# Early echocardiographic predictors of death or early severe morbidity in extremely low gestational age neonates: a prospective study

Elisa Mosca, Lionel Moulis, Illies Ouhab, Arthur Gaudaire, Renaud Mesnage, Laurene Gautheyrou, Gilles Cambonie, Arthur Gavotto

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Elisa Mosca, Lionel Moulis, Illies Ouhab, Arthur Gaudaire, Renaud Mesnage, et al.. Early echocardiographic predictors of death or early severe morbidity in extremely low gestational age neonates: a prospective study. European Journal of Pediatrics, 2025, 184 (8), pp.508. 10.1007/s00431-025-06364-6. hal-05192478

HAL Id: hal-05192478

https://hal.science/hal-05192478v1

Submitted on 21 Feb 2026

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
Early echocardiographic predictors of death or early
severe morbidity in extremely low gestational age
neonates: a prospective study

Elisa Mosca ¹, Lionel Moulis ² ³, Illies Ouhab ¹ ⁴, Arthur Gaudaire ¹ ⁴, Renaud Mesnage ¹, Laurene Gautheyrou ¹, Gilles Cambonie ¹ ³, Arthur Gavotto ⁵ ⁶

¹ Department of Neonatal Medicine and Pediatric Intensive Care, Arnaud de Villeneuve Hospital, Montpellier University Hospital Centre, 371 Avenue du Doyen Giraud, 34295, Montpellier, France.

² Clinical Research and Epidemiology Unit, Montpellier University Hospital, 39 Avenue Charles Flahault, 34090, Montpellier, France.

³ Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Univ of Antilles, Univ Montpellier, INSERM, 60 Rue de Navacelles, 34394, Montpellier, EFS, France.

⁴ PhyMedExp, CNRS, INSERM, University of Montpellier, 371 Avenue du Doyen Giraud, 34295, Montpellier, France.

⁵ Department of Neonatal Medicine and Pediatric Intensive Care, Arnaud de Villeneuve Hospital, Montpellier University Hospital Centre, 371 Avenue du Doyen Giraud, 34295, Montpellier, France. a-gavotto@chu-montpellier.fr.

⁶ PhyMedExp, CNRS, INSERM, University of Montpellier, 371 Avenue du Doyen Giraud, 34295, Montpellier, France. a-gavotto@chu-montpellier.fr.

**Keywords:**

Death; ELGAN; Echocardiography; Severe morbidity.
# Abstract

**Purpose:**

To identify early echocardiographic markers predictive of death or early severe morbidity in extremely low gestational age neonates (ELGANs).

**Methods and results:**

Prospective observational single-centre study in level 3 neonatal intensive care unit, Montpellier University Hospital, France. Fifty live-born ELGANs (< 28 weeks' gestational age) admitted between January 2023 and January 2024, excluding major malformations and congenital heart disease. Neonatologist-performed echocardiography (NPE) at 12 ± 12 h (Day 1) and 72 ± 12 h (Day 3), assessing biventricular function, ductal flow, and systemic output.

**Primary outcome:**

Death or early severe morbidity (severe intraventricular haemorrhage or bronchopulmonary haemorrhage). Associations between echocardiographic parameters and the composite outcome were assessed using ROC curves and 1:1 propensity score matching (sex, birthweight, gestational age). The composite outcome occurred in 21/50 infants (42%). On Day 1, lower tricuspid annular plane systolic excursion (TAPSE < 4.8 mm) and right ventricular velocity-time integral (RV VTI < 7.8 cm) were independently associated with the outcome (AUCs: 0.76 and 0.83, respectively). On Day 3, lower ductal flow velocities were significantly associated with adverse outcomes, suggesting persistent hemodynamically significant PDA. Other parameters (e.g., left ventricular function or systemic output) were not predictive after adjustment.

**Conclusion:**

Early echocardiographic indicators of right ventricular dysfunction (TAPSE, RV VTI) are associated with mortality or early severe morbidity in ELGANs. These markers may reflect myocardial immaturity and elevated pulmonary vascular resistance, underscoring the importance of heart-lung interaction in early neonatal care. Further multicentre studies are needed to confirm these findings and refine targeted hemodynamic management strategies.

**What is known: •**

Extremely low gestational age neonates (ELGANs) are at high risk of early death and severe morbidity due to cardiovascular immaturity • Neonatologist-performed echocardiography (NPE) is increasingly used for bedside hemodynamic assessment in preterm infants, but robust early prognostic markers are still lacking What is new: • This study identifies two early echocardiographic parameters-TAPSE < 4.8 mm and RV VTI < 7.8 cm on day 1-as significantly associated with death or early severe morbidity in ELGANs • These findings support the incorporation of early targeted echocardiographic assessment of right ventricular function into standard care for ELGANs.
What is known:

* Extremely low gestational age neonates (ELGANs) are at high risk of early death and severe morbidity due to cardiovascular immaturity

* Neonatologist-performed echocardiography (NPE) is increasingly used for bedside hemodynamic assessment in preterm infants, but robust

early prognostic markers are still lacking

What is new:

* This study identifies two early echocardiographic parameters—TAPSE< 4.8 mm and RV VTI< 7.8 cm on day 1—as significantly associated

with death or early severe morbidity in ELGANs

* These findings support the incorporation of early targeted echocardiographic assessment of right ventricular function into standard care for ELGANs

Introduction

Extremely low gestational age neonates (ELGANs), born before 28 weeks' gestational age (GA) represent approximately 0.4% to 0.7% of births in high-income countries [1]. In these infants, immaturity of the cardiovascular system can lead to severe systemic hypotension or low systemic blood flow in the first days of life, which are both linked to high mortality and morbidity rates [2]. In addition, sepsis or persistence of the ductus arteriosus (PDA) can threaten this fragile hemodynamic state [3, 4]. Arterial blood pressure (MAP) is the most commonly used parameter to monitor haemodynamic in ELGANs [5-9]. Early isolated arterial hypotension affects nearly 50% of ELGANs, but its association with mortality or severe morbidity is controversial [7]. Blood pressure and other clinical markers such as heart rate, capillary refill time and urine output are indices of systemic perfusion, but their reliability is insufficient for accurate assessment of circulatory function in these patients.

Neonatologist-performed echocardiography (NPE) is a valuable non-invasive technique for estimating cardiac output in critically ill neonates, providing insights into the underlying pathophysiological mechanisms of circulatory failure [10]. Observational studies, at the scale of a country or a high-performance centre, have suggested the impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes [11, 12]. Practice guidelines now exist for NPE [13], and in 2020, the ESPNIC (European Society of Paediatric and Neonatal Intensive Care) validated a training program to provide hemodynamic information to facilitate clinical decision-making [14].
Factors contributing to impaired circulation in ELGANS are multiple, including abnormal pulmonary or systemic vascular tone, intra- and extracardiac shunts, and cardiac dysfunction. Recognition of the hemodynamic profile is essential for the clinician to choose the best therapeutic options [15].

We hypothesized that rigorous hemodynamic investigation would identify the pathophysiological mechanisms underlying early hemodynamic failure in ELGANS. The objective of this study was to individualize echocardiographic parameters, at an optimal timepoint during the first postnatal week, allowing prediction of death or early severe morbidity.

# Materials and methods

## Study design and population

This prospective observational study was conducted between January 2023 and January 2024 in the level 3 neonatal intensive care unit (NICU) of Montpellier University Hospital, France. All live-born ELGANS (born before 28 weeks' GA) were eligible for this study if they were actively managed in the delivery room and admitted to the NICU. Exclusion criteria were congenital heart disease (other than small to moderate patent foramen oval and PDA) and major congenital malformation requiring neonatal surgery.

## Hemodynamic policies during the study period

Heart rate was recorded continuously, and arterial blood pressure was measured hourly within the first 72 h after birth by oscillometric method, using appropriately sized cuffs, while the infant was in a quiet state. Low mean arterial blood pressure (MABP) was defined as a minimal MABP (mmHg)<72 weeks' GA [6, 16]. The physician in charge of the patient made the decision to treat and the treatment modalities.

The management of the PDA primarily involved early selective treatment, guided by echocardiography, using ibuprofen for large PDAs[17]. We specify that the randomised controlled trial TREOCAPA (Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen vs placebo) was ongoing during the study period [18]. Most of the infants included in this study were also enrolled in TREOCAPA.
## NPE procedure

NPE were performed by 5 neonatologists (EM, RM, LG, GC, AG) with advanced hemodynamic training [13, 19]. Each clip or photograph recorded on the echocardiograph was archived and validated by one of the investigators, also qualified in paediatric cardiology (AG). Studies were conducted using a Phillips CX50, with the S12-4 probe. They included standard apical 4-chamber, 5-chamber, parasternal and subcostal views to assess systemic and pulmonary hemo- dynamics, left and right ventricular function, and to characterize shunts [13]. The first NPE was performed 12±12 h after birth (i.e. "Day-1 echocardiography"), and the second 72±12 h after birth (i.e. "Day-3 echocardiography").

## Data collection

Perinatal data for each infant were collected prospectively in a database created in 2003 for neonates born<33 weeks' GA and/or with a birthweight <1500 g. The database uses a predetermined form with detailed definitions for each item. More than 150 variables were assessed for each infant concerning prenatal history and the neonatal period throughout the hospital stay, up to the patient's discharge or death. The Clinical Risk Index for Babies II (CRIB II)[20], SF ratio (SpO2/FiO2) and Oxygenation Saturation Index (OSI)[21] was calculated for each included infant.

NPE parameters included, for the left ventricle (LV), diastolic and systolic internal diameters (LVIDd, LVIDs), diastolic and systolic posterior wall thickness (LVPWd, LVPWs), diastolic and systolic interventricular septum thickness (IVSd, IVSs), ejection fraction (LVEF), end-systolic wall stress (LVESWS), outflow tract diameter, velocity time integral (LV VTI), and mean aortic velocity. For the right ventricle, they included pulmonary artery diameter, VTI at the level of the pulmonary valve (RV VTI), and tricuspid annular plane systolic excursion (TAPSE). For the superior vena cava (SVC), diameter and VTI were measured. For PDA, internal diameter, maximum and minimal velocities, left atrium to aortic root ratio (LA/Ao) and right pulmonary artery end-diastolic velocity (EDV) were recorded.

Three to five consecutive Doppler waveforms were recorded to measure VTI and mean velocity. Output from the left ventricle output (LVO), the right ventricle output (RVO), and the superior vena cava (SVCO) were calculated using the following formula [0.785×(diameter)2 ×VTI ×heart rate] and expressed in ml/kg/min [13].
**Outcome**

The primary outcome was defined as death during neonatal hospitalisation or early severe morbidity during the first neonatal week. Early severe morbidity was defined as the occurrence of at least one of the following conditions during the first postnatal week: (a) bronchopulmonary haemorrhage (BPH) characterized by the sudden discharge of bloody fluid from the upper respiratory tract [22]; (b) grade 3 to 4 intra-ventricular haemorrhage (IVH) according to Volpe's classification. [23].

**Statistical analysis**

Values are expressed as numbers (%) or mean± standard deviation (SD) or median [interquartile—IQR]; P< 0.05 was considered statistically significant. Quantitative variables were compared using the Student's t-test or Wilcoxon- Mann-Whitney tests, according to their distribution. Comparisons for qualitative variables used Chi-squared or Fisher test, as appropriate.

Receiver operating characteristic (ROC) curves were used to evaluate the ability of the echocardiographic parameters recorded to predict death or early severe morbidity.

To address potential biases in the primary outcome (survival without morbidity vs. death or early severe morbidity), a 1:1 propensity score matching without replacement was performed. Propensity scores were calculated using a logistic regression model including the following normalized covariates: sex, birth weight and gestational age. Mean and frequency imputations were used in case of covariate missing data. Patients within the survival without morbidity group were matched to patients from the death or early severe morbidity group by nearest neighbour matching with a calliper value of 0.2 of the standard deviation of the logs of the propensity score. Standardized mean differences (SMD) were calculated to compare baseline characteristics after matching. A post-matching SMD below 0.2 was considered an acceptable difference.

Statistical analysis was performed with EasyMedStat version 3.42 software (www.easymedstat.com, Paris, France).
## Ethical considerations

The study was conducted in compliance with Good Clinical Practice (GCP) guidelines and the principles of the Declaration of Helsinki. The Institutional Review Board of Montpellier University Hospital approved the study (IRB- MTP_2023_01_202201260). In accordance with national legislation and institutional requirements, written informed consent to participate in this study was not required from the participants or the participant's legal guardians.

# Results

## Study population

Sixty-one patients were eligible during the study period. One newborn infant was excluded due to the presence of total abnormal pulmonary venous return. NPE was not performed in 10 infants: (a) 3 premature deaths within the first post-natal day, (b) 7 investigator's unavailability (Supplementary Fig. 1-Flowchart).

Fifty patients were included. The mean gestational age was 25.5 ±1.1 weeks' GA, with a majority of boys (sex ratio 1.4), and mean birth weight of 792 ± 166 g, including 3 small for gestational age. The primary outcome was observed in 21 patients (42%), including 14 who died, at a median age of 13.5 [8.5-21.5] days, and 7 who developed severe morbidity. The causes of death were withdrawal of life-sustaining treatment for severe IVH (n = 9), circulatory failure with multiple organ dysfunction syndrome (n= 4), and severe respiratory failure (n = 1). The early severe morbidities observed among the 36 survivors were severe IVH (n = 5) and BPH (n = 2). The differences between groups according to occurrence of the primary outcome are shown in Table 1 (and Supplementary Tables 2 & 3). Death or early severe morbidity was associated with male sex, lower GA and head circumference, higher CRIB II score, lower SF ratio and higher OSI. No difference was found between the groups regarding early treatment of arterial hypotension or treatment of the ductus arteriosus with ibuprofen.
<table><caption>**Table 1** Comparison of neonatal characteristics according to the death or early severe morbidity</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Death or early severe morbidity</th><th rowspan="2">P-value</th></tr><tr><th>No (n=29)</th><th>Yes (n=21)</th></tr></thead><tbody><tr><td colspan="4"><strong>Neonatal characteristics</strong></td></tr><tr><td>Gestational age (weeks)</td><td>26.0 [25.0-27.0]</td><td>25.0 [23.0-27.0]</td><td>&lt;0.01</td></tr><tr><td>Inborn</td><td>27 (93.1)</td><td>18 (85.7)</td><td>0.64</td></tr><tr><td>Male</td><td>13 (44.8)</td><td>16 (76.2)</td><td>0.04</td></tr><tr><td>Birth weight (grams)</td><td>831 ± 163</td><td>739 ± 163</td><td>0.06</td></tr><tr><td>Small-for-gestational-age</td><td>2 (6.9)</td><td>1 (4.8)</td><td>1</td></tr><tr><td>Birth height (cm)</td><td>33.3 ± 2.5</td><td>33.1 ± 2.3</td><td>0.77</td></tr><tr><td>Birth head circumference (cm)</td><td>23.2 ± 1.5</td><td>22.4 ± 1.4</td><td>0.04</td></tr><tr><td>5-min Apgar score</td><td>7.0 [3.0-10.0]</td><td>8.0 [1.0-10.0]</td><td>0.70</td></tr><tr><td>Umbilical arterial pH</td><td>7.30 [7.15-7.41]</td><td>7.34 [6.95-7.41]</td><td>0.22</td></tr><tr><td>Umbilical lactate (mmol/L)</td><td>2.5 [1.6-9.0]</td><td>2.8 [1.0-22.0]</td><td>0.59</td></tr><tr><td>CRIB II score</td><td>10.4 [8.0-13.0]</td><td>12.5 [7.0-20.0]</td><td>&lt;0.01</td></tr><tr><td>Surfactant administration</td><td></td><td></td><td></td></tr><tr><td>0</td><td>8 (27.6)</td><td>1 (4.8)</td><td>0.03</td></tr><tr><td>1</td><td>15 (51.7)</td><td>9 (42.9)</td><td>-</td></tr><tr><td>&gt;1</td><td>6 (20.7)</td><td>11 (52.4)</td><td>-</td></tr></tbody></table>

Legend: CRIB II, Clinical Risk Index for Babies II

Values are presented as numbers with percentages (%) or mean ± SD or median [IQR]

<table><caption>**Table 2** Day 1. Comparison of echocardiographic parameters according to the occurrence of death and/or severe morbidity after 1:1 propensity score matching for sex, birth weight, and gestational age</caption><thead><tr><th rowspan="2">Echography parameters</th><th colspan="2">Death or early severe morbidity</th><th rowspan="2">P-value</th></tr><tr><th>No (N=12)</th><th>Yes (N=12)</th></tr></thead><tbody><tr><td colspan="4"><strong>LV parameters</strong></td></tr><tr><td>LVID<sub>diameter</sub> (mm)</td><td>10.1 ± 1.7</td><td>9.9 ± 1.9</td><td>0.85</td></tr><tr><td>LV ejection fraction (%)</td><td>72.0 ± 11.9</td><td>67.8 ± 7.9</td><td>0.34</td></tr><tr><td>Mean Ao velocity (cm/s)</td><td>36.4 ± 8.9</td><td>33.6 ± 8.2</td><td>0.46</td></tr><tr><td>LV VTI (cm)</td><td>7.2 ± 2.5</td><td>6.6 ± 1.7</td><td>0.52</td></tr><tr><td>LV output (ml/kg/min)</td><td>229 ± 83</td><td>183 ± 46</td><td>0.11</td></tr><tr><td>Left atrial diameter (mm)</td><td>7.4 ± 1.6</td><td>6.9 ± 1.1</td><td>0.39</td></tr><tr><td colspan="4"><strong>RV parameters</strong></td></tr><tr><td>TAPSE (mm)</td><td>5.4 ± 0.9</td><td>4.1 ± 0.8</td><td>&lt;0.01</td></tr><tr><td>RV VTI (cm)</td><td>8.5 ± 0.8</td><td>6.4 ± 1.3</td><td>&lt;0.01</td></tr><tr><td>RV output (ml/kg/min)</td><td>305 ± 64</td><td>241 ± 84</td><td>0.05</td></tr><tr><td colspan="4"><strong>SVC parameters</strong></td></tr><tr><td>SVC VTI (cm)</td><td>11.2 [6.8-16.0]</td><td>8.4 [5.8-17.6]</td><td>0.26</td></tr><tr><td>SVC output (ml/kg/min)</td><td>110 [42-204]</td><td>100 [67-394]</td><td>0.70</td></tr><tr><td colspan="4"><strong>PDA parameters</strong></td></tr><tr><td>Closed duct (n/%)</td><td>1 (8.3)</td><td>1 (8.3)</td><td>1</td></tr><tr><td>Diameter (mm)</td><td>1.7 ± 0.7</td><td>1.7 ± 0.8</td><td>0.98</td></tr><tr><td>Max velocity (cm/s)</td><td>180 [85-224]</td><td>117 [71-247]</td><td>0.21</td></tr><tr><td>Min velocity (cm/s)</td><td>125 [20-150]</td><td>48 [-50-210]</td><td>0.30</td></tr><tr><td>EDV rPA (cm/s)</td><td>18.2 ± 7.5</td><td>18.8 ± 13.7</td><td>0.90</td></tr></tbody></table>

Legend: EDV, end-diastolic velocity; LV, left ventricular; LVID, LV internal diameter; PDA, patent ductus arteriosus; RV, right ventricular; SVC, superior vena cava; TAPSE, tricuspid annular plane systolic excursion; VTI, velocity time integral.

Values are presented as numbers with percentages (%) or mean ± SD or median [IQR]
# Echocardiography

Out of the 50 patients included, only one of two imaging sessions could be performed for 11 patients, and 2 deaths occurred between day 1 and day 3, resulting in a total of 87 echocardiographies being analysed (Supplementary Fig. 1).

All echocardiographic data collected are available in Supplementary Table 3 (day 1) and Supplementary Table 3 (day 3).

<table><caption>**Table 3** Day 3. Comparison of echocardiographic parameters according to the occurrence of death and/or severe morbidity after 1:1 propensity score matching for sex, birth weight, and gestational age</caption><thead><tr><th rowspan="2">Echography parameters</th><th colspan="2">Death or early severe morbidity</th><th rowspan="2">P-value</th></tr><tr><th>No (N=12)</th><th>Yes (N=12)</th></tr></thead><tbody><tr><td><strong>LV parameters</strong></td><td></td><td></td><td></td></tr><tr><td>LVID<sub>diastole</sub> (mm)</td><td>11.0±1.9</td><td>11.4±1.4</td><td>0.64</td></tr><tr><td>LV ejection fraction (%)</td><td>71.0±7.7</td><td>71.1±9.3</td><td>0.98</td></tr><tr><td>Mean Ao velocity (cm/s)</td><td>46.8±12.0</td><td>44.2±7.9</td><td>0.59</td></tr><tr><td>LV VTI (cm)</td><td>8.5±1.8</td><td>8.3±1.4</td><td>0.79</td></tr><tr><td>LV output (ml/kg/min)</td><td>282 [160–406]</td><td>260 [183–306]</td><td>0.60</td></tr><tr><td>Left atrial diameter (mm)</td><td>8.1±1.4</td><td>8.1±1.4</td><td>0.96</td></tr><tr><td><strong>RV parameters</strong></td><td></td><td></td><td></td></tr><tr><td>TAPSE (mm)</td><td>5.2±0.9</td><td>5.2±0.5</td><td>0.87</td></tr><tr><td>RV VTI (cm)</td><td>8.9±1.1</td><td>8.5±1.9</td><td>0.64</td></tr><tr><td>RV output (ml/kg/min)</td><td>365±49</td><td>331±120</td><td>0.44</td></tr><tr><td><strong>SVC parameters</strong></td><td></td><td></td><td></td></tr><tr><td>SVC VTI (cm)</td><td>16.1±4.4</td><td>11.3±4.5</td><td>0.07</td></tr><tr><td>SVC output (ml/kg/min)</td><td>180 [91–499]</td><td>183 [88–240]</td><td>0.49</td></tr><tr><td><strong>PDA parameters</strong></td><td></td><td></td><td></td></tr><tr><td>Closed duct (n/%)</td><td>3 (33.3)</td><td>1 (10.0)</td><td>0.30</td></tr><tr><td>Diameter (mm)</td><td>1.4 [0–2.6]</td><td>1.8 [0–3.1]</td><td>0.66</td></tr><tr><td>Max velocity (cm/s)</td><td>204±31</td><td>132±59</td><td>&lt;0.01</td></tr><tr><td>Min velocity (cm/s)</td><td>120±35</td><td>39±63</td><td>0.02</td></tr><tr><td>EDV rPA (cm/s)</td><td>19.4±9.1</td><td>20.9±12.8</td><td>0.78</td></tr></tbody></table>

Legend: EDV, end-diastolic velocity; LV, left ventricular; LVID, LV internal diameter; PDA, patent ductus arteriosus; RV, right ventricular; SVC, superior vena cava; TAPSE, tricuspid annular plane systolic excursion; VTI, velocity time integral

Values are presented as numbers with percentages (%) or mean ± SD or median [IQR]

# Association between echocardiographic parameters at day 1 and death or early severe morbidity

On day 1, several echocardiographic parameters were associated with occurrence of death or early severe morbidity, including lower values for left atrial diameter, TAPSE, right ventricular VTI, minimal and maximal PDA velocities, and mean aortic velocity (Supplementary Table 5). After 1:1 propensity score matching for sex, birth weight, and gestational age (all standardised mean differences (SMD)< 0.2), only lower TAPSE and right ventricular VTI remained significantly associated (Table 2). The area under the ROC curve (AUC) for TAPSE was 0.76 (95% CI: 0.62–0.91, P< 0.01). A cut-off value < 4.8 mm yielded a sensitivity of 84%, specificity of 65%, positive predictive value of 64%, and negative
predictive value of 85%. The AUC for right ventricular VTI was 0.83 (95% CI: 0.69-0.97, P<0.01). A cut-off value of < 7.8 cm had a sensitivity of 90%, specificity of 75%, positive predictive value of 74%, and negative predictive value of 90% (Fig. 1).

**Fig. 1** Receiver operating characteristic (ROC) curves for RV VTI and TAPSE measured on Day 1 to predict death or early severe morbidity in ELGANs. For right ventricular velocity time integral (RV VTI), the optimal cut-off was 7.8 cm, with an AUC of 0.83 (95% CI: 0.69-0.97, P<0.01), sensitivity 90%, specificity 75%, positive predictive value 74%, and negative predictive value 90%. For tricuspid annular plane systolic excursion (TAPSE), the optimal cut-off was 4.8 mm, with an AUC of 0.76 (95% CI: 0.62-0.91, P<0.01), sensitivity 84%, specificity 65%, positive predictive value 64%, and negative predictive value 85%. Abbreviations: AUC, area under the curve

<figure><img src="image_3.png" /></figure>

## Association between echocardiographic parameters at day 3 and death or early severe morbidity

On day 3, echocardiographic parameters associated with occurrence of death or early severe morbidity were lower right ventricular VTI, minimal and maximal PDA velocities, and PDA closure (Supplementary Table 5). After 1:1 propensity score matching for sex, birth weight, and gestational age (all SMD< 0.2), only lower ductal velocities remained significantly associated (Table 3).

## Discussion

This prospective study found significant associations between death or early severe morbidity and some echocardiographic parameters collected on days 1 and 3. These findings highlight the critical importance of early hemodynamic assessment in this vulnerable population [11].
Lower TAPSE and right ventricular VTI suggest that inadequate right ventricular adaptation on day 1 may be a key contributor to death or early severe morbidity in ELGANs. In the context of extreme prematurity, pulmonary disease and associated pulmonary hypertension (PH) are common complications, as underdeveloped lungs and elevated pulmonary vascular resistance lead to unstable pulmonary circulation [24]. Clinical indicators in our cohort were consistent with this assumption, as the most severely affected infants had the lowest gestational ages and birth-weights, and required more frequently invasive mechanical ventilation and exogenous surfactant [24]. Previous studies have identified TAPSE as a reliable marker of RV function, with lower values often associated with poor outcomes [25]. Decreased TAPSE and reduced RV VTI may together indicate impaired RV systolic function due to increased RV afterload, ie, persistent PH [26]. Indeed, studies have shown that RV VTI tends to decline as pulmonary vascular resistance rises, which aligns with our findings. [27] RV VTI is a simple method for assessing pulmonary blood flow at bedside. [28] It may offer a more accurate estimate than RV cardiac output, as it does not require measuring the pulmonary artery cross-sectional area, a parameter prone to significant error, since inaccuracies in diameter measurements are squared. Recently, a team has highlighted a correlation between impaired echocardiographic right ventricular performance (TAPSE, right ventricular global longitudinal strain, RV isovolumic relaxation time, RV myocardial performance index) and adverse neurological outcomes. This team linked cerebral blood flow to RV output [29]. Our study provides cut-off values for TAPSE and RV VTI, which may help alert clinicians to the risk of poorer survival, driven by persistent PH [30]. Alternatively, low TAPSE and RV VTI values may also indicate intrinsic RV dysfunction. Foetal myocardium studies have found structural, functional, and sympathetic innervation immaturity compared to the adult myocardium [31, 32], but specific research on the right ventricle remains limited. There is a lack of effective therapies in ELGANS with hypoxemic respiratory failure and PH. Notably, the role of inhaled nitric oxide (iNO) and other pulmonary vasodilators for PH treatment remains controversial [33]. While iNO lowers pulmonary vascular resistance and improves systemic perfusion [34], its use must be carefully targeted, as it may exacerbate left-to-right shunting through the PDA. Milrinone, which improves inotropy and promotes vasodilation, has shown variable efficacy in treating PH and is best considered an adjunctive therapy [35, 36].

The association between death or early severe morbidity and lower ductal velocities on echocardiography performed at day 3 is consistent with the potential modulator role of a hemodynamically significant PDA on these outcomes [12]. Low velocities correspond to large PDAs, associated with increase in odds of death or severe morbidity compared with neonates without PDA [37]. High velocities, usually>2 m/s, correspond to closed or closing patterns at such postnatal age [38]. The current literature does not support a definitive benefit of any specific PDA management strategy—whether active or conservative, medical or surgical [39]. Several observational studies, however, suggest that early systematic echocardiographic assessment and ultrasound-targeted PDA treatment may improve survival and reduce severe morbidity at discharge [11], even in extremely preterm infants born at 22–23 weeks’ GA [12]. Management decisions regarding PDA should rely on echocardiographic expertise but also take into account the infant’s overall clinical trajectory including respiratory, hemodynamic, nutritional, and metabolic status [40].
While the results of this observational study highlight the association between some echocardiographic parameters and infants' outcomes, daily NPE practice cannot be reduced to the search for only these critical parameters. Echocardiographic data are interdependent on each other and the aim of NPE training is to enable clinicians to interpret these data, for an understanding of the underlying pathophysiology and individualized adjustment of the treatment strategy [41]. Indeed, left ventricular function parameters such as LVEF and mean aortic velocity may be secondarily affected by severe PH, and influenced by interactions between the right and the left ventricle. [42] In the presence of a PDA, assessment of regional circulations is important to infer on hemodynamic significance of the shunt [43], and SVC evaluation appears to be the most reliable indicator of systemic blood flow. [44] Larger-scale studies are needed to establish normative reference values for all echocardiographic parameters and to support randomised controlled trials evaluating therapies adapted to specific hemodynamic profiles.

## Study limitations

Our study had several limitations. Firstly, the small sample size limits the generalisability of the results. Secondly, the difficulty of using large multivariate logistic regression models to account for confounding factors. However, we used propensity score matching based on important prognostic factors for death or early severe morbidity in this population, enabling us to balance the characteristics of the groups to be compared and to assess the association of echocardiographic parameters on the outcome independently. Thirdly, the presence of unmeasured confounding factors (such as variations in ELGAN clinical management) could have influenced the results. As with any observational, single-centre study, the relationships between patient characteristics and outcomes are hypothetical, requiring great caution for results interpretation.

Unlike some observatories, we included bronchopulmonary haemorrhage among the criteria of severe morbidity, given the established link between this event and PDA in ELGANs [17]. It occurred as a single event in only one patient.
# Conclusion

This prospective serial study using NPE in ELGAN patients highlights the critical importance of certain hemodynamic parameters in this vulnerable population. In particular, markers of right ventricular dysfunction, such as TAPSE and RV IVT, reflect underlying myocardial immaturity, potentially exacerbated by increased pulmonary vascular resistance due to respiratory disease. This heart-lung interaction occurring since the first postnatal day may emerge as a crucial, but yet underexplored factor, in neonatal care. Further studies, involving larger multicentre cohorts, are needed to validate these results and confirm their reproducibility in this population.

**Author Contributions** Study concept and design:

EM, AG Drafting of the manuscript: EM, GC, AG Statistical analysis: LM, AG Critical revision of the manuscript for important intellectual content: all.

**Funding**

This work was supported by the Montpellier University Hospital, France.

**Data availability**

No datasets were generated or analysed during the current study.

**Declarations**

**Competing interests**

The authors declare no competing interests.
References

1. Taylor GL, O'Shea TM (2022) Extreme prematurity: Risk and resiliency. Curr Probl Pediatr Adolesc Health Care 52:101132. https://doi.org/10.1016/j.cppeds.2022.101132

2. Barrington KJ (2008) Hypotension and shock in the preterm infant. Semin Fetal Neonatal Med 13:16-23. https://doi.org/10.1016/j.siny.2007.09.002

3. Stoll BJ, Hansen NI, Sánchez PJ et al (2011) Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics 127:817-26. https://doi.org/10.1542/peds.2010-2217

4. Singh Y, Fraisse A, Erdeve O et al (2020) Echocardiographic diagnosis and hemodynamic evaluation of patent ductus arteriosus in extremely low gestational age newborn (ELGAN) infants. Front Pediatr. https://doi.org/10.3389/fped.2020.573627

5. Durrmeyer X, Marchand-Martin L, Porcher R et al (2017) Abstention or intervention for isolated hypotension in the first 3 days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study. Arch Dis Child Fetal Neonatal Ed 102:490-496. https://doi.org/10.1136/archdischild-2016-312104

6. Barrington KJ, Janaillac M (2016) Treating hypotension in extremely preterm infants the pressure is mounting. Arch Dis Child Fetal Neonatal Ed 101:F188-189. https://doi.org/10.1136/ archdischild-2015-309814

7. Aldana-Aguirre JC, Deshpande P, Jain A et al (2021) Physiology of Low Blood Pressure During the First Day After Birth Among Extremely Preterm Neonates. J Pediatr 236:40-46.e3. https://doi.org/10.1016/j.jpeds.2021.05.026

8. Kluckow M (2018) The pathophysiology of low systemic blood flow in the preterm infant. Front Pediatr 6:29. https://doi.org/10.3389/fped.2018.00029
9. El-Khuffash AF, McNamara PJ (2011) Neonatologist-performed functional echocardiography in the neonatal intensive care unit. Semin Fetal Neonatal Med 16:50-60. https://doi.org/10.1016/j. siny.2010.05.001

10. Singh Y (2022) Use of echocardiography in the neonatal intensive care unit. Paediatr Child Health 32:351-356. https://doi.org/10.1016/j.paed.2022.07.005

11. Rozé J-C, Cambonie G, Marchand-Martin L et al (2015) Association between early screening for patent ductus arteriosus and in-hospital mortality among extremely preterm infants. JAMA 313:2441. https://doi.org/10.1001/jama.2015.6734

12. Giesinger RE, Hobson AA, Bischoff AR et al (2023) Impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes in “22-23” week and “24-26” infants. Semin Perinatol 47:151721. https://doi.org/10.1016/j.semperi.2023.151721

13. McNamara PJ, Jain A, El-Khuffash A et al (2024) Guidelines and recommendations for targeted neonatal echocardiography and cardiac point-of-care ultrasound in the neonatal intensive care unit: an update from the American Society of Echocardiography. J Am Soc Echocardiogr 37:171-215. https://doi.org/10.1016/j.echo.2023.11.016

14. Singh Y, Tissot C, Fraga MV et al (2020) International evidence-based guidelines on point of care ultrasound (POCUS) for critically ill neonates and children issued by the POCUS working group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Crit Care 24:65. https://doi.org/10.1186/s13054-020-2787-9

15. McNamara PJ, Barker P, Jain A et al (2021) Towards use of POCUS to evaluate hemodynamics in critically ill neonates: caution before adoption in this population. Crit Care 25:92. https://doi.org/10.1186/s13054-020-03394-4

16. Development of audit measures and guidelines for good practice in the management of neonatal respiratory distress syndrome. Report of a Joint Working Group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians. Arch Dis Child. 1992;67:1221-7. https://doi.org/10.1136/adc.67.10_spec_no.1221
17. Rozé J-C, Cambonie G, Le Thuaut A et al (2021) Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial. J Pediatr 233:33-42.e2.
https://doi.org/10.1016/j.jpeds.2020.12.008

18. Ursino M, Alberti C, Cambonie G, et al. (2024) TREOCAPA: Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen. Statistical analysis plan for the ran- domized phase III group sequential trial

19. Mertens L, Seri I, Marek J, Writing Group of the American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC) et al (2011) Targeted neonatal echocardiography in the neonatal intensive care unit: practice guidelines and recommendations for training. J Am Soc Echocardiogr 24:1057-78.
https://doi.org/10.1016/j.echo.2011.07.014

20. Parry G, Tucker J, Tarnow-Mordi W (2003) CRIB II: an update of the clinical risk index for babies score. Lancet 361:1789-1791. https://doi.org/10.1016/S0140-6736(03)13397-1

21. De Luca D, van Kaam AH, Tingay DG et al (2017) The montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity. Lancet Respir Med 5:657-666. https://doi.org/10.1016/S2213-2600(17)30214-X

22. Sahussarungsi S, Lapointe A, Villeneuve A et al (2025) Pulmonary hemorrhage in premature infants: pathophysiology risk factors and clinical management. Biomedicines 13:1744. https://doi.org/10.3390/biomedicines13071744

23. Papile LA, Burstein J, Burstein R et al (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 92:529-534. https://doi.org/10.1016/s0022-3476(78)80282-0

24. Arjaans S, Zwart EAH, Ploegstra M-J et al (2018) Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: a systematic review and meta- analysis. Paediatr Perinat Epidemiol 32:258-267. https://doi.org/10.1111/ppe.12444
25. Méndez-Abad P, Zafra-Rodríguez P, Lubián-López S et al (2020) Myocardial function maturation in very-low-birth weight infants and development of bronchopulmonary dysplasia. *Front Pediatr.* https://doi.org/10.3389/fped.2019.00556

26. Arjaans S, Zwart EAH, Roofthooft M et al (2021) Pulmonary hypertension in extremely preterm infants: a call to standardize echocardiographic screening and follow-up policy. *Eur J Pediatr* 180:1855–1865. https://doi.org/10.1007/s00431-021-03931-5

27. Kouzu H, Nakatani S, Kyotani S et al (2009) Noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hypertension. *Am J Cardiol* 103:872–876. https://doi.org/10.1016/j.amjcard.2008.11.039

28. Koestenberger M, Avian A, Grangl G et al (2016) Right ventricular outflow tract velocity time integral (RVOT VTI) and tricuspid regurgitation velocity/RVOT VTI ratio in pediatric pulmonary hypertension. *Int J Cardiol* 212:274–276. https://doi.org/10.1016/j.ijcard.2016.03.111

29. Oikonomopoulou N, Rodriguez-Castaño MJ, Corredera A, et al. (2025) Extremely preterm infants with adverse neuro-logical outcome present more frequently impaired right ventricular performance. *Pediatr Res.* https://doi.org/10.1038/s41390-025-03959-5

30. Arjaans S, Fries MWF, Schoots MH et al (2022) Clinical Significance of Early Pulmonary Hypertension in Preterm Infants. *J Pediatr* 251:74-81.e3. https://doi.org/10.1016/j.jpeds.2022.07.039

31. Friedman WF (1972) The intrinsic physiologic properties of the developing heart. *Prog Cardiovasc Dis* 15:87–111. https://doi.org/10.1016/0033-0620(72)90006-0

32. Anderson PAW (1989) Maturation and cardiac contractility. *Cardiol Clin* 7:209–225. https://doi.org/10.1016/S0733-8651(18)30431-4

33. Dyess NF, Palmer C, Soll RF et al (2023) Practices and outcomes from a prospective, multicenter registry for preterm newborns with pulmonary hypertension. *J Pediatr* 262:113614. https://doi.org/10.1016/j.jpeds.2023.113614
34. Humbert M, Kovacs G, Hoeper MM et al (2022) 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 43:3618–3731.
https://doi.org/10.1093/eurheartj/ehac237

35. Qasim A, Jain SK (2020) Milrinone use in persistent pulmonary hypertension of the newborn. Neo Reviews 21:e165–e178. https://doi.org/10.1542/neo.21-3-e165

36. Choobdar FA, Shahhosseini P, Vahedi Z et al (2023) Comparison of the efficacy of inhaled versus infused milrinone in the management of persistent pulmonary hypertension of the newborn in resource-limited settings: a randomized clinical trial. Pediatr Pulmonol 58:2132–2139. https://doi.org/10.1002/ppul.26451

37. Sellmer A, Bjerre JV, Schmidt MR et al (2013) Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 98:F505-510. https://doi.org/10.1136/archdischild-2013-303816

38. Su BH, Watanabe T, Shimizu M et al (1997) Echocardiographic assessment of patent ductus arteriosus shunt flow pattern in premature infants. Arch Dis Child Fetal Neonatal Ed 77:F36-40. https://doi.org/10.1136/fn.77.1.f36

39. Cambonie G, Masson F, Mesnage R et al (2024) Management of patent ductus arteriosus in preterm infants: abundant literature, low certainty of evidence for clinicians. Arch Pediatr 31:473–479. https://doi.org/10.1016/j.arcped.2024.10.001

40. McNamara PJ, Sehgal A (2007) Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 92:F424-427.
https://doi.org/10.1136/adc.2007.118117

41. de Boode WP, van der Lee R, Horsberg Eriksen B et al (2018) The role of neonatologist performed echocardiography in the assessment and management of neonatal shock. Pediatr Res 84:57–67. https://doi.org/10.1038/s41390-018-0081-1
42. Bussmann N, EL-Khuffash A, Breatnach CR et al (2019) Left ventricular diastolic function influences right ventricular — pulmonary vascular coupling in premature infants. Early Hum Dev 128:35–40. https://doi.org/10.1016/j.earlhumdev.2018.11.006

43. Ruoss JL, Bazacliu C, Giesinger RE et al (2020) Patent ductus arteriosus and cerebral, cardiac, and gut hemodynamics in pre-mature neonates. Semin Fetal Neonatal Med 25:101120. https://doi.org/10.1016/j.siny.2020.101120

44. Kluckow M (2000) Superior vena cava flow in newborn infants: a novel marker of systemic blood flow. Arch Dis Childhood - Fetal Neonatal Edit 82:182F – 187. https://doi.org/10.1136/fn.82.3.F182
**Conflict of interest statement**

Declarations. Competing interests: The authors declare no competing interests.
References

1. Taylor GL, O'Shea TM (2022) Extreme prematurity: Risk and resiliency. Curr Probl Pediatr Adolesc Health Care 52:101132. https://doi.org/10.1016/j.cppeds.2022.101132 - DOI

2. Barrington KJ (2008) Hypotension and shock in the preterm infant. Semin Fetal Neonatal Med 13:16-23. https://doi.org/10.1016/j.siny.2007.09.002 - DOI

3. Stoll BJ, Hansen NI, Sánchez PJ et al (2011) Early onset neonatal sepsis: the burden of group B streptococcal and E. coli disease continues. Pediatrics 127:817-26. https://doi.org/10.1542/peds.2010-2217 - DOI

4. Singh Y, Fraisse A, Erdeve O et al (2020) Echocardiographic diagnosis and hemodynamic evaluation of patent ductus arteriosus in extremely low gestational age newborn (ELGAN) infants. Front Pediatr. https://doi.org/10.3389/fped.2020.573627 - DOI

5. Durrmeyer X, Marchand-Martin L, Porcher R et al (2017) Abstention or intervention for isolated hypotension in the first 3 days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study. Arch Dis Child Fetal Neonatal Ed 102:490-496. https://doi.org/10.1136/archdischild-2016-312104 - DOI

6. Barrington KJ, Janaillac M (2016) Treating hypotension in extremely preterm infants the pressure is mounting. Arch Dis Child Fetal Neonatal Ed 101:F188-189. https://doi.org/10.1136/archdischild-2015-309814 - DOI

7. Aldana-Aguirre JC, Deshpande P, Jain A et al (2021) Physiology of Low Blood Pressure During the First Day After Birth Among Extremely Preterm Neonates. J Pediatr 236:40-46.e3. https://doi.org/10.1016/j.jpeds.2021.05.026 - DOI

8. Kluckow M (2018) The pathophysiology of low systemic blood flow in the preterm infant. Front Pediatr 6:29. https://doi.org/10.3389/fped.2018.00029 - DOI

9. El-Khuffash AF, McNamara PJ (2011) Neonatologist-performed functional echocardiography in the neonatal intensive care unit. Semin Fetal Neonatal Med 16:50-60. https://doi.org/10.1016/j.siny.2010.05.001 - DOI

10. Singh Y (2022) Use of echocardiography in the neonatal intensive care unit. Paediatr Child Health 32:351-356. https://doi.org/10.1016/j.paed.2022.07.005 - DOI

11. Rozé J-C, Cambonie G, Marchand-Martin L et al (2015) Association between early screening for patent ductus arteriosus and in-hospital mortality among extremely preterm infants. JAMA 313:2441. https://doi.org/10.1001/jama.2015.6734 - DOI

12. Giesinger RE, Hobson AA, Bischoff AR et al (2023) Impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes in "22-23" week and "24-26" infants. Semin Perinatol 47:151721. https://doi.org/10.1016/j.semperi.2023.151721 - DOI

13. McNamara PJ, Jain A, El-Khuffash A et al (2024) Guidelines and recommendations for targeted neonatal echocardiography and cardiac point-of-care ultrasound in the neonatal intensive care unit: an update from the American Society of Echocardiography. J Am Soc Echocardiogr 37:171-215. https://doi.org/10.1016/j.echo.2023.11.016 - DOI

14. Singh Y, Tissot C, Fraga MV et al (2020) International evidence-based guidelines on point of care ultrasound (POCUS) for critically ill neonates and children issued by the POCUS working group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Crit Care 24:65. https://doi.org/10.1186/s13054-020-2787-9 - DOI
15. McNamara PJ, Barker P, Jain A et al (2021) Towards use of POCUS to evaluate hemodynamics in critically ill neonates: caution before adoption in this population. Crit Care 25:92. https://doi.org/10.1186/s13054-020-03394-4 - DOI

16. Development of audit measures and guidelines for good practice in the management of neonatal respiratory distress syndrome. Report of a Joint Working Group of the British Association of Perinatal Medicine and the Research Unit of the Royal College of Physicians. Arch Dis Child. 1992;67:1221-7. https://doi.org/10.1136/adc.67.10_spec_no.1221

17. Rozé J-C, Cambonie G, Le Thuaut A et al (2021) Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial. J Pediatr 233:33-42.e2. https://doi.org/10.1016/j.jpeds.2020.12.008 - DOI

18. Ursino M, Alberti C, Cambonie G, et al. (2024) TREOCAPA: Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen. Statistical analysis plan for the randomized phase III group sequential trial

19. Mertens L, Seri I, Marek J, Writing Group of the American Society of Echocardiography (ASE) in collaboration with the European Association of Echocardiography (EAE) and the Association for European Pediatric Cardiologists (AEPC) et al (2011) Targeted neonatal echocardiography in the neonatal intensive care unit: practice guidelines and recommendations for training. J Am Soc Echocardiogr 24:1057-78. https://doi.org/10.1016/j.echo.2011.07.014 - DOI

20. Parry G, Tucker J, Tarnow-Mordi W (2003) CRIB II: an update of the clinical risk index for babies score. Lancet 361:1789-1791. https://doi.org/10.1016/S0140-6736(03)13397-1 - DOI

21. De Luca D, van Kaam AH, Tingay DG et al (2017) The montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity. Lancet Respir Med 5:657-666. https://doi.org/10.1016/S2213-2600(17)30214-X - DOI

22. Sahussarungsi S, Lapointe A, Villeneuve A et al (2025) Pulmonary hemorrhage in premature infants: pathophysiology risk factors and clinical management. Biomedicines 13:1744. https://doi.org/10.3390/biomedicines13071744 - DOI

23. Papile LA, Burstein J, Burstein R et al (1978) Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 92:529-534. https://doi.org/10.1016/s0022-3476(78)80282-0 - DOI

24. Arjaans S, Zwart EAH, Ploegstra M-J et al (2018) Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: a systematic review and meta-analysis. Paediatr Perinat Epidemiol 32:258-267. https://doi.org/10.1111/ppe.12444 - DOI

25. Méndez-Abad P, Zafra-Rodríguez P, Lubián-López S et al (2020) Myocardial function maturation in very-low-birth-weight infants and development of bronchopulmonary dysplasia. Front Pediatr. https://doi.org/10.3389/fped.2019.00556 - DOI

26. Arjaans S, Zwart EAH, Roofthooft M et al (2021) Pulmonary hypertension in extremely preterm infants: a call to standardize echocardiographic screening and follow-up policy. Eur J Pediatr 180:1855-1865. https://doi.org/10.1007/s00431-021-03931-5 - DOI

27. Kouzu H, Nakatani S, Kyotani S et al (2009) Noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hypertension. Am J Cardiol 103:872-876. https://doi.org/10.1016/j.amjcard.2008.11.039 - DOI
28. Koestenberger M, Avian A, Grangl G et al (2016) Right ventricular outflow tract velocity time integral (RVOT VTI) and tricuspid regurgitation velocity/RVOT VTI ratio in pediatric pulmonary hypertension. Int J Cardiol 212:274-276. https://doi.org/10.1016/j.ijcard.2016.03.111 - DOI

29. Oikonomopoulou N, Rodriguez-Castaño MJ, Corredera A, et al. (2025) Extremely preterm infants with adverse neurological outcome present more frequently impaired right ventricular performance. Pediatr Res. https://doi.org/10.1038/s41390-025-03959-5

30. Arjaans S, Fries MWF, Schoots MH et al (2022) Clinical Significance of Early Pulmonary Hypertension in Preterm Infants. J Pediatr 251:74-81.e3. https://doi.org/10.1016/j.jpeds.2022.07.039 - DOI

31. Friedman WF (1972) The intrinsic physiologic properties of the developing heart. Prog Cardiovasc Dis 15:87-111. https://doi.org/10.1016/0033-0620(72)90006-0 - DOI

32. Anderson PAW (1989) Maturation and cardiac contractility. Cardiol Clin 7:209-225. https://doi.org/10.1016/S0733-8651(18)30431-4 - DOI

33. Dyess NF, Palmer C, Soll RF et al (2023) Practices and outcomes from a prospective, multicenter registry for preterm newborns with pulmonary hypertension. J Pediatr 262:113614. https://doi.org/10.1016/j.jpeds.2023.113614 - DOI

34. Humbert M, Kovacs G, Hoeper MM et al (2022) 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 43:3618-3731. https://doi.org/10.1093/eurheartj/ehac237 - DOI

35. Qasim A, Jain SK (2020) Milrinone use in persistent pulmonary hypertension of the newborn. NeoReviews 21:e165-e178. https://doi.org/10.1542/neo.21-3-e165 - DOI

36. Choobdar FA, Shahhosseini P, Vahedi Z et al (2023) Comparison of the efficacy of inhaled versus infused milrinone in the management of persistent pulmonary hypertension of the newborn in resource-limited settings: a randomized clinical trial. Pediatr Pulmonol 58:2132-2139. https://doi.org/10.1002/ppul.26451 - DOI

37. Sellmer A, Bjerre JV, Schmidt MR et al (2013) Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 98:F505-510. https://doi.org/10.1136/archdischild-2013-303816 - DOI

38. Su BH, Watanabe T, Shimizu M et al (1997) Echocardiographic assessment of patent ductus arteriosus shunt flow pattern in premature infants. Arch Dis Child Fetal Neonatal Ed 77:F36-40. https://doi.org/10.1136/fn.77.1.f36 - DOI

39. Cambonie G, Masson F, Mesnage R et al (2024) Management of patent ductus arteriosus in preterm infants: abundant literature, low certainty of evidence for clinicians. Arch Pediatr 31:473-479. https://doi.org/10.1016/j.arcped.2024.10.001 - DOI

40. McNamara PJ, Sehgal A (2007) Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 92:F424-427. https://doi.org/10.1136/adc.2007.118117 - DOI

41. de Boode WP, van der Lee R, Horsberg Eriksen B et al (2018) The role of neonatologist performed echocardiography in the assessment and management of neonatal shock. Pediatr Res 84:57-67. https://doi.org/10.1038/s41390-018-0081-1 - DOI

42. Bussmann N, EL-Khuffash A, Breatnach CR et al (2019) Left ventricular diastolic function influences right ventricular – pulmonary vascular coupling in premature infants. Early Hum Dev 128:35-40. https://doi.org/10.1016/j.earlhumdev.2018.11.006 - DOI
43. Ruoss JL, Bazacliu C, Giesinger RE et al (2020) Patent ductus arteriosus and cerebral, cardiac, and gut hemodynamics in premature neonates. Semin Fetal Neonatal Med 25:101120. https://doi.org/10.1016/j.siny.2020.101120 - DOI

44. Kluckow M (2000) Superior vena cava flow in newborn infants: a novel marker of systemic blood flow. Arch Dis Childhood - Fetal Neonatal Edit 82:182F – 187. https://doi.org/10.1136/fn.82.3.F182 - DOI