Ibuprofen for the treatment of a patent ductus arteriosus in preterm and/or low birth weight infants.
BACKGROUND
A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gut. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective with fewer side effects.


OBJECTIVE
To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants.


METHODS
Randomized (or quasi-randomized) controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Controlled Trials Register (Issue 4, 2002), MEDLINE (1996 - January 2003), CINAHL (1982 - November 2002), EMBASE (1980 - January 2002), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - 2002). No language restrictions were applied.


METHODS
1) DESIGN: Randomized or quasi-randomized controlled trials 2) POPULATION: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 grams) with a clinically or echocardiographically diagnosed PDA 3) INTERVENTION: Administration of ibuprofen for the closure of PDA 4) OUTCOMES: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), CLD, sepsis, days on supplementary oxygen.


METHODS
At least two reviewers worked independently at each step of the review, then compared results and resolved differences. Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of followup. Weighted treatment effects, calculated using Revman 4.1, included typical relative risk (RR), typical risk difference (RD), number needed to treat (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests were performed to assess the appropriateness of pooling the data.


RESULTS
Eight studies including 509 patients were included. All studies compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. There was no statistically significant heterogeneity of treatment effect for any of the outcomes. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [RR 0.92 (95% CI 0.69, 1.22)]. There were no statistically significant differences in mortality, surgical duct ligation, duration of ventilator support, IVH, PVL, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed. For many of these outcomes the sample size was small and the estimates imprecise. The incidence of decreased urine output (< 1cc/kg/hr) was lower in the ibuprofen group as compared to the indomethacin group [NNT 9 (95% CI 5-14)]. This was the only statistically significant clinical finding favouring ibuprofen. Chronic lung disease defined as oxygen requirement at 28 days post-natally was statistically significantly more likely to occur in the ibuprofen group [RR 1.37 (95% CI 1.01, 1.86); NNH 7 (95% CI 3 - 100)]. No studies comparing ibuprofen versus placebo for the closure of PDA were identified.


CONCLUSIONS
We found no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA. Ibuprofen reduces the risk of oliguria. However, ibuprofen may increase the risk for chronic lung disease, and pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen. Based on currently available information ibuprofen does not appear to confer a net benefit over indomethacin for the treatment of a PDA. We conclude that indomethacin should remain the drug of choice for the treatment of a PDA. Future research may include a four arm trial where infants are randomized at birth, either to a prophylaxis arm starting at birth or to an arm in which treatment starts after a PDA is diagnosed by echocardiography within the first seven days of life. Within the prophylaxis and treatment arms, the infants would be randomized to either ibuprofen or indomethacin. The primary outcome should be intact survival (survival without handicap) at 18 months corrected age.
Ohlsson
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A
Paediatrics, Mount Sinai Hospital, 775A-600 University Avenue, Toronto, Ontario, Canada, M5G 1X5. aohlsson@mtsinai.on.ca
Walia
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R
Shah
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D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007052:Ibuprofen / Q000627:therapeutic use*; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D016032:Randomized Controlled Trials as Topic
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007052:Ibuprofen