Ibuprofen for the treatment of patent ductus arteriosus in
preterm and/or low birth weight infants
Ohlsson A, Walia R, Shah S
Dates
Date edited: 09/11/2007
Date of last substantive update: 19/09/2007
Date of last minor update: / /
Date next stage expected 31/08/2009
Protocol first published: Issue 1, 2002
Review first published: Issue 2, 2003
Contact reviewer
Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca
Contribution of reviewers
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 and in August, 2007
Rajneesh Walia - developing and writing the text of the protocol
Sachin Shah - data abstraction and analyses, editing the text of the review
Internal sources of support
Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, CANADA
External sources of support
NoneWhat's new
This 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.
Dates
Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /
Text of review
Synopsis
Ibuprofen is as effective as indomethacin at closing a PDA in a very preterm or very small newborn, and has fewer adverse effects on kidney function. Ibuprofen may be associated with an increased risk of pulmonary complications including chronic lung disease and rarely pulmonary hypertension.
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 is 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 16 trials found that ibuprofen is as effective as indomethacin and causes fewer transient adverse effects on the kidneys. Information on 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.
Abstract
Background
A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gastrointestinal tract. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin, with fewer side effects.
Objectives
To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants.
To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants.
Search strategy
Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1996 - August 2007), CINAHL (1982 - August 2007), EMBASE (1980 - August 2007), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005) or on their website (to August 2007). No language restrictions were applied.
Selection criteria
1) Design: Randomized or quasi-randomized controlled trials
2) Population: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) with a clinically or echocardiographically diagnosed PDA
3) Intervention: Administration of ibuprofen (orally or intravenously) for the closure of PDA
4) Outcomes: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ductal ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, pulmonary hemorrhage, pulmonary hypertension, duration of supplementary oxygen, duration of mechanical ventilation, duration of hospital stay, and serum creatinine levels following treatment.
Data collection & analysis
At least two review authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one review author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2.10, included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared test (I2) were performed to assess the appropriateness of pooling the data.
Main results
No studies using mefenamic acid were identified. Sixteen studies enrolling 876 infants were identified. Four additional trials were identified for this update and two studies published as abstracts were now available as full articles. One study compared ibuprofen to placebo, but the results were not reported unblinded to intervention group. Fifteen studies including 740 infants compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.99 (95% CI 0.78, 1.27); typical RD 0.00 (95% CI -0.06, 0.06)]. There were no statistically significant differences in mortality, reopening of the ductus, need for surgical duct ligation, duration of ventilator support, duration of supplementary oxygen, pulmonary hemorrhage, pulmonary hypertension, CLD, IVH, PVL, NEC, intestinal perforation, gastrointestinal bleed, time to full enteral feeds, time to regain birth weight, ROP, sepsis, duration of hospitalization. Ibuprofen treatment was associated with statistically significantly lower serum creatinine levels after treatment (6 trials, 336 infants; WMD - 8.2 (95% CI -13.3, -3.2) mmol/L and lower incidence of 'decreased urine output' [3 trials, 336 infants; typical RR; 0.22 (95% CI 0.09, 0.51); typical RD -0.12 (95% CI -0.18, -0.06); NNT 8 (95% CI 6,17)]. There was moderate heterogeneity of treatment effect for the outcomes 'time to regain birth weight' and 'decreased urine output". Heterogeneity was not noted for other outcomes. For several of these outcomes, the sample size was small and the estimates imprecise. There are not enough data available regarding the effectiveness of oral ibuprofen compared with indomethacin to close a PDA [3 trials, 69 infants; typical RR 1.41 (95% CI 0.68, 2.93); typical RD 0.10 (95% CI -0.10, 0.30)]. Pulmonary hypertension was noted in one infant receiving ibuprofen to close a PDA enrolled in a trial in this review and an additional report of such a case was identified from the literature.
Reviewers' conclusions
No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing a PDA was found. Ibuprofen compared with indomethacin reduces the risk of oliguria and is associated with lower serum creatinine levels following treatment. Pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen and one infant receiving ibuprofen for treatment in this review developed pulmonary hypertension. One additional case of pulmonary hypertension following treatment with ibuprofen to close a PDA was identified from the literature. The available data support the use of either drug for the treatment of a PDA. As both drugs are equally effective in closing a PDA, the clinician needs to weigh the potential side effects of one drug vs. the other when making a decision which drug to use. The most urgent research question to be answered is whether ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age and at the age of school entry.
Background
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 hemodynamic 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 necrotizing enterocolitis, 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 hemodynamics 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 = 3,779) of very low birth weight (VLBW < 1500 grams) 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).
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, necrotizing enterocolitis, gastrointestinal hemorrhage 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 reduces the frequency of PDA and severe periventricular and intraventricular hemorrhage (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 2002). The same review found no evidence of either benefit or harm concerning longer-term outcomes including neurodevelopment (Fowlie 2002).
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 hemodynamic disturbance and potentially harmful cerebral side effects (Coceani 1979; Varvarigou 1996; Chemtob 1991). 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 hemodynamics (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).
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 randomized 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 3 doses). The relative risk for failure of PDA closure using ibuprofen vs. indomethacin was 1.0 (95% confidence interval 0.85, 1.17) (Ohlsson 2000). This meta-analysis was included in a commentary on a publication of a randomized 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 to placebo or no intervention for closing a patent ductus arteriosus in preterm and/or low birth weight infants
- To determine the effectiveness and safety of ibuprofen compared to indomethacin or other cyclo-oxygenase inhibitors for closing a patent ductus arteriosus 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 - 32 weeks, 33 - 36 weeks)
- Birth weight (<1000 g, 1000 - 1500 g, 1501 - 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 vs. indomethacin (this has been added in 2007 as a new comparison as studies now have used oral ibuprofen)
Criteria for considering studies for this review
Types of studies
Randomized or quasi-randomized 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 to control infants who received no intervention, placebo, indomethacin or other cyclo-oxygenase inhibitors.
Types of outcome measures
Primary outcome:
- 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 hemorrhage*
- Pulmonary hypertension*
- Chronic lung disease (CLD) (defined as oxygen requirement at 28 days postnatal age in addition to compatible clinical and roentgenographic findings)
- Chronic lung disease (CLD) (defined as oxygen requirement at 36 weeks postmenstrual age in addition to compatible clinical and roentgenographic findings)
- Chronic lung disease (age at diagnosis not stated)*
- Intraventricular haemorrhage (IVH) (Grade I-IV)
- Severe intraventricular haemorrhage (IVH) (Grade III-IV)
- Periventricular leukomalacia (PVL)
- Necrotizing 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*
- Duration of hospitalization (total length of hospitalization from birth to discharge home or death) (days)
- Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized 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*
- Other side effects reported by the authors
Outcomes marked with an asterisk (*) were not included in the original protocol or previous updates of this review. These outcomes were included in the updated 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 vs. indomethacin.
Search strategy for identification of studies
See: Cochrane Neonatal Review Group search strategy.
This review is the second update of the original review.
For this update, the search started by review of personal files and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007); MEDLINE (1966 - August 2007) 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 - August 2007); CINAHL (1982 - August 2007); and the reference list of identified trials and abstracts published in Pediatric Research (1991 - April Issue, 2005, and electronically on the PAS web site from 2006 - 2007) 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 coauthors 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. Identified trials were entered into Science Citation Index to identify articles that quoted the original studies and to ascertain any additional potential studies for inclusion in the review. References lists of published narrative and systematic reviews were reviewed. Unpublished data were not sought, but authors of some published trials were contacted to clarify or provide additional information. In addition the literature was search for any reports (regardless of publication type) of pulmonary hypertension associated with the treatment with ibuprofen or indomethacin. No language restrictions were applied.
Methods of the review
The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of studies.
All abstracts and published full reports identified as potentially relevant by the literature search were assessed for inclusion in the review by two review authors (AO, SS). 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 4.2.10 and the other review author (SS) cross-checked the printout against his own data abstraction forms and errors were corrected by consensus.
For the studies identified as abstracts, some primary authors were contacted to ascertain whether a full publication is available if the full paper was not identified in an electronic data base. The current update (2007) and the update conducted in 2005 were performed by one review author (AO).
The quality of included trials was evaluated independently by the reviewers, using the following criteria:
Blinding of randomization?
Blinding of intervention?
Blinding of outcome measure assessment?
Completeness of follow up?
There were three potential answers to these questions - yes, can't tell, no
Information from the primary author was obtained if the published article provided inadequate information for the review. Retrieved articles were assessed and data were abstracted independently by the reviewers. 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 and 2007 were conducted by one review author (AO).
The statistical analyses followed the recommendations of the Cochrane Neonatal Review Group. A weighted treatment effect was calculated using the RevMan 4.2.10 package. The estimates of treatment effects included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNT) or number needed to harm (NNH) for dichotomous outcomes, and weighted mean difference (WMD) for continuous outcomes. All estimates of treatment effects are reported with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I- squared test (I2) were performed to assess the appropriateness of pooling the data. Planned subgroup analyses were performed according to the criteria listed under objectives. As we have noted discrepancies between numbers enrolled in trials as reported in abstracts and full text reports (Walia 2000), sensitivity analyses were performed excluding abstracts. No additional sensitivity analyses were planned a priori.
Description of studies
There was one study identified that compared ibuprofen to placebo (Aranda 2005). Fifteen studies comparing one or several doses of ibuprofen to one or several doses of indomethacin were identified and included in the review. Two additional studies are listed under "Classification pending" (Hammerman 2006; Hammerman 2007). In Hammerman 2006 the results were provided in graphic form and in Hammerman 2007 the number of infants enrolled in the two study groups were not stated. For details see "Table of Characteristics of Included Studies". No randomized controlled trials investigating the effectiveness of mefenamic acid were identified.
IBUPROFEN VERSUS PLACEBO
The study by Aranda and coworkers (Aranda 2005) was a multi-centre study conducted at 15 sites in the US:
- Objective: To compare the efficacy and safety of i.v. ibuprofen with placebo for the early treatment of PDA in preterm infants with evidence of ductal shunting by echocardiography.
- Population: 136 preterm infants (BW 500 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 i.v. 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) on or prior to study day 14. Secondary outcomes included mortality, need for PDA ligation, IVH, NEC, CLD and ROP.
Comment: The study has been reported in abstract form only and the results were not provided unblinded to group of allocation. As of August 2007, the study has not been published as a full publication (personal communication with Dr. Aranda).
IBUPROFEN VERSUS INDOMETHACIN
The study by Adamska and co-workers (Adamska 2005) was a single center study conducted in Poland (New inclusion):
- Objective: To assess the efficacy and safety of early treatment with ibuprofen or indomethacin in preterm infants.
- Population: 35 preterm (< 33 weeks of gestation and birth weight < 1500 g) infants with a PDA diagnosed by Doppler echocardiography.
- Intervention: The infants were randomized to receive three doses of indomethacin (0.2 mg/kg i.v. given at 24 hour intervals), (n = 19) or three doses of ibuprofen (10, 5, and 5 mg/kg i.v. 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 hemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.
The study by Akisu and co-workers (Akisu 2001) was conducted in one center in Turkey:
- Objective: To investigate the efficacy and safety of oral ibuprofen for the treatment of PDA and to compare it with oral indomethacin.
- Population: 23 preterm infants (< 35 weeks of gestation) with a PDA diagnosed by Doppler echocardiography.
- Intervention: Infants were randomized to receive either ibuprofen 10 mg/kg i.v. as the initial dose followed by 5 mg/kg 24 and 48 hours later (n = 12) or three doses of i.v. 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 hemorrhage, IVH, sepsis and mortality.
The study by Aly and co-workers (Aly 2007) was a single center study conducted in Egypt (New inclusion):
- Objective: To evaluate the feasibility of the use of oral ibuprofen suspension 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 randomized to receive three doses of i.v. 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 hemorrhage, 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 center in Thailand (Study now published as full publication):
- Objective: To compare efficacy and side effects of ibuprofen vs. indomethacin treatment for symptomatic PDA in preterm infants.
- Population: Preterm infants with a symptomatic PDA confirmed by echocardiogram
- Intervention: 30 infants were randomized to received either three oral doses of ibuprofen (dose not stated) given at 24 hourly intervals or three doses of 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 Gimeno Navarro and co-workers (Gimeno Navarro 2005) was conducted in one centre in Spain (New inclusion):
- Objective: To compare the safety and efficacy of ibuprofen and indomethacin in the treatment of PDA in preterm infants.
- Population: Preterm infants (< 34 weeks gestational age) with a hemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support.
- Intervention: During the first week of life (average 2 days of life) 47 ventilated infants, were randomized to receive either indomethacin 0.2 mg/kg/dose i.v. every 12 hours for a total of three doses (n = 24) or an initial dose of i.v. ibuprofen of 10 mg/kg, followed by two doses of ibuprofen i.v. 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 hemorrhage, pulmonary hemorrhage, 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).
The study by Lago and co-workers (Lago 2002) was conducted in two centers 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 gestation, postnatal age 48 - 72 hours) with RDS treated with mechanical ventilation and echocardiographic evidence of PDA.
- Intervention: 175 infants were randomized to either 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 indomethacin 0.2 mg/kg at 12 hours 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-randomized 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 hemodynamically 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, necrotizing enterocolitis, 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 center 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 gestation) with PDA and receiving mechanical ventilation.
- Intervention: 16 infants received either 10 mg/kg ibuprofen dissolved in 1 ml saline and infused over 1 minute i.v. or 0.2 mg/kg indomethacin i.v. (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 oxidized 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 center pilot study conducted in one center in England:
- Objective: To compare the cerebral effects of ibuprofen with indomethacin in preterm infants.
- Population: 33 infants with a median gestational age of 26 weeks (range 23 to 28) and a echocardiographically proven PDA.
- Intervention: Infants were randomized 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 i.v. 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 oxidized cytochrome aa3. Ductal closure was reported.
The second study by Patel and co-workers Patel 2000 was conducted in four centers in England:
- Objective: To compare the effects of ibuprofen to indomethacin on cerebral hemodynamics measured using near infrared spectroscopy in preterm infants during treatment for patent ductus arteriosus.
- Population: 33 preterm infants (< 35 weeks gestation).
- Intervention: Infants were randomly assigned to three intravenous doses of either ibuprofen (5 - 10 mg/kg, 24 hourly) or indomethacin (0.20 - 0.25 mg/kg, 12 hourly) and also received a dose of saline. Eighteen infants were randomized 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 center in Italy (New inclusion):
- 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 gestation) with a PDA diagnosed by Doppler echocardiography.
- Intervention: 17 infants were randomized to receive either i.v. indomethacin (0.2 mg/kg) or i.v. 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 centers in the Czech Republic:
- Objective: To compare adverse effects and efficacy of i.v. ibuprofen with i.v. 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 i.v. or indomethacin (n = 20) 0.2 mg/kg every 24 hours for three doses i.v. 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 Su and co-workers (Su 2003) was conducted in a single centre in Taiwan:
- Objective: To compare i..v. ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants.
- Population: 63 infants with echocardiographic evidence of a significant PDA
- Intervention: Infants were randomized to receive either i.v. ibuprofen 10 mg/kg initially followed by 5 mg/kg after 24 and 48 hours or i.v. 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 gestational age, IVH, PVL, ROP, hospital stay, duration of mechanical ventilation, days to full enteral feeds and gastric bleeding.
The study by Supapannachart and co-workers (Supapannachart 2002) was conducted in one center in Thailand (Study now published as full publication):
- 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 i.v. 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 center 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 with PDA diagnosed by echocardiography.
- Intervention: 40 infants were randomly assigned at day two to three days of life to receive either i.v. ibuprofen (n = 20) with an initial dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours later or i.v. 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 randomized treatment and at the age of 7 days. When a PDA was present after the randomized 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 centers in Belgium:
- Objective: To compare ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of patent ductus arteriosus in preterm infants.
- Population: 148 infants (gestational age 24 - 32 weeks) with RDS and a PDA confirmed by echocardiography.
- Intervention: Infants were randomized to receive i.v. 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 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 randomized 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, localized 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.
Methodological quality of included studies
These were all randomized controlled trials, but whether the randomization 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.
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 randomization 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 has been reported in abstract form only and therefore a full quality assessment is not possible.
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 i.v. one can assume that the care givers were aware of group assignment. The doses of ibuprofen and indomethacin given were not provided.
Gimeno Navarro 2005: Patients were randomly assigned to receive either i.v. indomethacin or i.v. ibuprofen. The randomization 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.
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) vs the indomethacin group (n = 81).
Mosca 1997: The authors do not provide details regarding randomization. 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 health care 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 randomized controlled trial.
Patel 2000: The Pharmacy Department at Queen Charlotte's Hospital performed randomization in blocks of 12 (six, ibuprofen; six, indomethacin) for each hospital and also 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 i.v. 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-hours 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 health care providers may have been blinded to group assignment as ibuprofen or indomethacin were given at the same time points.
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.
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 randomized 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 health care providers were aware of group assignment.
Results
IBUPROFEN VERSUS PLACEBO (Comparison 01):
PRIMARY OUTCOME:
Failure to close a PDA (after single or three doses) (Outcome 01.01):
The incidence of failure of permanent PDA closure within a week of administration of the first dose of ibuprofen (PDA diagnosed either clinically or by echocardiography criteria) could not be ascertained from the published reports. Aranda (Aranda 2005) reported "Preliminary review of data prior to unblinding shows a very significant difference (p < 0.01) in the primary outcome between the two groups". The first author was contacted in August 2007, and confirmed that the study has not yet been published as a full publication.
IBUPROFEN VERSUS INDOMETHACIN (Comparison 02):
PRIMARY OUTCOME:
Failure to close a PDA after single or three doses (Outcome 02.01):
Failure rates for PDA closure after one or three doses of ibuprofen compared to indomethacin were reported in all studies. Fifteen studies (n = 740 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 0.99 (95% CI 0.78, 1.27)]; typical RD 0.00 (95% CI -0.06, 0.06)]. There was no statistically significant between study heterogeneity (RR, p = 0.96, I2 = 0 %; RD, p = 0.97, I2 = 0 %).
SECONDARY OUTCOMES:
All cause mortality (Outcome 02.02):
Six studies (n = 366) 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 0.82 (95% CI 0.44, 1.54); typical RD -0.02 (95% CI -0.08, 0.04)]. There was no statistically significant between study heterogeneity (RR, p = 0.63, I2 = 0 %; RD, p = 0.59, I2 = 0 %).
Neonatal mortality (during first 28/30 days of life) (Outcome 02.03):
Two studies (n =178) 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 1.25 (95% CI 0.52, 3.01); typical RD 0.02 (95% CI -0.07, 0.11)]. There was no statistically significant between study heterogeneity (RR, p = 0.80, I2 = 0 %; RD, p = 0.70, I2 = 0 %).
Infant mortality (death during the first year of life) (Outcome 02.04):
None of the studies reported on this outcome.
Reopening of the ductus arteriosus (Outcome 02.05):
Five studies (n = 184) reported on this outcome. None of the individual studies found a statistically significant difference in the reopening of PDA. In the meta-analysis, there was no statistically significant difference between the groups [typical RR 1.28 (95% CI 0.48, 3.38); typical RD 0.02 (95% CI -0.06, 0.10)]. There was no statistically significant between study heterogeneity (RR, p = 0.93, I2 = 0 %; RD, p = 0.94, I2 = 0 %).
Need for surgical closure of the PDA (Outcome 02.06):
Nine studies (n = 604) 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 1.06 (95% CI 0.69, 1.65); typical RD 0.01 (95% CI -0.04, 0.06)]. There was no statistically significant between study heterogeneity (RR, p = 0.64, I2 = 0 %; RD, p = 0.37, I2 = 7.8 %).
Need for medical retreatment of the PDA (Outcome 02.07):
Five studies (n = 142) 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 1.34 (95% CI 0.71, 2.54); typical RD 0.06 (95% CI -0.07, 0.19)]. There was no statistically significant between study heterogeneity (RR, p = 0.74, I2 = 0 %; RD, p = 0.77, I2 = 0 %).
Duration of ventilator support (days) (Outcome 02.08):
Four studies (n = 305) reported on this outcome. One study (Adamska 2005) found a statistically significant difference in the duration of ventilation in favour of the ibuprofen group. In the meta-analysis, there was no statistically significant difference between the groups [WMD -1.96 days (95% CI -4.97, 1.05)]. There was no statistically significant heterogeneity between the studies (p = 0.13, I2 = 46 %). Gimeno Navarro and co-workers (Gimeno Navarro 2005) reported on this outcome as median and range [ibuprofen group six days (3 - 9); indomethacin group 8 days (1-16); p = 0.19].
Duration of supplementary oxygen (days) (Outcome 02.09):
Three studies (n = 242) 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 [WMD 7.68 days (95% CI -0.10, 15.47)]. There was no statistically significant between study heterogeneity for this outcome (p = 0.62, I2 = 0%). Van Overmeire and co-workers (Van Overmeire 2000) reported this outcome as median and range [ibuprofen group 29.5 days (3-270); indomethacin group 19 days (2-110); p = 0.41)]. Gimeno Navarro and co-workers (Gimeno Navarro 2005) reported on this outcome as median and range [ibuprofen group five days (1 - 10); indomethacin group six (1 - 11); p = 0.78].
Pneumothorax (Outcome 02.10):
No study reported on this outcome.
Pulmonary hemorrhage (Outcome 02.11):
Three studies (n = 103) reported on this outcome. No study found a statistically significant difference in the incidence of pulmonary hemorrhage between the groups. In the meta-analysis, there was no statistically significant difference between the groups [typical RR 1.23 (95% CI 0.37, 4.10); typical RD 0.02 (95% CI -0.09, 0.13)]. There was no statistically significant between study heterogeneity for RR but moderate inconsistency for RD (RR, p = 0.16, I2 = 44.7%; RD, p = 0.07, I2 = 63 %).
Pulmonary hypertension (Outcome 02.12):
One study (n = 35) reported on this outcome. There was no statistically significant difference between the groups [RR 3.53 (95% CI 0.15, 81.11; RD 0.06 (95% CI -0.09, 0.21)].
Chronic lung disease (at 28 days) (Outcome 02.13):
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 as compared to indomethacin group [typical RR 1.22 (95% CI 0.93, 1.59); typical RD 0.09 (95% CI -0.03, 0.22)]. There was no statistically significant between study heterogeneity (RR, p = 0.48, I2 = 0 %; RD, p = 0.44, I2 = 0 %).
Chronic lung disease (at 36 weeks PMA) (Outcome 02.14):
Two studies (n = 238) reported on this outcome. In the meta-analysis of these studies, there was no statistically significant difference between the groups [typical RR 1.28 (95% CI 0.77, 2.10); typical RD 0.05 (95% CI -0.05, 0.15)]. There was no statistically significant between study heterogeneity (RR, p = 0.28, I2 = 13 %; RD, p = 0.31, I2 = 1 %).
Chronic lung disease (age not stated) (Outcome 02.15):
Two studies (n = 65) reported on this outcome. In the meta-analysis of these studies, there was no statistically significant difference between the groups [typical RR 1.02 (95% CI 0.58, 1.79); typical RD 0.01 (95% CI -0.22, 0.23)]. There was no statistically significant between study heterogeneity (RR, p = 0.94, I2 = 0 %; RD, p = 0.96, I2 = 0 %).
Intraventricular haemorrhage (Grade I-IV) (Outcome 02.16):
Four studies (n = 144) 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 0.90 (95% CI 0.44, 1.86); typical RD -0.02 (95% CI -0.13, 0.10)]. There was no statistically significant between study heterogeneity (RR, p = 0.90, I2 = 0 %; RD, p = 0.93, I2 = 0 %).
Intraventricular haemorrhage (Grade III-IV) (Outcome 02.17):
Four studies (n = 312) reported on this outcome. No study found a statistically significant difference in the incidence of IVH (grade III-IV) between the groups. In the meta-analysis, there was no statistically significant difference between the groups [typical RR 1.19 (95% CI 0.62, 2.29); typical RD 0.02; (95% CI -0.05, 0.08]. There was no statistically significant between study heterogeneity (RR, p = 0.85, I2 = 0 %; RD, p = 0.77, I2 = 0 %).
Periventricular leukomalacia (PVL) (Outcome 02.18):
Four studies (n = 413) 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 1.34 (95% CI 0.66, 2.71); typical RD 0.02 (95% CI -0.03, 0.07)]. There was no statistically significant between study heterogeneity (RR, p = 0.49, I2 = 0 %; RD, p = 0.26, I2 = 24%).
Necrotizing enterocolitis (NEC) (any stage) (Outcome 02.19):
Ten studies (n = 586) reported this outcome. No 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 no statistically significant difference between the groups for RR [typical RR 0.63 (95% CI 0.38, 1.03); but typical RD -0.04 (95% CI -0.08, 0.00 was of borderline statistical significance)]. There was no statistically significant between study heterogeneity (RR, p = 0.97, I2 = 0 %; RD, p = 0.71, I2 = 0%).
Intestinal perforation (Outcome 02.20):
Three studies (n = 95) 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 0.19 (95% CI 0.02, 1.51); typical RD -0.10 (95% CI -0.20, 0.01)]. There was no statistically significant between study heterogeneity (RR, p = 0.94, I2 = 0 %; RD, p = 0.35, I2 = 4 %).
Gastrointestinal bleed (Outcome 02.21):
This outcome was reported in four studies (n = 154). There was no statistically significant difference between the groups in the individual studies or in the meta-analysis [typical RR 0.97 (95% CI 0.25, 3.70); typical RD 0.00 (-0.08, 0.07)]. There was no statistically significant between study heterogeneity (RR, p = 0.38, I2 = 0 %; RD, p = 0.49, I2 = 0 %).
Time to full enteral feeds (days) (Outcome 02.22):
This outcome was reported in four studies (n = 413). There was no statistically significant difference between the groups in the time to reach full feeds. In the meta-analysis, there was no statistically significant difference between the groups [WMD 0.7 days (95% CI -1.9, 3.3)]. There was no statistically significant between study heterogeneity (p = 0.22, I2 = 31%).
Time to regain birth weight (days) (Outcome 02.23):
This outcome was reported in two studies (n = 188). 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 [WMD -0.2 days (95% CI -2.6, 2.2)]. There was no statistically significant between study heterogeneity (p = 0.08, I2 = 68 %).
Retinopathy of prematurity (ROP) (according to the international classification of ROP) (Outcome 02.24):
This was reported in three studies (n = 133). 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 0.73 (95% CI 0.42, 1.26); typical RD -0.08 (95% CI -0.22, 0.06)]. There was no statistically significant between study heterogeneity (RR, p = 0.88, I2 = 0 %; RD, p = 0.87, I2 = 0 %).
Sepsis (Outcome 02.25):
Five studies (n = 416) 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 1.28 (95% CI 0.75, 2.19); typical RD 0.03 (95% CI -0.03, 0.08)]. There was no statistically significant between study heterogeneity (RR, p = 0.95, I2 = 0 %; RD, p = 1.00, I2 = 0 %).
Decreased urine output (defined as < 1 cc/kg/hr) (Outcome 02.26):
This was reported in three studies (n = 358). Two trials found a statistically significant decrease in the proportion of infants with oliguria in the ibuprofen group. In the meta-analysis, there was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group [typical RR 0.22 (95% CI 0.09, 0.51); typical RD -0.12 (95% CI -0.18, -0.06); NNT 8 (95% CI 6 -17)]. There was moderate between study heterogeneity (RR, p = 0.14, I2 = 53 %; RD, p = 0.08, I2 = 60 %).
Serum/plasma creatinine levels (mmol/L) 72 hours after treatment (Outcome 02.27):
Six studies (n = 336) reported on this outcome in a format that the data could be used to summarize the information in RevMan 4.2.10. Four 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 [WMD -8.2 mmol/L (-13.3, -3.2)]. There was no statistically significant heterogeneity (p = 0.48, I2 = 0%).
Pezzatin and co-workers (Pezzati 1999) noted significantly lower serum creatinine levels on day 3 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 3 (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).
Increase in serum/plasma creatinine levels (mmol/L) 72 hours after treatment (Outcome 02.28):
One study reported on this outcome (n = 21). The increase in serum creatinine levels, was significantly lower in the ibuprofen group compared with the indomethacin group (mean difference - 15.9 mmol/L (95% CI -31.8, - 0.04).
Duration of hospitalization (Outcome 02.29):
Two studies (n = 238) reported on this outcome. There was no statistically significant difference between the groups [WMD -3.5 days (%% CI -9.9, 2.8)]. There was no statistically significant heterogeneity between the studies (p = 0.30, I2 = 7 %). Gimeno Navarro and co-workers (Gimeno Navarro 2005) reported on duration of NICU stay as median and range [ibuprofen group 63 days (43-83); indomethacin group 64 days (42 - 86); p = 0.93].
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.
As oral ibuprofen has been introduced to close a PDA, a secondary (post hoc) analysis was conducted comparing oral ibuprofen with indomethacin for PDA closure.
ORAL IBUPROFEN VS. I.V. INDOMETHACIN (Comparison 03)
Failure to close a PDA (after 3 doses) (Outcome 03.01):
This outcome was reported in 3 trials (n = 69). There was no statistically significant difference in failure to close a PDA in any of the trials comparing oral ibuprofen to indomethacin and the meta-analysis showed no statistically significant difference [typical RR 1.41 (95% CI 0.68, 2.93); typical RD 0.10 (95% CI -0.10, 0.30)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.71, I2 = 0%) or for RD (p = 0.57, 12 = 0%).
SUBGROUP ANALYSES
Two prespecified sub-group analyses relating to the use of multiple doses of ibuprofen and indomethacin were performed.
Failure to close a PDA (after 3 doses) (Outcome 02.30):
Failure to close a PDA after three doses of ibuprofen versus indomethacin (excluding one study that used a single dose). Fourteen studies (n = 699) reported on this outcome [typical RR 1.00 (95% CI 0.77, 1.29); typical RD 0.00 (-0.06, 0.06)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.88, I2 = 0%) or RD (p = 0.92, I2 = 0%)
Failure to close a PDA (after 3 doses, abstracts excluded) (Outcome 02.31):
Failure to close a PDA after three doses of ibuprofen versus indomethacin (excluding one study that used a single dose and one abstract): Thirteen studies (n = 658) reported on this outcome [typical RR 1.00 (95% CI 0.77, 1.30); typical RD 0.00 (-0.07, 0.06)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.83, I2 = 0%) or RD (p = 0.88, I2 = 0%).
Subgroup analyses by gestational age and birth weight groups were not possible to perform. In all studies, the presence of a PDA was diagnosed by ECHO-criteria and therefore a subgroup analysis based on clinical criteria only was not performed. Subgroup analysis on the basis of dosing regimen used was not performed as the majority of the studies used a dosing regimen of 10 mg/kg of ibuprofen followed by 5 mg/kg of ibuprofen 24 and 48 hours later vs. 0.2 mg/kg of indomethacin at 12 hours intervals for 3 doses.
One secondary (post hoc) analysis was conducted in which all results of studies that reported on CLD (regardless of age at reporting) were combined. No study reported these outcomes at more than one time point, justifying this meta-analysis.
Chronic lung disease (at any age reported) (Outcome 02.32):
Eight studies (n = 548) reported on chronic lung disease at a specified or unspecified age of the infant. No study reported these outcomes at more than one time point. No single study found a significant difference in outcome. In the meta-analysis, there was not statistically significant difference for RR [typical RR 1.20 (95% CI 0.97, 1.50)], but the RD was of borderline statistical significance [typical RD 0.07 (95% CI -0.01, 0.14)]; there was no statistically significant heterogeneity for either RR (p = 0.77; I2 = 0%) or RD (p = 0.75; I2 = 0%).
One additional (post hoc) analysis was conducted excluding studies that used oral ibuprofen from the above analysis.
Chronic lung disease (at any age reported, studies using oral ibuprofen excluded) (Outcome 02.33):
Six studies (n = 500) reported on this outcome. No single study found a statistically significant difference between the groups. In the meta-analysis, there was no statistically significant difference between the groups for RR [typical RR 1.25 (95% CI 0.98, 1.60)]; but of borderline statistical significance for RD [typical RD 0.08 (95% CI 0.00, 0.15)]
There was no statistically significant heterogeneity for this outcome for either RR (p = 0.71, I2 = 0%) or for RD (p = 0.61, I2 = 0%).
Bilirubin albumin binding (No outcome table):
Hammerman et al (Hammerman 2007) reported that ibuprofen decreased the bilirubin albumin binding capacity, while indomethacin was associated with an increase in bilirubin binding ability. The authors reported the results to be statistically significantly different between the groups for the free bilirubin/total serum bilirubin ratio (p < 0.002) with higher ratio in the ibuprofen treated infants compared with the indomethacin treated infants (0.12 +/- 0.02 vs. 0.06 +/- 0.02). Data for only 4 infants receiving ibuprofen and 6 infants receiving indomethacin were analysed. It is not stated in the abstract if the numbers provided represent means and standard deviations or not. Therefore, analysis of the data in RevMan was not performed. The study is currently listed under "Classification pending".
No randomized 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, two funnel plots were conducted; one for the primary outcome of 'Failure to close a PDA (after single or three doses)' (Figure 01) and the second for 'Chronic lung disease at any age reported' (Figure 02). For 'Failure to close a PDA', the funnel plot was asymmetric with a relative absence of small studies having a protective effect of ibuprofen vs. indomethacin. For the outcome 'Chronic lung disease at any age' the funnel plot was asymmetric with a relative absence of small studies not having a protective effect of ibuprofen vs. indomethacin.
Discussion
One study (n = 136) (Aranda 2005) published in abstract form compared ibuprofen to placebo but the results were not reported according to intervention group. Two additional studies published in abstract form were identified and are currently listed as "Classification pending" (Hammerman 2006, Hammerman 2007).
To date, the outcomes of 740 neonates with echocardiographically diagnosed PDA enrolled in randomized controlled trials comparing ibuprofen to indomethacin for the closure of PDA have been reported. Biochemical and physiological data favour 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 in either primary or subgroup analyses. 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, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed. The incidence of decreased urine output (< 1 cc/kg/hr) was lower in the ibuprofen group as compared to the indomethacin group [NNT 8 (95% CI 6-17)]. These two outcomes were the only statistically significant clinical findings favouring ibuprofen.
In the 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 and for days in supplementary oxygen. There is no biologically plausible explanation for this finding. In this review, 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, 1.60) and the typical RD was 0.08 (95% CI 0.00, 0.15). As in another exploratory analysis, oral ibuprofen seemed less effective than indomethacin. It is postulated that the impact on the incidence of both ductal closure and CLD is decreased with oral ibuprofen. Prospective studies would have to be conducted to confirm this hypothesis. The funnel plot for the outcome of 'CLD (at any age reported)' was asymmetric with a relative absence of studies not having a protective effect of ibuprofen vs. indomethacin.
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. There was significant between-study heterogeneity for only two of the secondary outcomes ['time to regain birth weight' and 'decreased urine output (< 1 cc/kg/hr)']. The funnel plot for the primary outcome 'Failure to close a PDA' was asymmetric, with a relative absence of smaller studies having a protective effect of ibuprofen vs. indomethacin.
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 (Fowlie 2002; Schmidt 2001).
One study of the prophylactic use of ibuprofen was stopped after 135 infants had been enrolled (Gournay 2002). Three infants developed severe hypoxemia in the ibuprofen group. Hypoxemia was thought to be due to pulmonary hypertension, as echocardiography showed severely decreased pulmonary blood flow. Hypoxemia resolved quickly on inhaled nitric oxide (Gournay 2002). The authors postulated that this could be due to early administration of ibuprofen (< 6 hours) preventing the normal fall in pulmonary vascular resistance, acidification of their ibuprofen solution (buffered with tromethamine) causing precipitation and microembolism 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 (Shah 2006). In the current review, one randomized controlled trial reported one case of pulmonary hypertension (Adamska 2005) in the ibuprofen group.
In an extensive search of the literature, including study designs other than randomized controlled trials, one additional case-report following L-lysine ibuprofen therapy in a preterm infant with a patent ductus arteriosus (Bellini 2006) was identified.
Another potential side effect of ibuprofen is decreased bilirubin albumin binding capacity. In a randomized controlled trial reported in abstract form, Hammerman and co-workers (Hammerman 2007) reported that ibuprofen appears to interfere with bilirubin albumin binding to a greater degree than does indomethacin treatment. Data were reported for only 4 ibuprofen treated and 6 indomethacin treated infants. In this review, the study was classified with another abstract from the same group, and possibly from the same study, as "Classification pending" (Hammerman 2006, Hammerman 2007).
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.
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 2002; Shah 2006).
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.
Reviewers' conclusions
Implications for practice
No statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA was found. Ibuprofen reduces the risk of oliguria. However, ibuprofen may increase the risk for chronic lung disease, and 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. Based on currently available information ibuprofen does not appear to confer any net benefits over indomethacin for the treatment of a PDA. Either ibuprofen or indomethacin can be used to close a PDA, but the clinician needs to be aware that both drugs are associated with (potentially serious) 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).
Potential conflict of interest
None
Characteristics of included studies
Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
Adamska 2005 | Single-centre, randomized controlled trial. I Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - yes | Study conducted in one NICU in Poland 35 preterm (< 33 weeks of gestation and birth weight < 1500 g) infants with a PDA diagnosed by Doppler echocardiography. 16 randomized to ibuprofen group mean (SD) GA 27.7 (1.8) weeks; BW 1074 (264) g; 9 boys, 7 girls 19 randomized to indomethacin grooup mean (SD) GA 27.6 (2.0) weeks; BW 1003 (192) g; 11 boys, 8 girls.
| Ibuprofen (3 doses) was given at 24 hours intervals (10, 5, and 5 mg/kg i.v). Indomethacin (3 doses) was given at 24 hours intervals (0.2mg/kg/dose). | 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 hemorrhage, pulmonary hypertension, duration of mechanical ventilation, and days in supplemental oxygen.
| Study published in Polish 27 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 hemorrahge (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) | A |
Akisu 2001 | Single-centre, randomized controlled trial. I Blinding of randomization - can't tell II. Blinding of intervention - can't tell III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - can't tell | Study conducted in one NICU in Turkey 23 infants < 35 weeks GA with echocardiographically confirmed PDA 12 randomized 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 randomized 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) | Ibuprofen was given i.v. 10 mg/kg as the inital dose followed by 5 mg/kg 24 and 48 hours later. Indomethacin was given i.v. 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 | PDA closure Diuresis Serum creatinine Thrombocyte count Gastrointestinal bleed IVH Sepsis Mortality | Study published in Turkish | B |
Aly 2007 | Single-centre, randomized controlled trial. I Blinding of randomization - yes (sealed opaque envelopes) II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | 21 preterm infants (< 35 weeks gestation) age 2 to 7 days with respiratory distress and PDA diagnosed by Doppler echocardiography 12 infants were randomized to the oral ibuprofen group, mean (SD) GA 31.2 (2.5) weeks; BW 1521 (398) g; 8 boys, 4 girls 9 infants were ramdomized to i.v. indomethacin, mean (SD) GA 32.9 (1.6) weeks; BW 1884 (485) g; 4 boys, 5 girls | Ibuprofen was given as an inital oral dose of 10 mg/kg, followed by 2 doses orally of 5mg/kg after 24 and 48 hours. Indomethacin was given i.v. as 3 doses of 0.2 mg/kg at 12 hour intervals | The primary outcome was ductal closure. Secondary outcomes included biochemical tests (serum creatinine), pulmonary hemorrhage, gastrointestinal bleeding, NEC, gastrointestinal perforation and increase in serum creatinine following treatment.
| | A |
Aranda 2005 | Multi-centre, randomized controlled trial. I Blinding of randomization - can't tell II. Blinding of intervention - yes III. Complete follow-up - can't tell IV. Blinding of outcome measurement(s) - yes | Multi-centre study conducted in the USA 136 preterm infants (BW 500 to 1000 g) with evidence of ductal shunting by an echocardiogram Mean (SD) GA 26.2 (1.4) weeks Mean (SD) BW 798 (130.3) g 51% males and 49% females | Ibuprofen was given 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) | Proportion of infants who required rescue treatment for PDA (indomethacin or surgery) on or prior to study day 14 | In the published abstract the study had not been unblinded and therefore the results [a very significant difference (p < 0.01)in the primary outcome] cannot be assigned to ibuprofen or placebo The full publication is awaited | B |
Chotigeat 2003 | Single-centre, randomized, controlled trial I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Single-centre study conducted in Thailand 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 | Ibuprofen was given orally as a 3 day treatment course every 24 hours and indomethacin was given i.v. at 12-hours intervals The doses of ibuprofen and indomethacin given were not stated | PDA closure Need for surgical ligation NEC | | B |
Gimeno Navarro 2005 | Single-centre, randomized controlled trial. I Blinding of randomization - yes (sealed envelopes) II. Blinding of intervention - can't tell III. Complete follow-up - yes | 47 ventilated, preterm infants (< 34 weeks gestational age) with a hemodynamically significant PDA, confirmed by echocardiography in the first week of life and who required respiratory support. | 23 infants received i.v. ibuprofen of 10 mg/kg, followed by two doses of ibuprofen i.v. 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 i.v. 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 | The primary outcome was ductal closure. Other outcomes included mortality, ductal reopening, need for surgical ligation, NEC, isolated bowel perforation, intestinal hemorrahge, pulmonary hemorrahge, CLD (age not stated), IVH (grades III and IV), days on assisted ventilation (median and range), days in supplemetnal oxygen (median and range), days in NICU (median and range). | Study published in Spanish | A |
Lago 2002 | Single-centre, randomized, controlled trial I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Study conducted in Italy 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
| Ibuprofen was given i.v. 10 mg/kg as the inital dose Indomethacin was given i.v. 0.2 mg/kg for three doses at 12 hour intervals followed by 5 mg/kg 24 and 48 hours | PDA closure Serum creatinine Oliguria | An 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 efect of ibuproen and indomethacin on urinary antidiuretic hormone excretion. | B |
Mosca 1997 | Single-centre, randomized, controlled trial I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Study conducted in Italy 16 infants receiving mechanical ventilation (<31 weeks GA) with echocardiographic evidence of PDA were randomized 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 | Ibuprofen was given i.v. 10 mg/kg infused over 1 minute as a first dose and a second and third dose were administered provided that no significant adverse effect was observed Indomethacin 0.2 mg/kg was infused over one minute and a second and third dose of 0.1 mg/kg were administered provided no significant adverse effects were observed | PDA closure Cerebral blood flow velocity Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidized cytochrome oxidase concentration. | The 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).
| B |
Patel 1995 | Single-centre, randomized, controlled trial without the use of a placebo. I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Study conducted in the UK 33 infants with a median GA of 26 weeks (range 23 to 28) were enrolled. All infants had echocardiographically proven PDA 12 infants received ibuprofen 5 mg/kg; 6 received ibuprofen 10 mg/kg and 15 received indomethacin 0.1 mg/kg | The drugs were infused i.v. over 15 minutes | PDA 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.
| Published as a letter to the editor | B |
Patel 2000 | Four-centre, randomized, controlled trial I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - yes | Study conducted in 4 NICUs in the UK 33 preterm infants with a hemodynamically significant PDA diagnosed clinically and on echocardiographic criteria were randomized 18 infants received i.v. 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) | Ibuprofen was given i.v. 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 d 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 | PDA closure rate Near-infrared spectroscopy was used to measure changes in cerebral blood volume, cerebral blood flow, cerebral oxygen delivery | | A |
Pezzati 1999 | Single-centre, randomized controlled trial. I Blinding of randomization - can't tell II. Blinding of intervention - can't tell III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - can't tell | 17 preterm infants (< 33 weeks GA) 9 infants received ibuprofen, mean (SD) GA 29.1 (2.2) weeks; BW 1151 (426) g 8 infants received indomethacin, mean (SD) GA 29.5 (2.6); BW 1277 (440) g | Indomethacin (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. | The primary outcome was mesenteric and renal blood flow velocity. Secondary outcomes included: ductal closure, ductal reopening and NEC. | | A |
Plavka 2001 | Three-centre, randomized controlled trial I. Blinding of randomization - can't tell II. Blinding of intervention - can't tell III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - can't tell | Study conducted in 3 NICUs in the Czech Republic 41 preterm infants with clinical and echographic signs of PDA were randomized 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) | Ibuprofen was given i.v. 8 mg/kg every 24 hours for three doses Indomethacin was given i.v. 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 | Cerebral blood flow velocities Blood pressure Serum creatinine Mortality Ductal reopening | Published in abstract form only | B |
Su 2003 | Single-centre, randomized controlled trial I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Study conducted in Taiwan 63 preterm infants with BW </= 1500 g and a GA of </= 32 weeks and with echocardiographic evidence of a PDA were randomized between 2 and 7 days of age 32 infants [mean (SD) BW 1134 +/- 200 g; mean (SD) GA 28.7 +/- 2.2 weeks] received i.v. ibuprofen 10 mg/kg initially and followed by ibuprofen 5mg/kg after 24 and 48 hours 31 infants [mean (SD) BW 1110 +/- 244 g; mean (SD) GA 28.2 +/- 2.4] received i.v. indomethacin 0.2 mg/kg every 12 hours for three doses | Ibuprofen was given i.v. as 10mg/kg initially, followed by 5 mg/kg after 24 and 48 hours Indomethacin was given i.v. as 0.2 mg/kg every 12 hours for three doses | Rate 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 | | B |
Supapannachart 2002 | Single-centre, randomized, controlled trial I. Blinding of randomization - yes (sealed envelop) II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Single-centre study conducted in Thailand 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 | Ibuprofen was given orally (10 mg/kg/dose for three doses at 24 hourly intervals Indomethacin (oral or i.v. 0.2 mg/kg/dose) for three doses given at 12 hourly intervals | PDA closure rate, duration of ventilatory support, CLD (age not stated), IVH (grade not stated), NEC, mortality | | A |
Van Overmeire 1997 | Single-centre, randomized, controlled trial I. Blinding of randomization - yes II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Study conducted in one NICU in Belgium 40 preterm infants (GA , 33 weeks) were randomized 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 | Ibuprofen was given i.v. 10 mg/kg as the initial dose followed by 5 mg/kg 24 and 48 hours later Indomethacin was given i.v. 0.2 mg/kg every twelve hours for three doses Both drugs were infused over 15 minutes | PDA closure rate PDA ligation rate Mortality Sepsis NEC Age to regain birthweight ROP | It is possible that there is overlap between this study and a report in abstract form with 28 patients enrolled (Van Overmeire 1996). | A |
Van Overmeire 2000 | Single-centre, randomized, controlled trial without the use of a placebo. I. Blinding of randomization - Yes II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no | Study conducted in 5 NICUs in Belgium 148 infants (GA 24-32 weeks) with RDS and echocardiographically confirmed PDA were randomized 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
| Ibuprofen was given i.v. 10 mg/kg as the initial dose, followed at 24 hour intervals by two doses of 5 mg/kg Indomethacin was administered i.v. 0.2 mg/kg every 12 hours | PDA closure rate Oliguria PDA ligation rate Mortality by 30 days NEC Localized bowel perforation Sepsis PVL CLD at 28 days Time to regain birth weight Time to full enteral feeding | We 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.
| A |
BW = birth weight
C/S = cesarean section
g = grams
GA = gestational age
i.v. = intravenous
IVH = intraventricular haemorrhage
PDA = patent ductus arteriosus
RDS = respiratory distress syndromeCharacteristics of excluded studies
Study | Reason for exclusion |
Cherif 2007 | This study evaluated the use of oral ibuprofen for closure of PDA, but did not include a control group |
Desfrere 2005 | This was a dose-finding study |
References to studies
References to included studies
Adamska 2005 {published data only}Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. Porownanie ibuprofenu i indometacyny w leczeniu przetrwalego przewodu tetniczego u noworodkow urodzonych przedwczesnie [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants]. Medycyna wieku rozwojowego 2005;9:335-54.
Adamska E, Helwich E, Rutkowska M, Zacharska E, Piotrowska A. Porownanie ibuprofenu i indometacyny w leczeniu przetrwalego przewodu tetniczego u noworodkow urodzonych przedwczesnie [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants]. Medycyna wieku rozwojowego 2005;9:335-54.
Akisu 2001 {published data only}
Akisu M, Ozyurek AR, Dorak C, Parlar A, Kultursay N. Premature bebeklerde patent duktus arteriozusun tedavisinde enteral ibuprofen ve indometazinin etkinligi ve guvenilirligi [Enteral ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm newborn infants]. Cocuk Sagligi ve Hastaliklari Dergisi 2001;44:56-60.
Akisu M, Ozyurek AR, Dorak C, Parlar A, Kultursay N. Premature bebeklerde patent duktus arteriozusun tedavisinde enteral ibuprofen ve indometazinin etkinligi ve guvenilirligi [Enteral ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm newborn infants]. Cocuk Sagligi ve Hastaliklari Dergisi 2001;44:56-60.
Aly 2007 {published data only}
* Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel-Meguid IE, Hammad TA. Oral ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. American Journal of Perinatology 2007;24:267-70.
Lotfy W, Badrawi N, Ghawas M, Ehsan E, Aly H. Oral ibuprofen solution (O) is efficacioous for the treatment of patent ductus arteriosus (PDA) in premature infants: A randomized controlled trial. In: Pedaitric Academic Societies Annual Meeting 2005 http://www.abstracts2view.com. 2005.
Aranda 2005 {published data only}
Aranda JV. Multicentre randomized double-blind placebo controlled trial of ibuprofen L-Lysine intravenous solution (IV Ibuprofen) in premature infants for the early treatment of patent ductus arteriosus (PDA). In: www.pas-meeting.org (Pediatric Academic Societies Annual Meeting; 2005 Abstracts2viewTMonline). 2005.
Chotigeat 2003 {published data only}
Chotigeat U, Jirapapa K, Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. Journal of Medical Association of Thailand 2003;86:Suppl 3:S563-9.
Gimeno Navarro 2005 {published data only}
Gimeno Navarro A, Cano Sanchez A, Fernandez Gilino C, Carrasco Moreno JI, Izquierdo Macian I, Gutierrez Laso A, Morcillo Sopena F. Ibuprofeno frente a indometacina en el tratamiento del conducto arterioso persistente del prematuro [Ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm infants]. Anales de Pediatria 2005;63:212-8.
Lago 2002 {published data only}
* Lago P, Bettiol T, Salvadori S, Pitassi I, Vianello A, Chiandetti L, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. European Journal of Pediatrics 2002;161:202-7.
Lago P, Salvadori S, Bettiol T, Pitassi I, Chiandetti L, Saia OS. Effects of indomethacin and ibuprofen on renal function in preterm infants treated for patent ductus arteriosus: A randomized controlled trial. Pediatric Research 2001;49:375A.
Zanardo V, Vedovato S, Lago P, Piva D, Faggian D, Chiozza L. Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus. Fetal Diagnosis and Therapy 2005;20:534-9.
Mosca 1997 {published data only}
Mosca F, Bray M, Lattanzio M, Fumagalli M, Colnaghi MR, Compagnoni G. Comparison of the effects of indomethacin (INDO) and ibuprofen (IBU) on cerebral perfusion and oxygenation in preterm infants. Pediatric Research 1996;39:231A.
Mosca F, Bray M, Lattanzio M, Fumagalli M, Colnaghi M, Castoldi F, et al. Comparison of the effects of ibuprofen and indomethacin on PDA closure and cerebral perfusion and oxygenation. Pediatric Research 1997;41:165A.
* Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1997;131:549-54.
Patel 1995 {published data only}
Patel J, Marks KA, Roberts I, Azzopardi D, Edwards AD. Ibuprofen treatment of patent ductus arteriosus. Lancet 1995;346:255.
Patel 2000 {published data only}
Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47:36-42.
Pezzati 1999 {published data only}
Pezzati M, Bertini G, Vangi V, Biagiotti R, Cianciulli D, Rubaltelli FF. Mesenteric and renal perfusion in preterm infants with PDA: Indomethacin vs ibuprofen. Pediatric Research 1999;45:218A (Abstract).
Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubatelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135:733-8.
Plavka 2001 {published data only}
Plavka R, Svihovec P, Borek I, Biolek J, Kostirova M, Liska K, et al. Ibuprofen vs. indomethacin in the treatment of patent ductus arteriosus (PDA) in very premature neonates. Pediatric Research 2001;49:375A.
Su 2003 {published data only}
Su P-H, Chen J-Y, Su C-M, Huang T-C, Lee H-S. Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants. Pediatrics International 2003;45:665-70.
Supapannachart 2002 {published data only}
Supapannachart S, Limrungsikul A, Khowsathit P. Oral ibuprofen and indomethacin for treatment of patent ductus arteriosus in premature infants: a randomized trial at Ramathibodi hospital. Journal of Medical Association of Thailand 2002;85:Suppl 4:S1252-8.
Van Overmeire 1997 {published data only}
* Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Archives of Disease in Childhood 1997;76:F179-84.
Van Overmeire B, Follens I, Hartmann S, Mahieu L, Van Reempts PJ. Intravenous ibuprofen (IBU) for the treatment of patent ductus arteriosus (PDA) in preterm infants with respiratory distress syndrome (RDS). Pediatric Research 1996;39:250A.
Van Overmeire 2000 {published data only}
Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. Journal of Pediatrics 1999;135:733-8.
Van Overmeire B, Langhendries JP, Vanhaesebrouck P, Lecoutere D, Van de Broek. Ibuprofen for early treatment of patent ductus arteriosus, a randomized multicentre trial. Pediatric Research 1998;43:200A.
* Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, De Groote K, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. New England Journal of Medicine 2000;343:674-81.
References to excluded studies
Cherif 2007 {published data only}Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. American Journal of Perinatology 2007;24:339-45.
Desfrere 2005 {published data only}
Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. Journal of Clinical Pharmacy & Therpeutics 2005;30:121-32.
* indicates the primary reference for the study
Other references
Additional references
Aranda 2006Aranda JV, Thomas R. Systematic review: intravenous ibuprofen in preterm newborns. Seminars in Perintatology 2006;30:114-20.
Bellini 2006
Bellini C, Campone F, Serra G. Pulmonary hypertension following L-lysine ibuprofen therapy in a preterm infant with patent ductus arteriosus. Canadian Medical Association Journal 2006;174:1843-4.
Chemtob 1990
Chemtob S, Behary K, Rex J, Varma DR, Aranda JV. Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets. Stroke 1990;21:777-84.
Chemtob 1991
Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV. Differences in the effects in the newborn piglet of various nonsteroidal antiinflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins. Pediatric Research 1991;30:106-11.
Coceani 1979
Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the responses of the lamb ductus arteriosus to oxygen and ibuprofen. Canadian Journal of Physiology and Pharmacology 1979;57:825-31.
Coceani 2005
Coceani F, Barogi S, Brizza F, Ackerley C, Seidlitz, Kelsey L et al. Cyclooxygenase isoenzymes and patency of ductus arteriosus. Prostaglandins, Leukotrines and Essential Fatty Acids 2005;72:71-77.
Cotton 1978
Cotton RB, Stahlman MT, Bender HW, Graham TP, Catterton WZ, Kovar I. Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. Journal of Pediatrics 1978;93:647-51.
Cotton 1979
Cotton RB, Stahlman MT, Kovar I, Catterton WZ. Medical management of small preterm infants with symptomatic patent ductus arteriosus. Journal of Pediatrics 1979;2:467-73.
Dani 2000
Dani C, Bertini G, Reali MF, Fabris C, Vangi V, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatrica 2000;89:1369-74.
De Carolis 2000
De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. European Journal of Pediatrics 2000;159:364-8.
Donze 2007
Donze A, Smith JR, Bryowsky K. Safety and efficacy of ibuprofen versus indomethacin for the treatment of patent ductus arteriosus in the preterm infant: reviewing the evidence. Neonatal Network 2007;26:187-95.
Edwards 1990
Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delpy DT. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990;335:1491-5.
Ellison 1983
Ellison RC, Pecham GJ, Lang P, Talner NS, Lerer TJ, Lin L, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71:364-72.
Fowlie 2002
Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2002. Oxford: Update Software.
Gournay 2002
Gournay V, Savagner C, Thirez G, Kuster A, Roze J-C. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002;359:1486-88.
Grosfeld 1983
Grosfeld JL, Kamman K, Gross K, Cikrit D, Ross D, Wolfe M, et al. Comparative effects of indomethacin, prostaglandin E1, and ibuprofen on bowel ischaemia. Journal of Pediatric Surgery 1983;18:738-42.
Hardy 1996
Hardy P, Peri KG, Lahaie I, Varma DR, Chemtob S. Increased nitric oxide synthesis and action preclude choroidal vasoconstriction to hyperoxia in newborn pigs. Circulation Research 1996;79:504-11.
Ito 1994
Ito K, Niida Y, Sato J, Owada E, Ito K, Umetsu M. Pharmacokinetics of mefenamic acid in preterm infants with patent ductus arteriosus. Acta Paediatrica Japonica 1994;36:387-91.
Kaplan 1994
Kaplan BS, Restaino I, Raval DS, Gottlieb RP, Bernstein J. Renal failure in the neonate associated with in utero exposure to non-steroidal anti-inflammatory agents. Pediatric Nephrology 1994;8:700-4.
Lee 2000
Lee SK, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R, et al. Variations in practice and outcomes in the Canadian NICU Network 1996-1997. Pediatrics 2000;106:1070-9.
Mahony 1982
Mahony L, Carnero V, Brett C, Heymann MA, Clyman RI. Prophylactic indomethacin therapy for patent ductus arteriosus in very low birth weight infants. New England Journal of Medicine 1982;306:506-10.
Mathew 1998
Mathew R. Development of the pulmonary circulation: metabolic aspects. In: Polin RA, Fox WW, editor(s). Fetal and Neonatal Physiology. Vol. 1. Philadelphia: W.B.Saunders Company, 1998:924-9.
Naulty 1978
Naulty CM, Horn S, Conry J, Avery GB. Improved lung compliance after ligation of patent ductus arteriosus in hyaline membrane disease. Journal of Pediatrics 1978;93:682-4.
Niopas 1994
Niopas I, Mamzoridi K. Determination of indomethacin and mefenamic acid in plasma performance liquid chromatography. Journal of Chromatography. Biomedical Applications 1994;656:447-50.
Ohlsson 1993
Ohlsson A, Bottu J, Govan J, Ryan ML, Fong K, Myhr T. The effect of indomethacin on cerebral blood flow velocities in very low birth weight neonates with patent ductus arteriosus. Developmental Pharmacology and Therapeutics 1993;20:100-6.
Ohlsson 2000
Ohlsson A. Back to the drawing board. Pediatric Research 2000;47:4-5.
Patel 2000
Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD. Randomized double blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatric Research 2000;47:36-42.
Pellicer 1999
Pellicer A, Aparicio M, Cabanas F, Valverde E, Quero J, Stiris TA. Effect of the cyclo-oxygenase blocker ibuprofen on cerebral blood volume and cerebral blood flow during normocarbia and hypercarbia in newborn piglets. Acta Pediatrica 1999;88:82-8.
Sakhalkar 1992
Sakhalkar VS, Merchant RH. Therapy of symptomatic patent ductus arteriosus in preterms with mefenemic acid and indomethacin. Indian Pediatrics 1992;29:313-8.
Schmidt 2001
Schmidt B, Davis P, Moddeman D, Ohlsson A, Roberts RS, Saigal S et al. Long-term effect of indomethacin prophylaxis in extremely-low-birth-weight infants. New England Journal of Medicine 2001;344:1966-72.
Seyberth 1983
Seyberth HW, Rascher W, Hackenthal R, Wille L. Effect of prolonged inndomethacin therapy on renal function and selected vasoactive hormones in very low birth weight infants with symptomatic ductus arteriosus. Journal of Pediatrics 1983;103:979-84.
Shah 2006
Shah S, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 1, 2006.
Stefano 1991
Stefano JL, Abbasi S, Pearlman SA, Spear ML, Esterly KL, Bhutani VK. Closure of the ductus arteriosus with indomethacin in ventilated neonates with respiratory distress syndrome; effects on pulmonary compliance and ventilation. The American Review of Respiratory Disease 1991;143:236-9.
Thomas 2005
Thomas RL, Parker GC, Van Overmeire B, Aranda JV. A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus. European Journal of Pediatrics 2005;164:135-40.
Van Overmeire 1997
Van Overmeire B, Follens I, Hartman S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Archives of Disease in Childhood 1997;76:F179-84.
Van Overmeire 1998
Van Overmeire B, Langhendries JP, Vanhasebrouck P, Lecoutere D, Van de Broek H. Ibuprofen for early treatment of patent ductus arteriosus, a randomized multicentre trial. In: Pediatric Research. Vol. 43. 1998:200A.
Varvarigou 1996
Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, Aranda JV. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA 1996;275:539-44.
Walia 2000
Walia R, Ohlsson A. All is gold, is it? Differences between abstracts of randomised controlled trials in neonates submitted to a conference and their final publication - implications for meta-analysis. In: Archives of Disease in Childhood. Vol. 82 Suppl 1. 2000:A3.
Weir 1999
Weir FJ, Ohlsson A, Myhr TL, Fong K, Ryan ML. A patent ductus arteriosus is associated with reduced middle cerebral artery blood flow velocity. European Journal of Pediatrics 1999;158:484-7.
Wolf 1989
Wolf WM, Snover DC, Leonard AS. Localized intestinal perforation following intravenous indomethacin in premature infants. Journal of Pediatric Surgery 1989;24:409-10.
Other published versions of this review
Ohlsson 2003Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 2, 2003.
Ohlsson 2005
Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2005.
Classification pending
Hammerman 2006Hammerman C, Schimmel M, Bromiker R, Kaplan M. Is ibuprofen really safer than indomethacin in the treatment of PDA. In: Pediatric Academic Societies' Annual Meeting. E:PAS2006;59:3607.512.
Hammerman 2007
Hammerman C, Shchors I, Schimmel M, Bromiker R, Kaplan M. Differential effects of indomethacin vs. ibuprofen in the treatment of patent ductus arteriosus on plasma free bilirubin levels. In: Paediatrc Academic Societies Annual Meeting. E:PAS2007;61:8438.8.
Comparisons and data
Comparison or outcome |
Studies |
Participants |
Statistical method |
Effect size |
01 Ibuprofen vs placebo or no drug |
02 Ibuprofen vs. indomethacin |
01 Failure to close a PDA (after single or three doses) |
15 |
740 |
RR (fixed), 95% CI |
0.99 [0.78, 1.27] |
02 All cause mortality |
6 |
366 |
RR (fixed), 95% CI |
0.82 [0.44, 1.54] |
03 Neonatal mortality (during first 28/30 days of life) |
2 |
178 |
RR (fixed), 95% CI |
1.25 [0.52, 3.01] |
04 Infant mortality (death during the first year of life) |
0 |
0 |
RR (fixed), 95% CI |
Not estimable |
05 Reopening of the ductus arteriosus |
5 |
184 |
RR (fixed), 95% CI |
1.28 [0.48, 3.38] |
06 Need for surgical closure of the PDA |
9 |
604 |
RR (fixed), 95% CI |
1.06 [0.69, 1.65] |
07 Need for re-treatment with indomethacin or ibuprofen
to close the PDA |
5 |
142 |
RR (fixed), 95% CI |
1.34 [0.71, 2.54] |
08 Duration of ventilatory support |
4 |
305 |
WMD (fixed), 95% CI |
-1.96 [-4.97, 1.05] |
09 Duration of supplementary oxygen |
3 |
242 |
WMD (fixed), 95% CI |
7.68 [-0.10, 15.47] |
10 Pneumothorax |
0 |
0 |
RR (fixed), 95% CI |
Not estimable |
11 Pulmonary hemorrhage |
3 |
103 |
RR (fixed), 95% CI |
1.23 [0.37, 4.10] |
12 Pulmonary hypertension |
1 |
35 |
RR (fixed), 95% CI |
3.53 [0.15, 81.11] |
13 Chronic lung disease (at 28 days) |
4 |
245 |
RR (fixed), 95% CI |
1.22 [0.93, 1.59] |
14 Chronic lung disease (at 36 weeks corrected postmenstrual
age) |
2 |
238 |
RR (fixed), 95% CI |
1.28 [0.77, 2.10] |
15 Chronic lung disease (age not stated) |
2 |
65 |
RR (fixed), 95% CI |
1.02 [0.58, 1.79] |
16 Intraventricular haemorrhage (Grade I-IV) |
4 |
144 |
RR (fixed), 95% CI |
0.90 [0.44, 1.86] |
17 Intraventricular haemorrhage (III-IV) |
4 |
312 |
RR (fixed), 95% CI |
1.19 [0.62, 2.29] |
18 Periventricular leucomalacia (cystic) |
4 |
413 |
RR (fixed), 95% CI |
1.34 [0.66, 2.71] |
19 Necrotizing enterocolitis (any stage) |
10 |
586 |
RR (fixed), 95% CI |
0.63 [0.38, 1.03] |
20 Intestinal perforation |
3 |
95 |
RR (fixed), 95% CI |
0.19 [0.02, 1.51] |
21 Gastrointestinal bleed |
4 |
154 |
RR (fixed), 95% CI |
0.97 [0.25, 3.70] |
22 Time to full enteral feeds |
4 |
413 |
WMD (fixed), 95% CI |
0.70 [-1.89, 3.29] |
23 Time to regain birth weight (days) |
2 |
188 |
WMD (fixed), 95% CI |
-0.18 [-2.59, 2.22] |
24 Retinopathy of prematurity |
3 |
133 |
RR (fixed), 95% CI |
0.73 [0.42, 1.26] |
25 Sepsis |
5 |
416 |
RR (fixed), 95% CI |
1.28 [0.75, 2.19] |
26 Decreased urine output (<1 cc/kg/hr) |
3 |
358 |
RR (fixed), 95% CI |
0.22 [0.09, 0.51] |
27 Serum/plasma creatinine levels (micromol/L) 72 hours
after treatment |
6 |
336 |
WMD (fixed), 95% CI |
-8.24 [-13.26, -3.23] |
28 Increase in serum/plasma creatinine levels (mg/dL)
follwoing treatment |
1 |
21 |
WMD (fixed), 95% CI |
-15.91 [-31.78, -0.04] |
29 Duration of hospitalization |
2 |
238 |
WMD (fixed), 95% CI |
-3.52 [-9.87, 2.83] |
30 Failure to close a PDA (after 3 doses) |
14 |
699 |
RR (fixed), 95% CI |
1.00 [0.77, 1.29] |
31 Failure to close a PDA (after 3 doses, abstracts excluded) |
13 |
658 |
RR (fixed), 95% CI |
1.00 [0.77, 1.30] |
32 Chronic lung disease (at any age reported) |
8 |
548 |
RR (fixed), 95% CI |
1.20 [0.97, 1.50] |
33 Chronic lung disease (at any age reported; studies
using oral ibuprofen excluded) |
6 |
500 |
RR (fixed), 95% CI |
1.25 [0.98, 1.60] |
03 Oral ibuprofen vs. i.v. or oral indomethacin |
01 Failure to close a PDA (after three doses) |
3 |
69 |
RR (fixed), 95% CI |
1.41 [0.68, 2.93] |
01 Ibuprofen vs placebo or no drug02 Ibuprofen vs. indomethacin
02.01 Failure to close a PDA (after single
or three doses)
02.02 All cause mortality
02.03 Neonatal mortality (during first 28/30
days of life)
02.04 Infant mortality (death during the
first year of life)
02.05 Reopening of the ductus arteriosus
02.06 Need for surgical closure of the PDA
02.07 Need for re-treatment with indomethacin
or ibuprofen to close the PDA
02.08 Duration of ventilatory support
02.09 Duration of supplementary oxygen
02.10 Pneumothorax
02.11 Pulmonary hemorrhage
02.12 Pulmonary hypertension
02.13 Chronic lung disease (at 28 days)
02.14 Chronic lung disease (at 36 weeks corrected
postmenstrual age)
02.15 Chronic lung disease (age not stated)
02.16 Intraventricular haemorrhage (Grade
I-IV)
02.17 Intraventricular haemorrhage (III-IV)
02.18 Periventricular leucomalacia (cystic)
02.19 Necrotizing enterocolitis (any stage)
02.20 Intestinal perforation
02.21 Gastrointestinal bleed
02.22 Time to full enteral feeds
02.23 Time to regain birth weight (days)
02.24 Retinopathy of prematurity
02.25 Sepsis
02.26 Decreased urine output (<1 cc/kg/hr)
02.27 Serum/plasma creatinine levels (micromol/L)
72 hours after treatment
02.28 Increase in serum/plasma creatinine
levels (mg/dL) follwoing treatment
02.29 Duration of hospitalization
02.30 Failure to close a PDA (after 3 doses)
02.31 Failure to close a PDA (after 3 doses,
abstracts excluded)
02.32 Chronic lung disease (at any age reported)
02.32.01 Chronic lung disease (at 28 days)
02.32.02 Chronic lung disease (at 36 weeks post-menstrual age)
02.32.03 Chronic lung disease (age not stated)
02.33 Chronic lung disease (at any age reported;
studies using oral ibuprofen excluded)
02.33.01 Chronic lung disease (at 28 days)
02.33.02 Chronic lung disease (at 36 weeks post-menstrual age)
02.33.03 Chronic lung disease (age not stated)
03 Oral ibuprofen vs. i.v. or oral indomethacin
03.01 Failure to close a PDA (after three
doses)
Additional figures
Figure 01
![](OHLSSON-Figure 01.PNG)
Figure 02
![](OHLSSON-Figure 02.PNG)
Contact details for co-reviewers
Dr Sachin S Shah, MBBS, MD, DM
Director
Neonatal and Pediatric Intensive Care Services
Aditya Birla Memorial Hospital
Office no. 2, Arihant Building
39/32 Karve Road
Pune
INDIA
411004
Telephone 1: 91 20 30717644
Facsimile: 91 20 27277003
E-mail: sshahdoc@hotmail.com
Secondary address:
39/32 Karve Road
1st Floor, Arihant Building
Pune INDIA
411004
Telephone: 91 20 25442244
Dr Rajneesh Walia, MBBS, MD, DCH, MRCP, FRCPCH
Consultant
Children's Intensive Care, Children's Hospital
Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust
Infirmary Square
Leicester
Leicestershire UK
LE1 5WW
Telephone 1: +44 116 2586794
Telephone 2: +44 116 241414 extension: 6794
Facsimile: +44 116 2587637
E-mail: rajwalia@hotmail.com
Secondary address:
678 Uppingham Road, Thurnby
Leicester
Leicestershire UK
LE7 9RN
Telephone: +44 116 2419239
Facsimile: +44 116 2419239
This review is published as a Cochrane review in The Cochrane Library,
Issue 1, 2008 (see http://www.thecochranelibrary.com
for information). Cochrane reviews are regularly updated as new evidence
emerges and in response to feedback. The Cochrane Library should be consulted
for the most recent version of the review. |