Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2021 Jan 15;1(1):CD013133.
doi: 10.1002/14651858.CD013133.pub2.

Indomethacin for symptomatic patent ductus arteriosus in preterm infants

Peter Evans  1 , Deirdre O'Reilly  2 , Jonathan N Flyer  3 , Roger Soll  2 , Souvik Mitra  4
Affiliations
Meta-Analysis

Indomethacin for symptomatic patent ductus arteriosus in preterm infants

Peter Evans et al. Cochrane Database Syst Rev. .

Abstract

Background: Symptomatic patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. In these infants, prophylactic use of indomethacin, a non-selective cyclooxygenase inhibitor, has demonstrated short-term clinical benefits. The effect of indomethacin in preterm infants with a symptomatic PDA remains unexplored.

Objectives: To determine the effectiveness and safety of indomethacin (given by any route) compared to placebo or no treatment in reducing mortality and morbidity in preterm infants with a symptomatic PDA.

Search methods: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 7), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and Cumulative Index to Nursing and Allied Health Literature (CINAHL), on 31 July 2020. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs.

Selection criteria: We included RCTs and quasi-RCTs that compared indomethacin (any dose, any route) versus placebo or no treatment in preterm infants.

Data collection and analysis: We used the standard methods of Cochrane Neonatal, with separate evaluation of trial quality and data extraction by at least two review authors. We used the GRADE approach to assess the certainty of evidence for the following outcomes: failure of PDA closure within one week of administration of the first dose of indomethacin; bronchopulmonary dysplasia (BPD) at 28 days' postnatal age and at 36 weeks' postmenstrual age; proportion of infants requiring surgical ligation or transcatheter occlusion; all-cause neonatal mortality; necrotizing enterocolitis (NEC) (≥ Bell stage 2); and mucocutaneous or gastrointestinal bleeding.

Main results: We included 14 RCTs (880 preterm infants). Four out of the 14 included studies were judged to have high risk of bias in one or more domains. Indomethacin administration was associated with a large reduction in failure of PDA closure within one week of administration of the first dose (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.23 to 0.38; risk difference (RD) -0.52, 95% CI -0.58 to -0.45; 10 studies, 654 infants; high-certainty evidence). There may be little to no difference in the incidence of BPD (BPD defined as supplemental oxygen need at 28 days' postnatal age: RR 1.45, 95% CI 0.60 to 3.51; 1 study, 55 infants; low-certainty evidence; BPD defined as supplemental oxygen need at 36 weeks' postmenstrual age: RR 0.80, 95% CI 0.41 to 1.55; 1 study, 92 infants; low-certainty evidence) and probably little to no difference in mortality (RR 0.78, 95% CI 0.46 to 1.33; 8 studies, 314 infants; moderate-certainty evidence) with use of indomethacin for symptomatic PDA. No differences were demonstrated in the need for surgical PDA ligation (RR 0.66, 95% CI 0.33 to 1.29; 7 studies, 275 infants; moderate-certainty evidence), in NEC (RR 1.27, 95% CI 0.36 to 4.55; 2 studies, 147 infants; low-certainty evidence), or in mucocutaneous or gastrointestinal bleeding (RR 0.33, 95% CI 0.01 to 7.58; 2 studies, 119 infants; low-certainty evidence) with use of indomethacin compared to placebo or no treatment. Certainty of evidence for BPD, surgical PDA ligation, NEC, and mucocutaneous or gastrointestinal bleeding was downgraded for very serious or serious imprecision.

Authors' conclusions: High-certainty evidence shows that indomethacin is effective in closing a symptomatic PDA compared to placebo or no treatment in preterm infants. Evidence is insufficient regarding effects of indomethacin on other clinically relevant outcomes and medication-related adverse effects.

PubMed Disclaimer

Conflict of interest statement

PE is a Pediatric Resident at the Children's Hospital of Philadelphia. As a pediatric resident, he participated in the care of patients with PDA on his neonatology rotations.

DO has no interest to declare.

JNF is a Paediatric Cardiologist at the University of Vermont Medical Center.

RS is a Professor of Neonatology at the University of Vermont Medical Center. He needs to make the decisions detailed in the review on a daily basis.

SM is a neonatologist at a tertiary care neonatal intensive care unit in Halifax, Nova Scotia, Canada, where he attends to preterm infants diagnosed with a PDA. He has published review articles on PDA management in preterm infants.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Indomethacin vs placebo or control, outcome: 1.1 Failure of PDA closure within 1 week of administration of the first dose of indomethacin.
1.1
1.1. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 1: Failure of PDA closure within 1 week of administration of the first dose of indomethacin
1.2
1.2. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 2: Bronchopulmonary dysplasia at 28 days
1.3
1.3. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 3: Bronchopulmonary dysplasia at 36 weeks' gestation
1.4
1.4. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 4: All‐cause neonatal mortality before hospital discharge
1.5
1.5. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 5: Proportion of infants receiving rescue medical treatment
1.6
1.6. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 6: Proportion of infants requiring surgical ligation of PDA
1.7
1.7. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 7: Pulmonary hemorrhage
1.8
1.8. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 8: Late‐onset bacterial sepsis
1.9
1.9. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 9: NEC (≥ Bell stage 2)
1.10
1.10. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 10: IVH (any grade)
1.11
1.11. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 11: Severe IVH (grade III to IV)
1.12
1.12. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 12: Periventricular leukomalacia
1.13
1.13. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 13: Retinopathy of prematurity (any stage)
1.14
1.14. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 14: Severe retinopathy of prematurity (≥ stage III)
1.15
1.15. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 15: Surgery for severe retinopathy of prematurity*
1.16
1.16. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 16: Infant mortality (first year of life)
1.17
1.17. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 17: Use of inotropic agents
1.18
1.18. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 18: Duration of assisted ventilation (days)
1.19
1.19. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 19: Duration of hospital stay (days)
1.20
1.20. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 20: Intestinal perforation
1.21
1.21. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 21: Creatinine > 150 micromole during treatment
1.22
1.22. Analysis
Comparison 1: Indomethacin vs placebo or control, Outcome 22: Mucocutaneous or gastrointestinal bleeding
2.1
2.1. Analysis
Comparison 2: Indomethacin vs placebo or control (sensitivity analysis), Outcome 1: Failure of PDA closure within 1 week of administration of the first dose of indomethacin
2.2
2.2. Analysis
Comparison 2: Indomethacin vs placebo or control (sensitivity analysis), Outcome 2: Bronchopulmonary dysplasia at 28 days
2.3
2.3. Analysis
Comparison 2: Indomethacin vs placebo or control (sensitivity analysis), Outcome 3: Bronchopulmonary dysplasia at 36 weeks' gestation
2.4
2.4. Analysis
Comparison 2: Indomethacin vs placebo or control (sensitivity analysis), Outcome 4: All‐cause neonatal mortality before hospital discharge
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013133

References

References to studies included in this review

Cotton 1980 {published data only}
    1. Cotton RB, Hickey DE, Graham TP, Stahlman MT. Effect of early indomethacin (I) on ventilatory status of preterm infants with symptomatic patent ductus arteriosus (sPDA). Pediatric Research 1980;14:442.
Gersony 1983 {published data only}
    1. Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. Journal of Pediatrics 1983;102(6):895-906. [DOI: 10.1016/s0022-3476(83)80022-5] [PMID: ] - DOI - PubMed
    1. Peckham GJ, Miettinen OS, Ellison RC, Kraybill EN, Gersony WM, Zierler S, et al. Clinical course to 1 year of age in premature infants with patent ductus arteriosus: results of a multicenter randomized trial of indomethacin. Journal of Pediatrics 1984;105(2):285-91. [DOI: 10.1016/s0022-3476(84)80134-1] [PMID: ] - DOI - PubMed
Kluckow 2014 {published data only}
    1. Kluckow M, Evans N, Gill A, Jeffery M. Ductal echocardiographic targeting and early closure trial (DETECT): a pilot randomised controlled trial. In: Journal of Paediatrics and Child Health. Vol. 48. 2012:43-4.
    1. Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Archives of Disease in Childhood: Fetal & Neonatal Edition 2014;99(2):F99–F104. [DOI: 10.1136/archdischild-2013-304695] [PMID: ] - DOI - PubMed
    1. Varghese J, Gill A, McMichael J, Evans NJ, Rieger I, Bowen J, et al. Follow up at 2 years of an early ductal targeted treatment (DETECT) trial. Journal of Paediatrics and Child Health 2016;52(Suppl 2):102.
Knight 2011 {published data only}
    1. Knight D, Alkindi S, Buksh M, Kuschel C, Skinner J. Placebo-controlled pilot trial of indomethacin in preterm infants with a patent ductus arteriosus. Journal of Paediatrics and Child Health 2011;47:88.
Krauss 1989 {published data only}
    1. Krauss AN, Fatica N, Lewis BS, Cooper R, Thaler HT, Cirrincione C, et al. Pulmonary function in preterm infants following treatment with intravenous indomethacin. American Journal of Diseases of Children 1989;143(1):78–81. [DOI: 10.1001/archpedi.1989.02150130088021] [PMID: ] - DOI - PubMed
Merritt 1981 {published data only}
    1. Merritt TA, Harris JP, Roghmann K, Wood B, Campanella V, Alexson C, et al. Early closure of the patent ductus arteriosus in very low-birth-weight infants: a controlled trial. Journal of Pediatrics 1981;99(2):281-6. [DOI: 10.1016/s0022-3476(81)80479-9] [PMID: ] - DOI - PubMed
Monset‐Couchard 1983 {published data only}
    1. Monset-Couchard M, Dias-Mançano D, Murat I, Relier JP. [Controlled trial of intravenous lyophilized indomethacin in the treatment of persistent ductus arteriosus in premature infants]. Pediatrie 1983;38(6):365-77. [PMID: ] - PubMed
Nestrud 1980 {published data only}
    1. Nestrud RM, Hill DE, Arrington RW, Beard AG, Dungan WT, Lau PY, et al. Indomethacin treatment in patent ductus arteriosus. A double-blind study utilizing indomethacin plasma levels. Developmental Pharmacology and Therapeutics 1980;1(2-3):125-36. [PMID: ] - PubMed
Neu 1981 {published data only}
    1. Neu J, Ariagno RL, Johnson JD, Pitlick PT, Cohen RS, Beets CL, et al. A double blind study of the effects of oral indomethacin in preterm infants with patent ductus arteriosus who failed medical management. Pediatric Pharmacology (New York) 1981;1(3):245-9. [PMID: ] - PubMed
Osborn 2003 {published data only}
    1. Osborn DA, Evans N, Kluckow M. Effect of early targeted indomethacin on the ductus arteriosus and blood flow to the upper body and brain in the preterm infant. Archives of Disease in Childhood: Fetal & Neonatal Edition 2003;88(6):F477-82. [DOI: 10.1136/fn.88.6.f477] [PMID: ] - DOI - PMC - PubMed
Rudd 1983 {published data only}
    1. Rudd P, Montanez P, Hallidie-Smith K, Silverman M. Indomethacin treatment for patent ductus arteriosus in very low birthweight infants: double blind trial. Archives of Disease in Childhood 1983;58(4):267-70. [DOI: 10.1136/adc.58.4.267] [PMID: ] - DOI - PMC - PubMed
Valaes 1980 {published data only}
    1. Valaes T, Moylan FM, Cohn H, Chung K, Nagpaul K, Chrenoff HL, et al. Incidence and significance of PDA in preterm infants (PTI) and controlled blind trial of indomethacin (IND). Pediatric Research 1980;14:452.
Yanagi 1981 {published data only}
    1. Yanagi RM, Wilson A, Newfeld EA, Aziz KU, Hunt CE. Indomethacin treatment for symptomatic patent ductus arteriosus: a double-blind control study. Pediatrics 1981;67(5):647-52. [PMID: ] - PubMed
Yeh 1981a {published data only}
    1. Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS. Indomethacin and its effect on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus. Pediatrics 1981;68(1):99-102. [PMID: ] - PubMed
    1. Yeh TF, Goldbarg HR, Henek T, Thalji A, Pildes RS. Intravenous indomethacin therapy in premature infants with patent ductus arteriosus. Causes of death and one year follow‐up. American Journal of Diseases of Children 1982;136(9):803‐7. [DOI: 10.1001/archpedi.1982.03970450045012] [PMID: ] - DOI - PubMed
    1. Yeh TF, Luken JA, Thalji A, Raval D, Carr I, Pildes RS. Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus ‐ a double blind controlled study. Journal of Pediatrics 1981;98(1):137-45. [DOI: 10.1016/s0022-3476(81)80560-4] [PMID: ] - DOI - PubMed
    1. Yeh TF, Raval D, Lilien LD, Srinivasan G, Pildes RS. Decreased plasma glucose following indomethacin therapy in premature infants with patent ductus arteriosus. Pediatric Pharmacology (New York) 1982;2(3):171-7. [PMID: ] - PubMed
    1. Yeh TF, Raval D, Pyati S, Pildes RS. Retinopathy of prematurity (ROP) and indomethacin therapy in premature infants with patent ductus arteriosus (PDA). Prostaglandins 1983;25(3):385-91. [DOI: 10.1016/0090-6980(83)90041-2] [PMID: ] - DOI - PubMed

References to studies excluded from this review

Carmo 2009 {published data only}
    1. Carmo K, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. Journal of Pediatrics 2009;155(6):819-22. [DOI: 10.1016/j.jpeds.2009.06.013] [PMID: ] - DOI - PubMed
Mardoum 1991 {published data only}
    1. Mardoum R, Bejar R, Merritt T, Berry C. Controlled study of the effects of indomethacin on cerebral blood flow velocities in newborn infants. Journal of Paediatrics 1991;118(1):112-5. [DOI: 10.1016/s0022-3476(05)81860-8] [PMID: ] - DOI - PubMed
Mullett 1982 {published data only}
    1. Mullett M, Croghan T, Myerberg D, Krall J, Neal W. Indomethacin for closure of patent ductus arteriosus in prematures. Clinical Pediatrics 1982;21(4):217-20. [DOI: 10.1177/000992288202100404] [PMID: ] - DOI - PubMed
Nair 1986 {published data only}
    1. Nair P, Karan S. Indomethacin for closure of patent ductus arteriosous in preterm neonates. Indian Journal of Pediatrics 1986;53(4):499-503. [DOI: 10.1007/BF02749534] [PMID: ] - DOI - PubMed
Nuntnarumit 2011 {published data only}
    1. Nuntnarumit P, Chongkongkiat P, Khositseth A. N-terminal-pro-brain natriuretic peptide: a guide for early targeted indomethacin therapy for patent ductus arteriosus in preterm infants. Acta Pædiatrica 2011;100(9):1217-21. [DOI: 10.1111/j.1651-2227.2011.02304.x] [PMID: ] - DOI - PubMed
Yeh 1982a {published data only}
    1. Yeh TF, Wilks A, Singh J, Betkerur M, Lilien L, Pildes RS. Furosemide prevents the renal side effects of indomethacin therapy in premature infants with patent ductus arteriosus. Journal of Pediatrics 1982;101(3):433-7. [DOI: 10.1016/s0022-3476(82)80079-6] [PMID: ] - DOI - PubMed

References to studies awaiting assessment

Clyman 2019 {published and unpublished data}
    1. Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Håkansson S, et al, PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE trial: an exploratory randomized controlled trial of treatment of moderate-to-large patent ductus arteriosus at 1 week of age. Journal of Pediatrics 2019;205:41-8.e6. [DOI: 10.1016/j.jpeds.2018.09.012] [PMID: ] - DOI - PMC - PubMed

References to ongoing studies

NCT03456336 {published data only}
    1. NCT03456336. Management of the PDA Trial (PDA) [Management of the patent ductus arteriosus in premature infants trial (PDA Trial)]. clinicaltrials.gov/ct2/show/NCT03456336 (first received 7 March 2018).

Additional references

Ballabh 2010
    1. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatric Research 2010;67(1):1-8. [DOI: 10.1203/PDR.0b013e3181c1b176] [PMID: ] - DOI - PMC - PubMed
Bancalari 1979
    1. Bancalari E, Abdenour GE, Feller R, Gannon J. Bronchopulmonary dysplasia: clinical presentation. Journal of Pediatrics 1979;95(5 Pt 2):819-23. [DOI: 10.1016/s0022-3476(79)80442-4] [PMID: ] - DOI - PubMed
Bayley 2006
    1. Bayley N. Bayley Scales of Infant and Toddler Development: Administration Manual. Third edition. San Antonio, TX: Harcourt, 2006.
Bell 1978
    1. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187(1):1-7. [DOI: 10.1097/00000658-197801000-00001] [PMID: ] - DOI - PMC - PubMed
Bell 1980
    1. Bell EF, Warburton D, Stonestreet BS, Oh W. Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. New England Journal of Medicine 1980;302(11):598-604. [DOI: 10.1056/NEJM198003133021103] [PMID: ] - DOI - PubMed
Benitz 2010
    1. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? Journal of Perinatology 2010;30(4):241-52. [DOI: 10.1038/jp.2010.3] [PMID: ] - DOI - PubMed
Brown 1979
    1. Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. Journal of Pediatrics 1979;95(5 Pt 2):865-6. [DOI: 10.1016/s0022-3476(79)80454-0] [PMID: ] - DOI - PubMed
Cifuentes 1979
    1. Cifuentes RF, Olley PM, Balfe JW, Radde IC, Soldin SJ. Indomethacin and renal function in premature infants with persistent patent ductus arteriosus. Journal of Pediatrics 1979;95(4):583-7. [DOI: 10.1016/s0022-3476(79)80775-1] [PMID: ] - DOI - PubMed
Clyman 1977
    1. Clyman RI, Heymann MA, Rudolph AM. Ductus arteriosus responses to prostaglandin E1 at high and low oxygen concentrations. Prostaglandins 1977;13(2):219-23. [DOI: 10.1016/0090-6980(77)90003-x] [PMID: ] - DOI - PubMed
Clyman 1996
    1. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. Journal of Pediatrics 1996;128(5 Pt 1):601-7. [DOI: 10.1016/s0022-3476(96)80123-5] [PMID: ] - DOI - PubMed
Clyman 2000
    1. Clyman RI. Ibuprofen and patent ductus arteriosus. New England Journal of Medicine 2000;343(10):728-30. [DOI: 10.1056/NEJM200009073431009] [PMID: ] - DOI - PubMed
Coombs 1990
    1. Coombs RC, Morgan ME, Durbin GM, Booth IW, McNeish AS. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Archives of Disease in Childhood 1990;65(10 Spec No):1067-71. [DOI: 10.1136/adc.65.10_spec_no.1067] [PMID: ] - DOI - PMC - PubMed
Cotton 1978
    1. Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. Journal of Pediatrics 1978;92(3):467-73. [DOI: 10.1016/s0022-3476(78)80451-x] [PMID: ] - DOI - PubMed
Cotton 1981
    1. Cotton RB, Lindstrom DP, Stahlman MT. Early prediction of symptomatic patent ductus arteriosus from perinatal risk factors: a discriminant analysis model. Acta Paediatrica Scandinavica 1981;70(5):723-7. [DOI: 10.1111/j.1651-2227.1981.tb05775.x] [PMID: ] - DOI - PubMed
Davis 1990
    1. Davis JM, Hendricks-Munoz KD, Hagberg D, Manning JA. The effects of indomethacin on renal function and intracranial hemorrhage in infants with patent ductus arteriosus. Developmental Pharmacology and Therapeutics 1990;14(1):15-9. [PMID: ] - PubMed
Davis 1995
    1. Davis P, Turner-Gomes S, Cunningham K, Way C, Roberts R, Schmidt B. Precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus. Archives of Pediatrics & Adolescent Medicine 1995;149(10):1136-41. [DOI: 10.1001/archpedi.1995.02170230090013] [PMID: ] - DOI - PubMed
Dice 2007
    1. Dice JE, Bhatia J. Patent ductus arteriosus: an overview. Journal of Pediatric Pharmacology and Therapeutics 2007;12(3):138-46. [DOI: 10.5863/1551-6776-12.3.138] [PMID: ] - DOI - PMC - PubMed
Dollberg 2005
    1. Dollberg S, Lusky A, Reichman B. Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study. Journal of Pediatric Gastroenterology and Nutrition 2005;40(2):184-8. [DOI: 10.1097/00005176-200502000-00019] [PMID: ] - DOI - PubMed
Edwards 1990
    1. Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delpy DT, et al. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990;335(8704):1491-5. [DOI: 10.1016/0140-6736(90)93030-s] [PMID: ] - DOI - PubMed
Ellison 1983
    1. Ellison RC, Peckham GJ, Lang P, Talner NS, Lerer TJ, Lin L, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71(3):364-72. [PMID: ] - PubMed
Fowlie 2010
    1. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 7. Art. No: CD000174. [DOI: 10.1002/14651858.CD000174.pub2] - DOI - PMC - PubMed
Friedman 1976
    1. Friedman WF, Hirschklau MJ, Printz MP, Pitlick PT, Kirkpatrick SE. Pharmacologic closure of patent ductus arteriosus in the premature infant. New England Journal of Medicine 1976;295(10):526-9. [DOI: 10.1056/NEJM197609022951003] [PMID: ] - DOI - PubMed
Fujii 2002
    1. Fujii AM, Brown E, Mirochnick M, O'Brien S, Kaufman G. Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus. Journal of Perinatology 2002;22(7):535-40. [DOI: 10.1038/sj.jp.7210795] [PMID: ] - DOI - PubMed
GRADEpro GDT [Computer program]
    1. GRADEpro GDT. Version accessed 9 November 2018. Hamilton (ON): McMaster University (developed by Evidence Prime). Available at gradepro.org.
Grosfeld 1996
    1. Grosfeld JL, Chaet M, Molinari F, Engle W, Engum SA, West KW, et al. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Annals of Surgery 1996;224(3):350-5; discussion 355-7. [DOI: 10.1097/00000658-199609000-00011] [PMID: ] - DOI - PMC - PubMed
Hammerman 1986
    1. Hammerman C, Strates E, Valaitis S. The silent ductus: its precursors and its aftermath. Pediatric Cardiology 1986;7(3):121-7. [DOI: 10.1007/BF02424985] [PMID: ] - DOI - PubMed
Hammerman 1995
    1. Hammerman C. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clinics in Perinatology 1995;22(2):457-79. [PMID: ] - PubMed
Herrera 2007
    1. Herrera C, Holberton J, Davis P. Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No: CD003480. [DOI: 10.1002/14651858.CD003480.pub3] - DOI - PMC - PubMed
Heymann 1976
    1. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. New England Journal of Medicine 1976;295(10):530-3. [DOI: 10.1056/NEJM197609022951004] [PMID: ] - DOI - PubMed
Higgins 2011
    1. Higgins JP, Altman DG, Sterne JA, on behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group. Chapter 8: Assessing risk of bias in included studies. In: Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). Cochrane, 2011. Available from handbook.cochrane.org.
Higgins 2019
    1. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.1 (updated September 2020). Cochrane, 2020. Available from www.training.cochrane.org/handbook.
ICROP 2005
    1. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Archives of Ophthalmology 2005;123(7):991-9. [DOI: 10.1001/archopht.123.7.991] [PMID: ] - DOI - PubMed
Jacob 1980
    1. Jacob J, Gluck L, DiSessa T, Edwards D, Kulovich M, Kurlinski J, et al. The contribution of PDA in the neonate with severe RDS. Journal of Pediatrics 1980;96(1):79-87. [DOI: 10.1016/s0022-3476(80)80336-2] [PMID: ] - DOI - PubMed
Jones 2011
    1. Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I. Network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Archives of Disease in Childhood. Fetal & Neonatal Edition 2011;96(1):F45-52. [DOI: 10.1136/adc.2009.168682] [PMID: ] - DOI - PubMed
Kitterman 1972
    1. Kitterman JA, Edmunds LH Jr, Gregory GA, Heymann MA, Tooley WH, Rudolph AM. Patent ducts arteriosus in premature infants. Incidence, relation to pulmonary disease and management. New England Journal of Medicine 1972;287(10):473-7. [DOI: 10.1056/NEJM197209072871001] [PMID: ] - DOI - PubMed
Lago 2002
    1. Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. European Journal of Pediatrics 2002;161(4):202-7. [DOI: 10.1007/s00431-002-0915-y] [PMID: ] - DOI - PubMed
Malviya 2013
    1. Malviya MN, Ohlsson A, Shah SS. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No: CD003951. [DOI: 10.1002/14651858.CD003951.pub3] - DOI - PMC - PubMed
Matthew 1998
    1. Mathew R. Development of the pulmonary circulation: metabolic aspects. In: Polin RA, Fox WW, editors(s). Fetal and Neonatal Physiology. 2nd edition. Philadelphia (PA): WB Saunders, 1998:924-9.
Mitra 2018
    1. Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Angeliki Veroniki A, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA 2018;319(12):1221-38. [DOI: 10.1001/jama.2018.1896] [PMID: ] - DOI - PMC - PubMed
Mitra 2020
    1. Mitra S, McNamara PJ. Patent ductus arteriosus – time for a definitive trial. Clinics in Perinatology 2020;47(3):617-39. [DOI: 10.1016/j.clp.2020.05.007] [PMID: ] - DOI - PubMed
Moher 1998
    1. Moher D. CONSORT: an evolving tool to help improve the quality of reports of randomized controlled trials. Consolidated standards of reporting trials. JAMA 1998;279:1489-91. [DOI: 10.1001/jama.279.18.1489] [PMID: ] - DOI - PubMed
Moher 2009
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Journal of Clinical Epidemiology 2009;62(10):1006-12. [DOI: 10.1016/j.jclinepi.2009.06.005] [PMID: ] - DOI - PubMed
Nehgme 1992
    1. Nehgme RA, O'Connor TZ, Lister G, Bracken MB. Patent ductus arteriosus. In: Sinclair JC, Bracken MB, editors(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:281-324.
Noori 2009
    1. Noori S, Seri I. Treatment of the patent ductus arteriosus: when, how, and for how long? Journal of Pediatrics 2009;155(6):774-6. [DOI: 10.1016/j.jpeds.2009.07.053] [PMID: ] - DOI - PubMed
Ohlsson 2020
    1. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database of Systematic Reviews 2020, Issue 2. Art. No: CD003481. [DOI: 10.1002/14651858.CD003481.pub8] - DOI - PMC - PubMed
Papile 1978
    1. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. Journal of Pediatrics 1978;92(4):529-34. [DOI: 10.1016/s0022-3476(78)80282-0] [PMID: ] - DOI - PubMed
Review Manager 2020 [Computer program]
    1. Review Manager 5 (RevMan 5). Version 5.4. Copenhagen: The Cochrane Collaboration, 2020.
Schünemann 2013
    1. Schünemann H, Brożek J, Guyatt G, Oxman A, editor(s). Handbook for Grading the Quality of Evidence and the Strength of Recommendations Using the GRADE Approach (updated October 2013). GRADE Working Group, 2013. Available from gdt.guidelinedevelopment.org/app/handbook/handbook.html.
Semberova 2017
    1. Semberova J, Sirc J, Miletin J, Kucera J, Berka I, Sebkova S, et al. Spontaneous closure of patent ductus arteriosus in infants </=1500 g. Pediatrics 2017;140(2):e20164258. [DOI: 10.1542/peds.2016-4258] [PMID: ] - DOI - PubMed
Shennan 1988
    1. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82(4):527-32. [PMID: ] - PubMed
Stavel 2017
    1. Stavel M, Wong J, Cieslak Z, Sherlock R, Claveau M, Shah PS. Effect of prophylactic indomethacin administration and early feeding on spontaneous intestinal perforation in extremely low-birth-weight infants. Journal of Perinatology 2017;37(2):188-93. [DOI: 10.1038/jp.2016.196] [PMID: ] - DOI - PubMed
Thibeault 1975
    1. Thibeault DW, Emmanouilides GC, Nelson RJ, Lachman RS, Rosengart RM, Oh W. Patent ductus arteriosus complicating the respiratory distress syndrome in preterm infants. Journal of Pediatrics 1975;86(1):120-6. [DOI: 10.1016/s0022-3476(75)80722-0] [PMID: ] - DOI - PubMed
Webbe 2020
    1. Webbe JW, Duffy JM, Afonso E, Al-Muzaffar I, Brunton G, Greenough A, et al. Core outcomes in neonatology: development of a core outcome set for neonatal research. Archives of Disease in Childhood. Fetal & Neonatal Edition 2020;105(4):425-31. [DOI: 10.1136/archdischild-2019-317501] [PMID: ] - DOI - PMC - PubMed
Weir 1999
    1. Weir FJ, Ohlsson A, Myhr TL, Fong K, Ryan ML. A patent ductus arteriosus is associated with reduced middle cerebral artery blood flow velocity. European Journal of Pediatrics 1999;158(6):484-7. [DOI: 10.1007/s004310051125] [PMID: ] - DOI - PubMed
Weisz 2014
    1. Weisz DE, More K, McNamara PJ, Shah PS. PDA ligation and health outcomes: a meta-analysis. Pediatrics 2014;133(4):e1024-46. [DOI: 10.1542/peds.2013-3431] [PMID: ] - DOI - PubMed
Yeh 1981b
    1. Yeh TF, Thalji A, Luken L, Lilien L, Carr I, Pildes RS. Improved lung compliance following indomethacin therapy in premature infants with patent ductus arteriosus. Chest 1981;80(6):698-700. [DOI: 10.1378/chest.80.6.698] [PMID: ] - DOI - PubMed
Yeh 1982b
    1. Yeh TF, Goldbarg HR, Henek T, Thalji A, Pildes RS. Intravenous indomethacin therapy in premature infants with patent ductus arteriosus. Causes of death and one-year follow-up. American Journal of Diseases of Children 1982;136(9):803-7. [DOI: 10.1001/archpedi.1982.03970450045012] [PMID: ] - DOI - PubMed
Yeh 1982c
    1. Yeh TF, Raval D, Lilien LD, Srinivasan G, Pildes RS. Decreased plasma glucose following indomethacin therapy in premature infants with patent ductus arteriosus. Pediatric Pharmacology (New York) 1982;2(3):171-7. [PMID: ] - PubMed
Yeh 1983
    1. Yeh TF, Raval D, Pyati S, Pildes RS. Retinopathy of prematurity (ROP) and indomethacin therapy in premature infants with patent ductus arteriosus (PDA). Prostaglandins 1983;25(3):385-91. [DOI: 10.1016/0090-6980(83)90041-2] [PMID: ] - DOI - PubMed

References to other published versions of this review

Evans 2018
    1. Evans P, O'Reilly D, Flyer JN, Mitra S, Soll R. Indomethacin for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No: CD013133. [DOI: 10.1002/14651858.CD013133] - DOI - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources