http://pen.sagepub.

com/
Nutrition
Journal of Parenteral and Enteral
http://pen.sagepub.com/content/37/5/570
The online version of this article can be found at:

DOI: 10.1177/0148607113487216
2013 37: 570 originally published online 17 May 2013 JPEN J Parenter Enteral Nutr
Charlene Compher, Mark Puder and the American Society for Parenteral and Enteral Nutrition
Deepika Nehra, Sarah J. Carlson, Erica M. Fallon, Brian Kalish, Alexis K. Potemkin, Kathleen M. Gura, Edwin Simpser,
A.S.P.E.N. Clinical Guidelines: Nutrition Support of Neonatal Patients at Risk for Metabolic Bone Disease

Published by:
http://www.sagepublications.com
On behalf of:

The American Society for Parenteral & Enteral Nutrition

can be found at: Journal of Parenteral and Enteral Nutrition Additional services and information for

http://pen.sagepub.com/cgi/alerts Email Alerts:

http://pen.sagepub.com/subscriptions Subscriptions:
http://www.sagepub.com/journalsReprints.nav Reprints:

http://www.sagepub.com/journalsPermissions.nav Permissions:

What is This?

- May 17, 2013 OnlineFirst Version of Record

- Sep 4, 2013 Version of Record >>

at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
Journal of Parenteral and Enteral
Nutrition
Volume 37 Number 5
September 2013 570 598
2013 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607113487216
jpen.sagepub.com
hosted at
online.sagepub.com
Clinical Guidelines
Background
More than 30 years ago, it was observed that premature infants,
especially those with very low birth weight (<1500 g), are at
increased risk for metabolic bone disease, including delayed
longitudinal growth, osteopenia, and rickets.
1-3
Since that time
and with the continuous advances in neonatal intensive care,
the incidence of the condition has continued to rise with recent
studies reporting poor mineralization in up to 55% of infants
<1000 g and 23% of infants <1500 g at birth.
4,5
Approximately
80% of bone mineral stores occur during the last trimester of
intrauterine development. Preterm neonates are largely bereft
of this critical period of bone growth, which puts them at
higher risk for metabolic bone disease.
6
The mineral deficit
these infants have at birth is often worsened by the practical
difficulties of ensuring an adequate mineral intake during the
neonatal period. Metabolic bone disease, however, is not a
condition limited to the preterm infant, and there are factors
that place even term infants at risk for this condition.
Accurate diagnosis and evaluation coupled with a solid
understanding of the factors associated with the disease are
necessary to accurately identify high-risk patients in order to
effectively focus preventive efforts. Specific bone mineral den-
sity studies that have been used to assess the status and ade-
quacy of therapy in the infant include dual-energy x-ray
absorptiometry (DXA), quantitative computed tomography
(CT), and quantitative ultrasound (US). It must be highlighted
that these studies are not standard of care for neonates and
infants, and normative data are not available for all age groups
and particularly for the preterm infant. However, these studies
have been used within research study protocols and provide
some quantitative data with regard to the effect of different
variables on neonatal bone health. Certainly, the validation of
these imaging studies and the determination of normative
values for neonates and infants are imperative before these
487216PENXXX10.1177/0148607113487216<italic>Journal of Parenteral and Enteral Nutrition</italic> / Vol. XX, No. X, Month XXXXNehra et al research-article2013
From
1
Department of Surgery and The Vascular Biology Program,
Childrens Hospital Boston, Harvard Medical School, Boston,
Massachusetts;
2
Department of Pharmacy, Childrens Hospital Boston,
Boston, Massachusetts;
3
St Marys Hospital for Children, Bayside, New
York; and
4
University of Pennsylvania School of Nursing, Philadelphia,
Pennsylvania.
Financial disclosure: None declared.
The A.S.P.E.N. Clinical Guidelines Editorial Board guided the development
of and review of these guidelines using the GRADE system. The A.S.P.E.N.
Board of Directors approved the guidelines on March 20, 2013.
Received for publication March 30, 2013; accepted for publication April
1, 2013.
This article originally published online on May 17, 2013.
Corresponding Author:
Charlene Compher, PhD, RD, CNSC, LDN, FADA, University of
Pennsylvania School of Nursing, Claire M. Fagin Hall, 418 Curie Blvd,
Philadelphia, PA 19104-4217, USA.
Email: compherc@nursing.upenn.edu.
A.S.P.E.N. Clinical Guidelines: Nutrition Support of
Neonatal Patients at Risk for Metabolic Bone Disease
Deepika Nehra, MD
1
; Sarah J. Carlson, MD
1
; Erica M. Fallon, MD
1
; Brian Kalish,
BS
1
; Alexis K. Potemkin, RN, BSN
1
; Kathleen M. Gura, PharmD, BCNSP
2
; Edwin
Simpser, MD
3
; Charlene Compher, PhD, RD, CNSC, LDN, FADA
4
; Mark Puder,
MD, PhD
1
; and the American Society for Parenteral and Enteral Nutrition
Abstract
Background: Premature infants are at increased risk for metabolic bone disease, with resulting delayed bone growth, osteopenia, and
rickets. Method: A systematic review of the best available evidence to answer a series of questions regarding neonatal patients at risk of
metabolic bone disease receiving parenteral or enteral nutrition was undertaken and evaluated using concepts adopted from the Grading
of Recommendations, Assessment, Development and Evaluation working group. A consensus process was used to develop the clinical
guideline recommendations prior to external and internal review and approval by the American Society for Parenteral and Enteral Nutrition
Board of Directors. Questions: (1) What maternal risk factors predispose the neonate to metabolic bone disease? (2) What is the optimal
type of feeding to promote neonatal bone health? (3) When and how should vitamin D supplements be administered? (4) Does parenteral
nutrition (PN) predispose a neonate to metabolic bone disease, and if so, are there PN formulation recommendations to minimize this risk?
(JPEN J Parenter Enteral Nutr. 2013;37:570-598)
Keywords
neonates; parenteral nutrition; minerals/trace elements
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
Nehra et al 571
studies can be recommended for the evaluation of bone health
in this population.
In the current guidelines, we aim to identify maternal and
neonatal factors that place infants at risk for metabolic bone
disease and provide a rationale for nutrition strategies to pre-
vent and treat the condition.
Methodology
The American Society for Parenteral and Enteral Nutrition
(A.S.P.E.N.) is an organization composed of healthcare profes-
sionals representing the disciplines of medicine, nursing, phar-
macy, dietetics, and nutrition science. The mission of
A.S.P.E.N. is to improve patient care by advancing the science
and practice of clinical nutrition and metabolism. A.S.P.E.N.
vigorously works to support quality patient care, education,
and research in the fields of nutrition and metabolic support in
all healthcare settings. These Clinical Guidelines were devel-
oped under the guidance of the A.S.P.E.N. Board of Directors.
Promotion of safe and effective patient care by nutrition sup-
port practitioners is a critical role of the A.S.P.E.N. organiza-
tion. The A.S.P.E.N. Board of Directors has been publishing
Clinical Guidelines since 1986.
7-18
A.S.P.E.N. evaluates in an
ongoing process when individual Clinical Guidelines should
be updated.
These A.S.P.E.N. Clinical Guidelines are based upon gen-
eral conclusions of health professionals who, in developing
such guidelines, have balanced potential benefits to be derived
from a particular mode of medical therapy against certain risks
inherent with such therapy. However, the professional judg-
ment of the attending health professional is the primary com-
ponent of quality medical care. Because guidelines cannot
account for every variation in circumstances, the practitioner
must always exercise professional judgment in their applica-
tion. These Clinical Guidelines are intended to supplement, but
not replace, professional training and judgment.
A.S.P.E.N. Clinical Guidelines has adopted concepts of the
Grading of Recommendations, Assessment, Development and
Evaluation (GRADE) working group.
19-22
A full description of
the methodology as adapted by A.S.P.E.N. has been published.
23

Briefly, specific clinical questions where nutrition support is a
relevant mode of therapy are developed and key clinical out-
comes are identified. A rigorous search of the published litera-
ture is conducted, each included study is assessed for research
quality, tables of findings are developed, the body of evidence
for the question is evaluated, and a recommendation for clinical
practice that is based on both the best available evidence and the
risks and benefits to patients is developed by consensus.
Recommendations are graded as strong when the evidence is
strong and/or net benefits outweigh harms. Weak recommenda-
tions may be based on weaker evidence and/or important trade-
offs to the patient. When limited research is available to answer
a question, no recommendation can be made.
Results
For the current Clinical Guideline, a PubMed search was per-
formed to identify pertinent studies using the search terms
bone AND neonate* OR infant*. The search was further
focused by identifying studies containing at least 1 of the fol-
lowing additional key terms: aluminum; breastfed; breast
fed; breast-fed; breast milk; calcium; copper; cysteine; diet;
feeding; formula; human milk; magnesium; maternal; min-
eral; nutrition; parenteral nutrition; phosphorus; preterm
formula; rickets; risk factor; total parenteral nutrition; trace
element; Vitamin D or Vitamin K. Studies were excluded if
they contained 1 or more of the following key terms: bone
marrow transplant; bone marrow transplantation; cancer;
dialysis; hyperparathyroidism; hypoparathyroidism; osteo-
petrorickets; renal failure; renal tubular acidosis or trans-
plant, which allowed for the exclusion of studies addressing
bone disease in the setting of these other medical conditions
that were not consistent with the aims of the current Clinical
Guidelines. In addition, the following limits regarding the
type of study were used: humans; clinical trial; randomized
controlled trial (RCT); clinical trial: phase I, phase II, phase
III, phase IV; comparative study; controlled clinical trial;
guideline; journal article; multicenter study; English lan-
guage; and published within the last 10 years. The search was
conducted on July 22, 2011. A total of 941 abstracts were
reviewed, of which 29 papers met the inclusion criteria of the
Clinical Guidelines and were included. The questions are
summarized in Table 1.
Practice Guidelines and Rationales
Question 1. What maternal risk factors predispose the neo-
nate to metabolic bone disease?
Recommendation: Maternal vitamin D deficiency is a risk
factor for neonatal vitamin D deficiency and abnormal bone
health, and we suggest that pregnant women be screened for
vitamin D deficiency and those that are deficient be supple-
mented (Weak). Insufficient data are available to determine the
effect of maternal magnesium sulfate and folic acid use on neo-
natal bone health (Further research needed).
Evidence Grade: Low (Tables 2 and 3)
Rationale: Fetal bone development and growth occur dur-
ing pregnancy with maximal accretion rates for both calcium
and phosphorus occurring during the third trimester, making
it important for one to consider the maternal factors that may
have an impact on the development of the fetal skeleton and
neonatal bone health.
6
Our literature review identified a few
salient maternal nutrition factors that have been studied in
relation to neonatal bone health, including maternal vitamin
D deficiency, the administration of intravenous (IV) magne-
sium sulfate as a tocolytic agent, and maternal folic acid
intake.
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
572 Journal of Parenteral and Enteral Nutrition 37(5)
Several studies have attempted to correlate maternal vita-
min D status with neonatal bone health. Five observational
studies met inclusion criteria and were reviewed.
24-28
Taken
together, the available data suggest that maternal vitamin D
deficiency is a risk factor for neonatal vitamin D deficiency,
with the potential deleterious effects on both neonatal and later
childhood bone health.
Magnesium sulfate continues to be widely used as a toco-
lytic agent despite a paucity of evidence supporting its effi-
cacy,
29
and there has been recent concern regarding the effect
of prolonged administration of this drug on both maternal and
neonatal health. Given the paucity of data and the poor quality
of the available data,
30,31
it is difficult to determine whether the
prolonged administration of magnesium sulfate as a tocolytic
agent has a detrimental effect on neonatal bone health, and
thus, future prospective studies are necessary before any defin-
itive recommendation can be made.
Folic acid is known to play an important role in normal
growth and likely also plays a role in normal bone formation
and growth. Furthermore, data exist suggesting that folic acid
supplementation has beneficial effects on bone status in certain
adult populations.
32
Our literature search identified only 1
study that evaluated the effect of the duration of folic acid sup-
plementation during pregnancy on neonatal bone metabolism.
The authors found no difference in any neonatal biomarkers of
bone metabolism between neonates born to mothers who took
folic acid supplementation until the end of the second vs the
third trimester of pregnancy.
33
Based on the paucity of avail-
able data, we cannot comment on the effect of extending folic
acid supplementation through the third trimester of preg-
nancya period of rapid bone developmenton neonatal
bone health, and further studies are necessary.
Question 2. What is the optimal type of feeding to promote
neonatal bone health?
Recommendation: When available, we suggest human milk
with nutrient fortifier for the preterm infant (Weak). When
human milk is not available, we suggest that nutrient-enriched
formula be used (Weak).
Evidence Grade: Low (Tables 4 and 5)
Rationale: The goal in nourishing premature infants is
to minimize nutrient deficits and promptly address deficits
that are encountered. The best practices for accomplishing
this, particularly early after hospital discharge, have yet to
be defined. Although feeding human milk to premature
infants is widely acknowledged as being superior to for-
mula feedings because of immunological and developmen-
tal benefits, human milkfed infants often accrue the
greatest nutrition deficits by the time of hospital dis-
charge.
34-37
We sought to identify studies that evaluated the
effect of different types of feeds on metabolic bone disease
of the neonate.
Table 1. Nutrition Support Guideline Recommendations in Metabolic Bone Disease of the Neonate.
Question Recommendation Grade
1. What maternal risk factors predispose
the neonate to metabolic bone disease?
Maternal vitamin D deficiency is a risk factor for
neonatal vitamin D deficiency and abnormal bone
health, and we suggest that pregnant women be
screened for vitamin D deficiency and those that
are deficient be supplemented.
Weak
Insufficient data are available to determine the effect
of maternal magnesium sulfate and folic acid use
on neonatal bone health.
Further research needed
2. What is the optimal type of feeding to promote
neonatal bone health?
When available, we suggest human milk with nutrient
fortifier for the preterm infant.
Weak
When human milk is not available, we suggest that
nutrient-enriched formula be used.
Weak
3. When and how should vitamin D supplements be
administered?
We suggest vitamin D supplementation for healthy
breastfed infants and those with malnutrition and/or
rickets.
Weak
Further studies are needed to determine the optimal
dose, route, and duration of supplementation in each
of these conditions.
Further research needed
4. Does parenteral nutrition (PN)
predispose a neonate to metabolic bone disease,
and if so, are there PN formula recommendations
to minimize this risk?
We suggest that PN predisposes the infant to metabolic
bone disease.
We suggest the use of PN solutions with high-dose
calcium and phosphorus supplementation.
PN containing aluminum is a risk factor for metabolic
bone disease of the neonate, and we suggest that future
efforts be made to reduce aluminum content of PN.
Weak
Weak
Strong
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
573
T
a
b
l
e

2
.

E
v
i
d
e
n
c
e

T
a
b
l
e

Q
u
e
s
t
i
o
n

1
:

W
h
a
t

m
a
t
e
r
n
a
l

r
i
s
k

f
a
c
t
o
r
s

p
r
e
d
i
s
p
o
s
e

t
h
e

n
e
o
n
a
t
e

t
o

m
e
t
a
b
o
l
i
c

b
o
n
e

d
i
s
e
a
s
e
?
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
M
a
t
e
r
n
a
l

V
i
t
a
m
i
n

D

D
e
f
i
c
i
e
n
c
y
V
i
l
j
a
k
a
i
n
e
n
,

2
0
1
0
2
8
O
B
S
H
e
a
l
t
h
y

p
r
e
g
n
a
n
t

C
a
u
c
a
s
i
a
n

w
o
m
e
n

(
2
0

4
0

y
e
a
r
s
)

w
i
t
h

a
n

u
n
e
v
e
n
t
f
u
l

s
i
n
g
l
e
t
o
n

f
u
l
l
-
t
e
r
m

c
h
i
l
d

w
e
r
e

r
e
c
r
u
i
t
e
d

a
t

3
5

w
e
e
k
s

g
e
s
t
a
t
i
o
n
T
o

d
e
t
e
r
m
i
n
e

t
h
e

a
s
s
o
c
i
a
t
i
o
n

b
e
t
w
e
e
n

m
a
t
e
r
n
a
l

v
i
t
a
m
i
n

D

s
t
a
t
u
s

a
n
d

n
e
o
n
a
t
a
l

b
o
n
e

v
a
r
i
a
b
l
e
s
N
e
o
n
a
t
e
s

d
i
v
i
d
e
d

i
n
t
o

g
r
o
u
p
s

b
a
s
e
d

o
n

m
a
t
e
r
n
a
l

2
5
-
O
H
D

b
e
l
o
w

o
r

a
b
o
v
e

t
h
e

m
e
d
i
a
n

v
a
l
u
e

o
f

4
2
.
6

n
m
o
l
/
L
D
i
d

p
r
o
v
i
d
e

a

d
i
r
e
c
t

m
e
a
s
u
r
e

o
f

n
e
o
n
a
t
a
l

b
o
n
e

h
e
a
l
t
h

u
s
i
n
g

q
u
a
n
t
i
t
a
t
i
v
e

C
T

C
r
o
s
s
-
s
e
c
t
i
o
n
a
l

s
t
u
d
y

w
i
t
h

l
o
n
g
i
t
u
d
i
n
a
l

f
o
l
l
o
w
-
u
p
H
e
l
s
i
n
k
i

a
n
d

U
u
s
i
m
a
a

(
F
i
n
l
a
n
d
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

M
a
t
e
r
n
a
l

(
f
i
r
s
t

t
r
i
m
e
s
t
e
r

a
n
d

2

d
a
y
s

p
o
s
t
p
a
r
t
u
m
)

a
n
d

n
e
o
n
a
t
a
l

(
u
m
b
i
l
i
c
a
l

c
o
r
d
)

2
5
-
O
H
D
,

P
T
H
,

a
n
d

q
u
a
n
t
i
t
a
t
i
v
e

t
i
b
i
a
l

C
T

(
B
M
D
,

B
M
C
,

C
S
A
)
T
i
b
i
a
l

B
M
C

w
a
s

0
.
0
4
7

(
9
5
%

C
I
,

0
.
0
1
1

0
.
0
8
2
)

g
/
c
m

h
i
g
h
e
r

(
P

=

.
0
1
)

a
n
d

C
S
A

w
a
s

1
2
.
3

(
9
5
%

C
I
,

2
.
0

2
2
.
6
)

m
m
2

l
a
r
g
e
r

w
i
t
h

n
o

d
i
f
f
e
r
e
n
c
e

i
n

B
M
D

i
n

n
e
o
n
a
t
e
s

w
i
t
h

m
o
t
h
e
r
s

w
i
t
h

a

2
5
-
O
H
D

a
b
o
v
e

t
h
e

m
e
d
i
a
n

c
o
m
p
a
r
e
d

w
i
t
h

b
e
l
o
w

t
h
e

m
e
d
i
a
n
N
o

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

b
o
n
e

m
e
a
s
u
r
e
s

a
n
d

c
l
i
n
i
c
a
l

p
a
t
h
o
l
o
g
y

A
t
t
r
i
t
i
o
n

r
a
t
e
:

1
/
1
2
5
N

=

1
2
4

(
m
o
t
h
e
r

a
n
d

n
e
o
n
a
t
e

p
a
i
r
s
)
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
D
i
j
k
s
t
r
a
,

2
0
0
7
2
5
O
B
S
N
e
o
n
a
t
e
s

o
f

h
e
a
l
t
h
y

m
o
t
h
e
r
s

w
i
t
h

e
i
t
h
e
r

d
a
r
k

s
k
i
n

a
n
d
/
o
r

c
o
n
c
e
a
l
i
n
g

c
l
o
t
h
i
n
g

(
r
i
s
k

g
r
o
u
p
)

o
r

l
i
g
h
t

s
k
i
n

(
c
o
n
t
r
o
l

g
r
o
u
p
)
T
o

d
e
t
e
r
m
i
n
e

t
h
e

p
r
e
v
a
l
e
n
c
e

o
f

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

i
n

n
e
o
n
a
t
e
s

o
f

m
o
t
h
e
r
s

a
t

r
i
s
k

o
f

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

(
d
a
r
k

s
k
i
n
,

c
o
n
c
e
a
l
i
n
g

c
l
o
t
h
i
n
g
)

c
o
m
p
a
r
e
d

w
i
t
h

t
h
o
s
e

n
o
t

p
r
e
s
u
m
e
d

t
o

b
e

a
t

r
i
s
k
4
2
.
5
%

o
f

n
e
o
n
a
t
e
s

h
a
d

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
2
5

n
m
o
l
/
L
)
N
o
t

c
o
n
t
r
o
l
l
e
d

f
o
r

u
s
e

o
f

v
i
t
a
m
i
n

s
u
p
p
l
e
m
e
n
t
s

a
n
d

t
y
p
e

o
f

f
e
e
d
s

P
r
o
s
p
e
c
t
i
v
e
R
o
t
t
e
r
d
a
m

(
t
h
e

N
e
t
h
e
r
l
a
n
d
s
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

m
a
t
e
r
n
a
l

(
e
n
d

o
f

t
h
i
r
d

t
r
i
m
e
s
t
e
r
)

a
n
d

n
e
o
n
a
t
a
l

(
u
m
b
i
l
i
c
a
l

c
o
r
d
)

2
5
-
O
H
D
,

i
o
n
i
z
e
d

C
a
,

P
h
o
s
,

A
L
P
,

P
T
H
T
h
e
r
e

w
a
s

a

p
o
s
i
t
i
v
e

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

m
a
t
e
r
n
a
l

a
n
d

n
e
o
n
a
t
a
l

2
5
-
O
H
D

(
r

=

0
.
8
8
)
T
h
e

c
l
i
n
i
c
a
l

i
m
p
l
i
c
a
t
i
o
n
s

o
f

n
e
o
n
a
t
a
l

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

n
o
t

e
v
a
l
u
a
t
e
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

3
8
/
1
2
5
N

=

8
7

(
m
o
t
h
e
r

a
n
d

n
e
o
n
a
t
e

p
a
i
r
s
;

n

=

4
9

h
i
g
h
-
r
i
s
k

g
r
o
u
p
,

n

=

3
8

l
o
w
-
r
i
s
k

g
r
o
u
p
)
P
e
a
r
s
o
n

c
o
r
r
e
l
a
t
i
o
n
s

o
f

n
e
o
n
a
t
a
l

2
5
-
O
H
D

w
i
t
h

i
o
n
i
z
e
d

C
a
,

P
h
o
s
,

A
L
P
,

a
n
d

P
T
H

w
e
r
e

n
o
n
s
i
g
n
i
f
i
c
a
n
t
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e

a
n
d

h
i
g
h

a
t
t
r
i
t
i
o
n

r
a
t
e
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
574
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
J
a
v
a
i
d
,

2
0
0
6
2
6
O
B
S
P
r
e
g
n
a
n
t

w
h
i
t
e

w
o
m
e
n

(
>
1
6

y
e
a
r
s

o
f

a
g
e
,

<
1
7

w
e
e
k
s

g
e
s
t
a
t
i
o
n
)

w
i
t
h

s
i
n
g
l
e
t
o
n

g
e
s
t
a
t
i
o
n
s

b
o
r
n

a
t

t
e
r
m
.

D
i
v
i
d
e
d

i
n
t
o

g
r
o
u
p
s

b
a
s
e
d

o
n

m
a
t
e
r
n
a
l

2
5
(
O
H
)
-
v
i
t
a
m
i
n

D

c
o
n
c
e
n
t
r
a
t
i
o
n
:

v
i
t
a
m
i
n

D

r
e
p
l
e
t
e


(
>
2
0

g
/
L
)
,

i
n
s
u
f
f
i
c
i
e
n
t

(
1
1

2
0

g
/
L
)
,

a
n
d

d
e
f
i
c
i
e
n
t

(
<
1
1

g
/
L
)
T
o

i
n
v
e
s
t
i
g
a
t
e

t
h
e

e
f
f
e
c
t

o
f

m
a
t
e
r
n
a
l

v
i
t
a
m
i
n

D

s
t
a
t
u
s

d
u
r
i
n
g

l
a
t
e

p
r
e
g
n
a
n
c
y

o
n

c
h
i
l
d
h
o
o
d

s
k
e
l
e
t
a
l

g
r
o
w
t
h
4
9

o
f

1
9
8

(
3
1
%
)

m
o
t
h
e
r
s

h
a
d

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

1
1
-
2
0

g
/
L
)

a
n
d

2
8

o
f

1
9
8

(
1
8
%
)

h
a
d

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
1
1

g
/
L
)

d
u
r
i
n
g

p
r
e
g
n
a
n
c
y
D
i
d

p
r
o
v
i
d
e

a

d
i
r
e
c
t

m
e
a
s
u
r
e

o
f

n
e
o
n
a
t
a
l

b
o
n
e

h
e
a
l
t
h

u
s
i
n
g

D
X
A

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t

s
t
u
d
y

w
i
t
h

l
o
n
g
i
t
u
d
i
n
a
l

f
o
l
l
o
w
-
u
p
S
o
u
t
h
a
m
p
t
o
n

(
U
n
i
t
e
d

K
i
n
g
d
o
m
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

a
t

9

y
e
a
r
s

o
f

a
g
e

(
w
h
o
l
e

b
o
d
y

a
n
d

l
u
m
b
a
r

s
p
i
n
e

B
M
C
,

B
M
D
,

b
o
n
e

a
r
e
a
)
L
o
w

m
a
t
e
r
n
a
l

2
5
-
O
H
D

w
a
s

a
s
s
o
c
i
a
t
e
d

w
i
t
h

r
e
d
u
c
e
d

w
h
o
l
e
-
b
o
d
y

B
M
C


(
P

=

.
0
0
8
8
)
,

B
M
D


(
P

=

.
0
0
6
3
)
,

a
n
d

b
o
n
e

a
r
e
a

(
P

=

.
0
2
6
9
)

i
n

a
d
d
i
t
i
o
n

t
o

r
e
d
u
c
e
d

l
u
m
b
a
r

s
p
i
n
e

B
M
C

(
P

=

.
0
3
0
0
)

a
n
d

B
M
D

(
P

=

.
0
0
9
4
)

i
n

c
h
i
l
d
r
e
n

9

y
e
a
r
s

o
f

a
g
e
P
r
o
v
i
d
e
d

a

m
e
a
s
u
r
e

o
f

b
o
n
e

h
e
a
l
t
h

l
a
t
e
r

i
n

c
h
i
l
d
h
o
o
d


(
9

y
e
a
r
s

o
f

a
g
e
)

A
t
t
r
i
t
i
o
n

r
a
t
e
:

3
9
8

o
f

5
9
6

(
o
r
i
g
i
n
a
l

c
o
h
o
r
t

o
f

5
9
6

w
i
t
h

4
6
1

i
n
v
i
t
e
d

t
o

p
a
r
t
i
c
i
p
a
t
e

i
n

9
-
y
e
a
r

f
o
l
l
o
w
-
u
p

b
a
s
e
d

o
n

g
e
o
g
r
a
p
h
i
c

l
o
c
a
t
i
o
n

a
t

t
i
m
e

o
f

f
o
l
l
o
w
-
u
p

a
n
d

1
9
8

p
a
r
t
i
c
i
p
a
t
e
d
)
N

=

1
9
8

(
m
o
t
h
e
r

a
n
d

c
h
i
l
d

p
a
i
r
s
)
N
o

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

b
o
n
e

m
e
a
s
u
r
e
s

a
n
d

c
l
i
n
i
c
a
l

p
a
t
h
o
l
o
g
y
T
h
o
m
s
o
n
,

2
0
0
4
2
7
O
B
S
P
r
e
g
n
a
n
t

w
o
m
e
n

w
i
t
h

2
5
-
O
H
D

d
e
f
i
c
i
e
n
c
y

(
<
3
0

n
m
o
l
/
L
)

a
n
d

t
h
e
i
r

i
n
f
a
n
t
s

a
g
e
s

4

1
0

m
o
n
t
h
s
T
o

d
e
t
e
r
m
i
n
e

t
h
e

p
o
s
t
n
a
t
a
l

v
i
t
a
m
i
n

D

s
t
a
t
u
s

a
n
d

b
o
n
e

h
e
a
l
t
h

o
f

w
o
m
e
n

i
d
e
n
t
i
f
i
e
d

a
s

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
t

i
n

p
r
e
g
n
a
n
c
y

a
n
d

t
h
e
i
r

i
n
f
a
n
t
s
A
l
l

4
7

w
o
m
e
n

h
a
d

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
5
0

n
m
o
l
/
L
)

a
n
d

3
9

o
f

4
7

(
8
3
%
)

w
e
r
e

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
t

(
2
5
-
O
H
D

<
3
0

n
m
o
l
/
L
)
L
a
r
g
e

s
a
m
p
l
e

s
i
z
e
V
a
r
i
a
b
i
l
i
t
y

w
i
t
h

a
g
e

a
t

w
h
i
c
h

d
a
t
a

w
e
r
e

c
o
l
l
e
c
t
e
d

o
n

t
h
e

c
h
i
l
d
r
e
n

(
i
e
,

4

1
0

m
o
n
t
h
s
)
T
a
b
l
e

2
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
575
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

R
e
t
r
o
s
p
e
c
t
i
v
e

a
u
d
i
t

w
i
t
h

p
r
o
s
p
e
c
t
i
v
e

r
e
c
r
u
i
t
m
e
n
t

a
n
d

a
d
d
i
t
i
o
n
a
l

d
a
t
a

c
o
l
l
e
c
t
i
o
n
M
e
l
b
o
u
r
n
e

(
A
u
s
t
r
a
l
i
a
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

m
a
t
e
r
n
a
l

a
n
d

i
n
f
a
n
t

s
e
r
u
m

2
5
-
O
H
D
,

A
L
P
,

C
a
,

P
h
o
s
,

P
T
H
;

x
-
r
a
y

r
e
s
u
l
t
s

i
n

c
h
i
l
d
r
e
n

w
i
t
h

c
l
i
n
i
c
a
l

o
r

l
a
b
o
r
a
t
o
r
y

f
i
n
d
i
n
g
s

s
u
g
g
e
s
t
i
v
e

o
f

r
i
c
k
e
t
s
1
8

o
f

4
5

(
4
0
%
)

i
n
f
a
n
t
s

w
e
r
e

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
t

a
n
d

1
4

o
f

4
5

(
3
1
%
)

w
e
r
e

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
t
T
h
e

c
l
i
n
i
c
a
l

i
m
p
l
i
c
a
t
i
o
n
s

o
f

n
e
o
n
a
t
a
l

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

n
o
t

e
v
a
l
u
a
t
e
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

4
7

w
o
m
e
n
;

2

o
f

4
7

i
n
f
a
n
t
s

(
u
n
a
b
l
e

t
o

o
b
t
a
i
n

b
l
o
o
d

s
a
m
p
l
e
)
N

=

4
7

(
m
o
t
h
e
r

a
n
d

n
e
w
b
o
r
n

p
a
i
r
s
)
1
2

o
f

1
6

(
7
5
%
)

o
f

b
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s

c
o
m
p
a
r
e
d

w
i
t
h

o
n
l
y

2

o
f

2
9

(
6
.
9
%
)

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s

h
a
d

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e

1
2

i
n
f
a
n
t
s

w
e
r
e

o
f
f
e
r
e
d

a
n

x
-
r
a
y

(
l
o
w

2
5
-
O
H
D

a
n
d

h
i
g
h

A
L
P

a
n
d
/
o
r

r
a
i
s
e
d

P
T
H
)

a
n
d

1
0

a
t
t
e
n
d
e
d
,

w
i
t
h

1

o
f

1
0

h
a
v
i
n
g

r
i
c
k
e
t
s

A
n
d
i
r
a
n
,

2
0
0
2
2
4
O
B
S
H
e
a
l
t
h
y

b
r
e
a
s
t
f
e
d

n
e
w
b
o
r
n
s

a
n
d

t
h
e
i
r

m
o
t
h
e
r
s

(
a
g
e
d

1
8

3
9

y
e
a
r
s
)

w
h
o

h
a
d

n
o
t

p
r
e
v
i
o
u
s
l
y

r
e
c
e
i
v
e
d

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n
T
o

e
v
a
l
u
a
t
e

t
h
e

v
i
t
a
m
i
n

D

s
t
a
t
u
s

a
n
d

r
i
s
k

f
a
c
t
o
r
s

f
o
r

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

i
n

h
e
a
l
t
h
y

b
r
e
a
s
t
f
e
d

n
e
w
b
o
r
n
s

a
n
d

t
h
e
i
r

m
o
t
h
e
r
s
4
6

o
f

5
4

(
8
5
%
)

m
o
t
h
e
r
s

h
a
d

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
4
0

n
m
o
l
/
L
)

a
n
d

2
5

o
f

5
4

(
4
6
%
)

h
a
d

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
2
5

n
m
o
l
/
L
)
S
t
u
d
y

o
n
l
y

e
v
a
l
u
a
t
e
d

b
r
e
a
s
t
f
e
d

n
e
w
b
o
r
n
s

R
e
t
r
o
s
p
e
c
t
i
v
e

a
u
d
i
t

w
i
t
h

p
r
o
s
p
e
c
t
i
v
e

r
e
c
r
u
i
t
m
e
n
t

a
n
d

a
d
d
i
t
i
o
n
a
l

d
a
t
a

c
o
l
l
e
c
t
i
o
n
A
n
k
a
r
a

(
T
u
r
k
e
y
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

2
5
-
O
H
D
,

C
a
,

P
h
o
s
,

A
L
P
4
3

o
f

5
4

(
8
0
%
)

o
f

n
e
w
b
o
r
n
s

h
a
d

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y
T
h
e

c
l
i
n
i
c
a
l

i
m
p
l
i
c
a
t
i
o
n
s

o
f

n
e
o
n
a
t
a
l

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

n
o
t

e
v
a
l
u
a
t
e
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

5
4
N

=

5
4

(
m
o
t
h
e
r

a
n
d

n
e
o
n
a
t
e

p
a
i
r
s
)
T
h
e
r
e

w
a
s

a

s
i
g
n
i
f
i
c
a
n
t

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

m
a
t
e
r
n
a
l

a
n
d

n
e
o
n
a
t
a
l

2
5
-
O
H
D

l
e
v
e
l
s

(
r

=

0
.
6
3
;


P

=

.
0
1
)

a
n
d

t
h
e

m
o
s
t

i
m
p
o
r
t
a
n
t

r
i
s
k

f
a
c
t
o
r

f
o
r

l
o
w

n
e
o
n
a
t
a
l

2
5
-
O
H
D

w
a
s

a

m
a
t
e
r
n
a
l

l
e
v
e
l

<
2
5

n
m
o
l
/
L

(
O
R

=

1
5
.
2
;


P

=

.
0
0
2
)
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
T
a
b
l
e

2
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
576
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
M
a
t
e
r
n
a
l

M
a
g
n
e
s
i
u
m

S
u
l
f
a
t
e
Y
o
k
o
y
a
m
a
,

2
0
1
0
3
1
O
B
S
N
e
o
n
a
t
e
s

w
h
o
s
e

m
o
t
h
e
r
s

e
i
t
h
e
r

r
e
c
e
i
v
e
d

p
r
o
l
o
n
g
e
d

I
V

M
g
S
O
4

(
>
5

d
a
y
s
)

(
c
a
s
e
s
)

o
r

d
i
d

n
o
t

r
e
c
e
i
v
e

I
V

M
g
S
O
4

(
c
o
n
t
r
o
l
s
)
T
o

a
s
s
e
s
s

t
h
e

e
f
f
e
c
t
s

o
f

p
r
o
l
o
n
g
e
d

(
>
5

d
a
y
s
)

m
a
t
e
r
n
a
l

I
V

M
g
S
O
4

o
n

n
e
o
n
a
t
a
l

b
o
n
e

h
e
a
l
t
h
M
e
a
n

d
u
r
a
t
i
o
n

o
f

m
a
t
e
r
n
a
l

M
g
S
O
4

a
d
m
i
n
i
s
t
r
a
t
i
o
n

=

1
8
.
3

1
1
.
3

d
a
y
s

(
r
a
n
g
e
,

5

4
4

d
a
y
s
)
R
a
d
i
o
g
r
a
p
h
i
c

b
o
n
e

a
b
n
o
r
m
a
l
i
t
i
e
s

w
e
r
e

i
d
e
n
t
i
f
i
e
d

i
n

o
n
l
y

2

o
f

1
1
7

p
a
t
i
e
n
t
s

o
v
e
r
a
l
l
,

m
a
k
i
n
g

a

d
e
t
e
r
m
i
n
a
t
i
o
n

o
f

t
h
e

e
f
f
e
c
t

o
f

p
r
o
l
o
n
g
e
d

m
a
t
e
r
n
a
l

I
V

M
g
S
O
4

o
n

r
a
d
i
o
g
r
a
p
h
i
c

e
v
i
d
e
n
c
e

o
f

n
e
o
n
a
t
a
l

b
o
n
e

d
i
s
e
a
s
e

d
i
f
f
i
c
u
l
t

t
o

d
e
t
e
r
m
i
n
e

R
e
t
r
o
s
p
e
c
t
i
v
e

c
a
s
e
-
c
o
n
t
r
o
l

s
t
u
d
y
T
o
g
i
c
h
i

(
J
a
p
a
n
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

n
e
o
n
a
t
a
l

M
g
,

C
a
,

P
h
o
s
,

A
L
P
,

r
a
d
i
o
g
r
a
p
h
y

a
t

b
i
r
t
h

(
e
v
a
l
u
a
t
i
n
g

f
o
r

o
s
t
e
o
p
e
n
i
a

a
t

t
h
e

m
e
t
a
p
h
y
s
e
a
l

l
i
n
e
)
M
e
a
n

s
e
r
u
m

M
g
,

P
h
o
s
,

a
n
d

A
L
P

l
e
v
e
l
s

s
i
g
n
i
f
i
c
a
n
t
l
y

h
i
g
h
e
r

a
n
d

C
a

l
e
v
e
l
s

s
i
g
n
i
f
i
c
a
n
t
l
y

l
o
w
e
r

(
P

<

.
0
0
1

i
n

a
l
l

c
a
s
e
s
)

a
m
o
n
g

n
e
o
n
a
t
e
s

b
o
r
n

t
o

m
o
t
h
e
r
s

w
h
o

r
e
c
e
i
v
e
d

p
r
o
l
o
n
g
e
d

I
V

M
g
S
O
4
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e

A
t
t
r
i
t
i
o
n

r
a
t
e
:

N
A
N

=

1
1
7

(
n

=

5
8

c
a
s
e
s
;

n

=

5
9

c
o
n
t
r
o
l
s
)
R
a
d
i
o
g
r
a
p
h
i
c

b
o
n
e

a
b
n
o
r
m
a
l
i
t
i
e
s

e
v
i
d
e
n
t

i
n

2

o
f

5
8

c
a
s
e
s

a
n
d

0

o
f

5
9

c
o
n
t
r
o
l
s

a
t

b
i
r
t
h

(
P

=

.
4
9
6
)

N
a
s
s
a
r
,

2
0
0
6
3
0
O
B
S
P
r
e
g
n
a
n
t

w
o
m
e
n

w
h
o

r
e
c
e
i
v
e
d

I
V

M
g
S
O
4

a
d
m
i
n
i
s
t
r
a
t
i
o
n

f
o
r

>
4
8

h
o
u
r
s

(
c
a
s
e
s
)

o
r

f
o
r

4
8

h
o
u
r
s

(
c
o
n
t
r
o
l
s
)
T
o

d
e
t
e
r
m
i
n
e

t
h
e

e
f
f
e
c
t

o
f

p
r
o
l
o
n
g
e
d

(
>
4
8

h
o
u
r
)

I
V

M
g
S
O
4

a
d
m
i
n
i
s
t
r
a
t
i
o
n

o
n

m
a
t
e
r
n
a
l

a
n
d

n
e
o
n
a
t
a
l

o
u
t
c
o
m
e
N
o

d
i
f
f
e
r
e
n
c
e

i
n

n
e
o
n
a
t
a
l

C
a

l
e
v
e
l

b
e
t
w
e
e
n

g
r
o
u
p
s

(
8
.
5

1
.
1

m
g
/
d
L

i
n

b
o
t
h
)
I
m
a
g
i
n
g

s
t
u
d
i
e
s

n
o
t

r
o
u
t
i
n
e
l
y

p
e
r
f
o
r
m
e
d

o
n

a
l
l

n
e
o
n
a
t
e
s

e
x
p
o
s
e
d

t
o

p
r
o
l
o
n
g
e
d

m
a
t
e
r
n
a
l

I
V

M
g
S
O
4

s
o

u
n
a
b
l
e

t
o

c
o
m
p
a
r
e

g
r
o
u
p
s

w
i
t
h

r
e
g
a
r
d

t
o

t
h
e

i
n
c
i
d
e
n
c
e

a
b
n
o
r
m
a
l

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

R
e
t
r
o
s
p
e
c
t
i
v
e

c
h
a
r
t

r
e
v
i
e
w
B
e
i
r
u
t

(
L
e
b
a
n
o
n
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

m
a
t
e
r
n
a
l

a
d
v
e
r
s
e

e
f
f
e
c
t
s
,

n
e
o
n
a
t
a
l

a
d
v
e
r
s
e

e
f
f
e
c
t
s

(
b
i
r
t
h

w
e
i
g
h
t
,

A
p
g
a
r

s
c
o
r
e
s
,

M
g

a
n
d

C
a

l
e
v
e
l
s
,

n
u
r
s
e
r
y

s
t
a
y
,

h
y
p
o
t
o
n
i
a
,

m
o
r
b
i
d
i
t
y
,

m
o
r
t
a
l
i
t
y
)
A
b
n
o
r
m
a
l

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

s
e
e
n

i
n

n
e
o
n
a
t
e
s

o
f

3

o
f

7
8

c
a
s
e
s

v
s

0

o
f

7
7

c
o
n
t
r
o
l
s

(
n
o


P

v
a
l
u
e
)
N
o

f
o
l
l
o
w
-
u
p

i
m
a
g
e
s

o
r

l
o
n
g
-
t
e
r
m

o
u
t
c
o
m
e
s

p
r
o
v
i
d
e
d

f
o
r

t
h
e

3

p
a
t
i
e
n
t
s

w
i
t
h

r
a
d
i
o
g
r
a
p
h
i
c

e
v
i
d
e
n
c
e

o
f

a
b
n
o
r
m
a
l

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n
T
a
b
l
e

2
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
577
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

N
A
N

=

1
5
5

(
m
o
t
h
e
r

a
n
d

n
e
o
n
a
t
e

p
a
i
r
s
;

n

=

7
8

c
a
s
e
s
,

n

=

7
7

c
o
n
t
r
o
l
s
)
N
o

d
i
f
f
e
r
e
n
c
e

b
e
t
w
e
e
n

g
r
o
u
p
s

i
n

a
n
y

m
e
a
s
u
r
e

o
f

n
e
o
n
a
t
a
l

m
o
r
b
i
d
i
t
y

o
r

m
o
r
t
a
l
i
t
y
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
M
a
t
e
r
n
a
l

F
o
l
i
c

A
c
i
d
H
o
s
s
e
i
n
-
N
e
z
h
a
d
,

2
0
1
1
3
3
O
B
S
P
r
e
g
n
a
n
t

w
o
m
e
n

8

1
2

w
e
e
k
s

g
e
s
t
a
t
i
o
n

a
n
d

a
g
e
d

1
5

4
2

y
e
a
r
s

o
f

a
g
e

w
h
o

t
o
o
k

f
o
l
i
c

a
c
i
d

(
1

m
g
/
d
)

f
r
o
m

t
h
e

b
e
g
i
n
n
i
n
g

o
f

p
r
e
g
n
a
n
c
y

t
o

t
h
e

e
n
d

o
f

t
h
e

s
e
c
o
n
d

t
r
i
m
e
s
t
e
r

(
g
r
o
u
p

I
)

o
r

u
n
t
i
l

d
e
l
i
v
e
r
y

(
g
r
o
u
p

I
I
)
T
o

e
v
a
l
u
a
t
e

t
h
e

e
f
f
e
c
t

o
f

f
o
l
i
c

a
c
i
d

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

t
a
k
e
n

u
n
t
i
l

t
h
e

e
n
d

o
f

t
h
e

s
e
c
o
n
d

v
s

t
h
i
r
d

t
r
i
m
e
s
t
e
r

o
n

m
a
t
e
r
n
a
l

a
n
d

f
e
t
a
l

m
a
r
k
e
r
s

o
f

b
o
n
e

t
u
r
n
o
v
e
r
N
o

s
i
g
n
i
f
i
c
a
n
t

d
i
f
f
e
r
e
n
c
e

i
n

a
n
y

n
e
o
n
a
t
a
l

b
i
o
m
a
r
k
e
r
s

o
f

b
o
n
e

m
e
t
a
b
o
l
i
s
m

o
r

a
n
y

f
e
t
a
l

a
n
t
h
r
o
p
o
m
e
t
r
i
c

c
h
a
r
a
c
t
e
r
i
s
t
i
c
s

b
e
t
w
e
e
n

g
r
o
u
p
s
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t

s
t
u
d
y
T
e
h
r
a
n

(
I
r
a
n
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

m
a
t
e
r
n
a
l

a
n
d

n
e
o
n
a
t
a
l

(
c
o
r
d
)

s
e
r
u
m

l
e
v
e
l
s

o
f

m
a
r
k
e
r
s

o
f

b
o
n
e

m
e
t
a
b
o
l
i
s
m

(
2
5
-
O
H
D
,

P
T
H
,

O
C
,

c
r
o
s
s
l
a
p
s
)
;

f
e
t
a
l

a
n
t
h
r
o
p
o
m
e
t
r
i
c

m
e
a
s
u
r
e
s


A
t
t
r
i
t
i
o
n

r
a
t
e
:

n
o
t

s
p
e
c
i
f
i
e
d
N

=

1
1
3

(
n

=

5
4

g
r
o
u
p

I
;

n

=

5
9

g
r
o
u
p

I
I
)

A
L
P
,

a
l
k
a
l
i
n
e

p
h
o
s
p
h
a
t
a
s
e
;

B
M
C
,

b
o
n
e

m
i
n
e
r
a
l

c
o
n
t
e
n
t
;

B
M
D
,

b
o
n
e

m
i
n
e
r
a
l

d
e
n
s
i
t
y
;

C
a
,

c
a
l
c
i
u
m
;

C
I
,

c
o
n
f
i
d
e
n
c
e

i
n
t
e
r
v
a
l
;

C
S
A
,

c
r
o
s
s
-
s
e
c
t
i
o
n
a
l

a
r
e
a
;

C
T
,

c
o
m
p
u
t
e
d

t
o
m
o
g
r
a
p
h
y
;

D
X
A
,

d
u
a
l
-
e
n
e
r
g
y

x
-
r
a
y

a
b
s
o
r
p
t
i
o
m
e
t
r
y
;

I
V
,

i
n
t
r
a
v
e
n
o
u
s
;

M
g
,

m
a
g
n
e
s
i
u
m
;

M
g
S
O
4
,

m
a
g
n
e
s
i
u
m

s
u
l
f
a
t
e
;

N
A
,

n
o
t

a
v
a
i
l
a
b
l
e
;

P
h
o
s
,

p
h
o
s
p
h
o
r
u
s
;

P
T
H
,

p
a
r
a
t
h
y
r
o
i
d

h
o
r
m
o
n
e
;

O
B
S
,

o
b
s
e
r
v
a
t
i
o
n
a
l

s
t
u
d
y
;

O
C
,

o
s
t
e
o
c
a
l
c
i
n
;

O
R
,

o
d
d
s

r
a
t
i
o
;

2
5
-
O
H
D
,

2
5
-
h
y
d
r
o
x
y
v
i
t
a
m
i
n

D
.
T
a
b
l
e

2
.

(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
578 Journal of Parenteral and Enteral Nutrition 37(5)
Table 3. GRADE Table Question 1: What maternal risk factors predispose the neonate to metabolic bone disease?
Comparison Outcome
Quantity, Type
Evidence Findings
GRADE of Evidence
for Outcome
Maternal vitamin D deficiency and
neonatal vitamin D deficiency
24,25,27

Biochemical:
25-OHD
3 OBS
24,25,27
Biochemical:
Lower
24,25,27
Low

Maternal vitamin D deficiency and
neonatal
28
or childhood (9 years of age)
26

bone health

Bone: 2 OBS
26,28
Bone: Low
BMC Lower
26

BMD No difference
28
Lower
26

CSA Lower
28

Prolonged (>48 hour) vs short-term (48
hour)
30
or prolonged (>5 day) vs no
maternal IV MgSO
4
administration
31

Biochemical:
Ca
ALP, Mg, Phos
Bone:
Radiographic bone
abnormality
2 OBS
30,31
Biochemical:
No difference
30
Lower
31
Higher
31
Bone:
No difference
30,31
Low




Folic acid supplementation through second
vs third trimester of pregnancy
33

Biochemical:
25-OHD, PTH, OC,
crosslaps
1 OBS
33
Biochemical:
No difference
Low

25-OHD, 25-hydroxyvitamin D; ALP, alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; Ca, calcium; CSA, cross-section-
al area; IV, intravenous; Mg, magnesium; MgSO
4
, magnesium sulfate; Phos, phosphorus; PTH, parathyroid hormone; OBS, observational study; OC,
osteocalcin.
The available data suggest that exclusive breastfeeding is
associated with lower bone mineralization in both the preterm
and term infant
38-41
and that fortification has beneficial effects
on bone health for the human milkfed preterm neonate
42,43
;
however, further studies are necessary to determine the optimal
type, amount, and duration of nutrient fortification.
For the formula-fed infant, the available data suggest that a
nutrient-enriched preterm formula administered to preterm
infants from hospital discharge to approximately term has ben-
eficial effects on growth and bone health.
44-48
Of note, all of
these studies looked at relatively healthy preterm infants, and
thus sufficient data are not available to make a recommenda-
tion for the sicker and smaller preterm infant. In addition, the
available data are insufficient to allow for a recommendation
regarding the use of a nutrient-enriched preterm formula
beyond approximate expected term, and thus further studies
are necessary to address this time period.
Question 3. When and how should vitamin D supplements
be administered?
Recommendation: We suggest vitamin D supplementation
for healthy breastfed infants and those with malnutrition and/or
rickets (Weak). Further studies are needed to determine the
optimal dose, route, and duration of supplementation in each of
these conditions (Further research needed).
Evidence Grade: Low (Tables 6 and 7)
Rationale: Current recommendations for vitamin D intake
differ, and we sought to identify studies that provided guidance
with regard to indications and methods for vitamin D supple-
mentation in the neonate.
The available data suggest that vitamin D supplementation
is beneficial in healthy term
40,49,50
and preterm
51
breastfed
infants in addition to children with established malnutrition
and rickets,
52-54
but further studies are necessary to determine
the optimal dose, route of administration, and duration of treat-
ment; thus, specific recommendations cannot be made at this
time. There is also disagreement among professional organiza-
tions with regard to vitamin D dose in infants. The American
Academy of Pediatrics
55
recommends 400 IU (10 g) per day,
as does the Institute of Medicine with a goal 25-hydroxyvita-
min D level >20 ng/mL.
56
However, the Endocrine Society
57

recommends that infants require at least 400 IU and that 1000
IU daily may be needed to obtain an optimal 25-hydroxyvita-
min D level (>30 ng/mL) for nonskeletal health benefits.
Question 4. Does PN predispose a neonate to metabolic
bone disease, and if so, are there PN formulation recom-
mendations to minimize this risk?
Recommendation: We suggest that PN predisposes the
infant to metabolic bone disease (Weak). We suggest using PN
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
579
T
a
b
l
e

4
.

E
v
i
d
e
n
c
e

T
a
b
l
e

Q
u
e
s
t
i
o
n

2
:

W
h
a
t

i
s

t
h
e

o
p
t
i
m
a
l

t
y
p
e

o
f

f
e
e
d
i
n
g

t
o

p
r
o
m
o
t
e

n
e
o
n
a
t
a
l

b
o
n
e

h
e
a
l
t
h
?
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
H
u
m
a
n

M
i
l
k

v
s

F
o
r
m
u
l
a
K
i
m
,

2
0
1
0
6
6
O
B
S
H
e
a
l
t
h
y

t
e
r
m

i
n
f
a
n
t
s

d
i
v
i
d
e
d

i
n
t
o

3

g
r
o
u
p
s
:

A

(
f
o
r
m
u
l
a

f
e
d
)
,

B

(
b
r
e
a
s
t
f
e
d

o
n
l
y

w
i
t
h
o
u
t

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n
)

a
n
d
,

S

(
b
r
e
a
s
t
f
e
d

w
i
t
h

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

a
t

2
0
0

I
U

d
a
i
l
y

i
n

t
h
e

f
o
r
m

o
f

P
o
l
y
-
V
i
t
a
m
i
n

D
r
o
p
s

f
r
o
m

2

1
2

m
o
n
t
h
s

o
f

a
g
e
)
T
o

e
v
a
l
u
a
t
e

t
h
e

v
i
t
a
m
i
n

D

s
t
a
t
u
s

o
f

K
o
r
e
a
n

i
n
f
a
n
t
s

a
n
d

t
o

d
e
t
e
r
m
i
n
e

t
h
e

v
i
t
a
m
i
n

D

n
u
t
r
i
t
i
o
n

s
t
a
t
u
s

a
n
d

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

i
n

t
e
r
m

b
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s

w
h
o

w
e
r
e

f
o
r
m
u
l
a

f
e
d
,

b
r
e
a
s
t
f
e
d

o
n
l
y
,

o
r

b
r
e
a
s
t
f
e
d

w
i
t
h

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

(
2
0
0

I
U
/
d
)
6
-
m
o
n
t
h

f
o
l
l
o
w
-
u
p
:

2
5
-
O
H
D

d
i
f
f
e
r
e
n
t

a
m
o
n
g

g
r
o
u
p
s

w
i
t
h

A

>

S

>

B

(
P

<

.
0
0
1
)
N
o

d
i
f
f
e
r
e
n
c
e

a
m
o
n
g

g
r
o
u
p
s

i
n

d
e
m
o
g
r
a
p
h
i
c

c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
,

b
a
s
e
l
i
n
e

l
a
b
o
r
a
t
o
r
y

v
a
l
u
e
s
,

o
r

l
i
f
e
s
t
y
l
e

c
h
a
r
a
c
t
e
r
i
s
t
i
c
s

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t

s
t
u
d
y
C
h
u
n
g
b
u
k

N
a
t
i
o
n
a
l

U
n
i
v
e
r
s
i
t
y

(
C
h
e
o
n
g
j
u
,

K
o
r
e
a
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

2
5
-
O
H
D
,

C
a
,

P
h
o
s
,

A
L
P
,

P
T
H

a
n
d

D
X
A

(
B
M
D
,

B
M
C
)

a
t

b
i
r
t
h
,

6

m
o
n
t
h
s
,

a
n
d

1
2

m
o
n
t
h
s

o
f

a
g
e
P
r
e
v
a
l
e
n
c
e

o
f

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
1
1

n
g
/
m
L
)

a
n
d

i
n
s
u
f
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

1
1

3
0

n
g
/
m
L
)

w
a
s

0
%

a
n
d

1
2
%
,

1
1
%

a
n
d

6
8
%
,

a
n
d

0
%

a
n
d

4
5
%

f
o
r

g
r
o
u
p
s

A
,

B
,

a
n
d

S
,

r
e
s
p
e
c
t
i
v
e
l
y
M
u
l
t
i
v
i
t
a
m
i
n

s
o
l
u
t
i
o
n

u
s
e
d

c
o
n
t
a
i
n
e
d

v
i
t
a
m
i
n
s

i
n

a
d
d
i
t
i
o
n

t
o

v
i
t
a
m
i
n

D

(
v
i
t
a
m
i
n
s

A
,

C
,

a
n
d

E
;

t
h
i
a
m
i
n
;

r
i
b
o
f
l
a
v
i
n
;

n
i
a
c
i
n
;

p
y
r
i
d
o
x
i
n
e
;

i
r
o
n
;

f
l
u
o
r
i
d
e
)

A
t
t
r
i
t
i
o
n

r
a
t
e
:

1
3

o
f

7
4

(
r
e
a
s
o
n

n
o
t

s
p
e
c
i
f
i
e
d
)
N

=

7
4

(
n

=

2
5

g
r
o
u
p

A
;


n

=

2
8

g
r
o
u
p

B
;

n

=

2
1

g
r
o
u
p

S
)
C
a

a
n
d

A
L
P

n
o
t

d
i
f
f
e
r
e
n
t

b
u
t

P
h
o
s

w
i
t
h

A

>

S

>

B

(
P

<

.
0
0
1
)

a
n
d

P
T
H

h
i
g
h
e
r

i
n

g
r
o
u
p

B

w
i
t
h

B

>

A

=

S

(
P

=

.
0
0
1
)
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e

B
M
D

a
n
d

B
M
C

h
i
g
h
e
r

i
n

g
r
o
u
p

A

w
i
t
h

A

>

B

=

S

(
P

<

.
0
5
)


1
2
-
m
o
n
t
h

f
o
l
l
o
w
-
u
p
:

(
n

=

3
0

g
r
o
u
p

A
;

n

=

1
6

g
r
o
u
p

B
;

n

=

1
5

g
r
o
u
p

S
)


2
5
-
O
H
D

h
i
g
h
e
r

i
n

g
r
o
u
p
s

A

a
n
d

S

w
i
t
h

A

=

S

>

B

(
P

<

.
0
0
1
)


N
o

i
n
f
a
n
t
s

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
t
,

a
l
t
h
o
u
g
h

5
0
%

o
f

i
n
f
a
n
t
s

i
n

g
r
o
u
p

B

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
t

(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
580
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

C
a

a
n
d

A
L
P

n
o
t

d
i
f
f
e
r
e
n
t

b
u
t

s
e
r
u
m

P
h
o
s

l
o
w
e
r

i
n

g
r
o
u
p

S

t
h
a
n

i
n

A

w
i
t
h

A

>

S

(
P

=

.
0
0
0
9
)

b
u
t

A

=

B

a
n
d

B

=

S

a
n
d

P
T
H

h
i
g
h
e
r

i
n

g
r
o
u
p

S

t
h
a
n

i
n

A

w
i
t
h

S

>

A

(
P

=

.
0
2
5
)

a
n
d

A

=

B

a
n
d

B

=

S


B
M
D

h
i
g
h
e
r

i
n

g
r
o
u
p

A

t
h
a
n

i
n

g
r
o
u
p
s

B

a
n
d

S

(
P

=

.
0
1
0
,

A

>

B

=

S
)

a
n
d

B
M
C

h
i
g
h
e
r

i
n

g
r
o
u
p

A

t
h
a
n

i
n

g
r
o
u
p

S

(
P

=

.
0
2
5
,

A

>

S
,

A

=

B
,

B

=

S
)

H
a
r
v
e
y
,

2
0
0
9
3
9
O
B
S
I
n
f
a
n
t
s

b
o
r
n

t
o

w
o
m
e
n

p
r
e
v
i
o
u
s
l
y

e
n
r
o
l
l
e
d

i
n

S
o
u
t
h
a
m
p
t
o
n

W
o
m
e
n

s

S
u
r
v
e
y

(
a

s
t
u
d
y

o
f

l
i
f
e
s
t
y
l
e

f
a
c
t
o
r
s
,

d
i
e
t
,

a
n
d

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s

a
m
o
n
g

n
o
n
p
r
e
g
n
a
n
t

w
o
m
e
n

a
g
e
s

2
0

3
4

y
e
a
r
s
)
T
o

e
v
a
l
u
a
t
e

t
h
e

r
e
l
a
t
i
o
n
s
h
i
p

b
e
t
w
e
e
n

c
h
i
l
d
h
o
o
d

b
o
n
e

s
i
z
e

a
n
d

d
e
n
s
i
t
y

a
t

4

y
e
a
r
s

w
i
t
h

t
h
e

d
u
r
a
t
i
o
n

a
n
d

t
y
p
e

o
f

m
i
l
k
-
f
e
e
d
i
n
g

i
n

i
n
f
a
n
c
y

a
n
d

c
o
m
p
l
i
a
n
c
e

w
i
t
h

i
n
f
a
n
t

f
e
e
d
i
n
g

g
u
i
d
a
n
c
e
D
u
r
a
t
i
o
n

o
f

b
r
e
a
s
t
f
e
e
d
i
n
g

d
i
d

n
o
t

p
r
e
d
i
c
t

a
n
y

m
e
a
s
u
r
e

o
f

b
o
n
e

s
i
z
e

o
r

d
e
n
s
i
t
y

i
n

c
h
i
l
d
r
e
n

a
t

4

y
e
a
r
s

o
f

a
g
e
D
a
t
a

r
e
g
a
r
d
i
n
g

f
e
e
d
s

b
a
s
e
d

o
n

m
a
t
e
r
n
a
l

r
e
c
a
l
l
,

i
n
t
r
o
d
u
c
i
n
g

s
i
g
n
i
f
i
c
a
n
t

p
o
t
e
n
t
i
a
l

b
i
a
s

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t
S
o
u
t
h
a
m
p
t
o
n

G
e
n
e
r
a
l

H
o
s
p
i
t
a
l

(
S
o
u
t
h
a
m
p
t
o
n
,

U
n
i
t
e
d

K
i
n
g
d
o
m
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

(
B
M
C
,

B
M
D
)

a
t

4

y
e
a
r
s
N
o

d
i
f
f
e
r
e
n
c
e

i
n

b
o
n
e

m
i
n
e
r
a
l

a
t

a
g
e

4

y
e
a
r
s

b
e
t
w
e
e
n

p
r
e
d
o
m
i
n
a
n
t
l
y

b
r
e
a
s
t
f
e
d

a
n
d

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s
U
n
c
l
e
a
r

w
h
e
t
h
e
r

b
r
e
a
s
t
f
e
d

g
r
o
u
p

r
e
c
e
i
v
e
d

f
o
r
t
i
f
i
e
r

Q
u
e
s
t
i
o
n
n
a
i
r
e
-
b
a
s
e
d

s
t
u
d
y

d
e
s
i
g
n
N

=

5
9
9
L
a
r
g
e

s
a
m
p
l
e

s
i
z
e

A
t
t
r
i
t
i
o
n

r
a
t
e
:

2
2

o
f

6
2
1

Y
o
u
n
g
,

2
0
0
5
3
8
O
B
S
H
e
a
l
t
h
y

4
-
y
e
a
r
-
o
l
d

c
h
i
l
d
r
e
n

b
o
r
n

a
t

t
e
r
m
T
o

d
e
t
e
r
m
i
n
e

w
h
e
t
h
e
r

t
h
e

t
y
p
e

o
f

f
e
e
d
i
n
g

d
u
r
i
n
g

t
h
e

f
i
r
s
t

4

m
o
n
t
h
s

o
f

l
i
f
e

a
f
f
e
c
t
s

b
o
n
e

m
i
n
e
r
a
l

d
e
n
s
i
t
y

a
t

4

y
e
a
r
s

o
f

a
g
e
B
M
C
,

B
M
D
,

a
n
d

a
n
t
e
r
o
p
o
s
t
e
r
i
o
r

s
p
i
n
e

z

s
c
o
r
e
s

n
o
t

s
i
g
n
i
f
i
c
a
n
t
l
y

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

g
r
o
u
p
s

a
t

4

y
e
a
r
s

o
f

a
g
e
G
r
o
u
p
s

d
i
d

n
o
t

d
i
f
f
e
r

w
i
t
h

r
e
s
p
e
c
t

t
o

a
g
e
,

s
e
x
,

o
r

b
o
d
y

m
a
s
s

i
n
d
e
x

b
u
t

t
h
e

H
M

g
r
o
u
p

h
a
d

m
o
r
e

C
a
u
c
a
s
i
a
n
s

(
P

=

.
0
5
)

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t
U
n
i
v
e
r
s
i
t
y

o
f

N
e
b
r
a
s
k
a

M
e
d
i
c
a
l

C
e
n
t
e
r

(
O
m
a
h
a
,

N
e
b
r
a
s
k
a
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

(
B
M
C
,

B
M
D
)

a
n
d

a
n
t
e
r
o
p
o
s
t
e
r
i
o
r

s
p
i
n
e

z

s
c
o
r
e
s

a
t

4

y
e
a
r
s

o
f

a
g
e
P
r
i
m
a
r
i
l
y

C
a
u
c
a
s
i
a
n

s
u
b
j
e
c
t
s

(
>
5
0
%
)
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
581
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

2
0

o
f

1
9
8

(
d
i
d

n
o
t

c
o
m
p
l
e
t
e

D
X
A

i
m
a
g
i
n
g
)
N

=

1
7
8

(
n

=

5
7

b
r
e
a
s
t
f
e
d
;

n

=

5
6

f
o
r
m
u
l
a

w
i
t
h
o
u
t

p
a
l
m

o
l
e
i
n
;

n

=

6
5

f
o
r
m
u
l
a

w
i
t
h

p
a
l
m

o
l
e
i
n
)
U
n
c
l
e
a
r

w
h
e
t
h
e
r

b
r
e
a
s
t
f
e
d

g
r
o
u
p

r
e
c
e
i
v
e
d

f
o
r
t
i
f
i
e
r
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
K
u
r
l
,

2
0
0
3
4
1
O
B
S
P
r
e
t
e
r
m

i
n
f
a
n
t
s

(
<
3
2

w
e
e
k
s

g
e
s
t
a
t
i
o
n
a
l

a
g
e
)
T
o

(
1
)

e
v
a
l
u
a
t
e

h
o
w

n
u
t
r
i
t
i
o
n

s
t
a
t
u
s

o
f

p
r
e
t
e
r
m

i
n
f
a
n
t
s

(
j
u
d
g
e
d

b
y

g
r
o
w
t
h

m
e
a
s
u
r
e
d

a
n
d

b
i
o
c
h
e
m
i
c
a
l

v
a
l
u
e
s
)

e
v
o
l
v
e
s

d
u
r
i
n
g

t
h
e

i
n
i
t
i
a
l

h
o
s
p
i
t
a
l
i
z
a
t
i
o
n

w
h
e
n

i
n
f
a
n
t
s

a
r
e

f
e
d

a
c
c
o
r
d
i
n
g

t
o

t
h
e

a
v
a
i
l
a
b
l
e

r
e
c
o
m
m
e
n
d
a
t
i
o
n
s
,

(
2
)

d
e
t
e
r
m
i
n
e

t
h
e

e
f
f
e
c
t

o
f

f
e
e
d
i
n
g

o
n

g
r
o
w
t
h

a
f
t
e
r

d
i
s
c
h
a
r
g
e
,

a
n
d

(
3
)

i
d
e
n
t
i
f
y

r
i
s
k

f
a
c
t
o
r
s

a
s
s
o
c
i
a
t
e
d

w
i
t
h

l
o
w

l
u
m
b
a
r

B
M
C

l
a
t
e
r

i
n

i
n
f
a
n
c
y
E
x
c
l
u
s
i
v
e
l
y

b
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s

w
i
t
h

l
a
r
g
e
r

w
e
i
g
h
t

f
o
r

l
e
n
g
t
h

t
h
a
n

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s

(
P

=

.
0
0
3
)
A
l
l

i
n
f
a
n
t
s

f
e
d

H
M

(
m
o
t
h
e
r

s

o
r

b
a
n
k
e
d

H
M
)

p
r
e
d
i
s
c
h
a
r
g
e

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t
K
u
o
p
i
o

U
n
i
v
e
r
s
i
t
y

H
o
s
p
i
t
a
l

(
K
u
o
p
i
o
,

F
i
n
l
a
n
d
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s

a
t

b
i
r
t
h

a
n
d

d
i
s
c
h
a
r
g
e
;

l
u
m
b
a
r

s
p
i
n
e

D
X
A

(
B
M
C
)

w
h
e
n

w
e
i
g
h
t

5

7

k
g
I
n
f
a
n
t
s

e
x
c
l
u
s
i
v
e
l
y

b
r
e
a
s
t
f
e
d

p
o
s
t
d
i
s
c
h
a
r
g
e

w
i
t
h

7
.
0

(
9
5
%

C
I
,

1
.
2

4
1
.
7
)

f
o
l
d

h
i
g
h
e
r

r
i
s
k

o
f

l
o
w

B
M
C

(
P

=

.
0
4
6
)
W
h
e
n

i
n
f
a
n
t
s

r
e
a
c
h
e
d

m
i
l
k

i
n
t
a
k
e

o
f

1
0
0

m
g
/
k
g
/
d
,

m
i
l
k

f
o
r
t
i
f
i
c
a
t
i
o
n

w
i
t
h

h
y
d
r
o
l
y
z
e
d

w
h
e
y

p
r
o
t
e
i
n

s
t
a
r
t
e
d
,

a
f
t
e
r

w
h
i
c
h

m
u
l
t
i
v
i
t
a
m
i
n
s

w
e
r
e

a
d
d
e
d

N
o
n
b
l
i
n
d
e
d
N

=

6
4

(
n

=

3
8

f
o
r
m
u
l
a

f
e
e
d
i
n
g

i
n
i
t
i
a
t
e
d

w
i
t
h
i
n

1

w
e
e
k

p
o
s
t
d
i
s
c
h
a
r
g
e
;

n

=

1
3

f
o
r
m
u
l
a

f
e
e
d
i
n
g

i
n
i
t
i
a
t
e
d

2

1
4

w
e
e
k
s

p
o
s
t
d
i
s
c
h
a
r
g
e
,

n

=

1
3

b
r
e
a
s
t
f
e
d

f
o
r

e
n
t
i
r
e

s
t
u
d
y

p
e
r
i
o
d
)
M
i
l
k

f
o
r
t
i
f
i
e
r
,

m
i
n
e
r
a
l

s
u
p
p
l
e
m
e
n
t
s
,

a
n
d

v
i
t
a
m
i
n

C

c
o
n
t
i
n
u
e
d

u
n
t
i
l

2
.
5

k
g

a
n
d

v
i
t
a
m
i
n

D

a
n
d

i
r
o
n

c
o
n
t
i
n
u
e
d

t
h
r
o
u
g
h
o
u
t

s
t
u
d
y

p
e
r
i
o
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

1
9

o
f

8
3

(
t
r
a
n
s
f
e
r

o
f

c
a
r
e

t
o

o
t
h
e
r

i
n
s
t
i
t
u
t
i
o
n

o
r

f
a
i
l
u
r
e

t
o

f
o
l
l
o
w
-
u
p
)
M
i
l
k
/
f
o
r
m
u
l
a

i
n
t
a
k
e

p
o
s
t
d
i
s
c
h
a
r
g
e

n
o
t

q
u
a
n
t
i
f
i
e
d
S
o
l
i
d

f
o
o
d
s

a
d
d
e
d

b
e
t
w
e
e
n

3

a
n
d

6

m
o
n
t
h
s
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
582
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
H
M

F
o
r
t
i
f
i
c
a
t
i
o
n
A
i
m
o
n
e
,

2
0
0
9
4
2
R
C
T
P
r
e
t
e
r
m

(
<
3
3

w
e
e
k
s

g
e
s
t
a
t
i
o
n
a
l

a
g
e
,

7
5
0

1
8
0
0

g

b
i
r
t
h

w
e
i
g
h
t
)

i
n
f
a
n
t
s

w
h
o

r
e
c
e
i
v
e
d

8
0
%

e
n
e
r
g
y

f
r
o
m

H
M

p
r
e

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e
T
o

e
v
a
l
u
a
t
e

t
h
e

i
m
p
a
c
t

o
f

f
o
r
t
i
f
y
i
n
g

H
M

w
i
t
h

a

m
u
l
t
i
n
u
t
r
i
e
n
t

H
M

f
o
r
t
i
f
i
e
r

(
a
p
p
r
o
x
i
m
a
t
e
l
y

5
0
%

o
f

f
e
e
d
s

f
o
r
t
i
f
i
e
d
)

f
o
r

1
2

w
e
e
k
s

p
o
s
t
d
i
s
c
h
a
r
g
e

o
n

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n
,

b
o
d
y

c
o
m
p
o
s
i
t
i
o
n
,

a
n
d

H
M

u
s
e

m
e
a
s
u
r
e
d

a
t

4

a
n
d

1
2

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
H
M
-
a
l
o
n
e

g
r
o
u
p

t
r
e
n
d
e
d

t
o
w
a
r
d

h
i
g
h
e
r

g
e
s
t
a
t
i
o
n
a
l

a
g
e

(
P

=

.
0
6
)

a
n
d

f
e
w
e
r

m
a
l
e
s

(
P

=

.
0
7
)
I
n
f
a
n
t
s

o
n

H
M

a
l
o
n
e

r
e
c
e
i
v
e
d

v
i
t
a
m
i
n

A

1
5
0
0

I
U
/
d
,

v
i
t
a
m
i
n

D

4
0
0

I
U
/
d
,

v
i
t
a
m
i
n

C

3
0

m
g
/
d
,

i
r
o
n

1
5

m
g
/
d
.

I
n
f
a
n
t
s

o
n

f
o
r
t
i
f
i
e
d

H
M

r
e
c
e
i
v
e
d

2
0
0

I
U
/
d

v
i
t
a
m
i
n

D

a
n
d

1
5

m
g
/
d

i
r
o
n

B
l
i
n
d
e
d

(
d
e
t
a
i
l
s

o
f

b
l
i
n
d
i
n
g

n
o
t

p
r
o
v
i
d
e
d
)
M
u
l
t
i
p
l
e

n
e
o
n
a
t
a
l

i
n
t
e
n
s
i
v
e

c
a
r
e

u
n
i
t
s

i
n

g
r
e
a
t
e
r

T
o
r
o
n
t
o

a
r
e
a

(
T
o
r
o
n
t
o
,

C
a
n
a
d
a
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s
;

D
X
A

(
B
M
C
,

B
M
D
)

a
t

4

a
n
d

1
2

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
I
n
f
a
n
t
s

w
i
t
h

f
o
r
t
i
f
i
e
d

H
M

h
a
d

i
n
c
r
e
a
s
e
d

w
e
i
g
h
t

(
P

=

.
0
7
)

a
n
d

l
e
n
g
t
h

(
P

=

.
0
2
)

a
t

t
h
e

e
n
d

o
f

t
h
e

1
2
-
w
e
e
k

f
e
e
d
i
n
g

i
n
t
e
r
v
e
n
t
i
o
n

a
n
d

b
o
t
h

w
e
i
g
h
t

(
P

=

.
0
0
3
5
)

a
n
d

l
e
n
g
t
h

(
P

=

.
0
0
1
)

h
i
g
h
e
r

1
2

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
D
u
r
a
t
i
o
n

o
f

H
M

f
e
e
d
i
n
g

d
i
d

n
o
t

d
i
f
f
e
r

b
e
t
w
e
e
n

g
r
o
u
p
s
,

b
u
t

t
h
e

v
o
l
u
m
e

o
f

H
M

c
o
n
s
u
m
e
d

w
a
s

h
i
g
h
e
r

f
o
r

t
h
e

H
M
-
a
l
o
n
e

g
r
o
u
p

a
t

6

m
o
n
t
h
s

(
P

=

.
0
3
5
)

b
u
t

n
o
t

a
t

1
2

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e

A
t
t
r
i
t
i
o
n

r
a
t
e
:

9

o
f

3
9

(
l
o
s
t

t
o

f
o
l
l
o
w
-
u
p
)
N

=

3
9

(
n

=

2
0

H
M

a
l
o
n
e
;


n

=

1
9

f
o
r
t
i
f
i
e
d

H
M
)
B
M
C

a
t

4

a
n
d

1
2

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e

h
i
g
h
e
r

i
n

i
n
f
a
n
t
s

o
n

f
o
r
t
i
f
i
e
d

H
M

(
P

=

.
0
2
)

b
u
t

w
h
e
n

c
o
r
r
e
c
t
e
d

f
o
r

l
e
n
g
t
h
,

e
f
f
e
c
t

d
i
s
a
p
p
e
a
r
e
d

(
P

=

.
2
5
)
I
n
t
e
n
t
-
t
o
-
t
r
e
a
t

a
n
a
l
y
s
i
s

B
M
D

w
a
s

n
o
t

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

g
r
o
u
p
s

a
t

4

o
r

1
2

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e
D
e

S
c
h
e
p
p
e
r
,

2
0
0
5
4
3
O
B
S
P
r
e
t
e
r
m

i
n
f
a
n
t
s

(
<
3
4

w
e
e
k
s

g
e
s
t
a
t
i
o
n
a
l

a
g
e
,

b
i
r
t
h

w
e
i
g
h
t

8
0
0

2
2
1
0

g
)
T
o

d
e
t
e
r
m
i
n
e

w
h
e
t
h
e
r

w
h
o
l
e
-
b
o
d
y

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

i
s

d
i
f
f
e
r
e
n
t

a
t

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

b
e
t
w
e
e
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

f
e
d

a

c
o
m
m
e
r
c
i
a
l

p
r
e
t
e
r
m

f
o
r
m
u
l
a

a
n
d

t
h
o
s
e

f
e
d

w
i
t
h

f
o
r
t
i
f
i
e
d

H
M
W
h
o
l
e
-
b
o
d
y

b
o
n
e

m
a
s
s

p
e
r
c
e
n
t
a
g
e

a
t

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

(
m
e
d
i
a
n

d
a
y

o
f

l
i
f
e

4
0
)

n
o
t

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

t
h
e

3

d
i
f
f
e
r
e
n
t

f
e
e
d
i
n
g

r
e
g
i
m
e
n
s

(
2
8

7

p
r
e
t
e
r
m

f
o
r
m
u
l
a
;

2
7

6

f
o
r
t
i
f
i
e
d

H
M
;

3
3

9

m
i
x
e
d

f
e
e
d
s
)
O
n
l
y

e
v
a
l
u
a
t
e
d

b
o
n
e

m
a
s
s

a
t

d
i
s
c
h
a
r
g
e

f
r
o
m

t
h
e

h
o
s
p
i
t
a
l
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
583
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t

s
t
u
d
y
A
c
a
d
e
m
i
c

H
o
s
p
i
t
a
l

o
f

t
h
e

F
r
e
e

U
n
i
v
e
r
s
i
t
y

o
f

B
r
u
s
s
e
l
s

(
B
r
u
s
s
e
l
s
,

B
e
l
g
i
u
m
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

(
w
h
o
l
e
-
b
o
d
y

b
o
n
e

m
i
n
e
r
a
l

m
a
s
s
)

a
n
d

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s

a
t

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

(
m
e
d
i
a
n

4
0

d
a
y
s

o
f

a
g
e
)
S
i
g
n
i
f
i
c
a
n
t

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

b
o
n
e

m
a
s
s

a
n
d

b
i
r
t
h

w
e
i
g
h
t

(
r

=

0
.
4
2
;


P

<

.
0
5
)

a
n
d

b
o
d
y

w
e
i
g
h
t

a
t

d
i
s
c
h
a
r
g
e

(
r

=

0
.
3
5
;


P

<

.
0
5
)
B
o
t
h

p
r
e
t
e
r
m

f
o
r
m
u
l
a

a
n
d

f
o
r
t
i
f
i
e
d

H
M

g
r
o
u
p
s

r
e
c
e
i
v
e
d

C
a

1
5
0

m
g
/
k
g
/
d

a
n
d

P
h
o
s

7
5

m
g
/
k
g
/
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

3
4
N

=

3
4

(
n

=

1
5

p
r
e
t
e
r
m

f
o
r
m
u
l
a
;

n

=

1
0

f
o
r
t
i
f
i
e
d

H
M
;

n

=

9

m
i
x
e
d
)
A
l
l

i
n
f
a
n
t
s

s
u
p
p
l
e
m
e
n
t
e
d

w
i
t
h

v
i
t
a
m
i
n

D

4
0
0

I
U
/
d
V
e
r
y

s
m
a
l
l

s
a
m
p
l
e

s
i
z
e
I
n
f
a
n
t

F
o
r
m
u
l
a

F
o
r
t
i
f
i
c
a
t
i
o
n
P
i
c
a
u
d
,

2
0
0
8
4
8
R
C
T
H
e
a
l
t
h
y

f
o
r
m
u
l
a
-
f
e
d

p
r
e
t
e
r
m

i
n
f
a
n
t
s

(
g
e
s
t
a
t
i
o
n
a
l

a
g
e

<
3
3

w
e
e
k
s
,

b
i
r
t
h

w
e
i
g
h
t

<
1
7
5
0

g
)
T
o

c
o
m
p
a
r
e

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

a
n
d

g
r
o
w
t
h

i
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

f
e
d

a
n

e
n
r
i
c
h
e
d

p
r
e
t
e
r
m

f
o
r
m
u
l
a

v
s

a

s
t
a
n
d
a
r
d

t
e
r
m

f
o
r
m
u
l
a

f
o
r

t
h
e

f
i
r
s
t

2

m
o
n
t
h
s

a
f
t
e
r

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

(
a
l
l

i
n
f
a
n
t
s

f
e
d

s
t
a
n
d
a
r
d

t
e
r
m

f
o
r
m
u
l
a

f
r
o
m

2

4

m
o
n
t
h
s

a
f
t
e
r

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e
)
B
M
C

a
n
d

B
M
D

a
t

2

m
o
n
t
h
s

h
i
g
h
e
r

i
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p

(
P

=

.
0
5

a
n
d

P

=

.
0
1
,

r
e
s
p
e
c
t
i
v
e
l
y
)
A
l
l

i
n
f
a
n
t
s

r
e
c
e
i
v
e
d

H
M

p
r
i
o
r

t
o

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

D
o
u
b
l
e
-
b
l
i
n
d
M
u
l
t
i
c
e
n
t
e
r

i
n
c
l
u
d
i
n
g

L
y
o
n

a
n
d

M
o
n
t
p
e
l
l
i
e
r
,

F
r
a
n
c
e
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

(
B
M
C
,

B
M
D
)
;

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s
B
M
C

a
n
d

B
M
D

a
t

4

m
o
n
t
h
s

h
i
g
h
e
r

i
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p

(
P

=

.
0
1

a
n
d

P

=

.
0
0
2
,

r
e
s
p
e
c
t
i
v
e
l
y
)
N
o

s
o
l
i
d

f
o
o
d
s

i
n
t
r
o
d
u
c
e
d

d
u
r
i
n
g

s
t
u
d
y

p
e
r
i
o
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

7

o
f

4
9
N

=

4
9

(
n

=

2
6

s
t
a
n
d
a
r
d

f
o
r
m
u
l
a
;

n

=

2
3

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a
)
B
o
d
y

w
e
i
g
h
t

a
t

2

a
n
d

4

m
o
n
t
h
s

p
o
s
t
d
i
s
c
h
a
r
g
e

h
i
g
h
e
r

i
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p

(
P

=

.
0
6

a
n
d

P

=

.
0
3
,

r
e
s
p
e
c
t
i
v
e
l
y
)
A
m
o
u
n
t

o
f

d
i
e
t
a
r
y

i
n
t
a
k
e

m
e
a
s
u
r
e
d
E
n
e
r
g
y

i
n
t
a
k
e

s
i
m
i
l
a
r

b
e
t
w
e
e
n

g
r
o
u
p
s

b
u
t

p
r
o
t
e
i
n
,

C
a
,

a
n
d

P
h
o
s

i
n
t
a
k
e

s
i
g
n
i
f
i
c
a
n
t
l
y

h
i
g
h
e
r

i
n

t
h
e

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
584
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
L
i
t
m
a
n
o
v
i
t
z
,

2
0
0
7
4
7
R
C
T
P
r
e
t
e
r
m

h
e
a
l
t
h
y

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s

(
b
i
r
t
h

w
e
i
g
h
t

<
1
5
5
0

g

a
n
d

a
p
p
r
o
p
r
i
a
t
e

f
o
r

g
e
s
t
a
t
i
o
n
a
l

a
g
e
)
T
o

e
v
a
l
u
a
t
e

d
i
f
f
e
r
e
n
c
e
s

i
n

b
o
n
e

s
t
r
e
n
g
t
h

b
e
t
w
e
e
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

f
e
d

a

n
u
t
r
i
e
n
t
-
e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

c
o
m
p
a
r
e
d

w
i
t
h

a

s
t
a
n
d
a
r
d

t
e
r
m

f
o
r
m
u
l
a

f
r
o
m

4
0

w
e
e
k
s

c
o
r
r
e
c
t
e
d

g
e
s
t
a
t
i
o
n
a
l

a
g
e

t
o

6

m
o
n
t
h
s

o
f

a
g
e

(
a
l
l

i
n
f
a
n
t
s

r
e
c
e
i
v
e
d

t
h
e

n
u
t
r
i
e
n
t
-
e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

u
n
t
i
l

4
0

w
e
e
k
s

c
o
r
r
e
c
t
e
d

a
g
e
)
N
o

d
i
f
f
e
r
e
n
c
e

b
e
t
w
e
e
n

g
r
o
u
p
s

i
n

S
O
S
,

w
e
i
g
h
t
,

l
e
n
g
t
h
,

o
r

h
e
a
d

c
i
r
c
u
m
f
e
r
e
n
c
e

a
t

t
e
r
m

o
r

3

o
r

6

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
A
l
l

i
n
f
a
n
t
s

r
e
c
e
i
v
e
d

t
h
e

n
u
t
r
i
e
n
t
-
e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

u
n
t
i
l

4
0

w
e
e
k
s

c
o
r
r
e
c
t
e
d

a
g
e

B
l
i
n
d
e
d

(
d
e
t
a
i
l
s

o
f

b
l
i
n
d
i
n
g

n
o
t

p
r
o
v
i
d
e
d
)
M
e
i
r

M
e
d
i
c
a
l

C
e
n
t
e
r

(
K
f
a
r

S
a
b
a
,

I
s
r
a
e
l
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

t
i
b
i
a
l

Q
U
S

(
S
O
S
)
;

o
s
t
e
o
b
l
a
s
t
i
c

b
o
n
e

a
c
t
i
v
i
t
y

(
B
S
-
A
L
P
)
;

o
s
t
e
o
c
l
a
s
t
i
c

b
o
n
e

r
e
s
o
r
p
t
i
o
n

a
c
t
i
v
i
t
y

(
I
C
T
P
)
;

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s

a
t

3

a
n
d

6

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
S
i
g
n
i
f
i
c
a
n
t

i
n
c
r
e
a
s
e

i
n

b
o
n
e

S
O
S

i
n

b
o
t
h

g
r
o
u
p
s

f
r
o
m

t
e
r
m

t
o

6

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e

(
P

<

.
0
0
1

f
o
r

b
o
t
h

g
r
o
u
p
s
)
Q
U
S

n
o
t

a

v
a
l
i
d
a
t
e
d

t
e
c
h
n
i
q
u
e

o
f

m
e
a
s
u
r
i
n
g

b
o
n
e

h
e
a
l
t
h

i
n

i
n
f
a
n
t
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

n
o
t

s
p
e
c
i
f
i
e
d
N

=

2
0

(
n

=

1
0

s
t
a
n
d
a
r
d

f
o
r
m
u
l
a
;

n

=

1
0

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a
)
N
o

d
i
f
f
e
r
e
n
c
e

b
e
t
w
e
e
n

g
r
o
u
p
s

i
n

s
e
r
u
m

m
a
r
k
e
r
s

o
f

b
o
n
e

t
u
r
n
o
v
e
r

a
t

t
e
r
m

o
r

3

o
r

6

m
o
n
t
h
s

c
o
r
r
e
c
t
e
d

a
g
e
N
o

a
d
d
i
t
i
o
n
a
l

f
o
o
d

i
n
t
a
k
e
V
e
r
y

s
m
a
l
l

s
a
m
p
l
e

s
i
z
e
K
o
o
,

2
0
0
6
4
5
R
C
T
H
e
a
l
t
h
y

p
r
e
t
e
r
m

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s

(
g
e
s
t
a
t
i
o
n
a
l

a
g
e

2
4

3
4

w
e
e
k
s
,

b
i
r
t
h

w
e
i
g
h
t

6
3
0

1
6
2
0

g
)
T
o

e
v
a
l
u
a
t
e

d
i
f
f
e
r
e
n
c
e
s

i
n

g
r
o
w
t
h
,

b
o
n
e

m
a
s
s
,

a
n
d

b
o
d
y

c
o
m
p
o
s
i
t
i
o
n

i
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

f
e
d

a

n
u
t
r
i
e
n
t
-
e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

c
o
m
p
a
r
e
d

w
i
t
h

a

s
t
a
n
d
a
r
d

t
e
r
m

f
o
r
m
u
l
a

f
r
o
m

d
i
s
c
h
a
r
g
e

u
n
t
i
l

1

y
e
a
r

o
f

a
g
e
I
n
f
a
n
t
s

o
n

t
e
r
m

f
o
r
m
u
l
a

w
i
t
h

h
i
g
h
e
r

w
e
i
g
h
t
,

l
e
n
g
t
h
,

a
n
d

h
e
a
d

c
i
r
c
u
m
f
e
r
e
n
c
e

z

s
c
o
r
e
s

(
P

<

.
0
5

f
o
r

a
l
l

c
o
m
p
a
r
i
s
o
n
s
)

a
t

2
,

4
,

6
,

9
,

a
n
d

1
2

m
o
n
t
h
s

p
o
s
t
d
i
s
c
h
a
r
g
e
D
e
t
a
i
l
s

r
e
g
a
r
d
i
n
g

p
r
e
d
i
s
c
h
a
r
g
e

f
o
r
m
u
l
a

n
o
t

p
r
o
v
i
d
e
d

D
o
u
b
l
e
-
b
l
i
n
d
W
a
y
n
e

S
t
a
t
e

U
n
i
v
e
r
s
i
t
y

(
D
e
t
r
o
i
t
,

M
I
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

(
B
M
C
)

a
t

2
,

4
,

6
,

1
2

m
o
n
t
h
s

a
f
t
e
r

d
i
s
c
h
a
r
g
e
;

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s

a
t

2
,

4
,

6
,

9
,

1
2

m
o
n
t
h
s

a
f
t
e
r

d
i
s
c
h
a
r
g
e
B
M
C

h
i
g
h
e
r

i
n

t
e
r
m

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s

c
o
m
p
a
r
e
d

w
i
t
h

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a
-
f
e
d

i
n
f
a
n
t
s

(
P

.
0
1
)

a
t

2
,

4
,

6
,

a
n
d

1
2

m
o
n
t
h
s

p
o
s
t
d
i
s
c
h
a
r
g
e
S
u
b
j
e
c
t
s

s
t
a
r
t
e
d

s
o
l
i
d

f
o
o
d
s

d
u
r
i
n
g

s
t
u
d
y

p
e
r
i
o
d
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
585
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

2
2

o
f

8
9

(
d
i
d

n
o
t

c
o
m
p
l
e
t
e

1
-
y
e
a
r

f
o
l
l
o
w
-
u
p
,

e
a
c
h

r
e
p
l
a
c
e
d

b
y

n
e
x
t

e
l
i
g
i
b
l
e

s
u
b
j
e
c
t
)
N

=

8
9

(
n

=

4
5

s
t
a
n
d
a
r
d

f
o
r
m
u
l
a
;

n

=

4
4

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a
)
D
e
t
a
i
l
s

o
n

a
m
o
u
n
t

o
f

f
o
r
m
u
l
a

a
n
d

s
o
l
i
d

f
o
o
d

i
n
t
a
k
e

n
o
t

m
e
a
s
u
r
e
d

N
o
t

i
s
o
c
a
l
o
r
i
c

f
o
r
m
u
l
a
s

L
o
n
g
e
r

f
o
l
l
o
w
-
u
p

p
e
r
i
o
d


(
1

y
e
a
r

o
f

a
g
e
)

M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
L
a
p
i
l
l
o
n
n
e
,

2
0
0
4
4
6
R
C
T
H
e
a
l
t
h
y

f
o
r
m
u
l
a
-
f
e
d

p
r
e
t
e
r
m

i
n
f
a
n
t
s

(
g
e
s
t
a
t
i
o
n
a
l

a
g
e

2
8

3
2

w
e
e
k
s
,

b
i
r
t
h

w
e
i
g
h
t

1
0
0
0

1
6
0
0

g
)

o
n

f
u
l
l

e
n
t
e
r
a
l

n
u
t
r
i
t
i
o
n

b
y

3

w
e
e
k
s

o
f

a
g
e
T
o

e
v
a
l
u
a
t
e

d
i
f
f
e
r
e
n
c
e
s

i
n

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

i
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

f
e
d

a
n

n
u
t
r
i
e
n
t
-
e
n
r
i
c
h
e
d

p
r
e
t
e
r
m

f
o
r
m
u
l
a

v
s

a
n

i
s
o
c
a
l
o
r
i
c

c
o
n
t
r
o
l

f
o
r
m
u
l
a

f
r
o
m

t
h
e

a
g
e

w
h
e
n

f
u
l
l

e
n
t
e
r
a
l

f
e
e
d
i
n
g
s

w
e
r
e

t
o
l
e
r
a
t
e
d

t
h
r
o
u
g
h

e
x
p
e
c
t
e
d

t
e
r
m

(
3

m
o
n
t
h
s

o
f

a
g
e
)
B
M
C

o
f

i
n
f
a
n
t
s

o
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

2
3
%

(
P

=

.
0
3
9
)

a
n
d

3
5
%

(
P

=

.
0
0
2
)

h
i
g
h
e
r

a
t

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

a
n
d

e
x
p
e
c
t
e
d

t
e
r
m
,

r
e
s
p
e
c
t
i
v
e
l
y
,

t
h
a
n

c
o
n
t
r
o
l
A
l
l

i
n
f
a
n
t
s

r
e
c
e
i
v
e
d

v
i
t
a
m
i
n

D

8
0
0

I
U
/
d

D
o
u
b
l
e
-
b
l
i
n
d
E
d
o
u
a
r
d

H
e
r
r
i
o
t

H
o
s
p
i
t
a
l

(
L
y
o
n
,

F
r
a
n
c
e
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

C
a
,

P
h
o
s
,

A
L
T
,

2
5
-
O
H
D
,

O
C
;

D
X
A

(
B
M
C
)
;

g
r
o
w
t
h
M
e
a
n

g
a
i
n

i
n

B
M
C

b
e
t
w
e
e
n

h
o
s
p
i
t
a
l

d
i
s
c
h
a
r
g
e

a
n
d

e
x
p
e
c
t
e
d

t
e
r
m

s
i
g
n
i
f
i
c
a
n
t
l
y

h
i
g
h
e
r

i
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p

(
5
3
.
6

2
1
.
7

v
s

3
8
.
9

1
7
.
7

g
,

P

=

.
0
3
7
)
I
s
o
c
a
l
o
r
i
c

f
o
r
m
u
l
a
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

4

o
f

4
1

(
n

=

2

e
a
r
l
y

f
e
e
d

i
n
t
o
l
e
r
a
n
c
e
;

n

=

1

w
o
r
s
e
n
i
n
g

b
r
a
d
y
c
a
r
d
i
a
/
a
p
n
e
a
/
c
y
a
n
o
s
i
s

u
n
r
e
l
a
t
e
d

t
o

f
e
e
d
i
n
g
s
;

n

=

1

f
a
m
i
l
y

r
e
q
u
e
s
t
)
N

=

4
1

(
n

=

2
0

s
t
a
n
d
a
r
d

f
o
r
m
u
l
a
;

n

=

2
1

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a
)
L
a
b
o
r
a
t
o
r
y

v
a
l
u
e
s

s
i
m
i
l
a
r

b
e
t
w
e
e
n

g
r
o
u
p
s
,

e
x
c
e
p
t

m
e
a
n

2
5
-
O
H
D

a
t

e
x
p
e
c
t
e
d

t
e
r
m

h
i
g
h
e
r

i
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p

(
P

=

.
0
0
2
)
M
e
a
n

w
e
i
g
h
t

g
a
i
n

b
e
t
w
e
e
n

e
n
t
r
y

i
n
t
o

t
h
e

s
t
u
d
y

a
n
d

e
x
p
e
c
t
e
d

t
e
r
m

h
i
g
h
e
r

i
n

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p


(
P

=

.
0
1
6
)
F
o
r
m
u
l
a

i
n
t
a
k
e

a
n
d

t
h
u
s

e
n
e
r
g
y

i
n
t
a
k
e

d
i
d

n
o
t

d
i
f
f
e
r

b
e
t
w
e
e
n

g
r
o
u
p
s
C
a

a
n
d

P
h
o
s

i
n
t
a
k
e

w
a
s

h
i
g
h
e
r

(
2
5
%

a
n
d

4
0
%
,

r
e
s
p
e
c
t
i
v
e
l
y
)

i
n

t
h
e

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p
S
h
o
r
t
-
t
e
r
m

f
o
l
l
o
w
-
u
p

(
~
3

m
o
n
t
h
s

o
f

a
g
e
)
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
586
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
D
e

C
u
r
t
i
s
,

2
0
0
2
4
4
R
C
T
H
e
a
l
t
h
y

f
o
r
m
u
l
a
-
f
e
d

p
r
e
t
e
r
m

i
n
f
a
n
t
s

(
g
e
s
t
a
t
i
o
n
a
l

a
g
e

<
3
5

w
e
e
k
s
,

b
i
r
t
h

w
e
i
g
h
t

<
1
7
5
0

g
)
T
o

e
v
a
l
u
a
t
e

d
i
f
f
e
r
e
n
c
e
s

i
n

g
r
o
w
t
h

a
n
d

w
e
i
g
h
t

g
a
i
n

c
o
m
p
o
s
i
t
i
o
n

i
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

f
e
d

s
t
a
n
d
a
r
d

t
e
r
m

f
o
r
m
u
l
a

v
s

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

a
f
t
e
r

d
i
s
c
h
a
r
g
e

f
r
o
m

t
h
e

h
o
s
p
i
t
a
l

d
u
r
i
n
g

t
h
e

f
i
r
s
t

2

m
o
n
t
h
s

o
f

l
i
f
e
N
o

d
i
f
f
e
r
e
n
c
e

i
n

g
r
o
w
t
h

o
r

w
h
o
l
e
-
b
o
d
y

c
o
m
p
o
s
i
t
i
o
n

b
e
t
w
e
e
n

s
t
a
n
d
a
r
d

a
n
d

e
n
r
i
c
h
e
d

p
o
s
t
d
i
s
c
h
a
r
g
e

f
o
r
m
u
l
a
-
f
e
d

g
r
o
u
p
s

a
t

b
i
r
t
h
,

a
t

d
i
s
c
h
a
r
g
e

f
r
o
m

t
h
e

h
o
s
p
i
t
a
l
,

o
r

a
t

2

m
o
n
t
h
s

o
f

a
g
e
D
e
t
a
i
l
s

r
e
g
a
r
d
i
n
g

p
r
e
d
i
s
c
h
a
r
g
e

f
o
r
m
u
l
a

n
o
t

p
r
o
v
i
d
e
d

B
l
i
n
d
e
d

(
d
e
t
a
i
l
s

o
f

b
l
i
n
d
i
n
g

n
o
t

p
r
o
v
i
d
e
d
)
U
n
i
v
e
r
s
i
t
y

o
f

L
i
e
g
e

(
L
i
e
g
e
,

B
e
l
g
i
u
m
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

w
h
o
l
e
-
b
o
d
y

D
X
A

(
B
M
C
)
;

a
n
t
h
r
o
p
o
m
e
t
r
i
c
s

a
t

d
i
s
c
h
a
r
g
e

f
r
o
m

t
h
e

h
o
s
p
i
t
a
l

a
n
d

2

m
o
n
t
h
s

o
f

a
g
e
M
e
a
n

B
M
C

i
n
c
r
e
a
s
e
d

f
r
o
m

9
.
4

0
.
8

t
o

1
0
.
2

0
.
6

m
g
/
c
m
3

i
n

t
h
e

s
t
a
n
d
a
r
d

t
e
r
m

f
o
r
m
u
l
a

g
r
o
u
p

a
n
d

f
r
o
m

9
.
4

0
.
9

t
o

1
0
.
3

1
.
1

m
g
/
c
m
3

i
n

t
h
e

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

g
r
o
u
p

(
P

<

.
0
1
)
S
t
u
d
y

p
o
w
e
r
e
d

t
o

d
e
t
e
c
t

a

b
o
n
e

m
i
n
e
r
a
l

c
o
n
t
e
n
t

g
a
i
n

o
f

3
0

m
g
/
k
g
/
d

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

3
3
N

=

3
3

(
n

=

1
7

s
t
a
n
d
a
r
d

f
o
r
m
u
l
a
;

n

=

1
6

e
n
r
i
c
h
e
d

f
o
r
m
u
l
a
)
N
o
t

i
s
o
c
a
l
o
r
i
c

f
o
r
m
u
l
a
s
S
h
o
r
t
-
t
e
r
m

f
o
l
l
o
w
-
u
p

(
2

m
o
n
t
h
s

o
f

a
g
e
)
V
e
r
y

s
m
a
l
l

s
a
m
p
l
e

s
i
z
e
A
L
P
,

a
l
k
a
l
i
n
e

p
h
o
s
p
h
a
t
a
s
e
;

B
M
C
,

b
o
n
e

m
i
n
e
r
a
l

c
o
n
t
e
n
t
;

B
M
D
,

b
o
n
e

m
i
n
e
r
a
l

d
e
n
s
i
t
y
;

B
S
-
A
L
P
,

b
o
n
e
-
s
p
e
c
i
f
i
c

a
l
k
a
l
i
n
e

p
h
o
s
p
h
a
t
a
s
e
;

C
a
,

c
a
l
c
i
u
m
;

D
X
A
,

d
u
a
l
-
e
n
e
r
g
y

x
-
r
a
y

a
b
s
o
r
p
t
i
o
m
e
t
r
y
;

H
M
,

h
u
m
a
n

m
i
l
k
;

I
C
T
P
,

c
r
o
s
s
-
l
i
n
k
e
d

c
a
r
b
o
x
y
-
t
e
r
m
i
n
a
l

t
e
l
o
p
e
p
t
i
d
e

o
f

t
y
p
e

I

c
o
l
l
a
g
e
n
;

O
B
S
,

o
b
s
e
r
v
a
t
i
o
n
a
l

s
t
u
d
y
;

O
C
,

o
s
t
e
o
c
a
l
c
i
n
;

P
h
o
s
,

p
h
o
s
p
h
o
r
u
s
;

P
T
H
,

p
a
r
a
t
h
y
r
o
i
d

h
o
r
m
o
n
e
;

Q
U
S
,

q
u
a
n
t
i
t
a
t
i
v
e

u
l
t
r
a
s
o
u
n
d
;

R
C
T
,

r
a
n
d
o
m
i
z
e
d

c
o
n
t
r
o
l
l
e
d

t
r
i
a
l
;

S
O
S
,

s
p
e
e
d

o
f

s
o
u
n
d
;

2
5
-
O
H
D
,

2
5
-
h
y
d
r
o
x
y
v
i
t
a
m
i
n

D
.
T
a
b
l
e

4
.

(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
Nehra et al 587
Table 5. GRADE Table Question 2: What is the optimal type of feeding to promote neonatal bone health?
Comparison Outcome
Quantity, Type
Evidence Findings
GRADE of Evidence
for Outcome
Breast vs formula feeding healthy
term
38-40
or preterm
41
infants during
the first year of life










Biochemical:
25-OHD
Ca, ALP
Phos
PTH
Growth:
Weight
Bone:
BMC
BMD
1 OBS
66
1 OBS
41
4 OBS
38-41
Biochemical:
Lower (6, 12 mo)
66
No difference (6, 12 mo)
66
Lower (6 mo), no difference
(12 mo)
66
Higher (6 mo), no difference
(12 mo)
66
Growth:
Higher
41
Bone:
Lower
40,41
Lower (6, 12 mo)
40
No difference (48 mo)
38,39
Low










Nutrient-fortified vs nonfortified HM
in preterm infants for 12 weeks after
hospital discharge
42

Growth: 1 RCT
42
Growth: Moderate
Weight Higher (12 wk, 12 mo)
42

Bone: Bone:
BMC Higher (4, 12 mo)
42

BMD No difference (4, 12 mo)
42

Fortified HM vs preterm formula
in preterm infants before hospital
discharge
43

Bone: 1 OBS
43
Bone: Low
Whole-body BM% No difference
43

Enriched formula vs standard formula
for preterm infants from hospital
discharge to 2,
44
3,
46
or 4
48
months
of age; 6 months gestational age
47
;
and 1 year of age
45
Growth:
Weight
Bone:
BMC
BMD
SOS
Biochemical:
BS-ALP
ICTP
5 RCT
44-48
Growth:
No difference
44,47
Higher
46,48
Lower
45
Bone:
No difference
46
Higher
45,48
Lower
47
Higher
45,48
No difference
47
Biochemical:
No difference
47
No difference
47
Moderate












ALP, alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; BM%, bone mass percentage; BS-ALP, bone-specific alkaline
phosphatase; Ca, calcium; HM, human milk; ICTP, cross-linked carboxy-terminal telopeptide of type I collagen; OBS, observational study; OC, osteo-
calcin; Phos, phosphorus; PTH, parathyroid hormone; RCT, randomized controlled trial; QUS, quantitative ultrasound; SOS, speed of sound; 25-OHD,
25-hydroxyvitamin D.
formulations with high-dose calcium and phosphorus content
(Weak). PN aluminum is a risk factor for metabolic bone dis-
ease of the neonate (Strong), and we suggest that future efforts
be made to reduce the aluminum content of PN.
Evidence Grade: Low/Moderate (Tables 8 and 9)
Rationale: Preterm and low birth weight infants are at
increased risk for low bone mass and metabolic bone disease
because they miss the period of greatest mineral accretion that
occurs during the last trimester of pregnancy. Most of these
infants are unable to tolerate full enteral feedings within the
first days or weeks after birth, and nutrients need to be deliv-
ered via PN. Unfortunately, the threshold for calcium and
phosphorus precipitation limits the delivery of appropriate
amounts of these minerals via PN. Given that the recom-
mended range of calcium and phosphorus delivered by PN in
preterm infants is wide, 40120 mg/kg/d for calcium and 31
71 mg/kg/d for phosphorus,
58,59
we sought to identify studies
that provided guidance with regard to PN formulations for pre-
term neonates.
The available data suggest that PN does predispose the
infant to metabolic bone disease
60
and that PN formulations
with high-dose calcium and phosphorus content should be
used.
61
We did not identify a study that addressed the vitamin D
content of PN formulations. PN formulations are routinely
supplemented with vitamin D; however, the optimal dose is not
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
588
T
a
b
l
e

6
.

E
v
i
d
e
n
c
e

T
a
b
l
e

Q
u
e
s
t
i
o
n

3
:

W
h
e
n

a
n
d

h
o
w

s
h
o
u
l
d

V
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
s

b
e

a
d
m
i
n
i
s
t
e
r
e
d
?
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
S
i
a
f
a
r
i
k
a
s
,

2
0
1
1
6
7
R
C
T
H
e
a
l
t
h
y

b
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s

w
i
t
h

i
n
t
e
r
m
e
d
i
a
t
e
l
y

p
i
g
m
e
n
t
e
d

s
k
i
n

(
s
k
i
n

p
h
o
t
o

t
y
p
e
s

I

a
n
d

I
I
)

b
o
r
n

d
u
r
i
n
g

s
u
m
m
e
r

a
n
d

w
i
n
t
e
r

m
o
t
h
s
T
o

c
o
m
p
a
r
e

t
h
e

e
f
f
i
c
a
c
y

o
f

2
5
0

I
U

v
s

5
0
0

I
U

o
f

o
r
a
l

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

d
a
i
l
y

a
n
d

t
o

q
u
a
n
t
i
f
y

s
u
n

e
x
p
o
s
u
r
e

a
n
d

a
n
a
l
y
z
e

m
a
t
e
r
n
a
l

f
a
c
t
o
r
s
M
o
s
t

i
n
f
a
n
t
s

w
i
t
h

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
c
y

a
t

i
n
i
t
i
a
l

p
o
s
t
n
a
t
a
l

v
i
s
i
t
,

a
n
d

a
l
l

v
a
l
u
e
s

n
o
r
m
a
l
i
z
e
d

w
i
t
h

n
o

d
i
f
f
e
r
e
n
c
e

b
e
t
w
e
e
n

g
r
o
u
p
s

a
t

6

w
e
e
k
s

(
P

=

.
4
8
)
B
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s

o
n
l
y

N
o
t

b
l
i
n
d
e
d
H
o
s
p
i
t
a
l

B
e
r
l
i
n
-
L
i
c
h
t
e
n
b
e
r
g
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

2
5
-
O
H
D
,

A
L
P
,

C
a
,

P
h
o
s
,

s
e
r
u
m

a
l
b
u
m
i
n
,

c
r
e
a
t
i
n
i
n
e

a
t

d
a
y

5

a
n
d

6

w
e
e
k
s
;

c
l
i
n
i
c
a
l

s
i
g
n
s

o
f

r
i
c
k
e
t
s
C
a

l
e
v
e
l
s

i
n
c
r
e
a
s
e
d

f
r
o
m

d
a
y

5

t
o

w
e
e
k

6

(
P

=

.
0
0
0
1
)

a
n
d

a
t

6

w
e
e
k
s

h
i
g
h
e
r

f
o
r

i
n
f
a
n
t
s

o
n

2
5
0

I
U
/
d

t
h
a
n

t
h
o
s
e

o
n

5
0
0

I
U
/
d

o
f

v
i
t
a
m
i
n

D

(
P

=

.
0
4
8
)
A
l
l

i
n
f
a
n
t
s

h
a
d

m
i
n
i
m
a
l

U
V
-
B

e
x
p
o
s
u
r
e

N
o
t

p
l
a
c
e
b
o

c
o
n
t
r
o
l
l
e
d
(
B
e
r
l
i
n
,

G
e
r
m
a
n
y
)
P
h
o
s

w
a
s

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

g
r
o
u
p
s

a
n
d

d
i
d

n
o
t

i
n
c
r
e
a
s
e

s
i
g
n
i
f
i
c
a
n
t
l
y

b
e
t
w
e
e
n

d
a
y

5

a
n
d

w
e
e
k

6
M
e
a
s
u
r
e
d

m
a
t
e
r
n
a
l

d
i
e
t
a
r
y

i
n
t
a
k
e

A
t
t
r
i
t
i
o
n

r
a
t
e
:

1
2

o
f

4
0

(
i
n
s
u
f
f
i
c
i
e
n
t

b
l
o
o
d

s
a
m
p
l
e
s
)
N

=

4
0

(
n

=

1
0

s
u
m
m
e
r

b
o
r
n

o
n

2
5
0

I
U
/
d
;

n

=

1
0

w
i
n
t
e
r

b
o
r
n

o
n

2
5
0

I
U
/
d
;

n

=

1
0

s
u
m
m
e
r

b
o
r
n

o
n

5
0
0

I
U
/
d
;

n

=

1
0

w
i
n
t
e
r

b
o
r
n

o
n

5
0
0

I
U
/
d
)
A
L
P

w
i
t
h
i
n

n
o
r
m
a
l

r
a
n
g
e

f
o
r

a
l
l

i
n
f
a
n
t
s

b
u
t

i
n
c
r
e
a
s
e
d

b
e
t
w
e
e
n

d
a
y

5

a
n
d

w
e
e
k

6

i
n
d
e
p
e
n
d
e
n
t

o
f

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

g
r
o
u
p

a
n
d

s
e
a
s
o
n

(
P

<

.
0
5
)
S
h
o
r
t

p
e
r
i
o
d

o
f

f
o
l
l
o
w
-
u
p

R
e
p
o
r
t
e
d

a
v
e
r
a
g
e

t
i
m
e

o
f

d
a
i
l
y

s
u
n

o
r

U
V
-
B

e
x
p
o
s
u
r
e

n
o
t

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

g
r
o
u
p
s
,

a
l
t
h
o
u
g
h

s
u
n
s
h
i
n
e

e
x
p
o
s
u
r
e

s
c
o
r
e

h
i
g
h
e
r

i
n

t
h
e

2
5
0
-
I
U
/
d

c
o
m
p
a
r
e
d

w
i
t
h

5
0
0
-
I
U
/
d

g
r
o
u
p

(
P

=

.
0
4
8
)
V
e
r
y

s
m
a
l
l

s
a
m
p
l
e

s
i
z
e
s
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
589
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
S
a
v
i
n
o
,

2
0
1
1
6
8
O
B
S
H
e
a
l
t
h
y

C
a
u
c
a
s
i
a
n

e
x
c
l
u
s
i
v
e
l
y

b
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s

<
1
2

m
o
n
t
h
s

w
i
t
h

n
o
r
m
a
l

s
k
e
l
e
t
a
l

s
t
a
t
u
s

a
n
d

w
h
o

h
a
d

n
o
t

r
e
c
e
i
v
e
d

a
n
y

c
a
l
c
i
u
m

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

a
n
d

w
h
o
s
e

m
o
t
h
e
r
s

w
e
r
e

n
o
t

t
a
k
i
n
g

c
a
l
c
i
u
m

o
r

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
s

w
e
r
e

d
i
v
i
d
e
d

i
n
t
o

2

g
r
o
u
p
s
:

g
r
o
u
p

1

(
b
r
e
a
s
t
f
e
d

w
i
t
h

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

a
t

4
0
0

I
U
/
d

s
t
a
r
t
i
n
g

a
t

b
i
r
t
h
)

a
n
d

g
r
o
u
p

2

(
b
r
e
a
s
t
f
e
d

w
i
t
h
o
u
t

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n
)
T
o

a
c
c
e
s
s

b
o
n
e

s
t
a
t
u
s

u
s
i
n
g

Q
U
S

o
f

t
h
e

s
e
c
o
n
d

m
e
t
a
c
a
r
p
u
s

a
n
d

t
o

d
e
t
e
r
m
i
n
e

t
h
e

e
f
f
e
c
t

o
f

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

f
r
o
m

b
i
r
t
h

t
o

1

y
e
a
r

o
f

a
g
e

o
n

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n
m
c
S
O
S

a
n
d

m
c
B
T
T

l
o
w
e
r

i
n

g
r
o
u
p

2

c
o
m
p
a
r
e
d

w
i
t
h

g
r
o
u
p

1

(
P

=

.
0
0
1

a
n
d

P

=

.
0
1
5
,

r
e
s
p
e
c
t
i
v
e
l
y
)
E
x
c
l
u
d
e
d

m
a
t
e
r
n
a
l

s
u
p
p
l
e
m
e
n
t

f
a
c
t
o
r

b
y

e
x
c
l
u
d
i
n
g

m
o
t
h
e
r
s

t
a
k
i
n
g

a
n
y

c
a
l
c
i
u
m

o
r

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
s

C
r
o
s
s
-
s
e
c
t
i
o
n
a
l

s
t
u
d
y
R
e
g
i
n
a

M
a
r
g
h
e
r
i
t
a

C
h
i
l
d
r
e
n

s

H
o
s
p
i
t
a
l

(
T
u
r
i
n
,

I
t
a
l
y
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

Q
U
S

o
f

t
h
e

s
e
c
o
n
d

m
e
t
a
c
a
r
p
u
s

(
m
c
S
O
S
,

m
c
B
T
T
)
z

s
c
o
r
e

o
f

m
c
S
O
S

f
o
r

a
g
e
,

z

s
c
o
r
e

o
f

B
T
T

f
o
r

a
g
e
,

a
n
d

t
h
e

z

s
c
o
r
e

o
f

B
T
T

f
o
r

l
e
n
g
t
h

a
l
s
o

l
o
w
e
r

i
n

g
r
o
u
p

2

(
P

=

.
0
0
3
,

P

=

.
0
2
6
,

a
n
d

P

=

.
0
2
9
,

r
e
s
p
e
c
t
i
v
e
l
y
)
N
o

l
a
b
o
r
a
t
o
r
y

m
e
a
s
u
r
e
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

7
7
N

=

7
7

(
n
=
3
8

g
r
o
u
p

1
,

n

=

3
9

g
r
o
u
p

2
)
N
e
w

a
n
d

u
n
v
a
l
i
d
a
t
e
d

m
e
a
s
u
r
e

o
f

b
o
n
e

h
e
a
l
t
h

a
n
d

n
o

r
e
f
e
r
e
n
c
e

v
a
l
u
e
s

f
o
r

Q
U
S

p
a
r
a
m
e
t
e
r
s

A
n
a
l
y
s
i
s

u
s
i
n
g

M
a
n
n
-
W
h
i
t
n
e
y

U

t
e
s
t

a
n
d

S
p
e
a
r
m
a
n

s

c
o
r
r
e
l
a
t
i
o
n
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e
K
i
m
,

2
0
1
0
6
6
O
B
S
H
e
a
l
t
h
y

t
e
r
m

i
n
f
a
n
t
s

d
i
v
i
d
e
d

i
n
t
o

3

g
r
o
u
p
s
:

A

(
f
o
r
m
u
l
a

f
e
d
)
,

B

(
b
r
e
a
s
t
f
e
d

o
n
l
y

w
i
t
h
o
u
t

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n
)
,

a
n
d

S

(
b
r
e
a
s
t
f
e
d

w
i
t
h

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

a
t

2
0
0

I
U

d
a
i
l
y

i
n

t
h
e

f
o
r
m

o
f

P
o
l
y
-
V
i
t
a
m
i
n

D
r
o
p
s

f
r
o
m

2

1
2

m
o
n
t
h
s

o
f

a
g
e
)
T
o

e
v
a
l
u
a
t
e

t
h
e

v
i
t
a
m
i
n

D

s
t
a
t
u
s

o
f

K
o
r
e
a
n

i
n
f
a
n
t
s

a
n
d

t
o

d
e
t
e
r
m
i
n
e

t
h
e

e
f
f
i
c
a
c
y

o
f

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

(
2
0
0

I
U
/
d

f
r
o
m

2

1
2

m
o
n
t
h
s
)

o
n

v
i
t
a
m
i
n

D

n
u
t
r
i
t
i
o
n

s
t
a
t
u
s

a
n
d

b
o
n
e

m
i
n
e
r
a
l
i
z
a
t
i
o
n

i
n

t
e
r
m

b
r
e
a
s
t
f
e
d

i
n
f
a
n
t
s
6
-
m
o
n
t
h

f
o
l
l
o
w
-
u
p
:

2
5
-
O
H
D

d
i
f
f
e
r
e
n
t

a
m
o
n
g

g
r
o
u
p
s

w
i
t
h

A

>

S

>

B

(
P

<

.
0
0
1
)
N
o

d
i
f
f
e
r
e
n
c
e

a
m
o
n
g

g
r
o
u
p
s

i
n

d
e
m
o
g
r
a
p
h
i
c

c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
,

b
a
s
e
l
i
n
e

l
a
b
o
r
a
t
o
r
y

v
a
l
u
e
s
,

o
r

l
i
f
e
s
t
y
l
e

c
h
a
r
a
c
t
e
r
i
s
t
i
c
s
T
a
b
l
e

6
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
590
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

P
r
o
s
p
e
c
t
i
v
e

c
o
h
o
r
t

s
t
u
d
y
C
h
u
n
g
b
u
k

N
a
t
i
o
n
a
l

U
n
i
v
e
r
s
i
t
y

(
C
h
e
o
n
g
j
u
,

K
o
r
e
a
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

2
5
-
O
H
D
,

C
a
,

P
h
o
s
,

A
L
P
,

P
T
H
,

a
n
d

D
X
A

(
B
M
D
,

B
M
C
)

a
t

b
i
r
t
h
,

6

m
o
n
t
h
s
,

a
n
d

1
2

m
o
n
t
h
s

o
f

a
g
e
P
r
e
v
a
l
e
n
c
e

o
f

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

<
1
1

n
g
/
m
L
)

a
n
d

i
n
s
u
f
f
i
c
i
e
n
c
y

(
2
5
-
O
H
D

1
1

3
0

n
g
/
m
L
)

0
%

a
n
d

1
2
%
,

1
1
%

a
n
d

6
8
%
,

a
n
d

0
%

a
n
d

4
5
%

f
o
r

g
r
o
u
p
s

A
,

B
,

a
n
d

S
,

r
e
s
p
e
c
t
i
v
e
l
y
O
n
l
y

e
v
a
l
u
a
t
e
d

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

a
t

2
0
0

I
U
/
d
,

w
h
i
c
h

m
a
y

n
o
t

b
e

s
u
f
f
i
c
i
e
n
t

(
s
o
m
e

s
t
u
d
i
e
s

s
u
g
g
e
s
t

4
0
0

8
0
0

I
U
/
d

i
s

n
e
c
e
s
s
a
r
y

i
n

l
a
t
e

i
n
f
a
n
c
y
)

A
t
t
r
i
t
i
o
n

r
a
t
e
:

1
3

o
f

7
4

(
r
e
a
s
o
n

n
o
t

s
p
e
c
i
f
i
e
d
)
N

=

7
4

(
n

=

2
5

g
r
o
u
p

A
,

n

=

2
8

g
r
o
u
p

B
,

n

=

2
1

g
r
o
u
p

S
)
C
a

a
n
d

A
L
P

n
o
t

d
i
f
f
e
r
e
n
t

b
u
t

P
h
o
s

w
i
t
h

A

>

S

>

B

(
P

<

.
0
0
1
)

a
n
d

P
T
H

h
i
g
h
e
r

i
n

g
r
o
u
p

B

w
i
t
h

B

>

A

=

S

(
P

=

.
0
0
1
)
M
u
l
t
i
v
i
t
a
m
i
n

s
o
l
u
t
i
o
n

u
s
e
d

c
o
n
t
a
i
n
e
d

v
i
t
a
m
i
n
s

i
n

a
d
d
i
t
i
o
n

t
o

v
i
t
a
m
i
n

D

(
v
i
t
a
m
i
n
s

A
,

C
,

a
n
d

E
;

t
h
i
a
m
i
n
;

r
i
b
o
f
l
a
v
i
n
;

n
i
a
c
i
n
;

B
6
;

i
r
o
n
;

f
l
u
o
r
i
d
e
)

F
u
n
d
e
d

b
y

t
h
e

K
o
r
e
a
n

g
o
v
e
r
n
m
e
n
t
B
M
D

a
n
d

B
M
C

h
i
g
h
e
r

i
n

g
r
o
u
p

A

w
i
t
h

A

>

B

=

S

(
P

<

.
0
5
)
N
o

d
a
t
a

p
r
o
v
i
d
e
d

o
n

m
a
t
e
r
n
a
l

c
a
l
c
i
u
m

o
r

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

b
u
t

m
a
t
e
r
n
a
l

s
u
n
l
i
g
h
t

e
x
p
o
s
u
r
e

a
n
d

d
i
e
t
a
r
y

i
n
t
a
k
e

w
e
r
e

e
s
t
i
m
a
t
e
d

1
2
-
m
o
n
t
h

f
o
l
l
o
w
-
u
p
:

(
n

=

3
0

g
r
o
u
p

A
,

n

=

1
6

g
r
o
u
p

B
,

n

=

1
5

g
r
o
u
p

S
)
D
X
A

i
s

n
o
t

a

v
a
l
i
d
a
t
e
d

m
e
a
s
u
r
e

o
f

b
o
n
e

h
e
a
l
t
h

i
n

i
n
f
a
n
t
s
,

a
n
d

t
h
e
r
e

a
r
e

n
o

a
c
c
e
p
t
e
d

n
o
r
m
a
l

r
a
n
g
e
s

2
5
-
O
H
D

h
i
g
h
e
r

i
n

g
r
o
u
p
s

A

a
n
d

S

w
i
t
h

A

=

S

>

B

(
P

<

.
0
0
1
)
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e

N
o

i
n
f
a
n
t
s

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
t
,

a
l
t
h
o
u
g
h

5
0
%

o
f

i
n
f
a
n
t
s

i
n

g
r
o
u
p

B

v
i
t
a
m
i
n

D

i
n
s
u
f
f
i
c
i
e
n
t


C
a

a
n
d

A
L
P

n
o
t

d
i
f
f
e
r
e
n
t

b
u
t

s
e
r
u
m

P
h
o
s

l
o
w
e
r

i
n

g
r
o
u
p

S

t
h
a
n

i
n

g
r
o
u
p

A

w
i
t
h

A

>

S

(
P

=

.
0
0
0
9
)

b
u
t

A

=

B

a
n
d

B

=

S

a
n
d

P
T
H

h
i
g
h
e
r

i
n

g
r
o
u
p

S

t
h
a
n

i
n

g
r
o
u
p

A

w
i
t
h

S

>

A

(
P

=

.
0
2
5
)

a
n
d

A

=

B

a
n
d

B

=

S

T
a
b
l
e

6
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
591
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

B
M
D

h
i
g
h
e
r

i
n

g
r
o
u
p

A

t
h
a
n

i
n

g
r
o
u
p
s

B

a
n
d

S

(
P

=

.
0
1
0
,

A

>

B

=

S
)

a
n
d

B
M
C

h
i
g
h
e
r

i
n

g
r
o
u
p

A

t
h
a
n

i
n

g
r
o
u
p

S

(
P

=

.
0
2
5
,

A

>

S
,

A

=

B
,

B

=

S
)

S
o
l
i
m
a
n
,

2
0
1
0
6
9
O
B
S
C
h
i
l
d
r
e
n

<
3

y
e
a
r
s

o
f

a
g
e

w
i
t
h

n
u
t
r
i
t
i
o
n

r
i
c
k
e
t
s
T
o

e
v
a
l
u
a
t
e

t
h
e

c
l
i
n
i
c
a
l
,

b
i
o
c
h
e
m
i
c
a
l
,

a
n
d

r
a
d
i
o
g
r
a
p
h
i
c

r
e
s
p
o
n
s
e

t
o

a

s
i
n
g
l
e

i
n
t
r
a
m
u
s
c
u
l
a
r

d
o
s
e

o
f

v
i
t
a
m
i
n

D

(
1
0
,
0
0
0

I
U
/
k
g
)

i
n

c
h
i
l
d
r
e
n

w
i
t
h

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
c
y

r
i
c
k
e
t
s
2
5
-
O
H
D
,

C
a
,

a
n
d

P
h
o
s

h
i
g
h
e
r

3

m
o
n
t
h
s

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t

(
P

<

.
0
5

i
n

a
l
l
)
T
y
p
e

o
f

f
e
e
d

n
o
t

c
o
n
t
r
o
l
l
e
d

f
o
r

b
u
t

m
a
j
o
r
i
t
y

o
f

i
n
f
a
n
t
s

(
3
5
/
4
0
)

e
x
c
l
u
s
i
v
e
l
y

b
r
e
a
s
t
f
e
d

>
6

m
o
n
t
h
s

w
i
t
h

3
6

o
f

4
0

b
e
i
n
g

b
r
e
a
s
t
f
e
d

a
t

b
a
s
e
l
i
n
e

a
n
d

2
4

o
f

4
0

s
t
i
l
l

b
e
i
n
g

b
r
e
a
s
t
f
e
d

a
t

6
-
m
o
n
t
h

f
o
l
l
o
w
-
u
p

P
r
o
s
p
e
c
t
i
v
e
H
a
m
a
d

M
e
d
i
c
a
l

C
e
n
t
r
e

(
D
o
h
a
,

Q
a
t
a
r
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

2
5
-
O
H
D
,

C
a
,

P
h
o
s
,

A
L
P
,

P
T
H
,

s
e
r
u
m

a
l
b
u
m
i
n
;

a
n
t
h
r
o
p
o
m
e
t
r
i
c

p
a
r
a
m
e
t
e
r
s
P
T
H

a
n
d

A
L
P

l
o
w
e
r

3

m
o
n
t
h
s

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t

(
P

<

.
0
5

i
n

b
o
t
h
)
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e

A
t
t
r
i
t
i
o
n

r
a
t
e
:

n
o
t

s
p
e
c
i
f
i
e
d
N

=

4
0
3
9

o
f

4
0

c
h
i
l
d
r
e
n

w
i
t
h

a

d
e
c
r
e
a
s
e

i
n

2
5
-
O
H
D

t
o

b
e
l
o
w

2
0

n
g
/
m
L

a
t

6

m
o
n
t
h
s

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t


R
a
d
i
o
g
r
a
p
h
i
c

(
e
p
i
p
h
y
s
e
a
l

a
n
d

d
i
a
p
h
y
s
e
a
l
)

c
h
a
n
g
e
s

n
o
r
m
a
l
i
z
e
d

i
n

9
5
%

o
f

c
a
s
e
s

3

m
o
n
t
h
s

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t

K
i
s
l
a
l
,

2
0
0
8
7
0
R
C
T
P
r
e
t
e
r
m

i
n
f
a
n
t
s

(
<
3
3

w
e
e
k
s
)

f
e
d

b
r
e
a
s
t

m
i
l
k

o
r

f
o
r
m
u
l
a

w
i
t
h
o
u
t

v
i
t
a
m
i
n

D

r
a
n
d
o
m
l
y

a
s
s
i
g
n
e
d

t
o

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

g
r
o
u
p
s
:

g
r
o
u
p

1

(
2
0
0

I
U
/
k
g
)
,

g
r
o
u
p

2

(
4
0
0

I
U
/
k
g
)
,

o
r

g
r
o
u
p

3

(
8
0
0

I
U
/
k
g
)
T
o

c
o
m
p
a
r
e

t
h
e

e
f
f
i
c
a
c
y

o
f

3

d
i
f
f
e
r
e
n
t

d
o
s
e
s

o
f

v
i
t
a
m
i
n

D

(
2
0
0

I
U
/
k
g
,

4
0
0

I
U
/
k
g
,

8
0
0

I
U
/
k
g
)

i
n

m
a
i
n
t
a
i
n
i
n
g

n
o
r
m
a
l

v
i
t
a
m
i
n

D

s
t
a
t
u
s

i
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s
C
a

a
n
d

P
h
o
s

w
e
r
e

n
o
t

d
i
f
f
e
r
e
n
t

b
e
f
o
r
e

a
n
d

a
f
t
e
r

t
r
e
a
t
m
e
n
t

i
n

a
n
y

g
r
o
u
p
G
i
v
e
n

n
o

d
i
f
f
e
r
e
n
c
e

b
e
t
w
e
e
n

g
r
o
u
p
s

i
n

O
C

l
e
v
e
l
s
,

2
0
0

I
U
/
d

o
f

v
i
t
a
m
i
n

D

s
e
e
m
s

t
o

b
e

a
s

e
f
f
e
c
t
i
v
e

a
s

8
0
0

I
U
/
d

w
i
t
h

r
e
g
a
r
d

t
o

O
C
T
a
b
l
e

6
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
592
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s

N
o

s
t
a
t
e
m
e
n
t

r
e
g
a
r
d
i
n
g

b
l
i
n
d
i
n
g
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

b
i
o
c
h
e
m
i
c
a
l

m
e
a
s
u
r
e
s

o
f

b
o
n
e

t
u
r
n
o
v
e
r

(
s
e
r
u
m

C
a
,

P
h
o
s
,

A
L
P
,

O
C
,

a
n
d

u
r
i
n
a
r
y

D
P
D
)

a
t

b
a
s
e
l
i
n
e

a
n
d

f
o
l
l
o
w
i
n
g

1
5

d
a
y
s

o
f

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n
A
L
P

i
n
c
r
e
a
s
e
d

f
o
l
l
o
w
i
n
g

t
h
e
r
a
p
y

i
n

g
r
o
u
p

1

(
P

=

.
0
3
3
)

a
n
d

g
r
o
u
p

3

(
P

=

.
0
1
6
)

b
u
t

n
o
t

g
r
o
u
p

2


(
P

=

.
4
6
0
)
T
h
e

s
i
g
n
i
f
i
c
a
n
t

i
n
c
r
e
a
s
e

i
n

D
P
D

e
x
c
r
e
t
i
o
n

w
i
t
h

8
0
0

I
U
/
d

o
f

v
i
t
a
m
i
n

D

s
u
g
g
e
s
t
s

t
h
a
t

h
i
g
h

v
i
t
a
m
i
n

D

d
o
s
e
s

m
a
y

a
c
c
e
l
e
r
a
t
e

b
o
n
e

t
u
r
n
o
v
e
r

a
n
d

r
e
s
o
r
p
t
i
o
n

i
n

t
h
e

p
r
e
t
e
r
m

i
n
f
a
n
t

N
o
t

p
l
a
c
e
b
o

c
o
n
t
r
o
l
l
e
d
Z
e
k
a
i

T
a
h
i
r

B
u
r
a
k

M
a
t
e
r
n
i
t
y

T
e
a
c
h
i
n
g

H
o
s
p
i
t
a
l

(
A
n
k
a
r
a
,

T
u
r
k
e
y
)
O
C

i
n
c
r
e
a
s
e
d

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t

i
n

g
r
o
u
p
s

1
,

2
,

a
n
d

3

(
P

=

.
0
0
6
,

P

=

.
0
2
0
,

a
n
d

P

=

.
0
4
5
,

r
e
s
p
e
c
t
i
v
e
l
y
)
O
n
l
y

a
d
d
r
e
s
s
e
s

p
r
e
t
e
r
m

i
n
f
a
n
t
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

1
1

o
f

4
8
N

=

3
7

(
n

=

1
1

g
r
o
u
p

1
,

n

=

1
5

g
r
o
u
p

2
,

n

=

1
1

g
r
o
u
p

3
)
T
h
e
r
e

w
a
s

a

l
i
n
e
a
r

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

v
i
t
a
m
i
n

D

d
o
s
e

a
n
d

u
r
i
n
a
r
y

D
P
D

e
x
c
r
e
t
i
o
n
,

b
u
t

t
h
e

d
i
f
f
e
r
e
n
c
e

t
r
e
n
d
e
d

t
o
w
a
r
d

s
i
g
n
i
f
i
c
a
n
c
e

o
n
l
y

i
n

g
r
o
u
p

3

(
P

=

.
0
5
9
)
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e
A
l
p
,

2
0
0
6
7
1
O
B
S
C
a
u
c
a
s
i
a
n

c
h
i
l
d
r
e
n

a
g
e
d

3

1
9

m
o
n
t
h
s

w
i
t
h

n
o

h
i
s
t
o
r
y

o
f

b
o
n
e

d
i
s
e
a
s
e

(
c
o
n
t
r
o
l
s
)

o
r

w
i
t
h

m
o
d
e
r
a
t
e

t
o

s
e
v
e
r
e

m
a
l
n
u
t
r
i
t
i
o
n

w
i
t
h
o
u
t

r
a
c
h
i
t
i
c

m
a
n
i
f
e
s
t
a
t
i
o
n
s

(
c
a
s
e
s
)

w
h
o

w
e
r
e

t
r
e
a
t
e
d

w
i
t
h

a

h
i
g
h

p
r
o
t
e
i
n

d
i
e
t

a
n
d

e
i
t
h
e
r

4
0
0

I
U

o
r

8
0
0

I
U

d
a
i
l
y

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

(
r
a
n
d
o
m
l
y

a
s
s
i
g
n
e
d
)

f
o
r

3

m
o
n
t
h
s
T
o

c
o
m
p
a
r
e

B
M
D

o
f

l
u
m
b
a
r

s
p
i
n
e

b
e
f
o
r
e

a
n
d

a
f
t
e
r

v
i
t
a
m
i
n

D

t
h
e
r
a
p
y

i
n

c
h
i
l
d
r
e
n

w
i
t
h

m
a
l
n
u
t
r
i
t
i
o
n

w
i
t
h
o
u
t

r
a
c
h
i
t
i
c

m
a
n
i
f
e
s
t
a
t
i
o
n
s

a
n
d

t
o

c
o
m
p
a
r
e

t
h
e
s
e

w
i
t
h

h
e
a
l
t
h
y

c
h
i
l
d
r
e
n

i
n

t
h
e

s
a
m
e

c
o
m
m
u
n
i
t
y
B
a
s
e
l
i
n
e

B
M
D

l
o
w
e
r

i
n

c
h
i
l
d
r
e
n

w
i
t
h

m
a
l
n
u
t
r
i
t
i
o
n

t
h
a
n

c
o
n
t
r
o
l
s

(
P

<

.
0
1
)

a
n
d

l
o
w
e
r

i
n

c
h
i
l
d
r
e
n

w
i
t
h

s
e
v
e
r
e

t
h
a
n

w
i
t
h

m
o
d
e
r
a
t
e

m
a
l
n
u
t
r
i
t
i
o
n

(
P

<

.
0
1
)
O
n
l
y

a
d
d
r
e
s
s
e
d

m
a
l
n
o
u
r
i
s
h
e
d

c
h
i
l
d
r
e
n

w
i
t
h
o
u
t

r
i
c
k
e
t
s

C
a
s
e
-
c
o
n
t
r
o
l
l
e
d

s
t
u
d
y
A
t
a
t
u
r
k

U
n
i
v
e
r
s
i
t
y

(
E
r
z
u
r
u
m
,

T
u
r
k
e
y
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
:

l
u
m
b
a
r

s
p
i
n
e

D
X
A

(
B
M
D
)
B
o
t
h

g
r
o
u
p
s

o
f

m
a
l
n
o
u
r
i
s
h
e
d

c
h
i
l
d
r
e
n

w
i
t
h

i
n
c
r
e
a
s
e
d

B
M
D

w
i
t
h

t
r
e
a
t
m
e
n
t


(
P

<

.
0
5

f
o
r

4
0
0

I
U
/
d

g
r
o
u
p
,


P

<

.
0
1

f
o
r

8
0
0

I
U
/
d

g
r
o
u
p
)
E
s
t
a
b
l
i
s
h

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

m
a
l
n
u
t
r
i
t
i
o
n

a
n
d

B
M
D

A
t
t
r
i
t
i
o
n

r
a
t
e
:

2
8

o
f

4
1
N

=

6
2

(
n

=

4
1

m
a
l
n
o
u
r
i
s
h
e
d
,

n

=

2
1

h
e
a
l
t
h
y

c
o
n
t
r
o
l
s
)
I
n
c
r
e
a
s
e
d

B
M
D

o
v
e
r

t
h
e

3
-
m
o
n
t
h

s
t
u
d
y

p
e
r
i
o
d

s
i
g
n
i
f
i
c
a
n
t
l
y

g
r
e
a
t
e
r

i
n

m
a
l
n
o
u
r
i
s
h
e
d

c
h
i
l
d
r
e
n

r
e
c
e
i
v
i
n
g

8
0
0

I
U

v
s

4
0
0

I
U

o
f

d
a
i
l
y

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

(
P

<

.
0
5
)
S
m
a
l
l

s
a
m
p
l
e

s
i
z
e
T
a
b
l
e

6
.

(
c
o
n
t
i
n
u
e
d
)
(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
593
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
A
k
c
a
m
,

2
0
0
6
7
2
O
B
S
T
e
r
m

b
r
e
a
s
t
f
e
d

o
t
h
e
r
w
i
s
e

h
e
a
l
t
h
y

i
n
f
a
n
t
s

a
g
e
d

5

1
3

m
o
n
t
h
s

w
i
t
h

n
u
t
r
i
t
i
o
n

r
i
c
k
e
t
s

d
i
v
i
d
e
d

i
n
t
o

2

g
r
o
u
p
s

b
a
s
e
d

o
n

v
i
t
a
m
i
n

D

t
h
e
r
a
p
y
:

g
r
o
u
p

1

(
s
i
n
g
l
e

h
i
g
h
-
d
o
s
e

v
i
t
a
m
i
n

D

6
0
0
,
0
0
0

I
U

o
r
a
l
l
y
)

o
r

g
r
o
u
p

2

(
2
0
,
0
0
0

I
U

o
r
a
l
l
y

d
a
i
l
y

f
o
r

3
0

d
a
y
s
)
T
o

c
o
m
p
a
r
e

t
h
e

i
n
c
r
e
a
s
e

i
n

B
M
D

i
n

2

d
i
f
f
e
r
e
n
t

t
h
e
r
a
p
y

r
e
g
i
m
e
n
s

o
f

v
i
t
a
m
i
n

D

i
n

i
n
f
a
n
t
s

w
i
t
h

v
i
t
a
m
i
n

D

d
e
f
i
c
i
e
n
t

r
i
c
k
e
t
s

(
V
D
R
)
C
a
,

P
h
o
s
,

a
n
d

A
L
P

l
e
v
e
l
s

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t

n
o
t

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

g
r
o
u
p
s
E
x
c
l
u
d
e
d

i
n
f
a
n
t
s

b
o
r
n

t
o

m
o
t
h
e
r
s

t
a
k
i
n
g

c
a
l
c
i
u
m

o
r

v
i
t
a
m
i
n

D

s
u
p
p
l
e
m
e
n
t
s

d
u
r
i
n
g

p
r
e
g
n
a
n
c
y

o
r

l
a
c
t
a
t
i
o
n

P
r
o
s
p
e
c
t
i
v
e
I
s
p
a
r
t
a

C
h
i
l
d
r
e
n

s

H
o
s
p
i
t
a
l

(
I
s
p
a
r
t
a
,

T
u
r
k
e
y
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

s
e
r
u
m

C
a
,

P
h
o
s
,

A
L
P
;

l
u
m
b
a
r

s
p
i
n
e

D
X
A

(
B
M
D
)

p
r
i
o
r

t
o

a
n
d

f
o
l
l
o
w
i
n
g

3
1

d
a
y
s

o
f

t
r
e
a
t
m
e
n
t
P
o
s
t
t
r
e
a
t
m
e
n
t

B
M
D

n
o
t

d
i
f
f
e
r
e
n
t

b
e
t
w
e
e
n

g
r
o
u
p
s

(
P

=

.
9
4
0
)
L
i
m
i
t
e
d

a
n
d

c
o
n
t
r
a
d
i
c
t
o
r
y

d
a
t
a

o
n

t
h
e

r
e
l
a
t
i
o
n
s
h
i
p

b
e
t
w
e
e
n

B
M
D

a
n
d

r
i
c
k
e
t
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

2
0
N

=

2
0

(
n

=

1
0

g
r
o
u
p

1
,

n

=

1
0

g
r
o
u
p

2
)
B
M
D

i
n
c
r
e
a
s
e
d

f
r
o
m

p
r
e
t
r
e
a
t
m
e
n
t

v
a
l
u
e
s

i
n

b
o
t
h

g
r
o
u
p
s

1

a
n
d

2

(
P

=

.
0
0
5

a
n
d

P

=

.
0
4
7
,

r
e
s
p
e
c
t
i
v
e
l
y
)
V
e
r
y

s
m
a
l
l

s
a
m
p
l
e

s
i
z
e

A
l
l

p
a
t
i
e
n
t
s

i
n

b
o
t
h

g
r
o
u
p
s

w
i
t
h

h
e
a
l
i
n
g

o
f

r
i
c
k
e
t
s

f
o
l
l
o
w
i
n
g

t
r
e
a
t
m
e
n
t

A
L
P
,

a
l
k
a
l
i
n
e

p
h
o
s
p
h
a
t
a
s
e
;

B
M
C
,

b
o
n
e

m
i
n
e
r
a
l

c
o
n
t
e
n
t
;

B
M
D
,

b
o
n
e

m
i
n
e
r
a
l

d
e
n
s
i
t
y
;

C
a
,

c
a
l
c
i
u
m
;

D
P
D
,

d
e
o
x
y
p
y
r
i
d
i
n
o
l
i
n
e
;

D
X
A
,

d
u
a
l
-
e
n
e
r
g
y

x
-
r
a
y

a
b
s
o
r
p
t
i
o
m
e
t
r
y
;

m
c
B
T
T
,

b
o
n
e

t
r
a
n
s
m
i
s
s
i
o
n

t
i
m
e
;

m
c
S
O
S
,

s
p
e
e
d

o
f

s
o
u
n
d
;

P
h
o
s
,

p
h
o
s
p
h
o
r
u
s
;

O
B
S
,

o
b
s
e
r
v
a
t
i
o
n
a
l

s
t
u
d
y
;

O
C
,

o
s
t
e
o
c
a
l
c
i
n
;

P
T
H
,

p
a
r
a
t
h
y
r
o
i
d

h
o
r
m
o
n
e
;

Q
U
S
,

q
u
a
n
t
i
t
a
t
i
v
e

u
l
t
r
a
s
o
u
n
d
;

2
5
-
O
H
D
,

2
5
-
h
y
d
r
o
x
y
v
i
t
a
m
i
n

D
.
T
a
b
l
e

6
.

(
c
o
n
t
i
n
u
e
d
)
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
594 Journal of Parenteral and Enteral Nutrition 37(5)
Table 7. GRADE Table Question 3: When and how should Vitamin D supplements be administered?
Comparison Outcome
Quantity, Type
Evidence Findings
GRADE of Evidence
for Outcome
In breastfed infants: Biochemical: 1 OBS
66
Biochemical: Low to moderate
Vitamin D oral supplementation
(200 IU/d)
66
or (400 IU/d)
68
vs no
supplementation from 212 months
25-OHD 1 RCT
26
Higher (6, 12 mo),
66
no
difference
67

Low (250 IU) vs high (500 IU) dose
daily oral vitamin D supplementation
during the initial 6 weeks of life
67








Ca
Phos
ALP
PTH
Bone:
BMD
BMC
mcSOS
mcBTT
No difference (6, 12 mo),
66

higher
67
Higher (6 mo), no difference
(12 mo),
66
6 weeks
67
No difference (6, 12 mo),
66

6 weeks
67
Lower (6 mo), no difference
(12 mo)
66
Bone:
No difference (6, 12 mo)
66
No difference
68









In preterm infants: Biochemical: 1 RCT
70
Biochemical: Moderate
Change in vitamin D status with
200 IU/kg/d (1), 400 IU/d (2),
or 800 IU/d (3) oral vitamin D
supplementation from 1530 days
of life
70
Ca
Phos
ALP
OC
Urinary DPD
No difference (1, 2, 3)
70
Higher (1, 3), no difference (2)
Higher (1, 2, 3)
No difference (1, 2), higher (3)





In malnourished children: Bone: 1 OBS
71
Bone: Low
High-dose (800 IU) vs low-dose
(400 IU) daily oral vitamin D
supplementation for 3 months
71
BMD Lower
71

In rachitic children: Biochemical: 2 OBS
69,72
Biochemical: Low
Low daily oral dose (20,000 IU)
for 30 days vs single oral dose
(600,000 IU) vitamin D therapy,
72

after single 10,000-IU/kg IM
injection of vitamin D
69

Ca
Phos
ALP
25-OHD
PTH
Bone:
BMD
No difference,
71
higher
69
No difference,
71
higher
69
No difference,
71
lower
69
Higher
69
Lower
69
Bone:
No difference
71







ALP, alkaline phosphatase; BMC, bone mineral content; BMD, bone mineral density; Ca, calcium; DPD, deoxypyridinoline; DXA, dual-energy x-ray
absorptiometry; IM, intramuscular; mcBTT, bone transmission time; mcSOS, speed of sound; OBS, observational study; OC, osteocalcin; Phos, phos-
phorus; PTH, parathyroid hormone; RCT, randomized controlled trial; QUS, quantitative ultrasound; 25-OHD, 25-hydroxyvitamin D.
known at this time. It is common practice to provide approxi-
mately 200 international units (5 mcg) vitamin D per day
62
;
however, further research is necessary to determine the ideal
vitamin D for neonates requiring PN therapy.
Beyond calcium, phosphorus, and vitamin D content, the
aluminum content of standard PN formulations deserves atten-
tion when discussing metabolic bone disease of the neonate.
Aluminum is a contaminant of PN components, and high doses
of aluminum have been shown to negatively affect both cogni-
tive development and short-term bone health.
63
In animals and
adult humans, excess aluminum has been shown to accumulate
at mineralization fronts and is associated with reduced bone
formation.
62
In addition, Sedman et al
64
reported that bone alu-
minum concentrations were 10-fold higher in preterm infants
who received PN for >3 weeks as compared with control sub-
jects. It has been recently demonstrated that the currently avail-
able PN products in the United States have an aluminum
content that makes it impossible to meet the new Food and
Drug Administration rule of <5 mcg/kg per day of aluminum
exposure in patients <50 kg.
65
Thus, it is imperative that manu-
facturers develop new methods to reduce the aluminum con-
tamination in their products and healthcare professionals be
aware of the aluminum exposure in our PN-dependent
neonates.
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
595
T
a
b
l
e

8
.

E
v
i
d
e
n
c
e

T
a
b
l
e

Q
u
e
s
t
i
o
n

4
:

D
o
e
s

P
N

p
r
e
d
i
s
p
o
s
e

a

n
e
o
n
a
t
e

t
o

m
e
t
a
b
o
l
i
c

b
o
n
e

d
i
s
e
a
s
e
?

A
r
e

t
h
e
r
e

P
N

f
o
r
m
u
l
a

r
e
c
o
m
m
e
n
d
a
t
i
o
n
s

t
o

m
i
n
i
m
i
z
e

t
h
i
s

r
i
s
k
?
L
e
a
d

A
u
t
h
o
r

(
R
e
f
e
r
e
n
c
e

N
o
.
)
,

Y
e
a
r
S
t
u
d
y

D
e
s
i
g
n
,

Q
u
a
l
i
t
y
P
o
p
u
l
a
t
i
o
n
,

S
e
t
t
i
n
g
,

N
S
t
u
d
y

O
b
j
e
c
t
i
v
e
R
e
s
u
l
t
s
C
o
m
m
e
n
t
s
P
e
r
e
i
r
a
-
d
a
-
S
i
l
v
a
,

2
0
1
1
6
1
R
C
T
H
e
a
l
t
h
y

p
r
e
t
e
r
m

n
e
o
n
a
t
e
s

(

3
3

w
e
e
k
s

g
e
s
t
a
t
i
o
n
a
l

a
g
e
)

o
n

P
N

f
o
r

>
1

w
e
e
k

a
s
s
i
g
n
e
d

t
o

r
e
c
e
i
v
e

l
o
w
-
d
o
s
e

C
a

a
n
d

P
h
o
s

(
4
5

m
g
/
k
g
/
d

C
a
;

2
6
.
5

m
g
/
k
g
/
d

P
h
o
s
)

o
r

h
i
g
h
-
d
o
s
e

C
a

a
n
d

P
h
o
s

(
7
5

m
g
/
k
g
/
d

C
a
;

4
4
.
1

m
g
/
k
g
/
d

P
h
o
s
)

b
y

P
N
T
o

a
s
s
e
s
s

w
h
e
t
h
e
r

e
a
r
l
y

h
i
g
h
e
r

C
a

a
n
d

P
h
o
s

i
n
t
a
k
e

d
e
l
i
v
e
r
e
d

v
i
a

P
N

c
a
n

p
r
e
v
e
n
t

b
o
n
e

s
t
r
e
n
g
t
h

d
e
c
l
i
n
e

i
n

p
r
e
t
e
r
m

i
n
f
a
n
t
s

d
u
r
i
n
g

t
h
e

f
i
r
s
t

w
e
e
k
s

o
f

l
i
f
e
S
O
S

v
a
l
u
e
s

f
o
r

l
o
w
-
d
o
s
e

g
r
o
u
p
s

d
e
c
r
e
a
s
e
d

s
i
g
n
i
f
i
c
a
n
t
l
y

o
v
e
r

f
i
r
s
t

6

w
e
e
k
s

o
f

l
i
f
e

(
P

=

.
0
2
7
)
,

w
h
e
r
e
a
s

t
h
e

v
a
l
u
e
s

f
o
r

t
h
e

h
i
g
h
-
d
o
s
e

g
r
o
u
p

d
i
d

n
o
t

(
P

=

.
9
7
6
)
P
h
o
s

w
a
s

a
d
d
e
d

t
o

P
N

a
s

a

f
i
x
e
d

C
a
:
P
h
o
s

r
a
t
i
o

o
f

1
.
7
:
1

T
r
i
p
l
e
-
b
l
i
n
d
H
o
s
p
i
t
a
l

D
o
n
a

E
s
t
e
f
a
n
i
a

(
L
i
s
b
o
n
,

P
o
r
t
u
g
a
l
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

t
i
b
i
a
l

Q
U
S

(
S
O
S
)

w
e
e
k
l
y

f
r
o
m

b
i
r
t
h

t
o

d
i
s
c
h
a
r
g
e
B
y

t
h
e

f
i
f
t
h

a
n
d

s
i
x
t
h

w
e
e
k
s

o
f

l
i
f
e
,

t
h
e

S
O
S

v
a
l
u
e
s

w
e
r
e

l
o
w
e
r

f
o
r

t
h
e

l
o
w
-
d
o
s
e

g
r
o
u
p
s

(
P

=

.
0
3
5

a
n
d

P

=

.
0
1
1
,

r
e
s
p
e
c
t
i
v
e
l
y
)
S
a
m
e

e
n
t
e
r
a
l

f
e
e
d
i
n
g

r
e
g
i
m
e
n

u
s
e
d

f
o
r

b
o
t
h

g
r
o
u
p
s

A
t
t
r
i
t
i
o
n

r
a
t
e
:

5

o
f

9
1

(
i
n
t
e
r
r
u
p
t
e
d

P
N

a
d
m
i
n
i
s
t
r
a
t
i
o
n

d
u
r
i
n
g

f
i
r
s
t

w
e
e
k

o
f

l
i
f
e
)
N

=

8
6

(
n

=

4
0

l
o
w

d
o
s
e
;

n

=

4
6

h
i
g
h

d
o
s
e
)
L
o
n
g
-
t
e
r
m

o
u
t
c
o
m
e
s

n
o
t

a
s
s
e
s
s
e
d

M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
F
e
w
t
r
e
l
l
,

2
0
0
9
6
3
R
C
T
P
r
e
v
i
o
u
s
l
y

p
r
e
t
e
r
m

(
<
3
4

w
e
e
k
s

g
e
s
t
a
t
i
o
n
a
l

a
g
e
,

<
1
8
5
0

g

b
i
r
t
h

w
e
i
g
h
t
)

a
d
o
l
e
s
c
e
n
t
s

(
1
3

1
5

y
e
a
r
s

o
l
d
)

p
r
e
v
i
o
u
s
l
y

r
a
n
d
o
m
l
y

a
s
s
i
g
n
e
d

t
o

a
l
u
m
i
n
u
m
-
d
e
p
l
e
t
e
d

v
s

s
t
a
n
d
a
r
d

P
N

s
o
l
u
t
i
o
n
s

d
u
r
i
n
g

t
h
e

n
e
o
n
a
t
a
l

p
e
r
i
o
d
T
o

a
s
s
e
s
s

w
h
e
t
h
e
r

n
e
o
n
a
t
a
l

a
l
u
m
i
n
u
m

e
x
p
o
s
u
r
e

a
f
f
e
c
t
s

l
o
n
g
-
t
e
r
m

b
o
n
e

m
a
s
s
L
u
m
b
a
r

s
p
i
n
e

B
M
C

a
n
d

B
A

h
i
g
h
e
r

i
n

l
o
w
-
a
l
u
m
i
n
u
m

g
r
o
u
p

(
P

=

.
0
1
7

a
n
d

P

=

.
0
3
1
,

r
e
s
p
e
c
t
i
v
e
l
y
)
C
o
m
p
o
s
i
t
i
o
n

o
f

P
N

s
o
l
u
t
i
o
n
s

i
d
e
n
t
i
c
a
l

o
t
h
e
r

t
h
a
n

a
l
u
m
i
n
u
m

a
n
d

c
h
l
o
r
i
d
e

c
o
n
t
e
n
t

D
o
u
b
l
e
-
b
l
i
n
d
M
u
l
t
i
p
l
e

h
o
s
p
i
t
a
l
s

(
C
a
m
b
r
i
d
g
e

a
n
d

N
o
r
w
i
c
h
,

U
n
i
t
e
d

K
i
n
g
d
o
m
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

l
u
m
b
a
r

s
p
i
n
e

a
n
d

w
h
o
l
e
-
b
o
d
y

D
X
A

(
B
M
C
,

B
M
D
,

B
A
)
W
h
o
l
e
-
b
o
d
y

B
M
C
,

B
A
,

B
M
D
,

a
n
d

B
M
D

z

s
c
o
r
e
s

a
n
d

l
u
m
b
a
r

s
p
i
n
e

B
M
D

z

s
c
o
r
e

t
r
e
n
d
e
d

h
i
g
h
e
r

i
n

l
o
w
-
a
l
u
m
i
n
u
m

g
r
o
u
p
Q
u
e
s
t
i
o
n
n
a
i
r
e
s

u
s
e
d

t
o

q
u
a
n
t
i
f
y

c
a
l
c
i
u
m

i
n
t
a
k
e
,

w
e
i
g
h
t
-
b
e
a
r
i
n
g

a
c
t
i
v
i
t
y
,

a
n
d

o
v
e
r
a
l
l

a
c
t
i
v
i
t
y

l
e
v
e
l

A
t
t
r
i
t
i
o
n

r
a
t
e
:

0

o
f

5
9

(
3
3
%

o
f

e
l
i
g
i
b
l
e

i
n
i
t
i
a
l

s
u
b
j
e
c
t
s

p
a
r
t
i
c
i
p
a
t
e
d
)
N

=

5
9

(
n

=

2
6

s
t
a
n
d
a
r
d

a
l
u
m
i
n
u
m
;

n

=

3
3

l
o
w

a
l
u
m
i
n
u
m
)
O
n
l
y

3
3
%

o
f

e
l
i
g
i
b
l
e

s
u
b
j
e
c
t
s

f
r
o
m

i
n
i
t
i
a
l

s
t
u
d
y

p
a
r
t
i
c
i
p
a
t
e
d

i
n

t
h
i
s

f
o
l
l
o
w
-
u
p

s
t
u
d
y

M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e
R
o
h
a
n
a
,

2
0
0
7
6
0
O
B
S
I
n
f
a
n
t
s

w
i
t
h

a

b
i
r
t
h

w
e
i
g
h
t

<
1
5
0
0

g
T
o

d
e
t
e
r
m
i
n
e

t
h
e

c
o
r
r
e
l
a
t
i
o
n

b
e
t
w
e
e
n

b
o
n
e

m
i
n
e
r
a
l

c
o
n
t
e
n
t

a
n
d

b
i
o
c
h
e
m
i
c
a
l

m
a
r
k
e
r
s

i
n

v
e
r
y

l
o
w

b
i
r
t
h

w
e
i
g
h
t

(
<
1
5
0
0

g
)

i
n
f
a
n
t
s
L
o
n
g
e
r

d
u
r
a
t
i
o
n

P
N

s
u
p
p
o
r
t

a
s
s
o
c
i
a
t
e
d

w
i
t
h

l
o
w
e
r

B
M
C

(
P

=

.
0
3
)
C
a

a
n
d

P
h
o
s

c
o
n
t
e
n
t

o
f

P
N

s
o
l
u
t
i
o
n
s

n
o
t

p
r
o
v
i
d
e
d

C
r
o
s
s
-
s
e
c
t
i
o
n
a
l

s
t
u
d
y
H
o
s
p
i
t
a
l

U
n
i
v
e
r
s
i
t
i

K
e
b
a
n
g
s
a
a
n

M
a
l
a
y
s
i
a

(
K
u
a
l
a

L
a
m
p
u
r
,

M
a
l
a
y
s
i
a
)
O
u
t
c
o
m
e

m
e
a
s
u
r
e
s
:

D
X
A

(
B
M
C
)

(
m
e
a
n

p
o
s
t
n
a
t
a
l

d
a
y

4
6
.
5

1
9
.
4
)
M
o
d
e
r
a
t
e

s
a
m
p
l
e

s
i
z
e

A
t
t
r
i
t
i
o
n

r
a
t
e
:

N
A

(
4
1
/
1
5
1

o
f

e
l
i
g
i
b
l
e

i
n
f
a
n
t
s

e
n
r
o
l
l
e
d
)
N

=

4
1

B
A
,

b
o
n
e

a
r
e
a
;

B
M
C
,

b
o
n
e

m
i
n
e
r
a
l

c
o
n
t
e
n
t
;

B
M
D
,

b
o
n
e

m
i
n
e
r
a
l

d
e
n
s
i
t
y
;

C
a
,

c
a
l
c
i
u
m
;

D
X
A
,

d
u
a
l
-
e
n
e
r
g
y

x
-
r
a
y

a
b
s
o
r
p
t
i
o
m
e
t
r
y
;

N
A
,

n
o
t

a
v
a
i
l
a
b
l
e
;

O
B
S
,

o
b
s
e
r
v
a
t
i
o
n
a
l

s
t
u
d
y
;

P
h
o
s
,

p
h
o
s
p
h
o
r
u
s
;

P
N
,

p
a
r
e
n
t
e
r
a
l

n
u
t
r
i
t
i
o
n
;

R
C
T
,

r
a
n
d
o
m
i
z
e
d

c
o
n
t
r
o
l
l
e
d

t
r
i
a
l
;

Q
U
S
,

q
u
a
n
t
i
t
a
t
i
v
e

u
l
t
r
a
s
o
u
n
d
;

S
O
S
,

s
p
e
e
d

o
f

s
o
u
n
d
.
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
596 Journal of Parenteral and Enteral Nutrition 37(5)
Table 9. GRADE Table Question 4: Does PN predispose a neonate to metabolic bone disease? Are there PN formula
recommendations to minimize this risk?
Comparison Outcome
Quantity, Type
Evidence Findings
GRADE of Evidence
for Outcome
Long- vs short-duration PN,
60
early
high-dose Ca, Phos (75 mg/kg/d Ca;
44.1 mg/kg/d Phos) vs low-dose Ca,
Phos (45 mg/kg/d Ca; 26.5 mg/kg/d
Phos) via PN
61
Bone:
BMC
SOS
1 OBS
60
1 RCT
61
Bone:
Lower
60
Higher
61
Weak to moderate


Aluminum-depleted vs standard PN
63
Bone: 1 RCT
63
Bone: Moderate
LS BMC, LS BA Higher
63

LS BMD, WB BMC, WB
BMD, WB BA
No difference
63

Abbreviations: BA, bone area; BMC, bone mineral content; BMD, bone mineral density; Ca, calcium; LS, lumbar spine; OBS, observational study;
Phos, phosphorus; PN, parenteral nutrition; RCT, randomized controlled trial; SOS, speed of sound; WB, whole body.
Acknowledgments
A.S.P.E.N. Board of Directors Providing Final Approval: Tom
Jaksic, MD, PhD; Ainsley Malone, MS, RD, CNSC; Lawrence A.
Robinson, MS, PharmD; Phil Ayers, PharmD, BCNSP, FASHP;
Praveen S. Goday, MBBS, CNSC; Carol Ireton-Jones, PhD, RD,
LD, CNSD; Jay Mirtallo, MS, RPh, BCNSP, FASHP; Daniel
Teitelbaum, MD; and Charles W. Van Way III, MD, FASPEN
A.S.P.E.N. Clinical Guidelines Editorial Board: Charlene
Compher, PhD, RD, CNSC, LDN, FADA, FASPEN; Nancy
Allen, MS, RD; Joseph I. Boullata, PharmD, RPh, BCNSP; Carol
L. Braunschweig, PhD, RD, FACN; Donald E. George, MD;
Edwin Simpser, MD; and Patricia A. Worthington, MSN, RN,
CNSN.
References
1. Steichen JJ, Gratton TL, Tsang RC. Osteopenia of prematurity: the cause
and possible treatment. J Pediatr. 1980;96(3, pt 2):528-534.
2. Greer FR, McCormick A. Bone growth with low bone mineral content
in very low birth weight premature infants. Pediatr Res. 1986;20(10):
925-928.
3. James JR, Congdon PJ, Truscott J, Horsman A, Arthur R. Osteopenia of
prematurity. Arch Dis Child. 1986;61(9):871-876.
4. Koo WW, Sherman R, Succop P, et al. Fractures and rickets in very low
birth weight infants: conservative management and outcome. J Pediatr
Orthop. 1989;9(3):326-330.
5. McIntosh N, De Curtis M, Williams J. Failure of mineral supplementa-
tion to reduce incidence of rickets in very-low-birthweight infants. Lancet.
1986;2(8513):981-982.
6. Hosking DJ. Calcium homeostasis in pregnancy. Clin Endocrinol (Oxf).
1996;45(1):1-6.
7. Guidelines for the use of parenteral and enteral nutrition in adult and
pediatric patients. JPEN J Parenter Enteral Nutr. 2002;26(1)(suppl):
1SA-138SA.
8. Guidelines for use of total parenteral nutrition in the hospitalized adult
patient. A.S.P.E.N. Board of Directors. JPEN J Parenter Enteral Nutr.
1986;10(5):441-445.
9. Guidelines for the use of parenteral and enteral nutrition in adult and
pediatric patients. American Society for Parenteral and Enteral Nutrition.
JPEN J Parenter Enteral Nutr. 1993;17(4)(suppl):1SA-52SA.
10. Arsenault D, Brenn M, Kim S, et al. A.S.P.E.N. clinical guidelines: hyper-
glycemia and hypoglycemia in the neonate receiving parenteral nutrition.
JPEN J Parenter Enteral Nutr. 2012;36(1):81-95.
11. Goldner WS, Stoner JA, Lyden E, et al. Finding the optimal dose of vita-
min D following Roux-en-Y gastric bypass: a prospective, randomized
pilot clinical trial. Obes Surg. 2009;19(2):173-179.
12. Jaksic T, Hull MA, Modi BP, Ching YA, George D, Compher C.
A.S.P.E.N. clinical guidelines: nutrition support of neonates supported
with extracorporeal membrane oxygenation. JPEN J Parenter Enteral
Nutr. 2010;34(3):247-253.
13. Jesuit C, Dillon C, Compher C, Lenders CM. A.S.P.E.N. clinical guide-
lines: nutrition support of hospitalized pediatric patients with obesity.
JPEN J Parenter Enteral Nutr. 2010;34(1):13-20.
14. Knox LS, Crosby LO, Feurer ID, Buzby GP, Miller CL, Mullen JL. Energy
expenditure in malnourished cancer patients. Ann Surg. 1983;197(2):152-162.
15. Mehta NM, Compher C. A.S.P.E.N. clinical guidelines: nutrition sup-
port of the critically ill child. JPEN J Parenter Enteral Nutr. 2009;33(3):
260-276.
16. Mueller C, Compher C, Ellen DM. A.S.P.E.N. clinical guidelines: nutri-
tion screening, assessment, and intervention in adults. JPEN J Parenter
Enteral Nutr. 2011;35(1):16-24.
17. Sabery N, Duggan C. A.S.P.E.N. clinical guidelines: nutrition support of
children with human immunodeficiency virus infection. JPEN J Parenter
Enteral Nutr. 2009;33(6):588-606.
18. Brown RO, Compher C. A.S.P.E.N. clinical guidelines: nutrition support
in adult acute and chronic renal failure. JPEN J Parenter Enteral Nutr.
2010;34(4):366-377.
19. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines, 1: introduc-
tionGRADE evidence profiles and summary of findings tables. J Clin
Epidemiol. 2011;64(4):383-394.
20. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines, 2: framing
the question and deciding on important outcomes. J Clin Epidemiol.
2011;64(4):395-400.
21. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines, 4: rating the
quality of evidencestudy limitations (risk of bias). J Clin Epidemiol.
2011;64(4):407-415.
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
Nehra et al 597
22. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines, 3:
rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-406.
23. Druyan ME, Compher C, Boullata JI, et al. Clinical guidelines for the use
of parenteral and enteral nutrition in adult and pediatric patients: apply-
ing the GRADE system to development of A.S.P.E.N. clinical guidelines.
JPEN J Parenter Enteral Nutr. 2012;36(1):77-80.
24. Andiran N, Yordam N, Ozon A. Risk factors for vitamin D deficiency in
breast-fed newborns and their mothers. Nutrition. 2002;18(1):47-50.
25. Dijkstra SH, van Beek A, Janssen JW, de Vleeschouwer LH, Huysman
WA, van den Akker EL. High prevalence of vitamin D deficiency in new-
born infants of high-risk mothers. Arch Dis Child. 2007;92(9):750-753.
26. Javaid MK, Crozier SR, Harvey NC, et al. Maternal vitamin D status dur-
ing pregnancy and childhood bone mass at age 9 years: a longitudinal
study. Lancet. 2006;367(9504):36-43.
27. Thomson K, Morley R, Grover SR, Zacharin MR. Postnatal evaluation
of vitamin D and bone health in women who were vitamin D-deficient in
pregnancy, and in their infants. Med J Aust. 2004;181(9):486-488.
28. Viljakainen HT, Saarnio E, Hytinantti T, et al. Maternal vitamin D sta-
tus determines bone variables in the newborn. J Clin Endocrinol Metab.
2010;95(4):1749-1757.
29. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing
preterm birth in threatened preterm labour. Cochrane Database Syst Rev.
2002;(4):CD001060.
30. Nassar AH, Sakhel K, Maarouf H, Naassan GR, Usta IM. Adverse mater-
nal and neonatal outcome of prolonged course of magnesium sulfate tocol-
ysis. Acta Obstet Gynecol Scand. 2006;85(9):1099-1103.
31. Yokoyama K, Takahashi N, Yada Y, et al. Prolonged maternal magne-
sium administration and bone metabolism in neonates. Early Hum Dev.
2010;86(3):187-191.
32. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and
mecobalamin on hip fractures in patients with stroke: a randomized con-
trolled trial. JAMA. 2005;293(9):1082-1088.
33. Hossein-Nezhad A, Mirzaei K, Maghbooli Z, Najmafshar A, Larijani B.
The influence of folic acid supplementation on maternal and fetal bone
turnover. J Bone Miner Metab. 2011;29(2):186-192.
34. Aggett PJ, Agostoni C, Axelsson I, et al. Feeding preterm infants after
hospital discharge: a commentary by the ESPGHAN Committee on
Nutrition. J Pediatr Gastroenterol Nutr. 2006;42(5):596-603.
35. Greer FR. Post-discharge nutrition: what does the evidence support?
Semin Perinatol. 2007;31(2):89-95.
36. Griffin IJ. Postdischarge nutrition for high risk neonates. Clin Perinatol.
2002;29(2):327-344.
37. OConnor DL, Jacobs J, Hall R, et al. Growth and development of pre-
mature infants fed predominantly human milk, predominantly premature
infant formula, or a combination of human milk and premature formula.
J Pediatr Gastroenterol Nutr. 2003;37(4):437-446.
38. Young RJ, Antonson DL, Ferguson PW, Murray ND, Merkel K, Moore
TE. Neonatal and infant feeding: effect on bone density at 4 years.
J Pediatr Gastroenterol Nutr. 2005;41(1):88-93.
39. Harvey NC, Robinson SM, Crozier SR, et al. Breast-feeding and adher-
ence to infant feeding guidelines do not influence bone mass at age 4
years. Br J Nutr. 2009;102(6):915-920.
40. Kim MJ, Na B, No SJ, et al. Nutritional status of vitamin D and the effect
of vitamin D supplementation in Korean breast-fed infants. J Korean Med
Sci. 2010;25(1):83-89.
41. Kurl S, Heinonen K, Lansimies E. Pre- and post-discharge feeding of very
preterm infants: impact on growth and bone mineralization. Clin Physiol
Funct Imaging. 2003;23(4):182-189.
42. Aimone A, Rovet J, Ward W, et al. Growth and body composition of human
milkfed premature infants provided with extra energy and nutrients early
after hospital discharge: 1-year follow-up. J Pediatr Gastroenterol Nutr.
2009;49(4):456-466.
43. De Schepper J, Cools F, Vandenplas Y, Louis O. Whole body bone min-
eral content is similar at discharge from the hospital in premature infants
receiving fortified breast milk or preterm formula. J Pediatr Gastroenterol
Nutr. 2005;41(2):230-234.
44. De Curtis M, Pieltain C, Rigo J. Body composition in preterm infants fed
standard term or enriched formula after hospital discharge. Eur J Nutr.
2002;41(4):177-182.
45. Koo WW, Hockman EM. Posthospital discharge feeding for pre-
term infants: effects of standard compared with enriched milk for-
mula on growth, bone mass, and body composition. Am J Clin Nutr.
2006;84(6):1357-1364.
46. Lapillonne A, Salle BL, Glorieux FH, Claris O. Bone mineralization and
growth are enhanced in preterm infants fed an isocaloric, nutrient-enriched
preterm formula through term. Am J Clin Nutr. 2004;80(6):1595-1603.
47. Litmanovitz I, Eliakim A, Arnon S, et al. Enriched post-discharge formula
versus term formula for bone strength in very low birth weight infants: a
longitudinal pilot study. J Perinat Med. 2007;35(5):431-435.
48. Picaud JC, Decullier E, Plan O, et al. Growth and bone mineralization in
preterm infants fed preterm formula or standard term formula after dis-
charge. J Pediatr. 2008;153(5):616-621, 621.e1-2.
49. Savino F, Viola S, Tarasco V, et al. Bone mineral status in breast-
fed infants: influence of vitamin D supplementation. Eur J Clin Nutr.
2011;65(3):335-339.
50. Siafarikas A, Piazena H, Feister U, Bulsara MK, Meffert H, Hesse V.
Randomised controlled trial analysing supplementation with 250 versus
500 units of vitamin D3, sun exposure and surrounding factors in breastfed
infants. Arch Dis Child. 2011;96(1):91-95.
51. Kislal FM, Dilmen U. Effect of different doses of vitamin D on osteo-
calcin and deoxypyridinoline in preterm infants. Pediatr Int. 2008;50(2):
204-207.
52. Akcam M, Yildiz M, Yilmaz A, Artan R. Bone mineral density in response
to two different regimes in rickets. Indian Pediatr. 2006;43(5):423-427.
53. Alp H, Orbak Z, Kermen T, Uslu H. Bone mineral density in malnourished
children without rachitic manifestations. Pediatr Int. 2006;48(2):128-131.
54. Soliman AT, El-Dabbagh M, Adel A, Al Ali M, Aziz Bedair EM, Elalaily
RK. Clinical responses to a mega-dose of vitamin D3 in infants and tod-
dlers with vitamin D deficiency rickets. J Trop Pediatr. 2010;56(1):19-26.
55. Wagner CL, Greer FR, American Academy of Pediatrics Section on
Breastfeeding, American Academy of Pediatrics Committee on Nutrition.
Prevention of rickets and vitamin D deficiency in infants, children, and
adolescents. Pediatrics. 2008;122(5):1142-1152.
56. Ross AC. The 2011 report on dietary reference intakes for calcium and
vitamin D. Public Health Nutr. 2011;14(5):938-939.
57. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treat-
ment, and prevention of vitamin D deficiency: an Endocrine Society clini-
cal practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930.
58. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutri-
tion. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70.
59. Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. 1. Guidelines on
paediatric parenteral nutrition of the European Society of Paediatric
Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the
European Society for Clinical Nutrition and Metabolism (ESPEN), sup-
ported by the European Society of Paediatric Research (ESPR). J Pediatr
Gastroenterol Nutr. 2005;41(suppl 2):S1-S87.
60. Rohana J, Hasmawati J, Zulkifli SZ. Risk factors associated with low
bone mineral content in very low birth weight infants. Singapore Med J.
2007;48(3):191-194.
61. Pereira-da-Silva L, Costa A, Pereira L, et al. Early high calcium and phos-
phorus intake by parenteral nutrition prevents short-term bone strength
decline in preterm infants. J Pediatr Gastroenterol Nutr. 2011;52(2):
203-209.
62. Klein GL. Metabolic bone disease of total parenteral nutrition. Nutrition.
1998;14(1):149-152.
63. Fewtrell MS, Bishop NJ, Edmonds CJ, Isaacs EB, Lucas A. Aluminum
exposure from parenteral nutrition in preterm infants: bone health at
15-year follow-up. Pediatrics. 2009;124(5):1372-1379.
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from
598 Journal of Parenteral and Enteral Nutrition 37(5)
64. Sedman AB, Klein GL, Merritt RJ, et al. Evidence of aluminum loading
in infants receiving intravenous therapy. N Engl J Med. 1985;312(21):
1337-1343.
65. Poole RL, Hintz SR, Mackenzie NI, Kerner JA Jr. Aluminum exposure
from pediatric parenteral nutrition: meeting the new FDA regulation.
JPEN J Parenter Enteral Nutr. 2008;32(3):242-246.
66. Kim MJ, Na B, No SJ, et al. Nutritional status of vitamin D and the effect
of vitamin D supplementation in Korean breast-fed infants. J Korean Med
Sci. 2010;25(1):83-89.
67. Siafarikas A, Piazena H, Feister U, Bulsara MK, Meffert H, Hesse V.
Randomised controlled trial analysing supplementation with 250 versus
500 units of vitamin D3, sun exposure and surrounding factors in breastfed
infants. Arch Dis Child. 2011;96(1):91-95.
68. Savino F, Viola S, Tarasco V, et al. Bone mineral status in breast-
fed infants: influence of vitamin D supplementation. Eur J Clin Nutr.
2011;65(3):335-339.
69. Soliman AT, El-Dabbagh M, Adel A, Al Ali M, Aziz Bedair EM, Elalaily
RK. Clinical responses to a mega-dose of vitamin D3 in infants and tod-
dlers with vitamin D deficiency rickets. J Trop Pediatr. 2010;56(1):19-26.
70. Kislal FM, Dilmen U. Effect of different doses of vitamin D on osteo-
calcin and deoxypyridinoline in preterm infants. Pediatr Int. 2008;50(2):
204-207.
71. Alp H, Orbak Z, Kermen T, Uslu H. Bone mineral density in malnourished
children without rachitic manifestations. Pediatr Int. 2006;48(2):128-131.
72. Akcam M, Yildiz M, Yilmaz A, Artan R. Bone mineral density in response
to two different regimes in rickets. Indian Pediatr. 2006;43(5):423-427.
at U DE G (CUCSH) on September 20, 2014 pen.sagepub.com Downloaded from