Maternal thiopurine metabolism during pregnancy in inflammatory bowel disease and clearance of thiopurine metabolites and outcomes in exposed neonates

• Published in: Alimentary pharmacology & therapeutics Vol. 53; no. 7; pp. 810 - 820
• Main Authors: Flanagan, Emma, Wright, Emily K., Hardikar, Winita, Sparrow, Miles P., Connell, William R., Kamm, Michael A., De Cruz, Peter, Brown, Steven J., Thompson, Alexander, Greenway, Anthea, Westley, Ian, Barclay, Murray, Ross, Alyson L., Kiburg, Katerina V., Bell, Sally J.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2021
• Subjects: 6-Mercaptopurine; Anemia; Azathioprine; Azathioprine - therapeutic use; Babies; Biochemistry; Colitis; Female; Humans; Immunosuppressive Agents - therapeutic use; Infant; Infant, Newborn; Infants; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - drug therapy; Intestine; Liver; Mercaptopurine - therapeutic use; Metabolism; Metabolites; Neonates; Pharmacokinetics; Pregnancy; Thionucleotides; Thrombocytosis
• ISSN: 0269-2813; 1365-2036; 1365-2036
• DOI: 10.1111/apt.16294

Summary Background Azathioprine and mercaptopurine are considered safe during pregnancy. However, the pharmacokinetic effects of pregnancy on thiopurine metabolism are undefined. Aims To characterise thiopurine metabolism in pregnancy and measure infant metabolite levels and outcomes. Methods Women with IBD who were taking a thiopurine and pregnant or trying to conceive were recruited. Maternal thiopurine metabolites were measured pre‐conception, in each trimester, at delivery and post‐partum. Infant metabolite levels, full blood examination and liver function testing were performed at birth, and repeated until levels undetectable and haematological and biochemical abnormalities resolved. Results Forty patients were included with measurements on at least two occasions, and two with only mother‐baby levels at delivery. The median maternal 6‐TGN level dropped in the second trimester compared with post‐partum (179.0 vs 323.5 pmol/8 × 108 RBCs, P < 0.001) and the median 6‐MMP level increased in the second trimester compared with post‐partum (1103.0 vs 329.5 pmol/8 × 108 RBCs, P < 0.01). At delivery, the median 6‐TGN level was lower in infants (n = 20) than mothers (78.5 vs 217 pmol/8 × 108 RBCs) (P < 0.001). Metabolites were not detected at 6 weeks in any infants. Anaemia was not seen, but thrombocytosis and abnormal liver biochemistry were detected in 80% of infants from 6 weeks, which gradually improved. Conclusions 6‐TGN levels decrease and 6‐MMP levels increase in the second trimester of pregnancy. Infants are exposed to thiopurine metabolites at low levels with clearance by 6 weeks and no anaemia. The cause of infant thrombocytosis and abnormal liver biochemistry in the absence of metabolites is unclear. Shunting of maternal thiopurine metabolites in pregnancy Infants exposed to metabolites with no neonatal anemia