Inositol for respiratory distress syndrome in preterm infants

Howlett A, Ohlsson A

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Cover sheet

Title

Inositol for respiratory distress syndrome in preterm infants

Reviewers

Howlett A, Ohlsson A

Dates

Date edited: 11/08/2003
Date of last substantive update: 24/07/2003
Date of last minor update: 26/10/1999
Date next stage expected / /
Protocol first published:
Review first published: Issue 4, 1997

Contact reviewer

Dr Alexandra Howlett
Staff Neonatologist
Paediatrics (Division of Neonatal Paediatrics)
Izaak Walton Killam-Grace Health Centre
5850/5980 University Avenue
Halifax
Nova Scotia CANADA
B3J 3G9
Telephone 1: 902 428 2961
Telephone 2: 902 420 6669
Facsimile: 902 420 6469
E-mail: aahowlet@is.dal.ca

Contribution of reviewers

Both reviewers contributed to all stages of this review, including the updates.

Internal sources of support

Izaak Walton Killam Health Centre, Halifax, Nova Scotia, CANADA
Women's College Hospital, Toronto, Ontario, CANADA

External sources of support

None

What's new

A search of the literature in early July, 2003 identified one additional report emanating from a study (Friedman 1995) included in the previous version of this review. However, the report provides no additional data in a form which can be used in the review at present. The results of this update remain as per the previous version of this review.

Dates

Date review re-formatted: 10/09/1999
Date new studies sought but none found: 15/10/1999
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Supplementing preterm babies who have respiratory distress with the nutrient inositol may reduce death and disability.

Inositol is an essential nutrient for cells, with high concentrations in breast milk (particularly breast milk when babies have been born early). A drop in inositol levels in babies with respiratory distress syndrome (RDS) can be a sign that their illness will be a severe one. The review found that initial evidence about supplementing babies with RDS with inositol is promising. Supplementation lowered rates of death, lung complications, and bleeding in the brain, with an important reduction in advanced eye problems as well. Inositol did not have serious adverse effects. Further research is warranted to confirm these preliminary findings.

Abstract

Background

Inositol is an essential nutrient required by human cells in culture for growth and survival. Inositol promotes maturation of several components of surfactant and may play a critical role in fetal and early neonatal life.

Objectives

To assess the effectiveness/safety of supplementary inositol in preterm infants with RDS in reducing adverse neonatal outcomes.

Search strategy

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched in July, 2003 using key words: inositol and infant-newborn and random allocation or controlled trial or randomized trial (RCT). The reference lists of identified RCTs, personal files and Science Citation Index were searched. Unpublished additional information was obtained from the authors of one RCT published in abstract form.

Selection criteria

All randomized controlled trials of inositol supplementation to preterm infants with a control group that received a placebo or no intervention were included. Outcomes of interest were bronchopulmonary dysplasia (BPD), death, BPD or death, retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and sepsis.

Data collection & analysis

Data on neonatal outcomes were abstracted independently by the two researchers and any discrepancy was resolved through consensus. Revman was used for analysis of the data.

Main results

Five reports of three RCTs were identified. One report was a duplicate publication. One new report included both randomized and non-randomized patients and data could not be extracted for the randomized neonates only and the study was excluded. An interim report of this study previously published as an abstract was included in the previous version of this review. The outcome of death or bronchopulmonary dysplasia was reported in two trials, and was found to be significantly reduced (RR 0.56, 95% CI 0.42, 0.77; RD -0.215, 95% CI -0.323, -0.107). The outcome of death was reported in two trials and was found to be significantly reduced (RR 0.48, 95% CI 0.28, 0.80; RD -0.131, 95% CI -0.218, -0.043). Retinopathy of prematurity, stage 4 or needing therapy, was reported in two trials, and was found to be significantly reduced (RR 0.09, 95% CI 0.01, 0.67; RD -0.078, 95% CI -0.128, -0.027). Intraventricular hemorrhage, grade III-IV, was significantly decreased (RR 0.55, 95% CI 0.32, 0.95; RD -0.090, 95% CI -0.170, -0.010). Neither sepsis nor necrotizing enterocolitis outcomes were increased. When a secondary analysis was done excluding a study published in abstract form, the results differed only in that there was a significant reduction in retinopathy of prematurity, any stage (RR 0.53, 95% CI 0.29, 0.97; RD -0.082, 95% CI -0.159,-0.005).

Reviewers' conclusions

Inositol supplementation results in statistically significant and clinically important reductions in important short-term adverse neonatal outcomes. A multi-center RCT of appropriate size is justified to confirm these findings.

Background

As more preterm infants survive beyond the neonatal period, the incidence of long-term complications such as bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) can be expected to increase. The relative contributions of risk factors such as barotrauma, oxygen therapy, and nutritional status have yet to be fully understood. Interest has recently focused on the use of myo-inositol (inositol) supplementation in preterm infants for the prevention of BPD and ROP (Hallman 1986, Hallman 1990, Hallman 1992). Inositol is a six-carbon sugar alcohol found widely throughout mammalian tissues in its free form as the phospholipid, phosphatidylinositol, and in cell membranes as a phosphoinositide (Hasan 1974, Dawson 1961). Inositol is an essential nutrient required by human cells in culture for growth and survival (Eagle 1957). The effects of deprivation and supplementation in animals have been studied extensively (Hallman 1984, Egberts 1986, Guarner 1992). Inositol promotes maturation of the surfactant phospholipids, phosphatidylcholine and phospatidylinositol, and the synthesis of phosphatidylinositol in type II pneumocytes appears to be dependent on extracellular inositol concentrations (Hallman 1980, Hallman 1984). Compositional changes in fetal rat lung surfactant correlate with changes in plasma inositol levels, and supplementation increases phospholipid levels to normal in the deprived rat pup (Egberts 1986, Guarner 1992, Hallman 1980).

In human infants with respiratory distress syndrome (RDS), a premature drop in serum inositol levels predicts a more severe course (Hallman 1985). Inositol supplementation increases the saturated phosphatidylcholine/sphingomyelin ratio in surfactant in newborns, and produces a rise in serum inositol concentration (Hallman 1987, Hallman 1992). In humans, free inositol levels in sera from preterm neonates are 2-20 times higher than are levels in maternal or adult sera (Lewin 1978, Bromberger 1986, Burton 1974). Human milk has a high concentration of inositol, with preterm milk being the richest source, and studies in newborns suggest an endogenous synthesis of inositol during fetal life (Bromberger 1986, Pereira 1990). Infants who are breast fed have higher serum inositol levels compared to those that are not at 1-2 weeks of life (Bromberger 1986, Pereira 1990). These facts suggest a critical role for inositol in fetal and early neonatal life. Several studies have been published assessing serum inositol levels in the preterm human infant (Hallman 1987, Lewin 1978, Bromberger 1986, Pereira 1990) as well as the effects of inositol supplementation. However, only two published RCTs of inositol supplementation (Hallman 1986, Hallman 1990) have been subjected to systematic review (Soll 1992). As additional evidence has become available, another critical overview of the use of inositol supplementation including all known trials to date is warranted.

This review updates the existing review 'Inositol for respiratory distress syndrome in preterm infants' which was first published in The Cochrane Library, Disk Issue 4, 1997 (Howlett 1997). MEDLINE, EMBASE and the Cochrane Registry of Randomized Controlled Trials were searched in mid October 1999. No new trials were identified at that time. This is a second update conducted in July, 2003.

Objectives

To use systematic review/meta-analytic techniques to determine if inositol administration to premature (<37 weeks gestational age) and/or low birth weight (LBW<2500 g) infants is effective in preventing adverse neonatal outcomes including: death, BPD, death or BPD, ROP, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and/or sepsis.

Criteria for considering studies for this review

Types of studies

Randomized controlled trials with a control group that received a placebo or no intervention.

Types of participants

Premature infants (<37 weeks gestational age) or LBW infants.

Types of interventions

Supplementation with inositol.

Types of outcome measures

Death, BPD, death or BPD, ROP, IVH, NEC, sepsis.

Search strategy for identification of studies

The search strategy used to identify studies was according to the Neonatal Cochrane Review Group. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched on July 6, 2003 using key words: inositol and infant-newborn and random allocation or controlled trial or randomized trial (RCT). The reference lists of identified RCTs, personal files and Science Citation Index were searched. Unpublished additional information was obtained from the authors of one RCT published in abstract form.

Methods of the review

The titles (and abstracts when available) in the MEDLINE, EMBASE, SCISEARCH, the Cochrane Library and HAND SEARCH printouts was reviewed by the two reviewers. Any article that either reviewer felt met the inclusion criteria or warranted having its reference list searched was retrieved. Attempts were made to locate additional unpublished information from published studies.

Assessment of Quality of Studies

An assessment of the quality of the included studies (excluding abstracts) was performed independently by AH and AO. The methodological criteria used to appraise each paper were the concealment of treatment allocation, blinding of intervention, blinding of observers and exclusion/withdrawals. Each criterion was graded 'A', 'B' or 'C': 'A' indicates a low risk of bias, where the plausibly postulated bias is unlikely to seriously alter the results: 'C' indicates a high risk of bias, where the plausibly postulated bias seriously weakens confidence in the results; a criterion was graded 'B' where it was partially met or where no data are available such that some doubt is raised about possible bias. Each paper was graded independently by the two reviewers with disagreements resolved by discussion. Methodological assessments were not conducted blind to author, institution, journal of publication or results, as the reviewers were familiar with most of the studies. In addition, the results sections of articles often included methodological information.

Data abstraction

Data abstraction forms were developed. The two reviewers independently abstracted information on each study and AH checked for any discrepancies and pooled the results. Data abstraction included: the time period and geographical location of the study, baseline characteristics of the patients, inclusion/exclusion criteria, preparation, route of administration and dosing regime of inositol and placebo.
Information on outcomes and numbers of affected infants was abstracted. The total number of infants with BPD at 28 days of life (oxygen requirements above the concentration in room air at 28 days of life and a chest roentgenogram compatible with BPD); BPD at 36 weeks gestational age (oxygen requirements above the concentration in room air at 36 weeks corrected gestational age and a chest roentgenogram compatible with BPD) was abstracted as well as information on deaths from all causes and deaths from causes other than congenital malformations, ROP (stage 0-4), IVH (grade 0-4), NEC and sepsis.

Statistical Analysis

The statistical package (Revman) provided by the Cochrane Collaboration was used. Relative risk (RR), Risk difference (RD) and their 95% confidence intervals were reported. The primary analysis for the supplementation of inositol included all accepted studies. A secondary analysis excluded a study with low quality scores that was published as an abstract.

Description of studies

The first RCT was reported by Hallman in 1986 (Hallman 1986), and assessed the effects of inositol supplementation for 10 days in 74 preterm infants (37 in each group) with RDS. No statistically significant differences were found in prenatal or infant characteristics between the two groups. Both intravenous and enteral inositol were used, and the control group received a placebo. The outcomes measured were death, BPD, death or BPD, PDA, NEC, ROP, IVH, sepsis and pulmonary air leaks.

A second RCT reported in 1990 and 1992 by Hallman (Hallman 1992) was a placebo-controlled, randomized, double blind trial looking at the effects of intravenous inositol supplementation in the first 5 days of life in preterm infants with RDS. 221 infants were enrolled, of which 119 were randomized to receive inositol. All enrolled infants were stratified according to whether they had received surfactant as part of another ongoing study. No statistically significant differences in infant characteristics were detected between the study group and the control group. Outcomes measured were pulmonary air leaks, BPD, death, death or BPD, ROP, PDA, IVH, NEC, and infection. An interim analysis was carried out in this study as well.

A third randomized, controlled trial was reported by Friedman (Friedman 1995) in abstract form only and the authors were contacted for further information. Forty-seven preterm infants were enrolled, of which 41 were randomized to receive either standard enteral feeds (SC 24) or supplemented formula high in inositol (SC 30). The other six infants were breast fed. Outcome measures looked at were BPD and ROP. A search of the literature in early July, 2003 identified one additional report of this trial published in J Pediatr Ophthalmol Strabismus 2000;37:79-86. This new report included a total of 48 randomized neonates (an increase by 7 from the 41 neonates included in the abstract report). However, an additional 23 non-randomized patients were included in the low-inositol formula group and were analysed together with the randomized patients. Data were not presented separately for the patients who were randomized. Therefore this report was excluded, and no new data were added to the analyses. We have contacted the primary author of this report to provide us with information on the patients who were randomized but to date (2003 07 23) we have had no response. If the data become available they will be added in a future update.

Methodological quality of included studies

Hallman, 1986

I Blinding of randomization - Can't tell
II Blinding of intervention - Yes
III Complete follow up - Yes
IV Blinding of outcome measurement - Can't tell

Hallman, 1992

I Blinding of randomization - Can't tell
II Blinding of intervention - Yes
III Complete follow up - Yes
IV Blinding of outcome measurement - Can't tell

Friedman, 1995

I Blinding of randomization - Can't tell
II Blinding of intervention - Can't tell
III Complete follow up - Yes
IV Blinding of outcome measurement - Can't tell

Results

The literature search detected five reports (Friedman 1995, Hallman 1986, Hallman 1990, Hallman 1992, Friedman 2000). However, these describe only three trials, as Hallman 1990 and Hallman 1992 are reports of the same trial as are Friedman 1995 and Friedman 2000. The study by Friedman 2000 included additional patients since the 1995 abstract report (Friedman 1995). However, additional non-randomized patients were included and data for the randomized patients only could not be abstracted. The chief investigator was contacted to obtain additional data on the randomized patients only and we are awaiting a response. Interim analyses occurred in all three studies.

Outcomes

Death or Bronchopulmonary Dysplasia
Only two trials reported this outcome. When these were combined, this outcome was found to be significantly reduced (RR 0.56, 95% CI 0.42, 0.77; RD -0.215, 95% CI -0.323, -0.107).

Bronchopulmonary Dysplasia at 28 days
All three studies examined the effect on BPD at 28 days. When all three were combined, there was a trend towards reduction which did not quite reach statistical significance (RR 0.68, 95% CI 0.45, 1.02; RD -0.085, 95% CI -0.172, 0.003).

Death
The outcome of death was reported in two trials, and a statistically significant reduction was found (RR 0.48, 95% CI 0.28, 0.80; RD -0.131, 95% CI -0.218, -0.043).

Retinopathy of Prematurity
All three trials reported the effect on the outcome ROP, any stage. There was a trend towards a reduced incidence of ROP, any stage, which was not quite statistically significant. When the abstract by Friedman was excluded from the analysis, ROP, any stage, showed a significant reduction (RR 0.53, 95% CI 0.29, 0.97; RD -0.082, 95% CI -0.159, -0.005). Only two studies reported on stage 4 ROP or ROP needing treatment, and analysis showed this outcome to be significantly reduced (RR 0.09, 95% CI 0.01, 0.67; RD -0.078, 95% CI -0.128, -0.027).

Intraventricular Hemorrhage, Grade III or IV
Two trials looked at the incidence of IVH Grade III or IV and when these results were combined, they showed a significantly decreased incidence (RR 0.55, 95% CI 0.32, 0.95; RD -0.090, 95% CI -0.170, -0.010).

Necrotizing Enterocolitis (NEC) and Sepsis/Infection
Only two studies reported these outcomes. The incidence of NEC was not affected. Similarly, there was no affect on the incidence of sepsis.

Discussion

While the number of studies available for analysis was small, we felt that the quality of the studies was such that a meta-analysis was appropriate. A statistically significant reduction in death or BPD in infants with inositol supplementation was demonstrated, and a striking reduction was found in ROP stage 4 or that needing treatment. When a secondary analysis was carried out, excluding the study in the abstract form, a significant reduction was seen in ROP, any stage, as well. No other differences were seen in the secondary analysis. When BPD was analyzed independently, no significant reduction was seen, although there was a trend towards a decrease in incidence. A significant reduction was found in IVH grade III or IV. There was no significant increase in adverse effects, such as sepsis or NEC.

While all these studies were RCTs, they each had an interim analysis that may have unblinded the researchers before the trial was completed. Future studies should avoid this potential source of bias.

These results suggest the need for more RCTs of inositol supplementation. The numbers in two of the reviewed trials were quite small. The estimates of effect, both in the individual trials and in the meta-analyses, are not very precise, as indicated by the large confidence intervals. Future multicenter RCTs of inositol supplementation are required both to confirm the benefits suggested in this review and to assess possible adverse effects on short and long term outcomes.

Reviewers' conclusions

Implications for practice

On the evidence from RCTs to date, inositol supplementation results in important reductions in the rates of death, death or bronchopulmonary dysplasia, intraventricular hemorrhage grades III or IV, and retinopathy of prematurity stage 4 or needing treatment. However, these conclusions are based on a limited number of patients. They require confirmation in large multicenter trials before inositol supplementation is routinely instituted as part of the nutritional management of preterm infants with RDS.

Implications for research

As there have been only three RCTs to date to assess the efficacy and safety of inositol supplementation, two of them quite small, very large trials with more power are warranted in order to assess more reliably the effects of this promising intervention and establish the generalizability of the results. Such trials should assess effects on a wide spectrum of short and long term outcomes including periventricular leukomalacia and neurodevelopmental status at 18 months corrected age. If the benefits of inositol supplementation in preterm infants with RDS are confirmed, further trials will also be needed to assess the effect in preterm infants without RDS, and to determine the best route of administration, dose and dose schedule, and duration of supplementation.

Acknowledgements

We are thankful to Dr. Friedman who provided us with additional unpublished information related to the abstract publication.

Potential conflict of interest

None

Characteristics of included studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Friedman 1995 Randomized, placebo controlled trial Preterm infants (birthweight<1500g) with a diagnosis of Respiratory Distress Syndrome, requiring mechanical ventilation.
n=47, placebo group=21, inositol group=20, breast milk=6
Study group enterally fed high-inositol SC30, while control group given SC24 enterally. A third group elected to breast feed. All three groups were compared for incidence of ROP and BPD at 28 days. Publiahed only in abstract form when included in this review. B
Hallman 1986 Randomized, placebo-controlled, double blind trial. Enrollment from 1983-1985. Preterm infants (birthweight<2000g) with a diagnosis of Respiratory Distress Syndrome, requiring mechanical ventilation.
n=74, placebo group=37, inositol group=37
IV or po supplemental inositol or placebo (5% glucose) given daily for ten days. Death, BPD, death or BPD, IVH, ROP, NEC, sepsis, PDA and pulmonary air leak. The outcomes of PDA and pulmonary air leaks were not considered in this review.
B
Hallman 1992 Randomized, placebo-controlled, double blind trial, occurring between 1985 to 1989. Preterm infants (birthweight<2000g and a gestational age of 24.0 to 31.9 weeks at birth) with evidence of Respiratory Distress Syndrome, requiring mechanical ventilation.
n=221, placebo group= 114, inositol group= 119
Age at enrollment 2-10 hours of life
The study group received intravenous inositol daily for five days, with repeated courses at day 10 and day 20 if necessary (infant continued to require ventilation, required supplemental O2 or did not tolerate enteral feeds). The control group recieved 5% glucose. Death, BPD, death or BPD, ROP, PDA. IVH, NEC, sepsis and pulmonary air leak.
B

References to studies

References to included studies

Friedman 1995 {published and unpublished data}

Friedman CA, McVey J, Borne MJ, James M, May WL, Temple DM. Relationship between serum inositol concentration and development of retinopathy of prematurity: A prospective study. J Pediatr Ophthalmol Strabismus 2000;37:79-86.

* Friedman CA, Temple DM, Robbins KK, Miller CJ, Rawson JE. Randomized controlled trial of high inositol and calorie supplementation in preterm infants at risk for chronic lung and eye disease. American Academy of Pediatrics Annual Meeting, October 1995, San Francisco, California, USA.

Hallman 1986 {published data only}

Hallman M, Jarvanpaa A-L, Pohjavuori M. Respiratory distress syndrome and inositol supplementation in preterm infants. Arch Dis Child 1986;61:1076.

Hallman 1992 {published data only}

* Hallman M, Bry K, Hoppu K, Lappi M, Pohjavuori M. Inositol supplementation in premature infants with respiratory distress syndrome. New Engl J Med 1992;326:1233.

Hallman M, Pohjavuori M, Bry K. Inositol supplementation in respiratory distress syndrome. Lung 1990;168 Suppl:877.

* indicates the primary reference for the study

Other references

Additional references

Bromberger 1986

Bromberger P, Hallman M. Myoinositol in small preterm infants: Relationship between intake and serum concentration. J Pediatr Gastroenterol Nutr 1986;5:455.

Burton 1974

Burton LE, Wells WW. Studies on the development pattern of the enzymes converting glucose-6-phosphate to myo-inositol in the rat. Dev Biol 1974;37:35.

Dawson 1961

Dawson RMC, Freinkel N. The distribution of free mesoinositol in mammalian tissues, including some observations on the lactating rat. Biochem J 1961;78:606.

Eagle 1957

Eagle H, Oyama VI, Levy M, Freeman AE. Myo-inositol as an essential growth factor for normal and malignant human cells in tissue culture. J Biol Chem 1957;266:191.

Egberts 1986

Egberts J, Noort WA. Gestational age-dependent changes in plasma inositol levels and surfactant composition in the fetal rat. Pediatr Res 1986;20:24.

Guarner 1992

Guarner V, Tordet C, Bourbon JR. Effects of maternal protein-calorie malnutrition on the phospholipid composition of surfactant isolated from the fetal and neonatal rat lungs. Compensation by inositol and lipid supplementation. Pediatr Res 1992;31:629.

Hallman 1980

Hallman M, Epstein BL. Role of myo-inositol in the synthesis of phosphatidylglycerol and phosphatidylinositol in the lung. Bioch Biophys Res Comm 1980;92:1151.

Hallman 1984

Hallman M. Effect of intracellular myo-inositol on the surfactant phospholipid synthesis in the fetal rabbit lung. Biochem Biophys Acta 1984;795:67.

Hallman 1985

Hallman M, Saugstad OD, Porreco RP, Epstein BL, Gluck L. Role of myo-inositol in regulation of surfactant phospholipids in the newborn. Early Human Dev 1985;10:245.

Hallman 1987

Hallman M, Arjomaa P, Hoppu K. Inositol supplementation in respiratory distress syndrome: Relationship between serum concentration, renal excretion, and lung effluent phospholipids. J Pediatr 1987;110:604.

Hasan 1974

Hasan SH, Nishigaki I, Tsutsui Y, Yagi K. Studies on myoinositol IX. Morphological examination of the effect of massive doses of myoinositol on the liver and kidney of rat. J Nutr Sci Vitaminol 1974;20:55.

Lewin 1978

Lewin LM, Melmed S, Passwell JH, Yannai Y, Brish M, Orda S, Boichis H, Bank H. Myoinositol in human neonates: serum concentrations and renal handling. Pediatr Res 1978;12:3.

Pereira 1990

Pereira GR, Baker L, Egler J, Corcoran L, Chiavacci R. Serum myoinositol concentrations in premature infants fed human milk, formula for infants, and parenteral nutrition. Am J Clin Nutr 1990;51:589.

Soll 1992

Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press, 1992.

Other published versions of this review

Howlett 1997

Howlett A, Ohlsson A. Inositol for respiratory distress syndrome in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 4, 1997. Oxford: Update Software.

Comparisons and data

01 Inositol supplementation versus control

01.01 Death

01.02 Bronchopulmonary dysplasia

01.03 Death or Bronchopulmonary Dysplasia

01.04 Intraventricular hemorrhage, any grade

01.05 Intraventricular hemorrhage, grades III or IV

01.06 Retinopathy of prematurity, stage 4 or needing treatment

01.07 Retinopathy of prematurity, any stage

01.08 Necrotizing Enterocolitis

01.09 Sepsis

Comparison or outcome Studies Participants Statistical method Effect size
01 Inositol supplementation versus control
01 Death 2 295 RR (fixed), 95% CI 0.48 [0.28, 0.80]
02 Bronchopulmonary dysplasia 3 336 RR (fixed), 95% CI 0.68 [0.45, 1.02]
03 Death or Bronchopulmonary Dysplasia 2 295 RR (fixed), 95% CI 0.56 [0.42, 0.77]
04 Intraventricular hemorrhage, any grade 2 307 RR (fixed), 95% CI 0.82 [0.61, 1.11]
05 Intraventricular hemorrhage, grades III or IV 2 307 RR (fixed), 95% CI 0.55 [0.32, 0.95]
06 Retinopathy of prematurity, stage 4 or needing treatment 2 262 RR (fixed), 95% CI 0.09 [0.01, 0.67]
07 Retinopathy of prematurity, any stage 3 336 RR (fixed), 95% CI 0.62 [0.38, 1.01]
08 Necrotizing Enterocolitis 2 307 RR (fixed), 95% CI 0.96 [0.39, 2.37]
09 Sepsis 2 307 RR (fixed), 95% CI 0.83 [0.53, 1.29]

Notes

Published notes

Amended sections

Cover sheet
Description of studies
References to studies
Other references

Contact details for co-reviewers

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario M5G 1X5 CANADA
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca


This review is published as a Cochrane review in The Cochrane Library 2003, Issue 4, 2003 (see www.CochraneLibrary.net for information).  Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the Review.