Inositol supplementation to preterm infants (repeat doses in any amount and any duration of treatment) compared to control for preterm infants at risk for or having respiratory distress syndrome

Patient or population: preterm infants at risk for or having respiratory distress syndrome
Setting: NICU
Intervention: Inositol supplementation to preterm infants (repeat doses in any amount and any duration of treatment)
Comparison: control

Infant death (age < 1 year)

RR 0.89
(0.71 to 1.13)

1115
(5 studies)

Low

Design (risk of bias): the risk of bias for random sequence generation was low in 2 studies and unclear in 3 studies; the risk of bias for allocation concealment was low in 3 studies and unclear in 2 studies; the risk of bias regarding performance bias and detection bias was low in 3 studies and unclear in 2 studies. We downgraded the quality of the evidence by 1 step

Heterogeneity/consistency across studies: there was high heterogeneity for RR (I² = 80 % ) and for RD (I² = 84%). We downgraded the quality of the evidence by 1 step

Directness of the evidence: Studies were conducted in the target population.

Precision of estimates: Results from 1115 infants have been reported in the studies to date and the confidence intervals around the point estimates for RR and RD were narrow.

Presence of publication bias: As only 5 studies were included in the analysis we did not perform a funnel plot.

Bronchopulmonary dysplasia (at 36 to 38 weeks' PMA)

RR 1.04
(0.90 to 1.20)

737
(2 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation was low in 1 study and unclear in 1 study; The risk of bias for allocation concealment was low in 1 study and unclear in 1 study; the risk of bias regarding performance bias and detection bias was low in 1 study and unclear in 1 study. We downgraded the quality of the evidence by 1 step

Heterogeneity/consistency across studies: there was no heterogeneity for RR (I² = 0%) and for RD (I² = 0%)

Directness of the evidence: studies were conducted in the target population

Precision of estimates: to date the results from 737 infants have been reported in the studies and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot

ROP, stage ≥ 3 or ≥ 2

RR 0.89
(0.75 to 1.06)

810
(3 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation was low in 1 study and unclear in 2 studies; the risk of bias for allocation concealment was low in 1 study and unclear in 2 studies; the risk of bias regarding performance bias and detection bias was low in 1 study and unclear in 2 studies. We downgraded the quality of the evidence by 1 step

Heterogeneity/consistency across studies: there was moderate heterogeneity for RR (I² = 63% ) and none for RD (I² = 23%)

Directness of the evidence: Studies were conducted in the target population

Precision of estimates: to date the results from 810 infants have been reported in the studies and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 3 studies were included in the analysis we did not perform a funnel plot

Sepsis (early or late onset)

RR 1.21
(0.95 to 1.54)

1067
(4 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation was low in 2 studies and unclear in 2 studies; the risk of bias for allocation concealment was low in 3 studies and unclear in 1 study; the risk of bias regarding performance bias and detection bias was low in 3 studies and unclear in 1 study. We downgraded the quality of the evidence by 1 step

Heterogeneity/consistency: across studies: There was no heterogeneity for RR (I² = 24% ) and low for RD (I² = 34%)

Directness of the evidence: studies were conducted in the target population

Precision of estimates: to date results from 1067 infants have been reported in the studies and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 4 studies were included in the analysis we did not perform a funnel plot

Necrotizing enterocolitis (suspected or proven)

RR 0.94
(0.64 to 1.39)

1115
(5 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation was low in 2 studies and unclear in 3 studies; the risk of bias for allocation concealment was low in 3 studies and unclear in 2 studies; the risk of bias regarding performance bias and detection bias was low in 3 studies and unclear in 2 studies. We downgraded the quality of the evidence by 1 step

Heterogeneity/consistency across studies: there was no heterogeneity for RR (I² = 0%) nor for RD (I² = 0%)

Directness of the evidence: studies were conducted in the target population

Precision of estimates: to date results from 1115 infants have been reported in the studies and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 5 studies were included in the analysis we did not perform a funnel plot

Intraventricular haemorrhage, grade > 2

RR 0.77
(0.58 to 1.01)

1103
(5 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation was low in 2 studies and unclear in 3 studies; the risk of bias for allocation concealment was low in 3 studies and unclear in 2 studies; the risk of bias regarding performance bias and detection bias was low in 3 studies and unclear in 2 studies. We downgraded the quality of the evidence by 1 step

Heterogeneity/consistency across studies: there was low heterogeneity for RR (I² = 48% ) and for RD (I² = 42%)

Directness of the evidence: studies were conducted in the target population

Precision of estimates: to date the results from 1103 infants have been reported in the studies and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: As only 5 studies were included in the analysis we did not perform a funnel plot

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval;PMA: Postmenstrual age; RD: Risk difference; ROP: Retinopathy of Prematurity; RR: Risk ratio;

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Inositol supplementation IV initially followed by enteral administration (repeat doses of 80 mg/kg/day) in preterm infants born at < 30 weeks' PMA compared to placebo for preterm infants at risk for or having respiratory distress syndrome

Patient or population: preterm infants at risk for or having respiratory distress syndrome
Setting:
Intervention: Inositol supplementation IV initially followed by enteral administration (repeat doses of 80 mg/kg/day) in preterm infants born at < 30 weeks' PMA
Comparison: placebo

Type 1 ROP or death before determination of ROP outcome using the adjudicated ROP outcome

RR 1.28
(0.99 to 1.67)

679
(2 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was high heterogeneity for RR (I² = 79 %) and for RD (I² = 85%). We downgraded the quality of the evidence by 1 step

Directness of the evidence: studies were conducted in the target population

Precision of estimates: this outcome was reported for 679 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: As only 2 studies were included in the analysis we did not perform a funnel plot

Type 1 ROP including adjudicated ROP outcome

RR 1.24
(0.82 to

1.86)

605
(2 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was low heterogeneity for RR (I² = 46 %) and moderate for RD (I² = 54%). We downgraded the quality of the evidence by 1 step

Directness of the evidence: studies were conducted in the target population

Precision of estimates: this outcome was reported on for 605 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot

All‐cause mortality (outcome collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)

RR 1.35
(0.91 to

2.00)

701
(2 studies)

Moderate

Design (risk of bias): the risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was moderate heterogeneity for RR (I² = 72%) and high for RD (I² = 84%). We downgraded the quality of the evidence by 1 step

Directness of the evidence: studies were conducted in the target population

Precision of estimates: this outcome was reported for 701 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot

BPD or death by it prior to 37 weeks' PMA (outcomes collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)

RR 1.01
(0.87 to

1.16)

616
(2 studies)

High

Design (risk of bias): the risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was no heterogeneity for RR (I² = 0%) nor for RD (I² = 0%)

Directness of the evidence: studies were conducted in the target population.

Precision of estimates: this outcome was reported for 616 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot

Severe IVH (grade 3 or 4)

RR 0.92
(0.65 to

1.29)

690
(2 studies)

Moderate

Design (risk of bias): The risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was moderate heterogeneity for RR (I² = 74%) and high for RD (I² = 82%)

Directness of the evidence: studies were conducted in the target population

Precision of estimates: this outcome was reported for 690 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot.

Late‐onset sepsis (> 72 hours of age)

RR 1.33
(1.00 to

1.75)

701
(2 studies)

HIgh

Design (risk of bias): the risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was no heterogeneity for RR (I² = 0%) nor for RD (I² = 0%)

Directness of the evidence: studies were conducted in the target population

Precision of estimates: this outcome was reported for 701 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot

Suspected or proven NEC

RR 0.88
(0.55 to

1.41)

701
(2 studies)

High

Design (risk of bias): the risk of bias for random sequence generation, for allocation concealment, for performance bias and detection bias was low in both studies

Heterogeneity/consistency across studies: there was low heterogeneity for RR (I² = 36%) and moderate for RD (I² = 53%).

Directness of the evidence: studies were conducted in the target population.

Precision of estimates: this outcome was reported on in 701 infants and the confidence intervals around the point estimates for RR and RD were narrow

Presence of publication bias: as only 2 studies were included in the analysis we did not perform a funnel plot.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; PMA: Postmenstrual age; RD: Risk difference; ROP: Retinopathy of prematurity; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.