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]. 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) Indicators 1st group (n=46) 2nd group (n=43) 3rd group (n=25) р 1st minute, points 4,16±1,03 4,38±1,45 6,83±1,57 р1-3≤0,001 р2-3≤0,001 5th minute, points 5,83±0,72 6,27±0,72 7,66±1,68 р1-2=0,006 р1-3≤0,001 р2-3≤0,001 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) Indicators Gestational age 24-27 weeks (1st group n = 46) Gestational age 28-31 weeks (2nd group, n = 43) Full-term babies (3rd group, n = 25) р рН 7,33±0,067 7,35±0,07 7,3±0,09 рСO2, mm Hg 37,14±8,15 39,7±11,49 46,47±9,49 р1-3=0,0001 р2-3=0,015 рO2, mm Hg 51,73±9,31 57,2±13,12 22,5±9,41 р1-2=0,028 р1-3=0,001 р2-3=0,001 cHCO3, mmol/L 19,85±3,76 21,46±4,03 20,2±3,22 р1-2=0,05 BEecf, mmol/L -4,99±4,14 -3,42±3,83 -4,06±3,58 сК+, mmol/L 9,15±3,36 10,07±8,65 4,67±0,68 р1-3=0,0001 р2-3=0,0001 сNa+, mmol/L 126,33±6,97 129±5,56 135,17±2,98 р1-2=0,05 р1-3=0,0001 р2-3=0,0001 сCa2+, mmol/L 1,13±0,11 1,17±0,15 0,99±0,38 р1-3=0,027 р2-3=0,007 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) Indicators 1st group (n=46) 2nd group (n=43) 3rd group (n=25) р Gestational age, weeks 25,89±1,26 29,13±1,32 39,32±0,8 р1-2≤0,001 р1-3≤0,001 р2-3≤0,001 weight, g 822,15±125,74 892,47±111,8 3451,87±470,72 р1-2=0,006 р1-3≤0,001 р2-3≤0,001 length, cm 33,38±4,16 33,62±2,7 51,16±2,83 р1-3≤0,001 р2-3≤0,001 head circumference, cm 24,25±1,93 25,63±2 34,83±1,63 р1-2=0,004 р1-3≤0,001 р2-3≤0,001 chest circumference, cm 21,77±2,07 24,22±2,19 34,33±1,65 р1-2=0,001 р1-3≤0,001 р2-3≤0,001 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. 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 Indicators 1st group (n=46) 2nd group (n=43) abs % abs % IGRS, total 8 17,4 36 83,7 р1-2=0,0001 IGRS hypoplastic option 6 13,04 27 62,79 р1-2=0,0002 IGRS hypotrophic variant 2 4,34 9 20,93 р1-2=0,02 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 2nd 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 (1st group - 93.48%, 2nd 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 Indicators 1st group (n=42) 2nd group (n=43) р IVL, day 11,61±10,77 2,93±4,34 р1-2=0,0001 CPAP, day 4,52±4,32 3±2,53 р1-2=0,05 NICU, day 19,78±12,83 8,9±5,76 р1-2=0,0001 NPU, day 54,63±12,61 55,94±16,15 Length of hospital stay, day 75,75±19 64,74±17,13 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 Nosological form 1st group (n=42) 2nd group (n=43) р abs % abs % RDS 42 100 43 100 р1-2≥0,05 Hypoxic-ischemic CNS damage: cerebral ischemia II degree 0 0 5 11,63 р1-2≥0,05 cerebral ischemia III degree 42 100 38 88,37 р1-2≥0,05 Ischemic-hemorrhagic lesions of the CNS: IVH I degree 7 16,7 8 18,6 IVH II degree 11 26,19 2 4,65 р1-2=0,02 IVH III degree 8 19,04 2 4,65 р1-2 =0,023 Pneumothorax 5 11,9 0 0 р1-2=0,019 BPD 17 40,48 3 6,98 р1-2=0,0001 Sepsis 15 35,71 3 6,98 р1-2=0,001 Pneumonia 27 64,29 10 23,26 р1-2=0,0001 Meningitis 2 4,76 0 0 Cytomegalovirus infection 4 9,52 1 2,32 HRFDA 6 14,28 1 2,32 р1-3=0,024 Anemia -severe severity 22 52,38 12 27,9 р1-2=0,017 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 2nd 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 2nd 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 1st 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 1st 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 1st 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) Indicators 1st group (n=42) 2nd group (n=43) р pH 7,36±0,04 7,36±0,04 рСO2, mm Hg. 46,62±6,55 44,91±5,37 рO2, mm Hg. 44,67±7,7 48,61±10,45 cHCO3, mmol/l 25,65±3,06 25,13±3,9 BEecf, mmol/l 0,71±3 0,22±3,73 сК+, mmol/l 5,68±0,87 5,38±1,18 сNa+, mmol/l 130,65±2,96 132,5±2,86 р1-2=0,0095 сCa2+, mmol/l 1,32±0,07 1,32±0,06 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 1st 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 2nd 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 Nosological form 1st group (n=42) 2nd group (n=43) р abs % abs % RDS 0 0 5 11,63 р1-2≥0,05 Hypoxic-ischemic CNS damage: cerebral ischemia II degree 42 100 38 88,37 р1-2≥0,05 cerebral ischemia III degree 27 64,3 16 37,2 р1-2=0,03 Ischemic-hemorrhagic lesions of the CNS: IVH I degree 8 19,04 11 25,58 р1-2≥0,05 IVH II degree 11 26,19 2 4,65 р1-2=0,001 IVH III degree 8 19,04 3 6,98 р1-2=0,042 BPD - moderately severe 12 28,57 6 13,95 р1-2≥0,05 -severe 11 26,19 6 13,95 р1-2=0,056 Pneumonia 27 64,29 10 23,26 р1-2=0,0001 Cytomegalovirus infection 6 14,28 4 9,3 р1-2≥0,05 PH I degree 5 11,9 12 27,9 р1-2=0,04 II degree 21 50 24 55,8 р1-2≥0,05 III degree 16 38 7 16,27 р1-2=0,039 Hernia - umbilical 1 2,38 3 6,97 р1-2≥0,05 - inguinal 10 23,8 14 32,55 р1-2≥0,05 Anemia severe 42 100 40 93 р1-2≥0,05 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 1st 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 1st 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 1st 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 Indicators 1st group (n=42) 2nd group (n=43) р Early neonatal period Breast-feeding, % 47,83 79 р1-2=0,015 Artificial feeding, % 52,17 21 р1-2=0,008 1 month of life Breast-feeding, % 42,85 65,12 р1-2>0,05 Artificial feeding, % 35,71 20,93 р1-2=0,04 Mixed feeding, % 21,44 13,95 р1-2>0,05 PCA 38-40 weeks Breast-feeding, % 19 34,88 р1-2>0,05 Artificial feeding, % 35,71 27,9 р1-2>0,05 Mixed feeding, % 45,29 37,22 р1-2>0,05 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) Indicators 1st group (n=42) 2nd group (n=43) р At the age of 1 month Weight, g gain since birth, g gain since birth,% 1149,57±195,2 295,65±124,82 34,4±13,05 1226±236,43 330,07±168,93 36,39±16,99 р1-2=0,006 At the age of 38-40 weeks Weight, g gain since birth, g gain since birth,% 2159±213,29 1288,24±264,13 156,22±46,35 2008,05±185,58 1177,41±264,44 126,83±41,7 р1-2=0,002 р1-2=0,08 р1-2=0,007 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 2nd group exceeded the indicators of children with a shorter gestation period. However, upon reaching the age of a full-term newborn, children of the 1st 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) Indicators 1st group (n=42) 2nd group (n=43) Р pH 7,37±0,03 7,37±0,04 рСO2, mm Hg. 46,5±7,22 45,17±5,11 рO2, mm Hg. 47,25±6,35 46,29±7,7 cHCO3, mmol/l 26,65±5,07 25,66±2,24 BEecf, mmol/l 1,73±5,02 0,97±2,2 сК+, mmol/l 5,63±1,6 5,27±1,03 сNa+, mmol/l 134,77±5,52 133,84±3 сCa2+, mmol/l 1,31±0,13 1,37±0,09 р1-2=0,051 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 1st and 2nd 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 1st and 2nd 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].

1. Ailamazyan E. K. Controversial problems of premature birth and nursing children with extremely low weight / E. K. Ailamazyan, I. I. Evsyukova // Journal of obstetrics and women's diseases. - 2011. - No. 3. - P.183-189.

2. Albitsky V.Yu. Neonatal Mortality with Extreme Low Birth Weight /Albitsky V.Yu., E.N. Baybarina, Z.Kh. Sorokin et al. // Public health and health care. - 2010. - No. 2. - P. 16-21.

3. Baybarina E.N. Outcomes of pregnancy in the period of 22-27 weeks in medical institutions of the Russian Federation / E. N.Baybarina, Z. Kh. Sorokina // Issues of modern pediatrics. - 2011. - No. 1. - P. 17-20.

4. Bashmakova N. V., Bashmakova N. V., Kovalev V. V., Litvinova A. M. et al. Survival rate and current perinatal technologies for nursing newborns with extremely low body weight. - 2012. - No. 1. - P. 4-7.

5. Simmons, L.E. Preventing preterm birth and neonatal mortality: exploring the epidemiology, causes, and interventions / L.E.Simmons, C.E.Rubens, G.L. Darmstadt et al. // Semin Perinatol. -2010. - Vol.34, № 6. -R.408-415.

6. 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. - R. 69-73.

7. 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.

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. - R. 2225-2233.

9. 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. Akhmadeeva, N.N. Kryvkina // Bulletin of modern clinical medicine. - 2013. - No. 6. - P. 34-41.

10. 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. - R. 967-974.

11. 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, № 6. - P. 716-723.

12. Bashmakova N. V. Monitoring of children born with extremely low body weight in the perinatal center / N. V. Bashmakova, A. M. Litvinova, G.B. Malgina and others // Obstetrics and gynecology. - 2015. - No. 9. - P. 80-86.

13. Antonov A. G. Intensive therapy and principles of nursing children with extremely low birth weight: methodological letter / A. G. Antonov, O. A. Borisevich, A. S. Burkov et al. - M.: Research Center of Obstetrics, Gynecology and Perinatology, 2011. - 70 p.

14. Management of children born with extremely low body weight (ELBW): a clinical review of international data // Family health: inf. - educ. bullet. - 2011. - No. 2. - P. 2 - 24.

15. Merzlova N.B. Catamnesis of children born with very low and extremely low body weight / N. B. Merzlova, Yu. V. Kurnosova, L. N. Vinokurova et al. // Fundamental research. - 2013. - No. 3. - P. 121-125.

16. Birenbaum, H.J. Reduction in the incidence of chronic lung disease in very low birth weight infant’s results of a quality improvement process in a testiary level neonatal intensive care unit / H.J.Birenbaum // Pediatrics. - 2009. - Vol. 123, № 1. - P. 44-50.

17. Stephanie D. V. Clinical immunology and immunopathology of childhood: a guide for doctors / D. V. Stephanie, Yu. E. Veltischev. – M.: Medicine, 1996. – P. 125-166.

18. Caron, J.E. Multiplex analysis of toll-like receptor-stimulated neonatal cytokine response /J.E.Caron, T.R.La Pine, N.H.Augustine et al.// Neonatology. - 2010. - Vol. 97, № 3. - P. 266-273.

19. Kapitanović Vidak, H. The association between proinflammatory cytokine polymorphisms and cerebral palsy in very preterm infants / H. Kapitanović Vidak, T.Catela Ivković, M.Jokić // Cytokine. -2012. -Vol. 58, №1. - P.57-64.

20. Matsuda, Y. T-cell activation in abnormal perinatal events / Y.Matsuda, H.Kato, K.Imanishi et al.// Microbiol Immunol. - 2010. - Vol. 54, № 1. - P. 38-45.

21. Gromada N. E. Diagnostic value of cytokines in newborns with serious hypoxic injuries of the central nervous system / N.Ye. Gromada // Ural Medical Journal. - 2008. - No. 12. - P. 140-145.

22. Gille, S. Clearance of apoptotic neutrophils is diminished in cord blood monocytes and does not lead to reduced IL-8 production / S.Gille, F.Steffen, K. Lauber et al. // Pediatr. Res. -2009. - Vol. 66, № 5. - R. 507-512.

23. Charipova B.T. Clinical characteristics of children with extremely low birth weight / B.T. Charipova, G.N. Chistyakova, M. N.Tarasova // Ural Medical Journal. - 2010. - No. 5. - P. 147-151.

24. Luciano, A.A. Alterations in regulatory T cell subpopulations seen in preterm infants /A.A.Luciano, I.M.Arbona-Ramirez, R.Ruiz // PLoS One. - 2014. -Vol.9, № 5. - P.958 - 967.

25. G.S. Koval 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. - No. 2. – P. 8 - 11.

26. Pertseva V.A. Characteristics of humoral immunity of premature newborns, depending on the characteristics of the course of the neonatal period / V. A. Pertseva, N. I. Zakharova // Russian medical journal. - 2011. - No. 31. - P. 11 - 15.