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Meta-Analysis
. 2020 Feb 11;2(2):CD003481.
doi: 10.1002/14651858.CD003481.pub8.

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants

Arne Ohlsson  1 , Rajneesh Walia  2 , Sachin S Shah  3
Affiliations
Meta-Analysis

Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants

Arne Ohlsson et al. Cochrane Database Syst Rev. .

Abstract

Background: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects.

Objectives: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-weight, or preterm and low-birth-weight infants.

Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 30 November 2017), Embase (1980 to 30 November 2017), and CINAHL (1982 to 30 November 2017). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants.

Data collection and analysis: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence.

Main results: We included 39 studies enrolling 2843 infants. Ibuprofen (IV) versus placebo: IV Ibuprofen (3 doses) reduced the failure to close a PDA compared with placebo (typical relative risk (RR); 0.62 (95% CI 0.44 to 0.86); typical risk difference (RD); -0.18 (95% CI -0.30 to -0.06); NNTB 6 (95% CI 3 to 17); I2 = 65% for RR and I2 = 0% for RD; 2 studies, 206 infants; moderate-quality the evidence). One study reported decreased failure to close a PDA after single or three doses of oral ibuprofen compared with placebo (64 infants; 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; I2 test not applicable). Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure (typical RR 1.07, 95% CI 0.92 to 1.24; typical RD 0.02, 95% CI -0.02 to 0.06; I2 = 0% for both RR and RD; moderate-quality evidence). A reduction in NEC (necrotising enterocolitis) was noted in the ibuprofen (IV or oral) group (18 studies, 1292 infants; typical RR 0.68, 95% CI 0.49 to 0.94; typical RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; I2 = 0% for both RR and RD; moderate-quality evidence). There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies, 576 infants; 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; I2 = 24% for RR and I2 = 69% for RD; moderate-quality evidence). The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants; MD -8.12 µmol/L, 95% CI -10.81 to -5.43). For this comparison, there was high between-study heterogeneity (I2 = 83%) and low-quality evidence. Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09; I2 = 0% for both RR and RD). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was low-quality evidence for these two outcomes. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants; typical RR 0.38, 95% CI 0.26 to 0.56; typical RD -0.22, 95% CI -0.31 to -0.14; NNTB 5, 95% CI 3 to 7; moderate-quality evidence). There was a decreased risk of failure to close a PDA with high-dose versus standard-dose of IV ibuprofen (3 studies 190 infants; typical RR 0.37, 95% CI 0.22 to 0.61; typical RD - 0.26, 95% CI -0.38 to -0.15; NNTB 4, 95% CI 3 to 7); I2 = 4% for RR and 0% for RD); moderate-quality evidence). Early versus expectant administration of IV ibuprofen, echocardiographically-guided IV ibuprofen treatment versus standard IV ibuprofen treatment, continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, and rectal ibuprofen versus oral ibuprofen were studied in too few trials to allow for precise estimates of any clinical outcomes.

Authors' conclusions: Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Therefore, of these two drugs, ibuprofen appears to be the drug of choice. The effectiveness of ibuprofen versus paracetamol is assessed in a separate review. Oro-gastric administration of ibuprofen appears as effective as IV administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically-guided versus standard IV ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.

PubMed Disclaimer

Conflict of interest statement

Arne Ohlsson ‐ none known.

Rajneesh Walia ‐ none known.

Sachin Shah ‐ none known.

Figures

1
1
Funnel plot of comparison: 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, outcome: 3.1 Failure to close a patent ductus arteriosus (PDA) (after single or 3 doses).
2
2
Funnel plot of comparison: 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, outcome: 3.17 Necrotising enterocolitis (any stage).
3
3
Study flow diagram: review update
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
5
5
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
6
6
Forest plot of comparison: 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, outcome: 3.1 Failure to close a patent ductus arteriosus (after single or three doses).
7
7
Forest plot of comparison: 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, outcome: 3.17 Necrotising enterocolitis (any stage).
1.1
1.1. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 1 Failure to close a patent ductus arteriosus (after 3 doses).
1.2
1.2. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 2 Need for surgical ligation.
1.3
1.3. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 3 Intraventricular haemorrhage (any grade).
1.4
1.4. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 4 Intraventricular haemorrhage (grades III and IV).
1.5
1.5. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 5 Periventricular leukomalacia.
1.6
1.6. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 6 Pulmonary haemorrhage.
1.7
1.7. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 7 Pulmonary hypertension.
1.8
1.8. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 8 Retinopathy of prematurity (any stage).
1.9
1.9. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 9 Retinopathy of prematurity (stage 3 or 4).
1.10
1.10. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 10 Retinopathy of prematurity (plus disease).
1.11
1.11. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 11 Chronic lung disease (supplemental oxygen at 28 days of age).
1.12
1.12. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 12 Chronic lung disease (supplemental oxygen at 36 weeks' postmenstrual age (PMA)).
1.13
1.13. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 13 Necrotising enterocolitis.
1.14
1.14. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 14 Mortality by 28 days of life.
1.15
1.15. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 15 Oliguria (urine output < 1 mL/kg/hour).
1.16
1.16. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 16 Creatinine (µmol/L) after treatment.
1.17
1.17. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 17 Blood urea nitrogen (µmol/L).
1.18
1.18. Analysis
Comparison 1 Intravenous ibuprofen versus placebo, Outcome 18 Mortality.
2.1
2.1. Analysis
Comparison 2 Oral ibuprofen versus placebo, Outcome 1 Failure to close a patent ductus arteriosus after single or 3 doses.
3.1
3.1. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 1 Failure to close a patent ductus arteriosus (PDA) (after single or 3 doses).
3.2
3.2. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 2 All‐cause mortality.
3.3
3.3. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 3 Neonatal mortality (during first 28/30 days of life).
3.4
3.4. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 4 Reopening of the ductus arteriosus.
3.5
3.5. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 5 Need for surgical closure of the PDA.
3.6
3.6. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 6 Need for re‐treatment with indomethacin or ibuprofen to close the PDA.
3.7
3.7. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 7 Duration of ventilator support (days).
3.8
3.8. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 8 Duration of need for supplementary oxygen (days).
3.9
3.9. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 9 Pulmonary haemorrhage.
3.10
3.10. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 10 Pulmonary hypertension.
3.11
3.11. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 11 Chronic lung disease (at 28 days).
3.12
3.12. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 12 Chronic lung disease (at 36 weeks' postmenstrual age).
3.13
3.13. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 13 Chronic lung disease (age not stated).
3.14
3.14. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 14 Intraventricular haemorrhage (any grade).
3.15
3.15. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 15 Intraventricular haemorrhage (grades III and IV).
3.16
3.16. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 16 Periventricular leukomalacia (cystic).
3.17
3.17. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 17 Necrotising enterocolitis (any stage).
3.18
3.18. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 18 Intestinal perforation.
3.19
3.19. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 19 Gastrointestinal bleed.
3.20
3.20. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 20 Time to full enteral feeds.
3.21
3.21. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 21 Time to regain birth weight (days).
3.22
3.22. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 22 Retinopathy of prematurity.
3.23
3.23. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 23 Sepsis.
3.24
3.24. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 24 Oliguria (urine output < 1 mL/kg/hour).
3.25
3.25. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 25 Serum/plasma creatinine levels (μmol/L) 72 hours after treatment.
3.26
3.26. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 26 Increase in serum/plasma creatinine levels (mg/dL) following treatment.
3.27
3.27. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 27 Duration of hospitalisation (days).
3.28
3.28. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 28 Significant decrease in urine output (> 20% decrease in urine output after starting therapy).
3.29
3.29. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 29 Daily urine output mL/kg/hr.
3.30
3.30. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 30 Serum bilirubin (µmol/L) after treatment.
3.31
3.31. Analysis
Comparison 3 Intravenous or oral ibuprofen versus intravenous or oral indomethacin, Outcome 31 Platelet count (x109/L).
4.1
4.1. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 1 Failure to close a patent ductus arteriosus (PDA) (after 3 doses).
4.2
4.2. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 2 All‐cause mortality.
4.3
4.3. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 3 Neonatal mortality (during first 28/30 days of life).
4.4
4.4. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 4 Reopening of the ductus arteriosus.
4.5
4.5. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 5 Need for surgical closure of the PDA.
4.6
4.6. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 6 Pulmonary haemorrhage.
4.7
4.7. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 7 Pulmonary hypertension.
4.8
4.8. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 8 Chronic lung disease (at 28 days).
4.9
4.9. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 9 Chronic lung disease (age not stated).
4.10
4.10. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 10 Intraventricular haemorrhage (any grade).
4.11
4.11. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 11 Intraventricular haemorrhage (grades III and IV).
4.12
4.12. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 12 Periventricular leukomalacia (cystic).
4.13
4.13. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 13 Necrotising enterocolitis (any stage).
4.14
4.14. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 14 Intestinal perforation.
4.15
4.15. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 15 Gastrointestinal bleed.
4.16
4.16. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 16 Retinopathy of prematurity.
4.17
4.17. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 17 Sepsis.
4.18
4.18. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 18 Oliguria (urine output < 1 mL/kg/hour).
4.19
4.19. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 19 Serum/plasma creatinine levels (µmol/L) 72 hours after treatment.
4.20
4.20. Analysis
Comparison 4 Oral ibuprofen versus intravenous (IV) or oral indomethacin, Outcome 20 Duration of hospital stay (days).
5.1
5.1. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 1 Failure to close a patent ductus arteriosus (after single or 3 doses).
5.2
5.2. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 2 Mortality (during first 28/30 days of life).
5.3
5.3. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 3 Mortality (during hospital stay).
5.4
5.4. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 4 Mean plasma cystatin‐C (mg/L) after treatment.
5.5
5.5. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 5 Need for surgical closure of the ductus.
5.6
5.6. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 6 Duration of ventilatory support.
5.7
5.7. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 7 Duration of hospitalisation (days).
5.8
5.8. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 8 Pneumothorax.
5.9
5.9. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 9 Pulmonary haemorrhage.
5.10
5.10. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 10 Pulmonary hypertension.
5.11
5.11. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 11 Chronic lung disease (at 36 weeks' postmenstrual age or at discharge).
5.12
5.12. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 12 Intraventricular haemorrhage (any grade).
5.13
5.13. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 13 Periventricular leukomalacia.
5.14
5.14. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 14 Necrotising enterocolitis (any stage).
5.15
5.15. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 15 Intestinal perforation.
5.16
5.16. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 16 Gastrointestinal bleed.
5.17
5.17. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 17 Sepsis.
5.18
5.18. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 18 Retinopathy of prematurity that required laser treatment.
5.19
5.19. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 19 Serum/plasma creatinine levels (μmol/L) after treatment.
5.20
5.20. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 20 Oliguria (Urine output < 1 mL/kg/hour).
5.21
5.21. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 21 Mental Developmental Index (Bayley II) at 18‐24 months.
5.22
5.22. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 22 Psychomotor Developmental Index at 18‐24 months.
5.23
5.23. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 23 Moderate/severe cerebral palsy at 18‐24 months.
5.24
5.24. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 24 Blindness at 18‐24 months.
5.25
5.25. Analysis
Comparison 5 Oral ibuprofen versus intravenous (IV) ibuprofen, Outcome 25 Deafness at 18‐24 months.
6.1
6.1. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 1 Failure to close a patent ductus arteriosus after 3 doses of ibuprofen.
6.2
6.2. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 2 Reopening after second course of ibuprofen.
6.3
6.3. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 3 Need for surgical closure.
6.4
6.4. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 4 Mortality during hospital stay.
6.5
6.5. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 5 Urine output on day 3 of treatment (mL/kg/hour).
6.6
6.6. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 6 Oliguria (< 1 mL/kg/hour during 24 hours).
6.7
6.7. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 7 Intraventricular haemorrhage (any grade).
6.8
6.8. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 8 Intraventricular haemorrhage (grades III and IV).
6.9
6.9. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 9 Periventricular leukomalacia.
6.10
6.10. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 10 Retinopathy of prematurity (any stage).
6.11
6.11. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 11 Retinopathy of prematurity (stage 3 or 4).
6.12
6.12. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 12 Necrotising enterocolitis.
6.13
6.13. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 13 Chronic lung disease (at 36 weeks' postmenstrual age).
6.14
6.14. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 14 Sepsis.
6.15
6.15. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 15 Hospital stay (days).
6.16
6.16. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 16 Oliguria (< 0.5 mL/kg/hour) after onset of treatment.
6.17
6.17. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 17 Gastrointestinal bleed.
6.18
6.18. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 18 Platelet count (x 109/L) after treatment.
6.19
6.19. Analysis
Comparison 6 High‐dose (oral or IV) versus standard‐dose ibuprofen (oral or IV), Outcome 19 Serum creatinine (µmol/L) after treatment.
7.1
7.1. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 1 Days on supplemental oxygen during the first 28 days.
7.2
7.2. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 2 Days on supplemental oxygen.
7.3
7.3. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 3 Days on mechanical ventilation first 28 days.
7.4
7.4. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 4 Days on mechanical ventilation.
7.5
7.5. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 5 Chronic lung disease (at 36 weeks' postmenstrual age (PMA)).
7.6
7.6. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 6 Mortality or chronic lung disease (at 36 weeks' PMA).
7.7
7.7. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 7 Mortality during hospital stay.
7.8
7.8. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 8 Pneumothorax.
7.9
7.9. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 9 Intraventricular haemorrhage (grades III and IV).
7.10
7.10. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 10 Periventricular leukomalacia.
7.11
7.11. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 11 Necrotising enterocolitis (requiring surgery).
7.12
7.12. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 12 Intestinal perforation.
7.13
7.13. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 13 Sepsis.
7.14
7.14. Analysis
Comparison 7 Early versus expectant administration of intravenous ibuprofen, Outcome 14 Retinopathy of prematurity (stage 3 or 4).
8.1
8.1. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 1 Failure to close a patent ductus arteriosus (PDA).
8.2
8.2. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 2 Reopening of PDA.
8.3
8.3. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 3 Number of ibuprofen doses.
8.4
8.4. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 4 Mortality during hospital stay.
8.5
8.5. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 5 Bronchopulmonary dysplasia (supplemental oxygen at 36 weeks' postmenstrual age).
8.6
8.6. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 6 Necrotising enterocolitis.
8.7
8.7. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 7 Intraventricular haemorrhage (grade II and III).
8.8
8.8. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 8 White matter damage.
8.9
8.9. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 9 Oliguria (urine output < 1 mL/kg/hour).
8.10
8.10. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 10 Serum/plasma creatinine (µmol/L) after treatment.
8.11
8.11. Analysis
Comparison 8 Echocardiographically (ECHO)‐guided intravenous ibuprofen treatment versus standard intravenous ibuprofen treatment, Outcome 11 Laser therapy for retinopathy of prematurity.
9.1
9.1. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 1 Failure to close a patent ductus arteriosus (PDA) after 1 course of ibuprofen.
9.2
9.2. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 2 Reopening of PDA.
9.3
9.3. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 3 Need for surgical ligation.
9.4
9.4. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 4 Mortality (in hospital).
9.5
9.5. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 5 Chronic lung disease (at 36 weeks' postmenstrual age).
9.6
9.6. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 6 Retinopathy of prematurity (any stage).
9.7
9.7. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 7 Retinopathy of prematurity (stage 3 or 4).
9.8
9.8. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 8 Intraventricular haemorrhage (any grade).
9.9
9.9. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 9 Intraventricular haemorrhage (grade III and IV).
9.10
9.10. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 10 Periventricular leukomalacia (cystic).
9.11
9.11. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 11 Necrotising enterocolitis.
9.12
9.12. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 12 Isolated intestinal perforation.
9.13
9.13. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 13 Oliguria (urine output ≤ 1 mL/kg/hour).
9.14
9.14. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 14 Serum/plasma creatinine after treatment (µmol/L).
9.15
9.15. Analysis
Comparison 9 Continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, Outcome 15 Gastrointestinal haemorrhage.
10.1
10.1. Analysis
Comparison 10 Rectal ibuprofen versus oral ibuprofen, Outcome 1 Failure to close a PDA after 3 doses.
10.2
10.2. Analysis
Comparison 10 Rectal ibuprofen versus oral ibuprofen, Outcome 2 Need for surgical ligation.
10.3
10.3. Analysis
Comparison 10 Rectal ibuprofen versus oral ibuprofen, Outcome 3 Plasma creatinine (µmol/L.
10.4
10.4. Analysis
Comparison 10 Rectal ibuprofen versus oral ibuprofen, Outcome 4 Plasma bilirubin (µmol/L) after treatment.
10.5
10.5. Analysis
Comparison 10 Rectal ibuprofen versus oral ibuprofen, Outcome 5 Urine output (mL/kg/hr) after treatment.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Adamska 2005 {published data only}
    1. Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants [Porownanie ibuprofenu i indometacyny w leczeniu przetrwalego przewodu tetniczego u noworodkow urodzonych przedwczesnie]. Medycyna Wieku Rozwojowego 2005;9(3 Pt 1):335‐54. [PUBMED: 16547381] - PubMed
Akar 2017 {published data only}
    1. Akar M, Yildirim TG, Sandal G, Bozdag S, Erdeve O, Altug N, et al. Does ibuprofen treatment in patent ductus arteriosus alter oxygen free radicals in premature infants?. Cardiology in the Young 2017;27(3):507–11. [PUBMED: 27319277] - PubMed
Akisu 2001 {published data only}
    1. Akisu M, Ozyurek AR, Dorak C, Parlar A, Kultursay N. Enteral ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm newborn infants [Premature bebeklerde patent duktus arteriozusun tedavisinde enteral ibuprofen ve indometazinin etkinligi ve guvenilirligi]. Cocuk Sagligi ve Hastaliklari Dergisi 2001;44(1):56‐60.
Aly 2007 {published data only}
    1. Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel‐Meguid IE, Hammad TA. Oral ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. American Journal of Perinatology 2007;24(5):267‐70. [PUBMED: 17484080] - PubMed
    1. Lotfy W, Badrawi N, Ghawas M, Ehsan E, Aly H. Oral ibuprofen solution (O) is efficacious for the treatment of patent ductus arteriosus (PDA) in premature infants: a randomized controlled trial. Pediatric Academic Societies Annual Meeting; 2005 May 14‐17; Washington DC, United States. 2005. [PAS2005:1410]
Aranda 2009 {published data only}
    1. Aranda JV. Multicentre randomized double‐blind placebo controlled trial of ibuprofen L‐Lysine intravenous solution (IV Ibuprofen) in premature infants for the early treatment of patent ductus arteriosus (PDA). Pediatric Academic Societies Annual Meeting; 2005 May 14‐17; Washington DC, United States. 2005.
    1. Aranda JV, Clyman R, Cox B, Overmeire B, Wozniak P, Sosenko I, et al. A randomized, double‐blind, placebo‐controlled trial of intravenous ibuprofen L‐lysine for the early closure of non‐symptomatic patent ductus arteriosus within 72 hours of birth in extremely low‐birth‐weight infants. American Journal of Perinatology 2009;26(3):235‐45. [DOI: 10.1055/s-0028-1103515; PUBMED: 19067286] - DOI - PubMed
Bagnoli 2013 {published data only}
    1. Bagnoli F, Rossetti A, Messina G, Mori A, Casucci M, Tomasini B. Treatment of patent ductus arteriosus (PDA) using ibuprofen: renal side‐effects in VLBW and ELBW newborns. Journal of Maternal‐Fetal & Neonatal Medicine 2013;26(4):423‐9. [DOI: 10.3109/14767058.2012.733775; PUBMED: 23057804] - DOI - PubMed
Bravo 2014 {published data only}
    1. Bravo MC, Cabaňas F, Riera J, Pérez‐Fernández E, Quero J, Pérez‐Rodriguez J, et al. Randomized controlled clinical trial of standard versus echocardiographically guided ibuprofen treatment for patent ductus arteriosus in preterm infants: a pilot study. Journal of Maternal‐Fetal & Neonatal Medicine 2014;27(9):904‐9. [DOI: 10.3109/14767058.2013.846312; PUBMED: 24047189] - DOI - PubMed
Cherif 2008 {published data only}
    1. Cherif A, Khrouf N, Jabnoun S, Mokrani C, Amara MB, Guellouze N, et al. Randomized pilot study comparing oral ibuprofen with intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. Pediatrics 2008;122(6):e1256‐61. [PUBMED: 19047225] - PubMed
Chotigeat 2003 {published data only}
    1. Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. Chotmaihet Thangphaet [Journal of the Medical Association of Thailand] 2003;86(Suppl 3):S563‐9. [PUBMED: 14700149] - PubMed
Dani 2012 {published data only}
    1. Dani C, Vangi V, Bertini G, Pratesi S, Lori I, Favelli F, et al. High‐dose ibuprofen for patent ductus arteriosus in extremely preterm infants: a randomized controlled study. Clinical Pharmacology and Therapeutics 2012;91(4):590‐6. [PUBMED: 22089267] - PubMed
Demir 2017 {published data only}
    1. Demir N, Peker E, Ece I, Balahoroglu R, Tuncer O. Efficacy and safety of rectal ibuprofen for ductus arteriosus closure in very low birth weight infants. European Journal of Pediatrics 2016;175(11):1705‐6. - PubMed
    1. Demir N, Peker E, Ece I, Balahoroglu R, Tuncer O. Efficacy and safety of rectal ibuprofen for patent ductus arteriosus closure in very low birth weight preterm infants. Journal of Maternal‐Fetal & Neonatal Medicine 2017;30(17):2119–25. [DOI: 10.1080/14767058.2016.1238897; PUBMED: 28052714] - DOI - PubMed
    1. Peker E, Demir N, Ece I, Balahorotlu R, Tuncer O. Efficacy and safety of rectal ibuprofen for ductus arteriosus closure in very low birth weight infants. Journal of Maternal‐Fetal & Neonatal Medicine 2016;29(Suppl 1):114. - PubMed
Ding 2014 {published data only}
    1. Ding YJ, Han B, Yang B, Zhu M. NT‐proBNP plays an important role in the effect of ibuprofen on preterm infants with patent ductus arteriosus. European Review for Medical and Pharmacological Sciences 2014;18(18):2596‐8. [PUBMED: 25317790] - PubMed
El‐Mashad 2017 {published data only}
    1. El‐Mashad AE, El‐Mahdy H, Amrousy DE, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. European Journal of Pediatrics 2017;176(2):233‐40. [DOI: 10.1007/s00431-016-2830-7; PUBMED: 28004188] - DOI - PubMed
Erdeve 2012 {published data only}
    1. Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2012;97(4):F279‐83. [DOI: 10.1136/archdischild-2011-300532; PUBMED: 22147286] - DOI - PubMed
Fakhraee 2007 {published data only}
    1. Fakhraee SH, Badiee Z, Mojtahedzadeh S, Kazemian M, Kelishadi R. Comparison of oral ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Zhongguo Dang Dai Er Ke za Zhi [Chinese Journal of Contemporary Pediatrics] 2007;9(5):399‐403. [PUBMED: 17937843] - PubMed
Fesharaki 2012 {published data only}
    1. Fesharaki HJ, Nayeri FS, Asbaq PA, Amini E, Sedagat M. Different doses of ibuprofen in the treatment of patent ductus arteriosus: a randomized controlled trial. Tehran University Medical Journal 2012;70(8):488‐93.
Gimeno Navarro 2005 {published data only}
    1. Gimeno Navarro A, Cano Sanchez A, Fernandez Gilino C, Carrasco Moreno JI, Izquierdo Macian I, Gutierrez Laso A, et al. Ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm infants [Ibuprofeno frente a indometacina en el tratamiento del conducto arterioso persistente del prematuro]. Anales de Pediatria 2005;63(3):212‐8. [PUBMED: 16219273] - PubMed
Gokmen 2011 {published data only}
    1. Eras Z, Gokmen T, Erdeve O, Ozyurt BM, Saridas B, Dilmen U. Impact of oral versus intravenous ibuprofen on neurodevelopmental outcome: a randomized controlled parallel study. American Journal of Perinatology 2013;30(10):857‐62. [DOI: 10.1055/s-0033-1333667; PUBMED: 23359230] - DOI - PubMed
    1. Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral verus intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. Journal of Pediatrics 2011;158(4):549‐54; Erratum in: Journal of Pediatrics; 2012;160(1):181. [10.1016/j.jpeds.2010.10.008; PUBMED: 21094951] - PubMed
Hammerman 2008 {published data only}
    1. Hammerman C, Shchors I, Jacobson S, Schimmel MS, Bromiker R, Kaplan M, et al. Ibuprofen versus continuous indomethacin in premature neonates with patent ductus arteriosus: is the difference in the mode of administration?. Pediatric Research 2008;64(3):291‐7. [DOI: 10.1203/PDR.0b013e31817d9bb0; PUBMED: 18458658] - DOI - PubMed
Lago 2002 {published data only}
    1. Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. European Journal of Pediatrics 2002;161(4):202‐7. [PUBMED: 12014386] - PubMed
    1. Lago P, Salvadori S, Bettiol T, Pitassi I, Chiandetti L, Saia OS. Effects of indomethacin and ibuprofen on renal function in preterm infants treated for patent ductus arteriosus: a randomized controlled trial. Pediatric Research 2001;49:375A. - PubMed
    1. Zanardo V, Vedovato S, Lago P, Piva D, Faggian D, Chiozza L. Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus. Fetal Diagnosis and Therapy 2005;20(6):534‐9. [DOI: 10.1159/000088046; PUBMED: 16260891] - DOI - PubMed
Lago 2014 {published data only}
    1. Lago P, Salvadori S, Opocher F, Ricato S, Chiandetti L, Frigo AC. Continuous infusion of ibuprofen for treatment of patent ductus arteriosus in very low birth weight infants. Neonatology 2014;105(1):46‐54. [DOI: 10.1159/000355679; PUBMED: 24281435] - DOI - PubMed
Lin 2012 {published data only}
    1. Lin XZ, Chen HQ, Zheng Z, Li YD, Lai JD, Huang LH. Therapeutic effect of early administration of oral ibuprofen in very low birth weight infants with patent ductus arteriosus. Zhongguo Dang Dai Er Ke za Zhi [Chinese Journal of Contemporary Pediatrics] 2012;14(7):502‐5. [PUBMED: 22809601] - PubMed
Lin 2017 {published data only}
    1. Lin YJ, Chen CM, Rehan VK, Florens A, Wu SY, Tsai ML, et al. Randomized trial to compare renal function and ductal response between Indomethacin and ibuprofen treatment in extremely low birth weight infants. Neonatology 2017;111(3):195–202. [DOI: 10.1159/000450822; PUBMED: 27842315] - DOI - PubMed
Mosca 1997 {published data only}
    1. Mosca F, Bray M, Lattanzio M, Fumagalli M, Colnaghi M, Castoldi F, et al. Comparison of the effects of ibuprofen and indomethacin on PDA closure and cerebral perfusion and oxygenation. Pediatric Research 1997;41:165A.
    1. Mosca F, Bray M, Lattanzio M, Fumagalli M, Colnaghi MR, Compagnoni G. Comparison of the effects of indomethacin (INDO) and ibuprofen (IBU) on cerebral perfusion and oxygenation in preterm infants. Pediatric Research 1996;39:231A.
    1. Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1997;131(4):549‐54. [PUBMED: 9386657] - PubMed
Patel 1995 {published data only}
    1. Patel J, Marks KA, Roberts I, Azzopardi D, Edwards AD. Ibuprofen treatment of patent ductus arteriosus. Lancet 1995;346(8969):255. [PUBMED: 7616831] - PubMed
Patel 2000 {published data only}
    1. Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized double‐blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47(1):36‐42. [PUBMED: 10625080] - PubMed
Pezzati 1999 {published data only}
    1. Pezzati M, Bertini G, Vangi V, Biagiotti R, Cianciulli D, Rubaltelli FF. Mesenteric and renal perfusion in preterm infants with PDA: indomethacin vs ibuprofen. Pediatric Research 1999;45:218A. - PubMed
    1. Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubatelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135(6):733‐8. [PUBMED: 10586177] - PubMed
Pistulli 2014 {published data only}
    1. Hoxha A, Gjyzari A, Tushe E. Renal effects of ibuprofen during the treatment of patent ductus arteriosus in low birth weight premature infants. Nephrology Dialysis Transplantation Conference. 50th ERA‐EDTA Congress; 2013 May 18‐21; Istanbul, Turkey. 2013.
    1. Pistulli E, Hamiti A, Buba S, Hoxha A, Kelmendi N, Vyshka G. The association between patent ductus arteriosus and perinatal infection in a group of low birth weight preterm infants. Iranian Journal of Pediatrics 2014;24(1):42‐8. [PUBMED: 25793044] - PMC - PubMed
    1. Prifti E, Enkeleda P, Rubena M, Alketa H. The impact of antenatal corticosteroids on PDA in low birth weight infants. Journal of Perinatal Medicine 2013;41:s1.
    1. Qosja A, Kuneshka N, Tushe E, Teneqexhi L. Oral versus intravenous ibuprofen for patent ductus arteriosus closure. Giornale Italiano di Cardiologia 2012;13(Suppl 1):15S‐6S.
Plavka 2001 {published data only}
    1. Plavka R, Svihovec P, Borek I, Biolek J, Kostirova M, Liska K, et al. Ibuprofen vs. indomethacin in the treatment of patent ductus arteriosus (PDA) in very premature neonates. Pediatric Research 2001;49:375A.
Pourarian 2008 {published data only}
    1. Pourarian SH, Pishva N, Madani A, Rastegari M. Comparison of oral ibuprofen and indomethacin on closure of patent ductus arteriosus in preterm infants. Eastern Mediterranean Health Journal 2008;14(2):360‐5. [PUBMED: 18561728] - PubMed
Pourarian 2015 {published data only}
    1. Pourarian S, Takmil F, Cheriki S, Amoozgar H. The effect of oral high‐dose ibuprofen on patent ductus arteriosus closure in preterm infants. American Journal of Perinatology 2015;32(12):1158‐63. [DOI: 10.1055/s-0035-1551671; PUBMED: 26007314] - DOI - PubMed
Salama 2008 {published data only}
    1. Salama H, Alsisi A, Al‐Rifai H, Shaddad A, Samawal L, Habboub L, et al. A randomized controlled trial on the use of oral ibuprofen to close patent ductus arteriosus in premature infants. Journal of Neonatal‐Perinatal Medicine 2008;1(3):153‐8.
Sosenko 2012 {published data only}
    1. Sosenko IR, Fajardo MF, Claure N, Bancalari E. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double‐blind randomized controlled trial. Journal of Pediatrics 2012;160(6):929‐35. [PUBMED: 22284563] - PubMed
Su 2003 {published data only}
    1. Su PH, Chen JY, Su CM, Huang TC, Lee HS. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatrics International 2003;45(6):665‐70. [PUBMED: 14651538] - PubMed
Su 2008 {published data only}
    1. Su BH, Lin HC, Chiu HY, Hsieh HY, Chen HH, Tsai YC. Comparison of ibuprofen and indomethacin for early‐targeted treatment of patent ductus arteriosus in extremely premature infants: a randomised controlled trial. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93(2):F94‐9. [DOI: 10.1136/adc.2007.120584; PUBMED: 17768157] - DOI - PubMed
Supapannachart 2002 {published data only}
    1. Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi Hospital. Chotmaihet Thangphaet [Journal of the Medical Association of Thailand] 2002;85(Suppl 4):S1252‐8. [PUBMED: 12549803] - PubMed
Van Overmeire 1997 {published data only}
    1. Overmeire B, Follens I, Hartmann S, Creten WL, Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Archives of Disease in Childhood. Fetal and Neonatal Edition 1997;76(3):F179‐84. [PUBMED: 9175948] - PMC - PubMed
    1. Overmeire B, Follens I, Hartmann S, Mahieu L, Reempts PJ. Intravenous ibuprofen (IBU) for the treatment of patent ductus arteriosus (PDA) in preterm infants with respiratory distress syndrome (RDS). Pediatric Research 1996;39:250A.
Van Overmeire 2000 {published data only}
    1. Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135(6):733‐8. [PUBMED: 10586177] - PubMed
    1. Overmeire B, Langhendries JP, Vanhaesebrouck P, Lecoutere D, Broek H. Ibuprofen for early treatment of patent ductus arteriosus, a randomized multicentre trial. Pediatric Research 1998;43:200A.
    1. Overmeire B, Smets K, Lecoutere D, Broek H, Weyler J, Groote K, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New England Journal of Medicine 2000;343(10):674‐81. [DOI: 10.1056/NEJM200009073431001; PUBMED: 10974130] - DOI - PubMed
Yadav 2014 {published data only}
    1. Yadav S, Agarwal S, Maria A, Dudeja A, Dubey NK, Anand P, et al. Comparison of oral ibuprofen with oral indomethacin for PDA closure in Indian preterm neonates: a randomized controlled trial. Pediatric Cardiology 2014;35(5):824‐30. [DOI: 10.1007/s00246-014-0861-2; PUBMED: 24435507] - DOI - PubMed

References to studies excluded from this review

Alipour 2016 {published data only}
    1. Alipour MR, Shamsi MM, Namayandeh SM, Pezeshkpour Z, Rezaeipour F, Sarebanhassanabadi M. The effects of oral ibuprofen on medicinal closure of patent ductus arteriosus in full‐term neonates in the second postnatal week. Iranian Journal of Pediatrics 2016;26(4):e5807. [DOI: 10.5812/ijp.5807; PUBMED: 27729962] - DOI - PMC - PubMed
Amoozgar 2010 {published data only}
    1. Amoozgar H, Ghodstehrani M, Pishva N. Oral ibuprofen and ductus arteriosus closure in full‐term neonates: a prospective case‐control study. Pediatric Cardiology 2010;31(1):40‐3. [DOI: 10.1007/s00246-009-9542-y; PUBMED: 19841966] - DOI - PubMed
Cherif 2007 {published data only}
    1. Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. American Journal of Perinatology 2007;24(6):339‐45. [DOI: 10.1055/s-2007-981853; PUBMED: 17564958] - DOI - PubMed
Desfrere 2005 {published data only}
    1. Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, et al. Dose‐finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. Journal of Clinical Pharmacy and Therapeutics 2005;30(2):121‐32. [DOI: 10.1111/j.1365-2710.2005.00630.x; PUBMED: 15811164] - DOI - PubMed
Kalani 2016 {published data only}
    1. Kalani M, Shariat M, Khalesi N, Farahani Z, Ahmadi S. A comparison of early ibuprofen and indomethacin administration to prevent intraventricular hemorrhage among preterm infants. Acta Medica Iranica 2016;54(12):788‐92. [PUBMED: 28120591] - PubMed

References to ongoing studies

ACTRN12616000195459 {published data only}
    1. ACTRN12616000195459. Early pharmacological treatment with supportive care versus supportive care alone in preterm infants with a patent ductus arteriosus. anzctr.org.au/ACTRN12616000195459.aspx (first received 08 February 2016).
ChiCTR‐TRC‐14004719 {published data only}
    1. ChiCTR‐TRC‐14004559. Comparison of the dose effect of oral ibuprofen suspension for PDA treatment in premature infants [Developmental pharmacokinetics and pharmacodynamics of chiral ibuprofen associated with the CYP2C8/9 gene polymorphism]. chictr.org.cn/showproj.aspx?proj=5014 (first received 15 April 2014).
EUCTR2016‐002974‐11‐ES {published data only}
    1. EUCTR2016‐002974‐11‐ES. Clinical trial to evaluate the impact on the intestinal prognosis of 2 ibuprofen administration regimens for the treatment of patent ductus arteriosus, guided by echocardiography [Phase III, randomized, multicenter, double‐blind clinical trial to evaluate two echo‐guided administration regimens of ibuprofen in the treatment of patent ductus arteriosus: impact on intestinal prognosis]. clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:2016‐00... (first received 26 September 2016).
IRCT201205029611N1 {published data only}
    1. IRCT201205029611N1. High dose oral ibuprofen in PDA closure in premature infants. en.irct.ir/trial/10178 (first received 25 August 2014).
IRCT2015111024977N1 {published data only}
    1. IRCT2015111024977N1. Comparison of oral Ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus [Comparison of oral Ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants]. en.irct.ir/trial/20973 (first received 16 December 2015).
ISRCTN13281214 {published data only}
    1. ISRCTN13281214. Closing patent ductus arteriosus in preterm babies by using a risk‐based score. isrctn.com/ISRCTN13281214?q=ISRCTN13281214&filters=&sort=&of... (first received 1 July 2016).
NCT01149564 {published data only}
    1. NCT01149564. Comparison of oral and intravenous ibuprofen for PDA treatment in premature infants. clinicaltrials.gov/show/NCT01149564 (first received 23 June 2010).
NCT01630278 {published data only}
    1. NCT01630278. Early ibuprofen treatment of patent ductus arteriosus (PDA) in premature infants (TRIOCAPI) [Impact of early targeted ibuprofene treatment of patent ductus arteriosus (PDA) on long term neurodevelopmental outcome in very premature infants (TRIOCAPI)]. clinicaltrials.gov/show/NCT01630278 (first received 28 June 2012).
NCT01758913 {published data only}
    1. NCT01758913. Closure of patent ductus arteriosus with indomethacin or ibuprofen in extreme low birth weight infants [Pharmacological closure of patent ductus arteriosus in extreme low birth weight infants. A comparison of efficacy, side effects and outcomes between indomethacin and ibuprofen]. clinicaltrials.gov/show/NCT01758913 (first received 1 January 2013).
NCT02128191 {published data only}
    1. NCT02128191. No treatment versus ibuprofen treatment for patent ductus arteriosus in preterm infants [Efficacy and safety of no treatment compared with oral ibuprofen treatment for patent ductus arteriosus in preterm infants: a randomized, double‐blind, placebo‐controlled, non‐inferiority clinical trial]. clinicaltrials.gov/show/NCT02128191 (first received 1 May 2014).
NCT02884219 {published data only}
    1. NCT02884219. Early treatment versus expectative management of PDA in preterm infants [Multi‐center, randomized non‐inferiority trial of early treatment versus expectative management of patent ductus arteriosus in preterm infants (BeNeDuctus Trial ‐ Belgium Netherlands Ductus Trial)]. clinicaltrials.gov/ct2/show/record/NCT02884219 (first received 30 August 2016).

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References to other published versions of this review

Ohlsson 2003
    1. Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD003481] - DOI - PubMed
Ohlsson 2005
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