Cochrane Review: Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Authors


Abstract

Background

Patent ductus arteriosus (PDA) and intraventricular haemorrhage (IVH) are both associated with increased mortality and morbidity in preterm infants. Indomethacin has been used successfully to treat symptomatic PDA and may also prevent or limit IVH in the neonatal period. There are however potential unwanted side effects of indomethacin, in particular a potential for reduced organ perfusion that might outweigh any clinical benefits. The prophylactic use of indomethacin, where infants who may not have gone on to develop a symptomatic PDA or IVH would be exposed to indomethacin, warrants particular scrutiny.

Objectives

This review examines the effectiveness of prophylactic intravenous indomethacin in reducing the mortality and morbidity associated with PDA and IVH in preterm infants.

Search strategy

An initial literature search was conducted in three computerised databases: MEDLINE; EMBASE; and the Oxford Database of Perinatal Trials in October 1994. The search was updated in February 1997 and October 2001.

Selection criteria

Strict selection criteria were applied to clinical trials: the population had to be newborn preterm infants (less than 37 completed weeks gestation); the intervention had to be prophylactic intravenous indomethacin; the trial had to be randomised and controlled; and at least one of several prespecified outcomes had to be reported in the results.

Data collection and analysis

The methodological quality of each study was assessed using explicit criteria. Data on relevant outcome measures were extracted and, where appropriate, the results of individual trials were combined using meta-analysis techniques to provide a pooled estimate of effect.

Main results

Nineteen eligible trials randomising 2872 infants were identified.

There is no evidence of difference in mortality at latest follow-up between infants receiving prophylactic indomethacin and controls, pooled relative risk (RR) = 0.96 [95% CI 0.81 to 1.12].

There is no evidence to suggest prophylactic indomethacin is associated with any reduction in long-term neurosensory impairment, ie no significant difference in rates of cognitive delay, cerebral palsy, blindness or deafness.

The incidence of symptomatic patent ductus arteriosus is significantly reduced in treated infants, pooled RR = 0.44 [0.38 to 0.50] but there is no evidence that treatment affects respiratory outcomes. Prophylactic indomethacin reduces the need for surgical PDA ligation [RR = 0.51 (0.37,0.71)].

Prophylactic indomethacin significantly reduces the incidence of Grade 3 and 4 intraventricular haemorrhage, pooled RR = 0.66 [0.53 to 0.82].

There is no evidence of difference in rates of necrotising enterocolitis, excessive clinical bleeding or sepsis. Increased incidence of oliguria is seen with prophylactic indomethacin [RR = 1.90 (1.45,2.47] but this is not associated with major renal impairment.

Authors' conclusions

Prophylactic treatment with indomethacin has a number of immediate benefits, in particular a reduction in symptomatic patent ductus arteriosus, the need for duct ligation and severe intraventricular haemorrhage. There is no evidence to suggest either benefit or harm in longer term outcomes including neurodevelopment. Depending on clinical circumstances and personal preferences, there may be a role for prophylactic indomethacin in some infants on some neonatal units.

Plain Language Summary

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants

Patent ductus arteriosus (PDA) occurs when an artery near the heart and lungs, which should close off soon after birth, stays open. Babies born too early (preterm) with PDA are at increased risk of severe illness and death. Indomethacin has been given to very small babies within 24 hours of birth to help close a PDA, at the same time reducing the risk of bleeding into the head - intraventricular hemorrhage (IVH). The review found that giving indomethacin to preterm babies reduced their risk of both PDA and IVH. Indomethacin may also reduce blood flow in some organs including the brain but this does not seem to cause any serious lasting adverse effects. However, giving prophylactic indomethacin has no effect on the development of the babies in the longer term - development is neither better nor worse than the development of babies who have not received the treatment - suggesting its use may be limited to achieving short-term benefits only.

Background

Premature infants with a patent ductus arteriosus are at increased risk of more prolonged and more severe respiratory distress syndrome, bronchopulmonary dysplasia and death when compared to similar infants whose ductuses have closed [Brown 1979]. This prompted, first, surgical intervention [Kitterman 1972] and, later, pharmacological treatment using indomethacin [Heymann 1976] in an attempt to improve the outcome in these infants. Because therapies that closed the patent ductus potentially influence the pulmonary circulation, the early outcomes examined included measures of ventilatory support, pneumothorax, chronic lung disease and mortality. It was subsequently postulated that medical therapy, via a variety of mechanisms, might prevent intraventricular haemorrhage and thus reduce the subsequent risk of neurodevelopmental impairment and disability [Lipman 1982, Ment 1983, Ment 1992].

Indomethacin does have potential side effects, however. By reducing cerebral blood flow, indomethacin may increase the risk of cerebral hypoxia [Edwards 1990]. It remains essential, therefore, to assess carefully long-term neurodevelopmental outcomes since this potential adverse effect may oppose any benefit of a possible reduction in the incidence of intraventricular haemorrhage. Similarly, although closure of the patent ductus may be expected to reduce the incidence of necrotizing enterocolitis, this needs to be balanced against any effect indomethacin might have directly on gut blood flow [Coombs 1990]. Indomethacin may also reduce renal blood flow, thus impairing renal function [Cifuentes 1979]. In addition, it may interfere with platelet aggregation, thus impairing haemostasis [Friedman 1978]. If there is a potential effect on the microvasculature and cerebral blood flow the incidence of retinopathy of prematurity may be affected by treatment. Finally, there has been at least one report of indomethacin being associated with an increased risk of sepsis [Herson 1988].

As well as having potential benefits, treatment with prophylactic indomethacin may, theoretically therefore, have serious adverse effects and these must be taken into consideration when assessing the overall effect of prophylaxis. Only some infants will ever actually experience a patent ductus arteriosus and/or intraventricular haemorrhage and it is only this proportion of the infant population that could benefit from prophylaxis. However, since all infants would be exposed to the therapy through prophylaxis, all infants would be exposed to possible harm. Using the evidence of individual trials to date, neonatologists are uncertain about the benefit(s) of prophylaxis, if any, and have been concerned in case this intervention might, in fact, do more harm than good.

Two systematic reviews of this intervention have been published elsewhere [Fowlie 1996 and Sinclair 1992]. Continuing neurodevelopmental follow-up of those infants enrolled in trials included in these reviews and new trials involving babies who have been exposed to antenatal steroids and surfactant replacement therapy means that the information available and conclusions have continued to evolve. This review updates the previous Cochrane review [Fowlie 1997].

Objectives

To determine the effectiveness of prophylactic intravenous indomethacin in reducing mortality and morbidity in preterm infants. To determine the extent of any unwanted side effects associated with the intervention.

Methods

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials were considered for inclusion.

Types of participants

Study infants had to be preterm newborn infants.

Types of interventions

The intervention had to be prophylactic treatment with intravenous indomethacin given within 24 hours of birth. No dosage regime was prespecified.

Types of outcome measures

The study had to include some measure of the incidence of at least one of the following:

Neonatal mortality

Intraventricular haemorrhage

Neurodevelopmental outcome

Patent ductus arteriosus

Pneumothorax

Duration of assisted ventilation

Duration of oxygen dependence

Chronic lung disease

Necrotizing enterocolitis

Renal function

Haemostasis

Retinopathy of prematurity

Sepsis

Duration of hospital stay

Search methods for identification of studies

An initial literature search (English only) was undertaken in October 1994 in three databases: MEDLINE at NLM (1980 - September 1994); EMBASE (1974 - 1994) in DIALOG; and the Oxford Database of Perinatal Trials (ODPT) (Version 1.3, Disk issue 7, Spring 1992). A search by first author of any abstracts was done in the Science Citation Index to try and identify any corresponding full manuscripts published. None were identified.

The literature search was updated in February 1997 by assessing a trials list supplied by the Cochrane Collaboration Neonatal Review Group and by searching in MEDLINE (September 1994 - January 1997) using a similar strategy to the original search. EMBASE was not searched again as the original search in this database failed to identify any appropriate trials not identified by searching MEDLINE.

The search was updated a third time in October 2001, searching in MEDLINE ["indomethacin AND infant AND (prophylactic OR prophylaxis OR prevention)"], and the Cochrane Controlled Trials Register, The Cochrane Library, Issue 3, 2001 ["indomethacin AND (infant OR newborn)"].

The following types of articles and reports were excluded on each occasion a search was conducted: letters, editorials/commentaries, reviews, lectures, unpublished studies and studies in progress. The most recent searches, in 2001, included non-English language reports.

Data collection and analysis

The methods used followed the guidelines issued by the Cochrane Collaboration:

Inclusion criteria.

All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review. In order to be included, trials had to meet each of four criteria: 1) the study infants had to be newborn preterm infants (less than 37 weeks completed gestation); 2) the intervention had to be prophylactic treatment with intravenous indomethacin given within 24 hours of birth; 3) the study had to be a randomised controlled trial; and 4) the study had to include some measure of at least one of the outcomes listed under "Selection criteria - Types of outcome measure."

Each of the articles identified by the original literature search in 1994 was assessed independently, using the inclusion criteria, by the first author (PWF) and a colleague training in research methodology. Agreement beyond chance on which articles to include/exclude was measured using Cohen's kappa (0.93) and any disagreement resolved by discussion. For the updated literature search in 1997, since agreement had been near perfect originally, the first author (PWF) assessed each of the new articles for inclusion alone without a second opinion. Following the revised search in 2001, both the current authors (PWF and PD) assessed each identified report independently for inclusion in the review. Agreement on inclusion/exclusion on this occasion was perfect.

Method used to assess the quality (validity) of the articles/abstracts selected for inclusion.

Four criteria of methodological importance in the design and performance of randomised controlled trials were used to assess the quality of each study: 1) the method of randomisation including concealment of allocation; 2) whether or not those who administered the drug/placebo and cared for the infant were blind to the treatment allocation; 3) whether or not > 90% follow-up of those randomised was achieved; and 4) whether or not those assessing outcome were blind to treatment allocation.

In the preparation of the first Cochrane review the same two investigators that selected the articles for inclusion in 1994 independently assessed the methodology reported in each article/abstract. For each of the four criteria, agreement beyond chance, measured by Cohen's kappa, was as follows: method of treatment allocation, 0.73; blinding of care-giver, 0.90; > 90% follow-up, 0.51; and blinding of person assessing outcome, 0.64. Disagreement was settled by discussion. Sixty-six percent of disagreement was found to be due to simple misreading. The methodology of those articles identified for inclusion after the search update in 1997 was assessed by the first author (PWF) alone. Following the updated literature search in 2001, the methodology of all included studies was reviewed independently by both current authors (PWF and PD). Any disagreement was resolved by discussion.

Method used to extract data.

Following the searches in 1994 and 1997, each selected article was reviewed by the first author (PWF) and the outcomes measured were recorded, initially without specific data. On two separate occasions the data were then extracted from the articles/abstracts and checked for consistency. Any discrepancies were resolved by a third data extraction. Following the updated search in 2001, data from any newly identified studies were extracted by PWF. PD independently extracted the data from all the study reports included in the review. All the data included in the review were then checked for consistency.

Analysis

Data measuring similar outcomes were combined in a meta-analysis where appropriate. For categorical outcomes, treatment effect was analysed using relative risk and risk difference. The risk difference has been converted to the number needed to treat (1/RD) for certain outcomes. For outcomes measured on a continuous scale, weighted mean differences were used. A fixed effect model was assumed for meta-analysis.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Nineteen studies were found to be eligible for inclusion in this review. Thirty-two additional studies were initially identified as possibly eligible but were excluded. For each trial included in the review, clinical details concerning the participants, interventions and outcomes are given in the table, Characteristics of Included Studies.

Twelve of the 19 identified studies were conducted within the United States of America. The others were conducted in Argentina [Gutierrez 1987], the United Kingdom [Rennie 1986a], Canada [Vincer 1985], Mexico [Gutierrez 1987], Thailand [Supapannachart 1999], Saudi Arabia [Yaseen 1997] and by an international collaboration involving Canada, USA, Australia, New Zealand and Hong Kong [TIPP 2001].

Clinical practices (cointerventions) would be expected to vary across centres and over time in the studies included in this review. However, when the studies were appropriately randomised and blinded, this only becomes an issue when generalising results. Two specific issues are worth noting however. The study reported by Gutierrez et al [Gutierrez 1987] took place in a unit that did not ventilate babies whereas assisted ventilation was offered in all other studies. Surfactant usage has increased over time and was given either as prophylaxis or rescue therapy in seven trials (Couser 1996, Domanico 1994, Ment 1994a, Ment 1994b, Supapannachart 1999, TIPP 2001, Yaseen 1997).

The size of the individual studies ranged from single centre studies enrolling less than 50 patients, [Bandstra 1988, Krueger 1987, Ment 1985, Puckett 1985 and Vincer 1985] to the international multicentre study (TIPP 2001) which enrolled over 1200 babies.

All babies were less than 37 weeks and most studies had an upper gestational age limit (or equivalent weight limit) for inclusion of less than this.

Bada 1989, Hanigan 1988, Krueger 1987, Ment 1985, Ment 1988, Ment 1994b; Morales-Suarez 1994 and Rennie 1986a performed cranial ultrasounds before study entry and excluded infants with intraventricular hemorrhage. Ment 1994a reported the results of a cohort of infants all of whom had grade 1 or 2 IVH on pre-study scan. The remaining studies enrolled infants without knowledge of pre-existing IVH.

All the studies used prophylactic intravenous indomethacin as treatment although the dosage schedules varied enormously from a single dose of 0.2 mg/kg at 24 hours of age [Krueger 1987] to a daily dose of 0.1 mg/kg given for 6 days [Couser 1996]. A placebo was used as control in all studies apart from the study reported by Krueger et al [Krueger 1987]. The placebo was unspecified in four studies, [Bada 1989, Gutierrez 1987, Mahony 1985 and Puckett 1985], with saline being used in the remainder.

The majority of the studies included in the review examined short-term clinical outcomes prior to discharge from hospital. Many of the outcome definitions varied slightly, in particular the definition of chronic lung disease. Several studies looked at a variety of measures pertaining to renal function including urine output and serum biochemistry, but there was little consistency between studies as to which measures and which cut-off points were used. The same difficulty arose when examining haemostasis when the platelet count, bleeding time and "clinical bleeding" were all used but in slightly different ways in different studies. There were relatively few data available examining long-term neurodevelopmental outcome [Bandstra 1988, Couser 1996, Ment 1994b, TIPP 2001, Vincer 1985]. Along with physical and sensory outcomes, two scoring systems are used to report outcome - Bayley scores and Stanford-Binet IQs. As well as reporting these cognitive outcomes separately, a pooled analysis of the outcome "severe developmental delay" was conducted by dichotomising both test results at 2 standard deviations below the mean.

Risk of bias in included studies

For each trial included in the review, assessments of the methodological quality are given in the table, Characteristics of Included Studies.

The methodological details for each study were extracted from the published information only. It may well be, therefore, that some studies were more rigorously conducted than appears from this assessment. This is particularly so of studies where data are still only found in published abstracts [Bada 1989, Domanico 1994 and Puckett 1985]. Although methodological information is limited in the abstract reporting the results of the study by Gutierrez et al [Gutierrez 1987], more details were obtained from the trial registration with the Oxford Database of Perinatal Trials.

The exact method of concealment of randomisation could be determined for twelve of the included studies [Bandstra 1988, Couser 1996, Gutierrez 1987, Hanigan 1988, Mahony 1985, Ment 1985, Ment 1988, Ment 1994a, Ment 1994b, TIPP 2001, Supapannachart 1999 and Yaseen 1997]. Methods included telephone randomisation, sealed envelopes and coded vials. In the remaining seven studies, from the published information, it was not possible to tell how well randomisation was blinded.

Blinding of the intervention to those caring for the infant was explicitly described in nine of the studies [Bandstra 1988, Couser 1996, Domanico 1994, Gutierrez 1987, Hanigan 1988, Mahony 1985, Ment 1985, Ment 1988, Vincer 1985 and TIPP 2001]. In the study reported by Krueger et al [Krueger 1987], it appears that the carer was clearly not blinded to the intervention group. Blinding of the intervention is unclear in the trials of Puckett 1985 and Rennie 1986a.

In three studies, [Krueger 1987, Puckett 1985 and Rennie 1986a], it is not possible to determine whether or not those responsible for assessing the outcomes of interest were blind to intervention group. In all the other studies, blinding was adequate.

For all the short-term outcome measures prior to discharge, follow-up was adequate for all the studies included, in that it was greater than 90%. In contrast, long-term outcome assessment was less complete. If all infants randomised form the denominator, and all infants on whom some follow-up data is available (including death) form the numerator, follow rates were as follows: Bandstra 1988 - 75%, Couser 1996 - 73%, Ment 1994b - 90%, TIPP 2001 - 95% and Vincer 1985 - 100%. For individual long-term outcomes, particularly cognitive testing, follow-up rates were much lower and this is a potential source of bias.

The study of Ment 1994b requires some explanation. Four hundred and thirty one infants were randomised within the study. Forty-five died before hospital discharge and their group of allocation is known. Follow-up testing was conducted at 36 months corrected age and again at 54 months corrected age. At 36 months, 343 were assessed clinically for the presence or absence of cerebral palsy. Fewer were formally assessed for hearing impairment (135) and visual impairment (158). 251 infants underwent objective cognitive function testing. Cognitive function testing was limited to children who spoke English as their first and only language because of concerns that the instruments used, the Stanford-Binet Intelligence Scale and the Peabody Picture Vocabulary - Revised, were not valid in non-English speaking or multilingual children. The proportions of survivors who were tested for cognitive function at follow-up were similar for the indomethacin and placebo groups. However, no data were provided on those children not assessed making it impossible to determine whether all eligible children were tested or whether those not tested might have differed significantly in other ways than ethnic origin to those children who were assessed. At 54-months vision and hearing were assessed in 337 infants, presence or absence of cerebral palsy in 323 and cognitive testing in 233. For the purposes of this review, we used the 54-month outcomes for vision and hearing and the 36-month outcome for cerebral palsy to minimise loss to follow-up.

Bandstra et al report neurodevelopmental follow-up on 123 of the 199 infants (28 deaths) enrolled in their study [Bandstra 1988]. The results are available in an abstract only and more complete data do not appear to have been published. This leads to two obvious problems: (1) the data refer to a selected subset of the trial population i.e. those who, at the time of writing the abstract, had turned up for review; and (2) it appears that the MDI and PDI scores were assessed at 6, 12, 18 and 24 months but the data for each individual infant refer to the most recent test for that infant. It may not be appropriate to compare results between infants when the scores were assessed at different times. This may lead to a biased result, and caution is needed in interpreting these results.

Effects of interventions

Nineteen studies contributed data to the review.

Neonatal mortality.

There is no statistically significant difference in neonatal mortality between the treatment and placebo groups. However, the 95% confidence interval around the pooled estimate suggests a trend toward a reduction in the early mortality rate in those infants treated with prophylactic indomethacin, pooled relative risk (RR) = 0.82 [95% CI 0.65 to 1.03]. However, when the outcome "death at latest follow-up" is examined a trend favouring prophylactic indomethacin is no longer apparent [RR = 0.96 (0.81,1.12)]. The difference in these results appears to be due to the contribution of TIPP 2001 to the latter outcome and the absence of data from TIPP 2001 on mortality before hospital discharge.

Patent ductus arteriosus.

Prophylactic indomethacin reduces the incidence of symptomatic patent ductus arteriosus, pooled RR = 0.44 [0.38 to 0.50], pooled risk difference (RD) = -0.24 (-0.28 to -0.21), number needed to treat (NNT) = 4. The incidence of echo-diagnosed patent ductus arteriosus, i.e., the sum of all patent ductuses whether symptomatic or not, is reduced even further by prophylactic indomethacin [RR = 0.29 [0.22 to 0.38], RD = -0.27 (-0.32,-0.21), NNT = 4]. Prophylactic indomethacin reduces the rate of surgical PDA ligation [RR = 0.51, (0.37,0.71), RD = -0.05 (-0.08, -0.03), NNT = 20]

Pulmonary outcomes.

There is no significant difference between treatment and placebo groups as regards any of the pulmonary outcomes examined: pneumothorax, duration of ventilation, duration of supplemental oxygen requirement or incidence of chronic lung disease (defined at either 28 days or 36 weeks). A trend towards reduction in rates of pulmonary haemorrhage in infants randomised to prophylactic indomethacin does not reach statistical significance [RR = 0.84 (0.66,1.08)]

Cranial ultrasound abnormalities:

The incidence of intraventricular haemorrhage of all grades is significantly reduced in infants who receive prophylactic indomethacin [RR = 0.88 (0.80 to 0.98), RD = -0.04 (-0.08,-0.01), NNT= 25]. There is evidence that the treatment effect on this outcome is not consistent across all studies, with statistical heterogeneity detected (p = 0.011) on chi-squared test. An analysis of the trials providing data on Grade 3 and 4 haemorrhage also shows an effect favouring prophylactic indomethacin [RR = 0.66 [0.53 to 0.82], pooled RD = -0.05 (-0.07 to -0.020), NNT = 20]. The reduction in severe IVH is similar whether or not infants were screened for IVH and excluded before study entry. There is no evidence that prophylactic indomethacin prevents the progression of Grade 1 IVH that is present before prophylaxis is commenced, although only two small studies contributed data to this outcome. Pooled results from the five trials reporting outcomes of either periventricular leukomalacia or ischaemic change showed a reduction in rate of adverse outcome in infants treated with prophylactic indomethacin [RR = 0.44 (0.24,0.81), RD = -0.05 (-0.08,-0.01)]. TIPP 2001 reported rates of white matter injury on ultrasound (including intraparenchymal echodensities, periventricular leukomalacia, porencephalic cysts and ventriculomegaly) which showed a trend in the same direction [RR = 0.88 (0.71,1.09), RD = -.03 (-0.08, 0.02)].

Neurodevelopmental outcome.

Caution should be exercised in the interpretation of these results because of the methodological limitations of some of the studies as mentioned above. The high rates of loss to follow-up for some trials and particularly for long-term cognitive outcomes limit the applicability of some results.

  • Cognitive functioning:

The two studies using Bayley examinations (TIPP 2001 and Bandstra 1988) showed no difference in rates of severe impairment (Mental Developmental Index < 68) [RR = 1.02 (0.83,1.26)]. Ment 1994b using the WIPPSI-R (full scale < 70) at 54 months found a non-significant trend favouring the prophylactic indomethacin group [RR = 0.55 (0.28,1.11)]. Combining these three studies results in no difference between treatment groups for the outcome severe developmental delay [RR = 0.96 (0.79,1.17)].

Ment 1994b also assessed the same cohort at 36 months. Mean Stanford-Binet IQ scores (SD) were not statistically different in the two groups: 89.6 (18.92) for indomethacin, 85.0 (20.79) for placebo, Mean Difference = 4.7 (95% CI -0.703 to 10.103) and there was no difference in Peabody Picture Vocabulary Test - Revised scores: 88.4 (20.01) for indomethacin, 83.7 (21.78) for placebo, Mean Difference = 4.6 (-0.352 to 9.552).

  • Cerebral palsy:

Four studies reporting this outcome showed no difference in rates of cerebral palsy [RR = 1.04 (0.77,1.40)].

  • Blindness and deafness:

There were no significant differences in rates of blindness [RR = 1.26 (0.50,3.18)] or deafness [RR = 1.02 (0.45,2.33)] in the 2 studies reporting these outcomes (Ment 1994b and TIPP 2001).

  • Combined outcomes:

There was no significant difference in rates of severe neurosensory impairment (CP, cognitive delay, blindness, deafness) [RR = 0.98 (0.81,1.18)] or death or severe neurosensory impairment [RR = 1.02 (0.90,1.15)]. TIPP 2001presented subgroup analyses based on birthweight (500-749g and 750-999g) and there were no significant differences in rates of composite adverse outcomes in either subgroup (indomethacin 63% and 36% vs control 61% and 35%).

Necrotizing enterocolitis.

There is no significant difference in rates of necrotizing enterocolitis [RR = 1.09 (0.82,1.46)]. The one trial (TIPP 2001) reporting gastrointestinal perforation found no significant difference in rates of this outcome [RR = 1.12 (0.71,1.79)].

Renal function.

The incidence of oliguria is increased in infants who receive prophylactic indomethacin [RR = 1.90 (1.45 to 2.47), RD = 0.06 (0.04,0.08), Number needed to harm = 16]. In two trials, Ment has also reported the number of infants in each group whose creatinine rose above 159 micromol/L. The pooled results show no difference between the groups, in keeping with Couser who found no difference in the number of infants whose creatinine rose beyond 18 mg/dl. Mahony reported mean serum sodium, potassium and creatinine on day three as well as mean urine output over the first four days. There is no statistically significant difference between the groups in any of these measures. Vincer reported mean serum sodium levels over the first seven postnatal days and points to a significantly higher level in the treatment group on days three and four. In addition to reporting reduced urine output in the treatment group, Rennie reported significantly higher peak creatinine levels on days one and two following treatment with indomethacin but no significant difference in serum sodium levels. Krueger reported a significant reduction in urinary output (as measured by the input/output ratio) affecting the treatment group in the 24 hours immediately following treatment. This difference is no longer apparent in the subsequent 24 hour period. In 1988, Ment reported no clinically important renal abnormalities but provides no data. Bada provided data that show statistically significant changes in plasma creatinine and sodium levels, osmolalities and urine output but comments that these differences were not abnormal, i.e. not clinically important.

Haemostasis

In three reports, Ment provides data on the number of infants whose platelet count fell to <50,000 per microlitre. Couser found no difference in the number of infants whose platelet count fell below 50,000 per microlitre although platelet counts were not routinely measured, only being estimated at the request of the clinician caring for the infant. The pooled estimate shows no difference in the rates of thrombocytopenia [RR = 0.50 (0.11,2.22)]. Likewise, combining the five trials reporting rates of excessive clinical bleeding shows no difference between the groups [RR = 0.74 (0.40,1.38)]

Retinopathy of prematurity (ROP)

There is no evidence of a significant difference in the rates of any ROP [RR = 1.02 (0.92,1.14)] or severe ROP [RR = 1.75 (0.92,3.34)].

Septic episodes

In four trials, the risk of sepsis was not significantly different between groups [RR = 0.78 (0.56,1.09)].

Discussion

An extensive literature search was conducted to identify appropriate trials for this review. The quality of the included studies overall was good suggesting that the data are valid. Most of the studies reviewed are relatively small, however, and there is obvious variation in study design, particularly birth weight eligibility criteria, the indomethacin dosage regimes used and some of the outcome definitions.

When considering the main apparent benefits of indomethacin, i.e., a reduced incidence of grades 3 and 4 IVH and PDA, the results of the trials examined appear remarkably homogeneous. In addition, although no formal assessment was undertaken, these findings appear consistent across the surfactant and presurfactant eras.

There seems little doubt that prophylactic intravenous indomethacin given to this population reduces the risk of IVH and PDA. Using the NNT, 20 babies would need to be treated prophylactically to prevent one severe IVH. Only four would need treatment to prevent a symptomatic patent ductus developing and 20 to prevent one surgical ligation. In this context, the failure of prophylactic indomethacin to significantly reduce short-term pulmonary morbidity challenges some of the notions regarding the relationship between patent ductus arteriosus and lung damage.

In previous versions of this review, caution was urged with respect to over-enthusiasm regarding the proven improvements in short-term outcomes with prophylactic indomethacin. These related to the lack of safety data on the intervention, particularly as applied to long-term outcomes. Cranial ultrasound findings have been used as surrogates for long-term neurodevelopmental outcome. Concerns have been expressed that prophylactic indomethacin may cause damage eg through vasoconstriction, which would remain undetected on cranial ultrasound and outweigh the benefits of reduced IVH rates. Further follow-up of existing cohorts and new studies, particularly the TIPP trial, mean that there is now long-term follow-up data available on 1778 infants. Conclusions drawn from these studies are heavily influenced by the largest trials (TIPP and Ment 94b). There is no evidence of long-term harm either in terms of individual outcomes of death, cognitive delay, cerebral palsy, blindness and deafness or composite outcomes including all of these. However, there is also no evidence of benefit with respect to these outcomes. In spite of the relatively large numbers of infants now available for follow-up it is possible that a real beneficial effect has been missed. Ment 94b described trends favouring the prophylactic indomethacin group in cognitive functioning, some of which became statistically significant with adjustment for certain baseline variables. It has been suggested that the 18-month follow-up performed in TIPP may have failed to detect subtle neurodevelopmental abnormalities that may became evident later in childhood. Therefore, while there is no evidence of long-term neurological harm from prophylactic indomethacin, the question of benefit is yet to be fully resolved. Later follow-up of the TIPP cohort may provide the definitive answer.

Initial evidence from the TIPP trial indicates that there is no reason to suspect that response to prophylactic indomethacin varies with birthweight or gestational age.

Other, short-term safety concerns have largely been allayed. In particular there is no evidence that prophylactic indomethacin causes an increased incidence of necrotising enterocolitis or clinically important bleeding.

Authors' conclusions

Implications for practice

The prophylactic use of indomethacin in very low birth weight infants results in clear short-term benefits: a reduction in the incidence of symptomatic PDA and the need for surgical PDA ligation and a reduction in the incidence of IVH, including grade 3 and 4 IVH. There is no evidence of a difference in rates of short or long-term mortality or short-term adverse effects such as necrotising enterocolitis although there is a temporary reduction in urine output in babies given indomethacin. Long-term neurodevelopmental outcome is not adversely affected, although some trials assessing this suffer from incomplete follow-up. Overall, however, the quality of the trials included in this review was good, and the results were consistent across trials.

The size of the effects on short-term outcomes appears to be clinically important. Using the pooled results, calculations of NNT suggest that for every 100 very low birth weight infants treated with prophylactic indomethacin, symptomatic PDA will be prevented in 25 infants, duct ligation will be prevented in five infants and IVH of grade 3 or 4 will be prevented in five infants. However, NNT clearly depends on the background incidence of the conditions of interest. IVH and PDA rates differ in the earlier trials when compared to more recent studies and as a result any NNT must be based on a background incidence based on appropriate local, up to date data and revised accordingly.

The decision as to whether or not to prescribe prophylactic indomethacin may depend on individual clinical circumstances and the values attached to any potential benefits. In units without ready access to cardiology services including cardiac surgery, a reduction in symptomatic PDA and a reduction in the need for surgical closure may be considered a greater benefit than in other tertiary units with ready access to these services.

Implications for research

A significant body of evidence is now available examining the role of prophylactic indomethacin in preterm infants. The results are on the whole homogeneous and it would seem unlikely that any significant benefit or adverse outcome is being missed. Further placebo controlled trials are therefore not likely to add to what is already known and efforts should perhaps now be addressed at examining dilemmas that remain: the optimal dosage regimen has yet to be determined and the optimal target population in terms of birth weight, gestation and perhaps even illness severity needs to be identified more clearly. Further secondary analyses of existing data may help clarify some of these issues. Although data are available on long term neurodevelopmental outcome up the age of 18 months or two years in many children and to seven years in a smaller cohort, continuing follow up of these children is justified as more subtle differences in later childhood/adulthood may become apparent.

Acknowledgements

Thanks to Dr. Sean Dinneen, MD, Attending Physician, Mayo Clinic, Rochester, Minnesota, USA, who assisted in the article selection and evaluation process following the original literature search and to Professor John C Sinclair, Department of Pediatrics and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario who provided expert advice on methodology.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bada 1989
MethodsBlinding of randomisation: can't tell Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow up: yes
Participants141 newborn infants, birthweight < 1500 grams. Cranial US before study entry - excluded IVH of grade 2 or above.
InterventionsIV prophylactic indomethacin, 3 doses (0.2; 0.1; 0.1 mg/kg), first dose at 6 hours of age, then 12 hourly thereafter versus placebo (not described)
OutcomesDeath before hospital disharge; IVH; Chronic lung disease (oxygen supplementation beyond 28 days of life); Pulmonary haemorrhage (blood up tube, consistent CXR findings, treatment inc. ventilation required); NEC (Bell stage 2 or 3 disease); Renal dysfunction (urine output, creatinine and urea)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Bandstra 1988
MethodsBlinding of randomisation: yes (envelopes) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: Short term outcomes prior to discharge - yes, (excluding the data on haemostasis); Long-term neurodevelopmental outcomes - no (76%).
Participants199 newborn infants, birthweight < 1300 grams. No cranial ultrasound screening before study entry. Data on 149 infants available for long-term follow-up. 59 newborn infants regarding haemostasis
InterventionsIV prophylactic indomethacin vs. an equal volume of saline placebo. Indomethacin dosage: 3 doses (0.2; 0.1; 0.1 mg/kg), first dose at less than 12 hours of age, 12 hourly thereafter
OutcomesDeath before hospital discharge and death at latest followup ie up to 24 months; IVH; Clinically significant PDA; PDA ligation; Duration of supplemental oxygen; Duration of ventilation; Chronic lung disease; Pneumothorax; Episodes of sepsis; NEC; ROP: any and severe; Renal function (oliguria < 1 ml/kg/hour) IVH grade II - IV; PVL; Long-term outcome assessed as the latest of 6, 12, 18, 24 months visits (numbers not specified). Bayley Mental Development Index (MDI) - Abnormal < 68; Questionable 68 - 83; Normal > 84; Bayley Physical Developmental Index (PDI) - Abnormal < 68; Questionable 68 - 83; Normal > 84. Death or neurosensory impairment (death or Bayley MDI <68); Heamostasis - bleeding time and platelet count
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Couser 1996
MethodsBlinding of randomisation: yes (pharmacy prepared vials) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes for short term outcomes but 73% for long term outcomes.
Participants90 (of 93 randomised) newborn infants 23 - 29 weeks gestation, birth weight 600 - 1250 grams. No cranial ultrasound screening before study entry. All infants received prophylactic surfactant at initial resuscitation. Follow-up data available on 68 of 93 infants randomised.
InterventionsIV indomethacin vs. normal saline placebo. Indomethacin dosage: 0.1 mg/kg, within 24 hours of birth followed by similar dose every 24 hours thereafter for a total of 6 doses.
OutcomesNeurodevelopmental impairment including cerebral palsy at 36 months corrected age Clinically significant PDA IVH grade 3 or 4 Mortality Duration of supplementary oxygen requirement NEC ROP stage 3 Chronic lung disease (supplementary oxygen at 28 days plus chest Xray changes) Urine output reduced to < 1.0 ml/kg/hour at any time during first 7 days.
NotesThis is only study in which all the infants have received surfactant. Data are also provided for the subpopulation of infants weighing < 1000 grams at birth.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Domanico 1994
MethodsBlinding of randomisation: can't tell Blinding of intervention: yes Blinding of outcome measurement: Yes Complete (> 90%) follow-up: yes
Participants100 newborn babies, birth weight < 1250 grams
InterventionsIV Indomethacin vs. equal volume of placebo (saline). Indomethacin dosage: 3 doses 0.2, 0.1, 0.1 mg/kg; first dose < 12 hours, second dose 12 hours later, final dose 36 hours after first dose
OutcomesPDA (Diagnosed by echocardiography on day 3-5); Pulmonary haemorrhage; IVH grade 3 or 4; Incomplete data on duration of ventilation and duration of supplementary oxygen requirement.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Gutierrez 1987
MethodsBlinding of randomisation: yes (sealed envelopes) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (>90%) follow-up:yes
Participants59 newborn infants less than 34 weeks gestation and less than 1751 grams birth weight
InterventionsIV indomethacin vs. placebo (saline). Indomethacin dosage: 3 doses, 0.2, 0.1, 0.1 mg/kg first dose less than 24 hours of age, then 12 hourly thereafter
OutcomesDeath Symptomatic PDA (Cabal-Siassi score > 3)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Hanigan 1988
MethodsBlinding of randomisation: yes (sealed envelopes) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes
Participants111 newborn infants, birthweight < 1500 grams. All had normal cranial US before study entry.
InterventionsIV prophylactic indomethacin versus saline placebo. Dose of study drug given before 12 hours of age and then at 24, 48 and 72 hours of age. Indomethacin dosage: 0.1 mg/kg.
OutcomesDeath; IVH (Krishnamoorthy classification); PDA; Duration of ventilation; Pneumothorax
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Krueger 1987
MethodsBlinding of randomisation: can't tell Blinding of intervention: no Blinding of outcome measurement: no Complete (> 90%) follow up: yes
Participants32 newborn infants, birthweight 750 - 1500 grams. Ventilator dependent at 24 hours of age with a diagnosis of RDS. Excluded infants with US or clinical evidence of IVH.
InterventionsIV prophylactic indomethacin, single dose (0.2 mg/kg) at 24 hours of age versus nothing (no placebo used)
OutcomesDeath; Symptomatic PDA; IVH; Duration of ventilation; Chronic lung disease; NEC; Renal insufficiency (Input/output ratio in fixed time period following treatment - 0-24 hour & 25 - 48 hours; serum creatinine)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Mahony 1985
MethodsBlinding of randomisation: yes (coded drugs) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes
Participants110 newborn infants, birthweight 700-1300 grams
InterventionsIV prophylactic indomethacin, 3 doses (0.2, 0.1, 0.1 mg/kg), first dose at 12 -18 hours of age, second dose 12 hours after the first and third dose 24 hours after the second versus placebo (unspecified)
OutcomesMortality; Symptomatic PDA and all PDA; IVH; Duration of oxygen dependence; Duration of ET ventilation; Incidence of sepsis; Incidence of NEC; Incidence of ROP; Parameters of renal function (serum creatinine and electrolytes)
NotesSix early deaths (3 in each group) which were not included in the denominators of any study outcome in the original article have been included for the purposes of this review.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Ment 1985
MethodsBlinding of randomisation: yes (coded drugs) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes
Participants48 newborn infants, birthweight 600 - 1250 grams. Excluded any IVH on pre-study US.
InterventionsIV prophylactic indomethacin, 5 doses (0.2; 0.1 x 4 mg/kg), first dose at 6 hours, then 12 hourly thereafter versus saline placebo. Study medication stopped if IVH detected, abnormal bleeding, platelets<50,000, elevated BUN or urine output<0.5 ml/kg/hr.
OutcomesMortality; IVH; All PDA; Parameters of renal function (urine output and serum electrolytes); Parameters of haemostasis Platelet abnormalities and bleeding problems)
NotesDosage schedule changed to 0.1 mg/kg x 5 in trial after concern expressed at diminished urine output in infants receiving indomethacin. On the advice of an advisory committee "the study was terminated when statistical significance was achieved".
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Ment 1988
MethodsBlinding of randomisation: yes (coded drugs) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes
Participants36 newborn infants, birthweight 600-1250 grams. Excluded infant with IVH on pre-study US.
InterventionsIV prophylactic indomethacin versus saline placebo. Indomethacin dosage: 3 doses (3 x 0.1 mg/kg), first dose 6 - 12 hours of age, 24 hourly thereafter. Study medication withheld if if IVH, abnormal bleeding, platelet count < 50,000, elevated BUN or creatinine or urine output < 0.5 ml/kg/hour.
OutcomesDeath; IVH; PDA; Renal function (electrolyte abnormality, urine output); Haemostasis (Platelet count, clinical bleeding)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Ment 1994a
MethodsBlinding of randomisation: yes (randomized centrally by telephone in blocks) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes
Participants61 newborn infants all with IVH (grade 1 or 2) at time of enrollment. Birthweight 600-1250 grams
InterventionsIV prophylactic indomethacin versus saline placebo. Indomethacin dosage: 3 doses (3 x 0.1 mg/kg), first dose at 6 - 12 hours of age, 24 hourly thereafter
OutcomesDeath; Extension of IVH; Closure of PDA; NEC; Renal function (urine output < 0.5 ml/kg/hour, serum creatinine > 159 micromol/L); Haemostasis (platelet count <50000/mm, clinical bleeding)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Ment 1994b
MethodsBlinding of randomisation: yes (randomized centrally by telephone, block randomisation stratified within treatment group and within centre according to birthweight, inborn/outborn, antenatal steroid use and surfactant use.) Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: Outcomes prior to hospital discharge - yes; long-term neurodevelopmental outcomes at 36 months - no.
Participants431 newborn infants, birthweight 600 - 1250 grams. Newborn infants followed up to 36 months (corrected for gestation). Excluded non-English mono-lingual children for follow-up. Excluded infants with any IVH on pre-study US.
InterventionsIV prophylactic indomethacin versus saline placebo. Indomethacin dosage: 3 doses (3 x 0.1 mg/kg), first dose at 6 - 12 hours of age, 24 hourly thereafter by slow infusion (5 - 10 minutes)
OutcomesDeath; IVH; PDA; NEC; Renal impairment (serum creatinine > 1.8 mg/dL); Impaired haemostasis (platelet count < 50000/mm, clinical bleeding) Stanford-Binet Intelligence Scale Peabody Picture Vocabulary Test- Revised Cerebral palsy on clinical examination - spastic diplegia, tetraplegia, hemiplegia Blindness (not further defined) Deafness (not further defined)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Morales-Suarez 1994
MethodsBlinding of randomisation: can't tell Blinding of intervention: yes Complete followup: yes Blind outcome assessment: yes
Participants80 newborn infants with gestational ages between 28 and 36 weeks, intubated in the delivery room and requiring ventilation in ICU. Excluded those with IVH on admission US, platelet count < 50,000, oliguria and pneumothorax
InterventionsIV prophylactic indomethacin 0.1 mg/kg in first 12 hours then 2 further doses 12 hours apart versus equal volume of normal saline placebo.
OutcomesDeath to hospital discharge; IVH - all and grade 3 and 4; symptomatic PDA, pneumothorax; sepsis.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Puckett 1985
MethodsBlinding of randomisation: can't tell Blinding of intervention: can't tell Blinding of outcome measurement: can't tell Complete (> 90%) follow-up: no
Participants32 newborn infants, birthweight < 1400 grams
InterventionsIV prophylactic indomethacin vs. placebo (unspecified). Indomethacin dosage: 3 doses (3 x 0.2 mg/kg), first dose at less than 24 hours, 12 hourly thereafter
OutcomesDeath; PDA; IVH; Duration of IMV; Duration of supplemental oxygen requirement
NotesDetails of this study are available in abstract only
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Rennie 1986a
MethodsBlinding of randomisation: can't tell Blinding of intervention: can't tell Blinding of outcome measurement: can't tell. One member of the nursing staff prepared the study vials. Complete (> 90%) follow-up: yes
Participants50 newborn infants, birthweight < 1750 grams. Excluded infants with IVH on pre-study US.
InterventionsIV prophylactic indomethacin versus an equal volume of saline placebo. Indomethacin dosage: 3 doses (3 x 0.2 mg/kg), first dose at less than 24 hours, 24 hourly thereafter
OutcomesDeath; Clinical PDA requiring treatment; IVH; Duration of ventilation; Duration of oxygen supplementation; Chronic lung disease; Pneumothorax; Renal impairment (peak serum creatinine, "renal impairment", serum sodium on days 1 and 2); Impaired haemostasis ("GI bleed", bleeding time)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Supapannachart 1999
MethodsBlinding of randomisation: yes (sealed envelopes) Blinding of intervention: yes Complete followup: yes Blind outcome assessment: yes.
Participants30 newborn infants with birth weights < 1250g and <24 hours old. Excluded: thrombocytopenia, elevated creatinine, overt bleeding, poor urine output and major congenital anomalies.
InterventionsIV prophylactic indomethacin 0.2 mg/kg initially, then 0.1 mg/kg x 2 doses, 12 hurs apart versus an equal volume of saline placebo.
OutcomesDeath; symptomatic PDA; PDA ligation; BPD; IVH: all and grade 3 and 4; NEC; diminished urine output; any ROP; sepsis
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
TIPP 2001
MethodsBlinding of randomisation: yes (computer generated randomisation scheme with allocation by pharmacy). Stratified by centre and birthweight. Blinding of intervention: yes Blind outcome assessment: yes Complete follow up (>90%): yes
Participants1202 newborn infants, birthweight 500-999 grams between 2 and 6 hours of age. Excluded known cardiac or renal disease, dysmorphic features, platelet count < 50,000/ml, maternal indomethacin therapy or overt bleeding. No screening for IVH before study entry.
InterventionsIV prophylactic indomethacin versus an equal volume of normal saline placebo (both masked using yellow tape). Indomethacin dose: 0.1 mg/kg every 24 hours for 3 doses starting between 2 and 6 hours of age.
OutcomesDeath; PDA; PDA ligation; BPD (36 weeks); IVH (all and Gr 3 and 4); White matter injury on cranial US; Bayley Mental Developmental Index; Blindness; Deafness; Cerebral palsy; Death or major impairment; NEC; Gastrointestinal perforation; Diminished urine output; Excessive clinical bleeding; Pulmonary haemorrhage; ROP (any and grade 3 or worse);
NotesFollow up outcomes assessed at 18 months.
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate
Vincer 1985
MethodsBlinding of randomisation: can't tell Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes
Participants30 newborn infants, birthweight < 1500 grams
InterventionsIV prophylactic indomethacin vs. an equal volume of normal saline. Indomethacin dosage: 3 doses (3 x 0.2 mg/kg), first dose at 12 hours of age, 12 hourly thereafter
OutcomesCerebral palsy at 2 years corrected age. Death; IVH; Symptomatic PDA; Chronic lung disease (clinical signs, pCO2 > 60 mm Hg at 2 weeks of age); NEC; ROP, Renal impariment (serum urea)
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear
Yaseen 1997
  1. ROP=retinopathy of prematurity

  2. CP=cerebral palsy

  3. BPD=bronchopulmonary dysplasia

  4. NEC=necrotising enterocolitis

  5. PDA=patent ductus arteriosus

MethodsBlinding of randomisation: yes - sealed, sequentially numbered and coded envelopes Blinding of intervention: yes Blind outcome assessment: yes Complete follow up (>90%): yes
Participants27 preterm infants, birthweight <1750g, RDS requiring ventilation with > 30% oxygen. Excluded if platelets < 75,000/ml, creatnine >180 micromol/l, SBR > 90 in first 8 hours
InterventionsIV prophylactic indomethacin versus an equal volume of saline. First dose 0.2 mg/kg at 12 hours then repeated twice at 24 hour intervals.
OutcomesDeath before hospital discharge; IVH grades 3 and 4: BPD at 28 days; duration of supplemental oxygen; NEC; duration of hospital stay.
Notes 
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Characteristics of excluded studies [ordered by study ID]

Bada 1996These data are presented in abstract only. From the limited published information, it is not possible to determine if this is follow-up of an RCT or not, hence the data are not included in the review. However, it seems likely it may relate to the study listed in the "included studies" - Bada 1989.
Cotton 1980Not a study of indomethacin given prophylactically.
Cotton 1983No original data on prophylactic indomethacin
Gersony 1983Not a study of indomethacin given prophylactically.
Hammerman 1986Not an RCT
Hammerman 1987Not a study of indomethacin used prophylactically. All the infants enrolled had echocardiographic evidence of a PDA at 48-72 hours of life.
Hammerman 1990Not a study of indomethacin used prophylactically.
Hammerman 1995Not RCT
Kaapa 1983Not a study of indomethacin used prophylactically. In addition, although all infants were less than 37 weeks gestation they were not entered in trial on basis of birth weight and from published data it is not possible to identify those infants less than 1750 grams.
Krauss 1989Not a study of indomethacin used prophylactically.
Lai 1990This is an RCT of ORAL indomethacin used prophylactically.
Mahony 1982Not a study of prophylactic indomethacin - all infants had "subclinical PDA".
Mardoum 1991This is not an RCT of indomethacin given prophylactically. It also includes infants with a birth weight greater than 1750 grams birth weight and the outcome of interest - cerebral blood flow - is not one of the clinical outcomes examined in this review.
Ment 1987This is probably the same study as Ment 1994b. Because it is not possible to determine this with certainty from the published information it has been labelled as a separate study. However, it probably reports interim analyes of the data included in this review taken from Ment 1994b and would not contibute any unique data.
Ment 1993From the published information, it is unclear if this was truly prophylactic indomethcin so the data presented cannot be included in this review. In fact, this might well be an analysis of a selected population from two studies that are included in this review - Ment 1994a and Ment 1994b. It is therefore likely that the findings are already incorporated into the review.
Merritt 1981Not a study of indomethacin used prophylactically.
Monset-Couchard 1983Not a trial of indomethacin used prophylactically: all infants had symptomatic PDA.
Mullett 1982This is an RCT of oral indomethacin and the treatment is not used prophylactically: all infants had clinical evidence of a PDA.
Nestrud 1980Not a trial of indomethacin given prophylactically: all the infants had PDA. In addition, intervention was ORAL indomethacin versus placebo.
Neu 1980Not a study of indomethacin given prophylactically. Also uses oral preparation.
Rennie 1991Intervention was not indomethacin given prophylactically.
Rhodes 1988Not a trial of indomethacin used prophylactically.
Rudd 1983Not a study of indomethaicn used prophylactically.
Valaes 1980Not a study of indomethacin used prophylactically.
van Overmeire 1995Not an RCT of indomethacin used prophylactically.
Vogtmann 1988This is a trial of ORAL prophylactic indomethacin.
Wagner 1984This is essentially a large case series of surgical closure of PDA. It is not an RCT and not a study of prophylactic indomethacin.
Weesner 1987Not strictly a study of prophylactic therapy - all infants enrolled had an asymptomatic PDA
Wurtzel 1990This is a trial examining the effects of maternal antenatal indomethacin on the renal function of the newborn infant.
Yanagi 1981Not a study of indomethacin used prophylactically.
Yeh 1981Not an RCT of indomethacin given prophylactically: all infants had a documented PDA at entry to the trial. It included infants with birthweight > 1750 grams and was a comparison of indomethacin versus indomethacin plus frusemide.
Zamboni 1993Not an RCT of indomethacin

Data and analyses

Download statistical data

Table Comparison 1.. Prophylactic indomethacin vs. control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Death to hospital discharge171567Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.65, 1.03]
2 Death at latest follow-up182769Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.81, 1.12]
3 All IVH142532Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.80, 0.98]
4 IVH Grade 3 and 4142588Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.53, 0.82]
5 IVH that progresses283Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.44, 1.47]
6 Periventricular leukomalacia/ ischaemic changes5811Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.24, 0.81]
7 White matter injury on cranial ultrasound11202Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.71, 1.09]
8 Symptomatic PDA142193Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.38, 0.50]
9 All PDA (echo-diagnosed, symptomatic or not)7965Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.22, 0.38]
10 PDA ligation81791Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.37, 0.71]
11 Pulmonary haemorrhage41591Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.07]
12 Pneumothorax6524Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.13]
13 Duration of supplementary oxygen requirement4342Mean Difference (IV, Fixed, 95% CI)3.76 [-4.23, 11.74]
14 Duration of assisted ventilation4417Mean Difference (IV, Fixed, 95% CI)-1.83 [-5.53, 1.87]
15 Chronic lung disease (28 days)91022Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.92, 1.26]
16 Chronic lung disease in surviving infants (36 weeks)1999Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.92, 1.22]
17 Necrotizing enterocolitis122401Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.82, 1.46]
18 Gastointestinal perforation11202Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.71, 1.79]
19 Any retinopathy of prematurity51571Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.92, 1.12]
20 Severe retinopathy of prematurity (grade 3 or greater)2289Risk Ratio (M-H, Fixed, 95% CI)1.75 [0.92, 3.34]
21 Hospital infection4413Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.56, 1.09]
22 Diminished urine output82115Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.45, 2.47]
23 Elevated serum creatinine4618Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.47, 2.51]
24 Thrombocytopaenia4618Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.11, 2.22]
25 Excessive clinical bleeding51776Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.40, 1.38]
26 Duration of hospital stay3258Mean Difference (IV, Fixed, 95% CI)7.99 [-1.16, 17.14]
27 Abnormal Bayley Mental Developmental Index (< 68 - 70) in survivors examined21053Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.83, 1.26]
28 Abnormal Bayley Physical Developmental Index (< 68) in survivors examined1152Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.24, 1.22]
29 WPPSI-R: full scale<70 in survivors examined1233Risk Ratio (M-H, Fixed, 95% CI)0.55 [0.28, 1.11]
30 Severe developmental delay in survivors examined31286Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.79, 1.17]
31 Cerebral palsy in survivors examined41372Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.77, 1.40]
32 Visual impairment (blind) in survivors examined21274Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.50, 3.18]
33 Hearing impairment (deaf) in survivors examined21259Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.45, 2.33]
34 Severe neurosensory impairment (CP, cognitive delay, blindness, deafness) in survivors examined31388Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.81, 1.18]
35 Death or severe neurosensory impairment31491Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.90, 1.15]
Figure Analysis 1.1.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 1 Death to hospital discharge.

Figure Analysis 1.2.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 2 Death at latest follow-up.

Figure Analysis 1.3.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 3 All IVH.

Figure Analysis 1.4.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 4 IVH Grade 3 and 4.

Figure Analysis 1.5.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 5 IVH that progresses.

Figure Analysis 1.6.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 6 Periventricular leukomalacia/ ischaemic changes.

Figure Analysis 1.7.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 7 White matter injury on cranial ultrasound.

Figure Analysis 1.8.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 8 Symptomatic PDA.

Figure Analysis 1.9.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 9 All PDA (echo-diagnosed, symptomatic or not).

Figure Analysis 1.10.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 10 PDA ligation.

Figure Analysis 1.11.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 11 Pulmonary haemorrhage.

Figure Analysis 1.12.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 12 Pneumothorax.

Figure Analysis 1.13.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 13 Duration of supplementary oxygen requirement.

Figure Analysis 1.14.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 14 Duration of assisted ventilation.

Figure Analysis 1.15.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 15 Chronic lung disease (28 days).

Figure Analysis 1.16.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 16 Chronic lung disease in surviving infants (36 weeks).

Figure Analysis 1.17.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 17 Necrotizing enterocolitis.

Figure Analysis 1.18.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 18 Gastointestinal perforation.

Figure Analysis 1.19.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 19 Any retinopathy of prematurity.

Figure Analysis 1.20.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 20 Severe retinopathy of prematurity (grade 3 or greater).

Figure Analysis 1.21.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 21 Hospital infection.

Figure Analysis 1.22.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 22 Diminished urine output.

Figure Analysis 1.23.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 23 Elevated serum creatinine.

Figure Analysis 1.24.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 24 Thrombocytopaenia.

Figure Analysis 1.25.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 25 Excessive clinical bleeding.

Figure Analysis 1.26.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 26 Duration of hospital stay.

Figure Analysis 1.27.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 27 Abnormal Bayley Mental Developmental Index (< 68 - 70) in survivors examined.

Figure Analysis 1.28.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 28 Abnormal Bayley Physical Developmental Index (< 68) in survivors examined.

Figure Analysis 1.29.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 29 WPPSI-R: full scale<70 in survivors examined.

Figure Analysis 1.30.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 30 Severe developmental delay in survivors examined.

Figure Analysis 1.31.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 31 Cerebral palsy in survivors examined.

Figure Analysis 1.32.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 32 Visual impairment (blind) in survivors examined.

Figure Analysis 1.33.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 33 Hearing impairment (deaf) in survivors examined.

Figure Analysis 1.34.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 34 Severe neurosensory impairment (CP, cognitive delay, blindness, deafness) in survivors examined.

Figure Analysis 1.35.

Comparison 1 Prophylactic indomethacin vs. control, Outcome 35 Death or severe neurosensory impairment.

What's new

History

Protocol first published: Issue 3, 1997

Review first published: Issue 3, 1997

26 April 2002New citation required and conclusions have changedSubstantive amendment

Declarations of interest

None.

PWF was an MRC Training Fellow in Health Services Research when the original systematic review was undertaken in 1994-5.

Sources of support

Internal sources

  • Department of Child Health, University of Dundee, UK.

  • Murdoch Children's Research Institute, Melbourne, Australia.

  • Royal Women's Hospital, Melbourne, Australia.

  • Tayside University Hospital Trust, Dundee, UK.

External sources

  • MRC (UK), UK.

  • McMaster University, Department of Clinical Epidemiology and Biostatistics, Canada.

Ancillary