Oral Ibuprofen Therapy for Patent Ductus Arteriosus in Very Low Birth Weight Infants

Document Type : Original Article


Background- Patent ductus arteriosus is found in 45% of infants under 1500gr and in infants
weighing < 1000gr, the incidence is closer to 80%. Indomethacin has been shown to close the
ductus arteriosus in a large fraction of premature infants. Intravenous ibuprofen was recently
shown to be as effective and to have fewer adverse reactions in preterm infants. If equally
effective, then oral ibuprofen for patent ductus arteriosus (PDA) closure would have several
important advantages over the intravenous route. This study was designed to determine
whether oral ibuprofen treatment is efficacious and safe in closure of PDA in very low birth
weight infants with respiratory distress syndrome (RDS).
Methods- 30 preterm newborns (gestational age 28.3±2.6 weeks), mean weight 1130±312gm, with
PDA and RDS were studied prospectively. They received oral ibuprofen suspension
10mg/kg/body weight for the first dose, followed at 24 hour intervals by two additional doses
of 5mg/kg each, if needed, starting on the second day of life. Echocardiographies were
performed before treatment and 24 hours after the second dose. The rate of ductal closure, the
need for additional treatment, side effects, complications and the infants’ clinical courses
were recorded.
Results- Ductal closure was achieved in 28 newborns (93.3%), and in two others partial closure was
achieved with no important shunts persisting. No infants required surgical ligation of ducts.
There was no reopening of the ductus after closure had been achieved. 21 newborns were
treated with one dose of ibuprofen, five were treated with two doses and the remaining two
were treated with three doses. There were no significant differences in the levels of serum
creatinine before and after treatment with oral ibuprofen.
Conclusion- Oral ibuprofen suspension may be an effective and safe alternative for PDA closure in
premature infants with PDA. However larger comparative studies are warranted (Iranian
Heart Journal 2008; 9 (2):23-28).


Fatemeh Haji Ebrahim Tehrani MD, Hadi Kazemi MD, Saied Mojtahedzadeh MD*, Jahan Oudj MD

1. The Vermont-Oxford Trials Network: Very low
birth weight outcomes for 1990. Pediatrics
1993; 91: 540 –545.
2. Aranda RB, Thomas HW, Graham WZ.
Pharmacology Review: Intravenous ibuprofen
for preterm newborns. NeoReviews 2005; 6:
3. 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 –
4. Dani A, Abbasi SA, Esterly ML. Prophylactic
ibuprofen for the prevention of intraventricular
hemorrhage among infants. Pediatrics 2005;
115: 1529-1535.
5. Osborn M, Cotton RB, Heyman MT. Effect of
early targeted indomethacin on the ductus
arteriosus and blood flow to the body and brain
n the preterm infant. Arch Dis Child Fetal
Neonatal Ed 2003; 88: F477-482.
6. Narayanan E, Sankar M, Clyman D.
Pharmacology Review: Pharmacologic closure
of patent ductus arteriosus in the newborns.
NeoReviews 2003; 4: 215-221.
7. Hammerman C, Glaser J, Schimmel MS, Ferber
B, Kaplan M, Eidelman AI. Continuous versus
multiple rapid infusion of indomethacin: effects
on cerebral blood flow velocity. Pediatrics
1995; 95: 244 –248.
8. Van Bel F, Guit GL, Schipper J, Van de Bor M,
Baan J. Indomethacin-induced changes in renal
blood flow velocity waveform in premature
infants investigated with color Doppler imaging.
J Pediatr 1991; 118: 621–626.
9. Overmeire BV, Smet K, Lecoutere DA.
Comparison of ibuprofen and indomethacin for
closure of patent ductus arteriosus. NEJM 2000;
343: 674-681.
10. Clyman D, Schipper J, Guit GL. Ibuprofen and
patent ductus arteriosus. NEJM 2000; 343:
11. Sharma F, Stijnen T, Ruys JH. Pharmacokinetics
of oral ibuprofen in premature infants. J Clin
Pharmacol 2003; s43: 986-973.
12. Pryds O, Greisen G, Johansen K. Indomethacin
and cerebral blood flow in preterm infants
treated for patent ductus arteriosus. Eur J
Pediatr 1988; 147: 315 –316.
13. Mardoum R, Bejar R, Merritt A, Berry C.
Controlled study of the effects of indomethacin
on cerebral blood flow velocities in newborn
infants. J Pediatr 1991; 118: 112 –115.
14. Heyman E, Morag I. Closure of patent ductus
arteriosus with oral ibuprofen suspension
Pediatrics; 2003; 112; 354.
15. Coceani F, White E, Bodach E, Olley PM. Agedependent
changes in the response of the lamb
ductus arteriosus to oxygen and ibuprofen. Can
J Physiol Pharmacol 1979; 57: 825 –831.
16. Varvarigou N, Bardin CL, Beharry K, Chemtob
S, Papageorgiou A, Aranda JV. Early ibuprofen
administration to prevent patent ductus
arteriosus in premature infants. JAMA 1996;
275: 539 –544.
17. Van Overmeire B, Smets K, Lecoutere D, Van de
Broek H, Weyler J. A comparison of ibuprofen
and indomethacin for closure of patent ductus
arteriosus. N Engl J Med 2000; 343: 674 –681.
18. Chemtob S, Laudignon N, Beharry K, Rex J,
Wolfe, Varma DR, Aranda JV. Effects of
prostaglandins and indomethacin on cerebral
blood flow and oxygen consumption of
conscious newborn piglets. Dev Pharmacol Ther
1990; 14: 1 –14.
19. Chemtob S, Beharry K, Rex J, Varma DR,
Aranda JV. Prostanoids determine the range of
cerebral blood flow autoregulation of newborn
piglets. Stroke 1990; 21: 777 –784.
20. Chemtob S, Beharry K, Barna T, Varma DR,
Aranda JV. Differences in the effect in the
newborn piglet of various nonsteroidal antiinflammatory
drugs on cerebral blood flow but
not on cerebrovascular prostaglandins. Pediatr
Res 1991; 30: 106 –111.
21. Mosca F, Bray M, Lattanzio M, Fumagalli M,
Tosetto C. 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 –554.
22. Malcolm DD, Segar JL, Robillard E, Chemtob S.
Indomethacin compromises hemodynamics
during positive-pressure ventilation,
independently of prostanoids. J Appl Physiol
1993; 74:1672 –1678.
23. 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 –
24. Van Overmeire B, Touw D, Schepens PJC,
Kearns GL, van den Anker J. Ibuprofen
pharmacokinetics in preterm infants with patent
ductus arteriosus. Clin Pharmacol Ther 2001;
70: 336 –343.
25. Kauffman RE, Nelson MV. Effect of age on
ibuprofen pharmacokinetics and antipyretic
response. J Pediatr 1992; 121: 969 –973.
26. Kelley MT, Walson PD, Edge JH, Cox S,
Mortensen ME. Pharmacokinetics and
pharmacodynamics of ibuprofen isomers and
acetaminophen in febrile children. Clin
Pharmacol Ther 1992; 52: 181 –189.
27. Raju NV, Bharadwaj RA, Thomas R, Konduri
GG. Ibuprofen use to reduce the incidence and
severity of bronchopulmonary dysplasia: a pilot
study. J Perinatol 2000; 1:13 –16.
28. Lesko SM, Mitchell AA. An assessment of the
safety of pediatric ibuprofen: a practitionerbased
randomized clinical trial. JAMA 1995;
273: 929 –933.
29. Lesko SM, Mitchell AA. The safety of
acetaminophen and ibuprofen among children
younger than two years old. Pediatrics 1999;
104 (4).
30. Devine ST, Rosenberg HK, Kumar LS, Bhandari
V. Esophageal perforation in the preterm
newborn: case report and review of the
literature. Conn Med 2002; 66: 131 –135.
31. Ojala R, Ruuska T, Karikoski R, Ikonen RS,
Tammela O. Gastroesophageal endoscopic
findings and gastrointestinal symptoms in
preterm neonates with and without perinatal
indomethacin exposure. J Pediatr Gastroenterol
Nutr 2001; 32: 182 –188.
32. Vanhesebrouck P, Thiery M, Leroy JG, et al.
Oligohydramnios, renal insufficiency, and ileal
perforation in preterm infants after intrauterine
exposure to indomethacin. J Pediatr 1988; 113:
738 –743.
33. Gournay V, Savagner C, Thiriez G, Kuster A,
Roze JC. Pulmonary hypertension after
ibuprofen prophylaxis in very preterm infants.
Lancet 2002; 359: 1486 –1488.