S S Shah1, A Ohlsson. 1. Shared Program in Neonatal-Perinatal Medicine, Division of Neonatology, University of Toronto, 600, University Avenue, Room 775A, Toronto, Ontario, Canada, M5G 1X5. sshahdoc@hotmail.com
Abstract
BACKGROUND: A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and death. The standard treatment to close a PDA is indomethacin. Its use is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has been shown to be effective in closing a PDA without reducing blood flow velocity to the brain, gut or kidneys. OBJECTIVES: To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants. SEARCH STRATEGY: Randomized controlled trials comparing prophylactic ibuprofen use with placebo/no intervention/indomethacin were identified by searching the Cochrane Controlled Trial Register (The Cochrane Library, Issue 4, 2002), MEDLINE (1966-November 2002), CINAHL (1982-November 2002), EMBASE (1980-November 2002), reference lists of published trials and abstracts published in Pediatric Research (1990-2002). No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing use of ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) for the prevention of PDA in preterm and/or low birth weight infants. DATA COLLECTION AND ANALYSIS: Data regarding the clinical outcomes including presence of PDA on day three and day seven, need for surgical ligation, need for rescue treatment with cyclo-oxygenase inhibitors, IVH, mortality, renal and gastrointestinal complications were extracted. Meta-analyses were performed using RevMan 4.1 and treatment estimates were reported as weighted mean difference (WMD), typical relative risk (RR), typical risk difference (RD) and, if statistically significant, number needed to treat (NNT) or number needed to harm (NNH), along with their 95% confidence intervals (CI). MAIN RESULTS: Four trials (n = 623) were included in the review. There was a statistically significant decrease in the incidence of PDA on day three in the ibuprofen group [typical RR 0.36 (95% CI 0.26, 0.49); typical RD -0.29 (95% CI -0.37, -0.21); NNT 3 (95% CI 3, 5); 3 trials, n = 488]. There was a significant increase in the serum creatinine levels in the ibuprofen group [WMD 0.11 mg/dl (95% CI 0.06, 0.17); 2 trials, n = 438]. There were no statistically significant differences in mortality, grade 3 or 4 IVH, CLD at 28 days or 36 weeks, need for surgical closure of PDA, NEC, GI hemorrhage, time to reach full feeds and urine output. One trial (Gournay 2002) (n = 135) reported on three infants in the ibuprofen group who developed pulmonary hypertension responsive to nitric oxide treatment. REVIEWER'S CONCLUSIONS: Prophylactic use of ibuprofen reduces the incidence of PDA. However, further trials, which address potential adverse effects including pulmonary hypertension, are needed. Such trials should include long-term neurodevelopmental outcomes. Trials comparing the effectiveness of prophylactic use of indomethacin versus ibuprofen may be warranted with particular reference to IVH, need for surgical ligation and neurodevelopmental outcome.
BACKGROUND: A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants and increases the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD) and death. The standard treatment to close a PDA is indomethacin. Its use is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has been shown to be effective in closing a PDA without reducing blood flow velocity to the brain, gut or kidneys. OBJECTIVES: To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants. SEARCH STRATEGY: Randomized controlled trials comparing prophylactic ibuprofen use with placebo/no intervention/indomethacin were identified by searching the Cochrane Controlled Trial Register (The Cochrane Library, Issue 4, 2002), MEDLINE (1966-November 2002), CINAHL (1982-November 2002), EMBASE (1980-November 2002), reference lists of published trials and abstracts published in Pediatric Research (1990-2002). No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing use of ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) for the prevention of PDA in preterm and/or low birth weight infants. DATA COLLECTION AND ANALYSIS: Data regarding the clinical outcomes including presence of PDA on day three and day seven, need for surgical ligation, need for rescue treatment with cyclo-oxygenase inhibitors, IVH, mortality, renal and gastrointestinal complications were extracted. Meta-analyses were performed using RevMan 4.1 and treatment estimates were reported as weighted mean difference (WMD), typical relative risk (RR), typical risk difference (RD) and, if statistically significant, number needed to treat (NNT) or number needed to harm (NNH), along with their 95% confidence intervals (CI). MAIN RESULTS: Four trials (n = 623) were included in the review. There was a statistically significant decrease in the incidence of PDA on day three in the ibuprofen group [typical RR 0.36 (95% CI 0.26, 0.49); typical RD -0.29 (95% CI -0.37, -0.21); NNT 3 (95% CI 3, 5); 3 trials, n = 488]. There was a significant increase in the serum creatinine levels in the ibuprofen group [WMD 0.11 mg/dl (95% CI 0.06, 0.17); 2 trials, n = 438]. There were no statistically significant differences in mortality, grade 3 or 4 IVH, CLD at 28 days or 36 weeks, need for surgical closure of PDA, NEC, GI hemorrhage, time to reach full feeds and urine output. One trial (Gournay 2002) (n = 135) reported on three infants in the ibuprofen group who developed pulmonary hypertension responsive to nitric oxide treatment. REVIEWER'S CONCLUSIONS: Prophylactic use of ibuprofen reduces the incidence of PDA. However, further trials, which address potential adverse effects including pulmonary hypertension, are needed. Such trials should include long-term neurodevelopmental outcomes. Trials comparing the effectiveness of prophylactic use of indomethacin versus ibuprofen may be warranted with particular reference to IVH, need for surgical ligation and neurodevelopmental outcome.