Letter: thiopurines during pregnancy and intrauterine exposure to metabolites



Sirs, We read with great interest the review of literature and proposed management-algorithm concerning the often challenging questions on fertility and pregnancy in inflammatory bowel disease (IBD) patients.[1] The risks and benefits of continuation of azathioprine (AZA) or mercaptopurine (MP) therapy should indeed be balanced in each pregnant IBD patient. In general, maintenance thiopurine therapy throughout pregnancy is considered safe and there is no necessity for cessation of administration.

The authors state that the foetus is protected from potential teratogenic effects of thiopurines, as it lacks the enzyme inosinate phosphorylase, which is required to convert AZA or MP to its active metabolites. We feel that this statement needs some refinement. The unborn child is only marginally exposed to the parent compounds AZA or MP themselves,[2] as these drugs are rapidly absorbed and metabolised intracellularly by enterocytes and hepatocytes into several metabolites. Therefore, it is to be expected that there will be no, or limited, metabolism of AZA or MP in the foetus itself.

Recently, we demonstrated that the human foetus is exposed to the pharmacologically active metabolite 6-tioguanine nucleotides generated from maternal AZA use.[3] Surprisingly, in the vast majority of newborns, the thiopurine metabolite 6-methylmercaptopurine could not be detected in red blood cells directly drawn from the umbilical cord after delivery.[4] Based on these observations, it appears that the placenta plays a critical role in the transfer of maternal thiopurine metabolites.

To our knowledge, the enzyme inosinate phosphorylase does not play a role in the metabolism of thiopurines. Therefore, the statement that the foetus is protected from teratogenic effects as it lacks the enzyme inosinate phosphorylase cannot hold true.

Perhaps the manuscript should have stated that maintenance thiopurine therapy during pregnancy is considered safe, despite intrauterine exposure to thiopurine metabolite 6-tioguanine nucleotides.


Declaration of personal and funding interests: None.