Article

evidence-based medicine

Scientifically Based Strategies for Enteral

Feeding in Premature Infants
Leslie A. Parker, PhD,
ARNP, NNP-BC,*
Josef Neu, MD, Roberto
Murgas Torrazza, MD,
Yuefeng Li, MDx

Educational Gap
Decisions regarding enteral feeding in very low birthweight infants are often not based
on sound scientific evidence.

Abstract

Author Disclosure
Drs Murgas Torrazza
and Li have disclosed
no financial
relationships relevant
to this article. Dr Neu
has disclosed that he
serves as a consultant
to Abbott Nutrition,
Mead Johnson, Medela,
and Fonterra Foods; he
receives honoraria from
Nestle and Danone; and
he has research grants
with Covidien and
Gerber. Dr Parker has
disclosed that she has
a research grant
1R01NR014019-01A1
from N1NR. This
commentary does
contain a discussion of
an unapproved/
investigative use of
a commercial product/
device.

Feeding intolerance and necrotizing enterocolitis are relatively common occurrences

in very low birthweight infants in the NICU. Fear of these disorders can signicantly
affect decisions regarding initiation, advancement, and withholding of enteral feedings.
Lack of sufcient enteral feedings and complications related to parenteral nutrition increase neonatal morbidity, thereby emphasizing the need for safe evidence-based feeding decisions and guidelines. Unfortunately, evidence to guide feeding practices is
often limited, making clinical decisions and the formulation of guidelines difcult. This
article discusses controversies regarding the enteral feeding of very low birthweight
infants and includes current scientic evidence supporting and/or refuting specic
feeding practices.

Objectives

After completing this article, readers should be able to:

1. Discuss the risks and benefits of providing enteral nutrition to very low birthweight
infants.
2. Explore current controversies in neonatal feeding practices.
3. Understand evidence supporting and refuting controversial feeding practices.
4. Discuss feeding practices requiring additional evidence to guide clinical decisionmaking.

Introduction
Provision of optimal nutrition to very low birthweight (VLBW) infants in the NICU is one
of the most challenging and important aspects of neonatal care. (1) Although the enteral
route is the preferred method of nutritional delivery, the risk of necrotizing enterocolitis
(NEC) and feeding intolerance (FI) causes decisions regarding initiation and advancement of enteral nutrition to be both difcult and controversial. The ultimate goal of enteral nutrition is optimal growth and development without increasing complications,
including NEC and FI. Unfortunately, decisions regarding enteral nutrition, including
timing of initiation and rate of advancement, as well as indications for discontinuing
and the mechanisms for delivery, are controversial and often based on individual or institutional preference rather than scientic evidence. Thus, to determine best practices for
the NICU, this article summarizes the available evidence regarding enteral nutrition for
VLBW infants.

Benefits of Enteral Nutrition

The birth of a VLBW infant has been described as a nutritional emergency, and prompt
attention is essential to avoid complications, including parenteral nutrition (PN)-associated liver disease, osteopenia of prematurity, poor neurologic outcomes, and extrauterine
growth retardation (EUGR). Although the nutritional goal for premature infants is

*Clinical Assistant Professor, College of Nursing, University of Florida, Gainesville, FL.

Associate Editor. Professor of Pediatrics, College of Medicine, University of Florida, Gainesville, FL.

College of Medicine, University of Florida, Gainesville, FL.

x
Department of Neonatology, Baoan Maternity and Child Health Hospital of Shenzhen, Guangdong, China.

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evidence-based medicine

achievement of intrauterine growth rates, this goal may

be impossible due to limitations in PN, the increased
metabolic demands of critically ill infants, and the necessity of uid restriction. Enteral nutrition decreases the
need for PN and thereby reduces PN-associated complications, including PN-associated liver disease and lateonset sepsis. Although nutrition and growth can be
sustained with PN, when infants are maintained nil per
os (NPO), impaired intestinal growth, mucosal atrophy,
intestinal barrier dysfunction, decreased enzymatic activity,
and abnormal intestinal bacterial colonization can occur.
(2)(3) Intestinal dysfunction may occur quickly, with intestinal atrophy occurring after only 23 days of NPO status
in animal models. (4)
Despite tremendous progress in neonatology, unanswered questions regarding enteral nutrition in extremely premature infants result in remarkable practice
variation among institutions and individual clinicians.
Decisions regarding enteral feeding are often not based
on sound scientic evidence; instead, they are based
on a fear of NEC and FI. Thus, safe, comprehensive,
evidence-based feeding guidelines are necessary to avoid
complications, including poor growth, prolonged hospitalization, PN-associated complications, and a delay
in achievement of full enteral feedings. In another review in this issue, evidence-based nutritional guidelines
are addressed.

Abbreviations
COX:
ELBW:
EUGR:
FI:
GE:
GR:
GRV:
MEN:
NEC:
NG:
NPO:
OG:
PDA:
PN:
PRBC:
RCT:
TANEC:
VLBW:

cyclooxygenase
extremely low birthweight
extrauterine growth retardation
feeding intolerance
gastric emptying
gastric residual
gastric residual volume
minimal enteral nutrition
necrotizing enterocolitis
nasogastric
nil per os
orogastric
patent ductus arteriosus
parenteral nutrition
packed red blood cell
randomized controlled trial
transfusion-associated necrotizing enterocolitis
very low birthweight

nutrition

Risks Associated With Feeding VLBW Infants

Necrotizing Enterocolitis
NEC, a potentially devastating disease, affects 7% to 14%
of VLBW infants and is characterized by hemorrhagic, ischemic, and necrotic intestines. (5) NEC has a mortality
rate of 20% to 40% and is associated with complications,
including intestinal strictures, short bowel syndrome, and
an increased risk of neurodevelopmental delay. (6)(7)
The etiology of NEC is poorly understood but seems
multifactorial and related to gastrointestinal and immune
system immaturity. Because greater than 90% of infants
diagnosed with NEC have received enteral nutrition, prevention of this disease signicantly inuences feeding decisions in VLBW infants. (8)

Feeding Intolerance
VLBW infants frequently experience what is clinically described as FI due to intestinal immaturity, which includes
decreased gastric emptying (GE) and intestinal motility.
Although the denition of FI varies, the term is historically based on the presence of increased gastric residuals
(GRs), abdominal distention, and emesis. Symptoms associated with FI are often nondistinguishable from more
serious conditions, including NEC. GE is slower in preterm infants due to intrinsic immaturities of the gastrointestinal tract, including immature lower esophageal tone
and function, low percentage of gastric (gastrointestinal)
electrical slow wave, and slower intestinal transit time. (9)
(10) Furthermore, intestinal motor patterns during fasting and feeding are immature in preterm infants and are
characterized by short episodes of quiescence alternating
with irregular contractions, with no clear migrating motor complexes. (11) Similarly, during fasting, the cluster
amplitude and mean duration of duodenum motor activity are less in preterm than in term infants, and cluster frequency is higher in preterm infants. (12) Taken together,
these intrinsic, physiologic characteristics are responsible
for delayed GE and potential FI in preterm infants.

Evidence Regarding Enteral Feeding in VLBW

Infants
Because of an increased risk of NEC and FI in VLBW infants, clinicians are often hesitant to initiate, advance, and
fortify feedings; they also often discontinue feedings in
infants who are undergoing blood transfusions and who
are diagnosed with or being treated for a patent ductus arteriosus (PDA). (13)(14) Although decisions regarding
enteral feeding in this population must be made cautiously, practice guidelines and feeding decisions should
be based on current evidence. The following discussion
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evidence-based medicine

Table 1.

nutrition

Evidence Regarding Feeding Strategies

Feeding Strategy

Evidence

Unanswered Questions

MEN

Improves weight gain, decreases time to full

feedings, decreases PN complications,
decreases days to discharge
Earlier attainment of full feedings, increased
weight, decreased PN usage

Influence of diet, optimal duration, and

dosage. Risks and benefits in ELBW and
clinically unstable infants
Timing of initiation in ELBW infants.
Risk and/or benefits of initiation before
2 days
Influence of diet, timing of initiation, and
duration of MEN before advancement.
Risks and benefits in ELBW infants

Timing of initiation of MEN

2 to 4 days after birth
Advancement of enteral
feedings (15L20 vs
30 mL/kg per day)
Delivery of enteral nutrition
(continuous versus bolus)

Advancement by 30 mL/kg per day is

associated with an earlier attainment of full
feedings, fewer days of PN, shorter hospital
stay, and improved weight gain
No difference in time to attain full feedings
or weight gain

Evaluation of gastric
residuals
Feeding during blood
transfusions

No documented evidence

Feeding infants who have

a PDA
Feeding during
indomethacin or
ibuprofen therapy
Fortification of human milk

Infants who have a PDA have decreased

mesenteric blood flow
COX inhibitors decrease mesenteric blood
flow, but normal postprandial blood flow
is maintained
No increase in feeding intolerance or NEC
with fortification. Human milkbased
fortifiers may decrease the incidence
of NEC

Blood transfusions seem to be associated with

NEC

Influence on apneic episodes. Effect on

weight gain and hospital days in ELBW
infants
Usefulness as an indicator of FI or an early
symptom of NEC
Whether feeding during transfusions are
associated with an increased risk of
TANEC
The risk and benefit of feeding infants
diagnosed as having a PDA
The risk and benefit of feeding infants who
are taking COX inhibitors
Influence of human milkbased fortifiers
on FI

COXcyclooxygenase; ELBWextremely low birthweight; FIfeeding intolerance; MENminimal enteral nutrition; NECnecrotizing enterocolitis;
PDApatent ductus arteriosus; PNparenteral nutrition; TANECtransfusion-associated necrotizing enterocolitis.

summarizes the current evidence regarding issues pertaining to enteral nutrition in VLBW infants. Table 1 summarizes the current evidence and unanswered questions for
each issue presented.

Minimal Enteral Nutrition

Minimal enteral nutrition (MEN), also called trophic or
nonnutritive nutrition, is the provision of nutritionally insignicant amounts of feeding, usually 12 to 24 mL/kg
per day, to nourish and stimulate gastrointestinal development and to prevent intestinal atrophy. (3)(15)
MEN has been associated with improved gut motility
and GE, enhanced intestinal structure and function, increased activity of digestive enzymes, and promotion of
mature migrating motor activity in preterm pigs. (15)
(16) Although the use of MEN is now a well-established
practice in the NICU, evidence regarding its clinical benet is controversial. MEN reportedly improves weight
gain as well as decreases PN complications, days to discharge, and time to attain full enteral feedings. (17)

(18) Signicantly, there have been no reports of adverse

outcomes from MEN, especially NEC or FI. However,
small study populations, inconsistent FI denitions, and
variations in duration of MEN and type of diet make
comparison of available studies difcult and suggest that
the results of a recent Cochrane review indicating a lack
of benet in administering MEN should be questioned.
(19) In addition, research regarding both the benets
and timing of initiation of MEN often fails to either include extremely low birthweight (ELBW) infants or differentiate between VLBW infants and ELBW infants
despite their physiologic and developmental differences.

Timing of Initiation of MEN

During gestation, the fetus swallows signicant amounts
of amniotic uid, which contains growth factors and cytokines essential for intestinal development. When an infant is born prematurely, ingestion of amniotic uid
ceases, and if the infants gastrointestinal tract no longer
receives such enteral stimulation, proper gastrointestinal

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evidence-based medicine

development and function may be compromised. (20)

Thus, provision of human milk (especially colostrum) immediately after delivery may be particularly benecial to
physiologic gastrointestinal development due to its similarity to amniotic uid. (16) In addition, earlier initiation
of enteral feeding after birth could limit the adverse effects of NPO status. Unfortunately, because the majority
of studies investigating the timing MEN initiation used
a combination of human milk and formula, the clinical
benets of using exclusive human milk feedings for
MEN are unknown.
Several studies have found that initiation of MEN 2 to
4 days after birth is associated with decreased PN, increased weight gain, and an earlier attainment of full feedings compared with initiation at 5 to 7 days. (19)(21)
Although long-term outcomes were not reported in
this study, these early benets could translate into less
EUGR, shorter hospitalizations, and fewer PN complications. The American Society for Parenteral and Enteral
Nutrition recommends initiation of MEN within the rst
2 days in infants weighing greater than 1,000 g. (22) For
various reasons, including patient acuity, clinicians often
use these recommendations inconsistently, and initiation
of enteral feedings may be delayed for up to 10 days after
birth.
Although research exists regarding initiating MEN between 2 to 4 days after birth, no studies were found that
evaluated the risks and benets of initiating MEN earlier
than 48 hours after delivery. When considering the value
of continued exposure to nutrients, growth hormones,
and other bioactive components present in amniotic uid
and human milk, as well as the negative consequences of
NPO status, such a delay may have deleterious consequences. It is also possible that current recommended
volumes of MEN may be insufcient to promote benecial clinical outcomes; however, administration of larger
volumes could be unrealistic in very premature infants
due the risk of NEC and FI.
In conclusion, administration of MEN has shown positive clinical outcomes in most small studies conducted
thus far and is becoming a well-accepted practice in the
NICU. However, unanswered questions, including optimal dosage and duration, use of human milk exclusively,
risks versus benets in clinically unstable infants, and benets of provision earlier than 48 hours after delivery, potentially limit its advantages.

Advancement of Enteral Feeds

After MEN is provided, feedings are gradually advanced
until full feedings are attained and PN is discontinued.
The daily rate of advancement often varies depending

nutrition

on institutional and clinician preference, thereby affecting

time to attainment of full enteral feedings and inuencing
duration of PN usage. Several randomized controlled trials (RCTs) have compared feeding advancement by 15 to
20 mL/kg per day with advancement by 30 mL/kg per
day and have found that those infants who experienced
a faster advancement of feedings reached full feedings
faster, required fewer days of PN, had a shorter hospital
stay, and regained birthweight more quickly without an
increased risk of either NEC or FI. (23)(24)(25) These
ndings were supported by a recent Cochrane review
and American Society for Parenteral and Enteral Nutrition recommendations that feedings be advanced by
30 mL/kg per day in infants weighing greater than
1,000 g. (22)(26) Again, discrepancies regarding diet,
initiation, and duration of MEN and lack of information
regarding ELBW infants limit our knowledge concerning
the optimal rate for advancement of feedings. In addition, because practice parameters that focus on feeding
VLBW infants generally do not differentiate between infants born ELBW and VLBW, a more conservative approach to feeding advancement is often used.

Delivery of Enteral Nutrition

The most common methods for enteral nutrition delivery
in the NICU are either via continuous or intermittent bolus orogastric (OG) or nasogastric (NG) tube. Decisions
regarding administration are also generally based on institutional and clinician preference, not scientic evidence.
Potential benets of bolus feedings include improved
feeding tolerance due to faster GE, enhanced duodenal
motor responses, more normal feedingfasting hormonal
levels, and greater muscle protein synthesis. (27) However, a recent Cochrane review reported no difference
in time to full feedings or growth when the two modalities were compared. (28) Individual studies suggest continuous feedings may increase apnea in VLBW infants
(29) and weight gain in infants less than 1,250 g, as well
as result in an earlier discharge for ELBW infants. (30) In
addition, compared with infants fed via OG tube, those
fed via NG tube are signicantly more likely to experience
lower saturation levels during feeding tube insertion and
during feeding administration. (31)

Evaluation of Gastric Residuals

GR is the volume of milk remaining in the stomach before a feeding and is often considered an indicator of FI,
delayed GE, and an early symptom of NEC. (32)(33) Although assessment of GRs is generally accepted as routine care, standards for evaluation and management are
generally lacking. (24)(34) Reports in the literature
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nutrition

indicate a wide variation in practice regarding the presFinally, the color of GRs has been evaluated as an inence of large or abnormally colored GRs, and 70% to
dicator of NEC, and although several studies have exam93% of NICUs use GRs to determine when to alter feedined this relationship, most have failed to establish a clear
ing volume or advance feedings. (14) This lack of uniconnection. For example, Bertino et al (32) reported
form standards can lead to EUGR and a discontinuation
a correlation between bloody residuals and NEC, but
or delay in advancement of feedings, resulting in prolonthe correlation did not extend to bilious-colored residuals.
gation of PN. In addition, GR aspiration may not reliably
Similarly, Mihatsch et al (34) found that green GRs (<2 to
measure gastric residual volume (GRV) because accurate
3 mL) were not associated with an increased incidence of
measurement depends on body position, size of the feedNEC in ELBW infants. However, despite these ndings,
ing tube, and placement of the OG/NG port in the gasenteral feedings are frequently discontinued because of
tric antrum. (35) GRV can be underestimated by 25%,
yellowish or slightly green GR, potentially resulting in unand this variability increases as GRV decreases, which may
necessary delays in attainment of full enteral feedings.
be particularly important in VLBW infants whose gastric
No consensus exists regarding the usefulness of GR in
contents are small. (36)
determining whether to continue, advance, or withhold
Aspiration and evaluation of GR can be associated
feeding. Mihatsch et al found that green GRs were not
with potentially signicant complications, including damindicative of FI and suggested feeding advancement
age of the fragile gastric mucosa from negative pressure
not be delayed in the absence of other clinical signs
created by aspiration of GR and close contact between
and symptoms. Shulman et al (42) also suggested that
the tip of the NG/OG tube and the gastric mucosa.
GRV is an unreliable predictor of attainment of full feedIn addition, because GRs contain nutrients, gastric acid,
ings. Based on these ndings, it is clear that signicant
and enzymes that might promote intestinal motility and
research, including a randomized trial, is required. To
maturation, discarding GRs may negatively inuence GE
address this issue, we are currently conducting an
and gastrointestinal system maturation. (37) Decisions reRCT in our NICU to determine the usefulness of GR
garding when to discard GRs are not based on evidence
evaluation in this population (Table 2).
but are done according to nurses experience, unit tradiFeeding During Blood Transfusions
tion, and physician advice. Indeed, in a small study of
Although no causal effect has been established, statistical
NICU nurses, only 4% consistently replaced GR after asassociation in some studies links administration of packed
piration. (38)
red blood cells (PRBCs) to NEC. Transfusion-associated
Variation in acceptable GR volume restricts its usefulNEC (TANEC) could result in a higher mortality and
ness as an FI indicator. FI by some authors has been demorbidity rate, including an increased need for surgical
ned as a GRV greater than 2 to 3 mL depending on
intervention. (43)(44) A recent meta-analysis of observaweight, (32)(34) greater or equal to 2 mL/kg, or greater
tional studies reported an increased incidence of NEC 48
than 50% of the previous feeding volume. (39)(40) Alto 72 hours after PRBC transfusions, especially in less mathough some studies suggest that increased GRV may
ture, smaller, and more critically ill infants. (44)
be an early indicator of NEC, this relationship has not
Several theories have been proposed to explain the rebeen clearly substantiated. Cobb et al (33) reported a siglationship between PRBC transfusions and NEC. Infants
nicantly greater maximum GRV in infants during the 6
days before the diagnosis of NEC
compared with infants who do
not have NEC, but the clinical sig- Table 2.
nicance of these ndings is uncerCharacteristics Association With NEC
Association With FI
tain. Similarly, Bertino et al, (32) in
a case control study of 34 infants,
Color of GR
Bloody
No information
Green (<23 mL)
reported a statistically greater maxGRV
Higher maximum GRV within
2L3 mL depending on
imum GRV from birth to onset of
the 6 days before diagnosis
weight
NEC. The amount of GRV considHigher maximum GRV from
>2 mL/kg
ered signicant is also unclear and
birth to diagnosis
may range from greater than 3.5 to
>50% of feeding
4 mL, greater than 1.2 mL, or be
FIfeeding intolerance; GRgastric residual; GRVgastric residual volume; NECnecrotizing
based on a percentage of the preenterocolitis.
vious feeding volume. (41)

Reported Significance of Gastric Residuals

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with lower hematocrit levels have an increased risk of

TANEC, possibly related to impaired intestinal oxygen
delivery due to severe anemia and reperfusion injury.
In addition, infants may also be predisposed to TANEC
due to bowel ischemia resulting from increased blood viscosity, decreased superior mesenteric artery blood ow,
and an intestinal immunologic reaction from exposure
to biologically active mediators such as free hemoglobin,
cytokines, or broken red cell fragments. (45)(46) Transfusion of older blood is associated with organ dysfunction
and increased morbidity in adult patients, and dedicated
donor policies (which are used to decrease exposure to
multiple donors) make the transfusion of older blood a
common practice in the NICU. Using older blood for
transfusion exposes the infant to storage medium, cytokines,
red blood cell membrane abnormalities, and additional
chemical changes that are potentially harmful to the intestinal mucosa. (47) However, compared with blood less than
7 days old, transfusion of blood older than 14 days has not
been shown to increase the risk of TANEC. (48)
A highly controversial issue surrounding TANEC is
whether feeding before, during, or after a transfusion affects its incidence. An RCT by Krimmel et al found no
increase in postprandial mean blood ow velocity in
transfused VLBW infants, potentially resulting in intestinal hypoperfusion. Two observational studies suggest
that withholding feedings during blood transfusions decreases the risk of TANEC. (43)(46)(49) El-Dib et al
(43) used a case-controlled, retrospective study and
found a reduction in NEC, but not TANEC, after a practice change to withholding feedings during transfusions.
Perciaccante and Young found a decrease in TANEC
from 39% to 0% after a change to withholding feedings
before, during, and after transfusions. Unfortunately,
there are no published RCTs evaluating the association
of feeding during blood transfusions and the incidence
of TANEC. If withholding feedings during PRBC transfusions is found benecial, additional research will be required to determine the necessary duration of NPO
status and the inuence of diet. Although mesenteric
blood ow after transfusions is not affected by diet, formula-fed infants are more likely to develop TANEC. (46)
Although many NICUs are changing feeding practices to
withhold feedings before or during blood transfusions,
there is currently no compelling evidence that withholding feedings affects the incidence of NEC.

Feeding Infants Who Have a PDA

A PDA is a common phenomenon in premature infants,
occurring in 65% to 80% of infants weighing less than
1,000 g. (50) The presence of a clinically signicant

nutrition

PDA decreases mesenteric blood ow due to diversion

of blood away from the systemic circulation, potentially
increasing the risk for FI and NEC. Both a reduction
in postductal blood ow and the lack of a normal postprandial intestinal blood ow have been reported in animal models, potentially limiting the infants ability to
meet the increased metabolic demands of an active gastrointestinal system. (51)
Retrospective studies have also reported an association
between a PDA diagnosed via echocardiogram and an increased incidence of NEC. (52)(53) In addition, delayed
treatment and a persistent PDA have been correlated with
an increased risk of NEC in VLBW infants. In contrast,
several trials have failed to show an association between
PDAs and NEC, (54)(55) including a large multicenter
study of ELBW infants. (56) Because infants diagnosed
with PDAs are generally more immature, clinically less stable, and have often undergone treatment for PDA closure, comparing complication rates can be difcult. (57)
Due to the perceived risk of NEC and FI, clinicians are
often hesitant to feed infants who have a clinically significant PDA; only 30% of NICUs and 29% of US-based
neonatologists continue feeding after a diagnosis, potentially delaying full enteral feedings and resulting in
less optimal growth. (13)(14) However, this hesitancy
may be unwarranted; it has been shown that small feedings increase gastrointestinal blood ow, theoretically
providing intestinal tract protection. In addition, FI has
not been shown to increase in infants who have PDAs.
Despite these ndings, more research is needed to clarify issues regarding the risk and benets of feeding infants who have PDAs as well as the impact of initiation
timing, duration of MEN, and rate of advancement
and diet.

Feeding During Indomethacin or Ibuprofen

Therapy
Cyclooxygenase (COX) inhibitors such as indomethacin
and ibuprofen are often used in the treatment of PDAs,
but due to their negative effect on mesenteric blood ow,
they have been theorized to contribute to intestinal injury
and increase the risk of NEC and FI. (1) This perception
stems from the ndings of retrospective studies, which
have linked treatment with COX inhibitors to an increased
risk of NEC, as well as a Cochrane review, which found
that infants who received a shorter course of indomethacin
also had a lower incidence of NEC. (1)(58) In addition,
several early studies indicated an association between indomethacin for intraventricular hemorrhage prophylaxis
and NEC. However, these studies did not consistently differentiate between spontaneous intestinal perforation and
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nutrition

NEC, and due to the well-established relationship between early indomethacin therapy and spontaneous intestinal perforation, the association between indomethacin
and NEC may have been overrepresented. (1)(5)
In contrast, numerous investigations have failed to
nd an association between NEC and treatment with
COX inhibitors even though these treatment groups
were often smaller and less clinically stable. (54)(59)
Sharma et al, (31) in a prospective study of 992 infants,
found that infants treated with indomethacin actually had
a decreased incidence of NEC and suggested a protective
element due to indomethacins ability to modulate intestinal inammatory mediators.
Although both indomethacin and ibuprofen are used
for treating PDAs, ibuprofen may be preferable due to
its milder effect on mesenteric blood ow. Several studies, including a 2011 Cochrane review, have indicated
a decreased risk of NEC in infants treated with ibuprofen. (60)
In conclusion, investigations regarding feeding infants
treated with COX inhibitors are limited. Although COX
inhibitors decrease mesenteric blood ow, they do not
prevent normal postprandial increases in intestinal blood
ow and are not associated with increased FI. Future
RCTs are needed to investigate specic feeding strategies
for infants being treated with COX inhibitors.

Fortification of Human Milk

Concerns regarding the impact of human milk fortication with bovine-based products on the rate of NEC
and FI in VLBW infants may inuence clinical decisions
to provide nutritionally necessary fortication. Unfortunately, limited information exists regarding the impact
of human milk fortication on either NEC or FI. One
study by Ewer and Yu, (61) which explored the effect
of human milk fortication on GE in preterm infants, reported that human milk fortier may slow GE due to an
increased osmolality and change in milk composition.
However, several studies (including a systematic review)
found no increase in FI or NEC when human milk was
fortied. (31) Sullivan et al (62) reported a signicantly
higher incidence of NEC in infants receiving a cows
milkbased fortier compared with a human milkbased
fortier. Actual differences in frequency of NEC were
small and may have been due to the increased use of human milk rather than fortication.

Summary
Delivery of nutrition to critically ill VLBW infants is one
of the most important challenges in neonatology and

requires the interdisciplinary work of nurses, nurse practitioners, physicians, and nutritionists to provide optimal
nutrition and to prevent complications. Current practice
is largely based on NICU tradition and individual clinical
preference rather than sound evidence; in addition, few
high-quality RCTs regarding feeding practices in this
population are available to determine standards. Thus,
for new research to be relevant, it is imperative that certain factors (fortication of human milk, advancement of
feedings, denitions of FI and NEC, and timing of initiation and duration of MEN) are consistent. Although
clinical decisions regarding continuing, discontinuing,
or advancing enteral feedings must always be based on
a thorough assessment of the individual patient, additional research is needed to guide and optimize clinical
decision-making.

American Board of Pediatrics NeonatalPerinatal

Content Specification
Know the pathophysiology and prevention
of NEC.

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NeoReviews Quiz
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1. A 1-day-old 29-weeks-gestational-age male who had a birthweight of 1 kg is started on feedings of 2 mL of

human milk every 3 hours. This type of feeding is associated with which of the following in preterm animal
models?
A. Decrease in gut motility.
B. Increased activity of digestive enzymes.
C. Increased risk of early-onset, but not late-onset, necrotizing enterocolitis (NEC).
D. Intestinal atrophy.
E. Formation of ileal strictures.
2. The 29-weeks-gestational-age patient in question 1 would be considered as receiving minimal enteral
nutrition (MEN). Which of the following is true regarding MEN for premature infants?
A. The use of either human milk or infant formula for MEN likely has equivalent beneficial effects.

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evidence-based medicine

nutrition

B. The initiation of MEN within the first 2 to 4 days after delivery, as opposed to later, may result in decreased
parenteral nutrition use, increased weight gain, and earlier attainment of full enteral feedings.
C. The evidence behind starting MEN within the first hour after delivery is well established, and MEN should
therefore be used for all preterm infants with less than 1,500 g birthweight soon after birth.
D. Because colostrum has higher caloric density than regular milk, it should not be used as the initial MEN but
withheld until full enteral feedings are established.
E. Most of the research on MEN for very preterm infants has studied initiation of MEN before 48 hours.
Further studies will need to focus on the benefit of initiation of MEN from 3 to 7 days.
3. A 6-day-old 31-weeks-gestational-age female with a birthweight of 1,100 g is receiving approximately 50%
parenteral nutrition by umbilical venous catheter and 50% enteral nutrition with maternal human milk. She is
receiving 11 mL of human milk every 3 hours. She has apnea of prematurity but is currently on room air and
being monitored. Which of the following is true regarding her current nutrition management?
A. Advancing her feedings by 4 mL per feeding daily, as opposed to 2 mL per feeding, is more likely to lead to
decreased overall parenteral nutrition use without an increase in risk of NEC.
B. Because parenteral nutrition will provide better nutrition than enteral feedings of human milk or infant
formula, the umbilical line should be kept in place for the first 10 days after delivery for parenteral
nutrition, regardless of feeding tolerance.
C. The feedings should be changed to continuous feedings at 4 mL per hour to reduce the risk of apnea.
D. The optimal approach to feeding this infant is by nasogastric tube, which should be alternated between
each nostril every three to four feedings.
E. From the second week on, the patient should receive one half of her feedings with infant formula to
provide adequate protein and calcium intake.
4. During morning rounds, the bedside nurse shows you the gastric residual of a 6-week-old 24-weeksgestational-age male who is now receiving full enteral feedings by gavage tube. The infant now weighs 1 kg and
is receiving 20 mL of human milk every 3 hours. The gastric residual is light green and measures approximately 2
mL in volume. Which of the following is true regarding gastric residuals for patients such as this one?
A. Although the research on significance of gastric residuals is ongoing, the lack of harmful effects in
checking residuals makes it the standard of care because it may provide some useful information.
B. Due to the appearance of this residual, it should be discarded, and the patients next feeding should be held.
C. The lack of residuals is a strong negative predictive factor for NEC and can be a reassuring sign to continue
feedings even in the presence of other symptoms such as abdominal distension and blood-tinged stools.
D. Gastric residuals contain nutrients, gastric acid, and enzymes that may promote motility and maturation.
E. This patient should have a sepsis evaluation and be started on antibiotic therapy until culture results are
negative for at least 48 hours.
5. A 4-day-old 26-weeks-gestational-age male has a patent ductus arteriosus diagnosed by echocardiogram,
a hematocrit value of 21%, and is intubated on mechanical ventilation requiring the fraction of inspired
oxygen in a gas mixture to be 40%. You are planning to give a packed red blood cell transfusion. Given the
current state of evidence, which of the following statements can you confidently state regarding this patients
clinical condition?
A. The presence of a patent ductus arteriosus alone is an absolute contraindication to feeding this patient.
B. It is safer to accept this patients current hematocrit level than to provide a transfusion in regard to
avoiding feeding intolerance and other morbidities.
C. To promote gut motility and development, the patient should be fed human milk before, during, and
immediately after the transfusion.
D. If there is a decision to treat this patients patent ductus arteriosus, indomethacin may be preferable to
ibuprofen because of its potentially milder effect on mesenteric blood flow and reduced risk for NEC.
E. Although some studies have linked packed red blood cell transfusions to NEC, further studies are needed to
determine if withholding feedings is beneficial and, if so, to determine the optimal timing of feeding
practice surrounding transfusion.

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Scientifically Based Strategies for Enteral Feeding in Premature Infants

Leslie A. Parker, Josef Neu, Roberto Murgas Torrazza and Yuefeng Li
NeoReviews 2013;14;e350
DOI: 10.1542/neo.14-7-e350

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Scientifically Based Strategies for Enteral Feeding in Premature Infants

Leslie A. Parker, Josef Neu, Roberto Murgas Torrazza and Yuefeng Li
NeoReviews 2013;14;e350
DOI: 10.1542/neo.14-7-e350

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/14/7/e350

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