Research

JAMA Pediatrics | Original Investigation

Influence of Vitamin D Supplementation on Growth, Body Composition,

and Pubertal Development Among School-aged Children
in an Area With a High Prevalence of Vitamin D Deficiency
A Randomized Clinical Trial
Davaasambuu Ganmaa, PhD; Sabri Bromage, ScD; Polyna Khudyakov, PhD; Sumiya Erdenenbaatar, BSc;
Baigal Delgererekh, MD; Adrian R. Martineau, PhD

Supplemental content
IMPORTANCE Vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] <20 ng/mL)
is prevalent among children living in temperate climates and has been reported to associate
independently with stunting, obesity, and early activation of the hypothalamic-pituitary-
gonadal axis. Phase 3 randomized clinical trials to investigate the influence of long-term
vitamin D replacement on growth, body composition, and pubertal development of
school-aged children with vitamin D deficiency are lacking.

OBJECTIVE To determine whether weekly oral vitamin D supplementation influences linear

growth, body composition, or pubertal development in school-aged children living in a
setting where vitamin D deficiency is highly prevalent.

DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of a double-blind,

placebo-controlled randomized clinical trial was conducted from June 2016 to June 2019 at
18 grade schools in Ulaanbaatar, Mongolia. School-aged children (6 to 13 years at baseline)
attending participating schools were included. Exclusion criteria included a positive
QuantiFERON-TB Gold in-tube assay result, conditions or medications associated with altered
vitamin D metabolism, use of vitamin D supplements, signs of rickets, or intention to move
from Ulaanbaatar within 4 years. Of 11 475 children invited to participate in the study, 9814
underwent QFT testing, and 8851 with negative results were included in the study. All but 1
participant in the placebo group completed follow-up and were included in the present
analysis. Data were analyzed from November 2021 to February 2022.

INTERVENTIONS Weekly oral doses of vitamin D3, 14 000 IU, (n = 4418), or placebo
(n = 4433) for 3 years.

MAIN OUTCOMES AND MEASURES Mean z scores for height for age, body mass index for age,
and waist-to-height ratio; mean percentage body fat, fat mass, and fat-free mass; and mean
Tanner scores for pubertal development.

RESULTS Of 8851 participants, 4366 (49.3%) were female, and 8165 (92.2%) were of Khalkh
ethnicity; the mean (SD) age was 9.4 (1.6) years. A total of 8453 participants (95.5%) were
vitamin D deficient at baseline, and mean end-of-study 25(OH)D concentrations among
participants randomized to vitamin D vs placebo were 31.0 vs 10.7 ng/mL (mean difference,
20.3; 95% CI; 19.9-20.6). However, vitamin D supplementation did not influence mean height
for age, body mass index for age, waist-to-height ratio, percentage body fat, fat mass, fat-free
Author Affiliations: Author
mass, or Tanner scores, either overall or within subgroups defined by baseline 25(OH)D
affiliations are listed at the end of this
concentration less than 10 ng/mL vs 10 ng/mL or greater, estimated calcium intake less than article.
500 mg/d vs 500 mg/d or greater, or male vs female sex. Corresponding Author:
Davaasambuu Ganmaa, PhD,
CONCLUSIONS AND RELEVANCE In school-aged children in this study with low baseline vitamin Department of Nutrition, Harvard
D status, oral vitamin D3 supplementation at a dose of 14 000 IU per week for 3 years was T.H. Chan School of Public Health,
effective in elevating 25(OH)D concentrations but did not influence growth, body Bldg 2, Room 211, 655 Huntington
Ave, Boston, Massachusetts 02115
composition, or pubertal development.
([email protected]);
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02276755 Adrian R. Martineau, PhD, Blizard
Institute, Barts and the London
School of Medicine and Dentistry,
Queen Mary University of London,
4 Newark St, London E1 2AT,
JAMA Pediatr. 2023;177(1):32-41. doi:10.1001/jamapediatrics.2022.4581 United Kingdom
Published online November 28, 2022. ([email protected]).

32 (Reprinted) jamapediatrics.com

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency Original Investigation Research

T
he US Institute of Medicine recommends maintenance
of 25(OH)D concentrations of 20 ng/mL or higher (to Key Points
convert to nanomoles per liter, multiply by 2.496) to
Question Does oral vitamin D replacement influence linear
support optimal skeletal health in children.1 Vitamin D af- growth, body composition, or pubertal development in
fects growth by promoting adequate bone mineralization and school-aged children living in areas with a high prevalence of
mass and influences somatic growth and macronutrient me- vitamin D deficiency?
tabolism through regulation of the cell cycle and cell
Findings This secondary analysis of a randomized clinical trial
proliferation.2 It may also exert effects on body composition including 8851 children with a high prevalence of vitamin D
via effects on myocyte function and development3 and by regu- deficiency at baseline found that oral vitamin D supplementation
lating insulin signaling, adipogenesis, and adipocyte was effective in elevating 25(OH)D levels into the physiological
apoptosis.4 Through its actions on macrophage, dendritic, and range. However, this intervention had no impact on height for age,
T cell function, vitamin D is a potent mediator of innate and body mass index, body composition, or pubertal development,
either in the study population as a whole or within subgroups
adaptive immunity,5 and vitamin D deficiency may contrib-
defined by baseline 25(OH)D concentration, estimated calcium
ute to systemic inflammation.6 Thus, by modulating diverse intake, and sex.
physiological pathways, vitamin D status is a potentially im-
portant determinant of growth, body composition, and meta- Meaning In this study, weekly oral administration of vitamin D for
3 years did not influence linear growth, body composition, or
bolic health—a concept supported by the observation that these
pubertal development among school-aged children with a high
diverse axes are simultaneously perturbed in animal models prevalence of vitamin D deficiency at baseline.
of vitamin D deficiency.7 Given the high global prevalence of
vitamin D deficiency8 and the rising prevalence of cardiometa-
bolic disease,9 there is interest in evaluating the potential re- velopment. Principal inclusion criteria were ages 6 to 13 years
lationship between vitamin D status—an actionable target for at screening and attendance at a participating school; princi-
supplementation and fortification—and measures of meta- pal exclusion criteria were a positive QuantiFERON-TB Gold
bolic health and fitness. in-tube assay (QFT) result, presence of conditions associated
A potential role for vitamin D supplementation in with vitamin D hypersensitivity (primary hyperparathyroid-
improving anthropometric and metabolic outcomes is ism or sarcoidosis) or immunocompromise (taking immuno-
supported by findings of increased lean mass, decreased fat suppressant medication or cytotoxic therapy), use of vitamin
mass, and decreased body mass index (BMI; calculated as D supplements, signs of rickets (all participants were screened
weight in kilograms divided by height in meters squared) in for rickets via physical examination by a pediatrician), or in-
long-term follow-up with infants who received vitamin D tention to move from Ulaanbaatar within 4 years of enroll-
supplementation10,11 and observational studies reporting in- ment. Of 11 475 children invited to participate in the study, 9814
dependent associations between vitamin D deficiency and un- underwent QFT testing, and 8851 with negative results were
derweight and stunting in infants and toddlers12; lower lean included in the study. All but 1 participant in the placebo group
mass,13 slowed growth,14 childhood obesity15-17; and preco- completed follow-up and were included in the present analy-
cious puberty.18 Findings of observational studies may be ex- sis. Eligible participants were individually randomized to re-
plained by confounding or reverse causation, and random- ceive a weekly capsule containing 14 000 IU vitamin D3 or pla-
ized clinical trials of vitamin D supplementation are required cebo for 3 years with a 1-to-1 allocation ratio and stratification
to evaluate causality. We have previously reported results of by school of attendance. Treatment allocation was concealed
a phase 2 randomized clinical trial showing that a 6-month from participants, clinicians, and all trial staff (including se-
course of vitamin D supplementation increased height gain in nior investigators and those assessing outcomes) so that the
113 Mongolian children aged 12 to 15 years with vitamin D double-blinding was maintained. Each child and their parent
deficiency.19 We therefore wished to verify this finding by con- or guardian provided written informed assent and consent, re-
ducting a definitive phase 3 randomized clinical trial of sus- spectively, prior to participation. Because Khalkha is the larg-
tained vitamin D replacement in a similar population and ex- est ethnic group in Mongolia (constituting more than 80% of
tend the investigation to test for potential effects of vitamin the population), Khalkh vs non-Khalkh ethnicity was gath-
D on BMI, body composition, and pubertal development. ered by interview. The study was approved by institutional re-
view boards of the Mongolian Ministry of Health, Mongolian
National University, and Harvard T. H. Chan School of Public
Health. The study report followed the Consolidated Standards
Methods of Reporting Trials (CONSORT) reporting guideline. Data were
Study Design, Setting, Participants, and Randomization analyzed from November 2021 to February 2022. The trial
We conducted a parallel 2-arm double-blind individually ran- protocol can be found in Supplement 1.
domized placebo-controlled trial from June 2016 to June 2019
in 18 public schools in Ulaanbaatar, Mongolia, as previously Baseline Procedures
described.20 The primary outcome of the trial was acquisi- At baseline, participants’ parents were asked to complete ques-
tion of latent tuberculosis infection. This study assessed the tionnaires detailing their socioeconomic circumstances, life-
effects of the intervention on prespecified secondary out- style, and dietary factors influencing vitamin D status, includ-
comes relating to growth, body composition, and pubertal de- ing intake of foods previously shown to be major contributors

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2023 Volume 177, Number 1 33

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Research Original Investigation Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency

to dietary calcium intake in urban Mongolia.21 Participating the primary end point (incident latent tuberculosis infection)
children’s height was then measured using a portable stadi- as described previously.20 Estimated calcium intake values
ometer (seca GmbH & Co), weight was measured using a digi- were calculated on the basis of parental responses to a 1-time
tal floor scale (seca GmbH & Co), waist circumference was mea- food frequency questionnaire administered in March 2018
sured using a tape measure, and percentage body fat, fat mass, (eTable 1 in Supplement 2), which captured participants’ fre-
and fat-free mass were determined using the SC-331S body quency of intake of certain calcium-containing foods and the
composition analyzer (Tanita). Finally, a blood sample was calcium content of those foods based on food composition data
drawn for separation and storage of serum for determination compiled from analysis of their calcium content.21 Anthropo-
of baseline 25(OH)D concentrations. metric measurements and data on participants’ age and sex
were then used to compute z scores for height for age, BMI for
Follow-up Procedures age, and waist-to-height ratio for age using the who2007 Shiny
During school terms, study participants had weekly in- App (Canadian Pediatric Endocrine Group) based on 2007
person visits at which time study medication was adminis- World Health Organization growth reference data for chil-
tered and adverse events were recorded. During school holi- dren aged 5 to 19 years.25
days, either children were given a single bolus dose of up to Serum 25(OH)D values were adjusted for seasonal varia-
36 000 IU (shorter holidays), study staff traveled to partici- tion prior to analysis using a sinusoidal model.26 Anthropo-
pants’ homes to administer medication, or parents were sup- metric and body composition outcomes were analyzed over-
plied with sufficient trial medication to cover the holiday pe- all and in each subgroup using mixed models for repeated
riod, along with instructions on its storage and administration. measures with fixed effects for treatment and time and treat-
Weight, height, waist circumference, and body composition ment-by-time interaction adjusted for school of attendance and
were reassessed at 12, 24, and 36 (end of study) months’ fol- random effects for individuals. Adjusted treatment mean dif-
low-up using the same methods as at baseline. Pubertal sta- ferences at different time points were presented with 95% CIs,
tus was evaluated at 3-year follow-up in a randomly selected and significance tests were conducted for the treatment ef-
subset of 1356 participants who completed Tanner self- fect at each time point and the overall treatment-by-time in-
assessment questionnaires.22 A second blood sample was teraction. Where overall P values were less than the signifi-
drawn from all participants at 3-year follow-up for separation cance threshold of .05, we applied a Benjamini Hochberg
and storage of serum for determination of end-of-study 25 procedure with a 5% false discovery rate27 to the relevant fam-
(OH)D concentrations. ily of P values to adjust for multiple comparisons. End-of-
study pubertal development analyses were done using gen-
Measurement of Vitamin D Status eral linear models with gaussian distribution and identity link
Concentrations of 25(OH)D were determined in serum samples function for all outcomes except for the proportion of female
from baseline and 3-year follow-up using the VIDAS 25OH participants menstruating at the end of the trial, which was ana-
Vitamin D total enzyme-linked fluorescent assay (bio- lyzed using binomial distribution and log link function. Pre-
Mérieux). These measurements were validated and standard- specified subgroup analyses were conducted according to par-
ized using standards provided by the Vitamin D External Qual- ticipants’ sex (male vs female), estimated calcium intake
ity Assessment Scheme.23 Total coefficient of variation was (<500 mg/d vs ≥500 mg/d), baseline deseasonalized 25(OH)D
7.9%, mean bias was 7.7%, and the limit of quantitation was concentration (<10 ng/mL vs ≥10 ng/mL), and baseline z scores
8.1 ng/mL. Nonzero 25(OH)D values were standardized using (−2.00 vs ≥−2.00 for height for age and <−2.00 vs −2.00 to 1.00
a published method,24 using a set of 40 serum samples pro- vs 1.01 to 2.00 vs >2.00 for BMI for age and waist-to-height ra-
vided by the Vitamin D External Quality Assessment Scheme tio, percentage body fat, fat mass, and fat-free mass). An ex-
(DEQAS). Values below the limit of quantitation were classi- ploratory subgroup analysis was conducted according to par-
fied as less than 8.1 ng/mL. ticipants’ age at baseline (≤8 vs >8 years) in response to a
reviewer request. The primary P values for outcome model-
Outcomes ing were the overall P values, that is, those associated with the
The primary anthropometric outcome of interest was mean interaction between follow-up time point and treatment
height-for-age z score at 1, 2, and 3 years’ follow-up. Second- allocation.
ary outcomes were mean BMI-for-age z score; mean waist-to-
height ratio z score; mean percentage body fat; mean fat mass;
mean fat-free mass; mean Tanner scores for pubic hair (male
and female), external genitalia (male only), and breast devel-
Results
opment (female only); the proportion of participants reach- Participants
ing menarche by the end of the trial (female only); and mean Of 8851 children with negative QFT results who were in-
age at onset of menarche (female individuals who had reached cluded in the trial (mean [SD] age, 9.4 [1.6] years; 4366 [49.3%]
menarche by the end of the trial only). female; 8165 [92.2%] of Khalkh ethnicity), 4418 were ran-
domly assigned to receive vitamin D3 and 4433 to receive pla-
Sample Size and Statistical Methods cebo, all but 1 of whom (allocated to placebo) had anthropom-
The sample size calculation was based on the power needed etry data available at baseline and contributed to the current
to detect a clinically significant effect of the intervention on analysis (Figure). Table 1 shows baseline characteristics of par-

34 JAMA Pediatrics January 2023 Volume 177, Number 1 (Reprinted) jamapediatrics.com

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency Original Investigation Research

ticipants contributing data to analyses of anthropometric out-

Figure. Participant Flow Diagram
comes. Mean (SD) baseline serum 25(OH)D concentration was
11.9 (4.2) ng/mL; 8453 participants (95.5%) had 25(OH)D lev- 11 475 Children were invited to participate
els less than 20 ng/mL and 2813 (31.8%) less than 10 ng/mL.
Baseline prevalence of stunting was 3.7%; underweight, 1.2%; 1661 Not randomized
overweight, 4.5%; and obesity, 1.1%. Baseline characteristics 1065 Declined
596 Were ineligible
were balanced between participants randomized to vitamin D
vs placebo, both for those contributing data to anthropomet-
9814 Participants had baseline QuantiFERON-TB
ric analyses and for the subset of 1356 participants whose pu- Gold in-tube assay (QFT)
bertal status was assessed at the end of the trial (eTable 2 in
Supplement 2). End-of-trial anthropometric outcomes were 963 Not randomized
946 QFT positive
available for 8128 participants (91.8% of those randomized).
13 QFT-negative but
Mean (SD) end-of-trial serum 25(OH)D was 31.0 (9.1) ng/mL in declined randomization
4 QFT indeterminate
the treatment group and 10.7 (5.3) in the placebo group (mean
difference, 20.3; 95% CI, 19.9-20.6). End-of-study 25(OH)D lev-
els were 20 ng/mL or higher in 3528 participants randomized 8851 QFT-negative participants randomized
to vitamin D (89.8%) vs 187 randomized to placebo (5.6%).
4418 Allocated to intervention arm, 4433 Allocated to control arm,
Outcomes of whom all had baseline of whom 4432 had baseline
anthropometry anthropometry
Allocation to vitamin D vs placebo did not influence mean
height-for-age z score, either overall or within subgroups de-
1-y Follow-up 1-y Follow-up
fined by male vs female sex, age at baseline 8 years or younger 4219 Had anthropometry 4230 Had anthropometry
vs older than 8 years, estimated calcium intake less than 500
vs 500 or more mg/d, baseline 25(OH)D concentration less than 2-y Follow-up 2-y Follow-up
3803 Had anthropometry 3830 Had anthropometry
10 vs 10 or more ng/mL, or presence vs absence of stunting at
baseline (Table 2). Similarly, no effect of the intervention was
3-y Follow-up 3-y Follow-up
seen on mean BMI-for-age z score (Table 3), mean waist-to- 4076 Had anthropometry 4052 Had anthropometry
height ratio z score (eTable 3 in Supplement 2), mean percent-
age body fat (eTable 4 in Supplement 2), mean fat mass
(eTable 5 in Supplement 2), or mean fat-free mass (eTable 6 in
Supplement 2), either overall or by subgroups defined by sex,
age, estimated calcium intake, baseline 25(OH)D concentra- tial and sustained increased in 25(OH)D levels was achieved
tion, or baseline anthropometry. Among the subset of 1356 par- among participants randomized to the intervention arm of the
ticipants in whom end-of-trial pubertal development was as- study. However, vitamin D supplementation did not influ-
sessed, no interarm differences were seen in mean Tanner ence any anthropometric or developmental outcome stud-
scores for pubic hair (male and female), external genitalia (male ied, either in the trial population as a whole or in subgroups
only), or breast development (female only), either overall or defined by baseline vitamin D status, sex, calcium intake, or
within subgroups defined by calcium intake and baseline 25 baseline anthropometric status.
(OH)D concentration (Table 4). When Tanner scores were di- To our knowledge, there have been only 2 other random-
chotomized to distinguish prepubertal vs pubertal status ized clinical trials conducted to evaluate effects of vitamin D
(Tanner score 1 vs 2-5, respectively), the proportions of par- on growth and development in school-aged children, both of
ticipants reporting Tanner score 2 to 5 did not differ between which we conducted, also in Mongolia. In those studies, where
study arms, either overall or by subgroup (eTable 7 in Supple- the baseline prevalence of vitamin D deficiency was also very
ment 2). The proportion of female participants reaching men- high, we observed a greater increase in stature among chil-
arche by the end of the trial did not differ between arms, either dren randomized to vitamin D vs placebo.19 This contrasts with
overall or by subgroup. Among female participants who the null findings from the current trial. Differing results from
reached menarche by the end of the trial, no difference in mean the 2 trials may relate to differences in participant age (chil-
age at onset of menarche was seen between arms, either over- dren aged 6 to 13 years at enrollment in the current trial vs 12
all or by subgroup (Table 4). to 15 years in our previous studies) or outcome (height-for-
age z scores in the current trial vs change in absolute height
previously). Additionally, the duration of vitamin D supple-
mentation and follow-up in our previous trials was only 2 to 6
Discussion months, and doses of vitamin D administered were lower at
We present results of what is to our knowledge the first phase 300 to 800 IU per day; it is therefore possible that the longer
3 randomized clinical trial to investigate whether vitamin D period of vitamin D supplementation (3 years), the weekly dos-
supplementation influences child growth, body composi- ing regimen, or the higher dose of vitamin D administered
tion, or pubertal development. Vitamin D deficiency was highly (14 000 IU per week) in the current trial may have been less
prevalent in the study population at baseline, and a substan- effective in boosting growth than the shorter, lower-dose daily

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2023 Volume 177, Number 1 35

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Research Original Investigation Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency

Table 1. Baseline Characteristics of Participants by Allocation

No. (%)
Characteristic Overall (n = 8851) Placebo (n = 4432) Vitamin D (n = 4418)
Age, mean (SD), y 9.4 (1.6) 9.4 (1.6) 9.4 (1.6)
Female 4366 (49.3) 2224 (50.2) 2142 (48.5)
Male 4485 (50.7) 2209 (49.8) 2276 (51.5)
Ethnic origina
Khalkh 8165 (92.2) 4103 (92.6) 4062 (91.9)
Abbreviations: 25(OH)D,
Non-Khalkh 686 (7.8) 330 (7.4) 356 (8.1) 25-hydroxyvitamin D; BMI, body
Parental educationb mass index.
≤Secondary school 4858 (54.9) 2457 (55.4) 2401 (54.3) SI conversion factor: To convert
25(OH)D to nmol/L, multiply by
≥University/polytechnic school 3993 (45.1) 1976 (44.6) 2017 (45.7)
2.496.
Type of residence a
Because Khalkha is the largest
Ger (yurt) 3271 (37.0) 1628 (36.7) 1643 (37.2) ethnic group in Mongolia
House without central heating 3387 (38.3) 1722 (38.9) 1665 (37.7) (constituting more than 80% of the
population), Khalkh vs non-Khalkh
House with central heating 2193 (24.8) 1083 (24.4) 1110 (25.1)
ethnicity was gathered by interview.
Home ownership, yes 6963 (78.7) 3470 (78.3) 3493 (79.1) b
Highest educational level attained
Monthly household income, mean (SD), $c 848 (579) 846 (604) 851 (554) by either parent.
c
Household environmental tobacco smoked 3143 (35.5) 1573 (35.5) 1570 (35.5) Household income missing for 1
Child actively smoking 47 (0.5) 21 (0.5) 26 (0.6) participant in each arm; baseline
BMI-for-age z score missing for 1
BMI-for-age z score, mean (SD)c 0.2 (1.1) 0.2 (1.1) 0.2 (1.0) participant in placebo arm; baseline
Height-for-age z score, mean (SD)c −0.3 (1.0) −0.3 (1.0) −0.3 (1.0) height-for-age z score missing for 1
Serum 25(OH)D, mean (SD), ng/mLc,e 11.9 (4.2) 11.9 (4.2) 11.9 (4.2) participant in placebo arm; baseline
serum 25(OH)D missing for 4
Serum 25(OH)D, ng/mLc,e participants in placebo arm and 1
<10 2813 (31.8) 1420 (32.1) 1393 (31.5) participant in vitamin D arm.
d
10-19.9 5640 (63.7) 2812 (63.5) 2828 (64.0) Defined as 1 or more people in the
household smoking indoors.
20-29.9 381 (4.3) 193 (4.4) 188 (4.3)
e
Baseline 25(OH)D values
≥30 12 (0.1) 4 (0.1) 8 (0.2)
deseasonalized.

intervention previously investigated. Head-to-head studies di- equate power for studying the primary end point (latent tu-
rectly comparing the effects of different vitamin D supple- berculosis infection). This is relevant because child growth and
mentation regimens on anthropometric outcomes are needed development trajectories differ by age: increases in height,
to resolve this discrepancy. weight, and accretion of lean mass accelerate considerably dur-
Our trial has several strengths. Its large size afforded ample ing early adolescence,33 as do levels of growth hormone and
power to detect small differences in anthropometric out- insulin-like growth factor 1, which have been postulated to in-
comes. In contrast with several recent phase 3 trials of vita- teract with vitamin D to stimulate growth.34 A second limita-
min D supplementation,28-30 our study population had a high tion relates to our use of self-assessed pubertal status as
baseline prevalence of vitamin D deficiency; null effects of the opposed to Tanner staging performed by a health care profes-
intervention cannot therefore be attributed to a paucity of par- sional, which involves examination of pubic hair (male and fe-
ticipants with low vitamin D status at baseline. The supple- male), genitalia (male), and breasts (female). Major issues with
mentation regimen we used was highly effective in correct- acceptability of such examinations would have seriously com-
ing this among participants randomized to the intervention arm promised recruitment to the study since many children and
of the trial. Weekly administration of vitamin D3 allowed us their parents would likely have concerns about such assess-
to directly observe and optimize adherence during term-time ments. Thus, use of self-assessment questionnaires maxi-
while avoiding large fluctuations in 25(OH)D that may result mized participation and generalizability of our findings. Due
from larger and more widely spaced bolus doses used in some to the double-blind design of our study, any imprecision in-
other studies and potential enzymatic dysregulation that could troduced by use of self-assessment is likely to be equally dis-
attenuate vitamin D’s pharmacological activity.31,32 Other im- tributed between trial arms and should not therefore have in-
portant strengths of our study were the high retention rate troduced bias. A third limitation relates to the fact that 25
(91.7% over 3 years) and standardization of serum 25(OH)D (OH)D concentrations were only established at baseline and
measurements. at 3 years; as a result, seasonal fluctuations in 25(OH)D con-
centrations during follow-up would not have been captured.
Limitations However, we highlight that steady state 25(OH)D concentra-
Our trial also has limitations. One such relates to our need to tions among participants randomized to the intervention arm
recruit children across different age groups—spanning 6 to 13 of the trial are likely to have been attained within 2 to 3 months
years at baseline and 9 to 15 at end-of-trial—to ensure ad- of initiating supplementation. Given the high degree of ad-

36 JAMA Pediatrics January 2023 Volume 177, Number 1 (Reprinted) jamapediatrics.com

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency Original Investigation Research

Table 2. Mean Height-for-Age z Scores by Allocation, Overall and by Subgroup

Mean (SD); No.

Follow-up time Adjusted mean difference P value for
Group point, y Placebo Vitamin D (95% CI)a time point Overall P valueb
Overall 1 −.0.29 (1.00); 4230 −0.30 (1.00); 4219 −0.01 (−0.02 to 0.01) .24
2 −0.27 (1.00); 3830 −0.30 (1.00); 3803 −0.01 (−0.03 to 0.00) .17 .45
3 −0.17 (1.00); 4052 −0.17 (1.02); 4076 0.00 (−0.02 to 0.01) .80
By sex
Female 1 −0.35 (1.02); 2126 −0.34 (0.99); 2036 −0.01 (−0.04 to 0.01) .20
2 −0.34 (1.00); 1927 −0.32 (0.99); 1851 −0.01 (−0.03 to 0.02) .66 .48
3 −0.22 (0.99); 2043 −0.19 (0.98); 1975 0.00 (−0.02 to 0.02) .84
Male 1 −0.23 (0.98); 2104 −0.26 (1.00); 2183 0.00 (−0.02 to 0.02) .77
2 −0.21 (1.01); 1903 –0.29 (1); 1952 −0.01 (−0.03 to 0.00) .14 .49
3 −0.12 (1.03); 2009 −0.16 (1.05); 2101 0.00 (−0.02 to 0.01) .64
By age at baseline, y
≤8 1 −0.24 (1.00); 1076 −0.24 (0.92); 1079 −0.02 (−0.05 to 0.01) .12
2 −0.21 (0.99); 1040 −0.21 (0.94); 1049 −0.01 (−0.04 to 0.01) .37 .42
3 −0.13 (1.03); 1027 −0.11 (0.98); 1056 −0.02 (−0.04 to 0.01) .21
>8 1 −0.31 (1.00); 3239 −0.32 (1.02); 3216 −0.01 (−0.02 to 0.01) .52
2 −0.30 (1.01); 2868 −0.34 (1.01); 2822 −0.01 (−0.03 to 0.01) .22 .52
3 −0.19 (1.00); 3106 −0.20 (1.03); 3094 0.00 (−0.02, 0.02) .90
By calcium intake
<500 mg/d 1 −0.30 (1.00); 2171 −0.30 (1.02); 2161 −0.01 (−0.03 to 0.01) .50
2 −0.29 (1.01); 1973 −0.33 (1.01); 1927 −0.01 (−0.03 to 0.01) .23 .42
3 −0.19 (1.02); 2141 −0.18 (1.02); 2143 0.00 (−0.02 to 0.02) .71
≥500 mg/d 1 −0.25 (0.99); 1210 −0.27 (0.98); 1261 −0.01 (−0.03 to 0.01) .50
2 −0.24 (1.01); 1095 −0.27 (0.98); 1151 −0.01 (−0.03 to 0.01) .23 .42
3 −0.10 (1.01); 1194 −0.14 (1.01); 1241 0.00 (−0.02 to 0.02) .71
By baseline 25(OH)D
concentration, ng/mLc
<10 1 −0.33 (1.02); 1348 −0.31 (0.98); 1340 0.01 (−0.02 to 0.03) .56
2 −0.33 (1.02); 1223 −0.32 (0.98); 1212 0.00 (−0.02 to 0.03) .75 .90
3 −0.24 (1.00); 1305 −0.21 (1.00); 1290 0.01 (−0.02 to 0.04) .46
≥10 1 −0.28 (0.99); 2878 −0.29 (1.00); 2878 −0.02 (−0.03 to 0.00 .08
2 −0.25 (1.00); 2604 −0.29 (1.01); 2590 −0.02 (−0.03 to 0.00) .07 .20
3 −0.14 (1.01); 2744 −0.16 (1.02); 2785 −0.01 (−0.02 to 0.01) .43
By presence/absence of
stuntingd at baseline
Present 1 −2.37 (0.60); 164 −2.38 (0.41); 149 −0.04 (−0.13 to 0.05) .43
2 −2.30 (0.62); 155 −2.28 (0.51); 144 −0.01 (−0.10 to 0.08) .78 .78
3 −2.10 (0.72); 153 −2.13 (0.62); 140 −0.04 (−0.13 to 0.05) .37
Absent 1 −0.21 (0.92); 4065 −0.22 (0.93); 4070 −0.02 (−0.06 to 0.02) .38
2 −0.19 (0.93); 3674 −0.23 (0.93); 3659 −0.02 (−0.06 to 0.02) .31 .56
3 −0.10 (0.94); 3898 −0.10 (0.96); 3936 −0.01 (−0.05 to 0.03) .62
b
Abbreviation: 25(OH)D, 25-hydroxyvitamin D. P value for treatment-by-time interaction.
c
SI conversion factor: To convert 25(OH)D to nmol/L, multiply by 2.496. 25(OH)D values deseasonalized.
a d
Adjusted for random effects of school and individual. Stunting was defined as weight-for-height z score <−2.00.

herence achieved by directly observing administration of study teristics were similar for children with QFT positive vs nega-
supplements, we anticipate that the large interarm differ- tive results at screening.
ence in end-of-study 25(OH)D levels noted at 3-year fol-
low-up is likely to have been sustained throughout follow-
up. A fourth limitation relates to exclusion of children who were
found to have QFT-positive results at baseline: this design fea-
Conclusions
ture potentially reduces the generalizability of our findings, In conclusion, this prespecified secondary analysis of a ran-
although baseline demographic and anthropometric charac- domized clinical trial found that oral vitamin D3 supplemen-

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2023 Volume 177, Number 1 37

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Research Original Investigation Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency

Table 3. Mean BMIa-for-Age z Scores by Allocation, Overall and by Subgroup

Mean (SD), No. P value

Follow-up time Adjusted mean difference for time Overall
Group point, y Placebo Vitamin D (95% CI)b point P valuec
Overall 1 0.17 (1.08); 4229 0.16 (1.08); 4219 0.00 (−0.01 to 0.02) .70
2 0.19 (1.08); 3829 0.16 (1.09); 3803 0.00 (–0.02 to 0.02) .90 .95
3 0.15 (1.11); 4051 0.14 (1.12); 4076 0.00 (–0.02 to 0.02) .76
By sex
Male 1 0.31 (1.11); 2104 0.26 (1.11); 2183 0.01 (–0.02 to 0.04) .47
2 0.31 (1.13); 1903 0.23 (1.12); 1952 0.01 (–0.02 to 0.03) .66 .91
3 0.22 (1.17); 2009 0.16 (1.17); 2101 0.00 (–0.02 to 0.03) .72
Female 1 0.03 (1.03); 2125 0.06 (1.03); 2036 0.00 (–0.03 to 0.02) .96
2 0.07 (1.02); 1926 0.10 (1.05); 1851 –0.01 (–0.03 to 0.02) .71 .78
3 0.08 (1.04); 2042 0.13 (1.07); 1975 0.01 (–0.02 to 0.03) .50
By age at baseline, y
≤8 1 0.35 (1.09); 1076 0.33 (1.02); 1079 0.03 (–0.01 to 0.06) .17
2 0.38 (1.11); 1040 0.37 (1.08); 1049 0.04 (0.00 to 0.07) .05 .17
3 0.35 (1.16); 1027 0.36 (1.13); 1056 0.04 (0.00 to 0.07) .06
>8 1 0.11 (1.07); 3239 0.11 (1.09); 3216 0.00 (–0.02 to 0.02) .76
2 0.12 (1.07); 2868 0.09 (1.08); 2822 –0.02 (–0.04 to 0.01) .15 .50
3 0.08 (1.08); 3106 0.07 (1.11); 3094 –0.01 (–0.03 to 0.01) .42
By calcium intake
<500 mg/d 1 0.16 (1.08); 2171 0.16 (1.07); 2161 0.01 (–0.02 to 0.03) .54
2 0.18 (1.08); 1973 0.17 (1.06); 1927 0.00 (–0.02 to 0.03) .76 .94
3 0.14 (1.11); 2141 0.15 (1.10); 2143 0.01 (–0.02 to 0.03) .69
≥500 mg/d 1 0.18 (1.06); 1210 0.20 (1.10); 1261 0.00 (–0.03 to 0.04) .77
2 0.19 (1.07); 1095 0.22 (1.12); 1151 0.01 (–0.02 to 0.04) .61 .96
3 0.16 (1.09); 1194 0.21 (1.16); 1241 0.00 (–0.03 to 0.03) .94
By baseline 25(OH)D
concentration, mg/ML
<10 1 0.08 (1.08); 1347 0.14 (1.05); 1340 0.00 (–0.02 to 0.02) .83
2 0.07 (1.08); 1222 0.15 (1.06); 1212 –0.01 (–0.03 to 0.02) .61 .86
3 0.04 (1.10); 1304 0.10 (1.11); 1290 0.00 (–0.02 to 0.03) .76
≥10 1 0.22 (1.08); 2878 0.17 (1.09); 2878 –0.26 (–0.47 to –0.05) .01
2 0.24 (1.08); 2604 0.17 (1.10); 2590 –0.26 (–0.49 to –0.04) .02 .01d
3 0.20 (1.10); 2744 0.16 (1.13); 2785 –0.25 (–0.46 to –0.05) .02
By baseline BMIa
category
Underweighte 1 −2.05 (0.61); 48 −2.27 (0.53); 54 0.00 (–0.04 to 0.04) .98
2 −1.95 (0.72); 39 −2.20 (0.59); 47 0.00 (–0.04 to 0.03) .86 1.00
3 −1.97 (0.84); 49 −2.18 (0.76); 55 0.00 (–0.04 to 0.03) .88
Normal rangef 1 −0.16 (0.76); 3381 −0.16 (0.74); 3386 0.05 (–0.01 to 0.11) .12
2 −0.14 (0.79); 3072 −0.14 (0.79); 3085 0.04 (–0.02 to 0.10) .22 .29
3 −0.17 (0.83); 3240 −0.16 (0.85); 3270 0.06 (0.00 to 0.12) .05
Overweightg 1 1.35 (0.50); 562 1.40 (0.48); 542 0.02 (–0.05 to 0.09) .55
2 1.37 (0.56); 508 1.41 (0.57); 471 0.02 (–0.06 to 0.09) .67 .92
3 1.30 (0.63); 536 1.36 (0.63); 525 0.02 (–0.05 to 0.09) .58
Obeseh 1 2.55 (0.65); 238 2.51 (0.59); 237 0.04 (–0.13 to 0.20) .68
2 2.50 (0.61); 210 2.48 (0.60); 200 0.04 (–0.14 to 0.22) .65 .93
3 2.37 (0.65); 226 2.34 (0.61); 226 –0.01 (–0.18 to 0.16) .92
Abbreviations: BMI, body mass index; 25(OH)D, 25-hydroxyvitamin D. procedure, this P value was .14.
e
SI conversion factor: To convert 25(OH)D to nmol/L, multiply by 2.496. Defined as BMI-for-age z score <–2.00.
a f
Calculated as weight in kilograms divided by height in meters squared. Defined as BMI-for-age z score −2.00 to 1.00.
b g
Adjusted for random effects of school and individual. Defined as BMI-for-age z score 1.01 to 2.00.
c h
P value for treatment-by-time interaction. Defined as BMI-for-age z score >2.00.
d
After adjustment for multiple comparisons using the Benjamini-Hochberg

38 JAMA Pediatrics January 2023 Volume 177, Number 1 (Reprinted) jamapediatrics.com

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency Original Investigation Research

Table 4. End-of-Study Stage of Pubertal Development by Allocation and Sex, Overall and by Subgroup

Mean (SD); No.

Adjusted mean Adjusted risk ratio
Outcome measure Subgroup Placebo Vitamin D difference (95% CI)a P value (95% CI)a P value
Male
Pubic hair, Tanner score
Overall NA 2.02 (1.06); 358 2.06 (1.04); 337 0.06 (−0.10 to 0.22) .48 NA NA
Calcium intake <500 mg/d 1.96 (1.05); 192 2.09 (1.05); 184 0.15 (−0.06 to 0.36) .17 NA NA
≥500 mg/d 2.04 (1.09); 97 2.01 (1.01); 104 0.04 (−0.26 to 0.34) .79 NA NA
Baseline 25(OH)D <10 ng/mL 2.31 (1.15); 129 2.21 (1.13); 98 0.09 (−0.21 to 0.39) .56 NA NA
concentration, ng/mL
≥10 ng/mL 1.86 (0.98); 229 2.00 (0.99); 239 0.14 (−0.04 to 0.32) .13 NA NA
External genitalia, Tanner
score
Overall NA 2.18 (1.02); 358 2.14 (0.98); 337 −0.04 (−0.19 to 0.11) .59 NA NA
Calcium intake <500 mg/d 2.11 (1.01); 192 2.14 (0.97); 184 0.04 (−0.16 to 0.24) .70 NA NA
≥500 mg/d 2.26 (1.01); 97 2.15 (1.02); 104 −0.05 (−0.34 to 0.24) .74 NA NA
Baseline 25(OH)D <10 ng/mL 2.36 (1.04); 129 2.31 (1.08); 98 0.06 (−0.23 to 0.34) .70 NA NA
concentration, ng/mL
≥10 ng/mL 2.09 (1); 229 2.07 (0.93); 239 −0.01 (−0.18 to 0.17) .94 NA NA
Female
Pubic hair, Tanner score
Overall NA 2.08 (1.08); 327 2.13 (0.99); 334 0.05 (−0.11 to 0.20) .57 NA NA
Calcium intake <500 mg/d 2.07 (1.09); 168 2.15 (0.99); 196 0.06 (−0.15 to 0.28) .57 NA NA
≥500 mg/d 2.09 (1.07); 104 2.17 (1.03); 88 0.05 (−0.25 to 0.34) .75 NA NA
Baseline 25(OH)D <10 ng/mL 2.22 (1.12); 125 2.16 (1.01); 135 −0.10 (−0.35 to 0.15) .43 NA NA
concentration, ng/mL
≥10 ng/mL 2.00 (1.04); 202 2.12 (0.97); 199 0.12 (−0.08 to 0.31) .25 NA NA
Breast development, Tanner
score
Overall NA 2.61 (0.93); 327 2.69 (0.94); 334 0.07 (−0.07 to 0.21) .33 NA NA
Calcium intake <500 mg/d 2.62 (0.95); 168 2.72 (0.97); 196 0.08 (−0.12 to 0.28) .44 NA NA
≥500 mg/d 2.63 (0.92); 104 2.55 (0.84); 88 −0.12 (−0.67 to 0.14) .20 NA NA
Baseline 25(OH)D <10 ng/mL 2.67 (0.97); 125 2.69 (0.97); 135 0.01 (−0.22 to 0.24) .92 NA NA
concentration, ng/mL
≥10 ng/mL 2.57 (0.90); 202 2.69 (0.93); 199 0.11 (−0.07 to 0.29) .24 NA NA
Proportion menstruating,
No./total No.
Overall NA 160/327 161/334 NA NA 1.00 (0.86 to 1.17) .96
Calcium intake <500 mg/d 79/168 100/196 NA NA 0.96 (0.78 to 1.19) .73
≥500 mg/d 53/104 40/88 NA NA 1.17 (0.80 to 1.72) .41
Baseline 25(OH)D <10 ng/mL 72/125 67/135 NA NA 1.05 (0.86 to 1.29) .64
concentration, ng/mL
≥10 ng/mL 88/202 84/199 NA NA 0.90 (0.73 to 1.11) .33
Age at menarche, y
Overall NA 12.19 (1.14); 160 12.20 (1.14); 161 −0.04 (−0.29 to 0.21) .75 NA NA
Calcium intake <500 mg/d 12.05 (1.18); 79 12.22 (1.19); 100 0.07 (−0.27 to 0.42) .67 NA NA
≥500 mg/d 12.34 (1.02); 53 12.15 (1.10); 40 −0.38 (−0.82 to 0.06) .09 NA NA
Baseline 25(OH)D <10 ng/mL 12.42 (1.16); 72 12.31 (1.12); 67 −0.10 (−0.49 to 0.29) .62 NA NA
concentration, ng/mL
≥10 ng/mL 12.01 (1.10); 88 12.13 (1.15); 94 0.02 (−0.30 to 0.34) .91 NA NA

Abbreviations: 25(OH)D, 25–hydroxyvitamin D; NA, not applicable.

SI conversion factor: To convert 25(OH)D to nmol/L, multiply by 2.496.
a
Adjusted for random effects of school and individual.

tation at a dose of 14 000 IU per week was effective in ence growth, body composition, or pubertal development,
elevating 25(OH)D concentrations in a large population either in the study population as a whole or within subgroups
of Mongolian school-aged children with low baseline having the lowest baseline 25(OH)D concentrations or cal-
vitamin D status. However, this intervention did not influ- cium intake values.

ARTICLE INFORMATION Published Online: November 28, 2022. Author Affiliations: Channing Division of Network
Accepted for Publication: August 28, 2022. doi:10.1001/jamapediatrics.2022.4581 Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts (Ganmaa);

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2023 Volume 177, Number 1 39

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Research Original Investigation Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency

Department of Nutrition, Harvard T.H. Chan School University of Texas at Austin; and Erdenebaatar Epidemiol. 2015;44(3):894-905. doi:10.1093/ije/
of Public Health, Boston, Massachusetts (Ganmaa, Chadraa, PhD, Minnesota State University, dyv116
Bromage); Sage Therapeutics, Cambridge, Mankato); independent members of the Trial 12. Mokhtar RR, Holick MF, Sempértegui F, et al.
Massachusetts (Khudyakov); Mongolian Health Steering Committee (Walter C. Willett, DrPH, Vitamin D status is associated with underweight
Initiative, Royal Plaza, Bayanzurkh District, Edward L. Giovannucci, ScD, and Barry R. Bloom, and stunting in children aged 6-36 months residing
Ulaanbaatar, Mongolia (Erdenenbaatar); Global PhD, Harvard T.H. Chan School of Public Health; in the Ecuadorian Andes. Public Health Nutr. 2018;
Laboratory, Royal Plaza, Bayanzurkh District, Nymdawa Naranbat, PhD, Gyals Medical 21(11):1974-1985. doi:10.1017/S1368980017002816
Ulaanbaatar, Mongolia (Delgererekh); Blizard Laboratory, Ulaanbaatar, Mongolia; and the late
Institute, Barts and the London School of Medicine Danzan Malchinkhuu, MD, National Center for 13. Foo LH, Zhang Q, Zhu K, et al. Relationship
and Dentistry, Queen Mary University of London, Maternal and Child Health of Mongolia, between vitamin D status, body composition and
London, United Kingdom (Martineau). Ulaanbaatar, Mongolia); board members at the physical exercise of adolescent girls in Beijing.
Mongolian Health Initiative (Jambal Tuyatsetseg, Osteoporos Int. 2009;20(3):417-425. doi:10.1007/
Author Contributions: Drs Ganmaa and Martineau s00198-008-0667-2
had full access to all of the data in the study and PhD, Mongolian University of Science and
take responsibility for the integrity of the data and Technology, Ulan Bator, Mongolia; Jazag 14. Gilbert-Diamond D, Baylin A, Mora-Plazas M,
the accuracy of the data analysis. Amarsanaa, PhD, Happy Veritas Laboratory, et al. Vitamin D deficiency and anthropometric
Concept and design: Ganmaa, Martineau. Ulaanbaatar, Mongolia; Purevdorj Erkhembulgan, indicators of adiposity in school-age children:
Acquisition, analysis, or interpretation of data: PhD, and Gunchin Batbaatar, PhD, Mongolian a prospective study. Am J Clin Nutr. 2010;92(6):
All authors. National University of Medical Sciences, Ulan Bator, 1446-1451. doi:10.3945/ajcn.2010.29746
Drafting of the manuscript: Ganmaa, Bromage, Mongolia; Mark C. Elliott, PhD, Harvard University, 15. Zakharova I, Klimov L, Kuryaninova V, et al.
Baigal, Martineau. Cambridge, Massachusetts; and Tsend Munh-Orgil, Vitamin D insufficiency in overweight and obese
Critical revision of the manuscript for important Member of the Mongolian Parliament); and the children and adolescents. Front Endocrinol
intellectual content: Khudyakov, following individuals for advice and helpful (Lausanne). 2019;10:103. doi:10.3389/fendo.2019.
Erdenenbaatar, Martineau. discussions: Winthrop Burr, MD (Anadyne 00103
Statistical analysis: Bromage, Khudyakov, Psychotherapy, Dedham, Massachusetts), and
Masae Kawamura, MD (Qiagen USA, Germantown, 16. Plesner JL, Dahl M, Fonvig CE, et al. Obesity is
Erdenenbaatar, Martineau. associated with vitamin D deficiency in Danish
Obtained funding: Ganmaa, Martineau. Maryland).
children and adolescents. J Pediatr Endocrinol Metab.
Administrative, technical, or material support: 2018;31(1):53-61. doi:10.1515/jpem-2017-0246
Ganmaa, Erdenenbaatar, Baigal. REFERENCES
Supervision: Ganmaa, Baigal, Martineau. 1. Institute of Medicine, Food and Nutrition Board. 17. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP.
Dietary Reference Intakes for Calcium and Vitamin D. Vitamin D and multiple health outcomes: umbrella
Conflict of Interest Disclosures: Dr Martineau review of systematic reviews and meta-analyses of
reported grants from National Institutes of Health; National Academy Press; 2010.
observational studies and randomised trials. BMJ.
consultancy fees from DSM Nutritional Products; 2. Samuel S, Sitrin MD. Vitamin D’s role in cell 2014;348:g2035. doi:10.1136/bmj.g2035
speaker fees from Linus Pauling Institute; research proliferation and differentiation. Nutr Rev. 2008;66
grants from Pharma Nord, DSM Nutritional (10)(suppl 2):S116-S124. doi:10.1111/j.1753-4887.2008. 18. Lee HS, Kim YJ, Shim YS, Jeong HR, Kwon E,
Products, Thorton & Ross, and Hyphens Pharma; 00094.x Hwang JS. Associations between serum vitamin D
provision of capsules for clinical trial use from levels and precocious puberty in girls. Ann Pediatr
3. Polly P, Tan TC. The role of vitamin D in skeletal Endocrinol Metab. 2014;19(2):91-95. doi:10.6065/
Cytoplan, Synergy Biologics, and Pharma Nord; and cardiac muscle function. Front Physiol. 2014;5:
other support from Pharma Nord and Abiogen apem.2014.19.2.91
145. doi:10.3389/fphys.2014.00145
Pharma; participation on data and safety 19. Ganmaa D, Stuart JJ, Sumberzul N, et al.
monitoring boards for the VITALITY trial (Vitamin D 4. Szymczak-Pajor I, Śliwińska A. Analysis of Vitamin D supplementation and growth in urban
for Adolescents with HIV to reduce musculoskeletal association between vitamin D deficiency and Mongol school children: Results from two
morbidity and immunopathology, Pan African insulin resistance. Nutrients. 2019;11(4):794. doi:10. randomized clinical trials. PLoS One. 2017;12(5):
Clinical Trials, registry: PACTR20200989766029) 3390/nu11040794 e0175237. doi:10.1371/journal.pone.0175237
and the Trial of Vitamin D and Zinc 5. Aranow C. Vitamin D and the immune system. 20. Ganmaa D, Uyanga B, Zhou X, et al. Vitamin D
Supplementation for Improving Treatment J Investig Med. 2011;59(6):881-886. doi:10.2310/ supplements for prevention of tuberculosis
Outcomes Among COVID-19 Patients in India JIM.0b013e31821b8755 infection and disease. N Engl J Med. 2020;383(4):
(ClinicalTrials.gov ID: NCT04641195); unpaid work 6. Prasad P, Kochhar A. Interplay of vitamin D and 359-368. doi:10.1056/NEJMoa1915176
as a program committee member for the Vitamin D metabolic syndrome: A review. Diabetes Metab Syndr.
Workshop; and receipt of vitamin D capsules for 21. Bromage S, Daria T, Lander RL, et al. Diet and
2016;10(2):105-112. doi:10.1016/j.dsx.2015.02.014 nutrition status of Mongolian adults. Nutrients.
clinical trial use from Pharma Nord, Synergy
Biologics, and Cytoplan. No other disclosures were 7. Knuth MM, Mahapatra D, Jima D, et al. Vitamin D 2020;12(5):1514. doi:10.3390/nu12051514
reported. deficiency serves as a precursor to stunted growth 22. Chavarro JE, Watkins DJ, Afeiche MC, et al.
and central adiposity in zebrafish. Sci Rep. 2020;10 Validity of self-assessed sexual maturation against
Funding/Support: This study was supported by an (1):16032. doi:10.1038/s41598-020-72622-2
award from the US National Institutes of Health physician assessments and hormone levels. J Pediatr.
(1R01HL122624-01). 8. Roth DE, Abrams SA, Aloia J, et al. Global 2017;186:172-178.e3. doi:10.1016/j.jpeds.2017.03.050
prevalence and disease burden of vitamin D 23. Ganmaa D, Khudyakov P, Buyanjargal U, et al.
Role of the Funder/Sponsor: The funder had no deficiency: a roadmap for action in low- and
role in the design and conduct of the study; Prevalence and determinants of QuantiFERON-
middle-income countries. Ann N Y Acad Sci. 2018; diagnosed tuberculosis infection in 9810 Mongolian
collection, management, analysis, and 1430(1):44-79. doi:10.1111/nyas.13968
interpretation of the data; preparation, review, or schoolchildren. Clin Infect Dis. 2019;69(5):813-819.
approval of the manuscript; and decision to submit 9. Eckel RH, Grundy SM, Zimmet PZ. The metabolic doi:10.1093/cid/ciy975
the manuscript for publication. syndrome. Lancet. 2005;365(9468):1415-1428. 24. Sempos CT, Betz JM, Camara JE, et al. General
doi:10.1016/S0140-6736(05)66378-7 steps to standardize the laboratory measurement
Data Sharing Statement: See Supplement 3.
10. Hazell TJ, Gallo S, Vanstone CA, Agellon S, Rodd of serum total 25-hydroxyvitamin D. J AOAC Int.
Additional Contributions: We thank the children C, Weiler HA. Vitamin D supplementation trial in 2017;100(5):1230-1233. doi:10.5740/jaoacint.17-0259
who participated in the trial and their parents and infancy: body composition effects at 3 years of age
guardians. We also thank independent members of 25. de Onis M, Onyango AW, Borghi E, Siyam A,
in a prospective follow-up study from Montréal. Nishida C, Siekmann J. Development of a WHO
the Data Safety Monitoring Board (Sarah M. Pediatr Obes. 2017;12(1):38-47. doi:10.1111/ijpo.12105
Fortune, MD, and Page L. Williams, PhD, Harvard growth reference for school-aged children and
T.H. Chan School of Public Health, Boston, 11. Trilok-Kumar G, Kaur M, Rehman AM, et al. adolescents. Bull World Health Organ. 2007;85(9):
Massachusetts; Michael F. Holick, MD, and Robert Effects of vitamin D supplementation in infancy on 660-667. doi:10.2471/BLT.07.043497
C. Horsburgh, MD, Boston University, Boston, growth, bone parameters, body composition and 26. Sachs MC, Shoben A, Levin GP, et al. Estimating
Massachusetts; Perenlei Enkhbaatar, PhD, gross motor development at age 3-6 years: mean annual 25-hydroxyvitamin D concentrations
follow-up of a randomized controlled trial. Int J

40 JAMA Pediatrics January 2023 Volume 177, Number 1 (Reprinted) jamapediatrics.com

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024
 Vitamin D Supplementation and Development Among School-aged Children in an Area With Vitamin D Deficiency Original Investigation Research

from single measurements: the Multi-Ethnic Study 29. Manson JE, Bassuk SS, Lee IM, et al. The 32. Vieth R. How to optimize vitamin D
of Atherosclerosis. Am J Clin Nutr. 2013;97(6):1243- Vitamin D and Omega-3 Trial (VITAL): rationale and supplementation to prevent cancer, based on
1251. doi:10.3945/ajcn.112.054502 design of a large randomized controlled trial of cellular adaptation and hydroxylase enzymology.
27. Benjamini Y, Hochberg Y. Controlling the false vitamin D and marine omega-3 fatty acid Anticancer Res. 2009;29(9):3675-3684.
discovery rate—a practical and powerful approach supplements for the primary prevention of cancer 33. Wells JC, Williams JE, Chomtho S, et al.
to multiple testing. J Roy Stat Soc B Met. 1995;57(1): and cardiovascular disease. Contemp Clin Trials. Body-composition reference data for simple and
289-300. doi:10.1111/j.2517-6161.1995.tb02031.x 2012;33(1):159-171. doi:10.1016/j.cct.2011.09.009 reference techniques and a 4-component model:
28. Scragg R, Waayer D, Stewart AW, et al. The 30. Neale RE, Armstrong BK, Baxter C, et al. The a new UK reference child. Am J Clin Nutr. 2012;96
Vitamin D Assessment (ViDA) Study: design of a D-Health Trial: A randomized trial of vitamin D for (6):1316-1326. doi:10.3945/ajcn.112.036970
randomized controlled trial of vitamin D prevention of mortality and cancer. Contemp Clin 34. Esposito S, Leonardi A, Lanciotti L, Cofini M,
supplementation for the prevention of Trials. 2016;48:83-90. doi:10.1016/j.cct.2016.04.005 Muzi G, Penta L. Vitamin D and growth hormone in
cardiovascular disease, acute respiratory infection, 31. Martineau AR, Jolliffe DA, Hooper RL, et al. children: a review of the current scientific
falls and non-vertebral fractures. J Steroid Biochem Vitamin D supplementation to prevent acute knowledge. J Transl Med. 2019;17(1):87. doi:10.1186/
Mol Biol. 2016;164:318-325. doi:10.1016/j.jsbmb. respiratory tract infections: systematic review and s12967-019-1840-4
2015.09.010 meta-analysis of individual participant data. BMJ.
2017;356:i6583. doi:10.1136/bmj.i6583

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2023 Volume 177, Number 1 41

© 2022 American Medical Association. All rights reserved.

Downloaded from jamanetwork.com by Ferdous Fatema on 05/07/2024