Dose-Response Effects of Early Vitamin D Supplementation on Neurodevelopmental and Respiratory Outcomes of Extremely Preterm Infants at 2 Years of Age: A Randomized Trial

Abstract

Background: Many extremely preterm infants have low vitamin D concentrations at birth, but early childhood outcomes after vitamin D supplementation have not been reported. Objective: To determine a dose-response relationship between increasing doses of enteral vitamin D in the first 28 days after birth and cognitive scores at 2 years of age. Methods: In this phase II double-blind dose-response randomized trial, infants with gestational ages between 23 and 27 weeks were randomly assigned to receive placebo or a vitamin D dose of 200 or 800 IU/day from day 1 of enteral feeding to postnatal day 28. The primary outcome of this follow-up study was Bayley III cognitive score at 22-26 months of age. Results: Seventy of 80 survivors had a follow-up evaluation at 2 years of age (88%). There were no significant differences in cognitive scores between supplementation groups (p = 0.47). Cognitive scores did not differ between the higher vitamin D dose group and the placebo group (median difference favoring the 800 IU group: +5 points; 95% CI: −5 to 15; p = 0.23). The linear trend between increasing doses of vitamin D and reduction of neurodevelopmental impairment (placebo group: 54%; 200 IU group: 43%; 800 IU group: 30%; p = 0.08) or language impairment (placebo group: 64%; 200 IU group: 57%; 800 IU group: 45%; p = 0.15) was not statistically significant. Respiratory outcomes at 2 years of age (need for supplemental oxygen or asthma medications) did not differ between groups. Conclusion: In extremely preterm infants, early vitamin D supplementation did not significantly improve cognitive scores. Though underpowered for clinically meaningful differences in early childhood outcomes, this trial may help determine dosing for further investigation of vitamin D supplementation.

Vitamin D Intake in Preterm Infants: Too Little, Too Much, or Just the Right Amount?

“…As indicated by the title of this commentary, the report by Salas et al [1] in this issue reflects the classic paradox posed in the children's tale of Goldilocks and the Three Bears. It addresses the vitamin D requirements of very premature infants and the potential impact of vitamin D on functional outcomes, namely cognitive development and reactive airway disease.…”

The Role of Nutrients in Child’s Brain Development

“…According to clinical trials carried out on premature infants, the timely administration of vitamin D supplements did not significantly improve cognitive development. Nonetheless, further research needs to be done so as the dosage of vitamin D supplement to be determined (Salas et al, 2018).…”

Vitamin D Status Is Not Associated with Cognitive or Motor Function in Pre-School Ugandan Children

“…There are few epidemiological studies of the effect of vitamin D status on neurobehavioural outcomes in children and their findings are inconsistent [ 15 ]. One small randomized controlled trial, without a placebo arm, reported a beneficial effect of supplementation with lower doses of vitamin D compared to higher doses [ 16 ] while another found no beneficial effect of vitamin D supplementation on cognitive development in extremely preterm infants compared to no supplementation [ 17 ].…”