Azathioprine

Drug Levels and Effects:




Summary of Use during Lactation:


Authors of some older papers recommend against breastfeeding during azathioprine use, citing concern over possible immunosuppression, growth retardation and carcinogenesis.[1][2][3] However, these concerns appear to be based on theoretical grounds and more recent expert opinion is that azathioprine is a low risk to the nursing infant and breastfeeding can continue during therapy for inflammatory bowel disease. Studies women with inflammatory bowel disease, systemic lupus erythematosus or transplantation taking doses of azathioprine up to 200 mg daily for immunosuppression have found either low or unmeasurable levels of the active metabolites in milk and infant serum. No adverse infant effects have been reported. Some evidence indicates a lack of adverse effects on the health and development of infants exposed to azathioprine during breastfeeding up to 3 years of age, but long-term follow-up for effects such as carcinogenesis have not been performed. Mothers with decreased activity of the enzyme that detoxifies azathioprine metabolites may transmit higher levels of drug to their infants in breastmilk. Breastfeeding during azathioprine use is usually acceptable.[4][5] It might be desirable to monitor exclusively breastfed infants with a complete blood count with differential, and liver function tests if azathioprine is used during lactation, although some authors feel that monitoring is unnecessary.[6] Avoiding breastfeeding for 4 to 6 hours after a dose should markedly decrease the dose received by the infant in breastmilk.


Drug Levels:


Azathioprineis rapidly metabolized to the active metabolite mercaptopurine which is further metabolized to active metabolites including 6-methylmercaptopurine, thioguanine, 6-thioguanine nucleoside (6-TGN) and 6-methylmercaptopurine nucleosides (6-MMPN). The enzyme thiopurine methyltransferase (TPMT) is responsible for metabolism of 6-TGN. Deficiencies in this enzyme can lead to excessive toxicity.

Maternal Levels.

Mercaptopurine milk levels were measured in 2 patients receiving azathioprine following renal transplantation. In one mother who was 2 days postpartum, peak colostrum levels occurred 2 and 8 hours after a 75 mg oral dose and were 3.4 and 4.5 mcg/L, respectively. In the other mother who was 7 days postpartum, a peak mercaptopurine milk level of 18 mcg/L occurred 2 hours after a 25 mg oral dose.[7] The milk levels of these 2 mothers correspond to 0.05% and 0.6% of the maternal weight-adjusted dosages, respectively. Infant serum levels were not measured.

Four women receiving an immunomodulator to treat inflammatory bowel disease had metabolite levels measured in milk during the first 6 weeks postpartum. The abstract does not mention the specific drug and dose being taken, but the azathioprine metabolites 6-methylmercaptopurine (6-MMP) and 6-thioguanine nucleoside (6-TGN) were measured. Although therapeutic levels were found in maternal serum, 6-MMP (<650 mcg/L) and 6-TGN (<123 mcg/L) were undetectable in milk (time of collection not stated).[8]

A case series described 2 mothers who took azathioprine 100 mg daily while breastfeeding. Each mother collected milk samples over a 24-hour period, 5 and 6 samples, respectively. Mercaptopurine was undetectable (<5 mcg/L) in all of the samples. The authors estimated that the maximum dose of mercaptopurine that a completely breastfed infant would receive would be 0.09% of the maternal weight-adjusted dosage or 0.07% of the dose given to infants following cardiac transplantation.[9]

Ten women who were taking azathioprine 75 to 150 mg daily at the time of delivery for systemic lupus erythematosus (n = 7), renal transplant (n = 2) or Crohn's disease (n = 1) donated milk samples on days 3 to 4, 7 to 10 and 28 postpartum. Milk was collected before the single daily dose and at each breastfeed for 12 to 18 hours for a total of 31 samples. Only one woman taking azathioprine 100 mg daily had mercaptopurine detected in her milk. On day 28 postpartum, milk mercaptopurine concentrations were 1.2 mcg/L at 3 hours and 7.6 mcg/L at 6 hours after the dose.[10]

Eight lactating women who were 1.5 to 7 months postpartum were taking azathioprine in dosages ranging from 75 to 200 mg daily for inflammatory bowel disease. All of the women had normal TPMT phenotypes. Peak mercaptopurine milk concentrations occurred within the first 4 hours after ingesting of the dose of azathioprine and ranged from 2 to 50 mcg/L. By 5 hours after the dose, the milk concentrations of mercaptopurine had dropped markedly in all patients. The authors estimated that the "worst case" infant intake of mercaptopurine would 0.0075 mg/kg daily which is less than 1% of the maternal weight-adjusted dosage.[11]

Infant Levels.

Four infants were breastfed (3 exclusively, 1 rarely received formula) during maternal use of azathioprine orally in dosages of 1.2 to 2.1 mg/kg daily. All of the mothers and infants had the normal TPMT *1/*1 genotype and all of the mothers had normal enzyme activity. At 3 to 3.5 months of age, all of the infants had undetectable blood levels of 6-TGN and 6-MMPN.[12] The authors later updated this report to include 2 previously unreported mother-infant pairs. These infant also had undetectable blood levels of 6-TGN and 6-MMPN.

Seven infants were breastfed during maternal intake of azathioprine in single oral doses of 75 to 150 mg daily. None had detectable mercaptopurine or thioguanine in their blood obtained between days 1 and 28 postpartum.[10]

Three infants whose mothers were taking azathioprine for inflammatory bowel disease (n = 2) or systemic lupus erythematosus (n = 1) were breastfed during maternal use of azathioprine .Azathioprinedoses were 100 mg (plus prednisolone), 150 mg (plus infliximab) and 175 mg daily. In 1 infant, thioguanine was low, but detectable in blood at 3 days of age and 6-MMPN was undetectable; at 3 weeks of age, neither metabolite was detectable. In another infant, neither metabolite was detectable at 3 weeks of age. Neither assay limits nor specific maternal doses were stated in the published abstract.[13]

A woman began taking azathioprine 100 mg (1.4 mg/kg) daily for Crohn's disease while breastfeeding (extent not stated) her 3-month-old infant. On two occasions, after 8 days and after 3 months of maternal therapy, neither 6-MMPN nor 6-thioguaninenucleotides were detectable in the blood of the infant. The assay limit was not stated.[14]


Effects in Breastfed Infants:


Three infants were breastfed during long-term maternal azathioprine 75 to 100 mg daily and methylprednisolone use following renal transplantation. All three infants had no abnormal blood counts, no increased frequency of infections and above average growth rates.[7][15] In one mother, the IgA levels in breastmilk were measured and found to be normal.[7]

One infant was breastfed for 6 days after birth in a mother who was taking azathioprine 75 mg daily in addition to cyclosporine. Nursing was interrupted for 4 days, then partial breastfeeding was reestablished. The infant showed no signs of renal or neurologic toxicity or hirsutism during long-term follow up.[16]

Twelve infants were breastfed for up to 12 months during maternal use of azathioprine 50 to 100 mg daily (6 with concomitant cyclosporine) following kidney or kidney-pancreas transplantation. Kidney function was normal in all infants when measured after breastfeeding had ceased. The growth and psychomotor development of all infants was normal.[17]

One infant was exclusively breastfed for 10.5 months during maternal use of azathioprine 100 mg daily, cyclosporine and prednisone. Partial breastfeeding continued for 2 years. The infant thrived with normal growth at 12 months. The mother also breastfed a second child while on the same drug regimen.[18]

Four infants were breastfed (3 exclusively, 1 rarely received formula) during maternal use of azathioprine orally in dosages of 1.2 to 2.1 mg/kg daily. At 3 to 3.5 months of age, all infants were healthy and were within the 50th to 95th percentiles on growth charts.[12] The authors reported 2 additional infants who received azathioprine via breastmilk with no adverse reactions detected.[19]

In another case series, 4 infants were breastfed (partially in 1 case, not stated in the others) during maternal use of azathioprine . Two mothers were taking 100 mg daily, 1 took 75 mg daily and 1 took 50 mg daily and partially breastfed her preterm infant. All were taking several other medications concurrently. One infant was followed up at 1 month, 2 at 2 months and 1 at 1 year of age. No adverse event were reported in any of the infants and were growing and developing normally.[9]

Six infants whose mothers were breastfeeding and taking azathioprine were monitored monthly for the duration of their breastfeeding with blood counts and for evidence of infection. One infant developed a low blood count and breastfeeding was discontinued; the other 5 infants continued to breastfeed apparently without harm. The dosages of azathioprine , concurrent medications and the extent of breastfeeding were not reported in the brief published abstract.[20]

Ten infants, 3 preterm, were breastfed during maternal intake of azathioprine in single oral doses of 75 to 150 mg daily. No signs of immunosuppression were seen in the infants during the first 28 days postpartum. In 7 of the infants, white cell and neutrophil counts were performed between days 1 and 28 postpartum. One infant had a borderline low neutrophil count but a normal white cell count.[10]

Three infants whose mothers were taking azathioprine for inflammatory bowel disease (n = 2) or systemic lupus erythematosus (n = 1) were breastfed during maternal use of azathioprine .Azathioprinedoses were 100 mg (plus prednisolone), 150 mg (plus infliximab) and 175 mg daily. The first infant was breastfed for 12 months and the other 2 were breastfed for up to 4 months; the extent of breastfeeding was not stated. The infants' blood cell counts were normal at birth or 3 weeks of age and follow-ups at 24, 22 and 4 months of age, respectively, found normal growth and no recurrent infections.[13]

A survey of women with autoimmune hepatitis found that 8 infants of 4 women had been breastfed (extent not stated) during maternal azathioprine use in unspecified dosages. No adverse effects were reported by the mothers.[21]

An infant was breastfed (extent not stated) from birth to the age of 3 months during maternal therapy with azathioprine 100 mg (1.4 mg/kg) daily. During the 6 months of follow-up, the infant thrived and had no infections.[14]

A nonrandomized, prospective study followed the infants of 23 women with inflammatory bowel disease who were treated in one clinic. Mothers who received azathioprine (median dose 150 mg daily; range 100 to 250 mg daily) for treatment breastfed for a median of 6 months (range 1 to 18 months) and those who did not take azathioprine breastfed for a median of 8 months (range 3.5 to 23 months). Follow-up occurred at a median of 3.3 years in the azathioprine -exposed infants (n = 15) and 4.7 years in the unexposed infants (n = 15). No differences were found in mental or physical development between the two groups of infants. More infants who were unexposed to azathioprine had more than 2 colds annually and conjunctivitis episodes than in the unexposed group. No difference was seen in the numbers of other infections between the groups.[22]


Possible Effects on Lactation:


Relevant published information was not found as of the revision date.


Alternate Drugs to Consider:


(Immunosuppression) Cyclosporine,Tacrolimus,(Inflammatory Bowel Disease) Budesonide,Infliximab,Mesalamine,Prednisone,(Systemic Lupus Erythematosus) Hydroxychloroquine,Prednisone


References:


1. Ramsey-Goldman R, Schilling E. Optimum use of disease-modifying and immunosuppressive antirheumatic agents during pregnancy and lactation. Clin Immunother. 1996;5:40-58.
2. Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy and lactation. Arch Intern Med. 2000;160:610-9. PMID:10724046
3. Rayburn WF. Connective tissue disorders and pregnancy. Recommendations for prescribing. J Reprod Med. 1998;43:341-9. PMID:9583066
4. Ha C, Dassopoulos T. Thiopurine therapy in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4 :575-88. PMID:20932143
5. van der Woude CJ, Kolacek S, Dotan I et al. European evidenced-based consensus on reproduction in inflammatory bowel disease. J Crohn's Colitis. 2010;4:493-510. PMID:21122553
6. Christensen LA, Dahlerup JF, Nielsen MJ et alK.Azathioprinetreatment during lactation: authors' reply. Aliment Pharmacol Ther. 2009 ;30:91. PMID:19566905
7. Coulam CB, Moyer TP, Jiang NS et al. Breast-feeding after renal transplantation. Transplant Proc. 1982;13:605-9. PMID:6817481
8. Kane SV, Present DH. Metabolites to immunomodulators are not detected in breast milk. Am J Gastroenterol. 2004;99 (10 Suppl. S):S246-7. Abstract 761.
9. Moretti ME, Verjee Z, Ito S, Koren G. Breast-feeding during maternal use of azathioprine . Ann Pharmacother. 2006;40:2269-72. PMID:17132809
10. Sau A, Clarke S, Bass J et al.Azathioprineand breastfeeding-is it safe? BJOG. 2007;114:498-501. PMID:17261122
11. Christensen LA, Dahlerup JF, Nielsen MJ et al.Azathioprinetreatment during lactation. Aliment Pharmacol Ther. 2008;28:1209-13. PMID:18761704
12. Gardiner SJ, Gearry RB, Roberts RL et al. Exposure to thiopurine drugs through breast milk is low based on metabolite concentrations in mother-infant pairs. Br J Clin Pharmacol. 2006;62:453-6. PMID:16995866
13. Bernard N, Garayt C, Chol F et al. Prospective clinical and biological follow-up of three breastfed babies from azathioprine -treated mothers. Fundam Clin Pharmacol. 2007;21 (Suppl. 1) :62-3. Abstract.
14. Zelinkova Z, De Boer IP, Van Dijke MJ et al.Azathioprinetreatment during lactation. Aliment Pharmacol Ther. 2009;30:90-1; author reply 91. PMID:19566905
15. Grekas DM, Vasiliou SS, Lazarides AN. Immunosuppresive therapy and breast-feeding after renal transplantation. Nephron. 1984;37:68. Letter. PMID:6371564
16. Madill JE, Levy G, Greig P. Pregnancy and breast-feeding while receiving cyclosporine A. In: Williams BAH S-GD, eds. Trends in organ transplantation. New York: Springer Publishing Company, 1996:109-21.
17. Nyberg G, Haljamae U, Frisenette-Fich C et al. Breast-feeding during treatment with cyclosporine. Transplantation. 1998;65:253-5. PMID:9458024
18. Munoz-Flores-Thiagarajan KD, Easterling T, Davis C et al. Breast-feeding by a cyclosporine-treated mother. Obstet Gynecol. 2001;97(5 pt 2):816-8. PMID:11336764
19. Gardiner SJ, Gearry RB, Roberts RL et al. Comment: breast-feeding during maternal use of azathioprine . Ann Pharmacother. 2007. PMID:17389671
20. Khare MM, Lott J, Currie A, Howarth E. Is it safe to continue azathioprine in breast feeding mothers? J Obstet Gynaecol. 2003;23 (Suppl 1):S48. Abstract 53.
21. Werner M, Bjornsson E, Prytz H et al. Autoimmune hepatitis among fertile women: strategies during pregnancy and breastfeeding? Scand J Gastroenterol. 2007;42:986-91. PMID:17613929
22. Angelberger S, Reinisch W, Messerschmidt A et al. Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding. J Crohns Colitis. 2011;5:95-100. PMID:21453877



Substance Identification:




Substance Name:

Azathioprine

CAS Registry Number:

446-86-6

Drug Class:


  • Immunosuppressants


  • Administrative Information:




    LactMed Record Number:


    20


    Last Revision Date:


    Disclaimer:Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.