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A micronutrient-fortified young-child formula improves the iron and Vitamin D status of healthy young European children: A randomized, double-blind controlled trial

Authors:
  • Willem-Alexander Children's Hospital - Leiden University Medical Center
  • Danone Nutricia Research

Abstract and Figures

Background: Iron deficiency (ID) and vitamin D deficiency (VDD) are common among young European children because of low dietary intakes and low compliance to vitamin D supplementation policies. Milk is a common drink for young European children. Studies evaluating the effect of milk fortification on iron and vitamin D status in these children are scarce. Objective: We aimed to investigate the effect of a micronutrient-fortified young-child formula (YCF) on the iron and vitamin D status of young European children. Design: In this randomized, double-blind controlled trial, healthy German, Dutch, and English children aged 1-3 y were allocated to receive either YCF (1.2 mg Fe/100 mL; 1.7 μg vitamin D/100 mL) or nonfortified cow milk (CM) (0.02 mg Fe/100 mL; no vitamin D) for 20 wk. Blood samples were taken before and after the intervention. The primary and secondary outcomes were change from baseline in serum ferritin (SF) and 25-hydroxyvitamin D [25(OH)D], respectively. ID was defined as SF <12 μg/L in the absence of infection (high-sensitivity C-reactive protein <10 mg/L) and VDD as 25(OH)D <50 nmol/L. Statistical adjustments were made in intention-to-treat analyses for sex, country, age, baseline micronutrient status, and micronutrient intake from food and supplements (and sun exposure in the case of vitamin D outcomes). Results: The study sample consisted of 318 predominantly Caucasian (∼95%) children. The difference in the SF and 25(OH)D change between the treatment groups was 6.6 μg/L (95% CI: 1.4, 11.7 μg/L; P = 0.013) and 16.4 nmol/L (95% CI: 9.5, 21.4 nmol/L; P < 0.001), respectively. The probability of ID (OR 0.42; 95% CI:0.18, 0.95; P = 0.036) and VDD (OR 0.22; 95% CI: 0.01, 0.51; P < 0.001) after the intervention was lower in the YCF group than in the CM group. Conclusion: Micronutrient-fortified YCF use for 20 wk preserves iron status and improves vitamin D status in healthy young children in Western Europe. This trial was registered at www.trialregister.nl as NTR3609.
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A micronutrient-fortified young-child formula improves the iron and
vitamin D status of healthy young European children: a randomized,
double-blind controlled trial
1
Marjolijn D Akkermans,
2
* Simone RBM Eussen,
3
Judith M van der Horst-Graat,
3,6
Ruurd M van Elburg,
3,4
Johannes B van
Goudoever,
4,5
and Frank Brus
2
2
Department of Pediatrics, Juliana Children’s Hospital/Haga Teaching Hospital, The Hague, Netherlands;
3
Danone Nutricia Research, Utrecht, Netherlands;
4
Department of Pediatrics, Emma Children’s Hospital/Academic Medical Center, Amsterdam, Netherlands; and
5
Department of Pediatrics, VU University
Medical Center, Amsterdam, Netherlands
ABSTRACT
Background: Iron deficiency (ID) and vitamin D deficiency (VDD)
are common among young European children because of low di-
etary intakes and low compliance to vitamin D supplementation
policies. Milk is a common drink for young European children.
Studies evaluating the effect of milk fortification on iron and vita-
min D status in these children are scarce.
Objective: We aimed to investigate the effect of a micronutrient-
fortified young-child formula (YCF) on the iron and vitamin D
status of young European children.
Design: In this randomized, double-blind controlled trial,
healthy German, Dutch, and English children aged 1–3 y were
allocated to receive either YCF (1.2 mg Fe/100 mL; 1.7 mg vita-
min D/100 mL) or nonfortified cow milk (CM) (0.02 mg
Fe/100 mL; no vitamin D) for 20 wk. Blood samples were taken
before and after the intervention. The primary and secondary out-
comes were change from baseline in serum ferritin (SF) and
25-hydroxyvitamin D [25(OH)D], respectively. ID was defined
as SF ,12 mg/L in the absence of infection (high-sensitivity
C-reactive protein ,10 mg/L) and VDD as 25(OH)D ,50 nmol/L.
Statistical adjustments were made in intention-to-treat analyses for
sex, country, age, baseline micronutrient status, and micronutrient
intake from food and supplements (and sun exposure in the case of
vitamin D outcomes).
Results: The study sample consisted of 318 predominantly Cauca-
sian (w95%) children. The difference in the SF and 25(OH)D change
between the treatment groups was 6.6 mg/L (95% CI: 1.4, 11.7 mg/L;
P= 0.013) and 16.4 nmol/L (95% CI: 9.5, 21.4 nmol/L; P,0.001),
respectively. The probability of ID (OR 0.42; 95% CI:0.18, 0.95;
P= 0.036) and VDD (OR 0.22; 95% CI: 0.01, 0.51; P,0.001)
after the intervention was lower in the YCF group than in the
CM group.
Conclusion: Micronutrient-fortified YCF use for 20 wk preserves
iron status and improves vitamin D status in healthy young children
in Western Europe. This trial was registered at www.trialregister.nl
as NTR3609. Am J Clin Nutr doi: 10.3945/ajcn.116.136143.
Keywords: iron deficiency, vitamin D deficiency, cow milk, young-
child formula, vitamin D supplements, micronutrient fortification,
young children
INTRODUCTION
Micronutrient deficiency is a major public health problem that
even in industrialized countries contributes to the global burden
of disease. Iron deficiency (ID)
7
and vitamin D deficiency
(VDD) are among the most common micronutrient deficiencies
in young children worldwide (1). ID can lead to iron deficiency
anemia (IDA) (2), and both of these conditions are associated
with impaired neurodevelopment (3–6). It has been suggested
that vitamin D has an important role in immune system func-
tioning and in preventing cancers, whereas VDD can lead to
rickets (7, 8).
Despite national nutritional recommendations, the iron and
vitamin D intake of young children in Europe has been shown to
often be insufficient in preventing ID and VDD (9–13). Further-
more, although the use of vitamin D supplements is associated
with a lower prevalence of VDD, compliance seems to be low (7,
9, 10). To increase compliance, fortification of commonly used
food products has been suggested. Fortification produces a more
gradual increase in serum micronutrient concentration; in ad-
dition, if consumed on a regular and frequent basis, fortified
products will maintain body stores of nutrients more efficiently
and effectively than intermittent supplements (1).
Several international trials have shown beneficial effects of
food fortification (e.g., milk, bread, and margarine) on iron
(14–23) and vitamin D (24–27) status in children. Milk is a
1
Supported by Danone Nutricia Research. This is a free access article,
distributed under terms (http://www.nutrition.org/publications/guidelines-and-
policies/license/) that permit unrestricted noncommercial use, distribution, and
reproduction in any medium, provided the original work is properly cited.
6
Present address: Food and Biobased Research, University of Wagenin-
gen, Wageningen, Netherlands.
*To whom correspondence should be addressed. E-mail: m.d.akkermans@
hagaziekenhuis.nl.
Received April 5, 2016. Accepted for publication December 5, 2016.
doi: 10.3945/ajcn.116.136143.
7
Abbreviations used: AE, adverse event; CM, cow milk; hsCRP, high-
sensitivity C-reactive protein; ID, iron deficiency; IDA, iron deficiency ane-
mia; ITT, intention to treat; PP, per protocol; SF, serum ferritin; VDD, vitamin
D deficiency; YCF, young-child formula; 25(OH)D, 25-hydroxyvitamin D.
Am J Clin Nutr doi: 10.3945/ajcn.116.136143. Printed in USA. Ó2017 American Society for Nutrition 1of9
AJCN. First published ahead of print January 4, 2017 as doi: 10.3945/ajcn.116.136143.
Copyright (C) 2017 by the American Society for Nutrition
popular source for delivering fortification because of its wide
availability and acceptance. However, randomized controlled
trials investigating the effect of this strategy in young European
children are scarce. Existing studies differ in fortification dosage
and outcome parameters, which hampers the comparison of
results (14, 15, 17, 23, 25). Moreover, the influence of an in-
fection [e.g., on serum ferritin (SF)] or the season (on vitamin D
status) on outcome variables is not always taken into account.
The primary objective of this study (NTR3609) was to in-
vestigate the effect of a micronutrient-fortified young-child
formula (YCF) given for 20 wk on ferritin concentrations of
healthy children aged 12–36 mo living in Western Europe
compared with the use of nonfortified cow milk (CM). Sec-
ondary objectives were to establish the effect of the intervention
on the prevalence of ID and IDA, serum 25-hydroxyvitamin
D [25(OH)D] concentrations, and the prevalence of VDD.
METHODS
This randomized, double-blind controlled trial was performed
in Western Europe from 2012 October to 2014 September. The
participating countries were Germany, (9 private pediatric clinics
spread throughout the country), Netherlands, (Juliana Children’s
Hospital/Haga Teaching Hospital in The Hague, VU University
Medical Center in Amsterdam, and Sophia Children’s Hospital/
Erasmus Medical Center in Rotterdam) and the United Kingdom
(Royal National Orthopedic Hospital in London and St. Mary’s
Hospital in Newport, Isle of Wight). The study was approved by
the medical ethical review board of all participating sites. The
prevalence of and risk factors for ID and VDD at baseline have
previously been published (9).
Inclusion and exclusion criteria
Children aged 12–36 mo with a stable health status (i.e., without
any known chronic or recent acute disease) were eligible for this
study. The children were familiar with and currently drinking
milk products and were expected to have a study product in-
take $150mL/d.Exclusioncriteriawere:beingbornpreterm
(,32 wk, or ,37 wk with a birth weight ,1800 g); known in-
fection within the last week or infection needing medical assistance
or treatment within the last 2 wk; known hemoglobinopathies; any
case of anemia treated within the last 3 mo; a blood transfusion
received within the last 6 mo; the presence of a relevant congenital
abnormality; chromosomal disorder or severe disease (such as major
congenital heart disease or Down syndrome); having a disorder
requiring a special diet (such as food intolerance or food allergy
or complaints such as reflux, constipation, and cramps); current use
of antiregurgitation, antireflux, or laxative medication; participation
in any other study involving investigational or marketed products
within 2 wk before entering the study; known allergy or intolerance
to components of the study products (e.g., milk powder, lactose, or
fish protein); and vaccination with a live or live-attenuated vaccine
received within the last 2 wk. Finally, parents had to be able to
understand the local language and read and fill out questionnaires.
Study procedure
Subjects were recruited in 2 ways based on the local situation
at the individual sites. In the Netherlands and the United
Kingdom, parents of eligible subjects were informed about the
study during a preoperative visit before an elective nonemergency
surgical procedure (e.g., urologic surgeries, inguinal or umbilical
hernia operations, or ear-nose-throat procedures). After written
informed consent was obtained, the first blood drawn was
combined with the placement of an intravenous catheter needed
for administering general anesthesia. The subjects from Germany
were recruited during a regular visit to their pediatrician. After
taking the blood sample, the included children were randomly
allocated to receive either micronutrient-fortified YCF (test
product) or nonfortified CM (control product) for a period of
20 wk. A computer model was used for block randomization in
which stratification was applied for country and sex. Parents (and
their children), investigators, and treating physicians were
blinded to product allocation by coding the cans containing the
study products. Parents then answered questions about their
child’s demographic and socioeconomic characteristics, day
care center attendance, sun exposure, and medical history. Food
intake was measured by a food-frequency questionnaire that was
adapted and translated from previously published dietary ques-
tionnaires (28–30). Micronutrient intake was calculated with the
use of a Dutch nutrient databank (31). The results reflected the
intake 1 mo before the baseline visit.
During the intervention period, parents were asked not to
change their child’s dietary habits, including the use of sup-
plements. After 1, 5, and 15 wk, parents were contacted by
phone to discuss study product compliance and completion of
diaries. These diaries included daily study product intake, pos-
sible adverse events (AEs) and serious AEs, and the use of
medication. Diaries on stool frequency and consistency were
completed 7 d before the last 2 scheduled visits (weeks 10 and
20). Stool frequency was measured as the number of stools
passed on each day of the 7 d, and stool consistency was mea-
sured on an ordered 5-point scale with pictures (1: watery;
2: soft, pudding-like; 3: soft-formed; 4: dry-formed; 5: dry hard
pellets). Halfway through the study, parents were asked to visit
the study center to collect a new study product and to discuss
potential issues. After 20 wk in all 3 countries, a second venous
blood sample was taken while subjects visited the hospital or
clinic for the last time (Figure 1). During all 3 visits (baseline,
10 wk, and 20 wk), height or length and weight were measured.
Body weight was measured to the nearest 0.1 kg with the use
of a calibrated weighing scale. Height was measured to the
nearest 0.2 cm, standing and without wearing shoes, with the use
of a calibrated stadiometer. In those children who were not able
to stand, length was measured lying down with the use of a
length board to a precision of 0.2 cm. Weight-for-age zscores,
height- or length-for-age zscores, and BMI-for-age zscores
following WHO growth charts were calculated.
Test and control products: YCF and CM
The detailed nutrient profiles of both study products are shown
in Table 1. The test product was a commercially available
micronutrient-fortified YCF containing 1.2 mg Fe/100 mL and
1.7 mg vitamin D/100 mL. The control product was a non-
fortified CM that contained 0.02 mg Fe/100 mL and no vitamin D.
The energy concentrations of both products were comparable
(46 kcal/100 mL for CM compared with 50 kcal/100 mL for
YCF). Both YCF and CM were supplied in powdered form with
instructions for preparing the milk by diluting the powder with
2of9 AKKERMANS ET AL.
water. The study products were produced, provided, and coded
(for blinding purposes) by Nutricia Cuijk (commissioned by
Danone Nutricia Research).
Definitions and laboratory analyses
Blood samples were stored at Nutricia Research Analytic
Science Laboratory at 2808C before being analyzed in 4 batches.
Some parameters were analyzed at Reinier de Graaf Groep
Laboratory. SF and serum 25(OH)D were analyzed with the use
of an Abbott Architect i2000 immunology analyzer with a
chemiluminesent immunoassay and chemoluminescent micro-
particle immunoassay, respectively.
IDwasdenedasSF,12 mg/L and IDA as ID combined with a
hemoglobin concentration ,110 g/L according to the WHO (2).
Ferritin is an acute-phase protein that may increase when an
infection is present, even in the presence of low iron stores.
Therefore, high-sensitivity C-reactive protein (hsCRP), also an
acute-phase protein, was determined in all venous blood samples,
and all children with elevated hsCRP concentrations ($10 mg/L)
were excluded from the ID and IDA analyses.
VDD was defined as serum 25(OH)D ,50 nmol/L because
this concentration is the cutoff recommended by most experts (7,
10, 32). As previously described (9), mean annual vitamin D
concentrations were calculated from the single values to adjust
for seasonal variations in circulating 25(OH)D concentrations
with the use of the cosinor model of Sachs et al. (33).
Statistical analysis
Sample size calculations were based on the primary parameter
(SF) with the use of data from Szymlek-Gay et al. (20).
Assuming a difference between treatment groups in SF change
(from baseline to endpoint) of 8.1 mg/L (621 mg/L), 216
subjects (108/group) were required for a statistical power of 0.8
(a= 0.05) in a 2-sided ttest. In addition, to account for strati-
fication and dropout (w25%), 288 subjects were anticipated to
be required for inclusion in the study.
Statistical analyses, described in a statistical analysis plan
that was finalized before unblinding of the study, were performed
with the use of SPSS version 21.0 (IBM). As a first step, the
distribution of variables was assessed with the use of histograms
and quantile-quantile plots. Categorical variables were then
summarized by frequency and percentage distributions, and
normally distributed continuous variables were summarized
by means and SDs. Nonnormally distributed continuous var-
iables were expressed as medians (IQRs) (quantiles 1 and 3).
The basic principle of our analyses was to analyze data on an
intention-to-treat (ITT) basis, in which all children for whom
there was information were analyzed in the groups to which they
were originally allocated, irrespective of whether they actually
followed the treatment regimen. Vitamin D status and hemo-
globin concentrations were analyzedinthisITTstudysample.
Analyses regarding iron status (including IDA) were then
performed in the modified ITT study sample. This sample in-
cluded all subjects from the ITT study sample in whom normal
hsCRP concentrations (,10 mg/L) were measured at both
baseline and at the end of the study.
The effect of the study products on SF and serum 25(OH)D
concentration was investigated with the use of linear regression
analyses, whereas its effect on the prevalence of both micro-
nutrient deficiencies was determined with the use of logistic
regression analyses. In principle, these analyses were performed
while adjusting for sex and country (stratification factors), age,
micronutrient status at baseline, and iron or vitamin D intake
(from food and supplements) at baseline. In the case of vitamin D
analyses, we also adjusted for sun exposure of $1 h/d.
FIGURE 1 Flowchart of the study design showing the study procedure during the 20-wk intervention period and 2-wk follow-up period. C, phone contact;
V, visit.
IMPROVING IRON AND VITAMIN D STATUS OF CHILDREN 3of9
Finally, all previously mentioned analyses, including adjust-
ments for the predefined variables, were also performed in the 2
per-protocol (PP) samples. These samples consisted of subjects
from the ITTand the modified ITT sample that demonstrated good
compliance with instructions for consuming the assigned study
product. Good compliance was defined as consuming $151 mL
study product/d for $80% of the days within the last 28 d of
study product intake. All CIs are 2-sided with a confidence level
of 95%. Statistical significance was defined as P,0.05.
RESULTS
Study sample and baseline characteristics
Because of a higher rate of dropouts than anticipated, 318
subjects were finally included in the ITT study sample: 158 in the
YCF group and 160 in the CM group (Figure 2). This ITT sample
consisted of 264 children from Germany (83.0%), 42 from the
Netherlands (13.2%), and 12 from the United Kingdom (3.8%).
Tables 2 and 3show the baseline characteristics and baseline iron
and vitamin D status of the 2 treatment groups, respectively.
These tables show a higher educational and working status of the
parents of the YCF group than the CM group, although more data
on this are missing in the CM group than the YCF group. Fur-
thermore, the CM group had a higher iron intake from milk and
higher vitamin D intake from food than the YCF group (Table 2).
Figure 2 shows the number of children included in our different
study groups and analysis sets. There were no differences in the
number of or reasons for early termination (Figure 2) or in the
percentage of children demonstrating good compliance (69.6%
compared with 71.9%; P= 0.659) between YCF and CM users.
The aforementioned observed differences in educational status,
working status, and iron and vitamin D intake between CM and
YCF users were also found in our modified ITT sample and the
PP and modified PP sample (data not shown).
Iron status and ID and IDA prevalence
In the (complete) modified ITT sample, the difference in
change from baseline in SF between the treatment groups was
6.6 mg/L (95% CI: 1.4, 11.7 mg/L; P= 0.013). The estimated mean 6
SEM change in SF concentration from baseline was 24.9 6
2.2 mg/L for the CM group and +1.7 62.4 mg/L for the YCF
group (Table 3). We then performed explorative analyses in which
the modified ITT sample was divided into 4 subgroups repre-
senting categories of most frequently consumed daily volume
within the last 4 wk (1–150, 151–300, 301–500, and .500 mL/d).
The effect sizes in these subgroups were analyzed while adjusting
for sex, country, and baseline SF concentration. In children con-
suming .500 mL/d, the group difference in change from baseline
in SF was 11.2 mg/L (95% CI: 1.8, 20.6 mg/L).
Tab le 4 shows the prevalence rates of ID and IDA before and
after the intervention. The probability of ID after the intervention
was lower in the YCF group than the CM group (OR: 0.42; 95%
CI: 0.18, 0.95; P= 0.036). The IDA prevalence rates were too low
to evaluate the effect of the intervention on IDA prevalence.
Hemoglobin concentrations and anemia
At baseline, 18.9% of the children were anemic: 23 in the YCF
group and 37 in the CM group. After the intervention, 4 YCF
users and 13 CM users were anemic (P= 0.021). In contrast, the
mean change from baseline in hemoglobin was comparable for
YCF and CM users (Table 3).
Vitamin D status and VDD prevalence
In the (complete) ITT sample, the difference in change from
baseline in 25(OH)D between the treatment groups was 16.4 nmol/L
(95% CI: 9.5, 21.4 nmol/L; P,0.001). The estimated mean 6SEM
change in 25(OH)D concentration from baseline was 27.2 6
2.5 nmol/L for the CM group and 9.2 62.8 nmol/L for the YCF
group (Table 3). We then performed explorative analyses in which
we determined the effect sizes in subgroups based on the most fre-
quently consumed daily volume within the last 4 wk while adjusting
for sex, country, and baseline 25(OH)D concentration. In children
who consumed .500 mL/d, the group difference in change from
baseline in 25(OH)D was 18.1 nmol/L (95% CI: 3.0, 33.2 nmol/L).
Table 4 shows the prevalence rates of VDD before and after the
intervention. The probability of VDD after the intervention was
lower in the YCF group than the CM group (OR: 0.22; 95% CI:
0.01, 0.51; P,0.001).
ID and VDD
At baseline, 8.2% of the YCF group and 5.6% of the CM group
were iron- and vitamin D–deficient. These prevalence rates in-
creased in the CM group to 15.3% and decreased for YCF users
to 4.0% after 20 wk of study product intake.
TABLE 1
CM and YCF content per 100 mL of prepared product
1
CM YCF
Macronutrients, g
Proteins 3.5 1.1
Carbohydrates 5.2 6.6
Fats 1.7 1.9
Fibers 0.0 0.8
Micronutrients
Sodium, mg 40.0 20.0
Potassium, mg 174.0 56.0
Chloride, mg 101.0 31.0
Calcium, mg 127.0 110.0
Phosphorus, mg 100.0 67.0
Magnesium, mg 12.0 10.0
Nonheme iron, mg 0.02 1.2
Zinc, mg 0.40 0.90
Copper, mg 2.4 59.0
Manganese, mg 0.91 16.0
Selenium, mg 0.90 2.3
Iodine, mg 9.8 17.0
Vitamin A, mg REs 13.0 65.0
Vitamin D
3
,mg 0.0 1.7
a-Tocopherol (vitamin E), mg 0.0 1.3
Vitamin K, mg 0.0 5.0
Thiamin (vitamin B-1), mg 28.0 70.0
Riboflavin (vitamin B-2), mg 142.0 87.0
Vitamin B-6, mg 30.0 60.0
Folic acid, mg 1.6 18.0
Vitamin B-12, mg 0.24 0.13
Biotin, mg 2.0 1.7
Vitamin C, mg 0.55 14.0
1
CM, cow milk; RE, retinol equivalent; YCF, young-child formula.
4of9 AKKERMANS ET AL.
PP analyses
PP and modified PP analyses confirmed the results from the
ITT and modified ITT analyses, although the effect sizes were
larger in the PP analyses (data not shown).
Safety of study products: AEs, gastrointestinal tolerance,
and growth
Overall, there were no statistically significant differences in
the number and severity of reported AEs between the YCF and
FIGURE 2 Flowchart of the study sample. Children with elevated hsCRP concentrations ($10 mg/L) were excluded from the analyses regarding iron status to
prevent falsely elevated or normal ferritin concentrations in the case of an infection. The PP groups consisted thereafter of children that demonstrated good compliance
with instructions for consuming the assigned study product. Good compliance was defined as consuming $151 mL study product/d $80% of the days within the last
28 d of study product intake. CM, cow milk; hsCRP, high-sensitivity C-reactive protein; ITT, intention to treat; PP, per protocol; YCF, young-child formula.
IMPROVING IRON AND VITAMIN D STATUS OF CHILDREN 5of9
CM groups (data not shown). Of the reported AEs (939 in 258
subjects), 33 events in 27 subjects were considered to be related
to the study product. Most of these supposedly related AEs
compromised gastrointestinal complaints. There were 30 reports
of diarrhea in 26 subjects (17%) from the YCF group and 17
reports of diarrhea in 14 subjects (9.2%) from the CM group
(P= 0.061). In both groups, most of these reports were
documented in the first week after the start of the study product,
and the diarrhea lasted ,5 d (data not shown). The complaints
were not severe, and most of the complaints were resolved
without any medication. Furthermore, there were 9 serious AEs
reported in 8 subjects. These events were diverse and evenly
distributed over the treatment groups (data not shown). All were
considered to be unrelated to the study product.
Table 5 shows the stool characteristics (frequency and con-
sistency) recorded before each hospital or clinic visit (baseline,
10 wk, and 20 wk) by treatment group. No statistically signifi-
cant differences in gastrointestinal tolerance were observed be-
tween the treatment groups. Finally, there were also no statistically
significant differences in the anthropometric data between the 2
treatment groups during the intervention period (data not shown).
DISCUSSION
To our knowledge, this is the first randomized, double-blind
controlled trial to describe the effect of micronutrient-fortified YCF
on both the iron and vitamin D status of healthy children aged 12–36
mo in Western Europe. The results of this study indicate that the
daily consumption of YCF for 20 wk preserves iron status and
TABLE 3
Adjusted mean changes in iron and vitamin D status after the intervention
1
CM YCF
Serum ferritin, mg/L
n143 147
Baseline 28.9 617.1 25.6 614.8
20 wk 22.0 617.5 27.9 617.4
Change from baseline 24.9 62.2
2
1.7 62.4
2,3
Hemoglobin, g/L
n160 158
Baseline 118.5 610.7 119.8 68.8
20 wk 121.9 69.8 123.9 68.2
Change from baseline 3.5 69.1 3.1 68.9
Serum 25(OH)D, nmol/L
n160 158
Baseline 70.2 626.7 69.4 627.0
20 wk 62.0 629.9 77.8 626.6
Change from baseline 27.2 62.5
2
9.2 62.8
2,3
1
Values are means 6SDs unless otherwise indicated. The change from
baseline in serum ferritin and serum 25(OH)D were analyzed while adjusting
for sex and country (stratification factors), age, micronutrient status at base-
line, and the iron or vitamin D intake from food and supplements (and sun
exposure in the case of vitamin D). The iron analyses were performed in the
modified intention-to-treat sample in which the children with an elevated
high-sensitivity C-reactive protein were excluded to prevent falsely elevated
or normal ferritin concentrations in the case of an infection. CM, cow milk;
YCF, young-child formula; 25(OH), 25-hydroxyvitamin D.
2
Estimated mean 6SEM (all such values).
3
The group difference in the change from baseline in serum ferritin and
serum 25(OH)D between treatment groups was 6.6 mg/L (95% CI: 1.4, 11.7 mg/L;
P= 0.013) and 16.4 nmol/L (95% CI: 9.5, 21.4 nmol/L; P,0.001), respectively.
TABLE 2
Baseline characteristics of the intention-to-treat study sample
1
CM
(n= 160)
YCF
(n= 158)
Demographic and general characteristics
Male, n(%) 91 (56.9) 89 (56.3)
Caucasian, n(%) 151 (94.4) 152 (96.2)
Age, mo 20.5 67.72 20.8 67.3
Gestational age, wk 39.0 61.9 39.3 61.4
Birth weight, g 3238 6553 3400 6513
Educational status of either parent,
n(%)
None 1 (0.6) 0 (0)
Primary school 30 (18.8) 21 (13.3)
High school or trade school 66 (41.2) 80 (50.6)
University 30 (18.8) 35 (22.2)
Unknown 33 (20.6) 22 (13.9)
Professional status of parents, n(%)
$1 working 118 (73.8) 126 (79.7)
None working 3 (1.9) 8 (5.1)
Unknown 39 (24.3) 24 (15.2)
Daycare attendance, n(%)
Yes 75 (46.9) 66 (41.8)
No 84 (52.5) 91 (57.6)
Unknown 1 (0.6) 1 (0.6)
$1 h spent outside/d, n(%)
Yes 135 (84.4) 124 (78.5)
No 25 (15.6) 34 (21.5)
Use of sunscreen or protective
clothing, n(%)
Yes 37 (23.1) 51 (32.3)
No 117 (73.1) 103 (65.2)
Unknown 6 (3.8) 4 (2.5)
Characteristics at baseline
Weight-for-age zscore 0.15 60.98 0.28 60.92
Height- or length-for-age zscore 0.19 60.99 0.11 61.00
BMI-for-age zscore 0.3 61.1 0.3 61.0
Milk intake during previous month
CM, n(%) 68 (42.5) 73 (46.2)
YCF, n(%) 85 (53.1) 79 (50.0)
Other, n(%) 7 (4.4) 6 (3.8)
Amount per day, mL 517 6223 512 6230
Use of supplements containing
iron, n(%)
Yes 2 (1.3) 3 (1.9)
No 152 (95.0) 151 (95.6)
Unknown 6 (3.7) 4 (2.5)
Use of supplements containing
vitamin D, n(%)
Yes 51 (31.8) 43 (27.2)
No 103 (64.4) 111 (70.3)
Unknown 6 (3.8) 4 (2.5)
Iron intake at baseline,
2
mg/d
From milk
3
3.1 (0.0–5.2) 2.3 (0.0–4.8)
From food 6.8 (5.0–9.9) 6.7 (4.3–10.1)
Vitamin D intake at baseline,
2
mg/d
From milk
3
4.4 (0.0–7.0) 4.4 (0.0–6.3)
From food 5.3 (1.1–7.7) 2.0 (0.8–7.0)
1
Values are n(%) or means 6SDs unless otherwise indicated. CM,
cow milk; YCF, young-child formula.
2
Medians (IQRs) because of no normal distribution.
3
Includes YCF and CM.
6of9 AKKERMANS ET AL.
improves vitamin D status in young European children. Further-
more, neither study product was related to the incidence of serious
AEs. The use of YCF may therefore be an effective and practical
strategy for preventing ID and VDD in young European children.
Iron status
We observed a modest increase in SF among the children who
consumed YCF. Explorative analyses based on the type of milk
before the start of the study (formula or CM) showed a higher
increase in SF in original CM users than in original formula users
(data not shown). Therefore, young children who consumed CM
would probably benefit the most from micronutrient-fortified
YCF. One would normally expect a decrease of SF over time
because blood volume expands rapidly during growth, requiring
increasing erythropoiesis with the use of stored iron and sub-
sequently decreasing SF concentrations (14, 15, 20, 23). Because
the SF concentration increased modestly in the YCF group, we
suggest that the use of micronutrient-fortified YCF preserves iron
stores in young European children.
Four European studies have also reported on the effect of
fortified formula on iron status (14, 15, 17, 23), although only 2
(14, 17) used formula with a comparable iron content of
1.2 mg/100 mL. First, Daly et al. (14) investigated the hema-
tologic effects of a follow-on formula in a group of inner-city
toddlers whose mothers had already switched to pasteurized
CM by 6 mo of age. SF concentrations in formula users remained
stable but decreased significantly in the toddlers that continued on
CM. The second study that used the same iron dosage focused on
the mental and psychomotor developmental indexes at the age of
18 mo after 9 mo of consuming fortified formula. The authors
reported significantly higher SF concentrations at 18 mo in the
fortified formula users than the nonfortified formula and CM
users. Unfortunately, they did not report on SF concentrations at
baseline (17). Therefore, the results of our study are only
comparable to Daly et al. (14). However, they included younger
children, had a longer intervention period, and did not specify
details on the ethnicity and socioeconomic status of the par-
ticipating children. Furthermore, they did not take into account
the influence of a possible infection on SF concentrations. These
differences in study design make it difficult to compare results.
Vitamin D status
Our observed increase in serum 25(OH)D concentrations in the
YCF group is confirmed by a study from Hower et al. (25) among
German children. In contrast, Madsen et al. (26) found a decrease
in serum 25(OH)D concentration in both formula and CM users in
Denmark. In the latter study, a lower fortification dosage of only
0.38 mg vitamin D/100 mL was used compared with 1.7 mg/100 mL
in our YCF. This lower fortification dosage may not be sufficient for
maintaining adequate serum 25(OH)D concentrations.
The VDD prevalence in our study decreased in the YCF group
but increased in the CM group (to 33.3%). In Hower et al. (25),
higher prevalence rates #79.2% were found in CM users. In this
study, the influence of vitamin D–fortified formula (2.85 mg
vitamin D/100 mL) on vitamin D status was investigated in
children aged 2–6 y. Vitamin D status was determined before
and after winter. It is known that the risk for VDD increases
during the winter (7, 10), which may explain why VDD preva-
lence rates were higher than in our study.
Only a minority of the children (w30%) in our study received
vitamin D supplements (mean content: 10.7 mg/d), although
policies regarding vitamin D supplementation exist in all 3 par-
ticipating countries. This emphasizes the need for new strategies,
such as the use of fortified food products.
Advantage of fortification with iron and vitamin D (and
other micronutrients)
Most of the previously mentioned randomized controlled trials
studied the effect of single iron- or single vitamin D–fortified
food products. However, a comprehensive review by Best et al.
TABLE 5
Gastrointestinal tolerance: stool frequency and consistency
1
CM (n= 153) YCF (n= 153)
Stool frequency,
2
stools/d
Baseline 2 (1–2)
3
2 (1–2)
10 wk 1 (1–2) 1 (1–2)
20 wk 2 (1–2) 1 (1–2)
Stool consistency
4
(%)
Baseline Soft-formed (54.6) Soft-formed (55.3)
10 wk Soft-formed (52.8) Soft-formed (45.0)
20 wk Soft-formed (57.8) Soft-formed (47.1)
1
Analyses were performed in all children from the intention-to-treat
sample that actually drank any study product. There were no statistically
significant differences between the 2 treatment groups. CM, cow milk; YCF,
young-child formula.
2
Values at baseline were recorded as a single integer; values at 10 and
20 wk were derived from 7 daily frequency values.
3
Median; IQR in parentheses (all such values).
4
Presented on an ordered scale as the most frequently recorded stool
consistency. The options were watery; soft, pudding-like; soft-formed; dry-
formed; and dry hard pellets.
TABLE 4
Iron and vitamin D deficiency before and after the intervention
1
CM YCF
OR
(95% CI)
Iron deficiency, n(%) 0.42
(0.18, 0.95)*
Baseline 17 (11.9) 21 (14.3)
20 wk 29 (29.6) 14 (13.9)
Iron deficiency anemia, n(%) —
Baseline 8 (5.6) 4 (2.7)
20 wk 4 (4.0) 0 (0.0)
Vitamin D deficiency, n(%) 0.22
(0.01, 0.51)*
Baseline 35 (21.9) 40 (25.3)
20 wk 37 (33.3) 15 (13.5)
1
Iron deficiency was defined as serum ferritin ,12 mg/L in children
without an elevated high-sensitivity C-reactive protein. Iron deficiency
anemia was defined as iron deficiency combined with a hemoglobin concen-
tration ,110 g/L. Vitamin D deficiency was defined as serum 25-hydroxy-
vitamin D ,50 nmol/L. OR column shows the odds of having iron deficiency
andvitaminDdeciencyinYCFuserscomparedwithCMusers.ORswere
calculated while adjusting for sex and country (stratification factors), age,
micronutrient status at baseline, and the iron or vitamin D intake from food
and supplements (and sun exposure in the case of vitamin D). *P,0.05.
CM, cow milk; YCF, young-child formula.
IMPROVING IRON AND VITAMIN D STATUS OF CHILDREN 7of9
(34) showed that multimicronutrient fortification, such as our
YCF, results in more positive effects on biochemical indicators
of micronutrient status. In general, it is believed that micro-
nutrients can interact with each other (e.g., by competing for the
same transporter) and hereby lead to a different absorption of
other micronutrients (34, 35).
For example, ID and VDD seem to influence each other in a
negative way, but the precise pathogenesis is unclear (36–39).
Vitamin D has been suggested to increase the storage and re-
tention of iron by reducing the activity of proinflammatory cy-
tokines that inhibit iron absorption. On the other hand, it is known
that ID impairs the intestinal absorption of fat and the fat-soluble
vitamin A and therefore maybe also the absorption of fat-soluble
vitamin D. Moreover, iron is a cofactor for the enzyme 1a-
hydroxylase, which is responsible for the hydroxylation of 25(OH)D
to 1,25(OH)
2
D (40). Combined fortification of iron and vitamin D
may therefore have a synergistic effect on iron and vitamin D
status. On the other hand, the bioavailability of iron also depends
on the composition of the diet. Food products containing heme
iron (e.g., meat) are better absorbed than those containing non-
heme iron (e.g., vegetables, milk). Furthermore, several factors
enhance (e.g., vitamin C) or inhibit (e.g., calcium) iron absorp-
tion. The amount of calcium is lower and the amount of vitamin C
is higher in our YCF than in our CM, and this could have also
influenced the found effect of our YCF on the change in iron
status. Another impact of multimicronutrient fortification is that,
in addition to iron, several other micronutrients can also influence
hemoglobin concentrations (34).
Safety of micronutrient-fortified YCF
Iron could theoretically increase pro-oxidant stress with po-
tential adverse effects, including infection risk, and possibly
affect stool pattern. However, consistent with previous reports
(41), we observed no difference either in the frequency and
severity of AEs (15) nor in the stool characteristics between YCF
and CM users. Consistent with 2 other studies, we also did not
find differences in anthropometric variables between YCF and
CM users (14, 17).
Strengths and limitations
The strength of our study is that it was a randomized, double-
blind controlled trial in a well-defined sample of healthy young
Caucasian children in Western Europe. Furthermore, we took into
account the influence of infections and the season on iron and
vitamin D status variables, respectively.
Most of our study sample consisted of German children, and
almost all children were Caucasians. This lack of diversity may
hamper generalizing our results to other parts of the world.
However, although country and race may influence baseline
micronutrient status, we do not believe that it will change the
observed effect of our intervention. Another limitation of our
study is the use of an adapted food-frequency questionnaire that
was not validated for determining iron and vitamin D intake in
young children. However, these kind of questionnaires have been
found suitable for determining iron and vitamin D intake in
infants and preschoolers (42). Finally, the percentage of dropouts
(mostly because of nonacceptance of the study product), although
similar for both treatment groups, was higher than expected.
Approximately 40% of the children consumed CM before the
start of the study. During the intervention period, these children
were exposed to milk with a different consistency and possibly a
different taste. These differences can explain the refusal of some
children to drink the study products. Future studies should
therefore investigate the best form and taste of fortified YCF.
In conclusion, the daily use of micronutrient-fortified YCF
instead of nonfortified CM for 20 wk preserves iron status and
improves vitamin D status in children aged 12–36 mo in Western
Europe. The current recommendations state that CM is accept-
able after the age of 1 y, although the iron and vitamin D intake
in these children, including the use of vitamin D supplements, is
insufficient for preventing ID and VDD. YCF, as part of a tod-
dler’s diet, could play a role in ensuring sufficient intake of
certain micronutrients. The long-term benefits of fortified YCF
on neurodevelopment and overall health remain to be elucidated.
We thank the following pediatricians for their contribution to this study:
Wolfgang Landendo
¨rfer, Gerhard Bleckmann, Klaus Helm, Eivy Franke-
Beckmann, Peter A Soemantri, Thomas Adelt, Manfred Praun, Michael
Horn, Franziskus Schuhboeck, Hugo Heij, Koen Joosten, Benjamin Jacobs,
and Carina Venter.
The authors’ responsibilities were as follows—MDA: analyzed the data
and had primary responsibility for the final content; and all authors: designed
and conducted the research, wrote the manuscript, and read and approved the
final manuscript. JBvG is a member of the Dutch National Breastfeeding
Council, European Society for Paediatric Gastroenterology Hepatology and
Nutrition, Health Council of the Netherlands, and neonatal nutrition section
of the Dutch Pediatric Association and director of the Dutch National Donor
Human Milk Bank; he has received honoraria for presentations and consul-
tations from Danone, Nutricia, Mead Johnson Nutrition, Nestl´
e, Nutrition
Institute, Hipp, Prolacta, and Nutrinia in the past 3 y. SRBME and RMvE are
employees and JMvdH-G a former employee of Danone Nutricia Research.
Danone Nutricia Research was involved in the study design and implemen-
tation. The statistical analyses and interpretation of the data were performed
independently. None of the remaining authors reported a conflict of interest
related to the study.
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IMPROVING IRON AND VITAMIN D STATUS OF CHILDREN 9of9
... A recent study by Sacri et al. (2021) support these findings as French children with higher serum ferritine levels are more often YCF users [21]. In an intervention study funded by the YCF-industry, Akkermans et al. (2017) showed that among Dutch, German and English children aged 12-36 months receiving YCF, baseline serum ferritine levels did not change after 20 weeks, while those receiving a non-fortified alternative had lower baseline levels [22]. ...
... A recent study by Sacri et al. (2021) support these findings as French children with higher serum ferritine levels are more often YCF users [21]. In an intervention study funded by the YCF-industry, Akkermans et al. (2017) showed that among Dutch, German and English children aged 12-36 months receiving YCF, baseline serum ferritine levels did not change after 20 weeks, while those receiving a non-fortified alternative had lower baseline levels [22]. ...
... This study does not conclude if sufficient sunlight can be assumed for Dutch children. Vitamin D levels raised among YCF users in the trial by Akkermans et al. (2017), decreasing vitamin D deficiency to 14%, while this increased in the control group to 33% [22]. For children in the Netherlands, a vitamin D supplement of 10 µg/day is advised [23]. ...
Article
Full-text available
Purpose Adequate micronutrient intakes are essential for young children. Special young child formulae (YCF) intended for children from 1 year old are available in the Dutch market. Since YCF are enriched with many micronutrients, it has the potential to have a beneficial effect on young children, or might pose a risk on excessive micronutrient intakes. The current study investigated the characteristics of YCF users, and the effect of YCF use on micronutrient intakes. Methods Data from the Dutch National Food Consumption Survey (2012–2016; n = 440 children aged 1–2 year old) and the Dutch Food Composition Database (NEVO version 2016) were used to assess micronutrient intakes. Habitual intakes of users and non-users of YCF were calculated using Statistical Program to Assess Dietary Exposure (SPADE) and compared. Results In the Netherlands, YCF was consumed by 21% of the 1–2-year-olds. YCF contributed mostly to total vitamin D intake (76%) and between 0 and 50% for other micronutrients. Higher vitamin A, B1, C, D, E, total folate, iron and zinc intakes were observed among users, and higher potassium and phosphorus intakes were found among non-users. Risk of inadequate intake was low among both users and non-users for most nutrients, and the only elevated risk of excessive intake found was for zinc among YCF users. Conclusion YCF increased micronutrient intake, however, for most of the micronutrients there is already a low risk of inadequate intake. YCF increased the risk of excessive zinc intake. It is important that the addition of micronutrients to YCF is regulated, to prevent excessive intake.
... However, clinical studies highlighted the positive benefits of YCF in toddlers by improvement of their dietary intakes and functional outcomes (which include various parameters of the child's physical and mental development and morbidity and mortality rates). Studies have indicated YCF to be associated with improved diet quality scores (PANDiet scoring system), better nutrient adequacy (predominantly micronutrients like iron and vitamin D, when used as a replacement to cow's milk) (14) , and increased feasibility to meet all EFSA-stated nutrient recommendations in young children (13,15) . In addition, there are data to demonstrate the benefits of YCF on gut microbiota and stool characteristics (16) , with reduced incidence of infections when supplemented with short-chain galacto-oligosaccharides/longchain fructo-oligosaccharides (scGOS/lcFOS; 9:1) prebiotic mixture and n-3 long-chain polyunsaturated fatty acids (LCPUFA) (16,17) . ...
... A number of studies have demonstrated the improved nutritional intake upon implementing YCF. However, these studies have focussed on European countries (like Germany, the UK and France (13,15,18,19) ), Australia (20) , New Zealand (20) and Asia (17) . To specify the relevant criteria for toddlers in the Middle East, the experts compiled a series of four statements ( Table 2). ...
... Moreover, the panellists agreed that the ideal YCF composition should provide adequate amounts of macro-and micronutrients to the children without using artificial sweeteners, industrially produced trans fatty acids and taste modifiers, consistent with the global recommendations. The rationale for this consensus was confirmed by a recent study in Polish children (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) months) that evaluated their dietary preferences based on supplementation with YCF or standard cow's milk. The results showed that the introduction of YCF significantly elevated the consumption of sweetened dairy products, beverages and juice, with a decrease in plain fermented kinds of milk. ...
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The transition of foods during toddlerhood and the suboptimal diets consumed in the Middle East make children susceptible to malnutrition and micro-nutrient deficiencies. Based on international recommendations, coupled with the merits of clinical studies on the application of young child formula (YCF), a group of fourteen experts from the Middle East reached a consensus on improving the nutritional status of toddlers. The recommendations put forth by the expert panel comprised twelve statements related to the relevance of YCF in young children; the impact of YCF on their nutritional parameters and functional outcomes; characteristics of the currently available YCF and its ideal composition; strategies to supply adequate nutrition in young children and educational needs of parents and healthcare professionals (HCPs). This consensus aims to serve as a guide to HCPs and parents, focusing on improving the nutritional balance in toddlers in the Middle Eastern region. The panellists considere YCF to be one of the potential solutions to improve the nutritional status of young children in the region. Other strategies to improve the nutritional status of young children include fortified cow's milk and cereals, vitamin and mineral supplements, early introduction of meat and fish, and the inclusion of diverse foods in children's diets..
... The studies conducted on toddlers included two cohorts comparing the administration of VD-fortified milk formula with cow's milk or meat-derived food [36,37]. Both studies found that VD-fortified milk, especially in the second year of life, was significantly associated with an improvement in VD status. ...
... Eight trials investigated the supplementation of VD in children only [30][31][32][33][34][35][36][37]. The studies included a total of 961 subjects aging from 0 to 36 months ( Table 1). ...
... To promote compliance to VD supplements, the fortification of commonly used food products has also been suggested [36,37,87]. Indeed, VD fortified products may be more efficient than intermittent supplements in maintaining adequate stores [37]. ...
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Vitamin D (VD) is an essential micronutrient with multiple functions for human growth, and adequate intake should be guaranteed throughout life. However, VD insufficiency is observed in infants all over the world. Low VD concentration in the breast milk of non-supplemented mothers and low compliance to VD daily supplementation are the main causes of VD insufficiency, especially in the long term. Furthermore, VD supplementation dosages are still debated and differ by country. We conducted a systematic review to compare the most recent evidence on different postnatal VD supplementation strategies, determining whether supplementation given to the mother is as effective as that administered directly to the child, and whether different dosages and administration schedules differ significantly in terms of efficacy and safety. We identified 18 randomized controlled trials (RCTs) addressing the role of infant (n = 961), maternal (n = 652) or combined infant and maternal VD supplementation (n = 260 pairs). In all studies, similar outcomes emerged in terms of efficacy and safety. According to our findings, alternative approaches of VD supplementation may be adopted, especially in cases where the adherence to daily supplementation strategies is poor. This review shows that different dosages and supplementation strategies result in similar VD sufficiency rates. Therefore, international guidelines may be revised in the future to offer multiple and different options of supplementation for specific settings and ages.
... There are also a growing number of published clinical studies showing value with beneficial short-term effects of YCFs (Table 2). These double-blind, randomized, controlled, clinical trials were of strong study designs, although there were a limited number and heterogeneity in populations, formulations, duration, serving sizes, and ages [35][36][37][38]. All but one clinical study demonstrated beneficial effects of primary outcomes that ranged from nutrient status with improved lipid profile, increased folate levels [36], and preserved iron status [35] to body composition with a lower percentage of body fat [37] to immune parameters with increased total blood immunoglobulin A level [38]. ...
... These double-blind, randomized, controlled, clinical trials were of strong study designs, although there were a limited number and heterogeneity in populations, formulations, duration, serving sizes, and ages [35][36][37][38]. All but one clinical study demonstrated beneficial effects of primary outcomes that ranged from nutrient status with improved lipid profile, increased folate levels [36], and preserved iron status [35] to body composition with a lower percentage of body fat [37] to immune parameters with increased total blood immunoglobulin A level [38]. These findings are encouraging; however, more clinical studies are needed. ...
Article
The first 1000 days is a critical window to optimize nutrition. Young children, particularly 12–24 month-olds, are an understudied population. Young children have unique nutrient needs and reach important developmental milestones when those needs are met. Intriguingly, there are differences in the dietary patterns and recommendations for young children in the US vs. globally, notably for breastfeeding practices, nutrient and food guidelines, and young child formulas (YCFs)/toddler drinks. This perspective paper compares these differences in young child nutrition and identifies both knowledge gaps and surveillance gaps to be filled. Parental perceptions, feeding challenges, and nutrition challenges are also discussed. Ultimately, collaboration among academia and clinicians, the private sector, and the government will help close young child nutrition gaps in both the US and globally.
... In Ireland, just 29% of children <5 y old consume vitamin D-fortified foods, whereas only 20% consume vitamin D supplements (17). The effectiveness of micronutrient-fortified young-child formula products in improving intake and status of vitamin D has been previously reported in the current cohort of Irish children (20) and in other European, and New Zealand and Australian, children (41,42). It is noteworthy that current requirements for vitamin D (the EFSA AI and IOM EAR) assume no skin synthesis of vitamin D from sunlight exposure (11,43). ...
... In addition, although the current results show that lacto-ovo vegetarian and nonvegetarian diets can provide comparable iron intakes, the bioavailability of nonheme iron (i.e., that from plant-based foods) is known to be considerably lower than that of heme iron from a meat-based diet (11,12). In the current study, shortfalls in predicted iron intakes among 1-to 3-y-olds were addressed by FUF and DYC or an iron supplement-approaches shown to be effective elsewhere (41,42,49). Given concerns regarding potential adverse effects of iron supplementation, however, targeting only children identified at risk (1-to 3-y-olds at ≤25 th percentile level) and using a lowdose supplement seems prudent (47,49). ...
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Background Dietary habits formed in early childhood can track into later life with important impacts on health. Food-based dietary guidelines (FBDGs) may have a role in improving population health but are lacking for young children. Objectives We aimed to establish a protocol for addressing nutrient shortfalls in 1- to 5-y-old children (12–60 mo) using diet modeling in a population-based sample. Methods Secondary analysis of 2010–2011 Irish National Pre-School Nutrition Survey data (n = 500) was conducted to identify typical food consumption patterns in 1- to 5-y-olds. Nutrient intakes were assessed against dietary reference values [European Food Safety Authority (EFSA) and Institute of Medicine (IOM)]. To address nutrient shortfalls using diet modeling, 4-d food patterns were developed to assess different milk-feeding scenarios (human milk, whole or low-fat cow milk, and fortified milks) within energy requirement ranges aligned with the WHO growth standards. FBDGs to address nutrient shortfalls were established based on 120 food patterns. Results Current mean dietary intakes for the majority of 1- to 5-y-olds failed to meet reference values (EFSA) for vitamin D (≤100%), vitamin E (≤88%), DHA (22:6n–3) + EPA (20:5n–3) (IOM; ≤82%), and fiber (≤63%), whereas free sugars intakes exceeded recommendations of <10% energy (E) for 48% of 1- to 3-y-olds and 75% of 4- to 5-y-olds. “Human milk + Cow milk” was the only milk-feeding scenario modeled that predicted sufficient DHA + EPA among 1- to 3-y-olds. Vitamin D shortfalls were not correctable in any milk-feeding scenario, even with supplementation (5 µg/d), apart from the “Follow-up Formula + Fortified drink” scenario in 1- to 3-y-olds (albeit free sugars intakes were estimated at 12%E compared with ≤5%E as provided by other scenarios). Iron and vitamin E shortfalls were most prevalent in scenarios for 1- to 3-y-olds at ≤25th growth percentile. Conclusions Using WHO growth standards and international reference values, this study provides a protocol for addressing nutrient shortfalls among 1- to 5-y-olds, which could be applied in country-specific population health.
... Based on the improvement in the 600 ml group from 67.0 nmol/L 25OHD at baseline to 78 nmol/L after 6 months, the response factor appears to be high (1.8 nmol/l per µg oral vitamin D) as might be expected in malnourished children (56). In healthy European children aged 1-3 years, receiving 8.5 µg additional vitamin D daily (64), and in Australian and New Zealand 1-y-old participants receiving 1.4 µg additional vitamin D daily (65), the response factor was around 1.1. Vitamin A deficiency (VAD) in Nigerian children under 5 years of age was earlier reported to be about 29.5% (66) despite the mandatory fortification of vegetable oil, wheat flour and sugar with vitamin A (67,68). ...
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Malnutrition results in a high prevalence of stunting, underweight, and micronutrient deficiencies. This study investigated the effect of a multi-nutrient fortified dairy-based drink on micronutrient status, growth, and cognitive development in malnourished [height-for-age z-score (HAZ) and/or weight-for-age z-score (WAZ) < -1 SD and >−3 SD] Nigerian toddlers ( n = 184, 1–3 years). The product was provided in different daily amounts (200, 400, or 600 ml) for 6 months. At baseline and endline, venous blood and urine samples were collected to determine micronutrient status. Bodyweight, height, waist, and head circumference were measured, and corresponding Z-scores were calculated. The Bayley-III Screening Test was used to classify the cognitive development of the children. In a modified per-protocol (PP) population, the highest prevalence's of micronutrient deficiencies were found for vitamin A (35.5%) and selenium (17.9%). At endline, there were no significant improvements in iodine, zinc, vitamin B12, and folate status in any of the three groups. Regarding vitamin D status (25OHD), consumption of 600 and 400 ml resulted in an improved status as compared to baseline, and in a difference between the 600- and 200-ml groups. Consumption of 600 ml also increased vitamin A and selenium status as compared to baseline, but no differences were found between groups. Within the groups, WAZ, weight-for-height z-score (WHZ), and BMI-for-age z-score (BAZ) improved, but without differences between the groups. For HAZ, only the 600 ml group showed improvement within the group, but it was not different between groups. For the absolute weight, height, and head circumference only trends for differences between groups were indicated. Cognition results did not differ between the groups. Within groups, all showed a decline in the per cent of competent children for receptive language. To study the effects of a nutritional intervention on linear growth and cognition, a longer study duration might be necessary. Regarding the improvement of micronutrient status, 600 ml of fortified dairy-based drink seems most effective. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT03411590?term=NCT03411590.&draw=2&rank=1 , identifier: NCT03411590.
... A double-blind, randomized placebo-controlled trial [102] was conducted on healthy toddlers aged 12 to 36 months to investigate the benefits of YCF (containing 12 mg/L iron and 17 μg/L vitamin D) compared to unmodified CM (containing 0.02 mg/L iron and no vitamin D). After 20 weeks, the probability of developing iron deficiency and vitamin D deficiency was significantly inferior in toddlers consuming YCF. ...
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The complementary feeding (CF) period that takes place between 6 and 24 months of age is of key importance for nutritional and developmental reasons during the transition from exclusively feeding on milk to family meals. In 2021, a multidisciplinary panel of experts from four Italian scientific pediatric societies elaborated a consensus document on CF, focusing in particular on healthy term infants. The aim was to provide healthcare providers with useful guidelines for clinical practice. Complementary feeding is also the time window when iron deficiency (ID) and iron deficiency anemia (IDA) are most prevalent. Thus, it is appropriate to address the problem of iron deficiency through nutritional interventions. Adequate iron intake during the first two years is critical since rapid growth in that period increases iron requirements per kilogram more than at any other developmental stage. Complementary foods should be introduced at around six months of age, taking into account infant iron status.
Article
Objective Undernutrition, stunted growth and obesity remain a concern in Algeria. Currently, limited data are available on nutrient intakes among children. Our study aimed to describe food and nutrient intakes and the role of milk formulas among Algerian children. Design Dietary intakes were collected using a 4-day interview-based survey for children aged 0-24 months, living in urban areas in Algeria in 2019. Setting Food consumptions were described. For children aged 6-24 months, nutrient intakes and adequacy were estimated. Modelling was used to estimate the nutritional impact of substituting cow’s milk for age-appropriate infant formulas. Participants 446 children aged 0-24 months. Results Before 6 months, 91.6% of infants were breastfed. Breastmilk was also the main milk consumed between 6 and 12 months, whereas cow’s milk predominated after 12 months. In children aged 6-24 months, nutrient adequacy prevalence was above 75% for the majority of nutrients. However, less than 30% of the children had adequate intakes for total fats, iron and vitamin D. Simulated substitution of cow’s milk for infant formulas led to improved adequacy for proteins, iron, vitamins D and E. Conclusions Our study showed that breastfeeding rates were high until 6 months, then declined with age. Consumed foods allowed Algerian children aged 6-24 months to meet most of their nutritional needs, but inadequate intakes were reported for some key nutrients. Our modelling suggested that formulas may help to improve nutrient adequacy among non-breastfed infants. Other dietary changes could also be further investigated to enable children to meet all nutritional recommendations.
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In 2021 a multidisciplinary expert panel of four Italian scientific Pediatric Societies produced a Document on Complementary feeding (CF). The aim was to provide useful clinical advice for pediatricians working in Pediatric Divisions, the Primary Care Services, residents or Ph.D. students, pediatric nurses, and specialists. The nutrition committees of the Italian Society for Preventive and Social Pediatrics (SIPPS), the Italian Society for Developmental Origins of Health and Disease (SIDOHaD), the Italian Federation of Pediatricians (FIMP), and the Italian Society of Pediatric Nutrition (SINUPE) provided an update of the available clinical literature. The complementary feeding phase is characterized by rapid growth and development, exposing infants at an increased risk of nutrient excesses or deficiencies. Consequently, complementary foods (semisolid, solid foods and liquids other than breast milk, infant formula, follow-on formula, and young-child formula ) and correct feeding practices can prevent malnutrition.
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Iron and zinc are essential micronutrients for human health. Deficiencies in these 2 nutrients remain a global problem, especially among women and children in developing countries. Supplementation with iron and zinc as single micronutrients enhances distinct and unique biochemical and functional outcomes. These micronutrients have the potential to interact when given together; thus, it is important to assess the biochemical and functional evidence from clinical trials before supplementation policies are established. We reviewed randomized trials that assessed the effects of iron and zinc supplementation on iron and zinc status. On the basis of this review, zinc supplementation alone does not appear to have a clinically important negative effect on iron status. However, when zinc is given with iron, iron indicators do not improve as greatly as when iron is given alone. In most of the studies, iron supplementation did not affect the biochemical status of zinc, but the data are not clear regarding morbidity outcomes. Although some trials have shown that joint iron and zinc supplementation has less of an effect on biochemical or functional outcomes than does supplementation with either mineral alone, there is no strong evidence to discourage joint supplementation. Supplementation programs that provide iron and zinc together are an efficient way to provide both micronutrients, provided the benefits of individual supplementation are not lost. Further research is needed before health policies on joint supplementation programs can be established.
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Iron and zinc are essential micronutrients for human health. Deficiencies in these 2 nutrients remain a global problem, especially among women and children in developing countries. Supplementation with iron and zinc as single micronutrients enhances distinct and unique biochemical and functional outcomes. These micronutrients have the potential to interact when given together; thus, it is important to assess the biochemical and functional evidence from clinical trials before supplementation policies are established. We reviewed randomized trials that assessed the effects of iron and zinc supplementation on iron and zinc status. On the basis of this review, zinc supplementation alone does not appear to have a clinically important negative effect on iron status. However, when zinc is given with iron, iron indicators do not improve as greatly as when iron is given alone. In most of the studies, iron supplementation did not affect the biochemical status of zinc, but the data are not clear regarding morbidity outcomes. Although some trials have shown that joint iron and zinc supplementation has less of an effect on biochemical or functional outcomes than does supplementation with either mineral alone, there is no strong evidence to discourage joint supplementation. Supplementation programs that provide iron and zinc together are an efficient way to provide both micronutrients, provided the benefits of individual supplementation are not lost. Further research is needed before health policies on joint supplementation programs can be established.
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In recent years, reports suggesting a resurgence of vitamin D deficiency in the Western world, combined with various proposed health benefits for vitamin D supplementation, have resulted in increased interest from health care professionals, the media, and the public. The aim of this position paper is to summarise the published data on vitamin D intake and prevalence of vitamin D deficiency in the healthy European paediatric population, to discuss the health benefits of vitamin D and to provide recommendations for the prevention of vitamin D deficiency in this population. Vitamin D plays a key role in calcium and phosphate metabolism and is essential for bone health. There is insufficient evidence from interventional studies to support vitamin D supplementation for other health benefits in infants, children, and adolescents. The pragmatic use of a serum concentration >50 nmol/L to indicate sufficiency and a serum concentration <25 nmol/L to indicate severe deficiency is recommended. Vitamin D deficiency occurs commonly among healthy European infants, children, and adolescents, especially in certain risk groups, including breast-fed infants, not adhering to the present recommendation for vitamin D supplementation, children and adolescents with dark skin living in northern countries, children and adolescents without adequate sun exposure, and obese children. Infants should receive an oral supplementation of 400 IU/day of vitamin D. The implementation should be promoted and supervised by paediatricians and other health care professionals. Healthy children and adolescents should be encouraged to follow a healthy lifestyle associated with a normal body mass index, including a varied diet with vitamin D-containing foods (fish, eggs, dairy products) and adequate outdoor activities with associated sun exposure. For children in risk groups identified above, an oral supplementation of vitamin D must be considered beyond 1 year of age. National authorities should adopt policies aimed at improving vitamin D status using measures such as dietary recommendations, food fortification, vitamin D supplementation, and judicious sun exposure, depending on local circumstances.
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Iron deficiency is the most common nutritional disorder in the world. Young children are particularly vulnerable to the consequences of iron deficiency because of their rapidly developing brain. This review evaluates the prevalence of inadequate iron intake and iron deficiency (anaemia) in European children aged 6-36 months. Computerized searches for relevant articles were performed in November 2013. A total of 7,297 citations were screened and 44 studies conducted in 19 European countries were included in this review. In both infants (6-12 months) and young children (12-36 months), the mean value of iron intakes in most countries was close to the RDA. Nevertheless, proportions of inadequate intakes were considerable, ranging from about 10% in the Netherlands up to 50% in Austria, Finland and the United Kingdom. The prevalence of iron deficiency varied between studies and was influenced by children's characteristics. Two to 25% of infants aged 6-12 months were found to be iron deficient, with a higher prevalence in those who were socially vulnerable and those who were drinking cow's milk as a main type of drink in their first year of life. In children aged 12-36 months, prevalence rates of iron deficiency varied between 3 and 48%. Prevalence of iron deficiency anaemia in both age groups was high in Eastern Europe, as high as 50%, whereas the prevalence in Western Europe was generally below 5%. Key Messages: In most European countries, mean iron intakes of infants and children aged 6 to 36 months were found to be close to the RDA. Nevertheless, high proportions of inadequate intakes and high prevalence rates of iron deficiency were observed. Health programs should (keep) focus(ing) on iron malnutrition by educating parents on food choices for their children with iron-rich and iron-fortified foods, and encourage iron supplementation programmes where iron intakes are the lowest. © 2015 S. Karger AG, Basel.
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Iron deficiency (ID) and iron deficiency anemia (IDA) during the first years of life are associated with delayed motor and neurological development. Many studies evaluated iron status without assessment of an acute-phase protein to identify infection. Since most parameters on iron status are influenced by infection these data might underestimate ID prevalence. A recent food consumption survey in the Netherlands showed that the mean iron intake of children aged 2 to 3 years was below the advised adequate intake of 7 mg/day.Aim: To investigate the iron status in a well-defined, healthy population of young children in the Southwestern region of the Netherlands and to identify risk factors for ID. We conducted a multi center, observational study in healthy children aged 0.5 to 3 years. We defined ID as ferritin <12 μg/L and IDA when, in addition, hemoglobin was <110 g/L. Children with elevated C-reactive protein levels (>5 mg/L) or underlying causes for anemia were excluded. Parents filled in a questionnaire to identify risk factors for ID. We included 400 children. ID and IDA were detected in 18.8% and 8.5% respectively. The current use of formula and visit of preschool/daycare were associated with a lower prevalence of ID and a high intake of cow's milk was associated with a higher prevalence of ID, after adjustment for age. ID is present in 18.8% of healthy children aged 0.5 to 3 years and living in the Southwestern region of the Netherlands. The present visit of preschool/daycare and the use of formula are associated with a reduced risk of ID while a high intake of cow's milk is associated with an increased risk of ID.
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Vitamin D plays an important role in human health. Current recommendations for vitamin D intake and endogenous supply through sun exposure are not met in German pre-school children, and suboptimal serum 25-hydroxyvitamin D concentrations, especially during the winter months, are common. Consequently, vitamin D supplementation or fortification have gained increased acceptance. The KiMi trial (Kindermilch = growing up milk) was a prospective, randomized, and double-blind study in which young children (2-6 years of age, n = 92) were assigned to receive either vitamin D-fortified growing up milk (2.85 μg/100 ml) or semi skimmed cow's milk without added vitamin D. Daily consumption of fortified growing up milk contributed to the prevention of an otherwise frequently observed decrease in serum 25-hydroxyvitamin D concentration during winter (before winter: median 21.5 ng/mL (10.1-43.0 ng/mL) intervention vs. median 18.4 ng/mL (11.0-44.9 ng/mL) control; after winter: median 24.8 ng/mL (7.0-48.2 ng/mL) intervention vs. median 13.6 ng/mL (7.0-36.8 ng/mL) control) and proved to be safe during summer (median 27.6 ng/mL (18.8-40.5 ng/mL) intervention vs. median 27.4 ng/mL (17.8-38.7 ng/mL) control). Due to the high prevalence of vitamin D deficiency, fortification of growing up milk with vitamin D at a level used in this study could be an effective measure to improve vitamin D status.
Article
Background and aim: Iron deficiency (ID) and vitamin D deficiency (VDD) are the two most common micronutrient deficiencies in young children worldwide and may lead to impaired neurodevelopment and rickets, respectively. Risk factors for ID and VDD differ between populations. The objective of this study was to determine the prevalence of and risk factors for ID and VDD in 12-36 months old children in Western-Europe. Methods: This study took place in Germany, the Netherlands and the United Kingdom from 2012 to 2014. A venous blood sample was taken to establish iron and vitamin D status. ID was defined as serum ferritin < 12 μg/l in the absence of infection (hsCRP <10 mg/l). VDD was defined as serum 25-hydroxyvitamin D <50 nmol/l (20 ng/ml). Furthermore, parents were asked to fill out a questionnaire regarding their child's demographic- and socio-economic characteristics, food intake, sun exposure and medical history. Results: In 325 children (Caucasian race 95%; male 56%; mean age 20.7 months) the overall prevalence of ID and VDD was 11.8% and 22.8%, respectively. The use of primarily cow's milk as major type of milk was associated with ID (OR 3.20, 95% CI 1.12-8.53) and VDD (OR 7.17, 95% CI 3.10-16.57). The use of vitamin D supplements (OR 0.20, 95% CI 0.07-0.56) was associated with a lower prevalence of VDD. Conclusion: Despite current nutritional recommendations, ID and VDD are common in healthy young Caucasian children. Health programs focusing on adequate iron and vitamin D intake at an early age should be implemented to prevent deficiencies.
Article
Extensive data from animal and human studies indicate a role of vitamin D in erythropoiesis. Iron and vitamin D deficiencies are implicated with adverse health effects in children even if they are asymptomatic. The potential relationship between the two remains poorly understood. A cross-sectional study was performed in the period from 1st May 2012 through 30th April 2013 and subjects were classified into vitamin D deficiency (VDD), vitamin D insufficiency (VDI) and vitamin D sufficiency (VDS) groups according to their 25(OH) D levels. A total of 263 children were included in the analysis. Anaemia was present in 66 % of 25(OH) D deficient subjects compared with 35 % in vitamin D sufficient individuals (p < 0.0001). The association of breast feeding and development of VDD was also significant (p < 0.05). Serum levels of 25(OH) D were found lower in female sex and if the analysis was performed in the winter/spring season. Physicians should therefore assess vitamin D levels in all anaemic children and ensure adequate supplementation to prevent deficiencies.
Article
Background: We aimed to examine the association between vitamin D deficiency and anemia in a nationally representative sample of Korean children and adolescents. Methods: Cross-sectional data on 2526 children and adolescents aged 10-20 years from the Korea National Health and Nutrition Examination Survey-V (2010-2012) were used. Anemia was defined according to specifications of the World Health Organization. Iron deficiency was defined as serum ferritin level of <12 ng/mL and transferrin saturation (TSAT) <16%. Results: The prevalence of vitamin D deficiency in Korean children and adolescents was high especially in female (35.7% vs. 50.9%, P < 0.001). The prevalence of anemia was also higher in female (1.1% vs. 6.8%; P < 0.001). In logistic regression, risk factors for anemia were female sex, old age, post-menarche, low household income, vitamin D deficiency, and iron deficiency. The Odds Ratio for anemia, iron deficiency and iron deficiency anemia (IDA) in subjects with vitamin D deficiency (<15 ng/mL) were 1.81(95% CI, 1.13-2.88), 1.94(95% CI, 1.27-2.97), and 2.26 (95% CI, 1.20-4.24) after controlling for other risk factors. However, after examining the sexes separately, only female subjects showed statistical significance. After further controlling for iron deficiency, the risk of anemia was not significant (P = 0.261). Conclusions: Vitamin D deficiency is associated with increased risk of anemia, especially iron deficiency anemia, in healthy female children and adolescents. However, the association is attenuated after adjustment for iron deficiency. Further studies are needed to determine whether vitamin D deficiency is the cause of anemia, or bystander of nutritional deficiency which cause iron deficiency.