Summary of Use during Lactation

In the treatment of conditions such as ulcerative colitis and Crohn's disease, most professional guidelines and other experts consider breastfeeding to be acceptable during mercaptopurine therapy.[1-7] No active metabolites of mercaptopurine were found in the blood of breastfed infants whose mothers were taking azathioprine and no adverse effects attributable to mercaptopurine or azathioprine have been noted. See the Azathioprine record for details. Mothers with decreased activity of the enzyme that detoxifies mercaptopurine metabolites may transmit higher levels of drug to their infants in breastmilk. It might be desirable to monitor exclusively breastfed infants with a complete blood count with differential, and liver function tests if mercaptopurine is used during lactation, although some authors feel that monitoring is unnecessary.[8] Avoiding breastfeeding for 4 hours after a dose should markedly decrease the dose received by the infant in breastmilk.[9]

Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy, although antimetabolites such as mercaptopurine appear to pose the least risk to breastfed infants.[10] After high-dose chemotherapy, it might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence. Although no data are available to determine an appropriate period to withhold breastfeeding, the drug's terminal half-life suggests that withholding breastfeeding for 1 to 2 days may be sufficient. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk.[11]

Drug Levels

Mercaptopurine is the active metabolite of azathioprine. It is further metabolized to active metabolites including 6-methylmercaptopurine, thioguanine, 6-thioguanine nucleosides (6-TGNs) and 6-methylmercaptopurine nucleosides (6-MMPN). The enzyme thiopurine methyltransferase (TPMT) is responsible for metabolism of 6-TGNs. 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, peak milk 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, a peak milk level of 18 mcg/L occurred 2 hours after a 25 mg oral dose. Serum levels were not measured.[12]

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 nucleosides (6-TGNs) were measured. Although therapeutic levels were found in maternal serum, 6-MMP (<650 mcg/L) and 6-TGNs were undetectable (<123 mcg/L) in milk (time of collection not stated).[13]

A woman was taking 50 mg daily of mercaptopurine for Crohn’s disease during pregnancy and postpartum. A milk sample taken on the first day postpartum 4 hours after ingestion of the dose had no detectable levels (<25 pmol/L) of mercaptopurine or its metabolites, 6-thioguanine and 6-methylmercaptopurine.[14]

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 mothers and infants had the wild type TPMT *1/*1 genotype and all mothers had normal enzyme activity. At 3 to 3.5 months of age, all of the infants' had undetectable blood levels of 6-TGNs and 6-MMPN.[15]

Effects in Breastfed Infants

In The Netherlands, 30 infants of mothers taking either azathioprine (n = 28) or mercaptopurine (n = 2) for inflammatory bowel disease during pregnancy and postpartum were followed at 1 to 6 years of age using a 43-item quality of life questionnaire. Of this cohort, 9 infants were breastfed for a mean of 7 months (range 3 to 13 months) No statistically significant differences were found between breastfed and formula-fed infants in any of the 12 domains of the survey.[16]

A prospective cohort study followed pregnant women with inflammatory bowel disease throughout pregnancy and for 12 months postpartum. Women were assigned to one of the following groups: unexposed (no thiopurines or anti-TNF agents); group A (azathioprine or mercaptopurine); group B (infliximab, adalimumab or certolizumab pegol) and group AB (both a thiopurine and an anti-TNF agent). Of 1052 women enrolled in the study, 72% breastfed their infants, although the extent and duration were not stated in the abstract. A total of 264 women were exposed to a thiopurine and 59 were exposed to a thiopurine plus an anti-TNF agent. The use of a thiopurine alone was not associated with any complication in the infants and their growth and development were normal throughout the 12 months. Infants exposed to both a thiopurine and an anti-TNF agent had a 50% increase in the number of infections between 9 and 12 months of age. The relationship of this increase with breastfeeding could not be determined from the available data.[17]

A national survey of gastroenterologists in Australia identified 21 infants who were breastfed by mothers taking a combination of allopurinol and a thiopurine (e.g. azathioprine, mercaptopurine) to treat inflammatory bowel disease. All had taken the combination during pregnancy also. Two postpartum infant deaths occurred, both at 3 months of age. One was a twin (premature birth-related) and the other from SIDS. The authors did not believe the deaths were medication related.[18] No information was provided on the extent of breastfeeding, drug dosages or the outcomes of the other infants.

Effects on Lactation and Breastmilk

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

Alternate Drugs to Consider

(Immunosuppression) Cyclosporine, Tacrolimus; (Inflammatory Bowel Disease) Adalimumab, Azathioprine, Budesonide, Certolizumab Pegol, Infliximab, Mesalamine, Prednisone; (Systemic Lupus Erythematosus) Hydroxychloroquine, Prednisone

References

1.

Ha C, Dassopoulos T. Thiopurine therapy in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2010;4:575–88. [PubMed: 20932143]

2.

Van Assche G, Dignass A, Reinisch W, et al. The second European evidence-based consensus on the diagnosis and management of Crohn's disease: Special situations. J Crohns Colitis. 2010;4:63–101. [PubMed: 21122490]

3.

Nielsen OH, Maxwell C, Hendel J. IBD medications during pregnancy and lactation. Nat Rev Gastroenterol Hepatol. 2014;11:116–27. [PubMed: 23897285]

4.

Nguyen GC, Seow CH, Maxwell C, et al. The Toronto Consensus Statements for the Management of IBD in Pregnancy. Gastroenterology. 2016;150:734–57.e1. [PubMed: 26688268]

5.

van der Woude CJ, Ardizzone S, Bengtson MB, et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis. 2015;9:107–24. [PubMed: 25602023]

6.

Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: A report from the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology. 2019;156:1508–24. [PubMed: 30658060]

7.

Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2020;72:529–56. [PubMed: 32090480]

8.

Christensen LA, Dahlerup JF, Nielsen MJ, et al. Azathioprine treatment during lactation. Aliment Pharmacol Ther. 2008;28:1209–13. [PubMed: 18761704]

9.

Bar-Gil Shitrit A, Grisaru-Granovsky S, Ben Ya'acov A, et al. Management of inflammatory bowel disease during pregnancy. Dig Dis Sci. 2016;61:2194–204. [PubMed: 27068171]

10.

Pistilli B, Bellettini G, Giovannetti E, et al. Chemotherapy, targeted agents, antiemetics and growth-factors in human milk: How should we counsel cancer patients about breastfeeding? Cancer Treat Rev. 2013;39:207–11. [PubMed: 23199900]

11.

Urbaniak C, McMillan A, Angelini M, et al. Effect of chemotherapy on the microbiota and metabolome of human milk, a case report. Microbiome. 2014;2:24. [PMC free article: PMC4109383] [PubMed: 25061513]

12.

Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982;14:605–9. [PubMed: 6817481]

13.

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. doi: 10.1111/j.1572-0241.2004.001_1.x. [CrossRef]

14.

Ter Horst P, Smolders EJ, den Besten D. Mercaptopurine and metabolites in breast milk. Breastfeed Med. 2020;15:277–9. [PubMed: 31414890]

15.

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. [PMC free article: PMC1885151] [PubMed: 16995866]

16.

de Meij TG, Jharap B, Kneepkens CM, et al. Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38:38–43. [PubMed: 23675854]

17.

Mahadevan U, Martin CF, Sandler RS, et al. PIANO: A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142(5) Suppl. 1:S-149–Abstract 865. [CrossRef]

18.

Beswick L, Shukla D, Friedman AB, et al. National audit: Assessing the use and safety of allopurinol thiopurine co-therapy in pregnant females with inflammatory bowel disease. J Gastroenterol Hepatol 2016;31 (Suppl 2):128-9. Abstract. doi: 10.1111/jgh.13521. [CrossRef]

Substance Name

Mercaptopurine

CAS Registry Number

50-44-2

Drug Class

Breast Feeding

Lactation

Antineoplastic Agents

Antimetabolites

Immunosuppressive Agents