The role of zinc in the growth and development of children.

Abstract

This review concerns the importance of zinc in growth, development, and cognitive function in children and the deleterious consequences of its deficiency on children's health. Possible strategies to overcome zinc deficiency and the results of some supplementation trials are discussed.

Full text

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REVIEW ARTICLE
The Role of Zinc in the Growth and Development
of Children
Marı ´a J. Salgueiro, BS, Marcela B. Zubillaga, PhD, Alexis E. Lysionek, BS,
Ricardo A. Caro, PhD, Ricardo Weill, Eng, and Jose ´ R. Boccio, PhD
From the Radioisotope Laboratory, School of Pharmacy and Biochemistry,
University of Buenos Aires, Buenos Aires, Argentina and the Agrarian Industries
Department, School of Agronomy, University of Moro ´n, Buenos Aires, Argentina
This review concerns the importance of zinc in growth, development, and cognitive function in children
and the deleterious consequences of its deficiency on children’s health. Possible strategies to overcome
zinc deficiency and the results of some supplementation trials are discussed.
510–519. ©Elsevier Science Inc. 2002
Nutrition 2002;18:
KEY WORDS: zinc, iron, fortification, supplementation, children, growth
INTRODUCTION
Marginal and moderate zinc deficiencies in children with impair-
ment in their growth has been reported from developed and de-
veloping countries.1Severe zinc deficiency is less common among
humans, but it has been useful to understand the seriousness of the
consequences of zinc deficiency in animal experiments.1The ef-
fects of such a deficient state in humans can be devastating because
zinc is essential for normal fetal growth and development and for
milk production during lactation, and it is extremely necessary
during the first years of life when the body is growing rapidly.2,3
Intrauterine growth retardation, one consequence of zinc defi-
ciency, increases the risk of morbidity and mortality of the new-
born. Zinc is a metal with great nutritional importance and is
particularly necessary in cellular replication and the development
of the immune response.4Therefore, if the growing fetus and
infant are at risk of developing zinc deficiency, then an adequate
supply of it is essential for normal growth and development.5Zinc
deficiency triggers an array of health problems in children, many
of which can become chronic, such as weight loss, stunted growth,
weakened resistance to infections, and early death.3,6There is
evidence that zinc deficiency impairs immune responses of young
children and that zinc supplementation can prevent and reduce the
severity of common diseases such as diarrhea and lower respira-
tory tract infections. The severe negative effects of zinc deficiency
on human health in developing countries have been recognized by
the United Nations.6The United Nations Children’s Fund and
World Health Organization supported many studies designed to
demonstrate the effect of zinc on growth, prevalence of diarrhea,
and anemia by administering a combined oral supplement of iron
and zinc to infants at age 3–6 mo for 6 mo.7The main cause of
human zinc deficiency is a diet that is low in highly bioavailable
zinc, but it also may be caused by illnesses that impair food intake,
provoke catabolism or malabsorption, or increase zinc excretion.8
Factors responsible for zinc deficiency in premature infants may
also include high fecal losses and low body stores of zinc at birth
aside from the increased zinc requirement during rapid growth.1
Marginal zinc deficiency is associated with diets based on plant
foods, especially those diets rich in phytate, a potent inhibitor of
zinc absorption.9,10Zinc-rich foods tend to be expensive, so zinc
fortification is an important consideration, especially because daily
intakes appear to be more useful physiologically than intermittent
doses.6,11On the one hand, a wide variety of foods in the United
States are now fortified with zinc.11On the other hand, multivita-
min and mineral supplements are used widely in industrialized
countries, although there is no consensus on their effectiveness and
no guideline on their composition.7Basically they contain iron,
folic acid, zinc, and vitamin A and in some cases riboflavin,
calcium, and magnesium. These kinds of supplements also may be
considered for pregnant women in developing countries. However,
potential interactions between components of the supplement that
may reduce bioavailability of some micronutrients have to be
investigated.7It seems clear that prevention of zinc deficiency
among young children remains the best policy, not only on moral
grounds, but also on economic ones. There is a great deal of work
yet to be done to find an adequate way to prevent zinc deficiency,
but it appears that zinc supplementation or food fortification with
an adequate zinc compound may be the key to overcome such a
worldwide nutritional problem.
ZINC AND GROWTH
Zinc plays an important role in growth; it has a recognized action
on more than 300 enzymes by participating in their structure or in
their catalytic and regulatory actions.12It is a structural ion of
biological membranes and closely related to protein synthesis.10
The concept of zinc fingers explains the role of zinc in gene
expression and endocrine function, and mechanisms of action of
zinc involve the effects of the metal on DNA synthesis, RNA
synthesis, and cell division.13Zinc also interacts with important
hormones involved in bone growth such as somatomedin-c, osteo-
calcin, testosterone, thyroid hormones, and insulin.14Zinc is inti-
mately linked to bone metabolism, thus, zinc acts positively on
growth and development. Zinc concentration in bone is very high
compared with that in other tissues, and it is considered an essen-
tial component of the calcified matrix. Zinc also enhances vitamin
D effects on bone metabolism through the stimulation of DNA
synthesis in bone cells.12In a study conducted in our laboratory
with growing animals, incorporation of zinc to bone resulted in
greater zinc levels than in other organs. Conversely, when grown
animals were evaluated,12,16incorporation of zinc to bone were
lower than in young animals. This indicated that zinc in bone is
very important during the stages of rapid growth and during
Correspondence to: Marı ´a J. Salgueiro, BS, Radioisotope Laboratory,
School of Pharmacy and Biochemistry, University of Buenos Aires, Junı ´n
956 Piso Bajo, 1113 Buenos Aires, Argentina. E-mail: jsalgueiro@-
huemul.ffyb.uba.ar
Nutrition 18:510–519, 2002
©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved.
0899-9007/02/$22.00
PII S0899-9007(01)00812-7

Page 2

development.15Zinc acts on growth at many levels, which are
described in Figure 1.12,16
Zinc may alter appetite control by acting directly on the central
nervous system, altering the responsiveness of receptors to neuro-
transmitters.12Zinc deficiency also is accompanied by alterations
in smell and taste and by anorexia and weight loss.12,17At another
level, zinc participates in DNA and RNA synthesis, which is
ultimately related to cell replication; differentiation of chondro-
cytes, osteoblasts, and fibroblasts; cell transcription; and synthesis
of somatomedin-c, collagen, osteocalcin, and alkaline phospha-
tase. Alkaline phosphatase is produced in osteoblasts and provides
calcium deposition in bone diaphyses. Zinc acts on the synthesis of
alkaline phosphatase, forms part of its structure, and is essential for
its activity. Zinc also participates in the metabolism of carbohy-
drates, lipids, and proteins, which in turn leads to good food
utilization. In another level, zinc plays an important role in hor-
monal mediation because it participates in growth hormone (GH)
synthesis, secretion, and action on liver somatomedin-c produc-
tion. In addition, zinc is involved in the activation of
somatomedin-c in bone cartilage. Zinc deficiency and protein
malnutrition are intimately related and both are associated with
depressed synthesis and activity of somatomedin-c. However, zinc
supplementation rather than protein supplementation could in-
crease somatomedin-c levels in zinc-deficient animals.12Another
animal experiment showed that the administration of bovine
growth hormonetozinc-deficient
somatomedin-c activity did not increase zinc concentrations to
normal levels unless the animals were treated with zinc. Therefore,
somatomedin-c synthesis depends not only on the stimulation of
GH but also on the presence of zinc. Although the improvement in
growth in response to zinc supplementation has been reported in
humans, the relation between zinc and somatomedin-c action is not
well understood because it has not been fully investigated. Zinc
potentiates the action of GH in the liver because it stimulates
somatomedin-c synthesis and action on bone cartilage, and it can
increase GH binding to other receptors such as those present in
adipocytes. At the last level, in addition to vitamin D, there are
several hormones indirectly related to growth such as insulin,
thyroid hormones, and testosterone. Among androgens, testoster-
one is one of the most potent anabolic agents; it increases weight
and muscle mass and accelerates linear growth. There is a direct
relation between blood levels of zinc and testosterone and changes
in steroidogenesis provoked by zinc-deficiency caused hypogonad-
animals withlow
ism. In fact, the first clinical manifestations related to zinc defi-
ciency and its essential role in human nutrition were hypogonad-
ism and growth retardation.12,14,16–20
However, it is important to remember that zinc has no phar-
macologic effect on growth, so its improvements on growth rates
are the result of the correction of a pre-existing zinc deficiency.19,21
In addition to affecting the growth of newborns, infants, and
adolescents, zinc deficiency has an important role in intrauterine
growth. Several studies have demonstrated the nutritional impor-
tance of adequate maternal zinc nutrition for normal fetal growth
and development.12
PREGNANCY
Maternal nutrition status is an important determinant of perinatal
and neonatal well-being. There are many nutrition programs de-
signed to prevent iron-deficiency anemia during pregnancy, but in
the case of zinc, which is also very important for maternal and
infant survival, much less has been done. It is estimated that 82%
of pregnant women worldwide usually have an inadequate regular
intake of zinc and likely suffer health consequences of zinc defi-
ciency.20In humans the research concerning maternal zinc status
and birth weight has not provided consistent results.20The effect of
maternal zinc deficiency on progeny growth on experimental an-
imals is very clear. It results in late effects several months after
birth such as decreased immunity and learning or memory disor-
ders. In the case of humans, not all the studies found a link
between maternal zinc status and birth weight.16However, conse-
quences of maternal zinc deficiency are well known (Table
I).1,12,22,23
Zinc deficiency leads to increased risk of maternal and neonate
morbidity and mortality. Many studies have shown that pregnant
women are at risk of zinc deficiency because their zinc intakes are
very low compared with those recommended, and the diet con-
sumed by most of these women has a high content of
phytate.14,24,25Women with mature infants born by normal deliv-
ery had significantly higher serum zinc during pregnancy than did
women with abnormal deliveries and/or abnormally developed
infants. Teenage girls, women with multiple pregnancies, women
with impaired intestinal absorption due to disease or drugs, and in
particular women consuming a low-protein, high-phytate diet seem
to risk developing zinc deficiency during pregnancy.26
FIG. 1.
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Ortega et al. found that subjects with intakes lower than 50% of
that recommended had significantly lower serum and mature milk
zinc levels than did those with higher intakes (although all subjects
had zinc intakes lower than those recommended).27In addition,
mean dietary zinc intake of postpartum women was less than 42%
of the recommended dietary allowances, as reported by Moser et
al.28Anthropometric, biochemical, and dietary data evaluated by
Huddle et al. indicates that zinc deficiency could be a factor
limiting pregnancy outcome in rural Malawian women.24Vruwink
et al. found that hair zinc concentration evaluated in pregnant
women decreases significantly between 12 and 36 wk of gestation.
In those subjects, mean zinc intake at 20 and 36 wk of gestation
was about 60% of the recommended dietary allowance. Neverthe-
less, zinc nutriture was found to be adequate for normal growth
and development of the fetus.29
In some cases, the iron and folate supplements routinely pre-
scribed significantly decreased the oral bioavailability of zinc in
pregnant women despite dietary intakes.5The combined dietary
and supplementary intake of iron in some subjects provided total
dietary intakes of over 200% those recommended. Those subjects
showed significantly lower serum and mature milk zinc levels than
did those with lower iron intakes.30A study performed with stable
isotopes demonstrated that zinc absorption in women who do not
receive iron supplement from the third trimester of pregnancy to
the lactation period is higher (20% to 31%) than in those receiving
18 mg of iron daily (18%).31In contrast, Tamura et al. found no
evidence of an adverse effect of folic supplementation on maternal
zinc nutriture and pregnancy outcome.32It seems preferable to
provide multisupplements balanced in minerals and vitamins be-
cause iron supplements alone resulted, in some cases, in zinc
deficiency. Zinc requirements and interactions are also important
to consider when designing mineral supplements for preterm ba-
bies, infant formulas, and food fortification.5
There are few data available on whether prenatal zinc supple-
mentation improves maternal and neonatal zinc status.22,33There-
fore, the nutrition status of pregnant women should be monitored
carefully and supplementation should be tailored to the needs of
each individual.30Pregnancy outcome is related to incidence of
fetal growth retardation, maternal infections during the perinatal
period, birth weight, and Apgar score. Although a weak associa-
tion was found in some studies between umbilical cord blood zinc
levels and anthropometric measurements of newborns,34there is
no consensus in the literature as to whether maternal zinc nutriture
is associated with pregnancy outcome or fetal growth.35The lack
of a reliable method to estimate zinc nutrition status may be one of
the problems in finding such an association. Nonetheless, in a
study performed in 1997 with 289 women in Birmingham, Ala-
bama, neither the concentrations of serum zinc nor those of vita-
mins A and E and proteins showed a significant correlation with
measures of pregnancy outcome.36Tamura et al. also reported that
plasma zinc concentrations decline as gestation progresses and,
when adjusted for gestational age, are not significantly associated
with any measure of pregnancy outcome or neonate condition.35
Thus, plasma zinc during the late first trimester to the early third
trimester is not a predictor of pregnancy outcomes.35Caulfield et
al. reviewed zinc supplementation trials in pregnant women and its
effects on birth weight and concluded that, although the increase in
the average birth weight of infants of supplemented mothers is
small, it is comparable to the effects observed in energy and
protein supplementation.33A possible explanation for the in-
creased birth weights of babies of zinc-supplemented mothers may
be that zinc affects the duration of pregnancy rather than fetal
growth per se.14,20Caulfield et al. reported that 15 mg of zinc
prenatally added to iron and folate improves maternal and neonatal
zinc status, although zinc concentrations in both cases remained
lower than values reported for well-nourished populations.33Gold-
enberg et al. found that supplementation with 25 mg of zinc daily
in early pregnancy is related to greater infant birth weights and
head circumferences in some cases.37Women who were supple-
mented with 45 mg of zinc orally daily from the day of reporting
pregnancy until delivery showed significant increases in serum
zinc and their babies had higher birth weights and gestational ages
than did subjects in the control group. Garg et al. reported that
those results were obtained in women supplemented for more than
3 mo and were related to the duration of the treatment.38Golden-
berg et al. also reported that daily zinc supplementation in women
with relatively low plasma zinc in early pregnancy had beneficial
effects on birth weight and head circumference.37In this way, zinc
supplementation with 25 mg of zinc from 19 wk until delivery
resulted in greater birth weights and head circumferences in in-
fants, predominantly in women with a body mass index below
26.37
Mild maternal zinc depletion has been strongly associated with
intrauterine growth retardation.5,39Prematurity and intrauterine
growth retardation have been associated with low serum zinc and
insulin-like growth factor-I.40Zinc supplementation may be ben-
eficial to women at risk of delivering small-for-gestational-age
babies.5However, George et al. in a prospective study found no
differences in plasma, red blood cells, and white blood cells zinc
across 65 women with small-for-gestational-age babies and 51
women with appropriate-for-gestational-age babies.39Perhaps an-
other factor was the cause of the condition in that population.
Serum zinc decreases during pregnancy, but the range of individ-
ual values at the end of normal gestation may be rather large.
Zapata et al. suggested that high levels of maternal serum zinc in
healthy women at delivery may be related to maternal tissue
distribution that could favor diffusional components of maternal-
to-fetal transfer of zinc.41Studies in animals have suggested that,
with inadequate zinc intakes, pregnant rats mobilize zinc from
metabolically active pools for transfer to the fetus, and deposition
of zinc into non-mobilizable maternal pools is reduced to preserve
zinc for essential functions. Therefore, adjustments in zinc metab-
olism maintain embryogenesis even when zinc intakes are mar-
ginal, whereas gross developmental defects occur in humans and
animals with severe zinc deficiency.42Studies have shown that the
proportion of zinc bound to albumin increases in pregnant women
who are marginally deficient in zinc. On the one hand, zinc bound
to albumin is more labile than that bound to ?2-macroglobulin;
thus zinc is more available to be supplied to the placenta in humans
or transferred to the fetus.42On the other hand, even in marginal
zinc deficiency, there is a fall in food consumption; thus, tissue
catabolism is increased in these cases and pregnant dams may
mobilize tissue zinc and deliver apparently normal pups.
Earlier studies in animals have suggested that diets that in-
crease catabolism reduce the teratogenic effects of zinc deficiency
because of the possibility that zinc is released from body tissues
when the metabolic state is altered. There are two major pools of
zinc in the organism: bone and muscle. Masters et al. reported that
most of the specific activity (65Zn) in fetuses of zinc-deficient or
zinc- and calcium-deficient dams came from breakdown of mater-
nal muscle with a relatively small contribution of bone zinc. In
contrast, specific activity of zinc in fetuses from zinc- and calcium-
TABLE I.
CONSEQUENCES OF MATERNAL ZINC DEFICIENCY
Spontaneous abortion
Congenital malformations
Low birth weight intrauterine growth retardation
Preterm and post-term delivery
Prolonged or inefficient first-stage labor
Protracted second-stage labor
Premature rupture of membranes
Pregnancy-related toxemia
512 Salgueiro et al.
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adequate dams was less than 30%, indicating that most of the zinc
came from the diet.43Lowe et al. concluded that in marginal zinc
deficiency, the flux of zinc to the maternal hepatic pool or to other,
more slowly turning over tissue is reduced.42This situation in
addition to a reduction in food consumption and tissue catabolism
in late gestation support a normal pregnancy outcome.42In addi-
tion to the clinical manifestations of zinc deficiency cited in Table
I, the main teratogenic effect of maternal zinc deficiency during
pregnancy seems to be a defective closing of the neural tube.
Numerous studies have shown a high prevalence of zinc deficiency
in populations where this defect is frequent. Favier reviewed this
hypothesis and concluded that zinc is lower in children with neural
tube defects, not as a result of the total absence of a carrier but
perhaps of a non-optimal structure.23Thus, zinc deficiency reduces
the activity of numerous enzymes in the brain, which may lead to
a cessation in cell multiplication at a crucial period of morpho-
genesis.23Velie et al., in more than 430 fetuses or infants with
neural tube defects and 429 controls, associated increased total
preconceptional zinc intake with a reduced risk for neural tube
defects.44The quality of the food source of zinc was very impor-
tant because zinc-rich foods such as animal products were related
to a reduced risk of neural tube defects.44In contrast, Hambidge et
al. studied 27 women with a pregnancy-associated neural tube
defect and found no differences in serum zinc compared with
matched controls. They also concluded that folic supplements do
not alter zinc status of the mother or the embryo.45
LACTATION
The lactation period poses a different threat to maternal zinc
homeostasis because zinc requirements during this period are very
high.46The nearly two-fold increase in zinc absorption during
lactation likely was in response to the demand for zinc to synthe-
size breast milk.2In some cases, plasma zinc concentrations in-
creased from the time of delivery to 1 mo postpartum, possibly to
meet lactating zinc demands, whereas erythrocyte zinc concentra-
tions decreased.28There is a common consensus that bioavailabil-
ity of zinc from human milk is higher than that from cow’s milk or
formulas. Casey et al. evaluated plasma zinc response with human
milk, cow’s milk, and formulas and corroborated that consensus.47
This difference can be attributed to the existence of a citrate-rich
fraction, the presence of lactoferrin, and the lower casein or
phosphorous content of breast milk.16Colostrum, which is rich in
proteins and zinc, is gradually replaced by mature milk. As lacta-
tion proceeds, there is a gradual increase in milk output and a
substantial drop in zinc concentration.48,49After the first month of
lactation, human milk zinc concentrations are low in comparison
with cow’s milk concentrations and declines further as lactation
progresses. Perrone et al. reported a time-dependent decline of
copper, zinc, and selenium in human milk, with similar 10 d
half-times.50Fung et al. reported that the amount of zinc in breast
milk averages 2 mg/d at lactation 7 to 9 wk postpartum.2Wal-
ravens et al. reported that the zinc content of human milk declines
from 40 ?M/L at 1 mo to 10 to 15 ?M/L at 6 mo.19Krebs reported
that, in the early weeks postpartum, zinc excretion in milk is 30 to
40 ?M/d (2 to 3 mg) and declines to 15 ?M/d (1 mg) by 2 to 3 mo
postpartum.46Krebs also reported that the zinc level in breast milk
is about 3 mg/L at 2 wk postpartum.49Therefore, breast milk may
provide only a small percentage of the zinc requirements of infants
after the age of 6 mo.51
Nevertheless, although mechanisms of zinc excretion in milk
are not well understood, high zinc concentrations in milk may be
associated with low zinc intakes. This may be due to a greater
secretion by the mammary gland of zinc bound to stress-mediated
carrier proteins such as ?2-macroglobulin, which may bind zinc,
and it was detected in high concentrations in women of low
socioeconomic status.46
Although evidence suggests that zinc bioavailability from hu-
man milk is very high, the fact that zinc concentrations decline as
lactation proceeds has led to concerns about the risk that fully
breast-fed infants may have suboptimal zinc intakes after the early
months of lactation.16,52Krebs also concluded that zinc concen-
trations in human milk decline sharply during the early months
postpartum, regardless of maternal zinc intake or adequate zinc
status, but zinc requirements of the fully breast-fed infant are
easily achieved because of the high bioavailability of zinc in
human milk.52This situation is optimal; however, up to 5 to 6 mo
thereafter, infants may become marginally zinc deficient if breast-
feeding continues.52Further, if this period is accompanied by
potentially increased losses of zinc, such as the presence of diar-
rhea, zinc supplementation should be considered. At this time,
decline in weight gain is often a sign of marginal zinc deficiency.19
Therefore, among breast-fed infants, growth faltering in compar-
ison with reference growth curves may be common in developing
and developed countries.19Decreased growth rates in breast-fed
infants become apparent after 4 to 6 mo of nursing. In developing
countries, growth velocity decreases earlier, from about 12 wk of
breastfeeding.19Walravens et al. found that growth faltering may
be due in part to inadequate zinc intake in infants breast fed for
longer than 4 mo.19
A major determinant of postnatal survival is the ability of the
infant to resist infection and respiratory and diarrheal diseases.20
Newborns are at particularly higher risk for infections during the
first 6 mo of life because adaptive immunity is not fully functional
and exposure to pathogens is significant. Therefore, because zinc
has a central role in immunity and health development, its defi-
ciency might be a previously unrecognized cause of decreased
vaccine efficacy in infants.20Exclusive breast feeding is protec-
tive, so the introduction of complementary foods is not encouraged
before age 5 to 6 mo; after that age, the choice of high-quality
complementary food is very important and beneficial in providing
an adequate amount of the essential nutrients and energy.46,49
Krebs et al. studied healthy infants who were fed human milk
exclusively for at least 5 mo and then evaluated at ages 2 wk and
3, 5, and 7 mo and found that zinc intakes (mean ? standard error
of the mean) from breast milk were 2.3 ? 0.68, 1.0 ? 0.43, 0.81
? 0.42, and 0.52 ? 0.31 mg/d, respectively.53They concluded
that, although zinc intake seemed to be adequate on average
through 5 mo, it is advisable to consider the introduction of
weaning foods at this point to avoid possible future marginal zinc
deficiency.53Whatever the type of feeding, zincemia in the new-
born decreases during the first 2 mo after birth. This decrease lasts
longer in premature babies born with lower reserves of zinc,
because zinc mainly accumulates in the liver during the last week
of gestation.16Therefore, the term infant’s zinc status is not a
concern during the first months of life because the infant can use
zinc from hepatic thionein reservoirs, which are high and provide
an adequate amount to cover the infant’s requirements, to supple-
ment zinc derived from milk. However, in the case of preterm
infants, caution must be used because zinc thionein and hepatic
reservoirs may be not adequate since the reservoirs are completed
or formed during the last days of gestation.16The possibility of
suboptimal zinc status has to be considered after age 6 mo, when
zinc milk concentrations begin to decline. Krebs et al. factorially
estimated zinc requirements in infants and found that calculated
requirements for retention and for urine and sweat losses, and thus
for apparent absorption, are approximately 10% lower in girls.
That finding could explain the observed sex differences in the
growth response of infants to dietary zinc supplements.54Krebs et
al. also determined that male infants of non–zinc-supplemented
mothers cannot meet zinc requirements after the 7 mo of lactation
even considering 100% absorption of dietary zinc. Although fe-
male requirements are consistently low, the estimated net absorp-
tion necessary to meet their zinc requirements after 7 mo of
lactation would have to be higher than 90%.54
These estimated percentages of zinc absorption necessary to
meet zinc requirements in females and males are much higher than
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Page 5

published values of zinc absorption from human milk; thus, after
the 7 mo of lactation, infants could be at risk of zinc deficiency and
its consequences.54Therefore, although the bioavailability of zinc
in maternal milk is high, even a well-nourished mother may
provide only 7 to 10 ?M of zinc daily. Thus, zinc absorption
would have to approach 80% to 100% to meet zinc requirements
of nursing infants to allow zinc deposition in soft tissues and
especially in bone.19,54However, growth velocity, which is the
main determinant of zinc requirements, also declines as infants
age, so the decline in zinc concentrations of human milk could be
a control mechanism to prevent an unnecessary burden to maternal
zinc status.54In another study, Krebs et al. concluded that the
needs for dietary zinc are adequately met by most fully breast-fed
infants despite relatively low zinc intakes in relation to estimated
requirements.55This may result from the combination of a high
fractional absorption and the efficient conservation of intestinal
endogenous zinc.55Although a diet of breast milk can in rare
circumstances cause insufficient zinc intakes,56there are several
case reports of exclusively breast-fed infants who presented clin-
ical evidence of zinc deficiency with symptoms such as erosive
skin changes, alopecia, a failure to thrive, irritability, and diarrhea.
Zinc supply was low in all these cases, but different zinc supple-
mentation strategies resulted in the normalization of laboratory
values of zinc deficiency and the amelioration of symptoms.56–59
Although the cause of inadequate zinc concentration in breast milk
is not known, there may be a defect in the transfer of zinc from
maternal serum to breast milk related to the alteration of a zinc
transporter. There are reports of severe zinc deficiency, fatal in
most of the cases, in pups born of mothers with a mutation in
ZnT-4, which is expressed in the mammary gland. A mutation in
a gene of the zinc transporter ZnT-4 may account for abnormally
low milk zinc concentrations associated with severe zinc defi-
ciency in breast-fed infants.52,60
INFANCY
Marginal zinc deficiency is a common nutritional problem around
the world, especially in children of developing countries where
diets have less available zinc. Nevertheless, zinc deficiency re-
mains difficult to identify because of the lack of a reliable labo-
ratory index to estimate zinc nutrition status.13This is the reason
zinc supplementation trials have become the best source of infor-
mation about zinc nutriture around the world and especially in risk
groups such as children.
The existence of marginal zinc deficiency among children
produces serious consequences for health such as retarded growth,
an increase in infectious diseases, and the impairment of cognitive
function.10
Diet
The high intakes of phytate relative to zinc in the diet of children
from many countries, but predominantly developing countries,
suggest that these children are at great risk for inadequate zinc
nutriture, with all the consequences that this may provoke for child
health.61–64However, it is important to remember that high cereal
intake is not exclusive to diets of developed countries.65Thus, it is
noteworthy that mild, growth-limiting zinc deficiency might be
prevalent in healthy children and in developed countries.65,66Due
to dietary modifications including the intake of cereals, vegetables,
and the frequent use of soy formulas instead of breast milk,
children from developed and developing countries may suffer from
zinc deficiency.21,67It is estimated that 10% to 15% of the formu-
las fed to US infants currently is soy formula.68With regard to
feeding strategies in premature infants, studies have demonstrated
that feeding with human milk is better than with any other strategy.
In the case of fortified human milk, the data suggest that its
properties compared with those of formula are more beneficial in
the improvement of health, and some investigators have proposed
the promotion of feeding preterm infants with fortified human
milk.69
The use of zinc-fortified formulas has been demonstrated to
improve growth and immune function in children recovering from
malnutrition. Schlesinger et al. reported higher linear growth to-
gether with increased salivary concentrations of immunoglobulin
A.70
Lo ¨nnerdal et al also evaluated various types of infant formulas
and weaning foods in the suckling rat pup model and found that
regular, preterm, hydrolisate, and weaning formulas have high
bioavailabilities of zinc comparable to human and cow’s milk.
However soy-, rice-, and cereal-based formulas had very low zinc
bioavailabilities (45% to 55%) because of the presence of
phytate.71
When casein hydrolysate formula was compared with cow’s
milk formula with respect to zinc absorption, Krebs et al. found
that net zinc absorption from casein hydrolysate is higher.72Pro-
tein digestibility was higher from ultrahigh-temperature–treated
formula than from conventionally heat-treated formula. When
whey-predominant, ultrahigh-temperature–treated formula with 13
or 15 g of protein per liter was evaluated, using breast-fed infants
as controls, iron, zinc, and copper status were satisfactory in all
groups.73Knowing which factors in infant formulas negatively
affect trace element absorption would be helpful when making
dietary choices of weaning foods and for possible changes in the
composition of these foods to improve mineral bioavailability.71In
the case of soy formulas, soy protein was thought to have an
inhibitory effect on zinc bioavailability, but Lo ¨nnerdal et al. dem-
onstrated that it is the high phytate content that reduces zinc
bioavailability from these formulas.68Lo ¨nnerdal et al also dem-
onstrated that there is no threshold level of a phytate:zinc ratio that
needs to be exceeded to observe the inhibitory effect, but there is
a linear negative correlation between zinc absorption and phytate
content.68Therefore, although soy formulas have been designed to
meet the nutrient requirements of human infants, their high phytate
content may negatively affect trace element absorption. However,
reducing the phytate content and partially hydrolyzing the protein
in soy formula had a beneficial effect on zinc absorption in many
cases.74Zinc absorption was higher from low-phytate soy formula
than from regular soy formula in rhesus monkeys (36% versus
22%) and rat pups (78% versus 51%).74Infant formulas in the
United States are supplemented with zinc to 5 to 7 mg/L.68Tyrala
et al. reported that a formula that provides 12.5 mg/L of zinc
allows a positive zinc balance for preterm infants.75In the case of
iron, the recommended level is 12 mg/L.76There has been some
concern as to whether the increased intake of iron via food-
fortification programs could have a negative effect on the absorp-
tion of zinc. Studies in humans have shown that high concentra-
tions of iron interfere with zinc absorption when the minerals are
administered in an aqueous solution but not when given in a meal;
this result may be due to an alternative absorption pathway for zinc
bound to low-weight ligands formed during digestion.77,78Whit-
taker, with reference to Lo ¨nnerdal et al.,68suggested that, when
infant formulas contain 7 mg of iron per liter, the relation of iron
to zinc would be 1:1, with satisfactory hematologic indexes and the
exclusion of possible interactions between these minerals.77Met-
abolic studies to determine the effect of iron fortification in infant
formulas on zinc absorption demonstrated that iron:zinc ratios of
5.4:1 and 1.3:1 do not alter zinc absorption.77Fairweather-Tait et
al. did not find an adverse effect from adding iron to an infant
formula on zinc absorption. However, they used reduced iron for
which bioavailability is variable and its gastric solubility is low.79
A solution providing 10 mg of zinc and 25 mg of iron per 0.5 mL
would supply the child’s requirement for iron and zinc, with no
interference by iron on zinc absorption or by zinc on copper
absorption.51Many experiments evaluating the interaction be-
tween iron and zinc suggest that, when dietary ligands are present,
there is little or no interaction between the absorption of zinc and
514Salgueiro et al.
Nutrition Volume 18, Number 6, 2002