Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants

Ohlsson A, Walia R, Shah S

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Contact reviewer

Contribution of reviewers

Internal sources of support

External sources of support

What's new

This update of the review conducted in August 2007 identified four previously not included trials (Adamska 2005, Aly 2007, Gimeno Navarro 2005, Pezzati 1999). In addition, two trials previously included as abstracts have now been published as full articles (Chotigeat 2003, Supapannachart 2002).

The current review includes a total of 16 trials enrolling 876 infants. The increase in sample size made the point estimates more precise and changed the results of one important outcome. In the previous review there was a statistically significant increase in chronic lung disease in the ibuprofen group. Although a trend towards an increase in chronic lung disease remained in this review, the summary estimates did not reach statistical significance. In this review, the outcome of serum/plasma levels of creatinine following treatment was included and the results showed significantly lower levels in the ibuprofen group. As in previous reviews, the risk of decreased urine output was lower in the ibuprofen group. There is not enough data available regarding the effectiveness of oral ibuprofen to close a patent ductus arteriosus. One case of pulmonary hypertension associated with ibuprofen treatment was reported in one trial.

Long-term neurodevelopmental data are still lacking.

Based on the available evidence clinicians may prefer one of the two drugs currently available for closure of a patent ductus arterious over the other:
a) Either drug is effective in closing a patent ductus arterious
b) Ibuprofen may be preferred because of its less negative impact on the kidney function
c) Indomethacin may be preferred because of the trend towards increase in chronic lung disease in the ibuprofen group and the potential risk of pulmonary hypertension associated with the use of ibuprofen

This review has previously been updated in 2005 (Ohlsson 2005). An updated search in July 2005 identified one trial of ibuprofen versus placebo, but the results were not reported unblinded to group. However, the search identified three trials that compared ibuprofen to indomethacin for the treatment of a PDA. The addition of the results from these three trials confirmed our previous findings that ibuprofen is no more effective than indomethacin and may cause more adverse effects. There were no important changes to the conclusions of that review.

An updated search in October 2004 found no new eligible trials for inclusion in this review.

There was no trial identified using mefenamic acid in the original review or in any of the updates.

Dates

Text of review

Synopsis

Abstract

Background

Objectives

Search strategy

Selection criteria

Data collection & analysis

Main results

Reviewers' conclusions

Background

Objectives

• To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a patent ductus arteriosus in preterm and/or low birth weight infants
• To determine the effectiveness and safety of ibuprofen compared to indomethacin or other cyclo-oxygenase inhibitors for closing a patent ductus arteriosus in preterm and/or low birth weight infants

• Gestational age (<28 weeks, 28 - 32 weeks, 33 - 36 weeks)
• Birth weight (<1000 g, 1000 - 1500 g, 1501 - 2500 g)
• Method used to diagnose a PDA (by ECHO criteria or only by clinical criteria)
• A dosing regimen of 10 mg/kg of ibuprofen followed by 5 mg/kg of ibuprofen 24 and 48 hours later, or 0.2 mg/kg of indomethacin at 12 hours intervals for three doses
• Oral ibuprofen vs. indomethacin (this has been added in 2007 as a new comparison as studies now have used oral ibuprofen)

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

• Failure of permanent PDA closure within a week of administration of the first dose of ibuprofen (PDA diagnosed either clinically or by ECHO criteria).

• All cause mortality during initial hospital stay
• Neonatal mortality (death during the first 28 days of life)
• Infant mortality (death during the first year of life)
• Reopening of the ductus arteriosus
• Need for surgical closure of the PDA
• Need for treatment with indomethacin to close the PDA*
• Duration of ventilator support (days)
• Duration of need for supplementary oxygen (days)
• Pneumothorax
• Pulmonary hemorrhage*
• Pulmonary hypertension*
• Chronic lung disease (CLD) (defined as oxygen requirement at 28 days postnatal age in addition to compatible clinical and roentgenographic findings)
• Chronic lung disease (CLD) (defined as oxygen requirement at 36 weeks postmenstrual age in addition to compatible clinical and roentgenographic findings)
• Chronic lung disease (age at diagnosis not stated)*
• Intraventricular haemorrhage (IVH) (Grade I-IV)
• Severe intraventricular haemorrhage (IVH) (Grade III-IV)
• Periventricular leukomalacia (PVL)
• Necrotizing enterocolitis (NEC) (any stage)
• Intestinal perforation*
• Gastrointestinal bleed
• Time to full enteral feeds (postnatal age at time of achieving full enteral feeds)
• Time to regain birth weight* (days)
• Retinopathy of prematurity (ROP) (according to the international classification of ROP)
• Definite sepsis (clinical symptoms and signs of sepsis and a positive bacterial culture in a specimen obtained from normally sterile fluids or tissue obtained at autopsy)
• Decreased urine output (defined as < 1 cc/kg/hr)
• Serum/plasma levels of creatinine (mmol/L) after treatment*
• Increase in serum/plasma levels of creatinine (mmol/L) after treatment*
• Duration of hospitalization (total length of hospitalization from birth to discharge home or death) (days)
• Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized and validated assessment tool and/or a child developmental specialist) at any age reported (outcome data will be grouped at 12, 18, 24 months if available)
• Bilirubin albumin binding*
• Other side effects reported by the authors

Search strategy for identification of studies

Methods of the review

Description of studies

• Objective: To compare the efficacy and safety of i.v. ibuprofen with placebo for the early treatment of PDA in preterm infants with evidence of ductal shunting by echocardiography.
• Population: 136 preterm infants (BW 500 to 1000 g) with evidence of ductal shunting by an echocardiogram within 72 hours after birth.
• Intervention: Infants were allocated to either a three day treatment course of i.v. ibuprofen of 10 mg/kg, 5 mg/kg and 5 mg/kg (n = 68) or placebo (saline) (n = 68).
• Outcomes:The primary outcome measure was the proportion of infants that required rescue treatment for PDA (indomethacin or surgery) on or prior to study day 14. Secondary outcomes included mortality, need for PDA ligation, IVH, NEC, CLD and ROP.

• Objective: To assess the efficacy and safety of early treatment with ibuprofen or indomethacin in preterm infants.
• Population: 35 preterm (< 33 weeks of gestation and birth weight < 1500 g) infants with a PDA diagnosed by Doppler echocardiography.
• Intervention: The infants were randomized to receive three doses of indomethacin (0.2 mg/kg i.v. given at 24 hour intervals), (n = 19) or three doses of ibuprofen (10, 5, and 5 mg/kg i.v. given at 24 hour intervals), (n = 16).
• Outcomes: The primary outcome was ductal closure. Other outcomes included; need for surgical ligation, IVH, PVL, NEC, intestinal perforation, oliguria, time to full oral feeds, CLD (at 28 days of age), pulmonary hemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.

• Objective: To investigate the efficacy and safety of oral ibuprofen for the treatment of PDA and to compare it with oral indomethacin.
• Population: 23 preterm infants (< 35 weeks of gestation) with a PDA diagnosed by Doppler echocardiography.
• Intervention: Infants were randomized to receive either ibuprofen 10 mg/kg i.v. as the initial dose followed by 5 mg/kg 24 and 48 hours later (n = 12) or three doses of i.v. indomethacin (0.2 mg/kg) every twelve hours (n = 11).
• Outcomes: The primary outcome was ductal closure. Other outcomes included need to retreat a PDA with indomethacin or ibuprofen, urine output, serum creatinine after treatment, thrombocyte counts, gastrointestinal hemorrhage, IVH, sepsis and mortality.

• Objective: To evaluate the feasibility of the use of oral ibuprofen suspension in the treatment of PDA in preterm infants.
• Population: 21 preterm infants (< 35 weeks gestation) age two to seven days with respiratory distress and PDA diagnosed by Doppler echocardiography.
• Intervention: Infants were randomized to receive three doses of i.v. indomethacin (0.2 mg/kg at 12 hour intervals) (n = 9) or an initial oral dose of ibuprofen (10 mg/kg), followed by two doses of 5 mg/kg after 24 and 48 hours (n = 12).
• Outcomes: The primary outcome was ductal closure. Secondary outcomes included biochemical tests (serum creatinine), pulmonary hemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and increase in serum creatinine following treatment.

• Objective: To compare efficacy and side effects of ibuprofen vs. indomethacin treatment for symptomatic PDA in preterm infants.
• Population: Preterm infants with a symptomatic PDA confirmed by echocardiogram
• Intervention: 30 infants were randomized to received either three oral doses of ibuprofen (dose not stated) given at 24 hourly intervals or three doses of indomethacin (dose not stated) given at 12 hourly intervals starting within 10 days of life.
• Outcomes: The primary outcome measure was ductal closure. Secondary outcomes included the need for surgical closure of a PDA, the need for re-treatment with ibuprofen or indomethacin, death by 28 days, CLD (at 28 days), sepsis, ROP, serum creatinine levels after treatment.

• Objective: To compare the safety and efficacy of ibuprofen and indomethacin in the treatment of PDA in preterm infants.
• Population: Preterm infants (< 34 weeks gestational age) with a hemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support.
• Intervention: During the first week of life (average 2 days of life) 47 ventilated infants, were randomized to receive either indomethacin 0.2 mg/kg/dose i.v. every 12 hours for a total of three doses (n = 24) or an initial dose of i.v. ibuprofen of 10 mg/kg, followed by two doses of ibuprofen i.v. every 24 hours (n = 23).
• Outcomes: The primary outcome was ductal closure. Other outcomes included mortality, ductal reopening, need for surgical ligation, NEC, isolated bowel perforation, intestinal hemorrhage, pulmonary hemorrhage, CLD (age not stated), IVH (grades III and IV), days on assisted ventilation (median and range), days in supplemental oxygen (median and range), days in NICU (median and range).

• Objective: To compare indomethacin and ibuprofen with regard to efficacy and safety for the early treatment of PDA.
• Population: Preterm infants (< 34 weeks gestation, postnatal age 48 - 72 hours) with RDS treated with mechanical ventilation and echocardiographic evidence of PDA.
• Intervention: 175 infants were randomized to either ibuprofen (n = 94) in an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each after 24 and 48 hours or three doses of indomethacin 0.2 mg/kg at 12 hours intervals (n = 81). When the ductus arteriosus was still patent after the randomly assigned treatment in patients in either group receiving mechanical ventilation, another three doses of the same medication were given as a non-randomized rescue treatment. If this therapy failed to induce ductal closure, the patient continued to receive mechanical ventilation and, if the ductus was judged to be hemodynamically significant or if further pharmacological treatment was contraindicated, surgical ligation of the ductus was performed.
• Outcomes:The primary outcome was ductal closure. Other outcomes included mortality,oliguria, IVH, PVL, surgical ligation of PDA, serum creatinine, CLD at 36 weeks, necrotizing enterocolitis, sepsis, death, duration of ventilator support, days in oxygen, duration of hospital stay, time to full feeds.

• Objective: To compare the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with PDA.
• Population: Preterm infants (< 31 weeks gestation) with PDA and receiving mechanical ventilation.
• Intervention: 16 infants received either 10 mg/kg ibuprofen dissolved in 1 ml saline and infused over 1 minute i.v. or 0.2 mg/kg indomethacin i.v. (n = 8). A second and third dose of ibuprofen (5 mg/kg) at 24 hour intervals or indomethacin (0.1 mg/kg), respectively were administered, provided no significant adverse effect was observed.
• Outcomes: Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidized cytochrome oxidase concentration. Cerebral blood flow velocity in the pericallosal artery was measured using Doppler ultrasonography. Ductal closure was reported as was reopening of a PDA and the need for re-treatment with indomethacin or ibuprofen.

• Objective: To compare the cerebral effects of ibuprofen with indomethacin in preterm infants.
• Population: 33 infants with a median gestational age of 26 weeks (range 23 to 28) and a echocardiographically proven PDA.
• Intervention: Infants were randomized to receive either ibuprofen 5 mg/kg (n = 12) or ibuprofen 10 mg/kg (n = 6) or indomethacin 0.1 mg/kg (n = 15). The drugs were infused i.v. over 15 minutes.
• Outcomes: Near infrared spectroscopy was used to observe the effect of treatment on cerebral perfusion, indicated by changes in cerebral blood volume and cerebral mitochondrial oxygenation, determined by the change in concentration of oxidized cytochrome aa3. Ductal closure was reported.

• Objective: To compare the effects of ibuprofen to indomethacin on cerebral hemodynamics measured using near infrared spectroscopy in preterm infants during treatment for patent ductus arteriosus.
• Population: 33 preterm infants (< 35 weeks gestation).
• Intervention: Infants were randomly assigned to three intravenous doses of either ibuprofen (5 - 10 mg/kg, 24 hourly) or indomethacin (0.20 - 0.25 mg/kg, 12 hourly) and also received a dose of saline. Eighteen infants were randomized to the ibuprofen group and 15 to the indomethacin group.
• Outcomes: The primary endpoints of the study were the effects of the first dose on cerebral blood flow and cerebral blood volume. The PDA closure rates were reported as were need for surgical ligation of PDA and need for re-treatment with indomethacin or ibuprofen

• Objective: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of PDA on mesenteric and renal blood flow velocity in preterm infants.
• Population: Preterm mechanically ventilated infants (< 33 weeks gestation) with a PDA diagnosed by Doppler echocardiography.
• Intervention: 17 infants were randomized to receive either i.v. indomethacin (0.2 mg/kg) or i.v. ibuprofen (10 mg/kg) as a continuous infusion over 15 minutes. Regardless of ductal closure after the first dose, all patients received a second and third dose of indomethacin (0.1 mg/kg) or ibuprofen (5 mg/kg) at 24 hour intervals.
• Outcomes: The primary outcome was mesenteric and renal blood flow velocity. Secondary outcomes included ductal closure, ductal reopening and NEC.

• Objective: To compare adverse effects and efficacy of i.v. ibuprofen with i.v. indomethacin for treatment of PDA in very preterm infants.
• Population: 41 preterm infants with clinical and echo signs of PDA
• Intervention: Infants received either ibuprofen (n = 21) 8 mg/kg every 24 hours for three doses i.v. or indomethacin (n = 20) 0.2 mg/kg every 24 hours for three doses i.v. If PDA persisted, treatment was repeated at 1/2 dose every 24 hours for six doses. Resistant PDA was ligated.
• Outcomes: The primary outcome was PDA closure. Secondary outcomes included reopening of the duct, need for surgical ligation rates and cerebral blood flow velocities.

• Objective: To compare i..v. ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.
• Population: 63 infants with echocardiographic evidence of a significant PDA
• Intervention: Infants were randomized to receive either i.v. ibuprofen 10 mg/kg initially followed by 5 mg/kg after 24 and 48 hours or i.v. indomethacin 0.2 mg/kg every 12 hours for three doses.
• Outcomes: Primary outcome was PDA closure. Secondary outcomes included need for surgical ligation, mortality, NEC, CLD at 36 weeks gestational age, IVH, PVL, ROP, hospital stay, duration of mechanical ventilation, days to full enteral feeds and gastric bleeding.

• Objective: To assess whether oral ibuprofen at 10 mg/kg/dose daily for three days was as effective as indomethacin to treat symptomatic PDA in preterm infants and to compare the side effects of oral ibuprofen to indomethacin.
• Population: 18 preterm (< 34 weeks PMA) infants with a symptomatic PDA
• Intervention: Infants were randomly assigned to receive either oral ibuprofen (10 mg/kg/dose) for three doses given at 24 hourly intervals or three doses of oral or i.v. indomethacin (0.2 mg/kg/dose) given at 12 hourly intervals.
• Outcomes: Primary outcome was PDA closure. Secondary outcomes included mortality, CLD (age not stated), IVH (grade not stated), and NEC.

• Objective: To evaluate the efficacy and side effects of ibuprofen for the early treatment of PDA and compare it with indomethacin.
• Population: Preterm infants with PDA diagnosed by echocardiography.
• Intervention: 40 infants were randomly assigned at day two to three days of life to receive either i.v. ibuprofen (n = 20) with an initial dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours later or i.v. indomethacin (n = 20) 0.2 mg/kg every 12 hours for three doses. Presence of a PDA was verified by Doppler echocardiography prior to enrolment, after the last dose of the randomized treatment and at the age of 7 days. When a PDA was present after the randomized treatment and the patient required mechanical ventilation, the infant was treated with indomethacin (0.2 mg/kg every 12 hours for three doses).
• Outcomes: The primary outcome was ductal closure. Secondary outcomes included need for surgical ligation of a PDA, need for re-treatment with indomethacin, mortality, CLD (at 28 days of age), duration of assisted ventilation, duration of supplemental oxygen, sepsis, NEC, age to regain birth weight, and ROP.

• Objective: To compare ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants.
• Population: 148 infants (gestational age 24 - 32 weeks) with RDS and a PDA confirmed by echocardiography.
• Intervention: Infants were randomized to receive i.v. 10 mg/kg of ibuprofen as an initial dose followed by two doses of 5 mg/kg at 24 and 48 hours (n = 74) or 0.2 mg/kg of indomethacin every 12 hours for three doses (n = 74). When the ductus arteriosus was still patent after the randomly assigned treatment in a patient in either group who was still receiving mechanical ventilation, indomethacin (three doses of 0.2 mg/kg) at 12-hour intervals) was given as non randomized rescue treatment. If this therapy failed to promote ductal closure and the patient continued to receive mechanical ventilation, or if there was a contraindication to the second pharmacologic treatment, surgical ligation of the ductus was performed.
• Outcomes: The primary outcome was ductal closure. Other outcomes included mortality by one month, NEC, localized bowel perforation, extension of IVH during treatment, PVL, CLD (need for supplemental oxygen for more than 28 days), duration of supplemental oxygen, duration of mechanical ventilation, time to regain birth weight, time to full enteral feeding, urine output and serum creatinine.

Methodological quality of included studies

Results

Discussion

Reviewers' conclusions

Implications for practice

Implications for research

Acknowledgements

Potential conflict of interest

Characteristics of included studies

Characteristics of excluded studies

References to studies

References to included studies

Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. Porownanie ibuprofenu i indometacyny w leczeniu przetrwalego przewodu tetniczego u noworodkow urodzonych przedwczesnie [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants]. Medycyna wieku rozwojowego 2005;9:335-54.

Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. Porownanie ibuprofenu i indometacyny w leczeniu przetrwalego przewodu tetniczego u noworodkow urodzonych przedwczesnie [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants]. Medycyna wieku rozwojowego 2005;9:335-54.

Akisu 2001 {published data only}

Akisu M, Ozyurek AR, Dorak C, Parlar A, Kultursay N. Premature bebeklerde patent duktus arteriozusun tedavisinde enteral ibuprofen ve indometazinin etkinligi ve guvenilirligi [Enteral ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm newborn infants]. Cocuk Sagligi ve Hastaliklari Dergisi 2001;44:56-60.

Akisu M, Ozyurek AR, Dorak C, Parlar A, Kultursay N. Premature bebeklerde patent duktus arteriozusun tedavisinde enteral ibuprofen ve indometazinin etkinligi ve guvenilirligi [Enteral ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm newborn infants]. Cocuk Sagligi ve Hastaliklari Dergisi 2001;44:56-60.

Aly 2007 {published data only}

* Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel-Meguid IE, Hammad TA. Oral ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. American Journal of Perinatology 2007;24:267-70.

Lotfy W, Badrawi N, Ghawas M, Ehsan E, Aly H. Oral ibuprofen solution (O) is efficacioous for the treatment of patent ductus arteriosus (PDA) in premature infants: A randomized controlled trial. In: Pedaitric Academic Societies Annual Meeting 2005 http://www.abstracts2view.com. 2005.

Aranda 2005 {published data only}

Aranda JV. Multicentre randomized double-blind placebo controlled trial of ibuprofen L-Lysine intravenous solution (IV Ibuprofen) in premature infants for the early treatment of patent ductus arteriosus (PDA). In: www.pas-meeting.org (Pediatric Academic Societies Annual Meeting; 2005 Abstracts2viewTMonline). 2005.

Chotigeat 2003 {published data only}

Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. Journal of Medical Association of Thailand 2003;86:Suppl 3:S563-9.

Gimeno Navarro 2005 {published data only}

Gimeno Navarro A, Cano Sanchez A, Fernandez Gilino C, Carrasco Moreno JI, Izquierdo Macian I, Gutierrez Laso A, Morcillo Sopena F. Ibuprofeno frente a indometacina en el tratamiento del conducto arterioso persistente del prematuro [Ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm infants]. Anales de Pediatria 2005;63:212-8.

Lago 2002 {published data only}

* Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. European Journal of Pediatrics 2002;161:202-7.

Lago P, Salvadori S, Bettiol T, Pitassi I, Chiandetti L, Saia OS. Effects of indomethacin and ibuprofen on renal function in preterm infants treated for patent ductus arteriosus: A randomized controlled trial. Pediatric Research 2001;49:375A.

Zanardo V, Vedovato S, Lago P, Piva D, Faggian D, Chiozza L. Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus. Fetal Diagnosis and Therapy 2005;20:534-9.

Mosca 1997 {published data only}

Mosca F, Bray M, Lattanzio M, Fumagalli M, Colnaghi MR, Compagnoni G. Comparison of the effects of indomethacin (INDO) and ibuprofen (IBU) on cerebral perfusion and oxygenation in preterm infants. Pediatric Research 1996;39:231A.

Mosca F, Bray M, Lattanzio M, Fumagalli M, Colnaghi M, Castoldi F, et al. Comparison of the effects of ibuprofen and indomethacin on PDA closure and cerebral perfusion and oxygenation. Pediatric Research 1997;41:165A.

* 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. Journal of Pediatrics 1997;131:549-54.

Patel 1995 {published data only}

Patel J, Marks KA, Roberts I, Azzopardi D, Edwards AD. Ibuprofen treatment of patent ductus arteriosus. Lancet 1995;346:255.

Patel 2000 {published data only}

Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47:36-42.

Pezzati 1999 {published data only}

Pezzati M, Bertini G, Vangi V, Biagiotti R, Cianciulli D, Rubaltelli FF. Mesenteric and renal perfusion in preterm infants with PDA: Indomethacin vs ibuprofen. Pediatric Research 1999;45:218A (Abstract).

Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubatelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135:733-8.

Plavka 2001 {published data only}

Plavka R, Svihovec P, Borek I, Biolek J, Kostirova M, Liska K, et al. Ibuprofen vs. indomethacin in the treatment of patent ductus arteriosus (PDA) in very premature neonates. Pediatric Research 2001;49:375A.

Su 2003 {published data only}

Su P-H, Chen J-Y, Su C-M, Huang T-C, Lee H-S. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatrics International 2003;45:665-70.

Supapannachart 2002 {published data only}

Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi hospital. Journal of Medical Association of Thailand 2002;85:Suppl 4:S1252-8.

Van Overmeire 1997 {published data only}

* Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Archives of Disease in Childhood 1997;76:F179-84.

Van Overmeire B, Follens I, Hartmann S, Mahieu L, Van Reempts PJ. Intravenous ibuprofen (IBU) for the treatment of patent ductus arteriosus (PDA) in preterm infants with respiratory distress syndrome (RDS). Pediatric Research 1996;39:250A.

Van Overmeire 2000 {published data only}

Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135:733-8.

Van Overmeire B, Langhendries JP, Vanhaesebrouck P, Lecoutere D, Van de Broek. Ibuprofen for early treatment of patent ductus arteriosus, a randomized multicentre trial. Pediatric Research 1998;43:200A.

* Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, De Groote K, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New England Journal of Medicine 2000;343:674-81.

References to excluded studies

Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. American Journal of Perinatology 2007;24:339-45.

Desfrere 2005 {published data only}

Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. Journal of Clinical Pharmacy & Therpeutics 2005;30:121-32.

* indicates the primary reference for the study

Other references

Additional references

Aranda JV, Thomas R. Systematic review: intravenous ibuprofen in preterm newborns. Seminars in Perintatology 2006;30:114-20.

Bellini 2006

Bellini C, Campone F, Serra G. Pulmonary hypertension following L-lysine ibuprofen therapy in a preterm infant with patent ductus arteriosus. Canadian Medical Association Journal 2006;174:1843-4.

Chemtob 1990

Chemtob S, Behary K, Rex J, Varma DR, Aranda JV. Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke 1990;21:777-84.

Chemtob 1991

Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Differences in the effects in the newborn piglet of various nonsteroidal antiinflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins. Pediatric Research 1991;30:106-11.

Coceani 1979

Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the responses of the lamb ductus arteriosus to oxygen and ibuprofen. Canadian Journal of Physiology and Pharmacology 1979;57:825-31.

Coceani 2005

Coceani F, Barogi S, Brizza F, Ackerley C, Seidlitz, Kelsey L et al. Cyclooxygenase isoenzymes and patency of ductus arteriosus. Prostaglandins, Leukotrines and Essential Fatty Acids 2005;72:71-77.

Cotton 1978

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. Journal of Pediatrics 1978;93:647-51.

Cotton 1979

Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. Journal of Pediatrics 1979;2:467-73.

Dani 2000

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

De Carolis 2000

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. European Journal of Pediatrics 2000;159:364-8.

Donze 2007

Donze A, Smith JR, Bryowsky K. Safety and efficacy of ibuprofen versus indomethacin for the treatment of patent ductus arteriosus in the preterm infant: reviewing the evidence. Neonatal Network 2007;26:187-95.

Edwards 1990

Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delpy DT. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990;335:1491-5.

Ellison 1983

Ellison RC, Pecham GJ, Lang P, Talner NS, Lerer TJ, Lin L, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71:364-72.

Fowlie 2002

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Other published versions of this review

Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 2, 2003.

Ohlsson 2005

Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2005.

Classification pending

Hammerman C, Schimmel M, Bromiker R, Kaplan M. Is ibuprofen really safer than indomethacin in the treatment of PDA. In: Pediatric Academic Societies' Annual Meeting. E:PAS2006;59:3607.512.

Hammerman 2007

Hammerman C, Shchors I, Schimmel M, Bromiker R, Kaplan M. Differential effects of indomethacin vs. ibuprofen in the treatment of patent ductus arteriosus on plasma free bilirubin levels. In: Paediatrc Academic Societies Annual Meeting. E:PAS2007;61:8438.8.

Comparisons and data

02 Ibuprofen vs. indomethacin

02.01 Failure to close a PDA (after single or three doses)

02.02 All cause mortality

02.03 Neonatal mortality (during first 28/30 days of life)

02.04 Infant mortality (death during the first year of life)

02.05 Reopening of the ductus arteriosus

02.06 Need for surgical closure of the PDA

02.07 Need for re-treatment with indomethacin or ibuprofen to close the PDA

02.08 Duration of ventilatory support

02.09 Duration of supplementary oxygen

02.10 Pneumothorax

02.11 Pulmonary hemorrhage

02.12 Pulmonary hypertension

02.13 Chronic lung disease (at 28 days)

02.14 Chronic lung disease (at 36 weeks corrected postmenstrual age)

02.15 Chronic lung disease (age not stated)

02.16 Intraventricular haemorrhage (Grade I-IV)

02.17 Intraventricular haemorrhage (III-IV)

02.18 Periventricular leucomalacia (cystic)

02.19 Necrotizing enterocolitis (any stage)

02.20 Intestinal perforation

02.21 Gastrointestinal bleed

02.22 Time to full enteral feeds

02.23 Time to regain birth weight (days)

02.24 Retinopathy of prematurity

02.25 Sepsis

02.26 Decreased urine output (<1 cc/kg/hr)

02.27 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment

02.28 Increase in serum/plasma creatinine levels (mg/dL) follwoing treatment

02.29 Duration of hospitalization

02.30 Failure to close a PDA (after 3 doses)

02.31 Failure to close a PDA (after 3 doses, abstracts excluded)

02.32 Chronic lung disease (at any age reported)

02.32.01 Chronic lung disease (at 28 days)

02.32.02 Chronic lung disease (at 36 weeks post-menstrual age)

02.32.03 Chronic lung disease (age not stated)

02.33 Chronic lung disease (at any age reported; studies using oral ibuprofen excluded)

02.33.01 Chronic lung disease (at 28 days)

02.33.02 Chronic lung disease (at 36 weeks post-menstrual age)

02.33.03 Chronic lung disease (age not stated)

03 Oral ibuprofen vs. i.v. or oral indomethacin

03.01 Failure to close a PDA (after three doses)

Additional figures

Figure 01

Figure 02

Contact details for co-reviewers

Dr Rajneesh Walia, MBBS, MD, DCH, MRCP, FRCPCH
Consultant
Children's Intensive Care, Children's Hospital
Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust
Infirmary Square
Leicester
Leicestershire UK
LE1 5WW
Telephone 1: +44 116 2586794
Telephone 2: +44 116 241414 extension: 6794
Facsimile: +44 116 2587637
E-mail: rajwalia@hotmail.com
Secondary address:
678 Uppingham Road, Thurnby
Leicester
Leicestershire UK
LE7 9RN
Telephone: +44 116 2419239
Facsimile: +44 116 2419239

This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2008 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.