Thiopurine administered to pregnant women contributes to fetal lethality
Involvement of fetus' NUDT15 genotype
Shiga University of Medical Science and others clarify using mice

Thiopurine is a drug that is widely used for inflammatory bowel diseases such as ulcerous colitis and Crohn's disease, rheumatic diseases such as systemic lupus erythematosus, and acute lymphocytic leukemia in children, youths, and adults. It is also used for patients who are pregnant. A research group consisting of Professor Akira Andoh and lecturer Masahiro Kawahara of the Department of Internal Medicine, School of Medicine, Shiga University of Medical Science, and their colleagues carried out joint research with Assistant Professor Yoichi Kakuta of the Tohoku University School of Medicine. Using a mouse model, the research clarified that thiopurine administered to mothers could cause fetal lethality depending on the fetus' NUDT15 genotype. Andoh stated that, "Administering thiopurine during pregnancy itself has significant advantages. Based on the outcomes of this research, I want to make it safer to administer this by carrying out clinical research." This research was published in Cellular and Molecular Gastroenterology and Hepatology.

It is known that leukopenia is a side effect of thiopurine, and we have recently learned that genetic polymorphisms in the NUDT15 gene are involved in this side effect. NUDT15 is a thiopurine-metabolizing enzyme. Past research has reported that the presence of a polymorphism (NUDT15/R139C) that changes the 139th amino acid means that there is decreased enzyme activity, and hematopoietic stem cell damage and leukopenia caused by thiopurine occurs. Furthermore, we understand that one in five Japanese people have this polymorphism.

On the other hand, inflammatory bowel diseases and rheumatic diseases mainly manifest in young or middle-aged people, and thiopurine is administered to around 30% of patients with inflammatory bowel diseases. In the past, administering this to pregnant women was contraindicated, but a notice from the Ministry of Health, Labour and Welfare in 2018 removed this from contraindication.

The relationship between thiopurine toxicity and NUDT15 polymorphisms has become clear, but we did not understand fetal safety when administering thiopurine during pregnancy from the perspective of NUDT15 polymorphisms.

This research used knock-in mice harboring an equivalent of NUDT15/R139C, which were developed by the research group and are unique in the world, to study this safety. The results showed that when the mother mouse was heterozygous Nudt15/R138C and the fetal mouse was homozygous Nudt15/R138C, or the mother mouse was a wild-type and the fetal mouse was heterozygous Nudt15/R138C, it was implied that due to the administration of a therapeutic dose of thiopurine to the mother mouse, there was a possibility that the fetal mouse would die. On the other hand, if the mother mouse and fetal mouse had the same NUDT15 genotype, the fetal mouse was born without any issues even if a therapeutic dose of thiopurine was administered to the mother mouse, and so it is thought that the likelihood of there being any influence is low.

The outcomes of research on mice cannot be applied to humans in their current state, but the outcomes of this research could become vital knowledge in further increasing fetal safety with the administration of thiopurine during pregnancy by assuming the fetus' NUDT15 genotype. The father's genotype is involved in determining the fetus' NUDT15 genotype. For example, if both parents possess a normal genotype, the fetus will too. In this case, thiopurine can be administered safely. However, if both parents have a heterozygous genotype, there is a 25% probability that the fetus will have a homozygous genotype, and in this case it might be better to choose medications other than thiopurine.

Currently, clinical research that is confirming whether the same phenomena occur in humans is taking place within the research group. Professor Kakuta, who is responsible for the clinical research, says, "We are investigating the genotypes of both parents and their children in 20 facilities across the country. We hope to provide a certain amount of data within the year. However, the problem we have is that once this is understood, even if people want to check the father's genotype via treatment covered by health insurance, the father isn't ill so they have to bear the costs themselves. Pregnancy is an important issue, so we need to create a new framework that will cover this area."