In November of 2004, the study by Gournay (Gournay 2004), previously included as a letter and the study by Van Overmeire (Van Overmeire 2004), previously included as an abstract, were published in the same issue of the Lancet. The full report by Gournay included the same number of patients. The full report by Van Overmeire included 415 patients, whereas the abstract included in our previous review reported on 358 patients.
Inclusion of an additional 57 randomized patients made the outcome estimates slightly more precise. In addition, data for several outcomes of interest were published in the full reports (not previously included in the abstract and the letter to the editor).
Based on these updated data, the outcome "Need for surgical ligation of PDA " is now significantly reduced. The incidence of oliguria reached borderline statistical significance. There were no other statistically significant changes in the results.
In view of no important short term benefits and important side effects, prophylactic ibuprofen is not recommended.
Until long-term follow-up results are published from the trials included in this review, no further research is recommended.
No study was identified using mefenamic acid.
Ibuprofen may prevent PDA, a common complication for preterm or very small babies, but more research is needed into possible serious adverse effects
A common complication for very preterm (premature) or very small babies is patent ductus arteriosus (PDA). PDA is an open vessel that channels blood from the lungs to the body. It should close after birth, but sometimes remains open because of the baby's premature stage of development. PDA can lead to life-threatening complications. Indomethacin is successful in causing PDA closure, but can cause serious adverse effects. Another option is the drug ibuprofen, which can be given to try and prevent PDA. The review of trials found that ibuprofen can prevent PDA, but more research is needed on possible serious adverse effects.
A patent ductus arteriosus (PDA) often complicates the clinical course of preterm infants with or without respiratory distress syndrome (RDS) (Ramanathan 1997). In a large Canadian cohort (n = 3,779) of very-low-birth-weight infants (< 1500 g), the incidence of symptomatic PDA needing treatment was 28 percent (Lee 2000). The failure of the ductus arteriosus to constrict after birth is due to lower intrinsic tone, less ductal muscle fibres and fewer subendothelial cushions in the preterm infants as compared to term infant (Hammerman 1995). The immature ductus arteriosus has higher sensitivity to the vasodilating effects of prostaglandins and nitric oxide (Hammerman 1995). This is aggravated by hemodynamic derangements due to respiratory distress syndrome and surfactant therapy (Hammerman 1995).
The clinical consequences of a PDA are related to the degree of left to right shunting through the ductus. Despite the ability of the left ventricle in preterm infants to increase its output in face of a left to right shunt, blood flow distribution to vital organs is altered owing to drop in diastolic pressure and localized vasoconstriction (Clyman 2000). Substantial left to right shunting through the ductus may increase the risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis, bronchopulmonary dysplasia, and death (Cotton 1979).
Inhibiting prostaglandin synthesis with non selective blockers of both cyclo-oxygenases 1 and 2 seems effective for the nonsurgical closure of PDA (Clyman 2000). Intravenous indomethacin is the standard pharmacological treatment for promoting closure of PDA in preterm infants and has been used since 1976 (Friedman 1976) with a reported efficacy of 66 - 80% (Gersony 1983; Van Overmeire 2000; Lago 2002).
The prophylactic use of indomethacin for the prevention of PDA has been shown to reduce the incidence of a symptomatic PDA, need for surgical ligation, and the occurrence of pulmonary hemorrhage (Couser 1996, Domanico 1994). In a recent large trial it was shown that prophylactic use of indomethacin in extremely low birth weight infants reduces the frequency of PDA and severe intraventricular hemorrhage, but there was no evidence of effect on the rate of survival without neurosensory impairment at 18 months (Schmidt 2001). A meta analysis of 19 eligible studies showed that prophylactic indomethacin reduces the incidence of symptomatic PDA, need for surgical ligation, and incidence of grade 3 and 4 IVH in preterm infants, but without evidence of effect on the incidence of long-term neurosensory impairment (Fowlie 2002).
However, the use of indomethacin may be followed by side effects such as decreased cerebral blood flow (Edwards 1990; Van Bel 1989; Ohlsson 1993), decreased cerebral blood volume and cerebral oxygen delivery (Patel 2000), oliguria or transient renal failure (Betkerur 1981; Gersony 1983; Lago 2002; Van Overmeire 2000), and necrotizing enterocolitis, isolated bowel perforation or gastrointestinal hemorrhage (Gersony 1983; Grosfeld 1996). These indomethacin related complications have tempered the enthusiasm for its use, encouraging many researchers to seek new, safer pharmacological strategies for the closure of a PDA. The only major side effect reported in the Cochrane review by Fowlie (Fowlie 2002) was an increased incidence of oliguria, but this was not associated with major renal impairment. In the same review there was no evidence of difference in rates of necrotizing enterocolitis, excessive clinical bleeding or sepsis.
Mefenamic acid, another cyclo-oxygenase inhibitor drug, has been reported to close a PDA (Sakhalkar 1992; Ito 1994; Niopas 1994).
Ibuprofen, another cyclo-oxygenase inhibitor drug, has been used for ductal closure in animals (Coceani 1979). Preliminary experimental and clinical studies (Varvarigou 1996; Van Overmeire 1997) have shown that ibuprofen is effective in closing PDA without reducing cerebral flow (Patel 2000; Mosca 1997) or affecting intestinal (Speziale 1999), or renal circulation (Pezzati 1999). Furthermore, ibuprofen enhances cerebral blood flow auto regulation (Chemtob 1990) and has been shown to protect neurological functions following an oxidative stress in a piglet model (Chemtob 1993). Trials reporting on the prophylactic use of ibuprofen in preterm neonates have been published over the years justifying the need for a Cochrane review.
This review aims to examine the role of prophylactic use of ibuprofen for the prevention of PDA in preterm infants by comparing it to indomethacin or other cyclo-oxygenase inhibitors.
Primary objectives
1. To determine the effectiveness and safety of ibuprofen compared to
placebo or no intervention in the prevention of PDA in preterm and/or low
birth weight infants.
2. To determine the effectiveness and safety of ibuprofen compared to
other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc)
in the prevention of PDA in preterm and/or low birth weight infants.
3. To compare the effectiveness of prophylactic ibuprofen versus rescue treatment with ibuprofen.
Secondary objectives
To determine in subgroup analyses the effectiveness and safety of
prophylactic ibuprofen to close a PDA in relation to the following criteria;
Dose of ibuprofen used,
Gestational age (< 28 weeks, 28 - 32 weeks, 33 - 37 weeks) or birth
weight (< 1000 gms, 1000 - 1500 gms, > 1500 - < 2500 gms),
Method used to diagnose a PDA (only by clinical criteria or by echocardiography criteria).
Prophylactic use of ibuprofen for prevention of PDA compared to control infants who received no intervention, placebo, other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) or rescue treatment with ibuprofen.
Primary outcome
The presence of patent ductus arteriosus (clinically symptomatic or diagnosed by ECHO in response to clinical suspicion or diagnosed on routine screening by ECHO) by 72 hours (three days) of age
Secondary outcomes
Neonatal mortality (death during the first 28 days of life)
All cause mortality during initial hospital stay
Mortality before 36 weeks after conception
Infant mortality (death during the first year of life)
Need for rescue treatment with cyclo-oxygenase inhibitors for closure of PDA
Need for surgical closure of PDA
Duration of ventilator support
Oxygen requirement (postnatal age at time of last day with need for supplemental oxygen)
Chronic lung disease (defined as oxygen requirements at 28 days postnatal
age in addition to compatible clinical and roentgenographic findings)
Chronic lung disease [defined as oxygen requirements at 36 weeks corrected
gestational age (CGA) in addition to compatible clinical and roentgenographic
findings]
Pneumothorax
Pulmonary hypertension
Intraventricular haemorrhage (Grade III,IV) (Papile 1978)
PVL
Necrotizing enterocolitis (NEC) (any stage) (Bell 1978)
Gastrointestinal hemorrhage
Gastrointestinal perforation (defined by presence of free air in peritoneal cavity on an abdominal x-ray)
Time to full enteral feeds (postnatal age at time of achieving full enteral feeds)
Urine output after treatment (ml/kg/hr)
Renal complications [decreased urine output defined as < 1 cc/kg/hr (oliguria)]
Serum creatinine levels after treatment
Retinopathy of prematurity (ROP) (according to the international classification of ROP) (ICROP 1984)
Definite sepsis (clinical symptoms and signs of sepsis and a positive
bacterial culture in a specimen obtained from normally sterile fluids or
tissue obtained at autopsy)
Probable sepsis (clinical symptoms and signs of sepsis and an abnormal findings on a laboratory screening test for infection)
At least one episode of severe hypoxemia
Nitric oxide during first week of life
Neurodevelopmental outcome (neurodevelopmental outcome assessed by a
standardized and validated assessment tool and/or a child developmental specialist)
at any age (outcome data will be grouped at 12, 18, 24 months if available)
Duration of hospitalization (total length of hospitalization from birth to discharge home or death)
Side effects not listed as an outcome above but reported by the authors as a side effect
See: Cochrane Neonatal Review Group search strategy.
MEDLINE database (1966 - July 2005) was searched using MeSH terms: cyclo-oxygenase inhibitors, ibuprofen or mefenamic acid, newborn, infant, premature (or preterm) or low birth weight infant, patent ductus arteriosus or PDA. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), EMBASE (1980 - July 2005) and CINAHL (1982 - July 2005), abstracts (American Pediatric Society and European Society for Pediatric Research annual meetings) published in Pediatric Research (1990 - April Issue 2005) were searched. No new trials since the first publication of this review were identified in the searches undertaken in October 2004 (latest update of this review) but one trial previously published as an abstract (Van Overmeire 2004) and one trial previously published as a letter to the editors (Gournay 2004) were identified as full publications in November 2004 when published in the Lancet. The reference lists of identified trials were searched. References lists of published narrative and systematic reviews were reviewed. Unpublished data were not sought, but authors of published trials were contacted to clarify or provide additional information. No language restrictions were applied. The retrieved articles were screened by two review authors (SS, AO) to identify articles eligible for inclusion in the review. No language restrictions were applied
The standardized review methods of the Cochrane Neonatal Review Group (CNRG) were used to assess the methodological quality of the studies.
All abstracts and published full reports identified as potentially relevant by the literature search were assessed for the inclusion in the review by the two authors. Each author extracted data separately on to pre designed data abstraction forms, then compared and resolved differences. One reviewer (AO) entered the data into RevMan 4.2 and the other (SS) cross checked the printout against his own data abstraction forms and errors were corrected by consensus. The current update was conducted by one reviewer (AO).
Quality of included trials were evaluated independently by the review authors, 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 review authors. Independent quality assessments were conducted by the two review authors, who were not blinded to authors, institution or journal of publication.
The statistical analyses followed the recommendations of the Cochrane Neonatal Group. A weighted treatment effect was calculated using the RevMan 4.2 package. The treatment effect estimates included typical relative risk (RR), typical risk difference (RD), number needed to treat (NNT) or number needed to harm (NNH) for dichotomous outcomes, and weighted mean difference (WMD) for continuous outcomes. All estimates of treatment effects were reported with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including I2 were performed to assess the appropriateness of pooling the data. Planned subgroup analyses were performed according to the criteria listed under objectives. No sensitivity analyses were performed.
Four studies comparing prophylactic ibuprofen with placebo or no medications qualified for inclusion in this review (Van Overmeire 2004; Dani 2000; De Carolis 2000; Gournay 2004). All have been published as full text articles. Rubaltelli published an abstract in 1998 which reported an interim analysis of Dani 2000. The dose and duration of prophylactic ibuprofen was similar in all the studies, but the age of commencement of ibuprofen varied from two to 24 hours in the different studies. PDA at 72 hours was diagnosed as a study outcome using echocardiographic criteria in all studies. Echocardiographic criteria of a significant PDA were similar between the studies. Backup medical treatment with cyclo-oxygenase inhibitors (indomethacin or ibuprofen) was permitted in the presence of significant PDA (after initial trial of ibuprofen, placebo or no medication) in all trials (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004). Further details can be found in "Table of included studies."
Van Overmeire 2004 - In this multicenter trial 415 preterm infants < 31 weeks of gestation were randomized to receive either three doses of intravenous ibuprofen lysine (10 mg/kg followed by 5 mg/kg after 24 and 48 hours interval) or saline (1 ml/kg as initial dose, 0.5 ml/kg as subsequent doses). The initial dose of medication was given within six hours after birth and subsequent doses were given at 24 and 48 hours interval after the initial dose. Two hundred five infants received ibuprofen (10 mg/ml) while 210 received saline. Cerebral and cardiac ultrasound were performed before and after treatment. The trial was conducted double blind. Perinatal characteristics and possible side-effects were registered. The primary outcome variable was IVH grade 3 or 4. Secondary outcomes included: echocardiographically confirmed PDA after day three of life and the need for its pharmacological rescue treatment or surgical ligation, occurrence of renal dysfunction measured by urine production, NEC and death.
Dani 2000 - This trial enrolled 80 preterm neonates with gestational age < 34 weeks with RDS requiring either continuous positive airway pressure (CPAP) with fractional inspired oxygen concentration (FiO2) > 30% or mechanical ventilation (synchronized intermittent mandatory ventilation or high frequency ventilation). The infants were randomized to receive intravenous ibuprofen lysine (10 mg/kg, followed by 5 mg/kg after 24 and 48 hours) either within 24 hours of life (prophylactic) or after echocardiographic diagnosis of PDA (selective). When PDA was still present after the first course of ibuprofen, a second course was administered. Failure to respond to ibuprofen was an indication for surgical ligation. Primary outcome was incidence of significant PDA as determined by echocardiographic analysis. Echocardiographic evaluation was performed on day 3, 7 and 21 of life. Other studied variables were ventilatory support, renal function, biochemical and hematological profiles, frequency of CLD at 36 weeks CGA, IVH, NEC, ROP and time to reach full feeds.
De Carolis 2000 - The trial enrolled 50 preterm neonates with gestational age < 31 weeks. The infants were randomly assigned at two hours of age to prophylaxis group or control group. Two infants in each group died during the first 24 hours after birth and were not included by the authors in the final analysis. The prophylaxis group (n = 23) received intravenous (i.v.) treatment with ibuprofen lysine (10 mg/kg) followed by 5 mg/kg after 24 and 48 hours. No placebo was given to the control group (n = 23). In the presence of a significant PDA at the completion of the ibuprofen cycle, treatment with indomethacin (3 times 0.2 mg/kg at 12 hourly intervals, administered by i.v. infusion over 20 minutes) was carried out. The same treatment was administered to infants in the control group who had a significant PDA on day three of life. Failure to respond to medical treatment was an indication for surgical treatment. Primary outcome was incidence of significant PDA as determined by echocardiographic analysis. Echocardiographic evaluation was performed immediately after birth, on day three of life and whenever there was a clinical suspicion of PDA. Other studied variables were ventilatory support, renal function, biochemical and hematological profiles, need for surgical ligation for PDA, frequency of CLD at 28 days, IVH, NEC, ROP and time to reach full feeds.
Gournay 2004 - This multicenter trial enrolled 135 infants < 28 weeks and postnatal age < 6 hours. The infants were randomly assigned to prophylactic ibuprofen or placebo group, both of which were given as three successive doses 24 hours apart. The initial dose of ibuprofen was 10 mg/kg, and the two following doses were 5 mg/kg, infused intravenously over 20 minutes. The primary outcome was need for surgical ligation. Other outcomes included: mortality, PDA on day three by echocardiogram, need of back-up treatment with indomethacin, PVL, grade III or IV IVH, NEC, intestinal perforation, duration of mechanical ventilation, BPD at 36 weeks corrected GA, renal function, actuarial curve of survival during the study period. Occurrence of pulmonary hypertension within one hour of administration of ibuprofen was reported in three infants < 27 weeks and < 1000 g. The trial was stopped prematurely after enrolment of 135 infants due to this adverse effect.
Van Overmeire 2004 - Multicentre randomized controlled trial involving seven centres in Belgium. Randomization was done independently by the chief pharmacist at each hospital. The trial was conducted double blind and saline was used as placebo. Follow-up was complete and outcomes were reported for all infants enrolled in the study. An intention to treat analysis was performed. The study was published as an abstract when 358 infants had been enrolled. There is no mentioning of this interim analysis in the final publication.
Dani 2000 - This was a randomized controlled trial involving two centres in Italy. Randomization was performed using sealed envelopes. There was no blinding of intervention or assessment. Follow up was complete and outcomes were reported for all infants enrolled in the study. An intention to treat analysis was performed.
De Carolis 2000 - This was a randomized controlled trial involving a single centre in Italy. Method of randomization is unclear. We quote the authors. "Randomization was carried out at birth by random permuted blocks for both prophylaxis and control groups, envisaging 25 neonates in each". There was no blinding of the intervention. There was blinding of outcome measurement. An intention to treat analysis was not performed.
Gournay 2004 - This was a multicenter, randomized double blind, placebo-controlled trial conducted in 11 tertiary neonatal intensive care centres in France. The allocation was concealed. One hundred thirty five infants were included. However, four patients were not randomly assigned because of errors in study drug allocation (three mistakenly received open-label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10-day-old patient diagnosed with PDA was mistakenly given two doses of the randomised test drug (placebo) instead of curative ibuprofen. The per protocol analyses were performed on 131 infants. No patient was lost to follow-up. The trial was closed earlier than planned after three episodes of refractory hypoxemia with pulmonary hypertension happened after the first prophylactic injection in three different centres. The Agence Francaise du Medicament was notified and requested un blinding of the treatment received in these three cases. The treatment was ibuprofen in all three cases and the recruitment was closed on December 14, 2001. This study was industry sponsored. The sponsor of the study was involved in study design, data management, data analysis, and data interpretation; it had no role in writing the report or the decision to submit it for publication. All final data analyses were done by the sponsor and double checked by the first author who had free access to the raw data.
Primary outcome
The presence of patent ductus arteriosus (clinically symptomatic or diagnosed by ECHO in response to clinical suspicion or diagnosed on routine screening by ECHO) by 72 hours (three days) of age:
This was reported in all four trials (n = 672) (Van Overmeire 2004; Dani 2000; De Carolis 2000; Gournay 2004). Each of the trials noted a statistically significant decrease in the incidence of PDA on day three in the group receiving prophylactic ibuprofen. In the meta-analysis, there was a statistically significant decrease in the incidence of PDA on day three in the prophylactic ibuprofen group as compared to placebo group. The typical estimates were RR 0.37 (95% CI 0.29, 0.49); RD -0.29 (95% CI -0.35, -0.22; NNT 3 (95% CI 3, 5). There was no statistically significant between study heterogeneity for this outcome (p = 0.13; I2 47.4%). In subgroup analyses for the study by Van Overmeire (Van Overmeire 2004) for the gestational age group </= 28 weeks (n = 265) the RR was 0.45 (95% CI 0.30, 0.67); RD -0.24 (95% CI -0.35, -0.14); NNT 4 (95% CI 3, 7). For the gestational age group 29-30 weeks (n = 150) the RR was 0.29 (95% CI 0.13, 0.64); RD -0.23 (95% CI -0.35, -0.10); NNT 4 (95% CI 3, 10). For the birth weight group </= 1000 g (n = 196) the RR was 0.37 (95% CI 0.23, 0.61); RD -0.28 (95% CI -0.40, -0.16); NNT 4 (95% CI 3, 6). For the birth weight group 1001 - 1500 g (n = 185) the RR was 0.47 (95% CI 0.27, 0.81); RD -0.18 (95% CI -0.30, -0.06): NNT 6 (95% CI 3, 17). All secondary analyses were statistically significant.
Secondary outcomes
Neonatal mortality (at < 28 days of age):
Mortality at < 28 days was reported in two trials (n = 130) (Dani 2000; De Carolis 2000).
There was no statistically significant difference in the mortality between
the groups in either trial. In the meta-analysis there was no statistically
significant difference in the mortality between the two groups. The typical
estimates were RR 1.00 (95% CI 0.34, 2.98), RD 0.00 (95% CI -0.09, 0.09).
All cause mortality during initial hospital stay:
This was reported in three trials (n = 545) (Van Overmeire 2004; Dani 2000; De Carolis 2000).
None of the trials found a significant difference in the mortality between
the groups. In the meta-analysis there was no statistically significant difference
in the incidence of mortality. The typical estimates were RR 0.99 (95% CI
0.61, 1.58), RD 0.00 (95% CI -0.05, 0.05).
Mortality before 36 weeks after conception:
This was reported in one trial (n = 131) (Gournay 2004).
The relative risk was 0.96 (95% CI 0.56, 1.66) and the RD was -0.01 (95%
CI -0.17, 0.14), neither of which were statistically significant.
Infant mortality (death during the first year of life);
This outcome was not reported by any of the authors.
Need for rescue treatment with cyclo-oxygenase inhibitors for closure of PDA:
This outcome was reported in all four trials (n = 672) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004)
and each trial found a statistically significantly reduced need for rescue
medical treatment in the prophylaxis group. Dani et al (Dani 2000) used ibuprofen for rescue treatment and De Carolis et al (De Carolis 2000) used indomethacin for rescue treatment. Van Overmeire et al (Van Overmeire 2004) used either indomethacin or ibuprofen. Gournay et al (Gournay 2004)
initiated rescue treatment with ibuprofen and if this failed used indomethacin.
In the meta-analysis, there was decreased need for rescue medical treatment
in the group receiving prophylactic ibuprofen. The typical estimates were
RR 0.17 (95% CI 0.11, 0.27), RD -0.27 (95% CI -0.33, -0.22); NNT 4 (95%CI
3, 5). There was statistically significant between study heterogeneity for
this outcome (p = 0.04; I2 = 64.0%).
Need for surgical closure of PDA
This outcome was reported in all four trails (n =672) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004)
and all trials found no significant difference between the groups. In the
meta-analysis there was no statistically significant difference in the need
for surgical ligation between the two groups. The typical estimates from
the meta-analysis were RR 0.34 (95% CI 0.14, 0.81), RD -0.04 (95% CI -0.07,
-0.01).and NNT 25 (95% CI 14, 100).
Duration of mechanical ventilation (days):
Duration of mechanical ventilation was reported in two trials (n = 211) (Dani 2000; Gournay 2004)
and there was no statistically significant difference between the groups
in either trial. The typical WMD was -0.46 days (95% CI -5.19, 4.26). Van
Overmeire (n = 415) (Van Overmeire 2004)
also reported on this outcome but as medians and inter-quartile ranges. For
the ibuprofen group the results were four (2 - 10) days and in the placebo
group four (1 - 8) days; p = 0.49.
Oxygen requirement (postnatal age at time of last day with need for supplemental oxygen):
No study reported on this outcome. Van Overmeire (n = 415) (Van Overmeire 2004)
reported (in medians and inter-quartile ranges) on days on supplemental oxygen.
The results were for the ibuprofen group 25 (6 - 52) days and for the placebo
group 24 (6 - 44)days; p = 0.36.
Chronic lung disease among survivors (defined as oxygen requirements
at 28 days postnatal age in addition to compatible clinical and roentgenographic
findings):
This outcome was reported in one trial (n = 41) (De Carolis 2000).
There was no statistically significant difference in the incidence of CLD
between the groups. The estimates were RR 0.88 (95% CI 0.32, 2.42), RD -0.04
(95% CI -0.31, 0.24).
Chronic lung disease [defined as oxygen requirements at 36 weeks
corrected gestational age (CGA) in addition to compatible clinical and roentgenographic
findings]:
CLD at 36 weeks CGA was reported in three trials (Dani 2000; Gournay 2004; Van Overmeire 2004).
There was no statistically significant difference between the groups in the
individual trials. The typical estimates were RR 1.10 (95% CI 0.91, 1.33),
RD 0.04 (95% CI -0.03, 0.11).
Pneumothorax:
No trial reported on this outcome.
Pulmonary hypertension:
Pulmonary hypertension was reported in one trial (n = 131) (Gournay 2004).
Three infants in the ibuprofen group (n = 65) developed pulmonary hypertension
within one hour of administration of the drug which was responsive to nitric
oxide, as compared to none of the infants in placebo group (n = 66). The
estimates were RR 7.11 (95% CI 0.37, 134.91), RD 0.05 (95% CI -0.01, 0.10).
Intraventricular haemorrhage (Grade III, IV) (Papile 1978):
IVH grade 3 or 4 was reported in all four trials (n = 672) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004).
There was no significant difference in the incidence of IVH between the groups
in any of the trials. In the meta-analysis there was no statistically significant
difference in the incidence of grade 3 or 4 IVH between the two groups. The
typical estimates from the meta-analysis were RR 0.78 (95% CI 0.48, 1.26),
RD -0.02 (95% CI -0.06, 0.02).
PVL:
PVL was reported in three trials (n = 592) (De Carolis 2000; Gournay 2004; Van Overmeire 2004)
and there was no statistically significant difference in the incidence of
PVL between the groups in the individual trials. The typical estimates were
RR 1.31 (95% CI 0.67, 2.57), RD 0.01 (95% CI -0.02, 0.05).
Necrotizing enterocolitis (NEC) (any stage) (Bell 1978):
This was reported in all four trials (n = 672) (Dani 2000; De Carolis 2000; Gournay 2004; Van Overmeire 2004) and one of the trials (Gournay 2004)
found a significant difference in the incidence of NEC between the groups.
In the meta-analysis there was no statistically significant difference in
the incidence of NEC. The typical estimates were RR 1.02 (95% CI 0.53, 1.94),
RD 0.00 (95% CI -0.03, 0.03). There was statistically significant between
study heterogeneity for this outcome (p = 0.03; I2 = 72.9%).
Gastrointestinal hemorrhage:
This outcome was reported in one trial (n = 80) (Dani 2000)
and there was no statistically significant difference between the groups.
The estimates were RR 3.00 (95% CI 0.13, 71.51), RD 0.03 (95% CI -0.04, 0.09).
Gastrointestinal perforation (defined by presence of free air in peritoneal cavity on an abdominal x-ray):
This outcome was reported in one trial (n = 131) (Gournay 2004)
and there was no statistically significant difference between the groups.
The relative risk was 5.08 (95% CI 0.61, 42.28) and the RD was 0.06 (95%
CI -0.01, 0.13).
Time to reach full enteral feeds (days):
This was reported in one trial (Dani 2000)
and there was no statistically significant difference between the groups.
The estimates were WMD -0.30 days (95% CI -4.47, 3.87).
Urine output after treatment (ml/kg/hr):
Urine output after treatment was reported in two trials (n = 495) (Dani 2000; Van Overmeire 2004)
and there was no statistically significant difference between the groups
in the individual trials. The the typical WMD was -0.07 mL/kg/hr (95% CI
-0.32, 0.17). De Carolis et al (De Carolis 2000)
reported urine output on day three as median (range) in the ibuprofen group
3.3 (1.3-4.6) ml/kg/hr and in the control group 2.3 (1.1-4.9) ml/kg/hr.
Renal complications [decreased urine output defined as < 1 cc/kg/hr (oliguria)]:
One study (n = 131) (Gournay 2004) reported on this outcome. The RR was 1.08 (95% CI 0.59, 2.00) and the RD was 0.02 (95% CI -0.13, 0.16). One study (n = 415) Van Overmeire 2004
reported on oliguria defined as < 0.5 ml/kg/hour. The statistically significant
RR was 1.54 (95% CI 1.01, 2.34) and the RD (of borderline statistical significance)
was 0.08 (95% CI 0.00, 0.15). Combining the two studies (n = 546) the typical
RR was 1.38 (95% CI 0.98, 1.96) and the typical RD was 0.06 (95% CI 0.00.
0.13) (both estimates were of borderline statistical significance).
Serum creatinine levels (mg/dL):
Serum creatinine levels after treatment were reported in two trials (n = 495) (Van Overmeire 2004; Dani 2000). In the trial by Van Overmeire et al (Van Overmeire 2004)
there was a significant increase in the serum creatinine levels on day three
of life in the group receiving prophylactic ibuprofen as compared to the
placebo group. In the other trial (Dani 2000),
there was no significant difference in the serum creatinine levels between
the groups. In the meta-analysis, there was a statistically significant increase
in the serum creatinine levels on day three in the group receiving ibuprofen
as compared to the group receiving placebo. The typical estimate was WMD
0.13 mg/dL (95% CI 0.08, 0.17). There was significant between study heterogeneity
(p = 0.02) I2 = 80.4%. De Carolis et al (De Carolis 2000)
reported serum creatinine levels on day three as median (range) in the ibuprofen
group 1.3 (0.8-1.7) mg/dl and in the control group 1.2 (0.8-1.5) mg/dl. Gournay
(Gournay 2004) reported on "at least one episode
of serum creatinine > 140 micromol/L (1.6 mg/dl) (This outcome was not
included in our protocol). The RR was 1.44 (95% CI 1.00, 2.08); RD 0.18 (95%
CI 0.01, 0.34); Number needed to harm (NTH) was 6 (95% CI 3, 100).
Retinopathy of prematurity (ROP) (according to the international classification of ROP) (ICROP 1984):
ROP was reported in one trial (Dani 2000)
and there was no statistically significant difference between the groups.
The estimates were RR 0.77 (95% CI 0.38, 1.55), RD -0.08 (95% CI -0.27, 0.12).
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):
The incidence of sepsis was reported in one trial (n = 46) (De Carolis 2000)
and there was no statistically significant difference between the groups.
The estimates were RR 1.00 (95% CI 0.07, 15.04), RD 0.00 (95% CI -0.12, 0.12).
Probable sepsis (clinical symptoms and signs of sepsis and an abnormal findings on a laboratory screening test for infection):
This outcome was not reported.
At least one episode of severe hypoxemia:
One trial reported on this outcome (n = 131) (Gournay 2004). The RR was 1.69 (95% CI 0.80, 3.59); RD 0.09 (95% CI -0.04, 0.23).
Nitric oxide use during first week of life:
This outcome was reported in one study (n = 131) (Gournay 2004). The RR was 1.89 (95% CI 0.80, 4.42) and the RD 0.09 (95% CI -0.03, 0.22) (neither reached statistical significance).
Neurodevelopmental outcome (neurodevelopmental outcome assessed by
a standardized and validated assessment tool and/or a child developmental
specialist) at any age (outcome data will be grouped at 12, 18, 24 months
if available):
No data were available for long term neurodevelopment outcome.
Duration of hospitalization (total length of hospitalization from birth to discharge home or death):
This was reported in one trial (n = 80) (Dani 2000)
and there was no statistically significant difference between the groups.
The estimates were WMD -3.50 days (95% CI -15.55, 8.55).
Side effects not listed as an outcome above but reported by the authors as a side effect:
Reported side effects are all included under the specific headings above.
Subgroup analyses specified a priori could not be performed for the following reasons
1. Dose of ibuprofen used was the same in all the studies.
2. Echocardiographic criteria were used to diagnose PDA in all the studies.
3. Demographic and outcome data were available separately for the different birth weight or GA categories in one study (Van Overmeire 2004)
but did not completely correspond to our preset cut off points. However as
they were close we included them as subgroup analyses under the outcome of
"The presence of patent ductus arteriosus (clinically symptomatic or diagnosed
by ECHO in response to clinical suspicion or diagnosed on routine screening
by ECHO) by 72 hours (3 days) of age" (see above).
We were not able to identify any randomized controlled trials on the use of mefenamic acid for the prevention of PDA.
This review demonstrated that prophylactic ibuprofen is effective in reducing the incidence of PDA on day three, reducing the need for rescue treatment with cyclo-oxygenase inhibitors and reducing the need for surgical ligation of a PDA. There was statistically significant between study heterogeneity for the outcomes; need for rescue treatment with cyclo-oxygenase inhibitors, NEC and serum creatinine levels after treatment but for no other outcomes. This review did not find evidence of a statistically significant difference in mortality, duration of hospitalization, CLD at 28 days or 36 weeks CGA, duration of mechanical ventilation, IVH, PVL, NEC, GI hemorrhage, intestinal perforation, time to reach full enteral feeds, ROP, or sepsis between ibuprofen and placebo groups. There was a statistically significant increase in the serum creatinine levels on day three of treatment in the prophylactic ibuprofen group as compared to the placebo group. The occurrence of oliguria reached borderline statistical significance. One trial (Gournay 2004) reported the occurrence of pulmonary hypertension within one hour of administration of ibuprofen to 3 infants < 27 weeks and < 1000 g. The trial was stopped prematurely after enrolment of 135 infants due to this adverse effect. The authors postulated that this could be due to early administration of ibuprofen (< 6 hours) preventing the normal fall in pulmonary vascular resistance, acidification of their ibuprofen solution (buffered with tromethamine) causing precipitation and micro embolism in the lungs, or due to a specific effect of ibuprofen. This adverse effect has not been reported in other trials included in this review nor in the trials using ibuprofen for treatment of PDA (Van Overmeire 2000; Lago 2002; Mosca 2002). Gournay et al (Gournay 2004) concluded that prophylactic ibuprofen should not be preferred to early curative ibuprofen.
In the current review, there was a statistically significant increase
in the need for rescue treatment with cyclo-oxygenase inhibitors (indomethacin
or ibuprofen) in the placebo group as compared to prophylactic ibuprofen
group. This is an expected event and reflects common clinical practice in
the neonatal intensive care units for the management of a symptomatic PDA.
In the study by Dani et al (Dani 2000), the infants
were randomized to prophylactic ibuprofen or rescue group. In this respect
the trial was different from rest of the trials which randomized infants
to prophylactic ibuprofen or placebo group. However, the back-up management
protocol in the other three studies (De Carolis 2000; Gournay 2004; Van Overmeire 2004) and the rescue protocol in the study by Dani et al (Dani 2000)
were similar in that each was based on detection of significant PDA by echocardiography
performed at regular predetermined intervals. Hence, for practical purposes,
we considered the rescue ibuprofen group in the study by Dani et al (Dani 2000) to be comparable to the placebo group in other studies as far as management of PDA is concerned.
We did not find any trials comparing prophylactic ibuprofen with prophylactic indomethacin. Prophylactic indomethacin (Fowlie 2002)
has been shown to reduce need for surgical ligation of PDA and grade 3 and
4 IVH. In that review there was no significant effect on the long term neurodevelopmental
outcomes. It is of note that ibuprofen does not impact on IVH. It is presently
unknown whether preventing IVH with the use of indomethacin is preferable
to preventing ischemias with the use of ibuprofen.
In the present up-date of our review prophylactic ibuprofen was effective in reducing the incidence of PDA, the need for rescue treatment with cyclo-oxygenase inhibitors and the need for surgical ligation, but did not confer any substantial clinical advantages in the short term. Ibuprofen prophylaxis has a negative effect on kidney function. As 60% of the infants in the control group had closed the duct by three days of life a large proportion of neonates would be exposed to ibuprofen unnecessarily if used as prophylaxis. There are still no long term neurodevelopmental follow-up studies available.
Recently Coceani et al ( Coceani 2005) proposed that "... an mPGES (membrane bound prostaglandin E synthase) inhibitor, once developed for therapeutic use, could become the agent of choice for PDA treatment, particularly in those instances in which prematurity is complicated by infectious or inflammatory conditions" (Coceani 2005).
Prophylactic use of ibuprofen reduces the incidence of PDA, the need for rescue treatment with cyclo-oxygenase inhibitors and surgical closure. However, in the control group the PDA had closed spontaneously by day three in 60% of the neonates. Prophylactic treatment exposes a large proportion of infants unnecessarily to a drug that has important side effects without conferring any important short term benefit on outcomes .There was a significant increase in the serum creatinine levels in the ibuprofen group. There were no statistically significant differences in mortality, grade 3 or 4 IVH, CLD at 28 days or 36 weeks, NEC, GI hemorrhage or time to reach full feeds. Urine output is decreased following prophylactic use of ibuprofen. The prophylactic use of ibuprofen has been associated with severe pulmonary hypertension . Current evidence does not support the use of ibuprofen for prophylaxis of PDA.
Until long-term follow-up results are published from the trials included in this review no further trials of prophylactic ibuprofen are recommended.
We are thankful to Dr Dani and Dr Rubaltelli for providing additional information about their trials.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Dani 2000 | Two-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 period not stated. 2 centres, Italy Inclusion criteria: Enrolled within first 24 hours after birth. Demographic data: Prophylactic ibuprofen group Rescue ibuprofen group | Group
A (prophylactic ibuprofen group; n = 40) received intravenous ibuprofen lysine
(Arfen, Lisa-pharma, Italy) 10 mg/kg, within first 24 hours of life, followed
by 5 mg/kg after 24 and 48 hours. Group B (rescue ibuprofen group; n = 40) received the same pharmacological treatment after echocardiographic diagnosis of PDA. When significant PDA was still present after the first course of ibuprofen, a second course was administered. Failure to respond to ibuprofen was an indication for surgical ligation. | Echocardiographic diagnosis (Toshiba, Sonolayer SSH 140A with 7.5 MHz transducer) of PDA on day 3, 7 and 21 of life. A diagnosis of significant PDA was made by echocardiographic demonstration of a ductal left to right shunt, with left atrial to aortic root ratio > 1.3 or a ductal size > 1.5 mm.
| Patients enrolled in this study are the same as in the abstract of Rubaltelli 1998. This information was provided by Dr Dani and Dr Rubaltelli. | A |
| De Carolis 2000 | 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) - yes for the primary outcome | Fifty
infants < 2 hours of age and with GA < 31 weeks. Two infants in each
group died within 24 hours after birth and were not considered in the final
analysis. Single centre study, Italy. April 1, 1996 - July 30 th 1997 Assignment was performed within 2 hours after birth. Prophylaxis group Control group | 25
neonates received 10 mg ibuprofen lysine/kg i.v. over 20 minutes within 2
hrs of life, and 5 mg/kg of ibuprofen lysine at 24 and 48 hrs of life. 25 neonates received no placebo/control treatment. Two neonates in each group died within 24 hours of life and were not considered in the final evaluation In the presence of significant PDA at the completion of ibuprofen cycle, treatment with indomethacin (three times 0.2 mg/kg at 12 hourly interval, administered by i.v. infusion over 20 minutes was carried out. The same treatment was administered to control neonates having significant PDA on 3rd day of life. Failure to respond to medical treatment was an indication for surgical ligation. | PDA at 72 hours of age, need for treatment with indomethacin
after 72 hours, surgical ligation, time to full oral feeds, mortality to
28 days of age, CLD at 28 days of age among survivors, sepsis. In addition
a number of outcomes during the first 3 days of life were reported as median
and range and not as mean and SD. Echocardiographic evaluation (Esaote
Biomedica SPR 8000 ultrasound imaging system, using 5 MHz probe incorporating
pulsed and colour-flow | "Randomization
was carried out at birth by random permuted blocks for both prophylaxis and
control groups, envisaging 25 neonates in each." No further information is
provided regarding the randomization and allocation process. Out of the 50 randomized infants, 2 in each group died in the first 24 hours following birth and were not considered in the final analyses by the authors, but were included by us in the analyses reported in this review. | B |
| Gournay 2004 | Randomized , double blinded, controlled trial. I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow up - No (see notes) IV. Blinding of outcome measurement (s): yes | Study period: March 2001 - Dec 2001 Multicentre trial in 11 NICUs in France Inclusion criteria: 1. GA < 28 weeks 2. Postnatal age < 6 hours Exclusion criteria: 1. Congenital malformations 2. Shock or right to left ductal shunt evidenced by differential cyanosis 3. Cerebral complications 4. Bleeding disorders Demographic data: values presented as mean ± SD Prophylaxis group Placebo group | One
hundred and thirty five infants were enrolled in the trial and 131 were randomized
to receive either ibuprofen (n = 65) or placebo (n = 66). Both ibuprofen or placebo were given as 3 doses, 24 hours apart with the first dose being given within first 6 hours of life. The initial dose of ibuprofen was 10 mg/kg and the 2 following doses were 5 mg/kg, infused i.v. continuously over 20 minutes. | Decreased need for surgical ligation based on the presence of a significant PDA on echocardiogram Mortality PDA on day 3 by echocardiogram Need of back-up treatment with indomethacin PVL Grade III or IV IVH NEC Intestinal perforation Duration of mechanical ventilation BPD at 36 weeks corrected GA Renal function Actuarial curve of survival during the study period | 135 infants were included. However, four patients were not randomly assigned because of errors in study drug allocation (3 mistakenly received open-label ibuprofen prepared for the curative part of the study during their prophylactic course, and one 10-day-old patient diagnosed with PDA was mistakenly given 2 doses of the randomised test drug (placebo) instead of curative ibuprofen. The per protocol analyses were performed on 131 infants. No patient was lost to follow-up. The trial was closed earlier than planned after 3 episodes of refractory hypoxemia with pulmonary hypertension happened after the first prophylactic injection in three different centres. The Agence Francaise du Medicament was notified and requested un blinding of the treatment received in these 3 cases. The treatment was ibuprofen in all three cases and the recruitment was closed on December 14, 2001. The study was supported by the industry (Orphan Europe, Paris, France). | A |
| Van Overmeire 2004 | Seven-centre, randomized, double blinded, controlled trial I. Blinding of randomization - Yes II. Blinding of intervention - Yes III. Blinding of outcome measurement (s) - Yes IV. Complete follow-up - Yes | Study period: February 1, 1999 - September 30, 2001 7 centres, Belgium Inclusion criteria: gestational age 24-30 weeks Exclusion criteria: Major congenital malformation or chromosomal anomaly, intraventricular hemorrhage higher than grade 1 already detected during baseline cranial ultrasonography, an Apgar score at 5 minutes less than 5, signs of congenital infection or life-threatening septicemia, uncontrolled hypotension, contraindications for administration of ibuprofen. Demographic data: values presented as mean ± SD or as number (percentage) Prophylaxis group Placebo group | 205 infants received ibuprofen and 210 infants received placebo (saline). First dose of medication was given within 6 hours of birth and 2nd and 3rd doses were given at 24 hours and 48 hours after the first dose. The dose of ibuprofen used was 10 mg/kg for first dose and 5 mg/kg for subsequent doses. The dose of saline was 1 ml/kg for first dose and 0.5 ml/kg for subsequent doses. | The
primary outcome variable was IVH grade 3 or 4. Secondary outcomes included:
echocardiographically confirmed PDA after day three of life and the need
for its pharmacological rescue treatment or surgical ligation, occurrence
of renal dysfunction measured by urine production, NEC and death. | The
study was published as an abstract when 358 infants had been enrolled. There
is no mentioning of this interim analysis in the final publication. | A |
* Dani C, Bertini G, Reali MF, Murru P, Fabris C, Vangi V, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatrica 2000;89:1369-74.
Rubaltelli FF, Bertini G, Reali MF, Vangi V, Dani C. Does early closure of PDA with ibuprofen reduce the severity of RDS in premature infants? Pediatric Research 1998;43:296A.
De Carolis 2000 {published data only}
De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. European Journal of Pediatrics 2000;159:364-8.
Gournay 2004 {published data only}
* Gournay V, Roze JC, Daoud P et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1939-44.
Gournay V, Savagner C, Thirez G, Kuster A, Roze JC. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002;359:1486-8.
Van Overmeire 2004 {published data only}
Naulaers G, Delanghe G, Allegaert K et al. Ibuprofen and cerebral oxygenation and circulation. Archives of Disease in Childhood Fetal Neonatal Edition 2005;90:F75-6.
* Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwe W, Jespers A et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2004;364:1945-9.
Van Overmeire, Casaer A, Allegaert K, Debauche C, Decaluwe W, Jespers A. Multicenter ibuprofen prophylaxis study (MIPS) in preterm infants: preliminary data. Pediatric Research 2002;52:825.
* indicates the primary reference for the study
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| Comparison or outcome | Studies | Participants | Statistical method | Effect size |
|---|---|---|---|---|
| 01 Ibuprofen vs placebo or none | ||||
| 01 Presence of PDA on 3rd day of life (72 hours of age) | 4 | 672 | RR (fixed), 95% CI | 0.37 [0.29, 0.49] |
| 02 Neonatal mortality (during first 28 days of life) | 2 | 130 | RR (fixed), 95% CI | 1.00 [0.34, 2.98] |
| 03 Mortality during hospital stay | 3 | 545 | RR (fixed), 95% CI | 0.99 [0.61, 1.58] |
| 04 Mortality before 36 weeks after conception | 1 | 131 | RR (fixed), 95% CI | 0.96 [0.56, 1.66] |
| 05 Need for rescue medical treatment with cyclo-oxygenase inhibitors | 4 | 672 | RR (fixed), 95% CI | 0.17 [0.11, 0.27] |
| 06 Need for surgical ligation of PDA | 3 | 672 | RR (fixed), 95% CI | 0.34 [0.14, 0.81] |
| 07 Duration of mechanical ventilation (days) | 2 | 211 | WMD (fixed), 95% CI | -0.46 [-5.19, 4.26] |
| 08 CLD at 28 days of life among survivors | 1 | 41 | RR (fixed), 95% CI | 0.88 [0.32, 2.42] |
| 09 CLD at 36 weeks corrected GA | 3 | 626 | RR (fixed), 95% CI | 1.10 [0.91, 1.33] |
| 10 Pulmonary hypertension | 1 | 131 | RR (fixed), 95% CI | 7.11 [0.37, 134.91] |
| 11 IVH grade III - IV | 3 | 672 | RR (fixed), 95% CI | 0.78 [0.48, 1.26] |
| 12 PVL | 3 | 592 | RR (fixed), 95% CI | 1.31 [0.67, 2.57] |
| 13 NEC | 3 | 672 | RR (fixed), 95% CI | 1.02 [0.53, 1.94] |
| 14 Gastrointestinal hemorrhage | 1 | 80 | RR (fixed), 95% CI | 3.00 [0.13, 71.51] |
| 15 Isolated intestinal perforation | 1 | 131 | RR (fixed), 95% CI | 5.08 [0.61, 42.28] |
| 16 Time to full enteral feeds (days) | 1 | 80 | WMD (fixed), 95% CI | -0.30 [-4.47, 3.87] |
| 17 Urine output after treatment (mL/kg/hr) | 2 | 495 | WMD (fixed), 95% CI | -0.07 [-0.32, 0.17] |
| 18 Oliguria | 2 | 546 | RR (fixed), 95% CI | 1.38 [0.98, 1.96] |
| 19 Serum creatinine levels after treatment | 2 | 495 | WMD (fixed), 95% CI | 0.13 [0.08, 0.17] |
| 20 ROP | 1 | 80 | RR (fixed), 95% CI | 0.77 [0.38, 1.55] |
| 21 Sepsis | 1 | 46 | RR (fixed), 95% CI | 1.00 [0.07, 15.04] |
| 22 At least one episode of severe hypoxemia | 1 | 131 | RR (fixed), 95% CI | 1.69 [0.80, 3.59] |
| 23 Nitric oxide during first week of life | 1 | 131 | RR (fixed), 95% CI | 1.89 [0.80, 4.42] |
| 24 Length of hospital stay (days) | 1 | 80 | WMD (fixed), 95% CI | -3.50 [-15.55, 8.55] |
| 25 Presence of PDA on 3rd day of life in infants </= 28 weeks gestation at birth | 1 | 265 | RR (fixed), 95% CI | 0.45 [0.30, 0.67] |
| 26 Presence of PDA on 3rd day of life in infants 29-30 weeks gestation at birth | 1 | 150 | RR (fixed), 95% CI | 0.29 [0.13, 0.64] |
| 27 Presence of PDA on 3rd day of life in infants </= 1000 g | 1 | 196 | RR (fixed), 95% CI | 0.37 [0.23, 0.61] |
| 28 Presence of a PDA on 3rd day of life in infants 1001 - 1500 g | 1 | 185 | RR (fixed), 95% CI | 0.47 [0.27, 0.81] |
| 29 At least one episode of serum creatinine > 140 micromol/L (1.6 mg/dl) | 1 | 131 | RR (fixed), 95% CI | 8.12 [1.05, 63.13] |
| The review is published as a Cochrane review in The
Cochrane Library, Issue 1, 2006 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to comments and criticisms, and The Cochrane Library should
be consulted for the most recent version of the Review. |