Scolaris Content Display Scolaris Content Display

조산의 위험이 있거나 호흡장애증후군을 위한 이노시톨

Esta versión no es la más reciente

Contraer todo Desplegar todo

Referencias

Friedman 1995 {published and unpublished data}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. Journal of Pediatric Ophthalmoly and Strabismus 2000;37(2):79‐86. [PUBMED: 10779265]
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; San Francisco, California, USA. 1995 October.

Hallman 1986 {published data only}

Hallman M, Jarvanpaa AL, Pohjavuori M. Respiratory distress syndrome and inositol supplementation in preterm infants. Archives of Disease in Childhood 1986;61(11):1076‐83. [PUBMED: 3539028]

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 England Journal of Medicine 1992;326(19):1233‐9. [PUBMED: 1560798]
Hallman M, Pohjavuori M, Bry K. Inositol supplementation in respiratory distress syndrome. Lung 1990;168 Suppl:877‐82. [PUBMED: 2117207]

Phelps 2013 {published data only}

Phelps D, Ward R, Kerns S, on behalf of the Inositol Subcommittee of the Neonatal Research Network. Pharmacokinetics and safety of a single dose of inositol in preterm infants. E‐PAS2010. 2010:3737.387.
Phelps DL, Ward RM, Williams RL, Watterberg KL, Laptook AR, Wrage LA, et al. Pharmacokinetics and safety of a single intravenous dose of myo‐inositol in preterm infants of 23‐29 wk. Pediatric Research 2013;74(6):721‐9. [PUBMED: 24067395 ]

References to studies awaiting assessment

Phelps 2012NCT01954082 {published data only}

Phelps D, Watterberg K, Nolen T, Ward R, for the Inositol Subcommittee. Inositol serum concentrations and safety in a daily dose ranging study for extremely preterm infants. E‐PAS2012. 2012:1536.654.

NCT01954082 {published data only}

NCT01954082. Inositol to reduce retinopathy of prematurity (INS‐3). clinicaltrials.gov/ct2/show/NCT01954082 (accessed on 30 April 2014).

Bell 1978

Bell MJ, Ternberg KL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotising enterocolitis: therapeutic decisions based on clinical staging. Annals of Surgery 1978;187(1):1‐7. [PUBMED: 413500]

Bromberger 1986

Bromberger P, Hallman M. Myoinositol in small preterm infants: Relationship between intake and serum concentration. Journal of Pediatric Gastroenterology and Nutrition 1986;5(3):455‐8. [PUBMED: 3088251]

Burton 1974

Burton LE, Wells WW. Studies on the development pattern of the enzymes converting glucose‐6‐phosphate to myo‐inositol in the rat. Developmental Biology 1974;37(1):35‐42. [PUBMED: 4362962]

Dawson 1961

Dawson RM, Freinkel N. The distribution of free mesoinositol in mammalian tissues, including some observations on the lactating rat. The Biochemical Journal 1961;78:606‐10. [PUBMED: 13720328]

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. The Journal of Biological Chemistry 1957;266(1):191‐205. [PUBMED: 13428752]

Egberts 1986

Egberts J, Noort WA. Gestational age‐dependent changes in plasma inositol levels and surfactant composition in the fetal rat. Pediatric Research 1986;20(1):24‐7. [PUBMED: 3753753]

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. Pediatric Research 1992;31(6):629‐35. [PUBMED: 1635827]

Hallman 1980

Hallman M, Epstein BL. Role of myo‐inositol in the synthesis of phosphatidylglycerol and phosphatidylinositol in the lung. Biochemical and Biophysical Research Communications 1980;92(4):1151‐9. [PUBMED: 6245646]

Hallman 1984

Hallman M. Effect of intracellular myo‐inositol on the surfactant phospholipid synthesis in the fetal rabbit lung. Biochimica et Biophysica Acta 1984;795(1):67‐78.

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 Devevelopment 1985;10(3‐4):245‐54. [PUBMED: 3838720]

Hallman 1987

Hallman M, Arjomaa P, Hoppu K. Inositol supplementation in respiratory distress syndrome: Relationship between serum concentration, renal excretion, and lung effluent phospholipids. Journal of Pediatrics 1987;110(4):604‐10. [PUBMED: 3559811]

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. Journal of Nutritional Science and Vitaminology 1974;20(1):55‐8. [PUBMED: 4836951]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327(7414):557‐60. [PUBMED: 12958120]

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

ICROP 1984

The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Archives of Ophthalmology 1984;102(8):1130‐4. [PUBMED: 6547831]

Lewin 1978

Lewin LM, Melmed S, Passwell JH, Yannai Y, Brish M, Orda S, et al. Myoinositol in human neonates: serum concentrations and renal handling. Pediatric Research 1978;12(1):3‐6. [PUBMED: 643373]

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweights less than 1,500 grams. Journal of Pediatrics 1978;92(4):529‐34. [PUBMED: 305471]

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. American Journal of Clinical Nutrition 1990;51(4):589‐93. [PUBMED: 2108579]

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Shennan 1988

Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82(4):527‐32. [PUBMED: 3174313]

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.

References to other published versions of this review

Howlett 1997

Howlett A, Ohlsson A. Inositol for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 1997, Issue 4. [DOI: 10.1002/14651858.CD000366]

Howlett 2003

Howlett A, Ohlsson A. Inositol for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD000366]

Howlett 2012

Howlett A, Ohlsson A, Plakkal N. Inositol for respiratory distress syndrome in preterm infants. Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI: 10.1002/14651858.CD000366.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Friedman 1995

Methods

Randomised, placebo‐controlled trial

Participants

Preterm infants (birth weight < 1500 g) with a diagnosis of RDS, requiring mechanical ventilation

24 infants were randomised to high concentration inositol formula (SC 30) and 24 infants were randomised to a low concentration of inositol formula (SC 24). Randomisation ended when the high‐inositol formula was no longer available

Location: 2 NICUs in the US. Study period: October 1994 to June 1998

Interventions

The study group was enterally fed high‐inositol formula (2500 µmol/L inositol) , while the control group was given low‐inositol formula (242 µmol/L) enterally

Outcomes

Neonatal deaths, infant deaths, infants with bacteraemia, necrotizing enterocolitis (radio graphically documented), IVH > grade 2, BPD (oxygen therapy > 30 days), duration of mechanical ventilation, ROP (reported in unpublished data from 1995)

Notes

The results of this study have been reported 3 times; in abstract form in 1995 after 37 infants were enrolled; in a personal communication report to us in 1995 when 41 infants had been enrolled and in a final published report in 2000 when 48 infants had been entered

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information provided

Allocation concealment (selection bias)

Unclear risk

Infants were allocated to one of the two groups by sequential random card selection. No information provided whether the cards were enclosed in opaque and numbered envelopes

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Infants were blinded but no information provided whether the clinical staff and the researchers were

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcomes provided for all 48 infants randomised

Selective reporting (reporting bias)

Low risk

Outcomes were reported as per the methods section

Other bias

High risk

The results of this study have been reported 3 times: in abstract form in 1995 after 37 infants were enrolled; in a personal communication report to us in 1995 when 41 infants had been enrolled; and in a final published report in 2000 when 48 infants had been entered

Hallman 1986

Methods

Randomised, placebo‐controlled, double blind trial. Enrolment from 1983 to 1985

Participants

Preterm infants (birth weight < 2000 g) with a diagnosis of RDS, requiring mechanical ventilation
n = 74, placebo group = 37, inositol group = 37

Location: One NICU in Helsinki, Finland. Study period: January 1983 to August 1985

Interventions

IV or po supplemental inositol or placebo (5% glucose) given daily for ten days

Outcomes

Neonatal deaths, infant deaths, BPD (supplemental oxygen at 28 days and x‐ray findings compatible with BPD), IVH, ROP (ophthalmological exam at PMA of 9 and 13 months), NEC (clinical findings and abdominal x‐ray showing pneumatosis intestinalis and air in the portal circulation, and sepsis

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information provided

Allocation concealment (selection bias)

Low risk

"Infants were randomly and blindly assigned to be treated with inositol or placebo (glucose) after their parents had consented to their participation". For further details see "Blinding" below

Blinding (performance bias and detection bias)
All outcomes

Low risk

Each set of solutions, containing either inositol or glucose (5% weight/volume each) had a code number. Only the pharmacist preparing the doses knew the contents of the drug packages

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Of the 83 infants who entered the trial, nine did not fulfil the entrance criteria and were excluded from the final analysis. An explanation was provided for each excluded infant

Selective reporting (reporting bias)

Low risk

Outcomes of interest listed in the methods section were reported on

Other bias

High risk

The present report represents the third interim analysis and the researchers may have been influenced by the results of the two previous interim analyses. The study was not registered in a trials registry

Hallman 1992

Methods

Randomised, placebo‐controlled, double blind trial, occurring between 1985 to 1989

Participants

Preterm infants (birth weight < 2000 g and a PMA of 24.0 to 31.9 weeks at birth) with evidence of RDS, requiring mechanical ventilation
Total n = 233, placebo group = 114, inositol group = 119
Age at enrolment 2 to 10 hours of life

Interventions

The study group received IV 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 received 5% glucose

Outcomes

Neonatal death, infant death, BPD (supplemental oxygen at 28 days of age), BPD (supplemental oxygen at 38 weeks PMA or the week of discharge from hospital, ROP (as per International Classification assessed from 4 to 6 weeks and ending at 12 months), IVH (all grades, grade > 2), NEC (no definition provided), and sepsis (no definition provided)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information provided

Allocation concealment (selection bias)

Unclear risk

Unclear

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

5% glucose was given as placebo, but no information provided on whether staff was blinded to study drugs or not

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Four infants in the placebo group and three in the inositol group died before receiving any treatment, two had lethal malformations (one in each group), and three did not have RDS (two in the placebo group and one in the inositol group). These 12 infants were included only in the safety analysis

Selective reporting (reporting bias)

Unclear risk

This study was not registered in a trials registry. Outcomes of interest are listed in the methods section

Other bias

High risk

Interim analyses were to be performed after enrolment of 100, 200, 300 patients. Early termination of the trial was recommended by the monitoring committee after the second interim analysis, when the Chi2 test revealed a significant increase in neonatal survival without BPD and no trend towards serious morbidity in one study group. One interim analysis previously reported, Hallman 1992 (published in Lung 1990;168 Suppl:877‐82)

Phelps 2013

Methods

Randomised, double masked, placebo‐controlled pharmacokinetic (PK) study. Enrolment between June 2006 and December 2007. The trial was conducted by the National Institues of Child Health and Human Development Neonatal Research Network. Ten of the Neonatal Research Network Centers participated

Participants

Eligable subjects were of 23 0/7 to 29 6/7 weeks PMA and ≥ 600 g BW, had no major congenital anomalies, were between 12 hours and 6 days of age at randomisation, and had received no human milk or formula feedings since birth

Interventions

Inositol was given as a single low (60 mg/kg) (n = 25) or high (120 mg/kg) (n = 24) dose of 5% myo‐inositol IV over 20 min in a 1:1:1 randomisation with placebo delivered in one of two volumes to maintain masking (5% glucose) (n = 25). Drug or placebo was dispensed from the respective pharmacies in unit doses labelled as 'inositol study drug', and all clinical and research personnel except the pharmacist were masked to the study group

Outcomes

Pharmacokinetic data for inositol (central volume of distribution, clearance, endogenous production, the half‐life, renal inositol excretion during the first 12 h and after 48 h and diuretic side effect
In addition adverse events were reported for the first 7 days as well as neonatal morbidities from birth through hospital discharge (or 120 days if sooner)

Notes

Abbott Nutrition Division, Abbott Laboratories, supplied the inositol drug used in the study

Portions of this study were presented at the 2010 Pediatric Academic Societies Annual Meeting, Vancouver, Canada, May 1–4, 2010 (Abstract 3737.387)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed centrally via computer within two pre‐specified PMA strata (23 0/7 to 26 6/7 weeks and 27 0/7 to 29 6/7 weeks)

Allocation concealment (selection bias)

Low risk

There was central allocation to study group

Blinding (performance bias and detection bias)
All outcomes

Low risk

Drug or placebo was dispensed from the respective pharmacies in unit doses labelled as 'inositol study drug', and all clinical and research personnel except the pharmacist were masked to the study group

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Consent was obtained for 79 infants, 76 infants were randomised, and 74 infants received study drug. Two infants did not complete the minimum of four specified blood samples (three post drug infusion), and their randomisations were replaced with two additional enrollees from the same centre and of the same gestational age (GA) stratum, per protocol. Available data from the two replaced infants were included in the PK and safety analyses. One infant received placebo instead of the assigned 120 mg/kg dose, and for the PK analysis, this infant’s serum and urine data were included in the placebo group. However, this subject’s data on adverse events and clinical outcomes were included as randomised (intention to treat)

Selective reporting (reporting bias)

Low risk

The study was registered with ClinicalTrials.gov (NCT00349726) and there does not appear to be any deviations from the protocol

Other bias

Low risk

Appears free of other bias

BW = birth weight

PMA = postmenstrual age

PK = pharmacokinetics

Characteristics of studies awaiting assessment [ordered by study ID]

Phelps 2012NCT01954082

Methods

Randomised controlled trial

Participants

122 infants of 23 0/7 to 29 6/7 weeks PMA and BW ≥ 400 g

Interventions

Infants were randomised to placebo, 10, 40 or 80 mg/kg/day of IV inositol (divided every 12 hours) from enrolment on day 1 to 3 to 10 weeks of age, to 34 weeks PMA or to discharge. Once feedings were established the same dose of study drug was given enterally

Outcomes

Pharmacokinetics (PK) and adverse events (no data for clinical outcomes were presented)

Notes

This study has been published in abstract form only and we decided not to complete the risk of bias table as enough information was not provided in the abstract

Characteristics of ongoing studies [ordered by study ID]

NCT01954082

Trial name or title

Inositol to reduce retinopathy of prematurity (INS‐3)

Methods

This is a phase 3, randomised, double masked, placebo‐controlled study designed to determine the effectiveness of inositol in premature infants < 28 0/7 weeks gestation

Participants

1760 preterm infants < 28 0/7 weeks PMA

Interventions

Experimental: myo‐inositol 5% injection: within 12 to 72 hours of birth, infants will receive 80 mg myo‐inositol 5% injection/kg/day, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily and continued until the earliest of 34 completed weeks PMA, 10 weeks (70 days) chronological age, or the time of discharge. Myo‐inositol 5% injection will be administered IV until enteral feedings are established, at which time the same dose and formulation will be administered enterally every 12 hours

Placebo comparator: 5% glucose (dextrose) ‐ within 12 to 72 hours of birth, infants will receive 80 mg 5% glucose (dextrose) USP for intravenous infusion per kilogram per day, administered in divided doses every 12 hours (40 mg/kg/dose). Study drug will be administered daily and continued until the earliest of 34 completed weeks PMA, 10 weeks (70 days) chronological age, or the time of discharge. Myo‐inositol 5% Injection will be administered IV until enteral feedings are established, at which time the same dose and formulation will be administered enterally every 12 hours

Outcomes

Incidence of survival without severe retinopathy of prematurity (ROP) through acute and final ROP determination up to 55 weeks PMA

Starting date

April 2014

Contact information

Dale L Phelps, MD; phone: 707‐897‐9063; email: [email protected]

Notes

Final data collection date for primary outcome measure: January 2017. ClinicalTrials.gov identifier: NCT01954082

BW = birth weight

PMA = postmenstrual age

Data and analyses

Open in table viewer
Comparison 1. Inositol supplementation versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neonatal death (age < 28 days) Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.31, 0.91]

Analysis 1.1

Comparison 1 Inositol supplementation versus control, Outcome 1 Neonatal death (age < 28 days).

Comparison 1 Inositol supplementation versus control, Outcome 1 Neonatal death (age < 28 days).

2 Infant death (age < one year) Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.40, 0.77]

Analysis 1.2

Comparison 1 Inositol supplementation versus control, Outcome 2 Infant death (age < one year).

Comparison 1 Inositol supplementation versus control, Outcome 2 Infant death (age < one year).

3 Bronchopulmonary dysplasia (at 28 to 30 days of age) Show forest plot

3

343

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.54, 1.13]

Analysis 1.3

Comparison 1 Inositol supplementation versus control, Outcome 3 Bronchopulmonary dysplasia (at 28 to 30 days of age).

Comparison 1 Inositol supplementation versus control, Outcome 3 Bronchopulmonary dysplasia (at 28 to 30 days of age).

4 Bronchopulmonary dysplasia (at 36 to 38 weeks PMA) Show forest plot

1

177

Risk Ratio (M‐H, Fixed, 95% CI)

1.30 [0.64, 2.64]

Analysis 1.4

Comparison 1 Inositol supplementation versus control, Outcome 4 Bronchopulmonary dysplasia (at 36 to 38 weeks PMA).

Comparison 1 Inositol supplementation versus control, Outcome 4 Bronchopulmonary dysplasia (at 36 to 38 weeks PMA).

5 Retinopathy of prematurity, stage ≥ 3 Show forest plot

2

262

Risk Ratio (M‐H, Fixed, 95% CI)

0.09 [0.01, 0.67]

Analysis 1.5

Comparison 1 Inositol supplementation versus control, Outcome 5 Retinopathy of prematurity, stage ≥ 3.

Comparison 1 Inositol supplementation versus control, Outcome 5 Retinopathy of prematurity, stage ≥ 3.

6 Retinopathy of prematurity, any stage Show forest plot

3

336

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.38, 1.01]

Analysis 1.6

Comparison 1 Inositol supplementation versus control, Outcome 6 Retinopathy of prematurity, any stage.

Comparison 1 Inositol supplementation versus control, Outcome 6 Retinopathy of prematurity, any stage.

7 Necrotizing enterocolitis Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.51, 2.70]

Analysis 1.7

Comparison 1 Inositol supplementation versus control, Outcome 7 Necrotizing enterocolitis.

Comparison 1 Inositol supplementation versus control, Outcome 7 Necrotizing enterocolitis.

8 Sepsis Show forest plot

2

307

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.51, 1.37]

Analysis 1.8

Comparison 1 Inositol supplementation versus control, Outcome 8 Sepsis.

Comparison 1 Inositol supplementation versus control, Outcome 8 Sepsis.

9 Intraventricular haemorrhage, grade > 2 Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.31, 0.90]

Analysis 1.9

Comparison 1 Inositol supplementation versus control, Outcome 9 Intraventricular haemorrhage, grade > 2.

Comparison 1 Inositol supplementation versus control, Outcome 9 Intraventricular haemorrhage, grade > 2.

10 Intraventricular haemorrhage, all grades Show forest plot

2

307

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.61, 1.11]

Analysis 1.10

Comparison 1 Inositol supplementation versus control, Outcome 10 Intraventricular haemorrhage, all grades.

Comparison 1 Inositol supplementation versus control, Outcome 10 Intraventricular haemorrhage, all grades.

11 Minor neural developmental impairment at one year corrected age Show forest plot

1

169

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.38, 1.86]

Analysis 1.11

Comparison 1 Inositol supplementation versus control, Outcome 11 Minor neural developmental impairment at one year corrected age.

Comparison 1 Inositol supplementation versus control, Outcome 11 Minor neural developmental impairment at one year corrected age.

12 Major neural developmental impairment at one year corrected age Show forest plot

1

169

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.24, 1.16]

Analysis 1.12

Comparison 1 Inositol supplementation versus control, Outcome 12 Major neural developmental impairment at one year corrected age.

Comparison 1 Inositol supplementation versus control, Outcome 12 Major neural developmental impairment at one year corrected age.

Open in table viewer
Comparison 2. Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death during hospital stay Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.34, 4.21]

Analysis 2.1

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 1 Death during hospital stay.

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 1 Death during hospital stay.

2 Bronchopulmonary dysplasia at 36 weeks PMA Show forest plot

1

65

Risk Ratio (M‐H, Fixed, 95% CI)

2.74 [0.88, 8.48]

Analysis 2.2

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 2 Bronchopulmonary dysplasia at 36 weeks PMA.

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 2 Bronchopulmonary dysplasia at 36 weeks PMA.

3 Retinopathy of prematurity (infants who underwent surgery for ROP) Show forest plot

1

25

Risk Ratio (M‐H, Fixed, 95% CI)

0.35 [0.10, 1.22]

Analysis 2.3

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 3 Retinopathy of prematurity (infants who underwent surgery for ROP).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 3 Retinopathy of prematurity (infants who underwent surgery for ROP).

4 Necrotizing enterocolitis (stage 2A or worse) Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

0.41 [0.12, 1.39]

Analysis 2.4

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 4 Necrotizing enterocolitis (stage 2A or worse).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 4 Necrotizing enterocolitis (stage 2A or worse).

5 Necrotizing enterocolitis (infants who underwent surgery for NEC) Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.08, 3.41]

Analysis 2.5

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 5 Necrotizing enterocolitis (infants who underwent surgery for NEC).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 5 Necrotizing enterocolitis (infants who underwent surgery for NEC).

6 Sepsis (late onset) Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

1.46 [0.71, 2.97]

Analysis 2.6

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 6 Sepsis (late onset).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 6 Sepsis (late onset).

7 Intraventricular haemorrhage (grade 3 or 4) Show forest plot

1

72

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.29, 3.90]

Analysis 2.7

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 7 Intraventricular haemorrhage (grade 3 or 4).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 7 Intraventricular haemorrhage (grade 3 or 4).

8 Hearing test (failed both ears) Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.58 [0.09, 3.84]

Analysis 2.8

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 8 Hearing test (failed both ears).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 8 Hearing test (failed both ears).

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.1 Neonatal death (age < 28 days).
Figuras y tablas -
Figure 1

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.1 Neonatal death (age < 28 days).

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.2 Infant death (age < one year).
Figuras y tablas -
Figure 2

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.2 Infant death (age < one year).

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.5 Retinopathy of prematurity, stage ≥ 3.
Figuras y tablas -
Figure 3

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.5 Retinopathy of prematurity, stage ≥ 3.

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.6 Retinopathy of prematurity, any stage.
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.6 Retinopathy of prematurity, any stage.

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.9 Intraventricular haemorrhage, grade > 2.
Figuras y tablas -
Figure 5

Forest plot of comparison: 1 Inositol supplementation versus control, outcome: 1.9 Intraventricular haemorrhage, grade > 2.

Comparison 1 Inositol supplementation versus control, Outcome 1 Neonatal death (age < 28 days).
Figuras y tablas -
Analysis 1.1

Comparison 1 Inositol supplementation versus control, Outcome 1 Neonatal death (age < 28 days).

Comparison 1 Inositol supplementation versus control, Outcome 2 Infant death (age < one year).
Figuras y tablas -
Analysis 1.2

Comparison 1 Inositol supplementation versus control, Outcome 2 Infant death (age < one year).

Comparison 1 Inositol supplementation versus control, Outcome 3 Bronchopulmonary dysplasia (at 28 to 30 days of age).
Figuras y tablas -
Analysis 1.3

Comparison 1 Inositol supplementation versus control, Outcome 3 Bronchopulmonary dysplasia (at 28 to 30 days of age).

Comparison 1 Inositol supplementation versus control, Outcome 4 Bronchopulmonary dysplasia (at 36 to 38 weeks PMA).
Figuras y tablas -
Analysis 1.4

Comparison 1 Inositol supplementation versus control, Outcome 4 Bronchopulmonary dysplasia (at 36 to 38 weeks PMA).

Comparison 1 Inositol supplementation versus control, Outcome 5 Retinopathy of prematurity, stage ≥ 3.
Figuras y tablas -
Analysis 1.5

Comparison 1 Inositol supplementation versus control, Outcome 5 Retinopathy of prematurity, stage ≥ 3.

Comparison 1 Inositol supplementation versus control, Outcome 6 Retinopathy of prematurity, any stage.
Figuras y tablas -
Analysis 1.6

Comparison 1 Inositol supplementation versus control, Outcome 6 Retinopathy of prematurity, any stage.

Comparison 1 Inositol supplementation versus control, Outcome 7 Necrotizing enterocolitis.
Figuras y tablas -
Analysis 1.7

Comparison 1 Inositol supplementation versus control, Outcome 7 Necrotizing enterocolitis.

Comparison 1 Inositol supplementation versus control, Outcome 8 Sepsis.
Figuras y tablas -
Analysis 1.8

Comparison 1 Inositol supplementation versus control, Outcome 8 Sepsis.

Comparison 1 Inositol supplementation versus control, Outcome 9 Intraventricular haemorrhage, grade > 2.
Figuras y tablas -
Analysis 1.9

Comparison 1 Inositol supplementation versus control, Outcome 9 Intraventricular haemorrhage, grade > 2.

Comparison 1 Inositol supplementation versus control, Outcome 10 Intraventricular haemorrhage, all grades.
Figuras y tablas -
Analysis 1.10

Comparison 1 Inositol supplementation versus control, Outcome 10 Intraventricular haemorrhage, all grades.

Comparison 1 Inositol supplementation versus control, Outcome 11 Minor neural developmental impairment at one year corrected age.
Figuras y tablas -
Analysis 1.11

Comparison 1 Inositol supplementation versus control, Outcome 11 Minor neural developmental impairment at one year corrected age.

Comparison 1 Inositol supplementation versus control, Outcome 12 Major neural developmental impairment at one year corrected age.
Figuras y tablas -
Analysis 1.12

Comparison 1 Inositol supplementation versus control, Outcome 12 Major neural developmental impairment at one year corrected age.

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 1 Death during hospital stay.
Figuras y tablas -
Analysis 2.1

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 1 Death during hospital stay.

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 2 Bronchopulmonary dysplasia at 36 weeks PMA.
Figuras y tablas -
Analysis 2.2

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 2 Bronchopulmonary dysplasia at 36 weeks PMA.

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 3 Retinopathy of prematurity (infants who underwent surgery for ROP).
Figuras y tablas -
Analysis 2.3

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 3 Retinopathy of prematurity (infants who underwent surgery for ROP).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 4 Necrotizing enterocolitis (stage 2A or worse).
Figuras y tablas -
Analysis 2.4

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 4 Necrotizing enterocolitis (stage 2A or worse).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 5 Necrotizing enterocolitis (infants who underwent surgery for NEC).
Figuras y tablas -
Analysis 2.5

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 5 Necrotizing enterocolitis (infants who underwent surgery for NEC).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 6 Sepsis (late onset).
Figuras y tablas -
Analysis 2.6

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 6 Sepsis (late onset).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 7 Intraventricular haemorrhage (grade 3 or 4).
Figuras y tablas -
Analysis 2.7

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 7 Intraventricular haemorrhage (grade 3 or 4).

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 8 Hearing test (failed both ears).
Figuras y tablas -
Analysis 2.8

Comparison 2 Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg, Outcome 8 Hearing test (failed both ears).

Comparison 1. Inositol supplementation versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neonatal death (age < 28 days) Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.31, 0.91]

2 Infant death (age < one year) Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.40, 0.77]

3 Bronchopulmonary dysplasia (at 28 to 30 days of age) Show forest plot

3

343

Risk Ratio (M‐H, Fixed, 95% CI)

0.78 [0.54, 1.13]

4 Bronchopulmonary dysplasia (at 36 to 38 weeks PMA) Show forest plot

1

177

Risk Ratio (M‐H, Fixed, 95% CI)

1.30 [0.64, 2.64]

5 Retinopathy of prematurity, stage ≥ 3 Show forest plot

2

262

Risk Ratio (M‐H, Fixed, 95% CI)

0.09 [0.01, 0.67]

6 Retinopathy of prematurity, any stage Show forest plot

3

336

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.38, 1.01]

7 Necrotizing enterocolitis Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.51, 2.70]

8 Sepsis Show forest plot

2

307

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.51, 1.37]

9 Intraventricular haemorrhage, grade > 2 Show forest plot

3

355

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.31, 0.90]

10 Intraventricular haemorrhage, all grades Show forest plot

2

307

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.61, 1.11]

11 Minor neural developmental impairment at one year corrected age Show forest plot

1

169

Risk Ratio (M‐H, Fixed, 95% CI)

0.84 [0.38, 1.86]

12 Major neural developmental impairment at one year corrected age Show forest plot

1

169

Risk Ratio (M‐H, Fixed, 95% CI)

0.53 [0.24, 1.16]

Figuras y tablas -
Comparison 1. Inositol supplementation versus control
Comparison 2. Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death during hospital stay Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.34, 4.21]

2 Bronchopulmonary dysplasia at 36 weeks PMA Show forest plot

1

65

Risk Ratio (M‐H, Fixed, 95% CI)

2.74 [0.88, 8.48]

3 Retinopathy of prematurity (infants who underwent surgery for ROP) Show forest plot

1

25

Risk Ratio (M‐H, Fixed, 95% CI)

0.35 [0.10, 1.22]

4 Necrotizing enterocolitis (stage 2A or worse) Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

0.41 [0.12, 1.39]

5 Necrotizing enterocolitis (infants who underwent surgery for NEC) Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

0.51 [0.08, 3.41]

6 Sepsis (late onset) Show forest plot

1

74

Risk Ratio (M‐H, Fixed, 95% CI)

1.46 [0.71, 2.97]

7 Intraventricular haemorrhage (grade 3 or 4) Show forest plot

1

72

Risk Ratio (M‐H, Fixed, 95% CI)

1.06 [0.29, 3.90]

8 Hearing test (failed both ears) Show forest plot

1

57

Risk Ratio (M‐H, Fixed, 95% CI)

0.58 [0.09, 3.84]

Figuras y tablas -
Comparison 2. Inositol supplementation (single dose of 60 mg/kg or 120 mg/kg