CHILDREN WITH EXTREMELY LOW BODY WEIGHT: CLINICAL CHARACTERISTICS, FUNCTIONAL STATE OF THE IMMUNE SYSTEM, PATHOGENETIC MECHANISMS OF THE FORMATION OF NEONATAL PATHOLOGY

Monograph

Under the editorship of:

 Chistyakova G. N., Ustyantseva L. S., Remizova I. I.

Scientific reviewers: Levkovich M. A. - Doctor of Medical Sciences, Associate Professor, Leading Researcher Zelencova V. L. - Doctor of Medical Sciences, Full Professor

Melbourne, 2022

ISBN 978-1-922756-08-4

Chistyakova G.N., Ustyantseva L.S., Remizova I.I., Ryumin V.E., Bychkova S.V. Children with extremely low body mass: clinical characteristics, functional state of the immune system, pathogenetic mechanisms of formation of neonatal pathology. /Ed. by Chistyakova G.N., Ustyantseva L.S., Remizova I.I.  – Melbourne: AUS PUBLISHERS, 2022.  ISBN 978-1-922756-08-4

The purpose of the monograph, which contains a modern view of the problem of adaptation of children with extremely low body weight, is to provide a wide range of doctors with basic information about the clinical picture, functional activity of innate and adaptive immunity, prognostic criteria of postnatal pathology, based on their own research. The specific features of the immunological reactivity of premature infants of various gestational ages who have developed bronchopulmonary dysplasia (BPD) and retinopathy of newborns (RN) from the moment of birth and after reaching postconceptional age (37-40 weeks) are described separately. The mechanisms of their implementation with the participation of factors of innate and adaptive immunity are considered in detail. Methods for early prediction of BPD and RN with the determination of an integral indicator and an algorithm for the management of premature infants with a high risk of postnatal complications at the stage of early rehabilitation are proposed. The information provided makes it possible to personify the treatment, preventive and rehabilitation measures in premature babies. The monograph is intended for obstetricians-gynecologists, neonatologists, pediatricians, allergists-immunologists, doctors of other specialties, residents, students of the system of continuing medical education.

This work was done with financial support from the Ministry of Education and Science, grant of the President of the Russian Federation No. MK-1140.2020.7.

WRITING TEAM

Chistyakova Guzel Nukhovna - Doctor of Medical Sciences, Full Professor, Head of the Department of Immunology, Microbiology, Pathomorphology and Cytodiagnostics of the Federal State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia

Ustyantseva Lyudmila Stanislavovna - Candidate of Medical Sciences, Senior Researcher of the Department of Physiology and Pathology of Newborns and Young Children of the Federal State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia

Remizova Irina Ivanovna - Candidate of Biological Sciences, Senior Researcher of the Department of Immunology, Microbiology of Pathomorphology and Cytodiagnostics of the Federal State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia

Ryumin Vladislav Evgenievich - full-time postgraduate student, doctor anesthesiologist-resuscitator of the Federal State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia

Bychkova Svetlana Vladimirovna - Candidate of Medical Sciences, Leading Researcher, Federal State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia

Table of content

LIST OF ABBREVIATIONS. 7

INTRODUCTION.. 9

Chapter 1. RISK FACTORS OF BIRTH OF PREMATURE CHILDREN.. 13

1.1. Social and medical problems of childbirth to children with extremely low body weight 13

1.2. Perinatal risk factors for the birth of premature infants. 21

Chapter 2. FEATURES OF THE POSTNATAL PERIOD OF PREMATURE INFANTS. 28

2.1. Clinical aspects of perinatal complications in children with extremely low body weight 28

2.2. Clinical features of children with extremely low birth weight 35

2.3. Features of the course of the postnatal period in children with extremely low body weight 39

3.1. Formation of adaptive and innate immunity in children with extremely low body weight in the dynamics of the postnatal period. 50

3.2. Study of innate immunity indices in children with extremely low body weight in the dynamics of the postnatal period. 60

3.3. Evaluation of local immunity in children with extremely low body weight 72

Chapter IV. FEATURES OF THE FUNCTIONAL STATE OF THE IMMUNE SYSTEM OF NEWBORNS WITH BRONCHOPULMONARY DYSPLASIA. 80

4.1. Immunological reactivity of the immune system of children with bronchopulmonary dysplasia in the dynamics of the postnatal period. 83

4.2. A method for predicting the development of severe bronchopulmonary dysplasia in premature infants with extremely low body weight in the neonatal period. 102

Chapter 5. FUNCTIONAL STATE OF THE IMMUNE SYSTEM OF CHILDREN WITH RETINOPATHY OF PREMATURE IN THE DYNAMICS OF THE POSTNATAL PERIOD. 106

5.1. Dynamics of changes in indicators of adaptive and innate immunity in children with ELBW who developed retinopathy of prematurity. 108

5.2. A method for predicting the development of the threshold stage of retinopathy in premature infants with extremely low body weight 120

5.3. A method for predicting the formation of the threshold stage of retinopathy of prematurity in children with extremely low body weight in the early neonatal period. 123

5.4. Algorithm for additional examination of children born with extremely low body weight 127

LIST OF ABBREVIATIONS

IVH      intraventricular hemorrhage

IUI        intrauterine infection

GIT      Gastrointestinal tract

ALV     artificial lung ventilation

CI          cervical incompetence

ELISA     enzyme-linked immunosorbent assay

INF        interferon

ABB      acid-base balance of blood

UBFD    uteroplacental blood flow disorder

CPI        chronic placental insufficiency

NSG       neurosonography

PDA       patent ductus arteriosus

PVL        periventricular leukomalacia

PCA        postconceptional age

GA          gestional age

PACNS   perinatal affection of the central nervous system

RDS        respiratory distress syndrome

BPD        bronchopulmonary dysplasia

IGRS       intrauterine growth restriction syndrome 

US           ultrasound 

CPI         chronic placental insufficiency

CMV       cytomegalovirus

CNS         central nervous system

IVF          in vitro fertilization

ELBW      extremely low body weight

HRFDA    hemodynamically relevant functioning ductus arteriosis

ROP         retinopathy of prematurity

BEecf       buffer bases in extracellular fluid

CPAP       сonstant positive airway pressure

HCO₃ct             standard bicarbonate

IFN-γ                interferon gamma

CD                    сluster of differentiation

HLA-DR           numan leucocyte antigens  

MHC                major histocompatibility complex

TNF                  tumor necrosis factor  

NK                    natural killer cells  

Ig                      immunoglobulin

IL                      interleukin

РаО₂                 partial arterial oxygen tension

РаСО₂               partial tension of carbon dioxide in arterial blood

SaO₂                 oxygen saturation of arterial blood

INTRODUCTION

The birth of deeply premature babies with extremely low body weight (ELBW) is the most topical issue in modern perinatology due to the high risk of morbidity and mortality, despite the fact that the proportion of births with a gestational age of less than 32 weeks, as a rule, does not exceed 1.5- 2% [1, 2, 3, 4, 5]. According to foreign sources, the survival rate of this category of children over the past twenty years has significantly increased from 42 to 76% [6]. In recent years, there has been a decrease in the proportion of severe complications in children with EBMT against the background of improving organizational and medical technologies for nursing deeply premature babies, the quality of prenatal follow-up [7, 8]. However, the rates of chronic pathology and disability do not show a significant downward trend and remain high even in developed countries [9, 10, 11].

Functional immaturity of the respiratory, cardiovascular, immune, and central nervous systems (CNS) is prevalent among deeply premature newborns, which leads to a high susceptibility of children to the development of pathological conditions and is the cause of a high level of morbidity [12]. Undoubtedly, the improvement of methods of primary resuscitation care and respiratory support (sparing modes of artificial lung ventilation, preference for non-invasive ventilation with a decrease in oxygenation parameters), early use of a surfactant, improvement of neonatal care technologies, significantly improved prognosis of long-term postnatal use of corticosteroids 13 , 14, 15, 16].

The child's immune system plays a leading role in the pathogenesis, clinical course and outcome of hypoxic and infectious diseases, which largely determines the possibility of full rehabilitation of premature babies [17, 18]. In recent years, the role of the cytokine cascade has been actively studied in the development of pathology of the perinatal period. The theory of imbalance of pro- and anti-inflammatory cytokines is considered both in the pathogenesis of the infectious process [18, 19, 20] and in non-infectious post-hypoxic conditions [21, 22]. A large part of scientific research is devoted to assessing the state of adaptive immunity [23, 24], while data on the functioning of the innate link of immunity are presented fragmentarily. However, it is the immunocompetent cells of inborn immunity that are the main ones in the formation of protection against bacterial complications and the formation of immune dysfunction.

 In connection with the peculiarities of the immunological resistance of children with EBMT, the leading cause of death along with serious injuries of the CNS are infectious and inflammatory diseases [25]. In modern works, much attention is paid to the stage of nursing children with EBMT in the conditions of the intensive care unit [23, 26]. However, there are few works devoted to the study of this category of children at the stage of early rehabilitation, taking into account the characteristics of inborn and adaptive immunity at the systemic and local levels, depending on the gestational age. Against the background of a deficiency of humoral protection factors, markers of nonspecific resistance, insufficiency of inborn and adaptive immunity, increased infectious morbidity in children with EBMT, it is important to study the mechanisms of development of postnatal complications from the standpoint of clinical and immunological adaptation of a premature baby, which was the purpose of writing this monograph.

Reference:

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8. Fellman, V. One-year survival of extremely preterm infants after active perinatal care in Sweden / V.Fellman, L.Hellström-Westas, M.Norman // JAMA. -2009. -Vol. 301, № 21. - Р. 2225-2233.
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Chapter 1. RISK FACTORS OF BIRTH OF PREMATURE CHILDREN

1.1. Social and medical problems of childbirth to children with extremely low body weight

The gradual transition of the constituent entities of the Russian Federation (RF) to new technologies for nursing children with ELBW is a natural stage in the development of Russian perinatology, regulated by order No. 1687n dated December 27, 2011. From this moment on, the state registration of newborns with a body weight of 500 g at a gestational age of 22 weeks or more began in accordance with the birth criteria recommended by the World Health Organization (WHO), as well as the introduction of organizational and medical technologies for nursing deeply premature babies, improving the quality of prenatal observations [1, 2, 3]. In this regard, effective nursing and rehabilitation of newborns with ELBW is a task set for the constituent entities of the Russian Federation, the solution of which will lead to a decrease in perinatal and infant mortality, and will improve the quality of further development.

 According to the WHO recommendations, a child born in a preterm birth from 22 to 37 weeks is considered premature. According to the classification of premature birth, adopted in 1993 in the Russian Federation, depending on the gestational age, superearly (22-27 weeks), early (28-33 weeks) and premature birth (34-37 weeks) are distinguished. According to the body weight at birth, according to the WHO classification, 10 revisions distinguish groups of children up to 2500 grams i.e. from low, up to 1500 grams - from very low and up to 1000 grams of extremely low body weight.

 In recent years, the frequency of preterm birth on average in developed countries is 5-10%, in the world - 15% [1, 27], of which 1-1.8% is the share of children with VLBW, 0.4-0.5% - children with ELBW [4].

In many works, much attention is paid to the analysis of the reasons leading to the premature birth of children, the state of physical and neuropsychic development of newborns [5, 6, 7, 8], as well as genetic factors that contribute to premature birth, which are realized both by the mother and and a child. In addition to genetic factors, infectious and endocrine diseases, aggravated obstetric -gynecological history, preeclampsia, multiple pregnancy, chronic placental insufficiency (CPI), placental abruption [4, 9]. According to Russian researchers, there has been an increase in the number of women carriers of TORCH infections, which affect the fetation throughout pregnancy [10].

The leading place among the problems concerning children with ELBW are survival and mortality rates [8, 11, 12]. Modern approaches to perinatal care in Russia and in the world have increased the survival rate of newborns with ELBW up to 45% [13, 14].

The percentage of unfavorable outcomes among surviving children also depends on birth weight and reaches 40-50% in newborns with a weight of 750 to 1000 g, rising to 70-90% at the birth of children weighing from 500 to 749 g, which are, undoubtedly the most vulnerable and difficult contingent for rehabilitation [15, 16, 17]. According to world statistics, among newborns, 11.6% of children under 500 g, 50.7% - from 500 to 749 g, 83.9% - from 750 to 1000 g at birth survive [8, 18]. It is believed that newborns weighing from 500 to 749 g are in the "zone of the viability limit" and their nursing is very problematic. According to American perinatologists, the survival rate of newborns with a gestational age of 22-24 weeks before discharge from the hospital averages 13%, and with a gestational age of more than 26 weeks - 70%, in the future 70% and 30% of children have severe CNS damage, respectively [19]. In Japan, in 2011, the mortality rate of newborns with gestational ages of 22 and 23 weeks was 80% and 64%, respectively [20].

A study by V. Fellman et al. (2009) showed that in Sweden, by one year of age the survival rate among newborns at a gestational age of 22 to 26 weeks was 70%, with 9.8% of children born at 22 and 85% at 26 weeks of gestation. The authors note the absence of serious somatic and neurological complications in 45% of premature infants with ELBW [21]. Over the past two decades, the survival rate of newborns with ELBW has increased in Italy (from 42% to 76%). However, the percentage of the formation of bronchopulmonary dysplasia remains approximately at the same level, amounting to 30.5% and 39%, respectively [22].

The literature indicates a natural relationship between the mortality of children with ELBW and postnatal age. A study by T. Nakhla et al. [23], demonstrated that 49% of newborns with ELBW died in the 1st week of life, 17% - in the 2nd week and only 9% after the 2nd month of life. According to M.A. Mohamed (2010), the survival rate of premature newborns with birth weight from 500 to 750 grams increased to 70% with survival in the first three days and up to 80% - until the end of the 1st week of life [24]. According to the research results of H.V. Bashmakova et al. (2012) the mortality rate of children born with a body weight of 500 to 750 grams was 54.8%, from 750 to 1000 grams - 11.5%. Moreover, the mortality rate of premature babies in the 1st group at the 1st week of life was five times higher than in the 2nd group [8].

The reason for the high incidence of premature infants is the functional immaturity of the respiratory, cardiovascular, immune, and central nervous systems (CNS), which makes premature infants susceptible to the development of pathological conditions [25]. In connection with the peculiarities of the immunological resistance of deeply premature infants, the leading cause of death along with serious injuries of the central nervous system are infectious and inflammatory diseases [26]. Along with infectious and inflammatory pathology, the authors include respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), left ventricular failure and systemic hypotension, hemodynamically relevant functioning ductus arteriosis (HRFDA) [27 , 28, 29, 30, 31].

In recent years, there has been a decrease in the proportion of severe complications in children with ELBW [21, 28]. However, the rates of chronic pathology and disability do not show a significant tendency to decrease and remain high even in developed countries [32, 33, 34].

Children with ELBW are born in a serious condition, being maximally exposed to complications associated with prematurity. Therefore, their nursing refers to high-tech care, since they need support for all basic vital functions of the body [4]. Numerous studies confirm that in order to reduce perinatal and infant mortality, a favorable prognosis for the further development of deeply premature newborns in order to provide comprehensive high-tech medical care for women in high-risk groups, hospitalization is required in specialized perinatal centers of III level, where the neonatal intensive care unit operates [35, 36, 37, 38].

Measures to prevent premature birth are more effective than efforts to intensive care and rehabilitation of deeply premature babies even taking into account the modern level of diagnostic and treatment technologies [29]. Prevention of unfavorable outcomes in children with ELBW requires long-term and expensive rehabilitation treatment. Therefore, given the low health potential of children with ELBW, the high incidence of pathology and the low quality of life, the main reserves for reducing the incidence and mortality of deeply premature babies are full monitoring of pregnant women, the identification of high-risk groups and the use of modern nursing technologies in perinatal centers [29].

In large world perinatal centers with the ability to provide qualified high-tech care, 80-85% of newborns with ELBW and VLBW survive and leave these centers, this indicator varies widely depending on the body weight and gestational age of the child [39]. Subsequently, from 2 to 5% of them die within the first two years after discharge from delayed complications. Unfavorable outcomes of children born at 22-25 weeks of gestation are also noted by Russian authors [40, 41]. Researchers believe that in the indicated time frame there is a certain biological barrier that impedes the survival of newborns [8, 35]. To increase survival rates and minimize residual complications of diseases of the prematurity period in the Russian Federation, a three-stage system of nursing premature babies has been adopted in specialized perinatal centers:

Stage I - provision of primary resuscitation care in the delivery room, nursing in the NICU;

Stage II - nursing in specialized departments of pathology of premature infants of perinatal centers (stage of early rehabilitation);

Stage III - dispensary observation in a children's polyclinic, rehabilitation in the early recovery period in a day and round-the-clock hospital.

Despite the increase in the survival rate of such children, the risk of neurological impairment and cognitive impairment remains high [33, 31, 42, 43, 44]. The number of healthy newborns with ELBW does not exceed 10-25%, and the percentage of severe neurological outcomes ranges from 12 to 32% [24, 44].

In France, disability is much more often registered in children born at a very early preterm birth compared with children born at an early preterm birth (infantile cerebral paralysis (ICP) was 20% in children with a gestational age of 24-26 weeks and only 4 % at 32 weeks) [46].

In most modern works, much attention is paid to the stage of nursing children with ELBW in the conditions of the intensive care unit [47, 48, 49]. However, there are not enough publications in the literature devoted to the study of premature babies at the stage of early rehabilitation, where newborns are transferred after stabilization of the state and restoration of basic vital functions, due to the need for long-term respiratory support of morphofunctionally immature lungs, which dictates the need for further research.

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8. Bashmakova N. V. Survival rate and current perinatal technologies for nursing newborns with extremely low body weight. Bashmakova N.V., Kovalev V. V., Litvinova A.M. et al.  - 2012. - No. 1. - P. 4-7.
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16.  Nakhla, T. The time to death for extremely low birth weight infants in the neonatal intensive care Unit /T.Nakhla, S.Imaizumi, J.Saslow et al. //The Internet Journal of Pediatrics and Neonatology ISSN: 1528-8374. - 2007. -Vol. 6- № 2.
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19.  Nakhla, T. The time to death for extremely low birth weight infants in the neonatal intensive care Unit /T.Nakhla, S.Imaizumi, J.Saslow et al. //The Internet Journal of Pediatrics and Neonatology ISSN: 1528-8374. -2007. -Vol. 6- № 2.
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21.  Fellman, V. One-year survival of extremely preterm infants after active perinatal care in Sweden / V.Fellman, L.Hellström-Westas, M.Norman // JAMA. -2009. -Vol. 301, № 21. - Р. 2225-2233.
22. Latini, G. Survival rate and prevalence of bronchopulmonary dysplasia in extremely low birth weight infants / G.Latini, C.De Felice, R. Giannuzzi et al. // Early Hum. Dev. -2013. -Vol. 89, № 1. - Р. 69-73.
23.  Nakhla, T. The time to death for extremely low birth weight infants in the neonatal intensive care Unit /T.Nakhla, S.Imaizumi, J.Saslow et al. //The Internet Journal of Pediatrics and Neonatology ISSN: 1528-8374. -2007. -Vol. 6- № 2.
24.  Mohamed, M.A. Day-by-day postnatal survival in very low birth weight infants / M.A.Mohamed, A.Nada, H.Aly // Pediatr Neonatol. -2010. -Vol 51, № 3. - P. 160-165.
25.  Kulakov V. I. Problems and prospects of nursing children with extremely low body weight at the present stage / V. I. Kulakov, A.G. Antonov, E. N. Baybarina // Russian Bulletin of Perinatology and Pediatrics. - 2006. - No. 4. - P. 8-11.
26. Koval G. S. Features of the immunity of deeply premature newborns in infectious and inflammatory diseases / G. S. Koval, S. A. Samsygin, L. K. Kuznetsova // Russian Bulletin of Perinatology and Pediatrics .– 1999. - № 2. – P.8 – 11.
27. Ailamazyan E. K. Controversial problems of premature birth and nursing children with extremely low weight / E. K. Ailamazyan, I. I. Yevsyukova // Journal of Obstetrics and Women's Diseases. - 2011. - No. 3. - P. 183-189.
28. Vinogradova I. V. The state of health of children with extremely low body weight at birth and in long-term / I. V. Vinogradova, M. V. Krasnov // Bulletin of modern clinical medicine. - 2013. - V. 6. - No. 1. - P. 20-25.
29. Kovalenko T.V. The results of nursing children with extremely low body weight / T. V. Kovalenko, L.Yu. Zernova, N. V. Babintseva // Practical medicine. - 2013. - No. 6. - P. 84-89.
30. Hamrick, S.E. Patent ductus arteriosus of the preterm infant / S. E. Hamrick, G. Hansmann // Pediatrics. - 2010. - Vol. 125, No. 5. - P. 1020-1030.
31. Serenius, F. Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden / F. Serenius, K. Källén, M. Blennow et al. // JAMA. -2013. - Vol.309, No. 17. - P.1810-1820.
32. Valiulina A.Ya. Problems and prospects of successful nursing and rehabilitation of children born with low and extremely low body weight / A.Ya. Valiulina, E. N. Akhmadeyeva, N. N. Kryvkina // Bulletin of modern clinical medicine. - 2013. - No. 6. - P.34-41.
33. Moore, G.P. Neurodevelopmental outcomes at 4 to 8 years of children born at 22 to 25 weeks' gestational age. A Meta-analysis / G. P. Moore, B. Lemyre, N. Barrowman et al. // JAMA Pediatrics. - 2013. - Vol. 167, No. 10. - P. 967-974.
34. Orcesi, S. Neurodevelopmental outcomes of preterm very low birth weight infants born from 2005 to 2007 / S. Orcesi, I. Olivieri, S. Longo et al. // Eur. J. Paediatr. Neurol. - 2012. - Vol. 16, No. 6. - P. 716-723.
35. Volodin N.N. The modern concept of organizing perinatal care in Russia / N. N. Volodin, E. N. Baybarina, D. N. Degtyarev // Russian Bulletin of Perinatology and Pediatrics. - 2006. - No. 6. - P. 19-22.
36. Kurnosov Yu.V. Extremely preterm infants with very low and extremely low body weight who underwent transportation at early and late periods from remote areas (for example, the Perm Krai) / Kurnosov Y. V. , Merzlova N.B., L. N. Vinokurova // Fundamental research. - 2012. - No. 8. - P. 107-110.
37. Sakharova E.S. Dynamics of morbidity and developmental outcomes by 3 years of age in preterm infants observed in a specialized center / Y. S. Sakharova, Y. S. Keshishyan, G. A. Alyamovskaya // Russian Bulletin of Perinatology and Pediatrics. - 2015. - No. 3. - P. 108-112.
38. Kusuda, S. Morbidity and mortality of infants with very low birth weight in Japan: Center Variation / S. Kusuda, M. Fujimura, I. Sakuma et al. // Pediatrics. -2006. - Vol.118. - P. 1130-1138.
39. Thomas, W. Modern view of the prevention and treatment of bronchopulmonary dysplasia / W. Thomas, C. Speer // Children's medicine of the North-West. - 2012. - No. 2. - P.50-60.
40. Bashmakova N.V. Organizational principles of nursing and catamnesis of children born at the time of extremely early preterm birth in the perinatal center / N. V. Bashmakova, A. M. Litvinova, G. B. Malgina et al. // Russian Bulletin of Obstetrician - Gynecology - 2015. - No. 1. - P. 12-16.
41. Savelyeva G.M. Improvement of perinatal outcomes is one of the main problems of modern obstetrics / G.M. Savelyeva, L. G. Sichenova, R. I. Shalina et al. // Russian Bulletin of Obstetrician-Gynecology. - 2008. - No. 6. - P. 56-60.
42. 42. Gromada N.Ye. Psychomotor development of premature infants with very low and extremely low body weight during 3 years of life Gromada N.Y., Yakimova T.A. // Ural Medical Journal. - 2017. - No. 5. -P. 33-39.
43.  Klebermass-Schrehof, K. Impact of low-grade intraventricular hemorrhage on long-term neurodevelopmental outcome in preterm infants / K.Klebermass-Schrehof, C.Czaba, M.Olischar et al. // Childs Nerv. Syst. -2012. - Vol.28, № 12. - P. 2085-2092.
44.  Moore, G.P. Neurodevelopmental outcomes at 4 to 8 years of children born at 22 to 25 weeks’ gestational age. A Meta-analysis / G.P.Moore, B.Lemyre, N.Barrowman et al. // JAMA Pediatrics. -2013. - Vol. 167, № 10. - Р. 967-974.
45.  Demyanova T .G. Monitoring of deeply premature babies in the first year of life / T. G. Demyanova, L.Ya. Grigoryants, T. G. Avdeyeva et al. — M.: Medpraktika - M, 2006. — 148 p.
46. Ancel, P.Y. Cerebral palsy among very preterm children in relation to gestational age and neonatal ultrasound abnormalities: The EPIPAGE Cohort Study / P.Y. Ancel, F. Livinec, B. Larroque et al. // Pediatrics. - 2006. - Vol. 117. - P. 828-835.
47. Zakharova L. I. The reasons for the thanatogenesis of premature infants with extremely and very low body weight in the early neonatal period according to the perinatal center / L. I. Zakharova, N. S. Koltsova, S. A. Tupikova //Practical Paediatric Problems. — 2010. - No. 1. — P. 24.
48. Nikulin L. A. Immunocorrection in the neonatal period: a manual for doctors / L. A. Nikulin, D. A. Kayumova M.G., M. A. Kulagina and others - Krasnodar, 2005. - 56 p.
49. Charipova B.T. Clinical characteristics of children with extremely low birth weight Charipova B.T., Chistyakova G.N., Chistyakova M.N. Tarasova et al. // Ural Medical Journal. — 2010. — No. 5. — P. 147-151.

1.2. Perinatal risk factors for the birth of premature infants

To identify a complex of unfavorable factors of ante- and intranatal nature that caused the birth of premature infants with extremely low body weight, the obstetric and gynecological history, features of the gestational period and childbirth were studied in 114 women hospitalized at the FSBI "The Ural Research Institute of Maternity and Child Care" The Ministry of Health of the Russian Federation. This study was approved by the local ethics committee of the institute. We received informed voluntary consent from all women for the processing of personal data, treatment, examination.

The classification of preterm birth, adopted in 1993 in the Russian Federation, in which, depending on the gestational age was fundamental in the division of the groups, the following groups were identified:

1st group – early childbirth (22-27 weeks, the weight of the baby is within 500-999 grams)

2nd group – premature birth (28-33 weeks, 1000-2000 grams)

3rd group – full-term pregnancy (37-40 weeks, 2500 grams or more)

All surveyed women were comparable in age. The average age of women in groups 1 and 2 was: 30.13 ± 5.66 years and 30.27 ± 6.11 years, respectively. In the group of women who gave birth to full-term newborns, this indicator was slightly lower - 29.41 ± 2.97 years (р_{1-3, 2-3}>0,05). Most of the mothers of all groups had a permanent place of work (63 %, 74,4 %, 96 %, p_1-2>0,05, p_1-3,2-3<0,005). Less than half of women who gave birth at the time of very early preterm birth were married (47.8% and 60.5% in groups 1 and 2, 84% in the comparison group  (p_1-2>0,05, p_1-3=0,002_,p_2-3=0,015)) and less than a third lived in the city (23.9% in the 1st, 30% in the 2nd and 28% in the comparison group). Bad habits, such as nicotine addiction and alcohol consumption, were not practically observed (4.34% in the 1st, 4.65% in the 2nd and 0% in the comparison group).

The structure of extragenital pathology is shown in Table 1.

Table 1

The structure of extragenital pathology of mothers in premature infants

Note. In connection with the identification of several pathological signs in the same woman, the total number of cases exceeds 100%, p1-2, p1-3, p2-3 - the significance of differences between groups of mothers (χ2 test with a Yates correction): 1 - mothers, those who gave birth to children at 22-27 weeks' GP, 2 - mothers who gave birth to children at 28-31 weeks' GP, 3 - a comparison group.

Extragenital pathology is an unfavorable background that affects the capabilities of adaptive mechanisms, the limitation of which, in turn, leads to complications of pregnancy, childbirth and the postpartum period. The morbidity patterns of women who gave birth to children with ELBW was characterized by a high frequency of extragenital pathology. Hypertension was recorded significantly more often in women of the second group  - in 25.68% versus 8.69% of cases in the first group (p1-2 = 0.04).

HIV infection was noted in the anamnesis of two women of the main groups.

Comparative analysis of maternal medical history data showed an extremely unfavorable course of the antenatal period (Table 2).

                                                                                                                   Table 2

Obstetric history of the mothers of the observed children

Note. p1-2, p1-3, p2-3 - the significance of differences between the groups of mothers (χ2 test with a Yates correction): 1 - mothers who gave birth to children at 22-27 weeks' GP , 2 - mothers who gave birth to children at 28-31 weeks' GP, 3 - comparison group.

More than 60% of all women were re-pregnant (71.44%, 67.44% and 60% of cases). A burdened obstetric history was noted in half of the women examined, the leading factors were spontaneous miscarriages and induced abortions, no significant differences were found between the compared groups. Spontaneous miscarriages were recorded in every fifth woman in the main groups and in every sixth comparison group (р_1-2,1-3,2-3≥0,05). Artificial terminations of pregnancy among women with preterm birth were 1.55 and 1.91 times more frequent than women who gave birth to full-term infants. Agenesia (primary, secondary) in women who gave birth to children of gestational age of 22-27 weeks was diagnosed 3.75 times more often than in group 2. In the comparison group, this pathology was not registered. There were no significant differences in the incidence of regressing pregnancies in mothers of children of both groups. The onset of pregnancy by assisted reproductive technologies (ART) was noted in 2 and 3 cases among women in the main groups. In women in the comparison group, pregnancies occurred without medical intervention.

Among the complications of pregnancy in women of the main groups, preeclampsia of moderate severity was more common (р_1-2≥0,05, р_1-3=0,02, р_2-3=0,005), its severe course was observed only in every eighth patient (Table 3 ).

The threat of termination of this pregnancy was diagnosed in more than half of the women in the main groups. Chronic placental insufficiency (CPI) was more often observed in a subcompensated form (р_1-3=0,003, р_2-3=0,0001, р_1-2≥0,05), in the comparison group there was only a compensated form in one woman.

Uteroplacental blood flow disorder (UBFD) was recorded among all women with preterm labor. However, severe degree was found significantly more often in mothers of the 2nd group (р_1-2=0,006, р_1-3=0,026, р_2-3=0,00001), which is possibly associated with a longer course of CPI in this category. Low water level prevailed over polyhydramnios, being detected significantly more often in women who gave birth at 28-31 weeks of gestation period (р_1-2=0,005, р_1-3=0,00024, р_2-3=0,0001).

Table 3

Features of the course of this pregnancy

Note. Note. In connection with the identification of several pathological signs in the same woman, the total number of cases exceeds 100%, p1-2, p1-3, p2-3 - the significance of differences between groups of mothers (χ2 test with a Yates correction): 1 - mothers, those who gave birth to children at 22-27 weeks' GP, 2 - mothers who gave birth to children at 28-31 weeks' GP, 3 - a comparison group.

Gestational diabetes mellitus, which increases the likelihood of pregnancy complications due to increased insulin secretion and decreased sensitivity to it, was diagnosed in a quarter of women in group 2 (_p2-3 = 0.007, _p1-2.1-3≥0.05). Premature rupture of the fetal bladder (PRFB) was observed significantly more often in women who gave birth to children of gestational age of 22-27 weeks (_p1-2 = 0.024). It was also accompanied by a long anhydrous interval of more than 12 hours, which was one of the risk factors for preterm birth. Chorioanionitis was identified significantly more often in women of the 1st group (_p1-2 = 0.007, _p1-3 = 0.017). Premature detachment of the normally located placenta was detected only in the main groups (_p1-3 = 0.026, _p1-2.2-3≥0.05). Operative delivery of mothers of premature infants in the interests of the mother and the fetus by caesarean section was significantly higher compared to the comparison group (67.4% and 86% versus 60%, _p2-3 = 0.045). The main indications for surgery were preeclampsia of moderate and severe severity, sub- and decompensation of uterine-fetal blood flow, progressive placental abruption. In the comparison group, the delivery of women in a planned manner by caesarean section was carried out according to the indications of the mother.

Thus, the antenatal period of children with ELBW proceeded against the background of the threat of termination of pregnancy, preeclampsia of moderate severity, chronic placental insufficiency, oligohydramnios, and isthmic-cervical insufficiency. Chorioamnionitis and premature rupture of the membranes were found significantly more often in women with very early preterm birth, while in women with early preterm labor - grade III UBFD, which subsequently led to a complicated course of the postnatal period of newborns. In the course of the study, it was found that the antenatal period of children with ELBW proceeded against the background of the threat of termination of pregnancy, moderate preeclampsia, chronic placental insufficiency, oligohydramnios, and isthmic-cervical insufficiency. Chorioamnionitis and premature rupture of the fetal bladder were found significantly more often in women with early preterm labor, while in women with early preterm labor - grade III UBFD, which subsequently led to the more frequent development of infectious pathology (sepsis and pneumonia - 78.6%) and death (8.7%) in the early neonatal period in newborns with GA of22-27 weeks and FGRS in children with GA of28-31 weeks (83.7%).

According to the literature, along with infectious and inflammatory pathology, the causes of death include respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), left ventricular failure and systemic hypotension, hemodynamically relevant functioning ductus arteriosus (HRFDA) [1, 2, 3, 4, 5]. The severity of respiratory disorders in this category of children is associated with gestational age, body weight, sex of the child and the characteristics of the maternal medical history [6, 7]. The results obtained in this study also indicate that the Apgar score, severe somatic, infectious pathology and preeclampsia in mothers, which were significantly more common in women of the 1st group, were of significant importance in the severity of RDS. The mode of delivery is also a significant factor that affects the condition of the child at birth and further postnatal adaptation. Babies who later died were born via natural maternal passages, however, according to Adams M., planned cesarean section does not have any advantages over vaginal birth in this contingent of children [8]. According to N. V. Bashmakova, the best survival rate of deeply premature infants with ELBW was observed at a gestational age of more than 26 weeks, while it is preferable to use an operative method of delivery. Moreover, with a gestational age of less than 26 weeks, the mode of delivery did not affect the outcome [9].

Reference:

1. Ailamazyan E. K. Controversial problems of preterm birth and nursing children with extremely low weight / E. K. Ailamazyan, I. I.  Yevsyukova // Journal of Obstetrics and Women's Diseases. - 2011. - No. 3. - P. 183-189.

2. Volodin N.N. Bronchopulmonary dysplasia: teaching aid / N. N.  Volodin. — M.: SEI HVE "RSMU" Roszdrav, 2010. —  56 p.

3. Kovalenko T. V. The results of nursing children with extremely low body weight / T. V. Kovalenko, L.Yu. Zernova, N. V. Babintseva // Practical medicine. - 2013. - No. 6. - P. 84-89.

4. Hamrick, S.E. Patent ductus arteriosus of the preterm infant / S.E. Hamrick, G. Hansmann // Pediatrics. -2010. -Vol. 125, No. 5. -P. 1020-1030.

5. Rocha, G. On the limit of viability extremely low gestational age at birth / G. Rocha, H. Guimarães // Acta Med. Port. -2011. - Vol.24, No. 2. - P.181-188.

6. Pavlinova E. B. The course and outcomes of respiratory distress syndrome in newborns of various gestational ages / E. B. Pavlinova, T. V. Oksenchuk, N. G. Marenko et al. // Practical Paediatric Problems. -2010. - No. 3. - P.12 -15.

7. Xu, F.L. Perinatal conditions of preterm infants with different severities of respiratory distress syndrome / F.L.Xu, F.L. Zhuang, Q.D. Bai et al. // Zhongguo Dang Dai Er Ke Za Zhi. -2011. -Vol.13, No. 10. - P. 80-782.

8. Adams, M.M. The future of very preterm infants: learning from the past / M.M. Adams, W. D. Barfield // JAMA. -2008. - Vol.299, No. 12. - P. 1477-1478.

9. Bashmakova N. V. Analysis of the management of preterm labor that ended in the birth of children with ENMT: the first experience in the era of new criteria for live birth / N. V. Bashmakova, A. V. Kayumova, O. A. Melkozerova // Obstetrics and gynecology. - 2013. - No. 6. - P. 41-45.

Chapter 2. FEATURES OF THE POSTNATAL PERIOD OF PREMATURE INFANTS

2.1. Clinical aspects of perinatal complications in children with extremely low body weight

Perinatal hypoxia, together with morphofunctional immaturity, anatomical, physiological and adaptive capabilities of the body, has a pronounced effect on the course of the neonatal period and long-term prognosis of a deeply premature newborn [1]. Perinatal damaging factors and disruption of the child's adaptation to extrauterine life can disrupt the genetically determined normal development and differentiation of neurons and become a substrate for the implementation of the pathological process, especially in the periventricular zones taking into account the deep immaturity of the brain and compensation mechanisms that can protect it [2]. The lack of mechanisms for autoregulation of the vascular network in the periventricular zones directly depends on the state of systemic hemodynamics [3, 4]. In this regard, the problem of prevention of subependymal hemorrhages (SH) is especially urgent, given their frequency, high morbid and thanatogenic role [5, 6, 86]. There is an extremely thin line between the process of increasing the severity of SH and their transformation into intraventricular hemorrhages (IVH), therefore it is very important to prevent this process during the period of early neonatal adaptation of children with ELBW [7].

 Due to the anatomical and physiological characteristics of the nervous system, IVHs are prevalent mainly in premature infants, the frequency and severity of IVHs is inversely proportional to gestational age. With I and II degrees of hemorrhagic lesions of the central nervous system, the prognosis is usually favorable, with IVH of III degree, up to 40% of deeply premature infants have significant impairment of cognitive functions, and almost 90% with IVH of IV degree become disabled due to severe neurological disorders [8, 9]. Due to anatomical and physiological features and lack of vascular autoregulation mechanisms, the periventricular zones of the brain of deeply premature infants are threatened by the development of hypoperfusion and tissue ischemia, the formation of periventricular leukomalacia (PVL) -polyethiological lesion of the white matter of the brain, the leading provoking factors of development of which are       hypoxia/asphyxia at birth, infection (maternal chorioamnionitis, early sepsis), respiratory disorders leading to changes in blood pressure and gas homeostasis [3, 10, 11, 12, 13, 14]. PVL is diagnosed in up to 10-15% of deeply premature infants with ELBW and leads to the formation of cerebral palsy and visual impairment [9]. The development of cystic PVL, which is white matter gliosis in the brain, is the most unfavorable in terms of long-term neurological prognosis i.e. a high risk of severe retardation of psycho-motor development, neurosensory disorders, cerebral palsy (CP), epilepsy [3, 15].

In the literature, data are indicated on the relationship between the development of PVL and the severity of respiratory disorders, for example, deeply premature infants who retained spontaneous breathing from birth developed PVL in 6% of cases, while newborns unable to breathe on their own developed PVL in 60%. The incidence of PVL in children born at the time of early preterm birth who died after the end of the early neonatal period was 75%, while in surviving children it was 4-10% [3]. According to N. V. Bashmakova and co-authors, infectious pathology is in third place in the structure of morbidity in children with ELBW [15]. According to the literature data of national authors, the most significant infections (intrauterine generalized infections, bacterial sepsis, pneumonia, generalized candidiasis, necrotizing enterocolitis) occupy a leading place in the causes of mortality in deeply premature infants and are defined as the most important prognostic factor in relation to unfavorable delayed results [16, 17]. The predisposition of children with ELBW to a generalized infectious process is due to the failure of the immune system, immaturity of skin and epithelial barriers, and a high frequency of invasive manipulations [18].

 The mortality rate of deeply premature infants with infectious pathology reaches 25-65%, significantly (5-10 times) higher than the level in full-term newborns [19]. In recent years, the issue of the nosocomial nature of infectious pathology in children with ELBW who survived the early neonatal period and are in the NICU for a long time has been actively discussed [20].

The most significant cause of infectious pathology of the perinatal period of deeply premature infants is intrauterine infection (UI) [21], which is characterized by placentitis, leading to chronic placental insufficiency and the birth of premature infants [22]. Difficulty in the diagnosis of the infectious process is associated with the complexity of interpretation or the absence of a number of clinical symptoms and laboratory parameters in newborns with ELBW due to a protracted course that mimics RDS in the first days of life, CNS damage, especially with aggravation of FGRS, IVH, malformations, extreme immaturity [8 , 23]. Modern therapeutic and prophylactic approaches aimed at reducing the incidence of infectious pathology in this category of children are not effective enough [24], and the clinical and diagnostic aspects of sepsis are constantly being revised [25, 26, 27]. To make a diagnosis of sepsis, it is necessary to isolate the systemic inflammatory response syndrome with multiple organ failure [28].

Neonatal sepsis is a risk factor for delayed neurological complications and a leading cause of mortality, accounting for 25 to 45% according to the authors [29, 30, 31, 32]. At the same time, overdiagnosis of bacterial infection in deeply premature infants leads to the unjustified prescription of antibiotic therapy and polypharmacy. The authors argue that long-term routine prophylactic antibiotic therapy and administration of immunoglobulins with negative results of blood culture does not reduce the risk of developing an infectious process (pneumonia and sepsis) in children with ELBW [33] and can cause serious complications, increasing the risk of developing necrotizing enterocolitis (NEC) and death [34].

In recent years, the number of children with hemodynamically relevant functioning ductus arteriosus (HRFDA) has been increasing, and the number of cases of clinically pronounced functioning ductus arteriosus is inversely proportional to gestational age. Long-term preservation of HRFDA is observed mainly in children with ELBW, who were born at the time of very early preterm birth. HRFDA negatively affects lung tissue, is a risk factor for the formation of NEC, IVH and hypoxic lesions of the central nervous system [35]. On the background of HRFDA during the adaptation period in premature newborns, transient persistent pulmonary hypertension (PPH) can be observed, which occurs according to M. V. Fomichev (2006) in 15-35% [36]. The process develops after long-term oxygen therapy due to spasm and hyperplasia of the muscular sheath of small pulmonary arteries, which leads to a pronounced increase in vascular resistance [35, 36]. Treatment of HRFDA is carried out with cycooxygenase inhibitors, the effectiveness of which reaches 75-80% with early application [37].

One of the reasons that worsen the quality of life of children with ELBW is anemia of prematurity, which develops due to an increase in the volume of circulating blood against the background of the rapid growth of the child, incommensurate with the rate of erythropoiesis, a short life span of fetal erythrocytes, low production of erythropoietin. Therefore, repeated blood transfusions are concomitant component of therapy [38. 39]. Anemias develop the more often, the shorter the gestational age and the baby's body weight at birth. Term infants, in contrast to infants with ELBW, are capable of responding with rapid production of erythropoietin to hypoxia [38].

According to the literature, in the structure of neonatal morbidity in deeply premature infants, there is a combined pathology. The first places are traditionally occupied by respiratory distress syndrome (RDS), hypoxia and asphyxia. Infectious pathology in the structure of morbidity is in third place [40].

Respiratory distress syndrome (RDS) in newborns with ELBW is the most common cause of respiratory distress, often leading to death [9, 41]. Rates of neonatal mortality from RDS range from 20 to 95% [42]. The severity of respiratory disorders in this category of children is associated with gestational age, body weight, sex of the child and the characteristics of the maternal history [43, 44, 45]. The reason for the development of RDS is surfactant deficiency and morphological immaturity of the lung tissue. The synthesis of surfactant begins at the 26th week of gestation, therefore, the incidence of RDS is inversely proportional to the gestational age and body weight at birth. According to Russian authors, RDS develops in 78–88% with gestational age up to 28 weeks, 70% - up to 29–30 weeks, 50–55% - up to 31–32 weeks [42]. Previously, the main method of treatment of respiratory disorders in RDS was artificial lung ventilation (ALV) [46]. To date, there are several approaches to the use of surfactant drugs, the leading role, undoubtedly, is given to preventive therapy [42]. The advantages of early prophylactic surfactant administration in the delivery room versus delayed administration in the intensive care unit of newborns is a reduction in neurological complications, bronchopulmonary dysplasia, necrotizing enterocolitis, and mortality in premature infants. There is evidence in the literature that early administration of a surfactant and the use of respiratory support by the CPAP method after birth in children with ELBW with respiratory disorders reduces the length of stay of children in intensive care units for newborns and early rehabilitation [42]. Despite the improvement of life-saving treatment methods, it is not possible to completely prevent the most severe complication of RDS i.e. bronchopulmonary dysplasia (BPD), which has a great impact on the prognosis of the health of children with ELBW, and in severe cases, life [9].

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32. Mularoni, A. The role of coagulase-negative staphylococci in early-onset sepsis in a large European cohort of very low birth weight infants / A. Mularoni, M.Madrid, A.Azpeitia et al.// Pediatr. Infect. Dis J. - 2014. - Vol. 33, № 5- P.121-125.
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2.2. Clinical features of children with extremely low birth weight

Our study involved 89 children with ELBW of gestation at 22-31 weeks gestational age who were nursed at the Department of Early Neonatal Rehabilitation and 25 healthy preterm infants.

In the course of the study, all deeply premature infants with ELBW, depending on the gestational age at birth (body weight less than 1000 g at birth), were divided into two main groups with respect to 28 weeks - gestational age, which is the “zone of extreme immaturity” for newborns, according to ICD- X. The maturity of a newborn child is the most important indicator of intrauterine development, which is determined by the totality of clinical, morphological, biochemical and functional signs specific to a given gestational age of the child.

The distribution of children into groups by birth weight, namely from 500 to 749 grams (“zone of the viability limit”, gestation period 22-26 weeks) [176] and from 750 to 999 grams, we considered incorrect due to the high percentage of perinatal losses in the 1st group (39.1% versus 12.6% of children) [16] and the presence of survivors in the 1st group of children weighing from 500 to 749 g with fetal growth retardation syndrome (FGRS), born at an early stage premature birth.

Thus, with this in mind, premature infants were divided into two main groups:

Group 1 - 46 infants with ELBW, born at a gestational age of 22-27 weeks;

Group 2 - 43 infants with ELBW, born at a gestational age of 28-31 weeks.

Group 3 - a comparison group - 25 full-term healthy newborns born to conditionally healthy women of favorable reproductive age (20-34 years) with physiological pregnancy, childbirth and the postpartum period. The children of the comparison group having been breastfed from the moment of birth, had a physiological neonatal period and were discharged at the age of 4-5 days of life in a satisfactory condition.

Clinical observation and immunological studies were carried out from the moment of birth and after reaching the postconceptinal age (37-40 weeks).

Analysis of the clinical condition showed that all premature infants were born with low scores on the Apgar scale, which reflects the severity of asphyxia and intrauterine suffering. In children with GA of22-27 weeks in the first minute, severe asphyxia was more often detected (less than 3 points on the Apgar scale) in 26.19% of cases versus 16.27% (p1-2> 0.05) children with GA of28- 31 weeks (Table 4).

Table 4

 Assessment on the Apgar scale in children with ELBW (М ±σ)

Note. р1-2, р1-3, р2-3 - significance of differences between groups of children (Student's test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

30 (65.21%) and 23 (53.49%) premature infants (4-5 points on the Apgar scale at the 1st minute of life, p1-2> 0.05) had signs of a moderate degree of asphyxia. All full-term babies were born without signs of asphyxia.

Asphyxia is a state of disturbance of gas homeostasis, accompanied by hypercapnia, hypoxemia and metabolic (or mixed) acidosis [1]. Until the mid-80s of the last century, the main criterion for the severity of newborn asphyxia was the assessment according to the Apgar scale of the International Classification of Diseases (IX revision 1975), (rubrics 768, 768.5; 768.6). A number of authors believe that the Apgar scale is less informative in predicting hypoxic brain damage in newborns than pH and base deficiency (BE), and the dynamics of neurological complications is most important [2, 3]. Metabolic acidosis more adequately reflects the severity and duration of perinatal hypoxemia. The BE indicator is more informative in comparison with pH, ​​since it is not affected by respiratory acidosis, and it correlates with metabolic acidosis [4].

When assessing the parameters of the electrolyte and acid-base composition of blood in premature newborns of the 1st group in the first hours of life, a statistically significant decrease in the level of sodium and partial oxygen tension was revealed in comparison with the newborns of the 2nd group (Table 5).

Table 5

Indicators of the acid-base balance of children with ELBW at birth (M±s)

Note. р1-2 - significance of differences between groups of children (Student's test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

The deficiency of buffer bases in infants with a younger gestational age was more pronounced (p1-2 = 0.07) than in children of gestational age 28-31 weeks.

Premature infants of both groups were characterized by hyponatremia (p1-2 = 0.05) against the background of hyperkalemia, which indicates the extreme immaturity of the excretory system of children due to insufficient maturation of the kidney pores [5].

In the 1st group of children in the acid-base balance, metabolic acidosis was the leading disorder. This disorder was noted in 23.91% of cases, in the remaining children with ELBW, changes were diagnosed in the form of mixed acidosis (19.56%), respiratory acidosis (4.34%) and respiratory alkalosis (2.17%).

In group 2, metabolic acidosis also dominated in 27.9% of cases, mixed and respiratory acidosis was noted somewhat less frequently (18.6% and 23.26%).

The average gestational age of children born at the time of very early preterm birth significantly differed from the same indicator for children of the 2nd and 3rd groups (Table 6) (p <0.001 in all cases).

Table 6

Anthropometric data of children with ELBW (М ±σ)

Note. р1-2, р1-3, р2-3 - significant differences between groups of children (Student's test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

By gender, the main groups were comparable.

Anthropometric indicators of premature newborns, with the exception of body length, also significantly differed (p <0.001 in all cases).

Thus, children from very early preterm births had lower anthropometric data at birth, which is associated with a lower gestational age (22-27 weeks). All premature infants were born in a state of asphyxia, which is confirmed by low Apgar scores and metabolic acidosis based on the results of the study of gas homeostasis.

Reference:

1. Low, J. Antepartum fetal asphyxia in the preterm pregnancy / J.Low, E.Killen, J.Derrick // Am. J. Obstet Gynecol. - 2003. - Vol.45. - P.188-461.
2. Filkina O. M. Perinatal lesions of the nervous system and their consequences in children: clinical picture, prognosis, diagnosis, prevention and correction, somatic health. – Ivanovo, 2007. – 238p.
3. Shabalov N. P. Asphyxia of newborns / N. P. Shabalov, V. A. Lyubimenko, A. B. Palchik. - M.: Medpress-M, 2003. - 123 p.
4. Hummler, H. Accuracy of pulse oximetry readings in an animal model of low perfusion caused by emerging pneumonia and sepsis / H.Hummler, A.Engelmann, F.Pohlandt // Intensive Care Med. - 2004. - Vol. 231. - P.234-236.

5. Volodin N. N. Neonatology: national leadership / ed. by N. N. Volodina. — M.: GEOTAR-Media, 2007. - 848p.

2.3. Features of the course of the postnatal period in children with extremely low body weight

According to our data, fetal growth retardation syndrome (FGRS) in children born from early preterm birth was recorded much more often than in children with gestational age of 22-27 weeks (p1-2 = 0.0001) (Table 7), which associated with UBFD and clinical manifestations of chronic renal failure.

Table 7

Degree of incidence of FGRS in children with ELBW

Note. р1-2, р1-3 р2-3 - significance of differences between groups of children (Mann-Whitney test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

At the same time, hypoplastic (small fetal size for GA according to ICD X) and hypotrophic (“low weight” fetus for GA according to ICD X) variants of FGRS prevailed 4.5 times more often in children born at 28-31 weeks of GA.

From the operating and delivery unit, all deeply premature infants with ELBW in serious condition were transferred to the intensive care unit and neonatal intensive care unit (NICU) to create optimal conditions for nursing. All premature infants received enteral feeding from the first day of life, children of the 2^nd group in a greater percentage of cases were fed with breast milk (79% versus 47.83%, _p1-2 = 0.015).

Early neonatal mortality among children born at the very early preterm birth was 8.7% (4 children).

Infectious diseases (early neonatal sepsis), confirmed by laboratory data (high level of C-reactive protein, positive blood culture), were in the lead in the structure of the causes of death in children with GA of22-27 weeks. When analyzing the identified pathogens of blood culture, gram-negative flora prevailed i.e. in 75% of cases Klebsiella and E. coli were found, in 25% of cases - Staphylococcus haemolyticus.

With the stabilization of vital functions, effective spontaneous breathing, most children with ELBW (1^st group - 93.48%, 2^nd group - 100%) at the age of 1 month of life were transferred to the neonatal pathology department to continue nursing and treatment (Table. 8).

Table 8

Average duration of respiratory therapy, ICU stay and NPU

Note. р1-2 - significance of differences between groups of children (Student's criterion): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

Combined pathology was noted in the morbidity structure of very premature infants with ELBW. 100% of premature infants suffered from RDS of various degree of severity. However, mechanical ventilation was required for 89.1% and 58.1% of newborns in groups 1 and 2 (Table 9).

The need for long-term mechanical ventilation in children of group 1 was significantly higher than in children of group 2, which was due to the severity of the condition and greater immaturity of the alveoli (p1-2 = 0.0001). Term infants had no neurological and somatic pathology, they were discharged  in satisfactory condition, breastfed on 3-5 days of life.

 Table 9

The structure of morbidity in children with ELBW at the age of 1 month of life

Note: due to the detection of several pathological signs in the same child, the total number of observations does not correspond to 100%. р1-2 is the significance of differences between groups of children (χ2 criterion with Yates' correction): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

Most children with ELBW were diagnosed with hypoxic-ischemic damage to the central nervous system of severe severity, cerebral ischemia of the II degree in children with GA of 28-31 weeks did not exceed 12% of cases. According to the "Classification of Perinatal Nervous System Affections in Newborns" (2005), the severity of CNS affections was determined by the presence of neonatal seizures, the duration of the depression syndrome, and the dynamics of structural changes in the brain according to NSG [1].

In children of gestational age of 22-27 weeks, severe forms of intraventricular hemorrhage (IVH) were significantly more frequent. So, II degree of IVH was diagnosed 5.63 times (_p1-2 = 0.02), and III degree 4 times more often than in children of the 2^nd group (_p1-2 = 0.023), which is primarily due to good blood supply to the germinal matrix, the vessels of which have wide lumens without muscle fibers and basement membrane, which contributes to high vulnerability.

Due to the increased susceptibility of premature infants to infectious agents, there was a high frequency of infectious and inflammatory pathology, more characteristic of children of gestational age of 22-27 weeks, so pneumonia and sepsis were diagnosed reliably more often than in children of the 2^nd group (_p1-2 = 0.0001). Intrauterine sepsis of staphylococcal etiology in children of the 1st group occurred 4 times more often than in children of gestational age of 28-31 weeks (19.04% and 4.65%, p = 0.023). Early neonatal pneumonia was diagnosed in 23.8% of cases in newborns of the 1st group and in 13.95% of cases in newborns of the 2nd group. There were no significant differences in the incidence of cytomegalovirus infection (CMVI) and meningitis. Congenital cytomegalovirus infection was diagnosed in 4.76% and 2.32% of cases of children with ELBW. Anemia of severe prematurity was more often diagnosed in children of the 1^st group (p1-2 = 0.017), which is associated with factors of incomplete ontogenesis, and can also be one of the manifestations of infection and potentiate its postnatal development. Bronchopulmonary dysplasia by the age of 1 month of life was diagnosed in children of the 1^st group significantly more often (26.19% versus 2.32%), which was associated with a greater immaturity of the alveoli and the need for prolonged mechanical ventilation.

Patent ductus arteriosus was diagnosed reliably more often in children born at the time of very early preterm labor (_p1-2 = 0.024), which is consistent with the authors' data [2].

By the age of one month, more than half of premature infants of GA of 28-31 weeks remained breastfed, with the addition of a breast milk fortifier (65.12%), in contrast to children of the 1st group (42.85%, _p1-2> 0.05) , weight gain from the moment of birth of children of both groups did not differ significantly.

When analyzing the acid-base balance of premature infants at 1 month of age, no significant differences were found, with the exception of persistent hyponatremia, which was more pronounced for the 1^st group (_p1-2 = 0.0095) (Table 10).

Table 10

Indicators of acid-base balance in children with ELBW at the age of 1 month of life (M±s)

Note. р1-2 - significance of differences between groups of children (Student's criterion): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

In the 1^st  group of children, the dominant disorder in the acid-base balance at 1 month of life was respiratory acidosis, which was noted in 33.33% of cases, in 2.38% of children, disorders in the form of metabolic acidosis were noted.

In 2^nd group, respiratory acidosis also dominated in 25.58% of cases, metabolic acidosis was noted somewhat less frequently (4.65%).

Children with a shorter gestation period spent a longer time in the ICU on ALV, which led to a later transfer to the stage of early rehabilitation. By the age of 1 month, very premature babies had associated pathology. In children of the 1st group, IVH of II, III degree were significantly more often diagnosed, anemia of severe severity requiring blood transfusions, a higher frequency of infectious and inflammatory pathology (pneumonia, sepsis) was revealed. A higher incidence of BPD in this category of children was associated with prolonged exposure to mechanical ventilation and was accompanied by respiratory acidosis due to gas homeostasis.

Upon reaching PCA 38-40 weeks, both groups had concomitant pathology (Table 11).

Table 11

The morbidity patterns in children with ELBW to PCA 38-40 weeks

Note: due to the identification of several pathological signs in the same child, the total number of observations does not correspond to 100%, р1-2, р1-3, р2-3 - the significance of differences between groups of children (χ2 criterion with Yates' correction): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

After past RDS in case of clinical and radiological examination, moderate and severe bronchopulmonary dysplasia was diagnosed more often in children of group 1 (_p1-2> 0.05), which is consistent with the authors' data [3]. The classical form of BPD prevailed over the “new” one and was found significantly more often in children of the 1^st group (50% versus 34.9%, _p1-2 = 0.013).

The frequency of intraventricular hemorrhages of varying severity remained higher in children of the first group (p = 0.03). During the time of being at the stage of early rehabilitation, the number of IVH of the 1^st degree among children with ELBW increased to 19.04% and 25.58%. Occlusive hydrocephalus was diagnosed in two children with GA of22-27 weeks with IVH degree III, requiring surgical intervention (4.76%).

In the clinical picture of CNS damage in very premature infants with ELBW, the syndrome of motor disorders of the type of lower spastic paraparesis was the leader in 26.19% and 44.19% of children with GA of22-27 and 28-31 weeks (р1-3 = 0.0003, р2 -3 = 0.00007). Spastic tetraparesis was observed in premature infants of the 1^st  group in 11.9% of cases, the 2nd - in 2.32%. Hypertensive-hydrocephalic syndrome was detected in 80.1% and 65.11% of children in the main groups. Bulbar disorders and convulsive syndrome were diagnosed only in children born at the time of very early preterm birth, in 7.14% of cases.

The frequency of infectious and inflammatory pathology (pneumonia) also remained at a high level in children of gestational age of 22-27 weeks (_p1-2 = 0.0001). By the post-conceptual age of 38-40 weeks, the detection rate of cytomegalovirus infection in children of both groups increased by 1.5 and 4 times, which is possibly associated with repeated blood transfusions.

All children of the main groups were diagnosed with premature anemia. However, the number of blood transfusions performed was significantly higher in children of gestational age 22-27 weeks (2.59 ± 1.99 versus 1.49 ± 1.4 times, _p1-2 = 0.008).

Significant differences were found in the incidence of retinopathy, which is characteristic only of preterm infants, the severity of which is inversely proportional to the gestational age of the child [4]. The incidence of  retinopathy degree II in the groups was comparable, while  retinopathy degree III occurred 2.6 times more often in children born at the time of very early preterm labor (_p1-2 = 0.039), for which the children underwent repeated laser coagulation of the avascular zones retina. PH V degree was not detected in any child.

Inguinal hernias in children of both groups were more common than umbilical hernias, however, there were no significant differences in the frequency of hernias.

By PCV 38-40 weeks, the number of children exclusively breastfed with the addition of the fortifier decreased 3.42 and 1.23 times (up to 19.05% and 34.88%) of children of both groups (_р1-2> 0, 05) (Table 12).

 Table 12

Feeding patterns of children with ELBW

Note. р1-2 - the significance of differences between groups of children (Student's test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

When assessing the body weight of premature infants in the dynamics of the postnatal period after reaching the postconceptional age of 38-40 weeks, significant differences were revealed (Table 13).

Table 13

Dynamics of changes in body weight of very premature infants (М ±σ)

Note. р1-2 - the significance of differences between groups of children (Student's test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

At birth, the body weight of children born at the time of very early preterm birth was significantly lower (_p1-2 = 0.006), by the age of 1 month, the weight gain of children of the 2^nd group exceeded the indicators of children with a shorter gestation period. However, upon reaching the age of a full-term newborn, children of the 1^st group had higher body mass indices (_р1-2 = 0.002).

When the PCA reached 38-40 weeks, when studying the indicators of the acid-base balance, no significant differences were found (Table 14). The calcium level of children of gestational age 22-27.6 weeks was decreased at the level of the trend. According to some authors, in premature infants, the system that maintains a sufficient level of blood calcium is formed later, which creates special difficulties for them in phosphate-calcium homeostasis [5].

In both groups of premature infants, the dominant disorder in the acid-base balance was respiratory acidosis (11.9% and 6.98% of cases), which correlates in children with severe BPD.

Table 14

Indicators of acid-base balance in children with ELBW at 38-40 weeks of PCA (M±s)

Note. р1-2 - the significance of differences between groups of children (Student's test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation.

During the nursing period, all premature infants received antibiotic therapy, the duration of which was longer in the 1st group of children (43.19 ± 12.95 versus 28.79 ± 8.76 days, p = 0.0004), which is associated with more a high frequency of infectious and inflammatory pathology and a long stay in a hospital.

The frequency of use of immunobiological drugs, such as "Pentaglobin", was comparable in both groups (2.43 ± 1.88 and 2.39 ± 1.86 times, p <0.05). All premature infants diagnosed with CMV disease were treated by intravenous administration of "Neocytotect" and "Virolex" as prescribed by an Infectious Disease Physician.

Upon reaching PCA 38-40 weeks, children born in the term of very early preterm birth had a more complicated somatic pathology: a high level of ischemic-hemorrhagic affection of the central nervous system and bronchopulmonary dysplasia of severe severity, threshold retinopathy and infectious and inflammatory pathology (pneumonia) remained.

Thus, the postnatal period of deeply premature infants with ELBW was characterized by severe concomitant pathology.

Considering the deep immaturity of the brain and compensation mechanisms that can protect it, perinatal damaging factors and disruption of the child's adaptation to extrauterine life disrupt the genetically determined normal development and differentiation of neurons and become fertile ground for the implementation of the pathological process, especially in the periventricular zones [6]. All very premature infants were diagnosed with hypoxic-ischemic affection of the central nervous system against the background of postponed asphyxia at birth in the early neonatal period. Severe brain damage was more often detected in newborns with GA of22-27 weeks, in which subsequently severe IVH was diagnosed reliably more often due to the lack of mechanisms of autoregulation of the vascular network of the periventricular zones, which is consistent with the data of domestic and foreign authors [7, 8].

Due to anatomical and physiological features and the absence of vascular autoregulation mechanisms, the periventricular zones of the brain of deeply premature infants are threatened by the development of hypoperfusion and tissue ischemia, the formation of periventricular leukomalacia (PVL), the leading provoking factors of the development of which are severe hypoxia / asphyxia at birth, infection (chorioamnionitis in the mother, early sepsis), respiratory disorders leading to changes in blood pressure [7, 9, 10, 11]. PVL is formed in 10-15% of very premature infants with ELBW and causes the development of cerebral palsy and visual impairment [12]. The syndrome of movement disorders of the type of lower spastic paraparesis in every fourth and second child of the 1^st and 2^nd  groups, respectively, however, spastic tetraparesis was observed in premature infants of gestational age 22-27 weeks 5 times more often.

Despite the improvement in the methods of resuscitation care, more than half of premature infants by the post-conceptual age of 38-40 weeks were diagnosed with BPD of of various degree of severity (85.71% and 58.14% among the 1^st and 2^nd groups). Every fifth child who developed BPD suffered from sepsis in the early period of adaptation and every second child in the neonatal period suffered from pneumonia. Sepsis was diagnosed 5.5 times more often in children with GA of22-27 weeks.

Severe forms of the disease in children with GA of22-27 weeks occurred 1.8 times more often, which is undoubtedly associated with a significantly longer stay on mechanical ventilation against the background of incomplete processes of alveolo- and angiogenesis, aggravated somatic and obstetric history of the mother (chorioamnionitis, preeclampsia), extensive intraventricular hemorrhages, functioning patent ductus arteriosus, which is consistent with the authors' data [13, 14, 15, 16, 17].

Reference:

1. Classification of perinatal affection of the nervous system and their consequences in children of the first year of life: guidelines / ed. by N. N. Volodina, A. S. Petrukhina. – M.: FSEI "ALRESME of Roszdrav", 2005. - 88p.
2. Vinogradova I. V. Features of the state of the cardiovascular system in newborns with extremely low body weight / I. V. Vinogradova, M. V. Krasnov, N. N. Ivanova // Medical Almanac. – 2009. – No. 4. – P. 103 - 106.
3. Fomichev M. V. Respiratory distress in newborns / M. V. Fomichev. - Yekaterinburg: IRA UTK, 2007. - 481 p.
4. Vinogradova I. V. Follow-up observation of children with extremely low birth weight / I. V. Vinogradova, M. V. Krasnov, L. G. Nogteva // Practical medicine. – 2008. – No. 7. – P.67 - 69.
5. Vasilieva T. G. Features of calcium and phosphorus metabolism in young children / T. G. Vasilyeva, V. A.Kochetkova // Bulletin of the FEB RAS - 2006. - No. 2. - P. 91-96.
6. Hintz, S.R. Early-Childhood neurodevelopmental outcomes are not improving for infants born at <25 weeks' gestational age / S.R. Hintz, D.E. Kendrick, D.E. Wilson-Costello et al. // Pediatrics. -2011. - Vol. 127, No. 1. - P. 62-70.
7. Palchik A. B. Neurology of premature infants / A. B. Palchik, L. A. Fedorova, A. E. Ponyatishin. - M.: Medpress-inform, 2010. - 342 p.
8. Zhao, W.T. Research progress on periventricular white matter damage pathogenesis in preterm infants / W.T. Zhao, H.M. Yu // Zhongguo Dang Dai Er Ke Za Zhi. -2013. -Vol. 15, no. 5. -P. 396 - 400.
9. Burd, I. Models of fetal brain injury, intrauterine inflammation, and preterm birth / I. Burd, B. Balakrishnan, S. Kannan // Am. J. Reprod. Immunol. -2012. -Vol. 67, No. 2. - P. 87-94.
10. Resch, B. Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant / B. Resch, K. Neubauer, N. Hofer et al. // Early Hum. Dev. 2012. -Vol. 88, No. 1. - P. 27-31.
11. Xiong, T. An overview of risk factors for poor neurodevelopmental outcome associated with prematurity / T. Xiong, F. Gonzalez, D.Z. Mu // World. J. Pediatr. -2012. -Vol. 8, No. 4. - P. 293-300.
12. Kulakov V. I. Problems and prospects of nursing children with extremely low body weight at the present stage / V. I. Kulakov, A. G. Antonov, E. N. Baybarina // Russian Bulletin of Perinatology and Pediatrics. - 2006. - No. 4. - P. 8-11.
13. Volodin N. N. Bronchopulmonary dysplasia: teaching aid / N. N. Volodin. — M.: FEI HPE "RSMU" Roszdrav, 2010. — 56 p.
14. Chess, P.R. Pathogenesis of bronchopulmonary dysplasia / P.R.Chess, C.T.D'Angio, G.S.Pryhuber et al. // Semin. Perinatol. -2006. -Vol. 30, № 4. -P.171-178.
15.  Hartling, L. Chorioamnionitis as a risk factor for bronchopulmonary dyspla-sia: a systematic review and meta-analysis / L.Hartling, Y.Liang, T. Lacaze-Masmonteil //Arch. Dis. Child. Fetal Neonatal. -2012. -Vol.97, No. 1. -P.8-17.
16. Hofer, N. The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates / N.Hofer, R.Kothari, N.Morris et al. // Am.J.Obstet.Gynecol. - 2013. -Vol. 209, № 6. - P.542.
17.  Lacaze-Masmonteil T. That Chorioamnionitis is a risk factor for bronchopulmonary dysplasia - the case against / T. Lacaze-Masmonteil // Paediatr. Respir. Rev. - 2014. - Vol.15, № 1. - Р. 53-55.

Chapter 3. CHARACTERISTICS OF CONNECTED AND ADAPTIVE IMMUNITY OF CHILDREN WITH EXTREMELY LOW BODY WEIGHT OF DIFFERENT GESTIONAL AGE

3.1. Formation of adaptive and innate immunity in children with extremely low body weight in the dynamics of the postnatal period

The immune system is one of the most unique body systems with the ability to respond quickly to various pathogens and regulate the functions of homeostasis systems during pathological processes, which determines the survival of a premature infant, the features of the postnatal period of life, the effectiveness of therapeutic and rehabilitation measures.

At the moment, the individual links of the immune system in premature newborns with various pathological conditions have been described in detail. At the same time, there are very few sources containing information on the relationship between innate and adaptive immunity in children with ELBW in the dynamics of the postnatal period, which does not allow adequately assessing the coherence of immune processes and forming an idea of ​​various mechanisms of immunological response in very premature infants.

The maturity of the morphological substrate of the immune system of very premature infants with ELBW at the time of birth depends on the child's hepatitis B, antigen load, pathological influences, which the fetus is exposed to in the antenatal period during complicated pregnancy, as well as the violation of the relationship of immunity in the mother - fetus - newborn system [1 , 2].

 According to the literature, in very premature infants, the rate of maturation of the immune system differs from that in full-term infants. In contrast to full-term newborns, in children with gestational age less than 32 weeks, immunocompetent cells are immature, similar to fetal cells. Therefore, during the period of massive antigen load after birth, they are not able to provide  efficiently adequate protection for the child [3]. This state of immunity in premature infants prevents the formation of overreaction processes at a high antigen load in the intra- and neonatal periods, and the mechanisms of the innate immunity link prevent the development of infection at the earliest stages as a result of the elimination of pathogens.

Adaptive immunity is realized by lymphocytes, and it can also be divided into two components (links): humoral and cellular. The basis for the development of infectious and inflammatory pathology is the immaturity of the innate and adaptive links of immunity both at the systemic and local levels [4, 5, 6]. Humoral immunity is realized by B-lymphocytes and immunoglobulins produced by them. When meeting an antigen and recognizing it, B-lymphocytes are transformed into plasma cells that synthesize antibodies. Antibodies provide protection against bacteria, bacterial toxins, viruses that circulate freely in body fluids before entering cells.

The cellular link of the adaptive immunity of deeply premature newborns is characterized by an increased number of "naive" T-lymphocytes [7], which, in comparison with mature T-cells, when interacting with antigens, produce a smaller amount of gamma-interferon and other cytokines. In addition, the interaction of T and B lymphocytes is difficult in the course of the immune response and there is a reduced number of cells of immunological memory [4, 8]. According to E. L. Semikina (2008), an analysis of the expression of the main antigens of T-linear differentiation in very premature infants indicates a sufficient maturity of this system by the time of birth. The researchers noted an increase in the level of cells with the phenotype CD3 +, CD4 +, CD8 + and the prevalence of cells with a low specificity of their antigen-recognizing immunoglobulin receptors in the total pool of B-lymphocytes [9]. Evaluation of the cellular component of immunity in very premature infants with ELBW at birth showed a decrease in the relative number of T cells, CD4 + lymphocytes, the ratio of CD4 / CD8 populations, and an increase in the number of natural killer cells (NK) in umbilical cord blood [10].

A number of studies have shown that by the end of the neonatal period in children with ELBW, compared with full-term newborns, leukocytopenia and relative lymphocytosis persist. The decrease in the relative content of CD3 + and CD4 + - lymphocytes and the value of the immunoregulatory index is due to the suppressive direction of cellular reactions. The reduced amount of serum immunoglobulins is compensated by the increased content of B-lymphocytes. An increase in the number of NK cells characterizes a high cytotoxic potential and, in conditions of a decrease in the number of neutrophils, is one of the only factors of antigen-independent cell defense [7, 11].

The CD95 receptor transmits a cytotoxic signal when it binds to specific antibodies. The CD95 receptor plays an important role in the physiology of apoptosis: the peripheral removal of activated mature T cells in the final stages of the immune response.

The receptor for IL-2, CD25, is produced by T cells in response to antigenic and mitogenic stimulation. The cytokine IL-2 is required for the proliferation of the T-cell link and other processes that regulate the immune response. The CD71 receptor appears on leukocytes upon activation. It is found on most dividing cells. As a transferrin receptor, CD71 allows the entry of iron ions into the activated cell, which is necessary for cell division. There is evidence that CD71 + cells can have an anti-inflammatory effect in the postnatal period of a newborn's life [12]. These markers of leukocyte subpopulations serve as indicators of the competence of the cellular link of the newborn's immune system. The key point is the formation of the antigen-presenting function, when different populations of cells interact to protect the body from the action of the antigen.

When analyzing the immunological parameters of umbilical cord blood in all very premature infants with ELBW, a significant decrease in the number of leukocytes was recorded (_p1-3 = 0.06, _p2-3 = 0.007) in combination with an increase in the percentage of lymphocytes (_p1-3.2-3 = 0 , 0001) compared to term infants. The most pronounced changes were observed in children born at the time of very early preterm labor, which is associated with the peculiarity of early ontogenesis and defective leukopoiesis against the background of the pathological course of the antenatal period (Table 15).

Table 15

Population and subpopulation composition of umbilical cord blood lymphocytes in children with ELBW

Note. р1-2, р1-3, р2-3 - significance of differences between groups of children (Mann-Whitney test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

The results of phenotyping of leukocytes by flow cytofluorometry showed that mature T-lymphocytes with the CD3 phenotype accounted for more than 40% of cord blood lymphocytes in very premature infants of all examined groups. When comparing the indicators of the main subpopulations of T- and B-lymphocytes of the umbilical cord blood of the main groups, no significant differences were found.

One of the important results of activation is the expression of genes for growth factors and their receptors. Thus, an increase in the absolute number of regulatory cells with a receptor for IL-2, which is an activation marker (CD25 + CD4 +) (_p2-3 = 0.012), was observed in newborns with ELBW 28-31 weeks of GA, which contributes to the implementation of accelerated differentiation of regulatory lymphocyte populations [13 ]. In children born at the time of very early preterm birth, the expression of the CD25 + / CD4 + receptor did not differ from that of full-term infants.

To characterize the balance of cytokine-producing lymphocytes of the first and second order, the ratio of the percentage of Th1- / Th2- lymphocytes (CD4 + IFN +, CD4 + IL-4 +) was determined, which was calculated for each representative of the age group in spontaneous and induced tests.

When analyzing the indices of intracellular cytokines of the umbilical cord blood in all premature infants, a decrease in the content of T-helpers spontaneously synthesizing IL-4 was noted (Table 16).

At the same time, the level of IFN-γ expression did not differ from that of the comparison group. The ratio of regulatory subpopulations producing Th1 and Th2 cytokines in all premature infants in the spontaneous test had a pro-inflammatory orientation and was 1.7 and 1.9 times higher than the indices of full-term infants (_p1-3.2-3 = 0.001). Upon cell stimulation, the polarization index significantly increased in premature infants with a shorter gestation period (_p1-3 = 0.001).

Table 16

The content of cytokine-producing cells in the umbilical cord blood of children with ELBW

Note. р1-2, р1-3, р2-3 - significance of differences between groups of children: 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

The hypoxic effect on the fetus in the antenatal period affects the change in immunological parameters, directly reflects the negative effect of placental insufficiency on the development of the immune response of children with ELBW. In children with GA of22-27 weeks, positive correlations were found between the development of subcompensated CPI in the mother and the content of cytokine-producing cells (CD4⁺ IL-4⁺ and CD4⁺ IFN-γ ⁺, r = 0.87 at p = 0.010 in both cases ), the presence of preeclampsia of moderate severity and the index of polarization of cytokine-producing cells upon stimulation (r = 0.87 at p = 0.010).

We found a correlation between the presence of children of the 1^st group on ALV from birth and the level of regulatory cells (CD25 + CD4⁺) (r = 0.57, p = 0.001) as well as the induced production of intracellular IL-4 (r = 0.50, p = 0.01) reflects the effect of oxygen deficiency on the formation of cytokine balance and the reserve of cytokine-producing cells.

 By the end of the late neonatal period, a decrease in the number of leukocytes and relative lymphocytosis in the peripheral blood of all premature infants remained (Table 17).

Table 17

The main subpopulations of peripheral blood lymphocytes in children with ELBW at the age of 1 month of life

Note: р1-2 - significance of differences between groups of children (Mann-Whitney test): 1 - children 22 - 27 weeks of gestation, 2 - children 28 - 31 weeks of gestation, 3 - comparison group.

The number of T- and B-lymphocytes and their subpopulations did not differ from those of full-term newborns.

During this period, all premature infants showed an increase in the relative and absolute number of regulatory cells with a receptor for IL-2, which is an activation marker (CD25⁺ CD4⁺) (^p1-3.2-3 <0.015), which contributes to the accelerated differentiation of regulatory lymphocyte populations.

By the age of 1 month of life, all premature infants had a reduced number of T-helpers producing IL-4, as a result of which the first order lymphocytes predominated in the pool, which is associated with antigenic stimulation with bacterial agents (Table 18).

Table 18

The content of cytokine-producing cells in children with ELBW at the age of 1 month of life