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

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Arne Ohlsson,

    Corresponding author
    1. University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, Toronto, Ontario, Canada
    • Arne Ohlsson, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. aohlsson@mtsinai.on.ca.

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  • Rajneesh Walia,

    1. University of Birmingham and Walsall Manor Hospital, Paediatrics/Neonatology, Walsall, West Midlands, UK
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  • Sachin S Shah

    1. Aditya Birla Memorial Hospital, Neonatal and Pediatric Intensive Care Services, Pune, India
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Abstract

Background

Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer side effects.

Objectives

To determine the efficacy and safety of ibuprofen for closing a PDA in preterm and/or low birth weight infants. Seperate comparisons are presented for 1. ibuprofen (iv) compared with placebo; 2. ibuprofen (oral) compared with placebo; 3. ibuprofen (oral or iv) compared with other cyclo-oxygenase inhibitors (given iv or orally); 4. ibuprofen (oral) versus indomethacin (given iv or orally); 5. ibuprofen (oral) versus iv ibuprofen; 6. high dose versus standard dose of iv ibuprofen; 7. early versus expectant administration of iv ibuprofen.

Search methods

We searched The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, www.abstracts2view.com/pas, and personal files in July 2012.

Selection criteria

Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in newborn infants.

Data collection and analysis

Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group.

Main results

Twenty-seven studies are included in this review. One study (n = 136) compared iv ibuprofen versus placebo. Ibuprofen reduced the composite outcome of infant deaths, infants who dropped out or required rescue treatment; risk ratio (RR) 0.58 (95% confidence interval (CI) 0.38 to 0.89); risk difference (RD) -0.22 (95% CI -0.38 to -06); number needed to benefit (NNTB) 5 (95% CI 3 to 17). One study (n = 64) compared oral ibuprofen with placebo. There was a significant reduction in the failure rate to close a PDA; RR 0.26 (95% CI 0.11 to 0.62); RD -0.44 (95% CI -0.65 to -0.23); NNTB 2 (95% CI 2 to 4). Failure rates for PDA closure with ibuprofen (oral or iv) compared with indomethacin (oral or iv) was reported in 20 studies (n = 1019 infants). There was no significant difference between the groups; typical RR 0.98 (95% CI 0.80 to 1.20) I2 = 0%; typical RD -0.01 (95% CI -0.06 to 0.05); I2 = 0%. The risk of developing necrotising enterocolitis (NEC) was reduced for ibuprofen (15 studies (n = 865); typical RR 0.68 (95% CI 0.47 to 0.99); typical RD -0.04 (95% CI -0.08 to -0.00; (P = 0.04); NNTB 25 (95% CI 13, infinity); I2 = 0%). The duration of ventilatory support was reduced with ibuprofen (oral or iv) compared with iv or oral indomethacin (six studies, n = 471) mean difference (MD) -2.35 days (95% CI -3.71 to -0.99); I2 = 19%. Failure rates for PDA closure with oral ibuprofen compared with indomethacin (oral or iv) were reported in seven studies (n = 189 infants). There was no significant difference between the groups; typical RR 0.82 (95% CI 0.52 to 1.29); typical RD -0.06 (95% CI -0.18 to 0.06). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (oral or iv) six studies (n = 166); typical RR 0.44 (95% CI 0.23 to 0.82); RD -0.15 (95% CI -0.25 to -0.04); NNTB 7 (95% CI 4 to 25). There was no heterogeneity for this outcome. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with iv ibuprofen, three studies (n = 236) typical RR 0.37 (95% CI 0.23 to 0.61); typical RD -0.24 (95% CI -0.35 to -0.13); NNTB 4 (95% CI 3 to 8). There was less evidence of transient renal insufficiency in infants who received ibuprofen compared with indomethacin. High dose versus standard dose of iv ibuprofen and early versus expectant administration of iv ibuprofen have only been studied in two trials.

Authors' conclusions

Ibuprofen is as effective as indomethacin in closing a PDA and reduces the risk of NEC and transient renal insufficiency. Given the reduction in NEC ibuprofen currently appears to be the drug of choice. Oro-gastric administration of ibuprofen appears at least as effective as iv administration. Too few patients have been enrolled in studies assessing the effectiveness of a high dose of ibuprofen versus the standard dose and early versus expectant administration of ibuprofen to make recommendations. Studies are needed to evaluate the effect of ibuprofen compared with indomethacin treatment on longer-term outcomes in infants with PDA.

Plain language summary

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

A common complication for very preterm (premature) or very small babies is PDA (patent ductus arteriosus). PDA is an open channel between the lungs and heart. 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. The usual treatment for PDA has been indomethacin, a drug that will successfully close the PDA in the majority of cases, but can cause serious adverse effects. Another option is the drug ibuprofen. This review of 27 trials found that ibuprofen is as effective as indomethacin to close a PDA and causes fewer transient adverse effects on the kidneys and reduces the risk of necrotising enterocolitis, a serious condition that affects the gut. Whether ibuprofen confers any important long-term advantages on development or not is not known. Long-term follow-up studies to 18 months of age and to the age of school entry are needed to decide whether ibuprofen or indomethacin is the drug of choice for closing a PDA.

Background

Description of the condition

Normal fetal circulation is dependent on the placenta and the patency of the ductus arteriosus (PDA) (Mathew 1998). Following birth and with the separation of the placenta and initiation of breathing, the circulation changes and closure of the ductus starts immediately (Mathew 1998). However, in about a third of low birth weight ((LBW) < 2500 g) infants the PDA remains open, especially during early days of life (Ellison 1983). In preterm neonates, the PDA often fails to close. The haemodynamic instability caused by the left to right shunt and associated run off has been shown to cause renal or gastrointestinal effects including spontaneous perforation and necrotising enterocolitis (NEC), chronic lung disease and, if not managed, may lead to death (Cotton 1979). The presence of a PDA is associated with reduced middle cerebral artery blood flow velocity (Weir 1999).

The surgical closure of the symptomatic PDA reduces duration of mechanical ventilation, improves haemodynamics and improves lung compliance (Cotton 1978; Naulty 1978). However, medical treatment is still considered the treatment of choice in the majority of cases because of the risks related to the surgery. In a recent large Canadian cohort (n = 3779) of very low birth weight (VLBW < 1500 g) infants, 28% required treatment for a PDA; 75% were treated with indomethacin alone, 8% with surgical ligation alone, and 17% required both indomethacin and surgical ligation (Lee 2000). Infants with lower birth weight were more likely to be treated surgically (Lee 2000).

Description of the intervention

Prostaglandins play a significant role in keeping the ductus arteriosus patent (Mathew 1998). PDA-related morbidity and mortality have been shown to be reduced with the use of indomethacin, which acts as an inhibitor of prostaglandin forming cyclo-oxygenase enzymes (Mahony 1982; Stefano 1991). However, indomethacin use has been associated with transient or permanent derangement of renal function, NEC, gastrointestinal haemorrhage or perforation, alteration of platelet function and impairment of cerebral blood flow/cerebral blood flow velocity (Seyberth 1983; Wolf 1989; Edwards 1990; Ohlsson 1993). These negative effects of indomethacin are possibly related to mechanisms other than inhibition of prostaglandin synthesis.

In a large trial (n = 1202) in extremely low-birth-weight infants, indomethacin prophylaxis did not significantly improve the rate of survival without neurosensory impairment at 18 months despite the fact that it reduced the frequency of PDA and severe periventricular and intraventricular haemorrhage (Schmidt 2001). In a Cochrane review, it was confirmed that prophylactic treatment with indomethacin has a number of short-term benefits, in particular a reduction in symptomatic PDA, the need for ductal ligation and severe intraventricular haemorrhage (Fowlie 2010). The same review found no evidence of either benefit or harm concerning longer-term outcomes including neurodevelopment (Fowlie 2010).

How the intervention might work

The complications associated with the use of indomethacin have encouraged the search for an alternate drug to treat a PDA. Ibuprofen, a propionic acid derivative and non-selective cyclo-oxygenase inhibitor, has been reported to close a PDA, but without gastrointestinal haemodynamic disturbance and potentially harmful cerebral side effects (Coceani 1979; Chemtob 1991; Varvarigou 1996). Ibuprofen has been shown to have some neuroprotective effects in animal models (Chemtob 1990; Pellicer 1999). Ibuprofen also enhances cerebral autoregulation without affecting cerebral blood flow, cerebral metabolism or intestinal or renal haemodynamics (Grosfeld 1983; Kaplan 1994; Hardy 1996).

Another non steroidal anti-inflammatory drug, mefenamic acid, has been reported to close a PDA (Sakhalkar 1992; Ito 1994; Niopas 1994). Mefenamic acid is currently being used in Japan to close a PDA (Uchiyama 2011) but we have not been able to identify any randomised studies.

Why it is important to do this review

One previous meta-analysis of three trials of small sample size (Van Overmeire 1997; Van Overmeire 1998; Patel 2000) suggested that ibuprofen may be as effective as indomethacin in closing a PDA (Ohlsson 2000). The meta-analysis included a total of 176 neonates who were randomised to either ibuprofen (10 mg/kg followed at 24 and 48 hours later by a dose of 5 mg/kg) or indomethacin (0.2 mg/kg at 12 hours interval for three doses). The relative risk for failure of PDA closure using ibuprofen versus indomethacin was 1.0 (95% confidence interval 0.85 to 1.17) (Ohlsson 2000). This meta-analysis was included in a commentary on a publication of a randomised controlled trial (Patel 2000), and the publication type did not allow for detailed description of the methodology used or the inclusion of outcomes other than ductal closure (Ohlsson 2000). Additional trials have been published since the year 2000. A systematic review according to Cochrane methodology was therefore justified as were the current and previous updates as new trials were identified.

Objectives

Primary objectives

  • To determine the effectiveness and safety of ibuprofen compared with placebo or no intervention for closing a patent ductus arteriosus (PDA) in preterm and/or low birth weight infants.

  • To determine the effectiveness and safety of ibuprofen compared with indomethacin or other cyclo-oxygenase inhibitors for closing a PDA in preterm and/or low birth weight infants.

Secondary objectives

To determine in subgroup analyses the effectiveness and safety of ibuprofen to close a PDA in relation to the following criteria.

  • Gestational age (< 28 weeks, 28 to 32 weeks, 33 to 36 weeks).

  • Birth weight (< 1000 g, 1000 g to 1500 g, 1501 g 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.

  • Oral ibuprofen versus indomethacin (this was added in 2007 as a new comparison as studies now have used oral ibuprofen).

  • Oral ibuprofen versus intravenous (iv) ibuprofen (this was added in 2012 as a new comparison as studies have now reported on this comparison).

  • High dose ibuprofen versus standard dose ibuprofen (this was added in 2012 as a new comparison as one study has now reported on this comparison).

  • Early versus expectant treatment with iv ibuprofen (this was added in 2012 as a new comparison as one study has now reported on this comparison).

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled trials.

Types of participants

Preterm infants < 37 weeks gestational age or low-birth-weight infants (< 2500 g) with a PDA diagnosed either clinically or by ECHO criteria in the neonatal period (< 28 days).

Types of interventions

Therapeutic use of ibuprofen (orally or intravenously) for closure of PDA compared with control infants who received no intervention, placebo, indomethacin or other cyclo-oxygenase inhibitors given orally or intravenously. For this update in 2012, we included studies that compared the effectiveness of oral ibuprofen with placebo, studies that compared oral ibuprofen with intravenous ibuprofen, studies that compared high-dose ibuprofen versus standard dose ibuprofen and studies that compared "early" ibuprofen treatment versus expectant management for closure of PDA.

Types of outcome measures

Primary outcomes
  • Failure of permanent PDA closure within a week of administration of the first dose of ibuprofen (PDA diagnosed either clinically or by ECHO criteria).

Secondary outcomes
  • All cause mortality during initial hospital stay.

  • Neonatal mortality (death during the first 28 days of life).

  • Infant mortality (death during the first year of life).

  • Reopening of the ductus arteriosus.

  • Need for surgical closure of the PDA.

  • Need for treatment with indomethacin to close the PDA*.

  • Duration of ventilator support (days).

  • Duration of need for supplementary oxygen (days).

  • Pneumothorax.

  • Pulmonary haemorrhage*.

  • Pulmonary hypertension*.

  • Chronic lung disease (CLD) (defined as oxygen requirement at 28 days postnatal age in addition to compatible clinical and roentgenographic findings).

  • CLD (defined as oxygen requirement at 36 weeks postmenstrual age (PMA) in addition to compatible clinical and roentgenographic findings).

  • CLD (age at diagnosis not stated)*.

  • Intraventricular haemorrhage (IVH) (grades I-IV).

  • Severe IVH (grades III-IV).

  • Periventricular leukomalacia (PVL).

  • Necrotising enterocolitis (NEC) (any stage).

  • Intestinal perforation*.

  • Gastrointestinal bleed.

  • Time to full enteral feeds (postnatal age at time of achieving full enteral feeds).

  • Time to regain birth weight* (days).

  • Retinopathy of prematurity (ROP) (according to the international classification of ROP).

  • 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).

  • Decreased urine output (defined as < 1 cc/kg/hr).

  • Serum/plasma levels of creatinine (mmol/L) after treatment*.

  • Increase in serum/plasma levels of creatinine (mmol/L) after treatment*.

  • Cystatin-C plasma levels (mg/dL) after treatment***.

  • Duration of hospitalisation (total length of hospitalisation from birth to discharge home or death) (days).

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

  • Bilirubin albumin binding*.

  • The proportion of infants that required rescue treatment for PDA (indomethacin or surgery) died or dropped out through study day 14**.

  • Other side effects reported by the authors.

Outcomes marked with an asterisk (*) were not included in the original protocol but in the update of this review in August 2007. These outcomes were included in updates of the review as they were closely related to previous outcomes already included and were considered to be of importance to establish the effectiveness and safety of ibuprofen versus indomethacin. The outcome "The proportion of infants that required rescue treatment for PDA (indomethacin or surgery) died or dropped out through study day 14" (marked with two asterisks **) was the primary outcome of the only study that compared iv ibuprofen with placebo (Aranda 2005) and is, therefore, included. Cystatin-C plasma levels (mg/dL) after treatment*** were included in the 2012 update.

Search methods for identification of studies

See: Cochrane Neonatal Review Group search strategy.

This review is the fourth update of the original review. The Cochrane Library, MEDLINE, EMBASE, Clincialtrials.gov, Controlled-trials.com, www.abstracts2view.com/pas, the reference lists of identified studies, meta-analyses and personal files were searched in July 2012. We subscribed to weekly updates from Ovid AutoAlert on the topic (Ovid AutoAlert [autorun@ovid.com]).
For this update, as with previous updates, the search started by review of personal files and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library); MEDLINE (1966 to July 2012) was searched using MeSH terms: ibuprofen (or mefenamic acid), newborn, infant, premature (or preterm) or low birth weight infant, patent ductus arteriosus or PDA. Other data bases searched included: EMBASE (1980 to July 2012); CINAHL (1982 to July 2012); and the reference list of identified trials and abstracts published in Pediatric Research (1991 to April Issue, 2005, and electronically on the PAS web site from 2006 to 2012) (www.abstracts2view.com/pas) from conference proceedings of the Pediatric Academic Societies (PAS) and the European Society of Pediatric Research. No new trials since the first publication of this review were identified in the searches undertaken in October 2004. The searches in July 2005 identified four new trials of which one was published in abstract form. A search by first review author and co-authors of any abstracts identified in Pediatric Research was done in July 2005 in MEDLINE and EMBASE to try and identify any corresponding full manuscripts published. The searches in August 2007 identified four additional studies. In the 2012 update of the review, we identified six additional trials. We reviewed reference lists of published narrative and systematic reviews. We sought unpublished data. We contacted authors of some published trials to clarify or provide additional information. We searched the literature for any reports (regardless of publication type) of pulmonary hypertension associated with the treatment with ibuprofen or indomethacin. We did not apply any language restrictions.

Data collection and analysis

We used the standard review methods of the Cochrane Neonatal Review Group (CNRG) in data collection and analysis. The 2010 update and the updates conducted in 2005 and 2007 were performed by one review author (AO). The update in 2012 was conducted by all three authors (AO, RW, SS).

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). For this update all three authors assessed the articles for possible inclusion (AO, RW, 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 5.17 and the other review authors (RW and SS) cross-checked the printout against his own data abstraction forms and errors were corrected by consensus.

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

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

Assessment of risk of bias in included studies

The quality of included trials was evaluated independently by the review authors, 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, cannot tell, no.

For the update in 2010, the following issues were evaluated and entered into the 'Risk of bias' table.

(1) Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated? 

For each included study, we categorised the method used to generate the allocation sequence as: 

- adequate (any truly random process e.g. random number table; computer random number generator); 

- inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number); 

- unclear. 

(2) Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorised the method used to conceal the allocation sequence as: 

- adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes); 

- inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); 

- unclear. 

(3) Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?

For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorised the methods as: 

- adequate, inadequate or unclear for participants; 

- adequate, inadequate or unclear for personnel; 

- adequate, inadequate or unclear for outcome assessors. 

In some situations there may be partial blinding e.g. where outcomes are self-reported by unblinded participants but they are recorded by blinded personnel without knowledge of group assignment.  Where needed, “partial” was added to the list of options for assessing quality of blinding. 

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

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 categorised the methods as: 

- adequate (< 10% missing data); 

- inadequate (≥ 10% missing data): 

- unclear. 

(5) Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as: 

- 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); 

- 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. 

(6) Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of 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:

- yes; no; or unclear.  

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, who were not blinded to authors, institution or journal of publication. The updates in 2005, 2007 and 2010 were conducted by one review author (AO). The update in 2012 was conducted by all three authors.

Measures of treatment effect

The statistical analyses followed the recommendations of the Cochrane Neonatal Review Group. A weighted treatment effect was calculated using the RevMan 5.1.7. The estimates of treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. All estimates of treatment effects are 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 following categories for heterogeneity were used; < 25% no heterogeneity; > 25% to 49% low heterogeneity; 50% to 74 % moderate heterogeneity; and > 75% high heterogeneity (Higgins 2003).

Assessment of reporting biases

To ascertain the possibility of publication bias, a funnel plot was conducted for the primary outcome of 'Failure to close a PDA (after single or three doses)' (Analysis 3.1) and for the outcome of NEC (Analysis 3.17). Both funnel plots were quite symmetric indicating that there was no obvious indication of publication bias.

Data synthesis

Meta-analysis was performed using Review Manager software (RevMan 2011) 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 carried out using the fixed-effect model. We used the formulae proposed by Hozo and co-workers (Hozo 2005) to estimate means and standard deviations from medians and ranges presented by the authors of some of the included studies.

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 g to 1500 g, 1501 g 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;

  • oral ibuprofen versus indomethacin (this has been added in 2007 as a new comparison as studies now have used oral ibuprofen);

  • oral ibuprofen versus iv ibuprofen (this has been included as a new comparison in 2012 as studies now have been published assessing this comparison);

  • timing of ibuprofen administration as early versus expectant management (this has been included as a new comparison in 2012 as one study has studied this intervention);

  • a higher dosing regimen of 20 mg/kg/day of ibuprofen followed by 10 mg/kg/day for two doses compared with the standard dose of ibuprofen 10 mg/kg/day followed by 5 mg/kg/day for two doses (this has been included in 2012 as a new comparison as one study has studied this intervention).

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 updates in 2007 and 2010 and in this 2012 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.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

We identified one study comparing oral ibuprofen with placebo for this update in 2012 (Lin 2012). For this update, we added a comparison of oral ibuprofen versus iv ibuprofen as three studies (Cherif 2008; Gokmen 2011; Erdeve 2012) have studied this comparison. We included one study Dani 2012 that compared iv high dose of ibuprofen versus standard dose regimen of ibuprofen. One additional comparison was included for early versus expectant administration of iv ibuprofen (Sosenko 2012). Thus six additional studies were included for this update in 2012.

INTRAVENOUS IBUPROFEN VERSUS PLACEBO OR NO DRUG

The study by Aranda and co-workers (Aranda 2005) was a multi-centre study conducted at 11 sites in the US and published as an abstract in 2005 (full study published in 2009).

  • Objective: To compare the efficacy and safety of iv ibuprofen (L-lysine) with placebo for the early closure of a non-symptomatic PDA within 72 hours of birth in extremely low-birth-weight preterm infants with evidence of ductal shunting by echocardiography.

  • Population: 136 preterm infants (PMA < 30 weeks, birth weight (BW) 500 g to 1000 g) with evidence of ductal shunting by an echocardiogram within 72 hours after birth.

  • Intervention: Infants were allocated to either a three-day treatment course of iv ibuprofen of 10 mg/kg, 5 mg/kg and 5 mg/kg (n = 68) or placebo (saline) (n = 68).

  • Outcomes:The primary outcome measure was the proportion of infants that required rescue treatment for PDA (indomethacin or surgery) died or dropped out through study day 14. Secondary outcomes included mortality, need for PDA ligation, IVH, PVL, NEC, CLD and ROP.

ORAL IBUPROFEN VERSUS PLACEBO OR NO DRUG

The study by Lin and co-workers (Lin 2012) was a single-centre study conducted in Xiamen City, Xiamen, Fujian, China (New inclusion). The study was published in Chinese and only the information in the abstract published in English was understood by the review authors. We have written to the authors to obtain further details, but we have not received a response.

  • Objective: To study the therapeutic effect and safety of early administration of oral ibuprofen in VLBW infants with a PDA.

  • Population: 64 symptomatic VLBW infants with ECHO-confirmed PDA were enrolled within 24 hours after birth.

  • Intervention: Infants in the ibuprofen group received oral ibuprofen at 10 mg/kg as an initial dose within 24 hours after birth, followed by a second and a third dose of 5mg/kg of ibuprofen 24 and 48 hours after the initial dose. In the placebo group infants received 1 ml/kg of normal saline followed by 0.5 ml of saline 24 and 48 hours later.

  • Outcomes: The primary outcome was PDA closure rate following the initial course of treatment (three doses).

INTRAVENOUS OR ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN

The study by Adamska and co-workers (Adamska 2005) was a single-centre study conducted in Poland.

  • Objective: To assess the efficacy and safety of early treatment with iv ibuprofen or iv indomethacin in preterm infants.

  • Population: 35 preterm (< 33 weeks PMA and BW < 1500 g) infants with a PDA diagnosed by Doppler echocardiography.

  • Intervention: The infants were randomised to receive three doses of indomethacin (0.2 mg/kg iv given at 24 hour intervals), (n = 19) or three doses of ibuprofen (10, 5, and 5 mg/kg iv given at 24 hour intervals), (n = 16).

  • Outcomes: The primary outcome was ductal closure. Other outcomes included; need for surgical ligation, IVH, PVL, NEC, intestinal perforation, oliguria, time to full oral feeds, CLD (at 28 days of age), pulmonary haemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.

The study by Akisu and co-workers (Akisu 2001) was conducted in one centre in Turkey.

  • Objective: To investigate the efficacy and safety of enteral ibuprofen for the treatment of PDA and to compare it with enteral indomethacin.

  • Population: 23 preterm infants (< 35 weeks PMA) with a PDA diagnosed by Doppler echocardiography.

  • Intervention: Infants were randomised to receive either enteral ibuprofen 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later (n = 12) or three doses of enteral indomethacin (0.2 mg/kg) every twelve hours (n = 11).

  • Outcomes: The primary outcome was ductal closure. Other outcomes included need to retreat a PDA with indomethacin or ibuprofen, urine output, serum creatinine after treatment, thrombocyte counts, gastrointestinal haemorrhage, IVH, sepsis and mortality.

The study by Aly and co-workers (Aly 2007) was a single-centre study conducted in Egypt.

  • Objective: To evaluate the feasibility of the use of oral ibuprofen suspension versus iv indomethacin in the treatment of PDA in preterm infants.

  • Population: 21 preterm infants (< 35 weeks gestation) age two to seven days with respiratory distress and PDA diagnosed by Doppler echocardiography.

  • Intervention: Infants were randomised to receive three doses of iv indomethacin (0.2 mg/kg at 12-hour intervals) (n = 9) or an initial oral dose of ibuprofen (10 mg/kg), followed by two doses of 5 mg/kg after 24 and 48 hours (n = 12).

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included pulmonary haemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and change in serum creatinine following treatment.

The study by Chotigeat and co-workers (Chotigeat 2003) was conducted in one centre in Thailand.

  • Objective: To compare efficacy and side effects of ibuprofen versus indomethacin treatment for symptomatic PDA in preterm infants.

  • Population: Preterm infants with a symptomatic PDA confirmed by echocardiogram

  • Intervention: 30 infants were randomised to received either three oral doses of ibuprofen (dose not stated) given at 24-hourly intervals or three doses of iv indomethacin (dose not stated) given at 12-hourly intervals starting within 10 days of life.

  • Outcomes: The primary outcome measure was ductal closure. Secondary outcomes included the need for surgical closure of a PDA, the need for re-treatment with ibuprofen or indomethacin, death by 28 days, CLD (at 28 days), sepsis, ROP, serum creatinine levels after treatment.

The study by Fakhraee an co-workers (Fakhraee 2007) was conducted in one centre in Iran.

  • Objective: To compare the efficacy and safety of oral ibuprofen and oral indomethacin for the treatment of PDA in preterm infants.

  • Population: 36 preterm infants (< 34 weeks PMA).

  • Intervention: 18 infants were randomised to receive three oral doses of indomethacin (0.2 mg/kg, at 24-hour intervals) and 18 infants to three doses of oral ibuprofen (first does of 10 mg/kg, followed by 5mk/kg/dose at 24-hour intervals).

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included maximum serum blood urea nitrogen (BUN) and creatinine levels after treatment, NEC, mortality at one month of age, IVH (grades III and IV).

The study by Gimeno Navarro and co-workers (Gimeno Navarro 2005) was conducted in one centre in Spain.

  • Objective: To compare the safety and efficacy of ibuprofen and indomethacin in the treatment of PDA in preterm infants.

  • Population: Preterm infants (< 34 weeks PMA) with a haemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support.

  • Intervention: During the first week of life (average two days of life) 47 ventilated infants, were randomised to receive either indomethacin 0.2 mg/kg/dose iv every 12 hours for a total of three doses (n = 24) or an initial dose of iv ibuprofen of 10 mg/kg, followed by two doses of ibuprofen iv every 24 hours (n = 23).

  • Outcomes: The primary outcome was ductal closure. Other outcomes included mortality, ductal reopening, need for surgical ligation, NEC, isolated bowel perforation, intestinal haemorrhage, pulmonary haemorrhage, CLD (age not stated), IVH (grades III and IV), days on assisted ventilation, days in supplemental oxygen, days in NICU (neonatal intensive care unit).

The study by Hammerman (Hammerman 2008) was conducted in a single centre in Israel.

  • Objective: To show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function and blood flow velocities.

  • Population: 64 preterm (PMA < 33 weeks, BW <1750 g) infants with PDA.

  • Intervention: 31 infants received continuous iv infusion of indomethacin for 36 hours at a rate of 17 μcg/kg/hr and 32 infants received 10 mg/kg of ibuprofen iv followed by two doses of 5 mg/kg at 24 hr intervals.

  • Outcomes: The primary outcome was ductal closure. Other outcomes included need for surgical ligation, need for re-treatment with either indomethacin or ibuprofen, need for surgical treatment, bronchopulmonary dysplasia (BPD), IVH (grades III-IV), ROP, NEC.

The study by Lago and co-workers (Lago 2002) was conducted in two centres in Italy.

  • Objective: To compare indomethacin and ibuprofen with regard to efficacy and safety for the early treatment of PDA.

  • Population: Preterm infants (< 34 weeks PMA, postnatal age 48 to 72 hours) with respiratory distress syndrome (RDS) treated with mechanical ventilation and echocardiographic evidence of PDA.

  • Intervention: 175 infants were randomised to either iv ibuprofen (n = 94) in an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each after 24 and 48 hours or three doses of iv indomethacin 0.2 mg/kg at 12-hour intervals (n = 81). When the ductus arteriosus was still patent after the randomly assigned treatment in patients in either group receiving mechanical ventilation, another three doses of the same medication were given as a non-randomised rescue treatment. If this therapy failed to induce ductal closure, the patient continued to receive mechanical ventilation and, if the ductus was judged to be haemodynamically significant or if further pharmacological treatment was contraindicated, surgical ligation of the ductus was performed.

  • Outcomes:The primary outcome was ductal closure. Other outcomes included mortality,oliguria, IVH, PVL, surgical ligation of PDA, serum creatinine, CLD at 36 weeks, NEC, sepsis, death, duration of ventilator support, days in oxygen, duration of hospital stay, time to full feeds.

The study by Mosca and co-workers (Mosca 1997) was conducted in one centre in Italy.

  • Objective: To compare the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with PDA.

  • Population: Preterm infants (< 31 weeks PMA) with PDA and receiving mechanical ventilation.

  • Intervention: 16 infants received either 10 mg/kg ibuprofen dissolved in 1 mL saline and infused over one minute iv or 0.2 mg/kg indomethacin iv (n = 8). A second and third dose of ibuprofen (5 mg/kg) at 24 hour intervals or indomethacin (0.1 mg/kg), respectively were administered, provided no significant adverse effect was observed.

  • Outcomes: Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidised cytochrome oxidase concentration. Cerebral blood flow velocity in the pericallosal artery was measured using Doppler ultrasonography. Ductal closure was reported as was reopening of a PDA and the need for re-treatment with indomethacin or ibuprofen.

The study by Patel and co-workers Patel 1995 was a single-centre pilot study conducted in one centre in England.

  • Objective: To compare the cerebral effects of ibuprofen with indomethacin in preterm infants.

  • Population: 33 infants with a median PMA of 26 weeks (range 23 to 28) and a echocardiographically proven PDA.

  • Intervention: Infants were randomised to receive either ibuprofen 5 mg/kg (n = 12) or ibuprofen 10 mg/kg (n = 6) or indomethacin 0.1 mg/kg (n = 15). The drugs were infused iv over 15 minutes.

  • Outcomes: Near infrared spectroscopy was used to observe the effect of treatment on cerebral perfusion, indicated by changes in cerebral blood volume and cerebral mitochondrial oxygenation, determined by the change in concentration of oxidised cytochrome aa3. Ductal closure was reported.

The second study by Patel and co-workers Patel 2000 was conducted in four centres in England.

  • Objective: To compare the effects of ibuprofen to indomethacin on cerebral haemodynamics measured using near infrared spectroscopy in preterm infants during treatment for PDA.

  • Population: 33 preterm infants (< 35 weeks PMA).

  • Intervention: Infants were randomly assigned to three iv doses of either ibuprofen (5 to 10 mg/kg, 24 hourly) or indomethacin (0.20 to 0.25 mg/kg, 12 hourly) and also received a dose of saline. Eighteen infants were randomised to the ibuprofen group and 15 to the indomethacin group.

  • Outcomes: The primary endpoints of the study were the effects of the first dose on cerebral blood flow and cerebral blood volume. The PDA closure rates were reported as were need for surgical ligation of PDA and need for re-treatment with indomethacin or ibuprofen.

The study by Pezzati and co-workers Pezzati 1999 was conducted in one centre in Italy.

  • Objective: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of PDA on mesenteric and renal blood flow velocity in preterm infants.

  • Population: Preterm mechanically ventilated infants (< 33 weeks PMA) with a PDA diagnosed by Doppler echocardiography.

  • Intervention: 17 infants were randomised to receive either iv indomethacin (0.2 mg/kg) or iv ibuprofen (10 mg/kg) as a continuous infusion over 15 minutes. Regardless of ductal closure after the first dose, all patients received a second and third dose of indomethacin (0.1 mg/kg) or ibuprofen (5 mg/kg) at 24-hour intervals.

  • Outcomes: The primary outcome was mesenteric and renal blood flow velocity. Secondary outcomes included ductal closure, ductal reopening and NEC.

The study by Plavka and co-workers (Plavka 2001) was conducted in three centres in the Czech Republic.

  • Objective: To compare adverse effects and efficacy of iv ibuprofen with iv indomethacin for treatment of PDA in very preterm infants.

  • Population: 41 preterm infants with clinical and echo signs of PDA

  • Intervention: Infants received either ibuprofen (n = 21) 8 mg/kg every 24 hours for three doses iv or indomethacin (n = 20) 0.2 mg/kg every 24 hours for three doses iv If PDA persisted, treatment was repeated at 1/2 dose every 24 hours for six doses. Resistant PDA was ligated.

  • Outcomes: The primary outcome was PDA closure. Secondary outcomes included reopening of the duct, need for surgical ligation rates and cerebral blood flow velocities.

The study by Pourarian and co-workers (Pourarian 2008) was conducted in a single centre in Iran :

  • Objective: To evaluate the therapeutic effects of oral administration of indomethacin or ibuprofen suspension on closure of PDA in preterm infants.

  • Population: 20 preterm infants with echo-confirmed PDA

  • Intervention: For the indomethacin group, the powder content of a 25 mg indomethacin capsule was freshly prepared by dissolving in 25 mL distilled water. This was given orally as 0.2 mg/kg for three doses at 24-hour intervals. For the ibuprofen group, an ibuprofen oral suspension containing 100 mg/5 mL was given as an initial dose of 10 mg/kg, followed by two further doses of 5 mg/kg at 24-hour intervals. Administration of the second or third doses of each drug was dependent on achievement of ductal closure after the initial doses.

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included need for surgical closure, NEC, change in mean serum creatinine levels before and after treatment, increase in BUN level > 14 mmol/L, thrombocytopenia < 50 000 mm3.

The study by Salama and co-workers (Salama 2008) was conducted in a single centre in Qatar.

  • Objective: To compare the efficacy of oral ibuprofen with iv indomethacin for closure of a significant PDA in preterm infants.

  • Population: 41 preterm infants (PMA , < 34 weeks, BW < 2500 g) diagnosed with haemodynamically significant PDA.

  • Intervention: 20 infants received iv indomethacin (three doses of 0.2 mg/kg/dose every 24 hours) and 21 received oral ibuprofen (10 mg/kg on the first day followed by 5 mg/kg for two more days). Ibuprofen was mixed with 0.5 mL of milk before its administration via an oro-gastric tube.

  • Outcomes: The primary outcome was complete closure of the PDA. Secondary outcomes included need for surgical ligation, bowel perforation, mortality.

The study by Su and co-workers (Su 2003) was conducted in a single centre in Taiwan.

  • Objective: To compare iv ibuprofen and iv indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.

  • Population: 63 preterm infants (PMA < 32 weeks, BW < 1500 g) with echocardiographic evidence of a significant PDA.

  • Intervention: Infants were randomised to receive either iv ibuprofen 10 mg/kg initially followed by 5 mg/kg after 24 and 48 hours or iv indomethacin 0.2 mg/kg every 12 hours for three doses.

  • Outcomes: Primary outcome was PDA closure. Secondary outcomes included need for surgical ligation, mortality, NEC, CLD at 36 weeks PMA, IVH, PVL, ROP, hospital stay, duration of mechanical ventilation, days to full enteral feeds and gastric bleeding.

The study by Su and co-workers (Su 2008) was conducted in a single centre in Taiwan.

  • Objective: To ascertain whether ibuprofen is effective and safe in inducing PDA closure in extremely preterm infants.

  • Population: 119 infants (PMA < 28 weeks) with respiratory distress syndrome and PDA confirmed by ECHO.

  • Intervention: 59 infants received iv indomethacin 0.2 mg/kg (1 mL) as the initial dose and then 0.1 mg/kg in infants < 48 hours old, 0.2 mg/kg in infants over 48 hours at 24-hour intervals as indicated by PDA flow patterns. 60 infants received iv ibuprofen10 mg/kg (1 mL) and then 5 mg/kg at 24-hour intervals as indicated by PDA flow patterns.

  • Outcomes: PDA closure rate, need for ductal ligation, mortality, NEC, bowel perforation, gastrointestinal bleeding, BPD, sepsis, IVH, PVL, days to full enteral feeds, days to regain birth weight, days on ventilation, days of supplemental oxygen, post-treatment serum creatinine levels, oliguria (< 1 mL/kg/hr).

The study by Supapannachart and co-workers (Supapannachart 2002) was conducted in one centre in Thailand.

  • Objective: To assess whether oral ibuprofen at 10 mg/kg/dose daily for three days was as effective as indomethacin to treat symptomatic PDA in preterm infants and to compare the side effects of oral ibuprofen to indomethacin.

  • Population: 18 preterm (< 34 weeks PMA) infants with a symptomatic PDA.

  • Intervention: Infants were randomly assigned to receive either oral ibuprofen (10 mg/kg/dose) for three doses given at 24-hourly intervals or three doses of oral or iv indomethacin (0.2 mg/kg/dose) given at 12-hourly intervals.

  • Outcomes: Primary outcome was PDA closure. Secondary outcomes included mortality, CLD (age not stated), IVH (grade not stated), and NEC.

The study by Van Overmeire and co-workers (Van Overmeire 1997) was conducted in one centre in Belgium.

  • Objective: To evaluate the efficacy and side effects of ibuprofen for the early treatment of PDA and compare it with indomethacin.

  • Population: Preterm infants (PMA < 33 weeks) with PDA diagnosed by echocardiography.

  • Intervention: 40 infants were randomly assigned at day two to three days of life to receive either iv ibuprofen (n = 20) with an initial dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours later or iv indomethacin (n = 20) 0.2 mg/kg every 12 hours for three doses. Presence of a PDA was verified by Doppler echocardiography prior to enrolment, after the last dose of the randomised treatment and at the age of 7 days. When a PDA was present after the randomised treatment and the patient required mechanical ventilation, the infant was treated with indomethacin (0.2 mg/kg every 12 hours for three doses).

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included need for surgical ligation of a PDA, need for re-treatment with indomethacin, mortality, CLD (at 28 days of age), duration of assisted ventilation, duration of supplemental oxygen, sepsis, NEC, age to regain birth weight, and ROP.

The second study by Van Overmeire and co-workers (Van Overmeire 2000) was conducted in five centres in Belgium.

  • Objective: To compare ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.

  • Population: 148 infants (PMA 24 to 32 weeks) with RDS and a PDA confirmed by echocardiography.

  • Intervention: Infants were randomised to receive iv 10 mg/kg of ibuprofen as an initial dose followed by two doses of 5 mg/kg at 24 and 48 hours (n = 74) or iv 0.2 mg/kg of indomethacin every 12 hours for three doses (n = 74). When the ductus arteriosus was still patent after the randomly assigned treatment in a patient in either group who was still receiving mechanical ventilation, indomethacin (three doses of 0.2 mg/kg) at 12-hour intervals) was given as non-randomised rescue treatment. If this therapy failed to promote ductal closure and the patient continued to receive mechanical ventilation, or if there was a contraindication to the second pharmacologic treatment, surgical ligation of the ductus was performed.

  • Outcomes: The primary outcome was ductal closure. Other outcomes included mortality by one month, NEC, localised bowel perforation, extension of IVH during treatment, PVL, CLD (need for supplemental oxygen for more than 28 days), duration of supplemental oxygen, duration of mechanical ventilation, time to regain birth weight, time to full enteral feeding, urine output and serum creatinine.

ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN

The study by Akisu and co-workers (Akisu 2001) was conducted in one centre in Turkey.

  • Objective: To investigate the efficacy and safety of enteral ibuprofen for the treatment of PDA and to compare it with enteral indomethacin.

  • Population: 23 preterm infants (< 35 weeks PMA) with a PDA diagnosed by Doppler echocardiography.

  • Intervention: Infants were randomised to receive either enteral ibuprofen 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later (n = 12) or three doses of enteral indomethacin (0.2 mg/kg) every twelve hours (n = 11).

  • Outcomes: The primary outcome was ductal closure. Other outcomes included need to retreat a PDA with indomethacin or ibuprofen, urine output, serum creatinine after treatment, thrombocyte counts, gastrointestinal haemorrhage, IVH, sepsis and mortality.

The study by Aly and co-workers (Aly 2007) was a single-centre study conducted in Egypt.

  • Objective: To evaluate the feasibility of the use of oral ibuprofen suspension versus iv indomethacin in the treatment of PDA in preterm infants.

  • Population: 21 preterm infants (< 35 weeks PMA) age two to seven days with respiratory distress and PDA diagnosed by Doppler echocardiography.

  • Intervention: Infants were randomised to receive three doses of iv indomethacin (0.2 mg/kg at 12 hour intervals) (n = 9) or an initial oral dose of ibuprofen (10 mg/kg), followed by two doses of 5 mg/kg after 24 and 48 hours (n = 12).

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included biochemical tests (serum creatinine), pulmonary haemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and increase in serum creatinine following treatment.

The study by Chotigeat and co-workers (Chotigeat 2003) was conducted in one centre in Thailand.

  • Objective: To compare efficacy and side effects of ibuprofen versus indomethacin treatment for symptomatic PDA in preterm infants.

  • Population: Preterm infants with a symptomatic PDA confirmed by echocardiogram.

  • Intervention: 30 infants were randomised to receive either three oral doses of ibuprofen (dose not stated) given at 24-hourly intervals or three doses of iv indomethacin (dose not stated) given at 12-hourly intervals starting within 10 days of life.

  • Outcomes: The primary outcome measure was ductal closure. Secondary outcomes included the need for surgical closure of a PDA, the need for re-treatment with ibuprofen or indomethacin, death by 28 days, CLD (at 28 days), sepsis, ROP, serum creatinine levels after treatment.

The study by Fakhraee an co-workers (Fakhraee 2007) was conducted in on centre in Iran.

  • Objective: To compare the efficacy and safety of oral ibuprofen and oral indomethacin for the treatment of PDA in preterm infants.

  • Population: 36 preterm infants (< 34 weeks PMA).

  • Intervention: 18 infants were randomised to receive three oral doses of indomethacin (0.2 mg/kg, at 24-hour intervals) and 18 infants to three doses of oral ibuprofen (first does of 10 mg/kg, followed by 5mk/kg/dose at 24-hour intervals).

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included maximum serum BUN and creatinine levels after treatment, NEC, mortality at 1 month of age, IVH (grades III and IV).

The study by Pourarian and co-workers (Pourarian 2008) was conducted in a single centre in Iran.

  • Objective: To evaluate the therapeutic effects of oral administration of indomethacin or ibuprofen suspension on closure of PDA in preterm infants.

  • Population: 20 preterm infants with echo-confirmed PDA.

  • Intervention: For the indomethacin group, the powder content of a 25 mg indomethacin capsule was freshly prepared by dissolving in 25 mL distilled water. This was given orally as 0.2 mg/kg for three doses at 24-hour intervals. For the ibuprofen group, an ibuprofen oral suspension containing 100 mg/5 mL was given as an initial dose of 10 mg/kg, followed by two further doses of 5 mg/kg at 24-hour intervals. Administration of the second or third doses of each drug was dependent on achievement of ductal closure after the initial doses.

  • Outcomes: The primary outcome was ductal closure. Secondary outcomes included need for surgical closure, NEC, change in mean serum creatinine levels before and after treatment, increase in BUN level > 14 mmol/L, thrombocytopenia < 50 000 mm3.

The study by Salama and co-workers (Salama 2008) was conducted in a single centre in Qatar.

  • Objective: To compare the efficacy of oral ibuprofen with iv indomethacin for closure of a significant PDA in preterm infants.

  • Population: 41 preterm infants (PMA < 34 weeks, BW < 2500 g) diagnosed with haemodynamically significant PDA.

  • Intervention: 20 infants received iv indomethacin (three doses of 0.2 mg/kg/dose every 24 hours) and 21 received oral ibuprofen (10 mg/kg on the first day followed by 5 mg/kg for two more days). Ibuprofen was mixed with 0.5 mL of milk before its administration via an oro-gastric tube.

  • Outcomes: The primary outcome was complete closure of the PDA. Secondary outcomes included need for surgical ligation, bowel perforation, mortality.

The study by Supapannachart and co-workers (Supapannachart 2002) was conducted in one centre in Thailand.

  • Objective: To assess whether oral ibuprofen at 10 mg/kg/dose daily for three days was as effective as indomethacin to treat symptomatic PDA in preterm infants and to compare the side effects of oral ibuprofen to indomethacin.

  • Population: 18 preterm (< 34 weeks PMA) infants with a symptomatic PDA.

  • Intervention: Infants were randomly assigned to receive either oral ibuprofen (10 mg/kg/dose) for three doses given at 24-hourly intervals or three doses of oral or iv indomethacin (0.2 mg/kg/dose) given at 12-hourly intervals.

  • Outcomes: Primary outcome was PDA closure. Secondary outcomes included mortality, CLD (age not stated), IVH (grade not stated), and NEC.

ORAL IBUPROFEN VERSUS IV IBUPROFEN

The study by Cherif and co-workers (Cherif 2008) was conducted in one centre in Tunis, Tunisia (New inclusion).

  • Objective: To compare efficacy and tolerance between oral and iv ibuprofen in early closure of PDA in VLBW infants.

  • Population: 64 VLBW infants with ECHO-confirmed PDA, PMA < 32 weeks, BW < 1500 g, postnatal age between 48 and 96 hours, respiratory distress requiring > 25% oxygen supplementation.

  • Intervention: 32 infants were assigned to receive oral ibuprofen (10 mg/kg as the initial dose) and 32 infants were assigned to receive iv ibuprofen (10 mg/kg as the initial dose). After the first dose of treatment in both groups, ECHO evaluation was performed to determine the need for a second or a third dose. In each group, in case the ductus was still open after the third dose, iv ibuprofen (an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each, after 24 and 48 hours) as a non-randomised rescue treatment was given. If this therapy failed to promote ductal closure and the patient continued to receive mechanical ventilation, surgical ligation of the ductus was performed.

  • Outcomes: PDA closure rate, need for surgical ligation, rate of reopening of the ductus, oliguria, increase in serum creatinine level > 16 mg/dL, change in creatinine concentrations, IVH grades I-II and grades III-IV, PVL, NEC, bowel perforation, sepsis, duration of intubation, survival at one month, duration of hospital stay.

The study by Erdeve and co-workers (Erdeve 2012) was conducted in one centre in Ankara, Turkey (New inclusion):

  • Objective: To compare the efficacy and safety of oral versus iv ibuprofen for the pharmacological closure of PDA in less mature preterm infants.

  • Population: 80 infants with PMA < 28 weeks, BW < 1000 g, postnatal age 48 to 96 hours and with ECHO-confirmed significant PDA.

  • Intervention: Oral or iv ibuprofen at a dose of 10 mg/kg followed by 5 mg/kg at 24 and 48 hours.

  • Outcomes: Primary outcome was PDA closure rate. Secondary outcomes included mortality, need for re-treatment or surgical treatment of the PDA, duration of ventilation, duration of hospital stay, increase in serum bilirubin level after treatment (mg/dL), plasma creatinine (mg/dL) after the first course of treatment, rate of ductal reopening, pneumothorax, pulmonary haemorrhage, pulmonary hypertension, BPD (supplemental oxygen at 36 weeks PMA), IVH (grades 1-IV), NEC, ROP, ROP requiring laser treatment.

The study by Gokmen and co-workers (Gokmen 2011) was conducted in one centre in Ankara, Turkey (New inclusion).

  • Objective: To compare oral ibuprofen with iv ibuprofen for closure of PDA in VLBW infants.

  • Population: 102 VLBW infants with PDA, verified by ECHO (PMA < 32 weeks, birth weight < 1500 g, postnatal age 48 to 96 hours.

  • Intervention: Infants received either iv or oral ibuprofen at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours.

  • Outcomes: Renal tolerance, mean plasma creatinine after treatment, urine output after treatment, cystatin-C levels, failure to close a PDA, need for second course of ibuprofen, need for surgical ligation, oliguria, hospital stay, NEC, gastrointestinal bleeding, sepsis, pneumothorax, BPD (supplemental oxygen at 36 weeks PMA or at discharge, which ever came first), ROP requiring laser treatment, death during hospital stay.

INTRAVENOUS HIGH DOSE IBUPROFEN VERSUS STANDARD DOSE REGIMEN OF IBUPROFEN

The study by Dani and co-workers (Dani 2012) was conducted as a multi-centre study in four NICUs in Italy (New inclusion).

  • Objective: To assess whether a high-dose of iv ibuprofen (20-10-10 mg/kg/day) versus an iv standard dose (10-5-5 mg/kg/day) regimen is more effective in closing a PDA without increasing adverse effects.

  • Population: 95 infants underwent randomisation; 48 were allocated to standard ibuprofen and 47 to high dose ibuprofen and 70 infants with PMA < 29 weeks, ECHO evidence of significant PDA, age 12 to 24 hours and RDS necessitating respiratory support.

  • Intervention: 35 infants received a high-dose of iv ibuprofen (20-10-10 mg/kg/day) and 35 infants received a standard-dose of iv ibuprofen (10-5-5 mg/kg/day). 35 infants (mean PMA 25.6 (SD 1.8) weeks; BW 781 (SD 225) g) were randomised to a high-dose ibuprofen and 35 infants [mean PMA 26.0 (SD 1.7) weeks; BW 835 (SD 215) g) were randomised to standard-dose ibuprofen.

  • Outcomes: Ductal closure, serum creatinine (mg/dL) on day three of treatment, oliguria (< 1 mL/kg/hr during a 24-hour collection period), peak total serum bilirubin (mg/dL) during the first week of life, IVH (all grades and grades III to IV), PVL, ROP (all stages, stage > 2), NEC, BPD (oxygen requirement at 36 weeks PMA), sepsis, mortality, hospital stay (days).

EARLY VERSUS EXPECTANT ADMINISTRATION OF IV IBUPROFEN

The study by Sosenko and co-workers (Sosenko 2012) was conducted in one NICU in Miami, Florida, USA (New inclusion).

  • Objective: To determine whether "early" ibuprofen treatment at the onset of subtle PDA symptoms, would improve respiratory outcome in preterm infants compared with "expectant" management, with ibuprofen treatment only when the PDA becomes haemodynamically significant.

  • Population: Infants born with BW between 500 g and 1250 g and PMA between 23 weeks and 32 weeks, who were > 24 hours old but < 14 days old and who had ECHO for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses).

  • Intervention: Infants were randomised to "early" treatment (blinded ibuprofen, n = 54) or "expectant" management (blinded placebo, n = 51). If the PDA became haemodynamically significant (pulmonary haemorrhage, hypotension, respiratory deterioration), infants received open-label ibuprofen. Infants with haemodynamically significant PDA at enrolment were excluded from the study.

  • The dosing schedule for ibuprofen was an initial dose of 10 mg/kg, followed by two doses of 5 mg/kg each, every 24 hours, by slow iv infusion; dosing of placebo involved equivalent volumes of dextrose by slow iv infusion on the same schedule.

  • Outcomes: Days on supplemental oxygen during the first 28 days of life, death during hospital stay, supplemental oxygen at 36 weeks PMA, intestinal perforation, NEC requiring surgery, IVH (grades III and IV), PVL, sepsis, ROP (stage >/= 3).

Risk of bias in included studies

For details see the table 'Characteristics of included studies'.  These were all randomised controlled trials, but whether the randomisation was concealed or not was not always clear. In several studies, the timing of the doses of ibuprofen and indomethacin did not coincide, and therefore, the care givers would be aware of group assignment (for details see 'Riisk of bias' tables).

Adamska 2005: Sealed envelopes were used for random concealed allocation. As ibuprofen and indomethacin were given at the same times, it is assumed that the care givers were unaware of group assignment.

Akisu 2001: The authors do not provide detailed information concerning how the randomisation sequence was established. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Aly 2007: Sealed opaque envelopes were used for random assignment. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Aranda 2005: This was a double-blind placebo controlled study that used central randomisation to allocate infants to ibuprofen or placebo. The coded vials of study drug or placebo contained indistinguishable colourless solutions dispensed by the blinded research pharmacist of the participating sites.

Cherif 2008: No information provided for sequence generation. Patients were randomly assigned to a treatment group by means of cards in sealed,opaque envelopes.

Chotigeat 2003: The infants were assigned to the treatment group by random number. Clinical care was performed by physicians, who did not take part in the study. However, as ibuprofen was provided orally and indomethacin was given iv one can assume that the care givers were aware of group assignment. The doses of ibuprofen and indomethacin given were not provided.

Dani 2012: No information provided for sequence generation. Sealed opaque envelopes were used for group assignment.

Erdeve 2012: No information provided for sequence generation. Sequentially numbered, sealed, opaque envelopes were used to conceal allocation to groups.

Fakhraee 2007: The enrolled patients randomly received either oral ibuprofen or oral indomethacin.

Gimeno Navarro 2005: Patients were randomly assigned to receive either iv indomethacin or iv ibuprofen. The randomisation sequence was computer generated. Allocation was by sealed opaque envelopes. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Gokmen 2011: No information provided for sequence generation. Patients were assigned randomly using cards in opaque envelopes.

Hammerman 2008: Randomisation was based on computer-generated random numbers without sub-stratification. Because the methods of the drug administration were clearly different, the study could not be double blinded. The cardiologist performing the echocardiograms was blinded to study group.

Lago 2002: The infants enrolled at each unit were randomly assigned to either treatment group by means of cards in sealed envelopes. As indomethacin and ibuprofen were given at different times after the initial doses, one can assume that the care givers were aware of group assignment. The authors do not comment on the imbalance in the numbers enrolled in the ibuprofen group (n = 94) versus the indomethacin group (n = 81).

Lin 2012. Infants were randomly assigned to treatment and control groups (n = 32 in each). No other information provided.

Mosca 1997: The authors do not provide details regarding randomisation. Outcomes for all enrolled infants were provided. As ibuprofen and indomethacin were given at the same time points for each of the three doses and as the injected volume was the same, it is possible that the healthcare providers and the investigators were blinded to the two groups, although this is never stated by the authors.

Patel 1995: The results of this study were reported in a letter to the editor and therefore a full quality assessment is not possible. The authors have confirmed that this was a randomised controlled trial.

Patel 2000: The Pharmacy Department at Queen Charlotte's Hospital performed randomisation in blocks of 12 (six, ibuprofen; six, indomethacin) for each hospital and provided all trial medication. All other personnel were blinded to the identity of the drug administered. To prevent identification of the drug administered from the timing schedule, all infants received a fourth dose containing 0.9% saline; in the indomethacin group, 48 hours after the first dose and, in the ibuprofen group, 12 hours after the first dose.

Pezzati 1999: Infants were randomly assigned to receive either iv ibuprofen or indomethacin. Both drugs were continuously infused over 15 minutes. regardless of ductal closure the infants received a second and third dose of indomethacin or ibuprofen at 24-hour intervals. It is therefore possible that the researchers were blinded to the intervention.

Plavka 2001: To date this study has been published in abstract form only and therefore a full quality assessment is not possible. The healthcare providers may have been blinded to group assignment as ibuprofen or indomethacin were given at the same time points.

Pourarian 2008: "As soon as the diagnosis (of PDA) was made for the first eligible baby, he/she was enrolled to the ibuprofen group and then the next eligible baby was assigned to the indomethacin group, and so on". This statement clearly indicated that the infants were not allocated to the two groups in a concealed manner.

Salama 2008: Randomisation was conducted according to a pre-designed simple block randomisation. No description of possible concealment of allocation.

Sosenko 2012: A random number table was used for sequence generation. Sealed envelopes were used for allocation concealment.

Su 2003: Concealed allocation could not be ascertained from the information provided by the authors. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Su 2008: Randomisation was according to a random number table sequence that had been prepared by a study assistant who was not involved in the care of the infants. The drugs were prepared and dispensed through the hospital pharmacy department and the attending doctors were unaware of the drugs used.

Supapannachart 2002: The infant was randomly assigned to either the ibuprofen or the indomethacin group by choosing a sealed envelop. As ibuprofen and indomethacin were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Van Overmeire 1997: Enrolled patients were randomised using the sealed envelope technique. As indomethacin and ibuprofen were given at different times after the initial doses, one can assume that the care givers were aware of group assignment.

Van Overmeire 2000: The infants were randomly assigned to a treatment group by means of cards in sealed envelopes. As indomethacin was given every 12 hours and ibuprofen at 24 and 48 hours after the initial dose, it is likely that the healthcare providers were aware of group assignment.

Effects of interventions

INTRAVENOUS IBUPROFEN VERSUS PLACEBO (Comparison 1)
One study was published as a full article (Aranda 2005) in 2009. The primary outcome in that study was "Infant deaths, infants who dropped out or required rescue treatment" and as there is only one study available for that outcome the study has been included. However, as there is only one study available, heterogeneity tests are not applicable for any of the outcomes. All outcomes for the comparison of ibuprofen versus placebo refer to the study by Aranda and co-workers (Aranda 2005).

PRIMARY OUTCOME

Infant deaths, infants who dropped out or required rescue treatment (Outcome 1.1)
There was a statistically significant reduced risk ratio (RR) for a composite outcome of infant deaths, infants who dropped out or required rescue treatment (n = 136); RR 0.58 (95% confidence interval (CI) 0.38 to 0.89); risk difference (RD) -0.22 (95% CI -0.38 to -06); number needed to treat to benefit (NNTB) 5 (95% CI 3 to17).

SECONDARY OUTCOMES

Necrotising enterocolitis (NEC) (Outcome 1.2)
There was no statistically significant difference in the incidence of NEC (n = 130); RR 1.00 (95% CI 0.42 to 2.36); RD 0.00 (95% CI -0.12 to 0.12).

Intraventricular haemorrhage (IVH) (any grade) (Outcome 1.3)
There was no statistically significant difference in the incidence of IVH (any grade) (n= 134); RR 1.00 (95% CI 0.64 to 1.55); RD 0.00 (95% CI -0.16 to 0.16).

Intraventricular haemorrhage (grades III-IV) (Outcome 1.4)
There was no statistically significant difference in the incidence of IVH (grades III-IV) (n = 134); RR 1.00 (95% CI 0.47 to 2.15); RD 0.00 (95% CI -0.13 to 0.13).

Pulmonary haemorrhage (Outcome 1.5)
There was no statistically significant difference in the incidence of pulmonary haemorrhage (n = 136); RR 0.25 (95% CI 0.03 to 2.18); RD -0.04 (95% CI -0.11 to 0.02).

Pulmonary hypertension (Outcome 1.6)
There was no statistically significant difference in the incidence of pulmonary hypertension (n = 136); RR 2.00 (0.19 to 21.54); RD 0.01 (95% CI -0.03 to 0.06).

Retinopathy of prematurity (ROP) (any stage) (Outcome 1.7)
There was no statistically significant difference in the incidence of ROP (any stage) (n = 129); RR 1.19 (95% CI 0.88 to 1.62); RD 0.10 (95% CI -0.07 to 0.27).

Retinopathy of prematurity (stage 3 or 4) (Outcome 1.8)
There was no statistically significant difference in the incidence of ROP (stage 3 or 4) (n = 129); RR 1.18 (95% CI 0.38 to 3.68); RD 0.01 (95% CI -0.08 to 0.11).

Retinopathy of prematurity (plus disease) (Outcome 1.9)
There was no statistically significant difference in the incidence of ROP (plus disease) (n = 129); RR 1.31 (95% CI 0.31 to 5.63): RD 0.01 (95% CI 0.01 (95% CI -0.06 to 0.09).

Chronic lung disease (CLD) (supplemental oxygen at 28 days of age) (Outcome 1:10)
There was no statistically significant difference in the incidence of CLD (supplemental oxygen at 28 days of age) [(n = 130); RR 1.09 (95% CI 0.95 to 1.26); RD 0.08 (95% CI -0.04 to 0.20).

Chronic lung disease (supplemental oxygen at 36 weeks PMA) (Outcome 1.11)
There was no statistically significant difference in the incidence of CLD (supplemental oxygen at 36 weeks postmenstrual age (PMA)) (n = 98); RR 0.99 (95% CI 0.88 to 1.11); RD -0.01 (95% CI -0.12 to 0.10).

Periventricular leukomalacia (PVL) (Outcome 1.12)
There was no statistically significant difference in the incidence of PVL (n = 130); RR 0.11 (95% CI 0.01 to 2.02); RD -0.06 (95% CI -0.13 to 0.00) (P = 0.06).

Mortality (Outcome 1.13)
There was no statistically significant difference in mortality (n = 136); RR 0.80 (95% CI 0.34 to 1.90); RD -0.03 (95% CI -0.14 to 0.08).

Since this review was first published oral ibuprofen has been introduced to close a PDA. We therefore included additional comparisons that were not planned a priori.

ORAL IBUPROFEN VERSUS PLACEBO (Comparison 2)

Failure to close a PDA after single or three doses (Outcome 2.1)
One study (Lin 2012) reported on this outcome in 64 infants. There was a significant reduction in the failure rate to close a PDA (RR 0.26 (95% CI 0.11 to 0.62); RD -0.44 (95% CI -0.65 to -0.23); NNTB 2 (95% CI 2 to 4). Test for heterogeneity not applicable.

The authors reported that the incidence of PVL and BPD were significantly lower in the treatment group than in the control group (P < 0.05). The duration of mechanical ventilation and hospitalisation were significantly shorter in the treatment group than in the control group (P < 0.05). There were no significant differences in the incidence of IVH, early pulmonary haemorrhage and NEC between the two groups (P > 0.05). Only the abstract was available to us and numbers for these outcomes were not reported in the abstract. We have written to the authors to try and obtain more information, but we have not received any feedback.

INTRAVENOUS OR ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN (Comparison 3)

PRIMARY OUTCOME

Failure to close a PDA after single or three doses (Outcome 3.1) Figure 1
Failure rates for PDA closure after one or three doses of ibuprofen compared with indomethacin were reported in all studies included in this comparison. Twenty studies (n = 1019 infants) reported on this outcome. None found a statistically significant difference in failure to close a PDA. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 0.98 (95% CI 0.80 to 1.20); typical RD -0.01 (95% CI -0.06 to 0.05). There was no between study heterogeneity for RR or RD (I2 = 0% for both RR and RD).

Figure 1.

Forest plot of comparison: 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, outcome: 3.1 Failure to close a PDA (after single or three doses).

SECONDARY OUTCOMES

All cause mortality (Outcome 3.2)
Eight studies (n = 470) reported on mortality that occurred at an unspecified time while in hospital and none found a statistically significant difference. The meta-analysis showed no statistically significant difference between the groups; typical RR 0.77 (95% CI 0.45 to 1.29); typical RD -0.03 (95% CI -0.08 to 0.03). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Neonatal mortality (during first 28/30 days of life) (Outcome 3.3)
Four studies (n = 333) reported on death by 28 or 30 days of age. There was no statistically significant difference between the groups in the individual studies or in the meta-analysis; typical RR 1.12 (95% CI 0.59 to 2.11); typical RD 0.01 (95% CI -0.05 to 0.08). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Infant mortality (death during the first year of life)
None of the studies reported on this outcome.

Reopening of the ductus arteriosus (Outcome 3.4)
Six studies (n = 204) reported on this outcome. None of the individual studies found a statistically significant difference in the reopening of a PDA. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.28 (95% CI 0.48 to 3.38); typical RD 0.02 (95% CI -0.06 to 0.09). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Need for surgical closure of the PDA (Outcome 3.5)
Thirteen studies (n = 848) reported on this outcome. None of the studies found a statistically significant difference in the surgical closure of PDA. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.04 (95% CI 0.71 to 1.51); typical RD 0.00 (95% CI -0.04 to 0.05). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Need for re-treatment with indomethacin or ibuprofen to close the PDA (Outcome 3.6)
Seven studies (n = 241) reported on this outcome. None of the studies found a statistically significant difference in the need for medical treatment of the PDA between the groups. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.20 (95% CI 0.76 to 1.90); typical RD 0.04 (95% CI -0.06 to 0.14). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Duration of ventilator support (days) (Outcome 3.7)
Six studies (n = 471) reported on this outcome. Two studies (Adamska 2005; Gimeno Navarro 2005) found a statistically significant difference in the duration of ventilation in favour of the ibuprofen group. In the meta-analysis, there was a statistically significant difference between the groups; mean difference (MD) -2.35 days (95% CI -3.71 to -0.99) favouring ibuprofen. There was no heterogeneity between the studies (I2 = 19%).

Duration of supplementary oxygen (days) (Outcome 3.8)
Six studies (n = 556) reported on this outcome. None of the studies found a statistically significant effect. In the meta-analysis, there was no statistically significant difference between the groups; MD -0.33 days (95% CI -1.66 to 0.99). There was low between study heterogeneity for this outcome (I2 = 46%).

Pneumothorax
No study reported on this outcome.

Pulmonary haemorrhage (Outcome 3.9)
Three studies (n = 103) reported on this outcome. No study found a statistically significant difference in the incidence of pulmonary haemorrhage between the groups. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.23 (95% CI 0.37 to 4.10); typical RD 0.02 (95% CI -0.09 to 0.13). There was low between study heterogeneity for RR but moderate heterogeneity for RD (RR; I2 = 44.7%; RD; I2 = 63%).

Pulmonary hypertension (Outcome 3.10)
One study (n = 35) reported on this outcome. There was no statistically significant difference between the groups; RR 3.53 (95% CI 0.15 to 81.11; RD 0.06 (95% CI -0.09 to 0.21).

Test for heterogeneity not applicable.

Chronic lung disease (CLD) (at 28 days) (Outcome 3.11)
Four studies (n = 245) reported on this outcome. No study found a significant difference in the incidence of CLD at 28 days. In the meta-analysis, there was no statistically significant difference in the incidence of CLD at 28 days in the ibuprofen group compared with indomethacin group; typical RR 1.22 (95% CI 0.93 to 1.59); typical RD 0.09 (95% CI -0.03 to 0.22). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Chronic lung disease (at 36 weeks PMA) (Outcome 3.12)
Three studies (n = 357) reported on this outcome. No study found a significant difference in the incidence of CLD at 36 weeks PMA. In the meta-analysis of these studies, there was no statistically significant difference between the groups; typical RR 1.12 (95% CI 0.77 to 1.61); typical RD 0.03 (95% CI -0.06 to 0.12). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Chronic lung disease (age not stated) (Outcome 3.13)
Three studies (n = 128) reported on this outcome. No study found a significant difference in the incidence of CLD (age not stated). In the meta-analysis of these studies, there was no statistically significant difference between the groups; typical RR 1.04 (95% CI 0.83 to 1.30); typical RD 0.02 (95% CI -0.12 to 0.16). There was no statistically significant between study heterogeneity (I2 = 0% for both RR and RD).

Intraventricular haemorrhage (IVH) (grades I-IV) (Outcome 3.14)

Five studies (n = 180) reported on this outcome. No study found a statistically significant difference in the incidence of IVH. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 0.83 (95% CI 0.47 to 1.48); typical RD -0.04 (95% CI -0.15 to 0.08). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Intraventricular haemorrhage (IVH) (grades III-IV) (Outcome 3.15)
Eight studies (n = 571) reported on this outcome. No study found a statistically significant difference in the incidence of IVH (grades III-IV) between the groups. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.21 (95% CI 0.74 to 1.98); typical RD 0.02; (95% CI -0.03 to 0.07). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Periventricular leukomalacia (PVL) (Outcome 3.16)
Six studies (n = 573) reported on this outcome. No study found a statistically significant difference in the incidence of PVL. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.24; (95% CI 0.67 to 2.30); typical RD 0.01 (95% CI -0.03 to 0.05). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Necrotising enterocolitis (NEC) (any stage) (Outcome 3.17) Figure 2
Fifteen studies (n = 865) reported on this outcome. No individual study found a significant difference. In the study by Chotigeat (Chotigeat 2003), the rates of NEC were exceptionally high in both groups. In the meta-analysis, there was a statistically significant difference between the groups; typical RR 0.68 (95% CI 0.47 to 0.99); typical RD -0.04 (95% CI -0.08 to -0.00); (P = 0.04); NNTB 25 (95% CI 13, infinity). There was no statistically significant between study heterogeneity (I2 = 0% for both RR and RD).

Figure 2.

Forest plot of comparison: 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, outcome: 3.17 Necrotizing enterocolitis (any stage).

Intestinal perforation (Outcome 3.18)
Five studies (n = 255) reported on this outcome. No study found a statistically significant difference in the incidence of intestinal perforation. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 0.48 (95% CI 0.20 to 1.14); typical RD -0.06 (95% CI -0.13 to 0.01). There was no between study heterogeneity (I2 = 0% for RR and 6% for RD).

Gastrointestinal bleed (Outcome 3.19)
Six studies (n = 314) reported on this outcome. There was no statistically significant difference between the groups in the individual studies or in the meta-analysis; typical RR 1.11 (95% CI 0.57 to 2.15); typical RD 0.01 (-0.06 to 0.08). There was no statistically significant between study heterogeneity (I2 = 0% for both RR and RD).

Time to full enteral feeds (days) (Outcome 3.20)
Four studies (n = 413) reported on this outcome. There was no statistically significant difference between the groups in the time to reach full feeds in the individual studies. In the meta-analysis, there was no statistically significant difference between the groups; MD 0.70 days (95% CI -1.89 to 3.29). There was low between study heterogeneity (I2 = 31%).

Time to regain birth weight (days) (Outcome 3.21)
Two studies (n = 188) reported on this outcome. In the individual studies, there was no statistically significant difference between the groups in the time to regain birth weight. In the meta-analysis, there was no statistically significant difference between the groups; MD -0.18 days (95% CI -2.59 to 2.22). There was moderate between study heterogeneity (I2 = 67%).

Retinopathy of prematurity (ROP) (according to the international classification of ROP) (Outcome 3.22)
Five studies (n = 237) reported on this outcome. In the individual studies, there was no significant difference between the groups. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 0.86 (95% CI 0.54 to 1.38); typical RD -0.03 (95% CI -0.13 to 0.07). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Sepsis (Outcome 3.23)
Six studies (n = 535) reported on this outcome. No study found a statistically significant difference. In the meta-analysis, there was no statistically significant difference between the groups; typical RR 1.15 (95% CI 0.73 to 1.81); typical RD 0.02 (95% CI -0.03 to 0.06). There was no between study heterogeneity (I2 = 0% for both RR and RD).

Oliguria (defined as < 1 cc/kg/hr) (Outcome 3.24)
Six studies (n = 576) reported on this outcome. Two trials found a statistically significant decrease in the proportion of infants with oliguria in the ibuprofen group (Lago 2002; Van Overmeire 2000). In the meta-analysis, there was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group; typical RR 0.28 (95% CI 0.14 to 0.54); typical RD -0.09 (95% CI -0.14 to -0.05); NNTB 11 (95% CI 7 to 20). There was no between study heterogeneity for RR (I2 = 24%) and moderate for RD (I2 = 69%). Hammerman et al (Hammerman 2008) reported no statistically significant differences in urine output between the ibuprofen and indomethacin groups at pre-treatment and at 24 and 48 hours after treatment.

Serum/plasma creatinine levels (mmol/L) 72 hours after treatment (Outcome 3.25)
Eight studies (n = 491) reported on this outcome in such a format that the data could be used to summarize the information in RevMan 2011. Three individual studies found statistically significantly lower serum/plasma creatinine levels 72 hours after initiation of treatment in the ibuprofen group compared with the indomethacin group. In the meta-analysis, the serum/plasma creatinine level 72 hours after initiation of treatment was statistically significantly lower in the ibuprofen group; MD -4.70 mmol/L (-8.88 to -0.53). There was moderate between study heterogeneity (I2 = 51%).

Pezzatin and co-workers (Pezzati 1999) noted significantly lower serum creatinine levels on day three in the ibuprofen group compared with the indomethacin group (P < 0.05; data provided in graph form only). Plavka and co-workers (Plavka 2001) reported lower serum creatinine levels in the ibuprofen group compared with the indomethacin group in the first 96 hours of treatment (P < 0.01; data for the two groups not provided). Van Overmeire and co-workers (Van Overmeire 1997) noted the maximal difference in serum creatinine levels between the ibuprofen and the indomethacin group to occur on day three (P = 0.07; data provided in graph form only). The lower levels were observed in the ibuprofen group. In their second trial, Van Overmeire and co-workers (Van Overmeire 2000) noted significantly lower serum creatinine levels in the ibuprofen group compared with the indomethacin group (P = 0.04 overall; data provided in graph form only). Pourarian and co-workers (Pourarian 2008) reported that the mean differences in serum creatinine before and after treatment were 0.35 mg/dL in the ibuprofen group and 0.45 mg/dL in the indomethacin group (SDs were not provided).

Increase in serum/plasma creatinine levels (mmol/L) 72 hours after treatment (Outcome 3.26)
One study (Aly 2007) reported on this outcome (n = 21). The increase in serum creatinine levels, was significantly lower in the ibuprofen group compared with the indomethacin group; MD 15.91 mmol/L (95% CI -31.78 to - 0.04). Test for heterogeneity not applicable.

Duration of hospitalisation (Outcome 3.27)
Three studies (n = 285) reported on this outcome. There was no statistically significant difference between the groups; MD -2.19 days (95% CI -6.55 to 2.18). There was no heterogeneity between the studies (I2 = 0%).

Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized and validated assessment tool and/or a child developmental specialist) at any age reported (no outcome table)
No long-term outcome data were reported.

The effects on cerebral blood flow velocity or cerebral blood flow were not included as predetermined outcomes in this review. However, several authors reported on these outcomes. All results favoured the ibuprofen group with less reduction in cerebral blood flow velocity or cerebral blood flow.

ORAL IBUPROFEN VERSUS IV OR ORAL INDOMETHACIN (Comparison 4)

Failure to close a PDA (after three doses) (Outcome 4.1) Figure 3
This outcome was reported in seven trials (n = 189). There was no statistically significant difference in failure to close a PDA in any of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference typical RR 0.82 (95% CI 0.52 to 1.29); typical RD -0.06 (95% CI -0.18 to 0.06). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Figure 3.

Forest plot of comparison: 4 Oral ibuprofen versus iv or oral indomethacin, outcome: 4.1 Failure to close a PDA (after three doses).

All cause mortality (during hospital stay) (Outcome 4.2)
This outcome was reported in three studies (n = 82). There was no statistically significant difference in mortality in any of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 0.59 (95% CI 0.21 to 1.66); typical RD -0.08 (95% CI -0.24 to 0.08). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Neonatal mortality (during first 28/30 days of life) (Outcome 4.3)
Two studies reported on this outcome (n = 66). There was no statistically significant difference in mortality in either of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 1.33 (95% CI 0.33 to 5.39); typical RD 0.03 (95% CI -0.12 to 0.18). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Reopening of the ductus arteriosus (Outcome 4.4)
One study (n = 20) reported on this outcome. There was no case of reopening of the ductus in either of the two groups; RR not estimable; RD 0.00 (95% CI -0.17 to 0.17). Test for heterogeneity not applicable.

Need for surgical closure of the PDA (Outcome (4.5)
Three studies reported on this outcome (n = 91). There was no statistically significant difference in need for surgical closure of the PDA in any of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 0.63 (95% CI 0.24 to 1.70); typical RD -0.07 (95% CI -0.21 to 0.08). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Pulmonary haemorrhage (Outcome 4.6)
One study (n = 21) reported on this outcome. There was no statistically significant difference in pulmonary haemorrhage between the two groups in this single trial; RR 0.15 (95% CI 0.01 to 2.86); RD -0.22 (95% CI -0.51 to 0.07). Test for heterogeneity not applicable.

Pulmonary hypertension (Outcome 4.7)
No trial reported on this outcome.

Chronic lung disease (CLD) (at 28 days) (Outcome 4.8)
One trial (n = 30) reported on this outcome. There was no statistically significant difference in CLD at 28 days between the two groups comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 0.86 (95% CI 0.38 to 1.95); typical RD -0.07 (95% CI -0.42 to 0.29). Test for heterogeneity not applicable.

Chronic lung disease (36 weeks PMA) (Outcome 4.9)
No trial reported on this outcome.

Chronic lung disease (age not stated) (Outcome 4.10)
One trial (n = 18) reported on this outcome. There was no statistically significant difference in CLD (age not stated) between the two groups comparing oral ibuprofen with indomethacin; RR 1.00 (95% CI 0.52 to 1.92); typical RD 0.00 (95% CI -0.44 to 0.44). Test for heterogeneity not applicable.

Intraventricular haemorrhage (IVH) (grades I-IV) (Outcome 4.11)
Three trials (n = 77) reported on this outcome. There was no statistically significant difference in IVH (grades I-IV) in any of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 0.90 (95% CI 0.45 to 1.83); typical RD -0.03 (95% CI -0.03 (95% CI -0.22 to 0.16). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Intraventricular haemorrhage (grades III-IV) (Outcome 4.12)
One trial (n = 41) reported on this outcome. There was no statistically significant difference in IVH (grades III-IV) between the two groups comparing oral ibuprofen with indomethacin; RR 0.95 (95% CI 0.15 to 6.13); typical RD -0.00 (95% CI -0.19 to 0.18). Test for heterogeneity not applicable.

Periventricular leukomalacia (PVL) (Outcome 4.13)
One trial (n = 41) reported on this outcome. There was no statistically significant difference in PVL between the two groups comparing oral ibuprofen with indomethacin; RR 0.32 (95% CI 0.01 to 7.38); RD -0.05 (95% CI -0.18 to 0.08). Test for heterogeneity not applicable.

Necrotising enterocolitis (NEC) (Outcome 4.14) Figure 4
Six trials (n = 166) reported on this outcome. There was no statistically significant difference in necrotising enterocolitis in any of the trials comparing oral ibuprofen with indomethacin but the meta-analysis showed a statistically significant difference; typical RR 0.44 (95% CI 0.23 to 0.82); typical RD -0.15 (95% CI -0.25 to -0.04); NNTB 7 (95% CI 4, 25). There was no heterogeneity for this outcome (I2 = 0% for RR and 20% for RD).

Figure 4.

Forest plot of comparison: 4 Oral ibuprofen versus iv or oral indomethacin, outcome: 4.18 Necrotizing enterocolitis (any stage).

Intestinal perforation (Outcome 4.15)
Two trials (n = 62) reported on this outcome. There was no statistically significant difference in intestinal perforation in either of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 0.24 (95% CI 0.03 to 1.95); typical RD -0.10 (95% CI -0.25 to 0.04). In one trial (Aly 2007), no perforation occurred in either of the trials. Test for heterogeneity for RR not applicable (there were no outcomes in one trial and low heterogeneity for RD (I2 = 38%).

Gastrointestinal bleed (Outcome 4.16)
Three trials (n = 85) reported on this outcome. There was no statistically significant difference in gastrointestinal bleed in any of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 2.80 (95% CI 0.48 to 16.45); typical RD 0.07 (95% CI -0.05 to 0.18). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Retinopathy of prematurity (ROP) (Outcome 4.17)
Two studies (n =71) reported on this outcome. There was no statistically significant difference in retinopathy of prematurity in any of the trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 0.98 (95% CI 0.35 to 2.73); typical RD -0.00 (-0.18 to 0.17). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Sepsis (Outcome 4.18)
Two studies (n =53) reported on this outcome. There was no statistically significant difference in sepsis in either of the two trials comparing oral ibuprofen with indomethacin and the meta-analysis showed no statistically significant difference; typical RR 1.09 (95% CI 0.54 to 2.19); typical RD 0.03 (95% CI -0.22 to 0.28). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Decreased urine output (< 1 cc/kg/hr) (Outcome 4.19)
One study (n = 36) reported on this outcome. None of the infants in the study experienced decreased urine output; RR not estimable; RD 0.00 (95% CI -0.10 to 0.10) Test for heterogeneity not applicable.

Serum/plasma creatinine levels (micromol/L) 72 hours after treatment (Outcome 4.20)
Four studies (n = 107) reported on this outcome. Two studies showed a statistically significant reduction in serum/plasma creatinine levels comparing oral ibuprofen with indomethacin (Chotigeat 2003; Supapannachart 2002) and the meta-analysis showed a significant reduction; (MD -15.14 micromol/L (95% CI -25.00 to -5.28). There was no heterogeneity for this outcome (I2 = 0%).

ORAL IBUPROFEN VERSUS IV IBUPROFEN (Comparison 5)

Failure to close a PDA (after three doses) (Outcome 5.1) Figure 5
Three studies (n = 236) reported on this outcome. There was a statistically significant reduction in failure to close a PDA in one (Gokmen 2011) of the three trials comparing oral ibuprofen with iv ibuprofen and the meta-analysis showed a statistically significant difference; typical RR 0.37 (95% CI 0.23 to 0.61); typical RD -0.24 (95% CI -0.35 to -0.13); NNTB 4 (95% CI 3 to 8). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Figure 5.

Forest plot of comparison: 5 Oral ibuprofen versus iv ibuprofen, outcome: 5.1 Failure to close a PDA (after single or three doses).

Mortality (during first 28/30 days of life) (Outcome 5.2)
One study (n = 64) reported on this outcome. There was no significant difference in mortality (during the first 28/30 days of life) comparing oral ibuprofen with iv ibuprofen; RR 1.13 (95% CI 0.50 to 2.55); RD 0.03 (95% CI -0.19 to 0.25). Test for heterogeneity not applicable.

Mortality (during hospital stay) (Outcome 5.3)
Two studies (n = 188) reported on this outcome. There was no significant difference in mortality (during hospital stay) comparing oral ibuprofen with iv ibuprofen in either of the two studies and the meta-analysis showed no statistically significant difference; typical RR 0.83 (95% CI 0.38 to 1.82); RD -0.02 (95% CI-0.11 to 0.07). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Mean plasma cystatin-C (mg/dL) after treatment (Outcome 5.4)
One study (n = 102) reported on this outcome. There was a statistically significant difference comparing oral ibuprofen with iv ibuprofen; MD -0.25 (95% CI -0.37 to -0.13). Test for heterogeneity not applicable.

Need for surgical closure of the ductus (Outcome 5.5)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference in the need for surgical closure of the ductus comparing oral ibuprofen with iv ibuprofen in any of the three studies. The meta-analysis showed no statistically significant difference between the two groups; typical RR 0.49 (95% CI 0.12 to 1.91); typical RD -0.03 (95% CI -0.07 to 0.02). There was no heterogeneity for this outcome (I2 = 0% for RR and 12% for RD).

Duration of ventilatory support (days) (Outcome 5.6)
Two studies (n = 134) reported on this outcome. There was no statistically significant difference in the duration of ventilatory support comparing oral ibuprofen with iv ibuprofen in either of the two studies. The meta-analysis showed no statistically significant difference between the two groups; typical MD 0.54 (95% CI -0.01 to 1.10). There was no heterogeneity for this outcome (I2 = 10% for MD).

Duration of hospitalisation (days) (Outcome 5.7)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference in the duration of hospitalisation comparing oral ibuprofen with iv ibuprofen in any of the three studies. The meta-analysis showed no statistically significant difference between the two groups; typical MD -2.51 (95% CI -5.21 to 0.19). There was no heterogeneity for this outcome (I2 = 0% for MD).

Pneumothorax (Outcome 5.8)
Two studies (n = 172) reported on this outcome. There was no statistically significant difference in pneumothorax comparing oral ibuprofen with iv ibuprofen in either of the two studies. The meta-analysis showed no statistically significant difference between the two groups; typical RR 0.41 (95% CI 0.11 to 1.54); typical RD -0.05 (95% CI -0.12 to 0.02). There was no heterogeneity for this outcome (I2 = 19% for RR and 13% for RD).

Pulmonary haemorrhage (Outcome 5.9)
One study (n = 70) reported on this outcome. There was no statistically significant difference in pulmonary haemorrhage comparing oral ibuprofen with iv ibuprofen in this study; RR 0.14 (95% CI 0.01 to 2.52); RD -0.09 (95% CI -0.19 to 0.02). Test for heterogeneity not applicable.

Pulmonary hypertension (Outcome 5.10)
Two studies (n = 172) reported on this outcome. No cases of pulmonary hypertension occurred in either of the two studies; RR not estimable; RD 0.00 (95% CI -0.03 to 0.03). There was no heterogeneity (not applicable for RR; I2 = 0% for RD).

Chronic lung disease (CLD) (at 28 days) (Outcome 5.11)
No study reported on this outcome.

Chronic lung disease (at 36 weeks PMA or at discharge) (Outcome 5.12)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference in the rate of CLD at 36 weeks PMA comparing oral ibuprofen versus iv ibuprofen in any of the three studies. The meta-analysis showed no statistically significant difference between the two groups; RR 0.82 (95% CI 0.56 to 1.20); RD -0.06 (95% CI -0.16 to 0.05). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Chronic lung disease (age not stated) (Outcome 5.13)
No study reported on this outcome.

Intraventricular haemorrhage (IVH) (grades I-IV) (Outcome 5.14)
One study (n = 64) reported on this outcome. There was no statistically significant difference between oral ibuprofen versus iv ibuprofen for IVH (grades I-IV); RR 1.08 (95% CI 0.59 to 2.00); RD 0.03 (95% CI -0.21 to 0.27). Test for heterogeneity not applicable.

Intravenricular haemorrhage (grades III-IV) (Outcome 5.15)
No study reported on this outcome.

Periventricular leukomalacia (PVL) (Outcome 5.16)
One study (n = 64) reported on this outcome. There was no statistically significant difference for PVL between oral versus iv ibuprofen in this study; RR 1.00 (95% CI 0.15 to 6.67); RD 0.00 (95% CI -0.12 to 0.12). Test for heterogeneity not applicable.

Necrotising enterocolitis (NEC) (Outcome 5.17)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference between the oral ibuprofen versus the iv ibuprofen group for NEC in the individual studies nor in the meta-analysis; RR 0.86 (95% CI 0.35 to 2.15); RD -0.01 (95% CI -0.08 to 0.06). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Intestinal perforation (Outcome 5.18)
Two studies (n = 134) reported on this outcome. There was no statistically significant difference between the oral ibuprofen versus the iv ibuprofen group for intestinal perforation in the individual studies or in the meta-analysis; RR 0.32 (0.01 to 7.48); RD -0.02 (95% CI -0.07 to 0.04). Test for heterogeneity not applicable for RR and I2 = 0% for RD.

Gastrointestinal bleed (Outcome 5.19)
Two studies (n = 172) reported on this outcome. There was no statistically significant difference between the oral ibuprofen versus the iv ibuprofen group for gastrointestinal bleed in the individual studies or in the meta-analysis; RR 2.89 (0.12 to 69.24); RD 0.01 (95% CI -0.03 to 0.05). Test for heterogeneity not applicable for RR and I2 = 0% for RD.

Sepsis (Outcome 5.20)
Three studies (n = 236) reported on this outcome. There was no statistically significant difference between the oral ibuprofen group versus the iv ibuprofen group in the individual studies or in the meta-analysis (RR 0.82 ((95% CI 0.54 to 1.25); RD -0.05 (95% CI -0.16 to 0.06). There was no heterogeneity for this outcome (I2 = 0% for RR and 19% for RD).

Retinopathy of prematurity (ROP) that required laser treatment (Outcome 5.21)
Two studies (n = 172) reported on this outcome. There was no statistically significant difference between the oral ibuprofen group versus the iv ibuprofen group for ROP requiring laser treatment in either of the two trials or in the meta-analysis; RR 0.59 (95% CI 0.26 to 1.34); RD -0.06 (-0.16 to 0.03). There was no heterogeneity for this outcome (I2 = 0% for both RR and RD).

Serum/plasma creatinine levels (micromol/L) 72 hours after treatment (Outcome 5.22)
One study (n = 102) reported on this outcome. There was a statistically significant reduction in the oral ibuprofen group versus the iv ibuprofen group; MD -29.17 micromol/L (95% CI-40.67 to -17.67). Test for heterogeneity not applicable.

Oliguria (< 1cc/kg/hr) (Outcome 5.23)
Three studies (n = 236) reported on this outcome. No cases of oliguria occurred in the studies by Erdeve 2012 and Gokmen 2011. There was no statistically significant difference between the oral ibuprofen group versus the iv ibuprofen group for oliguria in the remaining study by Cherif 2008; RR 0.14 (95% CI 0.01 to 2.66); RD -0.03 (95% CI -0.06 to 0.01). Test for heterogeneity not applicable for RR but the heterogeneity was moderate for RD (I2 = 50%).

HIGH DOSE VERSUS STANDARD DOSE OF IBUPROFEN (Comparison 6)

Only one study has compared a high dose of ibuprofen (20-10-10 mg/kg/day) versus standard dose of ibuprofen (10-5-5 mg/kg/day) (Dani 2012). The study randomised 95 infants. We report on the outcomes included by the authors and these included 70 infants for all reported outcomes except for death during hospital stay which included 95 infants (all infants randomised) (a total of 25 infants were excluded because of 20 deaths and five infants with incomplete data). As only one study is included for each of the outcomes, test for heterogeneity is not applicable.

Failure to close a PDA (after three doses) (Outcome 6.1)
There was a significant reduction in the failure rate to close a PDA in favour of a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.38 (95% CI 0.15 to 0.96); RD -0.23 (95% CI -0.43 to -0.03); NNTB 4 (95% CI 2 to 33).

Reopening after a 2nd course of ibuprofen (Outcome 6.2)
There was no significant difference in reopening after a 2nd course of ibuprofen for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 2.00 (95% CI 0.39 to 10.22); RD 0.06 (95% CI -0.07 to 0.19).

Need for surgical closure (Outcome 6.3)
There was no significant difference in need for surgical closure for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.00 (95% CI 0.15 to 6.71); RD 0.00 (95% CI -0.11 to 0.11).

Death during hospital stay (Outcome 6.4)
There was no significant difference in deaths during hospital stay for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.96 (95% CI 0.54 to 1.71); RD -0.01 (95% CI -0.20 to 0.17).

Urine output on day three (mL/kg/hr) (Outcome 6.5)
There was no significant difference in urine output on day 3 (mL/kg/hr) for a high dose of ibuprofen versus a standard dose of ibuprofen; MD 0.10 (95% CI -0.70 to 0.90).

Oliguria (< 1ml/kg/hr during 24 hours) (Outcome 6.6)
There was no significant difference in the incidence of oliguria (< 1 mL/kg/hr) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.50 (95% CI 0.27 to 8.43); RD 0.03 (95% CI -0.09 to 0.15).

Intraventricular haemorrhage (IVH) (all grades) (Outcome 6.7)
There was no significant difference in IVH (all grades) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.67 (95% CI 0.21 to 2.16); RD -0.06 (95% CI -0.22 to 0.11).

Intraventricular haemorrhage (grades III-IV) (Outcome 6.8)
There was no significant difference in IVH (grades III to IV) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.50 (95% CI 0.10 to 2.56); RD -0.06 (95% CI -0.19 to 0.07).

Periventricular leukomalacia (PVL) (Outcome 6.9)
There was no significant difference in periventricular leukomalacia for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.50 (95% CI 0.27 to 8.43); RD 0.03 (95% CI -0.09 to 0.15).

Retinopathy of prematurity (ROP) (All stages) (Outcome 6.10)
There was no significant difference in ROP (all stages) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.00 (95% CI 0.27 to 3.69); RD 0.00 (95% CI -0.15 to 0.15).

Retinopathy of prematurity (Stage > 2) (Outcome 6.11)
There was no significant difference in ROP (stage > 2) for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 2.00 (95% CI 0.19 to 21.06); RD 0.03 (95% CI -0.07 to 0.12).

Necrotising enterocolitis (NEC) (Outcome 6.12)
There was no significant difference in NEC for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.33 (95% CI 0.32 to 5.53); RD 0.03 (95% CI -0.11 to 0.17).

Chronic lung disease (CLD) at 36 weeks PMA (Outcome 6.13)
There was no significant difference in CLD at 36 weeks PMA for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 1.60 (95% CI 0.85 to 3.02); RD 0.17 (95% CI -0.05 to 0.39).

Sepsis (Outcome 6.14)
There was no significant difference in sepsis for a high dose of ibuprofen versus a standard dose of ibuprofen; RR 0.93 (95% CI 0.51 to 1.68); RD -0.03 (95% CI -0.26 to 0.20).

Hospital stay (days) (Outcome 6.15)
There was no significant difference in hospital stay (days) for a high dose of ibuprofen versus a standard dose of ibuprofen; MD 21 days (95% CI -1.44 to 43.44).

EARLY VERSUS EXPECTANT ADMINISTRATION OF IV IBUPROFEN (Comparison 7)

Only one study has compared early versus expectant administration of ibuprofen (Sosenko 2012) The study enrolled 105 infants. We report on the outcomes included by the authors and these included 105 infants for all reported outcomes. As only one study is included for each of the outcomes, test for heterogeneity is not applicable.

PRIMARY OUTCOME

Days on supplemental oxygen during the first 28 days (Outcome 7.1)
This outcome was reported in 105 infants. There was a statistically significant difference between the early versus the expectant group for this outcome; MD 2.00 days (95% CI 0.04 to 3.96).

SECONDARY OUTCOMES

Days on supplemental oxygen (Outcome 7.2)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; MD 2.00 days (95% CI -8.20 to 12.20).

Days on mechanical ventilation first 28 days (Outcome 7.3)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; MD 2.00 days (95% CI -0.58 to 4.58).

Days on mechanical ventilation (Outcome 7.4)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; MD -1.00 days (95% CI -6.98 to 4.98).

Chronic lung disease (CLD) at 36 weeks PMA (Outcome 7.5)
This outcome was reported in 101 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.00 (95% CI 0.57 to 1.75).

Death or chronic lung disease at 36 weeks PMA (Outcome 7.6)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.00 (95% CI 0.59 to 1.67).

Death during hospital stay (Outcome 7.7)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.63 (95% CI 0.19 to 2.10).

Pneumothroax (Outcome 7.8)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.26 (95% CI 0.30 to 5.35).

Intraventricular haemorrhage (IVH) (grades III & IV) (Outcome 7.9)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.81 (95% CI 0.29 to 2.25).

Periventricular leukomalacia (Outcome 7.10)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.26 (95% CI 0.30 to 5.35).

Necrotising enterocolitis (NEC) (requiring surgery) (Outcome 7.11)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; [RR 2.36 (95% CI 0.48 to 11.63).

Intestinal perforation (Outcome 7.12)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.47 (95% CI 0.09 to 2.47).

Sepsis (Outcome 7.13)
This outcome was reported in 105 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 0.90 (95% CI 0.58 to 1.41); RD -0.03 (95% CI -0.26 to 0.20).

Retinopathy of prematurity (ROP) (Outcome 7.14)
This outcome was reported in 95 infants. There was no statistically significant difference between the early versus the expectant group for this outcome; RR 1.57 (95% CI 0.49 to 5.03); RD 0.05 (95% CI -0.08 to 0.18).

SUBGROUP ANALYSES

The prespecified subgroup analyses excluding studies that used only one dose of medication and studies that were published as abstracts only were abandoned for 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.

No randomised controlled trials on the use of mefenamic acid for the treatment or prevention of a PDA were identified.

Funnel plots

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 6) and for the outcome of NEC. Both funnel plots were quite symmetric indicating that there was no obvious indication of publication bias.

Figure 6.

Funnel plot of comparison: 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, outcome: 3.1 Failure to close a PDA (after single or three doses).

Discussion

For this update a total of 27 studies are included. Two ongoing studies were identified (Su 2010; Gournay 2012). Two studies are awaiting classification (Fesharaki 2012; Qosja 2012). Study quality was variable and the results of this review are based on small to moderately large trials. For many of the outcomes, the sample size was too small to detect a significant difference and the estimates are imprecise. The studies were conducted in 16 different countries (Belgium, China, Czech republic, Egypt, Iran, Israel, Italy, Poland, Qatar, Spain, Taiwan, Thailand, Tunisia, Turkey, UK, US). There was moderate between-study heterogeneity (I2 > 50%) for only three of the secondary outcomes ('pulmonary haemorrhage, 'time to regain birth weight', 'oliguria (< 1 cc/kg/hr)' and 'serum/plasma creatinine levels 72 hours after treatment for Comparison 3 and 'oliguria (< 1 cc/kg/hr)' for Comparison 5)). The funnel plot for the primary outcome 'Failure to close a PDA' is symmetric, with no obvious absence of smaller studies having a protective effect of ibuprofen versus indomethacin (Figure 6). In the 2010 update of this review (Ohlsson 2010) one study (n = 136) (Aranda 2005) that compared iv ibuprofen versus placebo was identified. The study showed a statistically significant reduction in a composite outcome of infant deaths, infants who dropped out or required rescue treatment with a low NNTB of 5 (95% CI 3,17). There were no statistically significant effects on common neonatal short-term outcomes.

For this update in 2012, one new inclusion (Lin 2012) compared oral ibuprofen with placebo. There was a significant reduction in the failure to close a patent ductus arteriosus (PDA) with a low NNTB of 2 (95% CI 2, 4). The report of the study was written in Chinese and we could include only the primary outcome in this update.

For the previous update (Ohlsson 2010), an additional five studies (n = 280) were added to the 15 previously included studies (Ohlsson 2008) for a total of 1092 neonates with echocardiographically-diagnosed PDA enrolled in randomised controlled trials comparing iv or oral ibuprofen with iv or oral indomethacin for the closure of PDA. No study was identified for this comparison in 2012. Biochemical and physiological data favoured ibuprofen, as it has potentially less adverse effects on the kidneys, the gut and the brain. For the main outcome (failure of ductal closure) in this review, there was no statistically significant difference between ibuprofen and indomethacin groups. There were no statistically significant differences in all cause mortality, neonatal mortality, reopening of the ductus arteriosus, surgical duct ligation, duration of ventilator support, IVH, PVL, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed. There was a statistically significant reduction in the incidence of NEC; typical RR 0.68 (95% CI 0.47 to 0.99); typical RD -0.04 (95% CI -0.08 to -0.00; (P = 0.04); NNTB 25 (95% CI 13, infinity). There was a reduction in duration of ventilatory support; MD -2.35 days (95% CI -3.71 to -0.99). The incidence of decreased urine output (< 1 cc/kg/hr) was lower in the ibuprofen group as compared with the indomethacin group; NNTB 11 (95% CI 7 to 20). The serum/plasma creatinine level 72 hours after initiation of treatment was statistically significantly lower in the ibuprofen group. These three outcomes were the only statistically significant clinical findings favouring ibuprofen. No studies for this comparison were included in this 2012 update.

In a previous update (Ohlsson 2005) of this review, 'Chronic lung disease defined as oxygen requirement at 28 days postnatally' was statistically significantly more likely to occur in the ibuprofen group. There was a similar trend for chronic lung disease at 36 weeks postmenstrual age (PMA) and for days in supplementary oxygen. There was no biologically plausible explanation for this finding. In the 2007 update of the review (Ohlsson 2008), a trend in the same direction remained. In a secondary post hoc analysis, the typical RR for 'Chronic lung disease (at any age reported and studies using oral ibuprofen excluded)' was 1.25 (95% CI 0.98 to 1.60) and the typical RD was 0.08 (95% CI 0.00 to 0.15). As in another exploratory analysis, oral ibuprofen seemed less effective than indomethacin. It was postulated that the impact on the incidence of both ductal closure and CLD is decreased with oral ibuprofen. In this 2012 update there is no significant reduction in the incidence of CLD for any of the comparisons.

In the 2010 update,an additional three studies were included that used oral ibuprofen versus oral or iv indomethacin. Oral ibuprofen appears as effective as iv ibuprofen in closing a PDA; typical RR 0.82 (95% CI 0.52 to 1.29) for oral ibuprofen versus indomethacin (seven studies, n = 189). No additional studies were included in this 2012 update for this outcome.

There are no data on long-term follow-up, which is a serious concern. As mentioned in the background, prophylactic use of indomethacin does reduce the risk of severe IVH and surgical duct ligation but does not confer any significant advantages at 18 months corrected age with regards to intact survival (Schmidt 2001; Fowlie 2010).

One study of the prophylactic use of ibuprofen was stopped after 135 infants had been enrolled (Gournay 2002). Three infants developed severe hypoxaemia in the ibuprofen group. Hypoxaemia was thought to be due to pulmonary hypertension, as echocardiography showed severely decreased pulmonary blood flow. Hypoxaemia resolved quickly on inhaled nitric oxide (Gournay 2002). The authors postulated that this could be due to early administration of ibuprofen (< six 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 has not been reported in other trials using ibuprofen for prophylaxis of PDA (Ohlsson 2011). In the 2007 update of the review (Ohlsson 2008), one randomised controlled trial reported one case of pulmonary hypertension (Adamska 2005) in the ibuprofen group. In the 2010 update there were three cases of pulmonary hypertension reported in the study by Aranda and co-workers (Aranda 2005); two in the ibuprofen group and one in the placebo group.

In an extensive search of the literature, including study designs other than randomised controlled trials, one additional case-report following L-lysine ibuprofen therapy in a preterm infant with a PDA (Bellini 2006) was identified in the 2007 update of the review (Ohlsson 2008). A repeat literature search in February, 2010 did not identify any new case of pulmonary hypertension associated with the treatment of a PDA in neonates. For this update, the literature was searched in July 2012 and an additional three case reports of pulmonary hypertension in preterm infants treated with ibuprofen were identified (Amendolia 2012; Sehgal 2012).

In the 2007 update of this review (Ohlsson 2008) we stated "In view of the lack of long-term outcome data and potential side effects for both drugs, one drug cannot be recommended over the other as the therapy of choice for a PDA". In the 2010 update of the review a significant reduction in the incidence of NEC in the ibuprofen versus indomethacin group was found . As the closure rates for PDA by ibuprofen and indomethacin are similar, the reduced rate of NEC is an important finding and favours the use of ibuprofen over indomethacin for the treatment of a PDA. Kidney function is less affected by ibuprofen. In this update we found no increased risk of CLD associated with ibuprofen treatment. Some results favour oral ibuprofen over iv ibuprofen. A recent systematic review including fewer trials has come to similar conclusions (Neumann 2012).

Indomethacin has been shown to decrease cerebral blood flow in a preterm infant with PDA (Ohlsson 1993), while ibuprofen has been shown to have some neuro-protective effects in animal models (Chemtob 1990; Pellicer 1999). Future studies comparing the two drugs should include long-term follow-up (intact survival) to at least 18 months of age. Sample size calculations could be based on this review and two related Cochrane reviews (Fowlie 2010; Ohlsson 2011).

Coceani and co-workers (Coceani 2005) suggested that a membrane bound prostaglandin E synthase inhibitor, once developed for therapeutic use, could become the agent of choice for PDA treatment, particularly when preterm birth is complicated by infectious or inflammatory conditions.

Authors' conclusions

Implications for practice

Ibuprofen is effective in closing a PDA compared with placebo. No statistically significant difference in the effectiveness of ibuprofen compared with indomethacin in closing the PDA was found. Ibuprofen reduces the risk of necrotising enterocolitis (NEC), time on assisted ventilation and has less negative effects on renal function. Pulmonary hypertension has been observed in three infants after the prophylactic use of ibuprofen, and in one case in this review and in an additional case report for the treatment of a PDA. Three new cases of pulmonary hypertension have been reported. Either ibuprofen or indomethacin can be used to close a PDA. Based on currently available information ibuprofen does appear to confer net benefits over indomethacin for the treatment of a PDA, but the clinician needs to be aware that both drugs are associated with adverse effects.

Implications for research

Future research should focus on long-term follow-up (intact survival) to at least 18 months corrected age, and preferably to the age of school entry.

Acknowledgements

We are thankful to Ms. Elizabeth Uleryk for her assistance in the search of the literature and to Ms. Tara Pourdowlat, RN, for help in translating the study by Akisu (Akisu 2001) from Turkish to English.
Dr. David Edwards provided additional information on the study by Patel et al (Patel 1995).
We appreciate the help of Ms. Ana Marie Nagy, RN, for helping with the interpretation of the study by Gimeno Navarro (Gimeno Navarro 2005).
We thank Dr. Z Badiee for providing an electronic copy of the paper by Fakhraee and co-workers (Fakhraee 2007) and to Dr. J Aranda for providing a copy of his paper Aranda 2005.
Dr. C. Dani provided clarifying information regarding his paper Dani 2012.
Dr Fatemeh Nayeri provided in January 2013 an English translation of their study originally published in Persian (Fesharaki 2012).

Data and analyses

Download statistical data

Comparison 1. Intravenous ibuprofen versus placebo or no drug
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Infant deaths, infants who dropped out or required rescue treatment1136Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.38, 0.89]
2 NEC1130Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.42, 2.36]
3 Intraventricular haemorrhage (any grade)1134Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.64, 1.55]
4 Intraventricular haemorrhage (grades III-IV)1134Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.47, 2.15]
5 Pulmonary haemorrhage1136Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.03, 2.18]
6 Pulmonary hypertension1136Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.54]
7 ROP (any stage)1129Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.88, 1.62]
8 ROP (stage 3 or 4)1129Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.38, 3.68]
9 ROP (plus disease)1129Risk Ratio (M-H, Fixed, 95% CI)1.31 [0.31, 5.63]
10 CLD (supplemental oxygen at 28 days of age)1130Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.26]
11 CLD (supplemental oxygen at 36 weeks PMA)198Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.88, 1.11]
12 Periventricular leukomalacia1130Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 2.02]
13 Mortality1136Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.34, 1.90]
Analysis 1.1.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 1 Infant deaths, infants who dropped out or required rescue treatment.

Analysis 1.2.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 2 NEC.

Analysis 1.3.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 3 Intraventricular haemorrhage (any grade).

Analysis 1.4.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 4 Intraventricular haemorrhage (grades III-IV).

Analysis 1.5.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 5 Pulmonary haemorrhage.

Analysis 1.6.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 6 Pulmonary hypertension.

Analysis 1.7.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 7 ROP (any stage).

Analysis 1.8.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 8 ROP (stage 3 or 4).

Analysis 1.9.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 9 ROP (plus disease).

Analysis 1.10.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 10 CLD (supplemental oxygen at 28 days of age).

Analysis 1.11.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 11 CLD (supplemental oxygen at 36 weeks PMA).

Analysis 1.12.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 12 Periventricular leukomalacia.

Analysis 1.13.

Comparison 1 Intravenous ibuprofen versus placebo or no drug, Outcome 13 Mortality.

Comparison 2. Oral ibuprofen versus placebo or no drug
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to close a PDA after single or three doses164Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.11, 0.62]
Analysis 2.1.

Comparison 2 Oral ibuprofen versus placebo or no drug, Outcome 1 Failure to close a PDA after single or three doses.

Comparison 3. Intravenous or oral ibuprofen versus iv or oral indomethacin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to close a PDA (after single or three doses)201019Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.80, 1.20]
2 All cause mortality8470Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.45, 1.29]
3 Neonatal mortality (during first 28/30 days of life)4333Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.59, 2.11]
4 Reopening of the ductus arteriosus6204Risk Ratio (M-H, Fixed, 95% CI)1.28 [0.48, 3.38]
5 Need for surgical closure of the PDA13848Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.71, 1.51]
6 Need for re-treatment with indomethacin or ibuprofen to close the PDA7241Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.76, 1.90]
7 Duration of ventilatory support6471Mean Difference (IV, Fixed, 95% CI)-2.35 [-3.71, -0.99]
8 Duration of supplementary oxygen6556Mean Difference (IV, Fixed, 95% CI)-0.33 [-1.66, 0.99]
9 Pulmonary haemorrhage3103Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.37, 4.10]
10 Pulmonary hypertension135Risk Ratio (M-H, Fixed, 95% CI)3.53 [0.15, 81.11]
11 Chronic lung disease (at 28 days)4245Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.93, 1.59]
12 Chronic lung disease (at 36 weeks postmenstrual age)3357Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.77, 1.61]
13 Chronic lung disease (age not stated)3128Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.83, 1.30]
14 Intraventricular haemorrhage (grades I-IV)5180Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.47, 1.48]
15 Intraventricular haemorrhage (grades III-IV)8571Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.74, 1.98]
16 Periventricular leukomalacia (cystic)6573Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.67, 2.30]
17 Necrotising enterocolitis (any stage)15865Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.47, 0.99]
18 Intestinal perforation5255Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.20, 1.14]
19 Gastrointestinal bleed6314Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.57, 2.15]
20 Time to full enteral feeds4413Mean Difference (IV, Fixed, 95% CI)0.70 [-1.89, 3.29]
21 Time to regain birth weight (days)2188Mean Difference (IV, Fixed, 95% CI)-0.18 [-2.59, 2.22]
22 Retinopathy of prematurity5237Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.54, 1.38]
23 Sepsis6535Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.73, 1.81]
24 Decreased urine output (<1 cc/kg/hr)6576Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.14, 0.54]
25 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment8491Mean Difference (IV, Fixed, 95% CI)-4.70 [-8.88, -0.53]
26 Increase in serum/plasma creatinine levels (mg/dL) following treatment121Mean Difference (IV, Fixed, 95% CI)-15.91 [-31.78, -0.04]
27 Duration of hospitalisation3285Mean Difference (IV, Fixed, 95% CI)-2.19 [-6.55, 2.18]
Analysis 3.1.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 1 Failure to close a PDA (after single or three doses).

Analysis 3.2.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 2 All cause mortality.

Analysis 3.3.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 3 Neonatal mortality (during first 28/30 days of life).

Analysis 3.4.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 4 Reopening of the ductus arteriosus.

Analysis 3.5.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 5 Need for surgical closure of the PDA.

Analysis 3.6.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 6 Need for re-treatment with indomethacin or ibuprofen to close the PDA.

Analysis 3.7.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 7 Duration of ventilatory support.

Analysis 3.8.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 8 Duration of supplementary oxygen.

Analysis 3.9.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 9 Pulmonary haemorrhage.

Analysis 3.10.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 10 Pulmonary hypertension.

Analysis 3.11.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 11 Chronic lung disease (at 28 days).

Analysis 3.12.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 12 Chronic lung disease (at 36 weeks postmenstrual age).

Analysis 3.13.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 13 Chronic lung disease (age not stated).

Analysis 3.14.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 14 Intraventricular haemorrhage (grades I-IV).

Analysis 3.15.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 15 Intraventricular haemorrhage (grades III-IV).

Analysis 3.16.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 16 Periventricular leukomalacia (cystic).

Analysis 3.17.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 17 Necrotising enterocolitis (any stage).

Analysis 3.18.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 18 Intestinal perforation.

Analysis 3.19.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 19 Gastrointestinal bleed.

Analysis 3.20.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 20 Time to full enteral feeds.

Analysis 3.21.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 21 Time to regain birth weight (days).

Analysis 3.22.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 22 Retinopathy of prematurity.

Analysis 3.23.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 23 Sepsis.

Analysis 3.24.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 24 Decreased urine output (<1 cc/kg/hr).

Analysis 3.25.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 25 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment.

Analysis 3.26.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 26 Increase in serum/plasma creatinine levels (mg/dL) following treatment.

Analysis 3.27.

Comparison 3 Intravenous or oral ibuprofen versus iv or oral indomethacin, Outcome 27 Duration of hospitalisation.

Comparison 4. Oral ibuprofen versus iv or oral indomethacin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to close a PDA (after three doses)7189Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.52, 1.29]
2 All cause mortality382Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.21, 1.66]
3 Neonatal mortality (during first 28/30 days of life)266Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.33, 5.39]
4 Reopening of the ductus arteriosus120Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Need for surgical closure of the PDA391Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.24, 1.70]
6 Pulmonary haemorrhage121Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.01, 2.86]
7 Pulmonary hypertension00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
8 Chronic lung disease (at 28 days)130Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.38, 1.95]
9 Chronic lung disease (at 36 weeks postmenstrual age)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
10 Chronic lung disease (age not stated)118Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.52, 1.92]
11 Intraventricular haemorrhage (grades I-IV)377Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.45, 1.83]
12 Intraventricular haemorrhage (grades III-IV)141Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.15, 6.13]
13 Periventricular leukomalacia (cystic)141Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.38]
14 Necrotising enterocolitis (any stage)6166Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.23, 0.82]
15 Intestinal perforation262Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.03, 1.95]
16 Gastrointestinal bleed385Risk Ratio (M-H, Fixed, 95% CI)2.80 [0.48, 16.45]
17 Retinopathy of prematurity271Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.35, 2.73]
18 Sepsis253Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.54, 2.19]
19 Oliguria (< 1 cc/kg/hr)136Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
20 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment4107Mean Difference (IV, Fixed, 95% CI)-15.14 [-23.00, -5.28]
Analysis 4.1.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 1 Failure to close a PDA (after three doses).

Analysis 4.2.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 2 All cause mortality.

Analysis 4.3.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 3 Neonatal mortality (during first 28/30 days of life).

Analysis 4.4.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 4 Reopening of the ductus arteriosus.

Analysis 4.5.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 5 Need for surgical closure of the PDA.

Analysis 4.6.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 6 Pulmonary haemorrhage.

Analysis 4.8.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 8 Chronic lung disease (at 28 days).

Analysis 4.10.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 10 Chronic lung disease (age not stated).

Analysis 4.11.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 11 Intraventricular haemorrhage (grades I-IV).

Analysis 4.12.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 12 Intraventricular haemorrhage (grades III-IV).

Analysis 4.13.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 13 Periventricular leukomalacia (cystic).

Analysis 4.14.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 14 Necrotising enterocolitis (any stage).

Analysis 4.15.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 15 Intestinal perforation.

Analysis 4.16.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 16 Gastrointestinal bleed.

Analysis 4.17.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 17 Retinopathy of prematurity.

Analysis 4.18.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 18 Sepsis.

Analysis 4.19.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 19 Oliguria (< 1 cc/kg/hr).

Analysis 4.20.

Comparison 4 Oral ibuprofen versus iv or oral indomethacin, Outcome 20 Serum/plasma creatinine levels (micromol/L) 72 hours after treatment.

Comparison 5. Oral ibuprofen versus iv ibuprofen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to close a PDA (after single or three doses)3236Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.23, 0.61]
2 Mortality (during first 28/30 days of life)164Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.50, 2.55]
3 Mortality (during hospital stay)2188Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.38, 1.82]
4 Mean plasma cystatin-C (mg/L) after treatment1102Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.37, -0.13]
5 Need for surgical closure of the ductus3236Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.12, 1.91]
6 Duration of ventilatory support2134Mean Difference (IV, Fixed, 95% CI)0.54 [-0.01, 1.10]
7 Duration of hospitalisation (days)3236Mean Difference (IV, Fixed, 95% CI)-2.51 [-5.21, 0.19]
8 Pneumothorax2172Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.11, 1.54]
9 Pulmonary haemorrhage170Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.52]
10 Pulmonary hypertension2172Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
11 Chronic lung disease (at 28 days)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Chronic lung disease (at 36 weeks postmenstrual age or at discharge)3236Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.56, 1.20]
13 Chronic lung disease (age not stated)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
14 Intraventricular haemorrhage (grades I-IV)164Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.59, 2.00]
15 Intraventricular haemorrhage (grades III-IV)00Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
16 Periventricular leukomalacia164Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.67]
17 Necrotising enterocolitis (any stage)3236Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.35, 2.15]
18 Intestinal perforation2134Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.48]
19 Gastrointestinal bleed2172Risk Ratio (M-H, Fixed, 95% CI)2.89 [0.12, 69.24]
20 Sepsis3236Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.54, 1.25]
21 Retinopathy of prematurity that required laser treatment2172Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.26, 1.34]
22 Serum/plasma creatinine levels (micromol/L) after treatment1102Mean Difference (IV, Fixed, 95% CI)-29.17 [-40.67, -17.67]
23 Oliguria (< 1cc/kg/hr)3236Risk Difference (M-H, Fixed, 95% CI)-0.03 [-0.06, 0.01]
Analysis 5.1.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 1 Failure to close a PDA (after single or three doses).

Analysis 5.2.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 2 Mortality (during first 28/30 days of life).

Analysis 5.3.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 3 Mortality (during hospital stay).

Analysis 5.4.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 4 Mean plasma cystatin-C (mg/L) after treatment.

Analysis 5.5.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 5 Need for surgical closure of the ductus.

Analysis 5.6.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 6 Duration of ventilatory support.

Analysis 5.7.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 7 Duration of hospitalisation (days).

Analysis 5.8.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 8 Pneumothorax.

Analysis 5.9.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 9 Pulmonary haemorrhage.

Analysis 5.10.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 10 Pulmonary hypertension.

Analysis 5.12.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 12 Chronic lung disease (at 36 weeks postmenstrual age or at discharge).

Analysis 5.14.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 14 Intraventricular haemorrhage (grades I-IV).

Analysis 5.16.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 16 Periventricular leukomalacia.

Analysis 5.17.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 17 Necrotising enterocolitis (any stage).

Analysis 5.18.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 18 Intestinal perforation.

Analysis 5.19.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 19 Gastrointestinal bleed.

Analysis 5.20.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 20 Sepsis.

Analysis 5.21.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 21 Retinopathy of prematurity that required laser treatment.

Analysis 5.22.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 22 Serum/plasma creatinine levels (micromol/L) after treatment.

Analysis 5.23.

Comparison 5 Oral ibuprofen versus iv ibuprofen, Outcome 23 Oliguria (< 1cc/kg/hr).

Comparison 6. High dose versus standard dose of ibuprofen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to close a PDA after three doses of ibuprofen170Risk Ratio (M-H, Fixed, 95% CI)0.38 [0.15, 0.96]
2 Reopening after 2nd course of ibuprofen170Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.39, 10.22]
3 Need for surgical closure170Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.15, 6.71]
4 Death during hospital stay195Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.54, 1.71]
5 Urine output on day 3 (mL/kg/hr)170Mean Difference (IV, Fixed, 95% CI)0.10 [-0.70, 0.90]
6 Oliguria (< 1 mL/kg/hr during 24 hrs)170Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.27, 8.43]
7 Intraventricular haemorrhage (all grades)170Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.21, 2.16]
8 Intraventricular haemorrhage (grades III-IV)170Risk Ratio (M-H, Fixed, 95% CI)0.5 [0.10, 2.56]
9 Periventricular leukomalacia170Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.27, 8.43]
10 Retinopathy of prematurity170Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.27, 3.69]
11 Retinopathy of prematurity (Stage ≥3)170Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.19, 21.06]
12 Necrotising enterocolitis170Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.32, 5.53]
13 Chronic lung disease at 36 weeks PMA170Risk Ratio (M-H, Fixed, 95% CI)1.6 [0.85, 3.02]
14 Sepsis170Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.51, 1.68]
15 Hospital stay (days)170Mean Difference (IV, Fixed, 95% CI)21.0 [-1.44, 43.44]
Analysis 6.1.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 1 Failure to close a PDA after three doses of ibuprofen.

Analysis 6.2.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 2 Reopening after 2nd course of ibuprofen.

Analysis 6.3.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 3 Need for surgical closure.

Analysis 6.4.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 4 Death during hospital stay.

Analysis 6.5.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 5 Urine output on day 3 (mL/kg/hr).

Analysis 6.6.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 6 Oliguria (< 1 mL/kg/hr during 24 hrs).

Analysis 6.7.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 7 Intraventricular haemorrhage (all grades).

Analysis 6.8.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 8 Intraventricular haemorrhage (grades III-IV).

Analysis 6.9.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 9 Periventricular leukomalacia.

Analysis 6.10.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 10 Retinopathy of prematurity.

Analysis 6.11.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 11 Retinopathy of prematurity (Stage ≥3).

Analysis 6.12.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 12 Necrotising enterocolitis.

Analysis 6.13.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 13 Chronic lung disease at 36 weeks PMA.

Analysis 6.14.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 14 Sepsis.

Analysis 6.15.

Comparison 6 High dose versus standard dose of ibuprofen, Outcome 15 Hospital stay (days).

Comparison 7. Early versus expectant administration of iv ibuprofen
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Days on supplemental oxygen during the first 28 days1105Mean Difference (IV, Fixed, 95% CI)2.0 [0.04, 3.96]
2 Days on supplemental oxygen1105Mean Difference (IV, Fixed, 95% CI)2.0 [-8.20, 12.20]
3 Days on mechanical ventilation first 28 days1105Mean Difference (IV, Fixed, 95% CI)2.0 [-0.58, 4.58]
4 Days on mechanical ventilation1105Mean Difference (IV, Fixed, 95% CI)-1.0 [-6.98, 4.98]
5 Chronic lung disease at 36 weeks PMA1101Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.57, 1.75]
6 Death or chronic lung disease at 36 weeks PMA1105Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.59, 1.67]
7 Death during hospital stay1105Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.19, 2.10]
8 Pneumothorax1105Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.30, 5.35]
9 Intraventricular haemorrhage (grades III & IV)1105Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.29, 2.25]
10 PVL1105Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.30, 5.35]
11 NEC (requiring surgery)1105Risk Ratio (M-H, Fixed, 95% CI)2.36 [0.48, 11.63]
12 Intestinal perforation1105Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.09, 2.47]
13 Sepsis1105Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.58, 1.41]
14 ROP stage ≥ 3195Risk Ratio (M-H, Fixed, 95% CI)1.58 [0.49, 5.03]
Analysis 7.1.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 1 Days on supplemental oxygen during the first 28 days.

Analysis 7.2.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 2 Days on supplemental oxygen.

Analysis 7.3.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 3 Days on mechanical ventilation first 28 days.

Analysis 7.4.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 4 Days on mechanical ventilation.

Analysis 7.5.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 5 Chronic lung disease at 36 weeks PMA.

Analysis 7.6.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 6 Death or chronic lung disease at 36 weeks PMA.

Analysis 7.7.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 7 Death during hospital stay.

Analysis 7.8.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 8 Pneumothorax.

Analysis 7.9.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 9 Intraventricular haemorrhage (grades III & IV).

Analysis 7.10.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 10 PVL.

Analysis 7.11.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 11 NEC (requiring surgery).

Analysis 7.12.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 12 Intestinal perforation.

Analysis 7.13.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 13 Sepsis.

Analysis 7.14.

Comparison 7 Early versus expectant administration of iv ibuprofen, Outcome 14 ROP stage ≥ 3.

What's new

DateEventDescription
16 November 2012New search has been performed

This updates the review "Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants" (Ohlsson 2010).

For this update six additional studies were included; one study compared oral ibuprofen with placebo (Lin 2012); three studies compared oral ibuprofen with iv ibuprofen (Cherif 2008; Erdeve 2012; Gokmen 2011, one study compared iv high dose of ibuprofen versus standard dose of ibuprofen (Dani 2012) and one study compared early versus expectant administration of iv ibuprofen (Sosenko 2012). Two studies are awaiting classification.

16 November 2012New citation required and conclusions have changed

The results, as before, show that ibuprofen is as effective as indomethacin in closing a patent ductus arteriosus (PDA). There is no statistically significant increase in the risk of chronic lung disease with ibuprofen.

The incidence of necrotising enterocolitis is lowered by ibuprofen compared to indomethacin.

Kidney function is less affected by ibuprofen than indomethacin and less by oral compared to intravenous (iv) ibuprofen.

Oral ibuprofen may be more effective in closing a PDA than iv ibuprofen and reduces the risk of necrotising enterocolitis.

Ibuprofen is now recommended over indomethacin to close a PDA.

Additional studies are warranted to assess the effectiveness of high-dose ibuprofen versus a standard dose regimen and early versus expectant administration of ibuprofen.

Long-term follow-up studies are still warranted.

History

Protocol first published: Issue 1, 2002
Review first published: Issue 2, 2003

DateEventDescription
28 February 2010New search has been performed

This updates the review "Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants" (Ohlsson 2008).

This review was updated in February, 2010. One study comparing ibuprofen to placebo was identified and 5 new trials comparing ibuprofen to indomethacin were identified.

The results, as before, show that ibuprofen is as effective as indomethacin in closing a PDA. There is now clearly no statistically significant increase in the risk of chronic lung disease with ibuprofen. A new important finding is that ibuprofen reduces the risk of necrotizing enterocolitis.

Ibuprofen is now recommended over indomethacin to close a PDA.

Long-term follow-up studies are still warranted.

26 June 2008AmendedConverted to new review format.
19 September 2007New citation required and conclusions have changedSubstantive amendment
19 September 2007New search has been performedThis review updates the existing review "Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants", published in Issue 4, 2005 of The Cochrane Library (Ohlsson 2005).

This update of the review conducted in August 2007 identified four previously not included trials (Adamska 2005, Aly 2007, Gimeno Navarro 2005, Pezzati 1999). In addition, two trials previously included as abstracts have now been published as full articles (Chotigeat 2003, Supapannachart 2002).

The current review includes a total of 16 trials enrolling 876 infants. The increase in sample size made the point estimates more precise and changed the results of one important outcome. In the previous review there was a statistically significant increase in chronic lung disease in the ibuprofen group. Although a trend towards an increase in chronic lung disease remained in this review, the summary estimates did not reach statistical significance. In this review, the outcome of serum/plasma levels of creatinine following treatment was included and the results showed significantly lower levels in the ibuprofen group. As in previous reviews, the risk of decreased urine output was lower in the ibuprofen group. There is not enough data available regarding the effectiveness of oral ibuprofen to close a patent ductus arteriosus. One case of pulmonary hypertension associated with ibuprofen treatment was reported in one trial.

Long-term neurodevelopmental data are still lacking.

Based on the available evidence clinicians may prefer one of the two drugs currently available for closure of a patent ductus arterious over the other:
a) Either drug is effective in closing a patent ductus arterious
b) Ibuprofen may be preferred because of its less negative impact on the kidney function
c) Indomethacin may be preferred because of the trend towards increase in chronic lung disease in the ibuprofen group and the potential risk of pulmonary hypertension associated with the use of ibuprofen

This review has previously been updated in 2005 (Ohlsson 2005). An updated search in July 2005 identified one trial of ibuprofen versus placebo, but the results were not reported unblinded to group. However, the search identified three trials that compared ibuprofen to indomethacin for the treatment of a PDA. The addition of the results from these three trials confirmed our previous findings that ibuprofen is no more effective than indomethacin and may cause more adverse effects. There were no important changes to the conclusions of that review.

An updated search in October 2004 found no new eligible trials for inclusion in this review.

There was no trial identified using mefenamic acid in the original review or in any of the updates.

Contributions of authors

Arne Ohlsson - developing and writing the text of the protocol and the review, data abstraction and analyses.
Arne Ohlsson - performing the updates of the review in July, 2005, in August, 2007 and in February 2010.
Rajneesh Walia - developing and writing the text of the protocol.
Sachin Shah - data abstraction and analyses, editing the text of the review.

Declarations of interest

None known.

Sources of support

Internal sources

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

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services , USA.

    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

Differences between protocol and review

Additional comparisons and outcomes have been added in the updates in 2007 and 2010 (listed under the heading of outcomes).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adamska 2005

MethodsSingle-centre, randomised controlled trial.
I Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes
Participants

Study conducted in one NICU in Warsaw in Poland

Study period: Not stated
35 preterm (< 33 weeks of gestation and birth weight < 1500 g) infants with a PDA diagnosed by Doppler echocardiography
16 infants randomised to ibuprofen group mean (SD) GA 27.7 (1.8) weeks; BW 1074 (264) g; 9 boys, 7 girls
19 infants randomised to indomethacin group mean (SD) GA 27.6 (2.0) weeks; BW 1003 (192) g; 11 boys, 8 girls

InterventionsIbuprofen (3 doses) was given at 24-hour intervals (10, 5, and 5 mg/kg iv). Indomethacin (3 doses) was given at 24-hour intervals (0.2mg/kg/dose iv)
OutcomesThe primary outcome was ductal closure. Other outcomes included; need for surgical ligation, IVH, PVL, NEC, intestinal perforation, oliguria, time to full oral feeds, CLD (at 28 days of age), pulmonary haemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.
NotesStudy published in Polish.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information other than "...randomly assigned"
Allocation concealment (selection bias)Low riskAdequate. Was done in a blinded manner
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of intervention - yes
Blinding of outcome measurement(s) - yes
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Selective reporting (reporting bias)Unclear risk27 infants (12 received ibuprofen and 15 received indomethacin) were treated as per protocol. In the remaining 8 infants treatment was stopped due to side effects. In the ibuprofen group the reasons to stop treatment was pulmonary haemorrhage (3/16) and pulmonary hypertension (1/16); in the indomethacin group it was increased serum creatinine and urea nitrogen concentrations (3/19) and IVH (grade IV) ( 1/19)
Other biasLow riskAppears free of other bias

Akisu 2001

MethodsSingle-centre, randomised controlled trial.
I Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in one NICU in Izmir, Turkey

Study period: July 1988 to January 2000
23 infants < 35 weeks GA with echocardiographically confirmed PDA
12 randomised to ibuprofen group mean (SD) GA 32.1 (1.2) weeks; BW 1706 g (187)
5 girls/7 boys; 9 born by c/s, 2 born vaginally, 10 had RDS, 7 received surfactant. PDA was diagnosed on day 3.9 (0.5)
11 randomised to indomethacin group mean (SD) GA 31.9 (1.3) weeks; BW 1645 g (190)
6 girls/5 boys; 8 born by c/s, 3 born vaginally, 8 had RDS, 7 received surfactant. PDA diagnosed on day 3.5 (0.6)

InterventionsIbuprofen was given via an oro-gastric tube (10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later). Indomethacin was given via an oro-gastric tube (0.2 mg/kg for three doses at 12-hour
intervals).
2 neonates in the ibuprofen group and 3 in the indomethacin group required a second treatment with the same drug.
OutcomesPDA closure
Diuresis
Serum creatinine
Thrombocyte count
Gastrointestinal bleed
IVH
Sepsis
Mortality
NotesStudy published in Turkish.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSingle-centre, randomised controlled trial. No other information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Indomethacin and ibuprofen were given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free from other bias

Aly 2007

MethodsSingle-centre, randomised controlled trial, conducted in Cairo, Egypt
I Blinding of randomisation - yes (sealed opaque envelopes)
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

21 preterm infants (< 35 weeks gestation) age 2 to 7 days with respiratory distress and PDA diagnosed by Doppler echocardiography

Study period: not stated
12 infants were randomised to the oral ibuprofen group, mean (SD) GA 31.2 (2.5) weeks; BW 1521 (398) g; 8 boys, 4 girls
9 infants were randomised to iv indomethacin, mean (SD) GA 32.9 (1.6) weeks; BW 1884 (485) g; 4 boys, 5 girls

InterventionsIbuprofen was given as an initial oral dose of 10 mg/kg, followed by 2 doses orally of 5mg/kg after 24 and 48 hours. Indomethacin was given iv as 3 doses of 0.2 mg/kg at 12-hour intervals
OutcomesThe primary outcome was ductal closure. Secondary outcomes included biochemical tests (serum creatinine), pulmonary haemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and increase in serum creatinine following treatment.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description provided
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes. Sealed opaque envelopes were used for random assignment
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen was given orally, whereas indomethacin was given iv Ibuprofen and indomethacin were given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Aranda 2005

MethodsMulti-centre, randomised controlled trial
I Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes
Participants

Multi-centre study conducted in 11 centres in the USA

Study period: March 2002 to March 2005
136 preterm infants (BW 500 to 1000 g; PMA < 30 weeks) with evidence of ductal shunting by an echocardiogram
Mean (SD) GA 26.2 (1.4) weeks Mean (SD) BW 798 (130.3) g
51% boys and 49% girls

InterventionsIbuprofen was given iv as a 3-day treatment course of 10 mg/kg, 5 mg/kg, and 5 mg/kg of ibuprofen (n = 68) or placebo (saline) (n = 68)
OutcomesProportion of infants who required rescue treatment for PDA (indomethacin or surgery), died or dropped on or prior to study day 14, mortality, NEC, IVH, pulmonary haemorrhage, pulmonary hypertension, ROP, BPD (supplemental oxygen at 28 days), BPD (supplemental oxygen at 36 weeks PMA), PVL.
NotesThis study was published in abstract form in 2005, but has been published in a complete report in 2009.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentral randomisation was implemented using a dynamic allocation method of biased coin randomisation, balancing within birth weight (500 to 750 g and 751 to 1000 g), within each site, and in the study overall
Allocation concealment (selection bias)Low riskI Blinding of randomisation - yes. The coded vials of study drug or placebo contained indistinguishable colourless solutions dispensed by the blinded research pharmacists of the participating sites
Blinding (performance bias and detection bias)
All outcomes
Low risk

See allocation concealment

Blinding of intervention - yes
Blinding of outcome measurement(s) - yes

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe outcome of BPD (supplemental oxygen at 36 weeks PMA) was not ascertained in the whole sample as randomised. The denominator in the ibuprofen group was 46 infants and in the placebo group it was 52, which is too low when accounting for deaths
Selective reporting (reporting bias)Unclear riskSee incomplete data addressed? above. The trials was registered with clinicaltrials.gov: ID # NCT00440804
Other biasLow riskAppears free of other bias

Cherif 2008

MethodsSingle-centre, randomised controlled trial. Conducted in the NICU of the Neonatal and Maternity Center of Tunis, Tunis,Tunisia over a period of one year (January 2007 to December 2007)
I Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no for most outcomes except for physicians performing ECHO
Participants64 VLBW infants with ECHO confirmed PDA, PMA < 32 weeks, BW < 1500 g, postnatal age between 48 and 96 hours, respiratory distress requiring > 25% oxygen supplementation and ECHO evidence of significant left-to-right shunting across PDA.
Interventions32 infants were assigned to receive oral ibuprofen (10 mg/kg as the initial dose) and 32 infants were assigned to receive iv ibuprofen (10 mg/kg as the initial dose). After the first dose of treatment in both groups, ECHO evaluation was performed to determine the need for a second or a third dose. In each group, in case the ductus was still open after the third dose, intravenous ibuprofen (an initial dose of 10 mg/kg followed by 2 doses of 5 mg/kg each, after 24 and 48 hours) as a non-randomised rescue treatment was given. If this therapy failed to promote ductal closure and the patient continued to receive mechanical ventilation, surgical ligation of the ductus was performed.
OutcomesPDA closure rate, need for surgical ligation, rate of reopening of the ductus, oliguria, increase in serum creatinine level > 16 mg/dL, change in creatinine concentrations, IVH grades I-II and grades III-IV, PVL, NEC, bowel perforation, sepsis, duration of intubation, survival at 1 month, duration of hospital stay.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskPatients were randomly assigned to a treatment group by means of cards in sealed, opaque envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskHealthcare providers were not blinded to treatment groups. Physicians performing ECHO and making the decision for second- and third-dose administration were unaware of assignment
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all enrolled infants
Selective reporting (reporting bias)Low riskThe protocol was available to us. Trial number: NCT00642330. There does not seem to be any definitive deviations from the protocol
Other biasLow riskAppears free of other bias

Chotigeat 2003

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Single-centre study conducted in Bangkok, Thailand

Study period: January 1, 2001 to May 31, 2002
30 preterm infants (GA =/< 35 weeks, postnatal age =/< 10 days) with a echocardiographically verified PDA
15 infants received ibuprofen mean (SD) GA 30.8 (2.3) weeks; BW 1412 (354) g
15 infants received indomethacin mean (SD) GA 29.9 (2.9) weeks; BW 1434 (421) g

InterventionsIbuprofen was given orally as a 3-day treatment course every 24 hours and indomethacin was given iv at 12-hour intervals
The doses of ibuprofen and indomethacin given were not stated
OutcomesPDA closure
Need for surgical ligation
NEC
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
The infants were assigned to treatment group by random number
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen was given orally and indomethacin was given iv
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we can therefore not ascertain whether there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Dani 2012

MethodsMulti-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants70 infants with PMA < 29 weeks, ECHO evidence of significant PDA, age 12-24 hours and RDS necessitating respiratory support.
Interventions35 infants [mean PMA 25.6 (SD 1.8) weeks; BW 781 (SD 225) g] were randomised to a high-dose ibuprofen (20-10-10 mg/kg/day) and 35 infants [mean PMA 26.0 (SD 1.7) weeks; BW 835 (SD 215) g] were randomised to standard-dose of iv ibuprofen (10-5-5 mg/kg/day).
OutcomesDuctal closure, serum creatinine (mg/dL - transcribed by us to mmol/L) on day 3 of treatment, oliguria (</= 1 mL/kg/hr during a 24-hour collection period), peak total serum bilirubin (mg/dL) during the first week of life, IVH (all grades and grades III-IV), PVL (all grades), ROP (all stages, stage > 2, NEC, BPD (oxygen requirement at 36 weeks PMA), sepsis, mortality, hospital stay (days).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskSealed opaque envelopes
Blinding (performance bias and detection bias)
All outcomes
Unclear riskECHO studies were performed by physicians, who were blinded as to the infants' treatment assignments. It is not stated if clinical outcomes other than the PDA status were assessed blinded to assigned group or not
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all enrolled infants
Selective reporting (reporting bias)Low riskThe trial was registered with ClinicalTrials.gov under identifier NCT01243996. There does not seem to have been any deviations from the published protocol
Other biasLow riskAppears free of other bias

Erdeve 2012

Methods

Single-centre, randomised, controlled trial, conducted in Ankara, Turkey

Study period: January 2010 and February 2011
I. Blinding of randomisation - yes- sequentially numbered, sealed, opaque envelopes
II. Blinding of intervention - no
III. Complete follow-up - no - see note
IV. Blinding of outcome measurement(s) - A paediatric cardiologist who was blinded to the treatment group determined the success rate of the treatment and the need for a second course via the same route

Participants80 infants with PMA </= 28 weeks, BW < 1000 g, postnatal age 48 to 96 hours and with ECHO-confirmed significant PDA
Interventions36 infants received oral ibuprofen and 34 infants received iv ibuprofen both at a dose of 10 mg/kg followed by 5 mg/kg at 24 and 48 hours. 4 infants in the oral group and 6 in the iv group were excluded because of death before complete treatment course
OutcomesPrimary outcome was PDA closure rate. Secondary outcomes included mortality, need for re-treatment or surgical treatment of the PDA, duration of ventilation, duration of hospital stay, increase in serum bilirubin level after treatment (mg/dL), plasma creatinine (mg/dL) after the first course of treatment, rate of ductal reopening, pneumothorax, pulmonary haemorrhage, pulmonary hypertension, BPD (supplemental oxygen at 36 weeks PMA), IVH (grades 1-IV), NEC, ROP, ROP requiring laser treatment
Notes4 infants in the oral group and 6 in the iv group were excluded because of death before complete treatment course. They were not included in an ITT analysis for the outcome of death. We did include these deaths in our analysis of mortality
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskSequentially numbered, sealed, opaque envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskIbuprofen was administered either orally or iv which would have been known to the care givers. A paediatric cardiologist was blinded to the treatment group to determine the success of the treatment and the need for a second course via the same route
Incomplete outcome data (attrition bias)
All outcomes
High risk4 infants in the oral group and 6 in the iv group were excluded because of death before complete treatment course. They were not included in an ITT analysis for the outcome of death. We did include these deaths in our analysis of mortality
Selective reporting (reporting bias)Low riskThe protocol for the study was available to us. Trial registration # NCT01261117. There does not seem to have been any deviations from the protocol
Other biasLow riskAppears free of other bias

Fakhraee 2007

MethodsSingle-centre (Tehran, Iran), randomised controlled trial
I Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - can't tell
Participants

Study period: June 2003 to June 2004

36 preterm infants PMA < 34 weeks, age < 14 days, platelet count > 100 000/microL, serum creatinine ≤ 1.6 mg/dL, absence of clinical manifestations of abnormal clotting function, absence of grades III-IV IVH. Color Doppler echocardiographic evidence of significant PDA.

18 infants received ibuprofen (PMA 31.5 +/-1.4 weeks; BW 1658 +/- 387 g)

18 infants received indomethacin (PMA 30.9 +/- 2.0 weeks; BW 1522 +/- 358 g)

Study period: June 2003 to June 2004

InterventionsIbuprofen was given orally as a suspension at a first dose of 10 mg/kg, followed at an interval of 24 hours by two doses of 5 mg/kg. Indomethacin was given orally three times at 0.2 mg/kg/dose at intervals of 24 hours.
OutcomesDuctal closure, need for re-treatment, reopening of the duct, mortality during the first 30 days of life, maximum serum BUN and creatinine levels, NEC, IVH (grades III and IV), oliguria.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
No description provided. "The enrolled patients randomly received either oral ibuprofen or oral indomethacin"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of intervention - cannot tell
Blinding of outcome measurement(s) - cannot tell
No description provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes were reported for all enrolled infants
Selective reporting (reporting bias)Unclear riskThe protocol was not available to us, so we cannot judge if there were any deviations
Other biasLow riskAppears to be free from other bias

Gimeno Navarro 2005

MethodsSingle-centre, randomised controlled trial, conducted in Valencia, Spain
I Blinding of randomisation - yes (sealed envelopes)
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
Participants

Study period: January 2003 to July 2004

47 ventilated, preterm infants (< 34 weeks gestational age) with a haemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support

Interventions23 infants received iv ibuprofen of 10 mg/kg, followed by two doses of ibuprofen iv every 24 hours
Median (25th and 75th centiles ) GA 28 (24,31) weeks; mean BW (SD) 1.169 (490) g
24 infants received indomethacin 0.2 mg/kg/dose iv every 12 hours for a total of 3 doses
Median (25th and 75th centiles ) GA 28.5 (27,30) weeks; mean BW (SD) 1.206 (513) g
OutcomesThe primary outcome was ductal closure. Other outcomes included mortality, ductal reopening, need for surgical ligation, NEC, isolated bowel perforation, intestinal haemorrhage, pulmonary haemorrhage, CLD (age not stated), IVH (grades III and IV), days on assisted ventilation (median and range), days in supplemental oxygen (median and range), days in NICU (median and range)
NotesStudy published in Spanish
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed envelopes)
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - cannot tell
Indomethaicin and ibuprofen were given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants
Other biasLow riskAppear free of other bias

Gokmen 2011

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Single-centre study conducted at Zekai Tahir Burak Maternity Teaching Hospital,
Ankara, Turkey, between January 2010 and February 2011

102 VLBW infants with PDA

InterventionsInfants received either iv or oral ibuprofen at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours.
OutcomesRenal tolerance, mean plasma creatinine after treatment, urine output after treatment, cystatin-C levels, failure to close a PDA, need for second course of ibuprofen, oliguria, hospital stay, NEC, gastrointestinal bleeding, sepsis, pneumothorax, BPD (supplemental oxygen at 36 weeks PMA or at discharge, which ever came first, ROP requiring laser treatment, death during hospital stay.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskPatients were assigned randomly using cards in opaque envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskIbuprofen was given either orally or intravenously and this would have been known to the staff
Incomplete outcome data (attrition bias)
All outcomes
Low risk6 infants (4 in the iv ibuprofen group and 2 in the oral group) died before they completed their treatment. These infants were not included in an ITT analysis. We included them
Selective reporting (reporting bias)Unclear riskThe protocol for this study was not available to us and we can not ascertain whether there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Hammerman 2008

MethodsSingle-centre, randomised, controlled trial, conducted in Jerusalem, Israel
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Population: 64 preterm (PMA < 33 weeks, BW <1750 g) infants with PDA

Study period: February 2002 to December 2006

InterventionsIntervention: 31 infants received continuous iv. infusion of indomethacin for 36 hours at a rate of 17 μcg/kg/hr and 32 infants received 10 mg/kg of ibuprofen iv followed by 2 doses of 5 mg/kg at 24-hour intervals.
OutcomesThe primary outcome was ductal closure, need for surgical ligation, need for re-treatment with either indomethacin or ibuprofen, need for surgical treatment, mortality, BPD (age not stated), IVH (grades III-IV), ROP, NEC.
NotesThe outcomes of BPD (age not stated), NEC, IVH (III-IV) and ROP (3-4), were reported in graphic form only and the numbers had to be estimated from the graph.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was based on computer-generated random numbers without sub-stratification
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Because the methods of drug administration were clearly different, the study could not be blinded. The cardiologist performing the echocardiograms was blinded to the study group
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
One infant assigned to the ibuprofen group was withdrawn by his parents before he started therapy, and he was not included in the analyses.
Selective reporting (reporting bias)Low riskThe protocol was available to us. Trial registration #: NCT00485160. There were no deviations from the protocol.
Other biasLow riskThe study appears to be free of other bias.

Lago 2002

MethodsTwo-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in Padova and Treviso, Italy

Study period: January 1998 to December 2000
175 preterm infants with echocardiographically verified PDA were enrolled
94 received ibuprofen mean (SD) GA 28 weeks (2); BW 1126 g (412); 52 boys, 42 girls
81 received indomethacin mean (SD) GA 29 weeks (3); BW 1214 g (427); 43 boys, 38 girls

InterventionsIbuprofen was given iv 10 mg/kg as the initial dose followed by 5 mg/kg each at 24 and 48 hours
Indomethacin was given iv 0.2 mg/kg for three doses at 12-hour intervals
OutcomesPDA closure
Serum creatinine
Oliguria
NotesAn interim report with 153 patients enrolled (ibuprofen group n = 82 and indomethacin group n = 71) has been published (Lago 2001). Zanardo 2005 represents a subpopulation of this study and examines the effect of ibuprofen and indomethacin on urinary antidiuretic hormone excretion
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description provided.
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes
Cards in sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants
Selective reporting (reporting bias)Unclear risk

The authors do not comment on the imbalance in the numbers enrolled in the ibuprofen group (n = 94) vs the indomethacin group (n = 81).

The protocol was not available to us, so we can not ascertain if there were deviations from the protocol.

Other biasLow riskAppears free of other bias.

Lin 2012

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - cannot tell
IV. Blinding of outcome measurement(s) - cannot tell
Participants

Study conducted at the Maternal and Child health Hospital of Xiamen City, Xiamen, Fujian, China

64 symptomatic VLBW infants with a PDA confirmed by bedside Color Doppler ultrasound were enrolled within 24 hours after birth

Interventions

32 infants received oral ibuprofen within 24 hours after birth at 10 mg/kg, followed 24 hours later by a second dose of 5 mg/kg and 48 hours ;later by a third dose of 5 mg/kg

32 infants received placebo (normal saline) at 1 mL/kg, followed 24 hours later by a second dose of 0.5 mL/kg and 48 hours later by a third dose of 0.5 mL/kg

Outcomes

PDA closure, PVL, BPD, duration of ventilator support, duration of hospital stay, IVH, pulmonary haemorrhage, NEC, adverse effects.

From the abstract we were only able to calculate the rates for PDA closure in the two groups. P-values were provided for some of the other outcomes, and we have quoted them in the results section.

NotesThis study was published in Chinese and only the abstract published in English could be understood by us.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided in the abstract
Allocation concealment (selection bias)Unclear riskInfants were randomly divided into two groups
Blinding (performance bias and detection bias)
All outcomes
Unclear riskIt is possible that the study was blinded as a placebo was used in the control group
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskWe could not judge this item from the abstract
Selective reporting (reporting bias)Unclear riskWe could not judge this item from the abstract
Other biasUnclear riskWe could not judge this item from the abstract

Mosca 1997

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in Milan, Italy

Study period: Not reported
16 infants receiving mechanical ventilation (<31 weeks GA) with echocardiographic evidence of PDA were randomised
8 neonates, median and range GA 29 weeks (27-31), BW 855 g (620 - 1620), postnatal age 24 hours (10-53), 4 boys and four girls were treated with ibuprofen
8 neonates, median and range GA 28 weeks (25-300, BW 820 g (600 - 1390), postnatal age 29 hours (5-120), 5 boys and 3 girls were treated with indomethacin

InterventionsIbuprofen was given iv 10 mg/kg infused over 1 minute as a first dose and a second and third dose were administered at 24-hour intervals provided that no significant adverse effect was observed
Indomethacin was given iv 0.2 mg/kg infused over one minute and a second and third dose of 0.1 mg/kg were administered at 24-hour intervals provided no significant adverse effects were observed
OutcomesPDA closure
Cerebral blood flow velocity
Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidised cytochrome oxidase concentration
NotesThe results of his study have been reported in abstract form with the same number of infants enrolled (Mosca 1996.) Whether there is any overlap with an additional study is unclear (Mosca 1997a).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Clinicians were aware of group assignment
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Patel 1995

MethodsSingle-centre, randomised, controlled trial without the use of a placebo
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in the UK

Study period: Not stated
33 infants with a median GA of 26 weeks (range 23 to 28) were enrolled. All infants had echocardiographically proven PDA

Interventions12 infants received ibuprofen 5 mg/kg; 6 received ibuprofen 10 mg/kg and 15 received indomethacin 0.1 mg/kg.The drugs were infused iv over 15 minutes
OutcomesPDA closure rate
Near infrared spectroscopy was used to observe the effect of treatment on cerebral perfusion, indicated by changes in cerebral blood volume, and cerebral mitochondrial oxygenation, determined by the change in concentration of oxidised cytochrome aa3.
NotesPublished as a letter to the editor.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
No information provided
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no randomised, controlled trial without the use of a placebo
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Patel 2000

MethodsFour-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes
Participants

Study conducted in 4 NICUs in the UK (Hammersmith, Queen Charlotte's, St George's and St Mary's Hospitals, London, UK)

Study period: January 1966 to December 1996
33 preterm infants with a haemodynamically significant PDA diagnosed clinically and on echocardiographic criteria were randomised
18 infants received iv ibuprofen, median and range GA 26.0 weeks (23.9-35.00); BW 790 g (620-2780); postnatal age 8 days (3-20); 9 boys, 9 girls
15 received indomethacin; GA 26.7 weeks (23.2-30.0); BW 838 g (458-1377); postnatal age 7 days (3-21)

InterventionsIbuprofen was given iv 10 mg/kg as the initial dose followed by 5 mg/kg at 24 and 48 hours after the initial dose
Indomethacin was given as 0.2 mg/kg as initial dose. Two further doses were administered after 12 and 24 hours: infants aged 2 to 7 days at the time of the first dose received 0.2 mg/kg and those infants 8 days or older received 0.25 mg/kg
To prevent identification of the drug administered from the timing schedule, all infants received a fourth dose containing 0.9% saline: in the indomethacin group, 48 hours after the first dose and, in the ibuprofen group, 12 hours after the first dose
Intravenous infusion of all drugs were performed over 15 minutes using an infusion pump
OutcomesPDA closure rate
Near-infrared spectroscopy was used to measure changes in cerebral blood volume, cerebral blood flow, cerebral oxygen delivery
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low risk

Blinding of randomisation - yes

The Pharmacy Department at Queen Charlotte's Hospital performed randomisation in block of 12 for each hospital and provided all trial medication. All other personnel were blinded to the identity of the drug administered

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of intervention - yes
Blinding of outcome measurement(s) - yes
See allocation concealment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Pezzati 1999

Methods

Single-centre, randomised controlled trial, conducted in Firenze, Italy

Study period: No information provided
I Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - cannot tell

Participants17 preterm infants (< 33 weeks GA)
9 infants received ibuprofen, mean (SD) GA 29.1 (2.2) weeks; BW 1151 (426) g8 infants received indomethacin, mean (SD) GA 29.5 (2.6); BW 1277 (440) g
InterventionsIndomethacin (0.2 mg/kg) or ibuprofen (10 mg/kg) were given as a continuous infusion over 15 minutes. Regardless of ductal closure after the first dose, all patients received a second and third dose of indomethacin (0.1 mg/kg) or ibuprofen (5 mg/kg) at 24-hour intervals
OutcomesThe primary outcome was mesenteric and renal blood flow velocity. Secondary outcomes included: ductal closure, ductal reopening and NEC
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Infants were randomly assigned - no further information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of intervention - cannot tell
Blinding of outcome measurement(s) - cannot tell
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Plavka 2001

MethodsThree-centre, randomised controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - cannot tell
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - cannot tell
Participants

Study conducted in 3 NICUs in the Czech Republic

Study period: Study period not stated
41 preterm infants with clinical and echographic signs of PDA were randomised
21 infants received ibuprofen, mean (SD) GA 27.6 weeks (2.3); BW 929 g (213)
20 received indomethacin
GA 26.9 weeks (1.7); BW 902 g (211)

InterventionsIbuprofen was given iv 8 mg/kg every 24 hours for three doses
Indomethacin was given iv 0.2 mg/kg every 24 hours for three doses
If PDA persisted, treatment was repeated at half dose every 24 hours for 6 doses. Persistent PDA was ligated
OutcomesCerebral blood flow velocities, blood pressure, serum creatinine, mortality, ductal reopening
NotesPublished in abstract form only
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Blinding (performance bias and detection bias)
All outcomes
Unclear riskBlinding of intervention - cannot tell
Blinding of outcome measurement(s) - cannot tell
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComplete follow-up - yes
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Pourarian 2008

Methods

One-centre, randomised controlled trial, conducted in Shiraz, Republic of Iran

Study period: 6 month period in 2001
I. Blinding of randomisation - no
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no

Participants

20 preterm infants with ECHO-confirmed PDA

Ibuprofen group (n = 10); mean (SD) PMA 31.3 (4.4) weeks; mean (SD) BW 1860 (402) g

Indomethacin group (n = 10); mean (SD) PMA 33.2 (3.1) weeks; Mean (SD) PMA 1720 (630) g

InterventionsFor the indomethacin group , the powder content of a 25 mg indomethacin capsule was freshly prepared by dissolving in 25 mL distilled water. This was given orally as 0.2 mg/kg for 3 doses at 24-hour intervals. For the ibuprofen group, an ibuprofen oral suspension containing 100 mg/5 mL was given as an initial dose of 10 mg/kg, followed by 2 further doses of 5 mg/kg at 24 hr intervals. Administration of the 2nd or 3rd doses of each drug was dependent on achievement of ductal closure after the initial doses.
OutcomesThe primary outcome was ductal closure. Secondary outcomes included need for surgical closure, NEC, change in mean serum creatinine levels before and after treatment, increase in BUN level > 14 mmol/L, thrombocytopenia < 50 000 mm3.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo mention of how the randomisation sequence was generated
Allocation concealment (selection bias)High risk

Blinding of randomisation - no

"As soon as the diagnosis (of PDA) was made for the 1st eligible baby, he/she was enrolled to the ibuprofen group and then the next eligible baby was assigned to the indomethacin group, and so on". This statement clearly indicated that the infants were not allocated to the two groups in a concealed manner

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
The researchers were aware of group assignment - see allocation concealment
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Results for all randomised infants are reported
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskThe study appears free of other bias

Salama 2008

Methods

Single-centre, randomised controlled trial conducted in Doha, State of Qatar

Study period: January 2005 to March 2007
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no

Participants41 preterm infants (PMA , 34 weeks, BW < 2500 g) diagnosed with haemodynamically significant PDA (confirmed by echocardiography)
Interventions20 infants [mean PMA = 27.8 (SD 2.8) weeks; mean BW 1050 (SD 440) g] received iv indomethacin (3 doses of 0.2 mg/kg/dose every 24 hours) and 21 infants [mean PMA 27.7 (SD 2.5); mean BW 1094 g (SD 480)] received oral ibuprofen (10 mg/kg on the first day followed by 5 mg/kg for 2 more days). Ibuprofen was mixed with 0.5 mL of milk before its administration via an oro-gastric tube
OutcomesThe primary outcome was complete closure of the PDA. Secondary outcomes included need for surgical ligation, bowel perforation, mortality
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was conducted according to a pre-designed simple block randomisation table "A" for indomethacin and "B" for ibuprofen (AABABBBBAA, BBBAAABBA, AABBABABAAB, etc
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
No description of possible concealment
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Indomethacin was given iv and ibuprofen was given via an oro-gastric tube
The paediatric cardiologist was aware of the patient's group allocation
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported on all randomised infants
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Sosenko 2012

Methods

Single-centre, double-blind, randomised controlled trial

I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no

Participants

Study conducted in Miami, Florida, US

Study period January 2008 to August 2010

Infants born with birth weights between 500 and 1250 g and PMA between 23 and 32 weeks, who were > 24 hours old but </= 14 days old and who had ECHO for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses)

Interventions

Infants were randomised to "early" treatment (blinded ibuprofen, n = 54) or "expectant" management (blinded placebo, n = 51). If the PDA became haemodynamically significant (pulmonary haemorrhage, hypotension, respiratory deterioration), infants received open-label ibuprofen. Infants with haemodynamically significant PDA at enrolment were excluded from the study.

The dosing schedule for ibuprofen was an initial dose of 10 mg/kg, followed by two doses of 5 mg/kg each, every 24 hours, by slow intravenous infusion; dosing of placebo involved equivalent volumes of dextrose by slow intravenous infusion on the same schedule.

OutcomesDays on supplemental oxygen during the first 28 days of life, death during hospital stay, supplemental oxygen at 36 weeks PMA, intestinal perforation, NEC requiring surgery, IVH (grades III and IV), PVL, sepsis, ROP (stage >/= 3).
NotesAfter 105 of 168 infants were enrolled the study drug (NeoProfen) was recalled by the manufacturer and was no longer available in the US.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low riskClinicians, investigators, and nursing staff were blinded to the study group to which the infant was assigned and the medication the infant was receiving. Only the neonatal pharmacists were aware of the study group of each infant and were responsible for preparing the "blinded" ibuprofen or "blinded" placebo study drug
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all enrolled infants
Selective reporting (reporting bias)Low riskThis study was registered, # NCT00802685, and there does not seem to be any deviations from the protocol, except that the study had to be stopped when the study drug was no longer available
Other biasLow riskAppears free of other bias

Su 2003

MethodsSingle-centre, randomised controlled trial
I. Blinding of randomisation - cannot tell
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in Taichung,Taiwan

Study period: January 2001 to December 2002
63 preterm infants with BW </= 1500 g and a GA of </= 32 weeks and with echocardiographic evidence of a PDA were randomised between 2 and 7 days of age
32 infants [mean (SD) BW 1134 +/- 200 g; mean (SD) GA 28.7 +/- 2.2 weeks] received iv ibuprofen 10 mg/kg initially and followed by ibuprofen 5 mg/kg after 24 and 48 hours
31 infants [mean (SD) BW 1110 +/- 244 g; mean (SD) GA 28.2 +/- 2.4] received iv indomethacin 0.2 mg/kg every 12 hours for three doses

InterventionsIbuprofen was given iv as 10mg/kg initially, followed by 5 mg/kg after 24 and 48 hours
Indomethacin was given iv as 0.2 mg/kg every 12 hours for three doses
OutcomesRate of PDA closure, rate of reopening of the duct, mortality, gastric bleeding, IVH, PVL, NEC, BPD at 36 weeks GA, duration of mechanical ventilation, time to full oral feeds, length of hospital stay
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - cannot tell
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin was given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all infants randomised
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free from other bias.

Su 2008

MethodsSingle-centre, randomised controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - yes
Participants

Study conducted in Taichung,Taiwan

Study period: February 2004 to October 2006

119 infants with echocardiographic evidence of a significant PDA

60 infants [PMA (median 25; range 23-28 weeks); BW (median 825; range 550-990 g)] received ibuprofen and 59 infants [PMA (median 25; range 23-28 weeks; BW (median 762; range 540-980 g) received indomethacin

InterventionsInfants were randomised to receive either iv ibuprofen 10 mg/kg initially followed by 5 mg/kg at 24 hours intervals or iv indomethacin 0.2 mg/kg as the initial dose and then 0.1 mg/kg in infants < 48 hours old, 0.2 mg/kg in infants > 48 hours at 24 hours intervals as indicated by PDA flow pattern.
OutcomesPrimary outcome was PDA closure. Secondary outcomes included need for surgical ligation, mortality within 30 days, NEC, CLD at 36 weeks gestational age, IVH, PVL, ROP, BPD at 36 weeks PMA, oliguria, post treatment serum creatinine, hospital stay, duration of mechanical ventilation, days to full enteral feeds and gastric bleeding.
NotesThe study included a sample size calculation
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAccording to a random number table sequence, which had been prepared by a study assistant who was not involved in the care of infants
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes
Blinding (performance bias and detection bias)
All outcomes
Low risk

Blinding of intervention - yes
Blinding of outcome measurement(s) - yes

The medication was infused iv continuously over 15 minutes. The drug was prepared and dispensed through the hospital pharmacy department and the attending doctors were unaware of the drug used

Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasUnclear riskAppears free of other bias

Supapannachart 2002

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - yes (sealed envelope)
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Single-centre study conducted in Bangkok,Thailand

Study period: April 1, 2000 to August 31, 2001
18 preterm infants (< 34 weeks GA) with symptomatic PDA
9 infants received ibuprofen, mean (SD) GA 30.1 (2.7); BW 1447 (39) g; 8 boys, 1 girl
9 infants received indomethacin, men (SD) GA 30.4 (2.6); BW 1432 (531); 6 boys, 3 girls

InterventionsIbuprofen was given orally (10 mg/kg/dose for three doses at 24-hourly intervals
Indomethacin (oral or iv 0.2 mg/kg/dose) for three doses given at 12-hourly intervals
OutcomesPDA closure rate, duration of ventilatory support, CLD (age not stated), IVH (grade not stated), NEC, mortality.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed envelope)
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all infants randomised
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias.

Van Overmeire 1997

MethodsSingle-centre, randomised, controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in Antwerp, Belgium

Study period: Not stated
40 preterm infants (GA, 33 weeks) were randomised
20 infants received ibuprofen, mean (SD) GA 29.0 (2.4); BW 1270 g (450) ; surfactant use 15
20 infants received indomethacin; mean (SD) GA 28.7 weeks (1.9); BW 1210 g (360), surfactant use 19

InterventionsIbuprofen was given iv 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later
Indomethacin was given iv 0.2 mg/kg every 12 hours for three doses.Both drugs were infused over 15 minutes
OutcomesPDA closure rate, PDA ligation rate, mortality, sepsis, NEC, age to regain birthweight, ROP
NotesIt is possible that there is overlap between this study and a report in abstract form with 28 patients enrolled (Van Overmeire 1996)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed envelopes)
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different time intervals
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all infants randomised
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskApperas free of other bias

Van Overmeire 2000

  1. a

    BPD: bronchopulmonary dysplasia
    BUN: blood urea nitrogen
    BW = birth weight
    CLD: chronic lung disease
    C/S = cesarean section
    ECHO = echocardiographically
    g = grams
    GA = gestational age
    ITT: intention-to-treat
    iv = intravenous
    IVH = intraventricular haemorrhage
    NEC: necrotising enterocolitis
    NIVU: neonatal intensive care unit
    PDA = patent ductus arteriosus
    PMA: postmenstrual age
    PVL: periventricular leukomalacia
    RDS = respiratory distress syndrome
    ROP: retinopathy of prematurity
    SD: standard deviation
    VLBW = very low birth weight (< 1500 g)

MethodsSingle-centre, randomised, controlled trial without the use of a placebo
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement(s) - no
Participants

Study conducted in 5 NICUs in Belgium (two hospitals in Antwerp, one hospital each in Ghent, Bruges and Rocourt

Study period: Not stated

148 infants with PMA 24 to 32 weeks, who had respiratory distress syndrome and echocardiographically confirmed PDA were randomised to two groups:
74 received ibuprofen mean (SD) GA 29.0 weeks(2.3); BW 1230 g (390); surfactant treatment 56
74 received indomethacin mean (SD) GA 29.0 weeks (2.1); BW 1230 g (380);
Surfactant treatment 63

InterventionsIbuprofen was given iv 10 mg/kg as the initial dose, followed at 24-hour intervals by two doses of 5 mg/kg
Indomethacin was administered iv 0.2 mg/kg every 12 hours
OutcomesPDA closure rate, oliguria, PDA ligation rate, mortality by 30 days, NEC,localised bowel perforation, sepsis, PVL, CLD at 28 days, time to regain birth weight, time to full enteral feeding.
NotesWe believe this study has been reported in abstract form when 103 preterm infants had been enrolled (Van Overmeire 1998), but we have not been able to verify this with the authors.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskBlinding of randomisation - yes (sealed opaque envelopes)
Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of intervention - no
Blinding of outcome measurement(s) - no
Ibuprofen and indomethacin were given at different times
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up - yes
Outcomes reported for all randomised infants
Selective reporting (reporting bias)Unclear riskThe study protocol was not available to us so we can not ascertain if there were deviations from the protocol or not
Other biasLow riskAppears free of other bias

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    PDA: patent ductus arteriosus

Amoozgar 2010A randomised controlled study of ibuprofen in term neonates
Cherif 2007This study evaluated the use of oral ibuprofen for closure of PDA, but did not include a control group
Desfrere 2005This was a dose-finding study

Characteristics of studies awaiting assessment [ordered by study ID]

Fesharaki 2012

Methods

Different doses of ibuprofen in the treatment of PDA: a randomised clinical trial [Article in Persian]

Randomised controlled clinical trial.

Participants

60 patients with echocardiographically confirmed PDA.

This study was done in NICU of Vali-Asr hospital.

Interventions

Group 1: loading dose of 10 mg/kg ibuprofen on the first day, followed by two doses of 5 mg/kg in the next two days.

Group 2: loading dose of 15 mg/kg ibuprofen on the first day followed by two doses of 7.5 mg/kg in next two days.

OutcomesPDA closure rates and complications of therapy between the two groups.
Notes

Thirty (100%) patients in 15-mg/kg group and 23 (76.7%) patients in 10 mg/kg group had successful PDA closure with no need for surgery (P = 0.011).

Dr. Fatemeh Nayeri (corresponding author) has kindly provided us with an English translation of the article in January 2013. We are awaiting some clarifications regarding the trial and the results will be included in the next update of the review.

Qosja 2012

  1. a

    iv: intravenous
    NICU: neonatal intensive care unit
    PDA: patent ductus arteriosus

MethodsRandomised controlled trial conducted in the NICU of the Maternity Koco Gliozheni Hospital, Tirana, Albania
Participants

32 preterm newborns, postnatal age 72-96 hours, with echocardiographically confirmed PDA

Study period January 2010 to December 2010

Interventions16 infants received oral ibuprofen and 16 received iv ibuprofen
OutcomesDuctal closure, reopening of the duct, bowel perforation, gastro-enteral bleeding
NotesThe study has been published in abstract form only

Characteristics of ongoing studies [ordered by study ID]

Gournay 2012

Trial name or titleEarly ibuprofen treatment of patent ductus arteriosus (PDA) in premature infants (TRIOCAPI)
MethodsRandomised controlled trial
Participants385 very premature (PMA < 28 weeks) infants with a large ductus, selected by an early echocardiogram
InterventionsIbuprofen or placebo before 12 hours of life. Follow-up will include repeated echocardiograms and cranial ultrasound at 36 hours, 14 days and 36 weeks of postconceptional age
Outcomes

Primary outcome measure:

2-year survival without cerebral palsy

Secondary outcome measures:
ASQ (Ages and Stages Questionnaire) score at 2 years
Incidence of other prematurity-related morbidities (pulmonary, digestive, neurological, renal)
To compare the outcome between the large and the small ductus groups
Comparison of outcome according to the McNamara stage at surgical ligation

Starting dateMarch 2012
Contact informationVéronique GOURNAY, Professor, Nantes University Hospital. Phone +33 2 40 08 77 84; veronique.gournay@chu-nantes.fr
NotesClinicalTrials.gov identifier: NCT01630278

Su 2010

  1. a

    iv: intravenous
    PMA: postmenstrual age

Trial name or titleComparison of oral and intravenous ibuprofen for PDA treatment in premature infants
MethodsDouble-blind, randomised controlled trial
Participants70 extremely preterm infants with ECHO confirmed PDA
InterventionsThe dosage of oral or ibuprofen is 10 mg/kg (1 mL) and then 5 mg/kg at 24-hour intervals as indicated by echocardiographic PDA flow pattern
Outcomes

The primary outcome is to ascertain whether oral ibuprofen is effective and safe in inducing PDA closure in extremely premature infants

A secondary objective is to compare the complications between infants treated with oral ibuprofen and those treated with iv ibuprofen

Starting dateDecember 2009
Contact information

Bai-Horng Su, MD, PhD, Medical University Hospital,Taichung, Taiwan, 404

Phone: 886-4-22052121 ext 2061 bais@ms49.hinet.net

Notes 

Ancillary