Pediatric Drugs

, Volume 1, Issue 2, pp 81–92 | Cite as

Patent Ductus Arteriosus in the Premature Neonate

Current Concepts in Pharmacological Management
Disease Management


In utero, the ductus arteriosus shunts deoxygenated blood away from the pulmonary artery and towards the placental circulation where foetal gas exchange occurs. As a result of an intricately intertwined network of both physiological and biochemical changes, this vessel constricts rapidly after birth. Deoxygenated blood is diverted away from the placenta and through the lungs now vital for gas exchange. Premature closure of the ductus in utero can cause pulmonary hypertension and even death. Conversely, failure to close after birth can exacerbate respiratory distress, precipitate congestive heart failure and increase the risk of subsequent intestinal ischaemia leading to necrotising enterocolitis, bronchopulmonary dysplasia, renal hypoperfusion and/or cerebral ischaemia.

In this review we summarise current knowledge of the delicately orchestrated control of the ductus arteriosus, focusing on the role of cyclo-oxygenase isoforms on prostaglandin production, on the interaction between prostaglandins and oxygen, and on the effects of these on ductal patency. We also seek to describe some of the standard and nonstandard therapeutic approaches available to the clinician when natural closure fails, reviewing alternative protocols for indomethacin administration and comparing indomethacin treatment with newer approaches such as ibuprofen. In summary, we will follow the course of this unique blood vessel as it is transformed over several hours from an organ absolutely vital to survival into programmed obsolescence.


Adis International Limited Indomethacin Ibuprofen Premature Infant Patent Ductus Arteriosus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ellison R, Peckham G, Lang P, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983; 71: 364–72PubMedGoogle Scholar
  2. 2.
    Emmanouilides G. Persistent patency of the ductus arteriosus in premature infants: incidence, perinatal factors and natural history. In: The 75th Ross Conference on Pediatric Research. Columbus (OH): Ross Laboratories, 1979Google Scholar
  3. 3.
    Kurzrok R, Lieb CC. Biochemical studies of human semen II: the action of semen on the human uterus. Proc Soc Exp Biol Med 1930; 28: 268–74Google Scholar
  4. 4.
    Von Euler US. On the specific vasodilating and plain muscle stimulating substance from accessory genital glands in man and certain animals. J Physiol Lond 1936; 88: 213–34Google Scholar
  5. 5.
    Guerguerian AM, Hardy P, Bhattacharya M, et al. Expression of cyclooxygenases in ductus arteriosus of fetal and newborn pigs. Am J Obstet Gynecol 1998; 179: 1618–26PubMedCrossRefGoogle Scholar
  6. 6.
    Hardy P, Guerguerian AM, Bhattacharya M, et al. Major role for cyclooxygenase (COX)-1 in the control of ductus arteriosus (DA) tone in fetal sheep [abstract]. Pediatr Res 1998; 43: 22ACrossRefGoogle Scholar
  7. 7.
    Noel S, Cassin S. Maturation of contractile response of ductus arteriosus to oxygen and drugs. Am J Physiol 1976; 231: 240–3PubMedGoogle Scholar
  8. 8.
    Rabinovitch M, Boudreau N, Vella G, et al. Oxygen related prostaglandin synthesis in ductus arteriosus and other vascular cells. Pediatr Res 1989; 26: 330–5PubMedCrossRefGoogle Scholar
  9. 9.
    McMurphy DM, Heymann MA, Rudolph AM, et al. Developmental changes in constriction of the ductus arteriosus: responses to oxygen and vasoactive substances in the isolated ductus arteriosus of the fetal lamb. Pediatr Res 1972; 6: 231–8PubMedCrossRefGoogle Scholar
  10. 10.
    Clyman RI. Ontogeny of the ductus arteriosus response to prostaglandins and inhibitors of their synthesis. Semin Perinatol 1980; 4: 115–24PubMedGoogle Scholar
  11. 11.
    Fay FS. Guinea pig ductus arteriosus: I. Cellular and metabolic basis for oxygen sensitivity. Am J Physiol 1971; 221: 470–9PubMedGoogle Scholar
  12. 12.
    Fay FS, Cooke PH. Guinea pig ductus arteriosus: II. Irreversible closure after birth. Am J Physiol 1972; 222: 841–9PubMedGoogle Scholar
  13. 13.
    Nakanishi T, Gu H, Hagiwara N, et al. Mechanisms of oxygen induced contraction of ductus arteriosus isolated from the fetal rabbit. Circ Res 1993; 72: 1218–28PubMedCrossRefGoogle Scholar
  14. 14.
    Hammerman C, Eidelman AI, Gartner LM. Hypocalcemia and the patent ductus arteriosus. J Pediatr 1979; 94: 961–3PubMedCrossRefGoogle Scholar
  15. 15.
    Coceani F, Kelsey L. Endothelin-1 release from lamb ductus arteriosus: relevance to postnatal closure of the vessel. Can J Physiol Pharmacol 1991; 69: 218–21PubMedCrossRefGoogle Scholar
  16. 16.
    Saugstad OD, Sanderud J. Circulatory effects of oxygen radicals. Biomed Biochim Acta 1989; 48: S20–4PubMedGoogle Scholar
  17. 17.
    Hammerman C, Aramburo MJ. Effects of hyperventilation on prostacyclin formation and on pulmonary vasodilation after GBS induced pulmonary hypertension. Pediatr Res 1991; 29: 282–7PubMedCrossRefGoogle Scholar
  18. 18.
    Hammerman C, Zangen D. Indomethacin and apnea of prematurity. Crit Care Med 1993; 21: 154–5PubMedCrossRefGoogle Scholar
  19. 19.
    Gonzalez A, Sosenko IR, Chandar J, et al. Incidence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less. J Pediatr 1996; 128: 470–8PubMedCrossRefGoogle Scholar
  20. 20.
    Clyman RI, Waleh N, Black SM, et al. Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension and vasavasorum. Pediatr Res 1998; 43: 633–44PubMedCrossRefGoogle Scholar
  21. 21.
    Gersony W, Peckham G, Ellison R, et al. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr 1983; 102: 895–906PubMedCrossRefGoogle Scholar
  22. 22.
    Siassi B, Blanco C, Cabal L, et al. Incidence and clinical features of patent ductus arteriosus in low birth weight infants: a prospective analysis of 150 consecutively born infants. Pediatrics 1976; 57: 347–51PubMedGoogle Scholar
  23. 23.
    Gal P, Gilman JT. Drug disposition in neonates with patent ductus arteriosus. Ann Pharmacother 1993; 27: 1383–8PubMedGoogle Scholar
  24. 24.
    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: 42–45PubMedCrossRefGoogle Scholar
  25. 25.
    Ramsay JM, Murphy DU, Vick GW, et al. Response of the patent ductus arteriosus to indomethacin treatment. Am J Dis Child 1987; 141: 294–7PubMedGoogle Scholar
  26. 26.
    Avery GB, Fletcher MA, MacDonald MG, editors. Neonatology: pathophysiology and management of the newborn. 4th ed. Philadelphia (PA): J.B. Lippincott Company, 1994Google Scholar
  27. 27.
    Landignon N, Chomtob S, Bard H, et al. Effect of indomethacin on cerebral blood flow velocity of premature newborns. Biol Neonate 1988; 54: 254–82CrossRefGoogle Scholar
  28. 28.
    Pryds O, Greisen G, Johansen K. Indomethacin and cerebral blood flow in premature infants treated for patent ductus arteriosus. Eur J Pediatr 1988; 147: 315–6PubMedCrossRefGoogle Scholar
  29. 29.
    Edwards A, Wyatt J, Richardson C, et al. Effects of indomethacin of cerebral haemodynamics in very preterm infants. Lancet 1990; 335: 1491–5PubMedCrossRefGoogle Scholar
  30. 30.
    Evans D, Levene M, Archer L. The effect of indomethacin on cerebral blood flow velocity in premature infants. Dev Med Child Neurol 1987; 29: 776–82PubMedCrossRefGoogle Scholar
  31. 31.
    Mardoum R, Bejar R, Merritt A, et al. Controlled study of the effects of indomethacin on cerebral blood flow velocities in newborn infants. J Pediatr 1991; 118: 112–5PubMedCrossRefGoogle Scholar
  32. 32.
    Van Bel F, Klautz R, Steendijk P, et al. The influence of indomethacin on the autoregulatory ability of the cerebral vascular bed in the newborn lamb. Pediatr Res 1993; 34: 178–81PubMedCrossRefGoogle Scholar
  33. 33.
    Van Bel F, Van De Bor M, Stijnen T, et al. Cerebral blood flow velocity changes in preterm infants after a single dose of indomethacin: duration of its effects. Pediatrics 1989; 84: 802–7PubMedGoogle Scholar
  34. 34.
    Leffler CW, Busija DW, Beasley DG, et al. Maintenance of cerebral circulation during hemorrhagic hypotension in newborn pigs. Circ Res 1986; 59: 562–7PubMedCrossRefGoogle Scholar
  35. 35.
    Cowan F. Indomethacin, patent ductus arteriosus and cerebral blood flow. J Pediatr 1986; 106: 341–4Google Scholar
  36. 36.
    Hanigan W, Kennedy G, Roemisch F, et al. Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in very low birth weight neonates. J Pediatr 1988; 112: 941–7PubMedCrossRefGoogle Scholar
  37. 37.
    Siesjo BK, Nilsson B. Prostaglandin and the cerebral circulations. In: Oates JA, editor. Prostaglandin and the cardiovascular system. New York: Raven Press, 1982; 367–80Google Scholar
  38. 38.
    Baerts W, Fetter WP, Hop WC, et al. Cerebral lesions in preterm infants after tocolytic indomethacin. Dev Med Child Neurol 1990; 32: 910–8PubMedCrossRefGoogle Scholar
  39. 39.
    Austin NC, Pairaudeau PW, Hames TK, et al. Regional cerebral blood flow velocity changes after indomethacin infusion in premature infants. Arch Dis Child 1992; 67: 851–4PubMedCrossRefGoogle Scholar
  40. 40.
    Colditz P, Murphy D, Rolfe P, et al. Effect of infusion rate of indomethacin on cerebrovascular responses in preterm neonates. Arch Dis Child 1989; 64: 8–12PubMedCrossRefGoogle Scholar
  41. 41.
    Simko A, Mardoum R, Merritt TA, et al. Effects on cerebral blood flow velocities of slow and rapid infusion of indomethacin. J Perinatology 1994; 14: 29–35Google Scholar
  42. 42.
    Hammerman C, Glaser J, Schimmel MS, et al. Continuous vs. multiple rapid infusions of indomethacin: effects on cerebral blood flow velocity. Pediatrics 1995; 95: 244–8PubMedGoogle Scholar
  43. 43.
    Mellander M, Jeheup B, Lindsterom D, et al. Recurrence of symptomatic patent ductus arteriosus in extremely premature infants treated with indomethacin. J Pediatr 1985; 105: 138–43Google Scholar
  44. 44.
    Seyberth H, Muller H, Wille L, et al. Recovery of prostaglandin reopening of the ductus arteriosus after indomethacin treatment in preterm infants with respiratory distress syndrome. Pediatr Pharmacol 1982; 2: 127–41Google Scholar
  45. 45.
    Clyman RI, Campbell D, Heymann MA, et al. Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin induced closure. Circulation 1985; 71: 141–5PubMedCrossRefGoogle Scholar
  46. 46.
    Rhodes PG, Ferguson MG, Reddy NS, et al. Effects of prolonged versus acute indomethacin therapy in very low birth weight infants with patent ductus arteriosus. Eur J Pediatr 1988; 147: 481–4PubMedCrossRefGoogle Scholar
  47. 47.
    Hammerman C, Aramburo MJ. Prolonged indomethacin therapy for the prevention of recurrences of patent ductus arteriosus. J Pediatr 1990; 117: 771–6PubMedCrossRefGoogle Scholar
  48. 48.
    Leonhardt A, Isken V, Kühl PG, et al. Prolonged indomethacin treatment in preterm infants with symptomatic patent ductus arteriosus: efficacy, drug level monitoring and patient selection. Eur J Pediatr 1987; 146: 140–4PubMedCrossRefGoogle Scholar
  49. 49.
    Mahoney L, Carnero V, Brett C, et al. Prophylactic indomethacin therapy for patent ductus arteriosus in very low birth-weight infants. N Engl J Med 1982; 306: 506–10CrossRefGoogle Scholar
  50. 50.
    Hammerman C, Strates E, Komar K, et al. Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Dev Pharmacol Ther 1987; 10: 393–404PubMedGoogle Scholar
  51. 51.
    Mahoney L, Caldwell RL, Girod D, et al. Indomethacin therapy on the first day of life in infants with very low birth weight. J Pediatr 1985; 106: 801–5CrossRefGoogle Scholar
  52. 52.
    Rennie JM, Doyle J, Cooke RW. Early administration of indomethacin to preterm infants. Arch Dis Child 1986; 61: 233–8PubMedCrossRefGoogle Scholar
  53. 53.
    Couser RJ, Ferrara TB, Wright GB, 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: 631–7PubMedCrossRefGoogle Scholar
  54. 54.
    Zuckerman H, Reiss U, Rubinstein I. Inhibition of human premature labor by indomethacin. Obstet Gynecol 1974; 44: 782–92Google Scholar
  55. 55.
    Arcilla R, Thilenius O, Ranniger K. Congestive heart failure from suspected ductal closure in utero. J Pediatr 1969; 75: 74–8PubMedCrossRefGoogle Scholar
  56. 56.
    Momma K, Konishi T, Hagiwara H. Characteristic morphology of the constricted fetal ductus arteriosus following maternal administration of indomethacin. Pediatr Res 1985; 19: 493–500PubMedCrossRefGoogle Scholar
  57. 57.
    Levin DL, Mills LJ, Parkey M, et al. Constriction of the fetal ductus arteriosus after administration of indomethacin to the pregnant ewe. J Pediatr 1979; 94: 647–50PubMedCrossRefGoogle Scholar
  58. 58.
    Olley PM, Bodach E, Heaton J, et al. Further evidence implicating E-type prostaglandins in the patency of the lamb ductus arteriosus. Eur J Pharmacol 1975; 34: 247–50PubMedCrossRefGoogle Scholar
  59. 59.
    Csaba IF, Sulyok E, Ertl T. Clinical note: relationship of maternal treatment with indomethacin to persistence of fetal circulation syndrome. J Pediatr 1978; 92: 484–8PubMedCrossRefGoogle Scholar
  60. 60.
    Manchester D, Margolis HS, Sheldon RE. Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. Am J Obstet Gynecol 1976; 126: 467–9PubMedGoogle Scholar
  61. 61.
    Moise KJ, Huhta J, Sharif D, et al. Indomethacin in the treatment of premature labor. N Engl J Med 1988; 319: 327–1PubMedCrossRefGoogle Scholar
  62. 62.
    Norton M, Merrill J, Cooper B, et al. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med 1993; 329: 1602–7PubMedCrossRefGoogle Scholar
  63. 63.
    Bandstra E, Montalvo B, Goldberg R, et al. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics 1988; 82: 533–42PubMedGoogle Scholar
  64. 64.
    Hammerman C, Glaser J, Kaplan M, et al. Indomethacin tocolysis increases postnatal patent ductus arteriosus severity. Pediatrics 1998; 102: E56–61PubMedCrossRefGoogle Scholar
  65. 65.
    Gittenberger-de Groot AC, Ertbruggen IV, Moulaert AJMG, et al. The ductus arteriosus: histological and clinical observations. J Pediatr 1980; 96: 88–93PubMedCrossRefGoogle Scholar
  66. 66.
    Clyman RI, Brett C, Mauray F. Circulating prostaglandin E2 concentrations and patent ductus arteriosus in preterm infants with respiratory distress syndrome. Pediatrics 1980; 66: 725–9PubMedGoogle Scholar
  67. 67.
    Clyman RI, Sylvan Chemtob S, Heymann MA, et al. Nitric oxide inhibits closure of the ductus arteriosus following antenatal exposure to indomethacin. Pediatr Res 1998; 43: 169ACrossRefGoogle Scholar
  68. 68.
    Momma K, Nisihara S, Ota Y. Constriction of the fetal ductus arteriosus by glucocorticoid hormones. Pediatr Res 1981; 15: 19–21PubMedCrossRefGoogle Scholar
  69. 69.
    Momma K, Takao A. Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats. Pediatr Res 1989; 25: 69–75PubMedCrossRefGoogle Scholar
  70. 70.
    Liggins G, Howie R. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972; 50: 515–25PubMedGoogle Scholar
  71. 71.
    Clyman RI, Ballard PL, Sniderman S, et al. Prenatal administration of betamethasone for prevention of patent ductus arteriosus. J Pediatr 1981; 98: 123–6PubMedCrossRefGoogle Scholar
  72. 72.
    Eronen M, Kari A, Pesonen E, et al. The effect of antenatal dexamethasone administration on the fetal and neonatal ductus arteriosus: a randomized double blind study. Am J Dis Child 1993; 147: 187–92PubMedGoogle Scholar
  73. 73.
    Lundgren J, Hirata F, Marom Z, et al. Dexamethasone inhibits respiratory glyconjugate secretion from feline airways in vitro by the induction of lipocortin (lipomodulin) synthesis. Am Rev Respir Dis 1988; 137: 353–7PubMedGoogle Scholar
  74. 74.
    Clyman RI, Mauray F, Roman C, et al. Effects of antenatal glucocorticoids administration on ductus arteriosus of preterm lambs. Am J Physiol 1981; 241: H415–20PubMedGoogle Scholar
  75. 75.
    Momma K, Nisihara S, Clyman RI, et al. Glucocorticoids alter the sensitivity of the lamb ductus arteriosus to prostaglandin E2.J Pediatr 1981; 98: 126–8CrossRefGoogle Scholar
  76. 76.
    Tsai M, Brown DM. Effect of dexamethasone on fetal lung 15 hydroxy prostaglandin dehydrogenase: possible mechanism for the prevention of patent ductus arteriosus by maternal dexamethasone therapy. Prostaglandins Leukot Med 1987; 27: 237–45PubMedCrossRefGoogle Scholar
  77. 77.
    Avery GB, Fletcher AB, Kaplan M, et al. Controlled trial of dexamethasone in respirator dependent infants with bronchopulmonary dysplasia. Pediatrics 1985; 75: 106–11PubMedGoogle Scholar
  78. 78.
    Heyman E, Ohlsson A, Shennan AT, et al. Closure of patent ductus arteriosus after treatment with dexamethasone. Acta Paediatr Scand 1990; 79: 698–700PubMedCrossRefGoogle Scholar
  79. 79.
    Varvarigou N, Bardin CL, Beharry K, et al. Early ibuprofen administration to prevent patent ductus arteriosus in premature infants. JAMA 1996; 275: 539–44PubMedCrossRefGoogle Scholar
  80. 80.
    Simons L, Mills J. Nonsteroidal antiinflammatory drugs. N Engl J Med 1980; 302: 1237–43CrossRefGoogle Scholar
  81. 81.
    Van Overmeire B, Follens I, Hartmann S, et al. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed 1997; 76: F179–84PubMedCrossRefGoogle Scholar
  82. 82.
    Van Overmeire B, Langhendries JP, Vanhaesebrouck P, et al. Ibuprofen for early treatment of patent ductus arteriosus: a randomized multicenter trial [abstract]. Pediatr Res 1998; 43: 200AGoogle Scholar
  83. 83.
    Speziale M, Barrington KJ, Allen GR, et al. Effects of indomethacin and ibuprofen on regional perfusion in the newborn piglet. Pediatr Res 1998; 43: 196ACrossRefGoogle Scholar
  84. 84.
    Mosca F, Bray M, Lattanzio M, et al. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J Pediatr 1997; 131: 549–54PubMedCrossRefGoogle Scholar
  85. 85.
    Aranda JV, Parker J, Glibetic M, et al. Comparative dose response effects of ibuprofen and indomethacin on prostaglandin E2, PGE2 synthesis in neonatal cerebral microvessels [abstract]. Pediatr Res 1998; 43: 58ACrossRefGoogle Scholar
  86. 86.
    Cooper-Peel C, Brodersen R, Robertson A. Does ibuprofen affect bilirubin-albumin binding in newborn infant serum? Pharmacol Toxicol 1996; 79: 297–9PubMedCrossRefGoogle Scholar
  87. 87.
    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: 530–3PubMedCrossRefGoogle Scholar
  88. 88.
    Van Overmeire B, Brus F, Van Acker KJ, et al. Aspirin versus indomethacin treatment of patent ductus arteriosus in preterm infants with respiratory distress syndrome. Pediatr Res 1995; 38: 886–91PubMedCrossRefGoogle Scholar
  89. 89.
    Sakhalkar VS, Merchant RH. Therapy of symptomatic patent ductus arteriosus in preterms using mefenamic acid and indomethacin. Indian Pediatr 1992; 29: 313–8PubMedGoogle Scholar
  90. 90.
    Smith GC. The pharmacology of the ductus arteriosus. Pharmacol Rev 1998; 50: 35–58PubMedGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Department of NeonatologyShaare Zedek Medical CenterJerusalemIsrael
  2. 2.The Hebrew University - Hadassah Medical SchoolJerusalemIsrael

Personalised recommendations