Embed Size (px)
Citation preview
http://pen.sagepub.com/Nutrition
Journal of Parenteral and Enteral
http://pen.sagepub.com/content/36/5/506The online version of this article can be found at:
DOI: 10.1177/0148607112449651
2012 36: 506 originally published online 29 June 2012JPEN J Parenter Enteral NutrSociety for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors and Mark Puder
Erica M. Fallon, Deepika Nehra, Alexis K. Potemkin, Kathleen M. Gura, Edwin Simpser, Charlene Compher, AmericanEnterocolitis
A.S.P.E.N. Clinical Guidelines : Nutrition Support of Neonatal Patients at Risk for Necrotizing
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 NutritionAdditional services and information for
http://pen.sagepub.com/cgi/alertsEmail Alerts:
http://pen.sagepub.com/subscriptionsSubscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
What is This?
- Jun 29, 2012OnlineFirst Version of Record
- Aug 16, 2012Version of Record >>
by guest on November 21, 2012pen.sagepub.comDownloaded from
Journal of Parenteral and Enteral NutritionVolume 36 Number 5September 2012 506-523© 2012 American Society for Parenteral and Enteral NutritionDOI: 10.1177/0148607112449651http://jpen.sagepub.comhosted athttp://online.sagepub.com
Clinical Guidelines
449651 PENXXX10.1177/0148607112449651A.S.P.E.N. Clinical Guidelines / Fallon et alJournal of Parenteral and Enteral Nutrition2012
From the 1Department of Surgery and The Vascular Biology Program, Chil-dren’s Hospital Boston, Harvard Medical School, Boston, Massachusetts; 2Department of Pharmacy, Children’s Hospital Boston, Boston, Massachu-setts; 3St. Mary’s Hospital for Children, Bayside, New York; and 4University of Pennsylvania School of Nursing, Philadelphia, Pennsylvania.
Financial disclosure: none declared.
Corresponding Author: Charlene Compher, PhD, RD, FADA, CNSD, LDN, University of Pennsylvania School of Nursing, Claire M. Fagin Hall, 418 Curie Blvd, Philadelphia, PA 19104-4217; e-mail: [email protected].
A.S.P.E.N. Clinical Guidelines: Nutrition Support of Neonatal Patients at Risk for Necrotizing Enterocolitis
Erica M. Fallon, MD1; Deepika Nehra, MD1; Alexis K. Potemkin, RN, BSN1; Kathleen M. Gura, PharmD, BCNSP2; Edwin Simpser, MD3; Charlene Compher, PhD, RD, CNSC, LDN, FADA4; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors; and Mark Puder, MD, PhD1
AbstractBackground: Necrotizing enterocolitis (NEC) is one of the most devastating diseases in the neonatal population, with extremely low birth weight and extremely preterm infants at greatest risk. Method: A systematic review of the best available evidence to answer a series of questions regarding nutrition support of neonates at risk of NEC 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 A.S.P.E.N. Board of Directors. Results/Conclusions: (1) When and how should feeds be started in infants at high risk for NEC? We suggest that minimal enteral nutrition be initiated within the first 2 days of life and advanced by 30 mL/kg/d in infants ≥1000g. (Weak) (2) Does the provision of mother’s milk reduce the risk of developing NEC? We suggest the exclusive use of mother’s milk rather than bovine-based products or formula in infants at risk for NEC. (Weak) (3) Do probiotics reduce the risk of developing NEC? There are insufficient data to recommend the use of probiotics in infants at risk for NEC. (Further research needed.) (4) Do nutrients either prevent or predispose to the development of NEC? We do not recommend glutamine supplementation for infants at risk for NEC (Strong). There is insufficient evidence to recommend arginine and/or long chain polyunsaturated fatty acid supplementation for infants at risk for NEC. (Further research needed.) (5) When should feeds be reintroduced to infants with NEC? There are insufficient data to make a recommendation regarding time to reintroduce feedings to infants after NEC. (Further research needed.) (JPEN J Parenter Enteral Nutr. 2012;36:506-523)
Keywords
neonates; outcomes research/quality; parenteral nutrition
Background
Necrotizing enterocolitis (NEC) is one of the most devastating diseases in the neonatal population, with extremely low birth weight (ELBW) and extremely preterm infants at greatest risk.1-3 Data from large, multicenter, neonatal network data-bases from the United States and Canada report a mean preva-lence of 7% in infants weighing <1500 g1,4,5 and an estimated mortality of 15%–30%,6-8 resulting in an estimated total cost up to $1 billion annually in the United States alone.9 NEC is classified into clinical stages (I, II, and III) based on the sever-ity of disease, as proposed by Bell et al in 1978,10 which were then modified (IA, IB, IIA, IIB, IIIA, IIIB) to include sys-temic, intestinal, and radiologic signs by Walsh and Kliegman in 1986.11 Although the etiology remains undefined, multiple risk factors imply a multifactorial etiology. As gastrointestinal integrity and function are compromised in NEC, it is without question that nutrition considerations are important in the pre-vention and management of this disease. These clinical guide-lines will address enteral nutrition practices, probiotic administration, and nutrient supplementation in patients at risk for and/or diagnosed with NEC.
Methodology
The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is an organization comprising healthcare profes-sionals representing the disciplines of medicine, nursing, pharmacy, dietetics, and nutrition science. The mission of A.S.P.E.N. is to improve patient care by advancing the science and practice of nutrition support therapy and metabolism. A.S.P.E.N. works vigorously to support quality patient care, education, and research in the fields of nutrition and metabolic
by guest on November 21, 2012pen.sagepub.comDownloaded from
A.S.P.E.N. Clinical Guidelines / Fallon et al 507
support in all healthcare settings. These Clinical Guidelines were developed under the guidance of the A.S.P.E.N. Board of Directors. Promotion of safe and effective patient care by nutrition support practitioners is a critical role of the A.S.P.E.N. organization. The A.S.P.E.N. Board of Directors has been pub-lishing Clinical Guidelines since 1986.12-23 The A.S.P.E.N. Clinical Guidelines editorial board 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. has adopted concepts of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group (http://www.gradeworkinggroup.org) for development of its clinical guidelines. The GRADE working group combined the efforts of evidence analysis methodologists and clinical guidelines developers from diverse backgrounds and health organizations to develop an evaluation system that would provide a transparent process for evaluating the best available evidence and integration of the evidence with clinical knowledge and consideration of patient priorities. These proce-dures provide added transparency by developing separate grades
for the body of evidence and for the recommendation. The pro-cedures listed below were adopted from the GRADE process for use with A.S.P.E.N. Clinical Guidelines with consideration of the levels of review (by internal and external content reviewers, by the A.S.P.E.N. Board of Directors).
A rigorous literature search is undertaken to locate clinical outcomes associated with practice decisions in the population of interest. Each pertinent paper is appraised for evidence qual-ity according to research quality (randomization, blinding, attrition, sample size, and risk of bias for clinical trials24 and prospective vs retrospective observation, sample size, and potential bias for observational studies) and placed into an evi-dence table. A second table is used to provide an overview of the strength of the available evidence according to the clinical outcomes, in order to support a consensus decision regarding the guideline recommendation. If the evidence quality is high, it is unlikely that further research will change our confidence in the estimate of effect. With moderate grade evidence, further research is likely to modify the confidence in the effect esti-mate and may change the estimate. With low grade evidence, further research is very likely to change the estimate, and with very low evidence quality, the estimate of the effect is very uncertain. A clinical recommendation is then developed by consensus of the Clinical Guidelines authors, based on the best available evidence. The risks and benefits to the patient are weighed in light of the available evidence. Conditional lan-guage is used for weak recommendations. For further details on the A.S.P.E.N. application of GRADE, see the “Clinical Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pediatric Patients: Applying the GRADE System to Development of A.S.P.E.N. Clinical Guidelines.”24
Table 1. Nutrition Support Guideline Recommendations for Neonatal Patients at Risk for Necrotizing Enterocolitis
Question Recommendation Grade
When and how should feeds be started in infants at high risk for NEC?
We suggest that minimal enteral nutrition should be initiated within the first 2 days of life and advanced by 30 mL/kg/d in infants ≥1000 g.
Weak
Does the provision of mother’s milk reduce the risk of developing NEC relative to bovine-based products or formula?
We suggest the exclusive use of mother’s milk rather than bovine-based products or formula in infants at risk for NEC.
Weak
Do probiotics reduce the risk of developing NEC?
There are insufficient data to recommend the use of probiotics in infants at risk for NEC.
Further research needed
Do certain nutrients either prevent or predispose to the development of NEC?
We do not recommend glutamine supplementation for infants at risk for NEC.
There is insufficient evidence at this time to recommend arginine and/or long-chain polyunsaturated fatty acid supplementation for infants at risk for NEC.
Strong
Further research needed
When should feeds be reintroduced to infants with NEC?
There are insufficient data to make a recommendation regarding time to reintroduce feedings to infants after NEC.
Further research needed
Abbreviation: NEC, necrotizing enterocolitis.
by guest on November 21, 2012pen.sagepub.comDownloaded from
508 Journal of Parenteral and Enteral Nutrition 36(5)
For the current Clinical Guideline, the search term necrotiz-ing enterocolitis was used in PubMed with inclusion criteria including infants (birth to 23 months); humans; clinical trial; randomized controlled trial; case reports; clinical trial: phase I, phase II, phase III, phase IV; comparative study; controlled clinical trial; guideline; journal article; multicenter study; English language; and published within the last 10 years. The search was conducted on April 21, 2011. The questions are summarized in Table 1. For questions 1 and 3, an additional limitation of randomized controlled trial was implemented due to the plethora of literature on these topics. For questions 2, 4, and 5, pertinent literature within the past 10 years, without restriction to evidence type, was included. A total of 1335 abstracts were reviewed, of which 24 papers met the inclusion criteria of the Clinical Guidelines and were included.
Practice Guidelines and Rationales
Question 1: When and how should feeds be started in infants at high risk for NEC (Tables 2 and 3)?
Recommendation: We suggest that minimal enteral nutrition be initiated within the first 2 days of life and advanced by 30 mL/kg/d in infants ≥1000 g.
Grade: WeakRationale: Several randomized controlled trials (RCTs)
have been conducted to gain insight into the optimal time of initiation and rate of advancement of enteral nutrition in infants at risk for NEC. Of the studies reviewed, 2 of 1025,26 evaluated NEC (Bell’s stage ≥II) as the primary outcome, whereas the remaining studies predominantly evaluated feed-ing tolerance and/or time to achievement of full enteral nutri-tion with NEC as a secondary outcome measure. With regard to the timing of initiation of EN, one RCT25 evaluated the effect of early (≤5 days; median 2 days) vs delayed (≥6 days; median 7 days) initiation of minimal enteral feeding (MEF) in infants with an age-adjusted birth weight (BW) ≤10th percen-tile and intrauterine growth restriction (IUGR). No difference in the incidence of NEC between groups was found, although it was concluded that a larger sample size would be needed to adequately evaluate for an effect. Two RCTs27,28 evaluated the effect of MEF vs nil per os (NPO) status within the first week of life with feeds beginning at a median age of 2 days in <1000-g and <2000-g infants, respectively, and found no sig-nificant differences in the incidence of NEC. For these studies, the quantity associated with MEF was ≤12 mL/kg/d.
Three RCTs29-31 evaluated the effect of slow (15–20 mL/kg/d) vs rapid (30 mL/kg/d) enteral nutrition advancement to a goal rate of between 150 and 180 mL/kg/d and found that rapid advancement was well tolerated by infants with an average BW 1000–2000 g without an increased incidence of NEC. In these studies, enteral nutrition was initiated at a median age of 6 hours29 or 2 days.30,31 However, these studies were not powered to detect statistically significant differences in the incidence of NEC. In addition, it is important to note that hemodynamic
instability can impact feeding practices, and thus, discretion should be employed under these circumstances. Last, one RCT26 evaluated the effect of stable (20 mL/kg/d) vs advancing (20 mL/kg/d to goal 140 mL/kg/d) feeding volumes for a 10-day period following the initiation of enteral nutrition and found a significantly higher incidence of NEC in infants fed advancing volumes. Due to the high incidence of NEC in the advancing group (10% vs 1.4%), the study was prematurely ter-minated. It is important to recognize that a major difference in this study compared with the previous RCTs29-31 is that enteral nutrition was initiated later in life, the timing of which was at the discretion of the neonatologist. Specifically, the earliest age of feed initiation was 4 days with a median age of 9.5 days in infants who developed NEC and 11 days for infants in the advancing group who developed NEC. This is a potentially important confounding variable, making the interpretation of these study results complicated and to be taken with caution.
Although the majority of these aforementioned studies have recommended larger, multicentered prospective trials to fur-ther evaluate questions on enteral nutrition initiation and advancement, based on the available data, early MEF within the first 2 days of life and advancement at 30 mL/kg/d in infants ≥1000 g can be suggested.
Question 2: Does the provision of mother’s milk reduce the risk of developing NEC relative to bovine-based prod-ucts or formula (Tables 4 and 5)?
Recommendation: We suggest the exclusive use of mother’s milk rather than bovine-based products or formula in infants at risk for NEC
Grade: WeakRationale: The type of enteral nutrition administered to
an infant at risk for NEC is important. Several studies have focused on whether the administration of human milk results in a reduction in the incidence of NEC compared with formula feeding. These studies used mother’s milk (MM) with the exception of one,32 which fed infants pasteurized donor milk (DM) if MM was unavailable. Exclusive feeding with MM is associated with a decreased risk of NEC as compared with pre-term formula (PF).33 As a substitute for MM, pasteurized DM has not been found to have any protective effect over PF with regard to the incidence of NEC,34 but feeding with MM and/or DM has been found to be associated with a decreased risk of NEC as compared with a combination of MM and/or DM and bovine milk (BOV)–based products.32 It is important to note that the source of enteral nutrition was explicitly evaluated; supplementation with milk fortifier was not evaluated. With respect to the quantity of MM administered, one prospective cohort study35 found enteral nutrition with ≥50% MM within the first 14 days was associated with a 6-fold decreased risk of NEC. An observational study36 found the amount of daily MM (1 to ≥50 mL/kg/d) fed through week 4 of life had no effect on the incidence of NEC. Based on the available data, exclusively fed MM has been shown to be beneficial in the prevention of
by guest on November 21, 2012pen.sagepub.comDownloaded from
A.S.P.E.N. Clinical Guidelines / Fallon et al 509
NEC and is therefore recommended over formula feeding. It is unclear whether the amount and/or timing of MM adminis-tered have an effect on the incidence of NEC, and therefore no recommendation regarding the optimal dose of MM can be made.
Question 3: Do probiotics reduce the risk of developing NEC (Tables 6 and 7)?
Recommendation: There are insufficient data to recom-mend the use of probiotics in infants at risk for NEC.
Grade: Further research neededRationale: There has been much debate over the admin-
istration of oral probiotics in the prevention of NEC. Seven RCTs evaluating the use of prophylactic probiotics in preterm and very low birth weight (VLBW) infants met inclusion crite-ria for these guidelines. NEC, defined as Bell’s stage ≥II, was the primary end point in 6 of 7 studies.37-42 The type of bacte-ria, dosage, frequency, and duration of treatment varied widely across studies. One study evaluated the effect of a probiotic with MM vs MM alone,40 whereas 2 studies evaluated the effect of a probiotic with human milk (HM; MM or DM) vs HM alone,37,42 and 3 studies evaluated the effect of a probiotic with MM or formula vs MM or formula alone.39,41,43 One study38 specifically compared the effect of killed probiotic (KP) vs living probiotic (LP) Lactobacillus acidophilus on the incidence of NEC and found no difference in the incidence of NEC between groups; LP and KP were both found to be pre-ventative against NEC in comparison to a placebo group, with KP retaining similar benefits to live bacteria with no adverse effect. All 7 RCTs demonstrated a lower incidence of NEC in the group of infants who received probiotics as compared with those who did not receive probiotics, although 1 of 7 studies43 did not demonstrate statistical significance between groups. Although the implementation of a “probiotic” resulted in a lower incidence of NEC across studies, it is important to emphasize that these studies used different types of probiotics, with some administering a combination of probiotics.37,39-42 It is additionally important to mention that there is no Food and Drug Administration (FDA) approval to date for routine use of these products. Further studies are necessary to determine the most effective type(s) of probiotic, dosage, and duration of treatment; thus, no recommendation on the use of probiotics in infants at risk for NEC can be made at this time.
Question 4: Do certain nutrients either prevent or predis-pose to the development of NEC (Tables 8 and 9)?
Recommendation: We do not recommend glutamine supplementation for infants at risk for NEC. There is insuf-ficient evidence at this time to recommend arginine and/or long-chain polyunsaturated fatty acid supplementation for infants at risk for NEC.
Grade: Strong (glutamine); further research needed (arginine, long-chain polyunsaturated fatty acids)
Rationale: A review of the literature suggests that cer-tain nutrients may reduce the incidence of NEC, whereas others may actually predispose infants to NEC. With respect to amino acids (AA), recent literature has focused on the effect of arginine and glutamine supplementation on the incidence of NEC. The plasma arginine and asymmetric dimethylarginine (ADMA, a metabolic by-product of protein modification pro-cesses) concentrations as well as the arginine:ADMA ratio have been found to be lower in premature infants with NEC, which have subsequently been shown to be associated with an increased mortality.44 Although there is not an abundance of literature, one RCT45 focuses on the effect of prophylactic L-arginine supplementation (1.5 mmol/kg/d), the results of which suggest that supplementation may be effective in reduc-ing the overall incidence of NEC. Of note, the results of this study must be taken with caution as the sample size was small and results demonstrated no difference in the reduction of Bell’s stage ≥II. Glutamine supplementation has additionally been evaluated in one large, well-conducted RCT, and no sta-tistically significant difference in the incidence of NEC between supplemented and nonsupplemented groups was found.46 Apart from individual amino acid supplementation, the administration of AA in parenteral nutrition (PN) has addi-tionally been studied. In a comparative pre- and postinterven-tion study,47 early AA administration was associated with an increased incidence of surgical NEC in VLBW infants. Last, fatty acid supplementation was evaluated in one RCT48; this study demonstrated a slightly increased incidence of NEC (5.3% vs 2%) in long-chain polyunsaturated fatty acid (LCPUFA)–supplemented (fat mixture containing linoleic, α-linolenic, and γ-linolenic acids) compared with nonsupple-mented infants, although the difference between groups was not statistically significant. Based on the aforementioned stud-ies, there is limited research on AA/fatty acid administration and supplementation, and it remains an important area for future research. However, based on the available literature, arginine supplementation may be effective, although the evi-dence is underpowered, whereas glutamine supplementation does not appear to prevent NEC, and LCPUFA supplementa-tion may predispose infants to NEC. Therefore, although glu-tamine supplementation is not recommended for infants at risk for NEC, there is insufficient evidence to recommend arginine and/or LCPUFA supplementation at this time.
Question 5: When should feeds be reintroduced to infants with NEC (Tables 10 and 11)?
Recommendation: There are insufficient data to make a recommendation regarding time to reintroduce feedings to infants after NEC.
Grade: Further research neededRationale: There is no standard recommendation as to
when enteral nutrition should be reinitiated after a defini-tive diagnosis of NEC. Historically, it has been suggested that
by guest on November 21, 2012pen.sagepub.comDownloaded from
510 Journal of Parenteral and Enteral Nutrition 36(5)
a period of fasting from 10 days to 3 weeks should be observed prior to the reintroduction of enteral nutrition for an infant with NEC; however, these recommendations are not founded on scientific data. It is without question that practices vary greatly among institutions and physicians. It has been suggested that prolonged fasting may actually be detrimental due to the potential need for prolonged central venous access and PN, and has prompted some institutions to introduce early feeding regimens in infants with NEC. To date, the literature on the impact of early feeding regimens is limited. In fact, only 2 ret-rospective reviews met the inclusion criteria for these guide-lines. Both of these studies suggest that, for infants with Bell’s stage II NEC, early feeding regimens may actually have
potential beneficial effects, including a reduced incidence of catheter-related sepsis and post-NEC intestinal stricture for-mation as well as shorter time to full enteral nutrition and shorter hospitalization. It is important to note that both studies have serious limitations given their retrospective nature, and both are underpowered to assess the impact of early enteral nutrition on NEC recurrence, a very important outcome vari-able. Although these studies suggest that prolonged fasting periods traditionally recommended for infants with NEC may not be necessary, further prospective and randomized con-trolled trials are necessary before recommendations can be made as to when feeds should be reintroduced in infants with NEC.
(Text continues on p. 522.)
by guest on November 21, 2012pen.sagepub.comDownloaded from
511
Tab
le 2
. Evi
den
ce T
able
Qu
esti
on 1
: W
hen
and
how
sho
uld
feed
s be
sta
rted
in in
fant
s at
hig
h ri
sk f
or N
EC
?
Auth
or, Y
ear
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Kri
shna
mur
thy,
29
2010
RC
TN
onbl
inde
d to
in
terv
enti
on
(inv
esti
gato
rs)
Rat
e of
att
riti
on:
10/1
00
Pre
term
infa
nts
<34
wee
ks
GA
wit
h B
W 1
000–
1499
g,
bor
n 2/
2008
to 9
/200
8,
and
foll
owed
unt
il th
ey h
ad
rega
ined
BW
or
deve
lope
d N
EC
Tert
iary
car
e ho
spit
al (
Indi
a)N
= 1
00 (
n =
50/
grou
p)
To e
valu
ate
the
effe
ct o
f sl
ow (
20
mL
/kg/
d) v
s ra
pid
(30
mL
/kg/
d)
ente
ral n
utri
tion
adv
ance
men
t by
nas
ogas
tric
bol
us o
n th
e ti
me
to a
chie
vem
ent o
f fu
ll e
nter
al
nutr
itio
n (1
80 m
L/k
g/d)
Pri
mar
y ou
tcom
e: T
ime
to a
ttai
nmen
t of
ful
l ent
eral
nut
riti
onSe
cond
ary
outc
ome:
Inc
iden
ce
of f
eedi
ng in
tole
ranc
e, N
EC
(B
ell’
s st
age
≥IIA
), m
orta
lity
, ap
nea,
dur
atio
n of
hos
pita
l sta
y/in
trav
enou
s fl
uids
, wei
ght g
ain,
an
d no
soco
mia
l sep
sis
Inci
denc
e of
NE
C:
2%
(1/5
0) in
the
slow
-fe
edin
g ad
vanc
emen
t gr
oup
and
4% (
2/50
) in
the
rapi
d-fe
edin
g ad
vanc
emen
t gro
up (
P
= 1
.0)
Rap
id e
nter
al n
utri
tion
adv
ance
men
t of
30
mL
/kg/
d is
wel
l tol
erat
ed
wit
hout
an
incr
ease
d in
cide
nce
of
NE
C in
sta
ble
pret
erm
neo
nate
s w
eigh
ing
1000
–149
9 g.
The
re w
as n
o st
atis
tica
lly
sign
ific
ant
diff
eren
ce in
mor
tali
ty b
etw
een
grou
ps.
The
stu
dy w
as n
ot p
ower
ed to
det
ect
clin
ical
or
stat
isti
cal d
iffe
renc
es in
th
e in
cide
nce
of N
EC
as
NE
C w
as
not t
he p
rim
ary
outc
ome.
Kar
agia
nni,25
20
10R
CT
Non
blin
ded
Pil
ot s
tudy
Rat
e of
att
riti
on:
3/84
Pre
term
infa
nts
27–3
4 w
eeks
G
A w
ith
age-
adju
sted
BW
≤1
0th
perc
enti
le (
IUG
R),
A
pgar
sco
re >
5, a
nd a
rter
ial
cord
blo
od p
H ≥
7.0
wit
h ab
norm
al a
nten
atal
Dop
pler
re
sult
s, a
dmit
ted
betw
een
5/20
04 a
nd 5
/200
8L
evel
III
NIC
U (
Gre
ece)
N =
84
(n =
42/
grou
p)
To e
xam
ine
the
effe
ct o
f ea
rly
(≤5
days
) vs
del
ayed
(≥6
day
s)
init
iati
on o
f M
EF
on
the
inci
denc
e of
NE
C a
nd f
eedi
ng in
tole
ranc
eP
rim
ary
outc
omes
: In
cide
nce
of
NE
C (
Bel
l’s
stag
e ≥I
I) a
nd f
eedi
ng
into
lera
nce
Seco
ndar
y ou
tcom
e: M
orta
lity
Inci
denc
e of
NE
C:
15%
(6
/40)
in th
e ea
rly
ME
F
grou
p an
d 9.
8% (
4/41
) in
the
dela
yed
ME
F
grou
p (R
R =
1.5
4 ea
rly
ME
F; 9
5% C
I 0.
469–
5.04
3)
Ear
ly M
EF
for
pre
term
infa
nts
wit
h IU
GR
and
abn
orm
al
ante
nata
l Dop
pler
res
ults
doe
s no
t si
gnif
ican
tly
impa
ct th
e in
cide
nce
of N
EC
.M
orta
lity
was
not
sig
nifi
cant
ly
diff
eren
t bet
wee
n gr
oups
(P
=
.512
).
Mos
qued
a,27
20
08R
CT
Non
blin
ded
Pil
ot s
tudy
Rat
e of
att
riti
on:
23/8
4
EL
BW
infa
nts
(BW
≤10
00 g
),
adm
itte
d be
twee
n 1/
2001
an
d 8/
2003
. Inf
ants
wer
e se
para
ted
into
ME
F a
nd
NP
O g
roup
s fr
om D
OL
2–
7. O
n D
OL
8, a
ll in
fant
s re
ceiv
ed b
olus
fee
ding
s (2
0 m
L/k
g/d)
and
wer
e fo
llow
ed u
ntil
1 w
eek
afte
r ac
hiev
emen
t of
full
ent
eral
nu
trit
ion
(150
mL
/kg/
d).
Sin
gle-
cent
er N
ICU
(Il
lino
is,
US
A)
N =
84
(n =
41
ME
F g
roup
, n
= 4
3 N
PO
gro
up)
To e
valu
ate
the
effi
cacy
of
earl
y M
EF
(12
mL
/kg/
d) o
n ov
eral
l fe
edin
g to
lera
nce
in in
fant
s fr
om
DO
L 2
–7P
rim
ary
outc
ome:
Fee
ding
tole
ranc
eSe
cond
ary
outc
omes
: In
cide
nce
of N
EC
, sep
sis,
mor
tali
ty,
intr
aven
tric
ular
hem
orrh
age,
leng
th
of h
ospi
tal s
tay
Inci
denc
e of
NE
C:
9%
(3/3
3) in
the
ME
F g
roup
an
d 14
% (
4/28
) in
the
NP
O g
roup
(P
= .5
3)M
orta
lity
was
17%
in th
e M
EF
gro
up a
nd 2
6% in
th
e N
PO
gro
up (
P =
.34)
; in
fant
s w
ho e
xpir
ed w
ere
excl
uded
fro
m th
e an
alys
is.T
here
was
no
diff
eren
ce in
the
inci
denc
e of
NE
C b
etw
een
ME
F
and
NP
O g
roup
s.B
ased
on
the
inci
denc
e of
NE
C
and
mor
tali
ty in
this
stu
dy, a
sa
mpl
e si
ze o
f 19
1 in
fant
s pe
r gr
oup
wou
ld b
e ne
eded
for
an
appr
opri
atel
y po
wer
ed s
tudy
.
(con
tinu
ed)
by guest on November 21, 2012pen.sagepub.comDownloaded from
512
Auth
or, Y
ear
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Cap
le,30
200
4R
CT
Non
blin
ded
Rat
e of
att
riti
on:
5/16
0In
tent
ion-
to-
trea
t ana
lysi
s
Infa
nts
≤35
wee
k G
A
wit
h B
W 1
000–
2000
g,
adm
itte
d be
twee
n 19
94 a
nd
1995
, and
fol
low
ed u
ntil
ho
spit
al d
isch
arge
or
the
deve
lopm
ent o
f N
EC
Sin
gle-
cent
er le
vel I
I an
d II
I N
ICU
at c
omm
unit
y-ba
sed
coun
ty h
ospi
tal (
Texa
s,
US
A)
N =
155
(n
= 7
2 ra
pid
grou
p,
n =
83
slow
gro
up)
To d
eter
min
e w
heth
er in
fant
s fe
d in
itia
lly
and
adva
nced
at 3
0 m
L/
kg/d
ach
ieve
ful
l ent
eral
nut
riti
on
soon
er th
an in
fant
s fe
d in
itia
lly
and
adva
nced
at 2
0 m
L/k
g/d
(goa
l 150
m
L/k
g/d)
Pri
mar
y ou
tcom
e: T
ime
to
achi
evem
ent o
f fu
ll e
nter
al
nutr
itio
nSe
cond
ary
outc
omes
: In
cide
nce
of
NE
C (
Bel
l’s s
tage
≥II
) an
d fe
edin
g co
mpl
icat
ions
, len
gth
of h
ospi
tal
stay
, dur
atio
n of
intr
aven
ous
flui
d,
wei
ght g
ain
Inci
denc
e of
NE
C:
4.2%
(3
/72)
in th
e ra
pid-
adva
ncem
ent g
roup
and
2.
4% (
2/83
) in
the
slow
-ad
vanc
emen
t gro
up; P
va
lue
not g
iven
3.2%
ove
rall
inci
denc
e of
N
EC
(R
R, 1
.73;
95%
C
I, 0
.30–
10.0
6; P
= .6
6)
for
infa
nts
enro
lled
in
stud
y; 4
.1%
in p
rete
rm
infa
nts
(100
0–20
00 g
) du
ring
the
sam
e pe
riod
no
t enr
olle
d in
the
stud
y
Adv
ance
men
t of
feed
s at
30
mL
/kg
/d is
as
safe
as
20 m
L/k
g/d
wit
h a
com
para
ble
inci
denc
e of
NE
C
betw
een
grou
ps.
No
info
rmat
ion
on m
orta
lity
rep
orte
dA
utho
rs r
ecom
men
d a
larg
e,
mul
tice
nter
pro
spec
tive
tria
l to
eval
uate
way
s of
opt
imiz
ing
ente
ral n
utri
tion
wit
hout
incr
easi
ng
mor
bidi
ty.
van
Elb
urg,
28
2004
RC
TN
onbl
inde
dR
ate
of a
ttri
tion
: 14
/56
Pre
term
infa
nts
<37
wee
ks
GA
wit
h B
W <
2000
g
and
BW
for
GA
<10
th
perc
enti
le (
IUG
R),
adm
itte
d fr
om 1
/199
8 to
11/
2000
, en
roll
ed w
ithi
n 48
hou
rs
of b
irth
and
fol
low
ed f
or
5 da
ys
Sin
gle-
cent
er N
ICU
in
tert
iary
car
e re
ferr
al c
ente
r (N
ethe
rlan
ds)
N =
56
(n =
28
ME
F g
roup
, n
= 2
8 N
PO
gro
up)
To e
valu
ate
the
effe
ct o
f M
EF
(12
×
0.5
mL
dai
ly if
BW
<10
00 g
or
12
× 1
mL
dai
ly if
BW
>10
00 g
) on
in
test
inal
per
mea
bili
ty a
nd f
eedi
ng
tole
ranc
e P
rim
ary
outc
ome:
Fun
ctio
nal
inte
grit
y of
the
smal
l bow
elSe
cond
ary
outc
omes
: F
eedi
ng
tole
ranc
e, g
row
th, a
nd in
cide
nce
of
NE
C (
Bel
l’s
stag
e ≥I
I)
Inci
denc
e of
NE
C:
0%
(0/2
0) in
the
ME
F a
nd
4.5%
(1/
22)
in th
e N
PO
gr
oup
(P =
.76)
ME
F o
f pr
eter
m in
fant
s w
ith
IUG
R
had
no e
ffec
t on
the
deve
lopm
ent
of N
EC
.N
o si
gnif
ican
t dif
fere
nce
in m
orta
lity
be
twee
n gr
oups
How
ever
, a la
rger
sam
ple
size
is
nee
ded
to d
raw
def
init
ive
conc
lusi
ons
on th
e ef
fect
of
ME
F
on m
easu
res
of c
lini
cal o
utco
me.
Sal
hotr
a,31
200
4R
CT
Non
blin
ded
Rat
e of
att
riti
on:
19/5
3
Infa
nts
wit
h B
W <
1250
g
subj
ect t
o ga
stro
inte
stin
al
prim
ing
(5 m
L/k
g/d)
via
in
term
itte
nt n
asog
astr
ic
tube
bol
us, o
n D
OL
1–
2, th
en r
ando
miz
ed a
t 48
hour
s of
life
Tert
iary
-lev
el te
achi
ng
hosp
ital
(In
dia)
N =
53
(n =
27
fast
gro
up, n
=
26 s
low
gro
up)
To e
valu
ate
the
tole
ranc
e of
rap
id (
30
mL
/kg/
d) v
s sl
ow (
15 m
L/k
g/d)
ad
vanc
emen
t of
ente
ral n
utri
tion
to
goal
of
180
mL
/kg/
dP
rim
ary
outc
ome:
Tim
e to
ach
ieve
fu
ll e
nter
al n
utri
tion
Seco
ndar
y ou
tcom
es:
Inci
denc
e of
N
EC
(B
ell’
s st
age
≥II)
and
apn
ea
Inci
denc
e of
NE
C:
7.4%
(2
/27)
in th
e ra
pid-
adva
ncem
ent g
roup
and
0%
(0/
26)
in th
e sl
ow-
adva
ncem
ent g
roup
; no
P v
alue
giv
enN
EC
-rel
ated
mor
tali
ty:
The
re w
ere
2 ca
ses
of
NE
C (
DO
L 6
and
8),
bo
th in
the
fast
gro
up,
and
thos
e in
fant
s di
ed w
ith
asso
ciat
ed
sept
icem
ia.
Sta
ble
VL
BW
infa
nts
appe
ar to
to
lera
te r
apid
adv
ance
men
ts
of e
nter
al n
utri
tion
wit
hout
an
incr
ease
d ri
sk o
f N
EC
.T
here
was
no
sign
ific
ant d
iffe
renc
e in
mor
tali
ty b
etw
een
grou
ps.
Of
note
, of
infa
nts
rand
omiz
ed to
th
e fa
st g
roup
, 74%
com
plet
ed th
e tr
ial v
s 53
.8%
in th
e sl
ow g
roup
.T
he s
mal
l sam
ple
size
pre
clud
es
any
firm
con
clus
ion
on th
e ri
sk o
f N
EC
.
Tab
le 2
. (co
ntin
ued)
(con
tinu
ed)
by guest on November 21, 2012pen.sagepub.comDownloaded from
513
Tab
le 2
. (co
ntin
ued)
Auth
or, Y
ear
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Ber
seth
,26 2
003
RC
TN
onbl
inde
dR
ate
of a
ttri
tion
: 3/
144
Infa
nts
<32
wee
ks a
ppro
pria
te
for
GA
, wit
h fe
eds
begu
n at
the
disc
reti
on o
f th
e ne
onat
olog
ist,
and
adm
itte
d be
twee
n 1/
1996
and
1/2
000
Sin
gle-
cent
er N
ICU
(Te
xas,
U
SA
)N
= 1
41 (
n =
70
adva
ncin
g gr
oup,
n =
71
cont
rol
grou
p)
To c
ompa
re th
e ri
sks
and
bene
fits
of
ent
eral
nut
riti
on a
dvan
cem
ent
(20
mL
/kg/
d to
goa
l 140
mL
/kg/
d)
com
pare
d w
ith
stab
le f
eedi
ng
volu
mes
(20
mL
/kg/
d) o
ver
a 10
-da
y pe
riod
Pri
mar
y ou
tcom
e: I
ncid
ence
of
NE
C
(Bel
l’s
stag
e ≥I
I)Se
cond
ary
outc
omes
: M
atur
atio
n of
inte
stin
al m
otor
pat
tern
s, ti
me
to r
each
ful
l ent
eral
nut
riti
on,
inci
denc
e of
late
sep
sis
Inci
denc
e of
NE
C:
10%
(7
/70)
in th
e ad
vanc
ing
grou
p an
d 1.
4% (
1/71
) in
the
cont
rol g
roup
(P
=
.03)
The
stu
dy w
as c
lose
d ea
rly
due
to th
e hi
gh
inci
denc
e of
NE
C in
the
adva
ncin
g gr
oup.
Hig
her
risk
for
NE
C in
pre
term
in
fant
s w
hen
fed
adva
ncin
g fe
edin
g vo
lum
es c
ompa
red
wit
h lo
w/s
tabl
e fe
edin
g vo
lum
es o
ver
a 10
-day
per
iod
Mor
tali
ty w
as s
imil
ar in
bot
h gr
oups
(4
.2%
vs
4.3%
, P =
.97)
.M
ean
age
of e
nter
al n
utri
tion
in
itia
tion
was
13
days
for
the
7 in
fant
s in
the
adva
ncin
g gr
oup
who
dev
elop
ed N
EC
. The
1
infa
nt in
the
cont
rol g
roup
who
de
velo
ped
NE
C w
as f
ed a
t age
4
days
. The
age
at f
eed
init
iati
on
was
onl
y gi
ven
for
infa
nts
who
de
velo
ped
NE
C.
Aut
hors
con
clud
e th
at m
inim
al
feed
ing
volu
mes
sho
uld
be
eval
uate
d un
til f
utur
e tr
ials
fur
ther
as
sess
the
safe
ty o
f ad
vanc
ing
feed
ing
volu
mes
.
BW, b
irth
wei
ght;
CI,
conf
iden
ce in
terv
al; D
OL,
day
of l
ife; E
LBW
, ext
rem
ely
low
birt
h w
eigh
t; G
A, g
esta
tiona
l age
; IU
GR,
intr
aute
rine
grow
th re
stric
tion;
MEF
, min
imal
ent
eral
feed
ing;
NEC
, nec
rotiz
ing
ente
roco
litis;
NIC
U, n
eona
tal i
nten
sive
care
uni
t; N
PO, n
il pe
r os;
RCT,
rand
omiz
ed co
ntro
lled
tria
l; RR
, rel
ativ
e ris
k; V
LBW
, ver
y lo
w b
irth
wei
ght.
Tab
le 3
. GR
AD
E T
able
Qu
esti
on 1
: W
hen
and
how
sho
uld
feed
s be
sta
rted
in in
fant
s at
hig
h ri
sk f
or N
EC
?
Com
paris
onO
utco
me
Qua
ntity
, Typ
e Ev
iden
ceFi
ndin
gsG
RAD
E of
Evi
denc
e fo
r O
utco
me
Ove
rall
Reco
mm
enda
tion
GRA
DE
Rap
id v
s sl
ow e
nter
al n
utri
tion
adv
ance
men
t29-3
1In
cide
nce
of N
EC
3 R
CTs
No
diff
eren
ceL
owW
eak
Ear
ly v
s de
laye
d m
inim
al e
nter
al f
eedi
ng25
Inci
denc
e of
NE
C1
RC
TN
o di
ffer
ence
Low
Wea
k
Min
imal
ent
eral
fee
ding
vs
nil p
er o
s27,2
8In
cide
nce
of N
EC
2 R
CTs
No
diff
eren
ceL
owW
eak
Adv
anci
ng v
s lo
w/s
tabl
e fe
edin
g vo
lum
e26In
cide
nce
of N
EC
1 R
CT
Hig
her
Low
Wea
k
NEC
, nec
rotiz
ing
ente
roco
litis;
RC
T, ra
ndom
ized
cont
rolle
d tr
ial.
by guest on November 21, 2012pen.sagepub.comDownloaded from
514
Tab
le 4
. Evi
den
ce T
able
Qu
esti
on 2
: D
oes
the
prov
isio
n of
mot
her’
s m
ilk
redu
ce th
e ri
sk o
f de
velo
ping
NE
C r
elat
ive
to b
ovin
e-ba
sed
prod
ucts
or
form
ula?
Auth
or, Y
ear
Stud
y D
esig
n, Q
ualit
yPo
pula
tion,
Set
ting,
NSt
udy
Obj
ectiv
eRe
sults
Com
men
ts
Sul
liva
n,32
20
10R
CT
Non
blin
ded
Rat
e of
att
riti
on: 3
1/20
7
Pre
mat
ure
infa
nts
wit
h B
W
500–
1250
g, f
ed H
M (
MM
an
d/or
DM
) w
ithi
n th
e fi
rst 2
1 da
ys a
fter
bir
th,
foll
owed
unt
il 9
1 da
ys o
ld,
hosp
ital
dis
char
ge, o
r th
e ac
hiev
emen
t of
50%
ora
l fe
eds
(goa
l 160
mL
/kg/
d)M
ulti
cent
er—
12 N
ICU
s (1
1 U
SA
; 1 A
ustr
ia)
Tota
l N =
207
(n
= 7
1, 4
0 m
L/k
g/d,
HM
40 g
roup
; (H
M40
mL
/kg/
d);
n =
67,
100
mL
/kg/
d,
HM
100
grou
p; (
HM
100
mL
/kg/
d); n
= 6
9, b
ovin
e m
ilk,
BO
V g
roup
)
To e
valu
ate
the
heal
th b
enef
its
of
an e
xclu
sive
ly H
M-b
ased
die
t (M
M a
nd/o
r D
M)
com
pare
d w
ith
a di
et o
f bo
th h
uman
and
B
OV
-bas
ed p
rodu
cts
Pri
mar
y ou
tcom
e:
PN
dur
atio
nSe
cond
ary
outc
omes
: In
cide
nce
of N
EC
(B
ell’
s st
age
≥II)
, lat
e-on
set s
epsi
s, g
row
th, m
orbi
dity
Inci
denc
e of
NE
C:
7% (
5/71
) in
the
HM
40 g
roup
, 4.5
% (
3/67
) in
the
HM
100
grou
p, a
nd 1
6% (
11/6
9) in
th
e B
OV
gro
up (
P =
.05
betw
een
3 gr
oups
)F
ewer
cas
es o
f N
EC
in th
e H
M40
an
d H
M10
0 gr
oups
, wit
h P
= .0
9 be
twee
n H
M40
and
BO
V g
roup
s,
P =
0.0
4 be
twee
n H
M10
0 an
d B
OV
, and
P =
.02
betw
een
HM
(4
0+10
0) a
nd B
OV
gro
ups
For
NE
C c
ases
req
uiri
ng s
urgi
cal
inte
rven
tion
, P =
.03
betw
een
the
HM
40 a
nd H
M10
0 gr
oups
in
depe
nden
tly
com
pare
d w
ith
the
BO
V g
roup
and
P =
.007
for
HM
(1
00+
40)
com
pare
d w
ith
the
BO
V
grou
pE
xclu
sive
HM
die
t (O
R 0
.23,
95%
C
I 0.
08-0
.66,
P=
0.00
7)
The
rat
es o
f N
EC
and
NE
C
requ
irin
g su
rger
y w
ere
mar
kedl
y lo
wer
in th
e gr
oups
fed
exc
lusi
vely
H
M (
MM
and
/or
DM
) co
mpa
red
wit
h B
OV
-ba
sed
prod
ucts
.50
% r
educ
tion
in th
e in
cide
nce
of N
EC
and
al
mos
t 90%
red
ucti
on in
th
e in
cide
nce
of s
urgi
cal
NE
C in
infa
nts
fed
excl
usiv
e H
M (
MM
and
/or
DM
) vs
BO
V-b
ased
pr
oduc
tsU
sing
exc
lusi
vely
HM
-bas
ed
diet
, NN
T to
pre
vent
1
case
of
NE
C is
10
and
to
prev
ent 1
cas
e of
sur
gica
l N
EC
or
deat
h is
8.
Sch
anle
r,34
2005
RC
TB
lind
ed to
gro
up
assi
gnm
ent
(car
egiv
ers)
Rat
e of
att
riti
on: 8
/243
Pre
mat
ure
infa
nts
<30
wee
ks
GA
, str
atif
ied
by G
A a
nd
rece
ipt o
f pr
enat
al s
tero
ids,
ad
mit
ted
betw
een
8/19
97
and
7/20
01, a
nd f
ollo
wed
fr
om b
irth
to 9
0 da
ys o
f ag
e or
hos
pita
l dis
char
geN
urse
ries
at T
exas
Chi
ldre
n’s
Hos
pita
l (Te
xas)
N =
243
(n
= 7
0 M
M o
nly,
n
= 8
1 D
M, n
= 9
2 P
F)
To d
eter
min
e th
e in
cide
nce
of N
EC
in
infa
nts
rece
ivin
g pa
steu
rize
d D
M v
s P
F a
s a
subs
titu
te f
or
MM
to a
chie
ve g
oal 1
60 m
L/
kg/d
Pri
mar
y ou
tcom
es:
Inci
denc
e of
NE
C (
Bel
l’s
stag
e ≥I
I) a
nd la
te-o
nset
sep
sis
Seco
ndar
y ou
tcom
es:
Dur
atio
n of
hos
pita
liza
tion
, gro
wth
, m
orta
lity
Inci
denc
e of
NE
C:
6% (
4/70
) in
the
MM
gro
up, 6
% (
5/78
) in
the
DM
gr
oup,
and
11%
(10
/88)
in th
e P
F
grou
p (P
= .3
9 be
twee
n M
M a
nd
DM
+P
F a
nd P
= .2
7 be
twee
n D
M
and
PF
)
As
a su
bsti
tute
for
MM
, pa
steu
rize
d D
M o
ffer
ed
no o
bser
ved
shor
t-te
rm
adva
ntag
e ov
er P
F f
or
feed
ing
prem
atur
e in
fant
s.T
here
was
no
sign
ific
ant
diff
eren
ce in
mor
tali
ty
betw
een
the
grou
ps.
Sis
k,35
200
7O
BS
Pro
spec
tive
coh
ort s
tudy
Rat
e of
att
riti
on: 3
/202
Ana
lysi
s of
cov
aria
nce
and
logi
stic
reg
ress
ion
anal
ysis
Infa
nts
wit
h B
W 7
00–1
500
g, b
orn
from
5/2
001
to
8/20
03, a
nd f
ollo
wed
du
ring
DO
L 1
–14.
Inf
ants
w
ere
star
ted
on P
N 1
–2
days
aft
er b
irth
if G
A <
30
wee
ks. G
oal f
eeds
wer
e 10
0–12
0 m
L/k
g/d.
To d
eter
min
e if
a h
igh
prop
orti
on
of M
M (
HM
M, ≥
50%
of
ente
ral
nutr
itio
n) p
rote
cts
agai
nst
the
deve
lopm
ent o
f N
EC
as
com
pare
d w
ith
a lo
w p
ropo
rtio
n of
MM
(L
MM
, <50
% o
f en
tera
l nu
trit
ion)
wit
hin
the
firs
t 14
days
of
life
Inci
denc
e of
NE
C:
3.2%
(5/
156)
in
the
HM
M g
roup
and
10.
6% (
5/46
) in
the
LM
M g
roup
(O
R, 0
.17;
95
% C
I, 0
.04–
0.68
; P =
.01
afte
r ad
just
men
t for
GA
) T
he o
vera
ll in
cide
nce
of N
EC
ne
gativ
ely
corr
elat
ed w
ith th
e pr
opor
tion
of M
M fe
d in
the
firs
t 14
day
s of
life
(OR
, 0.6
2; C
I,
0.51
–0.7
7; P
= .0
2) a
fter
adj
ustm
ent
for G
A.
Ent
eral
nut
riti
on c
onta
inin
g ≥5
0% M
M w
ithi
n th
e fi
rst 1
4 da
ys a
fter
bir
th
is a
ssoc
iate
d w
ith
a si
gnif
ican
t (6-
fold
) de
crea
sed
risk
of
NE
C.
No
diff
eren
ce in
the
inci
denc
e of
sur
gica
l NE
C
or m
orta
lity
bet
wee
n gr
oups
(con
tinu
ed)
by guest on November 21, 2012pen.sagepub.comDownloaded from
515
Auth
or, Y
ear
Stud
y D
esig
n, Q
ualit
yPo
pula
tion,
Set
ting,
NSt
udy
Obj
ectiv
eRe
sults
Com
men
ts
Stu
dy s
uppo
rted
by
Int
erna
tion
al
Lac
tati
on C
onsu
ltan
t A
ssoc
iati
on,
Uni
vers
ity
of
Nor
th C
arol
ina
(Gre
ensb
oro)
, an
d W
ake
For
est
Uni
vers
ity
Sch
ool o
f M
edic
ine
Lev
el I
II o
bste
tric
ref
erra
l ce
nter
for
wom
en (
Nor
th
Car
olin
a, U
SA
)N
= 2
02 (
n =
156
HM
M, n
=
46 L
MM
)
Pri
mar
y ou
tcom
e:
Inci
denc
e of
NE
C (
Bel
l’s
stag
e ≥I
I)
Seco
ndar
y ou
tcom
es:
Fee
ding
to
lera
nce,
late
-ons
et s
epsi
s,
chro
nic
lung
dis
ease
, ret
inop
athy
of
pre
mat
urit
y
For
eve
ry 2
5% in
crea
se in
MM
pr
opor
tion
, the
odd
s of
NE
C
decr
ease
d by
38%
.
Fur
man
,36
2003
OB
SP
rosp
ecti
ve
Rat
e of
att
riti
on: n
ot
spec
ifie
dR
egre
ssio
n an
alys
isS
uppo
rted
by
NIH
gr
ant M
0100
080
and
Uni
vers
ity
Hos
pita
ls
of C
leve
land
Ohi
o
Infa
nts
<33
wee
ks G
A w
ith
BW
600
–149
9 g,
adm
itte
d be
twee
n 1/
1997
and
2/
1999
, fol
low
ed th
roug
h w
eek
4 of
life
Urb
an te
rtia
ry c
are
NIC
U
(Ohi
o, U
SA
)N
= 1
19 (
n =
40
grou
p I:
P
F o
nly;
n =
29
grou
p II
: M
M 1
–24
mL
/kg/
d; n
= 1
8 G
roup
III
: MM
25–
49 m
L/
kg; n
= 3
2 gr
oup
IV: M
M
≥50
mL
/kg/
d)
To e
valu
ate
the
dose
eff
ect o
f M
M
com
pare
d w
ith
PF
on
neon
atal
m
orbi
dity
Pri
mar
y ou
tcom
e: N
eona
tal
mor
bidi
tySe
cond
ary
outc
omes
: In
cide
nce
of N
EC
(B
ell’
s st
age
≥II)
, se
psis
, len
gth
of h
ospi
tal s
tay
and
vent
ilat
or d
epen
denc
e,
reti
nopa
thy
of p
rem
atur
ity,
ch
roni
c lu
ng d
isea
se
Inci
denc
e of
NE
C:
8% (
3/40
) gr
oup
I (u
sed
as b
asis
of
com
pari
son
agai
nst g
roup
s II
–IV
), 7
% (
2/29
) gr
oup
II (
OR
, 1.1
5; 9
5% C
I,
0.8–
12.1
3), 1
1% (
2/18
) gr
oup
III
(OR
, 1.9
9; C
I, 0
.14–
21.0
3), 0
%
(0/3
2) g
roup
IV
0/3
2 (O
R, 0
; CI,
0–
3.56
)
The
am
ount
of
MM
ad
min
iste
red
does
not
af
fect
the
inci
denc
e of
N
EC
in V
LB
W in
fant
s.
Lam
bert
,33
2007
OB
SR
etro
spec
tive
R
ate
of a
ttri
tion
: 12/
30D
escr
ipti
ve s
tati
stic
s
Infa
nts
>36
wee
ks G
A, b
orn
from
2/2
001
to 6
/200
6In
term
ount
ain
Hea
lthc
are
NIC
Us
(Uta
h, U
SA
)N
= 5
877
(n =
30
wit
h N
EC
)
To d
eter
min
e po
ssib
le e
xpla
nati
ons
for
why
pat
ient
s de
velo
p N
EC
by
com
pari
son
to a
ge-m
atch
ed
pati
ents
wit
hout
NE
CP
rim
ary
outc
ome:
Inc
iden
ce o
f N
EC
(B
ell’
s st
age
≥II)
Seco
ndar
y ou
tcom
es:
Mor
bidi
ty,
feed
ing
tole
ranc
e, le
ngth
of
hosp
ital
sta
y
Inci
denc
e of
NE
C:
Ove
rall
inci
denc
e of
0.5
1% (
30/5
877)
Pat
ient
s w
ith
NE
C m
ore
like
ly
excl
usiv
ely
fed
wit
h P
F (
53%
, 16
/30)
or
PF
+M
M (
43%
, 13/
30)
vs e
xclu
sive
MM
(3%
, 1/3
0); n
o P
val
ueN
EC
-rel
ated
mor
tali
ty:
13%
m
orta
lity
in in
fant
s w
ith
NE
C
For
mul
a fe
edin
g co
mpa
red
wit
h ex
clus
ive
MM
fe
edin
g is
one
fac
tor
that
m
ay p
redi
spos
e in
fant
s to
th
e de
velo
pmen
t of
NE
C.
BOV,
bov
ine
milk
; BW
, birt
h w
eigh
t; C
I, co
nfid
ence
inte
rval
; DM
, don
or m
ilk; D
OL,
day
of l
ife; G
A, g
esta
tiona
l age
; HM
M, h
igh
mot
her’s
milk
; HM
, hum
an m
ilk; L
MM
, low
mot
her’s
milk
; MM
, m
othe
r’s m
ilk; N
EC, n
ecro
tizin
g en
tero
colit
is; N
ICU
, neo
nata
l int
ensiv
e ca
re u
nit;
NIH
, Nat
iona
l Ins
titut
es o
f Hea
lth; N
NT,
num
ber n
eede
d to
trea
t; O
BS, o
bser
vatio
nal s
tudy
; OR,
odd
s rat
io; P
F, pr
eter
m
form
ula;
PN
, par
ente
ral n
utrit
ion;
RC
T, ra
ndom
ized
cont
rolle
d tr
ial;
VLB
W, v
ery
low
birt
h w
eigh
t.
Tab
le 4
. (co
ntin
ued)
by guest on November 21, 2012pen.sagepub.comDownloaded from
516
Tab
le 5
. GR
AD
E T
able
Qu
esti
on 2
: D
oes
the
prov
isio
n of
mot
her’
s m
ilk
redu
ce th
e ri
sk o
f de
velo
ping
NE
C r
elat
ive
to b
ovin
e-ba
sed
prod
ucts
or
form
ula?
Com
paris
onO
utco
me
Qua
ntity
, Ty
pe
Evid
ence
Find
ings
GRA
DE
of E
vide
nce
for O
utco
me
Ove
rall
Reco
mm
enda
tion
GRA
DE
Hum
an m
ilk
(mot
her’
s or
don
or)
vs h
uman
mil
k (m
othe
r’s
or
dono
r) +
bov
ine-
base
d pr
oduc
ts32
Inci
denc
e of
NE
C1
RC
TL
ower
Low
Wea
k
Don
or m
ilk
vs p
rete
rm f
orm
ula34
Inci
denc
e of
NE
C1
RC
TN
o di
ffer
ence
Mod
erat
eW
eak
Mot
her’
s m
ilk
vs p
rete
rm f
orm
ula33
Inci
denc
e of
NE
C1
OB
SL
ower
Low
Wea
k
Mot
her’
s m
ilk
≥50%
vs
<50
% f
rom
day
s of
life
1–1
435In
cide
nce
of N
EC
1 O
BS
Low
erL
owW
eak
Mot
her’
s m
ilk
high
vs
low
dos
e (m
L/k
g/d)
36In
cide
nce
of N
EC
1 O
BS
No
diff
eren
ceL
owW
eak
NEC
, nec
rotiz
ing
ente
roco
litis;
OBS
, obs
erva
tiona
l stu
dy; R
CT,
rand
omiz
ed co
ntro
lled
tria
l.
Tab
le 6
. Evi
den
ce T
able
Qu
esti
on 3
: D
o pr
obio
tics
red
uce
the
risk
of
deve
lopi
ng N
EC
?
Auth
or,
Year
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Bra
ga,37
20
11R
CT
Dou
ble
blin
d R
ate
of a
ttri
tion
: 62
/243
Pre
term
infa
nts
wit
h B
W
750–
1499
g, w
ith
no c
onge
nita
l in
fect
ions
, fed
MM
or
DM
, and
ad
mit
ted
5/20
07 to
4/2
008
Ran
dom
ized
and
sta
rted
trea
tmen
t on
DO
L 2
, dur
atio
n of
tr
eatm
ent u
ntil
DO
L 3
0, N
EC
di
agno
sis,
hos
pita
l dis
char
ge,
or d
eath
Sin
gle-
cent
er N
ICU
(B
razi
l)N
= 2
31 (
n =
119
, pro
biot
ic
grou
p; n
= 1
12, c
ontr
ol g
roup
)
To a
sses
s w
heth
er o
ral
supp
lem
enta
tion
of
Lac
toba
cill
us
case
i and
Bif
idob
acte
rium
bre
ve
prev
ents
the
occu
rren
ce o
f N
EC
P
rim
ary
outc
ome:
NE
C (
Bel
l’s
stag
e ≥I
I)
Inci
denc
e of
NE
C:
0% (
0/11
9) in
th
e pr
obio
tic
grou
p an
d 3.
6%
(4/1
12)
in th
e co
ntro
l gro
up (
P
= .0
5)
Pro
biot
ic u
se d
ecre
ased
the
inci
denc
e of
NE
C.
No
diff
eren
ce in
mor
tali
ty b
etw
een
grou
psIn
fant
s in
the
prob
iotic
gro
up
reac
hed
full
ente
ral n
utri
tion
fast
er
than
the
cont
rol g
roup
(P =
.02)
, su
gges
ting
that
pro
biot
ics
may
pl
ay a
role
in in
test
inal
mot
ility
.T
he s
tudy
was
inte
rrup
ted
by a
n ex
tern
al c
omm
itte
e af
ter
1 ye
ar,
due
to th
e si
gnif
ican
t dif
fere
nces
fo
und
betw
een
grou
ps.
Aw
ad,38
20
10R
CT
Pla
cebo
con
trol
Dou
ble
blin
dR
ate
of a
ttri
tion
: 25
/150
Neo
nate
s 28
–41
wee
ks G
A w
ith
BW
110
0–43
00 g
, with
nor
mal
C
-rea
ctiv
e pr
otei
n an
d ne
gativ
e bl
ood
cultu
res,
adm
itted
fro
m
1/20
06 to
5/2
007
on D
OL
1 a
nd
follo
wed
unt
il ho
spita
l dis
char
geS
ingl
e-ce
nter
NIC
U (
Egy
pt)
N =
150
(n
= 6
0 L
P, n
= 6
0 K
P, n
=
30
plac
ebo)
To e
valu
ate
the
use
of th
e pr
obio
tic
Lac
toba
cill
us a
cido
phil
us in
the
prev
enti
on o
f ne
onat
al s
epsi
s an
d N
EC
and
to f
urth
er in
vest
igat
e di
ffer
ence
s be
twee
n L
P an
d K
P in
co
mpa
riso
n to
pla
cebo
Pri
mar
y ou
tcom
es:
NE
C (
Bel
l’s
stag
e ≥I
I), s
epsi
s
Inci
denc
e of
NE
C:
1.7%
(1/
60)
in th
e L
P gr
oup,
1.7
%
(1/6
0) in
the
KP
grou
p, a
nd
16.7
% (
5/30
) in
the
plac
ebo
grou
p; P
val
ue n
ot p
rovi
ded
LP
grou
p (O
R 0
.53,
95%
CI 0
.16-
1.74
), K
P gr
oup
(OR
0.0
85; 9
5%
CI 0
.009
-0.7
6), a
nd p
lace
bo g
roup
(O
R 3
.4, 9
5% C
I 2.4
4-4.
72)
Dec
reas
ed in
cide
nce
of N
EC
in
infa
nts
who
rec
eive
d pr
obio
tics
vs
pla
cebo
. How
ever
, the
re w
as
no d
iffe
renc
e in
the
inci
denc
e of
N
EC
bet
wee
n L
P an
d K
P gr
oups
.L
P an
d K
P w
ere
prev
enta
tive
ag
ains
t NE
C, w
here
as p
lace
bo
was
a r
isk
fact
or f
or th
e de
velo
pmen
t of
NE
C. (c
onti
nued
)
by guest on November 21, 2012pen.sagepub.comDownloaded from
517
Auth
or,
Year
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Mih
atsc
h,43
20
10R
CT
Dou
ble-
blin
ded
Pla
cebo
con
trol
led
Rat
e of
att
riti
on:
20/1
83In
tent
ion-
to-t
reat
an
alys
is
VL
BW
infa
nts
<30
wee
ks G
A
wit
h B
W <
1500
g, f
ed P
F
or M
M, a
dmit
ted
5/20
00 to
8/
2003
Sin
gle-
cent
er N
ICU
, Chi
ldre
n’s
Hos
pita
l (G
erm
any)
N =
180
(n
= 9
1 pr
obio
tic
grou
p,
n =
89
cont
rol g
roup
)
To in
vest
igat
e w
heth
er
supp
lem
enta
tion
wit
h th
e pr
obio
tic
Bif
idob
acte
rium
lact
is f
or a
du
rati
on o
f 6
wee
ks r
educ
es th
e in
cide
nce
of n
osoc
omia
l inf
ecti
on
Pri
mar
y ou
tcom
e: N
osoc
omia
l in
fect
ion
Seco
ndar
y ou
tcom
e: N
EC
(B
ell’
s st
age
≥II)
Inci
denc
e of
NE
C:
2.2%
(2/
91)
in
the
prob
ioti
c gr
oup
and
4.5%
(4
/89)
in th
e co
ntro
l gro
up (
P
= N
SN
EC
-rel
ated
mor
tali
ty:
1.1%
(1
/91)
in th
e pr
obio
tic
grou
p an
d 0%
(0/
89)
in th
e co
ntro
l gro
up,
P =
NS
No
sign
ific
ant e
ffec
t of
B la
ctis
on
the
inci
denc
e of
NE
C
The
se s
tudy
res
ults
em
phas
ize
the
impo
rtan
ce o
f an
ade
quat
ely
pow
ered
tria
l to
eval
uate
NE
C a
s th
e pr
imar
y ou
tcom
e.
Sam
anta
,40
2009
RC
TD
oubl
e-bl
inde
dR
ate
of a
ttri
tion
: 18
/186
VL
BW
infa
nts
<32
wee
ks G
A
wit
h B
W <
1500
g, h
avin
g su
rviv
ed b
eyon
d D
OL
2, f
ed
excl
usiv
ely
MM
, and
adm
itte
d be
twee
n 10
/200
7 an
d 3/
2008
Sin
gle-
cent
er N
ICU
(In
dia)
N =
186
(n
= 9
1 pr
obio
tic
grou
p,
n =
95
cont
rol g
roup
)
To e
valu
ate
the
effe
ct o
f pr
obio
tics
(m
ixtu
re o
f B
ifid
obac
teri
a bi
fidu
m,
Bif
idob
acte
ria
infa
ntis
, Bif
idob
ac-
teri
a lo
ngum
, and
Lac
toba
cill
us
acid
ophi
lus)
on
feed
ing
tole
ranc
e,
the
inci
denc
e/se
veri
ty o
f N
EC
(B
ell’
s st
age
≥II)
, and
mor
tali
ty
rela
ted
to N
EC
or
seps
isP
rim
ary
outc
omes
: F
eedi
ng
tole
ranc
e, le
ngth
of
hosp
ital
izat
ion,
m
orbi
diti
es (
NE
C, s
epsi
s, a
nd/o
r de
ath
due
to N
EC
or
seps
is)
NE
C in
cide
nce:
5.5
% (5
/91)
in th
e pr
obio
tic g
roup
and
15.
8% (1
5/95
) in
the
cont
rol g
roup
(P =
.042
)T
he s
ever
ity
of N
EC
was
sim
ilar
in
both
gro
ups
(P =
.62)
.M
orta
lity
due
to N
EC
or
seps
is
was
low
er in
the
prob
ioti
cs
grou
p co
mpa
red
wit
h th
e co
ntro
l gro
up (
4.4%
vs
14.7
%,
resp
ecti
vely
; P =
.032
).
Pro
biot
ics
give
n to
VL
BW
infa
nts
redu
ce th
e in
cide
nce
of N
EC
.
Lin
,39 2
008
RC
TIn
vest
igat
ors
at e
ach
cent
er a
nd th
e br
east
mil
k te
am
not b
lind
ed b
ut
wer
e no
t inv
olve
d in
the
care
of
the
stud
y in
fant
sM
ulti
cent
er
Rat
e of
att
riti
on:
20/4
43
Infa
nts
<34
wee
ks G
A w
ith
BW
<15
00 g
, fed
MM
or
PF,
ad
mit
ted
betw
een
4/20
05 a
nd
5/20
07S
even
leve
l III
NIC
Us
(Tai
wan
)N
= 4
34 (
n =
217
pro
biot
ic g
roup
, n
= 2
17 c
ontr
ol g
roup
)
To in
vest
igat
e th
e ef
fica
cy o
f or
al
prob
ioti
cs, B
ifid
obac
teri
um
bifi
dum
and
Lac
toba
cill
us
acid
ophi
lus
(Inf
lora
n); 1
25 m
g/kg
/do
se tw
ice
dail
y fo
r 6
wee
ks in
the
prev
enti
on o
f N
EC
P
rim
ary
outc
omes
: N
EC
(B
ell’
s st
age
≥II)
and
dea
thSe
cond
ary
outc
omes
: C
ultu
re-p
rove
n se
psis
wit
hout
NE
C, c
hron
ic
lung
dis
ease
, per
iven
tric
ular
le
ukom
alac
ia, i
ntra
vent
ricu
lar
hem
orrh
age,
fee
ding
am
ount
and
w
eigh
t gai
n pe
r w
eek,
day
s to
ful
l en
tera
l nut
riti
on
Inci
denc
e of
NE
C:
1.8%
(4/
217)
in
the
prob
ioti
c gr
oup
and
6.5%
(1
4/21
7) in
the
cont
rol g
roup
(P
=
.02)
NE
C-r
elat
ed m
orta
lity
: 0.
9%
(2/2
17)
in th
e pr
obio
tic
grou
p an
d 1.
4% (
3/21
7) in
the
cont
rol
grou
p (P
= .9
8)
The
adm
inis
trat
ion
of p
robi
otic
s to
pr
eter
m V
LB
W in
fant
s re
duce
d th
e in
cide
nce
of N
EC
but
did
not
af
fect
NE
C-r
elat
ed m
orta
lity
.B
ased
on
stud
y re
sult
s, N
NT
to
prev
ent 1
cas
e of
NE
C w
as 2
0 pa
tien
ts.
Tab
le 6
. (co
ntin
ued)
(con
tinu
ed)
by guest on November 21, 2012pen.sagepub.comDownloaded from
518
Auth
or,
Year
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Bin
-Nun
,41
2005
RC
TD
oubl
e-bl
ind
Pla
cebo
-con
trol
led
Rat
e of
att
riti
on:
11/1
45In
tent
ion-
to-t
reat
an
alys
is
Pre
term
neo
nate
s w
eigh
ing
≤150
0 g,
rec
ruit
ed a
nd e
nrol
led
whe
n en
tera
l nut
riti
on (
MM
or
PF
) be
gan,
adm
itte
d fr
om 9
/200
1 to
9/
2004
and
fol
low
ed u
ntil
36
wee
ks p
ost-
conc
eptu
al a
geS
ingl
e-ce
nter
NIC
U (
Isra
el)
N =
145
(n
= 7
2 pr
obio
tic
grou
p,
n =
73
cont
rol g
roup
)
To in
vest
igat
e w
heth
er th
e da
ily
prov
isio
n of
pro
phyl
acti
c pr
obio
tics
(m
ixtu
re o
f B
ifid
obac
teri
a in
fant
is,
Stre
ptoc
occu
s th
erm
ophi
lus,
and
B
ifid
obac
teri
a bi
fidu
s) d
ecre
ases
th
e in
cide
nce
and
seve
rity
of
NE
C
Pri
mar
y ou
tcom
e: N
EC
(B
ell’
s st
age
≥II)
Seco
ndar
y ou
tcom
es:
Fee
ding
to
lera
nce,
mor
tali
ty, m
orta
lity
re
late
d to
NE
C
Inci
denc
e of
NE
C (
all s
tage
s):
4%
(3/7
2) in
the
prob
ioti
c gr
oup
and
16.4
% (
12/7
3) in
the
cont
rol
grou
p (R
R, 0
.25;
95%
CI,
0.
075–
0.86
)In
cide
nce
of N
EC
(B
ell’s
sta
ge
≥II)
: 1%
(1/
72)
in th
e pr
obio
tic
grou
p an
d 14
% (
10/7
3) in
co
ntro
l gro
up (
P =
.013
) N
EC
-rel
ated
mor
tali
ty:
0% (
0/3)
in
the
prob
ioti
c gr
oup
and
25%
(3
/12)
in th
e co
ntro
l gro
up (
P
= .8
7)
Pro
biot
ic s
uppl
emen
tati
on r
educ
es
the
inci
denc
e an
d se
veri
ty o
f N
EC
in p
rete
rm V
LB
W in
fant
s.
Lin
,42 2
005
RC
TIn
vest
igat
ors
and
brea
st m
ilk
team
no
t bli
nded
but
w
ere
not i
nvol
ved
in th
e ca
re o
f th
e st
udy
infa
nts
Rat
e of
att
riti
on:
27/3
67L
ogis
tic
regr
essi
on
anal
ysis
Infa
nts
<34
wee
ks G
A a
nd B
W
<15
00 g
, sur
vive
d pa
st D
OL
7,
fed
MM
or
DM
, adm
itte
d fr
om 7
/199
9 to
12/
2003
, an
d fo
llow
ed u
ntil
hos
pita
l di
scha
rge
Sin
gle-
cent
er, l
evel
III
NIC
U
(Tai
wan
)N
= 3
67 (
n =
180
pro
biot
ic g
roup
, n
= 1
87 c
ontr
ol g
roup
)
To e
valu
ate
the
effe
ct o
f th
e pr
obio
tics
Lac
toba
cill
us
acid
ophi
lus
and
Bif
idob
acte
rium
in
fant
is (
Infl
oran
); 1
25 m
g/kg
/dos
e tw
ice
dail
y on
the
inci
denc
e an
d se
veri
ty o
f N
EC
Pri
mar
y ou
tcom
es:
NE
C (
Bel
l’s
stag
e ≥I
I) a
nd d
eath
Seco
ndar
y ou
tcom
e: S
epsi
s
Inci
denc
e of
NE
C:
1.1%
(2/
180)
in
the
prob
ioti
c gr
oup
and
5.3%
(1
0/18
7) in
the
cont
rol g
roup
(P
=
.04)
Inci
denc
e of
NE
C (
Bel
l’s s
tage
III
):
0% (
0/2)
in th
e pr
obio
tic
grou
p an
d 60
% (
6/10
) in
the
cont
rol
grou
p (P
= .0
3)
The
adm
inis
trat
ion
of p
robi
otic
s to
pr
eter
m V
LB
W in
fant
s re
duce
s th
e in
cide
nce
and
seve
rity
of
NE
C.
Sig
nifi
cant
dif
fere
nce
in m
orta
lity
be
twee
n th
e pr
obio
tic
and
cont
rol
grou
ps (
3.9%
vs
10.7
%; P
=
.009
)N
NT
to p
reve
nt 1
cas
e of
NE
C is
27
.
BW, b
irth
wei
ght;
CI,
conf
iden
ce in
terv
al; D
M, d
onor
milk
; DO
L, d
ay o
f life
; GA
, ges
tatio
nal a
ge; K
P, k
illed
pro
biot
ic; L
P, li
ve p
robi
otic
; MM
, mot
her’s
milk
; NEC
, nec
rotiz
ing
ente
roco
litis;
NIC
U, n
eona
tal i
nten
-siv
e ca
re u
nit;
NN
T, n
umbe
r nee
ded
to tr
eat;
NS,
not
sign
ifica
nt; O
R, o
dds r
atio
; PF,
pret
erm
form
ula;
RC
T, ra
ndom
ized
cont
rolle
d tr
ial;
RR, r
elat
ive
risk;
VLB
W, v
ery
low
birt
h w
eigh
t.
Tab
le 6
. (co
ntin
ued)
Tab
le 7
. GR
AD
E T
able
Qu
esti
on 3
: D
o pr
obio
tics
red
uce
the
risk
of
deve
lopi
ng N
EC
?
Com
paris
onO
utco
me
Qua
ntity
, Ty
pe E
vide
nce
Find
ings
GRA
DE
of E
vide
nce
for
Out
com
eO
vera
ll Re
com
men
datio
n G
RAD
E
Pro
biot
ic +
hum
an m
ilk
vs h
uman
mil
k37,4
2In
cide
nce
of N
EC
2 R
CTs
Low
erH
igh
Str
ong
Pro
biot
ic +
mot
her’
s m
ilk
vs m
othe
r’s
mil
k40In
cide
nce
of N
EC
1 R
CT
Low
erH
igh
Str
ong
Pro
biot
ic +
mot
her’
s m
ilk
or f
orm
ula
vs
mot
her’
s m
ilk
or f
orm
ula39
,41,
43In
cide
nce
of N
EC
2 R
CTs
1 R
CT
Low
erN
o di
ffer
ence
Mod
erat
eS
tron
g
Pro
biot
ic v
s pl
aceb
o38In
cide
nce
of N
EC
1 R
CT
Low
erM
oder
ate
Str
ong
NEC
, nec
rotiz
ing
ente
roco
litis;
RC
T, ra
ndom
ized
cont
rolle
d tr
ial.
by guest on November 21, 2012pen.sagepub.comDownloaded from
519
Tab
le 8
. Evi
den
ce T
able
Qu
esti
on 4
: D
o ce
rtai
n nu
trie
nts
eith
er p
reve
nt o
r pr
edis
pose
to th
e de
velo
pmen
t of
NE
C?
Auth
or, Y
ear
Stud
y D
esig
n,
Qua
lity
Popu
latio
n, S
ettin
g, N
Stud
y O
bjec
tive
Resu
ltsC
omm
ents
Poi
ndex
ter,46
20
04R
CT
Dou
ble-
blin
dR
ate
of
attr
itio
n:
251/
1432
EL
BW
infa
nts
401–
1000
g,
stra
tifi
ed b
y B
W (
401–
750
g an
d 75
1–10
00 g
), a
dmit
ted
betw
een
10/1
999
and
8/20
01, f
ollo
wed
un
til a
ge 1
20 d
ays,
dea
th, o
r ho
spit
al d
isch
arge
Mul
tice
nter
: 15
cent
ers
of th
e N
ICH
D N
eona
tal R
esea
rch
Net
wor
k (U
SA
)N
= 1
433
(n =
721
glu
tam
ine
supp
lem
enta
tion
gro
up, n
= 7
12
cont
rol g
roup
)
To e
valu
ate
whe
ther
su
pple
men
tati
on o
f P
N w
ith
20%
gl
utam
ine
decr
ease
s m
orta
lity
or
late
-ons
et s
epsi
s co
mpa
red
wit
h ad
min
istr
atio
n of
a s
tand
ard
neon
atal
am
ino
acid
inje
ctio
n (T
roph
Am
ine)
Pri
mar
y ou
tcom
es:
Dea
th, l
ate-
onse
t sep
sis
Seco
ndar
y ou
tcom
es:
NE
C,
num
ber
of e
piso
des
of la
te-o
nset
se
psis
, ven
tila
tor
days
, ent
eral
nu
trit
ion
tole
ranc
e, P
N d
urat
ion,
gr
owth
Inci
denc
e of
NE
C: 1
0% (6
9/72
1)
in th
e gl
utam
ine
grou
p an
d 10
%
(68/
712)
in th
e co
ntro
l gro
up (R
R,
0.99
; 95%
CI,
0.71
–1.4
0; P
= .9
9)W
hen
stra
tifi
ed b
y B
W (
401–
750
g an
d 75
1–10
00 g
), th
ere
was
no
sig
nifi
cant
dif
fere
nce
in
NE
C in
cide
nce
(P =
.20
and
.24,
re
spec
tive
ly).
Inci
denc
e of
sur
gica
l NE
C:
57%
(3
9/69
) in
the
glut
amin
e gr
oup
and
49%
(33
/68)
in th
e co
ntro
l gr
oup
(RR
, 1.1
4; 9
5% C
I,
0.90
–1.4
4; P
= .1
9)
Alt
houg
h pa
rent
eral
glu
tam
ine
supp
lem
enta
tion
see
ms
to
be w
ell t
oler
ated
in E
LB
W
infa
nts,
its
rout
ine
use
cann
ot b
e re
com
men
ded
give
n th
e la
ck o
f cl
inic
al e
ffic
acy.
Few
trel
l,48
2002
RC
T
Dou
ble-
blin
dR
ate
of
attr
itio
n:
43/2
83
Pre
term
infa
nts
<37
wee
ks G
A
wit
h B
W <
1750
g, t
oler
atin
g en
tera
l nut
riti
on b
y 10
day
s of
ag
e, f
ollo
wed
for
an
aver
age
of
32 d
ays
3 N
ICU
s (U
nite
d K
ingd
om)
N =
283
(n
= 1
00 P
F w
itho
ut
LC
PU
FA, n
= 9
5 P
F+
LC
PU
FA,
n =
88
MM
)
To e
valu
ate
the
effe
ct o
f L
CP
UFA
su
pple
men
tati
on in
PF
com
pare
d w
ith
nons
uppl
emen
ted
PF
an
d M
M o
n su
bseq
uent
ne
urod
evel
opm
enta
l out
com
eP
rim
ary
outc
omes
: B
ayle
y M
DI
and
PD
I at
age
18
mon
ths
Seco
ndar
y ou
tcom
es:
Neu
rode
velo
pmen
t (9
mon
ths)
, ne
urol
ogic
impa
irm
ent a
nd
anth
ropo
met
ry m
easu
rem
ents
(9
and
18
mon
ths)
, ent
eral
to
lera
nce,
infe
ctio
n, N
EC
, dea
th
Inci
denc
e of
NE
C:
3.6%
(7/
195)
in
the
PF
gro
up o
vera
ll a
nd 0
%
(0/8
8) in
the
MM
gro
up (
P =
.10)
2%
(2/
100)
in P
F w
itho
ut L
CP
UFA
an
d 5.
3% (
5/95
) in
PF
+L
CP
UFA
(P
= .1
1)T
hese
num
bers
incl
ude
2 in
fant
s w
ho re
ceiv
ed <
20 m
L L
CPU
FA-
supp
lem
ente
d fo
rmul
a an
d 1
infa
nt
who
had
no
cons
umpt
ion
of th
e co
ntro
l for
mul
a pr
ior t
o th
e N
EC
.In
cide
nce
of s
urgi
cal N
EC
: 0%
(0
/100
) in
PF
wit
hout
LC
PU
FA,
2.1%
(2/
95)
in P
F+
LC
PU
FA,
and
0% (
0/81
) in
the
MM
gro
up
(no
P v
alue
giv
en)
Incr
ease
d in
cide
nce
of N
EC
in
infa
nts
who
rec
eive
d P
F+
LC
PU
FA
supp
lem
enta
tion
, alt
houg
h th
e di
ffer
ence
bet
wee
n gr
oups
was
not
st
atis
tica
lly
sign
ific
ant
The
se f
indi
ngs
emph
asiz
e th
e ne
ed
for
addi
tion
al in
vest
igat
ion
to
eval
uate
the
effi
cacy
and
saf
ety
of L
CP
UFA
sup
plem
enta
tion
of
form
ula
for
pret
erm
infa
nts.
Am
in,45
200
2R
CT
Dou
ble-
blin
ded
Pla
cebo
-co
ntro
lled
Rat
e of
at
trit
ion:
5/
152
Pre
mat
ure
infa
nts
≤32
wee
ks G
A
wit
h B
W ≤
1250
g, a
dmit
ted
from
3/1
997
to 7
/199
9, tr
eatm
ent
dura
tion
day
s 1–
28 o
f li
fe,
mai
ntai
ned
on o
ral f
eeds
or
PN
Sin
gle-
cent
er N
ICU
(C
anad
a)N
= 1
52 (
n =
75
L-a
rgin
ine
grou
p,
n =
77
plac
ebo
grou
p)
To d
eter
min
e w
heth
er
supp
lem
enta
tion
wit
h
L-a
rgin
ine
(1.5
mm
ol/k
g/d)
re
duce
s th
e in
cide
nce
of N
EC
P
rim
ary
outc
ome:
NE
C, a
ll s
tage
sSe
cond
ary
outc
omes
: Mor
tali
ty,
feed
ing
tole
ranc
e, n
utri
ent
inta
ke, p
lasm
a am
mon
ia,
argi
nine
, glu
tam
ine,
am
ino
acid
co
ncen
trat
ions
Inci
denc
e of
NE
C (
over
all)
: 6.
7%
(5/7
5) in
the
L-a
rgin
ine
grou
p an
d 27
.3%
(21
/77)
in th
e pl
aceb
o gr
oup
(P <
.001
)In
cide
nce
of N
EC
(B
ell’s
sta
ge
II):
6.7
% (
5/75
) in
fant
s in
the
L-a
rgin
ine
grou
p co
mpa
red
wit
h 16
.9%
(13
/77)
of
infa
nts
in th
e co
ntro
l gro
up (
P =
.077
)N
one
of th
e in
fant
s de
velo
ped
Bel
l’s
stag
e II
I N
EC
req
uiri
ng
oper
ativ
e in
terv
enti
on.
Pro
phyl
acti
c ad
min
istr
atio
n of
ar
gini
ne a
ppea
rs to
be
effe
ctiv
e in
red
ucin
g th
e ov
eral
l inc
iden
ce
of N
EC
in p
rete
rm in
fant
s,
alth
ough
ther
e w
as n
o st
atis
tica
lly
sign
ific
ant d
iffe
renc
e in
the
inci
denc
e of
Bel
l’s
stag
e II
NE
C.
BW, b
irth
wei
ght;
CI,
conf
iden
ce in
terv
al; E
LBW
, ext
rem
ely
low
birt
h w
eigh
t; G
A, g
esta
tiona
l age
; IV,
intr
aven
ous;
LCPU
FA, l
ong-
chai
n po
lyun
satu
rate
d fa
tty a
cid;
MD
I, m
enta
l dev
elop
men
tal i
ndex
; M
M, m
othe
r’s m
ilk; N
EC, n
ecro
tizin
g en
tero
colit
is; N
ICH
D, N
atio
nal I
nstit
ute
of C
hild
Hea
lth &
Hum
an D
evel
opm
ent;
NIC
U, n
eona
tal i
nten
sive
care
uni
t; PD
I, ps
ycho
mot
or d
evel
opm
enta
l ind
ex; P
F, pr
eter
m fo
rmul
a; P
N, p
aren
tera
l nut
ritio
n; R
CT,
rand
omiz
ed co
ntro
lled
tria
l; RR
, rel
ativ
e ris
k.
by guest on November 21, 2012pen.sagepub.comDownloaded from
520
Tab
le 9
. GR
AD
E T
able
Qu
esti
on 4
: D
o ce
rtai
n nu
trie
nts
eith
er p
reve
nt o
r pr
edis
pose
to th
e de
velo
pmen
t of
NE
C?
Com
paris
onO
utco
me
Qua
ntity
, Typ
e
Evid
ence
Find
ings
GRA
DE
of E
vide
nce
for O
utco
me
Ove
rall
Reco
mm
enda
tion
GRA
DE
L-a
rgin
ine
supp
lem
enta
tion
vs
no
supp
lem
enta
tion
45In
cide
nce
of N
EC
1 R
CT
Low
erM
oder
ate
Fur
ther
res
earc
h ne
eded
Glu
tam
ine
vs n
o gl
utam
ine
supp
lem
enta
tion
46In
cide
nce
of N
EC
1 R
CT
No
diff
eren
ceM
oder
ate
Str
ong
Lon
g-ch
ain
poly
unsa
tura
ted
fatt
y ac
id
supp
lem
enta
tion
vs
no s
uppl
emen
tati
on48
Inci
denc
e of
NE
C1
RC
TN
o di
ffer
ence
Low
Fur
ther
res
earc
h ne
eded
NEC
, nec
rotiz
ing
ente
roco
litis;
RC
T, ra
ndom
ized
cont
rolle
d tr
ial.
Tab
le 1
0. E
vide
nce
Tabl
e Q
uest
ion
5: W
hen
shou
ld f
eeds
be
rein
trod
uced
to in
fant
s w
ith
NE
C?
Aut
hor,
Yea
rS
tudy
Des
ign,
Qua
lity
Pop
ulat
ion,
Set
ting
, NS
tudy
Obj
ecti
veR
esul
tsC
omm
ents
Bro
tsch
i,49
2009
OB
S
Ret
rosp
ecti
ve
No
attr
itio
n
No
fina
ncia
l di
sclo
sure
s
All
term
and
pre
term
infa
nts
wit
h N
EC
(B
ell’
s st
age
II)
adm
itte
d be
twee
n 1/
2000
an
d 12
/200
6
Mul
tice
nter
stu
dy a
t 5
NIC
Us
in te
rtia
ry c
are
cent
ers
(Sw
itze
rlan
d)
N =
47
(n =
30
in ≤
5-da
y gr
oup,
n =
17
in >
5-da
y gr
oup)
To c
ompa
re th
e ef
fect
of
fast
ing
peri
od d
urat
ion
(≤5
days
vs
>5
days
) on
the
com
plic
atio
n ra
tes
in in
fant
s w
ith
NE
C m
anag
ed
cons
erva
tive
ly
Pri
mar
y en
d po
ints
: B
owel
str
ictu
re,
NE
C r
elap
se, c
athe
ter-
rela
ted
seps
is
64%
(30
/47)
of
infa
nts
fast
ed f
or
≤5 d
ays
(ran
ge, 1
–5)
and
36%
(1
7/47
) fa
sted
for
>5
days
(r
ange
, 6–1
6).
NE
C r
elap
se:
3.3%
(1/
30)
in
the
≤5-d
ay g
roup
and
11.
8%
(2/1
7) in
the
>5-
day
grou
p (P
=
.27)
Low
er in
cide
nce
of e
arly
pos
t-N
EC
str
ictu
re (
1/30
vs
4/17
, P
= .0
5) a
nd c
athe
ter-
rela
ted
seps
is (
0/30
vs
5/17
, P =
.004
) in
the
≤5-d
ay g
roup
Fin
ding
s su
gges
t tha
t ear
ly
ente
ral n
utri
tion
aft
er
cons
erva
tive
ly m
anag
ed
NE
C m
ay lo
wer
mor
bidi
ty
afte
r th
e ac
ute
phas
e of
the
dise
ase.
Infa
nts
who
fas
ted
for
a sh
orte
r du
rati
on h
ad
a si
gnif
ican
tly
low
er
inci
denc
e of
cat
hete
r-re
late
d se
psis
.
Und
erpo
wer
ed s
tudy
fo
r de
tect
ing
pote
ntia
l di
ffer
ence
s in
the
inci
denc
e of
NE
C r
elap
se
(con
tinu
ed)
by guest on November 21, 2012pen.sagepub.comDownloaded from
521
Tab
le 1
1. G
RA
DE
Tab
le Q
ues
tion
5:
Whe
n sh
ould
fee
ds b
e re
intr
oduc
ed to
infa
nts
wit
h N
EC
?
Com
paris
onO
utco
me
Qua
ntity
, Typ
e
Evid
ence
Find
ings
GRA
DE
of
Evid
ence
for O
utco
me
Ove
rall
Re
com
men
datio
n
GRA
DE
Ear
ly v
s la
te in
trod
ucti
on
of e
nter
al n
utri
tion
aft
er
NE
C (
Bel
l’s
stag
e II
)49,5
0
NE
C r
elap
se
Cen
tral
acc
ess
dura
tion
Cat
hete
r-re
late
d se
psis
Pos
t-N
EC
str
ictu
re
Dur
atio
n ho
spit
al s
tay
2 O
BS
No
diff
eren
ce
Low
er
Low
er
Low
er
Low
er
Low
Low
Low
Low
Low
Fur
ther
res
earc
h ne
eded
Fur
ther
res
earc
h ne
eded
Fur
ther
res
earc
h ne
eded
Fur
ther
res
earc
h ne
eded
Fur
ther
res
earc
h ne
eded
NE
C, n
ecro
tizi
ng e
nter
ocol
itis
; OB
S, o
bser
vati
onal
stu
dy.
Aut
hor,
Yea
rS
tudy
Des
ign,
Qua
lity
Pop
ulat
ion,
Set
ting
, NS
tudy
Obj
ecti
veR
esul
tsC
omm
ents
Boh
nhor
st,50
20
03O
BS
Ret
rosp
ecti
ve
Com
pari
son
to
hist
oric
al c
ontr
ol
grou
p of
infa
nts
wit
h N
EC
adm
itte
d fr
om 1
993–
1997
No
fina
ncia
l di
sclo
sure
s
Infa
nts
<36
wee
ks G
A
adm
itte
d w
ith
NE
C (
Bel
l’s
stag
e ≥I
I) b
etw
een
1998
an
d 20
01
Sin
gle-
inst
itut
ion
NIC
U
(Ger
man
y)
N =
959
(n
= 5
23 in
fant
s in
sec
onda
ry 4
-yea
r ob
serv
atio
n pe
riod
, n =
43
6 in
fant
s in
his
tori
cal
cont
rol g
roup
)
To r
epor
t on
an in
stit
utio
nal
expe
rien
ce w
ith
earl
y in
itia
tion
of
ent
eral
nut
riti
on a
fter
NE
C
diag
nosi
s
Gro
up 1
: Fee
ds in
itia
ted
afte
r 3
cons
ecut
ive
days
wit
hout
evi
denc
e of
por
tal v
enou
s ga
s on
ult
raso
und;
da
y 1:
20
mL
/kg/
d di
stil
led
wat
er,
day
2: P
F o
r M
M, a
dvan
ced
20
mL
/kg/
d un
til a
chie
vem
ent o
f go
al
at 1
50 m
L/k
g/d.
Gro
up 2
(co
ntro
l): F
eeds
init
iate
d at
dis
cret
ion
of n
eona
tolo
gist
(t
ypic
ally
14
days
aft
er o
nset
of
NE
C).
Pri
mar
y en
d po
int:
Rec
urre
nce
of
NE
C
Seco
ndar
y en
d po
ints
: T
ime
to
full
ent
eral
nut
riti
on, d
urat
ion
of c
entr
al a
cces
s, in
cide
nce
of
cath
eter
-rel
ated
sep
tice
mia
, du
rati
on o
f ho
spit
al s
tay
Inc
iden
ce o
f NE
C:
5% (
26/5
23)
in th
e ea
rly
feed
ing
grou
p an
d 4%
(18
/436
) in
the
hist
oric
al
cont
rol g
roup
Ear
ly f
eedi
ng a
ssoc
iate
d w
ith:
1.
Sho
rter
tim
e to
rea
ch g
oal
feed
s: 1
0 da
ys (
rang
e, 8
–22)
vs
19
days
(ra
nge,
9–7
6); P
<
.001
2. R
educ
ed d
urat
ion
of c
entr
al
veno
us a
cces
s: 1
3.5
days
(r
ange
, 8–2
4) v
s 26
day
s (r
ange
, 8–3
9); P
< .0
13.
Les
s ca
thet
er-r
elat
ed
sept
icem
ia: 1
8% v
s 29
%; P
<
.01
4. S
hort
er d
urat
ion
of h
ospi
tal
stay
: 63
days
(ra
nge,
28–
133)
vs
69
days
(ra
nge,
36–
150)
; P
< .0
5
Ear
ly e
nter
al n
utri
tion
aft
er
NE
C is
ass
ocia
ted
wit
h si
gnif
ican
t ben
efit
s an
d no
ap
pare
nt a
dver
se e
vent
s.
The
stu
dy is
und
erpo
wer
ed
to e
xclu
de a
hig
her
NE
C
recu
rren
ce r
isk
as a
res
ult o
f ea
rly
inst
itut
ion
of e
nter
al
nutr
itio
n af
ter
NE
C.
GA
, ges
tati
onal
age
; MM
, mot
her’
s m
ilk;
NE
C, n
ecro
tizi
ng e
nter
ocol
itis
; NIC
U, n
eona
tal i
nten
sive
car
e un
it; O
BS
, obs
erva
tion
al s
tudy
; PF,
pre
term
for
mul
a.
Tab
le 1
0. (
cont
inue
d)
by guest on November 21, 2012pen.sagepub.comDownloaded from
522 Journal of Parenteral and Enteral Nutrition 36(5)
Acknowledgments
A.S.P.E.N. Board of Directors providing final approval
Jay M. Mirtallo, MS, RPh, BCNSP, FASHP (President); Phil Ayers, PharmD, BCNSP; Praveen S. Goday, MBBS, CNSC; Carol Ireton-Jones, PhD, RD, LD, CNSD; Tom Jaksic, MD, PhD; Elizabeth M. Lyman, RN, MSN; Ainsley M. Malone, RD, MS, CNSC; Lawrence A. Robinson, PharmD; Daniel Teitelbaum, MD; and Charles Van Way III, MD, FASPEN.
A.S.P.E.N. Clinical Guidelines Editorial Board
Charlene Compher, PhD, RD, FADA, CNSC (Editor in Chief); Joseph Boullata, PharmD, BCNSP; Carol Braunsch-weig, PhD, RD; Mary Ellen Druyan, PhD, MPH, RD, CNS, FACN; Donald George, MD; Edwin Simpser, MD; and Patricia Worthington, MSN, RN, CNSN.
References 1. Holman RC, Stoll BJ, Curns AT, Yorita KL, Steiner CA, Schonberger LB.
Necrotising enterocolitis hospitalisations among neonates in the United States. Paediatr Perinat Epidemiol. 2006;20(6):498-506.
2. Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007;92(3):F193-F198.
3. Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants. Pediatrics. 2002;109(3):423-428.
4. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and mor-bidity for very low birth weight infants, 1991-1999. Pediatrics. 2002;110 (1, pt 1):143-151.
5. Erasmus HD, Ludwig-Auser HM, Paterson PG, Sun D, Sankaran K. Enhanced weight gain in preterm infants receiving lactase-treated feeds: a randomized, double-blind, controlled trial. J Pediatr. 2002;141(4):532-537.
6. Fitzgibbons SC, Ching Y, Yu D, et al. Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg. 2009;44(6):1072-1075; discussion 1075-1076.
7. Clark RH, Gordon P, Walker WM, Laughon M, Smith PB, Spitzer AR. Characteristics of patients who die of necrotizing enterocolitis. J Perinatol. 2012;32(3):199-204.
8. Berman L, Moss RL. Necrotizing enterocolitis: an update. Semin Fetal Neonatal Med. 2011;16(3):145-150.
9. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med. 2011; 364(3):255-264.
10. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7.
11. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179-201.
12. A.S.P.E.N. Board of Directors. Guidelines for use of total parenteral nutrition in the hospitalized adult patient. JPEN J Parenter Enteral Nutr. 1986;10(5):441-445.
13. American Society for Parenteral and Enteral Nutrition. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr. 1993;17(4)(suppl):1SA-52SA.
14. A.S.P.E.N. Board of Directors, the Clinical Guidelines Task Force. Guide-lines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr. 2002;26(1)(suppl):1SA-138SA.
15. Mehta NM, Compher C, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. “A.S.P.E.N. Clinical Guide-lines: Nutrition support of the critically ill child.” JPEN J Parenter Enteral Nutr 2009, 33:260-276.
16. McClave SA, Martindale RG, Vanek VW, et al. ; A.S.P.E.N. Board of Directors; American College of Critical Care Medicine. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Criti-cally Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2009;33:277-316.
17. August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hema-topoietic cell transplantation. JPEN J Parenter Enteral Nutr. 2009 Sep-Oct;33(5):472-500.
18. Sabery N, Duggan C; American Society for Parenteral and Enteral Nutri-tion Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support of children with human immunodeficiency virus infection. JPEN J Par-enter Enteral Nutr. 2009 Nov-Dec; 33(6):588-606. No abstract available. PMID:19892900
19. Jesuit C, Dillon C, Compher C, Lenders CM, American Society for Par-enteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition support of Hospitalized Pediatric Patients with Obesity. JPEN J Parenter Enteral Nutr. 2010 Jan-Feb;34(1): 13-20.
20. Jaksic T, Hull MA, Modi BP, Ching YA, George D, Compher C; Ameri-can Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. Clinical guidelines: nutrition support of neonates supported with extracorporeal membrane oxygenation. JPEN J Parenter Enteral Nutr. 2010 May-Jun;34(3):247-53.
21. Brown RO, Compher C; American Society for Parenteral and Enteral Nutrition Board of Directors. A.S.P.E.N. clinical guidelines: nutrition sup-port in adult acute and chronic renal failure. JPEN J Parenter Enteral Nutr. 2010 Jul-Aug;34(4):366-77.
22. Mueller C, Compher C, Druyan ME, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition Screening, Assessment, and Interven-tion in Adults. JPEN J Parenter Enteral Nutr. 2011 January-February; 35(1):16-24.
23. Arsenault D, Brenn M, Kim S, Gura K, Compher C, Simper E, (A.S.P.E.N.)American Society for Parenteral and Enteral Nutrition Board of Directors, Puder M. A.S.P.E.N. Clinical Guidelines: Complications Unique to Neo-nates - Hyperglycemia and Hypoglycemia in the Parenterally-Fed Neo-nate. JPEN J Parenter Enteral Nutr. 2012;36(1):81-95.
24. Druyan M, Compher C, Boullata JI, et al. Clinical guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients: applying the GRADE system to development of A.S.P.E.N. clinical guidelines [pub-lished online ahead of print December 16, 2011]. JPEN J Parenter Enteral Nutr. doi:10.1177/0148607111420157.
25. Karagianni P, Briana DD, Mitsiakos G, et al. Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. Am J Perinatol. 2010;27(5):367-373.
26. Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics. 2003;111(3):529-534.
27. Mosqueda E, Sapiegiene L, Glynn L, Wilson-Costello D, Weiss M. The early use of minimal enteral nutrition in extremely low birth weight new-borns. J Perinatol. 2008;28(4):264-269.
28. van Elburg RM, van den Berg A, Bunkers CM, et al. Minimal enteral feed-ing, fetal blood flow pulsatility, and postnatal intestinal permeability in preterm infants with intrauterine growth retardation. Arch Dis Child Fetal Neonatal Ed. 2004;89(4):F293-F296.
29. Krishnamurthy S, Gupta P, Debnath S, Gomber S. Slow versus rapid enteral feeding advancement in preterm newborn infants 1000-1499 g: a randomized controlled trial. Acta Paediatr. 2010;99(1):42-46.
30. Caple J, Armentrout D, Huseby V, et al. Randomized, controlled trial of slow versus rapid feeding volume advancement in preterm infants. Pediat-rics. 2004;114(6):1597-1600.
by guest on November 21, 2012pen.sagepub.comDownloaded from
A.S.P.E.N. Clinical Guidelines / Fallon et al 523
31. Salhotra A, Ramji S. Slow versus fast enteral feed advancement in very low birth weight infants: a randomized control trial. Indian Pediatr. 2004;41(5):435-441.
32. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk–based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk–based products. J Pediatr. 2010;156(4):562-567.e1.
33. Lambert DK, Christensen RD, Henry E, et al. Necrotizing enterocolitis in term neonates: data from a multihospital health-care system. J Perinatol. 2007;27(7):437-443.
34. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feed-ing of extremely premature infants. Pediatrics. 2005;116(2):400-406.
35. Sisk PM, Lovelady CA, Dillard RG, Gruber KJ, O’Shea TM. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol. 2007;27(7):428-433.
36. Furman L, Taylor G, Minich N, Hack M. The effect of maternal milk on neonatal morbidity of very low-birth-weight infants. Arch Pediatr Adolesc Med. 2003;157(1):66-71.
37. Braga TD, da Silva GA, de Lira PI, de Carvalho Lima M. Efficacy of Bifido-bacterium breve and Lactobacillus casei oral supplementation on necrotiz-ing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial. Am J Clin Nutr. 2011;93(1): 81-86.
38. Awad H, Mokhtar H, Imam SS, Gad GI, Hafez H, Aboushady N. Com-parison between killed and living probiotic usage versus placebo for the prevention of necrotizing enterocolitis and sepsis in neonates. Pak J Biol Sci. 2010;13(6):253-262.
39. Lin HC, Hsu CH, Chen HL, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, ran-domized, controlled trial. Pediatrics. 2008;122(4):693-700.
40. Samanta M, Sarkar M, Ghosh P, Ghosh J, Sinha M, Chatterjee S. Pro-phylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. J Trop Pediatr. 2009;55(2):128-131.
41. Bin-Nun A, Bromiker R, Wilschanski M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr. 2005;147(2):192-196.
42. Lin HC, Su BH, Chen AC, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pedi-atrics. 2005;115(1):1-4.
43. Mihatsch WA, Vossbeck S, Eikmanns B, Hoegel J, Pohlandt F. Effect of Bifidobacterium lactis on the incidence of nosocomial infections in very-low-birth-weight infants: a randomized controlled trial. Neonatology. 2010;98(2):156-163.
44. Richir MC, Siroen MP, van Elburg RM, et al. Low plasma concentrations of arginine and asymmetric dimethylarginine in premature infants with necrotizing enterocolitis. Br J Nutr. 2007;97(5):906-911.
45. Amin HJ, Zamora SA, McMillan DD, et al. Arginine supplementation prevents necrotizing enterocolitis in the premature infant. J Pediatr. 2002;140(4):425-431.
46. Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics. 2004;113(5): 1209-1215.
47. Trintis J, Donohue P, Aucott S. Outcomes of early parenteral nutrition for premature infants. J Perinatol. 2010;30(6):403-407.
48. Fewtrell MS, Morley R, Abbott RA, et al. Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics. 2002;110(1, pt 1):73-82.
49. Brotschi B, Baenziger O, Frey B, Bucher HU, Ersch J. Early enteral feeding in conservatively managed stage II necrotizing enterocolitis is associated with a reduced risk of catheter-related sepsis. J Perinat Med. 2009;37(6):701-705.
50. Bohnhorst B, Muller S, Dordelmann M, Peter CS, Petersen C, Poets CF. Early feeding after necrotizing enterocolitis in preterm infants. J Pediatr. 2003;143(4):484-487.
by guest on November 21, 2012pen.sagepub.comDownloaded from
