agents later in pregnancy. Lymphopenia, hypogammaglobulinemia, and thymic hypoplasia have all been reported in children of mothers who took azathioprine in addition to prednisolone in pregnancy (21,22). These changes are generally regarded reversible, although there has been no detailed follow-up of these children’s immunological status. A more recent report described a syndrome characterized by defective sig(23). Maternal nal transduction in T lymphocytes treatment with azathioprine during pregnancy has also been associated with fetal bone marrow suppression, leukopenia, and thrombocytopenia (22,24). Fetal and neonatal infections with cytomegalovirus have also been reported (21). Patients with inactive IBD can expect no more complications of pregnancy than women in the general population (25). However, there is a suggestion that those with active disease, especially Crohn’s disease, may have a higher incidence of infertility, spontaneous abortion, and premature births or stillbirths. Azathioprine is used in the maintenance of remission of IBD in some patients in routine clinical practice and has proven to be beneficial (26). It has been said that azathioprine should not be used in pregnancy in IBD (12) and that azathioprine exposure is a sufficient reason for termination (14). There are numerous reports of female renal transplant recipients who have conceived while taking azathioprine and who have produced normal children (4-$13);

related

however, there are only limited anecdotal reports of the outcome of pregnancy in IBD patients (11,27). In a recent report of five patients taking 6-mercaptopurine for IBD who conceived, three had terminations on medical advice and two stopped the drug in early pregnancy. No fetal abnormalities occurred (11). This preliminary study suggests that azathioprine used in the doses given to the patients in this series is safe in pregnancy in IBD as it is safe in renal transplant recipients. Because complications are described during the first few months of treatment in a proportion of nonpregnant patients, it seems unwise to start azathioprine during pregnancy; however in patients who become pregnant while taking azathioprine, it should not necessarily be stopped. These observations may be particularly relevant for women with extensive disease in whom azathioprine treatment is established and is important for maintaining remission. The observations also indicate that termination of pregnancy is not mandatory for women who conceive while taking the drug. Thus, azathioprine appears not to be harmful to the fetus in early or late pregnancy in humans in the doses used in IBD. Our current practice in a case of a woman conceiving while taking azathioprine is to continue therapy throughout pregnancy if we consider that the drug plays an important part in the control of the disease. With patients who feel strongly that they do not wish to take the drug, we do not insist that they continue: however, at the same time we emphasize to them the importance of maintaining remission during pregnancy. With patients taking azathioprine who wish to conceive, we suggest full discussion about the drug. If the patient wishes to stop the drug, it seems the

446

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best course because any fetal malformation that might occur spontaneously would be attributed to the treatment. If the patient fears relapse on stopping the drug, she can be reassured that the drug, in light of the limited available information, appears to be compatible with a normal pregnancy and healthy baby.

References 1. Golby M. Fertility after renal transplantation.

Transplantation 1970;10:201-207. 2. Penn I, Makowski E, Droegemueller W. Halgrimson CG, Starzl TE. Parenthood in renal transplant recipients. JAMA 1971;216: 1755-1761. 3. Tuchmann-Duplessis H, Mercier-Parot L. Production in rabbits of malformations of the limbs by azathioprine and 6-mercaptopurine. C R Sot Biol1966;166:501-506. 4. Rosenkrantz JG, Githens JH, Cox SM, Kellum DL. Azathioprine (Imuran) in pregnancy. Am J Obstet Gynecol1967;97:387. 5. Erkman J, Blyth JG. Azathioprine therapy complicated by pregnancy. Obstet Gynecol1972:40:708-710. 6. Farber M. Kennison RD, Jackson HT. Successful pregnancy after renal transplantation. Obstet Gynecol1976;48 (Suppl1):2545. 7. Registration Committee of the European Dialysis and Transplant Association. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynaecol 1980;87:839-845. 8. Davidson AM, Guillon PJ. Successful pregnancies reported to the registry up to the end of 1982. Proc Eur Dialysis Transplant Assoc London 1984;21:54-55. 9. Meehan RT, Dorsey JK. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy. J Rheumatol1987;14:252-259. 10.Gillibrand PN. Systemic lupus erythematosus in pregnancy treated with azathioprine (abstr). Proc R Sot Med 1966;59:834. 11.Present DH. Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-mercaptopurine in the management of inflammatory bowel disease: short and long-term toxicity. Ann Intern Med 1989111: 641-649. 12.Vender RJ, Spiro HM. Inflammatory bowel disease and pregnancy. J Clin Gastroenterol1982;4:231-249. 13.Gaudier FL, Santiago-Delpin E, Rivera J, Gonzales Z. Pregnancy after renal transplantation. Surg Gynecol Obstet 1988;167: 533-543. 14.Sorokin JJ, Levine SM. Pregnancy and inflammatory bowel

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disease: a review of the literature. Obstet Gynecol 1983;62:247251. 15.Hou S. Pregnancy in organ transplant recipients. Med Clin North Am 1989;734:667-683. 16.Thiersch JP. Effect of 6(1-methyl-4-nitroso-5-imidazolyl)mercaptopurine and 2-amino-6-(l-methyl-4-nitroso-5-imidazolyl)-mercaptopurine on the rat litter in utero. J Reprod Fertil 1962;4:297-302. 17.Saarikoski S, Seppala M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolities from the mother to the fetus. Am J Obstet Gyneco11973:115:1100-1106. 18.Kucerova M, Kocandrle V, Matousek V, Polikova Z, Reneltova I. Chromosomal aberrations and sister-chromatid exchanges [SCEs) in patients undergoing long-term Imuran therapy. Mutat Res 1982;94:501-509. 19.Leb DE, Weiskopf B, Kanovitz BS. Chromosome aberrations in the child of a kidney transplant recipient. Arch Intern Med 1971;128:441-448. 20.Effects on gametogenesis and fertility. In: Imuran. Information for investigators. Beckenham: Wellcome Research Laboratories, 197757-58. 21.Cote CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr 1974;85:324-428. 22.Dewitte DB, Buick MK, Cyran SE, Maisells MJ. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. Pediatrics 1984,105:625-628. 23.Chatila T, Wong R, Young M, Miller R, Terhorst C, Geha RS. An immunodeficiency characterised by defective signal transduction in T lymphocytes. N Engl J Med 1989329696-702. 24.Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol1985;92:233-239. 25.Miller JP. Inflammatory bowel disease in pregnancy: a review. J R Sot Med 1986;79:221-225. 26.Willoughby JMT, Kumar PJ, Beckett J, Dawson AM. Controlled trial of azathioprine in Crohn’s disease. Lancet 1971;2:944-946. 27.Korelitz BI. Pregnancy, fertility, and inflammatory bowel disease. Am J Gastroenterol1985;80:365-370.

Received October 30.1989. Accepted February 12,199O. Address requests for reprints to: E. M. Alstead, M.D., Department of Gastroenterology, St. Bartholomew’s Hospital, London EClA 7BE, England. M.J.G.F. is a Wellcome Trust Senior Lecturer and gratefully acknowledges the financial support of the Wellcome Trust.