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. 2022 Apr 1;4(4):CD013846.
doi: 10.1002/14651858.CD013846.pub2.

Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis

Affiliations

Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis

Souvik Mitra et al. Cochrane Database Syst Rev. .

Abstract

Background: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Cyclooxygenase inhibitors (COX-I) may prevent PDA-related complications. Controversy exists on which COX-I drug is the most effective and has the best safety profile in preterm infants.

Objectives: To compare the effectiveness and safety of prophylactic COX-I drugs and 'no COXI prophylaxis' in preterm infants using a Bayesian network meta-analysis (NMA).

Search methods: Searches of Cochrane CENTRAL via Wiley, OVID MEDLINE and Embase via Elsevier were conducted on 9 December 2021. We conducted independent searches of clinical trial registries and conference abstracts; and scanned the reference lists of included trials and related systematic reviews.

Selection criteria: We included randomised controlled trials (RCTs) that enrolled preterm or low birth weight infants within the first 72 hours of birth without a prior clinical or echocardiographic diagnosis of PDA and compared prophylactic administration of indomethacin or ibuprofen or acetaminophen versus each other, placebo or no treatment.

Data collection and analysis: We used the standard methods of Cochrane Neonatal. We used the GRADE NMA approach to assess the certainty of evidence derived from the NMA for the following outcomes: severe intraventricular haemorrhage (IVH), mortality, surgical or interventional PDA closure, necrotizing enterocolitis (NEC), gastrointestinal perforation, chronic lung disease (CLD) and cerebral palsy (CP).

Main results: We included 28 RCTs (3999 preterm infants). Nineteen RCTs (n = 2877) compared prophylactic indomethacin versus placebo/no treatment, 7 RCTs (n = 914) compared prophylactic ibuprofen versus placebo/no treatment and 2 RCTs (n = 208) compared prophylactic acetaminophen versus placebo/no treatment. Nine RCTs were judged to have high risk of bias in one or more domains.We identified two ongoing trials on prophylactic acetaminophen. Bayesian random-effects NMA demonstrated that prophylactic indomethacin probably led to a small reduction in severe IVH (network RR 0.66, 95% Credible Intervals [CrI] 0.49 to 0.87; absolute risk difference [ARD] 43 fewer [95% CrI, 65 fewer to 16 fewer] per 1000; median rank 2, 95% CrI 1-3; moderate-certainty), a moderate reduction in mortality (network RR 0.85, 95% CrI 0.64 to 1.1; ARD 24 fewer [95% CrI, 58 fewer to 16 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and surgical PDA closure (network RR 0.40, 95% CrI 0.14 to 0.66; ARD 52 fewer [95% CrI, 75 fewer to 30 fewer] per 1000; median rank 2, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic indomethacin resulted in trivial difference in NEC (network RR 0.76, 95% CrI 0.35 to 1.2; ARD 16 fewer [95% CrI, 42 fewer to 13 more] per 1000; median rank 2, 95% CrI 1-3; high-certainty), gastrointestinal perforation (network RR 0.92, 95% CrI 0.11 to 3.9; ARD 4 fewer [95% CrI, 42 fewer to 137 more] per 1000; median rank 1, 95% CrI 1-3; moderate-certainty) or CP (network RR 0.97, 95% CrI 0.44 to 2.1; ARD 3 fewer [95% CrI, 62 fewer to 121 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty) and may result in a small increase in CLD (network RR 1.10, 95% CrI 0.93 to 1.3; ARD 36 more [95% CrI, 25 fewer to 108 more] per 1000; median rank 3, 95% CrI 1-3; low-certainty). Prophylactic ibuprofen probably led to a small reduction in severe IVH (network RR 0.69, 95% CrI 0.41 to 1.14; ARD 39 fewer [95% CrI, 75 fewer to 18 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and moderate reduction in surgical PDA closure (network RR 0.24, 95% CrI 0.06 to 0.64; ARD 66 fewer [95% CrI, from 82 fewer to 31 fewer] per 1000; median rank 1, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic ibuprofen may result in moderate reduction in mortality (network RR 0.83, 95% CrI 0.57 to 1.2; ARD 27 fewer [95% CrI, from 69 fewer to 32 more] per 1000; median rank 2, 95% CrI 1-4; low-certainty) and leads to trivial difference in NEC (network RR 0.73, 95% CrI 0.31 to 1.4; ARD 18 fewer [95% CrI, from 45 fewer to 26 more] per 1000; median rank 1, 95% CrI 1-3; high-certainty), or CLD (network RR 1.00, 95% CrI 0.83 to 1.3; ARD 0 fewer [95% CrI, from 61 fewer to 108 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty). The evidence is very uncertain on effect of ibuprofen on gastrointestinal perforation (network RR 2.6, 95% CrI 0.42 to 20.0; ARD 76 more [95% CrI, from 27 fewer to 897 more] per 1000; median rank 3, 95% CrI 1-3; very low-certainty). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (network RR 1.17, 95% CrI 0.04 to 55.2; ARD 22 more [95% CrI, from 122 fewer to 1000 more] per 1000; median rank 4, 95% CrI 1-4; very low-certainty), mortality (network RR 0.49, 95% CrI 0.16 to 1.4; ARD 82 fewer [95% CrI, from 135 fewer to 64 more] per 1000; median rank 1, 95% CrI 1-4; very low-certainty), or CP (network RR 0.36, 95% CrI 0.01 to 6.3; ARD 70 fewer [95% CrI, from 109 fewer to 583 more] per 1000; median rank 1, 95% CrI 1-3; very low-certainty). In summary, based on ranking statistics, both indomethacin and ibuprofen were equally effective (median ranks 2 respectively) in reducing severe IVH and mortality. Ibuprofen (median rank 1) was more effective than indomethacin in reducing surgical PDA ligation (median rank 2). However, no statistically-significant differences were observed between the COX-I drugs for any of the relevant outcomes.

Authors' conclusions: Prophylactic indomethacin probably results in a small reduction in severe IVH and moderate reduction in mortality and surgical PDA closure (moderate-certainty), may result in a small increase in CLD (low-certainty) and results in trivial differences in NEC (high-certainty), gastrointestinal perforation (moderate-certainty) and cerebral palsy (low-certainty). Prophylactic ibuprofen probably results in a small reduction in severe IVH and moderate reduction in surgical PDA closure (moderate-certainty), may result in a moderate reduction in mortality (low-certainty) and trivial differences in CLD (low-certainty) and NEC (high-certainty). The evidence is very uncertain about the effect of acetaminophen on any of the clinically-relevant outcomes.

PubMed Disclaimer

Conflict of interest statement

SM is the principal investigator of a Canadian Institutes of Health Research (CIHR)‐funded prospective study on the relative effectiveness and safety of pharmacotherapeutic agents for treatment of patent ductus arteriosus (PDA) in preterm infants. SM reports working as a neonatologist at a tertiary care neonatal intensive care unit in IWK Health Center (Halifax, Nova Scotia, Canada) where they attend to preterm infants diagnosed with a PDA.

CEG declares no conflict of interest.

AM declares no conflict of interest.

TD declares no conflict of interest.

DMS reports working as a Fellow (Resident PGY6) Neonatal‐Perinatal Medicine at Dalhousie University/IWK Health Center.

MCY declares no conflict of interest.

SK declares no conflict of interest.

BCJ declares no conflict of interest.

JD reports working at IWK Health as Neonatologist and therefore sometimes treat PDAs in preterm infants.

Figures

1
1
Study flow diagram.
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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Network plot for severe intraventricular hemorrhage
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for severe intraventricular hemorrhage. A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for severe intraventricular hemorrhage A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for severe intraventricular hemorrhage A RR<1 favors the intervention. CrI, Credible intervals
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Comparison‐adjusted funnel plot for severe intraventricular hemorrhage
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Ranking probability (rankogram) of each treatment modality for severe intraventricular hemorrhage Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for mortality
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for mortality A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for mortality A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between acetaminophen and placebo (conducted using Bayesian random‐effects model) for mortality A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for mortality A RR<1 favors the intervention. CrI, Credible intervals
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Comparison‐adjusted funnel plot for mortality
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Ranking probability (rankogram) of each treatment modality for mortality Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for pharmacotherapy for symptomatic PDA
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for pharmacotherapy for symptomatic PDA A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for pharmacotherapy for symptomatic PDA A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between acetaminophen and placebo (conducted using Bayesian random‐effects model) for pharmacotherapy for symptomatic PDA A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for pharmacotherapy for symptomatic PDA
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Comparison‐adjusted funnel plot for pharmacotherapy for symptomatic PDA
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Ranking probability (rankogram) of each treatment modality for pharmacotherapy for symptomatic PDA Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for surgical PDA closure
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for surgical PDA closure A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for surgical PDA closure A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for surgical PDA closure A RR<1 favors the intervention. CrI, Credible intervals
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Comparison‐adjusted funnel plot for surgical PDA closure
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Ranking probability (rankogram) of each treatment modality for surgical PDA closure Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for necrotizing enterocolitis
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for necrotizing enterocolitis A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for necrotizing enterocolitis A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for necrotizing enterocolitis A RR<1 favors the intervention. CrI, Credible intervals
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Comparison‐adjusted funnel plot for necrotizing enterocolitis
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Ranking probability (rankogram) of each treatment modality for necrotizing enterocolitis Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for gastrointestinal perforation
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for gastrointestinal perforation A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for gastrointestinal perforation A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for gastrointestinal perforation A RR<1 favors the intervention. CrI, Credible intervals
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Ranking probability (rankogram) of each treatment modality for gastrointestinal perforation Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for chronic lung disease
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for chronic lung disease A RR<1 favors the intervention. CrI, Credible intervals
43
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for chronic lung disease A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for chronic lung disease A RR<1 favors the intervention. CrI, Credible intervals
45
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Comparison‐adjusted funnel plot for chronic lung disease
46
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Ranking probability (rankogram) of each treatment modality for chronic lung disease Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for oliguria
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for oliguria A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for oliguria A RR<1 favors the intervention. CrI, Credible intervals
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for oliguria A RR<1 favors the intervention. CrI, Credible intervals
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Comparison‐adjusted funnel plot for oliguria
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Ranking probability (rankogram) of each treatment modality for oliguria Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
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Network plot for intraventricular hemorrhage (any grade)
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for intraventricular hemorrhage (any grade) A RR<1 favors the intervention. CrI, Credible intervals
55
55
Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for intraventricular hemorrhage (any grade) A RR<1 favors the intervention. CrI, Credible intervals
56
56
Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for intraventricular hemorrhage (any grade) A RR<1 favors the intervention. CrI, Credible intervals
57
57
Comparison‐adjusted funnel plot for intraventricular hemorrhage (any grade)
58
58
Ranking probability (rankogram) of each treatment modality for intraventricular hemorrhage (any grade) Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
59
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Network plot for periventricular leukomalacia
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for periventricular leukomalacia A RR<1 favors the intervention. CrI, Credible intervals
61
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Forest plot of pairwise meta‐analysis between ibuprofen and placebo (conducted using Bayesian random‐effects model) for periventricular leukomalacia A RR<1 favors the intervention. CrI, Credible intervals
62
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for periventricular leukomalacia A RR<1 favors the intervention. CrI, Credible intervals
63
63
Ranking probability (rankogram) of each treatment modality for periventricular leukomalacia Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position
64
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Network plot for cerebral palsy
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Forest plot of pairwise meta‐analysis between indomethacin and placebo (conducted using Bayesian random‐effects model) for cerebral palsy A RR<1 favors the intervention. CrI, Credible intervals
66
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Forest plot of the relative network effect estimates with placebo as the comparator (conducted using Bayesian random‐effects model) for cerebral palsy A RR<1 favors the intervention. CrI, Credible intervals
67
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Ranking probability (rankogram) of each treatment modality for cerebral palsy Each rank is represented by a color. The height of each colored bar corresponds to the probability of an intervention being ranked in that specific ranking position

Update of

  • doi: 10.1002/14651858.CD013846

References

References to studies included in this review

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Vogtmann 1988 {published data only}
    1. Vogtmann C, Grubbe G, Ruckhäberle KE, Böttcher H, Ockert C.Effects of early therapy with indomethacin on the manifestation of a persistent ductus arteriosus in extremely underweight premature infants [Auswirkungen einer Frühtherapie mit Indomethazin auf die Manifestation eines persistierenden Ductus arteriosus bei extrem untergewichtigen Frühgeborenen]. Monatsschrift Kinderheilkund 1988;136(9):636-9. - PubMed

References to studies excluded from this review

Alfaleh 2008 {published data only}
    1. Alfaleh K, Smyth JA, Roberts RS, Solimano A, Asztalos EV, Schmidt B, Trial of Indomethacin Prophylaxis in Preterms Investigators.Prevention and 18-month outcomes of serious pulmonary hemorrhage in extremely low birth weight infants: results from the trial of indomethacin prophylaxis in preterms. Pediatrics 2008;121(2):e233-8. - PubMed
Barrington 1986 {published data only}
    1. Barrington KJ, Finer NN, Ment LR.Indomethacin for prevention of intraventricular hemorrhage. Journal of Pediatrics 1986;109(2):396-8. - PubMed
Cotts 2009 {published data only}
    1. Cotts T.Escalating dose indomethacin for prophylactic closure of patent ductus arteriosus does not improve closure rates and is associated with increased complications. Journal of Pediatrics 2009;154(1):153. - PubMed
Domanico 1994 {published data only}
    1. Domanico RS, Waldman JD, Lester LA, McPhillips HA, Catrambone JE, Covert RF.Prophylactic indomethacin reduces the incidence of pulmonary hemorrhage and patent ductus arteriosus in surfactant-treated infants. Pediatric Research 1994;35:331A.
Gregoire 2004 {published data only}
    1. Gregoire N, Gualano V, Geneteau A, Millerioux L, Brault M, Mignot A, et al.Population pharmacokinetics of ibuprofen enantiomers in very premature neonates. Journal of Clinical Pharmacology 2004;44(10):1114-24. - PubMed
Gutierrez 1987 {published data only}
    1. Gutierrez NG, Lapasset M.Prophylactic indomethacin and the incidence of patent ductus arteriosus in preterm neonates. Proceedings of the 3rd Argentinian Congress of Perinatology, Buenos Aires 1987;62.
Hammerman 1986 {published data only}
    1. Hammerman C, Strates E, Valaitis S.The silent ductus: its precursors and its aftermath. Pediatric Cardiology 1986;7(3):121-7. - PubMed
Hammerman 2005 {published data only}
    1. Hammerman C, Kaplan M.Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Journal of Pediatrics 2005;146(5):709-10. - PubMed
Harma 2018 {published data only}
    1. Harma A, Harkin P, Leskinen M, Valkama M, Saarela T, Aikio O, et al.Does intravenous paracetamol offer neonatal brain protection? Study of hemodynamics and cerebral oxygenation in very premature infants. Neonatology 2018;113(4):417-8. [DOI: ]
Kääpä 1985 {published data only}
    1. Kääpä P.Early closure of ductus arteriosus with indomethacin [Der Frühverschluss des Ductus arteriosus mit Indomethazin]. Klinische Pädiatrie 1985;197(2):172. [DOI: doi: 10.1055/s-2008-1033961] - PubMed
Liebowitz 2017 {published data only}
    1. Liebowitz M, Clyman RI.Prophylactic indomethacin compared with delayed conservative management of the patent ductus arteriosus in extremely preterm infants: effects on neonatal outcomes. Journal of Pediatrics 2017;187:119-26. - PMC - PubMed
Mahony 1982 {published data only}
    1. Mahony L, Carnero V, Brett C, Heymann MA, Clyman RI.Prophylactic indomethacin therapy for patent ductus arteriosus in very-low-birth-weight infants. New England Journal of Medicine 1982;306(9):506-10. - PubMed
McGuire 2002 {published data only}
    1. McGuire W, Fowlie PW.Treating extremely low birthweight infants with prophylactic indomethacin. Evidence for short term benefits only. BMJ 2002;324(7329):60-1. - PMC - PubMed
Meau‐Petit 2005 {published data only}
    1. Meau-Petit V.Prophylactic ibuprofen vs placebo in very premature infants: a randomised, double blind, placebo-controlled trial. Archives de Pédiatrie 2005;12:605-8.
Ment 1987 {published data only}
    1. Ment LR.Randomized low-dose indomethacin trial for the prevention of intraventricular hemorrhage in very low birth weight neonates. Annals of Neurology 1987;22(3):406-7. - PubMed
Ment 1998 {published data only}
    1. Ment LR, Westerveld M, Makuch R, Vohr B, Allan WC.Cognitive outcome at 4 1/2 years of very low birth weight infants enrolled in the multicenter indomethacin intraventricular hemorrhage prevention trial. Pediatrics 1998;102(1 Pt 1):159-60. - PubMed
Ment 1999 {published data only}
    1. Ment LR, Vohr B, Allan W, Westerveld M, Katz KH, Schneider KC, et al.The etiology and outcome of cerebral ventriculomegaly at term in very low birth weight preterm infants. Pediatrics 1999;104(2 Pt 1):243-8. - PubMed
Morales‐Suarez 1992 {published data only}
    1. Morales-Suarez M, Lemus-Varela L, Udaeta-Mora E, Cardiel-Marmolejo L, Rodríguez-Balderrama I, Liz-Cedillo RE.Indomethacin in the prevention of subependymal-intraventricular hemorrhage in preterm newborns with conventional mechanical ventilation [Indometacina en la prevención de la hemorragia subependimaria-intraventricular del recién nacido pretérmino con ventilación mecánica convencional]. Boletín Médico del Hospital Infantil de México 1992;49(4):217-24. - PubMed
Naulaers 2005 {published data only}
    1. Naulaers G, Delanghe G, Allegaert K, Debeer A, Cossey V, Vanhole C, et al.Ibuprofen and cerebral oxygenation and circulation. Archives of Disease in Childhood. Fetal Neonatal Edition 2005;90(1):F75-6. - PMC - PubMed
Pleacher 2004 {published data only}
    1. Pleacher MD, Vohr BR, Katz KH, Ment LR, Allan WC.An evidence-based approach to predicting low IQ in very preterm infants from the neurological examination: outcome data from the indomethacin Indomethacin Intraventricular Hemorrhage Prevention Trial. Pediatrics 2004;113(2):416-9. - PubMed
Puckett 1985 {published data only}
    1. Puckett CG, Cox MA, Haskins KS, Fisher DJ.Prophylactic indomethacin (I) for the prevention of patent ductus arteriosus (PDA). Pediatric Research 1985;19:358.
Roze 2003 {published data only}
    1. Roze JC, Gournay V, Daoud P, Cambonie G, Chamboux C, Hascoet JM, et al.Multicenter double blind randomized placebo-controlled study comparing prophylactic versus curative ibuprofen treatment in premature infants less than 28 weeks of gestation. Pediatric Research 2003;53:386A.
Rubaltelli 1998 {published data only}
    1. Rubaltelli F, Bertini G, Reali MF, Vangi V, Dani C.Does early closure of PDA with ibuprofen reduce the severity of RDS in premature infants? Pediatric Research 1998;43:296A.
Schmidt 2002 {published data only}
    1. Schmidt B, Wright LL, Davis P, Solimano A, Roberts RS, Indomethacin Prophylaxis in Preterms Investigators.Ibuprofen prophylaxis in preterm neonates. Lancet 2002;360(9331):492. - PubMed
Schmidt 2011 {published data only}
    1. Schmidt B, Seshia M, Shankaran S, Mildenhall L, Tyson J, Lui K, et al, Trial of Indomethacin Prophylaxis in Preterms Investigators.Effects of prophylactic indomethacin in extremely low-birth-weight infants with and without adequate exposure to antenatal corticosteroids. Archives of Pediatrics and Adolescent Medicine 2011;165(7):642-6. - PMC - PubMed
Tyson 2002 {published data only}
    1. Tyson JE.Does indomethacin prophylaxis benefit extremely low birth weight infants? Results of a placebo-controlled multicenter trial. Pediatric Research 2002;51(1):1.
Valls‐i‐Soler 1999 {published data only}
    1. Valls-i-Soler A, Lopez-de-Heredia J, Roman L, Fernandez-Ruanova MB.Prophylactic indomethacin (INDO) in very low birth weight (VLBW) infants with RDS. A pilot study on the effects of a slow infusion rate. Pediatric Research 1999;45(6):901.
van Overmeire 2002 {published data only}
    1. Overmeire B, Casaer A, Allegaert K, Debauche C, Decaluwe W, Jespers A, et al.Multicenter randomized double-blind placebo-controlled trial of ibuprofen prophylaxis in very preterm infants. Pediatric Research 2002;51(4):379A.
Varvarigou 1996 {published data only}
    1. Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, Aranda JV.Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA 1996;275(7):539-44. [PMID: ] - PubMed
Vohr 1999 {published data only}
    1. Vohr B, Allan WC, Scott DT, Katz KH, Schneider KC, Makuch RW, et al.Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap. Seminars in Perinatology 1999;23(3):212-7. - PubMed
Zarkesh 2013 {published data only}
    1. Zarkesh MR, Nili F, Akbari Asbagh P, Nayeri FS, Naeem A.Prophylactic treatment with oral paracetamol for patent ductus arteriosus in preterm infants admitted in Nicu Vali-Asr Hospital In 2012. Iranian Journal Of Pediatrics 2013;23(Suppl 1):54-5.

References to studies awaiting assessment

Akbari Asbagh 2015 {published data only}
    1. Akbari Asbagh P, Zarkesh MR, Nili F, Nayeri FS, Tofighi Naeem A.Prophylactic teatment with oral paracetamol for patent ductus arteriosus in preterm infants: a randomized clinical trial. Tehran University Medical Journal 2015;73(2):86-92.
Kalani 2016 {published data only}
    1. Kalani M, Shariat M, Khalesi N, Farahani Z, Ahmadi S.A comparison of early ibuprofen and indomethacin administration to prevent intraventricular hemorrhage among preterm infants. Acta Medica Iranica 2016;54(12):788-92. - PubMed
Seok 1998 {published data only}
    1. Seok EJ, Kim EJ, Jeon SS, Seo SS.Effect of indomethacin therapy on prevention of intraventricular hemorrhage in very low birth weight infant. Journal of the Korean Society of Neonatal Science 1998;5(1):27-34.

References to ongoing studies

NCT03641209 {published data only}
    1. Aikio O.Extremely low gestatonal age infants' paracetamol study (Paras) [Extremely low gestational age infants' paracetamol study: a randomized trial]. https://clinicaltrials.gov/ct2/show/NCT03641209 (first received 21 August 2018).
NCT04459117 {published data only}
    1. Rozé JC.Prophylactic treatment of the ductus arteriosus in preterm Infants by acetaminophen (TREOCAPA). https://clinicaltrials.gov/ct2/show/NCT04459117 (first received 7 July 2020).

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References to other published versions of this review

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