Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes

NCT03782610 | Active Not Recruiting

• 2 other identifiers: 18006841R01HL145032
• Study Type: observational
• Target: 526
• Locations: 1 country
• Sites: 4

Brief Summary

Patent ductus arteriosus (PDA), very common in preterm infants, is the delayed closure of a fetal blood vessel that limits blood flow through the lungs. PDA is associated with mortality and harmful long term outcomes including chronic lung disease and neurodevelopmental delay. Although, treatments to close PDA likely benefit some infants, widespread routine treatment of all preterm infants with PDA may not improve important outcomes. Left untreated, most PDAs close spontaneously. Thus, PDA treatment is increasingly controversial and varies markedly between hospitals and individual providers. The relevant and still unanswered clinical question is not whether to treat all preterm infants with PDA, but whom to treat and when. Treatment detriments may outweigh benefits, since all forms of deliberate PDA closure have potential adverse effects, especially in infants destined for early, spontaneous PDA closure. Unfortunately, clinicians cannot currently predict in the 1st month which infants are at highest risk for persistent PDA, and which combination of clinical risk factors, echocardiographic (echo) measurements, and serum biomarkers may best predict PDA-associated harm. The American Academy of Pediatrics has acknowledged early identification of infants at high-risk from PDA as a key research goal for informing future PDA-treatment effectiveness trials. Our objective is to use a prospective cohort of untreated infants with PDA to predict spontaneous ductal closure timing and identify echo measurements and biomarkers that are present in the 1st postnatal month and associated with long-term impairment. Our central hypothesis is that these risk factors can be determined to inform appropriate clinical treatments when necessary. Clinical, serum and urine biomarkers (BNP, NTpBNP, NGAL, H-FABP), and echo variables sequentially collected during each of the first 4 postnatal weeks will be examined. In addition myocardial deformation imaging (MDI) and tissue Doppler imaging (TDI), innovative echo methods, will facilitate the quantitative evaluation of myocardial performance. Aim 1 will estimate the probability of spontaneous PDA closure and predict the timing of ductal closure using echo, biomarker, and clinical predictors. Aim 2 will specify which echo predictors and biomarkers are associated with mortality and severity of respiratory illness at 36-weeks PMA. Aim 3 will identify which echo predictors and biomarkers are associated with 22- to 26-month neurodevelopment. All models will be validated in a separate cohort. This project will significantly contribute to clinical outcomes and PDA management by reducing unnecessary and harmful overtreatment of infants with a high probability of early spontaneous PDA closure, and will permit the development of outcomes-focused trials to examine the effectiveness of PDA closure in those "high-risk" infants most likely to receive benefit.

Conditions

Patent Ductus Arteriosus; Preterm Infant; Bronchopulmonary Dysplasia; Neurodevelopmental Abnormality

Keywords

Patent Ductus Arteriosus; Preterm Infant; Echocardiogram; Prospective Cohort; Prediction Modeling

Outcome Measures

Primary Outcomes (3)

• Patent ductus arteriosus (PDA) closure documented via echocardiogram by 36-weeks postmenstrual age (PMA) (binary)

  Documented closure of PDA on echocardiogram. Echocardiograms to document the primary outcome will be conducted weekly for the first four postnatal weeks and every other week thereafter, between study entry and 36-weeks PMA until PDA-closure is documented

  Outcome will be documented between <72-hour screening echo and 36-weeks PMA.

• Mortality or supplemental oxygen or positive-pressure respiratory support at 36-weeks PMA (binary)

  Death occurring between study entry at \<72-hours postnatal and 36-weeks PMA OR an oxygen or positive-pressure ventilation requirement at 36-weeks gestational age (=moderate bronchopulmonary dysplasia \[BPD\] or severe BPD)

  Outcome will be documented between <72-hour screening echo and 36-weeks PMA

• Composite Bayley III Motor Score at 22-26 months corrected age (continuous)

  Composite motor score at 22 to 26-months postnatal as measured by Bayley Scales of Infant and Toddler Development- 3rd Edition (Bayley III)

  Bayley III Score Testing will occur at 22 to 26 months corrected age (CA) (age since birth - number of weeks born before 40-weeks gestation)

Secondary Outcomes (5)

• Mortality by 36-weeks PMA (binary)

  Death occuring between 72-hours postnatal and 36-weeks PMA

• Bayley III Gross Motor Development Scaled Standard Score at 22-26 months corrected age (continuous)

  Recorded at 22-26 months corrected age

• Bayley III Fine Motor Development Scaled Standard Score postnatal age at 22-26 months corrected age (continuous)

  Recorded at 22-26 months corrected age

• Bayley III Cognitive Composite Score at 22-26 months corrected age (continuous)

  Recorded at 22-26 months corrected age

• Bayley III Language Composite Score at 22-26 months corrected age (continuous)

  Recorded at 22-26 months corrected age

Other Outcomes (26)

• Normal cardiac function at 36-weeks PMA (binary)

  Recorded at 36-weeks PMA or discharge if prior to 36-weeks

• Quantitative myocardial deformation imaging (MDI) at 36-weeks PMA (continuous)

  Recorded at 36-weeks PMA or discharge if prior to 36-weeks

• Quantitative tissue Doppler imaging (TDI) at 36-weeks PMA (continuous)

  Recorded at 36-weeks PMA or discharge if prior to 36-weeks

Study Arms (2)

Primary Study Cohort

450 Infants

Validation Cohort

225 Infants. Will allow subsequent validation of models derived from the Primary Study Cohort.

Eligibility Criteria

• Age: Up to 72 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

A cohort of consecutively enrolled preterm infants born between 23- and 30-weeks gestation with patent ductus arteriosus (PDA) documented on echocardiogram within 72-hours postnatal.

You may qualify if:

• Born between 23-weeks + 0 days (23\_0/7 wks) and 29-weeks + 6 days (29\_6/7 wks) gestation, inclusive
• Admitted to a study neonatal intensive care unit (NICU) within 72-hours of birth
• PDA noted on initial screening echo at \<72 postnatal hours

You may not qualify if:

• Life-threatening congenital abnormalities, including congenital heart disease (other than PDA or small atrial septal defects/patent foramen ovale/muscular VSD)
• Parents have chosen to allow natural death (placed a do not resuscitate order)

Sponsors & Collaborators

• Nationwide Children's Hospital: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Ohio State University: collaborator
• OhioHealth: collaborator
• Mount Carmel Health System: collaborator

Study Sites (4)

Nationwide Children's Hospital Main Campus Neonatal Intensive Care Unit

Columbus, Ohio, 43205, United States

Location

Nationwide Children's Neonatal Intensive Care Unit at The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Nationwide Children's Neonatal Intensive Care Unit at OhioHealth Riverside Methodist Hospital

Columbus, Ohio, 43214, United States

Location

Nationwide Children's Hospital Neonatal Intensive Care Unit at OhioHealth Grant Medical Center

Columbus, Ohio, 43215, United States

Location

Related Publications (5)

• Benitz WE; Committee on Fetus and Newborn, American Academy of Pediatrics. Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016 Jan;137(1). doi: 10.1542/peds.2015-3730. Epub 2015 Dec 15.

  PMID: 26672023 BACKGROUND

• Slaughter JL, Reagan PB, Newman TB, Klebanoff MA. Comparative Effectiveness of Nonsteroidal Anti-inflammatory Drug Treatment vs No Treatment for Patent Ductus Arteriosus in Preterm Infants. JAMA Pediatr. 2017 Mar 6;171(3):e164354. doi: 10.1001/jamapediatrics.2016.4354. Epub 2017 Mar 6.

  PMID: 28046188 BACKGROUND

• Pavlek LR, Slaughter JL, Berman DP, Backes CH. Catheter-based closure of the patent ductus arteriosus in lower weight infants. Semin Perinatol. 2018 Jun;42(4):262-268. doi: 10.1053/j.semperi.2018.05.009. Epub 2018 Jun 13.

  PMID: 29909074 BACKGROUND

• Runte KE, Flyer JN, Edwards EM, Soll RF, Horbar JD, Yeager SB. Variation of Patent Ductus Arteriosus Treatment in Very Low Birth Weight Infants. Pediatrics. 2021 Nov;148(5):e2021052874. doi: 10.1542/peds.2021-052874. Epub 2021 Oct 21.

  PMID: 34675131 DERIVED

• Slaughter JL, Cua CL, Notestine JL, Rivera BK, Marzec L, Hade EM, Maitre NL, Klebanoff MA, Ilgenfritz M, Le VT, Lewandowski DJ, Backes CH. Early prediction of spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation. BMC Pediatr. 2019 Sep 13;19(1):333. doi: 10.1186/s12887-019-1708-z.

  PMID: 31519154 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum biomarkers: beta-natriuretic peptide (BNP); N-terminal pro-B-type natriuretic peptide (NTpBNP) Urine biomarkers: neutrophil gelatinase-associated lipocalin (NGAL); heart-fatty acid-binding protein (H-FABP)

MeSH Terms

Conditions

Ductus Arteriosus, Patent; Premature Birth; Bronchopulmonary Dysplasia

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases

Study Officials

• Jonathan L Slaughter, MD, MPH

  Nationwide Children's Hospital/The Ohio State University

  PRINCIPAL INVESTIGATOR

• Carl H Backes, MD

  Nationwide Children's Hospital/The Ohio State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 22 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 20, 2018
• Study Start: April 1, 2019
• Primary Completion: October 31, 2025
• Study Completion (Estimated): September 1, 2026
• Last Updated: March 10, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Data will become available after the completion of our planned investigation and publication of the results. We anticipate the completion of the investigation and publication will occur by December 2025
• Access Criteria: Email study co-PIs Jonathan Slaughter (Jonathan.Slaughter@nationwidechildrens.org) and Carl Backes (Carl.Backes@nationwidechildrens.org)

Locations

US (4)