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Meta-Analysis
. 2007 Apr 18;2007(2):CD003480.
doi: 10.1002/14651858.CD003480.pub3.

Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants

C Herrera  1 , J Holberton, P Davis
Affiliations
Meta-Analysis

Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants

C Herrera et al. Cochrane Database Syst Rev. .

Abstract

Background: Indomethacin is a prostaglandin inhibitor used to treat patent ductus arteriosus (PDA) in preterm infants. Although indomethacin produces ductal closure in the majority of cases, it is ineffective in up to 40% of patients. Furthermore, the ductus will re-open in up to 35% of infants who initially respond to the drug. Prolonging the course of indomethacin has the potential to achieve higher rates of ductal closure.

Objectives: To determine the effect of a prolonged course of indomethacin (compared to a short course) on the rate of treatment failure without unwanted side-effects in preterm infants with PDA.

Search strategy: The search included review of personal files, abstracts of conferences, and the following electronic databases: MEDLINE (1966 to December 2006), EMBASE (1974 to December 2006), and Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2006). No language restrictions were applied.

Selection criteria: Randomized or quasi-randomized controlled trials including preterm infants with PDA, diagnosed on clinical and/or echocardiographic examination that evaluated indomethacin treatment by any route given as a long course (four or more doses) vs. a short course (three or fewer doses) were included in the review. Trials needed to report on at least one of the following outcomes: failure of PDA to close, need for re-treatment, PDA re-opening, PDA ligation, mortality, duration of assisted ventilation, chronic lung disease (CLD), duration of supplemental oxygen dependence, intraventricular hemorrhage (IVH) (all and severe), diminished urine output, increased serum creatinine, necrotizing enterocolitis (NEC), bleeding diathesis, retinopathy of prematurity (ROP), and duration of hospital stay.

Data collection and analysis: The three review authors independently abstracted data from each study. Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effect model for meta-analysis are reported. When a statistically significant RD was found, the number needed to treat (NNT) or number needed to harm (NNH) was also calculated with 95% CIs. The I squared statistic was used to test for heterogeneity of results among included trials.

Main results: Five trials met inclusion criteria and included 431 infants. Prolonged indomethacin treatment when compared to the short course did not result in a statistically significant difference in PDA closure, re-treatment, re-opening, or ligation rates. The prolonged course was associated with an increased risk of NEC [typical RR 1.87 (95% CI 1.07, 3.27); typical RD 0.08 (95% CI 0.01, 0.15); NNH 13 (7, 100)] and a decreased incidence of renal function impairment, as evidenced by a lower proportion of infants having diminished urine output [typical RR 0.27 (95% CI 0.13, 0.6); typical RD -0.19 (95% CI -0.28, -0.09); NNT 5 (4, 11)] and increased serum creatinine level [typical RR 0.51 (95% CI 0.33, 0.77); typical RD -0.14 (95% CI -0.23, -0.06); NNT 7 (4, 16)].

Authors' conclusions: Implications for practiceProlonged indomethacin course does not appear to have a significant effect on improving important outcomes, such as PDA treatment failure, CLD, IVH, or mortality. The reduction of transient renal impairment does not outweigh the increased risk of NEC associated with the prolonged course. Based on these results, a prolonged course of indomethacin cannot be recommended for the routine treatment of PDA in preterm infants. Implications for researchThere is a paucity of data on optimal dosing and duration of indomethacin therapy for the treatment of PDA, in particular for extremely low birth weight infants (ELBW) premature infants. It is likely that a single standard indomethacin regime is not the ideal for every premature infant. Therefore, individual patient response should be considered and evaluated, in particular in ELBW infants. Future randomized clinical trials should include this high risk population and investigate the effect of tailoring dose and duration of therapy to individual response in terms of echocardiographic findings and/or prostaglandin levels, focusing on clinically significant outcomes, including long-term neurodevelopmental outcomes. In addition, factors that may influence treatment effect, such as birth weight, gestational age, age at the time of randomization, total fluid intake, feeding practice, and severity of PDA, need to be taken into account when designing such studies.

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Conflict of interest statement

None

Figures

1.1
1.1. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 1 Failure of PDA to close after completion of allocated treatment.
1.2
1.2. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 2 PDA reopening after treatment (after initial closure with allocated treatment).
1.3
1.3. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 3 Need for re‐treatment for PDA (indomethacin and/or ligation) after completion of allocated treatment.
1.4
1.4. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 4 PDA ligation after treatment.
1.5
1.5. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 5 Mortality.
1.6
1.6. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 6 Duration of assisted ventilation (days).
1.7
1.7. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 7 Chronic lung disease 36 wk (defined as need for supplemental oxygen at 36 weeks post‐menstrual age).
1.8
1.8. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 8 Duration of supplemental oxygen dependence (days).
1.9
1.9. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 9 IVH all.
1.10
1.10. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 10 IVH grades 3 or 4.
1.11
1.11. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 11 Diminished urine output (<1ml/kg/hr).
1.12
1.12. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 12 Increased serum creatinine.
1.13
1.13. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 13 Necrotizing enterocolitis (NEC).
1.14
1.14. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 14 Bleeding diathesis.
1.15
1.15. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 15 Any retinopathy of prematurity (ROP).
1.16
1.16. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 16 Duration of hospital stay (days).
1.17
1.17. Analysis
Comparison 1 Prolonged versus short course of indomethacin, Outcome 17 Chronic lung disease 28d (defined as need for supplemental oxygen at 28 days of life).
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Update of

References

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