Available via license: CC BY-NC-ND 4.0
Content may be subject to copyright.
Original Article
Effects of oral zinc supplementation on zinc
status and catch-up growth during the first
2 years of life in children with non-organic
failure to thrive born preterm and at term
Jin Min Cho
a
, Ju Young Kim
a
, Hye Ran Yang
a,b,
*
a
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, South Korea
b
Seoul National University College of Medicine, Seoul, South Korea
Received Feb 7, 2017; received in revised form Oct 16, 2017; accepted Jun 21, 2018
Available online 25 June 2018
Key Words
failure to thrive;
growth;
preterm;
treatment;
zinc
Abstract Background: We aimed to analyze the effect of oral zinc supplementation on serum
insulin-like growth factor-1 (IGF-1) levels and catch-up growth in infants with non-organic fail-
ure to thrive (NOFTT) who were born preterm as compared to those born at term.
Methods: Totally, 105 NOFTT infants aged 2 years or less were enrolled and divided into two
groups according to gestational age at birth. Oral zinc sulfate was administered for 6 months
to 49/66 children born at term, and 21/39 children born preterm. Serum zinc, IGF-1, weight,
and height were measured at baseline and at 6 months.
Results: There were no differences in baseline serum zinc levels between the two groups. In
preterm NOFTT infants, zinc supplementation significantly increased serum zinc levels
compared to those in the non-supplementation group (Dzinc
0e6 month
10.3 26.4 mg/dL vs.
8.8 23.7 mg/dL, pZ0.018), but it did not significantly change serum IGF-1 levels or weight-
and height for age Z-scores. In NOFTT infants born at term who received zinc supplementation,
serum zinc levels, IGF-1, weight for age Z-score, and height for age Z-score increased at 6
months (pZ0.001, pZ0.014, pZ0.049, and pZ0.029, respectively), but this increase
was not significantly greater than in the non-supplementation group. Only the increase in
serum zinc levels was significant after 6 months (Dzinc
0e6month
16.8 32.0 mg/dL vs.
10.0 22.6 mg/dL, pZ0.002).
Conclusion: Zinc supplementation in NOFTT infants improves serum zinc status, regardless of
gestational age at birth. Zinc supplementation in NOFTT infants born at term may improve
serum IGF-1 levels and growth, but it does not in NOFTT infants born preterm. Overall nutri-
tional support rather than supplementation of a single nutrient may be more effective for
catch-up growth in NOFTT infants born preterm.
* Corresponding author. Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of
Medicine, 82 Gumi-ro 173 Beon-gil Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea. Fax: þ82 31 787 4054.
E-mail address: hryang@snubh.org (H.R. Yang).
https://doi.org/10.1016/j.pedneo.2018.06.006
1875-9572/Copyright ª2018, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: http://www.pediatr-neonatol.com
Pediatrics and Neonatology (2019) 60, 201e209
Copyright ª2018, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
1. Introduction
Failure to thrive (FTT) is defined as an inadequate growth
rate in early childhood as compared with the norm for
children of the same age and sex (weight and/or height
below the 5th percentile).
1
Prolonged, severe malnutrition
or under nutrition of children with FTT negatively affects
future growth and cognitive development. It is mainly
related to non-organic causes, and underlying organic dis-
eases are found in only about 10% of children with FTT.
2
During the third trimester of pregnancy, accretion of pro-
tein, glycogen, fat-soluble vitamins, minerals, and trace ele-
ments occurs.
3,4
Preterm infants experience significant energy
and nutrient deficit due to inadequate nutritional intake along
with comorbid disease, incomplete digestion and absorption in
the immature gastrointestinal tract, and limited reserves of
trace elements. Consequently, FTT in early childhood and
nutritional deficits are very common in preterm infants.
5
Zinc, an essential nutrient, is an important cofactor of
many enzymes regulating cell growth and hormone levels.
Its deficiency is associated with growth retardation,
reduced appetite, delayed wound healing, and immune
dysfunction.
6
Several studies in children with FTT reported
positive effects of zinc supplementation on weight gain
and/or linear growth.
7,8
Similarly, improved weight gain
and linear growth was noted after zinc supplementation in
short children with mild to moderate zinc deficiency.
9
Decreased growth of children with NOFTT might therefore
be partly attributable to zinc deficiency. It is hypothesized
that zinc deficiency may start in infancy, and inadequate
provision of zinc is one of the factors contributing to
NOFTT.
10
The growth-enhancing action of zinc supplemen-
tation is likely mediated by insulin-like growth factor (IGF)-
1. In a previous study, induced zinc deficiency in rats
resulted in reduced circulating IGF-1 levels and decreased
IGF-1 gene expression in the liver.
11
However, to date, few have studied the influence of oral
zinc supplementation in children with FTT; and no study has
reported the effect of zinc supplementation on growth and
serum IGF-1 levels in growth-retarded children born pre-
term. Therefore, we aimed to analyze the effect of oral
zinc supplementation on serum IGF-1 and catch-up growth
in children with NOFTT born preterm compared to that in
those born at term.
2. Methods
2.1. Subjects
We enrolled 105 children with NOFTT aged 24 months
(range: 1.2e24 months). Participants were identified from
among those who visited the nutrition clinic for children at
the Seoul National University Bundang Hospital between
January 2012 and July 2015 for poor weight gain. Children
with underlying organic causes of FTT or children on multi-
vitamin and mineral supplementation within the previous 3
months were excluded. Children with acute weight loss or
poor appetite secondary to acute illness were also excluded.
FTT was defined as a decrease in body weight and/or
height beneath the fifth percentile, or a decrease across
two percentile curves on standardized Korean national
growth charts for at least 3 months.
12
NOFTT was defined in
cases of FTT without an organic condition associated with
growth retardation.
The subjects were divided into two groups according to
gestational age at birth: children born preterm (n Z39),
and children born at term (n Z66). Preterm birth was
defined as the delivery of an infant before 37 weeks of
gestation. The study subjects were further divided into two
subgroups according to the presence of oral zinc
supplementation.
2.2. Anthropometric and laboratory measurements
Demographic, parental socioeconomic, and clinical data
were retrospectively reviewed in all recruited subjects.
Paternal and maternal education were retrospectively
reviewed, based on the self-reported completed educa-
tional level. Paternal occupation was classified in 3 cate-
gories: professional/service, agricultural/manual, and not
working. Serum zinc, IGF-1 level, weight, and height were
assessed in all subjects, regardless of zinc supplementa-
tion, at baseline and 6 months.
Anthropometric measurements were performed in all
subjects at baseline and 6 months. Height was measured to
the nearest 1.0 mm in a supine or standing position ac-
cording to age; body weight was measured using a cali-
brated digital scale to the nearest 0.1 kg. The Z-score of
weight for age and the Z-score of height for age were
calculated from Korea National Center for Health Statistics
reference data.
Laboratory tests were performed on all subjects at
baseline and at 6 months, including serum zinc and serum
IGF-1 levels. To measure serum zinc concentrations, trace
element tubes were used, and levels were determined by
inductively coupled plasma mass spectrometry (ICP-MS;
Agilent Technologies, Santa Clara, California, USA). The
normal reference range of serum zinc was 70e150 mg/dL,
and serum zinc level <70 mg/dL was defined as zinc defi-
ciency. Serum IGF-1 levels were quantified using an
immunoradiometric assay with commercially available kits
(Immunotech, Marseille, France).
2.3. Zinc supplementation
The zinc-supplementation group (n Z70) received 5 mg
of elemental zinc per day, whereas the non-
202 J.M. Cho et al
supplementation group (n Z35) received none. Oral
zinc sulfate 22 mg (5 mg elemental zinc) was adminis-
teredfor6monthsto49of66childrenbornattermand
21 of 39 born preterm.
2.4. Statistics
The results were analyzed using the PASW Statistics for
Windows, version 22.0 (SPSS Inc., Chicago, IL, USA). Data
are presented as mean standard deviation for quantita-
tive continuous variables. Student’s t-test of two indepen-
dent samples was used to compare two continuous
variables because the data in each group showed normal
distribution. Chi-square tests were performed to compare
categorical variables. Paired t-test was used to assess and
compare the effect of oral zinc supplementation on serum
zinc, IGF-1 level, and growth (height and weight) between
baseline and at 6 months. Student’s t-test was applied to
evaluate the differences in the change in serum zinc and
IGF-1 levels and growth between the zinc-supplementation
group and the non-supplementation group. P-values <0.05
were considered significant.
2.5. Ethics
The study was conducted with the approval of the Institu-
tional Review Board of Seoul National University Bundang
Hospital (B-1606-349-104). Informed consent was waived by
the Institutional Review Board.
3. Results
3.1. Patient characteristics
Totally, 105 young children aged 24 months and diag-
nosed with NOFTT (55 boys and 50 girls, mean age
12.0 6.9 months) were included during the study period.
Table 1 shows baseline demographic and anthropometric
data of the study participants. There were no differences
between NOFTT children born preterm and those born at
term in regard to age, gender, baseline serum zinc levels,
and baseline height Z-scores (Table 1). Gestational age,
birth weight, and weight, height, weight Z-scores at
baseline were significantly lower in preterm NOFTT infants
than in term NOFTT infants (Table 1). The average base-
line serum IGF-1 level was significantly higher in preterm
NOFTT infants than in term NOFTT infants (83.9 56.5 ng/
mL vs. 45.6 24.4 ng/mL, pZ0.002) (Table 1). Parental
socioeconomic status based on paternal education, occu-
pation, and maternal education was not significantly
different between zinc-supplemented and non-
supplemented groups of NOFTT children born preterm
and term (Tables 2 and 3 ). Baseline serum zinc levels were
significantly different between zinc-supplemented and
non-supplemented groups of NOFTT children born preterm
and term (pZ0.001, and p<0.001, respectively) (Tab les
2and3).
3.2. Changes in zinc and growth status in NOFTT
children born preterm according to zinc
supplementation
Oral zinc sulfate was administered to 21 of the 39 NOFTT
children born preterm. The changes in serum zinc levels,
IGF-1 levels, weight Z-scores, and height Z-scores during
the 6-month follow-up period, with or without oral zinc
supplementation, in infants born preterm are shown and
compared in Table 4.
In the zinc-supplementation group, there were no sig-
nificant changes in serum zinc levels, IGF-1 levels, weight
for age Z-scores, and height for age Z-scores after 6 months
(Table 4). In the non-supplementation group of NOFTT
children born preterm, there were no significant changes in
serum zinc level or serum IGF-1 level, but there were sig-
nificant changes in weight for age Z-scores and height for
age Z-scores after 6 months (pZ0.022 and pZ0.047,
respectively) (Table 4).
In NOFTT infants born preterm, the increase in serum
zinc levels was higher in the zinc-supplementation group
after 6 months of oral zinc supplementation than in the
non-supplementation group (Dzinc
0e6 month
Table 1 Baseline demographic and anthropometric data of NOFTT infants according to gestational age at birth.
Variables Preterm NOFTT
(n Z39)
Term NOFTT
(n Z66)
pvalue
Age (months, corrected age) at first visit 10.8 7.2 (1.2e24) 12.0 6.0 (1.2e24) 0.071
Sex (male) (n, %) 23 (58) 32 (48) 0.201
Gestational age (wks) at birth 32.4 4.1 39.1 0.9 <0.001
Birth weight (kg) 1.4 0.6 2.8 0.4 <0.001
Serum zinc level at baseline (mg/dL) 89.5 5.2 81.4 18.7 0.064
Zinc deficiency (n, %) 9 (23) 20 (30) 0.285
Serum IGF-1 level at baseline (ng/mL) 83.9 56.5 45.6 24.4 0.002
Weight at baseline (kg) 7.0 2.0 7.8 1.7 0.032
Height at baseline (cm) 68.2 10.4 71.9 8.3 0.045
Weight for age z-scores at baseline 2.58 1.35 1.84 0.80 0.010
Height for age z-scores at baseline 1.89 1.42 1.35 1.05 0.119
Data are presented as mean standard deviation or numbers (%).
NOFTT, non-organic failure to thrive; IGF, insulin-like growth factor.
Bold values emphasize the statistically significant pvalue <0.05.
Zinc supplementation in growth-retarded infants 203
10.3 26.4 mg/dL vs.8.8 23.7 mg/dL, pZ0.018) (Table
4). However, the gains in weight Z-scores and height Z-
scores, as well as changes in serum IGF-1 levels, were not
significantly different between the zinc-supplementation
group and the non-supplementation group in NOFTT chil-
dren born preterm (Table 4).
3.3. Changes in zinc and growth status in NOFTT
children born at term according to zinc
supplementation
Oral zinc sulfate was supplied to 49 of the 66 NOFTT chil-
dren born at term. The changes in serum zinc levels, IGF-1
levels, weight Z-scores, and height Z-scores during the 6-
month follow-up period, with or without oral zinc supple-
mentation, in infants born at term are listed and compared
in Table 5.
In the zinc-supplementation group, serum zinc levels,
IGF-1 levels, weight for age Z-score, and height for age Z-
score significantly increased after 6 months of oral zinc
supplementation (pZ0.001,pZ0.014,pZ0.049, and
pZ0.029, respectively) (Table 5). Changes in serum zinc
levels of the zinc-supplementation group during the 6-
month period were significantly different from those of
the non-supplementation group (Dzinc
0e6 month
16.8 32.0 mg/dL vs.10.0 22.6 mg/dL, pZ0.002)
(Table 5). However, no significant differences were
observed between the two groups regarding the changes in
serum IGF-1 level, weight for age Z-scores, and height for
age Z-scores (Table 5).
4. Discussion
Adequate nutrition during first 2 years of life in FTT infants
is essential to promote catch-up growth and neuro-
development. If catch-up growth does not take place early
in life, the likelihood that it will occur later in life is
low.
13,14
In infants, this critical period includes the first
year of life with respect to development of head circum-
ference, and the first 3 years of life with respect to final
height.
15,16
During this period, the rapidly developing brain
is particularly vulnerable to nutrient deficiency.
17
There-
fore, nutritional management of FTT includes the provision
of adequate energy, and protein, as well as specific
micronutrient supplementation including iron, zinc, and
other vitamins or trace elements depending on the defi-
ciency status. Especially in preterm infants, FTT in early
childhood and nutritional deficits are very common. Pre-
term infants with weight or length below the 10th
percentile of the reference curve at post-conceptional age
35e36 weeks are at high-risk for long-term growth impair-
ment, neurodevelopmental abnormality, and behavior
problems.
18,19
Therefore, early “aggressive” nutrition
providing a diet high in energy, and protein, as well as
Table 2 Baseline demographic and anthropometric data of NOFTT infants born preterm, according to oral zinc
supplementation.
Variables Zinc supplemented group
(n Z21)
Non-supplemented group
(n Z18)
pvalue
Age (months, corrected age) at first visit 11.8 7.2 (1.2e24) 9.6 8.4 (1e24) 0.156
Sex (male) (n, %) 15 (71.4) 8 (44.4) 0.088
Gestational age (wks) at birth 31.5 4.7 33.3 3.2 0.331
Birth weight (kg) 1.3 0.6 1.6 0.6 0.102
Maternal education (n, %)* 0.560
Completed university or higher 12 (80) 12 (85.7)
Completed high school 3 (20) 2 (14.3)
Incomplete secondary 0 0
Paternal education (n, %)* 0.175
Completed university or higher 12 (80) 13 (92)
Completed high school 3 (20) 1 (8)
Incomplete secondary 0 0
Parental occupation (n, %)*
Professional, service occupation 15 (100) 14 (100)
Agricultural, manual labor 0 0
Not working 0 0
Serum zinc level at baseline (mg/dL) 78.0 17.8 102.8 26.4 0.001
Zinc deficiency (n, %) 9 (42.9) 0 (0) 0.002
Serum IGF-1 level at baseline (ng/mL) 104.5 67.4 57.1 41.5 0.069
Weight at baseline (kg) 7.5 2.1 6.4 1.9 0.078
Height at baseline (cm) 70.5 9.7 65.4 10.8 0.063
Weight for age z-scores at baseline 2.14 1.13 2.33 1.35 0.535
Height for age z-scores at baseline 1.38 1.26 1.80 1.57 0.526
Data are presented as mean standard deviation or numbers (%).
NOFTT, non-organic failure to thrive; IGF, insulin-like growth factor.
*Data were only available for 15 of 21 zinc-supplemented and 14 of 18 non-supplemented cases.
Bold values emphasize the statistically significant pvalue <0.05.
204 J.M. Cho et al
Table 3 Baseline demographic and anthropometric data of NOFTT infants born at term, according to oral zinc
supplementation.
Variables Zinc supplemented group
(n Z49)
Non-supplemented group
(n Z17)
pvalue
Age (months, corrected age) at first visit 13.9 6.3 (1e24) 10.9 6.1 (1e21.6) 0.104
Sex (male) (n, %) 25 (51) 7 (41.2) 0.484
Gestational age (wks) at birth 39.2 0.9 39.1 1.0 0.942
Birth weight (kg) 2.9 0.4 2.8 0.3 0.901
Maternal education (n, %)* 0.774
Completed university or higher 33 (80) 11 (78.5)
Completed high school 8 (20) 3 (21.5)
Incomplete secondary 0 0
Paternal education (n, %)* 0.885
Completed university or higher 34 (83) 12 (85.7)
Completed high school 7 (17) 2 (14.3)
Incomplete secondary 0 0
Parental occupation (n, %)*
Professional, service occupation 41 (100) 14 (100)
Agricultural, manual labor 0 0
Not working 0 0
Serum zinc level at baseline (mg/dL) 77.4 18.4 92.7 25.2 <0.001
Zinc deficiency (n, %) 19 (38.8) 1 (5.9) 0.011
Serum IGF-1 level at baseline (ng/mL) 47.1 24.7 37.7 20.2 0.433
Weight at baseline (kg) 8.0 1.7 7.3 1.7 0.170
Height at baseline (cm) 72.8 8.1 69.4 8.7 0.085
Weight for age z-scores at baseline 1.86 0.85 1.87 0.55 0.676
Height for age z-scores at baseline 1.35 0.99 1.58 1.04 0.233
Data are presented as mean standard deviation or numbers (%).
NOFTT, non-organic failure to thrive; IGF, insulin-like growth factor.
*Data were only available for 41 of 49 zinc-supplemented and 14 of 17 non-supplemented cases.
Bold values emphasize the statistically significant pvalue <0.05.
Table 4 Changes in serum zinc levels, IGF-1 levels, weight Z-scores, and height Z-scores during the 6-month follow-up period
in NOFTT infants born preterm.
Variables Zinc supplemented preterm group
(n Z21)
Non-supplemented preterm group
(n Z18)
pvalue
y
Baseline 6 months pvalue* Baseline 6 months pvalue*
Serum zinc (mg/dL) 78.0 17.8 88.4 27.6 0.068 102.8 26.4 94.0 20.6 0.134
Dzinc
0e6 month
10.3 26.4 8.8 23.7 0.018
Serum IGF-1 level (ng/mL) 104.5 67.4 97.9 70.5 0.643 57.1 41.5 75.9 61.0 0.121
DIGF-1
0e6 month
6.5 47.5 18.8 34.8 0.176
Weight (kg) 7.5 2.1 9.1 1.3 <0.001 6.4 1.9 8.0 1.6 <0.001
Dweight
0e6 month
1.6 1.3 1.7 0.6 0.068
Height (cm) 70.5 9.7 78.2 7.2 <0.001 65.4 10.8 72.9 7.7 <0.001
Dheight
0e6 month
7.6 3.7 8.5 3.8 0.475
Weight for age Z-scores 2.14 1.13 1.75 1.16 0.229 2.33 1.35 1.94 1.22 0.022
Dweight Z-score
0e6 month
0.39 1.45 0.39 0.63 0.997
Height for age Z-scores 1.38 1.26 1.07 1.00 0.071 1.80 1.57 1.34 1.29 0.047
Dheight Z-score
0e6 month
0.30 0.74 0.530.95 0.411
Data are presented as mean standard deviations.
*pvalue; Each of the 6 months values as compared to the baseline measurement, p-value calculated by paired t-test.
y
pvalue; Each of the Dvalues of zinc supplemented group as compared to those of non-supplemented group, p-value calculated by t-
test.
D;change in serum zinc levels, IGF-1 levels, weight, height, weight for age Z-scores, and height for age Z-scores during the 6-month
follow-up period.
NOFTT, non-organic failure to thrive; IGF-1, insulin-like growth factor-1.
Bold values emphasize the statistically significant pvalue <0.05.
Zinc supplementation in growth-retarded infants 205
micronutrient supplementation to promote early catch-up
growth are encouraged in preterm infants, especially very
low birth weight infants.
20,21
This study evaluated the effect of oral zinc supplemen-
tation over a 6-month period on serum zinc levels, serum
IGF-1 levels, and catch-up growth in NOFTT children aged
24 months born preterm as compared to that in those
born at term. Our results revealed that oral zinc supple-
mentation of 5 mg of elemental zinc for 6 months in young
children with NOFTT born preterm might improve serum
zinc status, revealing a significant difference in changes of
serum zinc levels compared to those without supplemen-
tation, but it had no significant effects on serum IGF-1
levels, weight or height gains over a 6 month follow-up
period. Furthermore, significant gains in weight Z-scores
and height Z-scores were found even in children with
NOFTT born preterm who did not receive zinc supplemen-
tation. As for zinc supplementation in children with NOFTT
born at term, we found a significant improvement in serum
zinc status and an increase in serum IGF-1 levels, as well as
weight and height gains. With respect to growth, these
weight and height gains were not significantly different
from those in patients who did not receive zinc supple-
mentation. The change in the serum zinc level was the only
significant difference observed as a result of zinc supple-
mentation in children with NOFTT born at term.
Zinc is an essential trace element that involves in
metabolic pathways through its catalytic, structural, and
biochemical functions. Thus, zinc is necessary for growth,
immunity, tissue repair, neuropsychological functions, and
hormone actions.
22
Growth retardation is one of the clinical
features related to zinc deficiency. The primary regulator
of growth is the growth hormone (GH)-insulin-like growth
factor 1 (IGF-1) system.
23
Animal studies have demon-
strated that zinc deficiency decreased expression of IGF-1
and GH receptor genes in the liver of growing rats.
11
Pre-
vious studies reported that zinc supplementation increased
plasma IGF-1 levels in short children with or without zinc
deficiency
24,25
and that zinc supplementation increased
growth and circulating IGF-1 level in growth-retarded chil-
dren.
8
However, the mechanism by which zinc supplemen-
tation affects GH secretion and IGF-1 levels is not well
understood.
In our study, zinc supplementation was associated with
an increase in serum zinc levels in NOFTT infants born at
term, and it had a positive effect on both serum IGF-1
levels and growth, as reported previously.
8,9,24,25
Addi-
tionally, in the present study, zinc supplementation in
NOFTT infants born preterm was, to some extent, effective
in maintaining serum zinc status. However, zinc supple-
mentation itself had no significant effect on serum IGF-1
levels, linear growth, or weight gain in this group.
Although a positive effect on growth and serum IGF-1 was
not apparent in the preterm group, the results from our
cohorts that included growth-retarded children born pre-
term might be meaningful in practice, as there are no
previous reports on the effect of zinc supplementation on
serum zinc and serum IGF-1 levels simultaneously in addi-
tion to growth effects in NOFTT children born preterm.
IGF-1 concentration is age-dependent, with a prominent
early postnatal increase, followed by a decrease between 2
and 6 weeks of age,
26,27
a typical pubertal peak for girls and
boys, and a pronounced decline after puberty.
28
Moreover,
IGF-1 is influenced by gestational age at birth. During the
first year, preterm infants had higher IGF-1 levels than term
infants at 2 through 12 months.
29
Our finding of a higher
Table 5 Changes in serum zinc levels, IGF-1 levels, weight Z-scores, and height Z-scores during the 6-month follow-up period
in NOFTT infants born at term.
Variables Zinc supplemented term group
(n Z49)
Non-supplemented term group
(n Z17)
pvalue
y
Baseline 6 months pvalue* Baseline 6 months pvalue*
Serum zinc (mg/dL) 77.4 18.4 94.2 28.2 0.001 92.7 25.2 82.7 10.8 0.075
Dzinc
0e6 month
16.8 32.0 10.0 21.6 0.002
Serum IGF-1 level (ng/mL) 47.1 24.7 64.5 42.9 0.014 37.7 20.2 48.2 17.1 0.108
DIGF-1
0e6 month
17.4 40.3 2.8 32.5 0.301
Weight (kg) 8.0 1.7 9.3 1.5 <0.001 7.3 1.7 8.6 1.1 <0.001
Dweight
0e6 month
1.3 0.9 1.5 1.2 0.435
Height (cm) 72.8 8.1 79.4 6.5 <0.001 69.4 8.7 75.3 5.4 <0.001
Dheight
0e6 month
6.6 3.1 7.1 2.7 0.564
Weight for age Z-scores 1.86 0.85 1.59 1.12 0.049 1.87 0.55 1.30 0.96 0.014
Dweight Z-score
0e6 month
0.27 0.92 0.57 0.82 0.253
Height for age Z-scores 1.35 0.99 1.07 1.05 0.029 1.58 1.04 1.29 0.88 0.241
Dheight Z-score
0e6 month
0.28 0.86 0.28 0.92 0.99
Data are presented as mean standard deviations.
*pvalue; Each of the 6 months values as compared to the baseline measurement, p-value calculated by paired t-test.
y
pvalue; Each of the Dvalues of zinc supplemented group as compared to those of non-supplemented group, p-value calculated by t-
test.
D; change in serum zinc levels, IGF-1 levels, weight, height, weight for age Z-scores, and height for age Z-scores during the 6-month
follow-up period.
NOFTT, non-organic failure to thrive; IGF-1, insulin-like growth factor-1.
Bold values emphasize the statistically significant pvalue <0.05.
206 J.M. Cho et al
baseline IGF-1 level in preterm NOFTT children compared
to term NOFTT infants was consistent with these reports.
Previous studies reported that plasma IGF-1 was lower in
intrauterine growth-retarded infants,
30
children with
constitutionally delayed growth,
31
and growth retarded
children with protein energy malnutrition.
32
In our study,
IGF-1 level at baseline was not significantly different be-
tween zinc-supplemented and non-supplemented groups of
NOFTT children born preterm and term (104.5 67.4 ng/
mL vs. 57.1 41.5 ng/mL, pZ0.069, and 47.1 2 4.7 ng/
mL vs. 37.7 20.2 ng/mL, pZ0.433). However, our cohort
included small for gestational age infants, with intrauterine
growth retardation or protein-energy malnutrition, and
without an age-matched study group, which made it diffi-
cult to elucidate the effect of zinc supplementation on IGF-
1 level in NOFTT children born preterm and term.
Regarding the duration of oral zinc supplementation for
growth-retarded children, zinc supplementation over a 6-
month period as adapted in our study has been previously
shown to have positive effects on weight gain in children
with FTT.
7,8
Weight and height gains, along with increased
plasma IGF-1 levels, were noted in growth-retarded chil-
dren over a 5-month period of oral zinc supplementation.
8
In contrast, zinc supplementation for 3 months had no ef-
fect on weight or height gain in infants with NOFTT,
although there was an increase in serum IGF-1 levels.
33
Considering oral zinc supplementation in preterm infants,
one previous study reported that zinc supplementation
from 36 weeks post-conceptional age until 6 months cor-
rected postnatal age had a positive effect on linear
growth.
34
However, to date, there are limited studies
addressing the duration of oral zinc supplementation for
catch-up growth, especially in children with NOFTT born
preterm.
In regard to the amount of oral zinc to give as a sup-
plement to children born at term, oral zinc supplementa-
tion varying from 5.7 mg to 10 mg of elemental zinc per day
was sufficient to demonstrate improvement in zinc status,
IGF-level, and growth in children with NOFTT or mild to
moderate zinc deficiency.
7e9
Regarding the amount of oral
zinc to give as a supplement to children born preterm, two
studies reported positive effects of zinc supplementation
immediately after birth on serum zinc status and linear
growth with a dose of oral elemental zinc varying between
3 mg and 10 mg per day.
34,35
However, these studies eval-
uated the effects of zinc supplementation in preterm in-
fants regardless of FTT and the primary outcomes evaluated
focused on growth. Serum zinc, IGF-1, and IGFBP3 levels
were not measured in these studies.
In our study, the duration and the amount of oral zinc
supplementation were similar to those described in previ-
ous studies that demonstrated an improvement in serum
zinc level, IGF-1 level, and growth in children with NOFTT
or mild to moderate zinc deficiency.
7e9
Therefore, factors
such as the duration and the amount of zinc supplemen-
tation may not explain the lack of effect of zinc supple-
mentation on serum IGF-1 level and catch-up growth in
study subjects, especially in those born prematurely. One
possible explanation for the lack of effect of zinc supple-
mentation on catch-up growth in children with NOFTT born
preterm could be the coexistence of additional micro-
nutrient deficiencies including vitamins, and minerals or
macronutrient deficiency such as protein-calorie
malnutrition.
Longitudinal growth is the combined result of genetic
endowment and nutrient availability. Certainly, the rele-
vance of nutrients is not limited to zinc; protein and other
micronutrient deficiencies can cause weight stunting or
growth impairment.
36
Rivera et al. showed that not only
zinc but also other micronutrients affected growth, and
that zinc deficiency strongly contributed to growth retar-
dation. Additionally, vitamin A and iron deficiencies are
also contributors to FTT, but only when the initial defi-
ciency is severe.
37
In this study, overall age-appropriate
nutritional counseling and intervention were provided to
all patients. Fifteen of 39 (38%) NOFTT children born pre-
term were younger than 12 months at first visit; among
these, breast feeding, formula feeding, and breast feeding
plus formula feeding were performed in 41.7%, 27.7%, and
30.6% of infants, respectively, with an average amount of
150 cc/kg/day. Thirty-five of 65 (53.8%) NOFTT children
born term were younger than 12 months at first visit; among
these, breast feeding, formula feeding, and breast feeding
plus formula feeding were performed in 45.8%, 20.9%, and
33.3% of infants, respectively, with an average amount of
160 cc/kg/day. There were no significant differences in
feeding method and amount between zinc-supplemented
and non-supplemented groups of NOFTT children born
preterm and term. For parents of breastfed infants, more
frequent breastfeeding, lactation support, and formula
supplementation until catch-up growth was achieved were
recommended.
12,38
Parents of formula-fed infants were
instructed on how to make energy-dense formula by
concentrating the ratio of formula to water during periods
of catch-up growth.
39
For toddlers, a diet high in energy
and protein was provided, and avoiding excessive juice or
snacks was recommended because these can interfere with
proper nutrition.
12
Although no positive response on growth
was noted in the zinc-supplemented group compared to the
non-zinc supplemented group, we found gains in the weight Z-
scores and the height Z-scores, even in the non-zinc supple-
mented group. This suggests that overall nutritional support
for other micronutrient deficiencies as well as protein-energy
malnutrition might have increased the weight Z-score and the
height Z-score, even in the non-zinc supplemented group of
our study. The potential controversies caused by a selection
bias for zinc supplementationin this retrospective study could
be resolved by a future prospective study. Furtherstudies with
adequate sample size and design are needed to evaluate the
role of energy, protein, and other micronutrient support in
catch-up growth in NOFTT infants born preterm.
Our study has several limitations. First, there are limi-
tations inherent to the retrospective design. In this study,
oral zinc was supplemented in NOFTT children with serum
zinc levels lower than 70 mg/dL or with clinical signs and
symptoms of zinc deficiency despite normal serum zinc
levels.
40
Therefore, baseline serum zinc level was signifi-
cantly different between zinc-supplemented and non-
supplemented groups of NOFTT children born preterm and
term (pZ0.001, and p<0.001, respectively). In addition,
several confounding factors such as protein-energy malnu-
trition and other micronutrient deficiencies make it diffi-
cult to evaluate the effect of zinc supplementation in
NOFTT children. Second, serum zinc status was evaluated in
Zinc supplementation in growth-retarded infants 207
this study by measuring serum zinc levels. However, it is
difficult to diagnose zinc deficiency by measuring serum
zinc levels, and measurements of zinc in tissues such as hair
may offer a more accurate diagnosis, in combination with
clinical symptoms and signs.
40
In conclusion, oral zinc supplementation in children with
NOFTT born preterm had no significant effect on serum IGF-
1 level, weight gain, or height gain, despite the fact that
greater changes in serum zinc levels were observed with 6
months of oral zinc supplementation as compared to those
who did not receive zinc supplementation. In contrast, in
children with NOFTT born at term, serum zinc levels, IGF-1
levels, weight for age Z-scores, and height for age Z-scores
all significantly increased after 6 months of oral zinc sup-
plementation. Additionally, the increase in serum zinc
levels was significantly higher after 6 months of oral zinc
supplementation as compared to those without supple-
mentation. However, the changes in serum IGF-1 levels,
weight for age Z-scores, and height for age Z-scores were
not significantly greater than in those who did not receive
zinc supplementation. Furthermore, even in non-zinc sup-
plemented children with NOFTT, born preterm or at term,
gains in weight Z-scores and height Z-scores were found but
statistically they were not significant.
Therefore, although oral zinc supplementation may
improve serum zinc status in children with NOFTT, overall
nutritional support rather than supplementation of a single
nutrient may be more effective for catch-up growth in
NOFTT children regardless of gestational age at birth.
Conflict of interest
The authors have no conflicts of interest relevant to this
article.
References
1. Olsen EM. Failure to thrive: still a problem of definition. Clin
Pediatr (Phila) 2006;45:1e6.
2. Gahagan S. Failure to thrive: a consequence of undernutrition.
Pediatr Rev 2006;27:e1e11.
3. Lapillonne A, Groh-Wargo S, Gonzalez CH, Uauy R. Lipid needs
of preterm infants: updated recommendations. J Pediatr 2013;
162:S37e47.
4. Abrams SA. In utero physiology: role in nutrient delivery and
fetal development for calcium, phosphorus, and vitamin D. Am
J Clin Nutr 2007;85:S604e7.
5. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF,
Wright LL, et al. Longitudinal growth of hospitalized very low
birth weight infants. Pediatrics 1999;104:280e9.
6. Halsted JA, Ronaghy HA, Abadi P, Haghshenass M,
Amirhakemi GH, Barakat RM, et al. Zinc deficiency in man. The
Shiraz experiment. Am J Med 1972;53:277e84.
7. Walravens PA, Hambidge KM, Koepfer DM. Zinc supplementa-
tion in infants with a nutritional pattern of failure to thrive: a
double-blind, controlled study. Pediatrics 1989;83:532e8.
8. Ninh NX, Thissen JP, Collette L, Gerard G, Khoi HH,
Ketelslegers JM. Zinc supplementation increases growth and
circulating insulin-like growth factor I (IGF-I) in growth-
retarded Vietnamese children. Am J Clin Nutr 1996;63:514e9.
9. Nakamura T, Nishiyama S, Futagoishi-Suginohara Y, Matsuda I,
Higashi A. Mild to moderate zinc deficiency in short children:
effect of zinc supplementation on linear growth velocity. J
Pediatr 1993;123:65e9.
10. Krebs NF, Hambidge KM, Walravens PA. Increased food intake
of young children receiving a zinc supplement. Am J Dis Child
1984;138:270e3.
11. McNall AD, Etherton TD, Fosmire GJ. The impaired growth
induced by zinc deficiency in rats is associated with decreased
expression of the hepatic insulin-like growth factor I and
growth hormone receptor genes. J Nutr 1995;125:874e9.
12. Cole SZ, Lanham JS. Failure to thrive: an update. Am Fam
Physician 2011;83:829e34.
13. Harding JE, McCowan LM. Perinatal predictors of growth pat-
terns to 18 months in children born small for gestational age.
Early Hum Dev 2003;74:13e26.
14. Gale CR, O’Callaghan FJ, Godfrey KM, Law CM, Martyn CN.
Critical periods of brain growth and cognitive function in
children. Brain 2004;127:321e9.
15. Eriksson J. Commentary: early ’catch-up’ growth is good for
later health. Int J Epidemiol 2001;30:1330e1.
16. Victora CG, Barros FC, Horta BL, Martorell R. Short-term ben-
efits of catch-up growth for small-for-gestational-age infants.
Int J Epidemiol 2001;30:1325e30.
17. Georgieff MK. Nutrition and the developing brain: nutrient
priorities and measurement. Am J Clin Nutr 2007;85:S614e20.
18. Richards M, Hardy R, Kuh D, Wadsworth ME. Birth weight and
cognitive function in the British 1946 birth cohort: longitudinal
population based study. BMJ 2001;322:199e203.
19. Strauss RS. Adult functional outcome of those born small for
gestational age: twenty-six-year follow-up of the 1970 British
Birth Cohort. JAMA 2000;283:625e32.
20. Thureen PJ, Hay Jr WW. Early aggressive nutrition in preterm
infants. Semin Neonatol 2001;6:403e15.
21. Aggett PJ, Agostoni C, Axelsson I, De Curtis M, Goulet O,
Hernell O, et al. Feeding preterm infants after hospital
discharge: a commentary by the ESPGHAN committee on
nutrition. J Pediatr Gastroenterol Nutr 2006;42:596e603.
22. Benton D. The influence of dietary status on the cognitive
performance of children. Mol Nutr Food Res 2010;54:457e70.
23. Underwood LE, Thissen JP, Lemozy S, Ketelslegers JM,
Clemmons DR. Hormonal and nutritional regulation of IGF-I and
its binding proteins. Horm Res 1994;42:145e51.
24. Imamo
gluS,BereketA,TuranS,TagaY,HaklarG.Effectof
zinc supplementation on growth hormone secretion, IGF-I,
IGFBP-3, somatomedin generation, alkaline phosphatase,
osteocalcin and growth in prepubertal children with idio-
pathic short stature. J Pediatr Endocrinol Metab 2005;18:
69e74.
25. Hamza RT, Hamed AI, Sallam MT. Effect of zinc supplementation
on growth hormone-insulin growth factor axis in short Egyptian
children with zinc deficiency. Ital J Pediatr 2012;38:21.
26. Lineham JD, Smith RM, Dahlenburg GW, King RA, Haslam RR,
Stuart MC, et al. Circulating insulin-like growth factor I levels
in newborn premature and full-term infants followed longitu-
dinally. Early Hum Dev 1986;13:37e46.
27. Bernardini S, Spadoni GL, Po
`voa G, Boscherini B, Hall K. Plasma
levels of insulin-like growth factor binding protein-1, and
growth hormone binding protein activity from birth to the third
month of life. Acta Endocrinol (Copenh) 1992;127:313e8.
28. Teale JD, Marks V. The measurement of insulin-like growth
factor I: clinical applications and significance. Ann Clin Bio-
chem 1986;23:413e24.
29. Rajaram S, Carlson SE, Koo WW, Rangachari A, Kelly DP. Insulin-
like growth factor (IGF)-I and IGF-binding protein 3 during the
first year in term and preterm infants. Pediatr Res 1995;37:
581e5.
30. Thieriot-Prevost G, Boccara JF, Francoual C, Badoual J, Job JC.
Serum insulin-like growth factor 1 and serum growth-
promoting activity during the first postnatal year in infants
208 J.M. Cho et al
with intrauterine growth retardation. Pediatr Res 1988;24:
380e3.
31. Bala RM, Lopatka J, Leung A, McCoy E, McArthur RG. Serum
immunoreactive somatomedin levels in normal adults, preg-
nant women at term, children at various ages, and children
with constitutionally delayed growth. J Clin Endocrinol Metab
1981;52:508e12.
32. Hintz RL, Suskind R, Amatayakul K, Thanangkul O, Olson R.
Plasma somatomedin and growth hormone values in children
with protein-calorie malnutrition. J Pediatr 1978;92:153e6.
33. Hershkovitz E, Printzman L, Segev Y, Levy J, Phillip M. Zinc
supplementation increases the level of serum insulin-like
growth factor-I but does not promote growth in infants with
nonorganic failure to thrive. Horm Res 1999;52:200e4.
34. Dı
´
az-Go
´mez NM, Dome
´nech E, Barroso F, Castells S,
Cortabarria C, Jime
´nez A. The effect of zinc supplementation
on linear growth, body composition, and growth factors in
preterm infants. Pediatrics 2003;111:1002e9.
35. Friel JK, Andrews WL, Matthew JD, Long DR, Cornel AM, Cox M,
et al. Zinc supplementation in very-low-birth-weight infants. J
Pediatr Gastroenterol Nutr 1993;17:97e104.
36. Allen LH. Nutritional influences on linear growth: a general
review. Eur J Clin Nutr 1994;48:S75e89.
37. Rivera JA, Hotz C, Gonza
´lez-Cossı
´o T, Neufeld L, Garcı
´a-
Guerra A. The effect of micronutrient deficiencies on child
growth: a review of results from community-based supple-
mentation trials. J Nutr 2003;133:S4010e20.
38. Hren I, Mis NF, Brecelj J, Campa AS, Sedmak M,
Krzisnik C, et al. Effects of formula supplementation in
breast-fed infants with failure to thrive. Pediatr Int 2009;
51:346e51.
39. Khoshoo V, Reifen R. Use of energy-dense formula for treating
infants with non-organic failure to thrive. Eur J Clin Nutr 2002;
56:921e4.
40. Willoughby JL, Bowen CN. Zinc deficiency and toxicity in pe-
diatric practice. Curr Opin Pediatr 2014;26:579e84.
Zinc supplementation in growth-retarded infants 209
