Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?

Journal of Perinatology volume 40, pages 1863–1870 (2020)Cite this article

Subjects

Abstract

Optimal management of patent ductus arteriosus (PDA) in extremely preterm infants remains controversial. There is paucity of evidence on the benefits of PDA treatment in reducing mortality and morbidities in extremely preterm infants. Failure of randomized clinical trials to demonstrate beneficial effects of PDA treatment on outcomes has often been attributed to open treatment of control subjects. This perspective examines the PDA treatment trials to date, with specific focus on rates of and ages of subjects at open rescue treatment. Although these trials demonstrate that ductal closure is significantly increased with treatment, that does not translate to a significant decrease in major morbidities or mortality in premature infants, even when trials with high rates of rescue treatment of controls are excluded. Trials in which enrollment occurred after 7 days of age include insufficient numbers of subjects to evaluate this relationship.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pooled results of randomized-controlled trials of treatment of persistently patent ductus arteriosus in preterm infants.
Fig. 2: Reports of open-label “rescue” treatment in randomized-controlled trials of treatment of persistently patent ductus arteriosus in preterm infants, stratified by age at initial treatment of subjects in the treatment arms.

Similar content being viewed by others

References

  1. Semberova J, Sirc J, Miletin J, Kucera J, Berka I, Sebkova S, et al. Spontaneous closure of patent ductus arteriosus in infants ≤1500 g. Pediatrics. 2017;140:e20164258.

    Article  PubMed  Google Scholar 

  2. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol. 2010;30:241–52.

    Article  CAS  PubMed  Google Scholar 

  3. Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol. 2012;36:123–9.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sankar MN, Bhombal S, Benitz WE. PDA: to treat or not to treat. Congenit Heart Dis. 2019;14:46–51.

    Article  PubMed  Google Scholar 

  5. Benitz WE, Bhombal S. The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants. Semin Fetal Neonatal Med. 2017;22:302–7.

    Article  PubMed  Google Scholar 

  6. Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, Lindqvist J, et al. Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320). J Perinatol. 2019;39:599–607.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Vali P, Lakshminrusimha S, Pelech A, Underwood M, Ing F. Patent ductus arteriosus in preterm infants: is early transcatheter closure a paradigm shift? J Perinatol. 2019;39:1449–61.

    Article  CAS  PubMed  Google Scholar 

  8. Evans N. Preterm patent ductus arteriosus: a continuing conundrum for the neonatologist? Semin Fetal Neonatal Med. 2015;20:272–7.

    Article  PubMed  Google Scholar 

  9. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr. 1996;128:601–7.

    Article  CAS  PubMed  Google Scholar 

  10. Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2003;2:CD003745.

    Google Scholar 

  11. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010;7:CD000174.

    Google Scholar 

  12. Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA. 2018;319:1221–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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. 2018;9:CD003481.

    PubMed  Google Scholar 

  14. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2019;6:CD004213.

    PubMed  Google Scholar 

  15. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 2020;1:CD010061.

    PubMed  Google Scholar 

  16. Asbagh PA, Zarkesh MR, Nili F, Sadat NS, Naeem AT. Prophylactic treatment with oral paracetamol for patent ductus arteriosus in preterm infants: a randomized clinical trial. Tehran Univ Med J. 2015;73:86–92.

    Google Scholar 

  17. Bagnoli F, Rossetti A, Messina G, Mori A, Casucci M, Tomasini B. Treatment of patent ductus arteriosus (PDA) using ibuprofen: renal side-effects in VLBW and ELBW newborns. J Matern Fetal Neonatal Med. 2013;26:423–9.

    Article  CAS  PubMed  Google Scholar 

  18. Ding YJ, Han B, Yang B, Zhu M. NT-proBNP plays an important role in the effect of ibuprofen on preterm infants with patent ductus arteriosus. Eur Rev Med Pharmacol Sci. 2014;18:2596–8.

    PubMed  Google Scholar 

  19. Neu J, Ariagno RL, Johnson JD, Pitlick PT, Cohen RS, Beets CL, et al. A double blind study of the effects of oral indomethacin in preterm infants with patent ductus arteriosus who failed medical management. Pediatr Pharmacol. 1981;1:245–9.

    CAS  Google Scholar 

  20. Cotton RB, Stahlman MT, Bender HW, Graham TP, Catterton WZ, Kovar I. Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. J Pediatr. 1978;93:647–51.

    Article  CAS  PubMed  Google Scholar 

  21. Osborn DA, Evans N, Kluckow M. Effect of early targeted indomethacin on the ductus arteriosus and blood flow to the upper body and brain in the preterm infant. Arch Dis Child Fetal Neonatal Ed. 2003;88:F477–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr. 1983;102:895–906.

    Article  CAS  PubMed  Google Scholar 

  23. Deeks JJ, Higgins JPT, on behalf of the Statistical Methods Group of The Cochrane Collaboration. Statistical algorithms in review manager 5. https://training.cochrane.org/handbook/statistical-methods-revman5 (2010). Accessed 24 August 2020.

  24. Yanagi RM, Wilson A, Newfeld EA, Aziz KU, Hunt CE. Indomethacin treatment for symptomatic patent ductus arteriosus: a double-blind control study. Pediatrics. 1981;67:647–52.

    Article  CAS  PubMed  Google Scholar 

  25. Mahony L, Carnero V, Brett C, Heymann MA, Clyman RI. Prophylactic indomethacin therapy for patent ductus arteriosus in very-low-birth-weight infants. N Engl J Med. 1982;306:506–10.

    Article  CAS  PubMed  Google Scholar 

  26. Nair PAK, Pai MG, Gazal HA, Da Costa DE, Al Khusaiby SM. Indomethacin prophylaxis for intraventricular hemorrhage in very low birth weight babies. Indian Pediatr. 2004;41:551–8.

    Google Scholar 

  27. 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;160:929–35.

    Article  PubMed  Google Scholar 

  28. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, et al. PDA-TOLERATE Trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age. J Pediatr. 2019;205:41–8.

    Article  PubMed  Google Scholar 

  29. Sung SI, Lee MH, Ahn SY, Chang YS, Park WS. Effect of nonintervention vs oral ibuprofen in patent ductus arteriosus in preterm infants: a randomized clinical trial. JAMA Pediatr. 2020. https://jamanetwork.com/journals/jamapediatrics/fullarticle/2766727.

  30. Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J Perinatol. 2003;23:451–6.

    Article  PubMed  Google Scholar 

  31. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ryan R, Hill S. How to GRADE the quality of the evidence [cited 2020 July 24]; Version 3.0. 2016. http://cccrg.cochrane.org/author-resources.

  33. Levitsky S, Fisher E, Vidyasagar D, Hastreiter AR, Bennett E, Raju TN, et al. Interruption of patent ductus arteriosus in premature infants with respiratory distress syndrome. Ann Thorac Surg. 1976;22:131–7.

    Article  CAS  PubMed  Google Scholar 

  34. Cotton RB, Hickey DE, Graham TP, Stahlman MT. Effect of early indomethacin on ventilatory status of preterm infants with symptomatic patent ductus arteriosus [abstract]. Pediatr Res. 1980;14:442.

    Google Scholar 

  35. Nestrud RM, Hill DE, Arrington RW, Beard AG, Dungan WT, Lau PY, et al. Indomethacin treatment in patent ductus arteriosus. A double-blind study utilizing indomethacin plasma levels. Dev Pharmacol Ther. 1980;1:125–36.

    Article  CAS  PubMed  Google Scholar 

  36. Valaes T, Moylan FMB, Cohn H, Chung K, Nagpaul K, Chrenoff HI, et al. Incidence and significance of PDA in preterm infants (PTI) and controlled trial of indomethacin. Pediatr Res. 1980;14:452.

    Article  Google Scholar 

  37. Merritt TA, Harris JP, Roghmann K, Wood B, Campanella V, Alexson C, et al. Early closure of the patent ductus arteriosus in very low-birth-weight infants: a controlled trial. J Pediatr. 1981;99:281–6.

    Article  CAS  PubMed  Google Scholar 

  38. Yeh TF, Luken JA, Thalji A, Raval D, Carr I, Pildes RS. Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus-a double-blind controlled study. J Pediatr. 1981;98:137–45.

    Article  CAS  PubMed  Google Scholar 

  39. Mullett MD, Croghan TW, Myerberg DZ, Krall JM, Neal WA. Indomethacin for closure of patent ductus arteriosus in prematures. Clin Pediatr. 1982;21:217–20.

    Article  CAS  Google Scholar 

  40. Yeh TF, Goldbarg HR, Henek T, Thalji A, Pildes RS. Intravenous indomethacin therapy in premature infants with patent ductus arteriosus. Causes of death and one-year follow-up. Am J Dis Child. 1982;136:803–7.

    Article  CAS  PubMed  Google Scholar 

  41. Kaapa P, Lanning P, Koivisto M. Early closure of patent ductus arteriosus with indomethacin in preterm infants with idiopathic respiratory distress syndrome. Acta Paediatr Scand. 1983;72:179–84.

    Article  CAS  PubMed  Google Scholar 

  42. Monset-Couchard M, Dias-Mancano D, Murat I, Relier JP. Controlled trial of intravenous lyophilized indomethacin in the treatment of persistent ductus arteriosus in premature infants. Pediatrie. 1983;38:365–77.

    CAS  PubMed  Google Scholar 

  43. Rudd P, Montanez P, Hallidie-Smith K, Silverman M. Indomethacin treatment for patent ductus arteriosus in very low birthweight infants: double blind trial. Arch Dis Child. 1983;58:267–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mahony L, Caldwell RL, Girod DA, Hurwitz RA, Jansen RD, Lemons JA, et al. Indomethacin therapy on the first day of life in infants with very low birth weight. J Pediatr. 1985;106:801–5.

    Article  CAS  PubMed  Google Scholar 

  45. Ment LR, Duncan CC, Ehrenkranz RA, Kleinman CS, Pitt BR, Taylor KJ, et al. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants. J Pediatr. 1985;107:937–43.

    Article  CAS  PubMed  Google Scholar 

  46. Puckett CG, Cox MA, Haskins KS, Fisher DJ. Prophylactic indomethacin for the prevention of patent ductus arteriosus [abstract]. Pediatr Res. 1985;19:358.

    Article  Google Scholar 

  47. Benson JW, Drayton MR, Hayward C, Murphy JF, Osborne JP, Rennie JM, et al. Multicentre trial of ethamsylate for prevention of periventricular haemorrhage in very low birthweight infants. Lancet. 1986;2:1297–300.

    Article  CAS  PubMed  Google Scholar 

  48. Rennie JM, Doyle J, Cooke RW. Early administration of indomethacin to preterm infants. Arch Dis Child. 1986;61:233–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gutierrez NG, Lapasset M. Prophylactic indomethacin and the incidence of patent ductus arteriosus in preterm neonates. In: Proceedings of the 3rd Argentinian Congress of Perinatology. 1987, 62: as cited in Fowlie PW, Davis PG, McGuire W: Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 7:CD000174, 002010, p. 000132.

  50. Hammerman C, Strates E, Komar K, Bui K. Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Dev Pharmacol Ther. 1987;10:393–404.

    Article  CAS  PubMed  Google Scholar 

  51. Krueger E, Mellander M, Bratton D, Cotton R. Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. J Pediatr. 1987;111:749–54.

    Article  CAS  PubMed  Google Scholar 

  52. Vincer M, Allen A, Evans J, Nwaesei C, Stinson D, Rees E, et al. Early intravenous indomethacin prolongs respiratory support in very low birth weight infants. Acta Paediatr Scand. 1987;76:894–7.

    Article  CAS  PubMed  Google Scholar 

  53. Weesner KM, Dillard RG, Boyle RJ, Block SM. Prophylactic treatment of asymptomatic patent ductus arteriosus in premature infants with respiratory distress syndrome. South Med J. 1987;80:706–8.

    Article  CAS  PubMed  Google Scholar 

  54. Bandstra ES, Montalvo BM, Goldberg RN, Pacheco I, Ferrer PL, Flynn J, et al. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics. 1988;82:533–42.

    Article  CAS  PubMed  Google Scholar 

  55. Hanigan WC, Kennedy G, Roemisch F, Anderson R, Cusack T, Powers W. Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in high-risk neonates. J Pediatr. 1988;112:941–7.

    Article  CAS  PubMed  Google Scholar 

  56. Ment LR, Duncan CC, Ehrenkranz RA, Kleinman CS, Taylor KJ, Scott DT, et al. Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J Pediatr. 1988;112:948–55.

    Article  CAS  PubMed  Google Scholar 

  57. Vogtmann C, Grubbe G, Ruckhaberle KE, Bottcher H, Ockert C. Effects of early therapy with indomethacin on the manifestation of a persistent ductus arteriosus in extremely underweight premature infants. Monatsschr Kinderheilkd. 1988;136:636–9.

    CAS  PubMed  Google Scholar 

  58. Bada HS, Green RS, Pourcyrous M, Leffler CW, Korones SB, Magill HL, et al. Indomethacin reduces the risks of severe intraventricular hemorrhage. J Pediatr. 1989;115:631–7.

    Article  CAS  PubMed  Google Scholar 

  59. Cassady G, Crouse DT, Kirklin JW, Strange MJ, Joiner CH, Godoy G, et al. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med. 1989;320:1511–6.

    Article  CAS  PubMed  Google Scholar 

  60. Krauss AN, Fatica N, Lewis BS, Cooper R, Thaler HT, Cirrincione C, et al. Pulmonary function in preterm infants following treatment with intravenous indomethacin. Am J Dis Child. 1989;143:78–81.

    CAS  PubMed  Google Scholar 

  61. Lai TH, Soong WJ, Hwang B. Indomethacin for the prevention of symptomatic patent ductus arteriosus in very low birth weight infants. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1990;31:17–23.

    CAS  PubMed  Google Scholar 

  62. Amato M, Huppi P, Markus D. Prevention of symptomatic patent ductus arteriosus with ethamsylate in babies treated with exogenous surfactant. J Perinatol. 1993;13:2–7.

    CAS  PubMed  Google Scholar 

  63. Domanico RS, Waldman JD, Lester LA, McPhillips HA, Catrambone JE, Covert RF. Prophylactic indomethacin reduces the incidence of pulmonary hemorrhage and patent ductus arteriosus in surfactant-treated infants <1250 g. Pediatr Res. 1994;35:331A.

    Google Scholar 

  64. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics. 1994;93:543–50.

    Article  CAS  PubMed  Google Scholar 

  65. Ment LR, Oh W, Ehrenkranz RA, Phillip AG, Vohr B, Allan W, et al. Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial. J Pediatr. 1994;124:951–5.

    Article  CAS  PubMed  Google Scholar 

  66. Morales-Suarez M, Danchez-Gil T, Lemus-Varela L, Udaeta-Mora E. Estudio comparitivo de dosis baja de indometicina profilactica para hemorragia subependimaria/intraventicular en neonatos pretermino con ventilation mechanica. Bol Med Hosp Infant Mex. 1994;51:389–94.

    Google Scholar 

  67. Couser RJ, Ferrara TB, Wright GB, Cabalka AK, Schilling CG, Hoekstra RE, et al. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr. 1996;128:631–7.

    Article  CAS  PubMed  Google Scholar 

  68. Yaseen H, al Umran K, Ali H, Rustum M, Darwich M, al-Faraidy A. Effects of early indomethacin administration on oxygenation and surfactant requirement in low birth weight infants. J Trop Pediatr. 1997;43:42–6.

    Article  CAS  PubMed  Google Scholar 

  69. Supapannachart S, Khowsathit P, Patchakapati B. Indomethacin prophylaxis for patent ductus arteriosus (PDA) in infants with a birth weight of less than 1250 grams. J Med Assoc Thai. 1999;82 Suppl 1:S87–92.

    CAS  PubMed  Google Scholar 

  70. Dani C, Bertini G, Reali MF, Murru P, Fabris C, Vangi V, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatr. 2000;89:1369–74.

    Article  CAS  PubMed  Google Scholar 

  71. De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr. 2000;159:364–8.

    Article  PubMed  Google Scholar 

  72. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001;344:1966–72.

    Article  CAS  PubMed  Google Scholar 

  73. van Overmeire B, van de Broek H, van Laer P, Weyler J, Vanhaesebrouck P. Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome. J Pediatr. 2001;138:205–11.

    Article  PubMed  Google Scholar 

  74. Gournay V, Roze JC, Kuster A, Daoud P, Cambonie G, Hascoet JM, et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:1939–44.

    Article  CAS  PubMed  Google Scholar 

  75. van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwe W, Jespers A, et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:1945–9.

    Article  PubMed  CAS  Google Scholar 

  76. Dani C, Bertini G, Pezzati M, Poggi C, Guerrini P, Martano C, et al. Prophylactic ibuprofen for the prevention of intraventricular hemorrhage among preterm infants: a multicenter, randomized study. Pediatrics. 2005;115:1529–35.

    Article  PubMed  Google Scholar 

  77. Sangtawesin V, Sangtawesin C, Raksasinborisut C, Sathirakul K, Kanjanapattanakul W, Khorana M, et al. Oral ibuprofen prophylaxis for symptomatic patent ductus arteriosus of prematurity. J Med Assoc Thai. 2006;89:314–21.

    CAS  PubMed  Google Scholar 

  78. Sangtawesin C, Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W, Khorana M, Ayudhaya JK. Prophylaxis of symptomatic patent ductus arteriosus with oral ibuprofen in very low birth weight infants. J Med Assoc Thai. 2008;91 Suppl 3:S28–34.

    PubMed  Google Scholar 

  79. Aranda JV, Clyman R, Cox B, Van Overmeire B, Wozniak P, Sosenko I, et al. A randomized, double-blind, placebo-controlled trial on intravenous ibuprofen L-lysine for the early closure of nonsymptomatic patent ductus arteriosus within 72 h of birth in extremely low-birth-weight infants. Am J Perinatol. 2009;26:235–45.

    Article  PubMed  Google Scholar 

  80. Ghanem S, Mostafa M, Shafee M. Effect of oral ibuprofen on patent ductus arteriosus in premature newborns. J Saudi Heart Assoc. 2010;22:7–12.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kanmaz G, Erdeve O, Canpolat FE, Oguz SS, Uras N, Altug N, et al. Serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus. Eur J Clin Pharmacol. 2013;69:1075–81.

    Article  CAS  PubMed  Google Scholar 

  82. 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:F99–104.

    Article  PubMed  Google Scholar 

  83. Harkin P, Harma A, Aikio O, Valkama M, Leskinen M, Saarela T, et al. Paracetamol accelerates closure of the ductus arteriosus after premature birth: a randomized trial. J Pediatr. 2016;177:72–7.

    Article  CAS  PubMed  Google Scholar 

  84. Kalani M, Shariat M, Khalesi N, Farahani Z, Ahmadi S. A comparison of early ibuprofen and indomethacin administration to prevent intraventricular hemorrhage among preterm infants. Acta Med Iran. 2016;54:788–92.

    PubMed  Google Scholar 

  85. de Waal K, Phad N, Stubbs M, Chen Y, Kluckow M. A double blind, randomised controlled pilot trial of early pharmacological treatment versus supportive management in preterm infants with a patent ductus arteriosus (PDA). E-PAS2019:2842.345.

  86. Hagadorn JI, Bennett MV, Brownell EA, Payton KSE, Benitz WE, Lee HC. Covariation of neonatal intensive care unit-level patent ductus arteriosus management and in-neonatal intensive care unit outcomes following preterm birth. J Pediatr. 2018;203:225–33.

    Article  PubMed  Google Scholar 

  87. Clyman RI. Patent ductus arteriosus, its treatments, and the risks of pulmonary morbidity. Semin Perinatol. 2018;42:235–42.

    Article  PubMed  Google Scholar 

  88. Liebowitz M, Katheria A, Sauberan J, Singh J, Nelson K, Hassinger DC, et al. Lack of equipoise in the PDA-TOLERATE trial: a comparison of eligible infants enrolled in the trial and those treated outside the trial. J Pediatr. 2019;213:222–6.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA

    Meera N. Sankar & William E. Benitz

Authors
  1. Meera N. Sankar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William E. Benitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

As the corresponding author and first author, I confirm that I have full access to the data in the study and final responsibility for the decision to submit for publication. Both myself and contributing co-author, WEB MD, were involved in conceiving the work that led to the submission and played an important role in interpreting the results. I wrote the initial draft of the paper and we were both involved in revising the paper. Both approve this final revised version and we agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Meera N. Sankar.

Ethics declarations

Conflict of interest

WEB has served as a paid member of a scientific advisory panel for Abbott Laboratories, which manufactures devices for transcatheter ductal occlusion. Neither MNS nor WEB has any other potential conflicts to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sankar, M.N., Benitz, W.E. Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?. J Perinatol 40, 1863–1870 (2020). https://doi.org/10.1038/s41372-020-00848-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41372-020-00848-z

This article is cited by

Search

Advanced search

Quick links