Current Knowledge of Neonatal Birth Asphyxia – a Review of Recent Literature and Novel Approach

Abstract

As neonatal intensive care has developed, there has been a growing focus on reducing mortality and morbidity. Hypoxic-ischemic injury remains the primary cause of neonatal brain dysfunction. Recently, notable advancements have been made in neuroprotection, particularly with the introduction of therapeutic hypothermia. Furthermore, identifying specific biomarkers has constituted another significant advance in neuroprotection, allowing clinicians to screen infants for brain injury, monitor disease progression, identify affected regions and assess the efficacy of neuroprotective trials. Erythropoietin (EPO) has demonstrated potential in the treatment of perinatal hypoxia, particularly in the reduction of neurological damage and improvement of outcomes in neonates with hypoxic-ischemic encephalopathy. While further research is required to ascertain the optimal usage, the existing evidence suggests that EPO could be a valuable component of a comprehensive treatment plan, potentially in conjunction with therapeutic hypothermia.

Keywords:birth asphyxia, biomarkers, hypothermia, erythropoietin.

INTRODUCTION

The issue of birth asphyxia continues to be a notable challenge in perinatal medicine, particularly due to the combination of decreased oxygen delivery through the bloodstream (hypoxia) and reduced blood flow to the brain (ischemia), which is referred to as hypoxic-ischemic encephalopathy (HIE) and represents a serious complication associated with adverse neonatal outcomes (1). The prevention of brain damage from HIE remains a challenge, given the serious consequences of neonatal mortality or severe neurological,cognitive and motor disabilities. It is of the utmost importance to accurately assess brain lesions following perinatal asphyxia to select the most appropriate early cerebral-protective treatment. The confirmation of hypoxia/ischemia-related neuropathology can be achieved through the utilization of neuroimaging or histopathological methods (2). Despite the lack of a defined panel for assessing the severity and prognosis of asphyxiation, biochemical markers of brain injury are not commonly used due to the aforementioned reasons. However, it is essential to manage ventilation, oxygenation, perfusion, metabolic, acid-base and fluid-electrolyte status to optimize the neurological prognosis. Prior research has demonstrated that preterm infants with intraventricular haemorrhage display elevated blood levels of S100 protein and neuron-specific enolase (NSE) before imaging assessment of the bleeding (3).

MATERIALS AND METHODS

A historical perspective

The term "asphyxia", first documented in 1700, is derived from the ancient Greek words: the letter "a" denotes the absence of something, while the Greek word "óönîéò-asphyxia" signifies the contraction of the arteries. Historically, a distinction was made between two forms of asphyxia, including "asphyxia livid", characterised by cyanosis and gasping, and the phenomenon"asphyxia pallida" or the "white apparent death”. The twentieth century witnessed the advent of a new era of measurement, with the introduction of blood gas analysis affording a more profound comprehension of the phenomenon of asphyxia.

In 1932, in Baltimore, Nicholson Eastman conducted multiple analyses of cord blood gases. The study included infants with asphyxia phenomena, which was primarily characterised by a significant drop in oxygen levels, with fatal cases showing umbilical vein blood oxygen levels below 1%. Additionally, it was observed that the serum pH of infants who had suffered asphyxiation reached the lowest levels compatible with life (4).

In 1953, Virginia Apgar, an anesthesiologist and paediatrician based in New York, devised a clinical scoring system to evaluate the level of asphyxia and enhance the efficacy of neonatal resuscitation. This was in response to concerns about the low specificity in neonatal reanimation methods and the low standard of asphyxia studies. Her subsequent investigation into the neurological development of 215 infants revealed no statistically significant correlation between IQ and oxygen levels or saturation within the initial three-hour period following the onset of life (5).

In 1958, Apgar's colleague, L. Stanley James, reported that some stage of asphyxiation, typically brief, was common in all births, leading to respiratory acidosis succeeded by metabolic acidosis. The term 'asphyxia' was initially subjected to criticism on the grounds of its semantic inaccuracy, given that its meaning was 'pulselessness'. However, it was not challenged based on its lack of a precise definition (6).

Results: prevalence, risk factors and clinical aspects

Perinatal asphyxia, which occurs during the first and second stages of labour due to impaired gas exchange, leading to fetal acidosis, hypoxemia and hypercarbia, affects approximately 1.5% of newborns in developed countries with advanced obstetric and neonatal care. The frequency of the condition is inversely related to gestational age and birth weight. It affects 0.5% of infants born after 36 weeks of gestation and accounts for 20% of perinatal deaths (or 50% when stillbirths are included). The prevalence of perinatal asphyxia is higher in newborns of diabetic or toxemic mothers, those with intrauterine growth restriction, breech presentation, or postmaturity (7).

The determinant factors for perinatal asphyxia can be broadly categorised as follows: impaired maternal oxygenation reduced maternal-to-placental blood flow, decreased placental-to-fetal blood flow, altered gas exchange at the placental or fetal tissue level and increased fetal oxygen demands. The causes of hypoxia-ischaemia are diverse and may involve a range of factors, including those related to the mother (e.g., hypertension, hypotension, infection, hypoxia from pulmonary or cardiac diseases, diabetes, vascular diseases, intrauterine cocaine exposure) and placental ones (e.g., abnormal placentation, detachment, infarction, fibrosis, hydrops). Additionally, other potential causes include uterine rupture and umbilical cord accidents (e.g., prolapse, coiling, true knot, and compression, abnormalities in umbilical vessels, fetal factors (e.g., anaemia, infection, cardiomyopathy, hydrops, severe circulatory or heart failure) and neonatal factors (e.g., cyanogenic congenital heart disease, persistent pulmonary hypertension of the newborn, respiratory failure due to meconium aspiration syndrome, neonatal pneumonia, pneumothorax and other forms of septic shock or neonatal cardiogenic shock) (8).

Pathophysiological mechanisms of brain lesions

Immediate neuronal death, or necrosis, can occur as a result of intracellular osmotic overload of Na+ and Ca2+ caused by ion pump failure or the action of excitatory neurotransmitters on ionotropic receptors (e.g., N-methyl-D-aspartate). The delayed form of neuronal death, also referred to as apoptosis, is the result of the continued activation of enzymes and second messenger systems within the cell (e.g., Ca2+-dependent lipases, proteases, caspases), disruption of the mitochondrial electron transport chain, generation of free radicals and leukotrienes, nitric oxide production through NO synthase and depletion of energy stores. The reoxygenation of previously ischemic tissue can result in additional injury due to the promotion of excessive reactive oxygen species formation. This can lead to the overwhelming of endogenous antioxidant mechanisms, causing damage to cellular lipids, proteins, nucleic acids and the blood-brain barrier. This can result in an influx of neutrophils, which, in conjunction with activated microglia, release proinflammatory cytokines (e.g., interleukin-1ß and tumour necrosis factor) (9).

Several antepartum (before labour) maternal conditions: placental issues, fetal conditions, maternal substance use and intrapartum (during labour) factors: umbilical cord problems, obstructed labour, prolonged or complicated labour, maternal hypotension, infections and fever, abnormal fetal heart rate can contribute to the risk of birth asphyxia, as shown in Table 1.

Complications

Hypoxic events can result in multi-organ failure, with adverse effects observed in the respiratory, renal, hepatic, digestive and myocardial systems. Additionally, coagulopathy and skin lesions have been documented in cases where hypoxia has been a contributing factor. Renal involvement is a particularly common occurrence, with a prevalence of 31% in a cohort studied by Wayenberg and colleagues. There is a discernible correlation between the incidence of renal involvement and the pH levels at birth. In a smaller percentage of cases, namely less than 15%, the brain can be the sole organ affected by systemic hypoxia-ischaemia. The frequency of organ involvement is contingent upon the specific mechanisms of asphyxia and resulting organ dysfunction (10).

The timing and location of asphyxial insults, combined with the severity of the insult, determine the specific outcomes and long-term disabilities. Early intervention, such as proper oxygenation and neurological care, can sometimes improve outcomes, but the degree of recovery depends on the extent of the injury. The timing of the asphyxial insult determines the vulnerability of the brain at different stages of development, while the location of the injury dictates the specific function affected (Table 2).

Laboratory assessment

The Apgar score is not a typical indicator of the extension of acidosis at birth, raising questions about its utility in assessing asphyxia. Zaigham et al (11) have highlighted that a low score does not necessarily indicate neonatal asphyxia. It is erroneous and inappropriate to utilise it primarily for the diagnosis of neonatal asphyxia. It is also an inadequate predictor of poor neonatal prognosis and neonatal mortality (12).

Furthermore, the Apgar score is not an appropriate tool for classifying neonates with asphyxia into severe or mild asphyxia, nor for assessing the presence of multiple organ damage or metabolic acidosis. In contrast to the aforementioned limitations, neonatal umbilical artery blood gas analysis can directly reflect blood oxygen levels and acidbase status with high specificity, thereby compensating for the aforementioned shortcomings of the Apgar score, which is easily influenced by various elements (13). Concerning cardiac assessment, CK-MB, troponin I, T and pro-NBT are known biomarkers, but they are not currently employed in clinical practice. In the context of neurological assessment, serum CK-BB does not demonstrate a correlation with long-term neurobehavioural prognosis. Furthermore, the following biomarkers have been identified: urea, creatinine, FENA (fractional excretion of sodium) and â2-microglobulin (Table 3) (14).

Paraclinical evaluation

Near-infrared spectroscopy (NIRS) represents a non-invasive technology that enables continuous monitoring of tissue oxygenation. The technology is connected with the relative transparency of biological tissue to light. The neonatal brain is readily penetrated by light with a wavelength of 700-1,000 nm due to the thin layers of skin and bone tissue (skull). Consequently, light waves from the near-infrared spectrum are transmitted through the brain tissue in a semi-curved trajectory to a detector situated approximately 2-3 cm beneath the surface. Haemoglobin exhibits different degrees of light absorption at varying wavelengths. The sensor is capable of detecting differences in light absorption and calculating concentrations in the same manner as the modified Lambert-Beer law. This provides an index of tissue oxygenation. NIRS is a useful tool in monitoring cerebral tissue oxygenation. A value of the cerebral oxygenation index > 85% indicates neuronal destruction and also a decrease in neuronal mass with reserved neurological prognosis. A value of the cerebral tissue oxygenation index <65% indicates a low supply of 02 (hypoperfusion) or increased consumption of 02, being useful in monitoring brain function immediately postnatal and in the optimization of the treatment (15).

Magnetic resonance imaging (MRI) provides valuable prognostic information that is not available from electroencephalogram (EEG) or clinical examination data. When performed at the optimal age, the pattern of brain involvement is typically correlated with the neurological prognosis. Significant damage to the cortex or subcortical nuclei is associated with both motor and intellectual disabilities. The degree of severity depends on the brain regions affected and the gravity of injury in each region (Figure 1) (16).

Computed tomography (CT) is an important imaging technique that employs X-rays to generate cross-sectional images of the human body. Given the considerable radiation exposure involved, this procedure is only indicated in cases of emergency.

Cranial ultrasound is a valuable tool for assessing the neurological status in cases of perinatal asphyxia. Modifications in the hemodynamic parameters of cerebral circulation facilitate the diagnosis and staging of intracranial haemorrhage, in addition to providing insight into the condition's immediate and long-term prognosis. Given its accessibility, increased specificity, and sensitivity, Doppler ultrasonography has become the preferred method for diagnosing neurological pathology in newborns, with sensitivity and accuracy comparable to computed tomography (CT). The resistive index (RI) is one of the most common vascular ultrasound indices used owing to its simplicity. It is proportional not only to vascular resistance but also to vascular compliance (Figures 2, 3) (17).

In cases of perinatal asphyxia, magnetic resonance imaging (MRI) is the recommended imaging modality. The first MRI should be performed by the end of the first week of life, with subsequent imaging at two weeks and one month, as indicated by the pediatric neurologist. Magnetic resonance imaging is the standard imaging modality for perinatal asphyxia. It provides both anatomic and functional information, which is used to determine prognosis and the severity of the disease. It offers a detailed description of the various patterns of injury observed, including watershed injury and involvement of the basal ganglia and thalami, which are indicative of more severe cases. Although head sonography is thought to be less accurate than MRI, it plays a crucial role in the rapid diagnosis of pathologies encountered in neonatal intensive care, particularly in cases of perinatal hypoxic lesions when MRI is unavailable in the hospital or transportation poses a risk to the newborn's life (Figures 4, 5) (18-19).

As shown by research, perinatal hypoxia can cause multi-organic damage, which can be identified with the help of ultrasound, which can be very useful in the long-term evolution of newborns (20-21).

Electroencephalogram (EEG) and amplitudeintegrated electroencephalography (aEEG) are two procedures used to evaluate post-asphyxia cerebral electrical activity in the first 72 hours, especially in those with therapeutic hypothermia. Amplitude-integrated electroencephalography has the role of monitoring and optimizing the treatment and also highlights the background pattern of cerebral activity with a prognostic role (Figure 6) (22).

DISCUSSIONS

The glycoprotein hormone, known as erythropoietin (EPO), is naturally produced by the renal peritubular cells and stimulates the production of red blood cells. The peritubular cells of the renal cortex represent the primary source of EPO in the human body. The partial pressure of oxygen (PO2) exerts a direct regulatory effect on EPO production, with lower PO2 levels inducing increased production. Erythropoietin therapy has been demonstrated to reduce the risk of death and disability in term infants with moderate to severe hypoxic encephalopathy (HIE). The authors posit that this renders EPO treatment an alternative and straightforward option with a low NNT (number needed to treat) in instances where hypothermia is not feasible. In cases where hypothermic therapy is a viable option, it can be employed as an adjunctive treatment due to its neuroprotective properties. Nevertheless, further studies are required to corroborate these findings. In cases of severe HIE, the use of hypothermia alone is insufficient to either reduce mortality or prevent significant neurodevelopmental impairment. A meta-analysis demonstrated that 44% of infants with HIE who underwent hypothermia treatment either died or exhibited moderate to severe disability (22, 23). The authors of a 2017 literature review concluded that hypothermia was the most significant innovation in the treatment of HIE at birth. However, it should be noted that this therapy was ineffective for a considerable number of newborns. Erythropoietin has anti-apoptotic, antioxidant and protective properties for neurons, astrocytes and oligodendrocytes. In human studies, administration of EPO to neonates with HIE has been demonstrated to significantly reduce hypoxic neurological damage and promote neurogenesis, oligodendrogenesis and angiogenesis, which are essential for normal neurodevelopment and injury repair. The beneficial effects have been well documented in experimental models, with emerging clinical data also proving the efficacy of this approach. The safety of highdose erythropoietin in neonates is also well-attested. It has long been used in premature infants to prevent and/or treat anaemia of prematurity; although EPO treatment reduces the frequency and volume of red blood cell transfusions, its use is not currently recommended as general practice. To cross the blood-brain barrier, EPO must be administered at a dose of 2 000–5 000 IU/kg (Zhang et al, 2010) (24).

Therapeutic hypothermia

Neuroprotection of neonates . 35 weeks' gestation with moderate to severe hypoxic-ischemic encephalopathy is optimized by starting hypothermic treatment without delay after resuscitation, in the first six hours of life. This must be strictly controlled and aimed at the rectal temperature range of 33-34 degrees C. Both total body and head cooling are safe and effective. New agents, including melatonin, erythropoietin, xenon and stem cells, are preliminary evaluated in phase I/II trials, with no data currently supporting any other therapeutic agent for neuroprotection (25).

Therapeutic hypothermia represents a standard treatment for moderate to severe neonatal encephalopathy (NE) that improves brain damage on neuroimaging and neurodevelopmental outcomes (26). Using current enrolment criteria, a significant number of infants who would benefit from hypothermia are not treated, and contrariwise, some infants receive hypothermia when its benefit will be limited. Better serum biomarkers are needed to upgrade management and treatment. In the present review, we study the latest research and highlight a central limitation of most current biomarkers: their predictive value can be very important after most neuroprotective therapies are no longer effective (27-28).

Neurological assessment

It is estimated that between 15% and 20% of newborns with asphyxia die immediately after birth. Of those who survive, 25% suffer from a range of neurological impairments, including cerebral palsy, intellectual disability and developmental delay. There are several reasons why these newborn follow-up programmes play a crucial role in identifying any special medical or developmental needs and ascertaining the long-term effects of treatments provided by the perinatal care system (29).

The latest protocols, the Amiel-Tison neurological assessment at term (ATNAT), comprise three distinct instruments based on a neuro-maturity structure. The application of a uniform methodology and a comparable scoring system allows the three assessments to be utilized for the monitoring of high-risk children from 32 weeks post-conception to six years of age. The ATNAT, which can be completed in approximately five minutes, is suitable for use in both clinical and research settings. The assembling of severe to mild neurocranial symptoms in the neonatal period enables the assessment of infants who may benefit from early intervention. The Prechtl general movement assessment (GMA) has been demonstrated to possess a high predictive value for neurodevelopmental outcomes in preterm and term infants with risk factors, as evidenced by a substantial body of empirical research (30, 31).

The GMA facilitates the early identification of patients at an elevated risk of developing cerebral palsy, mild neurological deficits, cognitive impairment, or autism spectrum disorder. The assessment is based on the visual perception of movement patterns, which are videotaped and presented in a way that allows for the observation of age-specific normal and abnormal movement patterns. This method is non-invasive, inexpensive and highly reliable (32, 33).

The motor optimality score (MOS) is a comprehensive GMA that assesses the age-specific motor repertoire, including fidgeting and other movement and postural patterns that are expected to be present in a given period. The reliability of this approach has been demonstrated in some different populations, with intraclass correlation coefficients of interobserver reliability ranging from 0.80 to 0.94, thereby substantiating its efficacy. Nevertheless, its application is confined to infants in the fidgety phase, which typically occurs between three and five months of age (34, 35).

Conclusions

The question of how to intercept brain damage from hypoxic-ischemic encephalopathy remains unanswered due to the serious consequences of neonatal death or severe intellectual, cognitive and motor disability. The history of perinatal asphyxia reflects the evolution of medical knowledge and practice over millennia. From the earliest recorded history to the present day, there have been significant advances in the understanding and treatment of birth asphyxia, contributing to improved survival and outcomes for newborns. Continued research and innovation remain crucial in the ongoing effort to reduce the impact of perinatal asphyxia. Through this publication, we hope to contribute to the awareness, validation and clinical use of established and novel biomarkers regarding neonatal brain injury and therapeutic modalities.

TABLE 1.

Antepartum, intrapartum and infant susceptible factors for birth asphyxia identified in hospital-based studies

TABLE 2.

Connections between the timing of asphyxial insults, brain injury locations and types of disability (8-10)

TABLE 3.

Biomarkers mentioned in the literature but not commonly used in medical practice for diagnosis of perinatal asphyxia (14)

FIGURE 1.

a) Sequence with axial T2 information – decrease in volume and increase in signal intensity of both thalami, globus pallidum and putamens (latin form) – in a patient born late preterm at 35 weeks by spontaneous vertex delivery; there is also a loss of volume and compensatory dilation of the ventricular system; b) IR sequence with axial T1 information: the affected regions are of high signal (image from the literature) (16).

FIGURE 2.

Anterior fontanel sagittal view on Doppler ultrasonography through the anterior cerebral artery of a one-week-old boy, with moderate hypoxic-ischemic encephalopathy. Moderate cerebral oedema, high diastole = half of the systole; low RI = 0.60 [personal research – echography from the neonatology department of County Clinical Hospital of Constanta, Romania (images taken with parental consent)]

FIGURE 3.

Anterior fontanel coronal view of a one-day-old boy, with Apgar 0 at birth showing necrotic brain lesions. Increased echogenicity in the basal nuclei characteristic for necrosis [personal research – echography from the neonatology department of County Clinical Hospital of Constanta, Romania (images taken with parental consent)]

FIGURE 4.

Ultrasonography of a one-week-old boy through the anterior fontanel – coronal view [personal research – echography from the neonatology department of County Clinical Hospital of Constanta, Romania (images taken with parental consent)]. On the coronal plane, there is a four-column sign caused by moderate bilateral hyperechogenity of the thalamus and putamen. Due to the acute insult, the thalami and basal ganglia on both sides appear hyperechogenic and are visualized as four pillars separated by a hypoechoic internal capsule.

FIGURE 5.

Renal ultrasound appearance, hypoxic renal injury, no adrenal haemorrhage detected [personal research – echography from the neonatology department of County Clinical Hospital of Constanta, Romania (images taken with parental consent)]

FIGURE 6.

Monitoring the cerebral activity of an infant with a four-channel amplitude-integrated electroencephalography (aEEG)

Conflicts of Interest

None declared.

Financial Support

None declared.

Informed Consent

The requisite informed consent was obtained from all patients, whom we want to thank and show our consideration for “Iuliu Hatieganu” and “Carol Davila” Universities of Medicine and Pharmacy of Cluj Napoca and Bucharest, respectively.