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Meta-Analysis
. 2018 Sep 28;9(9):CD003481.
doi: 10.1002/14651858.CD003481.pub7.

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

Arne Ohlsson  1 , Rajneesh Walia, Sachin S Shah
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. .

Update in

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.

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Conflict of interest statement

Arne Ohlsson ‐ none known.

Rajneesh Walia ‐ none known.

Sachin Shah ‐ none known.

Figures

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

References

References to studies included in this review

    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
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    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.
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    2. 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

References to studies excluded from this review

    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
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References to ongoing studies

    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).
    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).
    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).
    1. IRCT201205029611N1. High dose oral ibuprofen in PDA closure in premature infants. en.irct.ir/trial/10178 (first received 25 August 2014).
    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).

Additional references

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References to other published versions of this review

    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
    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 2005, Issue 4. [DOI: 10.1002/14651858.CD003481.pub2] - DOI - PubMed
    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 2008, Issue 1. [DOI: 10.1002/14651858.CD003481.pub3] - DOI - PubMed
    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 2010, Issue 4. [DOI: 10.1002/14651858.CD003481.pub4] - DOI - PubMed
    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 2013, Issue 4. [DOI: 10.1002/14651858.CD003481.pub5] - DOI - PubMed

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