Clinico-Prognostic Criteria for Severe Hypoxic Lesions of the Central Nervous System in Preterm Newborns

The dissertation is dedicated to the development of clinico-prognostic criteria for assessing the severity and prognosis of hypoxic lesions of the central nervous system in preterm newborns. The research is based on a comprehensive study of serum biomarkers — neuron-specific enolase, brain-derived neurotrophic factor, vascular endothelial growth factor, endothelin-1, and von Willebrand factor — depending on the severity of hypoxic encephalopathy and the state of cerebral blood flow. A comprehensive study of the hemostasis system was also conducted, and a mathematical model clarifying the development of severe hypoxic encephalopathy in the neonatal period was developed. The scientific work was carried out at the Department of Pediatrics of the Siberian State Medical University and includes clinico-laboratory, biochemical, and functional research methods in preterm newborns with varying degrees of severity of hypoxic lesions of the central nervous system.

INTRODUCTION

In the structure of early neonatal mortality, preterm newborns account for 60–70% of the total number of newborns, and 70–80% in childhood disability [93,198].

With the transition in the Russian Federation to new live birth criteria recommended by the WHO [Resolution of the XVI Congress of Russian Pediatricians, February 24–27, 2012], an increase in the number of 'low-birth-weight infants' and the number of preterm children is registered.

According to statistical data for the Russian Federation, in 2009 the increase in 'low-birth-weight infants' and preterm newborns per 100 live births was 5.2%; in 2010 – 5.3%; in 2011 – 5.28%, and the number of 'low-birth-weight infants' weighing from 1000 to 1500 grams per 1000 live births in 2009 was 5.48%; in 2010 – 5.57%; in 2011 – 5.65%, and a trend toward a decrease in stillbirth rates is observed, so in 2009 among preterm newborns with VLBW and ELBW, stillbirth at birth was 83.3%, in 2010 – 83.8%, in 2011 – 61.5% [72].

With the implementation of perinatal care regionalization in economically developed countries, where continuity of medical care is ensured, significant successes have been achieved in the survival of prematurely born children. Thus, in perinatal centers of economically developed countries, 85–90% of preterm newborns survive, and factors ensuring the survival of preterm children have also been identified, namely, temperature control, mechanical ventilation regime, and cardiovascular support [114,128,132,160,180].

Research conducted by the Neonatal Research Network group identified the need for predicting the viability of newborns located in the zone of viability (ZV) and determining the advisability of conducting resuscitation measures in the delivery room. An important criterion for all decisions made is patient viability, a positive response to primary resuscitation, and subsequent quality of life [97,103,132].

It is well known that a child born prematurely, due to general morphofunctional immaturity, exhibits organ and system dysfunction, accompanied by a imbalance of 'compensatory-autoregulatory' mechanisms, leading to ischemic and/or hemorrhagic damage to target organs, the consequences of which are pathologies of varying severity, early childhood disability, and deviations in neuropsychological development [18,19,20].

Among the causes of early neonatal morbidity, intrauterine hypoxia/asphyxia accounts for 93–98%, CNS damage 75–80%, myocardial damage 60–70%, respiratory disorders 40–41% [72,93].

In the structure of newborn mortality during the first week of life, respiratory disorders predominate at 32.3%; congenital anomalies – 18.8%, intrauterine hypoxia and asphyxia at birth – 12.7% [72,93].

Among the causes of stillbirth, intrauterine hypoxia remains in first place at 82.2% and congenital developmental anomalies – 8.0% [72,168].

More than 50% of children born with low birth weight are hospitalized repeatedly during the first two years of life due to infectious diseases of the bronchopulmonary system [108,119]. According to statistical data, during the first two years after discharge, 2–5% of preterm children die from various complications associated with premature birth [97,108,119,171,194].

According to statistical data, the incidence of hypoxic encephalopathy among preterm newborns in economically developed countries ranges from 40% to 50%. The severity of hypoxic encephalopathy is determined by gestational age, birth weight, and the original premorbid background of the newborn [110,112,194,205]. Among the causes of disability, CNS damage accounts for 98.6%, including neurosensory anomalies – 29%, disruption of the pace of mental development – 42%; bronchopulmonary dysplasia accounts for approximately 53%, cardiovascular system damage – 30% [104,120,127].

In jointly conducted research by the American Academy of Pediatrics, the American Medical Association, and the American Academy of Family Physicians, it was identified that subsequently, preterm newborns exhibit persistent CNS disorders manifesting as cognitive impairments, difficulties in learning, socialization in society, and high infectious morbidity [97,114,128,132,166,197].

Unfortunately, at the current stage, the rate of premature birth has a tendency to increase, which is explained by the active implementation of assisted reproductive technologies, an increase in the number of multiple pregnancies, the expansion of obstetric indications for premature delivery, and, simultaneously, an insufficient use of technologies aimed at preserving and prolonging pregnancy [97,119,132,160].

At present, a progressive decline in health indicators in the pediatric population is observed, to a large extent due to the population of preterm children, which dictates the necessity of actively searching for and implementing new approaches aimed at early diagnosis, prediction of development and outcomes of pathological conditions, as well as prevention and timely identification of factors leading to the development of pathological conditions in preterm newborns [128,151,168].

Additional research is needed aimed at studying the influence of low birth weight, the severity of transferred hypoxia in preterm newborns on the development of metabolic disorders, CNS pathology, the cardiovascular system, and subsequent neuropsychological development of the child, as well as studying the effectiveness of new medicinal preparations [166,180,181,182].

Objective of the Research

To establish additional clinico-prognostic and diagnostic criteria for assessing the risk of developing severe hypoxic lesions of the central nervous system and subsequent prognosis in preterm newborns.

Tasks of the Research:

1. To identify unfavorable prognostic factors associated with disabling neurological pathology in preterm newborns with severe hypoxic encephalopathy during the first year of life.

2. To assess serum levels of neuron-specific enolase, brain-derived neurotrophic factor, and vascular endothelial growth factor in preterm newborns with severe hypoxic encephalopathy depending on the state of cerebral blood flow.

3. To conduct an analysis of hemostasis system indicators, endothelin-1 levels, and von Willebrand factor activity in serum blood of preterm newborns depending on the severity of hypoxic encephalopathy during the neonatal period.

4. To develop a mathematical model clarifying the development of severe CNS damage in preterm newborns with hypoxic encephalopathy.

Scientific Novelty of the Work

For the first time, in preterm newborns with severe hypoxic encephalopathy, a comparative analysis of serum concentrations of neuron-specific proteins depending on morphostructural changes in the brain and the state of cerebral blood flow was conducted, with subsequent assessment of neuropsychological development of children up to one year. It was established that severe hypoxic encephalopathy in preterm newborns is characterized by high serum concentrations of neuron-specific enolase and low content of vascular endothelial growth factor in combination with decreased cerebral blood flow velocity in the main arteries of the cerebral vessels and venous outflow. A relationship between serum concentrations of neuron-specific proteins and sensorimotor development of children up to one year was demonstrated.

For the first time, a comprehensive study of serum concentrations of endothelin-1, von Willebrand factor activity, and hemostasis system indicators in preterm newborns depending on the severity of hypoxic encephalopathy during the neonatal period was conducted. It was established that for preterm newborns, regardless of the severity of hypoxic encephalopathy, endothelial dysfunction and disturbances in hemostasis system indicators are characteristic.

Practical Significance of the Work

Unfavorable prognostic factors for neuropsychological development in preterm newborns with severe hypoxic encephalopathy have been proposed.

The obtained results can be used in preterm newborns with hypoxic encephalopathy as additional prognostic criteria for unfavorable neurological development (determination of levels and relative units in serum blood).

A mathematical model clarifying the development of severe hypoxic encephalopathy in preterm newborns during the neonatal period has been developed (priority patent application No. 2012138516 dated 07.06.2012).

Main Propositions to be Defended:

1. Prognostic criteria for delayed neuropsychological development in preterm newborns up to one year of age with severe hypoxic encephalopathy are intrauterine growth restriction of III degree, high serum concentrations of neuron-specific enolase in the early neonatal period, and low content of vascular endothelial growth factor in serum blood by one month of life.

2. In preterm newborns with moderate-severe and severe hypoxic damage to the CNS during the neonatal period, endothelial dysfunction develops, accompanied by disturbances in the hemostasis system.

Presentation of Dissertation Materials:

The main propositions of the dissertation were reported at the scientific-practical conference 'Actual Questions of Pediatrics' (Seversk, 2011); International Conference 'Diagnosis, Treatment, and Prevention of Thromboses and Thromboembolisms' (Tomsk, 2011); International Scientific Conference on Applied and Fundamental Research (USA, St. Louis, 2012); All-Russian Conference with International Participation 'Information and Mathematical Technologies in Science, Engineering, and Medicine' (Tomsk, 2012); All-Russian Scientific-Practical Conference 'Non-Infectious Diseases and Health of the Population of Russia' (Moscow, 2013); V Congress of Russian Pediatricians with International Participation 'Actual Problems of Pediatrics' (Krasnoyarsk, 2013); XI World Congress of Perinatal Medicine (Moscow, 2013).

Publications:

The results of the dissertation work are presented in 12 printed works, 3 of which are published in journals from the VAK RF 'List', 2 articles in foreign journals, 7 conference abstracts.

Volume and Structure of the Work:

The dissertation is presented on 164 pages of typed text and contains an introduction, a literature review, 5 chapters reflecting the results of original research, discussion, conclusions, and practical recommendations. The reference list contains 217 sources, including 84 domestic and 130 foreign. The work is illustrated with 6 figures and 17 tables.

The work was carried out at the Department of Pediatrics of the Faculty of Advanced Training and Professional Retraining of the State Educational Institution of Higher Professional Education 'Siberian State Medical University' of the Ministry of Health of Russia (head of the department – Doctor of Medical Sciences, Professor Mikhaley E.V.); MBULP 'Maternity Hospital No. 1' (chief physician I.G. Zaeva); MAUZ 'Maternity Hospital No. 4' (chief physician L.A. Agarkova); MAUZ City Clinical Hospital No. 1 of Tomsk (chief physician A.P. Balanovsky) in the department of intensive care and resuscitation, neonatal pathology, and the second stage of care for preterm newborns (second stage of rehabilitation).

Author's Contribution:

The author determined the objective, tasks, and research methods, and selected the research object. Primary data collection was conducted with subsequent formation of an electronic database. The statistical analysis and description of the clinical material were personally performed by the author.