Investigation of 8-isoprostane and 12-hydroxyeicosatetraenoic acid in peripheral blood for predicting preterm birth in women with COVID-19

   Introduction. According to current research, the novel coronavirus infection (COVID-19) has an adverse impact on pregnancy and its outcomes. However, data on the causes of preterm birth in women who had COVID-19 during the current pregnancy remain insufficient.

   Aim. To determine serum concentrations of 8-isoprostane and 12-hydroxyeicosatetraenoic acid (12-HETE) as predictors of preterm birth in pregnant women with COVID-19.

   Materials and methods. This prospective comparative study involved three groups of pregnant women. The main group (n = 42) included patients diagnosed with moderately severe COVID-19 (community-acquired pneumonia) and threatened preterm labor. The comparison group (n = 51) comprised patients with moderately severe COVID-19 (community-acquired pneumonia) but with-out threatened preterm labor. The control group (n = 35) consisted of patients without threatened preterm labor and no history of COVID-19, either previously or at the time of examination. Diagnosis was confirmed by detecting SARS-CoV-2 RNA in oropharyngeal and nasopharyngeal swabs by polymerase chain reaction (PCR), as well as current clinical and radiological criteria of viral lung involvement using specialized imaging methods (as indicated). Serum 8-isoprostane was measured by enzyme-linked immunosorbent assay (ELISA) with Cayman Chemical (USA) reagent kits, and 12-HETE was determined using Enzo Life Sciences (USA) reagent kits.

   Results. In the main group, the median serum 8-isoprostane concentration was 381.85 (375.43–388.30) pg/mL and 12-HETE was 8.73 (8.48–8.81) ng/mL – both higher than in the comparison group (200.00 (185.33–210.99) pg/mL and 2.99 (2.31–3.41) ng/mL) and the control group (178.20 (173.35–184.00) pg/mL, p< 0.001; 2.22 (1.96–2.35) ng/mL, p< 0.001, respectively). Based on discriminant analysis, a mathematical model was developed to calculate a prognostic risk index for preterm birth (PRIPB): PRIPB = -7.607 + 0.022 × 8-isoprostane + 0.309 × 12-HETE. The threshold PRIPB value was 3.244. A PRIPB ≥3.244 indicates a high risk of preterm birth, meaning higher PRIPB values are directly proportional to the risk of preterm birth. A PRIPB < 3.244 suggests no risk of preterm birth. Among 38 women in the main group, the predicted outcome matched the actual result in 90 % of cases.

   Conclusion. For the first time, an elevated level of 12-HETE was identified alongside an increase in 8-isoprostane in women with COVID-19 during the third trimester of pregnancy. In patients with moderately severe COVID-19, serum concentrations of 8-isoprostane and 12-HETE appear to be markers of preterm birth risk.

1. Ellington S., Olson C.K. Safety of mRNA COVID-19 vaccines during pregnancy. Lancet Infect. Dis. 2022; 22(11):1514–1515. doi: 10.1016/S1473-3099(22)00443-1

2. Taylor M.M., Kobeissi L., Kim C., Amin A., Thorson A.E., Bellare N.B., Brizuela V., Bonet M., Kara E., Thwin S.S., Kuganantham H., Ali M., Oladapo O.T., Broutet N. Inclusion of pregnant women in COVID-19 treatment trials : a review and global call to action. Lancet Glob. Health 202; 9(3):e366–e371. doi: 10.1016/S2214-109X(20)30484-8

3. Yupatov Ye.Yu., Khayertdinov A.T., Osipov S.A., Selivanova Ye.E., Mukhametova R.R. [Clinical observation of delivery in a COVID-19-convalescent woman with preeclampsia developing fetal distress during preterm labor]. Akusherstvo, Ginekologiya i Reproduktsiya = Obstetrics, Gynecology and Reproduction 2023; 17(4):526–532 (in Russian). doi: 10.17749/2313-7347/ob.gyn.rep.2023.396

4. Jafari M., Pormohammad A., Sheikh Neshin S.A., Ghorbani S., Bose D., Alimohammadi S., Basirjafari S., Mohammadi M., Rasmussen-Ivey C., Razizadeh M.H., Nouri-Vaskeh M., Zarei M. Clinical characteristics and outcomes of pregnant women with COVID-19 and comparison with control patients : a systematic review and meta-analysis. Rev. Med. Virol. 2021; 31(5):1–16. doi: 10.1002/rmv.2208

5. Dutta E.H., Behnia F., Boldogh I., Saade G.R., Taylor B.D., Kacerovský M., Menon R. Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol. Human Reprod. 2016; 22(2):143–157. doi: 10.1093/molehr/gav074

6. Woods J.R. Reactive oxygen species and preterm premature rupture of membranes – a review. Placenta 2001; 22(Suppl.A):S38–S44. doi: 10.1053/plac.2001.0638

7. Ray A., Bhati T., Arora R., Parvez S., Rastogi S. Association of functional superoxide gene polymorphism with chlamydia trachomatis-associated recurrent spontaneous abortion. Mol. Biol. Rep. 2023; 50(6):4907–4915. doi: 10.1007/s11033-023-08405-5

8. Montuschi P., Barnes P.J., Roberts L.J. Isoprostanes: markers and mediators of oxidative stress. FASEB J. 2004; 18(15):1791–1800. doi: 10.1096/fj.04-2330rev

9. Ferguson K.K., Chen Y.H., VanderWeele T.J., McElrath T.F., Meeker J.D., Mukherjee B. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ. Health Perspect. 2017; 125(3):488–494. doi: 10.1289/EHP282

10. Rosen E.M., van't Erve T.J., Boss J., Sathyanarayana S., Barrett E.S., Nguyen R.H.N., Bush N.R., Milne G.L., McElrath T.F., Swan S.H., Ferguson K.K. Urinary oxidative stress biomarkers and accelerated time to spontaneous delivery. Free Radic. Biol. Med. 2019; 130:419–425. doi: 10.1016/j.freeradbiomed.2018.11.011

11. 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; 28(12):2429–2437. doi: 10.1097/HJH.0b013e32833e86aa

12. Graille M., Wild P., Sauvain J.J., Hemmendinger M., Guseva Canu I., Hopf N.B. Urinary 8-OHdG as a biomarker for oxidative stress : a systematic literature review and meta-analysis. Int. J. Mol. Sci. 2020; 21(11):3743 doi: 10.3390/ijms21113743

13. Debevec T., Burtscher J., Millet G.P. Preterm birth: Potential risk factor for greater COVID-19 severity? Respir. Physiol. Neurobiol. 2020; 280:103484. doi: 10.1016/j.resp.2020.103484

14. Challis J.R., Lockwood C.J., Myatt L., Norman J.E., Strauss J.F., Petraglia F. Inflammation and pregnancy. Reprod. Sci. 2009; 16(2):206–215. doi: 10.1177/1933719108329095

15. Polettini J., Behnia F., Taylor B.D., Saade G.R., Taylor R.N., Menon R. Telomere fragment induced amnion cell senescence: a contributor to parturition? PLoS One 2015; 10(9):e0137188. doi: 10.1371/journal.pone.0137188

16. Joo E.H., Kim Y.R., Kim N., Jung J.E., Han S.H., Cho H.Y. Effect of endogenic and exogenic oxidative stress triggers on adverse pregnancy outcomes: preeclampsia, fetal growth restriction, gestational diabetes mellitus and preterm birth. Int. J. Mol. Sci. 2021; 22(18):10122. doi: 10.3390/ijms221810122

17. Ferguson K.K., McElrath T.F., Chen Y.H., Loch-Caruso R., Mukherjee B., Meeker J.D. Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth. Am. J. Obstet. Gynecol. 2015; 212(2):208.e1–208.е8. doi: 10.1016/j.ajog.2014.08.007. Erratum in: Am. J. Obstet. Gynecol. 2019; 221(5):504. doi: 10.1016/j.ajog.2019.03.026

18. Aung M.T., Yu Y., Ferguson K.K., Cantonwine D.E., Zeng L., McElrath T.F., Pennathur S., Mukherjee B., Meeker J.D. Prediction and associations of preterm birth and its subtypes with eicosanoid enzymatic pathways and inflammatory markers. Sci. Rep. 2019; 1:17049. doi: 10.1038/s41598-019-53448-z