Course and outcomes of pregnancy in patients with chronic endometritis and impaired reproductive function after receiving complex treatment with drug Superlymph: randomized control trial in parallel groups “Tulip”

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

The prevalence of chronic endometritis (CE) in the general population varies from 14.1 to 24.4%. CE is potentially associated with poor reproductive outcomes.

Objective: To increase the effectiveness of complex treatment in the preconception period of patients with CE and impaired reproductive function using a complex of exogenous natural antimicrobial peptides and cytokines and to evaluate the effect of the treatment on the pregnancy rate, course and outcomes.

Materials and methods: This was an open prospective randomized controlled trial in parallel groups which included 2252 patients with CE and infertility. The patients were divided into two groups (1126 people in each): antibacterial (AB) therapy and a complex of exogenous natural antimicrobial peptides and cytokines (Superlymph) were administered in group I, and only AB therapy was used in group II. Two subgroups were identified: the patients received progestogens as part of complex therapy in groups IA and IIA, and they did not receive progestogens in groups IB and IIB.

Results: The overall pregnancy rate within 6 months after treatment was 44.9% versus 26.1% in groups I and II, respectively, p=0.0001. The use of Superlymph and AB increased the chances of pregnancy by 1.5 times (RR=1.58, 95% CI 1.40–1.78) compared with AB therapy, regardless of progesterone intake. After taking Superlymph/progesterone/AB, pregnancy rate increased almost 3-fold in patients with infertility for five years or more, compared with those who received only progesterone/AB, 19.6 vs. 11.2%, p<0.001 (RR=2.91, 95% CI 1.55–5.47). Spontaneous pregnancy was observed in 33.7% of patients in group I, and in 17.4% in group II, p=0.0001 (RR=1.93, 95% CI 1.66–2.25); after IVF it was in 11.2% and 8.5%, p=0.04 (RR=1.31, 95% CI 1.02–1.69), respectively. The live birth rate was 37.3 and 21.1%, respectively, p<0.001 (RR=1.77, 95% CI 1.55–2.03). The Superlymph/progesterone/AB complex reduced the risk of early miscarriage by 6.3 times compared with AB alone (RR=0.16, 95% CI 0.08–0.33, p<0.001) and 4.5 times compared with progesterone and AB (RR=0.22, 95% CI 0.11–0.44, p<0.001). None of the treatment options had a statistically significant effect on late miscarriage rate. The overall incidence of preterm birth in groups I and II was 11.3 vs. 16.7%, respectively, p=0.04; the risk of having a premature baby was decreased almost twice (RR=0.56, 95% CI 0.38–0.81). The Superlymph/progesterone/AB complex reduced the risk of preterm birth by 2.5 times compared with AB alone (RR=0.39, 95% CI 0.23–0.66, p<0.001) and also reduced the risk of preeclampsia (RR=0.51, 95% CI 0.28–0.93, p=0.004), hypoxia (RR=0.49, 95% CI 0.25–0.96, p=0.05) and fetal growth retardation (RR=0.43, 95% CI 0.21–0.88, p=0.03) by two times.

Conclusion: The treatment of CE with Superlymph at a dose of 25 IU for 20 days simultaneously with antibiotics and progesterone in the second phase of the cycle in the preconception period has high clinical efficacy and increases the chances of pregnancy with improved outcomes; it decreases the risk of preeclampsia, hypoxia and fetal growth retardation, spontaneous miscarriages in early terms, preterm birth and it increases the frequency of live births compared with patients who received only AB therapy.

Full Text

Restricted Access

About the authors

Galina B. Dikke

F.I. Inozemtsev Academy of Medical Education

Author for correspondence.
Email: galadikke@yandex.ru
ORCID iD: 0000-0001-9524-8962

Dr. Med. Sci., Professor, Department of Obstetrics and Gynecology with a Course of Reproductive Medicine

Russian Federation, St. Petersburg

Anton A. Sukhanov

Perinatal Centre of Tyumen region; Tyumen State Medical University, Ministry of Health of Russia

Email: galadikke@yandex.ru
ORCID iD: 0000-0001-9092-9136

PhD, Head of the Department of Family Planning and Reproduction; Associate Professor, Department of Obstetrics and Gynecology

Russian Federation, Tyumen;

Vladimir V. Ostromensky

F.I. Inozemtsev Academy of Medical Education

Email: galadikke@yandex.ru
ORCID iD: 0000-0001-8290-5767

PhD, Head of the Department of Obstetrics and Gynecology with a Course of Reproductive Medicine

Russian Federation, St. Petersburg

Irina I. Kukarskaya

Perinatal Centre of Tyumen region; Tyumen State Medical University, Ministry of Health of Russia

Email: galadikke@yandex.ru
ORCID iD: 0000-0002-8275-3553

Dr. Med. Sci., Professor at the Department of Obstetrics, Gynecology and Reanimatology with a Course of Clinical Laboratory Diagnostics; Chief Physician; Chief Specialist in Obstetrics and Gynecology, Department of Health

Russian Federation, Tyumen; Tyumen

References

  1. Kitaya K., Takeuchi T., Mizuta S., Matsubayashi H., Ishikawa T. Endometritis: new time, new concepts. Fertil. Steril. 2018; 110(3): 344-50. https://dx.doi.org/10.1016/j.fertnstert.2018.04.012.
  2. Yasuo T., Kitaya K. Challenges in clinical diagnosis and management of chronic endometritis. Diagnostics (Basel). 2022; 12(11): 2711. https://dx.doi.org/10.3390/ diagnostics1211271.
  3. Cicinelli E., Trojano G., Mastromauro M., Vimercati A., Marinaccio M., Mitola P.C. et al. Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link. Fertil. Steril. 2017; 108(2): 289-95.e1. https://dx.doi.org/10.1016/j.fertnstert.2017.05.016.
  4. Song D., Feng X., Zhang Q., Xia E., Xiao Y., Xie W., Li T.C. Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure. Reprod. Biomed. Online. 2018; 36(1): 78-83. https://dx.doi.org/10.1016/j.rbmo.2017.09.008.
  5. Bouet P.E., El Hachem H., Monceau E., Gariépy G., Kadoch I.J., Sylvestre C. Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis. Fertil. Steril. 2016; 105(1): 106-10. https://dx.doi.org/10.1016/j.fertnstert.2015.09.025.
  6. Kimura F., Takebayashi A., Ishida M., Nakamura A., Kitazawa J., Morimune A. et al. Review: Chronic endometritis and its effect on reproduction. J. Obstet. Gynaecol. Res. 2019; 45(5): 951-60. https://dx.doi.org/10.1111/ jog.13937.
  7. Liu Y., Chen X., Huang J., Wang C.C., Yu M.Y., Laird S., Li T.C. Comparison of the prevalence of chronic endometritis as determined by means of different diagnostic methods in women with and without reproductive failure. Fertil. Steril. 2018; 109(5): 832-9. https://dx.doi.org/10.1016/ j.fertnstert.2018.01.022.
  8. Hirata K., Kimura F., Nakamura A., Kitazawa J., Morimune A., Hanada T. et аl. Histological diagnostic criterion for chronic endometritis based on the clinical outcome. BMC Women's Health. 2021; 21: 94. https://dx.doi.org/10.1186/s12905-021-01239-y.
  9. McQueen D.B., Perfetto C.O., Hazard F.K., Lathi R.B. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil. Steril. 2015; 104(4): 927-31. https://dx.doi.org/10.1016/j.fertnstert.2015.06.044.
  10. Vitagliano A., Laganà A.S., De Ziegler D., Cicinelli R., Santarsiero C.M., Buzzaccarini G. et al. Chronic endometritis in infertile women: impact of untreated disease, plasma cell count and antibiotic therapy on IVF outcome-a systematic review and meta-analysis. Diagnostics (Basel). 2022; 12(9): 2250. https://dx.doi.org/10.3390/diagnostics12092250.
  11. Liu J., Liu Z.A., Liu Y., Cheng L., Yan L. Impact of antibiotic treatment for chronic endometritis on pregnancy outcomes in women with reproductive failures (RIF and RPL): a systematic review and meta-analysis. Front. Med. (Lausanne). 2022; 9: 980511. https://dx.doi.org/10.3389/fmed.2022.980511.
  12. Maltseva L.I., Sharipova R.I. Chronic endometritis – new time, new approaches to treatment. Practical Medicine. 2019; 17(4): 15-9. (in Russian). https://dx.doi.org/10.32000/2072–1757-2019-4-15-19.
  13. Pirtea P., Cicinelli E., De Nola R., de Ziegler D., Ayoubi J.M. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis. Fertil. Steril. 2021; 115(3): 546-60. https://dx.doi.org/10.1016/ j.fertnstert.2020.12.010.
  14. Huang W., Liu B., He Y., Xie Y., Liang T., Bi Y. et al. Variation of diagnostic criteria in women with chronic endometritis and its effect on reproductive outcomes: A systematic review and meta-analysis. J. Reprod. Immunol. 2020; 140: 103146. https://dx.doi.org/10.1016/j.jri.2020.103146.
  15. Kushnir V.A., Solouki S., Sarig-Meth T., Vega M.G., Albertini D.F., Darmon S.K. et al. Systemic inflammation and autoimmunity in women with chronic endometritis. Am. J. Reprod. Immunol. 2016; 75(6): 672-7. https://dx.doi.org/10.1111/aji.12508.
  16. Kofod L., Lindhard A., Hviid T.V.F. Implications of uterine NK cells and regulatory T cells in the endometrium of infertile women. Hum. Immunol. 2018; 79(9): 693-701. https://dx.doi.org/10.1016/j.humimm.2018.07.003.
  17. Park H.J., Kim Y.S., Yoon T.K., Lee W.S. Chronic endometritis and infertility. Clin. Exp. Reprod. Med. 2016; 43(4): 185-92. https://dx.doi.org/10.5653/cerm.2016.43.4.185.
  18. Polanski L.T., Barbosa M.A., Martins W.P., Baumgarten M.N., Campbell B., Brosens J. et al. Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature. Hum. Reprod. 2014; 29(1): 65-75. https://dx.doi.org/10.1093/humrep/det414.
  19. Li X., Zhou J., Fang M., Yu B. Pregnancy immune tolerance at the maternal-fetal interface. Int. Rev. Immunol. 2020; 39(6): 247-63. https://dx.doi.org/10.1080/08830185.2020.1777292.
  20. Melo P., Thornton T., Coomarasamy A., Granne I. Evidence for the effectiveness of immunologic therapies in women with subfertility and/or undergoing assisted reproduction. Fertil. Steril. 2022; 117(6): 1144-59. https://dx.doi.org/10.1016/ j.fertnstert.2022.04.015.
  21. Liu M., Yuan Y., Qiao Y., Tang Y., Sui X., Yin P., Yang D. The effectiveness of immunomodulatory therapies for patients with repeated implantation failure: a systematic review and network meta-analysis. Sci. Rep. 2022; 12(1): 18434. https://dx.doi.org/10.1038/s41598-022-21014-9.
  22. Wang C., Guan D., Li R., Bing Z., Yang Y., Yang K. Comparative efficacies of different immunotherapy regimens in recurrent implantation failure: A systematic review and network meta-analysis. J. Reprod. Immunol. 2021; 148: 103429. https://dx.doi.org/10.1016/j.jri.2021.103429.
  23. Tapilskaya N.I., Tolibova G.Kh., Savicheva A.M., Kopylova A.A., Glushakov R.I., Budilovskaya O.V., Krysanova A.A., Gorskii A.G., Gzgzyan A.M., Kogan I.Yu. The effectiveness of local cytokine therapy for chronic endometritis in patients with infertility. Obstetrics and Gynecology. 2022; (2): 91-100. (in Russian). https://dx.doi.org/10.18565/ aig.2022.2.91-100.
  24. Dobrokhotova Yu.E., Gankovskaya L.V., Borovkova E.I., Zaidieva Z.S., Skalnaya V.S. Modulation of local expression of innate immunity factors in patients with chronic endometritis and infertility. Obstetrics and Gynecology. 2019; (5): 125-32. (in Russian). https://dx.doi.org/10.18565/aig.2019.5.125-132.
  25. Dikke G.B., Sukhanov A.A., Kukarskaya I.I., Ostromensky V.V. Cytokine profile of patients with chronic endometritis and reproductive dysfunction. Issues of Gynecology, Obstetrics and Perinatology. 2021; 20(6): 82-91. (in Russian). https://dx.doi.org/10.20953/ 1726-1678-2021-6-82-91.
  26. Dikke G.B., Sukhanov A.A., Kukarskaya I.I., Ostromensky V.V. Restoration of reproductive function in patients with uterine infertility caused by chronic endometritis. Pharmateka. 2022; 29(6): 86-94. (in Russian). https://dx.doi.org/10.18565/ pharmateca.2022.6.00-00.
  27. Kato H., Yamagishi Y., Hagihara M., Hirai J., Asai N., Shibata Y., Iwamoto T., Mikamo H. Systematic review and meta-analysis for impacts of oral antibiotic treatment on pregnancy outcomes in chronic endometritis patients. J. Infect. Chemother. 2022; 28(5): 610-5. https://dx.doi.org/10.1016/j.jiac.2022.01.001.
  28. Cicinelli E., Matteo M., Tinelli R., Pinto V., Marinaccio M., Indraccolo U. et al. Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment. Reprod. Sci. 2014; 21(5): 640-7. https://dx.doi.org/10.1177/1933719113508817.
  29. Cicinelli E., Matteo M., Trojano G., Mitola P.C., Tinelli R. Vitagliano A. et al. Chronic endometritis in patients with unexplained infertility: prevalence and effects of antibiotic treatment on spontaneous conception. Am. J. Reprod. Immunol. 2018; 79(1). https://dx.doi.org/10.1111/aji.12782.
  30. Dobrokhotova Yu.E., Borovkova E.I., Skalnaya V.S., Ilyazov T.K., Rassokhina O.V. Clinical and immunological parallels in patients with infertility and chronic endometritis before and after exogenous cytokine therapy. Obstetrics and Gynecology. 2019; (12): 154-60. (in Russian). https://dx.doi.org/10.18565/aig.2019.12.154-160.
  31. Raperport C., Chronopoulou E., Homburg R., Khan K., Bhide P. Endogenous progesterone in unexplained infertility: a systematic review and meta-analysis. J. Assist. Reprod. Genet. 2023; 40(3): 509-24. https://dx.doi.org/10.1007/s10815-022-02689-5.
  32. Dobrokhotova Yu.E., Gankovskaya L.V., Borovkova E.I., Nugumanova O.R. Exogenous cytokine therapy in the treatment of patients with chronic endometritis. Obstetrics and Gynecology. 2021; (2): 119-26. (in Russian). https://dx.doi.org/10.18565/aig.2021.2.119-126.
  33. Ishchenko A.I., Unanyan A.L., Kogan E.A., Demura T.A., Kossovich Yu.M. Clinical and anamnestic, immunological, echographic and hysteroscopic features of chronic endometritis associated with reproductive dysfunction. Bulletin of the Russian Academy of Medical Sciences. 2018; 73(1): 5-15. (in Russian). https://dx.doi.org/10.15690/vramn927.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Figure. Study design flowchart

Download (246KB)
Indexing metadata

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies