The Role of Xanthine Oxidase in Pregnancy Complications: A Systematic Review

Abstract

Xanthine oxidoreductase (XOR) is an enzyme involved in the oxidation of hypoxanthine and xanthine to uric acid. XOR has two isoforms: xanthine dehydrogenase and xanthine oxidase (XO). XO plays a major role in oxidative stress, causing the formation of reactive oxygen species. In the present study, we aimed to summarize the evidence on the association between XO and pregnancy complications. The PRISMA checklist guided the reporting of the data. We conducted systematic searches in the PubMed and Web of Science databases to identify all human studies investigating XO in pregnancy diseases up to June 2024. A total of 195 references have been identified and 14 studies were included. Most studies focused on women with PE and GD. Overall, all the included studies found a statistically significant increase in maternal, placental, and/or fetal XO levels, activity, or tissue expression in women with pregnancy complications, compared to those with uncomplicated pregnancies. Although promising, the quality and dimension of the included studies do not allow for a definitive answer to the question of whether XO may play a crucial role in pregnancy complications. Future studies are warranted to confirm if XO could represent a prognostic and therapeutic marker in pregnancy complications and their impact on long-term maternal and offspring cardiovascular health.

Keywords: gestational diabetes; oxidative stress; placenta; preeclampsia; pregnancy; pregnancy complications; xanthine dehydrogenase; xanthine oxidase (XO); xanthine oxidoreductase.

Figure 1

Flow diagram illustrating the article selection process of this review. XO: xanthine oxidase.

Figure 2

Catabolism of purines up to the formation of uric acid by the two isoforms of the enzyme XOR: xanthine dehydrogenase and xanthine oxidase. In case of ischemia, hypoxia, or inflammation, the conversion of the xanthine dehydrogenase into the xanthine oxidase isoform causes the excessive formation of superoxide radicals that increase OS. Furthermore, the superoxide radical (O^2−•) reacts with the nitric oxide produced by the endothelium, determining the formation of peroxynitrite (ONNO-), which also contributes to OS. Then, OS causes damage at the subcellular, cellular, and tissue levels, inducing pregnancy complications and long-term cardiovascular dysfunction in both the mother and the offspring. List of abbreviations: OS, oxidative stress; XOR, xanthine oxidoreductase; ROS, reactive oxygen species; RNS, reactive nitrogen species. Image created with BioRender.com.