The decline of 6-thioguanine nucleotides is not linked to impaired efficacy or safety of thiopurines in pregnant women with inflammatory bowel disease

BACKGROUND: Thiopurines are used to maintain remission in inflammatory bowel disease (IBD). These drugs are metabolized into 6-thioguanine nucleotides (6-TGN), associated with efficacy, and 6-methylmercaptopurine ribonucleotides (6-MMPR), associated with adverse drug reactions. Pregnancy has been linked to a shift in thiopurine metabolism, characterized by reduced 6-TGN and increased 6-MMPR levels. The clinical impact of these changes remains unclear. To explore the association between changes in 6-TGN and 6-MMPR levels with disease activity and toxicity markers in women with IBD during pregnancy.

METHODS: This retrospective cohort study included pregnant women with IBD who used thiopurines from six Dutch hospitals (2017-2022). Linear mixed-effects models were used to model changes of 6-TGN and 6-MMPR before, during and after pregnancy, and to identify associations with markers of disease activity (faecal calprotectin) and toxicity (alanine aminotransferase [ALT], leukocytes, platelets).

RESULTS: A total of 87 women with 100 pregnancies were included (64.4% Crohn's disease, 32.2% ulcerative colitis). A significant reduction in 6-TGN was found in the second and third trimester, but no associations with changes in faecal calprotectin were detected. There were no significant increases in 6-MMPR. Increases in 6-MMPR were associated with modest elevations in ALT, but none of the other toxicity markers. Transient thrombocytopenia and leukopenia occurred thrice, and elevated liver enzymes were observed in nine pregnancies.

CONCLUSIONS: Although 6-TGN levels decreased during pregnancy, these fluctuations were not associated with increased disease activity or toxicity. No significant increase in 6-MMPR levels was observed. Proactive monitoring may therefore not be warranted in the pregnant population.