The role of 8-isoprostane and 15-hydroxyeicosatetraenoic acid in the pathogenesis of early pregnancy loss in COVID-19

In recent years, the role of oxidative stress and oxylipins in the pathogenesis of various diseases, including those affecting the female reproductive system and pregnancy complications, has been actively discussed. However, the role of 8-isoprostane and 15-hydroxyeicosatetraenoic acid (15-HETE) in the pathogenesis of pregnancy loss during COVID-19 has not been definitively established. Aim. To analyze the levels of 8-isoprostane and 15-HETE in peripheral blood and assess their prognostic significance in early pregnancy loss during COVID-19. Materials and methods. The study involved the main group of 48 women with a confirmed diagnosis of moderate COVID-19 (community-acquired pneumonia) in the first trimester (6–9 weeks). The control group consisted of 45 pregnant women who had not had COVID-19 previously and at the time of examination. The levels of 8-isoprostane in peripheral venous blood were measured using Cayman Chemical (USA) reagent kits, and 15-HETE was measured using Enzo 15(S)-HETE ELISA kits (USA) through an enzyme-linked immunoassay (ELISA). Results. Patients with moderate COVID-19 exhibited a significant increase in 8-isoprostane levels to 379.27±9.04 pg/mL (p<0.001) and 15-HETE to 3.66±0.12 ng/mL (p<0.001), compared to the control group values of 178.3±1.40 pg/mL and 1.57±0.06 ng/mL, respectively. To analyze the selected evaluation criteria, a discriminant function with a probability of differences of at least 95% was determined by deriving a discriminant equation, which for this study was as follows: PI = -59.765 + 0.261 × 8-isoprostane + 4.798 × 15-HETE, where PI is the prognostic index with a threshold value of 3.027. A PI equal to or greater than 3.027 indicated a risk of pregnancy loss in women with moderate COVID-19, while a PI lower than this threshold predicted a normal course of the first trimester of gestation. Conclusion. These findings suggest that elevated levels of 8-isoprostane and 15-HETE in women with moderate COVID-19 are pathologically significant in the development of early pregnancy loss.

1. Belokrinitskaya T.E., Artymuk N.V., Filippov O.S., Shifman Ye.M. [Clinical course, maternal and perinatal outcomes of 2019 novel coronavirus infectious disease (COVID-19) in pregnant women in Siberia and Far East]. Akusherstvo i ginekologiya = Obstetrics and Gynecology 2021; 2:48–54 (in Russian). https://doi.org/10.18565/aig.2021.2.48-54

2. Ovchinnikova M.B. [Risk problems in pregnancy complicated by COVID-19: clinical observations]. MEDICUS 2022; 1-43:24–30 (in Russian).

3. Adamyan L.V., Vechorko V.I., Konysheva O.V., Kharchenko E.I. [Pregnancy and COVID-19: current issues (literature review)]. Problemy reproduktsii = Russian Journal of Human Reproduction 2021; 27(3):70–77 (in Russian). https://doi.org/10.17116/repro20212703170

4. Gruzinova Ye.N., Oreshnikov YE.V., Denisova T.G., Shornikov A.I., Sidorov A.E., Petrova A.L., Sidorova T.N. [Non-developing pregnancy against the background of COVID-19]. Zdravookhraneniye Chuvashii 2022; 3:20–26 (in Russian). https://doi.org/10.25589/GIDUV.2022.11.34.003

5. Lautenshleger L.V., Kushkumbayeva M.D., Turmagambetova Ye.E. [Pregnancy and perinatal outcomes in women with pneumonia, caused by coronavirus (COVID-19)]. Universitetskaya meditsina Urala 2022; 8(4-31):21–22 (in Russian).

6. Andriyevskaya I.A., Ishutina N.A., Dovzhikova I.V., Lyazgiyan K.S., Zhukovets I.V., Krivoshchekova N.A. [Hypoxia and oxidative stress in COVID-19 as factors affecting the course of the disease and the development of complications in pregnancy]. Bûlleten' fiziologii i patologii dyhaniâ = Bulletin Physiology and Pathology of Respiration 2023; 90:74–82 (in Russian). https://doi.org/10.36604/1998-5029-2023-90-74-82

7. Duhig K., Chappell L.C., Shennan A.H. Oxidative stress in pregnancy and reproduction // Obstet. Med. 2016. Vol.9, Iss.3. P.113–116. https://doi.org/10.1177/1753495X16648495

8. Shahnawaz S., Nawaz U.S., Zaugg J., Hussain G., Malik N., Dogar M.Z., Malik S.A., Albrecht C. Dysregulated autophagy leads to oxidative stress and aberrant expression of ABC transporters in women with early miscarriage // Antioxidants (Basel). 2021. Vol.10, Iss.11. Article number:1742. https://doi.org/10.3390/antiox10111742

9. Joó J.G., Sulyok E., Bódis J., Kornya L. Disrupted balance of the oxidant-antioxidant system in the pathophysiology of female reproduction: oxidative stress and adverse pregnancy outcomes // Curr. Issues Mol. Biol. 2023. Vol.45, Iss.10. P.8091–8111. https://doi.org/10.3390/cimb45100511

10. Agarwal A., Aponte-Mellado A., Premkumar B.J., Shaman A., Gupta S. The effects of oxidative stress on female reproduction: a review // Reprod. Biol. Endocrinol. 2012. Vol.10. Article number:49. https://doi.org/10.1186/1477-7827-10-49

11. Vrachnis N., Karavolos S., Iliodromiti Z., Sifakis S., Siristatidis C., Mastorakos G., Creatsas G. Review: Impact of mediators present in amniotic fluid on preterm labour // In Vivo. 2012. Vol.26, Iss.5. P.799–812.

12. Ishii T., Miyazawa M., Takanashi Y., Tanigawa M., Yasuda K., Onouchi H., Kawabe N., Mitsushita J., Hartman P.S., Ishii N. Genetically induced oxidative stress in mice causes thrombocytosis, splenomegaly and placental angiodysplasia that leads to recurrent abortion // Redox. Biol. 2014. Vol.14, Iss.2. P.679–685. https://doi.org/10.1016/j.redox.2014.05.001

13. Wu F., Tian F., Zeng W., Liu X., Fan J., Lin Y., Zhang Y. Role of peroxiredoxin2 downregulation in recurrent miscarriage through regulation of trophoblast proliferation and apoptosis // Cell Death Dis. 2017. Vol.8, Iss.6. Article number:e2908. https://doi.org/10.1038/cddis.2017.301

14. Liang F., Huo X., Wang W., Li Y., Zhang J., Feng Y., Wang Y. Association of bisphenol A or bisphenol S exposure with oxidative stress and immune disturbance among unexplained recurrent spontaneous abortion women // Chemosphere. 2020. Vol.257. Article number:127035. https://doi.org/10.1016/j.chemosphere.2020.127035

15. Pearson T., Zhang J., Arya P., Warren A.Y., Ortori C., Fakis A., Khan R.N., Barrett D.A. Measurement of vasoactive metabolites (hydroxyeicosatetraenoic and epoxyeicosatrienoic acids) in uterine tissues of normal and compromised human pregnancy // J. Hypertens. 2010. Vol.28, Iss.12. P.2429–2437. https://doi.org/10.1097/HJH.0b013e32833e86aa

16. Sosnova E.A., Bolevich S.B., Pokaleneva M.Sh. [Pathophysiological role of free radical processes in pregnancies end in miscarriage]. Arkhiv akusherstva i ginekologii imeni V.F.Snegireva = V.F.Snegirev Archives of Obstetrics and Gynecology 2016; 3(3):136–140 (in Russian). http://dx.doi.org/10.18821/2313-8726-2016-3-3-136-140

17. Hirota Y., Osuga Y., Hasegawa A., Kodama A., Tajima T., Hamasaki K., Koga K., Yoshino O., Hirata T., Harada M., Takemura Y., Yano T., Tsutsumi O., Taketani Y. Interleukin (IL)-1beta stimulates migration and survival of first-trimester villous cytotrophoblast cells through endometrial epithelial cell-derived IL-8 // Endocrinology. 2009. Vol.150, Iss.1. P.350–356. https://doi.org:10.1210/en.2008-0264

18. Kikut J., Komorniak N., Ziętek M., Palma J., Szczuko M. Inflammation with the participation of arachidonic (AA) and linoleic acid (LA) derivatives (HETEs and HODEs) is necessary in the course of a normal reproductive cycle and pregnancy // J. Reprod. Immunol. 2020. Vol.141. Article number:103177. https://doi.org/10.1016/j.jri.2020.103177

19. Eghtedari A.R., Safizadeh B., Vaezi M.A., Kalantari S., Tavakoli-Yaraki M. Functional and pathological role of 15-Lipoxygenase and its metabolites in pregnancy and pregnancy-associated complications // Prostaglandins Other Lipid Mediat. 2022. Vol.161. Article number:106648. https://doi.org/10.1016/j.prostaglandins.2022.106648

20. Toy H., Camuzcuoglu H., Camuzcuoglu A., Celik H., Aksoy N. Decreased serum prolidase activity and increased oxidative stress in early pregnancy loss // Gynecol. Obstet. Invest. 2010. Vol.69, Iss.2. P.122–127. https://doi.org/10.1159/000262608