Early Prediction of Spontaneous Patent Ductus Arteriosus (PDA) Closure and PDA-Associated Outcomes
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Primary Study Cohort 450 Infants |
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| Validation Cohort 225 Infants. Will allow subsequent validation of models derived from the Primary Study Cohort. |
Outcome Measures
Primary Outcome Measures
- Patent ductus arteriosus (PDA) closure documented via echocardiogram by 36-weeks postmenstrual age (PMA) (binary) [Outcome will be documented between <72-hour screening echo and 36-weeks PMA.]
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
- Mortality or supplemental oxygen or positive-pressure respiratory support at 36-weeks PMA (binary) [Outcome will be documented between <72-hour screening echo and 36-weeks PMA]
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)
- Composite Bayley III Motor Score at 22-26 months corrected age (continuous) [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)]
Composite motor score at 22 to 26-months postnatal as measured by Bayley Scales of Infant and Toddler Development- 3rd Edition (Bayley III)
Secondary Outcome Measures
- 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
- Normal cardiac function at 36-weeks PMA (binary) [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
No functional abnormalities identified on the 36-week echocardiogram, as read by the study cardiologist
- 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) [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
Pulmonary hypertension noted on the 36-week echocardiogram, as read by the study cardiologist
- Normal left atrial size at 36-weeks PMA (binary) [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
No left atrial enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
- Normal left ventricular size at 36-weeks PMA (binary) [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
No left ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
- Normal right ventricular size at 36-weeks PMA (binary) [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
No right ventricular enlargement identified on the 36-week echocardiogram, as read by the study cardiologist
- 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 [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
Length in centimeters
- General Movements Assessment (GMA) at 36-weeks corrected age [Recorded at 36-weeks PMA]
Prechtl's method for the qualitative assessment of general movements dysfunction
- Time to enteral feed initiation [72 hours postnatal to 36-weeks PMA]
- Time to a full enteral feed diet [72 hours postnatal to 36-weeks PMA]
Infant is weaned from intravenous fluids to a full enteral feed diet (delivery of feeds may be via an enteric tube)
- Oral feeding status (binary) [Recorded at 36-weeks PMA]
Infant is taking all feeds by mouth (PO feeds) by 36-weeks PMA
- Weight at 36-weeks PMA [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
Weight in grams
- Occipitofrontal circumference (OFC) at 36-weeks PMA [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
OFC in centimeters
- Body Mass Index (BMI) at 36-weeks PMA [Recorded at 36-weeks PMA or discharge if prior to 36-weeks]
BMI calculated by (BMI= weight in kg/length in meters squared)
- 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 [Recorded at 22-26 months study follow-up visit]
Weight in kilograms
- Length at 22-26 months corrected age [Recorded at 22-26 months study follow-up visit]
Length in centimeters
- Body Mass Index (BMI) at 22-26 months corrected age [Recorded at 22-26 months study follow-up visit]
BMI calculated by (BMI= weight in kg/length in meters squared)
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Born between 23-weeks + 0 days (23_0/7 wks) and 29-weeks + 6 days (29_6/7 wks) gestation, inclusive
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Admitted to a study neonatal intensive care unit (NICU) within 72-hours of birth
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PDA noted on initial screening echo at <72 postnatal hours
Exclusion Criteria:
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Life-threatening congenital abnormalities, including congenital heart disease (other than PDA or small atrial septal defects/patent foramen ovale/muscular VSD)
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Parents have chosen to allow natural death (placed a do not resuscitate order)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nationwide Children's Hospital Main Campus Neonatal Intensive Care Unit | Columbus | Ohio | United States | 43205 |
| 2 | Nationwide Children's Neonatal Intensive Care Unit at The Ohio State University Wexner Medical Center | Columbus | Ohio | United States | 43210 |
| 3 | Nationwide Children's Neonatal Intensive Care Unit at OhioHealth Riverside Methodist Hospital | Columbus | Ohio | United States | 43214 |
| 4 | Nationwide Children's Hospital Neonatal Intensive Care Unit at OhioHealth Grant Medical Center | Columbus | Ohio | United States | 43215 |
Sponsors and Collaborators
- Nationwide Children's Hospital
- 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
Study Documents (Full-Text)
More Information
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.
- 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. Review.
- 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.
- 1800684
- 1R01HL145032