Phenotypic composition of umbilical blood monocytes and health status of newborns from mothers with COVID-19

Background. COVID-19 during pregnancy affects the  development of  inflammatory reactions in the fetus. However, data on the impact of maternal COVID-19 on the phenotypic composition of umbilical blood monocytes in newborns are insufficiently presented.

The aim. To investigate the phenotypic composition of umbilical blood monocytes in newborns and assess their health status in cases of COVID-19 in the third trimester of pregnancy.

Materials and methods. A comparative study was conducted involving 62 full-term newborns from  mothers with  COVID-19 in  the  third trimester of  pregnancy (main group) and 30 newborns from mothers not infected with SARS-CoV-2 (control group). Expression of CD14, HLA-DR, CD206, CD32, TNFR1, TNFR2, IL17R, and TRAIL on umbilical blood monocytes was determined using flow cytometry.

Results. According to the results, the number of monocytes in the umbilical blood of newborns in the main group expressing CD14, HLA-DR, and TNFR2 was reduced by 1.54, 1.41, and 2.36 times respectively (p < 0.001) compared to the control group. The expression levels of CD206, CD32, TNFR1, IL17R, and TRAIL were increased by 3.02 (p < 0.001), 1.1 (p < 0.01), 1.3 (p < 0.001), 17.68 (p < 0.001), and 3.6 times (p < 0.001), respectively. Birth weight (p  =  0.021) and  height (p  =  0.006) at  birth were lower in newborns compared to the control group. In the evaluation using the Apgar score, no differences were found between the study groups at the first minute (p = 0.170). At  the  fifth minute, the  values were  lower than in  the  control group (p  =  0.001). Regression analysis identified a  dependence of  increased morbidity in  newborns on the number of umbilical blood monocytes expressing TNFR1 and TRAIL. Newborns in  the  main group had  an  increased risk of  developing cerebral ischemia, motor disorder syndrome, and persistent fetal circulation.

Conclusion. Maternal infection in the third trimester of pregnancy caused by SARSCoV-2 leads to the development of a fetal inflammatory response, increasing the risk of neonatal complications.

1. Chen L, Li Q, Zheng D, Jiang H, Wei Y, Zou L, et al. Clinical characteristics of pregnant women with COVID-19 in Wuhan, China. N Engl J Med. 2020; 382(25): e100. doi: 10.1056/NEJMc2009226

2. Bui MT, Nguyen Le CA, Duong KL, Hoang VT, Nguyen TK. Transplacental transmission of SARS-CoV-2: A narrative review. Medicina (Kaunas). 2024; 60(9): 1517. doi: 10.3390/medicina60091517

3. Raschetti R, Vivanti AJ, Vauloup-Fellous C, Loi B, Benachi A, De Luca D. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections. Nat Commun. 2020; 11(1): 5164. doi: 10.1038/s41467-020-18982-9

4. Foo SS, Cambou MC, Mok T, Fajardo VM, Jung KL, Fuller T, et al. The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2. Cell Rep Med. 2021; 2(11): 100453. doi: 10.1016/j.xcrm.2021.100453

5. Muyayalo KP, Huang DH, Zhao SJ, Xie T, Mor G, Liao AH. COVID-19 and Treg/Th17 imbalance: Potential relationship to pregnancy outcomes. Am J Reprod Immunol. 2020; 84(5): e13304. doi: 10.1111/aji.13304

6. Al-Haddad BJS, Oler E, Armistead B, Elsayed NA, Weinberger DR, Bernier R, et al. The fetal origins of mental illness. Am J Obstet Gynecol. 2019; 221(6): 549-562. doi: 10.1016/j.ajog.2019.06.013

7. Abu-Raya B, Kollmann TR, Marchant A, MacGillivray DM. The immune system of HIV-exposed uninfected infants. Front Immunol. 2016; 7: 383. doi: 10.3389/fimmu.2016.00383

8. Andrievskaya IA, Lyazgiyan KS, Zhukovets IV, Ustinov EM. Effect of COVID-19 infection in the third trimester of pregnancy on innate immunity parameters, association with obstetric and perinatal outcomes. Bulletin of Siberian Medicine. 2024; 23(2): 5-13. (In Russ.). doi: 10.20538/1682-0363-2024-2-5-13

9. Matute JD, Finander B, Pepin D, Ai X, Smith NP, Li JZ, et al. Single-cell immunophenotyping of the fetal immune response to maternal SARS-CoV-2 infection in late gestation. Pediatr Res. 2022; 91(5): 1090-1098. doi: 10.1038/s41390-021-01793-z

10. Saines K. The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2. Cell Rep Med. 2021; 2(11): 100453. doi: 10.1016/j.xcrm.2021.100453

11. Gashimova NR, Pankratyeva LL, Bitsadze VO, Khizroeva JKh, Makatsariya NA, Tretyakova MV, et al. Intrauterine activation of the fetal immune system in response to maternal COVID-19 Obstetrics, Gynecology and Reproduction. 2023; 17(2): 188-201. (In Russ.). doi: 10.17749/2313-7347/ob.gyn.rep.2023.404

12. Goncu Ayhan S, Turgut E, Oluklu D, Ozden Tokalioglu E, Menekse Beser D, Moraloglu Tekin O, et al. Influence of COVID-19 infection on fetal thymus size after recovery. J Perinatal Med. 2022; 50(2): 139-143. doi: 10.1515/jpm-2021-0322

13. Liu P, Zheng J, Yang P, Wang X, Wei C, Zhang S, et al. The immunologic status of newborns born to SARS-CoV-2-infected mothers in Wuhan, China. J Allergy Clin Immunol. 2020; 146(1): e101-109. doi: 10.1016/j.jaci.2020.04.038

14. Andrievskaya IA, Lyazgyan KS. Expression of CD68 by macrophages and histopathology of the placenta in COVID-19: Association with obstetric and neonatal complications. Bulletin Physiology and Pathology of Respiration. 2024; 93: 91-99. (In Russ.). doi: 10.36604/1998-5029-2024-93-91-99

15. Kim SK, Romero R, Chaiworapongsa T, Kusanovic JP, Mazaki-Tovi S, Mittal P, et al. Evidence of changes in the immunophenotype and metabolic characteristics (intracellular reactive oxygen radicals) of fetal, but not maternal, monocytes and granulocytes in the fetal inflammatory response syndrome. J Perinat Med. 2009; 37(5): 543-552. doi: 10.1515/JPM.2009.106

16. van der Mark VA, Ghiboub M, Marsman C, Zhao J, van Dijk R, Hiralall JK, et al. Erratum to: Phospholipid flippases attenuate LPS-induced TLR4 signaling by mediating endocytic retrieval of Toll-like receptor 4. Cell Mol Life Sci. 2017; 74(7): 1365. doi: 10.1007/s00018-017-2475-3

17. Pugni L, Pietrasanta C, Milani S, Vener C, Ronchi A, Falbo M, et al. Presepsin (soluble CD14 subtype): Reference ranges of a new sepsis marker in term and preterm neonates. PLoS One. 2015; 10(12): e0146020. doi: 10.1371/journal.pone.0146020

18. Mengos AE, Gastineau DA, Gustafson MP. The CD14(+) HLA-DR(lo/neg) monocyte: An immunosuppressive phenotype that restrains responses to cancer immunotherapy. Front Immunol. 2019; 10: 1147. doi: 10.3389/fimmu.2019.01147

19. Fedorov AA, Ermak NA, Gerashchenko TS, Topolnitskii EB, Shefer NA, Rodionov EO, et al. Polarization of macrophages: Mechanisms, markers and factors of induction. Siberian Journal of Oncology. 2022; 21(4): 124-136. (In Russ.). doi: 10.21294/1814-4861-2022-21-4-124-136

20. Gabrilovich D, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009; 9(3): 162-174. doi: 10.1038/nri2506

21. Arsentieva NA, Batsunov OK, Kudryavtsev IV, Semenov AV, Totolian AA. CD32a receptor in health and disease. Medical Immunology (Russia). 2020; 22(3): 433-442. (In Russ.). doi: 10.15789/1563-0625-CRI-2029

22. Jin Z, El-Deiry WS. Distinct signaling pathways in TRAIL – versus tumor necrosis factor-induced apoptosis. Mol Cell Biol. 2006; 26(21): 8136-8148. doi: 10.1128/MCB.00257-06

23. Kostareva OS, Gabdulkhakov AG, Kolyadenko IA, Garber MB, Tishchenko SV. Interleukin-17: Functional and structural features, application as a therapeutic target. Biochemitry (Mosc). 2019; 84(1): 193-205. doi: 10.1134/S0006297919140116

24. Di Pietro R, Zauli G. Emerging non-apoptotic functions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/ Apo2L. J Cell Physiol. 2004; 201(3): 331-340. doi: 10.1002/jcp.20099