UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Management of patent ductus arteriosus in preterm infants

Author
Joseph B Philips III, MD, FAAP
Section Editors
Joseph A Garcia-Prats, MD
David R Fulton, MD
Deputy Editor
Melanie S Kim, MD

INTRODUCTION

During fetal life, the ductus arteriosus (DA) diverts blood from the pulmonary artery into the aorta, thereby bypassing the lungs (figure 1). After birth, the DA undergoes active constriction and eventual obliteration. A patent ductus arteriosus (PDA) occurs when the DA fails to completely close after delivery.

Preterm infants with moderate to large left-to-right shunts have a greater mortality rate than those without a PDA. They also have an increased risk of pulmonary edema and hemorrhage and bronchopulmonary dysplasia, as well as a decrease in perfusion and oxygen delivery to end-organs. As a result, management of preterm infants with clinically significant PDAs has been focused on PDA closure and prevention. The management of PDA in preterm infants will be reviewed here. The pathophysiology, clinical manifestations, and diagnosis of PDA in preterm infants are reviewed separately. (See "Pathophysiology, clinical manifestations, and diagnosis of patent ductus arteriosus in premature infants".)

OVERVIEW

Treatment and prevention — Over the last several decades, research efforts have focused on preventing and closing PDA in preterm infants. Current practice is primarily focused on PDA closure, as the benefit of preventive measures to reduce the incidence of PDA appears to be outweighed by the adverse effects of prophylactic therapy. (See 'Prophylactic therapy' below.)

The management of PDA in preterm infants includes three different approaches:

Conservative management with supportive therapy alone

                              

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Tue Nov 08 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Benitz WE, Committee on Fetus and Newborn, American Academy of Pediatrics. Patent Ductus Arteriosus in Preterm Infants. Pediatrics 2016; 137.
  2. Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed 2014; 99:F99.
  3. Rozé JC, Cambonie G, Marchand-Martin L, et al. Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants. JAMA 2015; 313:2441.
  4. Cotton RB, Lindstrom DP, Kanarek KS, et al. Effect of positive-end-expiratory-pressure on right ventricular output in lambs with hyaline membrane disease. Acta Paediatr Scand 1980; 69:603.
  5. Lister G, Hellenbrand WE, Kleinman CS, Talner NS. Physiologic effects of increasing hemoglobin concentration in left-to-right shunting in infants with ventricular septal defects. N Engl J Med 1982; 306:502.
  6. Green TP, Thompson TR, Johnson DE, Lock JE. Furosemide promotes patent ductus arteriosus in premature infants with the respiratory-distress syndrome. N Engl J Med 1983; 308:743.
  7. Andriessen P, Struis NC, Niemarkt H, et al. Furosemide in preterm infants treated with indomethacin for patent ductus arteriosus. Acta Paediatr 2009; 98:797.
  8. Stephens BE, Gargus RA, Walden RV, et al. Fluid regimens in the first week of life may increase risk of patent ductus arteriosus in extremely low birth weight infants. J Perinatol 2008; 28:123.
  9. Friedman WF, Hirschklau MJ, Printz MP, et al. Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med 1976; 295:526.
  10. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Engl J Med 1976; 295:530.
  11. Jones LJ, Craven PD, Attia J, et al. Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Arch Dis Child Fetal Neonatal Ed 2011; 96:F45.
  12. Gersony WM, Peckham GJ, Ellison RC, et al. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr 1983; 102:895.
  13. Bagnoli F, Rossetti A, Messina G, et al. Treatment of patent ductus arteriosus (PDA) using ibuprofen: renal side-effects in VLBW and ELBW newborns. J Matern Fetal Neonatal Med 2013; 26:423.
  14. Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Neonatology 2012; 102:9.
  15. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2015; :CD003481.
  16. Noori S, Seri I. Treatment of the patent ductus arteriosus: when, how, and for how long? J Pediatr 2009; 155:774.
  17. Yeh TF, Achanti B, Patel H, Pildes RS. Indomethacin therapy in premature infants with patent ductus arteriosus--determination of therapeutic plasma levels. Dev Pharmacol Ther 1989; 12:169.
  18. Gal P, Ransom JL, Schall S, et al. Indomethacin for patent ductus arteriosus closure. Application of serum concentrations and pharmacodynamics to improve response. J Perinatol 1990; 10:20.
  19. Gal P, Ransom JL, Weaver RL, et al. Indomethacin pharmacokinetics in neonates: the value of volume of distribution as a marker of permanent patent ductus arteriosus closure. Ther Drug Monit 1991; 13:42.
  20. Herrera C, Holberton J, Davis P. Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev 2007; :CD003480.
  21. Carmo KB, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. J Pediatr 2009; 155:819.
  22. Davis JM, Hendricks-Munoz KD, Hagberg D, Manning JA. The effects of indomethacin on renal function and intracranial hemorrhage in infants with patent ductus arteriosus. Dev Pharmacol Ther 1990; 14:15.
  23. Seri I, Tulassay T, Kiszel J, Csömör S. The use of dopamine for the prevention of the renal side effects of indomethacin in premature infants with patent ductus arteriosus. Int J Pediatr Nephrol 1984; 5:209.
  24. Brion LP, Campbell DE. Furosemide for symptomatic patent ductus arteriosus in indomethacin-treated infants. Cochrane Database Syst Rev 2001; :CD001148.
  25. Rasmussen LF, Ahlfors CE, Wennberg RP. Displacement of bilirubin from albumin by indomethacin. J Clin Pharmacol 1978; 18:477.
  26. Zecca E, Romagnoli C, De Carolis MP, et al. Does Ibuprofen increase neonatal hyperbilirubinemia? Pediatrics 2009; 124:480.
  27. Ahlfors CE. Effect of ibuprofen on bilirubin-albumin binding. J Pediatr 2004; 144:386.
  28. Rheinlaender C, Helfenstein D, Walch E, et al. Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants. Acta Paediatr 2009; 98:36.
  29. Desfrere L, Thibaut C, Kibleur Y, et al. Unbound bilirubin does not increase during ibuprofen treatment of patent ductus arteriosus in preterm infants. J Pediatr 2012; 160:258.
  30. Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. J Pediatr 2012; 160:929.
  31. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996; 128:601.
  32. Gudmundsdottir A, Johansson S, Håkansson S, et al. Timing of pharmacological treatment for patent ductus arteriosus and risk of secondary surgery, death or bronchopulmonary dysplasia: a population-based cohort study of extremely preterm infants. Neonatology 2015; 107:87.
  33. Chorne N, Jegatheesan P, Lin E, et al. Risk factors for persistent ductus arteriosus patency during indomethacin treatment. J Pediatr 2007; 151:629.
  34. Kim ES, Kim EK, Choi CW, et al. Intrauterine inflammation as a risk factor for persistent ductus arteriosus patency after cyclooxygenase inhibition in extremely low birth weight infants. J Pediatr 2010; 157:745.
  35. Richards J, Johnson A, Fox G, Campbell M. A second course of ibuprofen is effective in the closure of a clinically significant PDA in ELBW infants. Pediatrics 2009; 124:e287.
  36. Keller RL, Clyman RI. Persistent Doppler flow predicts lack of response to multiple courses of indomethacin in premature infants with recurrent patent ductus arteriosus. Pediatrics 2003; 112:583.
  37. van der Lugt NM, Lopriore E, Bökenkamp R, et al. Repeated courses of ibuprofen are effective in closure of a patent ductus arteriosus. Eur J Pediatr 2012; 171:1673.
  38. Weber SC, Weiss K, Bührer C, et al. Natural History of Patent Ductus Arteriosus in Very Low Birth Weight Infants after Discharge. J Pediatr 2015; 167:1149.
  39. Bellander M, Ley D, Polberger S, Hellström-Westas L. Tolerance to early human milk feeding is not compromised by indomethacin in preterm infants with persistent ductus arteriosus. Acta Paediatr 2003; 92:1074.
  40. Louis D, Torgalkar R, Shah J, et al. Enteral feeding during indomethacin treatment for patent ductus arteriosus: association with gastrointestinal outcomes. J Perinatol 2016; 36:544.
  41. Clyman R, Wickremasinghe A, Jhaveri N, et al. Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus. J Pediatr 2013; 163:406.
  42. Dang D, Wang D, Zhang C, et al. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 2013; 8:e77888.
  43. Allegaert K, Anderson B, Simons S, van Overmeire B. Paracetamol to induce ductus arteriosus closure: is it valid? Arch Dis Child 2013; 98:462.
  44. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database Syst Rev 2015; :CD010061.
  45. Terrin G, Conte F, Oncel MY, et al. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016; 101:F127.
  46. Roofthooft DW, van Beynum IM, de Klerk JC, et al. Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure. Eur J Pediatr 2015; 174:1433.
  47. Valerio E, Valente MR, Salvadori S, et al. Intravenous paracetamol for PDA closure in the preterm: a single-center experience. Eur J Pediatr 2016; 175:953.
  48. Clyman RI. Ibuprofen and patent ductus arteriosus. N Engl J Med 2000; 343:728.
  49. Clyman R, Cassady G, Kirklin JK, et al. The role of patent ductus arteriosus ligation in bronchopulmonary dysplasia: reexamining a randomized controlled trial. J Pediatr 2009; 154:873.
  50. Mirea L, Sankaran K, Seshia M, et al. Treatment of patent ductus arteriosus and neonatal mortality/morbidities: adjustment for treatment selection bias. J Pediatr 2012; 161:689.
  51. El-Khuffash AF, Jain A, McNamara PJ. Ligation of the patent ductus arteriosus in preterm infants: understanding the physiology. J Pediatr 2013; 162:1100.
  52. Dimas VV, Takao C, Ing FF, et al. Outcomes of transcatheter occlusion of patent ductus arteriosus in infants weighing ≤ 6 kg. JACC Cardiovasc Interv 2010; 3:1295.
  53. Backes CH, Cheatham SL, Deyo GM, et al. Percutaneous Patent Ductus Arteriosus (PDA) Closure in Very Preterm Infants: Feasibility and Complications. J Am Heart Assoc 2016; 5.
  54. Zahn EM, Nevin P, Simmons C, Garg R. A novel technique for transcatheter patent ductus arteriosus closure in extremely preterm infants using commercially available technology. Catheter Cardiovasc Interv 2015; 85:240.
  55. Francis E, Singhi AK, Lakshmivenkateshaiah S, Kumar RK. Transcatheter occlusion of patent ductus arteriosus in pre-term infants. JACC Cardiovasc Interv 2010; 3:550.
  56. Kaempf JW, Wu YX, Kaempf AJ, et al. What happens when the patent ductus arteriosus is treated less aggressively in very low birth weight infants? J Perinatol 2012; 32:344.
  57. Bose CL, Laughon MM. Patent ductus arteriosus: lack of evidence for common treatments. Arch Dis Child Fetal Neonatal Ed 2007; 92:F498.
  58. Sung SI, Chang YS, Chun JY, et al. Mandatory Closure Versus Nonintervention for Patent Ductus Arteriosus in Very Preterm Infants. J Pediatr 2016; 177:66.
  59. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol 2010; 30:241.
  60. Benitz WE. Patent ductus arteriosus: to treat or not to treat? Arch Dis Child Fetal Neonatal Ed 2012; 97:F80.
  61. Madan JC, Kendrick D, Hagadorn JI, et al. Patent ductus arteriosus therapy: impact on neonatal and 18-month outcome. Pediatrics 2009; 123:674.
  62. Alexander F, Chiu L, Kroh M, et al. Analysis of outcome in 298 extremely low-birth-weight infants with patent ductus arteriosus. J Pediatr Surg 2009; 44:112.
  63. Janz-Robinson EM, Badawi N, Walker K, et al. Neurodevelopmental Outcomes of Premature Infants Treated for Patent Ductus Arteriosus: A Population-Based Cohort Study. J Pediatr 2015; 167:1025.
  64. Cordero L, Nankervis CA, Delooze D, Giannone PJ. Indomethacin prophylaxis or expectant treatment of patent ductus arteriosus in extremely low birth weight infants? J Perinatol 2007; 27:158.
  65. Schmidt B, Roberts RS, Fanaroff A, et al. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr 2006; 148:730.
  66. Bose CL, Laughon M. Treatment to prevent patency of the ductus arteriosus: beneficial or harmful? J Pediatr 2006; 148:713.
  67. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010; :CD000174.
  68. Gournay V, Savagner C, Thiriez G, et al. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002; 359:1486.
  69. Gournay V, Roze JC, Kuster A, et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:1939.
  70. Van Overmeire B, Allegaert K, Casaer A, et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:1945.
  71. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2011; :CD004213.
  72. Härkin P, Härmä A, Aikio O, et al. Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. J Pediatr 2016; 177:72.
  73. van den Anker JN, Allegaert K. Acetaminophen to Prevent Symptomatic Patent Ductus Arteriosus: Another Drug Bites the Dust? J Pediatr 2016; 177:7.
  74. Sellmer A, Bjerre JV, Schmidt MR, et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013; 98:F505.
  75. Brooks JM, Travadi JN, Patole SK, et al. Is surgical ligation of patent ductus arteriosus necessary? The Western Australian experience of conservative management. Arch Dis Child Fetal Neonatal Ed 2005; 90:F235.
  76. Noori S, McCoy M, Friedlich P, et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics 2009; 123:e138.
  77. Kabra NS, Schmidt B, Roberts RS, et al. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr 2007; 150:229.
  78. Chorne N, Leonard C, Piecuch R, Clyman RI. Patent ductus arteriosus and its treatment as risk factors for neonatal and neurodevelopmental morbidity. Pediatrics 2007; 119:1165.
  79. Wickremasinghe AC, Rogers EE, Piecuch RE, et al. Neurodevelopmental outcomes following two different treatment approaches (early ligation and selective ligation) for patent ductus arteriosus. J Pediatr 2012; 161:1065.
  80. Saldeño YP, Favareto V, Mirpuri J. Prolonged persistent patent ductus arteriosus: potential perdurable anomalies in premature infants. J Perinatol 2012; 32:953.
  81. Clyman RI, Chorne N. Patent ductus arteriosus: evidence for and against treatment. J Pediatr 2007; 150:216.