RISK FACTORS OF BIRTH OF PREMATURE CHILDREN
Авторы:
1.
Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia
2.
Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia
3.
Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia
4.
the Federal State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia
5.
State Budgetary Institution "Ural Research Institute of Maternity and Infancy Care" of the Ministry of Health of Russia
Тип:
Глава
Страницы с - по
11 - 24
Издатель:
AUS PUBLISHERS
Язык материала:
английский
Ключевые слова:
Children, extremely low body mass, neonatal pathology, immune system, weight, immunity, postnatal pathology, newborns
Аннотация (русский):
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.
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.
Ключевые слова:
Children, extremely low body mass, neonatal pathology, immune system, weight, immunity, postnatal pathology, newborns
Children, extremely low body mass, neonatal pathology, immune system, weight, immunity, postnatal pathology, newborns
1.1. Social and medical problems of childbirth to children with extremely low body weight
The gradual transition of the constituent entities of the Russian Federation (RF) to new technologies for nursing children with ELBW is a natural stage in the development of Russian perinatology, regulated by order No. 1687n dated December 27, 2011. From this moment on, the state registration of newborns with a body weight of 500 g at a gestational age of 22 weeks or more began in accordance with the birth criteria recommended by the World Health Organization (WHO), as well as the introduction of organizational and medical technologies for nursing deeply premature babies, improving the quality of prenatal observations [1, 2, 3]. In this regard, effective nursing and rehabilitation of newborns with ELBW is a task set for the constituent entities of the Russian Federation, the solution of which will lead to a decrease in perinatal and infant mortality, and will improve the quality of further development.
According to the WHO recommendations, a child born in a preterm birth from 22 to 37 weeks is considered premature. According to the classification of premature birth, adopted in 1993 in the Russian Federation, depending on the gestational age, superearly (22-27 weeks), early (28-33 weeks) and premature birth (34-37 weeks) are distinguished. According to the body weight at birth, according to the WHO classification, 10 revisions distinguish groups of children up to 2500 grams i.e. from low, up to 1500 grams - from very low and up to 1000 grams of extremely low body weight.
In recent years, the frequency of preterm birth on average in developed countries is 5-10%, in the world - 15% [1, 27], of which 1-1.8% is the share of children with VLBW, 0.4-0.5% - children with ELBW [4].
In many works, much attention is paid to the analysis of the reasons leading to the premature birth of children, the state of physical and neuropsychic development of newborns [5, 6, 7, 8], as well as genetic factors that contribute to premature birth, which are realized both by the mother and and a child. In addition to genetic factors, infectious and endocrine diseases, aggravated obstetric -gynecological history, preeclampsia, multiple pregnancy, chronic placental insufficiency (CPI), placental abruption [4, 9]. According to Russian researchers, there has been an increase in the number of women carriers of TORCH infections, which affect the fetation throughout pregnancy [10].
The leading place among the problems concerning children with ELBW are survival and mortality rates [8, 11, 12]. Modern approaches to perinatal care in Russia and in the world have increased the survival rate of newborns with ELBW up to 45% [13, 14].
The percentage of unfavorable outcomes among surviving children also depends on birth weight and reaches 40-50% in newborns with a weight of 750 to 1000 g, rising to 70-90% at the birth of children weighing from 500 to 749 g, which are, undoubtedly the most vulnerable and difficult contingent for rehabilitation [15, 16, 17]. According to world statistics, among newborns, 11.6% of children under 500 g, 50.7% - from 500 to 749 g, 83.9% - from 750 to 1000 g at birth survive [8, 18]. It is believed that newborns weighing from 500 to 749 g are in the "zone of the viability limit" and their nursing is very problematic. According to American perinatologists, the survival rate of newborns with a gestational age of 22-24 weeks before discharge from the hospital averages 13%, and with a gestational age of more than 26 weeks - 70%, in the future 70% and 30% of children have severe CNS damage, respectively [19]. In Japan, in 2011, the mortality rate of newborns with gestational ages of 22 and 23 weeks was 80% and 64%, respectively [20].
A study by V. Fellman et al. (2009) showed that in Sweden, by one year of age the survival rate among newborns at a gestational age of 22 to 26 weeks was 70%, with 9.8% of children born at 22 and 85% at 26 weeks of gestation. The authors note the absence of serious somatic and neurological complications in 45% of premature infants with ELBW [21]. Over the past two decades, the survival rate of newborns with ELBW has increased in Italy (from 42% to 76%). However, the percentage of the formation of bronchopulmonary dysplasia remains approximately at the same level, amounting to 30.5% and 39%, respectively [22].
The literature indicates a natural relationship between the mortality of children with ELBW and postnatal age. A study by T. Nakhla et al. [23], demonstrated that 49% of newborns with ELBW died in the 1st week of life, 17% - in the 2nd week and only 9% after the 2nd month of life. According to M.A. Mohamed (2010), the survival rate of premature newborns with birth weight from 500 to 750 grams increased to 70% with survival in the first three days and up to 80% - until the end of the 1st week of life [24]. According to the research results of H.V. Bashmakova et al. (2012) the mortality rate of children born with a body weight of 500 to 750 grams was 54.8%, from 750 to 1000 grams - 11.5%. Moreover, the mortality rate of premature babies in the 1st group at the 1st week of life was five times higher than in the 2nd group [8].
The reason for the high incidence of premature infants is the functional immaturity of the respiratory, cardiovascular, immune, and central nervous systems (CNS), which makes premature infants susceptible to the development of pathological conditions [25]. In connection with the peculiarities of the immunological resistance of deeply premature infants, the leading cause of death along with serious injuries of the central nervous system are infectious and inflammatory diseases [26]. Along with infectious and inflammatory pathology, the authors include respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), left ventricular failure and systemic hypotension, hemodynamically relevant functioning ductus arteriosis (HRFDA) [27 , 28, 29, 30, 31].
In recent years, there has been a decrease in the proportion of severe complications in children with ELBW [21, 28]. However, the rates of chronic pathology and disability do not show a significant tendency to decrease and remain high even in developed countries [32, 33, 34].
Children with ELBW are born in a serious condition, being maximally exposed to complications associated with prematurity. Therefore, their nursing refers to high-tech care, since they need support for all basic vital functions of the body [4]. Numerous studies confirm that in order to reduce perinatal and infant mortality, a favorable prognosis for the further development of deeply premature newborns in order to provide comprehensive high-tech medical care for women in high-risk groups, hospitalization is required in specialized perinatal centers of III level, where the neonatal intensive care unit operates [35, 36, 37, 38].
Measures to prevent premature birth are more effective than efforts to intensive care and rehabilitation of deeply premature babies even taking into account the modern level of diagnostic and treatment technologies [29]. Prevention of unfavorable outcomes in children with ELBW requires long-term and expensive rehabilitation treatment. Therefore, given the low health potential of children with ELBW, the high incidence of pathology and the low quality of life, the main reserves for reducing the incidence and mortality of deeply premature babies are full monitoring of pregnant women, the identification of high-risk groups and the use of modern nursing technologies in perinatal centers [29].
In large world perinatal centers with the ability to provide qualified high-tech care, 80-85% of newborns with ELBW and VLBW survive and leave these centers, this indicator varies widely depending on the body weight and gestational age of the child [39]. Subsequently, from 2 to 5% of them die within the first two years after discharge from delayed complications. Unfavorable outcomes of children born at 22-25 weeks of gestation are also noted by Russian authors [40, 41]. Researchers believe that in the indicated time frame there is a certain biological barrier that impedes the survival of newborns [8, 35]. To increase survival rates and minimize residual complications of diseases of the prematurity period in the Russian Federation, a three-stage system of nursing premature babies has been adopted in specialized perinatal centers:
Stage I - provision of primary resuscitation care in the delivery room, nursing in the NICU;
Stage II - nursing in specialized departments of pathology of premature infants of perinatal centers (stage of early rehabilitation);
Stage III - dispensary observation in a children's polyclinic, rehabilitation in the early recovery period in a day and round-the-clock hospital.
Despite the increase in the survival rate of such children, the risk of neurological impairment and cognitive impairment remains high [33, 31, 42, 43, 44]. The number of healthy newborns with ELBW does not exceed 10-25%, and the percentage of severe neurological outcomes ranges from 12 to 32% [24, 44].
In France, disability is much more often registered in children born at a very early preterm birth compared with children born at an early preterm birth (infantile cerebral paralysis (ICP) was 20% in children with a gestational age of 24-26 weeks and only 4 % at 32 weeks) [46].
In most modern works, much attention is paid to the stage of nursing children with ELBW in the conditions of the intensive care unit [47, 48, 49]. However, there are not enough publications in the literature devoted to the study of premature babies at the stage of early rehabilitation, where newborns are transferred after stabilization of the state and restoration of basic vital functions, due to the need for long-term respiratory support of morphofunctionally immature lungs, which dictates the need for further research.
1.2. Perinatal risk factors for the birth of premature infants
To identify a complex of unfavorable factors of ante- and intranatal nature that caused the birth of premature infants with extremely low body weight, the obstetric and gynecological history, features of the gestational period and childbirth were studied in 114 women hospitalized at the FSBI "The Ural Research Institute of Maternity and Child Care" The Ministry of Health of the Russian Federation. This study was approved by the local ethics committee of the institute. We received informed voluntary consent from all women for the processing of personal data, treatment, examination.
The classification of preterm birth, adopted in 1993 in the Russian Federation, in which, depending on the gestational age was fundamental in the division of the groups, the following groups were identified:
1st group – early childbirth (22-27 weeks, the weight of the baby is within 500-999 grams)
2nd group – premature birth (28-33 weeks, 1000-2000 grams)
3rd group – full-term pregnancy (37-40 weeks, 2500 grams or more)
All surveyed women were comparable in age. The average age of women in groups 1 and 2 was: 30.13 ± 5.66 years and 30.27 ± 6.11 years, respectively. In the group of women who gave birth to full-term newborns, this indicator was slightly lower - 29.41 ± 2.97 years (р1-3, 2-3>0,05). Most of the mothers of all groups had a permanent place of work (63 %, 74,4 %, 96 %, p1-2>0,05, p1-3,2-3<0,005). Less than half of women who gave birth at the time of very early preterm birth were married (47.8% and 60.5% in groups 1 and 2, 84% in the comparison group (p1-2>0,05, p1-3=0,002,p2-3=0,015)) and less than a third lived in the city (23.9% in the 1st, 30% in the 2nd and 28% in the comparison group). Bad habits, such as nicotine addiction and alcohol consumption, were not practically observed (4.34% in the 1st, 4.65% in the 2nd and 0% in the comparison group).
The structure of extragenital pathology is shown in Table 1.
Table 1
The structure of extragenital pathology of mothers in premature infants
Class of diseases according to ICD-10
1st group (women who gave birth to children at 22-27 weeks’ gestation period, n = 46) 2nd group (women who gave birth to children at 28-31 weeks’ gestation period, n = 43) 3rd group (women who gave birth to full-term babies, n = 25) р
abs % abs % abs %
Class I. Certain infectious and parasitic diseases 4 8,69 6 13,95 0 0
Class II. Neoplasms (fibroids) 1 2,17 7 16,27 1 4 р1-2=0,026,
Class III. Diseases of the blood and blood-forming organs (mild to moderate anemia) 11 23,91 13 30,23
6
24
Class IV. Diseases of the endocrine system, nutritional disorders and metabolic disorders (including): 9 19,5 14 32,56 0 0
р1-3=0,017
р2-3=0,00005
Obesity 0 0 10 23,25 0 0 р1-2,2-3=0,00093
Type I diabetes mellitus 0 0 1 2,32 0 0
Hypothyroidism 9 19,5 3 6,97 0 0 ,
р1-3=0,017
Class VII. Diseases of the eye and adnexa 12 26 8 18,6 8 32
Class IX. Diseases of the circulatory system 4 8,69 11 25,58 0 0 р1-2=0,04
р2-3=0,0004
Class XI. Diseases of the digestive system 6 13 7 16,2 3 12
Class XIV. Diseases of the genitourinary system 6 13 9 20,93
0
0
р2-3=0,017
Note. In connection with the identification of several pathological signs in the same woman, the total number of cases exceeds 100%, p1-2, p1-3, p2-3 - the significance of differences between groups of mothers (χ2 test with a Yates correction): 1 - mothers, those who gave birth to children at 22-27 weeks' GP, 2 - mothers who gave birth to children at 28-31 weeks' GP, 3 - a comparison group.
Extragenital pathology is an unfavorable background that affects the capabilities of adaptive mechanisms, the limitation of which, in turn, leads to complications of pregnancy, childbirth and the postpartum period. The morbidity patterns of women who gave birth to children with ELBW was characterized by a high frequency of extragenital pathology. Hypertension was recorded significantly more often in women of the second group - in 25.68% versus 8.69% of cases in the first group (p1-2 = 0.04).
HIV infection was noted in the anamnesis of two women of the main groups.
Comparative analysis of maternal medical history data showed an extremely unfavorable course of the antenatal period (Table 2).
Table 2
Obstetric history of the mothers of the observed children
Nosological form 1st group (women who gave birth to children at 22-27 weeks’ gestation period, n = 46) 2nd group (women who gave birth to children at 28-31 weeks’ gestation period, n = 43) 3rd group (women who gave birth to full-term babies, n = 25) р
abs % abs % abs %
Agenesia 4 8,69 1 2,32 0 0 р1-2,1-3,2-3≥0,05
Justifiable artificial abortion 20 43,47 23 53,48 7 28 р1-2,1-3,2-3≥0,05
Miscarriage 2 4,34 3 6,97 1 4 р1-2,1-3,2-3≥0,05
Regression 2 4,34 2 4,65 2 8 р1-2,1-3,2-3≥0,05
Spontaneous miscarriages 10 21,73 9 20,93 4 16 р1-2,1-3,2-3≥0,05
Note. p1-2, p1-3, p2-3 - the significance of differences between the groups of mothers (χ2 test with a Yates correction): 1 - mothers who gave birth to children at 22-27 weeks' GP , 2 - mothers who gave birth to children at 28-31 weeks' GP, 3 - comparison group.
More than 60% of all women were re-pregnant (71.44%, 67.44% and 60% of cases). A burdened obstetric history was noted in half of the women examined, the leading factors were spontaneous miscarriages and induced abortions, no significant differences were found between the compared groups. Spontaneous miscarriages were recorded in every fifth woman in the main groups and in every sixth comparison group (р1-2,1-3,2-3≥0,05). Artificial terminations of pregnancy among women with preterm birth were 1.55 and 1.91 times more frequent than women who gave birth to full-term infants. Agenesia (primary, secondary) in women who gave birth to children of gestational age of 22-27 weeks was diagnosed 3.75 times more often than in group 2. In the comparison group, this pathology was not registered. There were no significant differences in the incidence of regressing pregnancies in mothers of children of both groups. The onset of pregnancy by assisted reproductive technologies (ART) was noted in 2 and 3 cases among women in the main groups. In women in the comparison group, pregnancies occurred without medical intervention.
Among the complications of pregnancy in women of the main groups, preeclampsia of moderate severity was more common (р1-2≥0,05, р1-3=0,02, р2-3=0,005), its severe course was observed only in every eighth patient (Table 3 ).
The threat of termination of this pregnancy was diagnosed in more than half of the women in the main groups. Chronic placental insufficiency (CPI) was more often observed in a subcompensated form (р1-3=0,003, р2-3=0,0001, р1-2≥0,05), in the comparison group there was only a compensated form in one woman.
Uteroplacental blood flow disorder (UBFD) was recorded among all women with preterm labor. However, severe degree was found significantly more often in mothers of the 2nd group (р1-2=0,006, р1-3=0,026, р2-3=0,00001), which is possibly associated with a longer course of CPI in this category. Low water level prevailed over polyhydramnios, being detected significantly more often in women who gave birth at 28-31 weeks of gestation period (р1-2=0,005, р1-3=0,00024, р2-3=0,0001).
Table 3
Features of the course of this pregnancy
Nosological form 1st group (women who gave birth to children at 22-27 weeks’ gestation period, n = 46) 2nd group (women who gave birth to children at 28-31 weeks’ gestation period, n = 43) 3rd group (women who gave birth to full-term babies, n = 25) р
abs % abs % abs %
The threat of termination of pregnancy 26 56,5 23 53,48 2 8
р1-3,2-3<0,01
Preeclampsia
- moderately severe 8 17,39 12 27,9
0
0
р1-3=0,02
р2-3=0,005
Preeclampsia
- severe 6 13 5 11,62 0
UBFD
- I degree 4 8,69 8 18,6 0 0
р2-3=0,026
- II degree 5 10,86 4 9,3 0 0
- III degree 8 17,39 20 46,51 0 0 р1-2=0,006
р1-3=0,026
р2-3=0,00001
CPI
- compensated 1 2,17 2 4,65 1 4
- subcompensated 13 28,33 19 36,58
0
0
р1-3=0,003
р2-3=0,0001
- decompensated 9 19,56 11 25,58 0 0 р1-3=0,017
р2-3=0,007
Low water level 12 26 20 46,51 0 0 р1-2=0,005
р2-3=0,0001
р1-3=0,00024
Polyhydramnios 6 13 7 16,27 0 0 Р2-3=0,039
Detachment of a normally located placenta 8 17,39 5 11,62 0 0 р1-3 =0,026
CI 14 30,43 11 25,58 0 0 Р2-3=0,007
Р1-3=0,002
PRFB 15 26,66 6 13,95 0 0 р1-2=0,024
р1-3=0,001
Long latency period 9 19,56 3 6,97 0 0 р1-3=0,017
Gestational diabetes mellitus 3 6,52 11 25,58 2 8 р2-3=0,007
Chorioamnionitis 9 19,56 1 2,32 0 0 р1-2=0,007
р1-3=0,017
Note. Note. In connection with the identification of several pathological signs in the same woman, the total number of cases exceeds 100%, p1-2, p1-3, p2-3 - the significance of differences between groups of mothers (χ2 test with a Yates correction): 1 - mothers, those who gave birth to children at 22-27 weeks' GP, 2 - mothers who gave birth to children at 28-31 weeks' GP, 3 - a comparison group.
Gestational diabetes mellitus, which increases the likelihood of pregnancy complications due to increased insulin secretion and decreased sensitivity to it, was diagnosed in a quarter of women in group 2 (p2-3 = 0.007, p1-2.1-3≥0.05). Premature rupture of the fetal bladder (PRFB) was observed significantly more often in women who gave birth to children of gestational age of 22-27 weeks (p1-2 = 0.024). It was also accompanied by a long anhydrous interval of more than 12 hours, which was one of the risk factors for preterm birth. Chorioanionitis was identified significantly more often in women of the 1st group (p1-2 = 0.007, p1-3 = 0.017). Premature detachment of the normally located placenta was detected only in the main groups (p1-3 = 0.026, p1-2.2-3≥0.05). Operative delivery of mothers of premature infants in the interests of the mother and the fetus by caesarean section was significantly higher compared to the comparison group (67.4% and 86% versus 60%, p2-3 = 0.045). The main indications for surgery were preeclampsia of moderate and severe severity, sub- and decompensation of uterine-fetal blood flow, progressive placental abruption. In the comparison group, the delivery of women in a planned manner by caesarean section was carried out according to the indications of the mother.
Thus, the antenatal period of children with ELBW proceeded against the background of the threat of termination of pregnancy, preeclampsia of moderate severity, chronic placental insufficiency, oligohydramnios, and isthmic-cervical insufficiency. Chorioamnionitis and premature rupture of the membranes were found significantly more often in women with very early preterm birth, while in women with early preterm labor - grade III UBFD, which subsequently led to a complicated course of the postnatal period of newborns. In the course of the study, it was found that the antenatal period of children with ELBW proceeded against the background of the threat of termination of pregnancy, moderate preeclampsia, chronic placental insufficiency, oligohydramnios, and isthmic-cervical insufficiency. Chorioamnionitis and premature rupture of the fetal bladder were found significantly more often in women with early preterm labor, while in women with early preterm labor - grade III UBFD, which subsequently led to the more frequent development of infectious pathology (sepsis and pneumonia - 78.6%) and death (8.7%) in the early neonatal period in newborns with GA of22-27 weeks and FGRS in children with GA of28-31 weeks (83.7%).
According to the literature, along with infectious and inflammatory pathology, the causes of death include respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), left ventricular failure and systemic hypotension, hemodynamically relevant functioning ductus arteriosus (HRFDA) [1, 2, 3, 4, 5]. The severity of respiratory disorders in this category of children is associated with gestational age, body weight, sex of the child and the characteristics of the maternal medical history [6, 7]. The results obtained in this study also indicate that the Apgar score, severe somatic, infectious pathology and preeclampsia in mothers, which were significantly more common in women of the 1st group, were of significant importance in the severity of RDS. The mode of delivery is also a significant factor that affects the condition of the child at birth and further postnatal adaptation. Babies who later died were born via natural maternal passages, however, according to Adams M., planned cesarean section does not have any advantages over vaginal birth in this contingent of children [8]. According to N. V. Bashmakova, the best survival rate of deeply premature infants with ELBW was observed at a gestational age of more than 26 weeks, while it is preferable to use an operative method of delivery. Moreover, with a gestational age of less than 26 weeks, the mode of delivery did not affect the outcome [9].
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