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
. 2003;2003(2):CD003745.
doi: 10.1002/14651858.CD003745.

Indomethacin for asymptomatic patent ductus arteriosus in preterm infants

L Cooke  1 , P Steer, P Woodgate
Affiliations
Meta-Analysis

Indomethacin for asymptomatic patent ductus arteriosus in preterm infants

L Cooke et al. Cochrane Database Syst Rev. 2003.

Abstract

Background: Patent Ductus Arteriosus (PDA remains a significant cause of mortality and morbidity in premature infants. Indomethacin is an effective treatment to close a PDA, and has been used for many years with several treatment regimes, including prophylactic use in all at risk premature infants. There are however concerns regarding adverse side effects of indomethacin. By targeting a group of infants with an asymptomatic PDA, rather than treating all VLBW infants prophylactically, indomethacin use would be restricted, limiting the possibility of significant side effects to those with greater chance of benefit.

Objectives: To assess whether in premature neonates with asymptomatic PDA, treatment with indomethacin improves short and long term outcomes; in particular: incidence of symptomatic PDA, mortality, chronic neonatal lung disease (CLD), intraventricular haemorrhage (IVH), retinopathy of prematurity (ROP), neurodevelopmental outcome, length of ventilation.

Search strategy: Standard strategies of the Cochrane Neonatal Review Group were used. Searches were made of the Oxford Database of Perinatal Trials, MEDLINE and EMBASE from 1966 to September 2002, CINAHL from 1982 to September 2002, and the Cochrane Controlled Trials Register (CENTRAL/CCTR) in The Cochrane Library, Issue 3, 2002. Searches were also made of previous reviews including cross-referencing, abstracts, and conference and symposia proceedings published in Pediatric Research.

Selection criteria: All randomised controlled trials of indomethacin compared with placebo or no intervention for the treatment of asymptomatic PDA in premature infants were eligible.

Data collection and analysis: Standard methods of the Cochrane Neonatal Review Group were used. Trials identified by the search strategy were independently reviewed by each author and assessed for eligibility and trial quality. Data were then extracted independently by each author and compared, with any differences resolved following discussion. Any additional information required was requested from trial authors. Only published data was available for review. Results are expressed as typical relative risk and typical risk difference for dichotomous outcomes, and weighted mean difference for continuous variables.

Main results: Three small trials involving a total of 97 infants were included. Meta analysis of combined data was possible for seven outcomes. Treatment of an asymptomatic PDA with indomethacin significantly reduced the incidence of symptomatic PDA (RR 0.36, 95% CI 0.19, 0.68) and duration of supplemental oxygen (WMD -12.5, 95% CI -23.8, -1.26). There was no evidence of effect on mortality (RR 1.32, 95% CI 0.45, 3.86), CLD (RR 0.91, 95% CI 0.62, 1.35), IVH (RR 1.21, 95% CI 0.62, 2.37), ROP (RR 0.68, 95% CI 0.26, 1.78), or length of ventilation (WMD -7.00 days, 95%CI -17.33, 3.34). Long term neurodevelopmental outcomes were not reported. One trial reported a significant reduction in the duration of supplemental oxygen following treatment with indomethacin in the subgroup of infants with birth weight less than 1000g.

Reviewer's conclusions: This review demonstrates a significant decrease in the incidence of symptomatic PDA following treatment of an asymptomatic PDA with indomethacin. There is also a small but statistically significant decrease in the duration of requirement for supplemental oxygen. There are no reported long term outcomes in the included trials, and so it is not possible to comment on possible long term effects. Further studies are required to determine the long term benefits or harms of closing a PDA prior to the onset of symptoms.

PubMed Disclaimer

Conflict of interest statement

None

Figures

1.1
1.1. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 2 Chronic lung disease in survivors.
1.3
1.3. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 3 Intraventricular haemorrhage ‐ all grades.
1.4
1.4. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 4 Necrotising enterocolitis.
1.5
1.5. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 5 Retinopathy of prematurity ‐ all grades (infants examined).
1.6
1.6. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 6 Symptomatic PDA.
1.7
1.7. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 7 PDA ligation.
1.8
1.8. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 8 Length of ventilation ‐ days.
1.9
1.9. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 9 Length of hospital stay ‐ Days.
1.10
1.10. Analysis
Comparison 1 Indomethacin vs Placebo, Outcome 10 Duration of supplemental oxygen ‐ days.
See this image and copyright information in PMC

References

References to studies included in this review

Hammerman 1987 {published and unpublished data}
    1. Hammerman C, Strates E, Komar K, Kim‐chi B. Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Developmental Pharmacology and Therapeutics 1987;10:393‐404. - PubMed
    1. Hammerman C, Strates E, Vailates S. The silent ductus: Its precursors and its aftermath. Pediatric Cardiology 1986;7:121‐7. - PubMed
Mahony 1982 {published data only}
    1. Mahony L, Carnero V, Brett C, Heymann M, Clyman R. Prophylactic indomethacin therapy for patent ductus arteriosus in very‐low‐birthweight infants. New England Journal of Medicine 1982;306:506‐10. - PubMed
    1. Mahony L, Heymann M, Carnero V, Brett C, Clymann R. When to treat the patent ductus arteriosus with indomethacin in very‐low‐birth‐weight infants. Advances in Prostaglandin, Thromboxane, and Leukotriene Research 1983;12:491‐4. - PubMed
Weesner 1987 {published data only}
    1. Weesner K, Dillard R, Boyle R, Block S. Prophlactic treatment of asymptomatic patent ductus arteriosus in premature infants with respiratory distress syndrome. Southern Medical Journal 1987;80:706‐8. - PubMed

References to studies excluded from this review

Kaapa 1983 {published data only}
    1. Kaapa P, Lanning P, Koivisto M. Early closure of patent ductus arteriosus with indomethacin in preterm infants with idiopathic respiratory distress syndrome. Acta Paediatrica Scandinavica 1983;72:179‐84. - PubMed
Merritt 1981 {published data only}
    1. Merritt T, Harris J, Roghmann K, Wood B, Campanella V, Alexson C, Manning J, Shapiro D. Early closure of the patent ductus arteriosus in very low birth weight infants: A controlled trial. Journal of Pediatrics 1981;99:281‐6. - 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;21:217‐20. - PubMed
Van Overmeire 2001 {published data only}
    1. Overmeire B, Broek H, LAer P, Weyler J, Vanbaesebrouck P. Early versus late indomethacin treatment for patent ductus arteriosus in premature babies with respiratory distress syndrome. Journal of Pediatrics 2001;138:205‐11. - PubMed
Vogtmann 1988 {published data only}
    1. Vogtmann C, Grubbe G, Ruckhaberle K‐E, Bottcher H, Ockert C. The effects of an early indomethacin treatment on the manifestation of a patent ductus arteriosus in very low birth weight infants [Auswirkungen einer Fruhtherapie mit Indomethazin auf die Manifestation eines persistierenden Ductus arteriosus bei extrem untergewichtigen Fruhgeborenen]. Monatsschr Kinderheilkd 1988;136:636‐639. - PubMed

Additional references

Armitage 1994
    1. Armitage PA, Berry G. Statistical Methods in Medical Research. 3rd Edition. Oxford: Blackwell, 1994:207‐11.
Betkurer 1981
    1. Betkurer 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;68:99‐102. - PubMed
Blakely 2001
    1. Blakely ML, Kennedy KA, Lally KP, Tyson JE. Intravenous indomethacin for symptomatic patent ductus arterious in preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: 10.1002/14651858.CD003479] - DOI
Brown 1979
    1. Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. Journal of Pediatrics 1979;95:865‐6. [MEDLINE: ] - PubMed
Clarke 2002
    1. Clarke M, Oxman AD, editors. Cochrane Reviewers' Handbook 4.1.5 [Updated April 2002] Updated quarterly. Cochrane Database of Systematic Reviews 2002, Issue 3.
Cotton 1978
    1. Cotton RB, Stahlman MT, Bender HW, Graham TP, Catterton WZ, Kovar I. Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. Journal of Pediatr 1978;93:647‐651. - PubMed
Davis 1995
    1. Davis P, Turner GS, 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 and Adolescent Medicine 1995;149:1136‐41. - PubMed
Dyess 1993
    1. Dyess DL, Peeples GL, Ardell JL, Tacchi EJ, Roberts WS, Ferrara JJ, et al. Indomethacin‐induced blood flow distribution in premature and full term piglets. Journal of Pediatric Surgery 1993;28:1396‐400. - 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;335:1491‐5. - PubMed
Evans 1990
    1. Evans N, Archer LN. Post natal circulatory adaptation in healthy term and preterm neonates. Archives of Disease in Childhood 1990;65:24‐6. - PMC - PubMed
Evans 1995
    1. Evans N, Iyer P. Longitudinal changes in the diameter of the ductus arteriosus in ventilated preterm infants: correlation with respiratory outcomes. Archives of Disease in Childhood. Fetal and Neonatal Edition 1995;72:F156‐61. [MEDLINE: ] - PMC - PubMed
Fowlie 2002
    1. Fowlie PW. Intravenous indomethacin for preventing mortality and morbidity in very low birth weight infants (Cochrane Review). Cochrane Database of Systematic Reviews 2002, Issue 2. [DOI: 10.1002/14651858.CD000174] - DOI - PubMed
Gersony 1983
    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;102:895‐906. - PubMed
Hirsmaki 1990
    1. Hirsmaki H, Kero P, Wanne O. Doppler ultrasound and clinical evaluation in detection and grading of patent ductus arteriosus in neonates. Critical Care Medicine 1990;18:490‐3. - PubMed
Kang 1999
    1. Kang NS, Yoo KH, Cheon H, Choi BM, Hong YS, Lee JW, et al. Indomethacin treatment decreases renal blood flow velocity in human neonates. Biology of the Neonate 1999;76:261‐5. - PubMed
Knight 1992
    1. Knight DB. Patent ductus arteriosus: how important to which babies?. Early Human Development 1992;29:287‐92. - PubMed
Knight 2001
    1. Knight DB. The treatment of patent ductus arteriosus in preterm infants. A review and overview of randomised trials. Seminars in Neonatology 2001;6:63‐73. - PubMed
Mellander 1987
    1. Mellander M, Larsson LE, Ekstrom‐Jodal B, Sabel KG. Prediction of symptomatic patent ductus arteriosus in preterm infants using Doppler and m‐mode echocardiography. Acta Paediatrica Scandinavica 1987;76:553‐9. - PubMed
Nestrud 1980
    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 using indomethacin plasma levels. Developmental Pharmacology and Therapeutics 1980;1:125‐36. - PubMed
Patel 2000
    1. Patel J, Roberts I, Azzopardi D, Hamilton P, Ewards AD. Randomized Double‐Blind Controlled trial Comparing the effects of ibuprofen with indomethacin on Cerebral haemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47:36‐42. - PubMed
Romagnoli 2000
    1. Romagnoli C, Carolis MP, Papacci P, Polimeni V, Luciano R, Piersigilli F, Delogu AB, Tortorolo G. Effects of prophylactic ibuprofen on cerebral and renal haemodynamics in very preterm neonates. Clinical Pharmacology and Therapeutics 2000;67:676‐83. - PubMed
Schmidt 2001
    1. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL. Long‐term effects of indomethacin prophylaxis in extremely‐low‐birth‐weight infants. New England Journal of Medicine 2001;344:1966‐72. - PubMed
Shorter 1999
    1. Shorter NA, Liu JY, Mooney DP, Harmon BJ. Indomethacin associated bowel perforations: a study of possible risk factors. Journal of Pediatric Surgery 1999;34:442‐4. - PubMed
Van Overmeire 2000
    1. Overmeire B, Smets K, Lecoutere D, Broek H, Weyler J, Degroote K, Langhendries JP. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New England Journal of Medicine 2000;343:674‐81. - PubMed
Yanagi 1981
    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;67:647‐52. - PubMed

MeSH terms