Optimizing iron adequacy and absorption to prevent iron deficiency anemia: The role of combination of fortified iron and vitamin C

Abstract

Iron is a vital nutrient to promote the availability of tissue oxygen, cell growth and control of differentiation, and energy metabolism. Preventing Iron Deficiency Anemia (IDA) is necessary because iron is vital to central nervous system growth and development especially in the first years of life. Iron-rich complementary foods are recommended in infants around 6 months of age because iron store is depleted. Better understanding of iron absorption process and factors affecting its absorption and bioavailability is necessary to prevent iron deficiency and can be a dietary strategy to mitigate iron deficiency. Meat and iron-fortified food are the main sources of iron in the diet, and it is essential to introduce supplementary food to improve iron absorption. Additional foods such as cereals, cow milk and soybeans such as phytate, polyphenol and calcium are inhibitors which require care to prevent IDA. Ascorbic acid is an effective iron-absorbing enhancer, which is useful to reduce the effects of any known nonheme iron inhibitor. In iron-fortified foods, Combination use of vitamin C (ascorbic acid) is recommended in molar ratio of 2:1 (with cow's milk and low-phytate cereal foods) and higher molar ratio of 4:1 (with higher phytate such as soybeans).

Full text

World Nutrition Journal |eISSN 2580-7013
LITERATURE REVIEW
World.Nutr.Journal | 33
Received 27 May 2021
Accepted 15 June 2021
Link to DOI:
10.25220/WNJ.V05.S1.0005
Journal Website:
www.worldnutrijournal.org
Optimizing iron adequacy and absorption to prevent iron
deficiency anemia: The role of combination of fortified iron and
vitamin C
Ray W. Basrowi1, Charisma Dilantika1
1.
Danone Specialized Nutrition, Indonesia
Abstract
Iron is a vital nutrient to promote the availability of tissue oxygen, cell growth and control
of differentiation, and energy metabolism. Preventing Iron Deficiency Anemia (IDA) is
necessary because iron is vital to central nervous system growth and development
especially in the first years of life. Iron-rich complementary foods are recommended in
infants around 6 months of age because iron store is depleted. Better understanding of
iron absorption process and factors affecting its absorption and bioavailability is necessary
to prevent iron deficiency and can be a dietary strategy to mitigate iron deficiency. Meat
and iron-fortified food are the main sources of iron in the diet, and it is essential to
introduce supplementary food to improve iron absorption. Additional foods such as
cereals, cow milk and soybeans such as phytate, polyphenol and calcium are inhibitors
which require care to prevent IDA. Ascorbic acid is an effective iron-absorbing enhancer,
which is useful to reduce the effects of any known nonheme iron inhibitor. In iron-fortified
foods, combination use of vitamin C (ascorbic acid) is recommended in molar ratio of 2:1
(with cow's milk and low-phytate cereal foods) and higher molar ratio of 4:1 (with higher
phytate such as soybeans).
Keywords iron, iron absorption, vitamin C, iron deficiency anemia
Introduction
Iron is a precondition for all human cells and is part
of almost all the living cells. Iron is required to
promote tissue oxygen, cell growth and the
regulation of differentiation and energy metabolism.
Body iron levels are mainly managed by controlling
iron absorption in small intestine, enabling accurate
absorption to match unregulated losses. Depending
on physiological demand, mechanisms regulating
iron absorption often allow appropriate increases or
decreases. Iron bioavailability is also limited, which
explains why people vary in iron and iron stores.
Various abnormalities and diseases can also
influence regulation of iron absorption rate and iron
storage. Therefore, dietary iron absorption by the
proximal intestine is regulated precisely by cellular
and systemic factors to ensure adequate body iron
levels.1
Body iron present at birth is necessary in the first
six months of life for the physiological requirements
of infants with an adequate birth weight. The infant
relies quickly on readily absorbed iron. The body
iron content could increase around 70% in between
4 and 12 months. The average dietary daily
requirement for iron in 7–12 months age was at 0.69
mg. The requirements reduced after 12 months, an
Corresponding author:
Ray W. Basrowi
Nutricia Indonesia Sejahtera
Email address: ray.basrowi1@danone.com

World.Nutr.Journal | 34
average 0.63 mg/day for a child aged 18 months.
Breast-fed babies with adequate weight rarely
experience iron deficiency by 6 months. However
there is a rapid rise in risk for those who remain
breastfed for the next three months when there is no
rich supply of iron in other dietary products.2
The World Health Organization estimates that an
iron deficiency anemia (IDA) is an estimated 25 %
of the world population. Most of this anemia due to
lack of iron diet, but iron absorption and available
iron can also be reduced due to infectious diseases
and other chronic inflammation. Micronutrient
deficiency is found worldwide, and iron deficiency
(ID) is the most common. Young children have
higher risk since they need high iron requirements to
grow. Some risk factors include higher IDA
prevalence, underweight baby birth, excess cow's
milk, small intake of iron-rich complementary
foodstuffs, low socioeconomic status, and
immigrants.3
IDA prevention is needed, since iron is important
for the growth of the central nervous system mainly
throughout the first year old. In vivo experiments
have demonstrated that iron is important for several
brain development aspects, eq. Myelination, activity
of the neurotransmitter, neuronal and glial energy
metabolism and dendritogenesis of the
hippocampus.4 Some studies show strong
correlation between infancy IDA and long-term low
cognitive and behavioral performance. Children
with IDA also have long term behavior issues such
as discomfort, reluctance, and outsourcing and
internalizing problems. ID without anemia was
suggested to be correlated with poor
cognitive/behavioral results, but this needed further
research. There is still a lack of research connecting
dose-by-dose indicators with later cognitive
outcomes.3,5
ID and IDA risk factors in infants include birth
weight underweight, early cord clamping, male, low
socio-economic status, low intake of iron ingestion
and iron fortified foods and excess consumption of
milk from cows. [3] In Indonesia, several problems
with hygiene and chronic infection worsen.
Suggested ID prevention interventions are
supplementation during pregnancy and infants,
delayed umbilical cord clamping, meat products,
cow's milk avoidance formula with fortification
and/or complementary food, also iron-fortified milk
use. A meta-analysis shows that iron
supplementation has a modest positive effect on
mental development and motor development.3,6
To prevent IDA, it is important to uunderstand
the sufficiency of iron and how to improve it. High
iron intakes can adversely affect iron adequate
infants, so it is crucial to diagnose iron status in
young children and understand intervention
strategies such as enhancer or iron absorption
inhibitors to achieve optimum iron adequacy.
The importance of iron adequacy and its
challenges
During early infancy, the small iron in human milk
meets iron requirements. Iron is found mostly in
hemoglobin in the neonate, but a healthy infant has
iron stores that depict 25% of total body iron. At
birth, newborn goes to transition from hypoxic
environment in the uterus to rich oxygen
environment. This transition stopped hemoglobin
synthesis and reduced hemoglobin to 120 g/dL in 6
weeks infants. Recirculating iron in erythrocytes is
transferred to iron storage augmenting it size. After
6 weeks, iron is transferred back from the storage to
blood as the infant continue to grow and expand
their blood volume. This regulation maintains infant
iron levels by themselves when they most needed it
to grow at around 4 to 6 months of age. Exclusive
breastfeeding during this period are adequate to
fulfill iron requirements eventhough breast milk
have low iron concentrations.3
Between age of 1 and 6 years old, the body iron
content is again doubled. Between the age of 6 and
24 months, infants rely on complementary dietary
iron and, due to higher requirements in growth than
during any other lifespan. Iron levels between 6 and
24 months needs to be doubled from 300 mg.3
Growth spurt in adolescents are also the time in need
of more iron. Girls usually spurt before menarche,
but boys shows increased hemoglobin concentration
during puberty which marked rise of iron
requirements.7
The iron role in brain development has been
revealed by over 50 human studies, including
observational studies, supplementation and iron
therapy studies. The development of normal fetal
brain anatomy, myelination, and dopamine,
serotonin, and norepinephrine systems is important

World.Nutr.Journal | 35
with iron. The sooner the brain is prevented from
being inferior to iron the better for instance, in
prenatal and early infancy. Various findings have
indicated that mothers who had iron
supplementation during pregnancy, their children
achieved better in multiple intellectual, executive,
and motor tests than placebo. Moreover, mistimed
or excessive iron can lead to worse
neurodevelopmental outcomes, as shown in a
decade follow-up study in a Chilean iron baby
supplement. In the study, children aged 6 months
receiving iron-enforced formulas with high
haemoglobin performed in a series of
neurodevelopmental tasks much poorer 10 years
later and children receiving iron-enforced medicines
with low-hemoglobin performed much better. These
results emphasize that the nutrient benefits differ at
one dose and can be toxic at another.8
The role of iron in neural transmitter synthesis
makes it antenatally and postnatally important for
brain development. Iron also alters brain epigenetic
landscape. Iron deficiency could result in reduced
myelin development, decreased synaptogenesis and
decreased basal ganglia performance, adverse
development of psychomotors and mental capacity.5
Some research suggests that anemia is correlated
with poor cognitive functions such as concentration,
intelligence, memory and learning skills. A research
by Hurtado et al. (1999) showed that the risk of
moderately mentally delayed children below the age
of a decade with IDA was increased. It was not based
on maternity, gender, nationality, birth weight,
social class, age and education. Children with
hemoglobin below 100 g/dL with an IDA have a low
score for international primary school development
rates. These results show how important childhood
anemia is to be monitored.9
Emotional and psychological behavior are also
affected by iron deficiency. This linked to persistent
changes in dopamine metabolism, GABA, function
and structure of the hippocampus, and
myelinization. Studies also shown that early iron
deficiency can significantly impact cognitive and
behavior also irreversible disturbance in motoric.
Other consequences of iron deficiency anemia is
extensive such as poor growth and development
which also school accomplishment.10 It is therefore
important that the iron deficiency is monitored and
detected as soon as possible.
It is critical to meet the daily intake of iron as the
impact of iron deficiency on brain development
may be irreversible. Recommended daily intakes of
iron are as follow: 11 mg for 6 to 11 months, 7.0
mg for 1 to 3 years, 10 mg for 4 to 6 months, and
10 mg/day for 7 to 9 years.11 This recommended
daily intake (RDA) for children is directed towards
children after 6 months as many authorities
recommend exclusive breast feeding, but exclusive
breast feeding after 6 months is strongly related to
IDA. The iron-rich complementary food is
recommended to avoid iron depletion after six
months of age. This comprises meat, iron-enforced
follow-up formulas and other iron-enforced
products, such as cereals. There is some evidence
that enhanced formulas reduce the risk of anemia in
comparison with pure cow's milk (unmodified).
Pure cow's milk should be avoided in infants under
12 months of age.3
In order to prevention ID and IDA in children, the
early introduction of these iron rich additional foods
such as meat and iron-fortified foods is likely to be
important. Several analyses have assessed the
effects of complementary iron-fortified foods on
iron conditions in children. Iron-fortified
complementary foods (6.2 g/L higher than controls)
significantly affected hemoglobin. It is shown to
reduced risk of anemia (defined as Hb<105 or 110
g/L), by 50% (95% CI 0.33–0.75) with
complementary, iron-fortified food. High-meat
supplementary foods are shown to improve
hemoglobin. One study shows that a substantial
meat intake affects the status of iron like iron-
fortified cereals, even though the cereal group's
daily intake is about five times higher. This is
compatible with previous studies which show that
the absorption of iron from meat is multiple times
higher than cereals.12 Supported by evidence, the
European Society for Hepatological and Nutritional
Paediatric Gastroenterology (ESPGHAN)
recommends that all infants 6 months and older
should be given supplementary food rich in iron
(meat products and/or iron-enforced foods).3
Since the focus of ESPGHAN recommendation is
on nutrition, the family availability of meat
products, a low socioeconomic status, especially in
Indonesia, is more sensitive to unmet iron adequacy.
Indonesia is a low-to-middle-income country; in
2017, 10.6% of its population remained poor.

World.Nutr.Journal | 36
Poverty is the main cause of most undernutrition,
such as iron deficiency. Children and adolescents
with poor socioeconomic status are more vulnerable
to iron deficiency due to low intake of iron, mainly
eating plant-based diets (predominantly non-Heme
iron sources) and low-level iron diets (mostly tofu or
tempeh eating, which may inhibit iron intake),
which are further compounded by chronic blood loss
due to parasite and malaria infections. Other factors
like chronic menstrual loss of blood and
gastrointestinal iron malabsorption can cause IDA in
older children and teenagers.6
The main goal of adequate iron intake is to
prevent childhood delays and cognitive impairment.
Iron is well absorbed in human milk but not enough
to satisfy the needs of infants for 6 months old.
Additional foods besides human milk must be
developed to accommodate the needs of the child
without replacing human milk. As additional foods
are intake limited especially when the iron
requirements are highest, it is crucial to provide the
iron in a highly bioavailable form. Iron rich
supplementary foodstuffs (meat products and iron-
fortified foodstuffs) are recommended in infants
after 6 months, but in the low socioeconomic status
families this challenge is obvious.3
Iron absorption to achieve iron adequacy and
how to obtain it
Most iron absorption takes place in the small
intestines through polarized intestinal epithelial cells
or enterocytes. Iron absorption is performed via
divalent metal conveyor 1 (DMT1), member of the
transported membrane protein solution carrier
group. It is then transferred into the blood through
the duodenum mucosa to produce red blood cells
(RBC) in the cells or in the bone marrow. Feedback
mechanisms are in place to improve the absorption
of iron in iron-deficient individuals. Hepcidin is one
pathway of reducing iron absorption in people
overloaded with iron. Ferroprotein is also known to
control iron absorption from the mucosal cell into
the plasma.7
The iron state in the duodenum influences greatly
its absorption. The iron ferrous (Fe+2) is quickly
oxidized to the ferrous insoluble (Fe+3) at the pH of
physiology. Gastric acid lowers the proximal
duodenum pH.13 This improves the solubility and
absorption of iron ferric. When the production of
gastric acid is impaired, the absorption of iron
decreases considerably. Dietary heme can also be
transported by unknown mechanisms via the apical
membrane and subsequently metabolized by heme
oxygenase 1 (HO-1) in enterocytes to release Fe+2.
This process is more efficient than inorganic
absorption of iron and is pH-independent.14
Two forms of dietary iron are heme and
nonheme. Hemoglobin and myoglobin from animal
meat (cow, chicken and fish) are the primary sources
of heme iron, while nonheme iron is made from
cereals, legumes, fruit and vegetables. In contrast to
heme iron with high bioavailability (15-35%) and
unrelated nutritional conditions, non-heme is easily
altered by other food elements and less bioavailable
(2-20 %). This magnifies the problem as the amount
of non-heme iron is plentiful in most meals. Iron
nutrition is more influenced to non-heme iron intake
than heme-iron despite the low bioavailability of
nonheme iron.15
Animal meat contains well absorbed heme and
promotes further absorption of iron from the diet.
Vegetables, however are rich in factors which inhibit
non-heme iron absorption. If the gastric juice can
pass through a meal containing nonheme iron, it
goes into a common pool. The interaction of iron in
that pool is more absorbed than the others by iron
inhibitors or enhancements in other food
components. Vegetable foods, especially in
developing countries, have inhibitory factors.
Phytates in cereal grains, peanuts, and polyphenols
in tea, coffee, cocoa, and certain vegetables and
grains are the most important. The absorption of
nonheme iron is reduced by calcium ,vegetable
proteins and animal protein other than its flesh.7
Increasing iron needs after 6 months of age can
be replaced by complementary food, but promoting
breastfeeding remains the main nutritional intake
during infancy and early childhood. It is important
to make sure that supplemental with additional foods
do not replace human milk. Iron source that used in
fortification must be readily available because the
quantity of complementary meals are small.2 The
incorporation of meat or fish products should be
encouraged where possible due to their heme iron's
high bioavailability. 25-50 % of the iron provided as
heme is expected to be absorbed in children because

World.Nutr.Journal | 37
they don’t have any significant iron storage.15
Methods to enhance non-heme iron bioavailability
are therefore important, particularly for
complementary foods used in cereals. The balance
between different dietary factors in weaning foods
that influences iron bioavailability must be
examined in order to identify ways to improve iron
balance during the weaning period. Recent studies
showed that increased meat intake in the weaning
period is associated with better iron nutrition. Infants
are unable to chew properly thus providing infant
with meat and in a form that can accommodate this
problem is tricky. Fine ground form of meat in
weaning foods are expected to have a favorable
effect in maintaining iron balance. Generally,
prolonged breastfeeding during weaning can
provide a small bit of iron but has other benefits.12
Some dietary factors that increase iron
absorption, such as fructose, copper, vitamin A and
b-carotene, major enhancer of the absorption of all
ascorbic acid, are also noted for further strategies to
enhance iron bioavailability.1 Contrary to the
striking effect of ascorbic acid on iron absorption, it
was debatable to improve iron condition in extended
vitamin C supplementation.16
Vitamin C and its Role in iron absorption
Ascorbic acid is the most effective iron absorption
enhancer. Moore and Dubach (1951) first
demonstrated ascorbic acid's enhancing properties.
They reported dose-related enhancing properties and
dependent on ascorbic acid in the upper
gastrointestinal tract lumen. Ascorbic acid acts as a
common nonheme pool ligand, increasing the
absorption in gastric fluid of both innate food iron
and iron fortified food. It works only when it is eaten
with food. In a report, 500 mg ascorbic acid taken
with the test meal was absorbed six times, compared
to a low absorption in 4 and 8 hours before meal with
the same quantity.2
The effect of all identified inhibitors of nonheme
iron absorption including phytates, polyphenols,
calcium, vegetable and certain animal proteins is
useful in reducing ascorbic acid. Cereal grains,
cow's milk and peanuts (especially soybeans) are
generally used as supplementary foods in
developing countries. Food sources and additional
food can be combined.12 Phytate is the major
inhibitor of iron absorption in cereal foods and is
expected to be the main inhibitor of these foods.
Ascorbic acid reverses the inhibitory effects of
phytate. Interaction among phytate, ascorbic acid
and iron interest researchers in order to develop
effective early childhood fortification strategies with
specific recommendations for phytate removal and
ascorbic acid addition to the cereal complementarity
foods.17
Cook et al.18 more rigorously evaluated ascorbic
acid efficacy to improve iron absorption from
several different cereal grains. From a practical
perspective there is a need to measure how much
iron is absorbed from complementary food such as
cereal under optimal conditions. This measurement
predict how much ascorbic acid are adequate to even
lowest phytate level. Full-term infants averaging 32
weeks absorbed iron 8.5% of low-phytate meal from
wheat flour and grain enhanced with 2.7 mg iron
sulfate and ascorbic acid (ascorbic acid molar ratio
to iron, 2:1). The food included 25 g of cereal. Lynch
[2] stated that in food containing phytate (70-140
mg/d in additional products designed to supply
enough of iron to meet the average calculated breast-
feeding requirements) the molar ratio between
ascorbic acid and iron should be between 2:1 and
4:1.
Human milk is better absorbed than cow's milk.
The reason is that the milk of cows is higher in
calcium and the milk protein prevents the
consumption of iron. The addition of ascorbic acid
is shown to improve iron in the cow's milk or cow's
milk-based formula significantly. The addition of
ascorbic acid to cow milk containing sulphate
ferrous in a concentration of 100 mg/L (ascorbic
acid-iron molar ratio, 2:1) increased absorption
approximately double. Soybean protein is different
for complementary foods or for milk with lower iron
absorption. Studies show that more ascorbic acid is
needed to ensure adequately bioavailable iron in
complementary soy foods than in cow's milk or
cereal-based foods. The molar ratio of 4:1 ascorbic
acid to iron should be used when weaning high
amounts of soy bean protein products in high phytate
cereals, cerenic foods containing polyphenols or
complimentary foods.2 Iron level in human milk is
very small and so it is important to have iron
fortified foods with high bioavailability. The
Estimated average requirement (EAR) and

World.Nutr.Journal | 38
Recommended Dietary Allowance (RDA) iron
requirements for infants aged 7 to 12 months are 6.9
mg and 11.0 mg for selecting the iron fortification
content in supplementary foods of all children.
Noted that complementary foods used in developing
countries are less bioavailable. The fortification iron
is required at 170 µg/g for meeting the EAR and 275
µg/g for meeting the RDA for infants aged 7-12
months (daily consumption, 40 g). For children aged
13-24 months (daily use, 60 g) 115 and 183 µg/g are
required, respectively.19
We can conclude that enough iron fortified in
additional food should be added to ensure the
infant's diet. Ascorbic acid is useful in reducing the
effect of nonheme absorption inhibitors in cereals,
soya, polyphenols and calcium in cow's milk, for
example. Experimental studies have shown that
absorption levels of approximately 10% for cow's
milk and low-phytate or dephytinized grain foods
can be anticipated if the iron molar ratio of 2:1 in
ascorbic acid is increased by ascorbic acid and
ferrous sulphate, while a molar ratio of higher 4:1 is
required if inhibitors foods such as soya are used.
Conclusion
Iron belongs to nearly all living cells and is a
necessity for all human cells. IDA prevention is
important because iron is critical to the growth and
development of the central nervous system,
especially during the first 12 months of age. In
infants around 6 months of age, iron rich
supplementary food is recommended because iron
shops are depleted. Meat and iron-fortified foods are
the main iron sources of dietary use and it is essential
to introduce complementary foods early to improve
iron absorption. Ascorbic acid is a good iron
absorption promoter and is useful to reduce the
impact of all known non-hemic iron inhibitors that
can help prevent IDs. Foods like cereal, cow's milk
and soya contain iron inhibitors such as phytate,
polyphenol and calcium. It is recommended that the
molar ratio of ascorbic acid 2:1 (for cow's milk and
cereal products) and the higher molar ratio 4:1 be
added to the ratio (for higher phytate, such as
soybeans).
Conflict of Interest
The authors declared no conflict of interest
regarding this article.
Open Access
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(http://creativecommons.org/licenses/by/4.0/),
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appropriate credit to the original author(s) and the
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license, and indicate if changes were made.
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