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

Study Overview
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Brief Summary
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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.

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

Conditions
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Patent Ductus Arteriosus, Preterm Infant, Bronchopulmonary Dysplasia, Neurodevelopmental Abnormality

Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 72 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Primary Study Cohort<br>450 Infants | |
| Validation Cohort<br>225 Infants. Will allow subsequent validation of models derived from the Primary Study Cohort. | |

What is the study measuring?
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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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Patent Ductus Arteriosus, Preterm Infant, Echocardiogram, Prospective Cohort, Prediction Modeling