Changes in the cytokine status in women with chronic liver pathology during reproductive losses in the first trimester




liver steatosis, non-alcoholic steatohepatitis, miscarriage, pregravid period, proinflammatory cytokines, anti-inflammatory cytokines, blood cytokine status, integral indices of oppositional cytokines


Research objective: to determine the level of serum cytokines in the pregravidar period in women with chronic diseases of the hepatobiliary system and reproductive losses in the first trimester in the anamnesis.
Materials and methods. 90 patients of reproductive age with chronic pathology of the hepatobiliary system (liver steatosis and non-alcoholic steatohepatitis) were examined. All patients had spontaneous miscarriages in the early stages of gestation in anamnesis. The research was conducted during the pregravid preparation period. The laboratory research included an additional study of the interleukins (ІL-2, ІL-6, ІL-8, ІL-10) and tumor necrosis factor (TNFα) in the blood serum using enzyme immunoferment assay. 8 female donors were examined to determine the reference norm of cytokines in the blood serum.
Results. The cytokine status in patients with chronic pathology of the hepatobiliary system against the background of early miscarriage was characterized by an increase in proinflammatory cytokines (TNFα in 2,29 times more, ІL-2 in 1,46 times, ІL-6
in 1,84 times and ІL-8 in 1,50 times) and anti-inflammatory cytokines (ІL-10 in 1,31 times). The integral indices that are characterizing the oppositional cytokines ratio increased (TNFα/ІL-10, ІL-2/ІL-10 and ІL-6/ІL-10) which indicates an inflammatory process in the body. Minimal changes were registered in patients with signs of steatosis – a moderate increase in proinflammatory cytokines (TNFα is 1,34 times more, ІL-2 in 1,18 times, ІL-6 in 1,33 times and ІL-8 in 1,13 times) and preservation within the reference norm of ІL-10. The maximum imbalance of serum cytokines was observed in the exacerbation of non-alcoholic steatohepatitis – a significant increase in proinflammatory cytokines (TNFα is 3,66 times more, ІL-2 in 1,95 times, ІL-6 in 2,57 times and ІL-8 in 2,18 times) against the background of a moderate increase in ІL-10 (1,30 times). In patients with clinical and laboratory signs of remission of non-alcoholic steatohepatitis a moderate increase in proinflammatory (TNFα is 1,87 times more, ІL-2 in 1,20 times, ІL-6 in 1,61 times and ІL-8 in 1,20 times) and anti-inflammatory (ІL-10 in 1,51 times) cytokines was diagnosed. The analysis of the integral indices of oppositional cytokines showed a tendency to increase their values in patients with liver steatosis and non-alcoholic steatohepatitis in the phase of clinical and laboratory remission. During the period of the non-alcoholic steatohepatitis exacerbation a considerable increase in the studied coefficients was revealed.
Conclusions. Changes in the cytokine status are noted in patients with early spontaneous miscarriages in anamnesis and chronic diseases of the hepatobiliary system, which are characterized by the severity of inflammatory reactions and progression of the pathological process in liver. Obtained results can be used to predict miscarriage and be taken into account in the program of drug preparation in the pregravid period.

Author Biographies

I.V. Loskutova, Lugansk State Medical University, Rubizhne

MD, professor, head of the Department of Intensive Care, Emergency and Anesthesiology

R.G. Bichevska, Maternity Hospital No. 7, Odesa

PhD, obstetrician gynecologist, Department of Pathology of Pregnant Women

N.V. Matsiukh, Luhansk State Medical University, Rubizhne

Assistant, Department of Intensive Care, Emergencies and Anesthesiology


  1. Adzhieva, R.K., Ibragimova E.I. “To the treatment of habitual miscarriage.” Problems of ecological medicine. VI Republican scientific and practical conference (2016): 170–3.
  2. Arzhanova, O.N., Selkov, S.A., Savicheva, A.M., et al. Miscarriage. Prevention and treatment (3rd edition, revised and expanded). Saint-Petersburg, 2019. 94 p.
  3. Barkovskyi, D.Y. “Changes in T-helper associated cytokines and the risk of miscarriage.” Zaporozhye Medical Journal 21.3 (2019): 373–76. DOI: 10.14739/2310-1210.2019.3.169191
  4. Batrak, N.V., Malyshkina, A.I., Sotnikova N.Y., et al. “Medical and social factors and pathogenetic mechanisms of early pregnancy loss in women with recurrent miscarriage.” Obstetrics and gynecology 7 (2020): 79–86. DOI: 10.18565/aig.2020.7.79-86
  5. Khobzey, M.K., Kharchenko, N.V., et al. Unified clinical protocol of primary, secondary (specialized) medical care: non-alcoholic steatohepatitis. Approved by the order of the Ministry of health of Ukraine on November 06, 2014 No. 826. Kyiv, 2014. 37 p.
  6. Birzhanova, G.T., Biktasheva, H.M. “Global trends in examination and therapy recurrent pregnancy loss.” Reproductive medicine 3.36 (2018): 46–50.
  7. Bitsadze, V.O., Makatsariya, A.D., Hizroeva, D.H., et al. “Thrombophilia as the most important link of the pathogenesis of pregnancy complications.” Practical medicine 5.60 (2012): 22–9.
  8. Dossova, S.Y., Stolnikova, I.I., Slyusar, N.N. “Study of markers of brain tissue damage, cytokines, apoptosis markers in patients with recurrent miscarriage.” Bulletin of Pirogov National Medical & Surgical Center 3.14 (2019): 75–7. DOI: 10.25881/BPNMSC.2019.13.29.015
  9. Dubossarskaya, Z.M., Duka, Y.M. “Experience of conducting pregnancy at women with pregnancy losses in the conditions of trombofiliya.” Woman's health 8.94 (2014): 85.
  10. Kislitsyna, N.D., Bezmenko, A.A. “Intestinal dysbiosis is a risk factor or a cause of miscarriage?” Journal of Obstetrics and Women's Diseases 2.67 (2018): 70–8. DOI: 10.17816/JOWD67270-78
  11. Kozelkova, E.V., Kroshkina, N.V. “Cytokine profile of patients with recurrent miscarriage.” Biomedical, clinical and social issues of human health and pathology. Proceedings of the conference. Ivanovo (2020): 147–49.
  12. Korenovsky, Y.V., Sinelnikova, L.M., Filchakova, O.N., et al. “Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases during pregnancy and delivery.” Acta Biomedica Scientifica 5-2.87 (2012): 146–49.
  13. Lemesh, A.V., Volchkevich, D.A. “Anatomical characteristics of the placenta in normal pregnancy with the threat of miscarriage.” Spring anatomical readings. Collection of articles of the scientific-practical conference dedicated to the memory of associate professor Kolesov M.A. (2016): 115–19.
  14. Makarkov, A.I., Buianova, S.N., Ivanova, O.G., et al. “The specific features of T-cell immunoregulation in miscarriage: paradigm evolution.” Russian bulletin of obstetrician-gynecologist 5.12 (2012): 10–6.
  15. Malyshkina, A.I., Sotnikova, N.Y., Kroshkina, N.V., et al. “Peculiarities of the content of peripheral blood cytokines in pregnant women with a habitual miscarriage.” Clinical laboratory diagnostics 5.65 (2020): 299–303. DOI: 10.18821/0869-2084-2020-65-5-299-303
  16. Radzinsky, V.E., Ordiyants, I.M., Pobedinskaya, O.S., et al. “Progesterone and reproductive losses.” Obstetrics and gynecology 8 (2017): 109–14. DOI: 10.18565/aig.2017.8.109-14
  17. Radzinskiy, V.E., Khamoshina, M.B., Tulupova, M.S., et al. “Progesteron: disputable issues of therapy and prevention of prematurity and preterm birth.” Obstetrics and gynecology. News. Opinions. Training 5.7 (2019): 74–82. DOI: 10.24411/2303-9698-2019-13910
  18. Rzaeva, R.N., Mozgovaya, E.V., Palgova, L.K., et al. “The features of pregnancy at women with liver steatosis and obesity.” Journal of obstetrics and women's diseases 6.62 (2013): 47–54.
  19. Sinyakova, A.A., Shipitsyna, E.V., Budilovskaya, O.V., et al. “Anamnestic and microbiological predictors of miscarriage.” Journal of obstetrics and women's diseases 2.68 (2019): 59-70. DOI: 10.17816/JOWD68259-70
  20. Fadieienko, G.D., Kolesnikova, O.V., Solomenseva, T.A. “The new opportunities of treatment of non-alcoholic steatohepatitis.” Modern gastroenterology 1.99 (2018): 53–60.
  21. Khvorostukhina, N.F., Stepanova, N.N., Novichkov, D.A., et al. “Features of hormonal homeostasis in miscarriage and premature birth.” International journal of experimental education 12.3 (2015): 445–46.
  22. Alghamdi, S., Fleckenstein. J. “Liver Disease in Pregnancy and Transplant.” Curr Gastroenterol Rep. 21.9 (2019): Р. 43. DOI: 10.1007/s11894-019-0711-8
  23. Alijotas-Reig, J., Llurba, E., Gris, J.M. “Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells.” Placenta 35.4 (2014): 241–48. DOI: 10.1016/j.placenta.2014.02.004
  24. Geenes, V., Williamson, C. “Liver disease in pregnancy.” Best Pract Res Clin Obstet Gynaecol. 29.5 (2015): 612–24. DOI: 10.1016/j.bpobgyn.2015.04.003
  25. Kieffer, T.E.C., Laskewitz, A., Scherjon, S.A., et al. “Memory T Cells in Pregnancy.” Front Immunol. 10 (2019): 625. DOI: 10.3389/fimmu.2019.00625
  26. Lee, S.K., Na, B.J., Kim, J.Y., et al. “Determination of clinical cellular immune markers in women with recurrent pregnancy loss.” Am J Reprod Immunol. 70.5 (2013): 398–411. DOI: 10.1111/aji.12137
  27. Ma, K., Berger, D., Reau, N. “Liver Diseases During Pregnancy.” Clin Liver Dis. 23.2 (2019): 345–61. DOI: 10.1016/j.cld.2018.12.013
  28. Matin, A., Sass, D.A. “Liver disease in pregnancy.” Gastroenterol Clin North Am. 40.2 (2011): 335–53, VIII. DOI: 10.1016/j.gtc.2011.03.010
  29. Mei-Dan, E., Wiznitzer, A., Sergienko, R., et al. “Prediction of preeclampsia: liver function tests during the first 20 gestational weeks.” J Matern Fetal Neonatal Med. 26.3 (2013): 250–53. DOI: 10.3109/14767058.2012.733771
  30. Sarkar, M., Grab, J., Dodge, J.L., et al. “Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.” J Hepatol. 73.3 (2020): 516–22. DOI: 10.1016/j.jhep.2020.03.049
  31. Shekhar, S., Diddi, G. “Liver disease in pregnancy.” Taiwan J Obstet Gynecol. 54.5 (2015): 475–82. DOI: 10.1016/j.tjog.2015.01.004
  32. Tran, T.T., Ahn, J., Reau, N.S. “ACG Clinical Guideline: Liver Disease and Pregnancy.” Am J Gastroenterol. 111.2 (2016): 176–96. DOI: 10.1038/ajg.2015.430
  33. Westbrook, R.H., Dusheiko, G., Williamson, C. “Pregnancy and liver disease.” J Hepatol. 64.4 (2016): 933–45. DOI: 10.1016/j.jhep.2015.11.030



How to Cite

Loskutova, I., Bichevska, R., & Matsiukh, N. (2021). Changes in the cytokine status in women with chronic liver pathology during reproductive losses in the first trimester. REPRODUCTIVE ENDOCRINOLOGY, (60), 60–66.



Interdisciplinary consilium