| Background: Patent ductus arteriosus（PDA）is a common disease in premature infants.The incidence of PDA is inversely proportional to gestational age and birth weight.The clinical consequences of a PDA are related to the degree of left-to-right shunting through the ductus.Hemodynamically significant PDA（hs PDA）,due to the significant left-to-right shunt,is associated with pulmonary overcirculation and systemic hypoperfusion and thus may lead to adverse effects on premature infants,such as bronchopulmonary dysplasia,pulmonary hemorrhage,necrotizing enterocolitis,intraventricular hemorrhage,renal insufficiency.Indomethacin,ibuprofen and acetaminophen are commonly used for the treatment of PDA in premature infants,but there is currently no consensus on the best option of drug and specific administration dosage,route and course at home and abroad.In addition,in view of the spontaneous closure rate of PDA and potential side effects of drug therapy,expectant treatment has attracted much attention in recent years.However,the short-term and long-term outcomes of expectant treatment are still unclear.Compared with preterm infants with older gestational age,infants with gestational age ≤32 weeks and/or birth weight ≤1500 g have certain differences in the incidence of PDA,spontaneous closure rate and clinical comorbidities.To our knowledge,there is currently no systematic review about the management of PDA in this particular preterm group.Objective: To systematically evaluate the efficacy and safety of indomethacin,ibuprofen,acetaminophen and placebo in the treatment of hs PDA in preterm infants with gestational age ≤32 weeks and/or birth weight ≤1500g.Methods: Pub Med,Embase,and the Cochrane Library were searched from inception until December,2021 with languages limited to English.We performed a network meta-analysis using a frequentist framework to compare the efficacy and safety of indomethacin,ibuprofen,acetaminophen,placebo or no treatment for treatment of an hs PDA in preterm infants with a gestational age ≤32weeks and/or birth weight ≤1500 g.Review Manager5.4 and R software were used for statistical analyses.Results: We included 31 eligible RCTs involving a total of 3321 preterm infants with gestational age ≤32 weeks and/or birth weight ≤1500 g.Thirteen different variations of treatment modalities were included for meta-analysis,including standard course of indomethacin（both intravenous and oral administrations）,prolonged course of intravenous indomethacin,standard dose of ibuprofen（oral,rectal,intermittent intravenous,continuous intravenous）,high dose of intravenous ibuprofen,standard or prolong course of acetaminophen（both intravenous and oral administrations）,placebo or no treatment.A standard course of indomethacin was defined as 0.1 to 0.2mg/kg administered every 12 to 24 hours for a total of 3 doses,and a prolong course was 0.1 to 0.2mg/kg administered every 24 hours for 5-7days.A standard dose of ibuprofen was defined as 10 mg/kg followed by 5 mg/kg administered for a total of 3 doses,and a high dose of ibuprofen was defined as 20mg/kg followed by 10 mg/kg administered for a total of 3 doses.A standard course of acetaminophen was defined as 7.5 to15mg/kg administered every 6 hours for 2-3days,and a prolong course was 7.5 to15mg/kg administered every 6 hours for 5-7days.Basing on the results of our study,oral standard-dose ibuprofen was relatively effective and safe for preterm infants with a hs PDA.Results of the network meta-analysis showed that:（1）Compared with a standard course of intravenous indomethacin,a standard dose of oral ibuprofen was associated with a significantly higher odds of PDA closure（OR:3.80,95%CI:2.16,6.67）and lower odds of oliguria（OR:0.12,95%CI:0.03,0.51）;（2）A standard dose of intravenous ibuprofen was significantly less effective than a standard dose of oral ibuprofen for PDA closure（OR:0.27,95%CI:0.17,0.43）;（3）There was no significant difference in the odds of mortality,necrotizing enterocolitis,renal insufficiency,periventricular leukomalacia and intraventricular hemorrhage with use of a standard dose of oral ibuprofen compared with placebo or no treatment.Conclusion: For the treatment of hs PDA in preterm infants with a gestational age ≤32 weeks and/or a birth weight ≤1500 g: 1.A standard dose of oral ibuprofen is more effective than a standard course of intravenous indomethacin,and the incidence of oliguria is lower than that of indomethacin;2.Oral administration of standard-dose ibuprofen is more effective than intravenous administration;3.A standard dose of oral ibuprofen doesn’t significantly increase the risk of mortality,necrotizing enterocolitis,renal insufficiency,periventricular leukomalacia or intraventricular hemorrhage compared with placebo or no treatment. |
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