Arne Ohlsson1, Sachin S Shah. 1. Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, Ontario, Canada, M5G 1X5.
Abstract
BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention in the prevention of PDA in preterm infants. SEARCH STRATEGY: Randomized controlled trials of prophylactic ibuprofen were identified by searching in The Cochrane Library, MEDLINE, CINAHL, EMBASE and trials registries in December 2010. SELECTION CRITERIA: Randomized or quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm and/or low birth weight infants. DATA COLLECTION AND ANALYSIS: Outcomes data including presence of PDA on day three, need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, intraventricular haemorrhage (IVH), renal, pulmonary and gastrointestinal complications were extracted. Meta-analyses were performed and treatment estimates are reported as typical weighted mean difference, relative risk (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNT) or number needed to treat to harm (NNH) along with their 95% confidence intervals (CI). MAIN RESULTS: In this update, seven studies (n = 931) comparing prophylactic ibuprofen with placebo/no intervention are included. Ibuprofen decreased the incidence of PDA on day three [typical RR 0.36 (95% CI 0.29 to 0.46); typical RD -0.27 (95% CI -0.32 to -0.21); NNT 4 (95% CI 3 to 5)], decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical ligation. Results from two studies administering oral ibuprofen had similar results, but showed an increased risk of gastrointestinal bleeding (NNH 4, 95% CI 2 to 17). In the control group the spontaneous closure rate was 58% by day three. Ibuprofen negatively affects renal function. No significant differences in mortality, IVH, chronic lung disease were found. AUTHORS' CONCLUSIONS: Prophylactic use of ibuprofen decreased the incidence of PDA, decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical closure. In the control group, the PDA closed spontaneously by day three in 58% of the neonates. Prophylactic treatment exposes many infants to a drug that has concerning renal and gastrointestinal side effects without conferring any important short-term benefits and is not recommended. Until long-term follow-up results are published from the trials included in this updated review, no further trials of prophylactic ibuprofen are recommended.
BACKGROUND: Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has less effect on blood flow velocity to important organs. OBJECTIVES: To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention in the prevention of PDA in preterm infants. SEARCH STRATEGY: Randomized controlled trials of prophylactic ibuprofen were identified by searching in The Cochrane Library, MEDLINE, CINAHL, EMBASE and trials registries in December 2010. SELECTION CRITERIA: Randomized or quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm and/or low birth weight infants. DATA COLLECTION AND ANALYSIS: Outcomes data including presence of PDA on day three, need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, intraventricular haemorrhage (IVH), renal, pulmonary and gastrointestinal complications were extracted. Meta-analyses were performed and treatment estimates are reported as typical weighted mean difference, relative risk (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNT) or number needed to treat to harm (NNH) along with their 95% confidence intervals (CI). MAIN RESULTS: In this update, seven studies (n = 931) comparing prophylactic ibuprofen with placebo/no intervention are included. Ibuprofen decreased the incidence of PDA on day three [typical RR 0.36 (95% CI 0.29 to 0.46); typical RD -0.27 (95% CI -0.32 to -0.21); NNT 4 (95% CI 3 to 5)], decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical ligation. Results from two studies administering oral ibuprofen had similar results, but showed an increased risk of gastrointestinal bleeding (NNH 4, 95% CI 2 to 17). In the control group the spontaneous closure rate was 58% by day three. Ibuprofen negatively affects renal function. No significant differences in mortality, IVH, chronic lung disease were found. AUTHORS' CONCLUSIONS: Prophylactic use of ibuprofen decreased the incidence of PDA, decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical closure. In the control group, the PDA closed spontaneously by day three in 58% of the neonates. Prophylactic treatment exposes many infants to a drug that has concerning renal and gastrointestinal side effects without conferring any important short-term benefits and is not recommended. Until long-term follow-up results are published from the trials included in this updated review, no further trials of prophylactic ibuprofen are recommended.