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CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Patent in Preterm Infants William E. Benitz, MD, FAAP, COMMITTEE ON AND NEWBORN

Despite a large body of basic science and clinical research and clinical abstract experience with thousands of infants over nearly 6 decades,1 there is still uncertainty and controversy about the signifi cance, evaluation, and management of patent ductus arteriosus in preterm infants, resulting in substantial heterogeneity in clinical practice. The purpose of this clinical report is to summarize the evidence available to guide evaluation and treatment of preterm infants with prolonged ductal patency in the fi rst few weeks after birth.

CLINICAL EPIDEMIOLOGY AND NATURAL HISTORY OF PATENT DUCTUS ARTERIOSUS This document is copyrighted and is property of the American In term infants, the ductus arteriosus normally constricts after birth Academy of and its Board of Directors. All authors have and becomes functionally closed by 72 hours of age.2 In preterm fi led confl ict of interest statements with the American Academy of Pediatrics. Any confl icts have been resolved through a process infants, however, closure is delayed, remaining open at 4 days of age in approved by the Board of Directors. The American Academy of approximately 10% of infants born at 30 through 37 weeks’ gestation, Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. 80% of those born at 25 through 28 weeks’ gestation, and 90% of those born at 24 weeks’ gestation.3 By day 7 after birth, those rates decline Clinical reports from the American Academy of Pediatrics benefi t from expertise and resources of liaisons and internal (AAP) and external to approximately 2%, 65%, and 87%, respectively. The ductus is likely reviewers. However, clinical reports from the American Academy of to close without treatment in infants born at >28 weeks’ gestation Pediatrics may not refl ect the views of the liaisons or the organizations or government agencies that they represent. (73%),4 in those with >1000 g (94%),5 and in infants born The guidance in this report does not indicate an exclusive course of at 26 through 29 weeks’ gestation who do not have respiratory distress treatment or serve as a standard of medical care. Variations, taking syndrome (93%).6 Rates of later spontaneous ductal closure among into account individual circumstances, may be appropriate. smaller, less mature infants with respiratory distress syndrome are not All clinical reports from the American Academy of Pediatrics known because of widespread use of treatments to achieve closure of the automatically expire 5 years after publication unless reaffi rmed, revised, or retired at or before that time. patent ductus arteriosus (PDA) in such infants. Data from placebo arms of controlled trials demonstrate that spontaneous ductal closure in these DOI: 10.1542/peds.2015-3730 infants is frequent, however. In the Trial of Indomethacin Prophylaxis PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). in Preterms, for example, which included infants with birth weight from Copyright © 2016 by the American Academy of Pediatrics 500 to 999 g, 50% of placebo recipients never developed clinical signs of a PDA.7 In a trial of early versus late indomethacin treatment of infants born at 26 through 31 weeks’ gestation in whom PDA was confirmed by To cite: Benitz WE and COMMITTEE ON FETUS AND NEWBORN. on day 3, the ductus closed spontaneously by 9 days of Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016;137(1):e20153730 age in 78% of those randomized to late intervention.8

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 :e 20153730 FROM THE AMERICAN ACADEMY OF PEDIATRICS While the ductus remains open, In addition to the presence of a for identification of infants at greatest typically flows left-to-right from the classic coarse systolic murmur at the risk for adverse sequelae have been into the pulmonary arteries. left sternal border, affected infants delineated. The predictive values As pulmonary vascular resistance may have an increased precordial of individual echocardiographic declines over the first several impulse, prominent or bounding measurements are low, but some days after birth, the proportion of arterial pulses, palpable pulses in the progress has been made toward aortic blood flow that is diverted palms of the hands, and either low correlation of composite scores into the pulmonary circulation systolic and diastolic with risks of adverse long-term correspondingly increases. This or low diastolic blood pressure outcome, including BPD18 or “ductal steal” results in excessive with a widened . neurodevelopmental outcome blood flow through the lungs, Nevertheless, these findings are at 2 years of age.12 Exploratory predisposing to development of nonspecific, do not correlate well studies suggest that elevated pulmonary congestion, pulmonary with echocardiographic findings,10 concentrations of either N-terminal edema, and worsening respiratory and have not been shown to reliably of the prohormone BNP or troponin failure. Diversion of blood flow predict responses to treatment or T at 48 hours of age may help from the systemic circulation may sequelae. In many instances, the predict death or severe IVH19 as exceed capabilities for compensatory presence of a large ductal shunt well as neurodevelopment at 2 increases in total , is suspected only on the basis years of age.12 The presence of a resulting in compromised perfusion of respiratory findings, such as “hemodynamically significant” PDA of vital organs, including bowel, radiographic signs of pulmonary has been correlated with lower kidney, and brain. Prolonged congestion, increasing requirements regional cerebral oxygen saturation patency is associated with for supplemental oxygen, or inability and higher fractional oxygen numerous adverse outcomes, to reduce mechanical ventilator extraction20 and with reduced including prolongation of assisted support. The presence of a PDA is celiac artery flow,21 supporting ventilation and higher rates of death, most definitively demonstrated by the hypothesis that prolonged bronchopulmonary dysplasia (BPD), color , ductal patency may have a causal pulmonary hemorrhage, necrotizing which permits confirmation of ductal role in substantial and enduring enterocolitis, impaired renal function, patency, measurement of ductal adverse outcomes. Development intraventricular hemorrhage (IVH), dimensions, and assessment of the of an integrated definition of periventricular leukomalacia, direction and velocity of ductal blood “hemodynamic significance” of PDA and cerebral palsy.9 The extent to flow throughout the cardiac cycle. will be essential to risk stratification which these adverse outcomes are Substantial ductal shunting may be for clinical trials of PDA treatment, attributable to the hemodynamic associated with an increased ratio of but this goal remains elusive. consequences of ductal patency, if left atrial to aortic root dimensions at all, has not been established. The ≥1.5:1, ductal diameter ≥1.5 mm, strength of these associations led to left ventricular volume and pressure EVIDENCE FOR BENEFITS OF the hypothesis that intervention to loading, and reversal of diastolic TREATMENT close the ductus might prevent or flow in the descending aorta or Since the early reports of feasibility reduce the severity of these common in cerebral or renal arteries.11,12 of surgical closure22 and efficacy complications of prematurity. The Serum concentrations of natriuretic of nonsteroidal antiinflammatory expectation that this hypothesis peptides (BNP or N-terminal of the drugs for medical treatment23,24 of would be confirmed, in turn, prohormone BNP) are elevated PDA, results have been reported resulted in widespread adoption of in preterm infants with PDA,13,14 for 50 randomized controlled trials interventions designed to achieve correlate with echocardiographic enrolling 4878 preterm infants.9,25 early closure of the ductus in preterm measures of shunt volume,14–16 and Although medical and surgical infants. decrease after ductal closure.14,16 treatments are efficacious in closing Concentrations of troponin T at 48 the PDA in a large proportion of hours of age are higher in infants infants, neither individual clinical ASSESSMENT OF HEMODYNAMIC with PDA.17 trials nor meta-analyses have SIGNIFICANCE demonstrated that closing the The hemodynamic effects of a large The term “hemodynamically ductus results in improved long- left-to-right shunt associated with significant” is frequently used to term outcomes. Odds ratios for a PDA may be evident by physical differentiate consequential from the most important outcomes examination, echocardiography, or inconsequential PDA. Neither the (BPD, necrotizing enterocolitis, measurement of serum biomarkers. best tool nor the optimal thresholds neurosensory impairment, death,

Downloaded from www.aappublications.org/news by guest on September 24, 2021 e2 FROM THE AMERICAN ACADEMY OF PEDIATRICS the combined outcomes of death Although surgical ligation is effective significantly compromised outcomes, or BPD and death or neurosensory for achievement of rapid, complete supporting equipoise regarding impairment) indicate that early, ductal closure, it is often followed by enrollment of preterm infants into routine treatment has no effect, with severe hemodynamic and respiratory randomized trials designed to assess narrow confidence intervals, so it is collapse, requiring marked treatment strategies for preterm unlikely that substantial differences escalation in supportive intensive infants with PDA. 34 have gone undetected.9 When given care. The risk of this as prophylaxis for IVH beginning appears to decline substantially 35 within 12 hours of birth, treatment over the first 6 weeks after birth. CLINICAL TRIAL OPPORTUNITIES with indomethacin reduces rates Long-term complications of of IVH, IVH greater than grade surgical ligation include paresis As previously noted, evidence- of the left vocal cord36,37 or II, and early, severe pulmonary based abandonment of early diaphragm,38 chylothorax,38–40 routine treatment to close the PDA hemorrhage but does not improve and scoliosis,41,42 and infants does not preclude other options long-term neurodevelopmental or who undergo surgical ligation are for management of infants with respiratory outcomes.7,26–28 The more likely to develop BPD,43–45 this condition. First, deciding not early neuroprotective effects of retinopathy of prematurity,45 and to intervene routinely to achieve indomethacin may not depend on neurodevelopmental impairment.45,46 earlier closure of the ductus should effects on ductal patency and are Treatment with cyclooxygenase not imply that consequences of not replicated with similar use inhibitors may lead to impaired renal ductal patency can be completely 29 of . In all published function,47 intestinal perforation,48,49 ignored.55 Although many strategies trials of prophylaxis or treatment, and altered cerebrovascular for management of the consequences interventions were initiated within regulation.50 In contrast to of PDA have been proposed, none 2 weeks after birth for almost all prophylactic use, treatment of have been subjected to systematic subjects in the treatment arms, and confirmed PDA with indomethacin evaluation in clinical trials, which later backup treatment to achieve is associated with an increased risk are urgently needed to guide ductal closure was common among of IVH.9 Treatment to close a patent management of these infants. control subjects.30,31 The available ductus may therefore not be entirely Studies of interventions designed evidence is therefore insufficient benign. to limit excessive pulmonary to permit assessment of potential blood flow (red cell transfusion, benefits of treatments initiated after Clinical experience with less increased positive airway pressure, 2 weeks of age. The cumulative aggressive strategies for PDA correction of alkalosis, avoidance evidence supports the conclusion management suggests that a more of pulmonary vasodilators such as that early (in the first 2 weeks after permissive approach does not oxygen or nitric oxide), to increase birth), routine (as prophylaxis or result in worse outcomes. Strategies systemic cardiac output (dopamine, for infants with echocardiographic avoiding use of indomethacin captopril, avoidance of hypovolemia), confirmation of ductal patency with or ibuprofen yield outcomes to ameliorate pulmonary edema or without clinical signs) treatment comparable to contemporaneous (fluid restriction, diuretics, external benchmarks.51,52 Less correction of hypoproteinemia), or to close the ductus arteriosus does frequent use of surgical ligation to minimize confounding insults not improve long-term outcomes for in infants with PDA after failure (nephrotoxic drugs, systemic preterm infants. There is insufficient of indomethacin prophylaxis was infection/inflammation, , evidence to determine whether associated with a lower rate of hypocarbia) may be appropriate. there are preterm infants who necrotizing enterocolitis and no Second, early identification of a might benefit from early treatment increase in rates of other adverse subset of infants with PDA who are or that later treatment has no outcomes.53 Reduced use of at particular risk on the basis of potential benefit. These data also indomethacin and ligation at 1 center echocardiographic, serum biomarker, cannot be extrapolated to novel was associated with an increased or hemodynamic monitoring (such treatments (such as acetaminophen, rate of the combined outcome of as measurement of cerebral oxygen recently reported to promote ductal death or chronic lung disease but saturation or fractional oxygen closure32,33) because the balance no increase in rates of individual extraction) may allow more selective between beneficial and adverse morbidities or mortality.54 These treatment in the first 2 weeks after effects of new treatments may differ experiences indicate that longer birth. Because few extremely preterm substantially from that for previously periods of exposure to left-to-right infants (those born at ≤25 weeks, studied treatments. ductal shunting may not result in for example) were included in extant

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 e3 trials, they may constitute a high-risk end points are clinically important AAP COMMITTEE ON FETUS AND NEWBORN, group with potential benefit from long-term outcomes and not simply 2014–2015 early, universal treatment. Similarly, rates of ductal closure or measures Kristi L. Watterberg, MD, FAAP, Chairperson criteria for intervention after the of short-term physiologic changes, Susan Aucott, MD, FAAP second postnatal week need to be are essential. In these trials, both William E. Benitz, MD, FAAP developed. Although early experience treatment arms must be explicitly James J. Cummings, MD, FAAP suggested that infants more than defined so that the superior strategy Eric C. Eichenwald, MD, FAAP 10 to 14 days of age are unlikely to can be replicated in clinical practice Jay Goldsmith, MD, FAAP Brenda B. Poindexter, MD, FAAP respond to medical treatment with and evaluated against alternatives Karen Puopolo, MD, FAAP 56,57 ductal closure, other analyses in future trials. If it is not feasible Dan L. Stewart, MD, FAAP have suggested that postmenstrual, to forgo use of rescue treatment Kasper S. Wang, MD, FAAP not postnatal, age is the critical in the control (placebo or late- determinant, with efficacy declining treatment) arm, strict criteria for LIAISONS sharply after approximately 33 to both a required time interval and Captain Wanda D. Barfi eld, MD, MPH, FAAP – 34 weeks’ postmenstrual age.58,59 diagnostic thresholds for such Centers for Disease Control and Prevention Therefore, selective treatment of treatment are desirable. Without James Goldberg, MD – American College of infants born at or before 28 weeks’ clear demonstration that adverse Obstetricians and Gynecologists gestation, who are at highest risk outcomes can be averted by medical Thierry Lacaze, MD – Canadian Pediatric Society Erin L. Keels, APRN, MS, NNP-BC – National of PDA, may remain an option well or surgical closure of the ductus, Association of Neonatal Nurses beyond 2 weeks’ postnatal age. the hypothesis that ductal patency Tonse N.K. Raju, MD, DCH, FAAP – National Deferral of treatment may allow is causal with respect to those Institutes of Health avoidance of treatment of those in outcomes remains unproven. whom spontaneous closure occurs STAFF without seriously compromising Jim Couto, MA the potential efficacy of medical CONCLUSIONS treatment. Delaying ligation may ABBREVIATIONS have similar advantages, avoiding A large body of evidence now exists in many infants in whom the demonstrating that early, routine BPD: bronchopulmonary ductus closes without treatment and treatment to induce closure of the dysplasia reducing the risk of postoperative ductus in preterm infants, either IVH: intraventricular hemorrhage hemodynamic compromise in those medically or surgically, in the PDA: patent ductus arteriosus who do require surgery, particularly first 2 weeks after birth does not if surgery can be deferred until after improve long-term outcomes (level 30 days of age. of evidence: 1A60). The role of more selective use of medical methods for REFERENCES Additional research is needed to induction of ductal closure, either 1. Burnard ED. A murmur from the address 2 broad questions related to for defined high-risk infants in the ductus arteriosus in the newborn prolonged ductal patency in preterm first 2 postnatal weeks, or more baby. 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Downloaded from www.aappublications.org/news by guest on September 24, 2021 e4 FROM THE AMERICAN ACADEMY OF PEDIATRICS 5. Nemerofsky SL, Parravicini E, Bateman a bedside assay for plasma B-type premature infant. N Engl J Med. D, Kleinman C, Polin RA, Lorenz JM. natriuretic peptide as a biomarker 1976;295(10):526–529 The ductus arteriosus rarely requires in the management of patent ductus 24. Heymann MA, Rudolph AM, Silverman treatment in infants > 1000 grams. Am arteriosus in premature neonates. J NH. Closure of the ductus arteriosus J Perinatol. 2008;25(10):661–666 Pediatr. 2005;147(1):38–42 in premature infants by inhibition of 6. Reller MD, Rice MJ, McDonald RW. 15. El-Khuffash AF, Amoruso M, Culliton synthesis. N Engl J Med. Review of studies evaluating ductal M, Molloy EJ. N-terminal pro- 1976;295(10):530–533 patency in the premature infant. J B-type natriuretic peptide as a Pediatr. 1993;122(6):S59–S62 marker of ductal haemodynamic 25. 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Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 e5 33. Oncel MY, Yurttutan S, Erdeve O, et in premature infants. J Pediatr Surg. enterocolitis in preterm infants: al. Oral paracetamol versus oral 1986;21(10):855–857 a 20-year experience. Pediatrics. ibuprofen in the management of patent 43. Chorne N, Leonard C, Piecuch R, 2007;119(1). Available at: www. ductus arteriosus in preterm infants: a Clyman RI. Patent ductus arteriosus pediatrics. org/ cgi/ content/ full/ 119/ 1/ randomized controlled trial. J Pediatr. and its treatment as risk factors for e164 2014;164(3):510–4.e1 neonatal and neurodevelopmental 52. Vanhaesebrouck S, Zonnenberg 34. Teixeira LS, Shivananda SP, Stephens morbidity. Pediatrics. I, Vandervoort P, Bruneel E, Van D, Van Arsdell G, McNamara PJ. 2007;119(6):1165–1174 Hoestenberghe MR, Theyskens C. Postoperative cardiorespiratory 44. Clyman R, Cassady G, Kirklin JK, Conservative treatment for patent instability following ligation of the Collins M, Philips JB III. The role of ductus arteriosus in the preterm. preterm ductus arteriosus is related patent ductus arteriosus ligation Arch Dis Child Fetal Neonatal Ed. to early need for intervention. J in bronchopulmonary dysplasia: 2007;92(4):F244–F247 Perinatol. 2008;28(12):803–810 reexamining a randomized controlled 53. Jhaveri N, Moon-Grady A, Clyman 35. Teixeira LS, McNamara PJ. Enhanced trial. J Pediatr. 2009;154(6):873–876 RI. Early surgical ligation versus intensive care for the neonatal 45. Kabra NS, Schmidt B, Roberts RS, a conservative approach for ductus arteriosus. Acta Paediatr. Doyle LW, Papile L, Fanaroff A; Trial management of patent ductus 2006;95(4):394–403 of Indomethacin Prophylaxis in arteriosus that fails to close after 36. Clement WA, El-Hakim H, Phillipos EZ, Preterms Investigators. Neurosensory indomethacin treatment. J Pediatr. Coté JJ. 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Laryngoscope. treatment approaches (early of the ductus arteriosus in preterm 2009;119(8):1606–1609 ligation and selective ligation) for infants. J Perinatol. 2011;31(suppl 1):S42–S48 38. Mandhan P, Brown S, Kukkady A, patent ductus arteriosus. J Pediatr. 2012;161(6):1065–1072 Samarakkody U. Surgical closure of 56. Halliday HL, Hirata T, Brady JP. patent ductus arteriosus in preterm 47. Fanos V, Benini D, Verlato G, Indomethacin therapy for large low birth weight infants. Congenit Errico G, Cuzzolin L. Effi cacy and patent ductus arteriosus in the Dis. 2009;4(1):34–37 renal tolerability of ibuprofen vs. very low birth weight infant: results 39. Gould DS, Montenegro LM, Gaynor JW, indomethacin in preterm infants with and complications. Pediatrics. et al. A comparison of on-site and off- patent ductus arteriosus. Fundam Clin 1979;64(2):154–159 Pharmacol. 2005;19(2):187–193 site patent ductus arteriosus ligation 57. Smith IJ, Goss I, Congdon PJ. in premature infants. Pediatrics. 48. 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McCarthy JS, Zies LG, Gelband H. ductus arteriosus: does standard 2004;114(6):1649–1657 Age-dependent closure of the patent posterolateral thoracotomy play a 50. Van Bel F, Van de Bor M, Stijnen T, ductus arteriosus by indomethacin. role in the development of the lateral Baan J, Ruys JH. Cerebral blood fl ow Pediatrics. 1978;62(5):706–712 curve of the spine? Pediatr Cardiol. velocity changes in preterm infants 60. Oxford Centre for Evidence-based 2009;30(7):941–945 after a single dose of indomethacin: Medicine—Levels of Evidence. 2009. 42. Shelton JE, Julian R, Walburgh E, duration of its effect. Pediatrics. Available at: http:// www.cebm. Schneider E. Functional scoliosis as 1989;84(5):802–807 net/ oxford- centre- evidence- based- a long-term complication of surgical 51. Pietz J, Achanti B, Lilien L, Stepka EC, medicine- levels- evidence- march- 2009/ . ligation for patent ductus arteriosus Mehta SK. Prevention of necrotizing Accessed June 25, 2015

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Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2015/12/13/peds.2 015-3730 References This article cites 58 articles, 20 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2015/12/13/peds.2 015-3730#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Fetus/Newborn Infant http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 24, 2021 Patent Ductus Arteriosus in Preterm Infants William E. Benitz and COMMITTEE ON FETUS AND NEWBORN Pediatrics originally published online December 15, 2015;

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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