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

doi:10.1002/14651858.CD012875.pub2

Cochrane Database of Systematic Reviews

Efectos de la administración oral de suplementos de vitamina D en el crecimiento lineal y otros desenlaces de salud en niños menores de cinco años

Información

DOI:

https://doi.org/10.1002/14651858.CD012875.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

11 diciembre 2020see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Problemas de desarrollo, psicosociales y de aprendizaje

Copyright:

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Samantha L Huey

Division of Nutritional Sciences, Cornell University, Ithaca, USA
Nina Acharya

Division of Nutritional Sciences, Cornell University, Ithaca, USA
Ashley Silver

Division of Nutritional Sciences, Cornell University, Ithaca, USA
Risha Sheni

Division of Nutritional Sciences, Cornell University, Ithaca, USA
Elaine A Yu

Division of Nutritional Sciences, Cornell University, Ithaca, USA
Juan Pablo Peña-Rosas

Department of Nutrition and Food Safety, World Health Organization, Geneva, Switzerland
Saurabh Mehta

Correspondencia a: Division of Nutritional Sciences, Cornell University, Ithaca, USA

[email protected]

Contributions of authors

Samantha Huey (SLH) and Nina Archarya (NA) drafted the review. Elaine Yu (EAY) wrote an earlier draft of this review. SLH, NA, EAY, Ashley Silver (AS), and Risha Sheni (RS) performed search strategy translation and screened records. SLH, NA, and AS extracted data and assessed 'Risk of bias' in included studies. SLH and NA performed the GRADE assessment. Juan Pablo Peña‐Rosas (JPP) and Saurabh Mehta (SM) revised and critically reviewed the protocol and the review, and arbitrated disagreements.

SM is the guarantor for the review.

Sources of support

Internal sources

Division of Nutritional Sciences, Cornell University, USA

SM is faculty, and SH and EY are doctoral candidates of the Division of Nutritional Sciences at Cornell University.
Department of Nutrition and Food Safety, World Health Organization (WHO), Switzerland

JPP is a full‐time member of staff of the Department of Nutrition and Food Safety at the WHO.

External sources

Bill & Melinda Gates Foundation, USA

WHO gratefully acknowledges financial support from the Bill & Melinda Gates Foundation. 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.

Declarations of interest

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.

Acknowledgements

We would like to thank the study authors who contributed additional data for this review. We would also like to thank Dr Zulfiqar A Bhutta for his contributions during the protocol stage (Yu 2017), and all staff at the Cochrane Developmental, Psychosocial and Learning Problems (CDPLP) editorial office for their support in preparation of this review.

We are grateful to the following reviewers for their time and comments on this review: Sina Gallo, Associate Professor, University of Georgia, USA; Rehana A Salam, Aga Khan University, Pakistan; and Yohanes Aditya Adhi Satria, Indonesia. We also thank Professor Pradeep Deshmukh for his comments on the protocol.

We gratefully acknowledge the following individuals for their contributions: Ms Sarah Young (for her expertise and assistance in developing the initial search strategy) and Ms Kate Ghezzi‐Kopel (for her expertise and guidance in translating the search strategies across our databases and in providing additional support in searching databases such as Embase).

The protocol for this review was developed during the WHO/Cochrane/Cornell University Summer Institute for Systematic Reviews in Nutrition for Global Policy Making, hosted at the Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA, from 27 July to 7 August 2015.

Version history

Published

Title

Stage

Authors

Version

2020 Dec 11

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

Review

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

https://doi.org/10.1002/14651858.CD012875.pub2

2017 Nov 16

The effects of oral vitamin D supplementation on linear growth and non‐communicable diseases among infants and children younger than five years of age

Protocol

Elaine A Yu, Samantha L Huey, Juan Pablo Peña‐Rosas, Saurabh Mehta

https://doi.org/10.1002/14651858.CD012875

Differences between protocol and review

Title. We changed the title to "Oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age" to focus our review on our primary and secondary outcomes related to linear growth, including adverse effects and rickets. We made this decision after reviewing the literature and noting that many of the trials investigating non‐communicable diseases, including atopy, allergy, metabolic disease, and bone health outcomes, had already been included in previous Cochrane Reviews.
Authorship. We added three new authors ‐ NA, AS, and RA ‐ for their substantial contributions to the review.
Description of the condition and Why it is important to do this review. We revised these sections to reflect updated estimates and statistics published since 2017.
Objectives. We edited our objectives to be in line with changes to the title and scope of the review (see #1 above).
Types of interventions. We had planned to conduct two comparisons: (1) vitamin D versus placebo or no intervention; and (2) vitamin D+micronutrient(s) versus micronutrient(s) alone. After conducting the search, we found that many studies compared higher‐dose vitamin D to lower‐dose vitamin D (across both arms, with or without micronutrient(s)). Upon discussion amongst all review authors, we chose to include such studies as a third and fourth comparison for the review, to more deeply describe, and to gain further clarity over, the literature base in this research area (Table 1).
Types of outcome measures.
1. We added 'gain in linear growth' as a relevant secondary outcome, as two studies included from our search results included this outcome.
2. We added 'change in vitamin D concentration' as a relevant secondary outcome, as several studies included from our search results included this outcome.
3. We added 'underweight' and 'wasting' as relevant secondary outcomes to include these dichotomised outcomes in parallel with including 'stunting' as a primary outcome.
4. We removed secondary outcomes #8 'Atopic diseases (i.e. asthma, including recurring wheeze, dermatitis, and/or rhinitis; as defined by trialists)' and #9, 'Other non‐communicable disease outcomes (i.e. bone health, number of fractures, bone mineral density, any type of cancer, type 1 and type 2 diabetes mellitus, insulin resistance, and other autoimmune disorders; congestive heart failure; as defined by trialists)', as they are covered by previous Cochrane Reviews (Winzenberg 2011; Martineau 2016), as well as by other reviews (Pojsupap 2015), and we sought to narrow our review scope to focus on linear growth and adverse effects (see #1 above).
Electronic searches. Our specific changes are detailed below.
1. PubMed.
  1. We removed quotation marks to increase sensitivity.
  2. We added wildcard to hydroxyvitamin D*
  3. We corrected the spelling of 'randomised controlled trial [pt]' to 'randomised controlled trial [pt]'.
2. Scopus.
  1. We did not limit to conference papers only, thereby conducting a broader search.
3. WPRO (WHO Western Pacific Regional Office).
  1. We corrected the name WPRO to WPRIM (Western Pacific Region Index Medicus); WPRO is the office.
4. IMSEAR (Indian Medicus for the South East Asia Region).
  1. This database was not available at the time of searching (14 March 2018 and 11 December 2019) and therefore was not included.
5. WHO ICTRP.
  1. In December 2019, we did not search WHO ICTRP directly because the trials records were available in CENTRAL.
6. IndMED.
  1. We tried to access IndMED in 2019 but the database was no longer available at the last known URL, and we could not find an alternative location.
Data extraction and management. After piloting our data extraction forms, we found additional information to capture beyond what we had originally proposed, which included only "intervention, participants, trial identification numbers if available, results, and adverse events". We recorded this and additional details in the aforementioned section because we considered these details to be relevant in making comparisons.
Measures of treatment effect.
1. After screening and extracting data, we found that many studies reported medians, ranges, interquartile ranges, and standard errors, rather than means and standard deviations, as described in our protocol (Yu 2017). Using methods in the Cochrane Handbook for Systematic Reviews of Interventions (Li 2020), we were able to include these data in comparisons by back‐calculating means and standard deviations, when appropriate.
2. To examine our secondary outcome 'rickets', we chose to include any study reporting on signs and symptoms of rickets as a dichotomous variable, and to combine these into one variable for meta‐analysis (see Included studies > Outcomes). We analysed rickets this way due to the heterogeneity in rickets' definitions across studies reporting this outcome.
3. We analysed two studies that reported rickets as an outcome using continuous measures, as reported in the original study (see Included studies > Outcomes). We analysed continuous data on rickets separately from categorical measures of rickets to include both types of data in our review.
Unit of analysis issues > Studies with more than two treatment groups.
1. After screening and extracting data, we found that some studies assessed effects of oral vitamin D compared to a control as well as compared to other forms of vitamin D administration, such as intramuscular injection. We did not anticipate this in our protocol (Yu 2017), but we have accounted for this in the Review by extracting data only from relevant trial arms.
2. Because we included another comparison to examine higher‐dose vitamin D compared to lower‐dose vitamin D (Table 1), if a study involved two or more comparison arms, we added our method to accommodate this, which was not described in our protocol (Yu 2017).
Assessment of reporting biases. To avoid repetition, we did not populate this section in our protocol (Yu 2017); we had explained how we would assess reporting bias under 'Selective reporting' in the 'Assessment of risk of bias' section. However, for clarity for the reader, we have explained how we assessed reporting bias in this section of the review.
Data synthesis. After screening and extracting data, we found that many outcomes included only one study in the analysis. For analyses including only one study, we used fixed‐effect models, as they are more appropriate than the random‐effects analyses originally proposed.
Potential biases in the review process. We searched 17 electronic databases and two trial registries to be as comprehensive as possible in examining all available evidence. However, we were not able to assess for publication bias using funnel plots due to lack of studies for comparison, thereby preventing us from drawing conclusions on publication bias of the included studies (Table 2).

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Child, Preschool; Humans; Infant; Infant, Newborn;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 1: Linear growth

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Analysis 1.2

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 2: Length/height‐for‐age

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Analysis 1.3

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 3: Stunting

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Analysis 1.4

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 4: Adverse effect: hypercalciuria

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Analysis 1.5

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 5: Adverse effect: hypercalcaemia

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Analysis 1.6

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 6: Weight‐for‐age

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Analysis 1.7

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 7: Underweight

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Analysis 1.8

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 8: Weight‐for‐length/height

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Analysis 1.9

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 9: Wasting

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Analysis 1.10

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 10: Serum 25‐hydroxyvitamin D

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Analysis 1.11

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 11: Change in 25(OH)D levels (nmol/L)

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Analysis 1.12

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 12: Vitamin D sufficiency (≥ 50 nmol/L)

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Analysis 1.13

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 13: Vitamin D sufficiency (≥ 75 nmol/L)

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Analysis 1.14

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 14: Vitamin D severe deficiency (< 25 to 30 nmol/L)

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Analysis 1.15

Comparison 1: Vitamin D versus placebo or no intervention, Outcome 15: Rickets (continuous)

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Analysis 2.1

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 1: Linear growth

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Analysis 2.2

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 2: Length/height‐for‐age

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Analysis 2.3

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 3: Adverse effect: hypercalciuria

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Analysis 2.4

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 4: Adverse effect: hypercalcaemia

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Analysis 2.5

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 5: Linear growth: gain in length

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Analysis 2.6

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 6: Weight‐for‐age

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Analysis 2.7

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 7: Weight‐for‐length/height

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Analysis 2.8

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 8: Serum 25‐hydroxyvitamin D

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Analysis 2.9

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 9: Change in 25(OH)D (nmol/L)

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Analysis 2.10

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 10: Vitamin D sufficiency (≥ 50 nmol/L)

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Analysis 2.11

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 11: Vitamin D sufficiency (≥ 75 nmol/L)

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Analysis 2.12

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 12: Vitamin D severe deficiency (< 25 to 30 nmol/L)

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Analysis 2.13

Comparison 2: Vitamin D (higher dose) versus vitamin D (lower dose), Outcome 13: Rickets (dichotomous)

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Analysis 3.1

Comparison 3: Vitamin D + micronutrient(s) versus micronutrient(s) alone, Outcome 1: Serum 25‐hydroxyvitamin D

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Analysis 3.2

Comparison 3: Vitamin D + micronutrient(s) versus micronutrient(s) alone, Outcome 2: Rickets (continuous)

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Analysis 4.1

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 1: Linear growth

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Analysis 4.2

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 2: Adverse effect: hypercalciuria

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Analysis 4.3

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 3: Adverse effect: hypercalcaemia

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Analysis 4.4

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 4: Linear growth: gain in length

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Analysis 4.5

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 5: Serum 25‐hydroxyvitamin D

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Analysis 4.6

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 6: Change in 25(OH)D (nmol/L)

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Analysis 4.7

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 7: Vitamin D sufficiency (≥ 50 nmol/L)

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Analysis 4.8

Comparison 4: Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s), Outcome 8: Rickets (dichotomous)

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Summary of findings 1. Vitamin D versus placebo or no intervention

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
Vitamin D versus placebo or no intervention
Patient or population: children under 5 years of age Setting: any country Intervention: oral vitamin D (doses: 200 to 2000 IU daily; or up to 300,000 IU bolus at enrolment) Comparison: placebo or no intervention
Outcomes	Risk with placebo or no intervention	Risk with vitamin D	Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
Linear growth (length/height) Unit: cm Time frame: 6.3 months (mean)	Mean length in control group was 62.7 cm	Mean length in intervention group was 0.66 cm longer (0.37 shorter to 1.68 longer).	‐	240 (3 RCTs)	⊕⊕⊝⊝ Low^a	Two studies showed an increase in linear growth, and 1 study found a decrease in linear growth. However, no difference was found overall
Length/height‐for‐age z‐score (L/HAZ) Time frame: 6 months	Mean height‐for‐age z‐score in control group was ‐1.95	Mean height‐for‐age z‐score in intervention group was 0.11 units higher (0.001 to 0.22 higher).	‐	1258 (1 RCT)	⊕⊕⊕⊝ Moderate^b	HAZ was higher among those receiving vitamin D
Stunting Definition: L/HAZ < ‐2 Time frame: 6 months	Study population		RR 0.90 (0.80 to 1.01)	1247 (1 RCT)	⊕⊕⊕⊝ Moderate^b
Stunting Definition: L/HAZ < ‐2 Time frame: 6 months	490 per 1000	441 per 1000 (392 to 495)	RR 0.90 (0.80 to 1.01)	1247 (1 RCT)	⊕⊕⊕⊝ Moderate^b
Adverse effect: hypercalciuria As defined by trialists Time frame: 6.5 months (mean)	Study population		RR 2.03 (0.28 to 14.67)	68 (2 RCTs)	⊕⊕⊕⊝ Moderate^c	There was no greater risk of increased calcium secretion in urine in groups receiving vitamin D
	29 per 1000	60 per 1000 (1 to 238)	RR 2.03 (0.28 to 14.67)	68 (2 RCTs)	⊕⊕⊕⊝ Moderate^c
Adverse effect: hypercalcaemia As defined by trialists Time frame: 7.5 months (mean)	Study population		RR 0.82 (0.35 to 1.90)	367 (2 RCTs)	⊕⊝⊝⊝ Very low^d	There was no greater risk of increased calcium concentration in blood in groups receiving vitamin D
	124 per 1000	101 per 1000 (43 to 235)	RR 0.82 (0.35 to 1.90)	367 (2 RCTs)	⊕⊝⊝⊝ Very low^d
Adverse effect: hyperphosphataemia^e	‐	‐	‐	‐	‐	Not measured
Adverse effect: kidney stones^e	‐	‐	‐	‐	‐	Not measured
*The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; 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.
^aDowngraded one level due to serious risk of bias. Evidence was downgraded an additional level due to inconsistency (as indicated by an I² value of 49%; P = 0.14), suggesting moderate heterogeneity. ^bDowngraded one level due to indirectness as only one study conducted in India was included, restricting the population analysed. ^cDowngraded one level due to imprecision, as the confidence interval was wide around the effect size which included 1.0, the null value. ^dDowngraded one level due to serious risk of bias. Evidence was downgraded an additional level due to imprecision, as the confidence interval around the effect size included 1.0, the null value. Evidence was downgraded an additional level due to inconsistency (as indicated by an I² value of 48%; P = 0.64), suggesting moderate heterogeneity. ^eNo data were available for this outcome.

Summary of findings 1. Vitamin D versus placebo or no intervention

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Summary of findings 2. Vitamin D (higher dose) versus vitamin D (lower dose)

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
Vitamin D (higher dose) versus vitamin D (lower dose)
Patient or population: children under 5 years of age Setting: any country Intervention: oral vitamin D (higher dose: 200 to 6000 IU daily; or up to 600,000 IU bolus at enrolment) Comparison: oral vitamin D (lower dose: 100 to 1000 IU daily; or up to 300,000 IU bolus at enrolment)
Outcomes	Risk with lower‐dose vitamin D	Risk with higher‐dose vitamin D	Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
Linear growth (length/height) Unit: cm Time frame: 4.2 months (mean)	Mean length in control group was 57.8 cm.	Mean length in intervention group was 1.00 cm shorter (2.22 shorter to 0.21 longer).	‐	283 (5 RCTs)	⊕⊝⊝⊝ Very low^a	Two studies showed an increase in linear growth, and 3 studies found a decrease in linear growth. However, no difference was found overall
Length/height‐for‐age z‐score (L/HAZ) Unitless Time frame: 7 months (mean)	Mean height‐for‐age z‐score in control group was ‐0.35.	Mean height‐for‐age z‐score in intervention group was0.40 units higher (0.06 units lower to 0.86 units higher).	‐	105 (2 RCTs)	⊕⊕⊝⊝ Low^b	No difference in HAZ was found between groups
Stunting^c	‐	‐	‐	‐	‐	Not measured
Adverse effect: hypercalciuria As defined by trialists Time frame: 3.9 months (mean)	Study population		RR 1.16 (1.00 to 1.35)	554 (6 RCTs)	⊕⊕⊝⊝ Low^b	There was no greater risk of increased calcium secretion in urine in groups receiving vitamin D
	276 per 1000	320 per 1000 (276 to 372)	RR 1.16 (1.00 to 1.35)	554 (6 RCTs)	⊕⊕⊝⊝ Low^b
Adverse effect: hypercalcaemia As defined by trialists Time frame: 8.6 months (mean)	Study population		RR 1.39 (0.89 to 2.18)	986 (5 RCTs)	⊕⊕⊝⊝ Low^b	There was no greater risk of increased calcium concentrations in blood in groups receiving vitamin D
	64 per 1000	88 per 1000 (57 to 139)	RR 1.39 (0.89 to 2.18)	986 (5 RCTs)	⊕⊕⊝⊝ Low^b
Adverse effect: hyperphosphataemia^c	‐	‐	‐	‐	‐	Not measured
Adverse effect: kidney stones^c	‐	‐	‐	‐	‐	Not measured
*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; RCT: randomised controlled trial; 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.
^aDowngraded one level due to serious risk of bias. Evidence was downgraded an additional level due to imprecision, as the confidence interval around the effect size included 0, the null value. Evidence was downgraded an additional level due to inconsistency between studies, indicated by an I² value of 71%, suggesting substantial heterogeneity. ^bDowngraded one level due to serious risk of bias. Evidence was downgraded an additional level due to imprecision, as the confidence interval around the effect size included 0 or 1.0, the null value. ^cNo data were available for this outcome.

Summary of findings 2. Vitamin D (higher dose) versus vitamin D (lower dose)

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Summary of findings 3. Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s)

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s)
Patient or population: children under 5 years of age Setting: any country Intervention: oral vitamin D (higher dose: 400 to 2000 IU daily, or up to 300,000 IU bolus at enrolment) + micronutrient(s), including minerals such as calcium phosphate, multi‐vitamin, or both Comparison: oral vitamin D (lower dose: 200 to 2000 IU daily, or up to 90,000 IU bolus at enrolment) + micronutrient(s), including minerals such as calcium phosphate, multi‐vitamin, or both
Outcomes	Risk with lower‐dose vitamin D + micronutrient(s)	Risk with higher‐dose vitamin D + micronutrient(s)	Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
Linear growth (length/height) Unit: cm Time frame: 3 months	Mean length in control group was 49.2 cm	Mean length in intervention group was 0.6 cm longer (3.33 shorter to 4.53 longer)	‐	25 (1 RCT)	⊕⊕⊝⊝ Low^a	No difference in linear growth was found between groups
Length/height‐for‐age z‐score (L/HAZ)^b	‐	‐	‐	‐	‐	Not measured
Stunting^b	‐	‐	‐	‐	‐	Not measured
Adverse effect: hypercalciuria As defined by trialists Time frame: 3 months	Study population		RR 1.00 (0.06 to 15.48)	86 (1 RCT)	⊕⊕⊝⊝ Low^c	There was no greater risk of increased calcium secretion in urine in groups receiving vitamin D
	23 per 1000	23 per 1000 (1 to 360)	RR 1.00 (0.06 to 15.48)	86 (1 RCT)	⊕⊕⊝⊝ Low^c
Adverse effect: hypercalcaemia As defined by trialists Time frame: 2.2 months (mean)	Study population		RR 1.00 (0.90 to 1.11)	126 (2 RCTs)	⊕⊕⊕⊝ Moderate^d	There was no greater risk of increased calcium concentrations in blood in groups receiving vitamin D
	145 per 1000	298 per 1000 (268 to 331)	RR 1.00 (0.90 to 1.11)	126 (2 RCTs)	⊕⊕⊕⊝ Moderate^d
Adverse effect: hyperphosphataemia^b	‐	‐	‐	‐	‐	Not measured
Adverse effect: kidney stones^b	‐	‐	‐	‐	‐	Not measured
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomised controlled trial; 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.
^aDowngraded one level due to risk of bias and imprecision, as the 95% CI for the effect measure included the null value of 0. Evidence was downgraded an additional level due to indirectness as only one study conducted in Finland was included, restricting the population analysed. ^bNo data were available for this outcome. ^cDowngraded one level due to risk of bias and imprecision, as the 95% CI for the effect measure included the null value of 1.0. Evidence was downgraded an additional level due to indirectness as only one study conducted in India was included, restricting the population analysed. ^dDowngraded one level due to risk of bias and imprecision, as the 95% CI for the effect measure included the null value of 1.0.

Summary of findings 3. Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s)

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Table 1. Intervention and comparator groups

Comparison
Name of comparison	Intervention group	Comparator group
1. Vitamin D supplementation vs placebo or no intervention	Oral vitamin D (cholecalciferol D₃, ergocalciferol D₂, calcitriol) supplementation^a	No intervention
1. Vitamin D supplementation vs placebo or no intervention		Placebo
2. Vitamin D supplementation (high dose) vs vitamin D (low dose)	Oral vitamin D (cholecalciferol D₃, ergocalciferol D₂, calcitriol) supplementation,^a at a higher dose	Oral vitamin D (cholecalciferol D₃, ergocalciferol D₂, calcitriol) supplementation,^a at a lower dose
3. Vitamin D supplementation + micronutrient(s) vs micronutrient(s) alone	Other micronutrient(s),^b including oral vitamin D (cholecalciferol D₃, ergocalciferol D₂, calcitriol) supplementation^a	Other micronutrient(s),^b not including vitamin D
4. Vitamin D supplementation (high dose) + micronutrient(s) vs vitamin D (low dose) + micronutrient(s)	Other micronutrient(s),^b including oral vitamin D (cholecalciferol D₃, ergocalciferol D₂, calcitriol) supplementation at a higher dose^a	Other micronutrient(s),^b including vitamin D at a lower dose
^aAny formulation, including capsules, tablets, soft gels, liquids, sprays/mists, or powders. ^bComparisons will include intervention and comparator groups with the same combination and content of vitamin(s) and/or mineral(s) to isolate the effects of vitamin D.

Table 1. Intervention and comparator groups

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Table 2. Unused methods

Data analysis	Unused method	Reason for non‐use
Unit of analysis issues	Cluster‐randomised trials Had we included cluster‐randomised trials, we would have accounted for randomisation of study participant groups by conducting analyses at the cluster level. We would have calculated effect estimates (with respective standard errors (SEs)) by using the generic inverse variance method presented in Review Manager 5 (RevMan 5) (Higgins 2020b; Review Manager 2014). Depending on analyses of included studies, we would have conducted approximately correct analyses, when possible (Higgins 2020b)	No cluster‐randomised trials included in review
Unit of analysis issues	Cross‐over trials We planned to assess data from a 2‐period, 2‐intervention cross‐over trial by using a paired t‐test to evaluate the difference between 2 measurements (subtracting the control measurement from the experimental measurement) for each study participant (Higgins 2020b). For studies with potential carry‐over effects, we planned to consider only the first period of trial intervention follow‐up (Higgins 2020b)	No cross‐over trials included in quantitative analysis
Subgroup analysis and investigation of heterogeneity	If at least 4 studies measuring a primary outcome had reported on age at time of intervention (birth to 6 months of age vs 7 to 12 months of age, 13 to 36 months of age, 37 to 59 months of age), frequency of supplementation (daily vs intermittent vs other), serum 25(OH)D at baseline (current cutoff levels recommended by the Institute of Medicine and the Endocrine Society (Holick 2011; Institute of Medicine 2011)), geographical latitude (between Tropics of Cancer and Capricorn, compared with north of Tropic of Cancer and south of Tropic of Capricorn), season at start of study (spring, summer, fall, winter), or baseline height/length‐for‐age z‐score, we would have performed subgroup analyses (see the protocol Yu 2017 for details). Subgroup analyses would have been undertaken in RevMan 5 (Review Manager 2014), using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2020)	Not enough studies available (≤ 3)
Sensitivity analysis	If at least 10 studies measuring a primary outcome had been available to compare in terms of being published or unpublished, high risk of bias, longer intervention durations or greater sample sizes, influence of methods, and use of filters such as imputation, language of publication, source of funding, and country, we would have performed statistical tests, including Egger's test to assess asymmetry of funnel plots and as indicators of bias (Egger 1997) (see the protocol Yu 2017 for details). Sensitivity analyses would have been undertaken in RevMan 5 (Review Manager 2014), using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2020)	Not enough studies available (≤ 10)
Publication bias	We searched 17 electronic databases and 2 trial registries to be as comprehensive as possible in examining all available evidence. However, we were not able to assess for publication bias using funnel plots due to lack of studies for comparison, thereby preventing us from drawing conclusions on publication bias of the included studies	Not enough studies available (≤ 10)

Table 2. Unused methods

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Table 3. Participant characteristics

Participants included	Studies included
Both infants and children	Alam 2011; Gordon 2008; Gupta 2016; Harnot 2017; Manaseki Holland 2010; Mittal 2014; Mittal 2018; Rianthavorn 2013; Sarhan 2019; Singh 2019; Thacher 2014
Children older than 1 year	Aglipay 2017; Ducharme 2019; Jensen 2016; Marchisio 2013; Principi 2013; Rao 2016; Sánchez‐Armendáriz 2018; Somnath 2017; Tang 2019
Studies with extended follow‐up data after no supplementation	Gallo 2013b; Greer 1981; Trilok‐Kumar 2011; Ziegler 2014
Baseline health status	Studies included
Healthy	Aglipay 2017; Ala‐Houhala 1985; Alizadeh 2006; Atas 2013; Chandy 2016; Feliciano 1994; Gallo 2013a; Gallo 2013b; Greer 1981; Greer 1989; Holmlund‐Suila 2012; Holst‐Gemeiner 1978; Huynh 2017; Lagomarsino 1996; Lava 2011; Manaseki‐Holland 2012; Marchisio 2013; Moodley 2015; Pehlivan 2003; Ponnapakkam 2010; Rodd 2011; Rosendahl 2018; Rueter 2019; Shajari 2009; Shakiba 2010; Siafarikas 2011; Singh 2018a; Specker 1992; Stögmann 1985; Zeghoud 1994; Ziegler 2014
Vitamin D deficiency	Gordon 2008; Gupta 2016; Rao 2016; Rianthavorn 2013; Tomimoto 2018
Preterm and/or very low birth weight	Abdel‐Hady 2019; Alizadeh 2006; Alizadeh Taheri 2014; Aly 2019; Anderson‐Berry 2017; Backström 1999a; Backström 1999b; Bozkurt 2017; Chan 1978; Evans 1989; Fort 2016; Hanson 2011; Hibbs 2018; Kislal 2008; Mathur 2016; Morawa 1963; Natarajan 2014; Robinson 1981; Tergestina 2016; Trilok‐Kumar 2011; Willi 1959
Rickets	Harnot 2017; Mittal 2014; Mittal 2018; Thacher 2014
Severe acute malnutrition	Saleem 2018
Acute or recurrent otitis media	Marchisio 2013; Principi 2013
Acute diarrhoea	Alam 2011
Bronchiolitis	Saad 2015; Sarhan 2019
Pneumonia	Choudhary 2012; Manaseki Holland 2010; Singh 2019
Upper or lower respiratory tract infection	Jensen 2016; Somnath 2017
Asthma	Ducharme 2019; Jensen 2016
Chronic kidney disease	Rianthavorn 2013
Chronic heart failure	Shedeed 2012
Juvenile idiopathic arthritis	Tang 2019
Atopic dermatitis	Sánchez‐Armendáriz 2018

Table 3. Participant characteristics

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Table 4. Sensitivity analyses: results of analyses using fixed‐effect models with ≥ 2 studies

Results of sensitivity analysis with fixed‐effect model
Comparison 1: vitamin D vs placebo or no intervention	Number of studies	Mean difference (95% CI)	Chi²	P value for overall effect	I²(%)
Linear growth (Analysis 1.1)	3	0.73 (0.01 to 1.45)	3.96	0.05	49
Adverse effect: hypercalciuria (Analysis 1.4)	2	2.03 (0.28 to 14.67)	0.63	0.48	0
Adverse effect: hypercalcaemia (Analysis 1.5)	2	0.79 (0.43 to 1.44)	1.93	0.44	48
Weight‐for‐height (z‐score) (Analysis 1.8)	2	0.06 (‐0.06 to 0.19)	13.61	0.33	93
Serum 25(OH)D (Analysis 1.10)	21	25.04 (23.10 to 26.98)	369.62	< 0.001	95
Change in 25(OH)D (Analysis 1.11)	3	34.09 (28.90 to 39.28)	17.35	< 0.001	88
Vitamin D sufficiency (≥ 50 nmol/L) (Analysis 1.12)	6	1.88 (1.66 to 2.14)	6.25	< 0.001	20
Vitamin D sufficiency (≥ 75 nmol/L) (Analysis 1.13)	2	2.47 (1.50 to 4.06)	11.30	0.0004	91
Vitamin D severe deficiency (Analysis 1.14)	3	0.26 (0.19 to 0.36)	1.68	< 0.001	0
Comparison 2: vitamin D (higher dose) vs vitamin D (lower dose)	Number of studies	Mean difference (95% CI)	Chi²	P value for overall effect	I²(%)
Linear growth (Analysis 2.1)	5	‐0.75 (‐1.33 to ‐0.17)	13.64	0.01	71
Length/height‐for‐age (z‐score) (Analysis 2.2)	2	0.40 (‐0.06 to 0.86)	0.04	0.09	0
Adverse effect: hypercalciuria (Analysis 2.3)	6	1.16 (1.00 to 1.35)	1.88	0.06	0
Adverse effect: hypercalcaemia (Analysis 2.4)	5	1.39 (0.89 to 2.18)	2.16	0.15	0
Linear growth: gain in length (Analysis 2.5)	3	‐0.01 (‐0.02 to 0.00)	0.68	0.06	0
Weight‐for‐age (z‐score) (Analysis 2.6)	2	0.07 (‐0.44 to 0.58)	0.01	0.78	0
Serum 25(OH)D (Analysis 2.8)	20	14.73 (13.24 to 16.22)	493.04	< 0.001	96
Change in 25(OH)D (Analysis 2.9)	3	1.68 (‐1.08 to 4.43)	3.67	0.23	46
Vitamin D sufficiency (≥ 50 nmol/L) (Analysis 2.10)	12	1.02 (1.00 to 1.03)	17.24	0.008	42
Vitamin D sufficiency (≥ 75 nmol/L) (Analysis 2.11)	6	1.25 (1.18 to 1.31)	8.05	< 0.001	38
Rickets (Analysis 2.13)	4	0.64 (0.46 to 0.90)	1.24	0.009	0
Comparison 4: vitamin D (higher dose) + micronutrient(s) vs vitamin D (lower dose) + micronutrient(s)	Number of studies	Mean difference (95% CI)	Chi²	P value for overall effect	I²(%)
Adverse effect: hypercalcaemia (Analysis 4.3)	2	1.00 (0.90 to 1.11)	0	1.00	0
Serum 25(OH)D (Analysis 4.5)	5	25.91 (20.50 to 31.32)	112.69	< 0.001	96
Vitamin D sufficiency (≥ 75 nmol/L) (Analysis 4.7)	3	1.13 (0.97 to 1.31)	25.65	0.12	92
Rickets (Analysis 4.8)	2	1.23 (0.24 to 6.30)	0.43	0.80	0
CI: confidence interval. Serum 25(OH)D: serum 25‐hydroxyvitamin D.

Table 4. Sensitivity analyses: results of analyses using fixed‐effect models with ≥ 2 studies

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Table 5. Sensitivity analysis: outcome 1.10

Serum 25(OH)D (nmol/L) (Analysis 1.10 )
Category	Number of studies	Mean difference (95% CI)	Tau²	Chi²	P value	I²(%)
All studies	20	30.91 (21.82 to 40.00)	385.01	369.62	< 0.001	95
Physiological doses only	15	31.00 (20.31 to 41.68)	388.92	306.64	< 0.001	95
Infants only	14	27.95 (17.36 to 38.54)	357.03	240.76	< 0.001	95
Children only (> 1 year)	5	42.50 (20.85 to 64.15)	460.98	31.74	< 0.001	87
CI: confidence interval.

Table 5. Sensitivity analysis: outcome 1.10

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Table 6. Sensitivity analysis: outcome 2.8

Serum 25(OH)D (nmol/L) (Analysis 2.8 )
Category	Number of studies	Mean difference (95% CI)	Tau²	Chi²	P value	I²(%)
All studies	20	16.13 (7.11 to 25.15)	333.01	493.04	< 0.001	96
Physiological doses only	14	18.62 (8.86 to 28.39)	268.61	243.46	< 0.001	95
Infants only	18	16.02 (6.16 to 25.87)	352.80	461.94	< 0.001	96
Preterm only	9	12.96 (2.23 to 23.68)	183.61	72.17	< 0.001	89
CI: confidence interval.

Table 6. Sensitivity analysis: outcome 2.8

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Comparison 1. Vitamin D versus placebo or no intervention

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Linear growth Show forest plot	3	240	Mean Difference (IV, Random, 95% CI)	0.66 [‐0.37, 1.68]

1.2 Length/height‐for‐age Show forest plot	1	1258	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.00, 0.22]

1.3 Stunting Show forest plot	1	1247	Risk Ratio (IV, Fixed, 95% CI)	0.90 [0.80, 1.01]

1.4 Adverse effect: hypercalciuria Show forest plot	2	68	Risk Ratio (IV, Random, 95% CI)	2.03 [0.28, 14.67]

1.5 Adverse effect: hypercalcaemia Show forest plot	2	367	Risk Ratio (IV, Random, 95% CI)	0.82 [0.35, 1.90]

1.6 Weight‐for‐age Show forest plot	1	1273	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.02, 0.20]

1.7 Underweight Show forest plot	1	1282	Risk Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]

1.8 Weight‐for‐length/height Show forest plot	2	1442	Mean Difference (IV, Random, 95% CI)	0.65 [‐0.67, 1.97]

1.9 Wasting Show forest plot	1	1282	Risk Ratio (IV, Fixed, 95% CI)	1.25 [0.82, 1.91]

1.10 Serum 25‐hydroxyvitamin D Show forest plot	21	2202	Mean Difference (IV, Random, 95% CI)	30.91 [21.82, 40.00]

1.11 Change in 25(OH)D levels (nmol/L) Show forest plot	3	495	Mean Difference (IV, Random, 95% CI)	28.36 [10.41, 46.32]

1.12 Vitamin D sufficiency (≥ 50 nmol/L) Show forest plot	6	982	Risk Ratio (IV, Random, 95% CI)	1.88 [1.63, 2.17]

1.13 Vitamin D sufficiency (≥ 75 nmol/L) Show forest plot	2	138	Risk Ratio (IV, Random, 95% CI)	5.75 [0.49, 67.59]

1.14 Vitamin D severe deficiency (< 25 to 30 nmol/L) Show forest plot	3	836	Risk Ratio (IV, Random, 95% CI)	0.26 [0.19, 0.36]

1.15 Rickets (continuous) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 1. Vitamin D versus placebo or no intervention

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Comparison 2. Vitamin D (higher dose) versus vitamin D (lower dose)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Linear growth Show forest plot	5	283	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐2.22, 0.21]

2.2 Length/height‐for‐age Show forest plot	2	105	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.06, 0.86]

2.3 Adverse effect: hypercalciuria Show forest plot	6	554	Risk Ratio (IV, Random, 95% CI)	1.16 [1.00, 1.35]

2.4 Adverse effect: hypercalcaemia Show forest plot	5	986	Risk Ratio (IV, Random, 95% CI)	1.39 [0.89, 2.18]

2.5 Linear growth: gain in length Show forest plot	3	378	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.02, 0.00]

2.6 Weight‐for‐age Show forest plot	2	103	Mean Difference (IV, Random, 95% CI)	0.07 [‐0.44, 0.58]

2.7 Weight‐for‐length/height Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.74, 0.37]

2.8 Serum 25‐hydroxyvitamin D Show forest plot	20	2765	Mean Difference (IV, Random, 95% CI)	16.13 [7.11, 25.15]

2.9 Change in 25(OH)D (nmol/L) Show forest plot	3	142	Mean Difference (IV, Random, 95% CI)	4.12 [‐5.82, 14.07]

2.10 Vitamin D sufficiency (≥ 50 nmol/L) Show forest plot	12	1735	Risk Ratio (IV, Random, 95% CI)	1.04 [1.00, 1.08]

2.11 Vitamin D sufficiency (≥ 75 nmol/L) Show forest plot	6	1172	Risk Ratio (IV, Random, 95% CI)	1.31 [1.19, 1.45]

2.12 Vitamin D severe deficiency (< 25 to 30 nmol/L) Show forest plot	1	142	Risk Ratio (IV, Fixed, 95% CI)	0.14 [0.02, 1.35]

2.13 Rickets (dichotomous) Show forest plot	4	212	Risk Ratio (IV, Random, 95% CI)	0.64 [0.46, 0.90]

Comparison 2. Vitamin D (higher dose) versus vitamin D (lower dose)

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Comparison 3. Vitamin D + micronutrient(s) versus micronutrient(s) alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Serum 25‐hydroxyvitamin D Show forest plot	1	50	Mean Difference (IV, Fixed, 95% CI)	18.90 [8.53, 29.27]

3.2 Rickets (continuous) Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.94 [‐2.10, 0.22]

Comparison 3. Vitamin D + micronutrient(s) versus micronutrient(s) alone

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Comparison 4. Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Linear growth Show forest plot	1	25	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐3.33, 4.53]

4.2 Adverse effect: hypercalciuria Show forest plot	1	86	Risk Ratio (IV, Fixed, 95% CI)	1.00 [0.06, 15.48]

4.3 Adverse effect: hypercalcaemia Show forest plot	2	126	Risk Ratio (IV, Random, 95% CI)	1.00 [0.90, 1.11]

4.4 Linear growth: gain in length Show forest plot	1	50	Mean Difference (IV, Fixed, 95% CI)	0.73 [0.12, 1.34]

4.5 Serum 25‐hydroxyvitamin D Show forest plot	5	325	Mean Difference (IV, Random, 95% CI)	27.94 [‐2.75, 58.63]

4.6 Change in 25(OH)D (nmol/L) Show forest plot	1	30	Mean Difference (IV, Fixed, 95% CI)	7.19 [2.97, 11.41]

4.7 Vitamin D sufficiency (≥ 50 nmol/L) Show forest plot	3	225	Risk Ratio (IV, Random, 95% CI)	1.34 [0.76, 2.35]

4.8 Rickets (dichotomous) Show forest plot	2	153	Risk Ratio (IV, Random, 95% CI)	1.23 [0.24, 6.30]

Comparison 4. Vitamin D (higher dose) + micronutrient(s) versus vitamin D (lower dose) + micronutrient(s)

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Efectos de la administración oral de suplementos de vitamina D en el crecimiento lineal y otros desenlaces de salud en niños menores de cinco años

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