Pulmonary Hypertension in Extremely Preterm Infants (PiEP)

Pulmonary Hypertension in Extremely Preterm Infants - A Prospective Cohort Study

Extremely preterm infants are at risk for developing bronchopulmonary dysplasia (BPD) and associated chronic pulmonary hypertension (PH), a consequence of altered pulmonary vasculature. This condition occurs in about 25% of babies with BPD, and the association grows with increasing BPD severity. Other risk factors have been described as well. Morbidity and mortality associated with prematurity and/or BPD increase significantly in the presence of PH.

Thus, international guidelines encourage the use of standardized screening protocols for this condition. However, several questions regarding these recommendations are left unanswered, such as a clear definition for PH in this population.

The research aim is to prospectively evaluate prevalence, risk factors and clinical course of PH in these children. The investigators aim to identify at-risk infants early on and ultimately improve survival making use of an early targeted intervention.

Study Overview

• Status: Not yet recruiting
• Conditions: Premature Birth; Pulmonary Hypertension; Bronchopulmonary Dysplasia
• Intervention / Treatment: Diagnostic test: Echocardiography; Diagnostic test: NT-proBNP

• Study Type: Interventional
• Enrollment (Anticipated): 350
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Barbara De Bisschop, MD; Phone Number: 0032 2 477 77 21; Email: barbara.debisschop@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria: Preterm infants with

• Gestational age <28 0/7 weeks
• Birth weight <1000 grams

Exclusion Criteria:

• Major congenital malformations
• Structural airway or lung disease
• Congenital heart disease
• Lack of parental consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Extremely preterm newborns; All extremely preterm newborns in Flanders will be included, it is a single arm study	Diagnostic test: Echocardiography; There will be screened for pulmonary hypertension by means of serial echocardiographies during the study period; Diagnostic test: NT-proBNP; At 36 weeks postmenstrual age there will be screened for pulmonary hypertension by means of an NT-proBNP measurement in a blood sample

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of pulmonary hypertension	Pulmonary hypertension will be defined as one or more of the following echocardiographic findings: Presence of a cardiac shunt with bidirectional or right-to-left flow; Estimated right ventricular systolic pressure (RVSP) >40 mmHg; RVSP/systemic systolic blood pressure (SBP) ratio >0.5; Presence of ventricular septal wall flattening	3-10 days of life (time depending on the timing of the first echocardiography)
Presence of pulmonary hypertension	Pulmonary hypertension will be defined as one or more of the following echocardiographic findings: Presence of a cardiac shunt with bidirectional or right-to-left flow; Estimated right ventricular systolic pressure (RVSP) >40 mmHg; RVSP/systemic systolic blood pressure (SBP) ratio >0.5; Presence of ventricular septal wall flattening	at 28 days of life
Presence of pulmonary hypertension	Pulmonary hypertension will be defined as one or more of the following echocardiographic findings: Presence of a cardiac shunt with bidirectional or right-to-left flow; Estimated right ventricular systolic pressure (RVSP) >40 mmHg; RVSP/systemic systolic blood pressure (SBP) ratio >0.5; Presence of ventricular septal wall flattening	at 36 weeks PMA
Presence of pulmonary hypertension	Pulmonary hypertension will be defined as one or more of the following echocardiographic findings: Presence of a cardiac shunt with bidirectional or right-to-left flow; Estimated right ventricular systolic pressure (RVSP) >40 mmHg; RVSP/systemic systolic blood pressure (SBP) ratio >0.5; Presence of ventricular septal wall flattening	at 6 months of age
Presence of pulmonary hypertension	Pulmonary hypertension will be defined as one or more of the following echocardiographic findings: Presence of a cardiac shunt with bidirectional or right-to-left flow; Estimated right ventricular systolic pressure (RVSP) >40 mmHg; RVSP/systemic systolic blood pressure (SBP) ratio >0.5; Presence of ventricular septal wall flattening	at 12 months of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of bronchopulmonary dysplasia	Assessment of supplemental oxygen	at 28 days of life
Presence of bronchopulmonary dysplasia	Classification of BPD with an oxygen reduction test	at 36 weeks PMA
Birth weight	Birth weight in grams	at birth
Gestational age	Gestational age in weeks	at birth
Small for gestational age	Birth weight <P3	at birth
Oligohydramnios	Presence of oligohydramnios during pregnancy	at birth
Maternal hypertensive disorders	Presence of maternal hypertensive disorders during pregnancy (pre-eclampsia, hypertension, HELLP)	at birth
ROP	Presence of retinopathy of prematurity	at 36 weeks
NEC	Presence of necrotizing enterocolitis	at 36 weeks
PDA	Presence of patent ductus arteriosus	at 36 weeks
Sepsis	Presence of sepsis	up to discharge from the NICU, an average of 16 weeks
VAP	Presence of ventilator associated pneumonia	at 36 weeks

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel
• Collaborators: Universitaire Ziekenhuizen KU Leuven; University Hospital, Ghent; AZ Sint-Jan AV; Ziekenhuis Netwerk Antwerpen (ZNA); Ziekenhuis Oost-Limburg; GZA Ziekenhuizen Campus Sint-Augustinus
• Investigators: Principal Investigator: Barbara De Bisschop, MD, Universitair Ziekenhuis Brussel; Study Chair: Filip Cools, PhD, Universitair Ziekenhuis Brussel; Study Chair: Daniël De Wolf, PhD, Universitair Ziekenhuis Brussel

Publications and helpful links

General Publications

• Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thebaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; and the American Thoracic Society. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99. doi: 10.1161/CIR.0000000000000329. Epub 2015 Nov 3. Erratum In: Circulation. 2016 Jan 26;133(4):e368.
• Arjaans S, Zwart EAH, Ploegstra MJ, Bos AF, Kooi EMW, Hillege HL, Berger RMF. Identification of gaps in the current knowledge on pulmonary hypertension in extremely preterm infants: A systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2018 May;32(3):258-267. doi: 10.1111/ppe.12444. Epub 2018 Jan 17.
• Hilgendorff A, Apitz C, Bonnet D, Hansmann G. Pulmonary hypertension associated with acute or chronic lung diseases in the preterm and term neonate and infant. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016 May;102 Suppl 2:ii49-56. doi: 10.1136/heartjnl-2015-308591.
• Krishnan U, Feinstein JA, Adatia I, Austin ED, Mullen MP, Hopper RK, Hanna B, Romer L, Keller RL, Fineman J, Steinhorn R, Kinsella JP, Ivy DD, Rosenzweig EB, Raj U, Humpl T, Abman SH; Pediatric Pulmonary Hypertension Network (PPHNet). Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr. 2017 Sep;188:24-34.e1. doi: 10.1016/j.jpeds.2017.05.029. Epub 2017 Jun 20. No abstract available.
• Levy PT, Jain A, Nawaytou H, Teitel D, Keller R, Fineman J, Steinhorn R, Abman SH, McNamara PJ; Pediatric Pulmonary Hypertension Network (PPHNet). Risk Assessment and Monitoring of Chronic Pulmonary Hypertension in Premature Infants. J Pediatr. 2020 Feb;217:199-209.e4. doi: 10.1016/j.jpeds.2019.10.034. Epub 2019 Nov 14. No abstract available.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: October 6, 2021
• First Submitted That Met QC Criteria: November 25, 2021
• First Posted (Actual): November 29, 2021

Study Record Updates

• Last Update Posted (Actual): November 29, 2021
• Last Update Submitted That Met QC Criteria: November 25, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Hypertension; Premature Birth; Hypertension, Pulmonary; Bronchopulmonary Dysplasia
• Other Study ID Numbers: PiEP study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No