P1033 The decrease of 6-TGN concentrations during pregnancy is not associated with an increase in fecal calprotectin in female patients with IBD on thiopurine-treatment
Authors: Bouwknegt D G , Mian P , Groen F , van den Berg-Zuiddam D , van der Meulen A E , Crouwel F , de Boer K H N , Deben D , Wong D R , Derijks L J J , Dijkstra G , Bourgonje A R , van der Woude C J , Visschedijk M C ,   Dutch Initiative on Crohn and Colitis (ICC)
Published: January 2025

Abstract

Background
Thiopurines, such as azathioprine (AZA), mercaptopurine (MP) and thioguanine (TG), are commonly used to maintain disease remission in inflammatory bowel disease (IBD). AZA and MP are metabolized to form the active 6-thioguanine nucleotides (6-TGN) and the 6-methylmercaptopurine ribonucleotides (6-MMPR), associated with intolerable adverse drug reactions. Previous studies report a shift in thiopurine metabolism during pregnancy, characterized by a decrease in 6-TGN and an increase in 6-MMPR levels 1,2. The influence of these changes on clinical outcomes remains unclear. This study aims to explore the association of changes in 6-TGN and 6-MMPR levels during pregnancy with disease activity and toxicity markers in women with IBD.

Methods
A retrospective cohort study was conducted recruiting patients with IBD from six Dutch medical centers. Adult women who were pregnant between 2017 and 2022, using thiopurines for IBD, and with at least one thiopurine metabolite measurement during pregnancy were included. Linear mixed effects models assessed 6-TGN and 6-MMPR levels during pregnancy (categorized to half trimesters) and within 6 months postpartum, compared to preconceptional levels, adjusting for dosage and repeated measurements. The influence of percentual changes in 6-TGN and 6-MMPR on disease activity (calprotectin &gt;250μg/g), hepatotoxicity (alanine aminotransferase (ALT) &gt;2xULN) and myelotoxicity (leukocytes &lt;4.0x109/L) were analyzed, adjusting for dosage and trimester.

Results
A total of 87 women with 100 pregnancies were included, of whom 64.4% were diagnosed with Crohn’s disease and 32.2% with ulcerative colitis. An adverse pregnancy outcome occurred in 13 pregnancies (13%), with rates comparable to the healthy Dutch population. Subtherapeutic levels of 6-TGN were measured in 32 pregnancies (32%). There were no instances of leukopenia; transient hepatotoxicity occurred thrice (3%). There was active disease in 30 pregnancies, corresponding to 37 metabolite measurements. Analysis showed a significant reduction in 6-TGN levels in the second trimester (Figure 1), with non-significant increases in 6-MMPR. Though disease activity coincided with subtherapeutic 6-TGN-levels 21 times (56.8%), the reduction in 6-TGN was not associated with changes in calprotectin (Estimated marginal mean difference (EMM) =5.435, p=0.104), ALT (EMM=-0.025, p=0.858) or leukocytes (EMM=0.068, p=0.536, Table 1).

Conclusion
Our study results indicate that despite that 6-TGN levels decrease and 6-MMP may increase during pregnancy, these fluctuations do not seem to associate with markers of disease activity, hepatotoxicity and myelotoxicity. Larger, prospective studies are needed to re-evaluate the postulated need for thiopurine monitoring in the third trimester.

References
1.Flanagan E, Wright EK, Hardikar W, et al. Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates. Aliment Pharmacol Ther. 2021;53:810-820.
2.Jharap B, De Boer NKH, Stokkers P, et al. Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease. Gut. 2014;63(3):451-457. doi:10.1136/gutjnl-2012-303615