5.

High‐dose oral or intravenous ibuprofen compared with standard‐dose oral or intravenous ibuprofen for patent ductus arteriosus
Patient or population: preterm infants with patent ductus arteriosus Settings: NICU Intervention: high‐dose oral or intravenous ibuprofen Comparison: standard‐dose oral or intravenous ibuprofen
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Standard‐dose ibuprofen	High‐dose ibuprofen
Failure to close a patent ductus arteriosus after 3 doses of ibuprofen	High risk population		RR 0.37 (0.22 to 0.61)	190 (3)	⊕⊕⊕⊝ moderate	Bias: there was unclear risk of bias for random sequence generation in all three studies. The allocation was concealed in two of the studies and unclear in one study. The blinding of personnel was unclear in all three studies and blinding of outcome assessments was unclear in one of the three studies, with low risk of bias in the other two studies. We downgraded the evidence by one step. Heterogeneity/consistency: we noted no heterogeneity for RR (4%) or for RD (0%). Directness of evidence: studies were conducted in the target population. Precision: the confidence intervals around the point estimates for RR and RD were quite narrow. Presence of publication bias: only 3 studies were included in the analysis so a funnel plot was not constructed.
	411 per 1000	147 per 1000 (0 to 300)
Necrotising enterocolitis	High risk population		RR 1.00 (0.40 to 2.50)	130 (2)	⊕⊕⊝⊝ low	Bias: there was unclear risk of bias for random sequence generation in both studies. The allocation was concealed in both studies. The blinding of personnel was unclear in both studies but there was low risk of bias for blinding of outcome assessments. We downgraded the evidence by one step. Heterogeneity/consistency: we noted no heterogeneity for RR or for RD (0% for both). Directness of evidence: studies were conducted in the target population. Precision: the confidence intervals around the point estimates for RR and RD were quite wide as the sample size was small. We downgraded the evidence by one step. Presence of publication bias: only 2 studies were included in the analysis so a funnel plot was not constructed.
	123 per 1000	123 per 1000 (114 to 133)
Oliguria	High risk population		RR 1.57 (0.44 to 5.63)	120 (2)	⊕⊕⊝⊝ low	Bias: there was unclear risk of bias for random sequence generation in both studies. The allocation was concealed in one study. The blinding of personnel was unclear in both studies but there was low risk of bias for blinding of outcome assessments (by cardiologist) in one study. We downgraded the evidence by one step. Heterogeneity/consistency: we noted no heterogeneity for RR or for RD (0% for both). Directness of evidence: studies were conducted in the target population. Precision: the confidence intervals around the point estimates for RR and RD were quite wide as the sample size was small. We downgraded the evidence by one step. Presence of publication bias: only 2 studies were included in the analysis so a funnel plot was not constructed.
	50 per 1000	83 per 1000 (33 to 133)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; NICU: Neonatal intensive care unit; RR: Risk Ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.