CHANGES IN CYTOKINE BALANCE IN PREGNANT WOMEN WITH CHRONIC ENDOMETRITIS IN THE PAST MEDICAL HISTORY AND THEIR ROLE IN THE DEVELOPMENT OF PREECLAMPSIA

Abstract

Few data regarding the levels of TNF-α, INF-γ and IL-10 in the cervical mucus of pregnant women with the past medical history of chronic endometritis have been found. The abovementioned cytokines have the impact on the course of pregnancy as well as the processes of trophoblast invasion into the spiral arteries of the uterus. Deviations in their levels at the early stages of pregnancy may be associated with the development of preeclampsia at later stages. Purpose: to assess the levels of TNF, INF-γ and cytokine IL-10 in the cervical mucus of pregnant women with a past medical history of chronic endometritis. Additionally, the study aims to determine their role in the development of preeclampsia and evaluate the eff ectiveness of comprehensive preconception treatment in preventing cytokine imbalance and the occurrence of gestational complications. Method and Materials. 135 pregnant women with the past medical history of chronic endometritis have been supervised during their pregnancy and received preconception treatment (Group I), as well as 168 women, whose pregnancy occurred in the presence of untreated chronic endometritis (Group II). The control group (CG) involved 20 healthy women. Preconception treatment included the administration of azithromycin, hormonal therapy with Femoston- Comb 2/10, and L-arginine aspartate in combination with folate prophylaxis. During the study, the principles of patient- centered care were followed in accordance with the requirements of the Tokyo Declaration of the World Medical Association, the International Recommendations of the Helsinki Declaration on Human Rights, the Convention on Human Rights and Biomedicine of the Council of Europe, the Laws of Ukraine, the Orders of the Ministry of Health of Ukraine and the requirements of the Ethical Code of the Ukrainian physician. The cytokine (TNF-α, INFγ, IL-10) analysis in the cervical mucus was performed at 5-, 17-18 and 32 weeks of pregnancy, using the enzyme- linked immunosorbent assay method with corresponding standard commercial reagent kits from the «Vector BEST» company. The obtained data were processed using mathematical statistical methods, calculating the mean sample values (M), variance (σ) and standard errors of the means (m). Student’s t-test was used for assessment and the likelihood ratio was calculated using the «STATISTICA» software (StatSoft Inc., USA). The paper is an excerpt from the initiative scientifi c research project of the Department of Obstetrics and Gynecology No. 2 at Poltava State Medical University, entitled «Optimization of approaches to the management of pregnancy in women at high risk of obstetric and perinatal pathology» (State registration number 0122U201228, duration:10.2022-09.2027). Results. In pregnant women with a past medical history of chronic endometritis an increase in the levels of INF-γ in cervical mucus by 2.1 times at 5-6 weeks (p<0.001), by 2.4 times at 17-18 weeks (p<0.001) and by 1.7 times at 32 weeks of pregnancy (p<0.001) compared to corresponding levels of this cytokine in healthy pregnant women, has been detected. Similarly, TNF-α was by 4.3 times greater at 5-6 weeks of pregnancy compared to the values in the control group (p<0.001), by 3.3 times greater at 17-18 weeks of pregnancy (p<0.001) and by 4.4 times at 32 weeks of pregnancy (p<0.001). All pregnant women with a past medical history of chronic endometritis who had levels of INF-γ in the cervical mucus greater than 66.4 pg/ml and/or levels of TNF-α greater than 90.9 pg/ml at 5-6 weeks of pregnancy subsequently manifested preeclampsia (OR 2.01; 95 % CI [1.1-7.12]; p<0.05 and OR 1.8; 95 % CI [1.2-6.29]; p<0.05 respectively). The level of IL-10 in their cervical mucus was by 4 times higher than the control values at 5-6 weeks of pregnancy (p<0.0001); by 3.1 times higher at 17-18 weeks of pregnancy (p<0.0001) and by 3 times higher at 32 weeks of pregnancy (p<0.0001). This compensates for the increase in pro-infl ammatory cytokines, allowing the TNF-α/IL-10 ratio to remain at a level characteristic of healthy women throughout pregnancy. In treated women, the concentration of INF-γ is by 1.8 times lower than in untreated patients at 5-6 weeks of pregnancy (p<0.0001), by 2.1 times at 17-18 weeks of pregnancy (p<0.0001), and by 1.4 times at 32 weeks of pregnancy (p<0.0001). Similarly, TNF-α in cervical mucus was found to be lower by 3.6 times (p<0.01), 2.6 times (p<0.0001), and 4 times (p<0.001) respectively, in the specifi ed terms. This helps to avoid excessive production of the anti-infl ammatory cytokine IL-10. Conclusions. In women who got pregnant with untreated chronic endometritis, an increased production of cytokines INF-γ and TNF-α at the early stages of pregnancy has been established. Comprehensive pregravidar treatment of chronic endometritis allows for the normalization of levels of anti-infl ammatory cytokines INF-γ and TNF-α at the beginning of gestation, which creates conditions for preventing the development of preeclampsia. This leads to a 1.9 times reduction in the frequency of this complication (OR 2.3; 95 % CI [1.25-4.31]; p<0.05), a 1.8 times decrease in the frequency of severe forms of preeclampsia (OR 4.64; 95 % CI [1.23-17.48]; p<0.05) and a delay in the average onset of its manifestations by 4.9 weeks (p<0.0001).

Keywords

• Preeclampsia; Chronic Endometritis; INF-γ; TNF-α; Trophoblast Invasion into the Spiral Arteries of the Uterus