Prognostic significance of interleukin-6, hypoxia-inducible factor-1 and ferritin in the development of placental insufficiency in pregnant women with COVID-19 and anaemia

Evidence indicates that COVID-19 adversely affects the course of pregnancy; however, the mechanisms underlying the associated placental insufficiency and anaemia remain inadequately explored.
Aim. To assess the prognostic value of serum interleukin-6 (IL-6), hypoxia-inducible factor-1α (HIF-1α) and ferritin for the development of placental insufficiency in pregnant women with moderate COVID-19 and anaemia.
Materials and methods. Seventy-eight pregnant women were followed prospectively at predefined control points. Baseline (12–14 weeks’ gestation): all participants had experienced moderate COVID-19 (community-acquired pneumonia). Second control point (19–20 weeks): women were allocated to two groups according to the presence of anaemia: group 1 –COVID-19 with mild anaemia (n = 54); group 2 – COVID-19 without anaemia (n = 24). Third control point (30–32 weeks): group 1 was subdivided into subgroup 1A – placental insufficiency present (n = 34) and subgroup 1B –placental insufficiency absent (n = 20). COVID-19 was confirmed by SARS-CoV-2 RNA detection in oropharyngeal and nasopharyngeal swabs using polymerase chain reaction and, where indicated, by radiological criteria of viral lung injury. Serum IL-6 (pg/mL), HIF-1α (ng/mL) and ferritin (μg/L) were measured by solid-phase enzyme-linked immunosorbent assay with Vector-Best (Russia) and BCM Diagnostics (Austria) kits. Red-blood indices (haemoglobin, erythrocyte count) were obtained on a Medonic M haematology analyser (Switzerland).
Results. Women with COVID-19 and anaemia exhibited significantly higher IL-6 (p < 0.001), HIF-1α (p < 0.001) and ferritin (p < 0.001) concentrations than those without anaemia. Placental insufficiency was diagnosed in 63 % of the affected group. Strong positive correlations were found between placental insufficiency and HIF-1α (r = 0.76; p < 0.05), IL-6 (r = 0.82; p < 0.05) and ferritin (r = 0.72; p < 0.05). A prognostic index of placental insufficiency (PIPI) was derived: PIPI = –12.84 + 2.486 × HIF-1α – 0.921 × IL-6 + 0.380 × ferritin, where variables represent serum concentrations. The threshold value was 1.204: PIPI ≥ 1.204 indicated a high risk of placental insufficiency, whereas PIPI < 1.204 indicated no risk. Absolute PIPI values were directly proportional to risk magnitude.
Conclusion. Elevated serum IL-6, HIF-1α and ferritin are informative predictors of placental insufficiency in pregnant women with moderate COVID-19 and anaemia.

1. Sinchikhin S.P., Stepanyan L.V., Atuyeva L.M., Nasri O., Sinchikhina Ye.S. [Relationship between COVID-19 and iron deficiency anemia in pregnant women]. Gynecology 2021; 23(6):592–596 (in Russian). https://doi.org/10.26442/20795696.2021.6.201340

2. Bant'yeva M.N., Manoshkina Ye.M. [The impact of the new coronavirus infection on pregnancy and delivery, as well as its outcomes for the mother and newborn (systematic review)]. Sotsial'n·yye aspekty zdorov'ya naseleniya = Social Aspects of Population Health 2023; 69(6):2 (in Russian). https://doi.org/10.21045/2071-5021-2023-69-6-2

3. Lipatov I.S., Tezikov Yu.V., Kalinkina O.B., Tyutyunnik V.L., Kan N.E., Mayorova M.O., Yakovleva M.A. [Association between new coronavirus infection and fetal growth restriction]. Obstetrics and Gynecology 2023; 2:53–62 (in Russian). https://doi.org/10.18565/aig.2022.260

4. Gaziyeva I.A., Chistyakova G.N., Remizova I.I. [Role of cytokine production disorders in genesis of placental insufficiency and early reproductive losses]. Medical Immunology (Russia) 2014; 16(6):539–550 (in Russian).

5. Khvorostukhina N.F., Novichkov D.A. [Features of the synthesis of cytokines and placental dysfunction in pregnant women with acute pancreatitis]. Medical Immunology (Russia) 2019; 21(2):239–250 (in Russian). https://doi.org/10.15789/1563-0625-2019-2-239-250

6. Babu P.A., Garg A.K., Patnaik S.K. Latent iron deficiency in neonates with and without risk factors for poor inutero iron status. Indian Pediatr. 2024; 61(11): 1034–1038.

7. Pogorelova T.N., Gun'ko V.O., Nikashina A.A., Mikhel'son A.A., Botasheva T.L., Kaushanskaya L.V. [Violation of the balance of free metals and metal-containing proteins in amniotic fluid in placental insufficiency]. Clinical Laboratory Diagnostics 2021; 66(5):266–270 (in Russian). https://doi.org/10.51620/0869-2084-2021-66-5-266-270

8. Aylamazyan E. K., Stepanova O. I., Sel'kov S. A., Sokolov D.I. [Cells of immune system of mother and trophoblast cells: constructive cooperation for the sake of achievement of the joint purpose]. Annals of the Russian Academy of Medical Sciences 2013; 11:12–21 (in Russian). https://doi.org/10.15690/vramn.v68i11.837

9. Botasheva T.L., Radzinskiy V.E., Khloponina A.V., Vasil'yeva V.V., Zavodnov O.P., Zheleznyakova Ye.V., Sargsyan O.D. [Role of fetus sex in expression of angiogenic factors and supporting of citokine balance in maternal organism in physiological pregnancy and in placentary insufficiency]. Medical Bulletin of the North Caucasus 2019; 14(2):325–239 (in Russian). https://doi.org/10.14300/mnnc.2019.14079

10. Haider S., Knöfler M. Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium // Placenta. 2009. Т. 30, №2. С.111–123. https://doi.org/10.1016/j.placenta.2008.10.012

11. Kuz'min V.N. [Fetoplacental insufficiency: a problem of modern obstetrics]. Lechaschi Vrach = The Attending Physician 2011; 3:50 (in Russian).

12. Wang W., Knovich M.A., Coffman L.G., Torti F.M., Torti S.V. Serum ferritin: Past, present and future. Biochim. Biophys. Acta 2010; 1800(8):760–769. https://doi.org/10.1016/j.bbagen.2010.03.011

13. Ruscitti P., Berardicurti O., Barile A., Cipriani P., Shoenfeld Y., Iagnocco A., Giacomelli R. Severe COVID-19 and related hyperferritinaemia: more than an innocent bystander? Ann. Rheum. Dis. 2020; 79(11):1515–1516. https://doi.org/10.1136/annrheumdis-2020-217618

14. Ignatko I.V. [Prevention of placental insufficiency in pregnant women at a high perinatal risk]. Gynecology, Obstetrics and Perinatology 2007; 6(5):11–18 (in Russian).

15. Strizhakov A.N., Kushlinskiy N.E., Timokhina Ye.V., Tarabrina T.V. [The role of angiogenic growth factors in predicting placental insufficiency]. Gynecology, Obstetrics and Perinatology 2009; 8(4):5–11 (in Russian).

16. Levchenkova O.S., Novikov V.E. [Inducers of the regulatory factor to hypoxia adaptation]. I.P. Pavlov Russian Medical Biological Herald 2014; 22(2):135–145 (in Russian).

17. Caniggia I., Winter J. Adriana and Luisa Castellucci Award lecture 2001. Hypoxia inducible factor-1: oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies – a review. Placenta 2002; 23(Suppl A):S47– S57. https://doi.org/10.1053/plac.2002.0815

18. Pavlov A.D., Morshchakova Ye.F., Rumyantsev A.G. [Erythropoiesis, erythropoietin, iron. Molecular and clinical aspects]. Moscow; GEOTAR-Media, 2011 (in Russian).

19. Bol'shakova M.V., Bezhenar' V.F., Pavlova N.G., Pastushenkov V.L., Gabayeva M.M. [Modern ideas about the pathogenesis of fetal hypoxia and the role of hypoxia-inducible factor (HIF) in it]. Akusherstvo i ginekologiya Sankt-Peterburga = Obstetrics and Gynaecology of St. Petersburg 2019; 1:19–24 (in Russian).

20. Kenchegowda D., Natale B., Lemus M.A., Natale D.R., Fisher S.A. Inactivation of maternal Hif-1α at mid-pregnancy causes placental defects and deficits in oxygen delivery to the fetal organs under hypoxic stress. Dev. Biol. 2017; 422(2):171–185. https://doi.org/10.1016/j.ydbio.2016.12.013

21. Trilla C., Mora J., Crovetto F., Crispi F., Gratacos E., Llurba E. First-trimester SARS-CoV-2 infection: clinical presentation, inflammatory markers, and obstetric outcomes. Fetal Diagn. Ther. 2022; 49(3):67–76. https://doi.org/10.1159/000523974

22. Rebrova O.Yu. [Statistical analysis of medical data. Using the STATISTICA application package]. Moscow: MediaSfera, 2003 (in Russian).