Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs
The incorporation of the large TIPP study, whose results typically contribute 40-75% of the total weight in the meta-analyses for short term outcomes, and 75-90% for long term outcomes, adds considerably to the precision of the estimates of treatment effect. This update confirms that prophylactic indomethacin has short term benefits. These include reductions in intraventricular haemorrhage and periventricular leukomalacia; reductions in symptomatic patent ductus arteriosus and the use of surgical ductal ligation; but there is no evidence of effect on pulmonary outcomes, late neurodevelopmental outcomes, or death.
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.
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].
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
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.
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.
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.
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.
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)].
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.
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.
PWF was an MRC Training Fellow in Health Services Research when the original systematic review was undertaken in 1994-5.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Bada 1989 | Blinding of randomisation: can't tell
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow up: yes |
141 newborn infants, birthweight < 1500 grams. Cranial US before study entry - excluded IVH of grade 2 or above. | IV 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) | Death 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) |
B | |
| Bandstra 1988 | Blinding 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%). |
199 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 |
IV 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 | Death 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 |
A | |
| Couser 1996 | Blinding 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. |
90 (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. | IV 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. | Neurodevelopmental 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. |
This 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. |
A |
| Domanico 1994 | Blinding of randomisation: can't tell
Blinding of intervention: yes Blinding of outcome measurement: Yes Complete (> 90%) follow-up: yes |
100 newborn babies, birth weight < 1250 grams | IV 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 | PDA (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. |
B | |
| Gutierrez 1987 | Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (>90%) follow-up:yes |
59 newborn infants less than 34 weeks gestation and less than 1751 grams birth weight | IV 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 | Death
Symptomatic PDA (Cabal-Siassi score > 3) |
A | |
| Hanigan 1988 | Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes |
111 newborn infants, birthweight < 1500 grams. All had normal cranial US before study entry. | IV 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. | Death;
IVH (Krishnamoorthy classification); PDA; Duration of ventilation; Pneumothorax |
A | |
| Krueger 1987 | Blinding of randomisation: can't tell
Blinding of intervention: no Blinding of outcome measurement: no Complete (> 90%) follow up: yes |
32 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. | IV prophylactic indomethacin, single dose (0.2 mg/kg) at 24 hours of age versus nothing (no placebo used) | Death;
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) |
B | |
| Mahony 1985 | Blinding of randomisation: yes (coded drugs)
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes |
110 newborn infants, birthweight 700-1300 grams | IV 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) | Mortality;
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) |
Six 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. | A |
| Ment 1985 | Blinding of randomisation: yes (coded drugs)
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes |
48 newborn infants, birthweight 600 - 1250 grams. Excluded any IVH on pre-study US. | IV 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. | Mortality;
IVH; All PDA; Parameters of renal function (urine output and serum electrolytes); Parameters of haemostasis Platelet abnormalities and bleeding problems) |
Dosage 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". | A |
| Ment 1988 | Blinding of randomisation: yes (coded drugs)
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes |
36 newborn infants, birthweight 600-1250 grams. Excluded infant with IVH on pre-study US. | IV 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. | Death;
IVH; PDA; Renal function (electrolyte abnormality, urine output); Haemostasis (Platelet count, clinical bleeding) |
A | |
| Ment 1994a | Blinding of randomisation: yes (randomized centrally by telephone in
blocks)
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes |
61 newborn infants all with IVH (grade 1 or 2) at time of enrollment. Birthweight 600-1250 grams | IV 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 | Death;
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) |
A | |
| Ment 1994b | Blinding 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. |
431 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. |
IV 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) | Death;
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) |
A | |
| Morales-Suarez 1994 | Blinding of randomisation: can't tell
Blinding of intervention: yes Complete followup: yes Blind outcome assessment: yes |
80 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 | IV prophylactic indomethacin 0.1 mg/kg in first 12 hours then 2 further doses 12 hours apart versus equal volume of normal saline placebo. | Death to hospital discharge; IVH - all and grade 3 and 4; symptomatic PDA, pneumothorax; sepsis. | B | |
| Puckett 1985 | Blinding of randomisation: can't tell
Blinding of intervention: can't tell Blinding of outcome measurement: can't tell Complete (> 90%) follow-up: no |
32 newborn infants, birthweight < 1400 grams | IV 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 | Death;
PDA; IVH; Duration of IMV; Duration of supplemental oxygen requirement |
Details of this study are available in abstract only | B |
| Rennie 1986a | Blinding 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 |
50 newborn infants, birthweight < 1750 grams. Excluded infants with IVH on pre-study US. | IV 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 | Death;
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) |
B | |
| Supapannachart 1999 | Blinding of randomisation: yes (sealed envelopes)
Blinding of intervention: yes Complete followup: yes Blind outcome assessment: yes. |
30 newborn infants with birth weights < 1250g and <24 hours old. Excluded: thrombocytopenia, elevated creatinine, overt bleeding, poor urine output and major congenital anomalies. | IV 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. | Death; symptomatic PDA; PDA ligation; BPD;
IVH: all and grade 3 and 4; NEC; diminished urine output; any ROP; sepsis |
A | |
| TIPP 2001 | Blinding 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 |
1202 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. |
IV 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. | Death;
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); |
Follow up outcomes assessed at 18 months. | A |
| Vincer 1985 | Blinding of randomisation: can't tell
Blinding of intervention: yes Blinding of outcome measurement: yes Complete (> 90%) follow-up: yes |
30 newborn infants, birthweight < 1500 grams | IV 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 | Cerebral 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) |
B | |
| Yaseen 1997 | Blinding of randomisation: yes - sealed, sequentially numbered and
coded envelopes
Blinding of intervention: yes Blind outcome assessment: yes Complete follow up (>90%): yes |
27 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 |
IV prophylactic indomethacin versus an equal volume of saline. First dose 0.2 mg/kg at 12 hours then repeated twice at 24 hour intervals. | Death before hospital discharge; IVH grades 3 and 4: BPD at 28 days;
duration of supplemental oxygen; NEC; duration of hospital stay. |
A |
| Study | Reason for exclusion |
| Bada 1996 | These 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 1980 | Not a study of indomethacin given prophylactically. |
| Cotton 1983 | No original data on prophylactic indomethacin |
| Gersony 1983 | Not a study of indomethacin given prophylactically. |
| Hammerman 1986 | Not an RCT |
| Hammerman 1987 | Not a study of indomethacin used prophylactically. All the infants enrolled had echocardiographic evidence of a PDA at 48-72 hours of life. |
| Hammerman 1990 | Not a study of indomethacin used prophylactically. |
| Hammerman 1995 | Not RCT |
| Kaapa 1983 | Not 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 1989 | Not a study of indomethacin used prophylactically. |
| Lai 1990 | This is an RCT of ORAL indomethacin used prophylactically. |
| Mahony 1982 | Not a study of prophylactic indomethacin - all infants had "subclinical PDA". |
| Mardoum 1991 | This 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 1987 | This 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 1993 | From 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 1981 | Not a study of indomethacin used prophylactically. |
| Monset-Couchard 1983 | Not a trial of indomethacin used prophylactically: all infants had symptomatic PDA. |
| Mullett 1982 | This is an RCT of oral indomethacin and the treatment is not used prophylactically: all infants had clinical evidence of a PDA. |
| Nestrud 1980 | Not a trial of indomethacin given prophylactically: all the infants had PDA. In addition, intervention was ORAL indomethacin versus placebo. |
| Neu 1980 | Not a study of indomethacin given prophylactically. Also uses oral preparation. |
| Rennie 1991 | Intervention was not indomethacin given prophylactically. |
| Rhodes 1988 | Not a trial of indomethacin used prophylactically. |
| Rudd 1983 | Not a study of indomethaicn used prophylactically. |
| Valaes 1980 | Not a study of indomethacin used prophylactically. |
| van Overmeire 1995 | Not an RCT of indomethacin used prophylactically. |
| Vogtmann 1988 | This is a trial of ORAL prophylactic indomethacin. |
| Wagner 1984 | This is essentially a large case series of surgical closure of PDA. It is not an RCT and not a study of prophylactic indomethacin. |
| Weesner 1987 | Not strictly a study of prophylactic therapy - all infants enrolled had an asymptomatic PDA |
| Wurtzel 1990 | This is a trial examining the effects of maternal antenatal indomethacin on the renal function of the newborn infant. |
| Yanagi 1981 | Not a study of indomethacin used prophylactically. |
| Yeh 1981 | Not 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 1993 | Not an RCT of indomethacin |
*Bada HS, Green RS, Pourcyrous M, et al. Indomethacin reduces the risks of severe intraventricular hemorrhage. J Pediatr 1989;115:631-7.
Bada HS, Green RS, Pourcyrous M, Leffler CW, Korones SB, Arheart K. Indomethacin reduces relative risks of severe intraventricular hemorrhage [Abstract]. Ped Res 1989;25:353A.
Pourcyrous M, Bada HS, Green RS, Korones SB. Safety of indomethacin use for newborn infants [Abstract]. Ped Res 1988;23:422A.
Bandstra 1988 {published data only}
*Bandstra ES, Montalvo BM, Goldberg RN, et al. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics 1988;82:533-542.
Setzer ES, Morse BM, Goldberg RN, Smith M, Bancalari E. Prophylactic indomethacin and intraventricular hemorrhage in the premature [Abstract]. Ped Res 1984;18:345A.
Setzer ES, Torres-Arraut E, Gomez-del-Rio M, Young ML, Pacheco I, Ferrer PL, et al. Cardiopulmonary effects of prophylactic indomethacin in the very low birth weight infant [Abstract]. Ped Res 1984;18:346A.
Setzer ES, Smith M, Goulding PJ, Bandstra TE. Severity of platelet dysfunction induced by prophylactic indomethacin in the premature [Abstract]. Pediatr Res 1984;18:346A.
Bandstra ES, Duenas ML, Rodriguez I, et al. Prophylactic indomethacin for the prevention of intraventricular hemorrhage (IVH): neurodevelopmental follow-up [Abstract]. Pediatr Res 1987;21:391.
Bandstra ES, Bauer CR, Duenas ML, Chao H, Montalvo BM, Bancalari E. Prophylactic indomethacin for prevention of intraventricular hemorrhage: neurodevelopmental follow-up [Abstract]. Ann Neurol 1987;22:427A.
Couser 1996 {published data only}
*Couser RJ, Ferrara TB, Wright GB, Cabalka AK, Schilling CG, et al. Prophylactic indomethacin therapy in the first 24 hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr 1996;128:631-637.
Couser RJ, Hoekstra RE, Ferrara B, Wright GB, Cabalka AK, Connet JE. Neurodevelopmental follow-up at 36 months' corrected age of preterm infants treated with prophylactic indomethacin. Arch Pediatr Adolesc Med 2000;154:598-602.
Domanico 1994 {published data only}
Domanico RS, Waldman JD, Lester LA, McPhillips HA, Catrambone JE, Covert RF. Prophylactic indomethacin reduces the incidence of pulmonary hemorrhage and patent ductus arteriosus in surfactant-treated infants < 1250 grams. Ped Res 1994;35:331A.
Gutierrez 1987 {published data only}
Gutierrez NG, Lapasset M. Prophylactic indomethacin and the incidence of patent ductus arteriosus in preterm neonates. In: Proceedings of the 3rd Argentinian Congress of Perinatology, Buenos Aires. Vol. 62. 1987.
Hanigan 1988 {published data only}
Hanigan WC, Kennedy G, Roemisch F, et al. Administration of indomethacin for the prevention of periventricular haemorrhage in high-risk neonates. J Pediatr 1988;112:941-7.
Krueger 1987 {published data only}
Krueger E, Mellander M, Bratton D, Cotton R. Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. J Pediatr 1987;111:749-54.
Mahony 1985 {published data only}
Mahony L, Caldwell RL, Girod DA, et al. Indomethacin therapy on the first day of life in infants with very low birth weight. J Pediatr 1985;106:801-5.
Ment 1985 {published data only}
Ment LR, Duncan CC, Ehrenkranz RA, et al. Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants. J Pediatr 1985;107:937-943.
Ment 1988 {published data only}
Ment LR, Duncan CC, Ehrenkranz RA, et al. Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J Pediatr 1988;112:948-55.
Ment 1994a {published data only}
Ment LR, Oh W, Ehrenkranz, Phillip AGS et al. Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial. J Pediatr 1994;124:951-5.
Ment 1994b {published data only}
Ment LR, Oh W, Ehrenkranz, Phillip AGS et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994;93:543-550.
Ment LR, Duncan CC, Ehrenkranz RA, Kleinman CS, Taylor KJW, Scott DT. Randomized low-dose indomethacin trial for the prevention of intraventricular hemorrhage in very low birth weight neonates [Abstract]. Ann Neurol 1987;22:406-407.
Ment LR, Vohr B, Oh W, Scott DT, Allen WC, Westerveld M, Duncan CC, Ehrenkranz RA, Katz KH, Schneider KC, Makuch RW. Neurodevelopmental outcome at 36 months corrected age of preterm infants in the multicenter indomethacin intraventricular hemorrhage prevention trial. Pediatrics 1996;98:714-718.
Ment L, Vohr B, Allan W, Westerveld M, Sparrow S, Schneider K, Katz K, Duncan C, Makuch R. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2000;105:485-491.
Morales-Suarez 1994 {published data only}
Morales-Suarez M, Sanchez-Gil T, Lemus-Varela L. Estudio comparavito de dosis baja de indometacina profilactica para hemorragia subependimaria/intraventricular en neonatos pretermino con ventilation mecanica [Low dose indomethacin for prevention of intraventricular hemorrhage in the preterm infant with mechanical ventilation: Final report of a randomized study]. Bol Med Hosp Infant Mex 1994;51:389 -394.
Puckett 1985 {published data only}
Puckett CG, Cox MA, Haskins KS, Fisher DJ. Prophylactic indomethacin (I) for the prevention of patent ductus arteriosus (PDA) [Abstract]. Pediatr Res 1985;19:358.
Rennie 1986a {published data only}
Rennie JM, Doyle J, Cooke RWI. Early administration of indomethacin to preterm infants. Arch Dis Child 1986;61:233-238.
Supapannachart 1999 {published data only}
Supapannachart S, Khowsathit P, Patchakapati B. Indomethacin prophylaxis for patent ductus arteriosus (PDA) in infants with a birth weight of less than 1250 grams. J Med Assoc Thai 1999;82:S87-S91.
TIPP 2001 {published data only}
Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, Solimano A, Vincer M, Wright LL and the TIPP investigators. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants (PMID: 11430325). New Engl J Med 2001;344:1966-1972.
Vincer 1985 {published data only}
*Vincer M, Allen A, Evans J, et al. Early intravenous indomethacin prolongs respiratory support in very low birth weight infants. Acta Paediatr Scand 1985;76:894-897.
Vincer M, Allen A. Does prophylactic indomethacin in VLBW (<1500 grams birth weight) infants cause cerebral palsy (CP)? Pediatr Res 1998;43:232.
Yaseen 1997 {published data only}
Yaseen H, al Umran K, Ali H, Rustum M, Darwich M, al-Faraidy A. Effects of early indomethacin administration on oxygenation and surfactant requirement in low birth weight infants. J Trop Pediatr 1997;43:42-46.
Bada HS, Yolton KA, Duncan C, Wong SP, Pourcyrous M, Korones SB. Indomethacin (INDO) prophylaxis and outcome at school age [abstract]. Ped Res 1996;39:373A.
Cotton 1980 {published data only}
Cotton RB, Hickey DE, Graham TP, Stahlman MT. Effects of early indomethacin (I) on ventilatory status of preterm infants with symptomatic patent ductus arteriosus (sPDA) [abstract]. Ped Res 1980;14:442A.
Cotton 1983 {published data only}
Cotton L, Hickey D, Stahlman MT. Management of premature infants with symptomatic patent ductus arteriosus Intensive. In: Stern L, editor(s). Care in the Newborn. IV edition. New York: Masson Publishing Co, 1983:225-231.
Gersony 1983 {published data only}
Gersony WM, Peckham GJ, Ellison RC, Miettinen OS, Nadas AS. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr 1983;102:895-906.
Peckham GJ, Miettinen OS, Ellison RC, Kraybill EN, Gersony WM, Zeirler S, Nadas AS. Clinical course to 1 year if age in premature infants with patent ductus arteriosus: results of a multicenter randomized trial of indomethacin. J Pediatr 1984;104:285-291.
Hammerman 1986 {published data only}
Hammerman C, Strates E, Valaitis S. The silent ductus: its precursors and its aftermath. Pediatric Cardiology 1986;7:121-127.
Hammerman 1987 {published data only}
Hammerman C, Strates E, Komar K, Bui K. Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Dev Pharmacol Ther 1987;10:393-404.
Hammerman 1990 {published data only}
Hammerman C, Aramburo MJ. Prolonged indomethacin therapy for the prevention of recurrences of patent ductus arteriosus. J Pediatr 1990;117:771-776.
Hammerman 1995 {published data only}
Hammerman C, Glaser J, Schimmel MS, Ferber B, Kaplan M, Eidelman AI. Continuous versus multiple rapid infusions of indomethacin: effects on cerebral blood flow velocity. Pediatrics 1995;95:244-248.
Kaapa 1983 {published data only}
Kaapa P, Lanning P, Koivisto M. Early closure of patent ductus arteriosus with indomethacin in preterm infants with idiopathic respiratory distress syndrome. Acta Paediatr Scand 1983;72:179-184.
Krauss 1989 {published data only}
Krauss AN, Fatica N, Lewis BS, Cooper R, Thaler HT, Cirrincione C, O'Loughlin J, Levin A, Engle MA, Auld PAM. Pulmonary function in preterm infants following treatment with intravenous indomethacin. Am J Dis Child 1989;143:78-81.
Lai 1990 {published data only}
Lai TH, Soong WJ, Hwang B. Indomethacin for the prevention of symptomatic patent ductus arteriosus in very low birth weight infants. Acta Paediatrica Sinica 1990;31:17-23.
Mahony 1982 {published data only}
*Mahony L, Carnero V, Brett C, Heymann MA, Clyman RI. Prophylactic indomethacin therapy for patent ductus arteriosus in very low birth weight infants. N Eng J Med 1982;306:506-510.
Mahony L, Heymann MA, Carnero V, Brett C, Clyman RI. When to treat the patent ductus arteriosus with indomethacin in very low birth weight infants. Adv Prostaglandin Thromboxane Leukot Res 1983;12:491-494.
Mardoum 1991 {published data only}
* Mardoum R, Bejar R, Merritt A, Berry C. Controlled study of the effects of indomethacin on cerebral blood flow velocities in newborn infants. J Pediatr 1991;118:112-115.
Mardoum R, Bejar R, McFeely E, Peterson B, Merritt TA. Controlled study of the effects of indomethacin (INDO) on the cerebral blood flow velocities in the newborn infant [Abstract]. Ped Res 1988;23:554.
Ment 1987 {published data only}
Ment LR, Duncan CC, Ehrenkranz RA, Kleinman CS, Taylor KJW, Scott DT. Randomized low-dose indomethacin trial for the prevention of intraventricular hemorrhage in very low birth weight neonates [Abstract]. Ann Neurol 1987;22:406-407.
Ment 1993 {published data only}
Ment LR, Oh W, Ehrenkrantz RA, Philip AGS, Schneider K, Katz KH, Taylor KJW, Duncan CC, Makuch. Risk period for intraventricular hemorrhage of the preterm neonate is independent of gestational age. Sem Perinatol 1993;17:338-341.
Merritt 1981 {published data only}
Merritt TA, Harris JP, Roghmann K, Wood B, Campanella V, Alexzon C, Manning J, Shapiro DL. Early closure of patent ductus arteriosus in very low birth weight infants: a controlled trial. J Pediatr 1981;99:281-286.
Monset-Couchard 1983 {published data only}
Monset-Couchard M, Dias-Mancano D, Murat I, Relier JP. Controlled trial of intravenous lyophilized indomethacin in the treatment of persistent ductus arteriosus in premature infants [French]. Pediatrie 1983;38:365-377.
Mullett 1982 {published data only}
*Mullett MD, Croghan TW, Myerberg DZ, Krall JM, Neal WA. Indomethacin closure of patent ductus arteriosus in prematures. Clin Pediatr 1982;21:217-220.
Mullett MD, Crogan TW, Myerberg DZ, Neal WA. Administration of oral indomethacin (I) to prematures with patent ductus arteriosus (PDA): a randomized double blind study [Abstract]. Ped Res 1980;14:606.
Nestrud 1980 {published data only}
Nestrud RM, Hill DE, Arrington RW, Beard AG, Dungan WT, Norton JB, Radinger RI. Indomethacin treatment in patent ductus arteriosus. A double blind study utilizing indomethacin plasma levels. Dev Pharmacol Ther 1980;1:125-136.
Neu 1980 {published data only}
Neu J, Ariagno RL, Johnson JD, Pitlick PT, Cohen JS, Beets CL. A double blind study of the effects of oral indomethacin (IN) in preterm infants with patent ductus arteriosus (PDA) who failed medical management [Abstract]. Ped Res 1980;14:607.
Rennie 1991 {published data only}
Rennie JM, Cooke RWI. Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Arch Dis Child 1991;66:55-58.
Rhodes 1988 {published data only}
Rhodes PG, Ferguson MG, Reddy NS, Joransen JA, Gibson J. Effects of prolonged versus acute indomethacin therapy in very low birth weight infants with patent ductus arteriosus. Eur J Paediatr 1988;147:481-484.
Rudd 1983 {published data only}
Rudd P, Montanez P, Hallidie-Smith K, Silverman M. Indomethacin treatment for patent ductus arteriosus in very low birthweight infants: double blind trial. Arch Dis Child 1983;58:267-270.
Valaes 1980 {published data only}
Valaes T, Moylan FMB, Cohn H, Chung K, Nagpaul K, Chrenoff HL, Kreidberg MB. Incidence and significance of PDA in preterm infants (PTI) and controlled blind trial of indomethacin (IND) [Abstract]. Ped Res 1980;14:452.
van Overmeire 1995 {published data only}
Van Overmeire B, Brus F, Van Acker KJ et al. Aspirin versus indomethacin treatment of patent ductus arteriosus in preterm infants with respiratory distress syndrome. Ped Res 1995;38:886-891.
Vogtmann 1988 {published data only}
Vogtmann C, Grubbe G, Ruckhaberle KE, Bottcher H, Ockert C. Effects of early therapy with indomethacin on the manifestation of a persistent ductus arteriosus in extremely underweight premature infants [German]. [Monatsschrift Kinderheilkunde 1988;136:636-639.
Wagner 1984 {published data only}
Wagner HR, Ellison C, Zierler S, Lang P, Purohit DM, Behrendt D, Waldhausen JA. Surgical closure of patent ductus arteriosus in 268 preterm infants. J Thorac Cardiovasc Surg 1984;87:870-875.
Weesner 1987 {published data only}
Weesner KM, Dillard RG, Boyle RJ, Block SM. Prophylactic treatment of asymptomatic ductus arteriosus in premature infants with respiratory distress syndrome. South Med J 1987;80:706-708.
Wurtzel 1990 {published data only}
Wurtzel D. Prenatal administration of indomethacin as a tocolytic agent: effect on neonatal renal function. Obstet Gynecol 1990;76:689-692.
Yanagi 1981 {published data only}
Yanagi RM, Wilson A, Newfeld EA, Aziz KU, Hubt CE. Indomethacin treatment for symptomatic patent ductus arteriosus: a double blind control study. Pediatrics 1981;67:647-652.
Yeh 1981 {published data only}
*Yeh TF, Luken JA, Thalji A, Raval D, Carr I, Pildes RS. Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus - a double blind controlled study. J Pediatr 1981;98:137-145.
Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS. Indomethacin and its effect on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus. Pediatrics 1981;68:99-102.
Yeh TF, Thalji A, Luken L, Lilien L, Carr I, Pildes RS. Improved lung compliance following indomethacin therapy in premature infants with patent ductus arteriosus. Chest 1981;80:698-700.
Yeh TF, Wilks A, Singh J, Betkerur M, Lilien L, Pildes RS. Furosemide prevents the renal side effects of indomethacin therapy in premature infants with patent ductus arteriosus. J Pediatr 1982;101:433-437.
Yeh TF, Goldbarg HR, Henek T, Thalji A, Pildes RS. Intravenous indomethacin therapy in premature infants with patent ductus arteriosus. Causes of death and one year follow-up. Am J Dis Child 1982;136:803-807.
Yeh TF, Raval D, Pyati S, Pildes RS. Retinopathy of prematurity (ROP) and indomethacin therapy in premature infants with patent ductus arteriosus (PDA). Prostaglandins 1983;25:385-391.
Zamboni 1993 {published data only}
Zamboni G, Piemonte G, Boner A et al. Influence of dietry taurine on vitamin D absorption. Acta Paediatrica 1993;82:811-815.
Morales-Suarez M, Lemus-Varella L, Udaeta-Mora E, Cardiel-Marmolejo L, Rodriguez-Balderrama I, Liz-Cedilla RE. Indomethacin in the prevention of subependymal-intraventricular hemorrhage in preterm newborns with conventional mechanical ventilation. Bol Med Hosp Infant Mex 1992;49:217-24.
* indicates the primary reference for the study
Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. J Pediatr 1979;95:865.
Cifuentes RF, Olley PM, Balfe JW et al. Indomethacin and renal function in premature infants with persistent patent ductus arteriosus. J Pediatr 1979;95:583-7.
Coombs RC, Morgan MEI, Durbin GM et al. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990;65:1067-71.
Edwards AD, Wyatt JS, Richardson C et al. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990;335:1491-5.
Fowlie PW. Prophylactic indomethacin: systematic review and meta-analysis. Arch Dis Child 1996;74:F81-F87.
Friedman Z, Whitman V, Maisels MJ et al. Indomethacin disposition and indomethacin-induced platelet dysfunction in premature infants. J Clin Pharmacol 1978;18:272-279.
Herson VC, Krause PJ, Eisenfeld LI et al. Indomethacin associated sepsis in the very low birth weight infant. Am J Dis Child 1988;142:555-58.
Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N Eng J Med 1976;295:530-3.
Kitterman JA, Edmunds LH Jn, Gregory GA, Heymann MA, et al. Patent ductus arteriosus in premature infants: incidence and relation to pulmonary disease and management. N Eng J Med 1972;287:473.
Lipman B, Server GA, Brazy JE. Abnormal cerebral haemodynamics in preterm infants with patent ductus arteriosus. Pediatrics 1982;69:778-781.
Ment LA, Stewart WB, Duncan CC et al. Beagle puppy model of intraventricular haemorrhage: effect of indomethacin on cerebral blood flow. J Neurosurgery 1983;58:857.
Ment LA, Stewart WB, Ardito TA et al. Indomethacin promotes germinal matrix maturation in the newborn beagle puppy. Stroke 1992;23:1132-37.
Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press:285-289, 403-405, 568-571, 606-607, 624-625.
Fowlie PW. Intravenous indomethacin for preventing mortality and morbidity in very low birth weight infants (Cochrane Review). In: The Cochrane Library, Issue 3, 1997. Oxford: Update Software.
01.01 Death to hospital discharge
01.02 Death at latest follow-up
01.03 All IVH
01.04 IVH Grade 3 and 4
01.05 IVH that progresses
01.06 Periventricular leukomalacia/ ischaemic
changes
01.07 White matter injury on cranial ultrasound
01.08 Symptomatic PDA
01.09 All PDA (echo-diagnosed, symptomatic
or not)
01.10 PDA ligation
01.11 Pulmonary haemorrhage
01.12 Pneumothorax
01.13 Duration of supplementary oxygen
requirement
01.14 Duration of assisted ventilation
01.15 Chronic lung disease (28 days)
01.16 Chronic lung disease in surviving
infants (36 weeks)
01.17 Necrotizing enterocolitis
01.18 Gastointestinal perforation
01.19 Any retinopathy of prematurity
01.20 Severe retinopathy of prematurity
(grade 3 or greater)
01.21 Hospital infection
01.22 Diminished urine output
01.23 Elevated serum creatinine
01.24 Thrombocytopaenia
01.25 Excessive clinical bleeding
01.26 Duration of hospital stay
01.27 Abnormal Bayley Mental Developmental
Index (< 68 - 70) in survivors examined
01.28 Abnormal Bayley Physical Developmental
Index (< 68) in survivors examined
01.29 WPPSI-R: full scale<70 in survivors
examined
01.30 Severe developmental delay in survivors
examined
01.31 Cerebral palsy in survivors examined
01.32 Visual impairment (blind) in survivors
examined
01.33 Hearing impairment (deaf) in survivors
examined
01.34 Severe neurosensory impairment (CP,
cognitive delay, blindness, deafness) in survivors examined
01.35 Death or severe neurosensory impairment