Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants

Skip sharing on social media links
Share this:

Authors

Arne Ohlsson1, Sachin S Shah2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]
2Neonatal and Pediatric Intensive Care Services, Aditya Birla Memorial Hospital, Pune, India [top]

Citation example: Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD004213. DOI: 10.1002/14651858.CD004213.pub3.

Contact person

Arne Ohlsson

# 14324 County Rd 29
Warkworth Ontario K0K 3K0
Canada

E-mail: aohlsson@mtsinai.on.ca

Dates

Assessed as Up-to-date: 04 April 2011
Date of Search: 20 December 2010
Next Stage Expected: 04 April 2013
Protocol First Published: Not specified
Review First Published: Issue 2, 2003
Last Citation Issue: Issue 7, 2011

What's new

Date / Event Description
02 April 2011
Updated

This updates the review "Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants" published in The Cochrane Library, Issue 3, 2009 (Ohlsson 2009).

02 April 2011
New citation: conclusions changed

The updated search identified one additional trial for inclusion in the review. The review now includes two trials of prophylactic ibuprofen administered orally and five trials of IV administration.

Oral administration of ibuprofen appears as effective as IV administration. There may be a higher risk of upper gastrointestinal bleed with orally administered ibuprofen.

History

Date / Event Description
28 February 2009
Updated

This updates the review "Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants" published in The Cochrane Library, Issue 1, 2006 (Shah 2006).

Updated search identified two additional trials for inclusion in this review.

No change to the conclusion of the review.

22 September 2005
New citation: conclusions changed

Substantive amendment

Abstract

Background

Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal and cerebral side-effects. Ibuprofen has less effect on blood flow velocity to important organs.

Objectives

To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention in the prevention of PDA in preterm infants.

Search methods

Randomized controlled trials of prophylactic ibuprofen were identified by searching in The Cochrane Library, MEDLINE, CINAHL, EMBASE and trials registries in December 2010.

Selection criteria

Randomized or quasi-randomised controlled trials comparing ibuprofen with placebo/no intervention or other cyclo-oxygenase inhibitor drugs to prevent PDA in preterm and/or low birth weight infants.

Data collection and analysis

Outcomes data including presence of PDA on day three, need for surgical ligation or rescue treatment with cyclo-oxygenase inhibitors, mortality, intraventricular haemorrhage (IVH), renal, pulmonary and gastrointestinal complications were extracted. Meta-analyses were performed and treatment estimates are reported as typical weighted mean difference, relative risk (RR), risk difference (RD) and, if statistically significant, number needed to treat to benefit (NNT) or number needed to treat to harm (NNH) along with their 95% confidence intervals (CI).

Results

In this update, seven studies (n = 931) comparing prophylactic ibuprofen with placebo/no intervention are included. Ibuprofen decreased the incidence of PDA on day three [typical RR 0.36 (95% CI 0.29 to 0.46); typical RD -0.27 (95% CI -0.32 to -0.21); NNT 4 (95% CI 3 to 5)], decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical ligation. Results from two studies administering oral ibuprofen had similar results, but showed an increased risk of gastrointestinal bleeding (NNH 4, 95% CI 2 to 17). In the control group the spontaneous closure rate was 58% by day three. Ibuprofen negatively affects renal function. No significant differences in mortality, IVH, chronic lung disease were found.

Authors' conclusions

Prophylactic use of ibuprofen decreased the incidence of PDA, decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical closure. In the control group, the PDA closed spontaneously by day three in 58% of the neonates. Prophylactic treatment exposes many infants to a drug that has concerning renal and gastrointestinal side effects without conferring any important short-term benefits and is not recommended. Until long-term follow-up results are published from the trials included in this updated review, no further trials of prophylactic ibuprofen are recommended.

Plain language summary

Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants

PDA is a common complication for very preterm (premature) or very small babies. PDA is an open vessel that channels blood from the lungs to the body. It should close after birth, but sometimes remains open because of the baby's premature stage of development. PDA can lead to life-threatening complications. Indomethacin is successful in causing PDA closure, but can cause serious adverse effects. Another option is the drug ibuprofen, which can be given to try and prevent PDA. This updated review of trials found that ibuprofen can prevent PDA, but does not confer any other short-term or long-term benefits.

[top]

Background

Description of the condition

Patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants with or without respiratory distress syndrome (RDS) (Ramanathan 1997). In a large Canadian cohort (n = 3, 779) of very-low-birth-weight infants (< 1500 g), the incidence of symptomatic PDA needing treatment was 28% (Lee 2000). The failure of the ductus arteriosus to constrict after birth is due to lower intrinsic tone, less ductal muscle fibres and fewer subendothelial cushions in the preterm infant as compared to the term infant (Hammerman 1995). The immature ductus arteriosus has higher sensitivity to the vasodilating effects of prostaglandins and nitric oxide (Hammerman 1995). This is aggravated by haemodynamic derangements due to respiratory distress syndrome and surfactant therapy (Hammerman 1995).

The clinical consequences of PDA are related to the degree of left to right shunting through the ductus. Despite the ability of the left ventricle in preterm infants to increase its output in face of a left to right shunt, blood flow distribution to vital organs is altered due to drop in diastolic pressure and localized vasoconstriction (Clyman 2000). Substantial left to right shunting through the ductus may increase the risk of intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), chronic lung disease (CLD), and death (Cotton 1979).

Description of the intervention

Inhibiting prostaglandin synthesis with non-selective blockers of both cyclo-oxygenase 1 and 2 is effective for the non-surgical closure of PDA (Clyman 2000). Intravenous indomethacin has become the standard pharmacological treatment for promoting closure of PDA in preterm infants and has been used since 1976 (Friedman 1976) with a reported efficacy of 66 to 80% (Gersony 1983; Van Overmeire 2000; Lago 2002).

The prophylactic use of indomethacin for the prevention of PDA has been shown to reduce the incidence of a symptomatic PDA, the need for surgical ligation, and the occurrence of pulmonary haemorrhage (Domanico 1994; Couser 1996). In a large trial, it was shown that prophylactic use of indomethacin in extremely low birth weight infants reduces the frequency of PDA and severe intraventricular haemorrhage, but there was no evidence of effect on the rate of survival without neurosensory impairment at eighteen months (Schmidt 2001). Similarly, a meta analysis of nineteen eligible studies showed that prophylactic indomethacin reduces the incidence of symptomatic PDA, need for surgical ligation, and incidence of grade 3 and 4 IVH in preterm infants, but without evidence of effect on mortality or the incidence of long-term neurosensory impairment (Fowlie 2010).

However, the use of indomethacin may be followed by side effects such as decreased cerebral blood flow (Van Bel 1989; Edwards 1990; Ohlsson 1993), decreased cerebral blood volume and cerebral oxygen delivery (Patel 2000), oliguria or transient renal failure (Betkerur 1981; Gersony 1983; Van Overmeire 2000; Lago 2002), NEC, isolated bowel perforation or gastrointestinal haemorrhage (Gersony 1983; Grosfeld 1996). Concern regarding these complications potentially related to indomethacin use has tempered the enthusiasm for its use, encouraging many researchers to seek new, safer pharmacological strategies for the closure of a PDA. The only major side effect reported in the Cochrane review by Fowlie (Fowlie 2010) was an increased incidence of oliguria, but this was not associated with major renal impairment. In the same review there was no evidence of difference in rates of NEC, excessive clinical bleeding or sepsis.

Other cyclo-oxygenase inhibitors have been reported to close a PDA. In Japan, mefenamic acid is frequently used in the treatment of PDA (Sakhalkar 1992; Ito 1994; Niopas 1994).

How the intervention might work

Ibuprofen, another cyclo-oxygenase inhibitor drug, has been used for ductal closure in animals (Coceani 1979). Preliminary experimental and clinical studies (Varvarigou 1996; Van Overmeire 1997) have shown that ibuprofen is effective in closing PDA without reducing cerebral flow (Mosca 1997; Patel 2000) or affecting intestinal (Speziale 1999), or renal circulation (Pezzati 1999). Furthermore, ibuprofen enhances cerebral blood flow auto regulation (Chemtob 1990) and has been shown to protect neurological functions following an oxidative stress in a piglet model (Chemtob 1993).

Why it is important to do this review

Trials reporting on the prophylactic use of ibuprofen in preterm neonates have been published over the years justifying the need for a Cochrane review. This review aims to examine the role of prophylactic use of ibuprofen for the prevention of PDA in preterm infants by comparing it to no intervention, placebo, indomethacin, or other cyclo-oxygenase inhibitors.

Objectives

Primary objectives

  1. To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention in the prevention of PDA in preterm and/or low birth weight infants.
  2. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid) in the prevention of PDA in preterm and/or low birth weight infants.

Secondary objectives

To determine in subgroup analyses the effectiveness and safety of prophylactic ibuprofen to close a PDA in relation to the following criteria:
dose of ibuprofen used, route of administration of ibuprofen (IV and oral), gestational age (< 28 weeks, 28 to 32 weeks, 33 to 37 weeks) or birth weight (< 1000 g, 1000 to 1500 g, > 1500 to < 2500 g), method used to diagnose a PDA (only by clinical criteria or by echocardiography criteria).

[top]

Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomised controlled trials with or without blinding.

Types of participants

Preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 g) in their first 72 hours of life (three days).

Types of interventions

Prophylactic use of ibuprofen for prevention of PDA compared to control infants who received no intervention, placebo, other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid) or rescue treatment with ibuprofen.

Types of outcome measures

Primary outcome

The presence of patent ductus arteriosus (clinically symptomatic or diagnosed by ECHO in response to clinical suspicion or diagnosed on routine screening by ECHO) by 72 hours (three days) of age.

Secondary outcomes
  • Neonatal mortality (death during the first 28 days of life).
  • All cause mortality during initial hospital stay.
  • Mortality before 36 weeks postmenstrual age (PMA).
  • Infant mortality (death during the first year of life).
  • Need for rescue treatment with cyclo-oxygenase inhibitors for closure of PDA.
  • Need for surgical closure of PDA.
  • Duration of mechanical ventilation (days).
  • Oxygen requirement (postnatal age in days at time of last day with need for supplemental oxygen).
  • Chronic lung disease (CLD) (defined as oxygen requirements at 28 days postnatal age in addition to compatible clinical and roentgenographic findings).
  • Chronic lung disease (CLD) (defined as oxygen requirements at 36 weeks PMA in addition to compatible clinical and roentgenographic findings) (Shennan 1988).
  • Chronic lung disease (CLD) (age at diagnosis not reported).
  • Pneumothorax.
  • Pulmonary hypertension (PH).
  • Intraventricular haemorrhage (IVH) (all grades).
  • Intraventricular haemorrhage (IVH) (Grade not stated).
  • Intraventricular haemorrhage (IVH) (Grade III, IV) (Papile 1978).
  • Periventricular leukomalacia (PVL).
  • Necrotizing enterocolitis (NEC) (any stage) (Bell 1978).
  • Gastrointestinal haemorrhage.
  • Gastrointestinal perforation (defined by presence of free air in peritoneal cavity on an abdominal x-ray).
  • Time to full enteral feeds (postnatal age in days at time of achieving full enteral feeds).
  • Length of hospitalisation in days from birth to discharge home or death.
  • Urine output after treatment (ml/kg/hr).
  • Oliguria (decreased urine output defined as < 1 cc/kg/hr).
  • Serum creatinine levels after treatment (micromol/L).
  • At least one episode of serum creatinine > 140 micromol/L (> 1.5 mg/dl).
  • At least one episode of severe hypoxaemia.
  • Inhaled nitric oxide administration during first week of life.
  • Retinopathy of prematurity (ROP) (according to the international classification of ROP) (ICROP 1984).
  • Definite sepsis (clinical symptoms and signs of sepsis and a positive bacterial culture in a specimen obtained from normally sterile fluids or tissue obtained at autopsy).
  • Probable sepsis (clinical symptoms and signs of sepsis and an abnormal findings on a laboratory screening test for infection).
  • Side effects not listed as an outcome above but reported by the authors as a side effect.
  • Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized and validated assessment tool and/or a child developmental specialist) at any age (outcome data will be grouped at 12, 18, 24 months if available).

Search methods for identification of studies

See: Cochrane Neonatal Review Group search strategy.

MEDLINE database (1966 to December 2010) was searched using MeSH terms: cyclo-oxygenase inhibitors, ibuprofen or mefenamic acid, newborn, infant, premature (or preterm) or low birth weight infant, patent ductus arteriosus or PDA. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, December Issue, 2010), EMBASE (1980 to December 2010) and CINAHL (1982 to December 2010), abstracts (American Pediatric Society and European Society for Pediatric Research annual meetings) published in Pediatric Research (1990 to December 2010) or electronically were searched. No new trials since the first publication of this review were identified in the searches undertaken in October 2004 but one trial previously published as an abstract (Van Overmeire 2004) and one trial previously published as a letter to the editors (Gournay 2004) were identified as full publications. The reference lists of identified trials were searched. References lists of published narrative and systematic reviews were reviewed. Web of Science was searched in April 2011 and each of two trials of prophylactic use of ibuprofen published in 2000 were entered to identify other publications that have quoted either of these two studies (Dani 2000; De Carolis 2000).

Controlled-Trials.com External Web Site Policy and ClinicalTrials.gov were searched in December 2010 for any registered trials of ibuprofen for prophylaxis of a PDA.

Unpublished data were not sought, but authors of published trials were contacted to clarify or provide additional information. No language restrictions were applied. The retrieved articles were screened by two review authors (SS, AO) to identify articles eligible for inclusion in the review. No language restrictions were applied. For the previous update in 2009 there was only one review author (AO). For the current update, both authors participated in all steps of the review process and both authors abstracted data from the three most current trials (Dani 2005; Sangtawesin 2006; Sangtawesin 2008).

Data collection and analysis

The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of the studies.

The updates conducted in 2005 and 2007 were performed by one review author (AO). The update in 2011 was conducted by both authors.

Selection of studies

All abstracts and published full reports identified as potentially relevant by the literature search were assessed for inclusion in the original review by two review authors (AO, SS).

Data extraction and management

Each review author extracted data separately using pre-designed data abstraction forms. The review authors compared results and resolved differences. One review author (AO) entered data into RevMan 5.1 and the other review author (SS) cross-checked the printout against his own data abstraction forms and errors were corrected by consensus.

For the studies identified as abstracts, some primary authors were contacted to ascertain whether a full publication is available if the full paper was not identified in an electronic data base.

Information from the primary author was obtained if the published article provided inadequate information for the review. Retrieved articles were assessed and data were abstracted independently by the reviewers.

Assessment of risk of bias in included studies

The quality of included trials was evaluated independently by the reviewers, using the following criteria:
Blinding of randomisation?
Blinding of intervention?
Blinding of outcome measure assessment?
Completeness of follow up?

There were three potential answers to these questions - yes, can't tell, no

For the update in 2011, the following issues were evaluated and entered into the Risk of Bias table:

Selection bias (random sequence generation and allocation concealment).

For each included study, we categorized the risk of selection bias as:

Random sequence generation
  • Low risk - adequate (any truly random process e.g. random number table; computer random number generator);
  • High risk - inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number);
  • Unclear risk - no or unclear information provided.
Allocation concealment

For each included study, we categorized the risk of bias regarding allocation concealment as:

  • Low risk - adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • High risk - inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
  • Unclear risk - no or unclear information provided
Performance bias

For each included study, we categorized the methods used to blind study personnel from knowledge of which intervention a participant received. (As our study population consisted of neonates they would all be blinded to the study intervention).

  • Low risk - adequate for personnel (a placebo that could not be distinguished from the active drug was used in the control group);
  • High risk - inadequate personnel aware of group assignment;
  • Uncelar risk - no or unclear information provided.
Detection bias

For each included study, we categorized the methods used to blind outcome assessors from knowledge of which intervention a participant received. (As our study population consisted of neonates they would all be blinded to the study intervention). Blinding was assessed separately for different outcomes or classes of outcomes. We categorized the methods used with regards to detection bias as:

  • Low risk - adequate follow-up was performed with assessors blinded to group assignment;
  • High risk - inadequate assessors at follow-up were aware of group assignment;
  • Unclear risk - no or unclear information provided.
Attrition bias

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods with respect to the risk attrition bias as:

  • Low risk - adequate (< 10% missing data);
  • High risk - inadequate (> 10% missing data);
  • Unclear risk - no or unclear information provided.
Reporting bias
  • For each included study, we described how we investigated the risk of selective outcome reporting bias and what we found. We assessed the methods as:
  • Low risk - adequate (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);
  • High risk - inadequate (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

Unclear risk - no or unclear information provided (the study protocol was not available).

Other bias

For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

  • Low risk - no concerns of other bias raised;
  • High risk - concerns raised about multiple looks at the data with the results made known to the investigators, difference in number of patients enrolled in abstract and final publications of the paper;
  • Unclear - concerns raised about potential sources of bias that could not be verified by contacting the authors.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

For the original review, independent quality assessments were conducted by two review authors (AO, SS), who were not blinded to authors, institution or journal of publication. The updates in 2005, 2007 were conducted by one review author (AO). The current update in 2011 was conducted by both authors (AO, SS).

Measures of treatment effect

The statistical analyses followed the recommendations of the Cochrane Neonatal Group. A weighted treatment effect was calculated using the RevMan 5.1 package. The treatment effect estimates included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous outcomes, and weighted mean difference (WMD) for continuous outcomes. All estimates of treatment effects were reported with 95% confidence intervals (CI).

Assessment of heterogeneity

Heterogeneity tests including the I- squared test (I2) were performed to assess the appropriateness of pooling the data. The degree of heterogeneity was roughly categorized according to Higgins and co-workers (Higgins 2003) as 25% = low, 50% = moderate, and 75% = high.

Planned subgroup analyses were performed according to the criteria listed under objectives. No sensitivity analyses were performed.

Assessment of reporting biases

To ascertain the possibility of publication bias, one funnel plot was conducted for the primary outcome of 'Failure to close a PDA (after single or three doses)' (Figure 3) and for the outcome of NEC (Figure 4). Both funnel plots were quite symmetric indicating that there was no obvious indication of publication bias.

Data synthesis

Meta-analyses were performed using Review Manager software (RevMan 5.1) supplied by the Cochrane Collaboration. For estimates of typical RR and RD, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

The following subgroup analyses were planned:

  • Gestational age (< 28 weeks, 28 to 32 weeks, 33 to 36 weeks)
  • Birth weight (< 1000 g, 1000 to 1500 g, 1501 to 2500 g)
  • Method used to diagnose a PDA (by ECHO criteria or only by clinical criteria)
  • A dosing regimen of 10 mg/kg of ibuprofen followed by 5 mg/kg of ibuprofen 24 and 48 hours later, or 0.2 mg/kg of indomethacin at 12 hours intervals for three doses

The prespecified subgroup analyses excluding studies that used only one dose of medication and studies that were published as abstracts only were abandoned for the previous and this update of the review. Only one study used a single dose and only one abstract was identified. The results of these studies are incorporated with the other studies.

For the current up date (2011) we added three post-hoc analyses

Oral ibuprofen has now been studied in two RCTs and to compare the effectiveness of oral versus IV ibuprofen we performed two additional analyses:

  • Comparison: Oral ibuprofen versus placebo; primary outcome "the presence of patent ductus arteriosus (diagnosed on routine screening by ECHO) by 72 hours (three days) of age".
  • Comparison IV ibuprofen versus placebo; primary outcome "the presence of patent ductus arteriosus (diagnosed on routine screening by ECHO) by 72 hours (three days) of age".
  • To try and explain the heterogeneity noted in the analysis for gastrointestinal haemorrhage where three trials were included; one trial used IV ibuprofen and two trials used oral ibuprofen. In the post-hoc analysis the two trials using oral ibuprofen were combined.

[top]

Results

Description of studies

Seven studies comparing prophylactic ibuprofen with placebo or no medication qualified for inclusion in this updated review (Van Overmeire 2004; Dani 2000; De Carolis 2000; Gournay 2004; Dani 2005; Sangtawesin 2006; Sangtawesin 2008). The addition of one study (Sangtawesin 2008) published since the last version of this review increased the total number enrolled in trials by 62 to 931. All have been published as full text articles. Rubaltelli published an abstract in 1998 which reported an interim analysis of Dani 2000. The dose and duration of prophylactic ibuprofen was similar in all the studies, but the age at which ibuprofen was started varied from two to 24 hours in the different studies. In two studies oral ibuprofen was used (Sangtawesin 2006; Sangtawesin 2008) and in all other studies ibuprofen was administered IV. PDA at 72 hours diagnosed using echocardiographic criteria was reported as an outcome in all studies. Echocardiographic criteria of a significant PDA were similar between the studies. Back-up medical treatment with cyclo-oxygenase inhibitors (indomethacin or ibuprofen) was permitted in the presence of significant PDA (after initial trial of ibuprofen, placebo or no medication) in all trials (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004; Dani 2005; Sangtawesin 2006; Sangtawesin 2008). Further details can be found in table 'Characteristics of Studies'. No study of ibuprofen versus other cyclo-oxygenase inhibitors was identified.

Dani 2000 - This trial enrolled 80 preterm neonates with gestational age < 34 weeks with RDS requiring either continuous positive airway pressure (CPAP) with fractional inspired oxygen concentration (FiO2) > 0.3 or mechanical ventilation (synchronized intermittent mandatory ventilation or high frequency ventilation). The infants were randomised to receive intravenous ibuprofen lysine (10 mg/kg, followed by 5 mg/kg after 24 and 48 hours) either within 24 hours of life (prophylactic) or after echocardiographic diagnosis of PDA (selective). When PDA was still present after the first course of ibuprofen, a second course was administered. Failure to respond to ibuprofen was an indication for surgical ligation. Primary outcome was incidence of significant PDA as determined by echocardiographic analysis. Echocardiographic evaluation was performed on day three, seven and 21 of life. Other studied variables were ventilatory support, renal function, biochemical and hematological profiles, frequency of CLD at 36 weeks PMA, IVH, NEC, ROP and time to reach full feeds.

De Carolis 2000 - The trial enrolled 50 preterm neonates with gestational age < 31 weeks. The infants were randomly assigned at two hours of age to prophylaxis group or control group. Two infants in each group died during the first 24 hours after birth and were not included by the authors in the final analysis. The prophylaxis group (n = 23) received intravenous (iv) treatment with ibuprofen lysine (10 mg/kg) followed by 5 mg/kg after 24 and 48 hours. No placebo was given to the control group (n = 23). In the presence of a significant PDA at the completion of the ibuprofen cycle, treatment with indomethacin (three times 0.2 mg/kg at 12 hourly intervals, administered by iv infusion over 20 minutes) was carried out. The same treatment was administered to infants in the control group who had a significant PDA on day three of life. Failure to respond to medical treatment was an indication for surgical treatment. Primary outcome was incidence of significant PDA as determined by echocardiographic analysis. Echocardiographic evaluation was performed immediately after birth, on day three of life and whenever there was a clinical suspicion of PDA. Other studied variables were ventilatory support, renal function, biochemical and hematological profiles, need for surgical ligation for PDA, frequency of CLD at 28 days, IVH, NEC, ROP and time to reach full feeds.

Gournay 2004 - This multicenter trial enrolled 135 infants < 28 weeks gestational age and postnatal age < 6 hours. The infants were randomly assigned to prophylactic ibuprofen or placebo group, both of which were given as three successive doses 24 hours apart. The initial dose of ibuprofen was 10 mg/kg, and the two following doses were 5 mg/kg, infused iv over 20 minutes. The primary outcome was need for surgical ligation. Other outcomes included: mortality, PDA on day three by echocardiogram, need of back-up treatment with indomethacin, PVL, grade III or IV IVH, NEC, intestinal perforation, duration of mechanical ventilation, CLD at 36 weeks PMA, renal function, actuarial curve of survival during the study period. Occurrence of pulmonary hypertension within one hour of administration of ibuprofen was reported in three infants < 27 weeks and < 1000 g. The trial was stopped prematurely after enrolment of 135 infants due to this adverse effect.

Van Overmeire 2004 - In this multicenter trial 415 preterm infants < 31 weeks of gestation were randomised to receive either three doses of intravenous ibuprofen lysine (10 mg/kg followed by 5 mg/kg after 24 and 48 hours interval) or saline (1 ml/kg as initial dose, 0.5 ml/kg as subsequent doses). The initial dose of medication was given within six hours after birth and subsequent doses were given at 24 and 48 hours interval after the initial dose. Two hundred five infants received ibuprofen (10 mg/ml) while 210 received saline. Cerebral and cardiac ultrasound were performed before and after treatment. The trial was conducted double blind. Perinatal characteristics and possible side-effects were registered. The primary outcome variable was IVH grade 3 or 4. Secondary outcomes included: echocardiographically confirmed PDA after day three of life and the need for its pharmacological rescue treatment or surgical ligation, occurrence of renal dysfunction measured by urine production, NEC and death.

Dani 2005 - This multicenter study enrolled 155 infants < 28 weeks gestational age and postnatal age < 6 hours in seven tertiary neonatal care units in Italy. Infants were assigned randomly to the treatment or the control group using sealed envelopes. Envelopes were prepared centrally and distributed to the different units. Infants in the prophylactic ibuprofen group received 3 doses of ibuprofen lysine (Arfen, Lisapharma, Erba, Italy; 10 mg/kg within 6 hours after birth, followed by 5 mg/kg after 24 and 48 hours. Infants in the control group received indistinguishable placebo. The medications were infused continuously iv over 15 minutes. The primary outcome was IVH (grade 2 to 4) at seven days of life. Other outcomes included IVH at days 15, 30 and at 40 weeks' PMA, PVL, PDA on day 3 (defined as echocardiographic evidence of a haemodynamically significant PDA), mortality, CLD at 36 weeks' PMA, NEC, sepsis (confirmed with positive blood culture), urine output after treatment, oliguria, increased serum creatinine levels after treatment, length of hospital stay and ROP.

Sangtawesin 2006 - This single centre trial enrolled 42 infants of 28 to 32 weeks gestational age and birth weight less than/or equal to 1500 g and postnatal age < 24 hours. The infants were randomly assigned to ibuprofen or control group by block randomisation. The prophylaxis group received ibuprofen suspension (Junifen, Boots Company, Thailand) at a dosage of 10 mg/kg via an orogastric tube, followed by 0.5 ml of distilled water. The first dose was given within the first 24 hours of life. The second and third doses were given within 24 and 48 hours after the first dose respectively. The patients in the control group were given three doses of an orange starch suspension as placebo that looked like ibuprofen. The primary outcome was presence of a PDA (defined as echocardiographic evidence of a haemodynamically significant PDA) on day three of treatment. Additional outcomes included neonatal mortality, duration of mechanical ventilation, pulmonary hypertension, NEC, gastrointestinal haemorrhage, time to full enteral feeds, ROP (grades not stated), length of hospital stay, CLD (age at diagnosis not stated), days of supplemental oxygen therapy, days of mechanical ventilation, IVH (grades not stated), need for rescue treatment with indomethacin or ibuprofen or surgical closure of the PDA and PH.

Sangtawesin 2008 (new inclusion) - This single centre trial enrolled 62 infants with birthweight < 1500 g and postnatal age < 24 hours. The infants were known to have a PDA diagnosed by echocardiography on entry into the trial. Infants were randomly assigned to three doses of oral ibuprofen suspension (Junifen, Boots Company, Thailand) at a dosage of 10 mg/kg for the first dose within 24 hours of life and 5 mg/kg for the second and third doses after 24 and 48 hours. The drug was given via an orogastric tube, followed by 0.5 ml of distilled water. The infants in the control group received three doses of orange starch suspension as placebo administered with the same method and time schedule as oral ibuprofen suspension in the study group. The external appearance of placebo was like ibuprofen suspension and could not be differentiated by naked eyes. The medical personnel who took care of the patients were blind to group assignment. The primary outcome was closure of PDA (defined as lack of echocardiographic evidence of a haemodynamically significant PDA) on day three of treatment. Other outcomes included PPHN, BPD, days of assisted ventilation, days in supplemental oxygen, serum BUN on day three, serum creatinine on day three, days to start feeding, days to reach full feeds, gastrointestinal bleeding, NEC greater than/or equal to stage 2, ROP ( total and stage 1 and stage 2), IVH (grade 1 and grades 1-3), length of hospital stay (days), mortality during the study period (28 days).

Risk of bias in included studies

For details see Risk of bias table.

Dani 2000 - This was a randomised controlled trial involving two centres in Italy. Randomization was performed using sealed envelopes. There was no blinding of intervention or assessment. Follow-up was complete and outcomes were reported for all infants enrolled in the study. An intention to treat analysis was performed.

De Carolis 2000 - This was a randomised controlled trial involving a single centre in Italy. Method of randomisation is unclear. We quote the authors. "Randomization was carried out at birth by random permuted blocks for both prophylaxis and control groups, envisaging 25 neonates in each". There was no blinding of the intervention. There was blinding of outcome measurement. An intention to treat analysis was not performed.

Gournay 2004 - This was a multicenter, randomised double blind, placebo-controlled trial conducted in 11 tertiary neonatal intensive care centres in France. The allocation was concealed. One hundred thirty five infants were included. However, four patients were not randomly assigned because of errors in study drug allocation [three mistakenly received open-label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10-day-old patient diagnosed with PDA was mistakenly given two doses of the randomised test drug (placebo) instead of curative ibuprofen]. The per protocol analyses were performed on 131 infants. No patient was lost to follow-up. The trial was closed earlier than planned after three episodes of refractory hypoxaemia with pulmonary hypertension happened after the first prophylactic injection in three different centres. The Agence Francaise du Medicament was notified and requested un blinding of the treatment received in these three cases. The treatment was ibuprofen in all three cases and the recruitment was closed on December 14, 2001. This study was industry sponsored. The sponsor of the study was involved in study design, data management, data analysis, and data interpretation.The study sponsor had no role in writing the report or the decision to submit the report for publication. All final data analyses were done by the sponsor and double checked by the first author who had free access to the raw data.

Van Overmeire 2004 - Multicentre randomised controlled trial involving seven centres in Belgium. Randomization was done independently by the chief pharmacist at each hospital. The trial was conducted double blind and saline was used as placebo. Follow-up was complete and outcomes were reported for all infants enrolled in the study. An intention to treat analysis was performed. The study was published as an abstract when 358 infants had been enrolled. There is no mention of this interim analysis in the final publication.

Dani 2005 - This was a multi-centre double-blind placebo-controlled randomised trial conducted in seven tertiary neonatal care units in Italy. The infants were assigned randomly to treatment groups with the sealed-envelope technique. Envelopes were prepared at Careggi University Hospital of Florence and then distributed to participating hospitals. The authors did not state how the randomisation sequence was created. Five infants were excluded after randomisation because of incomplete data collection (four in the ibuprofen group and one in the placebo group).

Sangtawesin 2006 - This was a single-centre placebo-controlled randomised trial conducted in Thailand. Patients were randomly assigned into the study and control group by block randomisation. It is not clear whether the allocation to study groups was concealed or not and how the randomisation sequence was created. The authors do not state how the randomisation sequence was created. The patients in the control group were given 3 doses of orange starch suspension as placebo that looked like ibuprofen. The medical personnel who took care of the patients were blind to group assignment. The outcomes for all 42 patients who were randomised are reported.

Sangtawesin 2008 - This was a single-centre placebo-controlled randomised trial conducted in Thailand. Patients were randomly assigned into the study and control group by block randomisation. It is not clear whether the allocation to study groups was concealed or not. The authors do not state how the randomisation sequence was created. The external appearance of placebo was like ibuprofen suspension and could not be differentiated by naked eyes. The medical personnel who took care of the patients were blind to group assignment. The outcomes for all 62 patients who were randomised are reported.

Effects of interventions

Primary outcome

IBUPROFEN VS. PLACEBO OR NONE (COMPARISON 1)
The presence of patent ductus arteriosus (diagnosed on routine screening by ECHO) by 72 hours (three days) of age (Outcome 1.1) Figure 1:

This was reported in all seven trials (n = 931) (Van Overmeire 2004; Dani 2000; De Carolis 2000; Gournay 2004; Dani 2005; Sangtawesin 2006; Sangtawesin 2008). All of the trials except one (Sangtawesin 2008) noted a statistically significant decrease in the incidence of PDA on day three in the group receiving prophylactic ibuprofen. In the meta-analysis, there was a statistically significant decrease in the incidence of PDA on day three in the prophylactic ibuprofen group as compared to the placebo group. The typical estimates were RR 0.36 (95% CI 0.29 to 0.46); RD -0.27 (95% CI -0.32 to -0.21); NNT 4 (95% CI 3 to 5). There was no statistically significant between study heterogeneity for this outcome [p = 0.28; I2 = 19% (low) for RR and p = 0.18; I2 = 32% (low) for RD]. A forest plot was quite symmetrical around the typical point estimate for RR Figure 2.

In subgroup analyses including two studies (Van Overmeire 2004; Dani 2005) for the gestational age group less than/or equal to 28 weeks (n = 420) the RR was 0.41 (95% CI 0.29 to 0.58); RD -0.23 (95% CI -0.31 to -0.15); NNT 4 (95% CI 3 to 7) (Outcome 1.30). There was no significant heterogeneity for this outcome RR p = 0.40, I2 = 0%; RD p = 0.62; I2 0%. For the gestational age group 29 to 30 weeks (n = 150) the RR was 0.29 (95% CI 0.13 to 0.64); RD -0.23 (95% CI -0.35 to -0.10); NNT 4 (95% CI 3 to 10) (Outcome 1.31). For the birth weight group less than/or equal to 1000 g (n = 196) the RR was 0.37 (95% CI 0.23 to 0.61); RD -0.28 (95% CI -0.40 to -0.16); NNT 4 (95% CI 3 to 6) (Outcome 1.32). For the birth weight group 1001 to 1500 g (n = 185) the RR was 0.47 (95% CI 0.27 to 0.81); RD -0.18 (95% CI -0.30 to -0.06): NNT 6 (95% CI 3 to 17) (Outcome 1.33). All secondary analyses were statistically significant.

Secondary outcomes

Neonatal mortality (death during the first 28 days of life) (Outcome 1.2):

Mortality at < 28 days was reported in four trials (n = 234) (Dani 2000; De Carolis 2000; Sangtawesin 2006; Sangtawesin 2008). There was no statistically significant difference in the mortality between the groups in either trial. In the meta-analysis there was no statistically significant difference in the mortality between the two groups. The typical estimates were RR 1.08 (95% CI 0.47 to 2.48), RD 0.01 (95% CI -0.06 to 0.08). There was no statistically significant heterogeneity for this outcome [RR p = 0.66; I2 0% (low); RD p = 0.55; I2 = 0% (low)].

All cause mortality during initial hospital stay (Outcome 1.3):

This was reported in four trials (n = 700) (Van Overmeire 2004; Dani 2000; De Carolis 2000; Dani 2005). None of the trials found a significant difference in the mortality between the groups. In the meta-analysis there was no statistically significant difference in the incidence of mortality. The typical estimates were RR 0.90 (95% CI 0.62 to 1.30) and RD -0.01(95% CI -0.06 to 0.03). There was no statistically significant heterogeneity for this outcome [RR p = 0.68; I2 = 0% (low); RD p = 0.72, I2 = 0% (low)].

Mortality before 36 weeks PMA (Outcome 1.4):

This was reported in one trial (n = 131) (Gournay 2004). The relative risk was 0.96 (95% CI 0.56 to 1.66) and the RD was -0.01 (95% CI -0.17 to 0.14), neither of which were statistically significant. Test for heterogeneity not applicable. Test for heterogeneity not applicable.

Infant mortality (death during the first year of life):

This outcome was not reported by any of the authors.

Need for rescue medical treatment with cyclo-oxygenase inhibitors for closure of PDA (Outcome 1.5) :

This outcome was reported in six trials (n = 776) (Dani 2000; De Carolis 2000; Gournay 2004; Sangtawesin 2006; Van Overmeire 2004; Sangtawesin 2008) and all studies found a statistically significantly reduced need for rescue medical treatment in the prophylaxis group based on RD. Dani et al (Dani 2000) used ibuprofen for rescue treatment and De Carolis et al (De Carolis 2000) used indomethacin for rescue treatment. Van Overmeire et al (Van Overmeire 2004) used either indomethacin or ibuprofen. Gournay et al (Gournay 2004) initiated rescue treatment with ibuprofen and if this failed used indomethacin. Sangtawesin (Sangtawesin 2006) used indomethacin and/or ibuprofen. Sangtawesin (Sangtawesin 2008) used indomethacin as rescue treatment. In the meta-analysis, there was decreased need for rescue medical treatment in the group receiving prophylactic ibuprofen. The typical estimates were RR 0.17 (95% CI 0.11 to 0.26), RD -0.27 (95% CI -0.32 to -0.22); NNT 4 (95% CI 3 to 5). There was statistically significant between study heterogeneity for this outcome for RD [P < 0.00001, I2 = 88% (high) but not for RR (p = 0.10; I2 45% (low)

Need for surgical closure of PDA (Outcome 1.6):

This outcome was reported in six trails (n = 889) (Dani 2000; De Carolis 2000; Gournay 2004; Dani 2005; Van Overmeire 2004; Sangtawesin 2008). One trial (Gournay 2004) found a significant difference between the groups. In the meta-analysis there was a statistically significant decrease in the need for surgical ligation between the two groups. The typical estimates from the meta-analysis were RR 0.40 (95% CI 0.18 to 0.88), RD -0.03 (95% CI -0.05 to -0.00).and NNT 33 (95% CI 20 to infinity). There was no statistically significant heterogeneity for this outcome [RR p = 0.55, I2 0% (low); RD p = 0.19, I2; 33% (low)].

Duration of mechanical ventilation (days) (Outcome 1.7):

Duration of mechanical ventilation was reported in five trials (n = 470) (Dani 2000; Dani 2005; Gournay 2004; Sangtawesin 2006; Sangtawesin 2008) and there was no statistically significant difference between the groups in any of the trials. The typical WMD was 1 day (95% CI -2 to 4). There was no statistically significant heterogeneity for this outcome [p = 0.80, I2 = 0% (low)]. Van Overmeire (n = 415) (Van Overmeire 2004) reported on this outcome but as medians and inter-quartile ranges. For the ibuprofen group the results were 4 (2 - 10) days and in the placebo group 4 (1 - 8) days; p = 0.49.

Days requiring supplemental oxygen (Outcome 1.8):

Three studies reported on this outcome (n =259) (Dani 2005, Sangtawesin 2006; Sangtawesin 2008) and all trials found no significant difference between the groups. The typical WMD was -0.18 days (95% CI -4.98 to 4.61). There was no statistically significant heterogeneity for this outcome [p = 0.22, I2 33% (low). Van Overmeire (n = 415) (Van Overmeire 2004) reported (in medians and inter-quartile ranges) on days on supplemental oxygen. The results were for the ibuprofen group 25 (6 to 52) days and for the placebo group 24 (6 to 44) days; p = 0.36.

Chronic lung disease among survivors (defined as oxygen requirements at 28 days postnatal age in addition to compatible clinical and roentgenographic findings) (Outcome 1.9):

This outcome was reported in one trial (n = 41) (De Carolis 2000). There was no statistically significant difference in the incidence of CLD between the groups. The estimates were RR 0.88 (95% CI 0.32 to 2.42), RD -0.04 (95% CI -0.31 to 0.24). Test for heterogeneity not applicable.

Chronic lung disease (defined as oxygen requirements at 36 weeks PMA in addition to compatible clinical and roentgenographic findings) (Outcome 1.10):

Chronic lung disease at 36 weeks PMA was reported in four trials (n = 781) (Dani 2000; Gournay 2004; Van Overmeire 2004; Dani 2005). There was no statistically significant difference between the groups in either of the individual trials. The typical estimates were RR 1.04 (95% CI 0.87 to 1.25), RD 0.02 (95% CI -0.05 to 0.08). There was no statistically significant heterogeneity for this outcome for [RR p = 0.50; I2 = 0% (low); RD p = 0.40, I2 = 0% (low)].

Chronic lung disease (age at diagnosis not stated) (Outcome 1.11):

Chronic lung disease (age at diagnosis not stated) was reported in two trials (Sangtawesin 2006; Sangtawesin 2008) (n = 99). There was no statistically significant difference between the groups in either of the two trials. The typical estimates were RR 0.94 (95% CI 0.51 to 1.72); RD -0.02 (95% CI -0.19 to 0.15)]. There was significant heterogeneity for this outcome [RR p =0.03, I2 79% (high); RD p = 0.01, I2 = 84% (high)].

Pneumothorax:

No trial reported on this outcome.

Pulmonary hypertension (Outcome 1.12):

Pulmonary hypertension was reported in four trials (n = 390) (Gournay 2004; Dani 2005; Sangtawesin 2006; Sangtawesin 2008). In the study by Gournay 2004 three infants in the ibuprofen group (n = 65) developed PH within one hour of administration of the drug which was responsive to inhaled nitric oxide, as compared to none of the infants in the placebo group (n = 66). In the other three studies no cases of PH developed. The typical RR was 7.11 (95% CI 0.37 to 135), RD 0.02 (95% CI -0.01 to 0.04). Test for heterogeneity not applicable for RR; for RD p = 0.40, I2 = 0% (low).

Intaventricular haemorrhage (All grades) (Outcome 1.13):

IVH (all grades) were reported in 5 trails (n = 839) (Dani 2000; Dani 2005; Gournay 2004; Sangtawesin 2008; Van Overmeire 2004). The typical RR was 1.00 (95% CI 0.82 to 1.23) and the RD was -0.00 (95% CI -0.06 to 0.06). There was no statistically significant heterogeneity for this outcome [RR p = 0.78, I2 = 0% (low); RD p = 0.77. I2 = 0% (low)].

Intraventricular haemorrhage (Grades not stated) (Outcome 1.14):

This outcome was reported in one study (n = 40) (Sangtawesin 2006). The RR was 0.45 (95% CI 0.09 to 2.20). The RD was -0.12 (95% CI -0.34 to 0.11). Test for heterogeneity not applicable.

Intraventricular haemorrhage (Grade III, IV) (Papile 1978) (Outcome 1.15):

IVH grade 3 or 4 was reported in five trials (n = 827) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004; Dani 2005). There was no significant difference in the incidence of IVH between the groups in any of the trials. In the meta-analysis there was no statistically significant difference in the incidence of grade 3 or 4 IVH between the two groups. The typical estimates from the meta-analysis were RR 0.82 (95% CI 0.54 to 1.26), and RD -0.02 (95% CI -0.06 to 0.02) There was no between study heterogeneity for this outcome [RR p = 0.44; I2 = 0% (low); RD p = 0.38, I 2 = 5% (low)].

Periventricular leukomalacia (PVL) (Outcome 1.16):

PVL was reported in four trials (n = 747) (De Carolis 2000; Gournay 2004; Van Overmeire 2004; Dani 2005) and there was no statistically significant difference in the incidence of PVL between the groups in the individual trials. The typical estimates were RR 1.19 (95% CI 0.64 to 2.18), RD 0.01 (95% CI -0.02 to 0.04). There was no statistically significant heterogeneity for this outcome [RR p = 0.62, I2 = 0% (low); RD p = 0.71, I2 = 0% (low)].

Necrotizing enterocolitis (NEC) (any stage) (Bell 1978) (Outcome 1.17):

This was reported in all 7 trials (n = 930) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004; Dani 2005; Sangtawesin 2006; Sangtawesin 2008) and one of the trials (Gournay 2004) found a significant difference in the incidence of NEC between the groups (RD 0.12 (95% CI 0.02 to 0.23). In the meta-analysis there was no statistically significant difference in the incidence of NEC. The typical estimates were RR 1.04 (95% CI 0.63, 1.70), RD 0.00 (95% CI -0.03 to 0.03). There was no statistically significant between study heterogeneity for this outcome for RR [p = 0.15; I2 = 38% (low) and for RD (p = 0.12, I2 = 41% (low)].

Gastrointestinal haemorrhage (Outcome 1.18):

This outcome was reported in three trials (n = 184) (Dani 2000; Sangtawesin 2006; Sangtawesin 2008) and there was no statistically significant difference between the groups in the individual trials. The typical estimates were RR 2.03 (95% CI 1.16 to 3.55) and RD 0.14 (95% CI 0.04 to 0.25) and were statistically significantly increased for the ibuprofen group. Test for heterogeneity showed no statistically significant heterogeneity for this outcome for RR [p = 0.92, I2 = 0% (low)] but for RD [p = 0.001, I2 = 85% (high)].

Gastrointestinal perforation (defined by presence of free air in peritoneal cavity on an abdominal x-ray) (Outcome 1.19):

This outcome was reported in one trial (n = 131) (Gournay 2004) and there was no statistically significant difference between the groups. The relative risk was 5.08 (95% CI 0.61 to 42.28) and the RD was 0.06 (95% CI -0.01 to 0.13). Test for heterogeneity not applicable.

Time to reach full enteral feeds (days) (Outcome 1.20):

This was reported in three trials (n = 184) (Dani 2000; Sangtawesin 2006; Sangtawesin 2008) and there was no statistically significant difference between the groups in the individual studies. The typical estimate was mean difference 0.47 days (95% CI -2.99 to 3.94). There was no statistically significant heterogeneity for this outcome [p = 0.80, I2 = 0% (low)].

Length of hospital stay (total length of hospitalisation from birth to discharge home or death in days) (Outcome 1.21):

This was reported in four trials (n = 339) (Dani 2000; Dani 2005; Sangtawesin 2006; Sangtawesin 2008) and there was no statistically significant difference between the groups. The typical WMD estimate was -2 days (95% CI -7 to 4). There was no statistically significant heterogeneity for this outcome [p = 0.49; I2 = 0% (low)].

Urine output after treatment (ml/kg/hr on day 3) (Outcome 1.22):

Urine output after treatment was reported in three trials (n = 650) (Dani 2000; Van Overmeire 2004; Dani 2005) and there was no statistically significant difference between the groups in the individual trials. The the typical WMD was -0.05 mL/kg/hr (95% CI -0.26 to 0.15). There was no statistically significant heterogeneity for this outcome [p = 0.46, I2 = 0% (low)]. De Carolis et al (De Carolis 2000) reported urine output on day three as median (range) in the ibuprofen group 3.3 (1.3 to 4.6) ml/kg/hr and in the control group 2.3 (1.1 to 4.9) ml/kg/hr.

Renal complications - Oliguria (urine output < 1 cc/kg/hr) (Outcome 1.23):

Two studies (n = 286) (Gournay 2004; Dani 2005) reported on this outcome. The RR was 1.23 (95% CI 0.71 to 2.12) and the RD was 0.03 (95% CI -0.05 to 0.11) (Outcome 1.23.2). One study (n = 415) Van Overmeire 2004 reported on oliguria defined as < 0.5 ml/kg/hour (Outcome 1.23.1). The statistically significant RR was 1.54 (95% CI 1.01 to 2.34) and the RD (of borderline statistical significance) was 0.08 (95% CI 0.00 to 0.15). Combining the three studies (n = 701) (Outcome 1.23) the typical RR was statistically significantly increased at 1.42 (95% CI 1.02, 1.98) and the typical RD was of borderline statistical significance at 0.06 (95% CI 0.00 to 0.11). There was no statistically significant heterogeneity for the meta-analysis of the three studies for RR [p = 0.60, I2 = 0% (low)] and for RD [p = 0.70, I2 = 0% (low)].

Serum creatinine levels (mg/dL) after treatment (Outcome 1.24):

Serum creatinine levels after treatment were reported in five trials (n = 754) (Van Overmeire 2004; Dani 2000; Dani 2005; Sangtawesin 2006; Sangtawesin 2008). In the meta-analysis, there was a statistically significant increase in the serum creatinine levels on day three in the group receiving ibuprofen as compared to the group receiving placebo. The typical estimate was WMD 0.09 mg/dL (95% CI 0.05 to 0.13). There was significant between study heterogeneity [p = 0.02; I2 = 65% (moderate)]. De Carolis et al (De Carolis 2000) reported serum creatinine levels on day three as median (range) in the ibuprofen group 1.3 (0.8 to 1.7) mg/dl and in the control group 1.2 (0.8 to 1.5) mg/dl.

At least one episode of serum creatinine > 140 micromol/L (1.6 mg/dL) (Outcome 1.25):

Gournay (Gournay 2004) and Dani (Dani 2005) reported on "at least one episode of serum creatinine > 140 micromol/L (1.6 mg/dL). The typical RR was 3.70 (95% CI 1.05, 12.98); and the typical RD was 0.06 (95% CI 0.01 to 0.11); Number needed to harm (NTH) was 17 (95% CI 9 to 100); 2 trials, n = 285. There was statistically significant heterogeneity for this outcome (RR p = 0.21, I2 = 36%; RD p = 0.05, I2 = 73%).

At least one episode of severe hypoxaemia (Outcome 1.26):

One trial reported on this outcome (n = 131) (Gournay 2004). The RR was 1.69 (95% CI 0.80 to 3.59); RD 0.09 (95% CI -0.04 to 0.23). Test for heterogeneity not applicable.

Inhaled nitric oxide use during first week of life (Outcome 1.27):

This outcome was reported in one study (n = 131) (Gournay 2004). The RR was 1.89 (95% CI 0.80 to 4.42) and the RD 0.09 (95% CI -0.03 to 0.22) (neither reached statistical significance). Test for heterogeneity not applicable.

Retinopathy of prematurity (ROP) (according to the international classification of ROP) (ICROP 1984) (Outcome 1.28):

ROP was reported in four trials (n = 333) (Dani 2000; Dani 2005; Sangtawesin 2006; Sangtawesin 2008) and there was no statistically significant difference between the groups. The estimates were typical RR 1.02 (95% CI 0.73 to 1.41), RD 0.00 (95% CI -0.09 to 0.10). there was no statistically significant heterogeneity for this outcome [RR p = 0.56, I2 = 0% (low); RD p = 0.54, I2 = 0% (low)].

Definite sepsis (clinical symptoms and signs of sepsis and a positive bacterial culture in a specimen obtained from normally sterile fluids or tissue obtained at autopsy) (Outcome 1.29):

The incidence of sepsis was reported in two trials (n = 201) (De Carolis 2000; Dani 2005) and there was a statistically significant difference between the groups. The estimates were typical RR 2.70 (95% CI 1.10 to 6.59), RD 0.10 (95% CI 0.02 to 0.19); NNTH 10 (95% CI 5 to 50).Test for heterogeneity [RR p = 0.45, I2 = 0% (low); RD p = 0.08, I2 68% (moderate)].

Probable sepsis (clinical symptoms and signs of sepsis and an abnormal findings on a laboratory screening test for infection):

This outcome was not reported.

Side effects not listed as an outcome above but reported by the authors as a side effect:

Reported side effects are all included under the specific headings above.

Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized and validated assessment tool and/or a child developmental specialist) at any age (outcome data will be grouped at 12, 18, 24 months if available):

No data were available for long-term neurodevelopment outcome.

Subgroup analyses specified a priori could not be performed for the following reasons:

  1. Dose of ibuprofen used was similar in all the studies.
  2. Echocardiographic criteria were used to diagnose PDA in all the studies.
  3. Demographic and outcome data were available separately for the different birth weight or GA categories in the study by Dani (Dani 2005) and in the study by Van Overmeire (Van Overmeire 2004) but did not completely correspond to our preset cut off points. However as they were close we included them as subgroup analyses under the outcome of "The presence of patent ductus arteriosus (clinically symptomatic or diagnosed by ECHO in response to clinical suspicion or diagnosed on routine screening by ECHO) by 72 hours (three days) of age" (see above).

Secondary (post-hoc) analyses

ORAL IBUPROFEN VS. PLACEBO OR NONE (COMPARISON 2)

Primary outcome:
The presence of patent ductus arteriosus (diagnosed on routine screening by ECHO) by 72 hours (three days) of age (Outcome 2.1). Figure 3

This outcome was reported in two trials (n = 104) (Sangtawesin 2006; Sangtawesin 2008). One of the two individual trials showed a reduction in the presence of a PDA by 72 hours of age (Sangtawesin 2006). The typical RR showed a significant reduction RR 0.34 (95% CI 0.16 to 0.73); typical RD -0.26 (95% CI -0.42 to -0.10); NNT = 4 (95% CI 2 to 10). There was no statistically significant heterogeneity for this outcome [RR p = 0.24, I2 = 28% (low); RD p =0.62, I2 = 0% (low)].

Gastrointestinal haemorrhage (Outcome 2.2). Figure 4

This outcome was reported in two trials (n = 104) (Sangtawesin 2006; Sangtawesin 2008). The typical RR was 1.99 (95% CI 1.13 to 3.50) and the typical RD was 0.23 (95% CI 0.06 to 0.41). There was no statistically significant heterogeneity for this outcome [RR p = 0.76, I2 = 0% (low); RD p = 0.92, I2 = 0% (low)].

IBUPROFEN (IV) VS. PLACEBO OR NONE (COMPARISON 3)

The presence of patent ductus arteriosus (diagnosed on routine screening by ECHO) by 72 hours (three days) of age (Outcome 3.1). Figure 5

This outcome was reported in five trials (n = 827) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004; Dani 2005). All trials showed a significant reduction in this outcome for the iv ibuprofen group compared to the control group. The typical RR was 0.37 (95% CI 0.29 to 0.47)and the typical RD was -0.27 (95% CI -0.33 to -0.21); NNT 4 (95% CI 3 to 5). There was some heterogeneity for this out come [RR p = 0.19, I2 = 34% (low); RD p = 0.07, I2 = 53% (moderate)].

We were not able to identify any randomised controlled trials comparing prophylactic ibuprofen to prophylactic indomethacin or any trials for the use of mefenamic acid for the prevention of PDA.

Discussion

This update of our review, including one additional study enrolling an additional 62 infants for a total of 931 infants, confirms the findings of the previous versions of this review published in 2003, 2006 and 2009. Study quality varied; only one study reported on the generation of the randomisation sequence, the allocation concealment was unclear in three studies, two studies did not use a placebo, all studies reported outcomes for the infants included in the studies, no study was registered in a trials registry, and one study reported results in abstract form before the study was completed. Several of the estimates of effect size have become more precise due to the increase in sample size. A forest plot for the primary outcome "Presence of PDA on the 3rd day of life (72 hours of treatment) was quite symmetrical around the typical point estimate for RR suggesting that there was no major publication bias favouring studies with larger effect sizes. This review confirmed that prophylactic ibuprofen is effective in reducing the incidence of PDA on day three, reducing the need for rescue treatment with cyclo-oxygenase inhibitors and reducing the need for surgical ligation of a PDA. It has been shown that the precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus are poor (Davis 1995). It is therefore reassuring that the diagnosis of a PDA on day three (72 hours after initiation of treatment) was made using ECHO cardiography in all studies. There was statistically significant between study heterogeneity for the outcomes; need for rescue treatment with cyclo-oxygenase inhibitors, NEC, serum creatinine levels after treatment and for gastrointestinal haemorrhage but for no other outcomes. The heterogeneity for the outcome of gastrointestinal bleed disappeared when the one trial that used IV ibuprofen and reported on the outcome was removed from the analysis. The two remaining trials using oral ibuprofen showed a significantly increased risk of gastrointestinal bleed [NNH = 4 (95% CI 2-17)]. This review did not find evidence of a statistically significant difference in mortality, duration of hospitalisation, CLD at 28 days or 36 weeks PMA, duration of mechanical ventilation, IVH, PVL, NEC, intestinal perforation, time to reach full enteral feeds or ROP between ibuprofen and placebo groups. In the 2007 update of the review there was a statistically significant increased risk of proven sepsis between ibuprofen and placebo groups. This outcome was reported only in two trials (n = 201) resulting in wide CIs around the point estimates and no new trial reported on this outcome for the current update. There was a statistically significant increase in the serum creatinine levels on day three of treatment in the prophylactic ibuprofen group as compared to the placebo group. The occurrence of "at least one episode of serum creatinine > 140 micromol/L" was statistically significantly increased. However, there was statistically significant heterogeneity for this outcome. The occurrence of oliguria was statistically significantly increased using RR but of borderline statistical significance using RD. There was no statistically significant heterogeneity for this outcome. In our previous review in 2007, one trial (Gournay 2004) reported the occurrence of PH within one hour of administration of ibuprofen to three infants < 27 weeks and < 1000 g. The trial was stopped prematurely after enrolment of 135 infants due to this adverse effect. The authors postulated that this could be due to early administration of ibuprofen (< 6 hours) preventing the normal fall in pulmonary vascular resistance, acidification of their ibuprofen solution (buffered with tromethamine) causing precipitation and micro-embolism in the lungs or due to a specific effect of ibuprofen. This adverse effect was not reported in the two trials included in the 2007 updated review (Dani 2005; Sangtawesin 2006), nor in this update including one more trial (Sangtawesin 2008) nor in the trials using ibuprofen for treatment of PDA (Van Overmeire 2000; Lago 2002; Mosca 2002). Gournay et al (Gournay 2004) concluded that prophylactic ibuprofen should not be preferred to early curative ibuprofen.

In this update there was a significantly increased risk of gastrointestinal bleeding with ibuprofen. Three studies reported on this outcome (Dani 2000; Sangtawesin 2006; Sangtawesin 2008) and two of the studies used oral ibuprofen (Sangtawesin 2006; Sangtawesin 2008). The incidence of gastrointestinal bleeding was much higher in the two studies that used oral ibuprofen and it may be that gastrointestinal bleeding is specific to the oral formulation of the drug. There was statistically significant heterogeneity for this outcome. We therefore undertook a post hoc analysis combining the results only from the two studies using the oral preparation and the heterogeneity was reduced to I2 = 0% for both the RR and the RD.

In the current review, there was a statistically significant increase in the need for rescue treatment with cyclo-oxygenase inhibitors (indomethacin or ibuprofen) in the placebo group as compared to prophylactic ibuprofen group. This is an expected event and reflects common clinical practice in the neonatal intensive care units for the management of a symptomatic PDA. In the study by Dani et al (Dani 2000), the infants were randomised to prophylactic ibuprofen or rescue group. In this respect the trial was different from rest of the trials which randomised infants to prophylactic ibuprofen or placebo group. However, the back-up management protocol in five other studies (De Carolis 2000; Gournay 2004; Van Overmeire 2004; Sangtawesin 2006; Sangtawesin 2008) and the rescue protocol in the study by Dani et al (Dani 2000) were similar in that each was based on the detection of a significant PDA by echocardiography performed at regular predetermined intervals. Hence, for practical purposes, we considered the rescue ibuprofen group in the study by Dani et al (Dani 2000) to be comparable to the placebo group in other studies as far as management of a PDA is concerned.

In a network meta-analysis of indomethacin versus ibuprofen versus placebo for PDA in preterm infants, Jones and co-workers reported an approximately 30% greater risk of CLD with intravenous ibuprofen given at > 24 hours of life compared to indomethacin or placebo (Jones 2011). We did not identify an increased risk of CLD with ibuprofen in this updated review nor in the review of ibuprofen for the treatment of a PDA (Ohlsson 2010 ). Their search strategy ended in August 2008 and included fewer studies than in our two ibuprofen reviews for Cochrane.

We did not find any trials comparing prophylactic ibuprofen with prophylactic indomethacin. Prophylactic indomethacin (Fowlie 2010) has been shown to reduce need for surgical ligation of PDA and grade 3 and 4 IVH. In that review there was no significant effect on the long-term neurodevelopmental outcomes. It is of note that ibuprofen does not impact on IVH. It is presently unknown whether preventing IVH with the use of indomethacin is preferable to preventing ischemias with the use of ibuprofen.

In the present update of our review, prophylactic ibuprofen was effective in reducing the incidence of PDA, the need for rescue treatment with cyclo-oxygenase inhibitors and the need for surgical ligation, but did not confer any substantial clinical advantages in the short-term. Ibuprofen prophylaxis has a negative effect on kidney function. A new finding in this review was an increased risk of gastrointestinal bleeding with oral ibuprofen. As 58% of the infants in the control group had closed the duct by three days of life, a large proportion of neonates would be exposed to ibuprofen unnecessarily if used as prophylaxis. There are still no long-term neurodevelopmental follow-up studies available.

In 2005 Coceani et al (Coceani 2005) proposed that ".. an mPGES (membrane bound prostaglandin E synthase) inhibitor, once developed for therapeutic use, could become the agent of choice for PDA treatment, particularly in those instances in which prematurity is complicated by infectious or inflammatory conditions" (Coceani 2005).

Authors' conclusions

Implications for practice

Prophylactic use of ibuprofen reduces the incidence of PDA, the need for rescue treatment with cyclo-oxygenase inhibitors and surgical closure. However, in the control group, the PDA had closed spontaneously by day three in 58% of the neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short-term benefit on outcomes. There was an increase in the serum creatinine levels in the ibuprofen group and in the risk of oliguria. There was a significant increased risk of gastrointestinal haemorrhage with oral ibuprofen. There were no statistically significant differences in mortality, grade 3 or 4 IVH, CLD at 28 days or 36 weeks PMA, NEC or time to reach full feeds. The prophylactic use of ibuprofen has been associated with severe PH in one of the trials included in the review but did not occur in the three most recent trials included in this updated review. Current evidence does not support the use of ibuprofen for prophylaxis of PDA.

Implications for research

Until long-term follow-up results are published from the trials included in this review no further trials of prophylactic ibuprofen are recommended.

Acknowledgements

We are thankful to Dr Dani and Dr Rubaltelli for providing additional information about their trials.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

Ohlsson A - contributed to all stages of the review and conducted the updates in July 2005 and February 2009.

Shah S - contributed to all stages of the protocol and the original review.

Ohlson A and Shah S contributed to all stages of the current (April 2011 update of the review).

Declarations of interest

  • None noted.

Differences between protocol and review

In two secondary analyses conduced for this update we report on the effectiveness of oral ibuprofen vs placebo and of IV ibuprofen vs. placebo to reduce the incidence of PDA on the 3rd day of life (after 73 hours of treatment).

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Dani 2000

Methods

Two-centre, randomised, controlled trial without the use of a placebo.

  1. Blinding of randomisation - yes
  2. Blinding of intervention - no
  3. Complete follow-up - yes
  4. Blinding of outcome measurement(s) - no
Participants

Study period February 1995 to January 1996
2 centres, Italy

Inclusion criteria:

  1. GA < 34 weeks
  2. Treatment with nasal continuous positive airway pressure with FiO2 > 30% or with synchronized mechanical ventilation or high frequency ventilation because of RDS.
  3. Platelet count greater than/or equal to 75000/cmm, serum creatinine less than/or equal to 1.5 mg/dl, absence of clinical manifestation of abnormal clotting function.
  4. absence of grade III or IV IVH before randomisation.

Enrolled within first 24 hours after birth.

Demographic data:
Values presented as mean ± SD or as appropriate

Prophylactic ibuprofen group
n = 40
Post menstrual age (weeks): 29.2 ± 2.4
Birth weight (g): 1231 ± 445

Rescue ibuprofen group
n = 40
Gestational age (weeks): 29.6 ± 5.6
Birth weight (g): 1226 ± 505

Interventions

Group A (prophylactic ibuprofen group; n = 40) received intravenous ibuprofen lysine (Arfen, Lisa-pharma, Italy) 10 mg/kg, within first 24 hours of life, followed by 5 mg/kg after 24 and 48 hours.

Group B (rescue ibuprofen group; n = 40) received the same pharmacological treatment after echocardiographic diagnosis of PDA.

When significant PDA was still present after the first course of ibuprofen, a second course was administered. Failure to respond to ibuprofen was an indication for surgical ligation.

Outcomes

Echocardiographic diagnosis (Toshiba, Sonolayer SSH 140A with 7.5 MHz transducer) of PDA on day 3, 7 and 21 of life.
A diagnosis of significant PDA was made by echocardiographic demonstration of a ductal left to right shunt, with left atrial to aortic root ratio > 1.3 or a ductal size > 1.5 mm.

Further endpoints were severity of RDS, CLD at 36 weeks CGA, IVH, ROP, NEC, need for surgical ligation of PDA, mortality, length of hospital stay, time to reach full feeds, renal function, biochemical and hematological profile and any significant adverse effects.

Notes

Patients enrolled in this study are the same as in the abstract of Rubaltelli 1998. This information was provided by Dr Dani and Dr Rubaltelli.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided.

Allocation concealment (selection bias) Low risk

Patients were randomised, using the sealed envelope technique, into two groups. Group A (prophylactic ibuprofen group; n = 40) received intravenous ibuprofen lysine (Arfen, Lisa-pharma, Italy) 10 mg/kg, within first 24 hours of life, followed by 5 mg/kg after 24 and 48 hours


Group B (rescue ibuprofen group; n = 40) received the same pharmacological treatment after echocardiographic diagnosis of PDA.

Blinding (performance bias and detection bias) High risk

No placebo was used. For details see above under 'Allocation concealment'. Health care providers and outcome assessors were not blinded to group assignment and thus a high risk of performance and detection bias existed.

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Low risk

Appears free of other bias.

Dani 2005

Methods

Study period not stated.

Multi-center randomised double-blind trial with the use of placebo.

  1. Blinding of randomisation - yes
  2. Blinding of intervention - yes
  3. Complete follow-up - yes
  4. Blinding of outcome measurement(s) - yes
Participants

155 infants < 28 weeks gestational age and postnatal age < 6 hours in 7 tertiary neonatal care units in Italy.

Prophylactic ibuprofen group:

N = 77

Postmenstrual age (weeks) 25.3 ± 1.2

Birth weight (g) 832 ± 215

Placebo group:

N = 78

Post menstrual age (weeks) 25.9 ± 1.1

Birth weight (g) 812 ± 209

Interventions

Infants were assigned randomly to the treatment or the control group using sealed envelopes. Envelopes were prepared centrally and distributed to the different units. Infants in the prophylactic ibuprofen group received 3 doses of ibuprofen lysine (Arfen, Lisapharma, Erba, Italy; 10 mg/kg within 6 hours after birth, followed by 5 mg/kg after 24 and 48 hours. Infants in the control group received indistinguishable placebo. The medications were infused continuously iv over 15 minutes.

Outcomes

The primary outcome was IVH (grade 2 to 4) at 7 days of life. Other outcomes included IVH at days 15, 30 and at 40 weeks' postconceptual age, PDA on day 3 (defined as echocardiographic evidence of a haemodynamically significant PDA), BPD at 36 weeks' postconceptional age, NEC, sepsis (confirmed with positive blood culture) and ROP.

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Low risk

Infants were assigned randomly to the treatment or the control group using sealed envelopes. Envelopes were prepared centrally and distributed to the different units.

Blinding (performance bias and detection bias) Low risk

Infants in the control group received indistinguishable placebo. Low risk for performance and detection bias.

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Low risk

Appears free of other bias.

De Carolis 2000

Methods

Single-centre, randomised, controlled trial without the use of a placebo.

  1. Blinding of randomisation - Can't tell
  2. Blinding of intervention - no
  3. Complete follow-up - yes
  4. Blinding of outcome measurement(s) - yes for the primary outcome
Participants

Fifty infants < 2 hours of age and with GA < 31 weeks. Two infants in each group died within 24 hours after birth and were not considered in the final analysis.

Single centre study, Italy. April 1, 1996 - July 30 th 1997

Assignment was performed within 2 hours after birth.

Demographic data: values presented as mean ± SD or as number (percentage)

Prophylactic ibuprofen group:
n = 25
Gestational age (weeks): 28.1 ± 1.1
Birth weight (g): 934 ± 288

Control group:
n = 25
Gestational age (weeks): 28.0 ± 1.9
Birth weight (g): 993 ± 308

Interventions

25 neonates received 10 mg ibuprofen lysine/kg iv over 20 minutes within 2 hrs of life, and 5 mg/kg of ibuprofen lysine at 24 and 48 hrs of life.
25 neonates received no placebo/control treatment. Two neonates in each group died within 24 hours of life and were not considered in the final evaluation

In the presence of significant PDA at the completion of ibuprofen cycle, treatment with indomethacin (three times 0.2 mg/kg at 12 hourly interval, administered by iv infusion over 20 minutes was carried out. The same treatment was administered to control neonates having significant PDA on 3rd day of life. Failure to respond to medical treatment was an indication for surgical ligation.

Outcomes

PDA at 72 hours of age, need for treatment with indomethacin after 72 hours, surgical ligation, time to full oral feeds, mortality to 28 days of age, CLD at 28 days of age among survivors, sepsis. In addition a number of outcomes during the first 3 days of life were reported as median and range and not as mean and SD.

Echocardiographic evaluation (Esaote Biomedica SPR 8000 ultrasound imaging system, using 5 MHz probe incorporating pulsed and colour-flow
doppler) was performed by the same investigator who was blinded to the treatment schedule. Neonates were studied immediately after birth, on day 3 of life, and then whenever clinical suspicion of PDA occurred. PDA was defined symptomatic in the presence of heart murmur, bounding pulses, hyperactive precordium, decrease in diastolic arterial pressure, tachypnoea, increasing FiO2 or ventilatory requirements. Diagnosis of PDA was always confirmed by colour doppler echocardiography and PDA was considered haemodynamically significant when the left atrial:aortic root ratio > 1.3.

Notes

"Randomization was carried out at birth by random permuted blocks for both prophylaxis and control groups, envisaging 25 neonates in each." No further information is provided regarding the randomisation and allocation process.
Out of the 50 randomised infants, 2 in each group died in the first 24 hours following birth and were not considered in the final analyses by the authors, but were included by us in the analyses reported in this review.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided.

Allocation concealment (selection bias) Unclear risk

Randomization was carried out at birth by random permuted blocks for both prophylaxis and control groups.

Blinding (performance bias and detection bias) High risk

No placebo was given to the control group. High risk for performance bias. Echocardioraphic evaluation was performed by an investigator who was blinded to the treatment schedule. Low risk of detection bias for the diagnosis of PDA by echocardiography.

Incomplete outcome data (attrition bias) Low risk

Two neonates in each group died within 24 hours of life and were not considered in the final evaluation.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Low risk

Appears free of other bias.

Gournay 2004

Methods

Randomized, double blinded, controlled trial.

  1. Blinding of randomisation - yes
  2. Blinding of intervention - yes
  3. Complete follow up - No (see notes)
  4. Blinding of outcome measurement (s): yes
Participants

Study period: March 2001 - Dec 2001
Multicentre trial including 11 NICUs in France

Inclusion criteria:

  1. GA < 28 weeks
  2. Postnatal age < 6 hours

Exclusion criteria:

  1. Congenital malformations
  2. Shock or right to left ductal shunt evidenced by differential cyanosis
  3. Cerebral complications
  4. Bleeding disorders

Demographic data: values presented as mean ± SD

Prophylactic ibuprofen group:
N = 65
GA 26.3 (0.9) weeks
BW 844 (181) g

Placebo group:

N = 66
GA 26.0 (0.9) weeks
BW 851 (164) g

Interventions

One hundred and thirty five infants were enrolled in the trial and 131 were randomised to receive either ibuprofen (n = 65) or placebo (n = 66).
Both ibuprofen or placebo were given as 3 doses, 24 hours apart with the first dose being given within first 6 hours of life. The initial dose of ibuprofen was 10 mg/kg and the 2 following doses were 5 mg/kg, infused iv continuously over 20 minutes.

Outcomes

Decreased need for surgical ligation based on the presence of a significant PDA on echocardiogram
Mortality
PDA on day 3 by echocardiogram
Need of back-up treatment with indomethacin
PVL
Grade III or IV IVH
NEC
Intestinal perforation
Duration of mechanical ventilation
BPD at 36 weeks corrected GA
Renal function
Actuarial curve of survival during the study period

Notes

135 infants were included.
However, four patients were not randomly assigned because of errors in study drug allocation (3 mistakenly received open-label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10-day-old patient diagnosed with PDA was mistakenly given 2 doses of the randomised test drug (placebo) instead of curative ibuprofen. The per protocol analyses were performed on 131 infants. No patient was lost to follow-up.
The trial was closed earlier than planned after 3 episodes of refractory hypoxaemia with pulmonary hypertension happened after the first prophylactic injection in three different centres. The Agence Francaise du Medicament was notified and requested un blinding of the treatment received in these 3 cases. The treatment was ibuprofen in all three cases and the recruitment was closed on December 14, 2001.

The study was supported by the industry (Orphan Europe, Paris, France).

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided.

Allocation concealment (selection bias) Low risk

Sealed envelope.

Blinding (performance bias and detection bias) Low risk

A placebo (saline) was used. Low risk of performance and detection bias.

Incomplete outcome data (attrition bias) Low risk

135 infants were included.
However, four patients were not randomly assigned because of errors in study drug allocation (3 mistakenly received open-label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10-day-old patient diagnosed with PDA was mistakenly given 2 doses of the randomised test drug (placebo) instead of curative ibuprofen. The per protocol analyses were performed on 131 infants. No patient was lost to follow-up.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Low risk

Appears free of other bias.

Sangtawesin 2006

Methods
  1. Blinding of randomisation - yes; The infants were randomly assigned to ibuprofen or control group by block randomisation.
  2. Blinding of intervention - yes
  3. Complete follow-up - yes
  4. Blinding of outcome measurement(s) - yes
Participants

Study period July 2003 - April 2004

This single centre trial conducted in Thailand enrolled 42 infants of 28-32 weeks gestational age and birth weight less than/or equal to 1500 g and postnatal age < 24 hours.

Prophylactic ibuprofen group:

N = 22

Post menstrual age (weeks) 30.64 ± 1.76

Birth weight (g) 1, 279.64 ± 80.33

Control group

N = 20

Post menstrual age (weeks) 30.20 ± 2.14

Birth weight (g) 1, 214.50 ± 217.52

Interventions

The prophylaxis group received ibuprofen suspension (Junifen, Boots Company, Thailand) at a dosage of 10 mg/kg via an orogastric tube, followed by 0.5 ml of distilled water. The first dose was given within the first 24 hours of life. The second and third doses were given within 24 and 48 hours after the first dose respectively. The patients in the control group were given 3 doses of an orange starch suspension as placebo that looked like ibuprofen.

Outcomes

The primary outcome was presence of a PDA (defined as echocardiographic evidence of a haemodynamically significant PDA) on day 3 of treatment. Additional outcomes included neonatal mortality, duration of mechanical ventilation, pulmonary hypertension, NEC, gastrointestinal haemorrhage, time to full enteral feeds, ROP (grades not stated), length of hospital stay, BPD (age at diagnosis not stated), days of supplemental oxygen therapy, days of mechanical ventilation, IVH (grades not stated), need for rescue treatment with indomethacin or ibuprofen, and PPHN.

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

"Patients were randomly assigned into the present study and control group by block randomisation".

Blinding (performance bias and detection bias) Low risk

The patients in the control group were given 3 doses of an orange starch suspension as placebo that looked like ibuprofen. The medical personnel who took care of the patients were blind to group assignment. Low risk for performance and detection bias.

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Low risk

Apears free of other bias.

Sangtawesin 2008

Methods
  1. Blinding of randomisation - cannot tell; The infants were randomly assigned to ibuprofen or control group by block randomisation.
  2. Blinding of intervention - yes; The medical personnel who took care of the patients were blind to group assignment.
  3. Complete follow-up - yes
  4. Blinding of outcome measurement(s) - yes
Participants

Study period October 2005 - October 2006

This single centre trial conducted in Thailand enrolled 62 infants with birthweight < 1500 g and postnatal age < 24 hours. The infants were known to have a PDA diagnosed by echocardiography on entry into the trial.

Prophylactic ibuprofen group:

N = 31

Post menstrual age (weeks) 29.32 ± 1.94

Birth weight (g) 1156.90 ± 263.6

Placebo group:

N 31

Post menstrual age (weeks) 29.29 ± 2.16

Birth weight (g) 1162.90 ± 261.0

Interventions

The prophylaxis group received 3 doses of oral ibuprofen suspension (Junifen, Boots Company, Thailand) at a dosage of 10mg/kg for the first dose within 24 hours of life and 5 mg/kg for the second and third doses after 24 and 48 hours. The drug was given via an orogastric tube, followed by 0.5 ml of distilled water. The infants in the control group received 3 doses of orange starch suspension as placebo administered with the same method and time schedule as oral ibuprofen suspension in the study group. The external appearance of placebo was like ibuprofen suspension and could not be differentiated by naked eyes.

Outcomes

The primary outcome was closure of PDA (defined as lack of echocardiographic evidence of a haemodynamically significant PDA) on day three of treatment. Other outcomes included PPHN, BPD, days of assisted ventilation, days in supplemental oxygen, serum BUN on day 3, serum creatinine on day 3, days to start feeding, days to reach full feeds, gastrointestinal bleeding, NEC greater than/or equal to stage 2, ROP (total and stage 1 and stage 2), IVH (grade 1 and grades 1-3), length of hospital stay (days), mortality during the study period (28 days).

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

"Patients were randomly assigned"

Blinding (performance bias and detection bias) Low risk

The infants in the control group received 3 doses of orange starch suspension as placebo administered with the same method and time schedule as oral ibuprofen suspension in the study group. The external appearance of placebo was like ibuprofen suspension and could not be differentiated by naked eyes. Low risk for performance and detection bias.

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Low risk

Appears free of other bias.

Van Overmeire 2004

Methods

Seven-centre, randomised, double blinded, controlled trial

  1. Blinding of randomisation - Yes
  2. Blinding of intervention - Yes
  3. Blinding of outcome measurement (s) - Yes
  4. Complete follow-up - Yes
Participants

Study period: February 1, 1999 - September 30, 2001
7 centres, Belgium
Inclusion criteria: gestational age 24-30 weeks
Exclusion criteria: Major congenital malformation or chromosomal anomaly, intraventricular haemorrhage higher than grade 1 already detected during baseline cranial ultrasonography, an Apgar score at 5 minutes less than 5, signs of congenital infection or life-threatening septicaemia, uncontrolled hypotension, contraindications for administration of ibuprofen.

Demographic data: values presented as mean ± SD or as number (percentage)

Prophylaxis group
N = 205
Gestational age (weeks) 28.1 ± 1.7
Birth weight 1048 (g) ± 315

Placebo group
N = 210
Gestational age (weeks) 28.1 ± 1.6
Birth weight (g) 1065 ± 324

Interventions

205 infants received ibuprofen-lysine and 210 infants received placebo (saline). First dose of medication was given within 6 hours of birth and 2nd and 3rd doses were given at 24 hours and 48 hours after the first dose. The dose of ibuprofen used was 10 mg/kg for first dose and 5 mg/kg for subsequent doses. The dose of saline was 1 ml/kg for first dose and 0.5 ml/kg for subsequent doses.

Outcomes

The primary outcome variable was IVH grade 3 or 4. Secondary outcomes included: echocardiographically confirmed PDA after day three of life and the need for its pharmacological rescue treatment or surgical ligation, occurrence of renal dysfunction measured by urine production, NEC and death.

Notes

The study was published as an abstract when 358 infants had been enrolled. There is no mentioning of this interim analysis in the final publication.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Randomisation was done independently by the chief pharmacist in a 1 to 1 ratio between ibuprofen and placebo.

Allocation concealment (selection bias) Low risk

Identical looking ibuprofen-lysine and normal saline as placebo provided by the pharmacy.

Blinding (performance bias and detection bias) Low risk

The attending and consulting physicians, nurses, study collaborators, and parents were unaware of treatment allocation. Low risk for performance and detection bias.

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants.

Selective reporting (reporting bias) Unclear risk

The trial was not registered in a trials registry and we could not ascertain if there were deviations from the original protocol in the final publication.

Other bias Unclear risk

The study was published as an abstract when 358 infants had been enrolled. There is no mentioning of this interim analysis in the final publication.

Abbreviations:
BW = birth weight
g = gram
GA = gestational age
IgG = immunoglobulin
iv = intravenous(ly)
IVIG = intravenous immunoglobulin
kg = kilogram
LBW = low birth weight (< 2.5kg)
mg = milligram
SEM = standard error of the mean
SD = standard deviation
FiO2 = Fraction of inspired oxygen concentration

Characteristics of excluded studies

Varvarigou 1996

Reason for exclusion

Not a randomised controlled study.

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.

[top]

References to studies

Included studies

Dani 2000

* Dani C, Bertini G, Reali MF, Murru P, Fabris C, Vangi V, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatrica 2000;89:1369-74.

Rubaltelli FF, 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.

Dani 2005

Dani C, Bertini G, Pezati M, Poggi C, Guerrini P, Martano C et al. Prophylactic ibuprofen for the prevention of intraventricular hemorrhage among preterm infants: A multicenter, randomized study. Pediatrics 2005;115:1529-35.

De Carolis 2000

De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. European Journal of Pediatrics 2000;159:364-8.

Gournay 2004

* Gournay V, Roze JC, Daoud P et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1939-44.

Gournay V, Savagner C, Thirez G, Kuster A, Roze JC. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002;359:1486-8.

Sangtawesin 2006

Sangtawesin V, Sangtawesin C, Raksasinborisut C, Sathirakul K, Kanjanapattanakul W, Khorana M, Horpaopan S. Oral ibuprofen prophylaxis for symptomatic patent ductus arteriosus of prematurity. Journal of the Medical Association of Thailand 2006;89:314-20.

Sangtawesin 2008

Sangtawesin C, Sangtawesin V, Lertsutthiwong W, Kanjanapattanakul W, Khorana M, Ayudhaya JK. Prophylaxis of symptomatic patent ductus arteriosus with oral ibuprofen in very low birth weight infants. Journal of the Medical Association of Thailand 2008;91:S28-34.

Van Overmeire 2004

Naulaers G, Delanghe G, Allegaert K et al. Ibuprofen and cerebral oxygenation and circulation. Archives of Disease in Childhood Fetal Neonatal Edition 2005;90:F75-6.

* Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwe W, Jespers A et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1945-9.

Van Overmeire, Casaer A, Allegaert K, Debauche C, Decaluwe W, Jespers A. Multicenter ibuprofen prophylaxis study (MIPS) in preterm infants: preliminary data. Pediatric Research 2002;52:825.

Excluded studies

Varvarigou 1996

Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, Aranda JV. Early ibuprofen administration to prevent ductus arteriosus in premature newborn infants. Journal of the American Medical Association 1996;275:539-44.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Bell 1978

Bell MJ, Ternberg KL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotising enterocolitis: Therapeutic decisions based on clinical staging. Annals of Surgery 1978;187:1-7.

Betkerur 1981

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;68:99-102.

Chemtob 1990

Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke 1990;21:777-84.

Chemtob 1993

Chemtob S, Roy MS, Abran D, Fernandez H, Varma DR. Prevention of post asphyxial increase in lipid peroxides and retinal function and deterioration in the newborn pig by inhibition of cyclooxygenase activity and free radical generation. Pediatric Research 1993;33:336-40.

Clyman 2000

Clyman RI. Ibuprofen and Patent ductus arteriosus. New England Journal of Medicine 2000;343:728-30.

Coceani 1979

Coceani F, White E, Bodach E, Olley PM. Age dependent changes in the response of lamb ductus arteriosus to oxygen and ibuprofen. Canadian Journal of Physiology and Pharmacology 1979;57:825-31.

Coceani 2005

Coceani F, Barogi S, Brizzi F, Ackerley C, Seidlitz E, Kelsey L, et al. Cyclooxygenase isoenzymes and patency of ductus arteriosus. Prostaglandins, Leukotrienes and Essential Fatty Acids 2005;72:71-7.

Cotton 1979

Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. Journal of Pediatrics 1979;2:467-73.

Couser 1996

Couser RJ, Ferrara TB, Wright GB, Cabalka AK, Schilling CG, Hoekstra RE, et al. Prophylactic Indomethacin therapy in the first twenty four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. Journal of Pediatrics 1996;128:631-7.

Davis 1995

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 Pediatric and Adolescent Medicine 1995;149:1136-41.

Domanico 1994

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 < 1250g. Pediatric Research 1994;35:331A.

Edwards 1990

Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delply DT, et al. Effects of indomethacin on cerebral hemodynamics in very preterm infants. Lancet 1990;335:1491-5.

Fowlie 2010

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.

Friedman 1976

Friedman WF, Hirschklau MJ, Printz MP, Pitlick PT, Kirkpatrick SE. Pharmacological closure of patent ductus arteriosus in the premature infant. New England Journal of Medicine 1976;95:526-9.

Gersony 1983

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.

Grosfeld 1996

Grosfeld JL, Chaedt M, Molinari F. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Annals of Surgery 1996;224:350-7.

Hammerman 1995

Hammerman C. Patent Ductus Arteriosus: Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clinics in Perinatology 1995;22:457- 79.

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal 2003;327:557-60.

ICROP 1984

The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Archives of Ophthalmology 1984;102:1130-4.

Ito 1994

Ito K, Niida Y, Sato J, Owada E, Ito K, Umetsu M. Pharmacokinetics of mefenamic acid in preterm infants with patent ductus arteriosus. Acta Paediatrica Japonica 1994;36:387-91.

Jones 2011

Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I. Network meta-analysis of indomethacin versus placebo for PDA in preterm infants. Archives of Disease in Childhood Neonatal Edition 2011;96:F45-F52.

Lago 2002

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;161:202-7.

Lee 2000

Lee Sk, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R, et al. Variations in practice and outcomes in the Canadian NICU network 1996-1997. Pediatrics 2000;106:1070-9.

Mosca 1997

Mosca F, Bray M, Lattnazio M, Fumagalli M, Toscetto C. Comparative evaluation of the effect of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1997;131:549-54.

Mosca 2002

Mosca F, Bray M, Stucchi I, Fumagalli M. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002;9338:1023-4.

Niopas 1994

Niopas I, Mamzoridi K. Determination of indomethacin and mefenamic acid in plasma performance liquid chromatography. Journal of Chromatography. Biomedical Applications 1994;656:447-50.

Ohlsson 1993

Ohlsson A, Bottu J, Govan J, Ryan ML, Fong K, Myhr T. The effect of indomethacin on cerebral blood flow velocities in very low birth weight neonates with patent ductus arteriosus. Developmental Pharmacology and Therapeutics 1993;20:100-6.

Ohlsson 2009

Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD004213. DOI: 10.1002/14651858.CD004213.pub2.

Ohlsson 2010

Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: CD003481. DOI: 10.1002/14651858.CD003481.pub4.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweights less than 1, 500 grams. Journal of Pediatrics 1978;92:529-34.

Patel 2000

Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomised double blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47:36-42.

Pezzati 1999

Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. Effects of indomethacin and ibuprofen on mesentric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135:733-8.

Ramanathan 1997

Ramanathan R, Siassi B, Gallagher R, DeLemos RA. Outcome of very low birth weight infants < 1500 g enrolled in the national database network: are there any trends in neonatology? Pediatric Research 1997;41:171A.

Sakhalkar 1992

Sakhalkar VS, Merchant RH. Therapy of patent ductus arteriosus in preterms with mefenamic acid and indomethacin. Indian Pediatrics 1992;29:313-8.

Schmidt 2001

Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts R, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. New England Journal of Medicine 2001;344:1966-72.

Shennan 1988

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;82:527-32.

Speziale 1999

Speziale MV, Allen RG, Henderson CR, Barrington KJ, Finer NN. Efffects of ibuprofen and indomethacin on the regional circulation in newborn piglets. Biology of the Neonate 1999;76:242-52.

Van Bel 1989

Van Bel F, Van de Bor M, Stijnen T, Baan J, Ruys JH. Cerebral blood flow velocity changes in preterm infants after a single dose after a single dose of indomethacin: duration of its effect. Pediatrics 1989;84:802-7.

Van Overmeire 1997

Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Archives of Disease in Childhood. Fetal and Neonatal Edition 1997;76:F179-84.

Van Overmeire 2000

Van Overmeire B, Smets K, Lecoutere D, Van De Broek H, Weyler J, De Groote K, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New England Journal of Medicine 2000;334:674-81.

Other published versions of this review

Shah 2003

Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD004213. DOI: 10.1002/14651858.CD004213.pub2.

Shah 2006

Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004213. DOI: 10.1002/14651858.CD004213.pub2.

Classification pending references

  • None noted.

[top]

Data and analyses

1 Ibuprofen (iv or oral) vs placebo or none

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

>
Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Presence of PDA on 3rd day of life (72 hours of treatment) 7 931 Risk Ratio (M-H, Fixed, 95% CI) 0.36 [0.29, 0.46]
1.2 Neonatal mortality (at < 28 days of life) 4 234 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.47, 2.48]
1.3 All cause mortality during hospital stay 4 700 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.62, 1.30]
1.4 Mortality before 36 weeks PMA 1 131 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.56, 1.66]
1.5 Need for rescue medical treatment with cyclo-oxygenase inhibitors 6 776 Risk Ratio (M-H, Fixed, 95% CI) 0.17 [0.11, 0.26]
1.6 Need for surgical closure of PDA 6 889 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.18, 0.88]
1.7 Duration of mechanical ventilation (days) 5 470 Mean Difference (IV, Fixed, 95% CI) 1.02 [-1.99, 4.03]
1.8 Days requiring supplemental oxygen 3 259 Mean Difference (IV, Fixed, 95% CI) -0.18 [-4.98, 4.61]
1.9 CLD at 28 days of life among survivors 1 41 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.32, 2.42]
1.10 CLD at 36 weeks corrected GA 4 781 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.87, 1.25]
1.11 CLD (age at diagnosis not stated) 2 99 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.51, 1.72]
1.12 Pulmonary hypertension 4 390 Risk Ratio (M-H, Fixed, 95% CI) 7.11 [0.37, 134.91]
1.13 IVH all grades 5 839 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.82, 1.23]
1.14 IVH (grades not stated) 1 40 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.09, 2.20]
1.15 IVH grade III - IV 5 827 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.54, 1.26]
1.16 PVL 4 747 Risk Ratio (M-H, Fixed, 95% CI) 1.19 [0.64, 2.18]
1.17 NEC 7 930 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.63, 1.70]
1.18 Gastrointestinal haemorrhage 3 184 Risk Ratio (M-H, Fixed, 95% CI) 2.03 [1.16, 3.55]
1.19 Gastro-intestinal perforation 1 131 Risk Ratio (M-H, Fixed, 95% CI) 5.08 [0.61, 42.28]
1.20 Time to full enteral feeds (days) 3 184 Mean Difference (IV, Fixed, 95% CI) 0.47 [-2.99, 3.94]
1.21 Length of hospital stay (days) 4 339 Mean Difference (IV, Fixed, 95% CI) -1.75 [-7.08, 3.58]
1.22 Urine output after treatment (mL/kg/hr) 3 650 Mean Difference (IV, Fixed, 95% CI) -0.05 [-0.26, 0.15]
1.23 Oliguria 3 701 Risk Ratio (M-H, Fixed, 95% CI) 1.42 [1.02, 1.98]
1.23.1 Oliguria < 0.5 ml/kg/hour 1 415 Risk Ratio (M-H, Fixed, 95% CI) 1.54 [1.01, 2.34]
1.23.2 Oliguria < 1.0 ml/kg/hour 2 286 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.71, 2.12]
1.24 Serum creatinine levels after treatment (mg/dL) 5 754 Mean Difference (IV, Fixed, 95% CI) 0.09 [0.05, 0.13]
1.25 At least one episode of serum creatinine > 140 micromol/L (>1.5 mg/dl) 2 285 Risk Ratio (M-H, Fixed, 95% CI) 3.70 [1.05, 12.98]
1.26 At least one episode of severe hypoxaemia 1 131 Risk Ratio (M-H, Fixed, 95% CI) 1.69 [0.80, 3.59]
1.27 Nitric oxide during first week of life 1 131 Risk Ratio (M-H, Fixed, 95% CI) 1.89 [0.80, 4.42]
1.28 ROP 4 333 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.73, 1.41]
1.29 Sepsis 2 201 Risk Ratio (M-H, Fixed, 95% CI) 2.70 [1.10, 6.59]
1.30 Presence of PDA on 3rd day of life in infants less than/or equal to 28 weeks gestation at birth 2 420 Risk Ratio (M-H, Fixed, 95% CI) 0.41 [0.29, 0.58]
1.31 Presence of PDA on 3rd day of life in infants 29-30 weeks gestation at birth 1 150 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.13, 0.64]
1.32 Presence of PDA on 3rd day of life in infants less than/or equal to 1000 g 1 196 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.23, 0.61]
1.33 Presence of a PDA on 3rd day of life in infants 1001 - 1500 g 1 185 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.27, 0.81]

2 Ibuprofen (oral) vs placebo or none

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Presence of PDA on day 3 of life (72 hours after treatment) 2 104 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.16, 0.73]
2.2 Gastrointestinal haemorrhage 2 104 Risk Ratio (M-H, Fixed, 95% CI) 1.99 [1.13, 3.50]

3 Ibuprofen (i.v.) vs placebo or none

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Presence of PDA on 3rd day of life (72 hours of treatment) 5 827 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.29, 0.47]

[top]

Figures

Figure 1 (Analysis 1.1)

Refer to figure 1 caption below.

Forest plot of comparison: 1 Ibuprofen vs placebo or none, outcome: 1.1 Presence of PDA on 3rd day of life (72 hours of age) (Figure 1 summary).

Figure 2 (Analysis 1.1)

Refer to figure 2 caption below.

Funnel plot of comparison: 1 Ibuprofen (iv or oral) vs placebo or none, outcome: 1.1 Presence of PDA on 3rd day of life (72 hours of treatment) (Figure 2 summary).

Figure 3 (Analysis 2.1)

Refer to figure 3 caption below.

Forest plot of comparison: 2 Ibuprofen (oral) vs placebo or none, outcome: 2.1 Presence of PDA on day 3 of life (72 hours after treatment) (Figure 3 summary).

Figure 4 (Analysis 2.2)

Refer to figure 4 caption below.

Forest plot of comparison: 2 Ibuprofen (oral) vs placebo or none, outcome: 2.2 Gastrointestinal haemorrhage (Figure 4 summary).

Figure 5 (Analysis 3.1)

Refer to figure 5 caption below.

Forest plot of comparison: 3 Ibuprofen (iv) vs placebo or none, outcome: 3.2 Presence of PDA on 3rd day of life (72 hours of treatment) (Figure 5 summary).

Sources of support

Internal sources

  • Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 7, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.