Patent ductus arteriosus (PDA), very common in preterm infants, is associated with mortality and harmful long- term outcomes including chronic lung disease and neurodevelopmental delay. Although, pharmacologic and/or interventional 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 by 44- weeks postmenstrual age (PMA). Thus, PDA treatment is increasingly controversial and varies markedly between institutions 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 first month which infants are at highest risk for persistent PDA, and which combination of clinical risk factors, echo measurements, and serum biomarkers may best predict PDA-associated harm. The American Academy of Pediatrics in their PDA Clinical Guidance Report acknowledged early identification of infants at high-risk from PDA as a key research goal for informing future PDA-treatment effectiveness-trials. The objective in this application is to use a prospective cohort of untreated infants with PDA to predict spontaneous ductal closure timing and to identify clinical risk factors, echo measurements, and biomarkers that are present in the first postnatal month and associated with long-term impairment. Clinical, serum and urine biomarkers (BNP, NTpBNP, NGAL, H-FABP), and echocardiographic 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 echocardiographic methods, will facilitate the quantitative evaluation of myocardial performance.
All Specific Aims will collect and examine data from preterm infants with PDA within the first postnatal month.
Aim 1 will estimate the probability of spontaneous PDA closure and predict the timing of ductal closure using echocardiographic, biomarker, and clinical predictors.
Aim 2 will specify which echocardiographic predictors and biomarkers are associated with mortality and severity of respiratory illness at 36-weeks PMA.
Aim 3 will identify which echocardiographic predictors and biomarkers are associated with 22- to 26-month neurodevelopment. All models will be validated in a separate cohort of infants. This project will significantly contribute to clinical outcomes and management of PDA 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.

Public Health Relevance

As more infants are surviving premature birth, patent ductus arteriosus (PDA), the delayed closure of a fetal blood vessel that limits blood flow through the lungs, can have serious public health implications on this vulnerable population. Since increasing evidence indicates that expensive or invasive pharmacologic or surgical PDA closure is not always needed, this project is relevant to NIH's mission to understand the processes of human growth and development by determining whether, and at what age, a preterm infant's untreated PDA is likely to close on its own, and predicting which preterm infants with PDA are at highest risk for PDA-associated mortality, respiratory disease, and/or neurodevelopmental delays.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cancer, Heart, and Sleep Epidemiology A Study Section (CHSA)
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Burns, Kristin
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Nationwide Children's Hospital
United States
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