Abstract (English):
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.

Keywords:
Children, extremely low body mass, neonatal pathology, immune system, weight, immunity, postnatal pathology, newborns

The most common pathology in children with ELBW is retinopathy of prematurity, the cause of which is a combination of various risk factors leading to impairment of full retinal vasculogenesis. The effect of free radicals on retinal membrane structures and vessels is one of the most important mechanisms of ROP pathogenesis. BPD, necrotizing enterocolitis, IVH, RDS and cardiopathy are all "free radical diseases", namely, the excessive accumulation of free radicals affects the development of ROP. Additional risk factors affecting the occurrence of retinopathy of prematurity are fetal hypoxia, intrauterine infections, respiratory distress syndrome, intracranial birth trauma, sepsis, anemia of prematurity. The relationship between the development of ROP and acidosis, anemia of prematurity, sepsis, and repeated blood transfusions was revealed. According to the international classification, there are five stages of active ROP according to the localization of the process and its length: Stage I ROP - a demarcation line appears between the vascular and avascular borders of the retina; Stage II ROP - a shaft (ridge) appears in place of the formed demarcation line; Stage III ROP - extraretinal fibrovascular proliferation (threshold ROP) is formed in the area of the shaft; Stage IV ROP - partial retinal detachment without involvement of the macular zone in the process (4a) and with retinal detachment in the macula (4c); Stage V - total retinal detachment. Therefore, it is extremely important to carefully monitor the parameters of oxygen homeostasis in children with ELBW and to provide consultations of a qualified ophthalmologist and surgical treatment if necessary (most often - laser therapy) from 4-6 weeks of life [1]. Thus, by the time of transfer to the stage of early rehabilitation, children with ELBW have a severe combined pathology - a severe ischemic or ischemic-hemorrhagic lesion of the CNS, IUI, RDS, are at a high risk for the development of BPD, syndrome of movement disorders, retinopathy of prematurity and hearing impairment , which calls for the search for and implement effective diagnostic and prognostic approaches that will help to reduce the rates of chronic pathology and disability. The increased attention to retinopathy of prematurity is due to the high risk of developing blindness and visual disability, as a result of nursing children who were previously considered incurable. The incidence of ROP varies in different countries, reaching 24.7 per 100 thousand live births, and correlates with the degree of immaturity of the child, reaching 67% in children with ELBW [2]. The question of the participation of immune mechanisms in the development of ROP remains unstudied. In the reference, there are only a few histological works on this issue [3]. 5.1. Dynamics of changes in indicators of adaptive and innate immunity in children with ELBW who developed retinopathy of prematurity During the study, children who subsequently developed retinopathy were divided into groups depending on gestational age and severity. Children with retinopathy of I-III degree at GA of 22-27 weeks: 1D group - PH of III degree, n = 14; 1E group - PH of I-II degree, n = 19. Children with retinopathy of I-III degree at GA 28-31 weeks: 2D group - PH of III degree, n = 8; 2E group - PH of I-II degree, n = 30. The number of girls and boys in the groups was comparable and amounted to 64.3% and 35.7% in group 1, 57.9% and 42.1% in group 2, and 87,5 and 12.5% in group 3, in the 4th group 53.3% and 46.7% by gender (p> 0.05 in all cases). However, girls were recorded more often in the groups with retinopathy of III degree. Children from very early preterm labor who subsequently developed retinopathy of III degree did not have significant differences in gestational age (26.0 ± 0.96 versus 26.4 ± 0.77 weeks, p> 0.05). However, the body weight of these children was statistically significantly lower (802.071±112.4 g versus 897.3±88.5 g, p = 0.014). In children with retinopathy of III degree, on the other hand, body weight did not differ from early preterm labor (845.0±182.5 and 915.0±90.2 g, p> 0.05), and the gestational age was significantly lower (28 , 4±0.74 versus 29.3±1.3 weeks, p = 0.017). According to the publication, children with less body weight and gestational age are more likely to develop severe ROP. In premature infants with GA of 22-27 weeks, threshold retinopathy of prematurity was significantly more often diagnosed, which is consistent with the authors' data on the dependence of the incidence of the disease on the maturity of the child, reaching 54-72% in children with ELBW [1, 2]. Similar results were obtained in the course of this study. Children from very early preterm labor who subsequently developed retinopathy of III degree had a lower body weight (802.071 ± 112.4 g versus 897.3 ± 88.5 g in children with ROPof stage I-II, p = 0.014), and children from early preterm birth - less gestational age (28.4 ± 0.74 versus 29.3 ± 1.3 weeks, p = 0.017). Girls from very early preterm birth were 2 times more likely to develop threshold retinopathy than boys. Other equally important causes of ROP are RDS, BLD, necrotizing enterocolitis, intraventricular hemorrhages and cardiopathies, as well as fetal hypoxia, intrauterine infections, sepsis, anemia, repeated blood transfusions. Severe anemia in the neonatal period, regardless of gestational age, suffered from half of the children with threshold ROP. However, repeated blood transfusions were significantly more often recorded in children with GA of 22-27 weeks (3.64 ± 2.34 versus 1.74 ± 1.24 times in children with ROP of I-II degree, p = 0.01), in children with GA of 28-31 weeks did not reveal significant differences in the frequency of blood transfusions (2.12±1.46 versus 1.22±1.23 times, p> 0.05). There were no significant differences in the frequency of detection of sepsis and pneumonia depending on the severity of retinopathy. Severe bronchopulmonary dysplasia was most often observed in children with threshold retinopathy (42.9% versus 21.5% in children with HV 22-27 weeks and 37.5% versus 6.5% in children with GA of 28-31 weeks). When studying the population and subpopulation composition of cord blood lymphocytes, the production of intracellular cytokines in children with ELBW, regardless of gestational age and stage of ROP, no significant differences were found (Table 55). Table 55 Population and subpopulation composition of umbilical cord blood lymphocytes of premature infants who subsequently developed retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) Leukocytes, 109/l 4,7 (4,03-6,05) 5,0 (4,24-7,41) 9,55 (6,75-12,9) 6,28 (4,8-11,29) Lymphocytes, % 68 (59-77,5) 74 (61,75-75,75) 58,5 (49,75-64) 70,5 (57,5-76,5) Lymphocytes, 109/l 3,44 (2,11-3,54) 3,78 (2,63-4,55) 5,81 (4,11-7,37) 4,02 (3,11-8,26) CD3+, % 43 (38,0-44,0) 34,5 (33,0-35) 50 (41,75-51,5) 44 (38-54) CD3+, 109/l 1,27 (0,73-1,31) 1,6 (1,42-2,4) 2,59 (1,67-3,02) 1,86 (1,26-3,2) CD19+, % 12(10-14) 9 (6-12) 14 (10,25-25,25) 14 (10-17) CD19+, 109/l 0,34 (0,24-0,43) 0,41 (0,22-0,78) 1,01 (0,56-2,19) 0,68 (0,44-0,73) CD4+, % 28 (26-31) 26,5(23,75-37,25) 33 (27,75-38,25) 32 (25-41) CD4+, 109/l 0,78 (0,47-0,87) 1,31 (1,18-1,79) 1,84 (1,32-4,06) 1,35 (0,85-2,43) CD8+, % 14 (13-15-14,75) 8,5 (5,75-13,0) 13 (11,5-18,5) 14 (10-17) CD8+, 109/l 0,47 (0,20-0,53) 0,36 (0,26-0,66) 0,7 (0,62-1,7) 0,59 (0,45-0,89) CD16+CD56+,, % 2,0 (1-3) 4,0 (2,75-6,0) 9,0 (6,5-12,25) 6 (3-10) CD16+CD56+, 109/l 0,04 (0,03-0,10) 0,12 (0,11-0,37) 0,36 (0,35-0,52) 0,27 (0,09-0,71) CD4/CD8 2,3/8 (1,86-3,11) 3,55 (2,99-4,33) 2,36 (1,65-2,72) 1,85 (1,71-3,3) CD25+CD4+, % 3 (3-6) 2 (1,25-2,0) 3 (2,5-9,0) 4 (2,75-4,25) CD25+CD4+, 109/l 0,1 (0,08-0,12) 0,09 (0,06-0,24) 0,37(0,17-0,47) 0,16 (0,12-0,28) Note.The significance of differences between groups of children (Student's test) in all cases, p> 0.05. The most important place in the immune system belongs, as you know, to CD4+ lymphocytes (T-helpers), which determine and direct the nature of the immune response during infectious aggression. Upon reaching 1 month of life in children born at the time of very early preterm labor, which formed PH of III degree, there was a significant decrease in T-helpers (p1D-1E = 0.014) and B-cells (p1D-1E = 0.002) (Table 56). Table 56 Population and subpopulation composition of peripheral blood lymphocytes of premature babies at the age of 1 month of life, subsequently developing retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP of III degree (Group 1D, n=14) ROP of I-II degree (Group 1E, n=19) ROP of III degree (Group 2D, n=8) ROP of I-II degree (Group 2E, n=30) Leukocytes, 109/l 6,3 (4,4-8,55) 7,5 (6,05-10) 10,85 (9,63-12,95) 7,55 (5,74-8,93) 2D-2E =0,008 Lymphocytes, % 59 (49-63) 60 (46-63) 54 (5071,5) 60 (56,75—74,25) Lymphocytes, 109/l 3,84 (2,14-5,8) 4,43 (3,65-6) 4,97 (3,26-5,75) 4,37 (3,44-5,67) CD3+, % 52,5 (49,75-53,75) 57,5 (48,75-67) 48 (44-58,5) 55 (44-62,75) CD3+, 109/l 1,80 (1,3-2,41) 2,41 (2,06-3,09) 2,38 (1,92-2,89) 2,44 (1,88-3,2) CD19+, % 8 (6-10) 10,5 (7,5-16,25) 18,5 (16,3-21,5) 14 (9-19) 1D-1E =0,013 CD19+, 109/l 0,17 (0,1-0,27) 0,51 (0,2-0,71) 0,57 (0,47-0,88) 0,60 (0,38-1,2) 1D-1E =0,002 CD4+, % 31,5 (24,5-39,25) 42,0 (39,0-52,0) 31 (24-41) 41 (31-46,5) 1D-1E =0,08 CD4+, 109/l 1,23 (0,79-1,65) 1,86 (1,5-2,34) 1,46 (1,1-1,7) 1,7 (1,29-2,06) 1D-1E =0,014 CD8+, % 16 (13,5-23) 18,5 (14,75-22,25) 17 (16-19,5) 15 (13-19) CD8+, 109/l 0,66 (0,4-1,07) 0,67 (0,57-1,03) 0,82 (0,69-0,92) 0,72 (0,43-0,98) CD16+CD56+,, % 17,5 (10,25-24,75) 10,5 (9,25-14,75) 12 (8-16,5) 9 (7-14) CD16+CD56+,, 109/l 0,53 (0,22-0,84) 0,45 (0,34-0,66) 0,4 (0,31-0,73) 0,39 (0,2-0,61) CD4/CD8 1,71 (1,08-3,05) 2,41 (1,99-3,03) 1,96 (1,69-2,16) 2,47 (1,95-3,37) 2D-2E =0,04 CD25+CD4+, % 5 (4-6) 6 (5-7) 4 (3,5-5,5) 6 (4-6) CD25+CD4+, 109/l 0,18 (0,11-0,19) 0,25 (0,18-0,42) 0,23 (0,17-0,25) 0,26 (0,18-0,31) 1D-1E =0,016 Note. p - the level of significance of differences between groups of children (Mann-Whitney criterion): group 1D - children with GA of 22-27 weeks, who formed ROP of severe III degree, group 1E - children with ROP at 22-27 weeks, who developed ROP of I-II degree; Group 2D - children with GA of 28-31 weeks, who developed ROP of severe severe III degree, 2E group - children with GA of 28-31 weeks, who developed ROP of I-II degree. A decrease in the absolute number of activated cells with the CD25+CD4+ receptor was also found in this group of newborns (p1D-1E = 0.016). By 38-40 weeks of PCA, a reduced number of CD4 cells (p1D-1E = 0.05) and B-lymphocytes (p1D-1E = 0.017) in the peripheral blood of children of group 1 persists against the background of an increase in NK cells (p1D-1E = 0.01) (Table 57). Table 57 Population and subpopulation composition of peripheral blood lymphocytes of premature infants with ELBW at 38-40 weeks of PCA, which formed retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm labor (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) Leukocytes, 109/l 6,2 (4,98-6,74) 6,45 (5,99-7,91) 7,5 (6,98,7) 6,33 (5,36-7,6) Lymphocytes, % 74 (67,5-81,5) 64,5 (60,25-69,25) 68 (63,5-69) 65,5 (60,75-75,75) Lymphocytes, 109/l 4,14 (3,63-4,62) 4,8 (3,59-5,09) 4,59 (4,39-6,19) 4,65(4-5,06) CD3+, % 50,5 (40,5-56) 56 (50-59) 47 (42,5-51) 50 (45-52,75) CD3+, 109/l 1,78 (1,6-2,37) 2,36 (2,03-2,73) 2,13 (1,94-2,49) 2,22 (1,99-2,55) CD19+, % 24 (16,25-32) 28 (19-30) 37 (31,5-42,5) 26 (19,5-29) 2D-2E =0,017 CD19+, 109/l 1,21 (0,63-1,3) 0,68 (0,58-1,53) 1,8 (1,43-2,44) 1,12 (0,84-1,33) 1D-1E =0,002 2D-2E =0,04 CD4+, % 27,5 (23,5-34,25) 39 (33-44) 29 (28-35,5) 34,5 (29,5-38,5) 1D-1E =0,05 CD4+, 109/l 1,07 (0,97-1,48) 1,71 (1,23-1,85) 1,36 (1,26-1,63) 1,56 (1,28-1,83) 1D-1E =0,07 CD8+, % 20,5 (12,75-26,25) 15 (15-19) 15 (13-18) 14,5 (12-19) CD8+, 109/l 0,72 (0,5-1,07) 0,62 (0,49-0,76) 0,87 (0,6-0,98) 0,64 (0,57-0,8) CD16+CD56+, % 20 (13-23,5) 9 (6-15) 10 (5,5-17,5) 13,5 (10,5-16,5) CD16+CD56+, 109/l 0,78 (0,51-1) 0,3 (0,29-0,59) 0,66 (0,26-0,95) 0,63 (0,4-0,77) 1D-1E =0,010 CD4/CD8 1,65 (1,26-1,94) 2,6 (2,11-2,8) 2,1 (1,36-2,64) 2,17 (1,78-3,17) CD25+CD4+, % 4 (3,75-5) 5 (4-6) 5 (4-5) 5 (4-6) 1D-1E =0,03 CD25+CD4+, 109/l 0,16 (0,14-0,18) 0,21 (0,18-0,25) 0,22 (0,2-0,23) 0,24 (0,19-0,28) 1D-1E =0,010 Note. p - the significance of differences between groups of children (Mann-Whitney criterion): groups 1 and 3 - children who developed ROP of III degree, groups 2 and 4 - children who developed ROP of I and II degree. The number of CD25+CD14+, both in absolute and relative numbers, remains at the same reduced level (p1D-1E = 0.01, p1D-1E = 0.03). On the other hand, for children born at the time of early preterm labor who have developed PH of III degree, an increase in the number of B-cell immunity is characteristic (p1D-1E = 0.017). The concentration of cytokines in serum or other biological fluids shows the current state of the immune system. However, the determination of the level of cytokine production by blood mononuclear cells reflects the functional state of cells (spontaneous production) or their potential ability to respond to an antigenic stimulus (induced production), then the method of intracellular staining of cytokines makes it possible, using flow cytometry, to determine the population belonging of cells that produce a particular cytokine [3]. The production of umbilical cord blood intracellular cytokines in all premature infants did not differ statistically significantly (Table 58). Table 58 Levels of intracellular cytokines in the umbilical cord blood of premature infants with retinopathy, IU (P25-P75) Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) CD4+CD3+IFN-γ+ self-existing, % 2,85(1,36-3,95) 3,0(1,76-5,82) 1,89(1,71-4,64) 2,36(1,66-5,82) CD4+IFN-γ+ suscitate, % 4,58(3-4,58) 4,92(2,94-8,8) 4,58(1,52-6,13) 3,47(1,64-7,67) CD4+IL-4+ self-existing, % 1,99(0,9-2,93) 1,74(0,88-3,16) 0,83(0,73-2,0) 2,08(0,83-3,17) CD4+IL-4+ suscitate, % 4,59(2,43-5,49) 4,05(2,89-5,01) 3,6(3,22-4,91) 3,8(2,97-5,78) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,6(1,36-1,77) 1,38(21,21-1,74) 1,49(1,39-1,84) 1,79(1,43-2,13) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 1,041(0,98-1,26) 1,25(1,08-1,46) 1,19(1,11-1,2) 1,18(0,65-1,36) Note. The significance of differences between groups of children (Student's test) in all cases, p> 0.05. When analyzing the indices of intracellular cytokines of peripheral blood in premature infants of the 3rd group, there was a decrease in the content of T-helpers spontaneously synthesizing IFN-γ (p2D-2E = 0.04) (Table 59). In children from very early preterm birth, no significant differences in the production of intracellular cytokines were found. Table 59 Levels of intracellular cytokines in the peripheral blood of premature infants at the age of 1 month of life, subsequently developing retinopathy, IU (P25-P75) Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) CD4+CD3+IFN-γ+ self-existing, % 1,54(1,04-3,2) 2,95(1,24-4,61) 2,52(1,47-2,83) 2,31 (1,29-6,38) CD4+IFN-γ+ suscitate, % 3,05 (2,27-5,87) 3,53 (2,61-5,35) 5,17 (3,17-5,24) 5,33 (2,48-7,27) 2D-2E=0,04 CD4+IL-4+ self-existing, % 1,17 (0,75-2,51) 1,66(1,02-2,51) 1,62 (0,94-1,96) 1,21 (1,03-2,84) CD4+IL-4+ suscitate, % 1,89 (1,6-3,28) 2,87 (1,71-4,75) 4,04 (2,15-4,25) 3,67 (2,31-4,84) CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,36 (1,22-1,55) 1,3(1,18-1,55) 1,53(1,37-1,62) 1,82 (1,32-2,17) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 1,73 (1,46-1,89) 1,64 (1,51-1,95) 2,41 (1,62-2,82) 1,29 (1,12-1,41) Note. p - the significance of differences between groups of children (Mann-Whitney test): group 1D - children with Ga of 22-27 weeks, who developed ROP of severe degree III, 1E group - children with ROP at 22-27 weeks, who developed ROP of degrees I-II; Group 2D - children with GA of 28-31 weeks, who developed ROP of severe degree III, 2E group - children with GA of28-31 weeks, who developed ROP of I-II stages. In children born at 28-31 weeks of gestation and formed degree III of PH, there was an increase in CD11b+CD14+, monocytes (p2D-2E = 0.045), which indicates the predominance of mature cells in the population and an increased readiness of effector cells to participate in processes of antigenic presentation and intercellular interaction (Table 60). The increase in CD14+HLA-DR+ monocytes of umbilical cord blood in children with Ga of 28-31 weeks with threshold retinopathy (p2D-2E = 0.01) may be associated with a higher frequency of infectious diseases (pneumonia) in relation to children with I-II degree of ROP (37.5% versus 26.7%). Table 60 Markers of activation of umbilical cord blood monocytes of premature infants who subsequently developed retinopathy, IU (P25-P75) Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) CD11b+CD14+, % 31,0 (15,0-60,0) 50(11,0-68) 56(46,7-61,5) 35(21,5-48,5) 2D-2E =0,045 CD11b+CD14+, abs. 0,09 (0,03-0,09) 0,14 (0,09-0,19) 0,33 (0,19-0,39) 0,19 (0,11-0,23) CD64+CD14+, % 8,0 (7,5-16,75) 42,0 (20,0-44,0) 20(15-32) 42 (38-44) 1D-1E =0,0001 2D-2E =0,07 CD64+CD14+, 109/l 0,05 (0,05-0,10) 0,19 (0,11-0,24) 0,10 (0,07-0,21) 0,19 (0,12-0,24) 1D-1E =0,01 CD14+HLA-DR+, % 39,0 (15,0-58,0) 25,0 (15,75-42,75) 56,5 (43,75-63,3) 28 (18,5-46,75) 2D-2E =0,010 CD14+HLA-DR+, 109/l 0,09 (0,08-0,12) 0,12 (0,08-0,17) 0,26 (0,19-0,35) 0,11 (0,06-0,17) CD71+CD14+, % 11,0 (10,5-12,5) 13,0 (7,75-19,75) 24 (12-24) 15 (12-22) CD71+CD14+, 109/l 0,12 (0,12-0,14) 0,18 (0,11-0,25) 0,11 (0,08-0,30) 0,20 (0,14-0,28) Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 1D - children with GA of 22-27 weeks, who developed ROP of severe degree III, 1E group - children with ROP at 22-27 weeks, who developed ROP of stages I-II; Group 2D - children with GA of 28-31 weeks, who developed ROP of severe degree III, 2E group - children with GA of 28-31 weeks, who developed ROP of I-II degrees. In children born at 22-27 weeks, who developed ROP of degree III, there was a significant decrease in both absolute and relative values of CD64+CD14+, (p1D-1E = 0.01, p1D-1E = 0.0001), which are capable of bind immune complexes and facilitate phagocytosis of pathogens. The incidence of pneumonia in group 1D is 78.57% versus 63.16% in group 1E, sepsis is 36.6% versus 21% of cases, respectively. The level of anti-inflammatory cytokine IL-6 in newborns of the 1D group (p1D-1E = 0.014) and IFN-γ of the 2D group (p2D-2E = 0.004) was significantly lower than in children with PH of I-II degree, which may indicate a violation of the protective properties of the immune system (Table 61). Table 61 Levels of umbilical cord blood cytokines in premature infants who subsequently developed retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) IFN- γ, pg/ml 13,32 (12,36-14,27) 11,26 (10,46-12,29) 0 (0,0-1,95) 10,33 (6,35-11,76) 2D-2E =0,004 IL-6, pg/ml 20,75 (17,32-105,9) 139,36 (101,5-155,5) 6,04 (3,37-15,0) 9,84 (4,07-19,85) 1D-1E =0,014 IL-8, pg/ml 118,85 (90,05-162,1) 69,31 (55,85-142,2) 28,28 (15,73-40,29) 25,9 (16,83-41,95) IL-4, pg/ml 0,61 (0,51-0,81) 0,35 (0,22-0,90) 0,93 (0,5-1,08) 0,61 (0,49-0,97) Note. p - significance of differences between groups of children (Mann-Whitney criterion): group 1D - children with GA of 22-27 weeks, who developed ROP of severe of III degree, 1E group - children with ROP at 22-27 weeks, who developed ROP of I-II degrees; Group 2D - children with GA of 28-31 weeks, who developed ROP of severe of III degree, 2E group - children with GA of 28-31 weeks, who developed ROP of I-II stages. At the age of 1 month of life, a significant decrease in the absolute and relative number of CD64+/CD14+ cells (р1D-1E = 0.01) was noted in premature babies of the 1st group (Table 62). Table 62 Markers of activation of peripheral blood monocytes in premature infants at the age of 1 month of life, subsequently developing retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) CD11b+CD14+, % 51(42-55,5) 68 (49-82) 56 (53,3-57,8) 70,5 (64,5-81,25) CD11b+CD14+, abs. 0,43 (0,38-0,47) 0,5 (0,29-0,75) 0,54 (0,37-0,89) 0,49 (0,36-0,61) CD64+CD14+, % 27,0 (20,25-37,8) 56,5 (34,0-73,0) 11,0 (8,5-18,0) 30 (14,25-55,75) 1D-1E=0,01 2D-2E =0,025 CD64+CD14+, 109/l 0,25 (0,13-0,30) 0,35 (0,22-0,65) 0,13 (0,07-0,18) 0,22 (0,06-0,37) 1D-1E =0,01 CD14+HLA-DR+, % 70 (67,5-73,25) 66,5 (48,5-83,3) 62 (56,8-67,3) 67,5 (59,25-75) 2D-2E =0,09 CD14+HLA-DR+, 109/l 0,43 (0,38-0,49) 0,54 (0,29-0,88) 0,61 (0,47-0,91) 0,51 (0,33-0,58) 2D-2E =0,025 CD71+CD14+, % 10 (3,75-15,5) 14 (9,75-17) 27 (20,5-30) 12,5 (6-20,75) CD71+CD14+, 109/l 0,08 (0,07-0,11) 0,09 (0,065-0,16) 0,22 (0,13-0,38) 0,08 (0,04-0,13) 2D-2E =0,08 Note. р - significance of differences between groups of children (Mann-Whitney criterion): group 1D - children with GA of 22-27 weeks, who developed ROP of severe of III degree, 1E group - children with ROP at 22-27 weeks, who developed ROP of I-II degrees; Group 2D - children with GA of 28-31 weeks, who developed ROP of severe III degree, 2E group - children with GA 28-31 of weeks, who developed ROP of I-II stages. An increase in the number of CD14 / HLA-DR (p1D-1E = 0.025) was typical for children of the 2nd group with ROP of stage III. When assessing serum cytokines in the peripheral blood of children of all groups, no statistically significant differences were found (Table 63). Table 63 Cytokine levels in children at the age of 1 month of life who subsequently developed retinopathy, IU (P25-P75) Indicators Babies at GA of 22-27 weeks Babies at GA of 28-31 weeks ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) IFN- γ, pg/ml 4,25 (3,87-9,51) 1,1(0,0-6,66) 2,05 (1,63-2,19) 1,86 (1,39-1,91) IL-6, pg/ml 7,55 (4,1—16,62) 6,12 (4,69-13) 22 (7,21-38,09) 5,53 (4,07-10,48) IL-8, pg/ml 30,63 (25,33-41,42) 27,9 (26,24-32,47) 24,58 (19,56-38,13) 14,73 (12,67-24,04) IL-4, pg/ml 1,8(1,74-1,84) 1,36(0,89-1,38) 2,05(1,63-2,19) 1,86 (1,39-1,9) Note. The significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. Analysis of intracellular cytokines showed that upon reaching 38-40 weeks of PCA, a significantly increased number of CD4+IL-4+ cells in the stimulated test was observed in children of the 2D group (p2D-2E = 0.036) (Table 64). Table 64 Levels of peripheral blood intracellular cytokines in children at 38-40 weeks of PCA who formed retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) CD4+CD3+IFN-γ+ self-existing, % 1,93(1,27-4,07) 3,23(2,28-5,18) 3,68 (1,88-3,87) 2,81 (2,26-5,89) CD4+IFN-γ+ suscitate, % 4,82 (2,06-6,3) 6,87 (4,95-8,87) 4,51 (2,4-5,08) 3,83 (2,63-6,41) CD4+IL-4+ self-existing, % 1,25 (0,91-4,32) 1,32(1,29-3,54) 2,1 (0,97-2,39) 1,34 (1,03-2,01) CD4+IL-4+ suscitate, % 2,22 (2,06-4,39) 3,7 (2,22-6,2) 4,35 (2,76-5,02) 3,77 (3,2-4,38) 2D-2E =0,036 CD4+IFN-γ+ / CD4+IL-4+ self-existing, c.u. 1,4 (1,22-1,48) 1,37(1,27-1,82) 1,72 (1,64-1,83) 1,79 (1,49-2,11) CD4+IFN-γ+ / CD4+IL-4+ suscitate, c.u. 2,15 (1,32-2,75) 1,73 (1,4—2,31) 0,96 (0,86-1,04) 1,06 (0,98-2,52) 2D-2E =0,005 Note. p - significance of differences between groups of children (Mann-Whitney criterion): groups 1 and 3 - children who have developed ROP of stage III, groups 2 and 4 - children who have developed ROP of stage I and II. Among the markers of monocyte activation, there was an increase in the number of CD14+HLA-DR in children of the 1D group (p1D-1E = 0.017) and a decrease in the absolute number of CD14+ CD64+ monocytes (p1D-1E = 0.01); in children of the 2D group, a decrease in the proportion of CD11b+ was recorded. CD14+, -cells (p2D-2E = 0.004) (Table 65). Table 65 Activation markers of peripheral blood monocytes in children at 38-40 weeks of PCA, who formed retinopathy, IU (P25-P75) Indicators Babies from very early preterm labor (22-27 weeks) Babies from early preterm birth (28-31 weeks) Р ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) CD11b+CD14+, % 77,0 (75,0-77,25) 72 (68-76) 71,5 (68,3-74,5) 82 (78,3-86,5) 2D-2E =0,004 CD11b+CD14+, abs. 0,24 (0,22-0,26) 0,39 (0,25-0,78) 0,52 (0,41-0,53) 0,54 (0,39-0,62) CD64+CD14+, % 22 (17,5-32,5) 29 (22,0-56,5) 49 (44,3-56,25) 73 (65-87) 2D-2E =0,09 CD64+CD14+,, 109/l 0,10 (0,09-0,12) 0,35 (0,25-063) 0,33 (0,24-0,44) 0,5 (0,42-0,6) 1D-1E =0,01 CD14+HLA-DR+, % 81 (77-83,25) 67 (57,3-69,8) 74 (65,5-85) 75,5 (63,25-79) 1D-1E =0,01 CD14+HLA-DR+, 109/l 0,32 (0,28-0,55) 0,35 (0,27-0,5) 0,66 (0,52-0,73) 0,5 (0,42-0,59) CD71+CD14+, % 11,5 (9,75-16,5) 15 (13-23) 17 (9,5-19,5) 15,5 (10,5-24) CD71+CD14+, 109/l 0,07 (0,03-0,09) 0,09 (0,08-0,14) 0,08 (0,06-0,14) 0,1 (0,06-0,15) Note. p - significance of differences between groups of children (Mann-Whitney criterion): groups 1 and 3 - children who developed ROP of stage III, groups 2 and 4 - children who developed ROP stage I and II. There were no significant differences in the comparative analysis of the cytokine status of all premature infants (Table 66). Table 66 Levels of peripheral blood cytokines in children at 38-40 weeks of PCA who have developed retinopathy, IU (P25-P75) Indicators Babies at GA of 22-27 weeks Babies at GA of 28-31 weeks ROP III (Group 1D, n=14) ROP I-II (Group 1E, n=19) ROP III (Group 2D, n=8) ROP I-II (Group 2E, n=30) IFN- γ, pg/ml 1,93 (1,1-3,6) 0 (0-5,2) 2,15 (0,556,69) 3,6 (0-5,7) IL-6, pg/ml 3,97 (3,77-4,8) 3,78 (2,46-4,35) 4,58 (3,33-11,32) 5,68 (2,89-12,24) IL-8, pg/ml 22,13 (14,99-29,28) 14,71 (12,18-19,89) 11,87 (11,71-12,88) 13,04 (12,22-34,06) IL-4, pg/ml 2,47 (2,12-2,76) 2,05(1,89-4,77) 1,97 (1,68-2,19) 2,22 (2,01-2,46) Note. Significance of differences between groups of children (Mann-Whitney test) in all cases, p> 0.05. According to the results of the immunological study, significant differences in children with threshold retinopathy were revealed in indicators of innate immunity of umbilical cord blood: a decrease in adhesion molecules on monocytes, statistically significant in children at GA of 22-27 weeks and at the tendency level in children at GA of 28-31 weeks. An increase in the percentage of activated CD14+HLA-DR monocytes in newborns from early preterm labor and the absence of such differences in infants at GA of 22-27 weeks, a decrease in IL-6 production in deeply premature infants and IFN-γ in premature at GA of 28-31 weeks. By the end of the neonatal period, the ROP development of stage III in children from very early preterm labor was accompanied by a decrease in the number of B-lymphocytes, immunoregulatory index (CD4/CD8), CD4+ lymphocytes, and regulatory CD4+CD25+cells. The results of a study on a decrease in the populations of lymphocytes and regulatory cells in premature infants are consistent with the publication data, indicating these changes with an increase in the severity of retinopathy [4]. By the end of the disease at 38-40 weeks of PCA, the revealed decrease in T-helpers and activated subpopulations persisted, an increase in the absolute number of natural killer cells and CD14+HLA-DR+ -monocytes was observed. In children from early preterm birth, which subsequently developed retinopathy of stage III at 1 month of life, there is an increase in leukocytes and a decrease in intracellular production of IFN-γ upon stimulation of CD4 + cells, the number of activated CD14+HLA-DR+ - and CD14+CD71+ - monocytes increases. Upon reaching 38-40 weeks of PCA in the indicators of adaptive immunity, an increase in the proportion of B-lymphocytes, intracellular production of IL-4 and a decrease in the adhesive ability of monocytes are recorded. Congenital immunity is characterized by a decrease at the level of a trend in the percentage of CD14+CD64 + monocytes and a significant decrease in the relative number of CD14+CD11b+ cells. The differences that we identified in the parameters of the immune system in premature infants with retinopathy in the active phase of the disease are apparently due to the degree of bronchopulmonary dysplasia transferred in the postnatal period: severe BPD, which was recorded 2.0 and 5.7 times more often with threshold retinopathy in children from very early and early preterm birth. 5.2. A method for predicting the development of the threshold stage of retinopathy in premature infants with extremely low body weight The most difficult task is to predict the development and nature of the course of the disease, given that the pathogenesis of ROP is not fully understood, despite many years of research. The principles of ROP screening currently accepted in Russia include examination of the fundus with a wide pupil by indirect ophthalmoscopy of all premature babies born before 35 weeks of gestation or weighing less than 2000 g (international criteria are gestational age at birth up to 32 weeks and weight less than 1500 g) with the first examination, as a rule, at the age of 4-6 weeks of life and subsequent periodic examinations carried out repeatedly until the process of retinal vascularization is completely completed or until the development of the so-called threshold stage of ROP, requiring therapeutic intervention. The threshold is considered to be the III stage of the active phase of the disease with the spread of the extraretinal process to 5 consecutive or 8 total hour meridians. The cost of existing methods for predicting the course of retinopathy of prematurity (ROP) makes it relevant to search for new simple and informative signs of disease progression. We have developed a method for predicting the development of the threshold stage of retinopathy in premature infants with extremely low body weight based on clinical and laboratory data using the method of mathematical modeling. The technical result when using the invention is to increase the efficiency of forming a risk group for the development of a threshold ROP. The method is carried out as follows: assess the sex of the child and body weight at birth, the level of hemoglobin in peripheral blood on the hematology analyzer "ABX Micros 60-OT18" (France) on the 1st day of life and the duration of the child's stay in the intensive care unit (ICU). A survey of 55 deeply premature infants with ELBW was carried out. It was divided into 2 groups (using the copy-pairs method): Group 1: children who did not have ROP of stage III (n = 23); Group 2: children with diagnosed ROP of stage III (n = 22). When forming the groups, the comparability of children for the main, competing and concomitant diseases was taken into account. Ophthalmological examination was carried out in children, starting from 4 weeks of life, regularly, every 1-2 weeks until the process of retinal vascularization is complete or until the threshold stage of ROP, requiring therapeutic intervention. As a result of our studies, we identified predictors of a high risk of stage III retinopathy in newborns with extremely low body weight. Using the method of discriminant analysis, a mathematical model for predicting this pathology has been developed, which consists in determining the prognostic index (PI1) according to the formula: PI = 1.804 × X1 - 0.0095 × X2 - 0.0285 × X3 + 0.0963 × X4 +9.563, where X1 - gender of the child (female/male) (1/0); X2 is body weight at birth, g; X3 - peripheral blood hemoglobin content on the 1st day of life, g/l; X4 is the number of days spent in the NICU; 9,563 - Const If PI is more than 0, a high risk of stage III retinopathy is predicted, and if PI is less than 0, a low risk of disease progression is predicted. The specificity of our proposed method is 80.6%, the sensitivity is 87.2%. The efficiency of the method is 83.9%. Example 1. A premature girl (labor and delivery record No. 3039), was born to a 23-year-old bipara woman, somatically weight down by hypertensive neurocirculatory dystonia. The anamnesis 1 has urgent labor. The second present pregnancy proceeded against the background of chronic fetal-placental insufficiency, decompensated form, III degree uteroplacental blood flow disorders without centralization of blood circulation, severe preeclampsia. There was premature operative delivery in a transverse position at GA of 28 weeks. Weight and body length at birth were 820 grams, 34 cm, 4/6 points on the Apgar scale. There was ALV from birth for 9 days, followed by respiratory support using the BNCPAP method for 9 days. She was transferred to the stage of rehabilitation at the age of 23 days of life. Indicators of red blood at birth were: hemoglobin 151 g/l, hematocrit 43.8%, erythrocytes 3.78×1012/l. The predictive index was calculated by the formula: PI = 1.804 × 1 - 0.0095 × 820 - 0.0285 × 151 + 0.0963 × 23 + 9.563 = 1.477, which is more than 0 and predicts a high risk of threshold retinopathy formation. At the age of 35 days of life, a routine ophthalmological examination was diagnosed with ROP of stage II, by 42 days of life - ROP of stage III in both eyes, which required surgical treatment. At the age of 82 days of life in a satisfactory condition, the child was discharged with a body weight of 2152 g. Example 2. A premature boy (labor and delivery record No. 649), was born to a 37-year-old primigravida woman. Pregnancy proceeded against the background of a weight down by obstetric history (primary infertility, in vitro fertilization, 4 attempts), chronic feto-placental insufficiency, decompensated form, impaired uteroplacental blood flow of the III degree, gestational diabetes mellitus, severe preeclampsia HELLP syndrome (cardiac form). There was delivery premature operative at 26 - 27 weeks, cephalic presentation. Weight and body length at birth were 690 grams, 28 cm, 4/6 points on the Apgar scale. There was from birth for 25 days, then respiratory support using the BNCPAP method for 15 days. He was transferred to the stage of rehabilitation at the age of 42 days of life. The indices of red blood at birth were: hemoglobin 146 g/l, hematocrit 42.6%, erythrocytes 3.58×1012/l. The predictive index was calculated by the formula: PI = 1.804 × 0 - 0.0095 × 690– 0.0285 × 146 + 0.0963 × 42 + 9.563 = 2.8916, which is more than 0 and predicts a high risk of threshold retinopathy formation. At the age of 42 days of life, during a routine ophthalmological examination, ROP of stage II was diagnosed, by day 92 - ROP of stage III in both eyes, which required surgical intervention. At the age of 108 days of life in a satisfactory condition, the child was discharged with a body weight of 2300 g. Example 3. A premature girl (labor and delivery record No. 434) was born to a 34-year-old bipara woman, weight down by B-20 of stage III. The anamnesis 1 has urgent delivery and 3 medical abortions at the request of the woman. Pregnancy 5 real proceeded against the background of a weight down by obstetric history (3 medical abortions), bacterial vaginosis (without debridement), genital herpes, grade I anemia. Delivery is quick premature at 29 weeks, occipital presentation. Birth weight and length were 840 grams, 32 cm, 5/6 points on the Apgar scale. There was ALV from birth for 6 days, then respiratory support using the BNCPAP method for 4 days. He was transferred to the stage of rehabilitation at the age of 14 days of life. The indices of red blood at birth were: hemoglobin 160 g/l, hematocrit 46.7%, erythrocytes 3.71×1012/l. The predictive index was calculated by the formula: PI = 1.804×1 - 0.0095×990– 0.0285×160 + 0.0963×14 + 9.563 = -1.2498, which is less than 0 and predicts a low risk of threshold retinopathy development. At the age of 30 days of life, during a routine ophthalmological examination, ROP of stage I was diagnosed, by the age of 65 - stage II ROP in both eyes without further progression. At the age of 73 days in a satisfactory state of life, the child was discharged with a body weight of 2256 g. Example 4. A premature boy (labor and delivery record No. 107), was born to a 41-year-old bipara woman, somatically weight down by a paranoid form of schizophrenia. The anamnesis 1 has artificial termination of pregnancy. This pregnancy, the second present, proceeded against the background of a weight down by obstetric history (medical abortion), chronic fetal-placental insufficiency, decompensated form, III degree uteroplacental blood flow disturbances without centralization of blood circulation, severe preeclampsia, bilateral hydrothorax, hydropericardium. There were delivery premature operative at 25 - 26 weeks, foot presentation. Weight and body length at birth - 770 grams, 30 cm, 5/5 points on the Apgar scale. Mechanical ventilation from birth for 7 days of life, then respiratory support using the BNCPAP method for 10 days. He was transferred to the stage of early rehabilitation at the age of 19 days of life. Indicators of red blood at birth: hemoglobin 168 g/l, hematocrit 49.5%, erythrocytes 4.31 × 1012/l. The predictive index was calculated by the formula: PI = 1.804 × 0 - 0.0095 × 770 - 0.0285 × 168 + 0.0963 × 19 + 9.563 = - 0.71, which is less than 0 and predicts a low risk of threshold retinopathy development. At the age of 35 days of life with a planned ophthalmological examination,ROP of stage I was diagnosed, at the age of 42 days - ROP of stage II without subsequent progression. At the age of 75 days of life in a satisfactory condition, the child was discharged with a body weight of 2356 g. Thus, predicting the development of threshold retinopathy of prematurity by the proposed method allows to reduce the number of severe stages of ROP due to early detection of children prone to the development of the disease. The inventive method for predicting the formation of the threshold stage of retinopathy in deeply premature infants with EBMT has the following advantages in comparison with the existing ones: the method is simple to execute, includes the assessment of clinical and laboratory studies, which are carried out in accordance with the standard in any medical institution, does not require expensive equipment. 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 We have developed a method for predicting the development of the threshold stage of retinopathy in premature infants with extremely low body weight in the early neonatal period based on the immunological parameters of umbilical cord blood using the method of mathematical modeling. The technical result when using the invention is the identification of a risk group for the implementation of threshold retinopathy in premature infants with ELBW. The method is carried out as follows: the collection of venous blood from the umbilical cord vein is carried out in two test tubes: the first test tube is used to determine the relative content of CD14+CD64+ - monocytes in blood plasma by flow cytofluorometry; the second - to determine the concentration of IL-4 and IL-6 by enzyme-linked immunosorbent assay in the blood serum of children with ELBW. To achieve this goal, 71 children with ELBW at GA of 22-31 weeks were examined, who formed ROP at 38-40 weeks of PCA, which were subdivided into groups depending on the stage of the disease: Group 1 - children with diagnosed with ROP of stage III (n = 22); Group 2 - children with diagnosed with ROP of stage I-II (n = 49). When forming the groups, the comparability of children for the main, competing and concomitant diseases was taken into account. Ophthalmologic examination was carried out in children, starting from the 4th week of life, regularly, every 1-2 weeks until the process of retinal vascularization is complete or until the threshold stage of ROP, requiring therapeutic intervention. As a result of the studies, the most informative indicators of a high risk of realization of retinopathy of prematurity of stage III in children with ELBW were revealed. Using the method of discriminant analysis, a mathematical model for predicting this pathology has been developed, which consists in determining the prognostic index (PI1) according to the formula: PI = -0,138×Х1 – 0,015×Х2 – 3,41×Х3 + 6,19, where Х1 – CD14+CD64+ monocytes, %; Х2 – IL-6 content, pg/ml; Х3 – IL-4 content, pg/ml; 6,19 – Const If PI is more than 0, a high risk of realization of threshold retinopathy of prematurity is predicted, and if PI is less than 0, a conclusion is made about a low risk of progression of this pathology. The sensitivity of the proposed method is 86.4%, the specificity is 91.9%. The efficiency of the method is 89.15%. Example 1. Premature girl G. (labor and delivery record No. 2516) was born in a 39-year-old bipara woman, somatically weight down by arterial hypertension of II degree, hypothyroidism. The anamnesis has antenatal fetal death. The second real pregnancy proceeded against the background of chronic placental insufficiency, subcompensated form, III degree disorders of uteroplacental blood flow without centralization of blood circulation, fetal growth retardation syndrome (FGRS). There were premature operative labor at 26 weeks. Birth weight and length were 820 grams, 31 cm, 6/7 points on the Apgar scale. Respiratory support using the BNCPAP method for 7 days, no ALV was performed. She was transferred to the stage of rehabilitation at the age of 15 days of life. Cord blood parameters at birth: CD14 + CD64 + monocytes - 8%, IL-6 - 20.75 pg/ml, IL-4 - 0.22 pg/ml. The predictive index was calculated by the formula: PI = -0.138 × 8 - 0.015 × 20.75 - 3.41 × 0.22 + 6.19 = 4.02, which is more than 0 and predicts a high risk of threshold retinopathy development. At the age of 43 days of life, a routine ophthalmological examination was diagnosed with ROP of stage II, by 56 days of life - ROP of stage III in both eyes, which required surgical treatment. At the age of 89 days of life in a satisfactory condition, the child was discharged with a body weight of 2065 g. Example 2. Premature girl Sh. (labor and delivery record No. 1893) was born in a 30-year-old primigravida pregnant woman, somatically weight down by obesity, arterial hypertension of the 1st degree, varicose veins. The anamnesis has infertility, uterine fibroids. Pregnancy proceeded against the background of gestational diabetes mellitus, chronic fetal hypoxia, threat of termination, chronic placental insufficiency, decompensated form, III degree of uteroplacental blood flow disturbance, FGRS. Labor premature operative at GA of 30 weeks. Weight and body length at birth were 520 grams, 26 cm, 4/5 points on the Apgar scale. There was ALV from birth for 1 day, then respiratory support using the BNCPAP method - 1 day. Cord blood parameters at birth: CD14 + CD64 + monocytes - 13%, IL-6 - 15.13 pg/ml, IL-4 - 0.93 pg/ml. The predictive index was calculated by the formula: PI = -0.138×13 - 0.015×15.13 - 3.41×0.93 + 6.19 = 0.99, which is more than 0 and predicts a high risk of developing threshold retinopathy. She was transferred to the stage of rehabilitation at the age of 8 days of life. At the age of 48 days of life, during a routine ophthalmological examination, ROP of stage II was diagnosed, by the 75th day of life - ROP of stage III in both eyes, which required surgical intervention. At the age of 123 days of life in a satisfactory condition, the child was discharged with a body weight of 2005 g. Example 3. Premature boy N. (labor and delivery record No. 537) was born to a 27-year-old multigravida woman, somatically not weight down. The anamnesis has urgent labor andone medical abortion at the request of the woman. Pregnancy proceeded against the background of the threat of termination, preeclampsia of moderate severity, chronic placental insufficiency, decompensated form, impaired uteroplacental blood flow of the III degree. Labor premature operative at GA of 27 weeks. Weight and body length at birth were 900 grams, 37 cm, 4/6 points on the Apgar scale. There was ALV from birth for 8 days, then respiratory support using the BNCPAP method - 6 days. He was transferred to the stage of rehabilitation at the age of 23 days of life. Cord blood parameters at birth: CD14 + CD64 + monocytes - 38%, IL-6 - 155.5 pg/ml, IL-4 - 0.8 pg/ml. The predictive index was calculated by the formula: PI = -0.138×38 - 0.015×155.5 - 3.41×0.8 + 6.19 = -5.08, which is less than 0 and predicts a low risk of threshold retinopathy development. At the age of 32 days of life, a routine ophthalmological examination was diagnosed with ROP of I degree, by 52 days of life - ROP of II stage in both eyes without subsequent progression. At the age of 70 days of life in a satisfactory condition, the child was discharged with a body weight of 2280 g. Example 4. Premature boy G. (labor and delivery record No. 370), was born to a 35-year-old bipara woman, somatically weight down by myopia of the II degree. Gynecological anamnesis has uterine fibroids. This pregnancy, the second present, proceeded against the background of a weight down by obstetric history (medical abortion), isthmic-cervical insufficiency, chorioamnionitis, colpitis. There was delivery premature operative at 28 weeks. Weight and body length at birth 990 grams, 33 cm, 5/6 points on the Apgar scale. There was ALV from birth for 2 days of life, then respiratory support using the BNCPAP method for 3 days. He was transferred to the stage of early rehabilitation at the age of 7 days of life. Cord blood parameters at birth: CD14 + CD64 + monocytes - 47%, IL-6 - 101.5 pg/ml, IL-4 - 0.0 pg/ml. The predictive index was calculated by the formula: PI = -0.138×47 - 0.015×101.5 - 3.41×0.0 + 6.19 = -1.82, which is less than 0 and predicts a high risk of the development of threshold retinopathy. At the age of 30 days of life with a planned ophthalmological examination, ROP of stage I was diagnosed, at the age of 42 days - ROP of stage II without subsequent progression. At the age of 46 days of life in a satisfactory condition, the child was discharged with a body weight of 2021 g. Thus, predicting the development of threshold retinopathy of prematurity by the proposed method allows to reduce the number of severe stages of ROP due to early detection of children prone to the development of the disease. The inventive method for predicting the development of the threshold stage of retinopathy in premature infants with ELBW has the following advantages in comparison with the existing ones. The method is minimally invasive (cord blood), it allows predicting the progression of active retinopathy of premature infants on the first day of life. 5.4. Algorithm for additional examination of children born with extremely low body weight Correlation analysis revealed positive and negative relationships between changes in the indices of innate and adaptive immunity in the blood with the development of ROP of stage III and severe BPD in children with ELBW (Fig. 1). Fig. 1. Correlations between the parameters of the immune system and the presence of BPD and ROP. Hypoxia, intrauterine infections, surfactant deficiency, genes responsible for the regulation, differentiation, growth and alveolarization of lung tissue, vasculogenesis, hyperoxygenation of the body lead to the progression of the inflammatory process at the systemic and local levels. Moreover, they have a damaging effect on the vascular-capillary network, including vessels of the retina and lungs, which affects the formation of BPD and ROP. Immaturity of the phagocytic link of the immune system and reduced production of anti-inflammatory IL-4 predetermines the development of the infectious process. Past hypoxia and prolonged exposure to ALV causes increased production of inflammatory mediators, which have a direct effect on the membrane of alveolar capillaries, simulate immune protection, mediate acute damage to the tissues of the lungs and retina, initiating or intensifying the inflammatory cascade against the background of an infectious process, and induce freely -radical oxidation processes. The rapidly growing structures of a deeply premature baby are especially sensitive to oxidative stress, which can lead to severe tissue disorders. Later, reparative processes of damaged organs and hyperproduction of interstitial fibroblasts begin, leading to fibrosis and the subsequent development of BPD and ROP. The methods developed by us, along with standard examination protocols, made it possible to recommend additional studies of newborns with ELBW to identify high-risk groups for the formation of severe postnatal pathology (Fig. 2). Fig. 2. Algorithm for additional examination of premature infants with ELBW in the neonatal period to predict the development of postnatal complications. It is necessary to determine the concentration of CD14+HLA-DR+ monocytes and CD4+CD25+ lymphocytes in umbilical cord blood, taking into account the presence of severe anemia in the neonatal period, requiring repeated hemotransfusions with the subsequent calculation of the prognostic indexin case of a high risk of bronchopulmonary dysplasia in premature infants with ELBW, in order to assess the severity of this pathology. To predict the risk of ROP of stage III for all children born with ELBW, it is recommended to determine the percentage of CD14+CD64+ monocytes, the level of IL-6 and IL-4 in the umbilical cord blood, peripheral blood hemoglobin in the first day of life, taking into account the sex of the child, body weight at birth, the length of stay in the ICU with the subsequent calculation of the prognostic index. Our proposed algorithm for additional examination of newborns in the neonatal period makes it possible to objectively assess the tactics of nursing, timely adjust the observation pattern and prescribe adequate therapy.

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