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A.S.P.E.N. Clinical Guidelines Nutrition Support of Neonatal Patients at Risk For Metabolic Bone Disease
A.S.P.E.N. Clinical Guidelines Nutrition Support of Neonatal Patients at Risk For Metabolic Bone Disease
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
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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
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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
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BMC
BMD
SOS
Biochemical:
BS-ALP
ICTP
5 RCT
44-48
Growth:
No difference
44,47
Higher
46,48
Lower
45
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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
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593
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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
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25-OHD
PTH
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71
higher
69
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71
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69
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71
lower
69
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69
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69
Bone:
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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
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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.
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