Early prediction of spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation

Carl H. Backes,Jonathan L. Slaughter,Jennifer L. Notestine,Laura Marzec,Clifford L. Cua,Brian K. Rivera,Dennis J. Lewandowski,Mark A. Klebanoff,Erinn M. Hade,Megan Ilgenfritz,Nathalie L. Maitre,Vi T. Le

doi:10.1186/s12887-019-1708-z

Carl H. Backes, Jonathan L. Slaughter + Show 10 more

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https://doi.org/10.1186/s12887-019-1708-z

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Abstract

BackgroundPatent ductus arteriosus (PDA), the most commonly diagnosed cardiovascular condition in preterm infants, is associated with increased mortality and harmful long-term outcomes (chronic lung disease, 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 outcomes. Most PDAs close spontaneously by 44-weeks postmenstrual age; treatment is increasingly controversial, varying markedly between institutions and providers. Because treatment detriments may outweigh benefits, especially in infants destined for early, spontaneous PDA closure, the relevant unanswered clinical question is not whether to treat all preterm infants with PDA, but whom to treat (and when). Clinicians cannot currently predict in the first month which infants are at highest risk for persistent PDA, nor which combination of clinical risk factors, echocardiographic measurements, and biomarkers best predict PDA-associated harm.MethodsProspective cohort of untreated infants with PDA (n=450) will be used to predict spontaneous ductal closure timing. Clinical measures, serum (brain natriuretic peptide, N-terminal pro-brain natriuretic peptide) and urine (neutrophil gelatinase-associated lipocalin, heart-type fatty acid-binding protein) biomarkers, and echocardiographic variables collected during each of first 4 postnatal weeks will be analyzed to identify those associated with long-term impairment. Myocardial deformation imaging and tissue Doppler imaging, innovative echocardiographic techniques, will facilitate quantitative evaluation of myocardial performance. Aim1 will estimate probability of spontaneous PDA closure and predict timing of ductal closure using echocardiographic, biomarker, and clinical predictors. Aim2 will specify which echocardiographic predictors and biomarkers are associated with mortality and respiratory illness severity at 36-weeks postmenstrual age. Aim3 will identify which echocardiographic predictors and biomarkers are associated with 22 to 26-month neurodevelopmental delay. Models will be validated in a separate cohort of infants (n=225) enrolled subsequent to primary study cohort.DiscussionThe current study will make significant contributions to scientific knowledge and effective PDA management. Study results will reduce unnecessary and harmful overtreatment of infants with a high probability of early spontaneous PDA closure and facilitate development of outcomes-focused trials to examine effectiveness of PDA closure in “high-risk” infants most likely to receive benefit.Trial registrationClinicalTrials.gov NCT03782610. Registered 20 December 2018.

Highlights

Patent ductus arteriosus (PDA), the most commonly diagnosed cardiovascular condition in preterm infants, is associated with increased mortality and harmful long-term outcomes
Because the majority of PDAs in preterm infants close spontaneously by 44-weeks postmenstrual age (PMA) when left untreated, the frequencies of both early medication treatment and surgical or catheter-based closure ligation for persistent PDA have declined over the last decade [17,18,19,20]
The objectives of this study are to use a prospective cohort of untreated preterm infants with PDA to accurately predict the timing of spontaneous ductal closure in preterm infants with PDA, and the identification of measurable echocardiographic predictors and biomarkers that are present in the first postnatal month that are associated with mortality, chronic lung disease (CLD), and long-term neurological impairment

Summary

Introduction

Patent ductus arteriosus (PDA), the most commonly diagnosed cardiovascular condition in preterm infants, is associated with increased mortality and harmful long-term outcomes (chronic lung disease, neurodevelopmental delay). Patent ductus arteriosus (PDA), the most commonly diagnosed cardiovascular condition in preterm infants, is associated with an eight-fold increase in mortality [1] and multiple, harmful longer-term outcomes including bronchopulmonary dysplasia (BPD) [2,3,4], intestinal injury [5, 6], brain damage [3, 7,8,9], cerebral volume loss [10, 11], and congestive heart failure [12, 13]. The effectiveness of more selective PDA treatment closure strategies remains unclear [3, 12, 13]

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