Atasay, Begüm

Erdeve, Ömer

Sallmon, Hannes

Singh, Yogen

Apollo (Cambridge)

EDITORIALpublished: 14 April 2021doi: 10.3389/fped.2021.681393Frontiers in Pediatrics | www.frontiersin.org 1 April 2021 | Volume 9 | Article 681393Edited and reviewed by:Arjan Te Pas,Leiden University, Netherlands*Correspondence:Hannes Sallmonhannes.sallmon@charite.de†These authors have contributedequally to this workSpecialty section:This article was submitted toNeonatology,a section of the journalFrontiers in PediatricsReceived: 16 March 2021Accepted: 22 March 2021Published: 14 April 2021Citation:Atasay B, Erdeve Ö, Sallmon H andSingh Y (2021) Editorial: Managementof Patent Ductus Arteriosus in PretermInfants. Front. Pediatr. 9:681393.doi: 10.3389/fped.2021.681393Editorial: Management of PatentDuctus Arteriosus in Preterm InfantsBegüm Atasay 1†, Ömer Erdeve 1†, Hannes Sallmon 2,3*† and Yogen Singh 4,5†1Division of Neonatology, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey, 2Department ofPediatric Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany, 3Department of Congenital Heart Disease,Pediatric Cardiology, Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany, 4Department of Neonatology and PediatricCardiology, Cambridge University Hospitals, Cambridge, United Kingdom, 5University of Cambridge School of ClinicalMedicine, Cambridge, United KingdomKeywords: neonate, hemodynamics, very low birth weight, ibuprofen, indomethacin, catheter intervention,surgical ligationEditorial on the Research TopicManagement of Patent Ductus Arteriosus in Preterm InfantsSince the first known description of the human ductus arteriosus by Galen almost 2,000 yearsago, basic scientists and medical professionals have extensively researched the ductus arteriosus(1, 2). In 1938, surgical patent ductus arteriosus (PDA) closure was the first corrective surgeryperformed for congenital heart disease by Robert E. Gross in Boston. Furthermore, interventionaltranscatheter PDA closure was described in 1967 by Werner Porstmann at the Charité Hospital inBerlin (1–3). In addition, the pivotal roles of prostaglandins and oxygen and their mechanismsin mediating DA closure were uncovered during the 1970’s, which led to the introduction ofpharmacological therapies for preterm infants with PDA (1–3). However, despite over 15,000Medline-listed publications related to the ductus (4), the PDA of preterm infants remains anelusive condition that still challenges neonatologists and pediatric cardiologists today. Specifically,there is significant uncertainty on when and how ductus arteriosus closure in preterm infantsshould be attempted (5, 6). Due to a high spontaneous closure rate even in very immaturepreterm infants, an expectant approach may be justified in numerous cases (7). On the otherhand, certain selected infants with hemodynamically significant PDA (hsPDA) may benefit fromintervention, be it pharmacological, interventional, or surgical (8, 9). However, there is noconsensus on the clinical and echocardiographic definition of hsPDA (10). In addition, althougha hsPDA may have an impact on common neonatal morbidities such as bronchopulmonarydysplasia (BPD), pulmonary and intraventricular hemorrhage (IVH), necrotizing enterocolitis(NEC), retinopathy of prematurity, neurodevelopmental impairment, and eventually mortality,clear evidence for a causal relationship between hsPDA and these conditions is scarce (5–10).Within this Research Topic we present a collection of 24 articles, including 13 original articles,6 systematic reviews/meta-analyses, and 6 review articles, that cover different aspects of PDA inpreterm infants.First, in a comprehensive review article, Ovali provides an overview on molecular andmechanical mechanisms that regulate ductus arteriosus closure in human preterm infants. Besidesa detailed description of biochemical and molecular pathways involved in physiological ductusarteriosus closure, the author also describes signaling and cellular pathways that contribute topersistently PDA in preterm infants. In their mini-review and systematic review articles, Sallmonet al. and Gonzalález-Luis et al. specifically focus on the controversial role of platelets in humanpreterm ductus arteriosus closure. Their combined evidence suggests that low platelet countsare associated with PDA in preterm infants, while the clinical significance of these findings isstill unclear. The meta-analysis by Liu et al. further explores risk and outcome factors that areAtasay et al. Editorial: PDA in Preterm Infantsassociated with PDA in preterm infants. The authors foundsignificant associations between PDA and immaturity,chorioamnionitis, sepsis and respiratory distress, but alsobetween PDA and BPD, IVH and NEC, among others. However,the causality between those associations remains unclear.Canpolat et al. present additional data that suggest thatsurfactant application beyond the first 2 h of life is associatedwith a higher incidence of PDA as compared to earliersurfactant administration.In the next article, Singh et al. provide an overview onthe echocardiographic diagnosis and hemodynamic evaluationof PDA with a special focus on extremely low gestationalage newborn infants. In a retrospective cohort study ofpreterm infants, Choi et al. further explore the relationshipbetween echocardiographically determined ductal size, markersof shunt volume, and postnatal age. They report that ductalsize within the first 3 days of life cannot adequately predictshunt magnitude, thus highlighting the need for a morecomplex echocardiographic evaluation of the rapidly evolvinghemodynamic changes that occur during the first few daysof life.The important topic of spontaneous PDA closure is coveredby a systemic review article by de Klerk et al.. In anotheroriginal article, Bravo et al. describe a predictive model forspontaneous PDA closure, which is based on echocardiographyand gestational age. In addition, Gonen et al. present theirpilot study on a scoring system for early prediction ofhsPDA development, which is entirely based on clinical criteriawithout echocardiographic examination. Three further originalarticles by Huizing et al., Coviello et al., and Bardanzelluet al. examine the associations between plasma amino acids,isoprostanes, and urinary metabolomics and PDA, respectively.Beyond, exploring the potential use of those substances asearly biomarkers, these investigations may also stipulate furthermechanistic research on the role of certain metabolites inneonatal PDA biology.The following articles focus on different aspects of treatmentin preterm infants with PDA. Nowadays, several cliniciansprefer a conservative management approach in most infantswith PDA. Sung et al. provide an overview on this optionwith a special focus on extremely immature infants. In theirmeta-analysis, Hundscheid et al. compare outcome measuresbetween retrospective and randomized controlled trial data onconservative PDA management. The authors conclude that therestill is a lack of high-quality studies on conservative PDAmanagement. Likewise, a meta-analysis by Jansen et al. whichfocusses on factors associated with benefit of PDA treatment,acknowledges a low quality of available evidence. In theiranalysis, the only benefit of PDA treatment was a reduction inIVH rate in certain infants, while other outcome parameterswere not influenced by PDA treatment. In a prospective,observational cohort study comparing conservative and medicalPDA management, Okulu et al. fail to demonstrate anyassociation between PDA treatment and outcome improvement.Of note, the authors even observed higher rates of BPDand mortality in infants treated before the first 7 days oflife as compared to those treated later and those who weremanaged conservatively. Two further original articles focuson different approaches to identify at-risk infants, therebylimiting the potential exposure to PDA therapies. Firstly,Terrin et al. present their initial results on echocardiography-guided PDA therapy and, secondly, Ibrahim et al. report ontheir experience after introduction of a selective treatmentapproach limited to high-risk infants ≤ 800 g or < 27 weeks ofgestational age.Next, Parkerson et al. present an excellent overview oncontemporary PDA-management strategies based on theirpioneer role in establishing transcatheter PDA closure asan alternative therapeutic option in very immature infants.Besides interventional approaches, the authors also coverconservative, pharmacologic and surgical treatment options.Interventional PDA closure in extremely premature infants isfurther discussed in detail in a review article by Fraisse et al.who advocate for a validation of the initially promising resultson interventional PDA closure by randomized controlled trials.While transcatheter PDA closure has been approved for infants≥ 700 g and after 3 days of birth, surgical PDA ligation may stillbe required in smaller infants and in PDA which are not suitablefor interventional closure. Olsson et al. present their results froma matched-cohort study on extremely preterm infants with andwithout PDA ligation. They show that infants in the ligatedgroup exhibited a higher rate of severe BPD, but did not differotherwise from the non-ligated group. Furthermore, Yang et al.report on their initial experience with PDA ligation in infantswith a bidirectional shunt pattern, traditionally considered acontraindication for PDA closure. They suggest that selectedinfants with bidirectional shunt may benefit from PDA closure,although a higher perioperative risk needs to be weighed againstthe potential benefits of closure. Finally, Engeseth et al. showthat infants who underwent surgical PDA ligation showeda higher incidence of exercise-induced breathing and voiceproblems during mid-childhood as compared to infants withoutPDA surgery.In conclusion, despite an improved pathophysiologicunderstanding of PDA, the articles presented in this ResearchTopic of Frontiers in Pediatrics illustrate that several aspectsof PDA management in preterm infants are still controversial.While a growing body of evidence suggests that a conservativeapproach is safe and efficient in most infants, the identificationof selected at-risk patients who likely benefit from treatmentis of utmost importance in order to provide tailored-care(5–9). Careful clinical and echocardiographic examinations arerequired to understand the current hemodynamic situation ofeach patient at each given time point. However, standardizedvalidated protocols for hsPDA assessment are still lacking(5, 10). Furthermore, the optimal timing of treatmentand the choice of the therapeutic modality (conservative,pharmacologic, interventional, surgical) are still subject todebate (5–8). Thus, there is a need for additional randomized-controlled trials that specifically address these issues in thehigh-risk population of extremely immature infants with PDA(9). In the meantime, adopting an individualized approachbased upon clinical and echocardiography parameters seemssensible and appropriate. We hope that the collection ofFrontiers in Pediatrics | www.frontiersin.org 2 April 2021 | Volume 9 | Article 681393Atasay et al. Editorial: PDA in Preterm Infantsarticles presented herein will further stipulate researchefforts in order to optimize the care of preterm infantswith PDA.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct and intellectualcontribution to the work, and approved it for publication.ACKNOWLEDGMENTSWe thank Professor Vineet Bhandari, Professor EugeneDempsey, and Professor Gunnar Naulaers for their editing work.They provided assistance where we had shared affiliations withthe authors of the papers. We also acknowledge the invaluablecontributions made by the peer reviewers of each article and theoffice support from the staff at Frontiers in Pediatrics.REFERENCES1. Raju TNK. From Galen to Gross and beyond: a brief history ofthe enigmatic patent ductus arteriosus. J Perinatol. (2019) 39:1442–8. doi: 10.1038/s41372-019-0517-42. Obladen M. History of the ductus arteriosus: 1. Anatomy and spontaneousclosure. Neonatology. (2011) 99:83–9. doi: 10.1159/0003083673. Obladen M. History of the ductus arteriosus: 2. Persisting patency in thepreterm infant. Neonatology. (2011) 99:163–9. doi: 10.1159/0003084484. Available online at: https://www.ncbi.nlm.nih.gov/search/all/?term=%22ductus$+$arteriosus%22 (accessed March 13, 2021).5. Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J,et al. Patent ductus arteriosus of the preterm infant. Pediatrics. (2020)146:e20201209. doi: 10.1542/peds.2020-12096. Smith A, El-Khuffash A. Patent ductus arteriosus clinical trials: lessons learnedand future directions. Children. (2021) 8:47. doi: 10.3390/children80100477. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson SLet al. PDA-TOLERATE trial: an exploratory randomized controlled trial oftreatment of moderate-to-large patent ductus arteriosus at 1 week of age. JPediatr. (2019) 205:41–8.e6. doi: 10.1016/j.jpeds.2018.09.0128. Gillam-Krakauer M, Hagadorn JI, Reese J. Pharmacological closure of thepatent ductus arteriosus: when treatment still makes sense. J Perinatol. (2019)39:1439–41. doi: 10.1038/s41372-019-0518-39. Mitra S, McNamara PJ. Patent ductus arteriosus-time for a definitive trial.ClinPerinatol. (2020) 47:617–39. doi: 10.1016/j.clp.2020.05.00710. Smith A, El-Khuffash AF. Defining “Haemodynamic significance” of thepatent ductus arteriosus: do we have all the answers? Neonatology. (2020)117:225–32. doi: 10.1159/000506988Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2021 Atasay, Erdeve, Sallmon and Singh. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Pediatrics | www.frontiersin.org 3 April 2021 | Volume 9 | Article 681393

Editorial: Management of Patent Ductus Arteriosus in Preterm Infants

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Editorial: Management of Patent Ductus Arteriosus in Preterm Infants

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