Effects of oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age

Samantha L Huey, Nina Acharya, Ashley Silver, Risha Sheni, Elaine A Yu, Juan Pablo Peña-Rosas, Saurabh Mehta, Samantha L Huey, Nina Acharya, Ashley Silver, Risha Sheni, Elaine A Yu, Juan Pablo Peña-Rosas, Saurabh Mehta

Abstract

Background: Vitamin D is a secosteroid hormone that is important for its role in calcium homeostasis to maintain skeletal health. Linear growth faltering and stunting remain pervasive indicators of poor nutrition status among infants and children under five years of age around the world, and low vitamin D status has been linked to poor growth. However, existing evidence on the effects of vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age has not been systematically reviewed.

Objectives: To assess effects of oral vitamin D supplementation on linear growth and other health outcomes among infants and children under five years of age.

Search methods: In December 2019, we searched CENTRAL, PubMed, Embase, 14 other electronic databases, and two trials registries. We also searched the reference lists of relevant publications for any relevant trials, and we contacted key organisations and authors to obtain information on relevant ongoing and unpublished trials.

Selection criteria: We included randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of oral vitamin D supplementation, with or without other micronutrients, compared to no intervention, placebo, a lower dose of vitamin D, or the same micronutrients alone (and not vitamin D) in infants and children under five years of age who lived in any country.

Data collection and analysis: We used standard Cochrane methodological procedures.

Main results: Out of 75 studies (187 reports; 12,122 participants) included in the qualitative analysis, 64 studies (169 reports; 10,854 participants) contributed data on our outcomes of interest for meta-analysis. A majority of included studies were conducted in India, USA, and Canada. Two studies reported for-profit funding, two were categorised as receiving mixed funding (non-profit and for-profit), five reported that they received no funding, 26 did not disclose funding sources, and the remaining studies were funded by non-profit funding. Certainty of evidence varied between high and very low across outcomes (all measured at endpoint) for each comparison. Vitamin D supplementation versus placebo or no intervention (31 studies) Compared to placebo or no intervention, vitamin D supplementation (at doses 200 to 2000 IU daily; or up to 300,000 IU bolus at enrolment) may make little to no difference in linear growth (measured length/height in cm) among children under five years of age (mean difference (MD) 0.66, 95% confidence interval (CI) -0.37 to 1.68; 3 studies, 240 participants; low-certainty evidence); probably improves length/height-for-age z-score (L/HAZ) (MD 0.11, 95% CI 0.001 to 0.22; 1 study, 1258 participants; moderate-certainty evidence); and probably makes little to no difference in stunting (risk ratio (RR) 0.90, 95% CI 0.80 to 1.01; 1 study, 1247 participants; moderate-certainty evidence). In terms of adverse events, vitamin D supplementation results in little to no difference in developing hypercalciuria compared to placebo (RR 2.03, 95% CI 0.28 to 14.67; 2 studies, 68 participants; high-certainty evidence). It is uncertain whether vitamin D supplementation impacts the development of hypercalcaemia as the certainty of evidence was very low (RR 0.82, 95% CI 0.35 to 1.90; 2 studies, 367 participants). Vitamin D supplementation (higher dose) versus vitamin D (lower dose) (34 studies) Compared to a lower dose of vitamin D (100 to 1000 IU daily; or up to 300,000 IU bolus at enrolment), higher-dose vitamin D supplementation (200 to 6000 IU daily; or up to 600,000 IU bolus at enrolment) may have little to no effect on linear growth, but we are uncertain about this result (MD 1.00, 95% CI -2.22 to 0.21; 5 studies, 283 participants), and it may make little to no difference in L/HAZ (MD 0.40, 95% CI -0.06 to 0.86; 2 studies, 105 participants; low-certainty evidence). No studies evaluated stunting. As regards adverse events, higher-dose vitamin D supplementation may make little to no difference in developing hypercalciuria (RR 1.16, 95% CI 1.00 to 1.35; 6 studies, 554 participants; low-certainty evidence) or in hypercalcaemia (RR 1.39, 95% CI 0.89 to 2.18; 5 studies, 986 participants; low-certainty evidence) compared to lower-dose vitamin D supplementation. Vitamin D supplementation (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s) (9 studies) Supplementation with a higher dose of vitamin D (400 to 2000 IU daily, or up to 300,000 IU bolus at enrolment) plus micronutrients, compared to a lower dose (200 to 2000 IU daily, or up to 90,000 IU bolus at enrolment) of vitamin D with the same micronutrients, probably makes little to no difference in linear growth (MD 0.60, 95% CI -3.33 to 4.53; 1 study, 25 participants; moderate-certainty evidence). No studies evaluated L/HAZ or stunting. In terms of adverse events, higher-dose vitamin D supplementation with micronutrients, compared to lower-dose vitamin D with the same micronutrients, may make little to no difference in developing hypercalciuria (RR 1.00, 95% CI 0.06 to 15.48; 1 study, 86 participants; low-certainty evidence) and probably makes little to no difference in developing hypercalcaemia (RR 1.00, 95% CI 0.90, 1.11; 2 studies, 126 participants; moderate-certainty evidence). Four studies measured hyperphosphataemia and three studies measured kidney stones, but they reported no occurrences and therefore were not included in the comparison for these outcomes.

Authors' conclusions: Evidence suggests that oral vitamin D supplementation may result in little to no difference in linear growth, stunting, hypercalciuria, or hypercalcaemia, compared to placebo or no intervention, but may result in a slight increase in length/height-for-age z-score (L/HAZ). Additionally, evidence suggests that compared to lower doses of vitamin D, with or without micronutrients, vitamin D supplementation may result in little to no difference in linear growth, L/HAZ, stunting, hypercalciuria, or hypercalcaemia. Small sample sizes, substantial heterogeneity in terms of population and intervention parameters, and high risk of bias across many of the included studies limit our ability to confirm with any certainty the effects of vitamin D on our outcomes. Larger, well-designed studies of long duration (several months to years) are recommended to confirm whether or not oral vitamin D supplementation may impact linear growth in children under five years of age, among both those who are healthy and those with underlying infectious or non-communicable health conditions.

Trial registration: ClinicalTrials.gov NCT02273843 NCT01419262 NCT03793309 NCT01469650 NCT02941185 NCT02197702 NCT01600430 NCT01190137 NCT00381914 NCT01042561 NCT01601847 NCT01723852 NCT01999907 NCT00548379 NCT01288950 NCT00846677 NCT03170479 NCT03799406 NCT00949832 NCT00415402 NCT00868738 NCT01532349 NCT00879424 NCT00536276 NCT02058186 NCT01229189 NCT03176849 NCT01838447 NCT02404623.

Conflict of interest statement

Samantha L Huey: none known.

Nina Acharya: none known.

Ashley Silver: none known.

Risha Sheni: none known.

Elaine Yu: none known.

Juan Pablo Peña‐Rosas: the WHO receives partial financial support from the Bill & Melinda Gates Foundation to support commissioning of systematic reviews of interventions for health throughout the life course. Donors do not fund specific guidelines and do not participate in any decision related to the guideline development process, including the composition of policy questions, membership of the guideline groups, the conduct and interpretation of systematic reviews, or the formulation of recommendations.

Disclaimer: Juan Peña‐Rosas is a full‐time staff member at the World Health Organization. The review authors alone are responsible for the views expressed in this publication, which do not necessarily represent the official position, decisions, policy, or views of the WHO.

Saurabh Mehta (SM) is an unpaid board member with an equity stake/stocks/stock options in a diagnostic start‐up company, VitaScan, which is focused on developing assays for low‐cost and point‐of‐care measurement of certain nutrients from a drop of blood, using results from his research as a faculty member at Cornell University. SM is also the principal investigator on competitive research grants from HarvestPlus/International Food Policy Research Institute to conduct efficacy trials for crops biofortified with iron, zinc, and vitamin A among children in India, for which the outcomes include child growth and nutritional status. SM was paid a consulting fee as external reviewer for the nutrition programme at New York Academy of Sciences and was paid travel and accommodation expenses by Foundation Merieux for a conference presentation on precision nutrition and gut microbiome. SM received partial financial support for this work from the WHO.