Perinatal asphyxia and left ventricular mass: Redefining cardiac assessment

Abstract

Perinatal asphyxia is a major cause of neonatal morbidity and mortality, with cardiovascular involvement often underrecognized despite its critical impact on systemic perfusion and multi-organ outcomes. While prior studies have largely focused on functional impairment and biochemical markers of myocardial injury, emerging evidence highlights the importance of structural cardiac alterations, particularly changes in left ventricular mass. Integrating echocardiographic assessment of left ventricular mass into the evaluation of perinatal asphyxia may enhance early risk stratification, guide hemodynamic management, and improve long-term cardiovascular surveillance. In this opinion review, we analyze the original study, which address this issue and tries to bridge an important gap in neonatal cardiology, where normative reference data and structural risk markers remain limited, especially in low-resource settings.

Key Words: Perinatal asphyxia; Hypoxic-ischemic encephalopathy; Left ventricular mass; Neonatal echocardiography; Myocardial remodeling

Core Tip: Structural cardiac assessment, particularly left ventricular mass estimation, provides complementary information to functional echocardiographic parameters and biochemical markers of myocardial injury, in neonates with perinatal asphyxia and may enhance early risk stratification, guide hemodynamic management, and improve long-term cardiovascular surveillance. Left ventricular mass correlates with gestational age, birth weight, and asphyxia severity and provide a framework for risk stratification and targeted intervention.

INTRODUCTION

Perinatal asphyxia, is an important cause of morbidity (both short- and long-term) and mortality in asphyxiated neonates[1] which results in multiorgan dysfunction leading to neonatal post-asphyxia syndrome. Compromised blood supply to heart causes cardiac dysfunction in 62%-78% of cases[2], and to other vital organs may lead to irreversible organ damage and death[3].

The changes in blood flow that happen with a baby's first breaths are crucial for a healthy shift from fetal to newborn circulation. Knowing how this transition normally works and how problems can affect it helps identify issues and guide treatment. Conditions like severe perinatal asphyxia, significant patent ductus arteriosus (and its surgical closure), and utero-placental insufficiency in fetal growth restriction can alter left ventricular (LV) function. After birth, the left ventricle is mainly responsible for pumping blood through the body. Cardiac output depends on afterload, which is influenced by arterial stiffness. Perinatal asphyxia can lower LV output, reduce blood flow in the superior vena cava and coronary arteries, and raise troponin levels. Premature infants with a large patent ductus arteriosus show several changes in blood flow, which must be carefully assessed to decide if and when surgery is needed. Closing the ductus can sharply increase afterload, sometimes reduce LV contractility and require ionotropic support. Infants with fetal growth restriction often have higher systolic blood pressure, a slightly thickened heart due to stiffer arteries, and increased resistance in the body's blood vessels. Point of care ultrasound (POCUS) can help distinguish between normal transition and changes caused by neonatal disorders[4].

Perinatal asphyxia remains one of the most challenging clinical scenarios in neonatal medicine, affecting approximately 3% of newborns in developing countries and contributing significantly to neonatal morbidity and mortality[5]. Perinatal asphyxia occurs due to any condition that affects the flow of blood or oxygen to the fetus. Most common etiologies include problems with maternal circulation and oxygenation, and placental factors. Maternal hemodynamic compromise (amniotic fluid embolus sepsis, shock), uterine conditions (uterine rupture), placenta and umbilical cord considerations (placental abruption, umbilical cord knot or compression), and infection; are commonly seen causes[6].

During asphyxia, oxygen delivery to the critical organs gets compromised. Cardiac output to these critical organs such as the adrenal gland, heart and brain; are often at the expense of the other organs such as the gut, kidneys and skin. This results in reduced perfusion, hypoxic ischemic injury and if persists to multi-organ failure. Liver injury, multi organ involvement, with coagulopathic disorders, all result from hypoxia, under-perfusion or both. Current clinical therapies need to be considered together with therapeutic hypothermia and cardiovascular recovery[7].

While the neurological sequelae of birth asphyxia have been extensively studied, the cardiovascular implications, particularly regarding LV mass alterations, have received considerably less attention. The recent hospital-based cross-sectional study by Chinawa et al[8], provides crucial insights into this understudied aspect of perinatal asphyxia, revealing significant alterations in LV mass that challenge our current understanding of cardiac adaptation in asphyxiated newborns.

Perinatal asphyxia can result in systemic effects, including multiple organ dysfunction. In Sarnat stage I, there is a generalized increased sympathetic tone, and the neonate may be hyperalert with prolonged periods of wakefulness, mydriasis, and increased deep tendon reflexes. In Sarnat stage II, the neonate may be lethargic or obtunded, with decreased tone, strong distal flexion, and generalized increased parasympathetic tone with miosis, bradycardia, and increased secretions. Seizures are common in Sarnat stage II. Sarnat stage III, the most severe, is characterized by a profoundly decreased level of consciousness, flaccid tone, decreased deep tendon reflexes, and very abnormal electroencephalogram (EEG) results[9].

Classification of the severity of the asphyxial exposure is always challenging since the nature of exposure is usually not known[10]. Perinatal asphyxia, often triggers a cascade of neuronal injury, leading to long term damage and neonatal encephalopathy (NE). The resultant complication of hypoxic-ischemic encephalopathy (HIE)/NE are wide-ranging. Therapeutic hypothermia is a time sensitive intervention, with a very narrow therapeutic window. The biomarkers identified from work in proteomics, metabolomics and transcriptomics as well as physiological markers such as heart rate variability, EEG analysis and radiological imaging when combined with neuroprotective measures have the potential to improve outcome in HIE/NE[11].

PERINATAL ASPHYXIA AND LV MASS

The findings present a paradigm shift in our conceptualization of cardiac involvement in perinatal asphyxia. Contrary to what might be expected from hypoxic-ischemic insults, the study demonstrates that newborns with perinatal asphyxia exhibit significantly reduced LV mass (7.9 ± 2.3 g) compared to controls (10.1 ± 0.7 g, P = 0.001). This counterintuitive finding warrants careful consideration of the underlying pathophysiology. During the critical transition from fetal to neonatal circulation, the left ventricle assumes primary responsibility for systemic perfusion, replacing the right heart dominance characteristic of fetal circulation[12]. Perinatal asphyxia disrupts this delicate transition through multiple mechanisms including utero-placental insufficiency, compromised arterial peripheral vascular resistance, and loss of arterial wall compliance.

The study’s methodology employs echocardiographic assessment, which remains the gold standard for non-invasive cardiac evaluation in neonates. The authors’ approach of correlating LV mass with various clinical parameters provides a comprehensive analysis that extends beyond simple morphometric measurements. The demonstration that 63% of asphyxiated newborns had LV mass below control values suggests this finding represents a consistent pathophysiological response rather than an isolated observation. This percentage is particularly significant as it indicates that the majority of affected infants experience some degree of LV mass reduction, potentially impacting long-term cardiovascular outcomes.

The primary causes of myocardial infarction during the perinatal period include congenital heart disease, coronary artery lesions, thromboembolism, and perinatal asphyxia. In cases of perinatal asphyxia, cardiac abnormalities such as tricuspid regurgitation and mitral regurgitation are often associated with transient myocardial ischemia (TMI) in the newborn. Patent foramen ovale commonly persists as a remnant of fetal circulation. Ongoing hypoxia may result in pulmonary arterial hypertension, leading to a right-to-left shunt across the patent ductus arteriosus and foramen ovale[13].

Newborns may exhibit transient tricuspid and mitral regurgitation associated with TMI. TMI should be considered in neonates presenting with asphyxia, respiratory distress, and diminished pulses, particularly when a murmur is detected. According to Rowe's classification, TMI is categorized into five types (A to E), with type B representing the most severe form, characterized by respiratory distress, congestive heart failure, and shock. Echocardiography is essential for excluding critical LV obstructive lesions, such as hypoplastic left heart syndrome or critical aortic stenosis. Electrocardiography (ECG) is crucial for diagnosing TMI and may reveal findings ranging from T wave inversion in a single lead to a classical segmental infarction pattern with abnormal Q waves. Elevated creatine phosphokinase-MB levels and echocardiographic evidence of impaired LV function, mitral and/or tricuspid regurgitation, and, occasionally, LV wall motion abnormalities may be observed. A reduced ejection fraction serves as a valuable indicator of severity and prognosis. Management includes fluid restriction, inotropic support, diuretics, and ventilatory assistance when necessary. Persistent pulmonary hypertension of the newborn may develop when hypoxia leads to sustained constriction of the fetal pulmonary vascular bed, resulting in pulmonary arterial hypertension and a right-to-left shunt across the patent ductus arteriosus and foramen ovale. This condition manifests as respiratory distress and cyanosis, which may be differential. Clinical assessment often reveals signs of pulmonary arterial hypertension and right ventricular failure, accompanied by a systolic murmur of the tricuspid valve and, occasionally, mitral regurgitation. Treatment for mild cases consists of oxygen therapy and supportive care, while severe cases may require ventilatory support, extracorporeal membrane oxygenation, and nitric oxide. Cardiac abnormalities in asphyxiated neonates are frequently underdiagnosed and necessitate a high index of suspicion. Early recognition through ECG and echocardiography facilitates improved management[14].

With the crucial exception of premature infants, simple ventricular septal defects do not substantially affect circulation during the fetal or the early postnatal period. The fetal right ventricle bears the burden of systemic and pulmonary blood flow in cases of severe left heart obstruction. Blood flow is reversed at the foramen ovale, and the ductus arteriosus transmits nearly all systemic blood flow. Because natural closure of the ductus arteriosus gradually reduces systemic blood flow and leads to circulatory failure and shock, this “ductal-dependent” systemic circulation is poorly tolerated in the infant. Because the total fetal cardiac output may be transmitted to the aorta and the ductus arteriosus primarily supplies lung blood flow, severe right heart obstruction is also easily tolerated in the fetus. The recognition, diagnosis, and treatment of neonates with severe congenital heart disease depend heavily on an understanding of fetal hemodynamics and the acute and chronic alterations that occur with the shift to the newborn circulation[15].

The constant features of perinatal stress, ST-T wave abnormalities on the ECG, and spontaneous resolution of the transient tricuspid insufficiency strongly suggest that this syndrome is secondary to a reversible form of myocardial insufficiency, mostly affecting the papillary muscle. In newborns hypoxia with or without hypoglycemia can precipitate a series of cardiac events[16].

GESTATIONAL AGE AND LV MASS

The correlation between LV mass and gestational age (r = 0.269, P = 0.028) provides important clinical implications. The term infants with perinatal asphyxia may have better preserved LV mass compared to their preterm counterparts. The mechanism likely involves the degree of myocardial maturation at birth, with more mature myocardium demonstrating greater resistance to hypoxic-ischemic injury[17]. This finding supports the clinical observation that preterm infants with perinatal asphyxia often experience more severe cardiovascular complications and may benefit from more intensive cardiac monitoring and intervention.

Birth weight (BW) and the interior diameters of the left ventricle during diastole and systole were positively correlated. While maternal insulin use during pregnancy was favorably correlated with interventricular septum thickness, higher maternal body mass index was linked to an increase in fractional shortening in large for gestational age (LGA) infants. Notably, male infants exhibited significantly higher LV internal dimensions in both diastole and systole, while gestational age negatively impacted the LV mass index. BW and cardiovascular health, including LV mass, LV mass index, interventricular septal thickness at diastole, interventricular septal thickness at systole, LV internal diameter at diastole, LV internal diameter at diastole, LV posterior wall diameter, and LV posterior wall diameter, were found to be significantly correlated. In both appropriate for gestational age and LGA babies, there is a positive and highly significant correlation between BW and LV mass, which is consistent with earlier research. A study by Sawyer et al[18] found a favorable correlation between birth body mass index and LV mass index. For babies with greater birth weights, a larger LV mass may be a sign of improved heart development during fetal growth or a possible adaptation to intrauterine environment. The positive correlation between BW and interventricular septal thickness at diastole in both groups provides more evidence that BW has a significant impact on cardiac parameters. However, no significant correlation was discovered between LV mass and BW in another study by Vijayakumar et al[19] that looked at the relationship between infant growth and LV mass in adulthood. Age, systolic blood pressure, body size, and other adult characteristics had little bearing on the association between weight at one year and LV mass. Both the interventricular septum and the LV posterior wall were impacted by the concentric increased LV mass linked to decreased development throughout infancy. Thus, more research is required to investigate this relationship[20].

LGA in infants is characterized by a BW that exceeds the 90^th percentile for gestational age, and it has been associated with several maternal risk factors, such as gestational diabetes mellitus (GDM). Cardiomyopathy is frequently observed in LGA infants born to mothers with GDM and mainly indicates maternal hyperglycemia during pregnancy. The latter is regarded as a teratogenic condition, resulting in fetal issues, such as negative impacts on cardiovascular development and fetal heart defects[21]. Despite this relationship being identified, numerous LGA infants exhibiting cardiac alterations, such as thickening of the interventricular septum and LV walls, are delivered by mothers lacking a GDM history[22].

BIRTH WEIGHT AND LV MASS

There is moderate positive correlation between LV mass and birth weight (r = 0.610, P = 0.001). This relationship underscores the importance of fetal growth in cardiac development and suggests that growth-restricted infants may be at higher risk for compromised cardiac function following perinatal asphyxia. Hence low birth weight combined with perinatal asphyxia may identify a subset of infants requiring enhanced cardiovascular surveillance and earlier intervention[23].

When compared to term-born controls, extreme low birth weight children have reduced LV mass throughout childhood. However, compared to controls, cases have a steeper increase in LV mass when systolic blood pressure rises. Our results raise concerns about whether general population cutoffs are sufficient to assess and treat hypertension and LV hypertrophy in children with extreme low birth weight[24].

Lower LV mass is typically seen in children with extreme low birth weight. Preterm delivery before 32 weeks of gestation was strongly linked to heart failure in childhood and early adulthood. Our results suggest that preterm delivery may be a yet unidentified risk factor for heart failure, even though the absolute risk of heart failure is minimal in early life[25]. Lower birth weight has a greater incidence of myocardial infarction and other cardiometabolic diseases with systemic inflammation[26].

ASPHYXIA SEVERITY AND LV MASS

The analysis of asphyxia severity using the Sarnat criteria reveals that severe asphyxia produces most pronounced reduction in LV mass (7.1 ± 1.5 g; Table 1). This dose-response relationship strengthens the causal association between hypoxic-ischemic injury and cardiac structural changes. The progressive nature of this relationship suggests that interventions aimed at limiting the severity of asphyxic insults may have protective cardiac benefits. Current practice of therapeutic hypothermia, which is primarily neuroprotective, may also confer cardiac benefits by limiting the extent of myocardial injury[27].

Table 1 Comprehensive summary of key findings.

Parameter/finding	Asphyxia group (n = 84)	Control group (n = 48)	Statistical result	Clinical significance
Primary LV mass comparison
Mean LV mass (g)	7.9 ± 2.3	10.1 ± 0.7	P = 0.001	Significantly reduced in asphyxia
%below controls threshold	63% of cases	Reference		Majority experience LV mass reduction
LV mass by asphyxia severity (Sarnat criteria)
Mild asphyxia	7.8 ± 2.3 g		ANOVA P = 0.289	Lower than controls despite mild injury
Moderate asphyxia	8.8 ± 2.5 g		Dose-response trend	Progressive LV mass decline with severity
Severe asphyxia	7.1 ± 1.5 g		Lowest LV mass	Most pronounced structural compromise
Correlation of LV mass with clinical parameters
Birth weight	Moderate positive correlation		r = 0.610, P = 0.001	Growth-restricted infants at higher cardiac risk
Gestational age	Weak positive correlation		r = 0.269, P = 0.028	Preterm infants more vulnerable
Sex (male vs female)	Trend toward higher LV mass in males		Not statistically significant	Larger studies needed; sexual dimorphism possible
Temporal changes in LV mass (days 1-3)
Day 1 of life	8.1 ± 2.5 g (highest)		ANOVA P = 0.728	Critical assessment window on day 1
Day 2 of life	7.7 g		Declining trend	Progressive deterioration over 72 hours
Day 3 of life	7.7 g		Plateau	Serial echocardiography recommended
Echocardiographic & methodological features
Assessment method	M-mode echo, Devereux formula, EACVI guidelines	Same protocol	Gold standard non-invasive tool	POCUS feasible in resource-limited settings
Study design	Hospital-based cross-sectional, Enugu Nigeria	Matched controls	n = 84 vs n = 48	Single-center; needs multicenter validation
Comparison with literature
Pakistani study (166 term neonates)	Pulmonary HTN 50%; PDA 37.2%		aOR severe asphyxia = 5.01	Confirms high cardiac morbidity in asphyxia
Vijayashankar et al[52]	11/69 neonates had LV dysfunction		Approximately 16% prevalence	Asphyxia is a leading cause of LV dysfunction
Myocardial dysfunction (HIE study)	53.3% of HIE cases had myocardial dysfunction		CK-MB, Troponin I correlated with severity	Biochemical + echo markers complement each other

LV: Left ventricular; EACVI: European Association of Cardiovascular Imaging; HTN: Hypertension; PDA: Patent ductus arteriosus; HIE: Hypoxic-ischemic encephalopathy; aOR: Adjusted odds ratio; CK-MB: Creatine kinase-MB; POCUS: Point of care ultrasound.

Therapeutic hypothermia, is a neuroprotective treatment. It has shown improved prognosis in cases of moderate to severe encephalopathy. Since hypothermia has a very narrow time sensitive therapeutic window, it has to be started within 6 hours or ideally sooner, to be effective[28-30]. Prompt identification of those who will benefit from current and emerging neuroprotective therapies will help guide appropriate application of resources and permit prognostication.

Our present understanding of the development and severity of newborn encephalopathy was made possible by the groundbreaking work of Sarnat and Sarnat. Nevertheless, more research is required to combine decades of cumulative expertise into a straightforward, validated screening method that can be used at the bedside to quickly determine the severity of newborn encephalopathy and offer precise prognostic information. Future research will focus heavily on the function of early ancillary tests to support the diagnosis of HIE. When accessible, EEG data should be used to inform provider discussions about outcomes and management.

The fields of neurology and neonatology should continue to prioritize research in this area. Neuroprotective medicines continue to show promise, but their usefulness will depend on how quickly and reliably our diagnostic tools can identify the neonates who would benefit most from intervention. Ongoing research is desperately needed to create and evaluate clinical screening instruments to detect HIE that can be readily used in a range of situations within the first few hours of life and offer trustworthy data regarding the spectrum of severity[31,32].

When assessing and evaluating a baby with newborn encephalopathy, the Sarnat score is crucial. The Modified Sarnat Score is a clinical instrument that gives doctors a standardized method for conducting systematic neurological examinations and documenting relevant neurological findings. The emergence of therapeutic hypothermia and the requirement to assess the neurological response to treatment have raised the Sarnat Score’s value.

Although it can currently be used clinically in nurseries, the proposal to update the Sarnat grading scale of NE is mainly meant to serve as a guide for future prospective research to ascertain whether the proposed modifications and additions are beneficial as criteria. To verify the validity of clinical diagnostic criteria for newborn encephalopathy, multicenter collaborative research is required. A comprehensive protocol is being developed to address potential improvements and updates to the Sarnat grading scale as well as to recommend a few items that we think should be evaluated objectively. This grading scale’s objective of providing a clinical description of the encephalopathy based on specific physical examination features is another crucial aspect. Its objective is not to determine the source of the encephalopathy; it can be used for neonatal encephalopathies of any kind, not simply hypoxia-ischemia, even though this is the most common cause[33].

Timely assessments will foster the generation of more beneficial neurotherapies in neurodevelopment through the lifespan. Early identification of brain problems in the fetus and neonates will contribute towards more efficient development of neurotherapies to rescue and heal the brain in critical/sensitive stages of brain development. Neurotherapies will be provided within the first 1000 days to patients with pre-clinical conditions as well as individuals with early signs of brain pathology to select the right therapeutic approach for maximum efficacy. Through site-specific treatments aimed at synapses, neurons, or neural circuits, therapies will correlate experience-dependent neuroplasticity to compensate for brain impairment from brain pathologies like hypoxia through biomarkers of epigenetics or omics.

The reduction of neurologic disease burden throughout the lifecycle is one of the key sustainability goals for maternal and pediatric health programs that should be adopted by the respective countries and the global health community as a whole. The contribution to the global burden of neurological diseases, expressed in terms of disability-adjusted life years, of a considerable share of children makes it necessary to assess the effect of the measures taken by medicine not only on the present generation but also on the following one from the point of view of plasticity, growth and neurocognitive development as well as the subsequent development of non-communicable diseases. The improvements in personalized medical care and health policy of any country reflect its overall state of health and economy, which contributes to the priorities in the field of global health. Collaboration between the government, industry and non-profit sectors can make them jointly promote health policy tailored specifically to particular demographics in developing and developed countries. Investigations of pre-natal and early childhood disorders of the brain within the framework of health disparity research will result in a more effective lowering of the burden and financial cost of these diseases. Neurotherapeutics offered during the first 1000 days contributes to improved scholastic success, employability, and quality of life which extend into adulthood[34].

TEMPORAL ANALYSIS OF LV MASS

The temporal analysis showing highest LV mass on day one (8.1 ± 2.5 g) with subsequent decline provides insights into the evolution of cardiac injury. This pattern shows the progressive deterioration occurring over the subsequent days. This finding has immediate clinical relevance, indicating that cardiac assessment should be performed serially rather than as a single evaluation, and that the first 72 hours represent a critical window for intervention.

From a clinical perspective, these findings necessitate a reevaluation of cardiac assessment protocols in newborns with perinatal asphyxia. The traditional focus on neurological outcomes, while essential, should be complemented by systematic cardiac evaluation including echocardiographic assessment of LV mass and function. The establishment of standardized reference values for LV mass in this population, as suggested by the authors, would facilitate early identification of at-risk infants and guide therapeutic decision-making.

The gender differences observed, while not statistically significant, deserve attention in larger studies. The trend toward higher LV mass in males (consistent with adult patterns) suggests that sexual dimorphism in cardiac development may influence responses to perinatal insults and could inform personalized therapeutic approaches[35].

Right ventricle myocardial infarction during early infancy shows its correlation with the mean QRS axis and the addition of V1R plus V6S voltages while the correlation of LV myocardial infarction with V6R-S voltage and V6(Q + S)-S voltage is found. The failure of finding any correlation of LV myocardial infarction with the V1S voltage and the V6R/S voltage ratio, and similarly Right ventricle myocardial infarction with V1R/S voltage ratio should make us cautious about using these factors for determining the ventricular hypertrophy in early infancy[36].

METHODOLOGICAL CONSIDERATIONS: ECHOCARDIOGRAPHIC MEASUREMENT

This is perhaps the most technically critical area of the paper, and it deserves careful attention. Echocardiographic measurement of LV mass in neonates is inherently challenging, and the reliability of derived measurements depends on multiple factors that the paper does not fully address.

The authors used M-mode echocardiography with the Devereux formula - a well-validated approach in adults and older children - and applied the European Association of Cardiovascular Imaging guidelines for chamber quantification. While the Devereux formula assumes an ellipsoid LV geometry (ratio 1:2), this assumption may be less reliable in neonates, where ventricular geometry differs from that in older individuals due to physiological right ventricular dominance in the early transitional period. The neonatal heart undergoes rapid structural and hemodynamic changes during the first 72 hours of life as the fetal circulation transitions to the postnatal state, including functional closure of the ductus arteriosus and foramen ovale. This transitional hemodynamics can significantly influence LV filling pressures, wall thickness, and internal dimensions - all of which feed directly into the LV mass calculation.

The fact that measurements were taken across days 1 to 3 of life introduces a temporal variable that the authors acknowledge but do not fully account for analytically. The LV mass was highest on day 1 (8.1 ± 2.5 g) compared to days 2 and 3 (both 7.7 g), though the ANOVA did not detect statistical significance (P = 0.728). This trend is clinically plausible - the myocardial response to acute hypoxic-ischemic injury may evolve over the first days of life - but the absence of a significant time-point difference could reflect insufficient power given the small subgroup sizes at each time point rather than a true null effect. A mixed-effects repeated measures model, had serial measurements been taken in the same neonates, would have provided stronger longitudinal inference.

One aspect that requires specific acknowledgement concern is operator variability. The authors state that because the study was performed by a single investigator, inter-observer variability testing was deemed unnecessary. While single-operator studies do eliminate inter-observer discrepancy, they introduce a different methodological concern: The absence of intra-observer reproducibility data. Echocardiographic measurements, even by an experienced single operator, can vary depending on the image plane selected, the neonatal position, respiratory phase during which measurements are taken, and the degree of neonatal agitation or movement. In small neonates, where LV wall thickness measurements are in the range of 2-4 mm, a measurement error of even 0.5 mm propagates substantially into the cubic Devereux formula. Without published intra-observer coefficients of variation for this dataset, it is difficult to assess the precision of the individual measurements upon which all subsequent correlations depend. Future studies in this field should incorporate formal reproducibility testing, ideally with a blinded second reader of a random subset of stored loops.

The hemodynamic status of the neonate at the time of echocardiography is another under-explored confounder. Asphyxiated neonates may be receiving inotropic support, fluid resuscitation, oxygen supplementation, or anticonvulsant therapy - all of which can acutely alter cardiac loading conditions and thus LV dimensions. The paper does not describe what proportion of the asphyxia group was on active medical treatment at the time of the scan, nor whether attempts were made to standardize the timing of echocardiography relative to clinical interventions. This is a meaningful gap that should be declared clearly as a limitation, as it prevents the study from isolating the pure structural effect of the hypoxic-ischemic insult from the secondary hemodynamic effects of treatment.

The study appropriately excluded neonates with echocardiographically confirmed congenital heart disease. However, it is worth noting that some structural defects - particularly small ventricular septal defects and patent ductus arteriosus with hemodynamic significance - may not always be identified on a standard clinical scan, particularly in a resource-limited setting with a portable echocardiography machine.

In addition to those maternal characteristics such as weight, obesity, blood pressure, and diabetes were not included in the analysis. This is an important consideration, because each of these factors can independently influence neonatal cardiac structure.

Several barriers exist in the routine use of echocardiography in asphyxiated neonates: Availability of echocardiography machines suitable for neonates, trained operators, adequate imaging conditions, and crucially, time - given the competing clinical demands on practitioners managing asphyxiated neonates who may simultaneously require resuscitation, seizure management, and organ support (Figure 1).

Figure 1 Echocardiogram in newborn with perinatal asphyxia. ECHO: Echocardiogram.

POCUS (neonatal point-of-care ultrasound) in hands of trained frontline neonatal providers, enables real time evaluation of LV performance. This guides for accurate decisions by determining acute physiology and etiology of cardiovascular compromise. Currently, overreliance on poorly predictive clinical parameters such as urine output, heart rate or capillary refill time has its own limitations[37].

Afterload pressures are very significant in defining myocardial function, thereby suggesting that systemic arterial mechanics is an important indicator. Several meta-analyses demonstrated that arterial stiffness is an independent risk marker for subsequent incidence of cardiovascular diseases[38,39]. Evaluation of longitudinal relationship between arterial stiffness and hypertension reveals the existence of a precursory relationship[40]. Current observations in neonates reveal that assessing arterial stiffness and distensibility might give useful indicators of early vascular abnormalities that might predispose individuals to the development of more vascular disorders[41,42]. Arterial intima-media thickness, stiffness index and compliance have been established as important markers of coronary artery disease and cerebrovascular accident among adults[43-46]. Fetal growth restriction is the paradigmatic condition that involves initial vascular remodeling that can possibly explain why these individuals become more prone to developing cardiovascular problems during adulthood[47].

The ability to transition from the more important RV to the LV might be obstructed by various diseases in premature and full-term newborns. The knowledge base of POCUS has a key contribution in defining physiologic parameters to achieve logical treatment. Inotropic treatment on time and appropriately in terms of physiologic parameters as suggested by clinical decision-making processes and assisted by POCUS may help improve the patient outcome. The evaluation of the LV to determine its significance as a contractile pump after birth becomes possible through the integration of clinical and echo parameters. Taking into consideration that there is sufficient training for echocardiographic investigation techniques, further research needs to be done to establish useful echo parameters depending on different clinical situations where time becomes the limiting factor.

PARACLINICAL EVALUATION

The near-infrared spectroscopy can be characterized as non-invasive technique providing for continuous assessment of tissue oxygenation. The application of this method is associated with relative transparency of biological tissue to light. The neonate brain can be easily accessed by light in range of 700-1000 nm due to the presence of rather thin layers of skin and bone tissues (the skull). Thus, the waves of light from near-infrared spectrum are transmitted to the brain tissue semi-circularly to a detector located some 2-3 cm beneath the surface of the head. At different wavelengths hemoglobin absorbs light at different degree. The detector is able to measure differences in light absorption and calculate concentrations of substance in accordance with modified Lambert-Beer law that provides a measure of tissue oxygenation. Near-infrared Spectroscopy is a good diagnostic instrument for assessing cerebral tissue oxygenation. If the index of cerebral oxygenation is higher than 85%, the process of neuronal destruction occurs, which is accompanied by reduction of the total neuronal mass and poor prognosis for future neurological state. If the value of the index is lower than 65%, there is a low amount of 02 or its elevated consumption[48].

Two techniques for evaluation of electrical activity of the brain in first 72 hours following asphyxia are EEG and amplitude-integrated electroencephalography, which are particularly useful for infants under therapeutic hypothermia. The task of amplitude-integrated electroencephalography is not only the monitoring and optimization of therapy but also detection of the brain electrical activity pattern with prognostic significance[49].

The most important advantage of magnetic resonance imaging compared to EEG or clinical data is that it gives the additional prognostic information about cerebral injury. Conducting magnetic resonance imaging at the optimal time period, one can observe a correlation between the brain lesion pattern and the prognosis for neurological function. The lesions of cortex or subcortical structures lead to motor and cognitive abnormalities depending on the degree of lesions in specific areas[50].

COMPARISON WITH OTHER STUDIES

Neonates’ myocardium is considered to have a resistance to hypoxia, while cardiac failure is one of the major presentations of myocardial dysfunction in asphyxiated infants. While the occurrence of severe cardiac pathology may not be common, milder presentations such as those affecting the heart can be relatively common among infants with asphyxia. Historically, the presence of murmur indicative of atrioventricular insufficiency, ECG findings suggesting myocardial ischemia, cardiogenic shock, hypotension, tricuspid incompetence or arrhythmia have been observed commonly in neonates with asphyxia[51].

There is a possibility of association between maternal gestational weight gain (GWG) and cardiopathic in the offspring throughout childhood to adulthood life. The objective of this study was to examine whether the maternal GWG is associated with the geometry and function of the LV, and determine the effects of the intrauterine environment on early childhood cardiac development. According to the results obtained in this study, it was found that the high maternal GWG was associated with increased thickness of the interventricular septum in the offspring, especially in the second and third trimesters. The high maternal GWG during the second and third trimesters was associated with eccentric and concentric hypertrophy of the LV in the offspring[52].

Chinawa et al[8] conducted a hospital-based cross-sectional study among 84 neonates with perinatal asphyxia and 48 matched controls in Enugu, Nigeria, using echocardiography to document LV mass values and their correlates. The study found a significantly lower mean LV mass in asphyxiated neonates (7.9 ± 2.3 g) compared to controls (10.1 ± 0.7 g, P = 0.001), with 63% of asphyxiated babies falling below the control threshold. A moderate positive correlation was observed between LV mass and birth weight (r = 0.610, P = 0.001), and a weak positive correlation with gestational age (r = 0.269, P = 0.028). Severe asphyxia carried the lowest mean LV mass (7.1 ± 1.5 g), though ANOVA did not reach statistical significance across severity grades (P = 0.289)[53].

A Pakistani cross-sectional study on 166 term asphyxiated neonates similarly found echocardiographic evidence of myocardial dysfunction, with pulmonary hypertension in 50% of cases and patent ductus arteriosus in 37.2%[54]. They identified severe asphyxia (adjust odds ratio = 5.01), patent ductus arteriosus (adjust odds ratio = 5.11), and caesarean section (adjust odds ratio = 2.65) as independent predictors of myocardial dysfunction. Vijayashankar et al[54], studying LV dysfunction in the immediate postnatal period, identified 11 of 69 screened neonates with LV dysfunction attributable to perinatal asphyxia[55]. Other studies also showed that BW and male gender, positively correlate with increased LV mass[56]. These studies confirmed male predominance in LV abnormalities, consistent with sex-related differences in myocardial mass programming. In terms of gestational-age effects, Chinawa et al’s finding[8] of a positive correlation between LV mass and gestational age echoes earlier evidence that lower gestational age amplifies LV vulnerability. A prospective cohort study using echocardiography at day 5 of life and again at 3 months showed gestational age varied inversely with ventricular wall thickness and LV mass, with no impact on systolic or diastolic function[57]. Together, these bodies of evidence suggest that prematurity and asphyxia compound LV structural compromise through overlapping hypoxic-ischemic pathways.

The incidence of myocardial dysfunction was seen in 53.3% of cases and indicated the severity and involvement of the heart in HIE. Significant positive correlation was shown between the levels of cardiac markers like creatine phosphokinase-MB, CK total, and troponin I, as well as their correlation with the severity of complications and adverse outcomes in terms of HIE staging. An accurate and detailed history taking, clinical signs, a higher index of suspicion, and early diagnosis of myocardial dysfunction by using various modalities not only help increase survival chances of an affected infant but also decrease the mortality rate of neonates. The severity of hypoxic ischemic encephalopathy and myocardial dysfunction had a significant positive correlation with a poor prognosis and unfavorable outcome in patients. Bedside 2D ECHOCARDIOGRAM is an important diagnostic test that can predict the functional status of the patient’s heart as well as the outcome of the case depending on the stages of HIE[58].

The prevalence of HIE in the perinatal population was 1.7 per 1000. While the incidence of perinatal HIE remained largely unchanged throughout the study period, there were statistically significant increases in hospital discharge diagnoses of HIE and use of therapeutic hypothermia for treating neonates with HIE. Sensitivity and positive predictive values for using a hospital discharge diagnosis of HIE to diagnose perinatal HIE were 72% and 79%, respectively[59].

Signal quality indicators give us practical real-time information about possible physiologic disruption during labor since they could be indicative of a period of asphyxiation that can occur by diminished variability and other subtle changes in the fetal heart rate patterns which the existing cardiotocography (CTG) analysis algorithms are not able to recognize. Previous research indicates the presence of associations between CTG signal quality problems and interpretation of CTG results; however, up to date, no systematic study has evaluated their contribution towards asphyxiation diagnosis. Kiely et al[60] conducted a systematic review of Food and Drug Administration reports on sentinel events and found out that 40% of 117 CTG-related deaths were associated with signal coincidence. Although many articles emphasize the importance of CTG signal quality for clinical practice, there is no evidence that systematically assesses how much signal quality can contribute to the problem of asphyxiation (cause of condition, death diagnosis). Gestation cut-off adopted in this study follows the existing literature based on HIE[61].

However, in another study, odds ratio for the clinically defined “late deceleration” was 3.3, which gives us a calculated number needed to treat value of 16. It is noteworthy that by combining dropout measures together with “late decelerations”, we will be able to improve asphyxia risk estimation and intervention in future studies since there is a considerable difference in asphyxia occurrence rate between our study and the “late deceleration” study[62].

The ZigZag pattern, as well as late decelerations within the last 2 hours of labor, were strongly related to cord blood acidemia on delivery and neonatal outcomes. First, the ZigZag pattern occurs before late decelerations, and, second, the finding that the normal fetal heart rate pattern occurs before the ZigZag pattern in most cases shows that the ZigZag pattern is a marker of hypoxia and, hence, is clinically important[63].

In our independent studies on using ensemble deep learning with clinical and time series data, we utilize timestamps of true labor stage transitions to facilitate accurate temporal mapping of fetal heart rate features. The current study, however, was intended to provide a basic, proof-of-concept study with a causal inference design focused on exploring associations between the cumulative proportion of missing valid signal and perinatal asphyxia, without focusing on modeling stage-specific physiological transitions. Consequently, signal metrics were not separated based on the influence of each labor stage in the analyzed interval. Another limitation of computer-based CTG interpretation lies in its dependence on pre-processed data that may affect clinical utility. Although some missing signal portions might be obvious even from visual analysis, clinicians are unlikely to appreciate the cumulative impact of signal dropout and may neglect necessary actions, such as readjusting probe placement or monitoring CTG more frequently. Thus, we suggest developing an easily integrable feature of the cumulative proportion of missing signal on the interface of the CTG machine to alert clinicians about the problem in real time at a specific time interval (for example, every 15 minutes).

Although some segments of lost signal are easily visible to clinicians, the cumulative weight of signal loss will remain unrecognized, leading to delays in adjusting the probe settings and/or vigilance level. To address this, we suggest that cumulative lost valid signal measurement be included on the CTG interface as an initial means of detecting lost signal integrity and updated periodically (every 15 minutes, for example). This can raise awareness of lost signal, which is otherwise likely to go unnoticed even though it is visible. This tool would also serve as a useful adjunct for secondary modeling for asphyxia risk prediction.

In another study, they noted post-casual inference modeling that both high signal dropout (threshold binary > 30%) and the fifth quintile of signal dropout have adjusted odds ratios of asphyxia with odds ratio 1.58 and 2.21, corresponding to the number needed to treat of 67 and 34, respectively. Although the results presented here are the proof of concept of using real-time signal dropout to provide decision support during the intrapartum period, their association with asphyxia should not be used independently for any clinical decisions as such an approach should generate hypotheses only for future model building and prediction. The value of this study is in its sound methodological framework and model development and validation on large and diverse data sets. Our data set includes one of the largest collections of digitally recorded CTGs associated with outcome.

While previous research has been done using CTG data, none have used a dataset on this scale and structure of neonatal outcomes. However, it can be observed that although the odds ratio in the Czech dataset is slightly higher, the incidence rate of asphyxia was considerably higher as compared to that of the Mercy dataset; 7.48% (95% confidence interval: 5.42%-10.01%) vs 2.67% (95% confidence interval: 2.49%-2.85%), z statistic = 6.84, P < 0.001. Also, many fewer covariates were present in the Czech dataset. Overall, the current study shows evidence of an association between high missing valid CTG signal and perinatal asphyxia from two large databases[62].

Tissue Doppler imaging should be considered as an integral part of cardiac function assessment particularly in neonates with perinatal asphyxia. Studies also suggest that many cases of diastolic dysfunction would be missed if assessment relies only on conventional pulsed wave Doppler. Tissue Doppler imaging is able to detect LV diastolic dysfunction more than conventional pulsed wave Doppler[64].

LIMITATIONS OF THE STUDY

The study's limitations, including the single-center, cross-sectional design and relatively small sample size, absence of reproducibility data, incomplete maternal covariate adjustment, highlight the need for larger prospective studies to validate these findings and establish their prognostic significance. Future research should focus on the long-term cardiovascular outcomes of infants with reduced LV mass following perinatal asphyxia, as these children may be at increased risk for adult cardiovascular disease through programming mechanisms established in early life.

Another study showed that there was a strong nonlinear correlation between height and LV mass. This study supports the possibility to have a single partition value across pediatric age group to identify LV hypertrophy, rather than specific percentiles for height and sex.

RECENT ADVANCES

Neonatal morbidity and mortality, results in long term neurodevelopmental challenges, where in perinatal asphyxia plays a major contribution. Early diagnosis is essential for timely interventions to reduce brain injury, with tools such as Magnetic Resonance Imaging, brain ultrasound, and emerging biomarkers playing a possible key role. Hypoxic injury, particularly to the olfactory bulb, affects the cognitive and social developments of infants. Further research in understanding the interplay between olfactory system development and perinatal brain injury could pave the way for novel diagnostic and prognostic tools.

CONCLUSION

Expanding cardiovascular evaluation in perinatal asphyxia to include structural markers such as LV mass represents an important step toward comprehensive neonatal cardiac care. This study fundamentally challenges our understanding of cardiac involvement in perinatal asphyxia by demonstrating significant LV mass reduction rather than the expected hypertrophic response. The correlations with gestational age, birth weight, and asphyxia severity provide a framework for risk stratification and targeted intervention. As clinicians with extensive experience managing these vulnerable infants, we must integrate these findings into our clinical practice by implementing systematic cardiac assessment protocols and considering the long-term cardiovascular implications of perinatal asphyxia events. The establishment of standardized measurement techniques and reference values, as proposed by the authors, represents a critical next step in advancing our understanding and management of cardiac complications in perinatal asphyxia.