The role of polyfunctional immunomodulatory proteins in premature birth. Summary of the doctoral thesis in medical sciences: 321.15 – Obstetrics and gynecology

Abstract

Current situation and importance of the problem Premature birth (PN) is one of the greatest challenges of contemporary obstetrics, a global perinatal health problem, representing the main cause of morbidity, neonatal and infant mortality worldwide. According to statistical data, in the last decade the frequency of prematurity has maintained a stable trend at the global level, moreover, in some highly developed countries, the rate of this obstetric pathology has increased [19, 22, 25]. Currently, contemporary methods of prognosis and prevention of prematurity are widely used in obstetric practice. However, despite this fact, approximately 1 million newborns die annually due to complications associated with prematurity, and millions of surviving premature babies remain disabled throughout their lives [21, 24]. Thus, the World Health Organization (2023) established new strategies for the prevention of preterm birth by deepening research in the field of identifying the mechanisms underlying preterm labor, as well as detecting effective predictors of this obstetric pathology. The literature data report that in the structure of premature birth 2/3 represent spontaneous premature birth [14, 15, 16], and scientific research in the field of contemporary obstetrics states that premature birth represents a syndrome that includes multiple causes and associated etiologies [1, 2, 8, 13]. Thus, among the certain causes of spontaneous premature birth, inflammatory ones have been demonstrated, especially intraamniotic inflammation [17, 18]. Intraamniotic inflammation can occur in two different contexts: through intraamniotic microbial invasion, while the second occurs in the absence of microbial substrate and is associated with a local increase in endogenous danger signals, thus called sterile inflammation [5, 9, 10]. It is important to note that a growing number of scientific publications emphasize that these two inflammatory conditions have similar clinical outcomes, and the correlation between the innate immune system and the evolution of sterile or nonsterile intraamniotic infection is crucial [3, 17, 18]. Recent studies have found a link between the immune system and the development of sterile or nonsterile inflammation (intraamniotic infection). Therefore, knowledge of the changes in the innate immune system that occur in the case of intraamniotic infection and sterile intraamniotic inflammation is essential for understanding the mechanisms of development of preterm birth and determining the correct management of patients at risk of prematurity [4, 6, 7, 11, 12]. And early identification of changes in the innate immune system would provide the possibility of a prognosis of the development of sterile or infectious (nonsterile) inflammation associated with the risk of preterm birth, would provide the possibility of developing an appropriate obstetrical conduct, which may contribute to improving perinatal outcomes [20, 23, 25]. Summarizing the above, we conclude that preterm birth represents an important perinatal problem due to the complexity and subtlety of the polyetiological mechanisms underlying it. And a more detailed understanding of the changes in the maternal immune system offers the possibility of developing new prognostic methods, which will facilitate the timely prevention of preterm birth and the development of therapeutic strategies that will improve the expected perinatal outcomes [20, 23, 25]. Therefore, the polyetiological and complex features underlying preterm birth have generated the development of the present study, defining the purpose and objectives of the research. Purpose of the study. The study was conducted to assess the role of polyfunctional immunomodulatory proteins in premature birth triggered to optimize obstetric management and improve perinatal outcomes. Objectives of the study: 1. Study the evolution of pregnancy, birth and perinatal outcomes in women with spontaneous premature birth. 2. Assessment of serum values of polyfunctional immunomodulatory proteins (LF and a2 – MG) in spontaneous premature birth. 3. Assessment of serum values of proinflammatory cytokines (Il-1b, Il-6 and TNF-a) in spontaneous premature birth. 4. Evaluation of the correlation between serum values of polyfunctional immunomodulatory proteins and proinflammatory cytokines in spontaneous premature birth. 5. Determining potential predictors for preterm birth with the development of an algorithm to optimize obstetric management and improve perinatal outcomes of pregnant women at risk of preterm birth. General research methodology. The research was organized and conducted based on the Department of Obstetrics and Gynecology within the Nicolae Testemițanu State University of Medicine and Pharmacy, in obstetric wards 1, 2, 3 of the Perinatology Center within the Gheorghe Paladi Municipal Clinical Hospital IMSP and the Biochemistry Laboratory of the Nicolae Testemițanu State University of Medicine and Pharmacy, with permission from the administration of the respective institutions for the collection and processing of primary data during the years 2018-2022. The research project and the study protocol were approved by the Research Ethics Committee of the Nicolae Testemițanu State University of Medicine and Pharmacy (minutes no. 16 of November 21, 2017) and by the Bioethics Committee of the Gheorghe Paladi Municipal Clinical Hospital IMSP (minutes no. 1-A of February 2, 2018). Scientific novelty and originality: The study elucidated the peculiarities of the evolution of pregnancy, childbirth and perinatal outcomes in pregnant women with spontaneous preterm birth. In the study, the serum values of LF and a2 – MG as well as proinflammatory cytokines (Il-1b, Il-6 and TNF-a) were assessed as a whole, as well as the correlation of these inflammatory markers in women with spontaneous preterm birth. A predictive model of preterm birth was developed, based on the anamnesis, comorbidities of women whose pregnancy was complicated by preterm birth. Based on the results obtained, a diagnostic and management algorithm for pregnant women at risk of spontaneous preterm birth was proposed to optimize clinical management and improve perinatal outcomes. The theoretical significance: The results of this study make important contributions to the understanding of the pathogenetic mechanisms of preterm birth, confirming the determining role of intrauterine inflammation and immunological imbalance in the initiation of preterm labor. The analysis of serum biomarkers, especially Lactoferrin (LF), α2-Macroglobulin (α2-MG) and proinflammatory cytokines (IL-1b, IL-6, TNF-α), provided new insights into the screening and prevention of prematurity, paving the way for the implementation of more efficient methods for the identification and management of patients at high risk of preterm birth. The applicative value of the study: Integrating biomarker testing into prenatal screening allows the identification of high-risk pregnant women before clinical signs of preterm labor become evident. Monitoring serum levels of LF and α2-MG could help obstetricians to establish the prognosis of pregnancy progression and adjust the individualized care plan. The predictive models developed in the current research can be used to guide clinical interventions, ensuring a better allocation of medical resources and avoiding excessive treatment of low-risk patients. The personalized therapeutic protocol proposed based on this study could lead to more effective prevention strategies, through the administration of antenatal corticosteroids to correctly selected patients, the use of anti-inflammatory therapies and preventive antibiotic therapy.

Identification of serum biomarkers of prematurity can optimize the monitoring of high- risk pregnancies, allowing for early diagnosis, better targeted treatments and the

reduction of unnecessary medical interventions. The implementation of an obstetric management algorithm, based on biomarkers of polyfunctional immunomodulatory proteins, proposed following the study, could improve diagnostic accuracy, guide treatment and reduce neonatal complications associated with prematurity. Implementation of scientific results: Based on the study, a predictive model of preterm birth was proposed, which was implemented in the Perinatological Center of the PMI Gheorghe Paladi Municipal Clinical Hospital. Based on the study, a Methodological Recommendation was developed and implemented in the teaching process of the Departament of Obstetrics and Gynecology of Nicolae Testemițanu PI SUMPh, as well as in the curent activites of PMI Gheorghe Paladi Municipal Clinical Hospital. Approval of scientific results. The basic principles of the work were reported and discussed in various national and international scientific forums: • Conference Days of the State University of Medicine and Pharmacy "Nicolae Testemițanu". Chișinău, October 15-19, 2018. • The 7th International Medical Congress for Students and Young Doctors MedEspera. Chișinău, May 3-5, 2018. • The 15th International Congress for Medical Students and Young Doctors. Romania, Iasi, May 3-6, 2018. • The 8th International Medical Congress for Students and Young Doctors MedEspera. Chișinău, September 24-26, 2020. • National Congress of Fetal and Neonatal Medicine with international participation. Romania, Bucharest, May 11-13, 2023. • The 28th EBCOG CONGRESS. Poland, Krakow, 18-20 May, 2023. • European Exhibition of Creativity and Innovation EUROINVENT l5th edition, 26- 28 May 2023. • The 37th Balkan Medical Week ”PERSPECTIVES OF BALKAN MEDICINE IN THE POST COVID-19 ERA”. Chisinau, 7-9 June 2023. • National scientific and practical conference “DAYS OF ACADEMICIAN GHEORGHE PALADI ON HIS 95TH ANNIVERSARY”. Chisinau, 17 May 2024. • 13th National Congress of the Romanian Society of Obstetrics and Gynecology. Romania, Bucharest, 21-23 November 2024. Publications on the topic of the thesis. Based on the study materials, 25 works

were published, of which 1 article in national journals, 4 articles in international peer- reviewed journals, 2 articles without co-authorship, 7 abstracts in the proceedings of

national and international scientific conferences, 1 innovator's certificate, 1 certificate of registration of objects of copyright and related rights, 4 communications at international and 2 national scientific forums, 5 international posters, 1 methodological recommendation. Thesis volume and structure. The thesis is presented on 162 typewritten pages and consists of: introduction, literature review (chapter 1), research material and methods (chapter 2), three chapters of own results (chapters 3, 4, 5), synthesis of the obtained results, general conclusions, practical recommendations, bibliography with 203 sources, 8 annexes, information on the use of research results. The work contains 20 tables, 22 figures.