Effects of vitamin A and vitamin D₃ supplementation on child growth and development in low- and middle-income countries: a systematic review and meta-analysis

Introduction

Background

Nutritional deficiencies, including inadequate intake of essential vitamins, minerals, and macronutrients, are key factors that affect the growth trajectory and developmental outcomes of children (1). Numerous studies have highlighted that many children’s diets are imbalanced, leading to insufficient intake of essential nutrients such as calcium, vitamin A, and vitamin D₃ (2-4). Long-term deficiencies in calcium, vitamin A, vitamin D₃, and other nutrients among children may lead to growth retardation, impaired immunity, and an increased risk of infectious diseases (5). Vitamin A and D₃ are essential nutrients for human growth and development, particularly during fetal and infant stages (6,7). Vitamin A is not only vital for the development of children’s vision but also plays a critical role in maintaining immune function. Inadequate intake can lead to weakened resistance and increased susceptibility to respiratory and digestive infections (8,9). Vitamin D₃ can enhance calcium absorption, is involved in bone formation, and promotes children’s bone development (10). It also plays a significant role in the prevention of many diseases in adulthood (11,12). Moreover, vitamin D₃ has been shown to boost the immune function of the monocyte-macrophage system, activate T cells, and promote the production of cytokines such as tumor necrosis factor and interleukin (13-15).

Rationale and knowledge gap

Micronutrient supplementation strategies—whether administered individually or in combination—have been widely used in various settings to prevent or correct nutritional deficiencies and promote optimal growth outcomes (16). Vitamin A and D₃ are often co-administered in pediatric practice, and are widely used pediatric formulations—such as United Nations International Children’s Emergency Fund (UNICEF) standard multiple micronutrient powders and disease-specific pediatric multivitamin drops—both including vitamins A and D₃ together with zinc and B-complex vitamins (17,18). However, the clinical efficacy of these interventions remains debated. Variations in supplementation protocols, population characteristics, and study quality across existing research have led to inconsistent findings regarding their impact on child growth and development. Despite the biological plausibility of their benefits, consensus is lacking regarding the effectiveness of vitamin A and D₃ supplementation, either alone or in combination, in improving key anthropometric outcomes such as height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ), and weight-for-height Z-score (WHZ). This inconsistency highlights the need for a comprehensive synthesis of high-quality evidence to clarify their role in promoting child growth.

Objective

This systematic review and meta-analysis aims to evaluate the effects of vitamin A supplementation, vitamin D₃ supplementation, and their combination with other micronutrients on growth outcomes in children (Primary population: children aged 0–5 years; Secondary exploratory analyses: 0–14 years). By synthesizing evidence from randomized controlled trials (RCTs), we seek to assess how these interventions influence childhood growth and development. We present this article in accordance with the PRISMA reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-507/rc).

Methods

Search strategy

We conducted a comprehensive literature search of PubMed, EMBASE, and the Cochrane Library to identify relevant RCTs evaluating the effects of vitamin A and vitamin D₃ supplementation on growth outcomes in children. The search covered publications from 1995 through June 2025. We used a combination of Medical Subject Headings (MeSH) and free-text terms to maximize comprehensive coverage and sensitivity. The search strategy included terms related to vitamin A (“Vitamin A”[MeSH], “Vitamin A”, Retinol, “Vitamin A supplementation”), vitamin D₃ (“Vitamin D”[MeSH], “Vitamin D₃”, Cholecalciferol, “Vitamin D₃ supplementation”), and growth parameters (“Body Height”[MeSH], “Height”, “Body Weight”[MeSH], “Weight”, “Growth”[MeSH], “Growth”, “BMI”, “Anthropometry”). To restrict the search to the pediatric population, we also included terms such as “Child” [MeSH], “Infant” [MeSH], “Adolescent” [MeSH], children, and pediatric. In addition, we manually screened relevant journals and reviewed the reference lists of the included articles to identify any additional studies meeting the inclusion criteria. The literature search identified a total of 182 records for screening (Figure 1). After removing duplicates and records flagged as ineligible by automation tools (Zotero and Rayyan; the latter was used as a semi-automated screening tool). After excluding clearly irrelevant records, a total of 51 records were assessed for eligibility in full text. Finally, 12 articles met the inclusion criteria and were included for further analysis.

Figure 1 Flowchart of literature inclusion of this research. *, records flagged as ineligible by automation tools (Rayyan automatic classification). HAZ, height-for-age Z-score; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score.

Eligibility criteria

Inclusion criteria

(I) The language of the literature was English; (II) the publication period was from 1995 to June 2025; (III) the research method was an RCT, and the results reported the changes of height and weight after the intervention; (IV) the participants aged 0–14 years, and the intervention time was >8 weeks. Although the inclusion criteria specify an intervention population of 0–14-year-old children, the focus of this study is on the 0–5-year-old group. The 0–5-year-old group is of particular interest as it represents a critical period of rapid growth and development.

Exclusion criteria

(I) duplicate publication; (II) studies with insufficient data for extraction or analysis; (III) the type of study was nonrandomized trial, and there was not enough data to calculate the change value; (IV) the included subjects had chronic diseases affecting growth and development, such as protein-energy malnutrition and anemia.

Data collection

Titles and abstracts were screened to identify potentially relevant records, which were then assessed against the pre-specified inclusion and exclusion criteria. Discrepancies between reviewers were resolved by discussion and consensus. We established an information extraction table, including country, author, title, publication years, article source, research object, inclusion criteria, age, number of people, and intervention time. Data extraction was performed in duplicate using a blinded method: two reviewers independently extracted data using piloted forms, and discrepancies were resolved by discussion with a third reviewer. During data extraction, reviewers were blinded to the authors’ affiliations and journal outlets to the extent feasible.

Quality assessment of included studies

Information including study type, sample size, effect indicator classification, and data were extracted from the included studies. Two researchers extracted the information independently, checked it for consistency, and entered it into the statistical software. The Cochrane Risk of Bias 2 tool (RoB 2) was used to assess the risk of bias in the included trials. The assessment criteria were as follows: grade A, low risk of bias; grade B, moderate risk of bias; and grade C, high risk of bias. The process and results of the literature search are detailed in Figure 1.

Statistical analysis

The statistical analysis was conducted using RevMan 5.3 software (Cochrane Collaboration, Oxford, UK). Heterogeneity was evaluated using the chi-square test (Q test) and quantified using the I-squared (I²) statistic. The Q-test assesses whether the observed variation in effect sizes across studies is greater than what would be expected by chance alone, with a significance level set at P<0.05. The I² statistic provides a measure of the proportion of total variation across studies that is due to heterogeneity rather than chance, with values of 0%, 25%, 50%, and 75% indicating no, low, moderate, and high heterogeneity, respectively. If the P value of the Q-test was ≥0.05 (indicating no significant heterogeneity), a fixed-effect model was employed, if all studies estimated a common underlying effect size. If the P value was <0.05 (indicating significant heterogeneity), a random-effects model was selected, acknowledging that the true effect sizes may vary across studies. The mean difference (MD) was used as the effect measure to combine studies with varying outcome scales. The pooled effect size and its 95% confidence interval (CI) were visually presented using a forest plot, which shows individual study effect sizes, their CIs, and the overall pooled effect. We did not perform funnel-plot analyses or Egger/Mazumdar tests because fewer than 10 studies were available for most outcomes, but we will discuss possible reporting biases qualitatively in the Discussion.

Results

Study selection and characteristics

A total of 12 RCTs published from 1995 to 2025 were identified and included. The studies included children aged 0–14 years. The intervention durations of most studies ranged from 23 weeks to 24 months. The total sample size was 6,340 children, of which 3,193 were in the intervention group and 3,147 were in the control group. The characteristics of each study and other relevant indices are summarized in Table 1.

Quality evaluation of the included literature

As shown in Figure 2, most of the 12 articles were low risk and high quality, meeting the requirements for further analyses. In this meta-analysis, all included studies employed random sequence generation and were assessed as having a low risk in terms of the completeness of follow-up data. For allocation concealment, seven studies were classified as having an unclear risk, while the remaining five studies were rated as low risk. This may be due to a lack of clear reporting or insufficient measures for allocation concealment in some studies. Regarding blinding of participants and personnel, four studies were rated as having an unclear risk, and one study was rated as high risk, as either the researchers or participants were not adequately blinded. The remaining seven studies were classified as low risk, indicating effective blinding in these studies. In terms of blinding of outcome assessment, four studies had an unclear risk, while the other eight studies were rated as low risk, suggesting that most studies implemented proper blinding procedures. For selective reporting and other biases, two studies were rated as having an unclear risk, and the remaining ten studies were classified as low risk. This indicates that most studies reported their pre-specified primary outcome measures without noticeable bias in data collection, analysis, or reporting.

Figure 2 Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Sensitivity analysis

In the sensitivity analysis, despite the removal of two studies [Khan A, 2023 (25) and Oelofse A, 2003 (28)] with wide CIs, overall heterogeneity remained high. We hypothesize that this persistent heterogeneity may be attributed to the fact that the included studies involved supplementation with multiple trace elements, with variations in both supplementation time and dosage. The differences in trace element combinations and supplementation schedules are likely the primary contributors to the observed heterogeneity. Further subgroup analyses or more detailed study designs could potentially address this issue. However, due to the limited number of studies, subgroup analysis is not feasible at this time, which may be one of the limitations of the current analysis.

Vitamin A and vitamin D3 supplementation

Children aged 0–14 years

Vitamin A supplementation did not significantly impact growth outcomes. The effect on HAZ (Z=1.59; 95% CI: −0.01 to 0.09, P=0.11; I²=0%) and WAZ (Z=0.99; 95% CI: −0.02 to 0.07, P=0.32; I²=0%) was non-significant. No effect on WHZ was observed (Z=0.03; 95% CI: −0.10 to 0.10, P=0.98; I²=0%) (Figure 3).

Figure 3 Forest plot of MD with 95% CI, Z-value, and I² statistic for the impact of micronutrient interventions on three anthropometric indicators in children (aged 0–14 years). (A-C) The effects of vitamin D₃ supplementation on HAZ (A), WAZ (B), and WHZ (C). (D-F) The corresponding effects of vitamin A supplementation on HAZ (D), WAZ (E), and WHZ (F). (G-I) The effects of multiple micronutrient interventions, including both vitamin A and D₃, on HAZ (G), WAZ (H), and WHZ (I). CI, confidence interval; HAZ, height-for-age Z-score; MD, mean difference; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score.

For combined micronutrient supplementation, including both vitamins A and D₃, no significant effect was found on HAZ (Z=0.57; 95% CI: −0.19 to 0.35, P=0.57; I²=72%, P=0.003), with substantial heterogeneity. A non-significant trend toward improvement was noted for WAZ (Z=1.58; 95% CI: −0.06 to 0.57, P=0.12; I²=83%, P<0.0001), and no effect was found on WHZ (Z=0.95; 95% CI: −0.10 to 0.29, P=0.34; I²=69%, P=0.006) (Figure 3).

Children aged 0–5 years

Vitamin D₃ supplementation showed no significant effect on anthropometric outcomes. Three RCTs on HAZ revealed no improvement (Z=0.43; 95% CI: −0.07 to 0.05, P=0.67; I²=0%). A statistically significant but modest effect on WAZ was found (Z=2.72; 95% CI: −0.17 to −0.03, P=0.007; I²=0%), but its clinical relevance is unclear. No effect was observed for WHZ (Z=0.52; 95% CI: −0.09 to 0.05, P=0.61; I²=0%) (Figure 3).

Vitamin A supplementation in children aged 0–5 years showed minimal effects on anthropometric outcomes. The effect on HAZ was small and non-significant (Z=1.61; 95% CI: −0.01 to 0.09, P=0.11; I²=0%), with no heterogeneity observed, suggesting consistency across studies. Similarly, no significant effect was found for WAZ (Z=1.00; 95% CI: −0.02 to 0.08, P=0.32; I²=0%) or WHZ (Z=0.44; 95% CI: −0.05 to 0.08, P=0.66; I²=0%) (Figure 4).

Figure 4 Forest plot of MD with 95% CI, Z-value, and I² statistic for the impact of micronutrient interventions on three anthropometric indicators in children (aged 0–5 years). (A-C) The effects of vitamin A supplementation on HAZ (A), WAZ (B), and WHZ (C). (D-F) The effects of multiple micronutrient interventions, including both vitamin A and D₃, on HAZ (D), WAZ (E), and WHZ (F). Since all participants in the vitamin D₃ supplementation studies were aged 0–5 years, the effects of vitamin D₃ supplementation on HAZ, WAZ, and WHZ are presented in Figure 3A-3C. CI, confidence interval; HAZ, height-for-age Z-score; MD, mean difference; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score.

In the case of combined micronutrient supplementation, including both vitamin A and D₃, no consistent effect on HAZ was observed (Z=0.25; 95% CI: −0.30 to 0.39, P=0.80; I²=77%), indicating variability across studies. However, a significant but modest effect was found on WAZ (Z=2.16; 95% CI: 0.03 to 0.65, P=0.03; I²=78%), suggesting potential benefits in promoting weight gain or preventing underweight in at-risk populations. No effect was found on WHZ (Z=0.90; 95% CI: −0.17 to 0.47, P=0.37; I²=72%), indicating no significant impact on acute nutritional status or wasting (Figure 4).

Discussion

Key findings

This meta-analysis evaluated how vitamin A and vitamin D₃ supplementation—alone or combined—affected childhood growth (HAZ, WAZ, WHZ). The results showed that neither vitamin alone led to clinically meaningful improvements in HAZ or WHZ. However, vitamin D₃ supplementation alone did produce a small statistical increase in WAZ among children under five. Although statistically significant, the mean change in WAZ was below thresholds typically considered clinically meaningful (≈0.2 standard deviation) and thus unlikely to reflect a perceptible or actionable improvement in child growth (31,32). These findings do not diminish the biological importance of these vitamins—they instead underscore the multifactorial determinants of child growth. Nutritional deficiencies do not typically occur in isolation. A child deficient in vitamin A or D₃ is often also lacking adequate protein, energy, or essential minerals such as zinc and iron (33). Targeting a single nutrient may leave other deficits unaddressed, which may explain why growth outcomes remain largely unchanged. The modest WAZ gains seen with combined supplementation may reflect improved short-term energy status or improved recovery from infection, rather than actual acceleration in linear growth.

These findings suggest that vitamin D₃ or vitamin A supplementation alone may be insufficient to significantly improve children’s physical development, particularly during the early growth stage when nutrition and health conditions are complex.

Strengths and limitations

This study presents a comprehensive comparison of both individual and combined micronutrient interventions across key anthropometric outcomes. However, several limitations should be acknowledged. First, the number of included studies for each outcome was relatively small, limiting statistical power. Second, in the meta-analysis of the combined micronutrient group, substantial heterogeneity remained even after removing two studies with wide confidence intervals, namely Oelofse A (2003) and Khan A (2023), due to variations in intervention protocols, resulting in clinical heterogeneity. Third, some studies in the combined micronutrient group used formulas containing other vitamins and minerals, making it difficult to isolate the effects of vitamin A or D₃ alone. Nearly all the included trials were conducted in low- and middle-income countries (LMICs), providing important insights into child health under resource-limited conditions. However, this also may limit generalizability of the findings to high-income settings, where baseline nutritional status, health care access, and dietary diversity differ substantially.

This study systematically evaluated the effects of vitamin D₃ supplementation on physical growth indicators (HAZ, WAZ, WHZ) in children aged 0–5 years. The meta-analysis results showed that vitamin D₃ supplementation had no significant effect on linear growth (HAZ or WHZ). While a statistically significant, albeit modest, improvement in WAZ was observed, its clinical significance was limited.

Comparison with similar research

Our findings are consistent with several previous studies. For instance, in a large RCT conducted in South Africa (the ViDiKids study), although vitamin D₃ supplementation (10,000 IU/week) significantly increased children’s serum 25(OH)D levels, no significant differences were observed in height, weight, BMI, or body composition (34). Similarly, a long-term follow-up study in India found no significant differences between children who received vitamin D supplementation during infancy and the placebo group in terms of height, weight, bone density, or motor development at 3–6 years of age (35). Additionally, two randomized trials in Mongolian school-age children indicated a dose-dependent effect of vitamin D₃ on height growth. Daily supplementation of 800 IU of vitamin D₃ consistently improved height growth, whereas daily supplementation of 300 IU through fortified milk alone showed no significant effect (36).

Regarding vitamin A, Kirkwood et al. (1996) conducted a large RCT in northern Ghana and found that, although vitamin A supplementation significantly improved children’s vitamin A nutritional status, it had no substantial effect on growth indicators such as weight, height, and upper arm circumference (37). Similarly, Hadi et al. (1999) found in Indonesia that vitamin A supplementation had a slight promoting effect on linear growth in children without respiratory infections, but the growth-promoting effect was significantly diminished in children with frequent infections (38). Additionally, Bahl et al. (1997) conducted a study in New Delhi, India, highlighting that the impact of vitamin A supplementation on children’s growth exhibited seasonal variations, with significant improvements in weight gain only observed in summer, while no notable differences were found in other seasons (23).

In terms of combined supplementation, Albelbeisi et al. (2020) found that multiple micronutrient supplementation, including vitamins A and D, significantly improved HAZ and reduced stunting, but the effect was more pronounced when combined with iron and zinc, not as a standalone vitamin A and D intervention (26). Similarly, Batra et al. (2016) reported that ready-to-use supplementary foods (RUSF) with higher dairy protein content improved weight gain and mid-upper arm circumference, but did not significantly affect HAZ, highlighting the importance of nutrient composition and delivery form in influencing growth outcomes (39).

Explanations of findings

Although vitamin D₃ supplementation can effectively improve vitamin D status, its effect on promoting physical growth in children aged 0–5 years is limited. Future intervention strategies should focus on comprehensive nutritional support, including the coordinated supplementation of protein, energy, and other micronutrients, while considering the individual’s baseline nutritional status, living environment, and the dose and duration of supplementation, to optimize growth outcomes (34-36). Similarly, while vitamin A supplementation provides clear benefits in addressing vitamin A deficiency and reducing child mortality, its impact on growth is limited when used as a standalone intervention (20,31,32). Future intervention strategies should focus more on multidimensional nutritional supplementation, combining vitamin A with other micronutrients like zinc and iron, and should also consider infection control, vaccination timing, and seasonal variations to achieve more significant improvements in growth (29,39,40). Most of the included RCTs were conducted in LMICs, where malnutrition and micronutrient deficiencies are common. This context likely contributes to the variability in results, since baseline nutritional status, infection rates, and dietary patterns in these settings differ substantially from those in wealthier countries. The modest improvement in WAZ observed in our subgroup analysis (0–5 years) is consistent with findings from the Vietnamese and Peruvian Infant and child micronutrient supplementation trials, where daily multiple micronutrient supplementation, including vitamins A and D, led to significant improvements in WAZ and iron status, although linear growth remained largely unaffected (25,33,41). This suggests that while vitamin A and D₃ may contribute to weight gain, their effect on linear growth may be limited without the inclusion of other growth-limiting nutrients such as zinc, iron, and protein (25,32,42).

Implications and actions needed

In conclusion, vitamin A and D₃ supplementation, whether individually or combined, did not significantly enhance growth outcomes in children. Future strategies should prioritize multi-nutrient approaches that address both macro- and micronutrient deficiencies and consider contextual factors like infection control, dietary diversity, and socio-economic conditions.

The high heterogeneity in the combined supplementation group emphasizes the need for standardized protocols and further long-term RCTs. Future research should consider standardized formulations and longer follow-up periods to better assess the long-term impact of vitamin A and D₃ on growth and development.

Conclusions

Our systematic review and meta-analysis has evaluated the effects of vitamin A and D₃ supplementation on growth outcomes in children. Neither vitamin alone significantly improved HAZ, WAZ, or WHZ. Vitamin D₃ showed a modest but statistically significant improvement in WAZ, though its clinical significance is unclear. Combined supplementation slightly improved WAZ in children aged 0–5 years but had no consistent effect on HAZ or WHZ.

These findings suggest that single-nutrient interventions are insufficient to address growth faltering. Future interventions should adopt multi-nutrient strategies, incorporating protein, energy, iron, and zinc, while also addressing contextual factors such as infection, dietary diversity, and socioeconomic conditions to promote child growth effectively.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-507/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-507/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-507/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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