Transition to extrauterine life in extremely preterm infants: a narrative review of physiology-based cardiovascular and cerebral monitoring

Introduction

Background

Preterm birth, defined as delivery before 37 weeks of gestation, is commonly stratified into extremely preterm (<28 weeks), very preterm (28 to <32 weeks), and moderate to late preterm (32 to <37 weeks) (1). Among these groups, extremely preterm infants carry the highest risk of neonatal mortality (2) and long-term adverse outcomes (3). Despite representing a small proportion of total births, they account for a disproportionate burden of morbidity and neurodevelopmental impairment (NDI) (4,5), with lifelong clinical and societal implications (6-8).

The transitional period is clinically extended to the first 72 hours of life and is characterized by rapid and complex physiological adaptations required for extrauterine life (9-12). These include the establishment of effective ventilation, a decrease in pulmonary vascular resistance (PVR), with increased pulmonary blood flow (PBF), a rise in systemic vascular resistance (SVR) following cord clamping and the reorganization of circulation through functional closure of fetal shunts (9-12).

While most term neonates complete this transition successfully, extremely preterm infants are particularly vulnerable during this phase due to profound biological immaturity (12-14). Immature myocardial function, persistence of transitional shunts, unstable vascular resistance, and impaired cerebrovascular autoregulation increase susceptibility to hemodynamic instability and organ injury (15). Disturbances during this critical window have been associated with adverse outcomes, such as intraventricular hemorrhage (IVH), white matter injury (WMI) and NDI.

Rationale and knowledge gap

Hemodynamic management of the transitional period in preterm infants has traditionally followed a one-size-fits-all approach, relying on gestational age (GA)-based thresholds and population-derived normative values for parameters such as blood pressure (BP), heart rate (HR), and oxygenation (16,17). However, increasing evidence suggests that such uniform strategies fail to capture the substantial biological heterogeneity within the preterm population (18). Infants of similar GA may exhibit different patterns of cardiovascular adaptation, pulmonary vascular transition, and cerebral vulnerability, challenging the validity of fixed hemodynamic targets and standardized treatment algorithms.

This heterogeneity is partly driven by differences in antenatal conditioning and the underlying pathophysiological pathways leading to preterm birth. Emerging recognition of distinct antenatal endotypes highlights that preterm infants enter postnatal life with variable physiological reserves and adaptive capacity (19,20). Consequently, the transitional period represents not only a phase of adaptation, but also a critical window of vulnerability to secondary injury.

Recent reviews (11,12) have advanced the understanding of transitional physiology and emphasized the role of hemodynamic monitoring tools, such as targeted neonatal echocardiography (TNE) (21) and near-infrared spectroscopy (NIRS) (22), primarily focusing on cardiovascular adaptation and systemic or regional perfusion. However, these approaches are largely considered monitoring modalities in isolation and remain centered on postnatal physiology (23). In contrast, a key gap remains in integrating multimodal monitoring, particularly cerebral functional assessment, such as integrated amplitude-integrated electroencephalography (aEEG), with cardiovascular adaptation and antenatal biological variability. Addressing this gap is essential to advance toward a personalized, physiology-based framework for transitional care, where real-time data are interpreted in the context of underlying endotypes and dynamic pathophysiology. An important limitation is that evidence specifically addressing extremely low gestational age newborns (ELGANs) remains limited. Much of the current understanding of transitional physiology and monitoring strategies is derived from studies in more mature preterm or term infants. Consequently, several physiological interpretations discussed in this review are based on extrapolation and should be interpreted with caution when applied to the most immature populations.

Objective

In this narrative review, we examine cardiovascular and cerebrovascular adaptations in extremely preterm infants during the transition to extrauterine life, with emphasis on contemporary hemodynamic and neuromonitoring strategies. We explore how cardiovascular and cerebral monitoring can be integrated into a multimodal framework, which also accounts for antenatal endotypes and biological heterogeneity, supporting a more individualized, physiology-based approach to transitional care. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-26-0019/rc).

Methods

This narrative review was informed by a focused, non-systematic literature search conducted in PubMed and Embase. Searches combined terms related to “extreme prematurity”, “neonatal transition”, “cardiovascular and cerebrovascular adaptation”, “targeted neonatal echocardiography”, “right ventricular function”, “pulmonary hemodynamics”, “systemic and cerebral blood flow”, “cerebrovascular autoregulation”, “near-infrared spectroscopy”, “amplitude-integrated electroencephalography”, “multimodal monitoring”, and “endotypes of prematurity”. The search primarily included studies published up to November 2025 and was limited to articles available in English or Spanish.

Additional relevant articles were identified through manual review of reference lists from key publications and consensus statements. In keeping with the narrative nature of this review, no formal inclusion or exclusion criteria, systematic study selection process, or methodological quality assessment were applied. Rather, the aim was to synthesize contemporary physiological concepts and clinically relevant evidence to support an integrated, physiology-based, and individualized perspective on transitional care in extremely preterm infants.

An overview of the literature search informing this narrative review is summarized in Table 1. A representative example of the PubMed search strategy is provided in Table S1.

Physiological basis of the neonatal transition

The transition from fetal to neonatal life transforms the fetal parallel circulation into a postnatal circulation in series through coordinated respiratory and cardiovascular events. These adaptations are initiated at birth and unfold over the first minutes to hours of extrauterine life, forming the physiological foundation of neonatal transition (9,12,14,24-26).

Pulmonary aeration: fetal lung fluid is rapidly cleared and replaced by air, initiating effective gas exchange. Lung aeration leads to a dramatic reduction in PVR and an increase in PBF, establishing pulmonary venous return as the primary source of left ventricular (LV) preload (9,12).

Umbilical cord clamping: Interruption of placental blood flow results in an abrupt increase in SVR and loss of umbilical venous return. This shift requires rapid adaptation of the LV to increased afterload while maintaining cardiac output through pulmonary venous return (11,14,27).

Functional closure of fetal shunts: increased pulmonary venous return raises left atrial pressure, promoting closure of the foramen ovale, while higher arterial oxygen tension and reduced prostaglandins trigger constriction of the ductus arteriosus (DA). The ductus venosus closes following cessation of umbilical flow (9,14,27).

Redistribution of cardiac output: these changes convert the circulation from a parallel to a series configuration, in which the entire cardiac output passes through the lungs before reaching the systemic circulation (25-27).

Why transition is different in extremely preterm infants

While the sequence described above provides the physiological framework of neonatal transition, it is largely derived from studies in term infants. In extremely preterm infants, this process is not simply delayed, but often altered by profound physiological immaturity. As a result, transition is often incomplete and unstable, in contrast to the rapid and coordinated adaptation observed in term neonates (25). Rather than a uniform process, extremely preterm infants undergo transition in the context of profound organ immaturity, resulting in marked physiological instability (24). Key differences between term and extremely preterm transitional physiology are summarized in Table 2.

Pulmonary immaturity is a central determinant of this altered transition. Deficient surfactant production, simplified alveolar structure, and limited capacity to establish functional residual capacity impair gas exchange, increasing the need for respiratory support (12). Exposure to positive pressure ventilation and supplemental oxygen carries a substantial risk of ventilation-induced lung injury, contributing to the development of bronchopulmonary dysplasia (BPD) (28,29). In contrast to term neonates, in whom lung aeration drives a rapid and sustained decrease in PVR, this process is frequently delayed and unstable in ELGANs (12), contributing to persistent right ventricle (RV) afterload and impaired PBF (30).

These abnormalities are closely linked to dynamic cardiorespiratory interactions. Respiratory interventions, including positive pressure ventilation and surfactant administration, can acutely modify intrathoracic pressures, venous return and shunt dynamics (9). Persistence of fetal shunts, particularly the DA, is common and may lead to variable redistribution of blood flow between pulmonary and systemic circulations (31). Such interactions appear to be more pronounced and less predictable than in term infants, contributing to fluctuations in systemic and cerebral perfusion.

Cardiovascular adaptation is further limited by intrinsic myocardial immaturity, characterized by reduced compliance and contractile reserve. As a result, extremely preterm infants have a diminished capacity to respond to changes in preload and afterload (15), and may develop low systemic blood flow even in the presence of adequate BP (32). In addition, immaturity of respiratory control and neuroendocrine responses likely contributes to physiological instability (33). Apnea and intermittent hypoxemia further compromise cerebral oxygen delivery (34), especially during the transitional period, when limited adrenal and autonomic responsiveness reduces the capacity to respond to stress (35).

Together, these factors underscore that transitional physiology in extremely preterm infants is not simply delayed but qualitatively different from that of term neonates. The combination of pulmonary, cardiovascular and regulatory immaturity creates a narrow margin for adaptation and highlights the need for careful and individualized interpretation of physiological data, particularly given the limited availability of ELGAN-specific evidence.

Ventricular adaptation and cardio-cerebral interactions

Right ventricular dominance and pulmonary vascular interaction

During fetal life, the RV is the primary contributor to cardiac output (26), directing blood flow through the DA toward the systemic circulation (9,36). In term infants, this pattern rapidly transitions after birth as PVR falls and LV output becomes dominant. However, in extremely preterm infants, this transition is frequently delayed, and RV dominance often persists during early postnatal life (33,37-39). As a result, systemic blood flow during early transition is likely influenced largely by RV performance and ventricular-vascular interactions rather than by LV systolic function alone (40-42).

Multiple factors contribute to impaired pulmonary vascular transition in extreme prematurity, including incomplete pulmonary vascular adaptation, persistent ductal patency and exposure to positive pressure ventilation, leading to elevated RV afterload and prolonged dependence on RV performance (43). In this context, the ability of the RV to match its contractile function to pulmonary vascular load, referred to as right ventricular-pulmonary vascular (RV-PV) coupling (44), is considered an important determinant of effective PBF (45,46). However, the immature RV is particularly vulnerable to afterload mismatch, increasing the risk of RV-PV uncoupling and compromised forward flow (37,39).

Impact of right ventricular function on cerebral perfusion

The central role of RV in transitional hemodynamics has important implications for cerebral perfusion. In extremely preterm infants, cerebral blood flow (CBF) is highly dependent on systemic circulation due to immature or absent autoregulatory mechanisms (47). While term infants can maintain relatively stable CBF across a defined range of systemic BP, ELGANs often exhibit pressure-passive cerebral circulation, making them particularly vulnerable to fluctuations in cardiac output and vascular resistance (48,49).

Under these conditions, alterations in RV performance and RV-PV coupling may influence PBF, LV preload and ultimately systemic and cerebral perfusion. In parallel, elevated right-sided pressures and persistent shunting can further disrupt flow distribution between pulmonary and systemic circulation (49,50). These dynamic interactions may result in episodes of hypo- or hyper-perfusion, even in the absence of overt systemic hypotension (51,52).

Structural vulnerability of the preterm brain, including the fragility of the germinal matrix and incomplete vascular network (53), amplifies the impact of these hemodynamic fluctuations. Importantly, the exact relationship between RV function and cerebral perfusion in ELGANs remains incompletely defined and current understanding is largely inferred from physiological reasoning and studies in more mature populations.

Clinical implications for integrated monitoring

The interplay between persistent RV dominance, pulmonary vascular adaptation, and immature cerebrovascular regulation places extremely preterm infants at high risk of cardio-cerebral mismatch during the transitional period. These observations underscore the limitations of relying on isolated clinical parameters, such as BP, and highlight the need for an integrated assessment of cardiovascular and cerebral physiology. In this context, functional evaluation of RV performance, loading conditions, and their downstream effects on cerebral perfusion is likely to support differentiation between adaptive and maladaptive responses and to support individualized, physiology-based care.

A multiple-hit model of neonatal transition: the role of prematurity endotypes

The vulnerability of extremely preterm infants during the neonatal transition is increasingly understood within a multiple-hit model, in which adverse outcomes arise from the cumulative impact of sequential insults rather than a single isolated event (54). Within this framework, antenatal pathophysiology constitutes the first hit, whereas the transitional and early postnatal periods represent a phase of heightened susceptibility to secondary insults that may amplify pre-existing biological vulnerability.

Central to this model is the concept of endotypes of prematurity. The term endotype, originally introduced in the field of asthma, refers to a subtype of a disease defined by a distinct pathobiological mechanism rather than by clinical phenotype or timing alone (55). Endotypes are characterized by specific molecular, cellular, or physiological pathways that drive disease in a subgroup of patients and may be identified through biomarkers, histopathology, or differential responses to targeted therapies (56). This mechanistic approach has since been applied to other heterogeneous conditions as a framework to support precision medicine.

In the context of prematurity, the endotype concept has been adopted to classify preterm birth into biologically distinct subgroups based on underlying pathophysiological pathways, rather than GA alone. Two major endotypes are consistently identified: infection/inflammation, typically represented by clinical or histological chorioamnionitis, and dysfunctional placentation, encompassing hypertensive disorders of pregnancy and placental insufficiency leading to fetal growth restriction (57). Importantly, these endotypes should not be viewed solely as triggers of extremely preterm birth, but rather as markers of distinct intrauterine environments that exert prolonged effects on fetal development.

Each endotype exposes the fetus to a unique pathophysiological milieu. The infection/inflammation endotype is characterized by exposure to pro-inflammatory cytokines, altered vascular reactivity, and potential disruption of fetal organ development, including the lung, myocardium and cerebral vasculature (58,59). In contrast, the dysfunctional placentation endotype is associated with chronic hypoxia, impaired nutrient delivery, altered hemodynamic loading conditions, and adaptive cardiovascular remodeling in utero (60,61). These antenatal conditions are thought to shape organ maturation, physiological reserve, and stress responsiveness at birth, thereby defining the infant’s baseline capacity to tolerate the rapid physiological changes of the neonatal transition. In this context, postnatal transition constitutes a critical second hit. Moreover, in extremely preterm infants, superimposed postnatal stressors—including respiratory support, hemodynamic instability, ductal shunting, and inflammatory responses—interact with antenatal conditioning to determine the trajectory of early adaptation (10). Crucially, the impact of these postnatal insults is not uniform, but is strongly modulated by the underlying endotype. Infants exposed to different antenatal pathophysiological environments may exhibit divergent cardiovascular responses, tolerance to hemodynamic fluctuations, and susceptibility to cerebral injury during the postnatal course (62). Thus, the neonatal transition should be viewed as a patient-specific physiological challenge shaped by both antenatal and postnatal factors.

This multiple-hit, endotype-informed framework, although conceptual and primarily based on physiological reasoning, provides a unifying conceptual model for understanding the heterogeneity of transitional physiology and outcomes in extremely preterm infants (Figure 1). The model highlights the limitations of uniform management strategies and underscores the need for individualized, physiology-based assessment and intervention. Within this context, advanced hemodynamic and cerebral monitoring are essential for detecting instability, interpreting physiology in light of biological trajectory, and potentially mitigating secondary insults.

Figure 1 Double-hit model of neonatal cardiovascular instability and brain injury. Antenatal conditioning (first hit) via infection/inflammation or placental dysfunction increases vulnerability to hemodynamic stress during neonatal transition (second hit), resulting in cardiovascular instability, disturbed cerebral perfusion, and increased risk of brain injury. BP, blood pressure; CBF, cerebral blood flow; PDA, patent ductus arteriosus; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance.

Hemodynamic monitoring in extremely preterm infants

Limitations of conventional clinical and laboratory parameters

There is growing recognition that conventional bedside clinical and laboratory markers are often insufficient to accurately characterize circulatory status in extremely preterm infants during the transitional period, likely reflecting the complex and rapidly evolving relationship between pressure, flow, and tissue perfusion during that period. Moreover, interpretation of these parameters in ELGANs is constrained by the limited availability of population-specific data.

BP has traditionally served as the cornerstone of neonatal hemodynamic assessment. However, mean BP (MBP) is an imperfect surrogate of systemic blood flow (32). Tissue perfusion depends on cardiac output, vascular resistance, hemoglobin concentration, and microcirculatory function, in addition to perfusion pressure (63). The absence of GA-specific, outcome-based reference ranges further complicates interpretation. Although BP increases with gestational and postnatal age, available data largely derive from retrospective cohorts using heterogeneous measurement techniques (16-18). Common definitions of hypotension, such as MBP below GA in weeks, are therefore based mainly on expert consensus rather than robust physiological evidence (64).

Importantly, therapeutic strategies aimed primarily at increasing BP have not consistently improved outcomes and may increase the risk of complications, including IVH (65,66). In many stable extremely preterm infants, low MBP more commonly reflects low SVR or the presence of a significant PDA, rather than impaired myocardial performance (67). These observations have contributed to the concept of permissive hypotension, which prioritizes clinical stability and end-organ perfusion over numerical thresholds (68). Recent studies suggest the use of both components of the BP, since systolic BP appears to reflect LV contractility, while diastolic BP reflects SVR and thus afterload (69).

HR plays a central role in maintaining cardiac output in preterm infants, who have limited capacity to augment stroke volume (43). Nevertheless, HR correlates poorly with systemic blood flow and is influenced by numerous non-hemodynamic factors, including temperature, pain, autonomic tone, and medications (30,70). Interest has therefore grown in HR variability (HRV) as a marker of autonomic regulation. However, its role in routine assessment remains under investigation and is primarily supported by data from more mature populations (71,72).

Peripheral perfusion markers, such as capillary refill time (CRT), provide simple bedside information but have limited diagnostic accuracy, substantial interobserver variability, and poor correlation with systemic blood flow (32). While prolonged values may indicate severe compromise, they often reflect advanced shock with limited reversibility (73). Emerging evidence suggests that CRT reflects microcirculatory reactivity and endothelial function rather than macrovascular flow alone, reinforcing the need for cautious interpretation within a broader clinical context (70,74), particularly in extremely preterm populations where data remain uncertain.

Serum lactate is widely used as a marker of anaerobic metabolism and tissue hypoxia. Elevated lactate levels during early postnatal life have been associated with increased risk of adverse outcomes (75). Single measurements have limited predictive accuracy, especially in extremely preterm infants, with serial measurements providing more meaningful information (76), although evidence supporting its use as a marker of tissue hypoperfusion in this population remains incompletely defined.

The interpretation of urine output, a traditional marker of systemic hemodynamic adequacy, in extremely preterm infants is confounded by renal immaturity, early physiological oliguria, and limited concentrating ability (70), with poorly defined normative values in this population. Normal urine output may coexist with significant cardiovascular compromise, while oliguria may reflect intrinsic renal pathology (77).

Taken together, conventional clinical and laboratory parameters provide valuable but incomplete insight into cardiovascular adaptation during the transitional period. Their indirect nature, combined with the limited availability of ELGAN-specific data, restricts their ability to discriminate between distinct physiological mechanisms. This has driven increasing interest in functional cardiovascular assessment tools capable of characterizing flow, ventricular performance, and organ perfusion more directly, forming the basis for contemporary approaches to neonatal hemodynamic monitoring.

TNE: functional assessment of transitional hemodynamics

TNE has emerged as a key tool to address the limitations of conventional clinical and laboratory parameters in the assessment of cardiovascular adaptation during the neonatal transitional period. TNE enables bedside, real-time evaluation of cardiac function, loading conditions, shunt physiology, and systemic and PBF, providing a functional and physiology-driven assessment of circulatory status (21,78-80). This is particularly necessary in extremely preterm infants, where static thresholds may obscure early maladaptive trajectories (78,81).

TNE differs fundamentally from conventional echocardiography performed by pediatric cardiologists. While comprehensive echocardiography focuses primarily on structural cardiac anatomy, TNE is designed to answer focused clinical questions related to hemodynamic instability, such as the adequacy of ventricular performance, or the interaction between myocardial function and vascular load. When appropriately implemented, TNE complements formal structural assessment by a pediatric cardiologist, which remains essential to exclude congenital heart disease (79,82,83).

Multiple studies have demonstrated the feasibility and clinical relevance of TNE in neonatal intensive care units (NICUs), including its use in the assessment of PDA, pulmonary hypertension, perinatal asphyxia, and hemodynamic instability in extremely preterm infants (23,46,84). More recent evidence suggests that early, systematic application of TNE may facilitate recognition of circulatory compromise before overt clinical deterioration, supporting more timely and targeted interventions (85,86).

Consensus statements from North American, European, and UK neonatal societies have provided guidance on the scope, indications, and training requirements for TNE (79,82,83). These recommendations emphasize that TNE should be integrated into a structured clinical framework, performed by appropriately trained clinicians, and interpreted in conjunction with the broader clinical context. All consensus documents underscore the need for standardized training, quality assurance, and collaboration with pediatric cardiology services to ensure safe and effective implementation.

From a physiological perspective, the strength of TNE lies in its ability to characterize transitional hemodynamics as a dynamic process rather than a static state. By enabling repeated assessments over time, TNE allows clinicians to track evolving ventricular performance, changes in shunt direction, and responses to therapeutic interventions (87-89). This longitudinal perspective is particularly valuable during the first hours of life, when cardiovascular adaptation is most rapid and vulnerability to secondary insults is highest (90,91).

In summary, TNE is increasingly considered a central component of modern hemodynamic monitoring during the neonatal transitional period. By providing functional insight into cardiovascular physiology, TNE allows clinicians to move beyond numerical targets toward individualized interpretation of postnatal cardiovascular transition. Nevertheless, while increasingly adopted in clinical practice, evidence supporting TNE-guided management specifically in ELGANs remains limited, and its impact on clinically meaningful outcomes is still being defined.

Right ventricular assessment during the transitional period

Historically, the assessment of RV function was limited by its complex geometry (9), leading to an overreliance on LV-centric parameters. Currently, TNE enables bedside evaluation of RV size, systolic function, and loading conditions, providing functional insight that cannot be inferred from BP alone (92-94). Conventional echocardiographic parameters such as tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity measured by tissue Doppler imaging (TDI), and fractional area change (FAC) have been validated in neonatal populations, both term and preterm, and offer reproducible markers of RV systolic performance (92,95,96). Among these, TAPSE is more frequently used due to its simplicity and favorable reproducibility.

Beyond systolic performance, assessment of RV dimensions and temporal changes in chamber size may offer insight into volume loading and adaptive remodeling during transition. Studies in stable preterm infants have demonstrated increases in RV stroke volume and chamber size over the first weeks of life, while diastolic maturation appears to lag systolic adaptation (25,27,42). These observations suggest that early RV dysfunction may be subtle and dynamic, reinforcing the need for serial rather than single-point assessments.

Indeed, emerging evidence suggests that early RV dysfunction may be associated with adverse neurological outcomes, both short- and long- term, in neonatal populations with challenging transitional physiology, such as asphyxiated infants (97,98), infants with congenital diaphragmatic hernia (99) or extremely preterm neonates (100).

Emerging echocardiographic techniques for neonatal hemodynamic assessment

While conventional echocardiographic parameters provide valuable information on ventricular size and systolic performance, they may lack sensitivity to detect subtle myocardial dysfunction. Emerging echocardiographic techniques have therefore gained interest as tools to refine functional assessment and improve physiological interpretation of transitional hemodynamics.

TDI

TDI enables direct quantification of myocardial velocities and provides simultaneous assessment of systolic and diastolic function from a single imaging plane. In neonatal practice, longitudinal myocardial velocities obtained at the atrioventricular annuli offer reproducible markers of ventricular performance that are less dependent on geometric assumptions than conventional indices (95,101).

In preterm infants, TDI studies have shown that myocardial velocities are strongly dependent on GA, with lower systolic and early diastolic velocities observed in more immature populations (102,103). Longitudinal studies during the transitional period have exhibited an initial reduction in myocardial velocities during the first hours of life, followed by progressive improvement over the first postnatal days, suggesting transient global myocardial dysfunction associated with early adaptation to extrauterine life (91).

Importantly, TDI allows calculation of a myocardial performance index derived from tissue velocities (MPI'), providing an integrated measure of systolic and diastolic function. In preterm infants, elevated MPI' values during early postnatal life have been associated with adverse respiratory and cardiovascular outcomes, supporting its potential role as a marker of maladaptive transition, although its validation in this population remains limited (91,100,104).

Speckle tracking echocardiography (STE)

Two-dimensional STE enables angle-independent assessment of myocardial deformation and offers a more direct evaluation of myocardial mechanics. By quantifying strain and strain rate, STE provides insight into intrinsic myocardial function that is less influenced by translational motion and geometric assumptions than conventional measures (105,106).

Feasibility studies have demonstrated that STE can be reliably performed in neonatal populations, including extremely preterm infants, with good intra- and inter-observer reproducibility for global longitudinal strain of both ventricles (89,107). In the context of neonatal transition, strain-based parameters have been shown to detect early ventricular dysfunction even when conventional indices such as ejection fraction or FAC remain within normal ranges (91,108).

Assessment of RV deformation is of particular interest in extremely preterm infants, given the dominant role of the RV during early transition. Reduced RV longitudinal strain has been associated with adverse respiratory outcomes and pulmonary vascular disease, highlighting its potential value as an early marker of impaired cardiopulmonary adaptation, although supporting evidence remains uncertain and requires further validation (109).

Limitations and current role

Despite their promise, emerging echocardiographic techniques have important limitations. Both TDI and STE are influenced by loading conditions and HR, and their accuracy depends on image quality and operator expertise. In addition, the lack of universally accepted neonatal reference ranges and standardized acquisition protocols currently limits routine clinical implementation.

Accordingly, current consensus statements recommend that these techniques should be used primarily in research settings or as adjuncts to conventional echocardiography, rather than as standalone diagnostic tools (79,83). Nevertheless, their ability to detect early and subtle myocardial dysfunction supports their potential role in advancing physiological understanding of neonatal transition and for supporting future precision-based monitoring strategies.

In summary, when integrated with conventional echocardiography and interpreted physiologically, these techniques may enhance individualized assessment of cardiovascular adaptation in extremely preterm infants.

Cerebral monitoring during the transitional period

As discussed previously in this review, extremely preterm infants are at high risk of cerebral injury during the early postnatal period, reflecting the interplay between immature cerebrovascular regulation and rapidly evolving systemic and cardiac hemodynamics (70). Therefore, cerebral monitoring during that period therefore aims to provide real-time information on cerebral oxygenation and function, complementing cardiovascular assessment and enabling earlier identification of high-risk physiological states.

NIRS

NIRS allows continuous, non-invasive monitoring of regional cerebral oxygen saturation (CrSO₂) and provides a surrogate measure of the balance between cerebral oxygen delivery and consumption (110). In extremely preterm infants, cerebral NIRS values are influenced by partial pressure of carbon dioxide (pCO₂), systemic blood flow, hemoglobin concentration, arterial oxygenation, and shunt-related circulatory patterns (48,111).

During the transitional period, NIRS studies have demonstrated marked interindividual variability in cerebral oxygenation trajectories, reflecting heterogeneity in cardiovascular adaptation and cerebral vulnerability (34,112). Sustained periods of cerebral hypoxia or hyperoxia detected by NIRS have been associated with increased risk of IVH and NDI (113-116). Nevertheless, multicenter trials have failed to demonstrate an improvement in survival without brain injury with protocolized NIRS monitoring and specific treatment guidelines to ensure CrSO₂ values met normal reference values, although this approach has been shown to reduce cerebral hypoxia burden (113,117,118).

Beyond absolute values, NIRS enables dynamic assessment of the relationship between cerebral oxygenation and systemic hemodynamic variables. Loss of coupling between cerebral oxygenation and physiological stability may indicate increased vulnerability, even in the absence of overt systemic hypotension (119). However, interpretation remains challenging due to device-related variability, lack of standardized thresholds, and sensitivity to extracerebral signal contamination, particularly given the limited evidence in extremely preterm populations.

aEEG

aEEG, also known as cerebral function monitoring (CFM), provides continuous bedside assessment of cerebral electrical activity (120). In extremely preterm infants, early aEEG background patterns could reflect both brain maturation and the impact of antenatal and postnatal insults (121,122).

Abnormal aEEG patterns during the transitional period—including excessive discontinuity, burst suppression, or delayed development of sleep-wake cycling—have been associated with increased risk of IVH and adverse neurodevelopmental outcomes (123-125). Although aEEG does not directly measure cerebral perfusion, changes in electrical activity may represent the functional consequence of impaired oxygen or substrate delivery (126).

Importantly, aEEG provides complementary information to hemodynamic monitoring, although evidence supporting its integration into hemodynamic assessment in extremely preterm infants remains limited. While cardiovascular parameters and NIRS reflect upstream determinants of cerebral perfusion, aEEG may captures downstream functional brain response, providing an integrated view of cerebral well-being during early postnatal adaptation (127,128).

Clinical integration and limitations

Cerebral monitoring modalities should not be interpreted in isolation. NIRS and aEEG provide different but complementary information and are most informative when integrated with cardiovascular assessment and clinical context. In extremely preterm infants, this integrated approach could allow identification of dissociation between apparent systemic stability and cerebral vulnerability, a phenomenon that is particularly relevant during the transitional period (22,129).

Limitations include the absence of universally accepted reference ranges, susceptibility to technical and motion-related artifacts, and uncertainty regarding optimal intervention thresholds, particularly in the context of uncertain evidence in extremely preterm infants. Consequently, cerebral monitoring should be viewed as a tool to support individualized physiological interpretation rather than as a trigger for protocolized interventions (120).

Combined multimodal, cardiovascular and cerebral, monitoring during the transitional period

As discussed throughout this review, neonatal transition in extremely preterm infants is marked by profound instability, high interindividual variability, and a narrow margin between adaptation and decompensation. Cardiovascular performance, pulmonary vascular adaptation, and cerebral perfusion are closely interdependent, yet no single monitoring modality captures this complexity in isolation. Each modality provides complementary information with distinct strengths and limitations (Figure 2). This physiological interconnection provides the foundation for combined multimodal monitoring (CMM), in which cardiovascular and cerebral assessments are integrated to support individualized interpretation of the transitional process (22,130).

Figure 2 Strengths and limitations of commonly used monitoring modalities during the neonatal transitional period. Comparison of conventional bedside monitoring, NIRS, aEEG, and TNE, highlighting their respective advantages and limitations in extremely preterm infants during the transitional period. aEEG, amplitude-integrated electroencephalography; Cons, disadvantages; EEG, electroencephalography; NIRS, near-infrared spectroscopy; Pros, advantages; TNE, targeted neonatal echocardiography.

Experience from adult and pediatric critical care suggests that CMM can reduce major neurological complications during high-risk interventions by enabling earlier recognition of CBF abnormalities (131,132). Translating this approach to neonatal care, particularly in extremely preterm infants, remains an area of active investigation. Deshpande et al. (130) demonstrated that integration of TNE, NIRS, and aEEG during the first 72 hours of life is feasible and safe, providing an important proof of concept for early multimodal monitoring in this population. Subsequent investigation has begun to explore the clinical implications of such approaches. Lalitha et al. (133) evaluated a multimodal hemodynamic monitoring strategy incorporating TNE and NIRS during early transition. Although the intervention did not improve the primary composite outcome, it was associated with fewer severe hemodynamic derangements and a lower incidence of BPD. These findings suggest that the value of CMM may lie less in immediate modification of global indices and more in facilitating earlier recognition of maladaptive physiological trajectories. However, in the context of extremely preterm infants, many of these concepts remain hypothesis-generating and are based on physiological reasoning rather than direct outcome-based evidence.

Importantly, CMM should not be conceptualized as a protocol-driven intervention aimed at achieving predefined numerical targets. Rather, it supports physiology-based clinical reasoning, enabling interpretation of cardiovascular and cerebral signals within the broader context of antenatal conditioning, postnatal adaptation, and ongoing clinical evolution. In this sense, CMM augments, rather replaces, clinical judgment, allowing more nuanced differentiation between adaptive and maladaptive responses during transition (Figure 3).

Figure 3 Physiology-based interpretation of neonatal transition. Neonatal transition in extremely preterm infants involves interdependent cardiovascular, pulmonary, and cerebral adaptations shaped by antenatal conditioning and early postnatal events. CMM integrates conventional clinical parameters with TNE, cerebral oxygenation, and neurophysiological data to support physiology-based interpretation and clinical decision-making during this vulnerable period. CMM, combined multimodal monitoring; TNE, targeted neonatal echocardiography.

In the current era of artificial intelligence (AI), the increasing complexity and data density generated by CMM can be more effectively integrated and interpreted. AI-based analytic approaches may help synthesize heterogeneous physiological signals, identify clinically relevant patterns, and track trajectories over time. These tools may support more individualized interpretation of neonatal transition, but require validation before clinical implementation (134).

Clinical integration and limitations

Despite its potential, important considerations regarding integration, feasibility and interpretation remain that constrain the widespread clinical implementation of CMM in extremely preterm infants. First, its application must be considered in the context of the extreme fragility of this population. Infants at the lowest GAs require minimal handling during the first days of life to maintain physiological stability and reduce brain injury. The use of multiple monitoring devices may increase handling and interfere with routine care. However, this limitation may be mitigated by standardized nursing protocols that integrate monitoring tools while minimizing handling. Future feasibility studies could better define the safety and practicality of implementing these techniques in this vulnerable population.

Second, CMM is resource-intensive and requires advanced technology, specialized expertise, and multidisciplinary coordination. Its implementation is therefore more feasible in highly specialized centers and may be difficult to generalize to resource-limited settings. This raises important considerations regarding equity of access and the external validity of existing studies.

Third, although CMM enables simultaneous acquisition of multiple physiological signals, it generates large volumes of complex data. In the absence of standardized interpretive frameworks, this may result in a “data-rich but decision-poor” environment. Consequently, there is a risk that data are collected without clear guidance on how they should inform clinical decision-making. Future research should focus on developing standardized interpretive frameworks and identifying clinically meaningful multimodal patterns to support clinical interpretation.

Furthermore, current evidence is largely based on feasibility and short-term physiological outcomes studies, with uncertain impact on clinically meaningful endpoints such as survival or NDI. Consequently, CMM should be approached cautiously until outcome-based evidence is available.

Finally, ELGANs are often underrepresented in preterm cohorts, limiting the applicability of existing data to the most immature populations. This subgroup may exhibit distinct physiological vulnerabilities and may not respond to monitoring strategies in the same manner as more mature preterm infants.

Strengths and limitations of the review and available evidence

This narrative review and the available literature also present several limitations. First, as a non-systematic review, it does not follow a structured study selection or quality assessment process and may be subject to selection bias. In addition, ELGAN-specific evidence remains incompletely defined, with many physiological concepts and monitoring approaches extrapolated from studies in more mature populations. Heterogeneity in study design, monitoring modalities, and reported outcomes further complicates direct comparison across studies. Moreover, most studies focus on feasibility and short-term physiological parameters, rather than clinically meaningful outcomes.

Despite these limitations, this review provides an integrative synthesis of cardiovascular and cerebral physiology within a unified framework. By incorporating emerging concepts such as prematurity endotypes and multimodal monitoring, it aims to offer a clinically relevant, physiology-based perspective on neonatal transition in extremely preterm infants and to highlight key areas for future research.

Conclusions

The transition to extrauterine life is a highly vulnerable and qualitatively distinct process in extremely preterm infants, characterized by persistent RV dominance, incomplete pulmonary vascular adaptation, and immature cerebrovascular regulation. These features, together with marked biological heterogeneity, limit the applicability of uniform hemodynamic targets and support individualized, physiology-based approaches. While TNE and cerebral monitoring provide complementary real-time insights, their combined use in a structured monitoring model remains limited by the absence of standardized frameworks and outcome-based validation. Further research is needed to determine whether CMM improve meaningful clinical outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-26-0019/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-26-0019/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-26-0019/coif). The authors have no conflicts of interest to declare.

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