Selected Macro/Micronutrient Needs of the Routine Preterm Infant

Jatinder Bhatia, MD, FAAP1, Ian Griffin, MD2, Diane Anderson, PhD, RD3, Neelam Kler, MD4, and Magnus Domell€of, MD, PhD5

Requirements for optimal nutrition, especially for micronutrients, are not well defined for premature infants. The “ref-
erence fetus,” developed by Ziegler et al,1 has served as a model to define nutritional needs and studies designed to
determine nutrient requirements. Revision of nutrient requirements and provision of optimal nutrition may lead to
improved outcomes in preterm infants. Appropriate provision of nutrients also may help prevent nutritional disor-
ders, such as metabolic bone disease and anemia. In this review, we discuss calcium, phosphorus, magnesium,
vitamin D, iron, and copper, and define optimal intakes based on the available published data. (J Pediatr
2013;162:S48-55).

O
ptimal micronutrient requirements for preterm infants are not well defined. Increasing numbers of these infants sur-
vive after birth at progressively lower gestational ages. It is important to define micronutrient needs and provide
appropriate amounts of these nutrients to prevent nutritional disorders, such as metabolic bone disease and neonatal
anemias. In this article we review current data from preterm infants and recommend the micronutrient intake necessary to meet
the estimated requirements for calcium, phosphorus, magnesium, vitamin D, copper, and iron.
Calcium and phosphorus homeostasis and formation of bone matrix are complex processes that require an adequate supply
of protein and energy, as well as calcium, phosphorus, magnesium, and vitamin D. Vitamin D is important for bone miner-
alization, supports physiological processes that affect neuromuscular and immune functions, and plays a role in the heart, lung,
pancreas, and brain. Iron is the oxygen-binding moieity of hemoglobin and myoglobin, which are essential for oxygen trans-
port. It is also a cofactor for cytochrome C and other enzymes, which are necessary for cellular energy metabolism. Iron is crit-
ically important for normal brain development, including myelin formation and neurotransmitter synthesis. Zinc is essential
for multiple enzymes involved in gene expression, signal transduction, apoptosis, cellular proliferation, differentiation, and
growth. Copper is essential for enzymes in the electron transport chain and the antioxidant systems; anemia, neutropenia,
and osteoporosis may result from copper deficiency.

Background: Calcium, Phosphorous, Magnesium, and Vitamin D

Physiology of Mineral Accretion and Bone Formation

The majority of fetal mineral accretion occurs during the third trimester.1 Peak calcium accretion rate, typically 120-160 mg/kg/
day (3-4 mmol/kg/day) in late gestation, is maintained through active transplacental calcium influx. Parathyroid hormone
(PTH), PTH-related peptide, and 25-hydroxy vitamin D [25(OH)D] play important roles in the transplacental transport of
calcium and bone remodeling.2 After birth, dramatic physiological changes in bone metabolism result from disruption of
the maternal mineral supply, stimulation of calciotropic hormone secretion, changes in the hormonal environment, and a rel-
ative reduction in mechanical stress. These events stimulate the remodeling process, leading to increased bone resorption and
decreased bone density.3

Calcium, Phosphorus, and Magnesium Intake

Low birth weight (LBW) infants, either preterm or infants with intrauterine growth restriction, have significantly lower calcium
and phosphorus stores compared with infants who are born at term and appropriate for gestational age. This might be the result
of low total body mineral content at birth, which is subsequently worsened by a suboptimal postnatal dietary calcium supply,
transient hypoparathyroidism, lack of mechanical stimulation, and the use of diuretics and other calciuric drugs.
Estimated daily enteral calcium and phosphorus requirements in preterm infants are 120-230 and 60-140 mg/kg/day, respec-
tively. These values may be overestimates, however, because the unique postnatal environment of preterm infants might modify
their mineral needs. Bone accretion in early infancy is not likely to occur at rates observed during the third trimester in utero.
Furthermore, bone remodeling increases after birth, and released minerals be-
come available to the pool of precursors necessary for early postnatal bone 1
From the Medical College of Georgia, Georgia Health
growth and turnover. Recent studies suggest that calcium retention in the range Sciences University, Augusta, GA; University of 2

California Davis Medical Center, Sacramento, CA;

3
Baylor College of Medicine, Houston, TX; 4Sir
Gangaram Hospital, New Delhi, India; and 5Department
25(OH)D 25-hydroxy vitamin D of Clinical Sciences, Pediatrics, Ume
a University, Ume
a,
ELBW Extremely low birth weight Sweden

LBW Low birth weight Please see the Author Disclosures at the end of this
article.
PTH Parathyroid hormone
VLBW Very low birth weight 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.
All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.11.053

S48

of 60-90 mg/kg/day ensures appropriate bone mineralization
in very low birth weight (VLBW) infants.4 An enteral intake
of 120-140 mg/kg/day will support this level of calcium reten-
tion, given an estimated absorption rate of 50%-65%.
Phosphorus accretion is linked to calcium and nitrogen
retention. Phosphorus absorption is efficient (up to 90%)
in infants fed either human milk or formula. If calcium reten-
tion is 60-90 mg/kg/day and nitrogen retention is 350-450
mg/kg/day, then phosphorus intake sufficient to meet accre-
tion by bone and soft tissues can be achieved by an intake of
65-90 mg/kg/day of a highly absorbable phosphate source,
and the resultant calcium:phosphorus would be 1.5-2.0:1.
Similar to calcium, magnesium has a high accretion rate in
utero during the third trimester. Thus, preterm infants
have a higher magnesium requirement than term infant,
estimated as 8-15 mg/kg/day.
Requirement for Vitamin D
The ideal definition of optimal vitamin D levels would be
based on functional biomarkers, such as intestinal calcium
absorption, extent of bone mineralization, and PTH concen-
trations. Recent studies based on adult vitamin D physiology
indicate that a serum 25(OH)D concentration <50 nmol/L is
consistent with vitamin D deficiency, and a concentration
50-80 nmol/L is consistent with vitamin D insufficiency.
25(OH)D concentrations >80 nmol/L are considered suffi-
cient. However, because no similar studies in preterm infants
are currently available, values from adult and pediatric pop-
ulations are extrapolated to neonates.
Low vitamin D level is not uncommon in neonates fed ei-
ther breast milk or infant formula. Preterm neonates are at
particular risk for metabolic bone disease, for reasons that
include: difficulty achieving adequate enteral intake of cal-
cium, phosphorus, and vitamin D; relative immobility; de-
pendence on total parenteral nutrition; use of unfortified
human milk; and adverse effects of medications (ie, diuretics
and steroids) administered during hospitalization. Metabolic
bone disease may be present in >50% of extremely low birth
weight (ELBW) infants and in up to 25% of VLBW infants.
Impact of Vitamin D Supplementation in Preterm
and Term Infants
Total and free 25(OH)D concentrations in cord blood of
preterm and full-term neonates are lower than those in ma-
ternal blood. Early supplementation with vitamin D has
been studied in neonates. Salle et al5 evaluated 25(OH)D
levels in 17 preterm infants who received 1000 IU of vita-
min D daily from birth. Mean levels increased from 20
nmol/L (range, 10-40 nmol/L) at birth to 92 nmol/L (range,
71-116 nmol/L) at 6 months. This dosage is sufficient to
raise vitamin D levels to the desired range when adminis-
tered for 6 months. Whether this leads to any functional
benefits is unclear, however. Several other clinical studies
have evaluated the relationship between vitamin D3 intake
and 25(OH)D concentrations.6-12 These findings support
the consensus opinion that a vitamin D intake of 800-
1500 IU/day is necessary to increase 25(OH)D concentra-
Selected Macro/Micronutrient Needs of the Routine Preterm Infant
Vol. 162, No. 3, Suppl. 1  March 2013
tions to above 75 nmol/L in preterm infants of mothers
with vitamin D deficiency. At best, 400 IU/day of vitamin
D—the amount recommended for term infants—is pro-
vided in some US neonatal intensive care units.13 It is likely
that an intake far lower than this is currently provided,
given that clear criteria for vitamin D sufficiency in preterm
infants have not yet been established.
Evidence from Randomized Controlled Trials
A randomized controlled trial investigating the effect of vita-
min D supplementation on bone density and biochemical
indices in preterm infants has demonstrated that doses of
200-400 IU/kg body weight/day is sufficient to maintain nor-
mal vitamin D status.14 However, a more recent trial that
compared 3 doses (200, 400, or 800 IU/kg/day) led the au-
thors to conclude that higher doses might accelerate bone
turnover.15 Although vitamin D provides clear short-term
benefits to preterm infants, the benefits of increased vitamin
D intake on bone mineral status in preterm-born children are
no longer evident at age 9-11 years.16
Factors Affecting Enteral Absorption of Calcium
and Phosphorus
Intestinal absorption of calcium and bone accretion are
affected by numerous factors. Calcium phosphate has low
solubility compared with calcium chloride, citrate, and car-
bonate. Organic calcium salts, such as calcium gluconate
and glycerophosphate, are more soluble and readibly
absorbed. A high palmitate content in fat reduces calcium ab-
sorption, secondary to the formation of insoluble calcium
soaps.
Supplementation of human milk with phosphorus im-
proves calcium retention and reduces calciuria in infants.
Human milk has an excellent calcium:phosphorus and,
thus, high bioavailability; however, it is relatively low in
calcium and phosphorus and requires fortification to
achieve adequate mineralization in preterm infants. When
human milk fortifier is provided with adequate amounts
of calcium and phosphorus, calcium retention reaches 60
mg/kg/day. The use of human milk fortifiers containing
highly soluble calcium glycerophosphate improves calcium
retention by up to 90 mg/kg/day in formula-fed infants, al-
though the percentage of net calcium absorption is less
than that seen with human milk. Because the poor bio-
availability of preterm formula is compensated for by
a higher calcium and phosphorus content, routine mineral
supplementation is not required in infants fed preterm in-
fant formula.
The reported effects of vitamin D supplementation on cal-
cium absorption have been inconsistent due to differences in
study design. Bronner et al17 showed that calcium absorption
in LBW infants was directly proportional to daily calcium in-
take and independent of vitamin D supplementation. In con-
trast, Senterre et al18 reported that calcium absorption in
preterm infants increased from 50% to 71% when human
milk was supplemented with 1200 IU/day of vitamin D3
with no additional calcium. This latter result suggests that
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THE JOURNAL OF PEDIATRICS  www.jpeds.com
vitamin D supplementation supports calcium absorption.
Calcium absorption increases in a relatively low-pH environ-
ment and with a high-lactose, high-casein formula.
Assessment of Bone Mineralization
Biochemical Markers. Plasma calcium and phosphorus,
serum alkaline phosphatase, and serum osteocalcin concen-
trations and urinary excretion of pyridium cross-links of col-
lagen are used to screen for metabolic bone disease in
preterm infants; however, these markers have limitations
and cannot be considered diagnostic of osteopenia. Never-
theless, elevated serum osteocalcin concentration, coupled
with high serum alkaline phosphatase activity and increased
excretion of cross-linked collagen, has been proposed as
a marker of osteopenia in preterm infants.
Radiologic Markers. Conventional radiologic evaluation
is an insensitive method for evaluating metabolic bone dis-
ease in preterm infants givens the variations in X-ray expo-
sure, as well as quantification. Bone mineral loss must be
significant before it can be appreciated radiologically. Efforts
to define bone density objectively on standard radiography
using a scoring system19 have been followed by more accurate
estimations of bone mineral content by bone absorptiometry.
Dual X-ray absorptiometry has been proven to provide the
most accurate determination of bone mineral content in pre-
term and term infants, and numerous studies have estab-
lished normative data.
Previous Guidelines
Early guidelines recommended a vitamin D dose of 200 IU/
day for : (1) all breastfed infants unless they are weaned to
at least 500 mL/day of vitamin D-fortified formula or milk;
(2) all non-breastfed infants who ingest <500 mL/day of vita-
min D-fortified formula or milk; and (3) children and adoles-
cents who do not get regular sunlight exposure, do not ingest
at least 500 mL/day of vitamin D–fortified milk, or do not
take a daily multivitamin supplement containing at least
200 IU of vitamin D20 (Table I). These recommendations
were based on data from the US, Norway, and China that
showed an intake of vitamin D of 200 IU/day prevents
physical signs of vitamin D deficiency and maintains serum
Table I. Recommended vitamin D supplement for
preterm infants by feeding method
Early breast milk
Early breast with human milk Preterm Suggested
milk only fortifier (4 g/100 mL) formula intake
20-70 IU/L 903 IU/L 400-800 IU/L 400-1000 IU/day
Standard term formula in the US is supplemented with 400 IU/L of vitamin D. A term infant with
formula consumption of 1 L/day will meet the daily requirement and needs no additional
supplementation. A breastfed term infant should be supplemented with a liquid preparation of
vitamin D at a dose of 400 IU/day. A preterm infant will not be able to achieve such a high daily
intake even with preterm formula containing more than 1000 IU/L of vitamin D until he or she
weighs more than 2 kg and achieves a daily enteral intake of 160 mL/kg. Thus, a preterm
infant, whether breastfed or formula-fed, will require vitamin D supplementation in the form of
an oral liquid preparation.
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Vol. 162, No. 3, Suppl. 1
25(OH)D concentrations at 27.5 nmol/L. In contrast, in
some parts of Europe there have been reports of low cord
blood levels of 25(OH) D (<10 mg/mL) in preterm infants,
suggesting a higher required daily intake of up to 1000 IU.
The American Academy of Pediatrics guidelines, revised
in 2008, recommend an increased minimal supplementation
of 400 IU/day to mantain serum 25(OH)D levels at >50
nmol/L.13 However, this dose might not be sufficient in
parts of world where dietary supplementation with vitamin
D is not routine, and the prevalence of vitamin D deficiency
is higher. Considering the prevalence of vitamin D defi-
ciency in pregnant mothers, the European Society of Pediat-
ric Gastroenterology, Hepatology, and Nutrition guidelines
issued in 2009 state that higher vitamin D supply in preterm
infants could be necessary to correct rapidly the low fetal
level.21 A vitamin D intake of 800-1000 IU/day during the
first months of life is recommended, as this dose may help
achieve vitamin D sufficiency without risk of toxicity. These
guidelines were based on several reports that documented
vitamin D doses in sufficient ranges with supplementation
of 800-1000 IU/day.
Gaps in Knowledge
Few studies have defined vitamin D requirements objectively
in neonates, particularly in preterm neonates. Future studies
are needed to define the threshold for adequate vitamin D
levels in neonates based on physiological functions. Guide-
lines for optimal vitamin D intake in preterm infants should
take into account maternal vitamin D intake and status, as
well as geographic, racial, and other constraints.
Copper
In Utero Copper Accretion
Factorial analysis suggests a net requirement of 30 mg cop-
per/kg/day in preterm infants is adequate to maintain normal
growth.22
Postnatal Copper Metabolism
Concentration of copper is high in early milk and declines
with lactation.23 Copper deficiency at 5 weeks to 8 months
postnatally has been reported in preterm infants.23-31 It is
notable, however, that most of these case reports are of in-
fants who received copper-free parenteral nutrition; there is
a paucity of similar recent reports.
Assessment of Copper Status
Copper status is estimated by measuring the plasma con-
centration of copper or ceruloplasmin, the main copper-
binding protein in plasma. Both of these indicators are
decreased in severe copper deficiency but are relatively
insensitive to marginal copper deficiency. The activity of
the enzyme copper-zinc superoxide dismutase in erythro-
cytes may be a more sensitive indicator of copper defi-
ciency. The main clinical features of copper deficiency
are anemia, thrombocytopenia, neutropenia, apnea, osteo-
porosis and other, characteristic changes in bone.24-31 Se-
rum copper concentrations are normally <35 mg/dL, and
Bhatia et al
March 2013
the ceruloplasmin concentration is <15 mg/dL in copper
deficiency.24,27,28
Previous Guidelines
The currently recommended enteral copper intake is 120-150
mg/kg/day.21,32-34 In a comprehensive review of the nutrient
composition of preterm infant formulas, Klein22 recommen-
ded a copper concentration of 100-250 mg/100 kcal. At an
energy intake is 120 kcal/kg/day, this recommendation is
equivalent to 120-300 mg/kg/day.
Newer Guidelines
The 9 published studies of copper balance in preterm infants
present summary data for 28 different groups of preterm
infants.35-43 Copper intake (mean  SD) was 162  128
mg/kg/day (range, 54-528 mg/kg/day), zinc intake was 1226
 653 mg/kg/day (range, 511-2360 mg/kg/day), and the zinc:-
copper ratio (mg/mg) was 8.62  3.14 (range, 3.9-16.9).
To assess the effect of zinc intake on copper retention, we
performed a multiple regression analysis, weighted by the
number of subjects in each of the 28 groups. Copper reten-
tion was positively related to copper intake (P < .0001), neg-
atively related to zinc intake (P < .0001) and postnatal age
(P = .0012), and unaffected by feeding type (human milk
vs formula; P = .83). Zinc and copper intake accounted for
most of the variability in copper retention (R2 = 0.776), as
did the full model (R2 = 0.787). Our analysis yielded the fol-
lowing equation:
Copper retention (mg/kg/day) = 7.8148 + [0.5871 
copper intake (mg/kg/day)] [0.0508  zinc intake (mg/
kg/day)].
From this model, the copper intake required to produce
copper retention of 30 mg/kg/day increases linearly with in-
creasing zinc intake (Figure 1). This retention would be
expected at a copper intake of 210 mg/kg/day if zinc intake
Figure 1. Interrelationship of copper and zinc intake. The
copper intake (mean and 2 SD) required to achieve a copper
retention of 30 mg/kg/day is shown for different zinc intakes.
Also shown are the current range of intakes recommended
by Tsang et al,32 Agostoni et al,21 and Klein.22
Selected Macro/Micronutrient Needs of the Routine Preterm Infant
SUPPLEMENT
were 2000 mg/kg/day, and at a copper intake of 232 mg/kg/
day if zinc intake were 2250 mg/kg/day.
Gaps in Knowledge
The main gaps in our current knowledge regarding copper
requirements for preterm infants involve the effects of copper
retention from diets containing a higher zinc intake (>1.5-2
mg/kg/day) and high intake of enteral copper on liver func-
tion and serum transaminase levels in preterm infants with
and without cholestasis.
Zinc
Zinc is essential for a multitude of enzymes and plays an
important role in cellular growth and differentiation. Zinc
deficiency leads to stunted growth (poor length gain),
increased risk for infection, skin rash, and possibly poor neu-
rodevelopment.44
Assessment of Status
Marginal zinc deficiency is notoriously difficult to diag-
nose, owing to the lack of a reliable biomarker.44 Even
though serum or plasma zinc is the most commonly used
biomarker, it is not a sensitive indicator of marginal zinc
deficiency.44
Current Recommendations
Most studies of zinc requirements in preterm infants have
recommended intakes in the range of 1-2 mg/kg/day.21,32
For formulas, these intakes are equivalent to a minimum
zinc content of 1.1 mg22 to 1.2 mg/100 kcal,21 and a maxi-
mum content of 1.522 to 1.8 mg/100 kcal.21 Intakes as high
as 3 mg/kg/day are sometimes recommended,23 especially
for infants who weigh <1000 g.32 There are concerns about
higher zinc intake because of the potential adverse effect of
zinc on copper absorption, however,44 and a zinc:copper of
<20:1 is recommended for preterm infants.21
Gaps in Knowledge
There remain large gaps in our knowledge of zinc require-
ments in preterm infants. Areas of uncertainty include:
(1) the in utero zinc accretion rate in the fetus; (2) the opti-
mal accretion rate in postnatal preterm infants; (3) bioavail-
ability and retention of zinc contained in human milk
fortified with modern human milk fortifiers and in modern
formulas; (4) effects of zinc intake on the absorption of other
minerals (eg, iron and copper) in preterm infants; (5) effect
of other minerals (eg, iron, copper) on the absorption of
zinc intake in preterm infants; and (6) effect of fat absorption
on zinc absorption in preterm infants.
In Utero Zinc Accretion
In a comprehensive appraisal of nutrient requirements in
preterm infants, Klein22 estimated zinc requirements in
preterm infants using a factorial method. The requirement
for retained zinc (ie, the amount by which that zinc ab-
sorption must exceed zinc losses) was estimated to be
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THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 162, No. 3, Suppl. 1

“approximately 400 mg/kg at 1500-2500 g (30-32 weeks of

postconceptional age).”22 Table II. Summary of significant findings from zinc
supplementation trials in preterm infants
Metabolic Balance Studies Significant
Low zinc High zinc differences,
The 14 reports on zinc balance in preterm infants published intake, intake, high versus
to date35-43,45-49 present summary data for a total of 35 dif- Reference mg/kg/day mg/kg/day low intake
ferent groups from studies examining infants at several dis- Haschke et al (1985)51 0.17* 0.48* \ serum zinc
tinct time points or with several different diets. When the Loui et al (2004)52 0.3-0.4† 0.6† None
Diaz-Gomez 0.55-0.71 0.94-1.43 \ serum zinc
analysis is weighed for the number of individuals in each et al (2003)53 \ red cell zinc
group, zinc retention is positively correlated with zinc in- \ linear growth
take (P = .0401), is greater in formula-fed infants compared Friel et al (1993)54 1.1-1.2‡ 1.9-2.2‡ \ serum zinc
\ linear growth
with human milk-fed infants (P = .0085), and is unaffected \ motor scores
by either gestational age (P = .44) or postnatal age (P = .30)
(Figure 2). Trials are ranked in increasing order of zinc intake in the high-zinc group.
*Assuming calorie intake of 120 kcal/kg/day.
If we assume that a zinc retention of 400 mg/kg/day is †At 6 weeks and at 3 weeks.
optimal, based on Klein’s data for infants weighing 1500- ‡At 3 months and at the start of the study.

2500 g, then a zinc intake of 2200 mg/kg/day is required in

formula-fed infants and an intake of 2025 mg/kg/day is
required in human milk-fed infants to meet that requirement
for absorbed zinc. These intakes are equivalent to 1.7-1.9 mg/
100 kcal. Assuming an energy intake of 120 kcal/kg/day, this
is equal to 1.3-1.5 mg/100 mL of an 80-kcal/100 mL formula
or 1.1-1.3 mg/100 mL of a 67-kcal/oz formula.
Supplementation Trials
Few studies have examined the effect of zinc supplementation
in preterm infants (Table II).50-54 The most relevant of these
is the study by Friel et al,54 who randomized 52 VLBW infants
to receive 66 kcal/100 mL of formula containing either 0.67
or 1.1 mg/100 mL zinc starting at 1 month before discharge
and continuing until 6 months after discharge. These formu-
las would be expected to provide approximately 1.2 or 2.0
mg/kg/day zinc (assuming an energy intake of 120 kcal/kg/
day). The group with the higher zinc intake demonstrated
improved linear growth (but no differences in weight gain
or head circumference increase), higher motor scores, and
(at some time points) higher plasma zinc concentrations.54
These results suggest that the higher zinc intake (in line
with our estimate from metabolic balance data) is preferred
over a lower zinc intake.
Safety of Higher Zinc Doses
Zinc is a relatively nontoxic mineral.44 The Institute of Med-
icine reviewed dietary reference intakes and identified the
potential adverse effect of oral zinc on copper absorption
as the most likely adverse effect of high zinc intake.44 Based
on data from balance studies,35-43,45-49 we conclude that
a zinc intake of 2.0-2.25 mg/kg/day is required to ensure an
adequate zinc retention of 400 mg/kg/day.
Iron
Preterm and LBW infants are at high risk for iron deficiency.
Iron is necessary for brain development, and iron deficiency
anemia in infants is associated with poor neurodevelopment.
In contrast to most other nutrients, however, there is no
mechanism for excretion of iron from the human body.
Excessive iron supplementation may increase the risk of in-
fections, cause poor growth, and interact with absorption
and metabolism of other minerals. Furthermore, iron is a po-
tent pro-oxidant, and iron overload may lead to free radical
disorders. Thus, it is important to avoid both iron deficiency
and iron overload in preterm infants.

Estimated Iron Requirements

Figure 2. Relationship between zinc intake and zinc reten-
tion. Mean zinc intake (mg/kg/day) and zinc retention (mg/
kg/day) reported in previous studies.35-43,45-49 For formula-
fed infants, y = 0.1358x + 100.6 (R2 = 0.12); for human milk-
fed infants, y = 0.450x 510.2 (R2 = 0.12).
S52
Owing to the physiological shift of iron from hemoglobin
into iron stores that occurs in newborns, a healthy term in-
fant is initially independent of exogenous iron and is able to
double its birth weight before iron stores are depleted.
Preterm and LBW infants have higher iron requirements
because of more rapid postnatal growth; small preterm in-
fants double their birth weight at 6-8 weeks, whereas term
infants do not achieve this until approximately 4-6 months
of age.
Bhatia et al
March 2013
Using a factorial approach, estimated iron requirements
for preterm infants with a birth weight of 1 kg are 1.4-2
mg/kg/day during the first year of life. However, these esti-
mates do not consider blood losses and blood transfusions,
which greatly influence iron status and iron requirements
in small preterm infants. Delayed umbilical cord clamping
causes blood to flow from the placenta to the newborn and
is associated with fewer blood transfusions and reduced inci-
dence of intraventricular hemorrhage in preterm infants.
Local practice regarding umbilical cord clamping, blood
sampling, blood transfusions, and erythropoietin treatment
greatly influences iron requirements of preterm infants dur-
ing the first months of postnatal life.
Iron Absorption
Preterm infants absorb 25%-40% of iron from iron supple-
ments given between feedings and 11%-27% of iron from
iron-fortified preterm formula, rates exceeding those seen
in term infants. Studies on iron bioavailability from
multinutrient-fortified human milk are lacking.
Randomized Controlled Trials
Relatively few randomized studies comparing different doses
of iron supplements or fortification of human milk or for-
mula given to preterm or LBW infants have been published
to date.
Iron versus Placebo. A meta-analysis of studies pub-
lished before 1992 showed that prophylactic iron given as
a supplement or in iron-fortified formula leads to signifi-
cantly reduced incidence of anemia at 6 months in preterm
infants.55 An enteral iron dose of 2 mg/kg/day was used in
that study. In a recent randomized controlled, blinded trial
(n = 285), Berglund et al56 showed that iron supplements of
2 mg/kg/day given from 6 weeks of age reduced the risk of
iron deficiency anemia at age 6 months in marginally LBW
infants (2000-2500 g). No adverse effects with regard to
infant growth, infection, or other morbidity were reported.
A recent follow-up of these children found that those sup-
plemented with 1-2 mg of iron per kg/day up to age
6 months exhibited significantly fewer behavioral problems
at age 3 years.57
Different Iron Doses. Several randomized controlled tri-
als have investigated the effects of preterm formulas contain-
ing different amounts of iron. All of these trials included
preterm infants with an average birth weight of 1.4-1.5 kg.
In one trial, an iron intake of 1.3 mg/kg/day resulted in higher
iron stores compared with an intake of 0.3 mg/kg/day, even
though the incidence of iron deficiency (defined as serum fer-
ritin <19 mg/L) at 2 months postdischarge was similar in both
groups (32%).58 A similar study found no difference in iron
status between preterm infants receiving 0.9 mg/kg/day or 1.2
mg/kg/day, and there were no cases of iron deficiency anemia
at age 6 months.59 In another study, the 2 intervention
groups (high-iron and low-iron) had iron intakes of 5.9
and 3.0 mg/kg/day, respectively, at discharge and approxi-
Selected Macro/Micronutrient Needs of the Routine Preterm Infant
SUPPLEMENT
mately 3 and 2 mg/kg/day, respectively, at age 3-9 months.
That study found no difference in neurodevelopment or in
the prevalence of anemia at age 12 months, but the high-
iron group had higher glutathione peroxidase concentrations
(a marker of oxidative stress), lower plasma zinc and copper
levels, and a higher rate of respiratory tract infections, sug-
gesting possible adverse effects of the higher iron concentra-
tions.60
In an iron supplementation trial in LBW infants (average
birth weight 2000 g), iron intake ranged from 1.0-1.6 mg/
kg/day to 3.6-6.8 mg/kg/day. Serum ferritin level was higher
at 20 weeks, but erythrocyte superoxide dismutase activity
was reduced in the high-iron group, suggesting that high
iron intake could alter copper metabolism. Furthermore,
there was no significant difference in hemoglobin concentra-
tion between the groups at 20 weeks.61
The study by Berglund et al56 found significant differ-
ences in iron status at 6 months between marginally
LBW infants (2000-2500 g) who had received 1 or 2 mg/
kg/day of iron between 6 weeks and 6 months of life. How-
ever, there were no significant differences in the proportion
of infants with iron deficiency or iron deficiency anemia in
the 2 groups. Furthermore, a secondary analysis taking
compliance and diet into account showed that an actual
dietary iron intake of 1 mg/kg/day effectively prevented
iron deficiency.
Timing of Iron Supplementation. Older studies have
shown that early iron supplementation does not improve
early anemia of prematurity (before 2 months), which is
believed to be caused by immature erythropoiesis rather
than by iron deficiency.55 However, 2 recent studies
have suggested that initiation of iron supplementation
or fortification at age 2 weeks, compared with 6-8 weeks,
leads to a reduced need for blood transfusions in VLBW
infants.62,63
Previous Guidelines
In 2002, Klein22 recommended an iron intake of 2-3.6 mg/kg/
day (1.7-3.0 mg/100 kcal based on 120 kcal/kg/day). In 2005,
Tsang et al32 recommended an intake of 2-4 mg/kg/day (1.3-
3.1 mg/100 kcal based on 130 kcal/kg/day for ELBW infants
and 1.5-3.6 mg/100 kcal based on 110 kcal/kg/day for
VLBW infants). In 2010, European Society of Pediatric Gas-
troenterology, Hepatology, and Nutrition recommended an
intake of 2-3 mg/kg/day (1.8-2.7 mg/100 kcal based on 110
kcal/kg/day) for infants with a birth weight <1800 g.21 The
World Health Organization recommends 2-4 mg/kg/day
for all LBW infants aged 2-24 months,64 and the American
Academy of Pediatrics recommends 2 mg/kg/day at age
1-12 months for all LBW infants.65
Gaps in Knowledge
To date, no studies have examined the effects of different
doses of iron supplementation or fortification in ELBW in-
fants, even though these infants are likely to be at increased
risk for iron deficiency and iron overload. In addition, there
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THE JOURNAL OF PEDIATRICS  www.jpeds.com
are no data on the long-term health consequences of different
dietary iron intakes in preterm and LBW infants.
Recommended Intakes for Preterm and
VLBW Infants
Calcium: 120-160 mg/kg/day; phosphorus: 60-90 mg/kg/day;
magnesium: 8-15 mg/kg/day; vitamin D: 400-1000 IU/day;
copper: 150-200 mg/kg/day; zinc: 2-2.25 mg/kg/day; iron:
2-3 mg/kg/day (birth weight < 1500 g); 2 mg/kg/day (birth
weight 1500-2500 g).
Conclusion
Traditionally, the high calcium and phosphorus require-
ments of preterm neonates have been proposed to match
the intrauterine accretion rate in the third trimester. How-
ever, recent studies suggest that a lower postnatal mineral
accretion (enteral calcium intake of 120-140 mg/kg/day and
phosphorus intake of 60-90 mg/kg/day) is sufficient to main-
tain adequate retention of these minerals. The goal of vitamin
D supplementation should be to achieve an intake of 400-
1000 IU/day. In countries and geographical areas with
a higher risk and/or prevalence of vitamin D deficiency, in-
take should be targeted at the higher end of the range, and
populations at low risk for vitamin D deficiency should re-
ceive vitamin D at the lower end of the range.
We recommend a dietary iron intake of 2 mg/kg/day for
infants with a birth weight of 1500-2500 g and 2-3 mg/kg/
day for infants with a birth weight of <1500 g. Prophylactic
iron should be started at age 2-6 weeks (at 2 weeks in
VLBW infants). Infants receiving erythropoietin treatment
and those with significant, uncompensated blood losses will
need a higher dose initially, requiring a separate iron supple-
ment in addition to preterm formula or fortified human milk.
A prolonged dietary iron intake of >3 mg/kg/day should be
avoided in most cases because of possible adverse effects. In
infants who have received multiple blood transfusions, serum
ferritin concentration should be determined before starting
iron supplementation/fortification, and prophylactic iron
should not be given while serum ferritin is above normal
levels for newborns.66 Iron supplements or intake of iron-
fortified formula in the recommended doses should be
continued after discharge, at least until age 6-12 months,
depending on diet. Hemoglobin and serum ferritin should
be checked at follow-up visits, taking the physiological
changes of iron status during infancy into consideration. n
Author Disclosures
All authors received honoraria from Mead Johnson Nutrition
for attendance, presentation, and manuscript preparation.
I. G. wrote the first draft of this manuscript.
Reprint requests: Jatinder Bhatia, MD, FAAP, Division of Neonatology,
Medical College of Georgia, Georgia Health Sciences University, BIW-6033,
Augusta, GA 30912. E-mail: jatindeb@georgiahealth.edu.
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Vol. 162, No. 3, Suppl. 1
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