Article nutrition

Vitamin D Needs of Preterm Infants

Sarah N. Taylor, MD,*
Objectives After completing this article, readers should be able to:
Bruce W. Hollis, PhD,*
Carol L. Wagner, MD* 1. Describe which form of vitamin D is the best indicator of nutritional vitamin D status.
2. List the current recommendation for minimum vitamin D supplementation in children.
3. Explain why evaluation of vitamin D status and functional biomarkers is needed for
Author Disclosure pediatric populations.
Drs Taylor, Hollis, and 4. Delineate the roles of vitamin D in health and disease among preterm infants.
Wagner have 5. Explain why preterm infants require supplemental vitamin D support.
disclosed that they
are supported by
grants from NIH
Abstract
The 2008 revised American Academy of Pediatrics (AAP) recommendation for
R01HD47511,
400 IU/day vitamin D intake makes progress toward achieving infant vitamin D
R01HD043921, sufficiency in the United States. Further study, however, is needed both to define
1K23RR021891, vitamin D sufficiency for preterm infants based on markers of vitamin D biologic
Thrasher Foundation, function and to develop supplementation strategies to ensure adequate vitamin D
and the MUSC intake and, thus, vitamin D sufficiency in this at-risk population. In this review, we
highlight some of the issues surrounding vitamin D status of the neonate and the
Clinical and
particular risks for the preterm infant. We review the evidence regarding the impact of
Translational Research
vitamin D deficiency in this population and the safety and efficacy of vitamin D
Center NIH M01RR0- supplementation. Based on previous study in preterm infants, the current AAP
1070. This guidelines to achieve serum 25-hydroxyvitamin D [25(OH)D] status of at least
commentary does not 50 nmol/L and to receive at least 400 IU/day are safe and possibly adequate. Because
contain a discussion of the nutritional difficulties in achieving consistent delivery of 400 IU/day of vitamin
D in the preterm infant, it is imperative to devise strategies for close monitoring of
of an unapproved/
each preterm infant’s vitamin D status and consider oral vitamin D supplementation as
investigative use of a
an important adjunct to dietary sources and multivitamin preparations.
commercial
product/device.
Introduction
The 2008 revised AAP recommendations for vitamin D supplementation for infants,
children, and adolescents respond to both the evolving identification of numerous roles for
vitamin D in health maintenance and the recent recognition
of pervasive vitamin D deficiency in populations throughout
the United States. The new AAP report recommends
Abbreviations 400 IU/day for all infants, children, and adolescents, with
AAP: American Academy of Pediatrics initiation of the supplementation in the “first few days” after
CI: confidence interval birth. (1)
DBP: vitamin D-binding protein The AAP statement includes preterm infants in this
DEXA: dual-energy x-ray absorptiometry global recommendation but does not mention the specific
ESPGAN: European Society for Pediatric Gastro- vitamin D needs of this population. The unique situation of
enterology and Nutrition preterm delivery requires blending of fetal and newborn
1,25(OH)2D: 1,25-dihydroxyvitamin D health needs, including those for vitamin D. In addition,
OR: odds ratio some study of vitamin D requirements points to a weight-
PTH: parathyroid hormone based requirement for supplementation. In this circum-
25(OH)D: 25-hydroxyvitamin D stance, preterm infants again represent a unique population.
VLBW: very low birthweight Awareness of the evidence examining vitamin D needs,
demonstrating vitamin D status, and evaluating the dosing

*Department of Pediatrics, Medical University of South Carolina, Charleston, SC.

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Figure. Primary sources and configurations of vitamin D. Adapted from Lucas et al. (2)
effect of supplementation for preterm infants is critical to
guarantee healthy supplementation. Further, the vitamin
D requirements of the preterm infant are understood
best in the context of the rapidly expanding knowledge
of vitamin D metabolism and physiology.
Vitamin D Metabolism
Vitamin D occurs as vitamin D3, a 27-carbon derivative
of cholesterol, and vitamin D2, a 28-carbon molecule
derived from the plant sterol ergosterol (Figure). Vita-
min D2 has an additional methyl group and a double
bond between carbons 22 and 23. Vitamin D has a
unique structure that makes the vitamin and its related
metabolites susceptible to oxidation, ultraviolet light-
induced conformational changes, and attack by free rad-
icals. Vitamin D3 is produced in the skin from provitamin
D3, 7-dehydrocholesterol. The exposure of skin to sun-
light in the ultraviolet B range of the spectrum (290 to
315 nm) results in the chemical reaction and conversion
of 7-dehydrocholesterol to previtamin D3, which is
transformed to vitamin D3 by heat-induced isomeriza-
tion in the epidermis.
The rate of sunlight catalysis of vitamin D production
is extremely dependent on latitude, season, skin pigmen-
tation, and skin exposure. With modern lifestyles, limita-
tions in both the duration of time and the amount of skin
exposed to ultraviolet B light has led to the current high
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nutrition vitamin D
prevalence of vitamin D deficiency
and insufficiency worldwide. Per-
sons most at risk are those who
have dark pigmentation, those who
cover themselves outdoors for reli-
gious or cultural reasons, or those
at higher latitudes, especially dur-
ing winter months. In addition, in-
creased urbanization and indoor
activities as well as the use of sun-
screen limit cutaneous vitamin D
production, even for light-skinned
persons in the tropics in the sum-
mer. With the potential association
of ultraviolet light and skin cancer,
the ability to rely on sunlight expo-
sure to achieve sufficient vitamin D
status is inadequate. For a hospital-
ized preterm infant, vitamin D pro-
duction from sun exposure is not
even an option. Phototherapy does
not provide light in the ultraviolet
B range and, consequently, does
not stimulate cutaneous vitamin D
production. Therefore, enteral supplementation must be
optimized.
Vitamin D3, along with vitamin D2, can be obtained
from the diet, although vitamin D is distributed very
poorly in natural foodstuffs. It is found primarily in fish
oils, egg yolk, butter, and liver. Because of its extremely
low abundance in foods, vitamin D commonly is fortified
in food products, the most common of which is milk at
low concentrations. All United States infant formulas
and human milk fortifiers are fortified with vitamin D
(⬃400 IU/L).
Once vitamin D enters the circulation, either through
epidermal transfer or intestinal absorption, it associates
with vitamin D-binding protein (DBP), a protein that
binds vitamin D and its metabolites. The initial step in
the metabolic activation of vitamin D is enzyme-
catalyzed insertion of a hydroxyl group at carbon 25.
Such oxidation is primarily a hepatic function and pro-
duces 25(OH)D, the most abundant circulating form of
vitamin D. Following formation in the liver, 25(OH)D
appears in the circulation bound primarily to DBP. DBP
preferentially binds 25(OH)D with higher affinity than
1,25-dihydroxyvitamin D [1,25(OH)2D] or vitamin D.
The high affinity of DBP for vitamin D and its metabo-
lites, coupled with the excessive binding capacity, keeps
“free” or unbound vitamin D and its metabolites at very
low concentrations. This is important because only the
NeoReviews Vol.10 No.12 December 2009 e591
nutrition vitamin D
“free” form of the vitamin has transmembrane diffusion
capabilities, thus exerting its biologic function. The half-
life of 25(OH)D in the circulation is about 2 to 3 weeks
in healthy individuals. Because of its relatively long half-
life compared with vitamin D (1 to 2 days) and
1,25(OH)2D (12 to 24 hours), circulating 25(OH)D is
the best indicator of nutritional vitamin D status.
In the kidney, circulating 25(OH)D is transformed
to 1,25(OH)2D and 24,25-dihydroxyvitamin D.
1,25(OH)2D is the most active and, thus, the hormonal
form of vitamin D. Measuring 1,25(OH)2D, however, to
identify vitamin D deficiency is problematic. In the pres-
ence of vitamin D deficiency, decreased serum calcium
concentrations stimulate the production of parathyroid
hormone (PTH). PTH promotes the conversion of
25(OH)D to 1,25(OH)2D. Therefore, in the presence
of vitamin D deficiency, 1,25(OH)2D concentrations
can be normal or elevated; they are rarely low.
The kidney is the primary site for production of
1,25(OH)2D to exert an endocrine effect on the kidney,
intestinal calcium absorption, and bone metabolism. De-
cades ago, numerous other cells in the body, including
immune cells, were recognized as having 25(OH)D re-
ceptors, but until recently, identification of the function
of these receptors eluded investigators. Recent evidence
demonstrates that vitamin D affects numerous organ
systems through locally derived 1,25(OH)2D formed
from 25(OH)D in the serum. The brain, heart, lungs,
immune cells, skin, pancreas, and many other organ
systems are capable of producing 1,25(OH)2D that tar-
gets cells in close proximity in a paracrine function.
Uncovering this local activity of 1,25(OH)2D and its
roles in organ physiology, especially immune function, is
a recent advancement that has led to greatly expanded
knowledge of the importance of vitamin D in disease
prevention. (1)(2)(3)(4)(5)(6)(7) Low serum 25(OH)D
concentrations are associated with the development of var-
ious types of cancers (including breast, prostate, and colon),
(8) autoimmune diseases (such as rheumatoid arthritis,
systemic lupus erythematosus, and multiple sclerosis), mus-
culoskeletal and neurologic dysfunction, and diabetes.
(3)(7) Other processes that have been related to poor
vitamin D status are preeclampsia, (9) osteoporosis, dental
decay, polycystic ovarian disease with menstrual problems
and infertility, psoriasis, cardiovascular disease (including
hypertension and heart failure), and schizophrenia.
(3)(7)(10) Recent in vitro experiments demonstrate that
low 25(OH)D status may explain the racial disparities in
susceptibility to bacterial infections. (4)
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Vitamin D Physiology
Concurrent with the discovery of serum 25(OH)D status
as the best marker of vitamin D health and its important
roles in many serious disease processes has been the
evolution of the definition of sufficient vitamin D status.
Recent studies in children, adolescents, and adults have
shown ill effects at 25(OH)D concentrations previously
considered within the normal range. (5)(6)(11) These
studies have led to new definitions of vitamin D suffi-
ciency for both adults and children. Studies in adults
evaluating intestinal calcium absorption, PTH concen-
trations, bone density, and glucose tolerance point to
serum 25(OH)D values less than 50 nmol/L as defi-
ciency and serum 25(OH)D values of 50 to 80 nmol/L
as insufficiency for adults. (5)(6)(7)(12)
A consistent definition of the serum 25(OH)D con-
centration in children that denotes vitamin D sufficiency
has not been created. The 2003 AAP vitamin D guide-
lines recommended a minimal vitamin D dose of
200 IU/day due to evidence demonstrating that this
dose would maintain serum 25(OH)D concentrations
greater than 27.5 nmol/L. (13) The 2008 AAP guide-
lines recommend an increased minimum supplementa-
tion of 400 IU/day to ensure serum 25(OH)D values
greater than 50 nmol/L to avoid vitamin D-deficient
rickets. (1)
Vitamin D Physiology for Preterm Infants
The classic rickets appreciated in term infants resulting
from vitamin D deficiency is marked by bony abnormal-
ities on physical examination, hypocalcemic seizures,
other neurologic abnormalities, growth failure, and in-
creased risk for respiratory infections. This type of rickets
often is found in breastfeeding infants who have high
maternal risk for vitamin D deficiency, such as dark
pigmentation, high latitudes, and minimal exposure to
sunlight. (1) As mentioned previously, infant formula in
the United States is fortified with vitamin D and, there-
fore, formula-fed infants avoid this clinical manifestation
of severe vitamin D deficiency. However, the question
remains whether more infants, including formula-fed
infants, have “insufficient” vitamin D status, with detri-
mental effects on bone or immune health without clini-
cally evident signs of disease. (1) Therefore, studies to
define the vitamin D status and supplementation require-
ments to optimize infant health are ongoing.
The role of vitamin D in preterm infant health also
continues to be investigated. Preterm infants are at risk
for bone disease of prematurity that is described by many
names: rickets of prematurity, osteopenia of prematurity,
or metabolic bone disease of prematurity. The disease is

multifactorial, with inadequate calcium and phosphorus
intake, vitamin D status, and mobility of extremities all
playing roles in its pathogenesis. Eighty percent of the
calcium and phosphorus retained during gestation is
acquired in the third trimester. With limitations in pro-
viding preterm infant nutrition, parenteral nutrition and
unfortified feedings add to the preterm infant’s nutri-
tional deficit in calcium and phosphorus. The exact inci-
dence of this disease is not known, but likely 55% of
infants born weighing less than 1,000 g and 23% of very
low-birthweight (VLBW) (⬍1,500 g) infants have low
bone mineralization due to preterm birth. In the past, up
to 25% of VLBW infants had overt fractures. Infants who
have metabolic bone disease also demonstrate increased
respiratory distress due to softening of the ribs, which
affects chest wall compliance, and decreased longitudinal
growth. (14)(15)(16)(17)
As is the case for many preterm infant diseases, this
severe complication of preterm birth has many causative
factors. However, the limitations in postnatal phospho-
rus delivery, with dose restriction in parenteral nutrition
and delay in fortification of phosphorus-depleted human
milk feedings, appear to be the primary factor in disease
progression. (15)(16)(17) Delineating the role of vita-
min D in preterm infant bone health has proven difficult.
Part of this difficulty is due to incomplete understanding
of vitamin D physiology leading to flawed study design.
The primary problem plaguing early vitamin D studies
in preterm infants was a focus on dose of vitamin D
supplementation instead of on infant vitamin D status.
Maternal vitamin D status is responsible for fetal and
newborn vitamin D status because a fetus receives all
vitamin D support from the mother. (18) Maternal
25(OH)D readily crosses the placenta and as early as
24 weeks’ gestation is metabolized to 1,25(OH)2D by
the fetal kidneys for endocrine action and by other tissues
for paracrine action. At birth, the neonate’s serum
25(OH)D status is 50% to 70% of maternal serum
25(OH)D concentrations, a relationship that is true for
term and preterm infants. (3)(18)(19)(20) The impor-
tance of vitamin D in fetal bone development is evi-
denced by reported cases of congenital rickets due to
severe maternal vitamin D deficiency and a longitudinal
study by Javaid and associates (21) that demonstrated a
relationship between maternal vitamin D status and child
bone mineralization at 9 years of age.
Investigation is ongoing to identify the maternal vita-
min D status required to ensure fetal vitamin D health,
but epidemiologic studies demonstrate a high prevalence
of maternal vitamin D deficiency and, therefore, a high
prevalence of vitamin D deficiency at birth. In their study
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nutrition vitamin D
of 400 mother/infant dyads in Pittsburgh, Bodnar and
associates (22) found 45.6% of African American infants
and 9.7% of white infants were born with serum
25(OH)D values less than 37.5 nmol/L. Ninety percent
of the mothers in the study took daily prenatal vitamins
that contained 400 IU/day vitamin D. In a study of 694
pregnant women in South Carolina, Wagner and col-
leagues (23) noted vitamin D deficiency at epidemic
proportions, with 51% of the group deficient in vitamin
D and 86% exhibiting vitamin D insufficiency. For Afri-
can American women, 73% and 97% were vitamin
D-insufficient and -deficient, respectively.
Such a high degree of inadequate vitamin D status
during pregnancy leads to vitamin D deficiency at birth.
In fact, Basile and colleagues (24) documented 100
infant samples in Charleston, North Carolina, at birth
demonstrating a mean serum 25(OH)D of
33.8 nmol/L, with African American infants exhibiting a
mean of 26 nmol/L and white infants a mean of
49 nmol/L. In both the Pittsburgh and Charleston
studies, the white mother/infant dyads demonstrated
significant seasonal variation, with lower vitamin D status
exhibited in the winter and early spring, but the African
American mother/infant dyads had similar vitamin D
status throughout the year. (22)(24) This difference is
due to the effects of pigmentation, season, and latitude
on cutaneous vitamin D production. These studies raise
concern that many infants, including preterm infants, are
born with vitamin D deficiency. Therefore, it is essential
that studies of vitamin D supplementation measure initial
vitamin D status to examine the effect of supplementa-
tion.
Vitamin D Function for Preterm Infants
Studies evaluating the effect of vitamin D supplementa-
tion on preterm infant calcium absorption have demon-
strated inconsistent results by comparing calcium ab-
sorption by vitamin D supplementation instead of by
serum 25(OH)D status. In 1982, Senterre and Salle (25)
published results of 3-day metabolic studies in preterm
infants (n⫽117), in which they found improved intesti-
nal calcium absorption with vitamin D supplementation
of 1,200 to 2,000 IU/day. Eleven years later, the same
group of investigators found that vitamin D supplemen-
tation did not significantly increase net intestinal calcium
absorption in 103 preterm infants. (26) The discrepancy
between these results is most likely due to a comparison
of vitamin D intake without a comparison of vitamin D
sufficiency status. The 1993 study did not even measure
the serum 25(OH)D status of the infants, yet this study is
quoted as demonstrating that intestinal calcium absorp-
NeoReviews Vol.10 No.12 December 2009 e593
nutrition vitamin D
tion in preterm infants is completely independent of
vitamin D.
Another problem that has plagued evaluations of the
vitamin D needs of preterm infants is performance of
studies that have the definition of “normal” vitamin D
status as serum 25(OH)D status greater than 12.5 to
27.5 nmol/L. (13)(27)(28)(29) As mentioned previ-
ously, evaluation of vitamin D status with functional
biomarkers in adults has permitted a revised definition of
vitamin D sufficiency as serum 25(OH)D status greater
than 80 nmol/L. (5)(6)(7) Unfortunately, study of the
relationship of vitamin D status and functional biomark-
ers for children is lacking. Evaluation of vitamin D status
and functional biomarkers such as intestinal calcium ab-
sorption, bone mineralization, and PTH concentrations
is needed for pediatric populations, including preterm
infants.
The studies that have been performed to evaluate the
role of vitamin D in preterm infant bone mineralization
have used a definition of “normal” as a serum 25(OH)D
concentration not associated with rickets. In addition,
studies evaluating the effect of vitamin D status on bone
mineralization are limited by technological inadequacies,
with bone health assessed by radiography and single-
photon absorptiometry instead of dual-energy x-ray ab-
sorptiometry (DEXA) or quantitative computed tomog-
raphy scan, which are better modalities for measuring
bone mineralization. (26) Among the studies that have
evaluated preterm infant bone mineralization with
DEXA, one group of investigators (29) compared two
doses of vitamin D (200 IU/kg of body weight per day
up to 400 IU/day versus 960 IU/day) and found that
the group of infants receiving up to 400 IU/day
achieved serum 25(OH)D concentrations of at least
86.4⫾23.9 nmol/L at the time of measurement. This
serum 25(OH)D status is most likely demonstrative of
vitamin D sufficiency, and, therefore, the finding of no
difference in bone mineralization between the two com-
parison groups is not surprising.
Kurl and colleagues (30) attempted to evaluate the
relationship between serum 25(OH)D status and bone
mineralization. They did not examine a direct correla-
tion; rather, when the preterm infants reached weights of
5 to 7 kg, their bone mineral content measurement was
used to calculate a “percentage of predicted bone mineral
content” based on the comparison with term infant
DEXA measurements. The serum 25(OH)D status of
the preterm infants, who received 400 IU/day vitamin D
once full enteral feedings were achieved, demonstrated
no linear correlation with the percentage of bone mineral
content calculation. Except for partial evaluation in this
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study, none of the evaluations of vitamin D health in
preterm infants was designed to define vitamin D suffi-
ciency in this population.
Identifying the role of vitamin D in maternal, fetal,
and neonatal immune function is extremely important to
optimize preterm infant health. Epidemiologic studies
raise the possibility for a positive association between
maternal vitamin D status in pregnancy and diseases such
as osteoporosis, multiple sclerosis, and schizophrenia.
(2)(3) With long-term programming in fetal develop-
ment, identifying the effect of vitamin D during devel-
opment and early life is critical. In evaluating the short-
term role of vitamin D in immune health, preliminary
results from two large randomized, controlled trials of
vitamin D in pregnancy demonstrated a significant asso-
ciation between vitamin D deficiency and an increased
risk for preterm birth before 32 weeks’ gestation (odds
ratio (OR) 0.558, confidence interval (CI) 0.347 to
0.898), preterm birth before 37 weeks’ gestation (OR
0.528, CI 0.345 to 0.809), and maternal infection (OR
0.739, CI 0.558 to 0.978), even after controlling for
race. (31)
In an investigation of the role of vitamin D health in
postnatal immune function, Karatekin and associates
(32) performed a case-control study of newborns who
had acute lower respiratory tract infection. The cases and
their mothers demonstrated significantly lower serum
25(OH)D concentrations than the healthy controls. The
newborns who had infection exhibited a mean serum
25(OH)D concentration of 22.8 nmol/L; controls dem-
onstrated a mean of 40.8 nmol/L.
Definitive risk factors for necrotizing enterocolitis in
preterm infants continue to elude investigators. Imma-
turity in production of an anti-inflammatory cytokine,
interleukin-10, however, has been associated with devel-
opment of this condition. (33) In 2004, Zitterman and
associates (34) reported a significant association of low
vitamin D status with low interleukin-10 concentrations
in umbilical cord blood. Studies evaluating the relation-
ship between preterm infant vitamin D status and im-
mune function are ongoing.
Preterm Infant Vitamin D Status With
Supplementation
With no definition of vitamin D sufficiency based on
biologic function available for preterm infants, examina-
tion of the vitamin D status achieved with supplementa-
tion is the best available evidence. Four trials have com-
pared the vitamin D status achieved following random
assignment to vitamin D supplementation (Table 1). The
wide range of vitamin D doses studied highlights the lack
 nutrition vitamin D

Table 1. Preterm Infant Vitamin D Supplementation Studies

Vitamin D Status at Vitamin D Status
Vitamin D doses Initiation (nmol/L) Achieved (nmol/L)
Study Population Dosing Duration (IU/day) (SD)* (SD)
Delvin et al Exclusively formula 3 months 1,000 above the Formula-fed: Formula-fed:
2005 (28) (80 IU/dL vitamin vitamin D in the 47.5 (25.6) 142.6 (90)
(nⴝ66) D)-fed or formula or Mother’s milk-fed: Mother’s milk-fed:
exclusively mother’s mother’s milk 34.4 (26.7) 181.9 (97.5)
milk-fed preterm
infants
Backstrom et al At birth, <33 weeks’ From full enteral Low-dose: Low-dose: Low-dose:
1999 (29) gestation and feedings until 200 IU/kg, up to 29.8 (10) 79.1 (30)
(nⴝ16) appropriate for 3 months of maximum of 400 High-dose: High-dose:
gestational age age High-dose: 960 29.2 (11.8) 113.5 (37.7)
Koo et al At birth, <1,500 g From full enteral Low-dose: Low-dose: Low-dose:
1995 (27) and appropriate for nutrition until mean, 161 70 (6.8) 65 (5.8)
(nⴝ62) gestational age and discharge or Middle-dose: Middle-dose: Middle-dose:
growing on full 2-kg weight mean, 361 63 (9.5) 80 (8)
enteral nutrition High-dose: High-dose: High-dose:
mean, 766 63 (9.5) 78 (7.8)
Pittard et al Preterm infants From birth until Low-dose: 400 Low-dose: Low-dose:
1991 (35) <2,500 g at birth 16 weeks of High-dose: 800 27.5 (12.5) 127.5 (47.5)
(nⴝ27) (mean gestational age High-dose: High-dose:
age, 30.9 weeks) 42.5 (20) 122.5 (62.5)
*SD⫽standard deviation

of understanding of vitamin D needs for the preterm
infant population. The revised AAP guidelines recom-
mend 400 IU/day. The European Society for Pediatric
Gastroenterology and Nutrition (ESPGAN) in 1987 rec-
ommended 800 to 1600 IU/day for preterm infants,
(36) but following the studies from Koo, (27) Back-
strom, (29) and Delvin, (28) European experts recom-
mended 800 to 1,000 IU/day to achieve vitamin D
sufficiency without toxicity. (17) Of note, the trial con-
ducted by Delvin (28) provided 1,000 IU/day vitamin
D supplementation and 80 IU/100 mL formula, so
some formula-fed infants received upwards of 1,500 IU/
day vitamin D without complications.
One case report in 1993 represents the only published
report of hypercalcemia possibly due to high vitamin D
intake. (37) The infant’s vitamin D status was not quan-
tified adequately because the vitamin D assay did not
measure 25(OH)D above 125 nmol/L. With concern
that Japanese preterm formula containing 2,700 IU/L
vitamin D causes hypervitaminosis D, the same authors
published in 2004 a comparison of vitamin D status in
preterm infants receiving preterm formula versus the
same preterm infants receiving term formula with
460 IU/L vitamin D after hospital discharge. (38) When
receiving the preterm formula, the infants demonstrated
a mean 25(OH)D of 175 nmol/L and when receiving
term formula or human milk, a mean 25(OH)D of
115 nmol/L. All serum and urine calcium and phospho-
rus values, measures of early hypervitaminosis D, were
normal, disputing the theory that the preterm formula
with 2,700 IU/L was the cause of hypercalcemia in the
earlier case report.
Preterm Infant Vitamin D Supplementation
The difference in vitamin D supplementation between
the standard Japanese preterm infant formula and term
infant formula highlights the next difficulty in vitamin D
supplementation of preterm infants, which is inconsis-
tent fortification of various preterm infant nutrition sup-
port systems. The goal of supplementation is to deliver
an adequate but nontoxic amount of vitamin D. With the
revised AAP recommendation that 400 IU/day meets
this goal, (1) careful attention is required to guarantee
that preterm infants receive the recommended intake. In
the United States, standard infant liquid vitamin supple-
mentation contains 400 IU per dose and standard term
formulas are supplemented with 400 IU/L. These doses
guarantee that a term breastfeeding infant receiving daily
standard vitamin supplementation and a term formula-
fed infant taking 1 L of formula receive at least 400 IU/
day. (1) For preterm infants, however, limitations in
nutritional intake, due to both intestinal immaturity and

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nutrition vitamin D

Daily Vitamin D Supplementation (IU) Provided by Standard

Table 2.

Preterm Infant Nutrition Regimens

Hypothetical patients by weight 500 g 1,000 g 1,250 g 1,500 g 2,000 g
Parenteral nutrition only 80 160 200 240 320
Parenteral nutrition and 100 mL/kg per day 83 165 206 248 330
unfortified mother’s milk
Parenteral nutrition and 100 mL/kg per day 131 to 190 261 to 380 326 to 475 392 to 570 523 to 760
preterm formula (20 to 24 kcal/oz)
160 mL/kg per day fortified human milk 100 to 124 200 to 248 250 to 310 300 to 372 400 to 496
(24 kcal/oz)
160 mL/kg per day preterm formula 97 to 176 195 to 352 244 to 440 292 to 528 390 to 704
(24 kcal/oz)
160 mL/kg per day fortified human milk 300 to 324 400 to 448 650 to 710 700 to 772 800 to 896
(24 kcal/oz) plus multivitamin preparation*
160 mL/kg per day preterm infant formula 297 to 376 395 to 552 644 to 840 692 to 928 790 to 1,104
(24 kcal/oz) plus multivitamin preparation*
*Standard multivitamin preparations recommend 0.5 mL (200 IU vitamin D) per day when weight ⬍1,250 g and 1 mL (400 IU vitamin D) per day when
weight ⱖ1,250 g.
Vitamin D concentrations for formula and human milk fortification based on data from Abbott Nutrition (Abbott Park, Ill.) and Mead Johnson Nutritionals
(Evansville, Ind).

volume restriction, elevate the risk for inadequate vita-
min D supplementation.
For example, in the United States, parenteral nutri-
tion vitamin D supplementation is weight-based at
160 IU/kg. Therefore, infants receiving parenteral nu-
trition alone do not receive 400 IU/day vitamin D
supplementation until reaching a weight of 2.5 kg. In-
fants taking preterm infant formula also may receive
inadequate vitamin D supplementation, depending on
weight and enteral intake. With ingestion of one major
United States preterm formula containing 1,220 IU/L
vitamin D, a baby must weigh at least 2.1 kg and be
taking 160 mL/kg per day of 24-kcal/oz formula to
receive the recommended 400 IU/day. Therefore, to
achieve intake of 400 IU/day, formula-fed preterm in-
fants may need supplemental daily vitamin D doses. In
addition, preterm infants receiving fortified mother’s
milk need supplemental vitamin D support because the
standard United States human milk fortifiers are formu-
lated to provide similar vitamin D support as the preterm
formulas.
To demonstrate the vitamin D supplementation re-
ceived by preterm infants in the first postnatal month,
Taylor and associates (39) calculated a mean vitamin D
intake of 507⫾223 IU/day for the 36 preterm infants
studied. With this amount of average vitamin D supple-
mentation, the infants achieved a mean serum 25(OH)D
of 59⫾26 nmol/L by the end of the month. These
findings and the four randomized trials mentioned pre-
viously negate concern that 400 IU/day is a toxic
amount of supplementation for preterm infants. In fact,
the current evidence indicates that further investigation
is needed to confirm 400 IU/day as sufficient supple-
mentation for all preterm infants. The ESPGAN recom-
mendation of 800 to 1,600 IU/day vitamin D for pre-
term infants, with validation of the safety of 800 to
1,000 IU/day doses by at least three randomized, con-
trolled trials, promotes guidelines to achieve at least
400 IU/day and up to 1,000 to 1,600 IU/day.
(1)(27)(29)(29)(35)
With the goal of 400 to 1,000 IU/day established,
providing such vitamin D intake for preterm infants who
are receiving supplementation from various nutrition
support systems can be complicated. Table 2 presents the
varying vitamin D intakes provided by common preterm
infant nutrition practices and outlines the differences
based on body weight. Preterm infants who weigh
1,000 g or less do not receive 400 IU/day vitamin D
unless additional vitamin D supplementation is provided.
In Table 2, the additional vitamin D supplementation is
presented as a multivitamin preparation, with 0.5 mL/
day given to infants who weigh less than 1,250 g and
1 mL/day to those who weight 1,250 g or more. A mul-
tivitamin preparation has been the mainstay of supple-
mentation for years, but other preparations that contain-
ing only vitamin D now are available in the United States.
Another compound that historically has been admin-
istered for preterm infant bone health is the active me-
tabolite, 1,25(OH)2D (calcitriol). Calcitriol is not phys-
iologic vitamin D supplementation, but rather a

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Table 3. Vitamin D Preparations Currently Available in the United States
Preparation
Baby Ddrops™ (The Ddrops Company, Toronto, Ontario,
Canada, www.ddrops.ca) (Distributed in United States
through Carlson Laboratories)
Bio-D-Mulsion™ (Biotics Research Laboratory, Rosenberg,
Texas, www.bioticsresearch.com)
Just D™ (Sunlight Vitamins, Inc., Carlson Laboratories,
www.carlsonlabs.com)
Multivitamin preparations; polyvitamins; A, D, and K
vitamin preparations
*Caregiver must be instructed to ensure proper dosing of the single drop per day regimen.
Adapted from the American Academy of Pediatrics Statement on Vitamin D Table 2 (1).
medicine with safety concerns. As early as 24 weeks’
gestation (likely earlier), fetal liver and kidney hydroxy-
lation produce 25(OH)D and 1,25(OH)2D, respec-
tively. With the ability to form these products from the
parent compound vitamin D, vitamin D supplementa-
tion offers the safest alternative for preterm infants. Also,
providing 1,25(OH)2D instead of vitamin D ignores the
extrarenal paracrine vitamin D health that is sustained by
vitamin D, with hydroxylation in the liver maintaining
available circulating 25(OH)D. In fact, patients who
have chronic renal failure and require 1,25(OH)2D sup-
plementation also require vitamin D supplementation to
support these extrarenal processes.
Table 3 provides the characteristics of oral vitamin D
preparations currently available in the United States. An
oil emulsion/1 drop daily regimen containing 400 IU
has been studied by Wagner and associates (40) in term
breastfeeding infants and found to be effective in achiev-
ing healthy vitamin D status. In addition, we have ad-
ministered the 1-drop preparation orally in our neonatal
intensive care unit for the past 4 years to otherwise
nonfeeding preterm and term infants with no gastric or
intestinal complications. Further evaluation is needed to
describe the safety and efficacy of all vitamin D supple-
mentation preparations for preterm infants, but for now,
the clinician must assess a preterm infant’s vitamin D
intake and the options for additional vitamin D supple-
mentation to establish adequate intake. For low-
birthweight infants who are likely born with some degree
of vitamin D deficiency and who receive inadequate
vitamin D intake during the first postnatal days when
enteral nutrition is limited, recognizing this inadequacy
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nutrition vitamin D
Dosage
● 1 drop provides 400 IU
● Coconut and palm oil preparation
● Also available in 2,000 IU/drop preparation
● Five-year shelf life
● 1 drop provides 400 IU
● Corn oil preparation
● Also available in 2,000 IU/drop preparation*
● One-year shelf life
● 1 mL provides 400 IU
● Corn oil preparation
● 1 gel cap provides 400 IU
● Also available in 2,000 IU gel caps*
● 1 mL provides 400 IU
of supplementation and establishing sufficient vitamin D
intake as soon as possible is the first step in supporting
preterm infant vitamin D health.
A further step is to monitor vitamin D status with
analysis of serum 25(OH)D. One new option for serum
25(OH)D monitoring that is especially applicable for
preterm infants is a blood spot test similar to state new-
born metabolic screening blood collection. In this test,
available through ZRT Labs (Beaverton, Ore.), only
three drops of blood are required for serum 25(OH)D
measurement. The goal for preterm infant serum
25(OH)D is greater than 50 nmol/L. (1)
Conclusion
The 2008 revised AAP recommendation for 400 IU/day
vitamin D intake makes substantial progress toward
achieving infant vitamin D sufficiency in the United
States. Crucial further study, however, is needed both to
define vitamin D sufficiency for preterm infants based on
markers of vitamin D biologic function and to develop
supplementation to ensure adequate vitamin D intake
and, thus, vitamin D sufficiency. Based on previous study
in preterm infants, the current AAP guidelines to achieve
serum 25(OH)D status of at least 50 nmol/L and to
provide at least 400 IU/day are safe and possibly ade-
quate. Given the difficulties in achieving consistent de-
livery of 400 IU/day of vitamin D in the preterm infant,
close monitoring of vitamin D status through each
change in parenteral and enteral feedings must occur to
assure adequate vitamin D status of these infants.
NeoReviews Vol.10 No.12 December 2009 e597
nutrition vitamin D
American Board of Pediatrics Neonatal-Perinatal
Medicine Content Specification
• Know the requirements for vitamins in
newborn infants and the differences
between preterm and full-term infants.
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NeoReviews Quiz
1. Vitamin D deficiency is highly prevalent worldwide, especially among persons who have dark pigmentation,
those who cover themselves for religious or cultural reasons, and those who live at high latitudes with
prolonged winters. Measurements of serum concentrations of vitamin D metabolites are helpful in
determining the vitamin D status of an individual. Of the following, the best indicator of nutritional
vitamin D status is the measurement of circulating:
A. Cholecalciferol.
B. 7-dehydrocholesterol.
C. 1,25-dihydroxycholecalciferol.
D. 25-hydroxycholecalciferol.
E. Vitamin D-binding protein.

2. Preterm infants are at high risk for bone disease of prematurity, which has many putative causes. Of the
following, the primary factor in the development of bone disease of prematurity is the deficiency of:
A. Calcium.
B. Mobility of extremities.
C. Parathyroid hormone.
D. Phosphorus.
E. Vitamin D.

3. Although the kidney is the primary site for production of 1,25-dihydroxyvitamin D to exert its endocrine
effects on the bone, kidney, and intestine, other cells in the body are also capable of producing 1,25-
dihydroxyvitamin D to exert its diverse paracrine effects. Vitamin D deficiency, therefore, is implicated in
the pathogenesis of several diseases in addition to disease involving defective bone mineralization. Of the
following, the most recent advancement in our understanding of the disease related to vitamin D deficiency
involves:
A. Autoimmune disease.
B. Dental decay.
C. Preeclampsia of pregnancy.
D. Psychiatric disorder of schizophrenia.
E. Skin disease of psoriasis.

NeoReviews Vol.10 No.12 December 2009 e599

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 Vitamin D Needs of Preterm Infants
Sarah N. Taylor, Bruce W. Hollis and Carol L. Wagner
NeoReviews 2009;10;e590
DOI: 10.1542/neo.10-12-e590

Updated Information & including high resolution figures, can be found at:
Services http://neoreviews.aappublications.org/content/10/12/e590
References This article cites 37 articles, 13 of which you can access for free at:
http://neoreviews.aappublications.org/content/10/12/e590.full#ref-list
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 Vitamin D Needs of Preterm Infants
Sarah N. Taylor, Bruce W. Hollis and Carol L. Wagner
NeoReviews 2009;10;e590
DOI: 10.1542/neo.10-12-e590

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/10/12/e590

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