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P536 Thiopurine metabolite levels in pregnant IBD patients and infants following intrauterine thiopurine exposure

E. Flanagan*1, A. Ross1, A. L. Hamilton1, S. J. Bell1

1St Vincent's Hospital, Gastroenterology, Melbourne, Australia

Background

Data regarding the pharmacokinetic effects of pregnancy on thiopurine metabolism and infant exposure to thiopurine metabolites is very limited. Data on 30 women suggested that maternal 6-thioguanine nucleotide (6-TGN) levels decreased in pregnancy, while infant 6-TGN correlated with maternal 6-TGN[1]. 6-methylmercaptopurine (6-MMP) was undetected in infants (lower limit of detection 100 pmol/8 × 108 RBCs).1 We aimed to measure thiopurine metabolites in each trimester and in infants at delivery.

Methods

Female patients with IBD on a thiopurine and pregnant or planning pregnancy were enrolled. Thiopurine metabolites were measured pre-conception when possible, in each trimester of pregnancy, at delivery and post-partum. Participants were offered thiopurine metabolite testing in the umbilical cord at delivery. The Wilcoxon signed-rank test was used to compare medians.

Results

22 patients were included with at least two measurements on stable dosing. Patient characteristics and metabolite levels are shown in Table 1. Median 6-TGN levels were lower during pregnancy than pre-conception and post-partum (Figure 1). Two patients required dose increases during pregnancy (levels post dose change not included). No significant difference was found between median 6-MMP levels. All patients to date (16/22) delivered babies at term with normal birth weight and no congenital anomalies. Thiopurine metabolite levels are available in five infants. In two infants, whose mothers were on low-dose thiopurine as co-therapy with anti-TNF, 6-TGNs were undetectable. One had undetectable 6-MMP, and one had 6-MMP of 27 pmol/8 × 108 RBCs. In the other three infants, both 6-MMP and 6-TGN were detected but were lower than maternal levels. One of these infants had a mild thrombocytopenia 102 × 109/l, which resolved (6-TGN 70 pmol/8 × 108 RBCs).

Table 1. Patient characteristics (mothers) (n = 22).

Figure 1. Maternal 6-TGN levels during pregnancy.

Conclusion

Thiopurine pharmacokinetics appear to be altered in pregnancy. Our preliminary results confirm 6-TGN levels may decrease in pregnancy. Infants can be exposed to both 6-TGN and 6-MMP, although at low levels. Improved knowledge of the metabolism of these drugs in pregnancy is imperative to inform dosing.

Reference

1. Jharap B, de Boer NK, Stokkers et al. Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease. Gut 2014;63:451–7.