Abstract: Six published randomised controlled trials were identified, with a total of 1177 infants. Study quality varied for the comparison 'Inositol supplementation to preterm infants (repeat doses in any amount and any duration of treatment) versus control' and interim analyses had occurred in several trials for the outcomes of interest. In this comparison, neonatal death was found to be significantly reduced (typical RR 0.53, 95% CI 0.31 to 0.91; typical RD −0.09, 95% CI −0.16 to −0.01; NNTB 11, 95% CI 6 to 100; 3 trials, 355 neonates). Infant deaths were not reduced (typical RR 0.89, 95% CI 0.71 to 1.13; typical RD −0.02, 95% CI −0.07 to 0.02; 5 trials, 1115 infants) (low-quality evidence). ROP stage 2 or higher or stage 3 or higher was not significantly reduced (typical RR 0.89, 95% CI 0.75 to 1.06; typical RD −0.04, 95% CI −0.10 to 0.02; 3 trials, 810 infants) (moderate-quality evidence). There were no significant findings for ROP (any stage), NEC (suspected or proven), sepsis, IVH grade greater than II (moderate-quality evidence). For the comparison 'Inositol supplementation IV initially followed by enteral administration (repeat doses of 80 mg/kg/day) in preterm infants born at less than 30 weeks' postmenstrual age (PMA) compared to placebo for preterm infants at risk for or having respiratory distress syndrome' the results from two studies of high quality were included (N = 760 neonates). Recruitment to the larger study (N = 638) was terminated because of a higher rate of deaths in the inositol group. We did not downgrade the quality of the study. The meta-analyses of the outcomes of 'Type 1 ROP or death before determination of ROP outcome using the adjudicated ROP outcome', 'Type 1 ROP including adjudicated ROP outcome', 'All-cause mortality (outcome collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)' and 'Severe IVH (grade 3 or 4)' did not show significant findings (moderate-quality evidence). There were no significant findings for the outcomes 'BPD or death by it prior to 37 weeks' postmenstrual age (outcomes collected through first event: death, hospital discharge, hospital transfer, or 120 days after birth)', 'Late onset sepsis (> 72 hours of age)', and 'Suspected or proven NEC' (high-quality evidence). Based on the evidence from randomised controlled trials to date, inositol supplementation does not result in important reductions in the rates of infant deaths, ROP stage 3 or higher, type 1 ROP, IVH grades 3 or 4, BPD, NEC, or sepsis. These conclusions are based mainly on two recent randomised controlled trials in neonates less than 30 weeks' postmenstrual age (N = 760), the most vulnerable population. Currently inositol supplementation should not be routinely instituted as part of the nutritional management of preterm infants with or without RDS. It is important that infants who have been enrolled in the trials included in this review are followed to assess any effects of inositol supplementation on long-term outcomes in childhood. We do not recommend any additional trials in neonates.

Plain-language summary: Six published randomised controlled trials met our inclusion criteria, with a total of 1177 infants enrolled. This update includes the results from two high-quality studies conducted in 760 infants of less than 30 weeks' postmenstrual age (PMA). In our previous update of our review, in 2015, we found that the initial evidence regarding inositol supplementation in preterm babies with RDS was promising. Inositol supplementation lowered rates of death and bleeding in the brain, with an important reduction in eye problems as well. Inositol did not have serious adverse effects. We suggested that further research was warranted to confirm these preliminary findings. Such research has now been published from two high-quality studies that included 760 infants of less than 30 weeks' PMA, the most vulnerable population. All results indicate that there are no reductions in adverse outcomes associated with inositol supplementation, including infant death, eye problems, bleeding in the brain, infections, chronic lung problems and gastrointestinal problems. Thus inositol supplementation in preterm infants is not recommended. Infants enrolled in these studies should be followed into childhood for assessment of any neuro-developmental problems. According to GRADE (a method to score the quality of the trials supporting each outcome), the quality of the evidence varied but was moderate to high for the important outcomes in the analyses for repeated high doses of inositol in infants born at less than 30 weeks' postmenstrual age.