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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Bronchopulmonary Dysplasia; Patent Ductus Arteriosus; Preterm Infant; Neurodevelopmental Abnormality

• Study Type: Observational
• Enrollment (Estimated): 675

Contacts and Locations

• Study Contact: Name: Jonathan L Slaughter, MD, MPH; Phone Number: 1-614-355-6643; Email: Jonathan.Slaughter@nationwidechildrens.org
• Study Contact Backup: Name: Carl H Backes, MD; Phone Number: 1-614-355-6729; Email: Carl.Backes@nationwidechildrens.org

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital Main Campus Neonatal Intensive Care Unit
    • Columbus, Ohio, United States, 43210
      • Nationwide Children's Neonatal Intensive Care Unit at The Ohio State University Wexner Medical Center
    • Columbus, Ohio, United States, 43214
      • Nationwide Children's Neonatal Intensive Care Unit at OhioHealth Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43215
      • Nationwide Children's Hospital Neonatal Intensive Care Unit at OhioHealth Grant Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: No

• 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.

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Primary Study Cohort; 450 Infants
Validation Cohort; 225 Infants. Will allow subsequent validation of models derived from the Primary Study Cohort.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normal cardiac function at 36-weeks PMA (binary)	No functional abnormalities identified on the 36-week echocardiogram, as read by the study cardiologist	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
Pulmonary Hypertension at 36-weeks PMA (binary)	Pulmonary hypertension noted on the 36-week echocardiogram, as read by the study cardiologist	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Normal left atrial size at 36-weeks PMA (binary)	No left atrial enlargement identified on the 36-week echocardiogram, as read by the study cardiologist	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Normal left ventricular size at 36-weeks PMA (binary)	No left ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Normal right ventricular size at 36-weeks PMA (binary)	No right ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Oxygen Dependency (Moderate BPD) (binary)		Recorded at 36-weeks PMA
Positive-Pressure Dependency (Severe BPD) (binary)		Recorded at 36-weeks PMA
Length at 36-weeks PMA	Length in centimeters	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
General Movements Assessment (GMA) at 36-weeks corrected age	Prechtl's method for the qualitative assessment of general movements dysfunction	Recorded at 36-weeks PMA
Time to enteral feed initiation		72 hours postnatal to 36-weeks PMA
Time to a full enteral feed diet	Infant is weaned from intravenous fluids to a full enteral feed diet (delivery of feeds may be via an enteric tube)	72 hours postnatal to 36-weeks PMA
Oral feeding status (binary)	Infant is taking all feeds by mouth (PO feeds) by 36-weeks PMA	Recorded at 36-weeks PMA
Weight at 36-weeks PMA	Weight in grams	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Occipitofrontal circumference (OFC) at 36-weeks PMA	OFC in centimeters	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Body Mass Index (BMI) at 36-weeks PMA	BMI calculated by (BMI= weight in kg/length in meters squared)	Recorded at 36-weeks PMA or discharge if prior to 36-weeks
Supplemental oxygen or positive-pressure respiratory support at 40-weeks PMA (binary)		Recorded at 40-weeks PMA
Mortality by 22-26 months corrected age		Death occuring between 72-hours postnatal and 22-26 months corrected age
Duration of ductal patency from 72-hours postnatal until 22 to 26-months corrected age follow-up		72 hours postnatal until 22-26 months follow-up visit
Supplemental oxygen support (binary) at 22-26 months corrected age		Recorded at 22-26 months study follow-up visit
Supplemental positive-pressure ventilation support (binary) at 22-26 months corrected age		Recorded at 22-26 months study follow-up visit
Weight at 22-26 months corrected age	Weight in kilograms	Recorded at 22-26 months study follow-up visit
Length at 22-26 months corrected age	Length in centimeters	Recorded at 22-26 months study follow-up visit
Body Mass Index (BMI) at 22-26 months corrected age	BMI calculated by (BMI= weight in kg/length in meters squared)	Recorded at 22-26 months study follow-up visit
Feeding status via full oral feeding or gastric-tube (binary) at 22-26 months corrected age		Recorded at 22-26 months study follow-up visit

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Ohio State University; OhioHealth; Mount Carmel Health System
• Investigators: Principal Investigator: 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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: December 17, 2018
• First Submitted That Met QC Criteria: December 18, 2018
• First Posted (Actual): December 20, 2018

Study Record Updates

• Last Update Posted (Estimated): November 20, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Echocardiogram; Preterm Infant; Patent Ductus Arteriosus; Prospective Cohort; Prediction Modeling
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Infant, Newborn, Diseases; Lung Injury; Heart Defects, Congenital; Cardiovascular Abnormalities; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia; Ductus Arteriosus, Patent
• Other Study ID Numbers: 1800684; 1R01HL145032 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We welcome the opportunity to share data from our investigation. All patient identifiers will be removed from the final dataset. Following the completion and publication of our investigation, we will make the data available to other users under a data sharing agreement. We will ask under the agreement that other users will commit to using the data only for research purposes, that they will not identify individual study subjects, that they will securely store the data electronically using password protection or encryption, that they will delete or destroy the data after the completion of their investigation, and that they will acknowledge the contribution of the funding agency (NIH NHLBI) and our investigative team in collecting the original data.
• IPD Sharing 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
• IPD Sharing Access Criteria: Email study co-PIs Jonathan Slaughter (Jonathan.Slaughter@nationwidechildrens.org) and Carl Backes (Carl.Backes@nationwidechildrens.org)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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