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Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease
  1. Bindia Jharap1,
  2. Nanne K H de Boer1,
  3. Pieter Stokkers2,3,
  4. Daniel W Hommes4,5,
  5. Bas Oldenburg6,
  6. Gerard Dijkstra7,
  7. C Janneke van der Woude8,
  8. Dirk J de Jong9,
  9. Chris J J Mulder1,
  10. Ruurd M van Elburg10,
  11. Adriaan A van Bodegraven1,
  12. for the Dutch Initiative on Crohn and Colitis
  1. 1Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
  3. 3Sint Lucas Andreas Hospital, Amsterdam, The Netherlands
  4. 4Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5UCLA Health System, Los Angeles, California, USA
  6. 6Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
  7. 7Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  8. 8Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
  9. 9Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
  10. 10Department of Pediatrics, VU University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Bindia Jharap, Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, Amsterdam 1007 MB, The Netherlands; b.jharap{at}vumc.nl

Abstract

Objective Several studies have demonstrated a favourable safety profile for thiopurine use for inflammatory bowel disease (IBD) during pregnancy. We performed a study in pregnant patients with IBD who were using thiopurines, in order to determine the influence of pregnancy on thiopurine metabolism and to assess intrauterine exposure of the fetus to thiopurines.

Design Female patients with IBD receiving steady-state thiopurines and planning a pregnancy were prospectively enrolled. 6-Thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) concentrations were determined, combined with routine laboratory tests, before, during and after pregnancy. Thiopurine metabolites were measured in umbilical cord blood immediately after delivery.

Results Thirty patients who were using azathioprine (28 patients, median dose 1.93 mg/kg) or mercaptopurine (two patients, doses 1.32 and 0.94 mg/kg) were included. During pregnancy, median 6-TGN decreased over time (p=0.001). while 6-MMP increased, without causing myelotoxicity or hepatotoxicity. After delivery, both 6-TGN and 6-MMP levels returned to preconception baseline levels. Fetal 6-TGN concentrations correlated positively with maternal 6-TGN levels (p<0.0001). No 6-MMP was detected in the newborns, except one born with pancytopenia and high alkaline phosphatase activity; the mother of this infant had severe pre-eclampsia. All infants had normal Apgar scores, but 60% had anaemia at birth. No major congenital abnormalities were observed.

Conclusions Pregnancy has a major effect on maternal thiopurine metabolism. In utero the unborn child is exposed to 6-TGN, but not to 6-MMP. Sixty per cent of the infants were born with anaemia, which raises the question whether infants should be tested for possible anaemia immediately after birth.

  • Inflammatory Bowel Disease
  • Drug Metabolism
  • Ibd Clinical
  • Pharmacokinetics

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