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Meta-Analysis
. 2010 Jul 7;2010(7):CD000174.
doi: 10.1002/14651858.CD000174.pub2.

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Peter W Fowlie  1 , Peter G Davis, William McGuire
Affiliations
Meta-Analysis

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Peter W Fowlie et al. Cochrane Database Syst Rev. .

Abstract

Background: Persistent patent ductus arteriosus (PDA) is associated with mortality and morbidity in preterm infants. Prostaglandin synthetase inhibitors such as indomethacin promote PDA closure but also have potential side effects. The effect of the prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA would be exposed to indomethacin, warrants particular scrutiny.

Objectives: To determine the effect of prophylactic indomethacin on mortality and morbidity in preterm infants.

Search strategy: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 5, 2010), MEDLINE, EMBASE and CINAHL (until April 2010), conference proceedings, and previous reviews.

Selection criteria: Randomised or quasi-randomised controlled trials that compared prophylactic indomethacin versus placebo or no drug in preterm infants.

Data collection and analysis: The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two review authors.

Main results: Nineteen eligible trials in which 2872 infants participated were identified. Most participants were very low birth weight, but the largest single trial restricted participation to extremely low birth weight infants (N = 1202). The trials were generally of good quality.The incidence of symptomatic PDA [typical relative risk (RR) 0.44, 95% confidence interval (CI) 0.38 to 0.50] and PDA surgical ligation (typical RR 0.51, 95% CI 0.37,0.71) was significantly lower in treated infants. Prophylactic indomethacin also significantly reduced the incidence of severe intraventricular haemorrhage (typical RR 0.66, 95% CI 0.53 to 0.82). Meta-analyses found no evidence of an effect on mortality (typical RR 0.96, 95% CI 0.81 to 1.12) or on a composite of death or severe neurodevelopmental disability assessed at 18 to 36 months old (typical RR 1.02, 95% CI 0.90, 1.15).

Authors' conclusions: Prophylactic indomethacin has short-term benefits for preterm infants including a reduction in the incidence of symptomatic PDA, PDA surgical ligation, and severe intraventricular haemorrhage. However, there is no evidence of effect on mortality or neurodevelopment.

PubMed Disclaimer

Conflict of interest statement

None.

Figures

1
1
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.1 Death to hospital discharge.
2
2
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.2 Death at latest follow‐up.
3
3
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.3 Death or severe neurosensory impairment.
4
4
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.4 Cerebral palsy, visual impairment, hearing impairment and severe neurodevelopmental impairment.
5
5
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.10 Cognitive assessments (18‐36 months).
6
6
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.6 School age neurological assessments.
7
7
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.7 School age cognitive and educational outcomes.
8
8
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.12 All PDA (echo‐diagnosed, symptomatic or not).
9
9
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.11 Symptomatic PDA.
10
10
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.13 PDA ligation.
11
11
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.14 All IVH.
12
12
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.15 Severe IVH: grades III ‐ IV.
13
13
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.16 Ventriculomegaly, periventricular leukomalacia or other white matter echo‐abnormalities.
14
14
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.17 IVH that progresses.
15
15
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.17 Duration of assisted ventilation.
16
16
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.18 Pneumothorax and/or pneumopericardium.
17
17
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.19 Bronchopulmonary dysplasia (28 days).
18
18
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.20 Bronchopulmonary dysplasia (36 weeks' PMA).
19
19
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.21 Duration of supplementary oxygen requirement.
20
20
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.22 Pulmonary haemorrhage.
21
21
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.23 Oliguria/anuria.
22
22
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.24 Elevated serum creatinine.
23
23
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.26 Necrotizing enterocolitis.
24
24
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.28 Gastointestinal perforation.
25
25
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.28 Excessive clinical bleeding.
26
26
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.29 Thrombocytopaenia (investigator defined).
27
27
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.30 Any retinopathy of prematurity.
28
28
Forest plot of comparison: 1 Prophylactic indomethacin vs. control, outcome: 1.31 Severe retinopathy of prematurity (stage 3 or more).
1.1
1.1. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 1 Death to hospital discharge.
1.2
1.2. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 2 Death at latest follow‐up.
1.3
1.3. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 3 Death or severe neurosensory impairment.
1.4
1.4. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 4 Neurological assessments (18‐54 months).
1.5
1.5. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 5 Cognitive assessments (18‐36 months).
1.6
1.6. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 6 School age neurological assessments.
1.7
1.7. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 7 School age cognitive and educational outcomes.
1.8
1.8. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 8 All PDA (echo‐diagnosed, symptomatic or not).
1.9
1.9. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 9 Symptomatic PDA.
1.10
1.10. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 10 PDA ligation.
1.11
1.11. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 11 All IVH.
1.12
1.12. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 12 Severe IVH (grades III ‐ IV).
1.13
1.13. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 13 Ventriculomegaly, periventricular leukomalacia or other white matter echo‐abnormalities.
1.14
1.14. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 14 IVH that progresses.
1.15
1.15. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 15 Duration of assisted ventilation.
1.16
1.16. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 16 Pneumothorax and pneumopericardium.
1.17
1.17. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 17 Bronchopulmonary dysplasia (28 days).
1.18
1.18. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 18 Bronchopulmonary dysplasia (36 weeks' PMA).
1.19
1.19. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 19 Duration of supplementary oxygen requirement.
1.20
1.20. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 20 Pulmonary haemorrhage.
1.21
1.21. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 21 Oliguria/anuria.
1.22
1.22. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 22 Elevated serum creatinine.
1.23
1.23. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 23 Necrotising enterocolitis.
1.24
1.24. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 24 Gastointestinal perforation.
1.25
1.25. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 25 Excessive clinical bleeding (investigator defined).
1.26
1.26. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 26 Thrombocytopaenia (investigator defined).
1.27
1.27. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 27 Any retinopathy of prematurity.
1.28
1.28. Analysis
Comparison 1 Prophylactic indomethacin vs. control, Outcome 28 Severe retinopathy of prematurity (stage 3 or more).
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Ment 1994a {published data only}
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Ment 1994b {published data only}
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Morales‐Suarez 1994 {published data only}
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Puckett 1985 {published data only}
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References to studies excluded from this review

Bada 1996 {published data only}
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Cotton 1980 {published data only}
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Cotton 1983 {published data only}
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Hammerman 1987 {published data only}
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Hammerman 1990 {published data only}
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Hammerman 1995 {published data only}
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Kaapa 1983 {published data only}
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Neu 1980 {published data only}
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Rhodes 1988 {published data only}
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Rudd 1983 {published data only}
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van Overmeire 1995 {published data only}
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Vogtmann 1988 {published data only}
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Wagner 1984 {published data only}
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Wurtzel 1990 {published data only}
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Yanagi 1981 {published data only}
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Yeh 1981 {published data only}
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References to other published versions of this review

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