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

. 2020 Dec 11;2020(12):CD012875. doi: 10.1002/14651858.CD012875.pub2

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

Samantha L Huey ¹, Nina Acharya ¹, Ashley Silver ¹, Risha Sheni ¹, Elaine A Yu ¹, Juan Pablo Peña-Rosas ², Saurabh Mehta ^1,^✉

Editor: Cochrane Developmental, Psychosocial and Learning Problems Group

PMCID: PMC8121044 PMID: 33305842

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for any relevant trials, and we contacted key organisations and authors to obtain information on relevant ongoing and unpublished trials.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 probably makes little to no difference in developing hypercalciuria compared to placebo (RR 2.03, 95% CI 0.28 to 14.67; 2 studies, 68 participants; moderate‐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, may make little to no difference in linear growth (MD 0.60, 95% CI −3.33 to 4.53; 1 study, 25 participants; low‐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.

Plain language summary

Effects of vitamin D on linear growth and other health outcomes among children under 5 years of age

Background

Vitamin D is an essential nutrient that plays a major role in skeletal health. Deficiency in vitamin D has also been linked to non‐skeletal health outcomes such as growth. Stunting and poor growth among children under five years of age remain a major global challenge. Previous literature has shown that blood vitamin D level is associated with stunting and poor growth. We examined the evidence regarding vitamin D supplements and their potential effects on linear growth. We also explored other outcomes related to vitamin D status, including adverse effects.

Study characteristics

We included 187 reports representing 75 studies (12,122 participants), conducted most frequently in India, USA, and Canada, among children under five years of age. In addition, 33 studies were classified as currently being conducted (ongoing) and 21 studies as 'awaiting classification' because they did not provide enough information to be categorised as included, ongoing, or excluded. Comparisons included oral vitamin D supplementation versus placebo (dummy pill) or no intervention; higher‐dose vitamin D versus lower‐dose vitamin D; vitamin D plus micronutrients (vitamins or minerals or both) compared to the same micronutrients alone; and higher‐dose vitamin D plus micronutrients (vitamins or minerals or both) compared to lower‐dose vitamin D plus the same micronutrients. Two studies reported for‐profit funding, two were categorised as mixed funding (non‐profit and for‐profit), five reported that they had received no funding, 26 did not disclose funding sources, and the remaining studies were supported by non‐profit funding.

Key findings

Supplementation with vitamin D in comparison with placebo or no intervention probably makes little to no difference in developing hypercalciuria, probably improves length or height compared to the child's age, probably makes little to no difference in stunting, and may make little to no difference in child length or height. It is uncertain whether vitamin D in comparison with placebo or no intervention impacts the development of hypercalcaemia.

Supplementation with a higher dose of vitamin D compared to a lower dose of vitamin D may make little to no difference in length or height compared to the child's age and developing hypercalciuria, or hypercalcaemia; and we are uncertain about the effects of higher‐dose vitamin D on linear growth.

Supplementation with a higher dose of vitamin D along with micronutrients (vitamins or minerals, or both) compared to a lower dose of vitamin D and the same micronutrients may make little to no difference in linear growth in children under five years of age and developing hypercalciuria, and probably makes little to no difference in developing hypercalcaemia.

Conclusions

Current evidence suggests that vitamin D probably slightly improves length/height‐for‐age z‐score compared to placebo; however, because of the quality of the evidence, we are uncertain about the true effects of vitamin D on linear growth or adverse effects among children under five years of age compared to placebo, no intervention, or lower doses of vitamin D, with or without micronutrients.

Summary of findings

Background

Description of the condition

Linear growth faltering and stunting

Suboptimal health among children under five years of age remains a major global challenge (UNICEF, WHO, World Bank 2020; WHO 2016). Most of the 5.9 million deaths among children under five years of age in 2015 could be attributed to preventable causes with available treatment options, such as malnutrition (UNICEF, WHO, World Bank 2020).

Linear growth faltering, or failure to reach one’s linear growth potential compared to normative standards (Leroy 2019; Perumal 2018), is associated with negative short‐ and long‐term outcomes among children under five years of age. Linear growth faltering is a marker for poor health, reduced earnings, and lower cognitive capacity, as well as a direct factor in the causal pathway to biological states such as foetal growth restriction and shorter maternal height (Leroy 2019; Perumal 2018). A subset of children suffering from linear growth faltering may become stunted, which is defined as more than two standard deviations (SDs) below the World Health Organization (WHO) reference standard (length‐ or height‐for‐age z‐score) (WHO 2006). The prevalence of stunting in a community offers a useful marker of well‐being at the population level (Perumal 2018); however, it is not without limitations. Recent studies have suggested that the classical definition of stunting is based on an arbitrary cutoff and may fail to accurately represent the true proportion of children facing inadequate growth (Leroy 2019). Therefore, this review will use both linear growth faltering and stunting to better evaluate interventions.

Linear growth faltering and stunting have multiple causes, including cumulative poor nutrition in utero and postnatally (Dewey 2011). In addition, repeated infections, environmental enteropathy, and inadequate care have all been suggested as contributory to inadequate growth (Leroy 2019; Perumal 2018). A recent review of child stunting pinpointed growth faltering during childhood as both a causal mechanism for some poor outcomes and a non‐causal indicator of other consequences (Leroy 2019). Linear growth faltering can lead to (1) cephalopelvic distortion leading to difficult birth, morbidity, and mortality; and (2) maternal short stature leading to smaller infants, who are more likely to die or not grow to optimal height (Ramakrishnan 1999). Linear growth faltering has additionally been shown to be associated with reduced earnings, lower school achievement and work capacity, reduced physical strength, chronic diseases, or poor cognition in adulthood (Black 2008; Dewey 2011; Haas 1996; Leroy 2019). Women stunted in childhood tend to bear stunted offspring, creating an intergenerational cycle of adverse physical, mental, and economic outcomes (Martorell 2012). A seminal study by Hoddinott et al followed a cohort of Guatemalan adults and, using instrumental variables, found that stunting played a causal role in adult economic productivity independent of childhood malnutrition and socioeconomic status. The mechanism behind this remains unknown, but it may be attributable to discrimination in schooling or when seeking employment. Although it is not generalisable to other populations, the analysis performed in this study remains important to support interventions to directly address inadequate childhood growth to improve economic disparities.

One risk factor for linear growth faltering of infants is maternal undernutrition; the intergenerational cycle of malnutrition is perpetuated by intrauterine growth restriction and restricted blood flow to the uterus, placenta, and foetus (Dewey 2011). Intrauterine growth restriction may lead to the infant being born premature (gestational age less than 32 weeks) and/or with low birth weight (birth weight less than 2.5 kg), both of which are risk factors for stunting (Danaei 2016). Another risk factor is recurrent infection (Caulfield 2006); as children age, their exposure to the environment increases, along with their risk of infection (Caulfield 2006). Stunting remains the most prevalent form of undernutrition among children under five years of age; 149 million suffer from stunting globally (WHO 2019). Global stunting decreased from 32.5% in 2000 to 21.9% in 2018 among children under five years of age (WHO 2019), but it remains a critical challenge in numerous geographical regions (De Onis 2012; De Onis 2013; Prendergast 2014). In India, for instance, 46 million children (nearly 40%) under five years of age are stunted, accounting for more than a third of the stunted children in the developing world (MoHFW 2019). The World Health Assembly aims to reduce stunting in children under five years of age by 40% between 2010 and 2025 (WHO 2012; WHO 2014a). Therefore, it is crucial to delineate modifiable causes of, and effective interventions against, stunting and linear growth faltering, including micronutrient supplementation.

Given the widely recognised burden of disease associated with childhood stunting in diverse populations (Black 2008; Black 2013; De Onis 2012; Prendergast 2014), many global research and policy efforts have sought to reduce growth faltering (Victora 2010; WHO 2014a). It has been estimated that improved understanding and scaling up of effective, evidence‐informed, safe, and effective interventions can prevent stunting among 33.5 million children (Bhutta 2013; Huey 2016; WHO 2014a). In particular, investigators have explored vitamin D supplementation as an intervention to prevent and mitigate childhood stunting (Kumar 2011). Optimal vitamin D status, which is often assessed by measuring serum concentrations of calcifediol (i.e. 25(OH)D), allows calcium absorption and growth to support active vitamin D (i.e. calcitriol (1,25{OH}₂D₃)) (Holick 2010). Prolonged inadequate vitamin D status impairs transcriptional regulation of skeletal homeostasis and linear growth, which could result in stunting (Holick 2010).

Prior observational studies have provided evidence that stunting is associated with suboptimal vitamin D status among children (Walli 2017). Therefore, vitamin D supplementation as a potentially modifiable risk factor that can have an effect on linear growth requires further evaluation.

Description of the intervention

Vitamin D status

One billion people have suboptimal vitamin D status, according to global estimates (Holick 2010). Even in countries with sun exposure all year round, low vitamin D status is a global problem among all age groups (Palacios 2014). Consequences of low vitamin D include poor skeletal and extraskeletal health outcomes (Holick 2008a; Holick 2008b; Holick 2010).

Low circulating 25(OH)D serum concentration is widely regarded as the biomarker for vitamin D status (Heaney 2009), although cut‐off values indicating deficiency and insufficiency are debated (Holick 2011; Ross 2011). Between 30% and 50% of children in numerous countries in Africa, Asia, Europe, and North America (Holick 2010), including geographical areas with ample sunlight and heterogeneous economic resources, have 25(OH)D less than 50 nmol/L. In the context of vitamin D deficiency, infants and young children are considered a high‐risk population, given that vitamin D intake is low during exclusive breastfeeding (Leroy 2014; Shrimpton 2001), and early life represents a critical period for linear growth and development of the immune system (Adkins 2004; Levy 2007). As further detailed in the next section, pleiotropic actions of vitamin D can impact skeletal, muscular, and immunological functions, all of which are related to optimal growth.

Vitamin D sources

Vitamin D can be acquired through consumption of a diet containing naturally vitamin D‐rich and fortified foods, or vitamin D supplements, or through endogenous production via skin exposure to ultraviolet irradiation (Holick 2010). In this review, we focus on vitamin D supplementation, given that it overcomes the challenges of inadequate sunlight at some geographical latitudes, as well as minimal sun exposure based on individual lifestyle decisions and limited consumption of naturally vitamin D‐rich or fortified foods (Holick 2010). Vitamin D supplements are available in two chemical forms (ergocalciferol (D2) and cholecalciferol (D3)), which differ in their side‐chain structure (Holick 2010). Vitamins D2 and D3 have been observed to increase serum 25‐hydroxyvitamin D (serum 25(OH)D), although at higher doses (50,000 IU), vitamin D2 appears less potent than equivalent doses of D3 in maintaining serum 25(OH)D levels (Holick 2010).

Vitamin D requirements

According to the WHO and the Food and Agriculture Organization (FAO), 200 international units (IU) of vitamin D is the daily recommended nutrient intake (RNI) among children under five years of age (WHO, FAO 2004). In the USA, the Institute of Medicine recommends that children between one and five years of age should consume a recommended dietary allowance of 600 IU per day, and have an estimated average requirement (EAR) of 400 IU per day (Institute of Medicine 2011). From birth to 12 months, it is recommended that children in the USA consume adequate intake (AI) of 400 IU per day (Institute of Medicine 2011).

No adverse effects occur at vitamin D intakes recommended by WHO and by FAO (WHO, FAO 2004). In the USA, the recommended upper limits of vitamin D consumption are based on age: 1000 IU from birth to six months, 1500 IU from six to 12 months, 2500 IU from one to three years, and 3000 IU from four to five years (Institute of Medicine 2011). Vitamin D toxicity has been observed in a few rare cases with long‐term consumption of extreme pharmaceutical dosages (Barrueto 2005; Blank 1995; Holick 2011; Klontz 2007; Vieth 1999); it is caused primarily by excessive intestinal calcium or phosphate absorption and bone resorption (Holick 2010). Excess vitamin D may contribute to hypercalciuria, hypercalcaemia, hyperphosphataemia, and kidney stones (nephrolithiasis) (Holick 2010). Hypercalciuria, or high levels of calcium in the urine, is linked to the role of vitamin D in increasing intestinal calcium reabsorption and is defined differently across different age groups (Leslie 2020). In children over two years of age, hypercalciuria is defined as daily urinary excretion of more than 4 mg calcium per kg of body weight, or a 24‐hour urinary calcium concentration less than 200 mg calcium per litre of urine (Leslie 2020). For children under two years, a random or spot urinary calcium‐to‐creatine ratio less than 0.2 mg calcium per mg creatine is considered normal (Leslie 2020). Hypercalcaemia is mainly caused by excess parathyroid hormone (PTH), which can be induced by high vitamin D intake, and is defined as high levels of calcium in blood; it can be classified as mild (10.5 to 11.9 mg/dL), moderate (12.0 to 13.9 mg/dL), or a hypercalcaemic crisis (14.0 to 16.0 mg/dL) (Sadiq 2020). Hyperphosphataemia indicates plasma phosphate greater than 7 mg/dL in children and can be induced by the role of vitamin D in increasing intestinal phosphate absorption (Goyal 2020). Kidney stones, detected via ultrasound, are calcium crystal concretions (composed primarily of calcium oxalate or calcium phosphate) travelling from the kidney through the genitourinary system. Kidney stones can occur in the setting of hypercalciuria (Nojaba 2020).

Metabolism of vitamin D

Evidence from mechanistic and dose‐response studies suggests that increasing intake of vitamin D (via consumption (supplementation, dietary intake) or cutaneous synthesis) improves serum 25(OH)D concentration (Holick 2010; Holick 2011). After it enters the body, vitamin D is stored in fat or is metabolised by the liver (Holick 2010; Holick 2011). A 25‐hydroxylase (CYP27B1) in the liver converts vitamin D to 25(OH)D, which is the major circulating form (Holick 2010; Holick 2011).

Available data from dose‐response studies show that vitamin D supplementation increases serum 25(OH)D concentration, regardless of age (Heaney 2003; Holick 2008b; Holick 2010; Institute of Medicine 2011). A non‐linear response of 25(OH)D to vitamin D has been observed in murine and human models (Institute of Medicine 2011). Dosages greater than or equal to 1000 IU daily have resulted in more gradual responses (e.g. 0.95 nmol/L to 1.4 nmol/L for every 100 IU; Smith 2009), and dosages below 1000 IU daily have achieved steeper responses (e.g. approximately 2.0 nmol/L for every 40 IU; Cashman 2008; Cashman 2009; Institute of Medicine 2011). Moreover, studies including young children with stunting have confirmed that vitamin D supplementation increases 25(OH)D (Kumar 2011). Widely ranging vitamin D supplementation dosages across studies have included daily physiological doses (200 IU to 400 IU; Alizadeh Taheri 2014; Fort 2016), as well as pharmacological doses (50,000 IU at birth; Moodley 2015), and even a single dose of 100,000 IU (Gupta 2016). In summary, preliminary data highlight the need for assessment of potential beneficial effects of vitamin D supplementation on stunting among children.

How the intervention might work

Cells of kidney, immune system, bone, and epithelium, and of other tissues in the body, use 1‐OHase (CYP27R1) to metabolise 25(OH)D to the biologically active steroid hormone 1,25(OH)₂D (Bikle 2014; Christakos 2016; Holick 2010). In its hormonally active form, vitamin D plays pleiotropic roles in the human body, promoting skeletal health, muscle development and growth, and immune function.

1,25(OH)₂D functions through genomic and non‐genomic mechanisms (Bikle 2014; Christakos 2016; Holick 2010). First, genomic effects occur through binding of 1,25(OH)₂D to vitamin D receptor and retinoid X receptor, which results in a heterodimer complex that regulates gene activity (Bikle 2014; Christakos 2016; Holick 2010). At least 100 to 1250 target genes of vitamin D are known (Adams 2010; Holick 2007; Hossein‐Nezhad 2013; Ramagopalan 2010; Tarroni 2012). These are directly targeted by vitamin D (via a vitamin D response element; e.g. 1,25(OH)₂D has been shown to bind to vitamin D response element in the calcium‐sensing receptor gene and subsequently to modulate calcium‐sensing receptor expression (Bikle 2014; Canaff 2002; Christakos 2016; Holick 2010)). Second, 'rapid' or non‐genomic responses occur extracellularly via interaction with plasma membrane vitamin D receptor (VDR) (Bikle 2014; Christakos 2016; Holick 2010). Examples of these include stimulation of intestinal calcium absorption and inhibition of apoptosis in osteoblasts (Bikle 2014; Christakos 2016; Holick 2010). This nuclear receptor has been identified in nearly all human tissues and cells assessed (Bikle 2014; Christakos 2016; Holick 2010).

Skeletal homeostasis and linear growth

Vitamin D has well‐established effects on skeletal health, including bone mineralization and maintenance (Holick 2010). Active vitamin D (1,25(OH)₂D) functions in conjunction with two other hormones (parathyroid hormone and calcitonin) to maintain endocrine control of calcium and phosphorus concentrations (Holick 2010). This tight regulation of calcium and phosphorus flux (extracellular (bones, blood), intracellular) is critical for development and maintenance of bones (Holick 2010), which impacts linear growth. Specific roles of active vitamin D include increasing intestinal calcium absorption (Christakos 2012), renal calcium reabsorption, and skeletal calcium resorption (in conjunction with parathyroid hormone) (Holick 2010).

Previous studies have demonstrated that vitamin D deficiency is associated with stunting (Holick 2010), including stunting among children (Holick 2006; Wacker 2013). Maternal vitamin D deficiency has been associated with greater risk of stunting among neonates and children (Finkelstein 2012; Toko 2016).

Possible negative effects on linear growth in children have been noted with higher‐dose vitamin D supplementation. An early case series of nine infants consuming over 1500 units of vitamin D daily from cod liver oil sources were found to have lowered growth rates after six months of age compared to infants consuming 300 to 600 units of vitamin D daily (Jeans 1938). These findings have been raised as a matter to concern by the Dietary Reference Intakes Committees in their review of vitamin D in both 1997 and 2010 (Institute of Medicine 1997; Institute of Medicine 2011). However, a population‐based cohort study conducted in 2011 (n = 10,060 singletons) found that supplementation with 2000 IU vitamin D per day during infancy was not associated with height at age 14 or 31 years, and was not associated with reduced height at any age studied (Hyppönen 2011).

Muscle development and growth

Vitamin D may influence muscle mass and function, as well as related indicators (weight‐for‐height (WFH) and ‐age (WFA)). Observational studies have corroborated the link between severe vitamin D deficiency (≤ 8 ng/mL) and poor muscle health among individuals age 10 to 65 years (Plotnikoff 2003). As an example, among infants with HIV exposure and no infection, low 25(OH)D concentration (< 10 ng/mL or ~ 25 nmol/L) was associated with a higher incidence of wasting (hazard ratio 1.71, 95% confidence interval (CI) 1.20 to 2.43; Sudfeld 2015).

Previous studies have identified mechanisms that link vitamin D with myopathy (Bischoff‐Ferrari 2012). In vitro studies have assessed human muscle tissues and isolated VDR (Bischoff‐Ferrari 2004; Bischoff‐Ferrari 2012; Ceglia 2010; Simpson 1985), which facilitate genomic and non‐genomic effects (Haussler 1998; McDonnell 1987; Norman 2004; Vazquez 1998). Furthermore, murine models have demonstrated that deletion of VDR (via gene knockout) resulted in impaired skeletal muscle growth and muscle‐related gene expression (Bouillon 2008; Endo 2003). Mice without VDR had smaller muscle fibres in all striated muscles (Endo 2003).

Why it is important to do this review

Linear growth retardation (including stunting) continues to affect many children worldwide (WHO 2018), and global stunting remains a critical and complex challenge in numerous geographical regions (De Onis 2013; Prendergast 2014; UNICEF, WHO, World Bank 2020). This is reflected in the World Health Assembly nutrition target to reduce stunting by 40% among children under five years of age by 2025, and Sustainable Development Goal 2.2 to reduce the prevalence of stunting and wasting in children under five years of age by 2025, highlighting the global importance of addressing this issue (United Nations 2015; WHO 2012; WHO 2014a). Although stunting among children under five years of age has decreased from 39.7% (in 1990) to 21.3% (in 2019) (De Onis 2012; Dewey 2020), the World Health Assembly nutrition target will not be achieved at this current trajectory (De Onis 2013).

Linear growth is considered an important overall indicator of child development (De Onis 2016). Critically, children with stunting often show minimal (if any) catch‐up growth in later life (Martorell 1994). However, nutritional interventions have been seen to allow catch‐up growth among children (Martorell 1994), especially during key developmental windows (including between birth and five years) (Prentice 2013). Vitamin D is already a known beneficial intervention for prevention of rickets in the same early, crucial childhood years, and despite conclusive evidence, the drive to reduce growth retardation is an important one with a plethora of potential beneficial effects.

The systematic method of our review is intended to achieve comprehensive assessment of current evidence on effects of vitamin D supplementation on growth faltering and other health outcomes among children. This approach facilitates consideration of other modulating factors, particularly in subgroup analyses. Given the multi‐factorial origin of stunting, which needs further elucidation (Stewart 2013), accounting for other factors is important. Aside from nutritional factors that affect stunting, potential influences include repeated infections, poor sanitation, household environmental contamination, mycotoxin exposure, the gut, and associated enteropathy (Casanovas 2013; Owino 2016; Semba 2016; Stewart 2013; Waterlow 1994).

Separately, an estimated one billion people have suboptimal vitamin D status (Holick 2007), which is linked to numerous skeletal and extraskeletal outcomes (Holick 2010). Given the relative ease of administration, widespread availability, and ongoing acceptability, the benefits of supplementation for growth in the first five years of life should be explored. Despite the multitude of studies that have focused on vitamin D supplementation and clinical health indicators (Ferguson 2014; Jagannath 2010), particularly among adults (Avenell 2014; Bjelakovic 2014a; Palacios 2019; Straube 2015), evidence regarding growth and stunting among children under five years of age remains unclear. Thus, it is necessary to draw overall conclusions from currently available evidence regarding how vitamin D supplementation impacts the growth of children under five years of age.

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.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs. Quasi‐RCTs included studies that did not involve a treatment regimen assignment with simple randomisation but systematically utilised another aspect of the study design (e.g. alternating assignments based on sequential study enrolment, medical record number). Cluster‐randomised and cross‐over trials were also eligible for inclusion.

Types of participants

Infants and children under five years of age who lived in any country, healthy and apparently non‐vitamin D‐deficient, as well as with diagnosed vitamin D deficiency, rickets, or other underlying health conditions (as defined by trialists). We included studies of children under five years of age and study participants who were both under and over five years of age (e.g. birth to 10 years) if study authors reported stratified outcomes; this review reports extracted results among children under five years of age. We included studies of vitamin D supplementation directly among infants and children under five years of age only. We excluded studies that provided vitamin D supplementation to mothers only and not to their offspring.

Types of interventions

Studies assessing effects of oral vitamin D supplementation, with or without micronutrients, compared to no intervention, placebo, a lower dose of vitamin D, or micronutrients alone in children under five years of age. Comparisons between intervention and comparator groups are described below (and in Table 4).

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

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)

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	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
	Risk with placebo or no intervention	Risk with vitamin D
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
	490 per 1000	441 per 1000 (392 to 495)
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)
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)
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.

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	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
	Risk with lower‐dose vitamin D	Risk with higher‐dose vitamin D
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)
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)
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.

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	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№. of participants (studies)	Certainty of evidence (GRADE)	Comments
	Risk with lower‐dose vitamin D + micronutrient(s)	Risk with higher‐dose vitamin D + micronutrient(s)
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)
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)
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.

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

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

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

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Linear growth	3	240	Mean Difference (IV, Random, 95% CI)	0.66 [‐0.37, 1.68]
1.2 Length/height‐for‐age	1	1258	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.00, 0.22]
1.3 Stunting	1	1247	Risk Ratio (IV, Fixed, 95% CI)	0.90 [0.80, 1.01]
1.4 Adverse effect: hypercalciuria	2	68	Risk Ratio (IV, Random, 95% CI)	2.03 [0.28, 14.67]
1.5 Adverse effect: hypercalcaemia	2	367	Risk Ratio (IV, Random, 95% CI)	0.82 [0.35, 1.90]
1.6 Weight‐for‐age	1	1273	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.02, 0.20]
1.7 Underweight	1	1282	Risk Ratio (IV, Fixed, 95% CI)	0.94 [0.80, 1.11]
1.8 Weight‐for‐length/height	2	1442	Mean Difference (IV, Random, 95% CI)	0.65 [‐0.67, 1.97]
1.9 Wasting	1	1282	Risk Ratio (IV, Fixed, 95% CI)	1.25 [0.82, 1.91]
1.10 Serum 25‐hydroxyvitamin D	21	2202	Mean Difference (IV, Random, 95% CI)	30.91 [21.82, 40.00]
1.11 Change in 25(OH)D levels (nmol/L)	3	495	Mean Difference (IV, Random, 95% CI)	28.36 [10.41, 46.32]
1.12 Vitamin D sufficiency (≥ 50 nmol/L)	6	982	Risk Ratio (IV, Random, 95% CI)	1.88 [1.63, 2.17]
1.13 Vitamin D sufficiency (≥ 75 nmol/L)	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)	3	836	Risk Ratio (IV, Random, 95% CI)	0.26 [0.19, 0.36]
1.15 Rickets (continuous)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Linear growth	5	283	Mean Difference (IV, Random, 95% CI)	‐1.00 [‐2.22, 0.21]
2.2 Length/height‐for‐age	2	105	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.06, 0.86]
2.3 Adverse effect: hypercalciuria	6	554	Risk Ratio (IV, Random, 95% CI)	1.16 [1.00, 1.35]
2.4 Adverse effect: hypercalcaemia	5	986	Risk Ratio (IV, Random, 95% CI)	1.39 [0.89, 2.18]
2.5 Linear growth: gain in length	3	378	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.02, 0.00]
2.6 Weight‐for‐age	2	103	Mean Difference (IV, Random, 95% CI)	0.07 [‐0.44, 0.58]
2.7 Weight‐for‐length/height	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐0.74, 0.37]
2.8 Serum 25‐hydroxyvitamin D	20	2765	Mean Difference (IV, Random, 95% CI)	16.13 [7.11, 25.15]
2.9 Change in 25(OH)D (nmol/L)	3	142	Mean Difference (IV, Random, 95% CI)	4.12 [‐5.82, 14.07]
2.10 Vitamin D sufficiency (≥ 50 nmol/L)	12	1735	Risk Ratio (IV, Random, 95% CI)	1.04 [1.00, 1.08]
2.11 Vitamin D sufficiency (≥ 75 nmol/L)	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)	1	142	Risk Ratio (IV, Fixed, 95% CI)	0.14 [0.02, 1.35]
2.13 Rickets (dichotomous)	4	212	Risk Ratio (IV, Random, 95% CI)	0.64 [0.46, 0.90]

*Study characteristics*
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: undisclosed Country: Egypt Study period: September 2014 to August 2016
Participants	Included criteria: prematurity with gestational age 28 weeks and < 37 weeks, postnatal age > 72 hours, and presence of clinical and haematological signs suggestive of late‐onset sepsis, ascertained by a scoring system containing 11 clinical and haematological domains including skin colour, capillary refill, tone, feeding intolerance, hepatomegaly, apnoea, bradycardia, metabolic acidosis, thrombocytopenia, leukocytosis, and shift to left. Total score is 25 points. Infants with a score < 5 were considered normal, with a score of 5 to 10 were suspected to have sepsis, and score > 10 were considered clinically septic Excluded criteria: major congenital anomalies, chromosomal anomalies, known inborn errors of metabolism, immunodeficiency disorders Group differences: average total vitamin D daily intake (feeding along with supplementation) was significantly greater in the 800 IU group (Table Supplement, Supplemental Digital Content; links.lww.com/MPG/B551) Baseline vitamin D status (mean ± standard deviation; nmol/L) Control group (400 IU D₃): 34.2 ± 16.5 Intervention group (800 IU D₃): 41.1 ± 19.0
Interventions	Intervention characteristics 400 IU D₃ Vitamin D content and type: 400 IU D₃ Formulation: not stated Frequency of dosage: daily Duration of administration (study time): until discharge from NICU (40 weeks' PMA) N per group (in analysis): 21 Brand/company: not reported 800 IU D₃ Vitamin D content and type: 800 IU D₃ Formulation: not stated Frequency of dosage: daily Duration of administration (study time): until discharge from NICU (40 weeks' PMA) N per group (in analysis): 23 Brand/company: not reported
Outcomes	Primary Adverse effect: kidney stones Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D < 50 nmol/L Notes: converted to vitamin D sufficiency ≥ 50 nmol/L for meta‐analysis Serum 25(OH)D < 75 nmol/L Notes: converted to vitamin D sufficiency ≥ 75 nmol/L for meta‐analysis Measurement Kidney stones: renal ultrasonography Notes: no events in either arm; data did not contribute to meta‐analysis Serum 25(OH)D (nmol/L): enzyme‐linked immunoabsorbent assay (ELISA) (Calbiotech, Spring Valley, CA, USA) Time points: baseline, 1 week, discharge from neonatal intensive care unit (40 weeks' PMA)
Notes	Sample size calculated as n = 50, but this was met only at randomisation and not during analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "infants with [late onset sepsis] were randomized using computer‐generated stratified randomization codes" Judgement comment: appropriate sequence generation method
Allocation concealment (selection bias)	Low risk	Quote: "the allocation sequence was concealed by using sealed opaque envelopes that contained the serial number and the group to which a subject would be enrolled" Judgement comment: appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "double blind... Clinicians and primary caregivers were masked to the intervention... Antibiotic therapy and supportive care were continued according to managing physician who was not aware of the group assignment... After each parental consent, an envelope would be opened by the principle [sic] investigator and group assignment would be established" Judgement comment: caregivers were blinded; although indicated to be double‐blind, the principal investigator was aware of group allocation and may have been biased toward a particular outcome, which could increase the risk of performance bias
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "clinicians and primary caregivers were masked to the intervention... Antibiotic therapy and supportive care were continued according to managing physician, who was not aware of the group assignment" Judgement comment: outcome assessors blinded; outcome measurements not subjective and unlikely to be influenced
Incomplete outcome data (attrition bias) All outcomes	High risk	Judgement comment: low loss to follow‐up (reasons given: mortality, discontinued intervention; flow diagram in Figure Supplement) similar in both arms; intent‐to‐treat analysis not performed
Selective reporting (reporting bias)	Low risk	Judgement comment: study was registered at ClinicalTrials.gov (ID: NCT02273843) prospectively; reported in text; prespecified outcomes and reported outcomes consistent
Other bias	Low risk	Judgement comment: no other risks observed

*Study characteristics*
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Canadian Institutes of Health Research Institute of Human Development, Child and Youth Health and Nutrition, Metabolism and Diabetes, and the Thrasher Research Fund Country: Canada Study period: winter months between 13 September 2011 and 30 June 2015
Participants	Included criteria: healthy children age 1 to 5 years Excluded criteria: gestational age under 32 weeks, chronic illness (other than asthma) Baseline vitamin D status (mean ± standard deviation; nmol/L) Control group (400 IU D₃): 89.6 ± 30.7 Intervention group (2000 IU D₃): 92.1 ± 29.2
Interventions	Intervention characteristics 400 IU D₃ Vitamin D content and type: 400 IU D₃ Formulation: drops Frequency of dosage: daily Duration of administration (study time): 4 to 8 months N per group (in analysis): 350 Brand/company: Kids Ddrops 2000 IU D₃ Vitamin D content and type: 2000 IU D₃ Formulation: drops Frequency of dosage: daily Duration of administration (study time): 4 to 8 months N per group (in analysis): 349 Brand/company: Kids Ddrops
Outcomes	Primary Adverse effect: hypercalcaemia Adverse effect: hyperphosphataemia Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D insufficiency: < 75 nmol/L Notes: converted to vitamin D sufficiency ≥ 75 nmol/L for meta‐analysis Measurement Hypercalcaemia (serum calcium): assay not reported Definition: not reported Notes: no events in either arm; data did not contribute to meta‐analysis Hyperphosphataemia (serum phosphorus): assay not reported Definition: not reported Notes: no events in either arm; data did not contribute to meta‐analysis Serum 25(OH)D (nmol/L): Roche Elecsys Vitamin D total assay (Roche Diagnostics Ltd., Basel, Switzerland) Notes: data presented as mean (95% CI), which we converted to standard deviation Time points: enrolment, 4 to 8 months
Notes	Sample size calculated and met
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the randomization sequence was generated using a computer‐based random‐number generator by the SickKids research pharmacy" Judgement comment: appropriate sequence generation method
Allocation concealment (selection bias)	Low risk	Quote: "the research pharmacy prepared the vitamin D formulations in sealed, serially numbered bottles identical in appearance and weight to maintain allocation concealment" Judgement comment: appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "study personnel, parents, attending physicians, laboratory personnel, investigators, and data analysts were all blinded to group allocation throughout the study period" Judgement comment: all personnel and participants blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "study personnel, parents, attending physicians, laboratory personnel, investigators, and data analysts were all blinded to group allocation throughout the study period" Judgement comment: all personnel and participants blinded; outcome measurements not subjective and unlikely to be influenced
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "complete case analysis was performed for all primary and secondary outcomes in which only cases with available data were analyzed... all analyses were conducted using the intention‐to‐treat principle" Judgement comment: complete case analysis violates the intention‐to‐treat principle and leads to bias unless data were missing at random, but study authors do not examine missingness. Few participants were lost to follow‐up (reasons not described), while 31 and 24 participants discontinued the intervention per arm, possibly increasing the risk of attrition bias
Selective reporting (reporting bias)	Low risk	Quote: "the primary outcome was the number of all‐cause laboratory‐confirmed viral upper respiratory tract infections per child. Secondary outcomes included time to first laboratory‐confirmed, total parent‐reported, laboratory‐confirmed influenza, and [non‐influenza] upper respiratory tract infections and serum 25‐hydroxyvitamin D levels. Other secondary outcomes not presented in this article included asthma exacerbations among children with asthma, physician‐diagnosed otitis media and pneumonia, emergency department visits, and hospitalizations. Trial procedures have been described in detail elsewhere (see Supplement 1)" Quote (from 2011 protocol): "the primary analysis will be a comparison of laboratory‐confirmed upper respiratory tract infection rate (per child) between study groups using a Poisson regression model. Secondary analyses will include a comparison of vitamin D serum levels, asthma exascerbations [sic] and the frequency of respiratory syncitial [sic] virus, adenovirus and influenza viruses between arms. Furthermore, a cost effectiveness analysis on the effect of wintertime vitamin D supplementation of preschoolers will be undertaken using the net benefit regression approach" Judgement comment: prespecified protocol in supplemental content; describes outcomes measured and reported on; study registered prospectively at ClinicalTrials.gov (ID: NCT01419262) and reported in text
Other bias	Low risk	Judgement comment: no other risks observed

*Study characteristics*
Methods	Study design: quasi‐randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Piltti grant from the Foundation of Pediatric Research, the National Board of Health, and the Academy of Finland Country: Finland Study period: winter 1981
Participants	Included criteria: healthy, term, breastfed infants and their mothers Excluded criteria: mother‐infant pairs that failed to complete breastfeeding Maternal pretreatment: "during pregnancy the mothers had vitamin D supplementation of 0‐500 IU/day: one‐half of the mothers had no supplementation during pregnancy; one‐fourth of the mothers received 500 IU/day vitamin D during middle pregnancy; and one‐fourth of mothers, 500 IU/day vitamin D during one entire pregnancy" (quote). However, study authors do not specify which group each of the infants' mothers fell into (winter or summer, Group 2 or 3) Baseline vitamin D status (mean ± standard error, nmol/L) Control group (400 IU D₃ (winter)): 14.4 ± 2.2 Control group (400 IU D₃ (summer)): 35.0 ± 5.2 Intervention group (1000 IU D₃ (winter)): 23.2 ± 4.6 Intervention group (1000 IU D₃ (summer)): 31.2 ± 3.5
Interventions	Intervention characteristics 400 IU D₂ (winter) Vitamin D content and type: 400 IU D₂ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 20 weeks N per group (in analysis): 15 Brand/company: Leiras, Turku, Finland 400 IU D₂ (summer) Vitamin D content and type: 400 IU D₂ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 20 weeks N per group (in analysis): 16 Brand/company: Leiras, Turku, Finland 1000 IU D₂ (winter) Vitamin D content and type: 1000 IU D₂ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 20 weeks N per group (in analysis): 15 Brand/company: Leiras, Turku, Finland 1000 IU D₂ (summer) Vitamin D content and type: 1000 IU D₂ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 20 weeks N per group (in analysis): 14 Brand/company: Leiras, Turku, Finland
Outcomes	Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Rickets Measurement Serum 25(OH)D (nmol/L): competitive protein‐binding assay (CPBA) Notes: these values are estimated from graphs, Figures 2, 3, and 5 (Ala‐Houhala 1985). Values with standard deviations were reported in abstract Notes: data were not included in meta‐analysis due to reported values as mean ± standard error, with fewer than 30 participants per group, limiting conversion of standard error to standard deviation Rickets: clinical or biochemical indicators Notes: no events in either arm; data did not contribute to meta‐analysis Time points: birth, 8 weeks of age, 20 weeks of age
Notes	No sample size calculation; study may be underpowered
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "they were randomly allocated to three groups with different supplementation protocols of vitamin D" Judgement comment: study authors state that they randomly allocated the interventions but did not describe the random sequence generation method
Allocation concealment (selection bias)	Unclear risk	Judgement comment: allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Judgement comment: if blinding was done, this was not described. Not blinding participants may lead caregivers in control arm to compensate by administering additional vitamin D doses to children, while investigators who know the intervention allocations may be biased toward a particular outcome; both increase the risk for performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Judgement comment: if blinding was done, this was not described. However, outcomes measured are not subjective in nature and are less likely to be influenced by knowledge of the intervention
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Judgement comment: no loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no trial registration or protocol identified. Outcomes in methods presented in results
Other bias	Low risk	Judgement comment: no other risks observed

*Study characteristics*
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: undisclosed Country: Bangladesh Study period: not reported
Participants	Included criteria: children age 6 to 36 months with acute diarrhoea attending the International Centre for Diarrhoeal Disease Research, Bangladesh Hospital Excluded criteria: not specified Baseline vitamin D status: not reported
Interventions	Intervention characteristics 1000 IU D₃ + milk suji Vitamin D content and type: 1000 IU D₃ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 5 days N per group (in analysis): 27 Brand/company: not reported Milk suji Vitamin D content and type: none Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 5 days N per group (in analysis): 26 Brand/company: not reported 1000 IU D₃ + L‐isoleucine + milk suji Vitamin D content and type: 1000 IU D₃ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 5 days N per group (in analysis): 26 Brand/company: not reported L‐isoleucine + milk suji Vitamin D content and type: none Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 5 days N per group (in analysis): 28 Brand/company: not reported
Outcomes	None within scope of this review
Notes	Meeting abstracts available only; milk suji: mixture of milk and rice powder (70 kcal/100 mL)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement comment: not described (meeting abstract)
Allocation concealment (selection bias)	Unclear risk	Judgement comment: not described (meeting abstract)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "double blind" Judgement comment: double‐blind but not further detailed
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "double blind" Judgement comment: double‐blind but not further detailed
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: no loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no trial registration or protocol identified; outcomes in methods presented in results
Other bias	Low risk	Judgement comment: no other risks observed

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Serum 25‐hydroxyvitamin D	1	50	Mean Difference (IV, Fixed, 95% CI)	18.90 [8.53, 29.27]
3.2 Rickets (continuous)	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.94 [‐2.10, 0.22]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Linear growth	1	25	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐3.33, 4.53]
4.2 Adverse effect: hypercalciuria	1	86	Risk Ratio (IV, Fixed, 95% CI)	1.00 [0.06, 15.48]
4.3 Adverse effect: hypercalcaemia	2	126	Risk Ratio (IV, Random, 95% CI)	1.00 [0.90, 1.11]
4.4 Linear growth: gain in length	1	50	Mean Difference (IV, Fixed, 95% CI)	0.73 [0.12, 1.34]
4.5 Serum 25‐hydroxyvitamin D	5	325	Mean Difference (IV, Random, 95% CI)	27.94 [‐2.75, 58.63]
4.6 Change in 25(OH)D (nmol/L)	1	30	Mean Difference (IV, Fixed, 95% CI)	7.19 [2.97, 11.41]
4.7 Vitamin D sufficiency (≥ 50 nmol/L)	3	225	Risk Ratio (IV, Random, 95% CI)	1.34 [0.76, 2.35]
4.8 Rickets (dichotomous)	2	153	Risk Ratio (IV, Random, 95% CI)	1.23 [0.24, 6.30]

*Study characteristics*
Methods	Study design: cross‐over trial Study grouping: parallel group Funding: no funding Country: Switzerland Study period: 1 March to 30 April 2010
Participants	Included criteria: Swiss singleton, newborn infants with gestational age of 36 weeks or more and neonatal body weight of 2 kg or more; not previously exposed to vitamin D Excluded criteria: not specified Baseline vitamin D status: not reported
Interventions	Intervention characteristics Vi‐De₃ Vitamin D content and type: 2.5 µg D₃ Formulation: drops ("alcoholic vitamin D₃", dissolved in 65% ethanol (113 µg/mL corresponding to 2.5 µg per drop)) Frequency of dosage: once Duration of administration (study time): 5‐ to 10‐minute session N per group (in analysis): 42 Brand/company: Wild AG, Basel, Switzerland Vitamin D₃ Wild Vitamin D content and type: 12.5 µg D₃ Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 5‐ to 10‐minute session N per group (in analysis): 42 Brand/company: Wild AG, Basel, Switzerland
Outcomes	None within scope of review
Notes	Target sample size described and met but not calculated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "an independent statistician had generated a randomization list to balance the order of presentation of the preparations so that each preparation was tasted first an equal number of times" Judgement comment: random sequence generation method not described
Allocation concealment (selection bias)	Low risk	Quote: "42 sequentially numbered, opaque sealed envelopes containing the assignment. The envelopes were opened in sequence after accompanying the infant with the mother to the test area" Judgement comment: appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "single‐blind" Judgement comment: only participants were blinded; if investigators know the intervention allocations, may be biased toward a particular outcome, increasing the risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Judgement comment: outcome assessors were not blinded; however, no outcomes were within the scope of this review
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: no loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol or trial registration found; outcomes in methods presented in results
Other bias	Low risk	Judgement comment: no other risks observed&&

*Study characteristics*
Methods	Study design: randomised‐controlled trial Study grouping: parallel group Funding: 100% non‐profit. Study drug was procured through Indian Council of Medical Research grant 5/7/305/08‐RHN Country: India Study period: August 2011 to March 2012
Participants	Included criteria: preterm infants born between 28 and 34 weeks’ gestational age and receiving ≥ 100 mL/kg/d of enteral feedings by 2 weeks’ postnatal age Excluded criteria: infants with major malformations, those who received parenteral nutrition for ≥ 2 weeks, those born to mothers receiving phenytoin therapy or with HIV infection Baseline vitamin D status (mean ± standard deviation; nmol/L) Control group (400 IU D3): 24.7 ± 12.0 Intervention group (800 IU D3): 30.7 ± 12.5
Interventions	Intervention characteristics 800 IU D₃ Vitamin D content and type: 800 IU D3 Formulation: drops Frequency of dosage: daily Duration of administration (study time): 3 months N per group (in analysis): 42 Brand/company: Basic Human Health Care Private Ltd., Delhi, India 400 IU D₃ Vitamin D content and type: 400 IU D3 Formulation: drops Frequency of dosage: daily Duration of administration (study time): 3 months N per group (in analysis): 45 Brand/company: Basic Human Health Care Private Ltd., Delhi, India
Outcomes	Primary Linear growth Adverse effect: hypercalciuria Adverse effect: hypercalcaemia Adverse effect: kidney stones Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D < 50 nmol/L Notes: converted to vitamin D sufficiency ≥ 50 nmol/L for meta‐analysis Measurement Length (cm): not reported Hypercalciuria (urinary calcium‐to‐creatinine ratio): Beckman Coulter assay Definition: > 0.8 mg/mg Hypercalcaemia (serum calcium): colorimetric method using a Beckman Coulter Synchron‐CX9 PRO clinical system (Beckman Coulter, Inc., Pasadena, CA, USA) Definition: not reported Kidney stones: method not reported Notes: no events in either arm; data did not contribute to meta‐analysis Serum 25(OH)D (nmol/L): chemiluminescence, autoanalyzer (DiaSorin Liaison, Stillwater, MN, USA) Time points: enrolment, 40 weeks' postmenstrual age, 3 months' corrected age
Notes	Sample size calculated and met at randomisation and analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "infants in both strata were randomly assigned to receive oral vitamin D3 at a dose of 800 or 400 IU/day. We used computer‐generated random numbers to allocate infants to 1 of the study groups with a fixed block size of 4" Judgement comment: appropriate sequence generation method
Allocation concealment (selection bias)	Low risk	Quote: "random allocation was concealed by assigning sequential numbers to identical‐appearing bottles containing 2 different amber‐colored, identical appearing drug suspensions" Judgement comment: appropriate allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "amber‐colored bottles containing identical‐appearing drug suspensions ensured blinding of investigator and parents" Judgement comment: participants and personnel were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: double‐blind implies blinding of outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "we enrolled 96 infants in the study (Fig 1). Clinical and baseline characteristics of the study population were comparable between the 2 groups (Table 1). Study intervention was initiated in 94 infants because consent was withdrawn by 2parentssoonafter randomization.Of these 94 infants, 3 infants died before follow‐up at 40 weeks (1 due to stage 3 necrotizing enterocolitis and 2 due to probable milk aspiration); another 4 infants were lost to follow‐up. Thus, a total of 87..." Quote: "analysis was performed by intention to treat" Judgement comment: low loss to follow‐up overall; reasons documented. Reasons for loss to follow‐up included death and loss to follow‐up not described. Balanced among groups. Intention‐to‐treat analysis but seems to include only those finishing follow‐up; possible attrition bias
Selective reporting (reporting bias)	Unclear risk	Judgement comment: study was registered retrospectively with Clinical Trial Registry of India (CTRI, ctri.nic.in) (ID: CTRI/2012/02/002459), as reported in text. All prespecified outcomes were reported
Other bias	Low risk	Judgement comment: no other risks observed

*Study characteristics*
Methods	flex Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit Country: Finland Study period: 14 January 2013 to 30 May 2016
Participants	Included criteria: Northern European, term, birth weight within 2 standard deviations of the mean for gestational age Excluded criteria: infants requiring intravenous glucose, antibiotics, nasal continuous positive airway pressure treatment longer than 1 day, phototherapy longer than 3 days, or nasogastric tube feeding longer than 1 day; infants with seizures Baseline vitamin D status (mean ± standard deviation; nmol/L) Control group (400 IU D₃): 81.7 ± 27.8 Intervention group (1200 IU D₃): 82.3 ± 24.0
Interventions	Intervention characteristics 400 IU D₃ Vitamin D content and type: 400 IU D₃ Formulation: drops Frequency of dosage: daily Duration of administration (study time): 24 months N per group (in analysis): 489 Brand/company: Orion Pharmaceuticals, Kamataka, India 1200 IU D₃ Vitamin D content and type: 1200 IU D₃ Formulation: drops Frequency of dosage: daily Duration of administration (study time): 24 months N per group (in analysis): 486 Brand/company: Orion Pharmaceuticals, Kamataka, India
Outcomes	Primary Adverse effect: hypercalcaemia Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D < 50 nmol/L Notes: converted to vitamin D sufficiency ≥ 50 nmol/L for meta‐analysis Measurement Hypercalcaemia (serum calcium): flex gas analyser Definition: not reported Serum 25(OH)D (nmol/L): fully automated immunoassay (IDS‐iSYS; Immunodiagnostic System Inc., Gaithersburg, MD, USA) Time points: enrolment, 24 months
Notes	Sample size calculated at n ~ 300/group, which was met by analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "infants were randomized (1:1) to receive 400 IU or 1200 IU of vitamin D₃ daily from age 2 weeks to 24 months. To ensure fair distribution across the year, a pharmacist at Helsinki University Hospital with no relation to the study performed randomization in blocks of 50" Judgement comment: random sequence generation method not described
Allocation concealment (selection bias)	Low risk	Quote: "both study preparations, manufactured by Orion Pharmaceuticals, contained vitamin D₃ dissolved in medium‐chain triglyceride oil and were identical in appearance. Participants and investigators were masked to group assignment, and no changes to the methods were made after trial commencement" Judgement comment: appropriate allocation concealment; however, no mention of sequentially labelled envelopes or containers
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "participants and investigators were masked to group assignment, and no changes to the methods were made after trial commencement" Judgement comment: all personnel and participants were blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Judgement comment: possible that outcome assessors were not blinded and grading was done by staff; subjective and possibly increasing risk of detection bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "we performed pQCT bone scans of the left tibia in 783 of the 823 children (95.1%) attending the age 24‐month follow‐up. Owing to motion artifacts, 79 (10.1%) of the scans failed and were excluded. A total of 704 scans (89.9%) were included in the analyses. Of these, scan quality was assessed as good in 165 (48.1%) of the 400‐IU group and 193 (53.5%) of the 1200‐IU group participants, moderate in 124 (36.2%) of the 400‐IU group and 133 (36.8%) of the 1200‐IU group, and poor in 54 (15.7%) of the 400‐IU group and 35 (9.7%) of the 1200‐IU group" Quote: "in the analyses, we applied the intention‐to‐treat principle. Per‐protocol analyses included participants with treatment adherence of at least 80%" Judgement comment: loss to follow‐up was balanced across groups and reasons were documented. Out of 975 children, 783 (80%) had bone scans. Uncertain if children whose scans had motion artifacts are different from children whose scans did not. Grading of scans was subjective. Possible intention‐to‐treat analysis in 83.5% of the cohort
Selective reporting (reporting bias)	Low risk	Quote: "the project protocol is provided in Supplement 1 and has been described in a previously published article" Judgement comment: registered on ClinicalTrials.gov (ID: NCT01723852); previously published protocol's prespecified outcomes are reported in study results
Other bias	Low risk	Judgement comment: no other risks observed

Study	Reason for exclusion
Abrams 2013	No stratified data available for study population; age group 4 to 8 years (study author contacted via email but no response received)
Atkinson 2017	No stratified data available for study population; age group 1 to 21 years (study author contacted via email but no response received)
Camargo 2014	No stratified data available for study population; age group 2 to 17 years (study author contacted via email and responded: no time to re analyse data)
Dehbroki 2019	No stratified data available for study population; age group 2 to 18 years (study author contacted via email but no response received)
Galli 2015	No stratified data available for study population; age group 6 to 195 months (study author contacted via email but no response received)
Gottschlich 2017	No stratified data available for study population; age group 0.7 to 18.4 years (study author contacted via email but no response received)
Hamidieh 2016	No stratified data available for study population; age group 1 to 15 years (study author contacted via email but no response received)
Homola 2011	No stratified data available for study population; age group not explicitly stated (study author contacted via email and responded: no time to share raw data)
Kakalia 2011	Age group above 5 years (study author contacted via email and responded that stratified data were available for study age group of 3 to 18 years, but only 3 participants were under 5 years of age; they did not provide the data in response to follow‐up emails)
Kashif 2014	No stratified data available for study population; age group 1 to 12 years (study author contacted via email and responded, but follow‐up attempts were unsuccessful)
Kazemi 2010	No stratified data available for study population; age group over 3 years; upper age range not stated (study author contacted via email but no response received)
Kerley 2017	No stratified data available for age group under 18 years (study author contacted via email and responded: data are not retrievable)
Lal 2018	No stratified data available for study population; age group 1.5 to 18 years (study author contacted via email but no response received)
Lara‐Corrales 2019	No stratified data available for study population; age group 0 to 18 years (study author contacted via email but no response received)
Lee 2018	No stratified data for study population; age group 3 to 20 years (study author contacted via email but no response received)
Loeb 2019	No stratified data for study population; data on age group 3 to 17 years were available via study authors (study authors contacted and responded: provided information via email)
Mazahery 2019	No stratified data for study population; age group 2.5 to 8 years (study author contacted via email but no response received)
Merrikhi 2018	No stratified data available for study population; age group 2 to 12 years (study author contacted via email but no response received)
Morcos 1998	No stratified data available for study population; age group 1.5 to 13 years (study author contacted via email but no response received)
Mortensen 2016	No stratified data available for study population; age group 4 to 8 years (study author contacted via email but no response received)
Muske 2018	No stratified data available for study population; age group 1 to 18 years (study author contacted via email but no response received)
Nwosu 2014	No stratified data available for study population; age group 3 to 18 years (study author contacted via email but no response received)
Rahmati 2018	No stratified data available for study population; age group 3 to 14 years (study author contacted via email but no response received)
Saad 2018	Retracted
Sharma 2017	No stratified data available for study population; age group 1 to 18 years (study author contacted via email but no response received)
Shroff 2012	No stratified data available for study population; age group under 18 years (study author contacted via email and responded: requested blank spreadsheet to provide stratified data, which was sent; no further response received)
Siafarikas 2009	Meeting abstract. No stratified data available for study population; age group ≤ 16 years (study author contacted via email but no response received)
Sidbury 2008	No stratified data available for study population; age group 1 to 18 years (study author contacted via email and responded: most study participants were older than 5 years; could not share stratified data)
Simon 2016	No stratified data available for study population; age group 1 to 18 years (study author contacted via email but no response received)
Singh 2018b	No stratified data available for study population; age group 1 to 18 years (study author contacted but no response received)  Note: study cites CTRI registration number as "CTRI/2015/10/009984" with the title, "Comparison of the efficacy of two dosing regimens of Vitamin D for bone protection in children with difficult nephrotic syndrome"; however, the correct CTRI number with this title is "CTRI/2016/10/007405," as referenced in this review
Suryanto 2018	No stratified data available for study population; age group 1 to 18 years (study author contacted via email but no response received)
Swangtrakul 2020	No children younger than 5 years included in study (study author contacted via email and responded with confirmation)
Talaat 2016	No stratified data available for study population; age group 2 to 16 years (study author contacted via email but no response received)
Tannous 2018	No stratified data available for study population; age group 1 to 18 years (study author contacted via email but no response received)
Udompataikul 2015	No stratified data available for study population; age group 1 to 18 years (study author contacted via email but no response received)
Wadia 2018	No stratified data available for study population; age group 5.5 months to 16 years (study author contacted via email but no response received)
Zulkarnain 2019	No stratified data available for study population; age group 2 to 12 years (study author contacted via email but no response received)

Methods	Study design: interventional randomised clinical trial Study grouping: parallel group Funding: not reported Country: Pakistan
Participants	Included criteria: pregnant women from 20 to 22 weeks' gestation and their infants Excluded criteria: pregnant women with preexisting type 1 or 2 diabetes, women with multiple foetuses/babies
Interventions	Intervention characteristics 400 IU Vitamin D content and type: 400 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months N per group (in analysis): not reported Brand/company: not reported Placebo Vitamin D content and type: none Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months N per group (in analysis): not reported Brand/company: not reported
Outcomes	Primary Adverse effect: hypercalciuria Adverse effect: hypercalcaemia Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Serum 25(OH)D (nmol/L): assay not reported Hypercalciuria (urinary calcium‐to‐creatinine ratio): not reported Definition: not reported Hypercalcaemia (serum calcium): not reported Definition: not reported Time point: 6 months
Notes	Notes: completed (August 2011). Study author contacted but no response received

Study name	Public trial: Can vitamin D supplementation in infants prevent food allergy in the first year of life? The VITALITY trial Scientific title: A placebo‐controlled, randomised trial of vitamin D supplementation for infants in their first year of life, to prevent the development of food allergy by age 12 months. The VITALITY trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Isabel & John Gilbertson Charitable Trust and Murdoch Children’s Research Institute. KJA, MP, JJK, SCD, A‐LP, LCG, MW all receive fellowship funding from National Health and Medical Research Council (NHMRC) of Australia. NC receives funding from University of Melbourne, McKenzie Postdoctoral Fellowship Country: Australia
Participants	Included criteria: healthy, term, 6– to 8‐week‐old breastfed infants whose mothers intend to continue to predominantly breastfeed until 6 months Excluded criteria: already receiving vitamin D supplementation, born premature (< 37 weeks) or at low birth weight (< 2500 g), multiple births, poor health due to current or past significant disease state or congenital abnormality or taking medication that interferes with vitamin D metabolism
Interventions	Intervention characteristics 400 IU D₃ Vitamin D content and type: 400 IU D₃ Formulation: drops Frequency of dosage: daily Duration of administration (study time): 10 to 11 months N per group (sample size calculation): 1506 Brand/company: D Drops Company (Ontario, Canada) Placebo Vitamin D content and type: none Formulation: drops Frequency of dosage: daily Duration of administration (study time): 10 to 11 months N per group (sample size calculation): 1506 Brand/company: not reported
Outcomes	Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Serum 25(OH)D deficiency, not defined Time point: endpoint (12 months of age)
Starting date	December 2014
Contact information	Michael Field, Murdoch Children's Research Institute; email: vitality@mcri.edu.au Jennifer Koplin, Murdoch Children's Research Institute; email: jennifer.koplin@mcri.edu.au
Notes	Notes: recruiting (estimated study completion: December 2022)

Study name	Public title: PREVARID ‐ PREVention of Acute Respiratory Infections with Vitamin D Scientific title: Does vitamin D supplementation prevent acute respiratory infection health care visits among children under 2 years old? A randomised controlled trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Cure Kids, Auckland, New Zealand Country: New Zealand
Participants	Included criteria: New Zealand residents, < 2 years old at the time of acute lower respiratory infection hospital admission, reside in Auckland District Health Board catchment area Excluded criteria: receiving vitamin D supplements, have a complex chronic condition known to be associated with recurrent hospital admission (e.g. cystic fibrosis, tracheostomy)
Interventions	Intervention characteristics 5000 IU D₃ Vitamin D content and type: 5000 IU D₃ Formulation: drops Frequency of dosage: weekly Duration of administration (study time): 12 months N per group (sample size calculation): 150 Brand/company: not reported Placebo Vitamin D content and type: none Formulation: drops (coconut oil) Frequency of dosage: weekly Duration of administration (study time): 12 months N per group (sample size calculation): 150 Brand/company: not reported
Outcomes	Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Notes: in 10% subsample Measurement Serum 25(OH)D (nmol/L): assay not reported Time points: enrolment, 6 months and 12 months after enrolment
Starting date	July 2016
Contact information	Cameron Grant, University of Auckland, Principal Investigator; email: cc.grant@auckland.ac.nz
Notes	Notes: not yet recruiting (estimated recruitment completion 30 November 2017)

Study name	Public title: Vitamin D supplementation and responses to vaccines in infants Scientific title: Vitamin D supplementation to improve immune responses to vaccines administered in early infancy ‐ the Nutrivac‐D trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Government funding agency Country: India
Participants	Included criteria: Inclusion criteria during pregnancy and labour are: pregnant at any gestation when screened antenatally; Pregnancy full term (> 37 and < 41 completed weeks) when screened again at labour (consent will only be taken in the antenatal period and not during labour); will stay in study area for a period of at least 6 months after delivery; delivery by vaginal route or by elective Cesarean section. Inclusion criteria at birth and within 24 hours: single term newborn (gestational age > 37 and < 41 weeks at birth) < 24 hours old; born by normal vaginal route or elective caesarean section; will stay in study area for a period of at least 6 months after delivery; breastfeeding established Excluded criteria: Exclusion criteria during pregnancy and intrapartum period: a mother with a history of > 5 pregnancies; multiple gestation; presence of any documented major maternal medical or surgical illness e.g. HIV, Hepatitis B, Tuberculosis, TORCH infections, syphilis, malignancy or immunodeficiency, etc; presence of fetal (major) congenital anomalies diagnosed in utero; any infection during pregnancy that required hospitalisation; blood transfusion during pregnancy; history of maternal eclampsia / preeclampsia / hypertension with significant proteinuria (> 3+) during pregnancy. Exclusion criteria at birth and within 24 hrs: one minute Apgar of < 7/10; birth weight < 1.8 kg; multiple gestation; major congenital anomalies diagnosed prior to birth or during a clinical examination by a paediatrician performed within the first 24 hours; newborn required admission to neonatal intensive care prior to randomisation; informed written consent not provided by parents
Interventions	Intervention characteristics 400 IU Vitamin D content and type: 400 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months of age N per group (target): 450 Brand/company: not reported Placebo Vitamin D content and type: none Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months of age N per group (target): 450 Brand/company: not reported
Outcomes	Primary Linear growth Measurements Length (not defined) Time point: 6 months of age
Starting date	December 2012
Contact information	Uma Chandra Mouli Natchu, Translational Health Science and Technology Institute, Principal Investigator; email: unatchu@thsti.res.in
Notes	Notes: open to recruitment (first recruitment 21 December 2012)

PERMALINK

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

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Linear growth faltering and stunting

Description of the intervention

Vitamin D status

Vitamin D sources

Vitamin D requirements

Metabolism of vitamin D

How the intervention might work

Skeletal homeostasis and linear growth

Muscle development and growth

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

1. Intervention and comparator groups.

Interventions

Comparators

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

2. Unused methods.

Selection of studies

Data extraction and management

Study information

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Studies with more than two treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Summary of findings

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

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

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

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Study design

Location/Setting

Participants

3. Participant characteristics.

Interventions

Comparison 1: vitamin D versus placebo or no intervention

Comparison 2: vitamin D (higher dose) versus vitamin D (lower dose)

Comparison 3: vitamin D + micronutrient(s) versus micronutrient(s) alone

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

Outcomes

Study name	Public title: A clinical trial to evaluate the need for routine vitamin D supplementation till six months age in full term babies who are being exclusively breastfed Scientific title: Vitamin D oral supplementation evaluation in full‐term, exclusively breastfed infants ‐ a randomised controlled study
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: not reported Country: India
Participants	Included criteria: born at 37 weeks' completed gestation or thereafter, birth weight ≥ 2500 g, exclusively breastfed, parents provided written consent for infant to participate in the study after detailed information was disseminated to them Excluded criteria: infants born before 37 completed weeks of gestation; low birth weight (i.e. birth weight < 2500 g); sick neonate, including birth asphyxia; neonate not exclusively breastfed from birth for any reason even though may afterward be on exclusive breastfeeds; neonate with major congenital anomaly; neonate whose parents decline consent to participate in the study (presence of any 1 criterion will result in exclusion)
Interventions	Intervention characteristics 400 IU Vitamin D content and type: 400 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months of age N per group (target): 150 Brand/company: not reported No intervention Duration of administration (study time): 6 months of age N per group (target): 150
Outcomes	Primary Linear growth Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurements Length (cm) Serum 25(OH)D (nmol/L): assay not reported Time points: birth (cord blood), 1 month of age, 6 months of age
Starting date	July 2015
Contact information	Shankar Narayan, Indian Naval Hospital Ship (INHS) Asvini, Principal Investigator; email: drshankarnarayan@gmail.com
Notes	Notes: open to recruitment (first enrolment 1 July 2015)

Study name	Public title: Vitamin D levels in preterm babies Scientific title: Vitamin D levels of the term small‐for‐date newborns at birth and at 3 month of age after vitamin D supplementation with 2 different doses 400 IU v/s 800 IU ‐ a randomised controlled trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Sri Devaraj Urs Academy of Higher Education and Research Country: India
Participants	Included criteria: healthy, small‐for‐gestational‐age infants born with normal delivery, gestational period ≥ 37 weeks, birth weight < 2500 g, exclusively breastfed for 3 months Excluded criteria: preterm babies with gestational age < 36 weeks; birth weight < 2500 g; liver, renal, intestinal, and other problems that can affect vitamin D metabolism; on medications such as anticonvulsants, glucocorticoids, antifungal medications; mother with systematic disease that can alter vitamin D metabolism (renal, hepatic); malignancy; features of rickets; repeated fractures
Interventions	Intervention characteristics 1400 IU Vitamin D content and type: 1400 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 3 months N per group (target): not clear* Brand/company: not reported 2800 IU Vitamin D content and type: 2800 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 3 months N per group (target): not clear* Brand/company: not reported Total target sample size: n = 35
Outcomes	Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Serum 25(OH)D (nmol/L): assay not reported Time points: birth, 3 months of age
Starting date	February 2016
Contact information	Syed Manazir Ali, Jawaharlal Nehru Medical College, Aligarh Muslim University, Principal Investigator; email: manazir1958@yahoo.com
Notes	Notes: open to recruitment (first enrolment 2 February 2016)

Study name	Public title: Role of vitamin D3 intake and decrease in respiratory infections Scientific title: Randomised trial of two different doses of vitamin D supplementation and risk of acute respiratory infection in children in rural Kolar, Karnataka
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Jawaharlal Nehru Medical College Aligarh Muslim University Aligarh Country: India
Participants	Included criteria: healthy, age 3 to 6 years, attends RL Jallappaschool in Kolar Excluded criteria: chronic illness (except asthma), clinical rickets, child on vitamin supplementation
Interventions	Intervention characteristics 3000 IU Vitamin D content and type: 3000 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 3 months, 6 months of no intervention, then 3 additional months of intervention (12 months of follow‐up) N per group (target): 85 Brand/company: not reported 600 IU Vitamin D content and type: 600 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 3 months, 6 months of no intervention, then 3 additional months of intervention (12 months of follow‐up) N per group (target): 85 Brand/company: not reported
Outcomes	Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Serum 25(OH)D (nmol/L): assay not reported Time points: 3 and 12 months
Starting date	January 2018
Contact information	Kanak N Venkateshwara Prasad, Sri Devraj Urs Medical College, Principal Investigator; email: drknvp@gmail.com
Notes	Notes: not yet recruiting (record last modified 28 October 2017)

Study name	Public title: Dose of vitamin D in children with chronic kidney disease Scientific title: Optimal dose of cholecalciferol supplementation in Indian children with chronic kidney disease ‐ a randomised controlled trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Navajbai Ratan Tata Trust, Bombay House, 24 Homi Mody Street, Mumbai ‐ 400 001, Maharashtra, India (reference no: Health‐CKCC‐20141118). This being an “Investigator initiated trial” will receive only partial support from the Trust towards supporting expenses of clinical tests and vitamin D supplements Country: India
Participants	Included criteria: 1 to 18 years of age, chronic kidney disease stages 2 to 4 (estimated glomerular filtration rate 15 to 90 mL/min/1.73 m²), serum 25‐hydroxyvitamin D level < 30 ng/mL Excluded criteria: therapy with cholecalciferol, including over‐the‐counter multi‐vitamin or intramuscular serum 25‐hydroxyvitamin D, in preceding 3 months; known nephrocalcinosis; refusal to give consent; known poor adherence to medications; inability to attend a follow‐up visit
Interventions	Intervention characteristics 3000 IU D₃ Vitamin D content and type: 3000 IU D₃ Formulation: sachet Frequency of dosage: daily Duration of administration (study time): 3 months + additional treatment, depending on serum 25(OH)D concentration* N per group (sample size attained, preliminary data): 30 Brand/company: Pharmacy of St John's Medical College Hospital Other micronutrient content: children with serum calcium less than expected by age they will receive calcium supplements (75 to 100 mg/kg/d) 25,000 IU D₃ Vitamin D content and type: 25,000 IU D₃ Formulation: sachet Frequency of dosage: weekly Duration of administration (study time): 3 months + additional treatment, depending on serum 25(OH)D concentration* N per group (sample size attained, preliminary data): 29 Brand/company: Pharmacy of St John's Medical College Hospital Other micronutrient content: children with serum calcium less than expected by age they will receive calcium supplements (75 to 100 mg/kg/d) 100,000 IU D₃ Vitamin D content and type: 100,000 IU D₃ Formulation: sachet Frequency of dosage: monthly Duration of administration (study time): 3 months + additional treatment, depending on serum 25(OH)D concentration* N per group (sample size attained, preliminary data): 31 Brand/company: Pharmacy of St John's Medical College Hospital Other micronutrient content: children with serum calcium less than expected by age they will receive calcium supplements (75 to 100 mg/kg/d) *After 3 months, children with serum 25‐hydroxyvitamin D ≥ 30 ng/mL will receive maintenance 1000 IU D₃ orally daily for 9 months. Children with serum 25‐hydroxyvitamin D < 30 ng/mL will be given a second course of intensive treatment, using same dosage schedule as per allocation at randomisation. Those who fail to achieve serum 25‐hydroxyvitamin D ≥ 30 ng/mL will receive a third course of intensive replacement therapy
Outcomes	Primary Adverse effect: hypercalcaemia Adverse effect: hypercalciuria Secondary Change in serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D deficiency Measurement Hypercalcaemia (serum calcium): not defined Hypercalciuria (urinary calcium‐to‐creatinine ratio): not defined Serum 25(OH)D (nmol/L): liquid chromatography‐tandem mass spectrometry Vitamin D deficiency: not defined Time points: end of an intensive phase
Starting date	January 2016
Contact information	Arpana Aprameya Iyengar, Government Medical College; email: drarpanaiyengar@gmail.com
Notes	Notes: trial completed (ended: 20 November 2019), trial protocol publication and meeting abstract with preliminary data available. Study author contacted and indicated manuscript is forthcoming Note: trial protocol lists Clinical Trials Registry of India registration number as "CTRI/2015/11/010180"; however; this was not found in the CTRI database. The CTRI registration referenced in this review, "CTRI/2017/11/010385", appears to be the correct number

Study name	Public title: Effect of vitamin D supplementation on postoperative surgical outcomes in children with cyanotic congenital heart disease undergoing open heart surgery: a randomised controlled trial Scientific title: Effect of vitamin D supplementation on outcome in children undergoing open heart surgery: a randomised controlled trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Institutional research fund, All India Institute of Medical Science (AIMS), New Delhi, India Country: India
Participants	Included criteria: 1 month to 12 years of age, transposition of great arteries, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, univentricular physiology, shunts with reversal of flow, left‐to‐right shunt like atrial septal defect, ventricular septal defect, undergoing open heart surgery electively under cardiopulmonary bypass Excluded criteria: urgent/emergency surgery, syndromic child, closed heart surgery, preoperative infection/antibiotic administration and ventilation
Interventions	Intervention characteristics 400,000 IU Vitamin D content and type: 10,000 IU/kg vitamin D body weight not exceeding 400,000 IU vitamin D Formulation: powder Frequency of dosage: once, at enrolment Duration of administration (study time): not clear N per group (target): 50 Brand/company: not reported Placebo Vitamin D content and type: none Formulation: powder (sugar) Vitamin D type: not applicable Frequency of dosage: Once, at enrolment Duration of administration (study time): not clear N per group (target): 50 Brand/company: not reported
Outcomes	Primary Adverse effect: hypercalcaemia Adverse effect: hypercalciuria Measurement Hypercalcaemia (not described) Hypercalciuria (not described) Time points: postoperative course in intensive care unit
Starting date	January 2018
Contact information	Manoj Kumar Sahu, AIMS, Principal Investigator; email: drmanojsahu@gmail.com
Notes	Notes: not yet recruiting (record last modified 26 November 2019)

Study name	Public title: A clinical trial to compare three different regimes for treatment of nutritional rickets in children Scientific title: To evaluate the efficacy of daily vitamin D therapy versus Stoss therapy in nutritional rickets in Indian children: a randomised controlled trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Maulana Azad Medical College and Lok Nayak Hospital Country: India
Participants	Included criteria: age 6 months to 12 years; diagnosis of nutritional rickets defined by clinical, biochemical, and radiological parameters; residence within 50 km of hospital; willing for follow‐up visits Excluded criteria: patients with confirmed or suspected diagnosis of malabsorption or chronic kidney or hepatic disease, severe systemic illness compromising oral intake (tachycardia, tachypnoea, shock, weak peripheral pulses, increased capillary refill time); have taken calcium supplements or vitamin D preparation in last 6 months
Interventions	Intervention characteristics 60,000 IU Vitamin D content and type: 60,000 IU vitamin D Formulation: liquid Frequency of dosage: weekly Duration of administration (study time): 3 or 6 weeks N per group (target): 66 Brand/company: not reported 2000 IU Vitamin D content and type: 2000 IU vitamin D Formulation: liquid Frequency of dosage: daily Duration of administration (study time): 12 weeks N per group (target): 66 Brand/company: not reported
Outcomes	Secondary Change in serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D < 12 ng/mL Measurement Serum 25(OH)D (nmol/L): assay not reported Time point: 12 weeks
Starting date	April 2018
Contact information	Aashima Dabas, Maulana Azad Medical College, Principal Investigator; email: dr.aashimagupta@gmail.com
Notes	Notes: not yet recruiting (record last modified 13 December 2018)

Study name	Public title: Daily versus bolus oral vitamin D3 for treatment of rickets In children Scientific title: Daily versus depot oral vitamin D3 for treating nutritional rickets
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. University College of Medical Sciences and GTB Hospital, Dilshad Garden, New Delhi, India 110095 Country: India
Participants	Included criteria: 3‐month‐old to 5‐year‐old children with nutritional rickets presenting in outpatient department, wards, emergency of paediatrics department based on history, examination, and biochemical (serum calcium ‐ normal/low, serum phosphorus ‐ normal/low and serum alkaline phosphatase ‐ high) and radiological features (Thacher score ≥ 1.5) Excluded criteria: previous treatment of rickets, child admitted to paediatric intensive care unit, secondary cause of rickets such as medication, vitamin D disorder of metabolism, fat malabsorption syndrome
Interventions	Intervention characteristics 60,000 IU to 150,000 IU Vitamin D content and type: 60,000 IU vitamin D (3 to 12 months of age); 150,000 IU vitamin D (1 to 5 years of age) Formulation: not reported Frequency of dosage: once, at enrolment Duration of administration (study time): 12 weeks Brand/company: not reported N per group (target): 33 Micronutrient content: calcium: 250 mg (3 to 12 months of age); 500 mg (1 to 5 years of age) 2000 IU to 4000 IU Vitamin D content and type: 2000 IU vitamin D (3 to 12 months of age); 4000 IU vitamin D (1 to 5 years of age) Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 12 weeks Brand/company: not reported N per group (target): 33 Micronutrient content: calcium: 250 mg (3 to 12 months of age); 500 mg (1 to 5 years of age)
Outcomes	Primary Adverse effect: hypercalcaemia Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Hypercalcaemia (serum calcium): not defined Serum 25(OH)D (nmol/L): assay not reported Time points: 4 weeks, 12 weeks
Starting date	January 2019
Contact information	Ravneet T Kaur Saluja, University College of Medical Sciences and Guru Teg Bahadur Hospital, Principal Investigator
Notes	Notes: closed to recruitment (last enrolment November 2019)

Study name	Public title: Effect of supplementation with vitamin D on acute bronchitis prevention during the first year of life Scientific title: Effect of supplementation with vitamin D on acute bronchitis prevention during the first year of life
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Grant from Spanish Ministry of Health (EC11‐476) Country: Spain
Participants	Included criteria: healthy, on‐term newborns of appropriate size for gestational age during first 2 weeks of age (range 5 days), on exclusive breastfeeding or exclusive formula feeding Excluded criteria: infant with gestational age < 37 weeks; low birth weight for gestational age (birth weight < 2500 g); mixed feeding at baseline; newborn with major congenital anomaly; infant with chronic gastrointestinal, hepatic, renal, respiratory, cardiac, neurological, or metabolic disorder; any disease that is accompanied by hypercalcaemia and hypercalciuria, calcium lithiasis, hypersensitivity to vitamin D, hypervitaminosis D, renal osteodystrophy with hyperphosphataemia
Interventions	Intervention characteristics 2000 IU D₃ Vitamin D content and type: 2000 IU D₃ Formulation: liquid Frequency of dosage: daily Duration of administration (study time): 1 year N per group (target): 359 Brand/company: VITAMINA D3 Kern Pharma Solución Oleosa, Kern Pharma, Terrassa, Spain Placebo Vitamin D content and type: none Formulation: liquid Frequency of dosage: daily Duration of administration (study time): 1 year N per group (target): 359 Brand/company: not reported
Outcomes	Primary Linear growth Adverse effect: hypercalcaemia Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Linear growth: length (not defined) Hypercalcaemia (not defined) Serum 25(OH)D (nmol/L): assay not reported Time point: 12 months
Starting date	February 2013
Contact information	Antonio Moreno Galdó, University Hospital Vall d'Hebron, Principal Investigator; email: amoreno@vhebron.net
Notes	Notes: completed recruitment (ended 20 August 2018). Meeting abstract (preliminary results) available; study author contacted and indicated publication is forthcoming

Study name	Study of daily vitamin D supplementation in preterm infants: a randomised trial
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: not reported Country: India
Participants	Included criteria: preterm neonates Excluded criteria: not reported
Interventions	Intervention characteristics 400 IU Vitamin D content and type: 400 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 40 weeks' postmenstrual age N per group (in preliminary analysis): 46 Brand/company: not reported 800 IU Vitamin D content and type: 800 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 40 weeks' postmenstrual age N per group (in preliminary analysis): 46 Brand/company: not reported
Outcomes	Secondary Serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Serum 25(OH)D deficiency Measurement Serum 25(OH)D (nmol/L): assay not reported Vitamin D deficiency: not defined Time point: 40 weeks' postmenstrual age
Starting date	Not reported
Contact information	Sai Sunil Kishore, Maharajah Institute of Medical Sciences; email: mssk81@gmail.com
Notes	Note: preliminary results included in meeting abstract; study author contacted but no response received

Study name	Public title: A randomised trial of vitamin D supplementation in healthy inner‐city children Official title: A randomised, controlled trial of vitamin D supplementation in infants and children: effects of vitamin D dose and genotype of the binding protein
Methods	Study design: randomised controlled trial Study grouping: parallel group Funding: 100% non‐profit. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Thrasher Research Fund Country: USA
Participants	Included criteria: 6 months to 6 years of age, healthy or free from any disease or condition that may affect nutritional status or bone metabolism, willingness of family to participate in a 6‐month study of vitamin D supplementation. In preliminary data (meeting abstract), children 2 to 10 years of age of predominantly Hispanic background were included Excluded criteria:* chronic disease, prematurity < 32 weeks' gestational age, liver disease such as hepatitis or renal/urologic disease (e.g. recurrent urinary tract infection), use of pharmacological or prescription‐level dosage of vitamin D or its metabolites. Also excluded are users of any systemic glucocorticoid preparation and users of inhaled steroids that are considered greater than medium dose for age 4 years. Specifically, this would exclude users of more than 1 mg/d of budesonide, and more than 352 mcg/d of fluticasone. Current or recent (within 1 month) use of anticonvulsants or other medications known to affect bone and mineral homeostasis or alkaline phosphatase levels also excluded
Interventions	Intervention characteristics 1000 IU Vitamin D content and type: 1000 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months N per group (in preliminary analysis): not clear* Brand/company: not reported 400 IU Vitamin D content and type: 400 IU vitamin D Formulation: not reported Frequency of dosage: daily Duration of administration (study time): 6 months N per group (in preliminary analysis): not clear* Brand/company: not reported Trial registration indicated total enrolment of 193 participants Intervention characteristics (preliminary data from meeting abstract)* 7000 IU D₃ Vitamin D content and type: 7000 IU D₃ Formulation: not reported Frequency of dosage: weekly Duration of administration (study time): 6 months N per group (in preliminary analysis): not reported Brand/company: not reported 2800 IU D₃ Vitamin D content and type: 2800 IU D₃ Formulation: not reported Frequency of dosage: weekly Duration of administration (study time): 6 months N per group (in preliminary analysis): not reported Brand/company: not reported
Outcomes	Secondary Change in serum 25‐hydroxyvitamin D (25(OH)D, nmol/L) Measurement Serum 25(OH)D (nmol/L): assay not reported Time point: 6 months
Starting date	January 2010
Contact information	Thomas Carpenter, Yale University, Principal Investigator; email: thomas.carpenter@yale.edu
Notes	Notes: recruitment completed (ended February 2013); study authors contacted, who indicated that data are currently being analysed (meeting abstract is available) and reflect trial registration NCT01050387; publication is forthcoming