Description of studies

We identified one study comparing oral ibuprofen with placebo for this update in 2012 (Lin 2012). For this update, we added a comparison of oral ibuprofen versus iv ibuprofen as three studies (Cherif 2008; Gokmen 2011; Erdeve 2012) have studied this comparison. We included one study Dani 2012 that compared iv high dose of ibuprofen versus standard dose regimen of ibuprofen. One additional comparison was included for early versus expectant administration of iv ibuprofen (Sosenko 2012). Thus six additional studies were included for this update in 2012.

INTRAVENOUS IBUPROFEN VERSUS PLACEBO OR NO DRUG

The study by Aranda and co‐workers (Aranda 2005) was a multi‐centre study conducted at 11 sites in the US and published as an abstract in 2005 (full study published in 2009).

• Objective: To compare the efficacy and safety of iv ibuprofen (L‐lysine) with placebo for the early closure of a non‐symptomatic PDA within 72 hours of birth in extremely low‐birth‐weight preterm infants with evidence of ductal shunting by echocardiography.

• Population: 136 preterm infants (PMA < 30 weeks, birth weight (BW) 500 g 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 iv 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) died or dropped out through study day 14. Secondary outcomes included mortality, need for PDA ligation, IVH, PVL, NEC, CLD and ROP.

ORAL IBUPROFEN VERSUS PLACEBO OR NO DRUG

The study by Lin and co‐workers (Lin 2012) was a single‐centre study conducted in Xiamen City, Xiamen, Fujian, China (New inclusion). The study was published in Chinese and only the information in the abstract published in English was understood by the review authors. We have written to the authors to obtain further details, but we have not received a response.

• Objective: To study the therapeutic effect and safety of early administration of oral ibuprofen in VLBW infants with a PDA.

• Population: 64 symptomatic VLBW infants with ECHO‐confirmed PDA were enrolled within 24 hours after birth.

• Intervention: Infants in the ibuprofen group received oral ibuprofen at 10 mg/kg as an initial dose within 24 hours after birth, followed by a second and a third dose of 5mg/kg of ibuprofen 24 and 48 hours after the initial dose. In the placebo group infants received 1 ml/kg of normal saline followed by 0.5 ml of saline 24 and 48 hours later.

• Outcomes: The primary outcome was PDA closure rate following the initial course of treatment (three doses).

INTRAVENOUS OR ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN

The study by Adamska and co‐workers (Adamska 2005) was a single‐centre study conducted in Poland.

• Objective: To assess the efficacy and safety of early treatment with iv ibuprofen or iv indomethacin in preterm infants.

• Population: 35 preterm (< 33 weeks PMA and BW < 1500 g) infants with a PDA diagnosed by Doppler echocardiography.

• Intervention: The infants were randomised to receive three doses of indomethacin (0.2 mg/kg iv given at 24 hour intervals), (n = 19) or three doses of ibuprofen (10, 5, and 5 mg/kg iv 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 haemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.

The study by Akisu and co‐workers (Akisu 2001) was conducted in one centre in Turkey.

• Objective: To investigate the efficacy and safety of enteral ibuprofen for the treatment of PDA and to compare it with enteral indomethacin.

• Population: 23 preterm infants (< 35 weeks PMA) with a PDA diagnosed by Doppler echocardiography.

• Intervention: Infants were randomised to receive either enteral ibuprofen 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later (n = 12) or three doses of enteral 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 haemorrhage, IVH, sepsis and mortality.

The study by Aly and co‐workers (Aly 2007) was a single‐centre study conducted in Egypt.

• Objective: To evaluate the feasibility of the use of oral ibuprofen suspension versus iv indomethacin 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 randomised to receive three doses of iv 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 pulmonary haemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and change in serum creatinine following treatment.

The study by Chotigeat and co‐workers (Chotigeat 2003) was conducted in one centre in Thailand.

• Objective: To compare efficacy and side effects of ibuprofen versus indomethacin treatment for symptomatic PDA in preterm infants.

• Population: Preterm infants with a symptomatic PDA confirmed by echocardiogram

• Intervention: 30 infants were randomised to received either three oral doses of ibuprofen (dose not stated) given at 24‐hourly intervals or three doses of iv 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.

The study by Fakhraee an co‐workers (Fakhraee 2007) was conducted in one centre in Iran.

• Objective: To compare the efficacy and safety of oral ibuprofen and oral indomethacin for the treatment of PDA in preterm infants.

• Population: 36 preterm infants (< 34 weeks PMA).

• Intervention: 18 infants were randomised to receive three oral doses of indomethacin (0.2 mg/kg, at 24‐hour intervals) and 18 infants to three doses of oral ibuprofen (first does of 10 mg/kg, followed by 5mk/kg/dose at 24‐hour intervals).

• Outcomes: The primary outcome was ductal closure. Secondary outcomes included maximum serum blood urea nitrogen (BUN) and creatinine levels after treatment, NEC, mortality at one month of age, IVH (grades III and IV).

The study by Gimeno Navarro and co‐workers (Gimeno Navarro 2005) was conducted in one centre in Spain.

• Objective: To compare the safety and efficacy of ibuprofen and indomethacin in the treatment of PDA in preterm infants.

• Population: Preterm infants (< 34 weeks PMA) with a haemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support.

• Intervention: During the first week of life (average two days of life) 47 ventilated infants, were randomised to receive either indomethacin 0.2 mg/kg/dose iv every 12 hours for a total of three doses (n = 24) or an initial dose of iv ibuprofen of 10 mg/kg, followed by two doses of ibuprofen iv 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 haemorrhage, pulmonary haemorrhage, CLD (age not stated), IVH (grades III and IV), days on assisted ventilation, days in supplemental oxygen, days in NICU (neonatal intensive care unit).

The study by Hammerman (Hammerman 2008) was conducted in a single centre in Israel.

• Objective: To show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function and blood flow velocities.

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

• Intervention: 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 two doses of 5 mg/kg at 24 hr intervals.

• Outcomes: The primary outcome was ductal closure. Other outcomes included need for surgical ligation, need for re‐treatment with either indomethacin or ibuprofen, need for surgical treatment, bronchopulmonary dysplasia (BPD), IVH (grades III‐IV), ROP, NEC.

The study by Lago and co‐workers (Lago 2002) was conducted in two centres in Italy.

• Objective: To compare indomethacin and ibuprofen with regard to efficacy and safety for the early treatment of PDA.

• Population: Preterm infants (< 34 weeks PMA, postnatal age 48 to 72 hours) with respiratory distress syndrome (RDS) treated with mechanical ventilation and echocardiographic evidence of PDA.

• Intervention: 175 infants were randomised to either iv 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 iv indomethacin 0.2 mg/kg at 12‐hour 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‐randomised 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 haemodynamically 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, NEC, sepsis, death, duration of ventilator support, days in oxygen, duration of hospital stay, time to full feeds.

The study by Mosca and co‐workers (Mosca 1997) was conducted in one centre in Italy.

• Objective: To compare the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with PDA.

• Population: Preterm infants (< 31 weeks PMA) with PDA and receiving mechanical ventilation.

• Intervention: 16 infants received either 10 mg/kg ibuprofen dissolved in 1 mL saline and infused over one minute iv or 0.2 mg/kg indomethacin iv (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 oxidised 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.

The study by Patel and co‐workers Patel 1995 was a single‐centre pilot study conducted in one centre in England.

• Objective: To compare the cerebral effects of ibuprofen with indomethacin in preterm infants.

• Population: 33 infants with a median PMA of 26 weeks (range 23 to 28) and a echocardiographically proven PDA.

• Intervention: Infants were randomised 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 iv 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 oxidised cytochrome aa3. Ductal closure was reported.

The second study by Patel and co‐workers Patel 2000 was conducted in four centres in England.

• Objective: To compare the effects of ibuprofen to indomethacin on cerebral haemodynamics measured using near infrared spectroscopy in preterm infants during treatment for PDA.

• Population: 33 preterm infants (< 35 weeks PMA).

• Intervention: Infants were randomly assigned to three iv doses of either ibuprofen (5 to 10 mg/kg, 24 hourly) or indomethacin (0.20 to 0.25 mg/kg, 12 hourly) and also received a dose of saline. Eighteen infants were randomised 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.

The study by Pezzati and co‐workers Pezzati 1999 was conducted in one centre in Italy.

• 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 PMA) with a PDA diagnosed by Doppler echocardiography.

• Intervention: 17 infants were randomised to receive either iv indomethacin (0.2 mg/kg) or iv 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.

The study by Plavka and co‐workers (Plavka 2001) was conducted in three centres in the Czech Republic.

• Objective: To compare adverse effects and efficacy of iv ibuprofen with iv 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 iv or indomethacin (n = 20) 0.2 mg/kg every 24 hours for three doses iv 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.

The study by Pourarian and co‐workers (Pourarian 2008) was conducted in a single centre in Iran :

• Objective: To evaluate the therapeutic effects of oral administration of indomethacin or ibuprofen suspension on closure of PDA in preterm infants.

• Population: 20 preterm infants with echo‐confirmed PDA

• Intervention: For 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 three 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 two further doses of 5 mg/kg at 24‐hour intervals. Administration of the second or third doses of each drug was dependent on achievement of ductal closure after the initial doses.

• Outcomes: The 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 mm^3.

The study by Salama and co‐workers (Salama 2008) was conducted in a single centre in Qatar.

• Objective: To compare the efficacy of oral ibuprofen with iv indomethacin for closure of a significant PDA in preterm infants.

• Population: 41 preterm infants (PMA , < 34 weeks, BW < 2500 g) diagnosed with haemodynamically significant PDA.

• Intervention: 20 infants received iv indomethacin (three doses of 0.2 mg/kg/dose every 24 hours) and 21 received oral ibuprofen (10 mg/kg on the first day followed by 5 mg/kg for two more days). Ibuprofen was mixed with 0.5 mL of milk before its administration via an oro‐gastric tube.

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

The study by Su and co‐workers (Su 2003) was conducted in a single centre in Taiwan.

• Objective: To compare iv ibuprofen and iv indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.

• Population: 63 preterm infants (PMA < 32 weeks, BW < 1500 g) with echocardiographic evidence of a significant PDA.

• Intervention: Infants were randomised to receive either iv ibuprofen 10 mg/kg initially followed by 5 mg/kg after 24 and 48 hours or iv 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 PMA, IVH, PVL, ROP, hospital stay, duration of mechanical ventilation, days to full enteral feeds and gastric bleeding.

The study by Su and co‐workers (Su 2008) was conducted in a single centre in Taiwan.

• Objective: To ascertain whether ibuprofen is effective and safe in inducing PDA closure in extremely preterm infants.

• Population: 119 infants (PMA < 28 weeks) with respiratory distress syndrome and PDA confirmed by ECHO.

• Intervention: 59 infants received iv indomethacin 0.2 mg/kg (1 mL) as the initial dose and then 0.1 mg/kg in infants < 48 hours old, 0.2 mg/kg in infants over 48 hours at 24‐hour intervals as indicated by PDA flow patterns. 60 infants received iv ibuprofen10 mg/kg (1 mL) and then 5 mg/kg at 24‐hour intervals as indicated by PDA flow patterns.

• Outcomes: PDA closure rate, need for ductal ligation, mortality, NEC, bowel perforation, gastrointestinal bleeding, BPD, sepsis, IVH, PVL, days to full enteral feeds, days to regain birth weight, days on ventilation, days of supplemental oxygen, post‐treatment serum creatinine levels, oliguria (< 1 mL/kg/hr).

The study by Supapannachart and co‐workers (Supapannachart 2002) was conducted in one centre in Thailand.

• 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 iv 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.

The study by Van Overmeire and co‐workers (Van Overmeire 1997) was conducted in one centre in Belgium.

• Objective: To evaluate the efficacy and side effects of ibuprofen for the early treatment of PDA and compare it with indomethacin.

• Population: Preterm infants (PMA < 33 weeks) with PDA diagnosed by echocardiography.

• Intervention: 40 infants were randomly assigned at day two to three days of life to receive either iv ibuprofen (n = 20) with an initial dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours later or iv 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 randomised treatment and at the age of 7 days. When a PDA was present after the randomised 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.

The second study by Van Overmeire and co‐workers (Van Overmeire 2000) was conducted in five centres in Belgium.

• Objective: To compare ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.

• Population: 148 infants (PMA 24 to 32 weeks) with RDS and a PDA confirmed by echocardiography.

• Intervention: Infants were randomised to receive iv 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 iv 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‐randomised 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, localised 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.

ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN

The study by Akisu and co‐workers (Akisu 2001) was conducted in one centre in Turkey.

• Objective: To investigate the efficacy and safety of enteral ibuprofen for the treatment of PDA and to compare it with enteral indomethacin.

• Population: 23 preterm infants (< 35 weeks PMA) with a PDA diagnosed by Doppler echocardiography.

• Intervention: Infants were randomised to receive either enteral ibuprofen 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later (n = 12) or three doses of enteral 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 haemorrhage, IVH, sepsis and mortality.

The study by Aly and co‐workers (Aly 2007) was a single‐centre study conducted in Egypt.

• Objective: To evaluate the feasibility of the use of oral ibuprofen suspension versus iv indomethacin in the treatment of PDA in preterm infants.

• Population: 21 preterm infants (< 35 weeks PMA) age two to seven days with respiratory distress and PDA diagnosed by Doppler echocardiography.

• Intervention: Infants were randomised to receive three doses of iv 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 haemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and increase in serum creatinine following treatment.

The study by Chotigeat and co‐workers (Chotigeat 2003) was conducted in one centre in Thailand.

• Objective: To compare efficacy and side effects of ibuprofen versus indomethacin treatment for symptomatic PDA in preterm infants.

• Population: Preterm infants with a symptomatic PDA confirmed by echocardiogram.

• Intervention: 30 infants were randomised to receive either three oral doses of ibuprofen (dose not stated) given at 24‐hourly intervals or three doses of iv 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.

The study by Fakhraee an co‐workers (Fakhraee 2007) was conducted in on centre in Iran.

• Objective: To compare the efficacy and safety of oral ibuprofen and oral indomethacin for the treatment of PDA in preterm infants.

• Population: 36 preterm infants (< 34 weeks PMA).

• Intervention: 18 infants were randomised to receive three oral doses of indomethacin (0.2 mg/kg, at 24‐hour intervals) and 18 infants to three doses of oral ibuprofen (first does of 10 mg/kg, followed by 5mk/kg/dose at 24‐hour intervals).

• Outcomes: The primary outcome was ductal closure. Secondary outcomes included maximum serum BUN and creatinine levels after treatment, NEC, mortality at 1 month of age, IVH (grades III and IV).

The study by Pourarian and co‐workers (Pourarian 2008) was conducted in a single centre in Iran.

• Objective: To evaluate the therapeutic effects of oral administration of indomethacin or ibuprofen suspension on closure of PDA in preterm infants.

• Population: 20 preterm infants with echo‐confirmed PDA.

• Intervention: For 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 three 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 two further doses of 5 mg/kg at 24‐hour intervals. Administration of the second or third doses of each drug was dependent on achievement of ductal closure after the initial doses.

• Outcomes: The 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 mm^3.

The study by Salama and co‐workers (Salama 2008) was conducted in a single centre in Qatar.

• Objective: To compare the efficacy of oral ibuprofen with iv indomethacin for closure of a significant PDA in preterm infants.

• Population: 41 preterm infants (PMA < 34 weeks, BW < 2500 g) diagnosed with haemodynamically significant PDA.

• Intervention: 20 infants received iv indomethacin (three doses of 0.2 mg/kg/dose every 24 hours) and 21 received oral ibuprofen (10 mg/kg on the first day followed by 5 mg/kg for two more days). Ibuprofen was mixed with 0.5 mL of milk before its administration via an oro‐gastric tube.

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

The study by Supapannachart and co‐workers (Supapannachart 2002) was conducted in one centre in Thailand.

• 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 iv 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.

ORAL IBUPROFEN VERSUS IV IBUPROFEN

The study by Cherif and co‐workers (Cherif 2008) was conducted in one centre in Tunis, Tunisia (New inclusion).

• Objective: To compare efficacy and tolerance between oral and iv ibuprofen in early closure of PDA in VLBW infants.

• Population: 64 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.

• Intervention: 32 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, iv ibuprofen (an initial dose of 10 mg/kg followed by two 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.

• Outcomes: PDA 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 one month, duration of hospital stay.

The study by Erdeve and co‐workers (Erdeve 2012) was conducted in one centre in Ankara, Turkey (New inclusion):

• Objective: To compare the efficacy and safety of oral versus iv ibuprofen for the pharmacological closure of PDA in less mature preterm infants.

• Population: 80 infants with PMA < 28 weeks, BW < 1000 g, postnatal age 48 to 96 hours and with ECHO‐confirmed significant PDA.

• Intervention: Oral or iv ibuprofen at a dose of 10 mg/kg followed by 5 mg/kg at 24 and 48 hours.

• Outcomes: Primary 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.

The study by Gokmen and co‐workers (Gokmen 2011) was conducted in one centre in Ankara, Turkey (New inclusion).

• Objective: To compare oral ibuprofen with iv ibuprofen for closure of PDA in VLBW infants.

• Population: 102 VLBW infants with PDA, verified by ECHO (PMA < 32 weeks, birth weight < 1500 g, postnatal age 48 to 96 hours.

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

• Outcomes: Renal tolerance, mean plasma creatinine after treatment, urine output after treatment, cystatin‐C levels, failure to close a PDA, need for second course of ibuprofen, need for surgical ligation, 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.

INTRAVENOUS HIGH DOSE IBUPROFEN VERSUS STANDARD DOSE REGIMEN OF IBUPROFEN

The study by Dani and co‐workers (Dani 2012) was conducted as a multi‐centre study in four NICUs in Italy (New inclusion).

• Objective: To assess whether a high‐dose of iv ibuprofen (20‐10‐10 mg/kg/day) versus an iv standard dose (10‐5‐5 mg/kg/day) regimen is more effective in closing a PDA without increasing adverse effects.

• Population: 95 infants underwent randomisation; 48 were allocated to standard ibuprofen and 47 to high dose ibuprofen and 70 infants with PMA < 29 weeks, ECHO evidence of significant PDA, age 12 to 24 hours and RDS necessitating respiratory support.

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

• Outcomes: Ductal closure, serum creatinine (mg/dL) on day three 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 to IV), PVL, ROP (all stages, stage > 2), NEC, BPD (oxygen requirement at 36 weeks PMA), sepsis, mortality, hospital stay (days).

EARLY VERSUS EXPECTANT ADMINISTRATION OF IV IBUPROFEN

The study by Sosenko and co‐workers (Sosenko 2012) was conducted in one NICU in Miami, Florida, USA (New inclusion).

• Objective: To determine whether "early" ibuprofen treatment at the onset of subtle PDA symptoms, would improve respiratory outcome in preterm infants compared with "expectant" management, with ibuprofen treatment only when the PDA becomes haemodynamically significant.

• Population: Infants born with BW between 500 g and 1250 g and PMA between 23 weeks 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).

• Intervention: Infants 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 iv infusion; dosing of placebo involved equivalent volumes of dextrose by slow iv infusion on the same schedule.

• Outcomes: Days 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).

Risk of bias in included studies

For details see the table 'Characteristics of included studies'.  These were all randomised controlled trials, but whether the randomisation was concealed or not was not always clear. In several studies, the timing of the doses of ibuprofen and indomethacin did not coincide, and therefore, the care givers would be aware of group assignment (for details see 'Riisk of bias' tables).

Adamska 2005: Sealed envelopes were used for random concealed allocation. As ibuprofen and indomethacin were given at the same times, it is assumed that the care givers were unaware of group assignment.

Akisu 2001: The authors do not provide detailed information concerning how the randomisation sequence was established. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Aly 2007: Sealed opaque envelopes were used for random assignment. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Aranda 2005: This was a double‐blind placebo controlled study that used central randomisation to allocate infants to ibuprofen or placebo. The coded vials of study drug or placebo contained indistinguishable colourless solutions dispensed by the blinded research pharmacist of the participating sites.

Cherif 2008: No information provided for sequence generation. Patients were randomly assigned to a treatment group by means of cards in sealed,opaque envelopes.

Chotigeat 2003: The infants were assigned to the treatment group by random number. Clinical care was performed by physicians, who did not take part in the study. However, as ibuprofen was provided orally and indomethacin was given iv one can assume that the care givers were aware of group assignment. The doses of ibuprofen and indomethacin given were not provided.

Dani 2012: No information provided for sequence generation. Sealed opaque envelopes were used for group assignment.

Erdeve 2012: No information provided for sequence generation. Sequentially numbered, sealed, opaque envelopes were used to conceal allocation to groups.

Fakhraee 2007: The enrolled patients randomly received either oral ibuprofen or oral indomethacin.

Gimeno Navarro 2005: Patients were randomly assigned to receive either iv indomethacin or iv ibuprofen. The randomisation sequence was computer generated. Allocation was by sealed opaque envelopes. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Gokmen 2011: No information provided for sequence generation. Patients were assigned randomly using cards in opaque envelopes.

Hammerman 2008: Randomisation was based on computer‐generated random numbers without sub‐stratification. Because the methods of the drug administration were clearly different, the study could not be double blinded. The cardiologist performing the echocardiograms was blinded to study group.

Lago 2002: The infants enrolled at each unit were randomly assigned to either treatment group by means of cards in sealed envelopes. As indomethacin and ibuprofen were given at different times after the initial doses, one can assume that the care givers were aware of group assignment. The authors do not comment on the imbalance in the numbers enrolled in the ibuprofen group (n = 94) versus the indomethacin group (n = 81).

Lin 2012. Infants were randomly assigned to treatment and control groups (n = 32 in each). No other information provided.

Mosca 1997: The authors do not provide details regarding randomisation. Outcomes for all enrolled infants were provided. As ibuprofen and indomethacin were given at the same time points for each of the three doses and as the injected volume was the same, it is possible that the healthcare providers and the investigators were blinded to the two groups, although this is never stated by the authors.

Patel 1995: The results of this study were reported in a letter to the editor and therefore a full quality assessment is not possible. The authors have confirmed that this was a randomised controlled trial.

Patel 2000: The Pharmacy Department at Queen Charlotte's Hospital performed randomisation in blocks of 12 (six, ibuprofen; six, indomethacin) for each hospital and provided all trial medication. All other personnel were blinded to the identity of the drug administered. 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.

Pezzati 1999: Infants were randomly assigned to receive either iv ibuprofen or indomethacin. Both drugs were continuously infused over 15 minutes. regardless of ductal closure the infants received a second and third dose of indomethacin or ibuprofen at 24‐hour intervals. It is therefore possible that the researchers were blinded to the intervention.

Plavka 2001: To date this study has been published in abstract form only and therefore a full quality assessment is not possible. The healthcare providers may have been blinded to group assignment as ibuprofen or indomethacin were given at the same time points.

Pourarian 2008: "As soon as the diagnosis (of PDA) was made for the first 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.

Salama 2008: Randomisation was conducted according to a pre‐designed simple block randomisation. No description of possible concealment of allocation.

Sosenko 2012: A random number table was used for sequence generation. Sealed envelopes were used for allocation concealment.

Su 2003: Concealed allocation could not be ascertained from the information provided by the authors. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Su 2008: Randomisation was according to a random number table sequence that had been prepared by a study assistant who was not involved in the care of the infants. The drugs were prepared and dispensed through the hospital pharmacy department and the attending doctors were unaware of the drugs used.

Supapannachart 2002: The infant was randomly assigned to either the ibuprofen or the indomethacin group by choosing a sealed envelop. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Van Overmeire 1997: Enrolled patients were randomised using the sealed envelope technique. As indomethacin and ibuprofen were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Van Overmeire 2000: The infants were randomly assigned to a treatment group by means of cards in sealed envelopes. As indomethacin was given every 12 hours and ibuprofen at 24 and 48 hours after the initial dose, it is likely that the healthcare providers were aware of group assignment.

Effects of interventions

INTRAVENOUS IBUPROFEN VERSUS PLACEBO (Comparison 1)
One study was published as a full article (Aranda 2005) in 2009. The primary outcome in that study was "Infant deaths, infants who dropped out or required rescue treatment" and as there is only one study available for that outcome the study has been included. However, as there is only one study available, heterogeneity tests are not applicable for any of the outcomes. All outcomes for the comparison of ibuprofen versus placebo refer to the study by Aranda and co‐workers (Aranda 2005).

PRIMARY OUTCOME

Infant deaths, infants who dropped out or required rescue treatment (Outcome 1.1)
There was a statistically significant reduced risk ratio (RR) for a composite outcome of infant deaths, infants who dropped out or required rescue treatment (n = 136); RR 0.58 (95% confidence interval (CI) 0.38 to 0.89); risk difference (RD) ‐0.22 (95% CI ‐0.38 to ‐06); number needed to treat to benefit (NNTB) 5 (95% CI 3 to17).

SECONDARY OUTCOMES

Necrotising enterocolitis (NEC) (Outcome 1.2)
There was no statistically significant difference in the incidence of NEC (n = 130); RR 1.00 (95% CI 0.42 to 2.36); RD 0.00 (95% CI ‐0.12 to 0.12).

Intraventricular haemorrhage (IVH) (any grade) (Outcome 1.3)
There was no statistically significant difference in the incidence of IVH (any grade) (n= 134); RR 1.00 (95% CI 0.64 to 1.55); RD 0.00 (95% CI ‐0.16 to 0.16).

Intraventricular haemorrhage (grades III‐IV) (Outcome 1.4)
There was no statistically significant difference in the incidence of IVH (grades III‐IV) (n = 134); RR 1.00 (95% CI 0.47 to 2.15); RD 0.00 (95% CI ‐0.13 to 0.13).

Pulmonary haemorrhage (Outcome 1.5)
There was no statistically significant difference in the incidence of pulmonary haemorrhage (n = 136); RR 0.25 (95% CI 0.03 to 2.18); RD ‐0.04 (95% CI ‐0.11 to 0.02).

Pulmonary hypertension (Outcome 1.6)
There was no statistically significant difference in the incidence of pulmonary hypertension (n = 136); RR 2.00 (0.19 to 21.54); RD 0.01 (95% CI ‐0.03 to 0.06).

Retinopathy of prematurity (ROP) (any stage) (Outcome 1.7)
There was no statistically significant difference in the incidence of ROP (any stage) (n = 129); RR 1.19 (95% CI 0.88 to 1.62); RD 0.10 (95% CI ‐0.07 to 0.27).

Retinopathy of prematurity (stage 3 or 4) (Outcome 1.8)
There was no statistically significant difference in the incidence of ROP (stage 3 or 4) (n = 129); RR 1.18 (95% CI 0.38 to 3.68); RD 0.01 (95% CI ‐0.08 to 0.11).

Retinopathy of prematurity (plus disease) (Outcome 1.9)
There was no statistically significant difference in the incidence of ROP (plus disease) (n = 129); RR 1.31 (95% CI 0.31 to 5.63): RD 0.01 (95% CI 0.01 (95% CI ‐0.06 to 0.09).

Chronic lung disease (CLD) (supplemental oxygen at 28 days of age) (Outcome 1:10)
There was no statistically significant difference in the incidence of CLD (supplemental oxygen at 28 days of age) [(n = 130); RR 1.09 (95% CI 0.95 to 1.26); RD 0.08 (95% CI ‐0.04 to 0.20).

Chronic lung disease (supplemental oxygen at 36 weeks PMA) (Outcome 1.11)
There was no statistically significant difference in the incidence of CLD (supplemental oxygen at 36 weeks postmenstrual age (PMA)) (n = 98); RR 0.99 (95% CI 0.88 to 1.11); RD ‐0.01 (95% CI ‐0.12 to 0.10).

Periventricular leukomalacia (PVL) (Outcome 1.12)
There was no statistically significant difference in the incidence of PVL (n = 130); RR 0.11 (95% CI 0.01 to 2.02); RD ‐0.06 (95% CI ‐0.13 to 0.00) (P = 0.06).

Mortality (Outcome 1.13)
There was no statistically significant difference in mortality (n = 136); RR 0.80 (95% CI 0.34 to 1.90); RD ‐0.03 (95% CI ‐0.14 to 0.08).

Since this review was first published oral ibuprofen has been introduced to close a PDA. We therefore included additional comparisons that were not planned a priori.

ORAL IBUPROFEN VERSUS PLACEBO (Comparison 2)

Failure to close a PDA after single or three doses (Outcome 2.1)
One study (Lin 2012) reported on this outcome in 64 infants. There was a significant reduction in the failure rate to close a PDA (RR 0.26 (95% CI 0.11 to 0.62); RD ‐0.44 (95% CI ‐0.65 to ‐0.23); NNTB 2 (95% CI 2 to 4). Test for heterogeneity not applicable.

The authors reported that the incidence of PVL and BPD were significantly lower in the treatment group than in the control group (P < 0.05). The duration of mechanical ventilation and hospitalisation were significantly shorter in the treatment group than in the control group (P < 0.05). There were no significant differences in the incidence of IVH, early pulmonary haemorrhage and NEC between the two groups (P > 0.05). Only the abstract was available to us and numbers for these outcomes were not reported in the abstract. We have written to the authors to try and obtain more information, but we have not received any feedback.

INTRAVENOUS OR ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN (Comparison 3)

PRIMARY OUTCOME

Failure to close a PDA after single or three doses (Outcome 3.1) Figure 1
Failure rates for PDA closure after one or three doses of ibuprofen compared with indomethacin were reported in all studies included in this comparison. Twenty studies (n = 1019 infants) reported on this outcome. None found a statistically significant difference in failure to close a PDA. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 0.98 (95% CI 0.80 to 1.20); typical RD ‐0.01 (95% CI ‐0.06 to 0.05). There was no between study heterogeneity for RR or RD (I² = 0% for both RR and RD).

Figure 1

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Forest plot of comparison: 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, outcome: 3.1 Failure to close a PDA (after single or three doses).

SECONDARY OUTCOMES

All cause mortality (Outcome 3.2)
Eight studies (n = 470) reported on mortality that occurred at an unspecified time while in hospital and none found a statistically significant difference. The meta‐analysis showed no statistically significant difference between the groups; typical RR 0.77 (95% CI 0.45 to 1.29); typical RD ‐0.03 (95% CI ‐0.08 to 0.03). There was no between study heterogeneity (I² = 0% for both RR and RD).

Neonatal mortality (during first 28/30 days of life) (Outcome 3.3)
Four studies (n = 333) reported on death by 28 or 30 days of age. There was no statistically significant difference between the groups in the individual studies or in the meta‐analysis; typical RR 1.12 (95% CI 0.59 to 2.11); typical RD 0.01 (95% CI ‐0.05 to 0.08). There was no between study heterogeneity (I² = 0% for both RR and RD).

Infant mortality (death during the first year of life)
None of the studies reported on this outcome.

Reopening of the ductus arteriosus (Outcome 3.4)
Six studies (n = 204) reported on this outcome. None of the individual studies found a statistically significant difference in the reopening of a PDA. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.28 (95% CI 0.48 to 3.38); typical RD 0.02 (95% CI ‐0.06 to 0.09). There was no between study heterogeneity (I² = 0% for both RR and RD).

Need for surgical closure of the PDA (Outcome 3.5)
Thirteen studies (n = 848) reported on this outcome. None of the studies found a statistically significant difference in the surgical closure of PDA. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.04 (95% CI 0.71 to 1.51); typical RD 0.00 (95% CI ‐0.04 to 0.05). There was no between study heterogeneity (I² = 0% for both RR and RD).

Need for re‐treatment with indomethacin or ibuprofen to close the PDA (Outcome 3.6)
Seven studies (n = 241) reported on this outcome. None of the studies found a statistically significant difference in the need for medical treatment of the PDA between the groups. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.20 (95% CI 0.76 to 1.90); typical RD 0.04 (95% CI ‐0.06 to 0.14). There was no between study heterogeneity (I² = 0% for both RR and RD).

Duration of ventilator support (days) (Outcome 3.7)
Six studies (n = 471) reported on this outcome. Two studies (Adamska 2005; Gimeno Navarro 2005) found a statistically significant difference in the duration of ventilation in favour of the ibuprofen group. In the meta‐analysis, there was a statistically significant difference between the groups; mean difference (MD) ‐2.35 days (95% CI ‐3.71 to ‐0.99) favouring ibuprofen. There was no heterogeneity between the studies (I² = 19%).

Duration of supplementary oxygen (days) (Outcome 3.8)
Six studies (n = 556) reported on this outcome. None of the studies found a statistically significant effect. In the meta‐analysis, there was no statistically significant difference between the groups; MD ‐0.33 days (95% CI ‐1.66 to 0.99). There was low between study heterogeneity for this outcome (I² = 46%).

Pneumothorax
No study reported on this outcome.

Pulmonary haemorrhage (Outcome 3.9)
Three studies (n = 103) reported on this outcome. No study found a statistically significant difference in the incidence of pulmonary haemorrhage between the groups. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.23 (95% CI 0.37 to 4.10); typical RD 0.02 (95% CI ‐0.09 to 0.13). There was low between study heterogeneity for RR but moderate heterogeneity for RD (RR; I² = 44.7%; RD; I² = 63%).

Pulmonary hypertension (Outcome 3.10)
One study (n = 35) reported on this outcome. There was no statistically significant difference between the groups; RR 3.53 (95% CI 0.15 to 81.11; RD 0.06 (95% CI ‐0.09 to 0.21).

Test for heterogeneity not applicable.

Chronic lung disease (CLD) (at 28 days) (Outcome 3.11)
Four studies (n = 245) reported on this outcome. No study found a significant difference in the incidence of CLD at 28 days. In the meta‐analysis, there was no statistically significant difference in the incidence of CLD at 28 days in the ibuprofen group compared with indomethacin group; typical RR 1.22 (95% CI 0.93 to 1.59); typical RD 0.09 (95% CI ‐0.03 to 0.22). There was no between study heterogeneity (I² = 0% for both RR and RD).

Chronic lung disease (at 36 weeks PMA) (Outcome 3.12)
Three studies (n = 357) reported on this outcome. No study found a significant difference in the incidence of CLD at 36 weeks PMA. In the meta‐analysis of these studies, there was no statistically significant difference between the groups; typical RR 1.12 (95% CI 0.77 to 1.61); typical RD 0.03 (95% CI ‐0.06 to 0.12). There was no between study heterogeneity (I² = 0% for both RR and RD).

Chronic lung disease (age not stated) (Outcome 3.13)
Three studies (n = 128) reported on this outcome. No study found a significant difference in the incidence of CLD (age not stated). In the meta‐analysis of these studies, there was no statistically significant difference between the groups; typical RR 1.04 (95% CI 0.83 to 1.30); typical RD 0.02 (95% CI ‐0.12 to 0.16). There was no statistically significant between study heterogeneity (I² = 0% for both RR and RD).

Intraventricular haemorrhage (IVH) (grades I‐IV) (Outcome 3.14)

Five studies (n = 180) reported on this outcome. No study found a statistically significant difference in the incidence of IVH. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 0.83 (95% CI 0.47 to 1.48); typical RD ‐0.04 (95% CI ‐0.15 to 0.08). There was no between study heterogeneity (I² = 0% for both RR and RD).

Intraventricular haemorrhage (IVH) (grades III‐IV) (Outcome 3.15)
Eight studies (n = 571) reported on this outcome. No study found a statistically significant difference in the incidence of IVH (grades III‐IV) between the groups. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.21 (95% CI 0.74 to 1.98); typical RD 0.02; (95% CI ‐0.03 to 0.07). There was no between study heterogeneity (I² = 0% for both RR and RD).

Periventricular leukomalacia (PVL) (Outcome 3.16)
Six studies (n = 573) reported on this outcome. No study found a statistically significant difference in the incidence of PVL. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.24; (95% CI 0.67 to 2.30); typical RD 0.01 (95% CI ‐0.03 to 0.05). There was no between study heterogeneity (I² = 0% for both RR and RD).

Necrotising enterocolitis (NEC) (any stage) (Outcome 3.17) Figure 2
Fifteen studies (n = 865) reported on this outcome. No individual study found a significant difference. In the study by Chotigeat (Chotigeat 2003), the rates of NEC were exceptionally high in both groups. In the meta‐analysis, there was a statistically significant difference between the groups; typical RR 0.68 (95% CI 0.47 to 0.99); typical RD ‐0.04 (95% CI ‐0.08 to ‐0.00); (P = 0.04); NNTB 25 (95% CI 13, infinity). There was no statistically significant between study heterogeneity (I² = 0% for both RR and RD).

Figure 2

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Forest plot of comparison: 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, outcome: 3.17 Necrotizing enterocolitis (any stage).

Intestinal perforation (Outcome 3.18)
Five studies (n = 255) reported on this outcome. No study found a statistically significant difference in the incidence of intestinal perforation. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 0.48 (95% CI 0.20 to 1.14); typical RD ‐0.06 (95% CI ‐0.13 to 0.01). There was no between study heterogeneity (I² = 0% for RR and 6% for RD).

Gastrointestinal bleed (Outcome 3.19)
Six studies (n = 314) reported on this outcome. There was no statistically significant difference between the groups in the individual studies or in the meta‐analysis; typical RR 1.11 (95% CI 0.57 to 2.15); typical RD 0.01 (‐0.06 to 0.08). There was no statistically significant between study heterogeneity (I² = 0% for both RR and RD).

Time to full enteral feeds (days) (Outcome 3.20)
Four studies (n = 413) reported on this outcome. There was no statistically significant difference between the groups in the time to reach full feeds in the individual studies. In the meta‐analysis, there was no statistically significant difference between the groups; MD 0.70 days (95% CI ‐1.89 to 3.29). There was low between study heterogeneity (I² = 31%).

Time to regain birth weight (days) (Outcome 3.21)
Two studies (n = 188) reported on this outcome. In the individual studies, there was no statistically significant difference between the groups in the time to regain birth weight. In the meta‐analysis, there was no statistically significant difference between the groups; MD ‐0.18 days (95% CI ‐2.59 to 2.22). There was moderate between study heterogeneity (I² = 67%).

Retinopathy of prematurity (ROP) (according to the international classification of ROP) (Outcome 3.22)
Five studies (n = 237) reported on this outcome. In the individual studies, there was no significant difference between the groups. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 0.86 (95% CI 0.54 to 1.38); typical RD ‐0.03 (95% CI ‐0.13 to 0.07). There was no between study heterogeneity (I² = 0% for both RR and RD).

Sepsis (Outcome 3.23)
Six studies (n = 535) reported on this outcome. No study found a statistically significant difference. In the meta‐analysis, there was no statistically significant difference between the groups; typical RR 1.15 (95% CI 0.73 to 1.81); typical RD 0.02 (95% CI ‐0.03 to 0.06). There was no between study heterogeneity (I² = 0% for both RR and RD).

Oliguria (defined as < 1 cc/kg/hr) (Outcome 3.24)
Six studies (n = 576) reported on this outcome. Two trials found a statistically significant decrease in the proportion of infants with oliguria in the ibuprofen group (Lago 2002; Van Overmeire 2000). In the meta‐analysis, there was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group; typical RR 0.28 (95% CI 0.14 to 0.54); typical RD ‐0.09 (95% CI ‐0.14 to ‐0.05); NNTB 11 (95% CI 7 to 20). There was no between study heterogeneity for RR (I² = 24%) and moderate for RD (I² = 69%). Hammerman et al (Hammerman 2008) reported no statistically significant differences in urine output between the ibuprofen and indomethacin groups at pre‐treatment and at 24 and 48 hours after treatment.

Serum/plasma creatinine levels (mmol/L) 72 hours after treatment (Outcome 3.25)
Eight studies (n = 491) reported on this outcome in such a format that the data could be used to summarize the information in RevMan 2011. Three individual studies found statistically significantly lower serum/plasma creatinine levels 72 hours after initiation of treatment in the ibuprofen group compared with the indomethacin group. In the meta‐analysis, the serum/plasma creatinine level 72 hours after initiation of treatment was statistically significantly lower in the ibuprofen group; MD ‐4.70 mmol/L (‐8.88 to ‐0.53). There was moderate between study heterogeneity (I² = 51%).

Pezzatin and co‐workers (Pezzati 1999) noted significantly lower serum creatinine levels on day three in the ibuprofen group compared with the indomethacin group (P < 0.05; data provided in graph form only). Plavka and co‐workers (Plavka 2001) reported lower serum creatinine levels in the ibuprofen group compared with the indomethacin group in the first 96 hours of treatment (P < 0.01; data for the two groups not provided). Van Overmeire and co‐workers (Van Overmeire 1997) noted the maximal difference in serum creatinine levels between the ibuprofen and the indomethacin group to occur on day three (P = 0.07; data provided in graph form only). The lower levels were observed in the ibuprofen group. In their second trial, Van Overmeire and co‐workers (Van Overmeire 2000) noted significantly lower serum creatinine levels in the ibuprofen group compared with the indomethacin group (P = 0.04 overall; data provided in graph form only). Pourarian and co‐workers (Pourarian 2008) reported that the mean differences in serum creatinine before and after treatment were 0.35 mg/dL in the ibuprofen group and 0.45 mg/dL in the indomethacin group (SDs were not provided).

Increase in serum/plasma creatinine levels (mmol/L) 72 hours after treatment (Outcome 3.26)
One study (Aly 2007) reported on this outcome (n = 21). The increase in serum creatinine levels, was significantly lower in the ibuprofen group compared with the indomethacin group; MD 15.91 mmol/L (95% CI ‐31.78 to ‐ 0.04). Test for heterogeneity not applicable.

Duration of hospitalisation (Outcome 3.27)
Three studies (n = 285) reported on this outcome. There was no statistically significant difference between the groups; MD ‐2.19 days (95% CI ‐6.55 to 2.18). There was no heterogeneity between the studies (I² = 0%).

Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized and validated assessment tool and/or a child developmental specialist) at any age reported (no outcome table)
No long‐term outcome data were reported.

The effects on cerebral blood flow velocity or cerebral blood flow were not included as predetermined outcomes in this review. However, several authors reported on these outcomes. All results favoured the ibuprofen group with less reduction in cerebral blood flow velocity or cerebral blood flow.

ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN (Comparison 4)

Failure to close a PDA (after three doses) (Outcome 4.1) Figure 3
This outcome was reported in seven trials (n = 189). There was no statistically significant difference in failure to close a PDA in any of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference typical RR 0.82 (95% CI 0.52 to 1.29); typical RD ‐0.06 (95% CI ‐0.18 to 0.06). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Figure 3

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Forest plot of comparison: 4 Oral ibuprofen versus iv or oral indomethacin, outcome: 4.1 Failure to close a PDA (after three doses).

All cause mortality (during hospital stay) (Outcome 4.2)
This outcome was reported in three studies (n = 82). There was no statistically significant difference in mortality in any of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 0.59 (95% CI 0.21 to 1.66); typical RD ‐0.08 (95% CI ‐0.24 to 0.08). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Neonatal mortality (during first 28/30 days of life) (Outcome 4.3)
Two studies reported on this outcome (n = 66). There was no statistically significant difference in mortality in either of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 1.33 (95% CI 0.33 to 5.39); typical RD 0.03 (95% CI ‐0.12 to 0.18). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Reopening of the ductus arteriosus (Outcome 4.4)
One study (n = 20) reported on this outcome. There was no case of reopening of the ductus in either of the two groups; RR not estimable; RD 0.00 (95% CI ‐0.17 to 0.17). Test for heterogeneity not applicable.

Need for surgical closure of the PDA (Outcome (4.5)
Three studies reported on this outcome (n = 91). There was no statistically significant difference in need for surgical closure of the PDA in any of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 0.63 (95% CI 0.24 to 1.70); typical RD ‐0.07 (95% CI ‐0.21 to 0.08). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Pulmonary haemorrhage (Outcome 4.6)
One study (n = 21) reported on this outcome. There was no statistically significant difference in pulmonary haemorrhage between the two groups in this single trial; RR 0.15 (95% CI 0.01 to 2.86); RD ‐0.22 (95% CI ‐0.51 to 0.07). Test for heterogeneity not applicable.

Pulmonary hypertension (Outcome 4.7)
No trial reported on this outcome.

Chronic lung disease (CLD) (at 28 days) (Outcome 4.8)
One trial (n = 30) reported on this outcome. There was no statistically significant difference in CLD at 28 days between the two groups comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 0.86 (95% CI 0.38 to 1.95); typical RD ‐0.07 (95% CI ‐0.42 to 0.29). Test for heterogeneity not applicable.

Chronic lung disease (36 weeks PMA) (Outcome 4.9)
No trial reported on this outcome.

Chronic lung disease (age not stated) (Outcome 4.10)
One trial (n = 18) reported on this outcome. There was no statistically significant difference in CLD (age not stated) between the two groups comparing oral ibuprofen with indomethacin; RR 1.00 (95% CI 0.52 to 1.92); typical RD 0.00 (95% CI ‐0.44 to 0.44). Test for heterogeneity not applicable.

Intraventricular haemorrhage (IVH) (grades I‐IV) (Outcome 4.11)
Three trials (n = 77) reported on this outcome. There was no statistically significant difference in IVH (grades I‐IV) in any of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 0.90 (95% CI 0.45 to 1.83); typical RD ‐0.03 (95% CI ‐0.03 (95% CI ‐0.22 to 0.16). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Intraventricular haemorrhage (grades III‐IV) (Outcome 4.12)
One trial (n = 41) reported on this outcome. There was no statistically significant difference in IVH (grades III‐IV) between the two groups comparing oral ibuprofen with indomethacin; RR 0.95 (95% CI 0.15 to 6.13); typical RD ‐0.00 (95% CI ‐0.19 to 0.18). Test for heterogeneity not applicable.

Periventricular leukomalacia (PVL) (Outcome 4.13)
One trial (n = 41) reported on this outcome. There was no statistically significant difference in PVL between the two groups comparing oral ibuprofen with indomethacin; RR 0.32 (95% CI 0.01 to 7.38); RD ‐0.05 (95% CI ‐0.18 to 0.08). Test for heterogeneity not applicable.

Necrotising enterocolitis (NEC) (Outcome 4.14) Figure 4
Six trials (n = 166) reported on this outcome. There was no statistically significant difference in necrotising enterocolitis in any of the trials comparing oral ibuprofen with indomethacin but the meta‐analysis showed a statistically significant difference; typical RR 0.44 (95% CI 0.23 to 0.82); typical RD ‐0.15 (95% CI ‐0.25 to ‐0.04); NNTB 7 (95% CI 4, 25). There was no heterogeneity for this outcome (I² = 0% for RR and 20% for RD).

Figure 4

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Forest plot of comparison: 4 Oral ibuprofen versus iv or oral indomethacin, outcome: 4.18 Necrotizing enterocolitis (any stage).

Intestinal perforation (Outcome 4.15)
Two trials (n = 62) reported on this outcome. There was no statistically significant difference in intestinal perforation in either of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 0.24 (95% CI 0.03 to 1.95); typical RD ‐0.10 (95% CI ‐0.25 to 0.04). In one trial (Aly 2007), no perforation occurred in either of the trials. Test for heterogeneity for RR not applicable (there were no outcomes in one trial and low heterogeneity for RD (I² = 38%).

Gastrointestinal bleed (Outcome 4.16)
Three trials (n = 85) reported on this outcome. There was no statistically significant difference in gastrointestinal bleed in any of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 2.80 (95% CI 0.48 to 16.45); typical RD 0.07 (95% CI ‐0.05 to 0.18). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Retinopathy of prematurity (ROP) (Outcome 4.17)
Two studies (n =71) reported on this outcome. There was no statistically significant difference in retinopathy of prematurity in any of the trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 0.98 (95% CI 0.35 to 2.73); typical RD ‐0.00 (‐0.18 to 0.17). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Sepsis (Outcome 4.18)
Two studies (n =53) reported on this outcome. There was no statistically significant difference in sepsis in either of the two trials comparing oral ibuprofen with indomethacin and the meta‐analysis showed no statistically significant difference; typical RR 1.09 (95% CI 0.54 to 2.19); typical RD 0.03 (95% CI ‐0.22 to 0.28). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Decreased urine output (< 1 cc/kg/hr) (Outcome 4.19)
One study (n = 36) reported on this outcome. None of the infants in the study experienced decreased urine output; RR not estimable; RD 0.00 (95% CI ‐0.10 to 0.10) Test for heterogeneity not applicable.

Serum/plasma creatinine levels (micromol/L) 72 hours after treatment (Outcome 4.20)
Four studies (n = 107) reported on this outcome. Two studies showed a statistically significant reduction in serum/plasma creatinine levels comparing oral ibuprofen with indomethacin (Chotigeat 2003; Supapannachart 2002) and the meta‐analysis showed a significant reduction; (MD ‐15.14 micromol/L (95% CI ‐25.00 to ‐5.28). There was no heterogeneity for this outcome (I² = 0%).

ORAL IBUPROFEN VERSUS IV IBUPROFEN (Comparison 5)

Failure to close a PDA (after three doses) (Outcome 5.1) Figure 5
Three studies (n = 236) reported on this outcome. There was a statistically significant reduction in failure to close a PDA in one (Gokmen 2011) of the three trials comparing oral ibuprofen with iv ibuprofen and the meta‐analysis showed a statistically significant difference; typical RR 0.37 (95% CI 0.23 to 0.61); typical RD ‐0.24 (95% CI ‐0.35 to ‐0.13); NNTB 4 (95% CI 3 to 8). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Figure 5

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Forest plot of comparison: 5 Oral ibuprofen versus iv ibuprofen, outcome: 5.1 Failure to close a PDA (after single or three doses).

Mortality (during first 28/30 days of life) (Outcome 5.2)
One study (n = 64) reported on this outcome. There was no significant difference in mortality (during the first 28/30 days of life) comparing oral ibuprofen with iv ibuprofen; RR 1.13 (95% CI 0.50 to 2.55); RD 0.03 (95% CI ‐0.19 to 0.25). Test for heterogeneity not applicable.

Mortality (during hospital stay) (Outcome 5.3)
Two studies (n = 188) reported on this outcome. There was no significant difference in mortality (during hospital stay) comparing oral ibuprofen with iv ibuprofen in either of the two studies and the meta‐analysis showed no statistically significant difference; typical RR 0.83 (95% CI 0.38 to 1.82); RD ‐0.02 (95% CI‐0.11 to 0.07). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Mean plasma cystatin‐C (mg/dL) after treatment (Outcome 5.4)
One study (n = 102) reported on this outcome. There was a statistically significant difference comparing oral ibuprofen with iv ibuprofen; MD ‐0.25 (95% CI ‐0.37 to ‐0.13). Test for heterogeneity not applicable.

Need for surgical closure of the ductus (Outcome 5.5)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference in the need for surgical closure of the ductus comparing oral ibuprofen with iv ibuprofen in any of the three studies. The meta‐analysis showed no statistically significant difference between the two groups; typical RR 0.49 (95% CI 0.12 to 1.91); typical RD ‐0.03 (95% CI ‐0.07 to 0.02). There was no heterogeneity for this outcome (I² = 0% for RR and 12% for RD).

Duration of ventilatory support (days) (Outcome 5.6)
Two studies (n = 134) reported on this outcome. There was no statistically significant difference in the duration of ventilatory support comparing oral ibuprofen with iv ibuprofen in either of the two studies. The meta‐analysis showed no statistically significant difference between the two groups; typical MD 0.54 (95% CI ‐0.01 to 1.10). There was no heterogeneity for this outcome (I² = 10% for MD).

Duration of hospitalisation (days) (Outcome 5.7)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference in the duration of hospitalisation comparing oral ibuprofen with iv ibuprofen in any of the three studies. The meta‐analysis showed no statistically significant difference between the two groups; typical MD ‐2.51 (95% CI ‐5.21 to 0.19). There was no heterogeneity for this outcome (I² = 0% for MD).

Pneumothorax (Outcome 5.8)
Two studies (n = 172) reported on this outcome. There was no statistically significant difference in pneumothorax comparing oral ibuprofen with iv ibuprofen in either of the two studies. The meta‐analysis showed no statistically significant difference between the two groups; typical RR 0.41 (95% CI 0.11 to 1.54); typical RD ‐0.05 (95% CI ‐0.12 to 0.02). There was no heterogeneity for this outcome (I² = 19% for RR and 13% for RD).

Pulmonary haemorrhage (Outcome 5.9)
One study (n = 70) reported on this outcome. There was no statistically significant difference in pulmonary haemorrhage comparing oral ibuprofen with iv ibuprofen in this study; RR 0.14 (95% CI 0.01 to 2.52); RD ‐0.09 (95% CI ‐0.19 to 0.02). Test for heterogeneity not applicable.

Pulmonary hypertension (Outcome 5.10)
Two studies (n = 172) reported on this outcome. No cases of pulmonary hypertension occurred in either of the two studies; RR not estimable; RD 0.00 (95% CI ‐0.03 to 0.03). There was no heterogeneity (not applicable for RR; I² = 0% for RD).

Chronic lung disease (CLD) (at 28 days) (Outcome 5.11)
No study reported on this outcome.

Chronic lung disease (at 36 weeks PMA or at discharge) (Outcome 5.12)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference in the rate of CLD at 36 weeks PMA comparing oral ibuprofen versus iv ibuprofen in any of the three studies. The meta‐analysis showed no statistically significant difference between the two groups; RR 0.82 (95% CI 0.56 to 1.20); RD ‐0.06 (95% CI ‐0.16 to 0.05). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Chronic lung disease (age not stated) (Outcome 5.13)
No study reported on this outcome.

Intraventricular haemorrhage (IVH) (grades I‐IV) (Outcome 5.14)
One study (n = 64) reported on this outcome. There was no statistically significant difference between oral ibuprofen versus iv ibuprofen for IVH (grades I‐IV); RR 1.08 (95% CI 0.59 to 2.00); RD 0.03 (95% CI ‐0.21 to 0.27). Test for heterogeneity not applicable.

Intravenricular haemorrhage (grades III‐IV) (Outcome 5.15)
No study reported on this outcome.

Periventricular leukomalacia (PVL) (Outcome 5.16)
One study (n = 64) reported on this outcome. There was no statistically significant difference for PVL between oral versus iv ibuprofen in this study; RR 1.00 (95% CI 0.15 to 6.67); RD 0.00 (95% CI ‐0.12 to 0.12). Test for heterogeneity not applicable.

Necrotising enterocolitis (NEC) (Outcome 5.17)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference between the oral ibuprofen versus the iv ibuprofen group for NEC in the individual studies nor in the meta‐analysis; RR 0.86 (95% CI 0.35 to 2.15); RD ‐0.01 (95% CI ‐0.08 to 0.06). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Intestinal perforation (Outcome 5.18)
Two studies (n = 134) reported on this outcome. There was no statistically significant difference between the oral ibuprofen versus the iv ibuprofen group for intestinal perforation in the individual studies or in the meta‐analysis; RR 0.32 (0.01 to 7.48); RD ‐0.02 (95% CI ‐0.07 to 0.04). Test for heterogeneity not applicable for RR and I² = 0% for RD.

Gastrointestinal bleed (Outcome 5.19)
Two studies (n = 172) reported on this outcome. There was no statistically significant difference between the oral ibuprofen versus the iv ibuprofen group for gastrointestinal bleed in the individual studies or in the meta‐analysis; RR 2.89 (0.12 to 69.24); RD 0.01 (95% CI ‐0.03 to 0.05). Test for heterogeneity not applicable for RR and I² = 0% for RD.

Sepsis (Outcome 5.20)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference between the oral ibuprofen group versus the iv ibuprofen group in the individual studies or in the meta‐analysis (RR 0.82 ((95% CI 0.54 to 1.25); RD ‐0.05 (95% CI ‐0.16 to 0.06). There was no heterogeneity for this outcome (I² = 0% for RR and 19% for RD).

Retinopathy of prematurity (ROP) that required laser treatment (Outcome 5.21)
Two studies (n = 172) reported on this outcome. There was no statistically significant difference between the oral ibuprofen group versus the iv ibuprofen group for ROP requiring laser treatment in either of the two trials or in the meta‐analysis; RR 0.59 (95% CI 0.26 to 1.34); RD ‐0.06 (‐0.16 to 0.03). There was no heterogeneity for this outcome (I² = 0% for both RR and RD).

Serum/plasma creatinine levels (micromol/L) 72 hours after treatment (Outcome 5.22)
One study (n = 102) reported on this outcome. There was a statistically significant reduction in the oral ibuprofen group versus the iv ibuprofen group; MD ‐29.17 micromol/L (95% CI‐40.67 to ‐17.67). Test for heterogeneity not applicable.

Oliguria (< 1cc/kg/hr) (Outcome 5.23)
Three studies (n = 236) reported on this outcome. No cases of oliguria occurred in the studies by Erdeve 2012 and Gokmen 2011. There was no statistically significant difference between the oral ibuprofen group versus the iv ibuprofen group for oliguria in the remaining study by Cherif 2008; RR 0.14 (95% CI 0.01 to 2.66); RD ‐0.03 (95% CI ‐0.06 to 0.01). Test for heterogeneity not applicable for RR but the heterogeneity was moderate for RD (I² = 50%).

HIGH DOSE VERSUS STANDARD DOSE OF IBUPROFEN (Comparison 6)

Only one study has compared a high dose of ibuprofen (20‐10‐10 mg/kg/day) versus standard dose of ibuprofen (10‐5‐5 mg/kg/day) (Dani 2012). The study randomised 95 infants. We report on the outcomes included by the authors and these included 70 infants for all reported outcomes except for death during hospital stay which included 95 infants (all infants randomised) (a total of 25 infants were excluded because of 20 deaths and five infants with incomplete data). As only one study is included for each of the outcomes, test for heterogeneity is not applicable.

Failure to close a PDA (after three doses) (Outcome 6.1)
There was a significant reduction in the failure rate to close a PDA in favour of a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.38 (95% CI 0.15 to 0.96); RD ‐0.23 (95% CI ‐0.43 to ‐0.03); NNTB 4 (95% CI 2 to 33).

Reopening after a 2nd course of ibuprofen (Outcome 6.2)
There was no significant difference in reopening after a 2nd course of ibuprofen for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 2.00 (95% CI 0.39 to 10.22); RD 0.06 (95% CI ‐0.07 to 0.19).

Need for surgical closure (Outcome 6.3)
There was no significant difference in need for surgical closure for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.00 (95% CI 0.15 to 6.71); RD 0.00 (95% CI ‐0.11 to 0.11).

Death during hospital stay (Outcome 6.4)
There was no significant difference in deaths during hospital stay for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.96 (95% CI 0.54 to 1.71); RD ‐0.01 (95% CI ‐0.20 to 0.17).

Urine output on day three (mL/kg/hr) (Outcome 6.5)
There was no significant difference in urine output on day 3 (mL/kg/hr) for a high dose of ibuprofen versus a standard dose of ibuprofen; MD 0.10 (95% CI ‐0.70 to 0.90).

Oliguria (< 1ml/kg/hr during 24 hours) (Outcome 6.6)
There was no significant difference in the incidence of oliguria (< 1 mL/kg/hr) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.50 (95% CI 0.27 to 8.43); RD 0.03 (95% CI ‐0.09 to 0.15).

Intraventricular haemorrhage (IVH) (all grades) (Outcome 6.7)
There was no significant difference in IVH (all grades) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.67 (95% CI 0.21 to 2.16); RD ‐0.06 (95% CI ‐0.22 to 0.11).

Intraventricular haemorrhage (grades III‐IV) (Outcome 6.8)
There was no significant difference in IVH (grades III to IV) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.50 (95% CI 0.10 to 2.56); RD ‐0.06 (95% CI ‐0.19 to 0.07).

Periventricular leukomalacia (PVL) (Outcome 6.9)
There was no significant difference in periventricular leukomalacia for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.50 (95% CI 0.27 to 8.43); RD 0.03 (95% CI ‐0.09 to 0.15).

Retinopathy of prematurity (ROP) (All stages) (Outcome 6.10)
There was no significant difference in ROP (all stages) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.00 (95% CI 0.27 to 3.69); RD 0.00 (95% CI ‐0.15 to 0.15).

Retinopathy of prematurity (Stage > 2) (Outcome 6.11)
There was no significant difference in ROP (stage > 2) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 2.00 (95% CI 0.19 to 21.06); RD 0.03 (95% CI ‐0.07 to 0.12).

Necrotising enterocolitis (NEC) (Outcome 6.12)
There was no significant difference in NEC for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.33 (95% CI 0.32 to 5.53); RD 0.03 (95% CI ‐0.11 to 0.17).

Chronic lung disease (CLD) at 36 weeks PMA (Outcome 6.13)
There was no significant difference in CLD at 36 weeks PMA for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.60 (95% CI 0.85 to 3.02); RD 0.17 (95% CI ‐0.05 to 0.39).

Sepsis (Outcome 6.14)
There was no significant difference in sepsis for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.93 (95% CI 0.51 to 1.68); RD ‐0.03 (95% CI ‐0.26 to 0.20).

Hospital stay (days) (Outcome 6.15)
There was no significant difference in hospital stay (days) for a high dose of ibuprofen versus a standard dose of ibuprofen; MD 21 days (95% CI ‐1.44 to 43.44).

EARLY VERSUS EXPECTANT ADMINISTRATION OF IV IBUPROFEN (Comparison 7)

Only one study has compared early versus expectant administration of ibuprofen (Sosenko 2012) The study enrolled 105 infants. We report on the outcomes included by the authors and these included 105 infants for all reported outcomes. As only one study is included for each of the outcomes, test for heterogeneity is not applicable.

PRIMARY OUTCOME

Days on supplemental oxygen during the first 28 days (Outcome 7.1)
This outcome was reported in 105 infants. There was a statistically significant difference between the early versus the expectant group for this outcome; MD 2.00 days (95% CI 0.04 to 3.96).

SECONDARY OUTCOMES

Days on supplemental oxygen (Outcome 7.2)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; MD 2.00 days (95% CI ‐8.20 to 12.20).

Days on mechanical ventilation first 28 days (Outcome 7.3)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; MD 2.00 days (95% CI ‐0.58 to 4.58).

Days on mechanical ventilation (Outcome 7.4)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; MD ‐1.00 days (95% CI ‐6.98 to 4.98).

Chronic lung disease (CLD) at 36 weeks PMA (Outcome 7.5)
This outcome was reported in 101 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.00 (95% CI 0.57 to 1.75).

Death or chronic lung disease at 36 weeks PMA (Outcome 7.6)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.00 (95% CI 0.59 to 1.67).

Death during hospital stay (Outcome 7.7)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.63 (95% CI 0.19 to 2.10).

Pneumothroax (Outcome 7.8)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.26 (95% CI 0.30 to 5.35).

Intraventricular haemorrhage (IVH) (grades III & IV) (Outcome 7.9)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.81 (95% CI 0.29 to 2.25).

Periventricular leukomalacia (Outcome 7.10)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.26 (95% CI 0.30 to 5.35).

Necrotising enterocolitis (NEC) (requiring surgery) (Outcome 7.11)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; [RR 2.36 (95% CI 0.48 to 11.63).

Intestinal perforation (Outcome 7.12)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.47 (95% CI 0.09 to 2.47).

Sepsis (Outcome 7.13)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.90 (95% CI 0.58 to 1.41); RD ‐0.03 (95% CI ‐0.26 to 0.20).

Retinopathy of prematurity (ROP) (Outcome 7.14)
This outcome was reported in 95 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.57 (95% CI 0.49 to 5.03); RD 0.05 (95% CI ‐0.08 to 0.18).

SUBGROUP ANALYSES

The prespecified subgroup analyses excluding studies that used only one dose of medication and studies that were published as abstracts only were abandoned for this update of the review. Only one study used a single dose and only one abstract was identified. The results of these studies are incorporated with the other studies.

No randomised controlled trials on the use of mefenamic acid for the treatment or prevention of a PDA were identified.

Funnel plots

To ascertain the possibility of publication bias, one funnel plot was conducted for the primary outcome of 'Failure to close a PDA (after single or three doses)' (Figure 6) and for the outcome of NEC. Both funnel plots were quite symmetric indicating that there was no obvious indication of publication bias.

Figure 6

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Funnel plot of comparison: 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, outcome: 3.1 Failure to close a PDA (after single or three doses).