Efficacy and Safety of Ibuprofen for Premature Infants with Patent Ductus Arteriosus: A Meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

 GUOMing ¹ ^# ,  WANGYa-nan ² ^# , XUJia-ke ³ , QINQian ³ , CHENKuang-yang ³ , SUXu ³ , FUWen-kang ³ , YANGJia-hui ³ ,  LIUDong-hai ¹

1. Department of Neonatology, Gansu Provincial Maternity and Child-care Hospital, Lanzhou 730000, China;
2. The Second Clinical Medical College of Lanzhou University, Lanzhou 73000, China;
3. The First Clinical Medical College of Lanzhou University, Lanzhou 73000, China;

Corresponding author：

LIUDong-hai, Email: anlanming-2009@163.com

Keywords：

Ibuprofen; Patent ductus arteriosus; Premature infants; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20160065

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Objective To systematically review the efficacy and safety of ibuprofen for premature infants with patent ductus arteriosus. Methods Databases including PubMed, Ovid-EMbase, The Cochrane Library (Issue 11, 2014), CNKI, WanFang Data and VIP were searched to collect randomized controlled trials (RCTs) and quasi-RCTs about ibuprofen for premature infants with patent ductus arteriosus from inception to December 2014. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was conducted by RevMan 5.3 software. Results A total of 37 RCTs, involving 2 370 patients were included. The results of meta-analysis showed that, compared with the placebo/blank group, ibuprofen could increase the closure rate of PDA (LBWI:RR=1.93, 95%CI 1.25 to 2.99，P=0.003; VLBW:RR=1.23, 95%CI 1.02 to 1.48, P=0.03; ELBWI:RR=2.86, 95%CI 1.51 to 5.41, P=0.001) and decrease the incidence of sepsis (VLBW:RR=0.21, 95%CI 0.07 to 0.64，P=0.006); Compared with the indometacin groups, ibuprofen could decrease the incidence of the increase of serum creatinine (LBWI:RR=0.11, 95%CI 0.04 to 0.37, P=0.000 2), NEC (LBWI, RR=0.52, 95%CI 0.29 to 0.95, P=0.03) and oliguria (LBWI: RR=0.30, 95%CI 0.16 to 0.56, P=0.000 2; VLBW:RR=1.40, 95%CI 1.03 to 1.92, P=0.03); Compared with the intravenous ibuprofen, Oral ibuprofen could increase the closure rate of PDA (VLBW: RR=1.35, 95%CI 1.12 to 1.62, P=0.002; ELBWI, RR=1.42, 95%CI 1.07 to 1.87, P=0.01). Conclusion Current evidence shows that there is not indeterminate between ibuprofen and paracetamol groups. Compared with other general drugs, ibuprofen has an advantage over curing PDA and obviously reduces side effects. Due to the limited quality and quantity of included studies, more high quality studies are needed to verify the above conclusion.

Citation： GUOMing, WANGYa-nan, XUJia-ke, QINQian, CHENKuang-yang, SUXu, FUWen-kang, YANGJia-hui, LIUDong-hai. Efficacy and Safety of Ibuprofen for Premature Infants with Patent Ductus Arteriosus: A Meta-analysis. Chinese Journal of Evidence-Based Medicine, 2016, 16(4): 415-426. doi: 10.7507/1672-2531.20160065 Copy

1.	Fanos V, Pusceddu M, Dessı` A, Marcialis MA. Should we definitively abandon prophylaxis for patent ductus arteriosus in preterm new-borns? Clinics, 2011, 66(12):2141-2149.
2.	Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics, 2010, 125(5):1020-1030.
3.	Sekar KC. Protective strategies to prevent patent ductus arteriosus. Chin Med J(Eng), 2010, 123(20):2914-2918.
4.	Friedman WF, Hirschklau MJ, Printz MP, et al. Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med, 1975, 295(10):526-529.
5.	Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Eng J Med, 1976, 295(10):530-533.
6.	Overmeirea BV, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Seminars infetal Neonata Medicine, 2005, 10(2):177-184.
7.	Itabashi K, Ohno T, Nishida H. Indomethacin responsiveness of patentnducus arteriosus and renal abnormalities in preterm infants treated with indomethacin. J Pediatr, 2003, 143(2):203-207.
8.	Shaffer CL, Gal P, Ronsom JL, et al. Effect of age birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Crit Care Med, 2002, 30(2):343-348.
9.	Hammerman C, Binnun A, Markovitch E, et al. Ductal closure with paracrtamol:A surprising new approach to patent ductus arteriosus treatment. Pediatrics, 2011, 128:e1618-e162.
10.	Overmerre BV, Follens I, Hartmann S, et al. Treatment of patent ductus arteriosus with ibprofen. Arch Dis Child, 1997, 76(3):179-184.
11.	张聪聪, 程国强. 早产儿动脉导管未闭治疗的进展. 中华儿科杂志, 2012, 50(11):871-873.
12.	Higgins JPT, Altman DG, Sterne JAC, et al. Chapter 8:Assessing risk of bias in included studies//Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011[OL]. Available at:www.cochrane-handbook.org.
13.	Gokmen T, Erdeve O, Altug N, et al. Efficacy and Safety of Oral Versus Intravenous Ibuprofen in Very Low Birth Weight Preterm Infants with Patent Ductus Arteriosus. The Gournal Of Pediatrics, 2011, 158:549-554.
14.	Pistull E, Qosja A H, Shtiza D, et al. Renal effects of ibuprofen during the treatment of patent ductus arteriosus in low birth weight premature infants. Open Science Journal of Clinical Medicine, 2014, 2(6):123-128.
15.	Cherif A, Khrouf N, Jabnoun S, et al. Randomized Pilot Study Comparing Oral Ibuprofen With Intravenous Ibuprofen in Very Low Birth Weight Infants With Patent Ductus Arteriosus. Pediatrics, 2008, 122:1256-1261.
16.	Erdeve O, Yurttutan S, Altug N, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure:a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed, 2012, 97(4):279-283.
17.	Jacob V. Aranda, Ronald Clyman, Blair Cox, et al. A Randomized, Double-Blind, Placebo-Controlled Trial on Intravenous Ibuprofen L-Lysine for the Early Closure of Nonsymptomatic Patent Ductus Arteriosus within 72 Hours of Birth in Extremely Low-Birth-Weight Infants. Am J Perinatol, 2009, 26(3):235-245.
18.	Sangtawesin C, Sangtawesin V, Lertsutthiwong W, et al. Prophylaxis of Symptomatic Patent Ductus Arteriosuswith Oral Ibuprofen in Very Low Birth Weight Infants. J Med Assoc Thai, 2008, 91 (Suppl 3):S28-34.
19.	Sangtawesin V, Sangtawesin C, Raksasinborisut C, et al. Oral Ibuprofen Prophylaxis for Symptomatic Patent Ductus Arteriosus of Prematurity. J Med Assoc Thai, 2006, 89(3):314-321.
20.	党丹. 对乙酰氨基酚与布洛芬治疗早产儿PDA的随机对照试验. 长春:吉林大学. 2013.
21.	Oncel MY, Yurttutan S, Erdeve O, et al. Oral Paracetamol versus Oral Ibuprofen in the Management of Patent Ductus Arteriosus in Preterm Infants. J Pediatr, 2014, 164(3):510-514.
22.	龚长富, 叶慧宁, 冯立文. 口服美林对早产儿动脉导管未闭的疗效观察. 小儿急救医学, 2004, 11(5):317-319.
23.	何莉, 王洁婷, 陆长东, 等. 口服布洛芬和消炎痛关闭早产儿动脉导管未闭的疗效和安全性的比较. 中国妇幼保健, 2005, 20(6):752-754.
24.	姜红, 吴莉华, 葛觉敏. 口服布洛芬治疗早产儿动脉导管未闭的疗效及安全性. 中国医学创新, 2009, 6(23):109-110.
25.	雷立容, 丘惠娴. 布洛芬治疗极低出生体重早产儿动脉导管未闭的疗效观察. 海南医学. 2013, 24(2):202-204.
26.	宋萃春, 张军. 布洛芬对关闭早产儿动脉导管疗效分析. 中外健康文摘, 2014, (14):167-167.
27.	杨春, 张春秀, 徐桂林. 口服布洛芬混悬剂治疗早产儿动脉导管未闭的疗效观察, 2006, 22(15):1811-1812.
28.	张磊, 唐建平. 布洛芬混悬液治疗新生儿动脉导管未闭的临床疗效分析. 现代诊断与治疗, 2013, 24(9):2014-2015.
29.	Fakhraee S H, Badiee Z, MojtahedzadehS, et al. Comparison of oral ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Zhongguo Dang Dai Er Ke Za Zhi, 2007, 9(5):399-403.
30.	Hammerman C, Shchors I, Jacobson S, et al. Ibuprofen Versus Continuous Indomethacin in Premature Neonates With Patent Ductus Arteriosus:Is the Difference in the Mode of Administration? Pediatr Res, 2008, 64(3):291-298.
31.	Yadav S, AgarwalS, Maria A, et al. Comparison of Oral Ibuprofen with Oral Indomethacin for PDA Closure in Indian Preterm Neonates:A Randomized Controlled Trial. Pediatr Cardiol, 2014, 35(5):824-830.
32.	Aly H, Lotfy W, Badrawi N, et al. Oral Ibuprofen and Ductus Arteriosus in Premature Infants:A Randomized Pilot Study. Am J Perinatol, 2007, 24(5):267-270.
33.	Adamska E, Helwich E, Rutkowska M, et al. Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants. Med Wieku Rozwoj, 2005, 9(3 Pt 1):335-354.
34.	Akisu M, Ruhi Ozyurek A, Dorak C, et al. Ballard and new ballard scoring systems in the assessment of gestational age in preterm infants. Cocuk Sagligi ve Hastaliklari Dergisi, 2001, 44(1):56-60.
35.	Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. J Med Assoc Thai, 2003, 86(Suppl 3):563-569.
36.	Salama H, Alsisi A, Al-Rifai, H, et al. A randomized controlled trial on the use of oral ibuprofen to close patent ductus arteriosus in premature infants. J Neonatal Perinatal Med, 2008, 153-158.
37.	敖桢桢, 王静. 早产儿动脉导管未闭的临床观察. 现代医院, 2012, 12(2):51-52.
38.	Overmeire B, Follens I, Hartmann S, et al. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed, 1997, 76(3):179-184.
39.	Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med, 2000, 343(10), 674-681.
40.	Lago P, Bettiol T, Salvador Si, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus:a randomised controlled trial. Eur J Pediatr, 2002, 161(4):202-207.
41.	俞建德, 来庆和, 邵波, 等. 布洛芬口服治疗新生儿呼吸窘迫综合症合并动脉导管未闭临床观察. 儿科药学杂志, 2005, 11(5):25-26.
42.	Pen-Hua Su, Jia-Yuh Chen, Chi-Ming Su, et al. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatr Int, 2003, 45(6):665-670.
43.	方文君. 布洛芬早期干预极低出生体重早产儿动脉导管未闭的研究. 福建医科大学, 2005.
44.	范小静. 观察口服布洛芬治疗早产儿动脉导管未闭的疗效. 求医问药, 2013, 11(4):286.
45.	陈芳芳, 陈艳林, 陈月华. 口服布洛芬早期干预早产儿肺动脉导管未闭的疗效观察. 心理医生, 2012,(7):296-297.
46.	胡颖宇, 林泳, 林治. 口服布洛芬治疗早产儿PDA的临床观察. 新余高专学报, 2009, 14(6):94.
47.	逯艳梅, 曹甦. 布洛芬混悬液治疗新生儿动脉导管未闭疗效观察. 中国误诊学杂志, 2010, 10(28):6849-6849.
48.	杨传忠, 杨晓东, 等. 口服布洛芬治疗早产儿动脉导管未闭的前瞻性随机对照研究. 中华围产医学杂志, 2010, 6(14):328-332.
49.	De Carolis MP, Romagnoli C, Polimeni V, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr, 2000, 159(5):364-368.
50.	Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev, 2011, 7:CD004213.
51.	徐春光, 肖昕, 熊爱华, 等. 布洛芬与吲哚美辛治疗早产儿动脉导管未闭对照研究的Meta分析. 实用儿科临床杂志, 2004, 19(6):489-491.
52.	杨琼芳. 布洛芬及吲哚美辛治疗婴儿动脉导管未闭的Meta分析. 重庆医学, 2014, 43(24):3176-3179.

1. Fanos V, Pusceddu M, Dessı` A, Marcialis MA. Should we definitively abandon prophylaxis for patent ductus arteriosus in preterm new-borns? Clinics, 2011, 66(12):2141-2149.
2. Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics, 2010, 125(5):1020-1030.
3. Sekar KC. Protective strategies to prevent patent ductus arteriosus. Chin Med J(Eng), 2010, 123(20):2914-2918.
4. Friedman WF, Hirschklau MJ, Printz MP, et al. Pharmacologic closure of patent ductus arteriosus in the premature infant. N Engl J Med, 1975, 295(10):526-529.
5. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Eng J Med, 1976, 295(10):530-533.
6. Overmeirea BV, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Seminars infetal Neonata Medicine, 2005, 10(2):177-184.
7. Itabashi K, Ohno T, Nishida H. Indomethacin responsiveness of patentnducus arteriosus and renal abnormalities in preterm infants treated with indomethacin. J Pediatr, 2003, 143(2):203-207.
8. Shaffer CL, Gal P, Ronsom JL, et al. Effect of age birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Crit Care Med, 2002, 30(2):343-348.
9. Hammerman C, Binnun A, Markovitch E, et al. Ductal closure with paracrtamol:A surprising new approach to patent ductus arteriosus treatment. Pediatrics, 2011, 128:e1618-e162.
10. Overmerre BV, Follens I, Hartmann S, et al. Treatment of patent ductus arteriosus with ibprofen. Arch Dis Child, 1997, 76(3):179-184.
11. 张聪聪, 程国强. 早产儿动脉导管未闭治疗的进展. 中华儿科杂志, 2012, 50(11):871-873.
12. Higgins JPT, Altman DG, Sterne JAC, et al. Chapter 8:Assessing risk of bias in included studies//Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011[OL]. Available at:www.cochrane-handbook.org.
13. Gokmen T, Erdeve O, Altug N, et al. Efficacy and Safety of Oral Versus Intravenous Ibuprofen in Very Low Birth Weight Preterm Infants with Patent Ductus Arteriosus. The Gournal Of Pediatrics, 2011, 158:549-554.
14. Pistull E, Qosja A H, Shtiza D, et al. Renal effects of ibuprofen during the treatment of patent ductus arteriosus in low birth weight premature infants. Open Science Journal of Clinical Medicine, 2014, 2(6):123-128.
15. Cherif A, Khrouf N, Jabnoun S, et al. Randomized Pilot Study Comparing Oral Ibuprofen With Intravenous Ibuprofen in Very Low Birth Weight Infants With Patent Ductus Arteriosus. Pediatrics, 2008, 122:1256-1261.
16. Erdeve O, Yurttutan S, Altug N, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure:a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed, 2012, 97(4):279-283.
17. Jacob V. Aranda, Ronald Clyman, Blair Cox, et al. A Randomized, Double-Blind, Placebo-Controlled Trial on Intravenous Ibuprofen L-Lysine for the Early Closure of Nonsymptomatic Patent Ductus Arteriosus within 72 Hours of Birth in Extremely Low-Birth-Weight Infants. Am J Perinatol, 2009, 26(3):235-245.
18. Sangtawesin C, Sangtawesin V, Lertsutthiwong W, et al. Prophylaxis of Symptomatic Patent Ductus Arteriosuswith Oral Ibuprofen in Very Low Birth Weight Infants. J Med Assoc Thai, 2008, 91 (Suppl 3):S28-34.
19. Sangtawesin V, Sangtawesin C, Raksasinborisut C, et al. Oral Ibuprofen Prophylaxis for Symptomatic Patent Ductus Arteriosus of Prematurity. J Med Assoc Thai, 2006, 89(3):314-321.
20. 党丹. 对乙酰氨基酚与布洛芬治疗早产儿PDA的随机对照试验. 长春:吉林大学. 2013.
21. Oncel MY, Yurttutan S, Erdeve O, et al. Oral Paracetamol versus Oral Ibuprofen in the Management of Patent Ductus Arteriosus in Preterm Infants. J Pediatr, 2014, 164(3):510-514.
22. 龚长富, 叶慧宁, 冯立文. 口服美林对早产儿动脉导管未闭的疗效观察. 小儿急救医学, 2004, 11(5):317-319.
23. 何莉, 王洁婷, 陆长东, 等. 口服布洛芬和消炎痛关闭早产儿动脉导管未闭的疗效和安全性的比较. 中国妇幼保健, 2005, 20(6):752-754.
24. 姜红, 吴莉华, 葛觉敏. 口服布洛芬治疗早产儿动脉导管未闭的疗效及安全性. 中国医学创新, 2009, 6(23):109-110.
25. 雷立容, 丘惠娴. 布洛芬治疗极低出生体重早产儿动脉导管未闭的疗效观察. 海南医学. 2013, 24(2):202-204.
26. 宋萃春, 张军. 布洛芬对关闭早产儿动脉导管疗效分析. 中外健康文摘, 2014, (14):167-167.
27. 杨春, 张春秀, 徐桂林. 口服布洛芬混悬剂治疗早产儿动脉导管未闭的疗效观察, 2006, 22(15):1811-1812.
28. 张磊, 唐建平. 布洛芬混悬液治疗新生儿动脉导管未闭的临床疗效分析. 现代诊断与治疗, 2013, 24(9):2014-2015.
29. Fakhraee S H, Badiee Z, MojtahedzadehS, et al. Comparison of oral ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Zhongguo Dang Dai Er Ke Za Zhi, 2007, 9(5):399-403.
30. Hammerman C, Shchors I, Jacobson S, et al. Ibuprofen Versus Continuous Indomethacin in Premature Neonates With Patent Ductus Arteriosus:Is the Difference in the Mode of Administration? Pediatr Res, 2008, 64(3):291-298.
31. Yadav S, AgarwalS, Maria A, et al. Comparison of Oral Ibuprofen with Oral Indomethacin for PDA Closure in Indian Preterm Neonates:A Randomized Controlled Trial. Pediatr Cardiol, 2014, 35(5):824-830.
32. Aly H, Lotfy W, Badrawi N, et al. Oral Ibuprofen and Ductus Arteriosus in Premature Infants:A Randomized Pilot Study. Am J Perinatol, 2007, 24(5):267-270.
33. Adamska E, Helwich E, Rutkowska M, et al. Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants. Med Wieku Rozwoj, 2005, 9(3 Pt 1):335-354.
34. Akisu M, Ruhi Ozyurek A, Dorak C, et al. Ballard and new ballard scoring systems in the assessment of gestational age in preterm infants. Cocuk Sagligi ve Hastaliklari Dergisi, 2001, 44(1):56-60.
35. Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. J Med Assoc Thai, 2003, 86(Suppl 3):563-569.
36. Salama H, Alsisi A, Al-Rifai, H, et al. A randomized controlled trial on the use of oral ibuprofen to close patent ductus arteriosus in premature infants. J Neonatal Perinatal Med, 2008, 153-158.
37. 敖桢桢, 王静. 早产儿动脉导管未闭的临床观察. 现代医院, 2012, 12(2):51-52.
38. Overmeire B, Follens I, Hartmann S, et al. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed, 1997, 76(3):179-184.
39. Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med, 2000, 343(10), 674-681.
40. Lago P, Bettiol T, Salvador Si, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus:a randomised controlled trial. Eur J Pediatr, 2002, 161(4):202-207.
41. 俞建德, 来庆和, 邵波, 等. 布洛芬口服治疗新生儿呼吸窘迫综合症合并动脉导管未闭临床观察. 儿科药学杂志, 2005, 11(5):25-26.
42. Pen-Hua Su, Jia-Yuh Chen, Chi-Ming Su, et al. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatr Int, 2003, 45(6):665-670.
43. 方文君. 布洛芬早期干预极低出生体重早产儿动脉导管未闭的研究. 福建医科大学, 2005.
44. 范小静. 观察口服布洛芬治疗早产儿动脉导管未闭的疗效. 求医问药, 2013, 11(4):286.
45. 陈芳芳, 陈艳林, 陈月华. 口服布洛芬早期干预早产儿肺动脉导管未闭的疗效观察. 心理医生, 2012,(7):296-297.
46. 胡颖宇, 林泳, 林治. 口服布洛芬治疗早产儿PDA的临床观察. 新余高专学报, 2009, 14(6):94.
47. 逯艳梅, 曹甦. 布洛芬混悬液治疗新生儿动脉导管未闭疗效观察. 中国误诊学杂志, 2010, 10(28):6849-6849.
48. 杨传忠, 杨晓东, 等. 口服布洛芬治疗早产儿动脉导管未闭的前瞻性随机对照研究. 中华围产医学杂志, 2010, 6(14):328-332.
49. De Carolis MP, Romagnoli C, Polimeni V, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr, 2000, 159(5):364-368.
50. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev, 2011, 7:CD004213.
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Chinese Journal of Evidence-Based Medicine

Efficacy and Safety of Ibuprofen for Premature Infants with Patent Ductus Arteriosus: A Meta-analysis

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