OBJECTIVES: Ibuprofen (IBU) is commonly used for the closure of patent ductus arteriosus (PDA) in preterm neonates. We sought to systematically review meta-analyses (MAs) of ibuprofen, including versus indomethacin (INDO) and paracetamol/acetaminophen (APAP), for the PDA. The systematic review of MAs is a relatively recent approach that filters top published contrasting evidence and enhance access to the evidence.

METHODS: The literature was comprehensively searched until May 2020. Quality of evidence was extracted directly from included studies based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment. A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) and the Risk of Bias in Systematic Reviews (ROBIS) tools were utilized to assess quality.

RESULTS: Seven MAs were included. Oral and/or intravenous (IV) IBU were as effective as INDO for PDA closure, associated with reduced necrotizing enterocolitis, oliguria, and elevated creatinine levels. INDO reduced bronchopulmonary dysplasia and intraventricular hemorrhage compared to IV IBU only. APAP was superior for PDA closure over IV IBU, reducing gastrointestinal bleeding compared to IBU. Oral IBU was associated with enhanced PDA closure relative to IV IBU, with favorable creatinine levels. Higher dose (HD) of oral IBU enhanced PDA closure and reduced the need for surgical ligation over INDO and IV IBU, and reduced the need for surgery compared to oral IBU. HD IV IBU had efficacy advantage over IV IBU only. HD IBU was not associated with any increase in adverse events. Except in support of HD IBU (high evidence quality), outcomes were associated with low/moderate evidence quality.

CONCLUSIONS: Including HD use, IBU is equivalent/superior to INDO, and inferior/equivalent to APAP. Oral IBU had higher efficacy than IV IBU, including compared to INDO and APAP. IBU had safety advantages over INDO. INDO and APAP had safety advantages over IV IBU. HD of IBU increases efficacy, but not toxicity.