Importance of vitamin D in acute and critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis

Abstract

Objectives: To estimate the prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency and investigate its association with mortality in children with acute or critical conditions.

Design: Systematic review and meta-analysis of observational studies.

Data sources: PubMed, OVID, Google Scholar and the Cochrane Library searched until 21 December 2018.

Eligibility criteria: Studies of children hospitalised with acute or critical conditions who had blood 25(OH)D levels measured.

Data extraction and synthesis: We obtained pooled prevalence estimates of 25(OH)D deficiency and ORs for mortality. We calculated 95% CI and prediction intervals and investigated heterogeneity and evidence of small-study effects.

Results: Fifty-two studies were included. Of 7434 children, 3473 (47.0%) were 25(OH)D deficient (<50 nmol/L). The pooled prevalence estimate of 25(OH)D deficiency was 54.6% (95% CI 48.5% to 60.6%, I²=95.3%, p<0.0001). Prevalence was similar after excluding smaller studies (51.5%). In children with sepsis (18 studies, 889 total individuals) prevalence was 64.0% (95% CI 52.0% to 74.4%, I²=89.3%, p<0.0001) and 48.7% (95% CI 38.2% to 59.3%; I²=94.3%, p<0.0001) in those with respiratory tract infections (RTI) (25 studies, 2699 total individuals). Overall, meta-analysis of mortality (18 cohort studies, 2463 total individuals) showed increased risk of death in 25(OH)D deficient children (OR 1.81, 95% CI 1.24 to 2.64, p=0.002, I²=25.7%, p=0.153). Four (22.0%) of the 18 studies statistically adjusted for confounders. There were insufficient studies to meta-analyse sepsis and RTI-related mortality.

Conclusions: Our results suggest that 25(OH)D deficiency in acute and critically ill children is high and associated with increased mortality. Small-study effects, reverse causation and other biases may have confounded results. Larger, carefully designed studies in homogeneous populations with confounder adjustment are needed to clarify the association between 25(OH)D levels with mortality and other outcomes.

Prospero registration number: CRD42016050638.

Keywords: intensive care; meta-analysis; mortality; paediatric; prevalence; respiratory tract infections; sepsis; systematic review; vitamin D.

Figure 1

Flow chart of study selection process. ICU, intensive care unit.

Figure 2

Pooled prevalence estimate for vitamin D deficiency in acute and critically ill children by study design. Forest plot shows results from the random-effects model. Each diamond represents the pooled proportion of 25(OH)D deficiency for each of the subgroups (case–control, cohort, cross-sectional study designs). The diamond at the bottom represents the overall pooled proportion of all the 52 studies together. Each square shows the prevalence estimate of each study and the horizontal line across each square represents the 95% CI of the prevalence estimate. VD, vitamin D.

Figure 3

Bubble plots of univariate meta-regressions. Each study is represented by a circle. Predictor variables: (A) clinical setting and (B) country groups are shown on the x-axis and the effect measure logit transformed proportion shown on the vertical (y-axis). Country group 1: USA, Chile, Australia, Canada, Ireland, Japan, Spain. Country group 2: South Africa, China, Egypt, Iran, Turkey, Saudi Arabia. Country group 3: Bangladesh, Thailand, India. grp, country group; NICU, neonatal intensive care unit; PICU, paediatric intensive care unit.

Figure 4

Pooled prevalence estimate for vitamin D deficiency in children with sepsis. Forest plot shows result from the random-effects model. The diamond represents the overall pooled proportion of 25(OH)D deficiency from the meta-analysis of the 18 studies. Each square shows the prevalence estimate of each study and the horizontal line across each square represents the 95% CI of the prevalence estimate. VD, vitamin D.

Figure 5

Pooled OR of risk of mortality in vitamin D deficient versus vitamin D non-deficient acute and critically ill children. Forest plot shows result from the random-effects model. Diamond represents the overall OR (with corresponding 95% CI). Each square shows the OR of each study and the horizontal line across each square represents the 95% CI of the estimate.