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. 2024 Nov 15;184(1):15.
doi: 10.1007/s00431-024-05841-8.

Longitudinal evaluation of hemodynamic blood and echocardiographic biomarkers for the prediction of BPD and BPD-related pulmonary hypertension in very-low-birth-weight preterm infants

Lukas Schroeder  1 , Fabian Ebach  2 , Tamene Melaku  2 , Brigitte Strizek  3 , Jorge Jimenez-Cruz  3 , Ramona Dolscheid-Pommerich  4 , Andreas Mueller  2 , Florian Kipfmueller  2
Affiliations

Longitudinal evaluation of hemodynamic blood and echocardiographic biomarkers for the prediction of BPD and BPD-related pulmonary hypertension in very-low-birth-weight preterm infants

Lukas Schroeder et al. Eur J Pediatr. .

Abstract

Very-low-birth-weight infants (VLBW, < 1500 g) are at risk of developing bronchopulmonary dysplasia (BPD) and are at risk for BPD-related pulmonary hypertension (PH). The longitudinal measurement of innovative blood and echocardiographic biomarkers might allow for a risk stratification of these infants. A prospective single-center cohort study was conducted between 01/2021 and 06/2023. Inclusion criteria were the combination of a birth weight < 1500 g and a gestational age (GA) ≤ 30/0 weeks. Assessment timepoints: T1 (day 7), T2 (day 28), and T3 (at 36 weeks post-menstrual age, PMA). Overall, 71 preterm infants were included for final analysis. The Zlog-transformed NTproBNPZlog (at T1 AUC 0.772; p = 0.019; at T2 AUC 0.874, p = 0.002), and endothelin-1 (ET1, at T1 AUC 0.789, p = 0.013) were identified as an early predictive biomarker for BPD/death in the univariate analysis. Additionally, echocardiographic markers of ventricular function and PH at T1 were predictive for BPD/death in the univariate analysis, with the highest predictivity found for the tricuspid annular plane systolic excursion-TAPSE (AUC 0.748, p = 0.016) and the pulmonary artery acceleration time to right ventricular ejection time (PAAT/RVET; AUC 0.744, p = 0.043). Regarding predictability of mortality alone NTroBNPZlog (at T1 AUC 0.973, p = 0.000), and CA125 (at T1 AUC 0.747, p = 0.008) were identified as potential predictors, as well as TAPSE (AUC 0.926, p = 0.000), and PAAT/RVET (AUC 0.985, p = 0.000) Several biomarkers including ET-1 (at T1 AUC 0.893, p = 0.000), TAPSE (AUC 0.974, p = 0.000), and PAAT/RVET (AUC 1.0, p = 0.000) at T1 were identified as univariate predictors for BPD-PH. In the multivariate analysis, no biomarker was identified as an independent predictor of the primary endpoint.

Conclusion: Mainly at an early stage of postnatal neonatal care in VLBW preterm infants, several biomarkers were found to be associated with the combined endpoint BPD/death and BPD-PH. New candidates of blood biomarkers (NTproBNPZlog, ET-1, and CA125) and echocardiographic markers (TAPSE, PAAT/RVET) might serve as innovative predictors for BPD, BPD-PH, and adverse outcomes in VBLW infants.

What is known: • VLBW infants are at risk for the development of BPD and BPD-related PH, which both are main contributors for short and long-term morbidity and mortality. Several studies in the past focused on the evaluation of circulating blood biomarkers and biomarkers from echocardiographic assessment of these infants. But to date, there is still a lack on longitudinal prospective studies especially in VLBW infants.

What is new: • For the first time, this set of selected blood biomarkers (with the first description of Zlog-transformed NTproBNP and CA125 in preterm infants) and several echocardiographic markers were analyzed in a prospective longitudinal study from birth until 36 weeks post menstrual age in VLBW infants. Our data help clinicians to identify preterm infants at risk for BPD, BPD-PH and death and to offer new candidates of biomarkers. This might help to facilitate decision making and guidance of therapy in these highly vulnerable patients.

Keywords: Biomarker; Bronchopulmonary dysplasia; Echocardiography; Mortality; Preterm infants; Pulmonary hypertension.

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Conflict of interest statement

Declarations Ethics approval and consent to participate The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review of the Medical Center of the University of Bonn (local running number 011/19). Patients were prospectively enrolled in the study after informed written consent was obtained from the parents or legal representative. The methods used for the clinical research were performed in accordance with the STROBE (strengthening the reporting of observational studies in epidemiology) guidelines [13] and in accordance with the Declaration of Helsinki. The study was registered at the German Clinical Trials Register (GCT; trial number DRKS00033219). Consent statement All legal guardians of the participants of the present study signed a consent form prior to study inclusion according to the local guidelines of the ethical committee. Competing interests The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Longitudinal data on blood biomarker measurements are displayed as mean values in Figs. 2A–D, with the corresponding values for Group A (BPD/death) and Group B (no BPD/death). A Zlog-transformed NTproBNP (correction for gestational age) values at T1–T3. B Cyfra 21–1 values at T1–T3. C CA125 values at T1–T3. D Endothelin-1 values at T1. Asterisks are indicating significant p-values (< 0.01) between subgroups
Fig. 2
Fig. 2
Illustration of the receiver operating characteristics (ROC) curves for the prediction of the primary combined endpoint BPD/death (A T1; B T2) and fatal outcome separately (C T1) using blood biomarkers
Fig. 3
Fig. 3
A Illustration of the mean values of TAPSE (tricuspid annular plane systolic excursion, cm/sec) at T1 (day 7) and T2 (day 28) with the corresponding values for Group A (BPD/death) and Group B (no BPD/death) and B mean values of PAAT/RVET (pulmonary artery acceleration time/right ventricular ejection time) at T1 and T2. Asterisks are indicating significant values (p <0.05) between subgroups
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