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

  1. Arne Ohlsson1,*,
  2. Rajneesh Walia2,
  3. Sachin S Shah3

Editorial Group: Cochrane Neonatal Group

Published Online: 30 APR 2013

Assessed as up-to-date: 16 JUL 2012

DOI: 10.1002/14651858.CD003481.pub5


How to Cite

Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD003481. DOI: 10.1002/14651858.CD003481.pub5.

Author Information

  1. 1

    University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, Toronto, Ontario, Canada

  2. 2

    University of Birmingham and Walsall Manor Hospital, Paediatrics/Neonatology, Walsall, West Midlands, UK

  3. 3

    Aditya Birla Memorial Hospital, Neonatal and Pediatric Intensive Care Services, Pune, India

*Arne Ohlsson, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. aohlsson@mtsinai.on.ca.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 30 APR 2013

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This is not the most recent version of the article. View current version (18 FEB 2015)

 
Characteristics of included studies [ordered by study ID]
Adamska 2005

MethodsSingle-centre, randomised controlled trial.
I Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes


ParticipantsStudy conducted in one NICU in Warsaw in Poland

Study period: Not stated
35 preterm (< 33 weeks of gestation and birth weight < 1500 g) infants with a PDA diagnosed by Doppler echocardiography
16 infants randomised to ibuprofen group mean (SD) GA 27.7 (1.8) weeks; BW 1074 (264) g; 9 boys, 7 girls
19 infants randomised to indomethacin group mean (SD) GA 27.6 (2.0) weeks; BW 1003 (192) g; 11 boys, 8 girls


InterventionsIbuprofen (3 doses) was given at 24-hour intervals (10, 5, and 5 mg/kg iv). Indomethacin (3 doses) was given at 24-hour intervals (0.2mg/kg/dose iv)


OutcomesThe 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 haemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.


NotesStudy published in Polish.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information other than "...randomly assigned"

Allocation concealment (selection bias)Low riskAdequate. Was done in a blinded manner

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of intervention - yes
Blinding of outcome measurement(s) - yes

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes

Selective reporting (reporting bias)Unclear risk27 infants (12 received ibuprofen and 15 received indomethacin) were treated as per protocol. In the remaining 8 infants treatment was stopped due to side effects. In the ibuprofen group the reasons to stop treatment was pulmonary haemorrhage (3/16) and pulmonary hypertension (1/16); in the indomethacin group it was increased serum creatinine and urea nitrogen concentrations (3/19) and IVH (grade IV) ( 1/19)

Other biasLow riskAppears free of other bias

Akisu 2001

MethodsSingle-centre, randomised controlled trial.
I Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in one NICU in Izmir, Turkey

Study period: July 1988 to January 2000
23 infants < 35 weeks GA with echocardiographically confirmed PDA
12 randomised to ibuprofen group mean (SD) GA 32.1 (1.2) weeks; BW 1706 g (187)
5 girls/7 boys; 9 born by c/s, 2 born vaginally, 10 had RDS, 7 received surfactant. PDA was diagnosed on day 3.9 (0.5)
11 randomised to indomethacin group mean (SD) GA 31.9 (1.3) weeks; BW 1645 g (190)
6 girls/5 boys; 8 born by c/s, 3 born vaginally, 8 had RDS, 7 received surfactant. PDA diagnosed on day 3.5 (0.6)


InterventionsIbuprofen was given via an oro-gastric tube (10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later). Indomethacin was given via an oro-gastric tube (0.2 mg/kg for three doses at 12-hour
intervals).
2 neonates in the ibuprofen group and 3 in the indomethacin group required a second treatment with the same drug.


OutcomesPDA closure
Diuresis
Serum creatinine
Thrombocyte count
Gastrointestinal bleed
IVH
Sepsis
Mortality


NotesStudy published in Turkish.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskSingle-centre, randomised controlled trial. No other information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Indomethacin and ibuprofen were given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free from other bias

Aly 2007

MethodsSingle-centre, randomised controlled trial, conducted in Cairo, Egypt
I Blinding of randomisation - yes (sealed opaque envelopes)
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


Participants21 preterm infants (< 35 weeks gestation) age 2 to 7 days with respiratory distress and PDA diagnosed by Doppler echocardiography

Study period: not stated
12 infants were randomised to the oral ibuprofen group, mean (SD) GA 31.2 (2.5) weeks; BW 1521 (398) g; 8 boys, 4 girls
9 infants were randomised to iv indomethacin, mean (SD) GA 32.9 (1.6) weeks; BW 1884 (485) g; 4 boys, 5 girls


InterventionsIbuprofen was given as an initial oral dose of 10 mg/kg, followed by 2 doses orally of 5mg/kg after 24 and 48 hours. Indomethacin was given iv as 3 doses of 0.2 mg/kg at 12-hour intervals


OutcomesThe primary outcome was ductal closure. Secondary outcomes included biochemical tests (serum creatinine), pulmonary haemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and increase in serum creatinine following treatment.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description provided

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes. Sealed opaque envelopes were used for random assignment

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen was given orally, whereas indomethacin was given iv Ibuprofen and indomethacin were given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Aranda 2005

MethodsMulti-centre, randomised controlled trial
I Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes


ParticipantsMulti-centre study conducted in 11 centres in the USA

Study period: March 2002 to March 2005
136 preterm infants (BW 500 to 1000 g; PMA < 30 weeks) with evidence of ductal shunting by an echocardiogram
Mean (SD) GA 26.2 (1.4) weeks Mean (SD) BW 798 (130.3) g
51% boys and 49% girls


InterventionsIbuprofen was given iv as a 3-day treatment course of 10 mg/kg, 5 mg/kg, and 5 mg/kg of ibuprofen (n = 68) or placebo (saline) (n = 68)


OutcomesProportion of infants who required rescue treatment for PDA (indomethacin or surgery), died or dropped on or prior to study day 14, mortality, NEC, IVH, pulmonary haemorrhage, pulmonary hypertension, ROP, BPD (supplemental oxygen at 28 days), BPD (supplemental oxygen at 36 weeks PMA), PVL.


NotesThis study was published in abstract form in 2005, but has been published in a complete report in 2009.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskCentral randomisation was implemented using a dynamic allocation method of biased coin randomisation, balancing within birth weight (500 to 750 g and 751 to 1000 g), within each site, and in the study overall

Allocation concealment (selection bias)Low riskI Blinding of randomisation - yes. The coded vials of study drug or placebo contained indistinguishable colourless solutions dispensed by the blinded research pharmacists of the participating sites

Blinding (performance bias and detection bias)
All outcomes
Low riskSee allocation concealment

Blinding of intervention - yes
Blinding of outcome measurement(s) - yes

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe outcome of BPD (supplemental oxygen at 36 weeks PMA) was not ascertained in the whole sample as randomised. The denominator in the ibuprofen group was 46 infants and in the placebo group it was 52, which is too low when accounting for deaths

Selective reporting (reporting bias)Unclear riskSee incomplete data addressed? above. The trials was registered with clinicaltrials.gov: ID # NCT00440804

Other biasLow riskAppears free of other bias

Cherif 2008

MethodsSingle-centre, randomised controlled trial. Conducted in the NICU of the Neonatal and Maternity Center of Tunis, Tunis,Tunisia over a period of one year (January 2007 to December 2007)
I Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no for most outcomes except for physicians performing ECHO


Participants64 VLBW infants with ECHO confirmed PDA, PMA < 32 weeks, BW < 1500 g, postnatal age between 48 and 96 hours, respiratory distress requiring > 25% oxygen supplementation and ECHO evidence of significant left-to-right shunting across PDA.


Interventions32 infants were assigned to receive oral ibuprofen (10 mg/kg as the initial dose) and 32 infants were assigned to receive iv ibuprofen (10 mg/kg as the initial dose). After the first dose of treatment in both groups, ECHO evaluation was performed to determine the need for a second or a third dose. In each group, in case the ductus was still open after the third dose, intravenous ibuprofen (an initial dose of 10 mg/kg followed by 2 doses of 5 mg/kg each, after 24 and 48 hours) as a non-randomised rescue treatment was given. If this therapy failed to promote ductal closure and the patient continued to receive mechanical ventilation, surgical ligation of the ductus was performed.


OutcomesPDA closure rate, need for surgical ligation, rate of reopening of the ductus, oliguria, increase in serum creatinine level > 16 mg/dL, change in creatinine concentrations, IVH grades I-II and grades III-IV, PVL, NEC, bowel perforation, sepsis, duration of intubation, survival at 1 month, duration of hospital stay.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskPatients were randomly assigned to a treatment group by means of cards in sealed, opaque envelopes

Blinding (performance bias and detection bias)
All outcomes
High riskHealthcare providers were not blinded to treatment groups. Physicians performing ECHO and making the decision for second- and third-dose administration were unaware of assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all enrolled infants

Selective reporting (reporting bias)Low riskThe protocol was available to us. Trial number: NCT00642330. There does not seem to be any definitive deviations from the protocol

Other biasLow riskAppears free of other bias

Chotigeat 2003

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsSingle-centre study conducted in Bangkok, Thailand

Study period: January 1, 2001 to May 31, 2002
30 preterm infants (GA =/< 35 weeks, postnatal age =/< 10 days) with a echocardiographically verified PDA
15 infants received ibuprofen mean (SD) GA 30.8 (2.3) weeks; BW 1412 (354) g
15 infants received indomethacin mean (SD) GA 29.9 (2.9) weeks; BW 1434 (421) g


InterventionsIbuprofen was given orally as a 3-day treatment course every 24 hours and indomethacin was given iv at 12-hour intervals
The doses of ibuprofen and indomethacin given were not stated


OutcomesPDA closure
Need for surgical ligation
NEC


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
The infants were assigned to treatment group by random number

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen was given orally and indomethacin was given iv

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants

Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we can therefore not ascertain whether there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Dani 2012

MethodsMulti-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


Participants70 infants with PMA < 29 weeks, ECHO evidence of significant PDA, age 12-24 hours and RDS necessitating respiratory support.


Interventions35 infants [mean PMA 25.6 (SD 1.8) weeks; BW 781 (SD 225) g] were randomised to a high-dose ibuprofen (20-10-10 mg/kg/day) and 35 infants [mean PMA 26.0 (SD 1.7) weeks; BW 835 (SD 215) g] were randomised to standard-dose of iv ibuprofen (10-5-5 mg/kg/day).


OutcomesDuctal closure, serum creatinine (mg/dL - transcribed by us to mmol/L) on day 3 of treatment, oliguria (</= 1 mL/kg/hr during a 24-hour collection period), peak total serum bilirubin (mg/dL) during the first week of life, IVH (all grades and grades III-IV), PVL (all grades), ROP (all stages, stage > 2, NEC, BPD (oxygen requirement at 36 weeks PMA), sepsis, mortality, hospital stay (days).


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskSealed opaque envelopes

Blinding (performance bias and detection bias)
All outcomes
Unclear riskECHO studies were performed by physicians, who were blinded as to the infants' treatment assignments. It is not stated if clinical outcomes other than the PDA status were assessed blinded to assigned group or not

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all enrolled infants

Selective reporting (reporting bias)Low riskThe trial was registered with ClinicalTrials.gov under identifier NCT01243996. There does not seem to have been any deviations from the published protocol

Other biasLow riskAppears free of other bias

Erdeve 2012

MethodsSingle-centre, randomised, controlled trial, conducted in Ankara, Turkey

Study period: January 2010 and February 2011
I. Blinding of randomisation - yes- sequentially numbered, sealed, opaque envelopes
II. Blinding of intervention - no
III. Complete follow-up - no - see note
IV. Blinding of outcome measurement(s) - A paediatric cardiologist who was blinded to the treatment group determined the success rate of the treatment and the need for a second course via the same route


Participants80 infants with PMA </= 28 weeks, BW < 1000 g, postnatal age 48 to 96 hours and with ECHO-confirmed significant PDA


Interventions36 infants received oral ibuprofen and 34 infants received iv ibuprofen both at a dose of 10 mg/kg followed by 5 mg/kg at 24 and 48 hours. 4 infants in the oral group and 6 in the iv group were excluded because of death before complete treatment course


OutcomesPrimary outcome was PDA closure rate. Secondary outcomes included mortality, need for re-treatment or surgical treatment of the PDA, duration of ventilation, duration of hospital stay, increase in serum bilirubin level after treatment (mg/dL), plasma creatinine (mg/dL) after the first course of treatment, rate of ductal reopening, pneumothorax, pulmonary haemorrhage, pulmonary hypertension, BPD (supplemental oxygen at 36 weeks PMA), IVH (grades 1-IV), NEC, ROP, ROP requiring laser treatment


Notes4 infants in the oral group and 6 in the iv group were excluded because of death before complete treatment course. They were not included in an ITT analysis for the outcome of death. We did include these deaths in our analysis of mortality


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskSequentially numbered, sealed, opaque envelopes

Blinding (performance bias and detection bias)
All outcomes
High riskIbuprofen was administered either orally or iv which would have been known to the care givers. A paediatric cardiologist was blinded to the treatment group to determine the success of the treatment and the need for a second course via the same route

Incomplete outcome data (attrition bias)
All outcomes
High risk4 infants in the oral group and 6 in the iv group were excluded because of death before complete treatment course. They were not included in an ITT analysis for the outcome of death. We did include these deaths in our analysis of mortality

Selective reporting (reporting bias)Low riskThe protocol for the study was available to us. Trial registration # NCT01261117. There does not seem to have been any deviations from the protocol

Other biasLow riskAppears free of other bias

Fakhraee 2007

MethodsSingle-centre (Tehran, Iran), randomised controlled trial
I Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - can't tell


ParticipantsStudy period: June 2003 to June 2004

36 preterm infants PMA < 34 weeks, age < 14 days, platelet count > 100 000/microL, serum creatinine ≤ 1.6 mg/dL, absence of clinical manifestations of abnormal clotting function, absence of grades III-IV IVH. Color Doppler echocardiographic evidence of significant PDA.

18 infants received ibuprofen (PMA 31.5 +/-1.4 weeks; BW 1658 +/- 387 g)

18 infants received indomethacin (PMA 30.9 +/- 2.0 weeks; BW 1522 +/- 358 g)

Study period: June 2003 to June 2004


InterventionsIbuprofen was given orally as a suspension at a first dose of 10 mg/kg, followed at an interval of 24 hours by two doses of 5 mg/kg. Indomethacin was given orally three times at 0.2 mg/kg/dose at intervals of 24 hours.


OutcomesDuctal closure, need for re-treatment, reopening of the duct, mortality during the first 30 days of life, maximum serum BUN and creatinine levels, NEC, IVH (grades III and IV), oliguria.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
No description provided. "The enrolled patients randomly received either oral ibuprofen or oral indomethacin"

Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of intervention - cannot tell
Blinding of outcome measurement(s) - cannot tell
No description provided

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes were reported for all enrolled infants

Selective reporting (reporting bias)Unclear riskThe protocol was not available to us, so we cannot judge if there were any deviations

Other biasLow riskAppears to be free from other bias

Gimeno Navarro 2005

MethodsSingle-centre, randomised controlled trial, conducted in Valencia, Spain
I Blinding of randomisation - yes (sealed envelopes)
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes


ParticipantsStudy period: January 2003 to July 2004

47 ventilated, preterm infants (< 34 weeks gestational age) with a haemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support


Interventions23 infants received iv ibuprofen of 10 mg/kg, followed by two doses of ibuprofen iv every 24 hours
Median (25th and 75th centiles ) GA 28 (24,31) weeks; mean BW (SD) 1.169 (490) g
24 infants received indomethacin 0.2 mg/kg/dose iv every 12 hours for a total of 3 doses
Median (25th and 75th centiles ) GA 28.5 (27,30) weeks; mean BW (SD) 1.206 (513) g


OutcomesThe primary outcome was ductal closure. Other outcomes included mortality, ductal reopening, need for surgical ligation, NEC, isolated bowel perforation, intestinal haemorrhage, pulmonary haemorrhage, 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)


NotesStudy published in Spanish


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed envelopes)

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - cannot tell
Indomethaicin and ibuprofen were given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants

Other biasLow riskAppear free of other bias

Gokmen 2011

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsSingle-centre study conducted at Zekai Tahir Burak Maternity Teaching Hospital,
Ankara, Turkey, between January 2010 and February 2011

102 VLBW infants with PDA


InterventionsInfants received either iv or oral ibuprofen at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours.


OutcomesRenal tolerance, mean plasma creatinine after treatment, urine output after treatment, cystatin-C levels, failure to close a PDA, need for second course of ibuprofen, oliguria, hospital stay, NEC, gastrointestinal bleeding, sepsis, pneumothorax, BPD (supplemental oxygen at 36 weeks PMA or at discharge, which ever came first, ROP requiring laser treatment, death during hospital stay.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskPatients were assigned randomly using cards in opaque envelopes

Blinding (performance bias and detection bias)
All outcomes
High riskIbuprofen was given either orally or intravenously and this would have been known to the staff

Incomplete outcome data (attrition bias)
All outcomes
Low risk6 infants (4 in the iv ibuprofen group and 2 in the oral group) died before they completed their treatment. These infants were not included in an ITT analysis. We included them

Selective reporting (reporting bias)Unclear riskThe protocol for this study was not available to us and we can not ascertain whether there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Hammerman 2008

MethodsSingle-centre, randomised, controlled trial, conducted in Jerusalem, Israel
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsPopulation: 64 preterm (PMA < 33 weeks, BW <1750 g) infants with PDA

Study period: February 2002 to December 2006


InterventionsIntervention: 31 infants received continuous iv. infusion of indomethacin for 36 hours at a rate of 17 μcg/kg/hr and 32 infants received 10 mg/kg of ibuprofen iv followed by 2 doses of 5 mg/kg at 24-hour intervals.


OutcomesThe primary outcome was ductal closure, need for surgical ligation, need for re-treatment with either indomethacin or ibuprofen, need for surgical treatment, mortality, BPD (age not stated), IVH (grades III-IV), ROP, NEC.


NotesThe outcomes of BPD (age not stated), NEC, IVH (III-IV) and ROP (3-4), were reported in graphic form only and the numbers had to be estimated from the graph.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was based on computer-generated random numbers without sub-stratification

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Because the methods of drug administration were clearly different, the study could not be blinded. The cardiologist performing the echocardiograms was blinded to the study group

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
One infant assigned to the ibuprofen group was withdrawn by his parents before he started therapy, and he was not included in the analyses.

Selective reporting (reporting bias)Low riskThe protocol was available to us. Trial registration #: NCT00485160. There were no deviations from the protocol.

Other biasLow riskThe study appears to be free of other bias.

Lago 2002

MethodsTwo-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in Padova and Treviso, Italy

Study period: January 1998 to December 2000
175 preterm infants with echocardiographically verified PDA were enrolled
94 received ibuprofen mean (SD) GA 28 weeks (2); BW 1126 g (412); 52 boys, 42 girls
81 received indomethacin mean (SD) GA 29 weeks (3); BW 1214 g (427); 43 boys, 38 girls


InterventionsIbuprofen was given iv 10 mg/kg as the initial dose followed by 5 mg/kg each at 24 and 48 hours
Indomethacin was given iv 0.2 mg/kg for three doses at 12-hour intervals


OutcomesPDA closure
Serum creatinine
Oliguria


NotesAn interim report with 153 patients enrolled (ibuprofen group n = 82 and indomethacin group n = 71) has been published (Lago 2001). Zanardo 2005 represents a subpopulation of this study and examines the effect of ibuprofen and indomethacin on urinary antidiuretic hormone excretion


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo description provided.

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes
Cards in sealed envelopes

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants

Selective reporting (reporting bias)Unclear riskThe authors do not comment on the imbalance in the numbers enrolled in the ibuprofen group (n = 94) vs the indomethacin group (n = 81).

The protocol was not available to us, so we can not ascertain if there were deviations from the protocol.

Other biasLow riskAppears free of other bias.

Lin 2012

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - cannot tell
IV. Blinding of outcome measurement(s) - cannot tell


ParticipantsStudy conducted at the Maternal and Child health Hospital of Xiamen City, Xiamen, Fujian, China

64 symptomatic VLBW infants with a PDA confirmed by bedside Color Doppler ultrasound were enrolled within 24 hours after birth


Interventions32 infants received oral ibuprofen within 24 hours after birth at 10 mg/kg, followed 24 hours later by a second dose of 5 mg/kg and 48 hours ;later by a third dose of 5 mg/kg

32 infants received placebo (normal saline) at 1 mL/kg, followed 24 hours later by a second dose of 0.5 mL/kg and 48 hours later by a third dose of 0.5 mL/kg


OutcomesPDA closure, PVL, BPD, duration of ventilator support, duration of hospital stay, IVH, pulmonary haemorrhage, NEC, adverse effects.

From the abstract we were only able to calculate the rates for PDA closure in the two groups. P-values were provided for some of the other outcomes, and we have quoted them in the results section.


NotesThis study was published in Chinese and only the abstract published in English could be understood by us.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided in the abstract

Allocation concealment (selection bias)Unclear riskInfants were randomly divided into two groups

Blinding (performance bias and detection bias)
All outcomes
Unclear riskIt is possible that the study was blinded as a placebo was used in the control group

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWe could not judge this item from the abstract

Selective reporting (reporting bias)Unclear riskWe could not judge this item from the abstract

Other biasUnclear riskWe could not judge this item from the abstract

Mosca 1997

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in Milan, Italy

Study period: Not reported
16 infants receiving mechanical ventilation (<31 weeks GA) with echocardiographic evidence of PDA were randomised
8 neonates, median and range GA 29 weeks (27-31), BW 855 g (620 - 1620), postnatal age 24 hours (10-53), 4 boys and four girls were treated with ibuprofen
8 neonates, median and range GA 28 weeks (25-300, BW 820 g (600 - 1390), postnatal age 29 hours (5-120), 5 boys and 3 girls were treated with indomethacin


InterventionsIbuprofen was given iv 10 mg/kg infused over 1 minute as a first dose and a second and third dose were administered at 24-hour intervals provided that no significant adverse effect was observed
Indomethacin was given iv 0.2 mg/kg infused over one minute and a second and third dose of 0.1 mg/kg were administered at 24-hour intervals provided no significant adverse effects were observed


OutcomesPDA closure
Cerebral blood flow velocity
Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidised cytochrome oxidase concentration


NotesThe results of his study have been reported in abstract form with the same number of infants enrolled (Mosca 1996.) Whether there is any overlap with an additional study is unclear (Mosca 1997a).


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Clinicians were aware of group assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Patel 1995

MethodsSingle-centre, randomised, controlled trial without the use of a placebo
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in the UK

Study period: Not stated
33 infants with a median GA of 26 weeks (range 23 to 28) were enrolled. All infants had echocardiographically proven PDA


Interventions12 infants received ibuprofen 5 mg/kg; 6 received ibuprofen 10 mg/kg and 15 received indomethacin 0.1 mg/kg.The drugs were infused iv over 15 minutes


OutcomesPDA closure rate
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 oxidised cytochrome aa3.


NotesPublished as a letter to the editor.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
No information provided

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no randomised, controlled trial without the use of a placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Patel 2000

MethodsFour-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes


ParticipantsStudy conducted in 4 NICUs in the UK (Hammersmith, Queen Charlotte's, St George's and St Mary's Hospitals, London, UK)

Study period: January 1966 to December 1996
33 preterm infants with a haemodynamically significant PDA diagnosed clinically and on echocardiographic criteria were randomised
18 infants received iv ibuprofen, median and range GA 26.0 weeks (23.9-35.00); BW 790 g (620-2780); postnatal age 8 days (3-20); 9 boys, 9 girls
15 received indomethacin; GA 26.7 weeks (23.2-30.0); BW 838 g (458-1377); postnatal age 7 days (3-21)


InterventionsIbuprofen was given iv 10 mg/kg as the initial dose followed by 5 mg/kg at 24 and 48 hours after the initial dose
Indomethacin was given as 0.2 mg/kg as initial dose. Two further doses were administered after 12 and 24 hours: infants aged 2 to 7 days at the time of the first dose received 0.2 mg/kg and those infants 8 days or older received 0.25 mg/kg
To prevent identification of the drug administered from the timing schedule, all infants received a fourth dose containing 0.9% saline: in the indomethacin group, 48 hours after the first dose and, in the ibuprofen group, 12 hours after the first dose
Intravenous infusion of all drugs were performed over 15 minutes using an infusion pump


OutcomesPDA closure rate
Near-infrared spectroscopy was used to measure changes in cerebral blood volume, cerebral blood flow, cerebral oxygen delivery


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes

The Pharmacy Department at Queen Charlotte's Hospital performed randomisation in block of 12 for each hospital and provided all trial medication. All other personnel were blinded to the identity of the drug administered

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of intervention - yes
Blinding of outcome measurement(s) - yes
See allocation concealment.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Pezzati 1999

MethodsSingle-centre, randomised controlled trial, conducted in Firenze, Italy

Study period: No information provided
I Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - cannot tell


Participants17 preterm infants (< 33 weeks GA)
9 infants received ibuprofen, mean (SD) GA 29.1 (2.2) weeks; BW 1151 (426) g8 infants received indomethacin, mean (SD) GA 29.5 (2.6); BW 1277 (440) g


InterventionsIndomethacin (0.2 mg/kg) or ibuprofen (10 mg/kg) were given 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


OutcomesThe primary outcome was mesenteric and renal blood flow velocity. Secondary outcomes included: ductal closure, ductal reopening and NEC


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Infants were randomly assigned - no further information provided

Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of intervention - cannot tell
Blinding of outcome measurement(s) - cannot tell

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Plavka 2001

MethodsThree-centre, randomised controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - cannot tell


ParticipantsStudy conducted in 3 NICUs in the Czech Republic

Study period: Study period not stated
41 preterm infants with clinical and echographic signs of PDA were randomised
21 infants received ibuprofen, mean (SD) GA 27.6 weeks (2.3); BW 929 g (213)
20 received indomethacin
GA 26.9 weeks (1.7); BW 902 g (211)


InterventionsIbuprofen was given iv 8 mg/kg every 24 hours for three doses
Indomethacin was given iv 0.2 mg/kg every 24 hours for three doses
If PDA persisted, treatment was repeated at half dose every 24 hours for 6 doses. Persistent PDA was ligated


OutcomesCerebral blood flow velocities, blood pressure, serum creatinine, mortality, ductal reopening


NotesPublished in abstract form only


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell

Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of intervention - cannot tell
Blinding of outcome measurement(s) - cannot tell

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComplete follow-up - yes

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Pourarian 2008

MethodsOne-centre, randomised controlled trial, conducted in Shiraz, Republic of Iran

Study period: 6 month period in 2001
I. Blinding of randomisation - no
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


Participants20 preterm infants with ECHO-confirmed PDA

Ibuprofen group (n = 10); mean (SD) PMA 31.3 (4.4) weeks; mean (SD) BW 1860 (402) g

Indomethacin group (n = 10); mean (SD) PMA 33.2 (3.1) weeks; Mean (SD) PMA 1720 (630) g


InterventionsFor the indomethacin group , the powder content of a 25 mg indomethacin capsule was freshly prepared by dissolving in 25 mL distilled water. This was given orally as 0.2 mg/kg for 3 doses at 24-hour intervals. For the ibuprofen group, an ibuprofen oral suspension containing 100 mg/5 mL was given as an initial dose of 10 mg/kg, followed by 2 further doses of 5 mg/kg at 24 hr intervals. Administration of the 2nd or 3rd doses of each drug was dependent on achievement of ductal closure after the initial doses.


OutcomesThe primary outcome was ductal closure. Secondary outcomes included need for surgical closure, NEC, change in mean serum creatinine levels before and after treatment, increase in BUN level > 14 mmol/L, thrombocytopenia < 50 000 mm3.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo mention of how the randomisation sequence was generated

Allocation concealment (selection bias)High riskBlinding of randomisation - no

"As soon as the diagnosis (of PDA) was made for the 1st eligible baby, he/she was enrolled to the ibuprofen group and then the next eligible baby was assigned to the indomethacin group, and so on". This statement clearly indicated that the infants were not allocated to the two groups in a concealed manner

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
The researchers were aware of group assignment - see allocation concealment

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Results for all randomised infants are reported

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskThe study appears free of other bias

Salama 2008

MethodsSingle-centre, randomised controlled trial conducted in Doha, State of Qatar

Study period: January 2005 to March 2007
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


Participants41 preterm infants (PMA , 34 weeks, BW < 2500 g) diagnosed with haemodynamically significant PDA (confirmed by echocardiography)


Interventions20 infants [mean PMA = 27.8 (SD 2.8) weeks; mean BW 1050 (SD 440) g] received iv indomethacin (3 doses of 0.2 mg/kg/dose every 24 hours) and 21 infants [mean PMA 27.7 (SD 2.5); mean BW 1094 g (SD 480)] received oral ibuprofen (10 mg/kg on the first day followed by 5 mg/kg for 2 more days). Ibuprofen was mixed with 0.5 mL of milk before its administration via an oro-gastric tube


OutcomesThe primary outcome was complete closure of the PDA. Secondary outcomes included need for surgical ligation, bowel perforation, mortality


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation was conducted according to a pre-designed simple block randomisation table "A" for indomethacin and "B" for ibuprofen (AABABBBBAA, BBBAAABBA, AABBABABAAB, etc

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
No description of possible concealment

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Indomethacin was given iv and ibuprofen was given via an oro-gastric tube
The paediatric cardiologist was aware of the patient's group allocation

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

Sosenko 2012

MethodsSingle-centre, double-blind, randomised controlled trial

I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in Miami, Florida, US

Study period January 2008 to August 2010

Infants born with birth weights between 500 and 1250 g and PMA between 23 and 32 weeks, who were > 24 hours old but </= 14 days old and who had ECHO for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses)


InterventionsInfants were randomised to "early" treatment (blinded ibuprofen, n = 54) or "expectant" management (blinded placebo, n = 51). If the PDA became haemodynamically significant (pulmonary haemorrhage, hypotension, respiratory deterioration), infants received open-label ibuprofen. Infants with haemodynamically significant PDA at enrolment were excluded from the study.

The dosing schedule for ibuprofen was an initial dose of 10 mg/kg, followed by two doses of 5 mg/kg each, every 24 hours, by slow intravenous infusion; dosing of placebo involved equivalent volumes of dextrose by slow intravenous infusion on the same schedule.


OutcomesDays on supplemental oxygen during the first 28 days of life, death during hospital stay, supplemental oxygen at 36 weeks PMA, intestinal perforation, NEC requiring surgery, IVH (grades III and IV), PVL, sepsis, ROP (stage >/= 3).


NotesAfter 105 of 168 infants were enrolled the study drug (NeoProfen) was recalled by the manufacturer and was no longer available in the US.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table

Allocation concealment (selection bias)Low riskSealed envelopes

Blinding (performance bias and detection bias)
All outcomes
Low riskClinicians, investigators, and nursing staff were blinded to the study group to which the infant was assigned and the medication the infant was receiving. Only the neonatal pharmacists were aware of the study group of each infant and were responsible for preparing the "blinded" ibuprofen or "blinded" placebo study drug

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all enrolled infants

Selective reporting (reporting bias)Low riskThis study was registered, # NCT00802685, and there does not seem to be any deviations from the protocol, except that the study had to be stopped when the study drug was no longer available

Other biasLow riskAppears free of other bias

Su 2003

MethodsSingle-centre, randomised controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in Taichung,Taiwan

Study period: January 2001 to December 2002
63 preterm infants with BW </= 1500 g and a GA of </= 32 weeks and with echocardiographic evidence of a PDA were randomised between 2 and 7 days of age
32 infants [mean (SD) BW 1134 +/- 200 g; mean (SD) GA 28.7 +/- 2.2 weeks] received iv ibuprofen 10 mg/kg initially and followed by ibuprofen 5 mg/kg after 24 and 48 hours
31 infants [mean (SD) BW 1110 +/- 244 g; mean (SD) GA 28.2 +/- 2.4] received iv indomethacin 0.2 mg/kg every 12 hours for three doses


InterventionsIbuprofen was given iv as 10mg/kg initially, followed by 5 mg/kg after 24 and 48 hours
Indomethacin was given iv as 0.2 mg/kg every 12 hours for three doses


OutcomesRate of PDA closure, rate of reopening of the duct, mortality, gastric bleeding, IVH, PVL, NEC, BPD at 36 weeks GA, duration of mechanical ventilation, time to full oral feeds, length of hospital stay


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin was given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all infants randomised

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free from other bias.

Su 2008

MethodsSingle-centre, randomised controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes


ParticipantsStudy conducted in Taichung,Taiwan

Study period: February 2004 to October 2006

119 infants with echocardiographic evidence of a significant PDA

60 infants [PMA (median 25; range 23-28 weeks); BW (median 825; range 550-990 g)] received ibuprofen and 59 infants [PMA (median 25; range 23-28 weeks; BW (median 762; range 540-980 g) received indomethacin


InterventionsInfants were randomised to receive either iv ibuprofen 10 mg/kg initially followed by 5 mg/kg at 24 hours intervals or iv indomethacin 0.2 mg/kg as the initial dose and then 0.1 mg/kg in infants < 48 hours old, 0.2 mg/kg in infants > 48 hours at 24 hours intervals as indicated by PDA flow pattern.


OutcomesPrimary outcome was PDA closure. Secondary outcomes included need for surgical ligation, mortality within 30 days, NEC, CLD at 36 weeks gestational age, IVH, PVL, ROP, BPD at 36 weeks PMA, oliguria, post treatment serum creatinine, hospital stay, duration of mechanical ventilation, days to full enteral feeds and gastric bleeding.


NotesThe study included a sample size calculation


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAccording to a random number table sequence, which had been prepared by a study assistant who was not involved in the care of infants

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of intervention - yes
Blinding of outcome measurement(s) - yes

The medication was infused iv continuously over 15 minutes. The drug was prepared and dispensed through the hospital pharmacy department and the attending doctors were unaware of the drug used

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasUnclear riskAppears free of other bias

Supapannachart 2002

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - yes (sealed envelope)
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsSingle-centre study conducted in Bangkok,Thailand

Study period: April 1, 2000 to August 31, 2001
18 preterm infants (< 34 weeks GA) with symptomatic PDA
9 infants received ibuprofen, mean (SD) GA 30.1 (2.7); BW 1447 (39) g; 8 boys, 1 girl
9 infants received indomethacin, men (SD) GA 30.4 (2.6); BW 1432 (531); 6 boys, 3 girls


InterventionsIbuprofen was given orally (10 mg/kg/dose for three doses at 24-hourly intervals
Indomethacin (oral or iv 0.2 mg/kg/dose) for three doses given at 12-hourly intervals


OutcomesPDA closure rate, duration of ventilatory support, CLD (age not stated), IVH (grade not stated), NEC, mortality.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed envelope)

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all infants randomised

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias.

Van Overmeire 1997

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in Antwerp, Belgium

Study period: Not stated
40 preterm infants (GA, 33 weeks) were randomised
20 infants received ibuprofen, mean (SD) GA 29.0 (2.4); BW 1270 g (450) ; surfactant use 15
20 infants received indomethacin; mean (SD) GA 28.7 weeks (1.9); BW 1210 g (360), surfactant use 19


InterventionsIbuprofen was given iv 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later
Indomethacin was given iv 0.2 mg/kg every 12 hours for three doses.Both drugs were infused over 15 minutes


OutcomesPDA closure rate, PDA ligation rate, mortality, sepsis, NEC, age to regain birthweight, ROP


NotesIt is possible that there is overlap between this study and a report in abstract form with 28 patients enrolled (Van Overmeire 1996)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed envelopes)

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different time intervals

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all infants randomised

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskApperas free of other bias

Van Overmeire 2000

MethodsSingle-centre, randomised, controlled trial without the use of a placebo
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no


ParticipantsStudy conducted in 5 NICUs in Belgium (two hospitals in Antwerp, one hospital each in Ghent, Bruges and Rocourt

Study period: Not stated

148 infants with PMA 24 to 32 weeks, who had respiratory distress syndrome and echocardiographically confirmed PDA were randomised to two groups:
74 received ibuprofen mean (SD) GA 29.0 weeks(2.3); BW 1230 g (390); surfactant treatment 56
74 received indomethacin mean (SD) GA 29.0 weeks (2.1); BW 1230 g (380);
Surfactant treatment 63


InterventionsIbuprofen was given iv 10 mg/kg as the initial dose, followed at 24-hour intervals by two doses of 5 mg/kg
Indomethacin was administered iv 0.2 mg/kg every 12 hours


OutcomesPDA closure rate, oliguria, PDA ligation rate, mortality by 30 days, NEC,localised bowel perforation, sepsis, PVL, CLD at 28 days, time to regain birth weight, time to full enteral feeding.


NotesWe believe this study has been reported in abstract form when 103 preterm infants had been enrolled (Van Overmeire 1998), but we have not been able to verify this with the authors.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided

Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed opaque envelopes)

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different times

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants

Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not

Other biasLow riskAppears free of other bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Amoozgar 2010A randomised controlled study of ibuprofen in term neonates

Cherif 2007This study evaluated the use of oral ibuprofen for closure of PDA, but did not include a control group

Desfrere 2005This was a dose-finding study

 
Characteristics of studies awaiting assessment [ordered by study ID]
Fesharaki 2012

MethodsDifferent doses of ibuprofen in the treatment of PDA: a randomised clinical trial [Article in Persian]

Randomised controlled clinical trial.

Participants60 patients with echocardiographically confirmed PDA.

This study was done in NICU of Vali-Asr hospital.

InterventionsGroup 1: loading dose of 10 mg/kg ibuprofen on the first day, followed by two doses of 5 mg/kg in the next two days.

Group 2: loading dose of 15 mg/kg ibuprofen on the first day followed by two doses of 7.5 mg/kg in next two days.

OutcomesPDA closure rates and complications of therapy between the two groups.

NotesThirty (100%) patients in 15-mg/kg group and 23 (76.7%) patients in 10 mg/kg group had successful PDA closure with no need for surgery (P = 0.011).

Dr. Fatemeh Nayeri (corresponding author) has kindly provided us with an English translation of the article in January 2013. We are awaiting some clarifications regarding the trial and the results will be included in the next update of the review.

Qosja 2012

MethodsRandomised controlled trial conducted in the NICU of the Maternity Koco Gliozheni Hospital, Tirana, Albania

Participants32 preterm newborns, postnatal age 72-96 hours, with echocardiographically confirmed PDA

Study period January 2010 to December 2010

Interventions16 infants received oral ibuprofen and 16 received iv ibuprofen

OutcomesDuctal closure, reopening of the duct, bowel perforation, gastro-enteral bleeding

NotesThe study has been published in abstract form only

 
Characteristics of ongoing studies [ordered by study ID]
Gournay 2012

Trial name or titleEarly ibuprofen treatment of patent ductus arteriosus (PDA) in premature infants (TRIOCAPI)

MethodsRandomised controlled trial

Participants385 very premature (PMA < 28 weeks) infants with a large ductus, selected by an early echocardiogram

InterventionsIbuprofen or placebo before 12 hours of life. Follow-up will include repeated echocardiograms and cranial ultrasound at 36 hours, 14 days and 36 weeks of postconceptional age

OutcomesPrimary outcome measure:

2-year survival without cerebral palsy

Secondary outcome measures:
ASQ (Ages and Stages Questionnaire) score at 2 years
Incidence of other prematurity-related morbidities (pulmonary, digestive, neurological, renal)
To compare the outcome between the large and the small ductus groups
Comparison of outcome according to the McNamara stage at surgical ligation

Starting dateMarch 2012

Contact informationVéronique GOURNAY, Professor, Nantes University Hospital. Phone +33 2 40 08 77 84; veronique.gournay@chu-nantes.fr

NotesClinicalTrials.gov identifier: NCT01630278

Su 2010

Trial name or titleComparison of oral and intravenous ibuprofen for PDA treatment in premature infants

MethodsDouble-blind, randomised controlled trial

Participants70 extremely preterm infants with ECHO confirmed PDA

InterventionsThe dosage of oral or ibuprofen is 10 mg/kg (1 mL) and then 5 mg/kg at 24-hour intervals as indicated by echocardiographic PDA flow pattern

OutcomesThe primary outcome is to ascertain whether oral ibuprofen is effective and safe in inducing PDA closure in extremely premature infants

A secondary objective is to compare the complications between infants treated with oral ibuprofen and those treated with iv ibuprofen

Starting dateDecember 2009

Contact informationBai-Horng Su, MD, PhD, Medical University Hospital,Taichung, Taiwan, 404

Phone: 886-4-22052121 ext 2061 bais@ms49.hinet.net

Notes

 
Comparison 1. Intravenous ibuprofen versus placebo or no drug

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Infant deaths, infants who dropped out or required rescue treatment1136Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.38, 0.89]

 2 NEC1130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.42, 2.36]

 3 Intraventricular haemorrhage (any grade)1134Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.64, 1.55]

 4 Intraventricular haemorrhage (grades III-IV)1134Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.47, 2.15]

 5 Pulmonary haemorrhage1136Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.18]

 6 Pulmonary hypertension1136Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.54]

 7 ROP (any stage)1129Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.88, 1.62]

 8 ROP (stage 3 or 4)1129Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.38, 3.68]

 9 ROP (plus disease)1129Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.63]

 10 CLD (supplemental oxygen at 28 days of age)1130Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.26]

 11 CLD (supplemental oxygen at 36 weeks PMA)198Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.88, 1.11]

 12 Periventricular leukomalacia1130Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 2.02]

 13 Mortality1136Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.34, 1.90]

 
Comparison 2. Oral ibuprofen versus placebo or no drug

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Failure to close a PDA after single or three doses164Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.11, 0.62]

 
Comparison 3. Intravenous or oral ibuprofen versus iv or oral indomethacin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Failure to close a PDA (after single or three doses)201019Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.80, 1.20]

 2 All cause mortality8470Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.45, 1.29]

 3 Neonatal mortality (during first 28/30 days of life)4333Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.59, 2.11]

 4 Reopening of the ductus arteriosus6204Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.48, 3.38]

 5 Need for surgical closure of the PDA13848Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.71, 1.51]

 6 Need for re-treatment with indomethacin or ibuprofen to close the PDA7241Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.76, 1.90]

 7 Duration of ventilatory support6471Mean Difference (IV, Fixed, 95% CI)-2.35 [-3.71, -0.99]

 8 Duration of supplementary oxygen6556Mean Difference (IV, Fixed, 95% CI)-0.33 [-1.66, 0.99]

 9 Pulmonary haemorrhage3103Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.37, 4.10]

 10 Pulmonary hypertension135Risk Ratio (M-H, Fixed, 95% CI)3.53 [0.15, 81.11]

 11 Chronic lung disease (at 28 days)4245Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.93, 1.59]

 12 Chronic lung disease (at 36 weeks postmenstrual age)3357Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.61]

 13 Chronic lung disease (age not stated)3128Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.83, 1.30]

 14 Intraventricular haemorrhage (grades I-IV)5180Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.47, 1.48]

 15 Intraventricular haemorrhage (grades III-IV)8571Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.74, 1.98]

 16 Periventricular leukomalacia (cystic)6573Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.67, 2.30]

 17 Necrotising enterocolitis (any stage)15865Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.47, 0.99]

 18 Intestinal perforation5255Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.20, 1.14]

 19 Gastrointestinal bleed6314Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.57, 2.15]

 20 Time to full enteral feeds4413Mean Difference (IV, Fixed, 95% CI)0.70 [-1.89, 3.29]

 21 Time to regain birth weight (days)2188Mean Difference (IV, Fixed, 95% CI)-0.18 [-2.59, 2.22]

 22 Retinopathy of prematurity5237Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.54, 1.38]

 23 Sepsis6535Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.73, 1.81]

 24 Decreased urine output (<1 cc/kg/hr)6576Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.14, 0.54]

 25 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment8491Mean Difference (IV, Fixed, 95% CI)-4.70 [-8.88, -0.53]

 26 Increase in serum/plasma creatinine levels (mg/dL) following treatment121Mean Difference (IV, Fixed, 95% CI)-15.91 [-31.78, -0.04]

 27 Duration of hospitalisation3285Mean Difference (IV, Fixed, 95% CI)-2.19 [-6.55, 2.18]

 
Comparison 4. Oral ibuprofen versus iv or oral indomethacin

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Failure to close a PDA (after three doses)7189Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.52, 1.29]

 2 All cause mortality382Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.21, 1.66]

 3 Neonatal mortality (during first 28/30 days of life)266Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.33, 5.39]

 4 Reopening of the ductus arteriosus120Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Need for surgical closure of the PDA391Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.24, 1.70]

 6 Pulmonary haemorrhage121Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.86]

7 Pulmonary hypertension00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Chronic lung disease (at 28 days)130Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.38, 1.95]

9 Chronic lung disease (at 36 weeks postmenstrual age)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 10 Chronic lung disease (age not stated)118Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.52, 1.92]

 11 Intraventricular haemorrhage (grades I-IV)377Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.45, 1.83]

 12 Intraventricular haemorrhage (grades III-IV)141Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.15, 6.13]

 13 Periventricular leukomalacia (cystic)141Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.38]

 14 Necrotising enterocolitis (any stage)6166Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.23, 0.82]

 15 Intestinal perforation262Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.03, 1.95]

 16 Gastrointestinal bleed385Risk Ratio (M-H, Fixed, 95% CI)2.80 [0.48, 16.45]

 17 Retinopathy of prematurity271Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.35, 2.73]

 18 Sepsis253Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.54, 2.19]

 19 Oliguria (< 1 cc/kg/hr)136Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 20 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment4107Mean Difference (IV, Fixed, 95% CI)-15.14 [-23.00, -5.28]

 
Comparison 5. Oral ibuprofen versus iv ibuprofen

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Failure to close a PDA (after single or three doses)3236Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.23, 0.61]

 2 Mortality (during first 28/30 days of life)164Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.50, 2.55]

 3 Mortality (during hospital stay)2188Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.38, 1.82]

 4 Mean plasma cystatin-C (mg/L) after treatment1102Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.37, -0.13]

 5 Need for surgical closure of the ductus3236Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.12, 1.91]

 6 Duration of ventilatory support2134Mean Difference (IV, Fixed, 95% CI)0.54 [-0.01, 1.10]

 7 Duration of hospitalisation (days)3236Mean Difference (IV, Fixed, 95% CI)-2.51 [-5.21, 0.19]

 8 Pneumothorax2172Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.11, 1.54]

 9 Pulmonary haemorrhage170Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.52]

 10 Pulmonary hypertension2172Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

11 Chronic lung disease (at 28 days)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 12 Chronic lung disease (at 36 weeks postmenstrual age or at discharge)3236Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.56, 1.20]

13 Chronic lung disease (age not stated)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 14 Intraventricular haemorrhage (grades I-IV)164Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.59, 2.00]

15 Intraventricular haemorrhage (grades III-IV)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Periventricular leukomalacia164Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.67]

 17 Necrotising enterocolitis (any stage)3236Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.35, 2.15]

 18 Intestinal perforation2134Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.48]

 19 Gastrointestinal bleed2172Risk Ratio (M-H, Fixed, 95% CI)2.89 [0.12, 69.24]

 20 Sepsis3236Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.54, 1.25]

 21 Retinopathy of prematurity that required laser treatment2172Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.26, 1.34]

 22 Serum/plasma creatinine levels (micromol/L) after treatment1102Mean Difference (IV, Fixed, 95% CI)-29.17 [-40.67, -17.67]

 23 Oliguria (< 1cc/kg/hr)3236Risk Difference (M-H, Fixed, 95% CI)-0.03 [-0.06, 0.01]

 
Comparison 6. High dose versus standard dose of ibuprofen

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Failure to close a PDA after three doses of ibuprofen170Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.15, 0.96]

 2 Reopening after 2nd course of ibuprofen170Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.39, 10.22]

 3 Need for surgical closure170Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.71]

 4 Death during hospital stay195Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.54, 1.71]

 5 Urine output on day 3 (mL/kg/hr)170Mean Difference (IV, Fixed, 95% CI)0.10 [-0.70, 0.90]

 6 Oliguria (< 1 mL/kg/hr during 24 hrs)170Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.27, 8.43]

 7 Intraventricular haemorrhage (all grades)170Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.21, 2.16]

 8 Intraventricular haemorrhage (grades III-IV)170Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.10, 2.56]

 9 Periventricular leukomalacia170Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.27, 8.43]

 10 Retinopathy of prematurity170Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.27, 3.69]

 11 Retinopathy of prematurity (Stage ≥3)170Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.06]

 12 Necrotising enterocolitis170Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.32, 5.53]

 13 Chronic lung disease at 36 weeks PMA170Risk Ratio (M-H, Fixed, 95% CI)1.6 [0.85, 3.02]

 14 Sepsis170Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.51, 1.68]

 15 Hospital stay (days)170Mean Difference (IV, Fixed, 95% CI)21.0 [-1.44, 43.44]

 
Comparison 7. Early versus expectant administration of iv ibuprofen

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Days on supplemental oxygen during the first 28 days1105Mean Difference (IV, Fixed, 95% CI)2.0 [0.04, 3.96]

 2 Days on supplemental oxygen1105Mean Difference (IV, Fixed, 95% CI)2.0 [-8.20, 12.20]

 3 Days on mechanical ventilation first 28 days1105Mean Difference (IV, Fixed, 95% CI)2.0 [-0.58, 4.58]

 4 Days on mechanical ventilation1105Mean Difference (IV, Fixed, 95% CI)-1.0 [-6.98, 4.98]

 5 Chronic lung disease at 36 weeks PMA1101Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.57, 1.75]

 6 Death or chronic lung disease at 36 weeks PMA1105Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.59, 1.67]

 7 Death during hospital stay1105Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.19, 2.10]

 8 Pneumothorax1105Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.30, 5.35]

 9 Intraventricular haemorrhage (grades III & IV)1105Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.29, 2.25]

 10 PVL1105Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.30, 5.35]

 11 NEC (requiring surgery)1105Risk Ratio (M-H, Fixed, 95% CI)2.36 [0.48, 11.63]

 12 Intestinal perforation1105Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.09, 2.47]

 13 Sepsis1105Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.58, 1.41]

 14 ROP stage ≥ 3195Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.49, 5.03]