Use of Prophylactic Indomethacin in Preterm Infants: A Systematic Review and Meta-analysis

DOI: https://doi.org/10.21203/rs.3.rs-111839/v1

Abstract

Background

Prophylactic indomethacin has been widely used as an effective intervention for reducing mortalities and morbidities in preterm infants including the cardiopulmonary and neurodevelopmental morbidities as intraventricular hemorrhage (IVH), but many studies have reported contraindicated outcomes of its significance. Therefore, we aim to systematically review and meta-analyze the data of prophylactic indomethacin on preterm infants.

Methods

Our systematic search included the following databases: Pubmed, Google Scholar, Scopus, Web of Science, The New York Academy of Medicine (NYAM), Virtual health library (VHL), and the System for Information on Grey Literature in Europe (SIGLE) to include studies that assessed the use of prophylactic indomethacin in preterm infants until August 12, 2020.

Results

The final list of our included studies is comprised of 22 randomized trials and cohort studies. Our analysis of observational data showed that intubation in the delivery room/first day (74%), bronchopulmonary dysplasia (BPD) (33.2%), and patent ductus arteriosus (PDA) (32.2%) were the most prevalent outcomes in infants that received prophylactic indomethacin. Among all the studies outcomes, the only significant favorable outcome was lowering the rate of PDA (P< 0.001) while no significance was recorded with BPD, pulmonary hemorrhage, neurodevelopmental delays (IVH), mortality, length of hospital stays, and time spent on ventilators outcomes (P = 0.106, 0.123, 0.460, 0.340, 0.625, and 0.732, respectively). Moreover, necrotizing enterocolitis was significantly increased when applying prophylactic indomethacin in these infants (P< 0.001).

Conclusion

The use of prophylactic indomethacin in preterm infants should be generally discouraged due to its neutral effect on most of the mortality and morbidity outcomes and the significant occurrence of its adverse events despite the positive effect on ductal closure.

Structured Summary

Background

Many authors believe neurologic disabilities have been associated with preterm labor presumed due to either over circulation or under circulation secondary to patent ductus arteriosus.

 Objectives

Systemically revied all published RCT and meta-analysis to find if prophylactic indomethacin can decrease CNS complications.

 Data sources

Following the Preferred Reporting Items for Systematic Review and Meta-analyses statement (PRISMA) recommendations, we performed this systematic review and meta-analysis (32). A systematic electronic database search was conducted for relevant studies published, from inception to 12th August 2020, in seven databases: Pubmed, Google Scholar, Scopus, Web of Science, The New York Academy of Medicine (NYAM), Virtual health library (VHL), and the System for Information on Grey Literature in Europe (SIGLE).

 Study eligibility criteria, participants, and interventions

Participants were any preterm infants, the intervention was the prophylactic indomethacin, the comparison was placebo or no treatment groups, and all possible outcomes were included. The systematic search was followed by a manual search in references of the included papers to include missed papers. We included all original studies that assessed the use of prophylactic indomethacin in preterm infants.

Papers were excluded if there were one of the following exclusion criteria:

  1. non-original studies
  2. in vitro or animal studies;
  3. data duplication, overlapping or unreliably extracted or incomplete data;
  4. abstract only articles, reviews, thesis, books, conference papers, or articles without available full texts (conferences, editorials, author response, letters, and comments.

Risk of bias

The revised Cochrane quality assessment tool (RoB 2) was used to determine the quality of randomized studies and the risk of bias in non-randomized studies - of interventions (ROBINS-I) tool for non-randomized studies.

Data analysis

All data were analyzed using R software version 4.0.2. Using the “meta” package, odds ratios (OR) and prevalence rates of different outcomes were calculated. The corresponding 95% confidence intervals (CI) of pooled effect size were calculated using a fixed-effects or random-effects, according to heterogeneity level. Heterogeneity was assessed with Q statistics and I2 test considering it significant with I2 value > 50% or P-value < 0.05.

The publication bias was assessed using Egger’s regression test and represented graphically by Begg’s funnel plot when there were ten or more studies/effect sizes. Egger’s regression test P-value < 0.10 was considered significant. Whenever publication bias was found, the trim and fill method of Duvall and Tweedie was applied to add studies that appeared to be missing to enhance the symmetry.

Limitations

Limitations to our study include the significant heterogeneity in the analysis of some outcomes due to the different study designs that were included in this study. However, we estimated the risk of bias in most cases when significant heterogeneity was estimated, and no significant risk was found in these events.

Conclusions

Prophylactic indomethacin in VLBW infants has proven efficient in preventing short-term events as PDA. My analysis, however, showed no significance on IVH despite the many investigations that were published before which showed that indomethacin can reduce the incidence of IVH and other neurodevelopmental abnormalities.

Implications of key findings

I tried to lose the debate in this matter, so the clinician can work on other interventions or quality projects to help in decreasing CNS complications in preterm infants.

Systematic review registration number

We could not obtain because there are a big waiting list and priority for UK researchers.

Background

Many cardiopulmonary and neurologic disabilities have been associated with preterm labor including patent ductus arteriosus (PDA), pulmonary hemorrhage, intracranial hemorrhage, and mental retardation (1-4). Although advances in modern medicine have improved the survival rates of very low birth weight (VLBW) infants, many neurodevelopmental complications are still present due to preterm birth such as blindness, deafness, and cerebral palsy. VLBW infants are liable to intraventricular hemorrhage (IVH) which is usually associated with the neurodevelopmental decays when related to the brain parenchyma. IVH grade 3-4 is a major risk factor for the occurrence of these complications in preterm infants (5-8). Although the incidence rate of IVH has been markedly reduced since the 1980s (9, 10), no or minimal reductions have been recorded recently (11, 12).

Many pre- and postnatal interventions have been reported to effectively treat IVH and reduce its incidence in preterm infants (13). One of these is indomethacin prophylaxis which is better administered within the first six hours after birth (14-17). Besides, it helps in the closure of ductus arteriosus and therefore, can prevent the complications of PDA as pulmonary hypertension (14, 15, 18). Its mechanisms of action include prostaglandin synthesis inhibition by inhibiting the cyclooxygenase pathways, reduction of hyperemic responses resulting from cerebrovascular hypoxia and hypercapnia, increasing the blood-brain barrier permeability, and prevention of cerebral perfusion-induced ischemia (19-23). Moreover, it enhances microvascular development in the germinal matrix (24). Perfusion-related factors as hypoxia, hypercapnia, and hypotension usually develop after birth in VLBW infants (25). Most cases of preterm infants develop IVH within 6-8 hours after birth regardless of the gestational age (26). It happens probably due to the increased levels of angiopoietin 2 and vascular endothelial growth factor in the germinal matrix that normally decreases within hours after birth (13).

The results of previously published randomized controlled trials (RCTs) have shown that early administration of indomethacin after birth lowers the incidence of symptomatic PDA and severe IVH as a prophylactic measurement (16, 27-29). Although indomethacin administration showed favorable outcomes in reducing IVH incidence, many concerns have aroused concerning its effect on cerebral perfusion (30, 31). The rates of mortalities, bronchopulmonary dysplasia (BPD), or long-term neurodevelopmental decays reportedly seem to have been not affected. A previously published large RCT advised against using indomethacin as a prophylactic agent (15). Although the study showed favorable outcomes in terms of reducing incidence rates of PDA, PDA ligation, IVH, and pulmonary hemorrhage, no improvement regarding the incidence of death and neurodevelopmental disorders rates has been found. Therefore, in this systematic review, we aim to analyze the data of previously published investigations on the use of prophylactic indomethacin in preterm infants.

Methods

Search strategy and study selection

In accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses statement (PRISMA) recommendations, we performed this systematic review and meta-analysis (32). A systematic electronic database search was conducted for relevant studies published, from inception to 12th August 2020, in seven databases: Pubmed, Google Scholar, Scopus, Web of Science, The New York Academy of Medicine (NYAM), Virtual health library (VHL), and the System for Information on Grey Literature in Europe (SIGLE). The search process conducted using keywords, medical subject (MeSH) terms, and publication types based on the PICO framework (participants, comparison, intervention, and outcomes). Participants were any preterm infants, the intervention was the prophylactic indomethacin, the comparison was placebo or no treatment groups, and all possible outcomes were included. The systematic search was followed by a manual search in references of the included papers to include missed papers (33).

We included all original studies that assessed the use of prophylactic indomethacin in preterm infants. Papers were excluded if there were one of the following exclusion criteria: i) non-original studies ii) in vitro or animal studies; iii) data duplication, overlapping or unreliably extracted or incomplete data; iv) abstract only articles, reviews, thesis, books, conference papers or articles without available full texts (conferences, editorials, author response, letters, and comments. The title and abstract screening were performed by four independent reviewers. Furthermore, three independent reviewers performed full-text screening to ensure the inclusion of relevant papers in our systematic review. Any disagreement was done by discussion and consulting the senior member when necessary. 

Data extraction

Two authors made the pilot extraction of a few papers for building the data extraction sheet. The data extraction sheet included: patient’s characteristics, outcomes, and risk of bias tool. Two authors extracted the data and reviewed by a third reviewer when necessary. If a disagreement occurs, a senior author was consulted.

Risk of bias

Three independent authors assessed the risk of bias among different included studies using the revised Cochrane quality assessment tool (RoB 2) was used to determine the quality of randomized studies (34) and the risk of bias in non-randomized studies - of interventions (ROBINS-I) tool for non-randomized studies (35). Any discrepancy between the reviewers was solved by discussion or in conjugation with the senior author.

Statistical analysis

All data were analyzed using R software version 4.0.2 (36). Using the “meta” package, odds ratios (OR) and prevalence rates of different outcomes were calculated (37). The corresponding 95% confidence intervals (CI) of pooled effect size were calculated using a fixed-effects or random-effects, according to heterogeneity level. Heterogeneity was assessed with Q statistics and I2 test considering it significant with I2 value > 50% or P-value < 0.05 (38).

The publication bias was assessed using Egger’s regression test (39, 40) and represented graphically by Begg’s funnel plot (41) when there were ten or more studies/effect sizes. Egger’s regression test P-value < 0.10 was considered significant. Whenever publication bias was found, the trim and fill method of Duvall and Tweedie was applied to add studies that appeared to be missing (42) to enhance the symmetry.

Results

Search results

We identified 3,801 records after excluding of 506 duplicates by using Endnote software version X9. Title and abstract screening resulted in 36 records for further full-text screening. The later yielded 20 eligible papers for inclusion in our study. Two papers were added after performing manual search trials. Finally, we included 22 studies for this systematic review and meta-analysis (Figure 1).

Study characteristics and risk of bias

Out of the 22 included studies; seven were randomized controlled trials and the remaining 15 were cohort in design. The sample size of the included studies was highly variable ranging from 19 and as high as 34,602 pre-term infants. The average mean age in all reported treatment groups was 28 weeks (ranging from 25 to 50 weeks), while it was 27 weeks in control ones (ranging from 26 to 29 weeks). Table 1 shows the main characteristics of the included studies.

The overall risk of bias in the included RCTs was low in more than 50% of all items. The domains with major problems were deviations from intended interventions, randomization processes, and missing outcome data (Figure 2). For non-randomized trials, the risk of bias was higher with more than 50% of all items showing serious of critical risks of bias. Domains with the biggest issues were deviations from intended interventions, selective reporting, and cofounding of the results (Figure 3).

Cardiopulmonary Outcomes

Eight studies, with a total of 20,708 preterm infants, were included in the analysis of patent ductus arteriosus (PDA) rates. Infants with prophylactic doses of indomethacin showed significantly lower rates of PDA compared to those who did not (OR= 0.33; 95% CI= 0.27-0.39; P-value< 0.001). However, there was significant heterogeneity among the included studies (I2= 72%; P-value< 0.001) (Figure 4).

In contrast, there was no significant differences among the two groups when compared in terms of BPD (OR= 1.08; 95% CI= 0.98-1.18; P-value= 106) and pulmonary hemorrhage rates (OR= 0.84; 95% CI= 0.67-1.05; P-value= 0.132). There was no significant heterogeneity among the included studies for both BPD (I2= 48%; P-value= 0.121) and pulmonary hemorrhage (I2= 0%; P-value= 0.786) outcomes (Figure 4).

Neuro-developmental Outcomes

Nine studies, with 17,949 pre-term infants, and five studies, with 20,116 pre-term infants, were included in the analyses of IVH and cerebral palsy (CP)/neurodevelopmental delay outcomes, respectively. There were no significant differences between prophylactic indomethacin group and the placebo/no treatment group in terms of IVH (OR= 0.90; 95% CI= 0.69-1.18; P-value= 0.460) and CP/neurodevelopmental delay (OR= 1.00; 95% CI= 0.81-1.23; P-value= 0.997). For heterogeneity, there was a significant heterogeneity in both analyses with (I2= 84%; P-value< 0.001) and (I2= 76%; P-value= 0.002) for IV and CP/neurodevelopmental delay, respectively (Figure 5).

Necrotizing enterocolitis/Intestinal perforation, and death

Nine studies, with 35,759 preterm infants, were included in the analysis of necrotizing enter colitis (NEC)/Intestinal perforation (IP) rates. There was a significant increase in NEC/IP rates in prophylactic indomethacin group when compared to the placebo/no treatment group (OR= 1.36; 95% CI= 1.24-1.49; P-value< 0.001). Moreover, there was no significant heterogeneity among the included studies (I2= 44%; P-value= 0.088) (Figure 6).

In the same context, death rates were compared in 47,265 patients of 13 included studies. There were no significant differences in death rates of prophylactic indomethacin group when compared to the placebo/no treatment group (OR= 1.06; 95% CI= 0.94-1.19; P-value= 0.340). However, there was significant heterogeneity among the included studies (I2= 69%; P-value< 0.001). There was no significant risk of bias when tested using Egger’s regression test (P-value= 0.428) (Figure 7).

Hospitalization outcomes

Two studies of 340 patients were included in the analyses of hospitalization days and days spent of ventilation. On comparing these outcomes among the prophylactic indomethacin and placebo/no treatment groups, there was no statistically significant difference for hospitalization days (MD= 3.67; 95%CI= -11.03-18.37; P-value= 0.625) and days spent of ventilation (MD= -1.00; 95%CI= -6.71-4.71; P-value= 0.732). There was a significant heterogeneity in the analysis of hospitalization days (I2= 56%; P-value= 0.132), while it was not present in the analysis of days spent of ventilation (I2= 0%; P-value= 1.000) (Figure 8).

Prevalence of different outcomes in indomethacin group

For studies with a single prophylactic indomethacin group (no placebo/no treatment group), they were pooled with all other studies (two-armed) with similar outcomes to get the overall prevalence. The highest prevalence observed in pre-term infants with prophylactic indomethacin was the intubation in delivery room/first day (74%; 95%CI= 52.9-100.0), followed by BPD (33.2%; 95%CI= 25.6-43.1), PDA (32.2%; 95%CI= 27.3-38.0) and IVH (26.1%; 95%CI= 19.1-35.7), respectively (Figure 9). All prevalence analyses showed a significant heterogeneity (I2> 50%; P-value< 0.001); however, there was no significant risk of bias in all analyses (Egger’s P-value > 0.10). Table 2 details the prevalence of different outcomes in the prophylactic indomethacin group.

Discussion

In this study, we have included 22 studies from the systematic and manual search to be analyzed to study indomethacin as a prophylactic measurement in pre-term infants from many aspects including the cardiopulmonary, neurodevelopmental delays, necrotizing enterocolitis/Intestinal perforation and death, days of hospitalization and the time spent on mechanical ventilation together with the prevalence of these outcomes from eligible study designs. The pooled results of our analysis showed that intubation on the first day at the delivery room was the most prevalent outcome, while pulmonary hemorrhage was the least. In general, these rates are like previously published reports. Laptook et al. (43) reported a prevalence rate of 29.2% for neurodevelopmental delays VLBW infants. PDA was prevalent in 65.57% in neonates at birth and 41% of the patient who received indomethacin did not have favorable outcomes in Koch et al. study (44). The quality of the included studies was good in general which is suggestive of valid data included in the analysis. However, analyzed data showed various heterogeneity in some outcomes which is probably due to the difference in study designs, the different dosages of indomethacin injection, and outcome definition between studies.

As for the cardiopulmonary outcomes, our analysis showed that prophylactic indomethacin administration in infants significantly lowers the rates of PDA formation (P-value< 0.001). Although, significant heterogeneity was estimated (I2= 72%; P-value< 0.001) due to the different study designs that were included in the analysis, our results were similar to previously published studies (45, 46). On the other hand, the effect of indomethacin on BPD and pulmonary hemorrhage rates was statistically non-significant (P-value =106 and 0.132, respectively). This is consistent with previously published meta-analysis studies of RCTs which found significance in terms of lowering PDA rates, but no difference in terms of BPD (45). Jensen et al. (46) in their analysis of observational data found that prophylactic indomethacin did not increase or decrease the risk of developing BPD. Moreover, the authors compared these results with another analysis of RCTs, however, the analysis indicated the same information that prophylactic indomethacin had no beneficial effects of BPD.

In terms of neurodevelopmental outcomes, our analysis showed that indomethacin prophylaxis did not significantly reduce the risk of IVH and CP/neurodevelopmental outcomes in preterm infants when compared to the placebo group (P-value =0.460 and 0.997, respectively). Our results are consistent with the results of Cooke et al. (47) which found no significance on the effect of prophylactic indomethacin on IVH and other neurodevelopmental abnormalities as retinopathy of prematurity. On the other hand, Fowlie et al. found a significant reduction in IVH incidence in infants that were prophylactically injected with indomethacin. However, significant heterogeneity in this study was estimated due to the inconsistency of treatment efficacy among their included studies (45). None of the studies, however, measured the long-term outcomes, they have only focused on the short ones. Schmidt et al. (15) in their big trial on 18-month infants reported statistical insignificance on long term neurodevelopmental outcomes although IVH grade 3 and 4 were significantly reduced. Therefore, concerns should be made to assess the overall quality of the effect of indomethacin on the long-term neurodevelopmental outcomes and the rate of adverse events incidence due to the vasoconstrictive nature of the drug which may alter the cerebral blood flow.

Other adverse events of prophylactic indomethacin application include increase incidence rates of necrotizing enter colitis (NEC)/Intestinal perforation (IP). In our study, a significant increase in the rate of these outcomes was estimated (P-value< 0.001). Our study results are inconsistent with the results of other previously published systematic reviews which found no significance on the effect of indomethacin on increasing the incidence of NEC (14, 45, 47). Additionally, other events were discussed by these studies as the effect of indomethacin on renal function. Fowlie et al. (14) found significance in the increased rate of oliguria but not creatinine levels.

Furthermore, we found no significance between the use of prophylactic indomethacin on infants in reducing the time of hospital stay and time spent on mechanical ventilation. Fowlie et al. (14) result favored the control groups in terms of time spent in the hospital with no significance (P =0.087), however, the opposite was reported with the time spent on ventilation with reported statistical significance (P =0.33). Besides, the data of 13 included studies showed no significance in reducing the rates of mortality in infants that received prophylactic indomethacin (P =0.34). Despite the heterogeneity in our analysis, the results are consistent with these shown by Fowlie et al. (14, 45). On the other hand, Jensen et al. (46) subgroup analysis showed a low rate of mortality in the infants that received prophylactic indomethacin with no intrauterine growth restriction and with no requirement for subsequent PDA treatment. However, the authors included observational data only.

Limitations to our study include the significant heterogeneity in the analysis of some outcomes due to the different study designs that were included in this study. However, we estimated the risk of bias in most cases when significant heterogeneity was estimated, and no significant risk was found in these events.

Conclusion

Prophylactic indomethacin in VLBW infants has proven efficient in preventing short-term events as PDA. Our analysis, however, showed no significance on IVH despite the many investigations that were published before which showed that indomethacin can reduce the incidence of IVH and other neurodevelopmental abnormalities. Consequently, and based on the findings that higher rates of NEC/IP and the neutral effect on infant mortality, the use of prophylactic indomethacin should be generally discouraged until a proper assessment of the case has been provided.

Abbreviations

Patent ductus arteriosus (PDA); Necrotizing enter colitis (NEC); Intestinal perforation (IP); Intraventricular hemorrhage (IVH); Bronchopulmonary dysplasia (BPD); Very low birth weight (VLBW).

Declarations

This study by analysis of existing publicaions and not involve with patient so consent was not indicated.

Ethical approval

Ethical approval was obtained from the Institutional Review Board in King Fahad Medical City, Riyadh, Saudi Arabia before any study started.  

Availability of the data and Materials

Data is available upon request. 

Competing interest

The authors have no conflicts of interest to declare

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributor

N/A

Acknowledgments

The author would like to thanks the Research Centre, King Fahad Medical City, Riyadh, Saudi Arabia, for providing support in preparing this manuscript.

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  46. Jensen EA, Foglia EE, Schmidt B. Association between prophylactic indomethacin and death or bronchopulmonary dysplasia: A systematic review and meta-analysis of observational studies. Seminars in perinatology. 2018;42(4):228-34.
  47. Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants. The Cochrane database of systematic reviews. 2003(2):Cd003745.

Tables

Table 1. Characteristics of the included studies

Author Year

Design

Sample Size

Gestational Age

Birth Weight

Male

Aim

Main conclusion(s)

Treatment Group

Control Group

Treatment Group

Control Group

Treatment Group

Control Group

Total

Mean

SD

Total

Mean

SD

Total

Mean

SD

Total

Mean

SD

Event

Total

Event

Total

Alfaleh et al. 2008

RCT

1202

1202

25.91

1.87

-

-

-

-

-

-

-

-

-

615

1202

-

-

To study the effect of prophylactic indomethacin on the prevention of serious hemorrhages in extremely low birth weight infants

Prophylactic indomethacin reduces the rate of early serious pulmonary hemorrhage, mainly through its action on patent ductus arteriosus. Prophylactic indomethacin is less effective in preventing serious pulmonary hemorrhages that occur after the first week of life.Z:AA

Bada et al. 1989

RCT

141

71

28

2.2

70

28

2.6

71

1103

253

70

1074

265

37

71

26

70

to determine the efficacy of indomethacin in preventing periventricular-intraventricular hemorrhage (PV-IVH).

indomethacin prophylaxis reduced the relative risk of grades 2 to 4 PV-IVH and severe PV-IVH, but other perinatal variables contributed significantly to the overall risk of PV-IVH.

Bandstra et al. 1988

RCT

199

99

29

2.3

100

29.3

2.1

99

970

174

100

970

183

51

99

43

100

To assess the impact of early prophylactic use of intravenous indomethacin on the incidence and severity of periventricular-intraventricular hemorrhage and patent ductus arteriosus in 199 oxygen-requiring premature infants

Early prophylactic indomethacm initiated within 12 hours of delivery is effective in reducing the incidence of intraventnicular hemorrhage as well as clinically significant patent ductus arteniosus in very low birth weight premature infants.

Bhat et al. 2019

Cohort

1154

912

25.1

1.94

-

-

-

912

687.6

179.39

-

-

-

442

912

-

-

To evaluate whether rates of perinatal brain injury among extremely low birth weight infants

Use of a single prophylactic indomethacin dose was as effective as a standard regimen in preventing perinatal brain injury.

Clyman et al. 2007

RCT

1202

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

to determine the association between the 2 trials and indomethacin use and to statistically assess the assumptions that led to the TIPP trial’s negative results

Two multicenter RCTs were associated with changes in indomethacin prophylaxis. After the Ment trial, the use of indomethacin prophylaxis increased. After the TIPP trial, which reported negative results based on an excessively large anticipated effect size, its use decreased

Foglia et al. 2018

RCT

1196

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

To determine whether the relative treatment effects of prophylactic indomethacin on severe IVH and the composite outcome of death or NDI vary based on the risk of severe IVH

These findings do not support selective prophylactic indomethacin treatment to improve longterm outcomes of ELBW infants at high risk for severe IVH.

Jensen et al. 2017

Cohort

7,831

2,587

25.9

1.5

5244

26.7

1.6

2,587

777

197

5244

913

246

1270

2,587

2744

5244

To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants

Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death.

Kelleher et al. 2014

Cohort

15751

-

-

-

-

-

-

-

-

-

-

-

-

2862

5874

4698

9877

To assecc the effect of the use of prophylactic indomethacin and early feeding on SIP in ELBW infants

The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.

Laughon et al. 2007

Cohort

34602

-

-

-

-

-

-

-

-

-

-

-

-

3293

6189

15406

28413

To describe the current use of treatments to prevent or treat patent ductus arteriosus (PDA) in preterm infants, examine the association between different treatment strategies and neonatal outcomes and review the variation in these practices between centers.

Indomethacin use for intraventricular hemorrhage prevention and/or treatment of a PDA is common, but the selection of infants for treatment, and the decision of when and how to treat vary widely between centers. Our findings suggest the need for randomized, placebo-controlled trials of the effect of treatment of the PDA in preterm infants.

Liebowitz et al. 2016

Cohort

313

215

26.1

1.1

98

26.1

1.1

215

833

203

98

826

205

114

215

37

98

To determine whether a moderate-to-large patent ductus arteriosus (PDA) is responsible for vasopressordependent hypotension, occurring at the end of the first postnatal week

prophylactic indomethacin treatment decreases vasopressor-dependent hypotension and the need for respiratory support at the end of the first postnatal week. These effects are mediated by closure of the PDA.

Liebowitz et al. 2017

Cohort

397

247

26.1

1.2

150

26

1.2

247

813

197

150

802

200

117

247

90

150

To determine whether prophylactic indomethacin (prophylactic indomethacin treatment) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA).

 

Maruyama et al. 2012

RCT

19

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

to investigate the effects of prophylactic low-dose indomethacin on renal and intestinal blood flow.

Prophylactic low-dose indomethacin increases the diastolic blood flow in the RAand SMAvia a reduction in the ductal shunt volume, with no change in the regional vascular resistance

Mirza et al. 2013

Cohort

868

868

26.36

1.97

-

-

-

868

864.82

210.84

-

-

-

431

868

-

-

To test the hypothesis that administration of indomethacin prophylaxis before 6 hours of life results in a lower incidence of intraventricular hemorrhage (IVH) compared with administration after 6 hours of life, and that the effects of early prophylaxis depend on gestational age (GA) and sex in very low birth weight infants (birth weight <1250 g)

Prophylactic indomethacin administered before 6 hours of life is not associated with lower incidence of IVH.

Mirza et al. 2015

Cohort

4255

4,255

50

0.65

-

-

-

4,255

744

147

-

-

-

2,077

4,255

-

-

To evaluate the effects of indomethacin prophylaxis administered at ≤6 hours compared to after 6 hours of age on the incidence of PDA receiving treatment (medical or surgical) or death in ELBW infants.

IP at ≤6 h of age is not associated with less IVH or death, but is associated with less PDA receiving treatment/ligation or death.

Narayanan et al. 2000

Cohort

300

130

25.5

1.1

170

25.5

1.1

130

798

172

170

803

180

68

130

87

170

To examine the role of prophylactic indomethacin in producing permanent DA closure and the mechanism by which this occurs

Prophylactic indomethacin improved the rate of permanent ductus closure by increasing the degree of initial constriction. Prophylactic indomethacin did not affect the remodeling process, nor did it alter the inverse relationship between infant maturity and subsequent reopening. Even when managed with prophylactic indomethacin, the rate of ductus reopening remained unacceptably high in the most immature infants.

Nelin et al. 2017

Cohort

671

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

to determine whether PI use in a contemporary cohort of EP infants admitted to an all-referral NICU continues to be associated with beneficial outcomes

PI administration was associated with improved survival in EP infants referred to a level IV Children’s Hospital NICU.

Rolnitsky et al. 2015

Cohort

3465

-

-

-

-

-

-

269

749

151

3,189

858

214

135

269

1,732

3,189

to evaluate the association of prophylactic antenatal steroids, indomethacin, and phototherapy with extremely preterm infant outcomes in a pragmatic setting.

Antenatal steroids were associated with reduced mortality and neurological injury, prophylactic indomethacin was not associated with reduction in neurological injury and phototherapy was not associated with any improvement in neonatal outcomes. In a pragmatic setting, outside randomized controlled trials, the effectiveness and safety of prophylactic interventions in extremely preterm neonates vary; ongoing monitoring is warranted.

Schmidt et al. 2001

RCT

1202

601

25.9

1.8

601

26

1.9

601

782

131

601

783

130

309

601

306

601

to determine whether the prophylactic administration of indomethacin improves survival without neurosensory impairment in extremely-low-birth-weight infants (those with birth weights below 1000 g)

In extremely-low-birth-weight infants, prophylaxis with indomethacin does not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of patent ductus arteriosus and severe periventricular and intraventricular hemorrhage

Schmidt et al. 2003

Cohort

910

910

26.2

1.8

-

-

-

910

793

127

-

-

-

454

910

-

-

To determine the individual and combined prognostic effects of bronchopulmonary dysplasia (BPD), ultrasonographic signs of brain injury, and severe retinopathy of prematurity (ROP) on 18-month outcomes of ELBW infants.

In ELBW infants who survive to a postmenstrual age of 36 weeks, a simple count of 3 common neonatal morbidities strongly predicts the risk of later death or neurosensory impairment.

Schmidt et al. 2006

Cohort

999

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

To determine the risk of bronchopulmonary dysplasia (BPD) in subgroups of infants with and without patent ductus arteriosus (PDA) who were randomized to indomethacin prophylaxis or placebo, and to examine whether adverse drug effects on edema formation and oxygenation may explain why indomethacin prophylaxis does not reduce BPD.

Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent BPD even though it reduces PDA.

Schmidt et al. 2011

Cohort

1202

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

To examine whether treatment with antenatal corticosteroids modifies the immediate and longterm effects of prophylactic indomethacin sodium trihydrate in extremely low-birth-weight infants

the effects of prophylactic indomethacin vary in extremely low-birthweight infants with and without adequate exposure to antenatal corticosteroids.

Stavel et al. 2017

Cohort

4268

-

-

-

-

-

-

-

-

-

-

-

-

244

498

1855

3770

To determine the effect of concomitant administration of prophylactic indomethacin and early enteral feeds on the risk of spontaneous intestinal perforation (SIP) in extremely low-birth-weight (ELBW) infants, and to describe the variation in prophylactic indomethacin use in Canada.

Prophylactic indomethacin was associated with increased odds of SIP independently from early feeding in this cohort; however, early enteral feeding was not associated with SIP. Marked variation in the use of prophylactic indomethacin was identified

SD: standard deviation; RCT: randomized controlled trial

Table 2. Prevalence of different outcomes in the prophylactic indomethacin group

Outcome

Prevalence

LCI

UCI

N

Event

Total

Heterogeneity measures

I2

τ2

P-value

Intubated in delivery room/First day

74.9

52.9

100.0

3

369

445

97%

0.09

< 0.001

Bronchopulmonary dysplasia

33.2

25.6

43.1

6

1772

4801

97%

0.10

< 0.001

Patent Ductus Arteriosus

32.2

27.3

38.0

13

4800

14003

97%

0.08

< 0.001

Intraventricular Hemorrhage

26.1

19.1

35.7

12

3526

14898

99%

0.28

< 0.001

CP/Neurodevelopmental delay

19.1

12.9

28.2

6

1889

9031

99%

0.23

< 0.001

Death

17.8

12.1

26.1

15

4722

23794

100%

0.53

< 0.001

NEC/Intestinal perforation

10.0

6.9

14.4

10

1460

15029

97%

0.29

< 0.001

Pulmonary Hemorrhage

8.3

5.4

12.8

5

212

2284

88%

0.19

< 0.001

LCI: 95% low confidence interval; N: number of the included studies; UCI: 95% upper confidence interval; NEC: necrotizing enterocolitis