title: Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease.
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.
  
  
  METHODS
  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.
authors: Department of Gastroenterology and Hepatology, VU University Medical Center, , Amsterdam, The Netherlands.
authors: Bindia
authors: B
authors: Jharap
authors: Nanne K H
authors: NK
authors: de Boer
authors: Pieter
authors: P
authors: Stokkers
authors: Daniel W
authors: DW
authors: Hommes
authors: Bas
authors: B
authors: Oldenburg
authors: Gerard
authors: G
authors: Dijkstra
authors: C Janneke
authors: CJ
authors: van der Woude
authors: Dirk J
authors: DJ
authors: de Jong
authors: Chris J J
authors: CJ
authors: Mulder
authors: Ruurd M
authors: RM
authors: van Elburg
authors: Adriaan A
authors: AA
authors: van Bodegraven
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000751:Anemia, Neonatal / Q000139:chemically induced; D001379:Azathioprine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D005260:Female; D005312:Fetal Blood / Q000737:chemistry*; D005500:Follow-Up Studies; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007231:Infant, Newborn; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000188:drug therapy*; D011256:Pregnancy Outcome; D011446:Prospective Studies; D013873:Thionucleotides / Q000097:blood*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D001379:Azathioprine
keywords: Drug Metabolism; Ibd Clinical; Inflammatory Bowel Disease; Pharmacokinetics