Clinical Research

Nutrition in Clinical Practice

Volume 00 Number 0
Improving Nutrition Outcomes for Infants < 1500 Grams xxx 2018 1–9

C 2018 American Society for

With a Progressive, Evidenced-Based Enteral Feeding Parenteral and Enteral Nutrition

DOI: 10.1002/ncp.10081
Protocol wileyonlinelibrary.com

Melissa K. Thoene, MS, RD1 ; Elizabeth Lyden, MS2 ;

and Ann Anderson-Berry, MD, PhD3

Abstract
Background: Growth is essential for very low birth weight infants. The purpose of this retrospective chart review was to evaluate the
impact of a new standardized, evidenced-based feeding protocol for infants born < 1500 g in correlation with growth and clinical
outcomes. Methods: Growth and nutrition data was reviewed from 2 groups of infants born < 1500 g within a level III newborn
intensive care unit (NICU). Epoch 1 infants (N = 32) received care following initial implementation of a standardized enteral
feeding protocol. Epoch 2 infants (N = 32) received care following aggressive modification of this initial protocol based on newly
available literature that promotes earlier initiation and advancement of enteral feedings. Results: Epoch 2 infants weighed more at
36 weeks (2562 vs 2304 g) with higher discharge weight percentiles (32nd vs 15th percentile). Epoch 2 infants started and achieved
full enteral feedings earlier (day of life 1 vs 4; 7 vs 22, P < 0.0001) and required less days of parenteral nutrition (5.5 vs 17.5 days,
P < 0.0001), with indwelling central line for parenteral access (6 vs 17.5). There were no differences in retinopathy of prematurity
(17% control vs 19% study), oxygen requirement at 36 weeks (22% epoch 1 vs 43%), necrotizing enterocolitis (3% epoch 1 vs 0%),
intraventricular hemorrhage grade 3–4, periventricular leukomalacia, or death. Conclusion: In this sample of very low birth weight
infants, a progressive standardized, evidence-based feeding protocol was associated with improved growth without increased risk
for necrotizing enterocolitis. (Nutr Clin Pract. 2018;00:1–9)

Keywords
clinical protocols; enteral nutrition; growth; infants, very low birth weight infants

Introduction ratory support remain an immediate forefront priority, it is

the persistent adequate nutrition support that will influence
It remains well recognized that adequate growth is critical these long-term adjunctive therapy requirements.
for every preterm infant, but most specifically in very
low birth weight infants born < 1500 g. These infants
have exceedingly high nutrient needs; therefore, providing
adequate nutrition is necessary to meet full potential for From the 1 Department of Pharmacy and Nutrition, Nebraska
growth and neurological outcomes. Despite this knowledge, Medicine, Omaha, Nebraska, USA; the 2 College of Public Health,
University of Nebraska Medical Center, Omaha, Nebraska, USA;
recent data reports that 50% of North American infants and the 3 Department of Pediatrics, University of Nebraska Medical
born < 1500 g are still experiencing postnatal growth failure, Center, Omaha, Nebraska, USA.
with discharge weights plotting below the 10th percentile on Financial disclosure: None declared.
their respective growth charts.1
Conflicts of interest: Anderson-Berry has received financial
Unaggressive, dated nutrition practices contribute to compensation as a speaker for Mead Johnson and Abbott Nutrition,
energy and protein deficits, all resulting in subsequent as well as a monetary grant from the Gerber Foundation. Mead
poor growth. These include but are not limited to a low Johnson, Abbott Nutrition, and the Gerber Foundation had no role in
optimization of parenteral nutrition (PN), delay in enteral the funding or design of the study; in the collection, analyses, or
feeding advancement, and delay in human milk fortifica- interpretation of the data; in the writing of the manuscript; and in the
decision to publish the results. The remaining authors declare no
tion. Poor nutrition management can lead to osteopenia, conflicts of interest.
cholestasis, chronic lung disease, and a multitude of other
This article originally appeared online on February 28, 2018.
issues that further deplete nutrient stores and affect growth.
Nutrition practices vary significantly among neonatal units, Corresponding Author:
Melissa K. Thoene, MS, RD, Department of Pharmacy and
but achieving adequate growth must remain a common and Nutrition, Nebraska Medicine, 981200 Nebraska Medical Center,
consistent priority. Nutrition management must be regarded Omaha, NE 68198, USA.
as a true medical therapy. Whereas therapies such as respi- Email: [email protected]
2 Nutrition in Clinical Practice 00(0)

In 2007, a standardized feeding protocol was imple- 4; periventricular leukomalacia (PVL); necrotizing entero-
mented in our level III newborn intensive care unit (NICU), colitis (NEC) based on Bell’s staging criteria; number of
focusing on a standardized earlier start and quicker ad- packed red blood cell transfusions; and use of steroids
vancement to full enteral feedings.2 This feeding protocol (dexamethasone).
was applied only to the NICU, not hospital-wide. This Weight was measured daily on a gram scale, and head
change resulted in a significant reduction in day of life circumference was measured weekly using a measuring tape.
(DOL) to achieve full enteral feedings (22 vs 30 days), Weight with associated growth percentiles on the Fenton
less days receiving PN (18 vs 27 days), a lower incidence growth curve were assessed at birth, 36 weeks GA, and
of chronic lung disease at 36 weeks gestational age (GA) discharge. We also evaluated how many infants had weights
(22% vs 51%), and fewer infants discharged with weights plotting < 10th percentile on the Fenton growth curve at
plotting < 10th percentile on their respective growth curve each of these time points. Head circumference size with
(28% vs 57%), all P < 0.05. Because our feeding protocol associated growth percentiles was assessed at 36 weeks GA
has subsequently been significantly updated based on newly and at discharge.
available published literature that promotes even faster Enteral feeding progression was evaluated, including
enteral feeding initiation and advancement, we continue to DOL feedings started, DOL full enteral feedings were
experience further improved outcomes. The purpose of this achieved, time interval between start of feedings to full
study is to assess the outcomes from our current feeding achievement, number of days receiving PN, number of days
practices (epoch 2) to those in the postimplementation with indwelling central line for PN access, and number of
group following changes in 2007 (epoch 1). abdominal films taken due to feeding tolerance concerns.
Both highest blood urea nitrogen (BUN) and highest base
Patients and Methods deficit were assessed during the first week of life while
receiving PN. Highest BUN was also collected while on
Participants and Data Collection full enteral feedings. Full enteral feedings were defined as
The institutional review board at the affiliated hospital’s an infant receiving a 150 mL/kg/d of either preterm infant
university medical center approved this study with a waiver formula or maternal breast milk fully fortified to 24 cal/oz
of consent, and all study procedures followed were in accor- using human milk fortifier and a protein modular.
dance with their ethical standards. Data was retrospectively
collected from inpatient electronic medical records of study Feeding Regimen
infants admitted to the NICU between June 2015 and May
2016 who were born < 1500 g. This time period was selected Similar strategies between groups consisted of initiating
because this is when the modified feeding protocol was im- PN immediately following birth at 80 mL/kg/d. Total fluids
plemented. There was no cutoff for minimum birth weight. were typically advanced toward 150 mL/kg/d over 4 days.
Thirty-two infants were included in the control group Following these initial goals, both PN and enteral nutrition
(epoch 1). These infants met birth weight criteria and were (EN) management differed between groups.
admitted to the same level III hospital NICU during Octo- For epoch 1, parenteral protein goals were 2.5 g/kg/d
ber 2007–July 2008. Data had been previously collected on with starter PN, followed by advancement to 4.0 g/kg/d
these infants by 4 investigators providing direct medical care over 3 days. Intralipids were started at 2 g/kg/d on DOL
to these eligible infants. Thirty-two study infants from an 2 and advanced over 3 days to 3.5 g/kg/d. Enteral feedings
eligible pool (born between June 2015–May 2016; N = 44) were initiated by DOL 3 at 20 ml/kg/d. This small feeding
were selected through randomization and matched 1:1 with volume was maintained for 5–7 days and then advanced by
control infants based on GA and weight plotting < 10th per- 20 ml/kg/d toward goal 150 mL/kg/d after this initial trophic
centile on the Fenton growth curve at birth. Data for epoch period. Fortification of milk with a powdered human milk
2 was collected by 1 investigator who had provided direct fortifier was started when enteral volume reached 100–120
medical care to these eligible infants. All infants in epoch 1 ml/kg/d. Fortification was started at 22 cal/oz for 24 hours,
and epoch 2 were cared for in the same level III NICU. increased to 24 cal/oz for 24 hours, and then a powdered
protein modular was added to achieve goal of 4.0 g/kg/d per
120 cal/kg/d. Because donor milk was not available during
Demographics, Growth, and Clinical Outcomes
this time, formula was used as a supplement to mother’s milk
Demographic information was collected for all infants, supply. If an infant was formula fed, feedings were initiated
including gender, GA at birth, and DOL at discharge. at 20 cal/oz and increased to 24 cal/oz when enteral feeding
Additional outcomes collected included the incidence of volume reached 100–120 ml/kg/d. The caloric density of
bronchopulmonary dysplasia (BPD), defined as oxygen use feedings was increased to 27 or 30 cal/oz at any point on
at 36 weeks GA; retinopathy of prematurity (ROP) stage full enteral feedings that growth was deemed inadequate, at
2 or greater; intraventricular hemorrhage (IVH) grades 3– the discretion of the medical team.
Thoene et al 3

Epoch 2 received a more aggressive nutrition regimen outcomes are displayed in Table 2. Feeding progression and
for both EN and PN management. Parenteral protein goals treatment outcomes are displayed in Table 3.
were minimum of 3.0 g/kg/d with starter PN, followed by There were no differences in the number of infants
increase to minimum of 4.0 g/kg/d with first bag of custom plotting < 10th percentile for age at birth or GA between
PN. Intralipids were started at 2 g/kg/d with the first bag of groups because this was matching criteria for study and
custom PN, then increased to goal minimum of 3.0 g/kg/d control infants. There were no differences in gender among
with the second bag of custom PN. Enteral feedings were groups. There were no statistical differences in the incidence
initiated within the first 24 hours of life (ideally within the of BPD, ROP, IVH grade 3–4, PVL, NEC, or death between
first 4 hours of life) at 30–35 mL/kg/d. Trophic feedings were combined groups. More infants in epoch 1 received steroids
continued for 48 hours for infants born < 28 weeks GA. compared with epoch 2 (81% vs 22%, P < 0.0001). Epoch
Infants born > 28 weeks did not receive trophic feedings. 1 infants were discharged by younger days of life (DOL 64
Feedings were then advanced by 30–35 mL/kg daily toward vs 84), although P = 0.08.
goal of 150 ml/kg/d. Fortification of milk to 24 cal/oz with a Whereas birth weight and percentile were similar be-
nonacidified liquid human milk fortifier was initiated when tween combined groups, weight and percentile at 36 weeks
enteral feedings reached 50–60 mL/kg/d. After 24 hours, a GA were higher in the epoch 2 infants (2563 vs 2304 g; 32nd
liquid protein modular was added to achieve goal protein vs 15th percentile). This was also similar at discharge, with
of 4.2 g/kg/d per 120 cal/kg/d in infants > 1250 g and epoch 2 infants having higher weight percentiles compared
goal protein of 4.4 g/kg/d per 120 cal/kg/d in infants < with the epoch 1 group (32nd vs 15th percentile). There were
1250 g. Enteral volume advancement and milk fortification no statistical differences between groups in the number of
were completed simultaneously. Donor milk was used as a infants, with head circumferences plotting < 10th percentile
bridge to mother’s own milk supply if parents consented. at 36 weeks GA and at discharge.
Donor milk was advanced and fortified similarly to mother’s Epoch 2 infants started enteral feedings earlier than
own milk to meet nutrition goals. Donor milk was not epoch 1 infants for all weight categories (DOL 1 vs 4, P <
used longer than 14 DOL, and some infants transitioned 0.0001) and achieved full feedings earlier (DOL 7 vs 22, P <
off donor milk before 14 days of life if early growth 0.0001). Epoch 2 infants also required less days PN (5.5 vs
was inadequate to maintain growth percentiles after initial 17.5 days, P < 0.0001) and required less days with indwelling
diuresis. If an infant was formula fed, feedings were initiated central line for PN access (6 vs 17.5 days). Epoch 2 infants
at 24 cal/oz. The caloric density of feedings were increased also required fewer abdominal films to assess for feeding
to 27 or 30 cal/oz at any point on full enteral feedings tolerance (median 0.5 vs 19 films) and received fewer blood
when growth was deemed inadequate to maintain growth transfusions (median 0 vs 3). Highest base deficit for all
percentiles, at the discretion of the medical team. infants in the first week of life was similar between groups.
Epoch 1 infants had higher BUN levels while on full enteral
Data Analysis feedings.
Comparison of continuous variables between groups was
completed using the Wilcoxon rank sum test, which com- Discussion
pares the medians of 2 groups. The Fisher’s exact test
was used to compare categorical data. A P value < 0.05 Evaluation of Growth
was considered statistically significant. Data was analyzed
Growth was better maintained for epoch 2 infants, given a
between epoch 1 vs epochs 2 as well as between birth weight
higher trend in percentiles compared with the control group.
categories (< 1000 g and 1000–1500 g). Additional analyses
This trend was evident in most all comparisons between
were completed, as reported in the Discussion section, such
groups for every weight category at both 36 weeks GA and
as when comparing head circumference growth for infants
at discharge. The only similar comparison was for infants
without high-grade IVH. Growth in g/kg/d (from DOL
< 1000 g, who had nonsignificant differences between
birth weight regained until first weight ࣙ 2 kg) and g/d (from
weight or percentiles at 36 weeks GA. Epoch 2 infants were
first weight ࣙ 2 kg until discharge) was analyzed for epoch
discharged at older days of life, which approached statistical
2 infants for further analysis of growth velocity (GV). The
significance (median DOL 64 vs 84, P = 0.08). It is of more
calculation for GV in g/kg/d was calculated as follows:3
clinical significance to assess trends in weight percentiles
from birth until discharge for combined weight categories
GV = [1000 × ln (Wn/W1)]/ (Dn − D1)
between groups. Control infants were born with median
weights plotting at the 45th percentile on the Fenton growth
Results chart, followed by the 15th percentile at both 36 weeks
There were 32 infants in each group. Baseline characteristics GA and discharge. Study infants were born with median
and incidence of disease are displayed in Table 1. Growth weights plotting at the 48th percentile, followed by the
4 Nutrition in Clinical Practice 00(0)

Table 1. Baseline Characteristics and Outcome Data.

Reported Median
(reported percentage or Epoch 2
range) Category Epoch 1 (n = 32) IQR (n = 32) IQR P Value

Weight category < 1000 g 18/32 (56%) 12/32 (38%)

1000–1500 g 14/32 (44%) 20/32 (62%) 0.21
GA at birth All infants 28ˆ0 (26,29) 28ˆ1 (26.7,29.5) 0.42
< 1000 g 26ˆ1 (23ˆ5–28ˆ2) (24.5,28) 26ˆ1 (23ˆ2–30ˆ3) (82,115) 0.67
1000–1500 g 29ˆ2 (27ˆ0–32ˆ2) (28.5,30.2) 29ˆ0 (26ˆ4–30ˆ6) (27.8,29.6) 0.29
DOL at discharge All infants 64 days (49, 90) 84 days (68,98.5) 0.08
< 1000 g 88.5 (29–140) (64,113) 96.5 (70–134) (82, 115) 0.34
1000–1500 g 51.5 (43–80) (46,59) 70 (36–112) (59.5,85.5) 0.0051
Gender All infants 34% female, 34% female, 1.00
66% male 66% male
BPD All infants 6/27 (22%) 13/30 (43%) 0.16
< 1000 g 6/16 (38%) 11/12 (92%) 0.006
1000–1500 g 0/11 (0%) 2/18 (11%) 0.51
ROP All infants 5/30 (17%) 6/32 (19%) 1.00
< 1000 g 4/16 (25%) 5/12 (42%) 0.43
1000–1500 g 1/14 (7%) 1/20 (5%) 1.00
IVH grade 3–4 All infants 0% 3/32 (9%) 0.24
< 1000 g 3/12 (25%) 0.06
1000–1500 g 0%
PVL All infants 2/32 (6%) 1/32 (3%) 1.00
< 1000 g 2/18 (11%) 1/12 (8%) 1.00
1000–1500 g 0% 0%
NEC All infants 1/32 (3%) 0% 1.00
< 1000 g 1/18 (6%)
1000–1500 g 0%
Use of steroids All infants 26/32 (81%) 7/32 (22%) <0.0001
< 1000 g 17/18 (94%) 6/12 (50%) 0.0086
1000–1500 g 9/14 (64%) 1/20 (5%) 0.0003
Death All infants 2/32 (6%) 0% 0.49
< 1000 g 2/18 (11%) 0.50
1000–1500 g 0%

BPD, bronchopulmonary dysplasia; DOL, day of life; GA, gestational age; IQR, interquartile range; IVH, intraventricular hemorrhage; NEC,
necrotizing enterocolitis; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity.
ˆ indicates GA (ie, 28ˆ0 = 28 weeks, 0 days).

32nd percentile at 36 weeks GA and the 32nd percentile at growth4,5 ; however, the drop from birth to 36 weeks GA
discharge. These trends demonstrate better growth main- appears more significant than clinically expected.
tenance in the study group to mimic that of intrauterine Nineteen percent of epoch 1 infants and 9% of
growth. This becomes most significant in the high-risk epoch 2 infants were discharged with weights plotting
infants born < 1000 g (ELBW). For this group of epoch < 10th percentile. Baseline rates of infants plotting
1 infants, median weight percentiles plotted at the 45th < 10th percentile on the Fenton growth curve for weight
percentile at birth, followed by the 12th percentile at both at birth were 6%, which means there were 4 infants in
36 weeks GA and discharge. For the ELBW epoch 2 infants, the control group and 1 infant in the study group who
median weight percentiles plotted at the 23rd percentile were not born < 10th percentile for weight but became
at birth, followed by the 16th percentile at 36 weeks and extrauterine growth-restricted (13% and 3% per group).
the 26nd percentile at discharge. One may argue that study These rates remain below the nationwide Vermont Oxford
infants had an additional week for catch-up growth if Network average in 2013, reporting 50.3% of infants born
needed, but it remains more likely that growth was better 501–1500 g discharging with weights < 10th percentile.1
maintained for study infants throughout hospitalization The Vermont Oxford Network also reported severe growth
considering a lower drop in percentiles from birth to 36 restriction with weight plotting < 3rd percentile at discharge
weeks GA. Epoch 1 infants did receive more dexamethasone in 27.5% of infants.1 None of the 32 study infants in epoch
than study infants, which may partially account for altered 2 discharged with weights < 3rd percentile. In further
Thoene et al 5

Table 2. Growth Outcomes.

Epoch 1 (n = 32) Epoch 2 (n =

Reported Median Category Median IQR 32) Median IQR P Value

Birth weight, grams All infants 968 (762,1323) 1125 (868,1360) 0.30
< 1000 g 804 (685,915) 820 (680,905) 0.90
1000–1500 g 1354 (1276,1428) 1310 (1150,1420) 0.44
Birth weight % All infants 45th percentile (20,50) 48th percentile (28,63) 0.34
< 1000 g 45th percentile (20,50) 23rd percentile (13,55) 0.75
1000–1500 g 50th percentile (45,50) 51st percentile (45,66) 0.42
36-week weight, grams All infants 2304 (N = 29) (2196, 2439) 2563 (N = 30) (2344,2751) 0.023
< 1000 g 2247 (1866,2398) 2341 (2104,2577) 0.32
All infants 2389 (2292,2734) 2684 (2542,2920) 0.065
36-week weight % All infants 15th percentile (10,25) 32nd percentile (16,44) 0.027
< 1000 g 12th percentile (3,20) 16th percentile (7,31) 0.49
1000–1500 g 23rd percentile (12,50) 41st percentile (29,58) 0.044
Discharge weight, grams All infants 2638 (2356.5,3049) 3321 (2902,3601) < 0.001
< 1000 g 2588 (2269,3003) 3197 (2951,3601) 0.0046
1000–1500 g 2662 (2377,3094) 3356 (2839,3662) 0.0028
Discharge weight % All infants 15th percentile (10,15) 32nd percentile (23,55) 0.0004
< 1000 g 12th percentile (9,15) 26th percentile (13,36) 0.042
1000–1500 g 23rd percentile (15,50) 43rd percentile (27,60) 0.019
36-week HC, cm All infants 32 (N = 26) (31,33) 32.4 (N = 30) (31,33) 0.88
< 1000 g 32 (30.5, 33) 31.1 (30.5,31.9) 0.32
1000–1500 g 32 (31,33) 32.8 (32,34) 0.45
36-week HC % All infants 33rd percentile (12,50) 37th percentile (11,63) 0.48
< 1000 g 15th percentile (10,50) 16th percentile (8,34) 0.49
1000–1500 g 40th percentile (20,50) 49th percentile (27,77) 0.27
Discharge HC, cm All infants 32.5 (31.9,34.8) 34.8 (33.4, 35.9) 0.002
< 1000 g 32.5 (32,33.5) 34.3 (33.3,35.9) 0.019
1000–1500 g 32.8 (31.8,35.5) 34.8 (33.4,35.9) 0.071
Discharge HC % All infants 25th percentile (14,50) 39th percentile (24,71) 0.031
< 1000 g 15th percentile (10,50) 32nd percentile (18,42) 0.38
1000–1500 g 33rd percentile (25,50) 55th percentile (32,78) 0.10
Weight < 10th percentile All infants 2/32 (6%) 2/32 (6%) 1.00
at birth < 1000 g 2/18 (11%) 2/12 (17%) 1.00
1000–1500 g 0/14 (0%) 0/20 (0%)
Weight < 10th percentile All infants 6/29 (21%) 5/30 (17%) 0.75
at 36 weeks GA < 1000 g 5/15 (33%) 5/12 (42%) 0.71
1000–1500 g 1/14 (7%) 0/18 (0%) 0.44
Weight < 10th percentile All infants 6/32 (19%) 3/32 (9%) 0.47
at discharge < 1000 g 5/18 (28%) 3/12 (25%) 1.00
1000–1500 g 1/14 (7%) 0/20 (0%) 0.41
HC < 10th percentile at All infants 1/26 (4%) 5/30 (17%) 0.20
36 weeks < 1000 g 1/15 (7%) 4/12 (33%) 0.14
1000–1500 g 0% 1/20 (6%) 1.00
HC < 10th percentile at All infants 4/32 (13%) 2/32 (6%) 0.67
discharge < 1000 g 4/18 (22%) 1/12 (8%) 0.62
1000–1500 g 0% 1/20 (5%) 1.00

GA, gestational age; HC, head circumference; IQR, interquartile range.

analyzing the study infant who became growth-restricted, 13.4 g/kg/d, which they estimate would be an additional 3
birth weight plotted at the 12th percentile and subsequently g/kg/d higher if initial days of diuresis were not included
discharged at the 6th percentile, therefore demonstrating a in the calculation.1 For comparison, we calculated the GV
less significant growth failure pattern than expected. in our groups. The average for epoch 1 was 12.8 g/kg/d,
The Vermont Oxford Network also reported GV for with epoch 2 being 13.3 g/kg/d. Epoch 2 (median DOL
> 360,000 infants, as reported in g/kg/d from birth until at discharge = 84 days) demonstrated a higher average
discharge.1 In 2013, the interquartile range for GV was 12.3– GV compared with the 2013 estimate of infants discharged
6 Nutrition in Clinical Practice 00(0)

Table 3. Feeding Progression and Treatment Outcomes.

Epoch 1 (n = 32) Epoch 2 (n = 32)

Reported Median Category Median Range IQR Median Range IQR P Value

DOL birth weight regained All infants 8 (5,9) 7 (6.10) 0.90

< 1000 g 8 2–17 (5,12) 7 3–21 (4.5,9) 0.64
1000–1500 g 8 2–11 (5,9) 7 5–12 (6,10.5) 0.50
DOL feedings started All infants 4 (3,7.5) 1 (1,1) < 0.0001
< 1000 g 5 3–22 (3,10) 1 1–4 (1,1) < 0.0001
1000–1500 g 3 2–11 (2.4) 1 1–2 (1,1) < 0.0001
DOL full enteral feedings All infants 22 (16,25) 7 (6,8) < 0.0001
achieved < 1000 g 22 13–50 (16,25) 8.5 6–16 (7,11.5) < 0.0001
1000–1500 g 21 9–39 (13,25) 6 5–10 (5,7) < 0.0001
Time interval to full feedings All infants 15 (11.5,19) 6 (5,7) < 0.0001
< 1000 g 14.5 9–36 (12,18) 7 5–15 (6,9.5) 0.0001
1000–1500 g 15.5 7–37 (11,23) 5 4–9 (4,6) < 0.0001
Days receiving parenteral All infants 17.5 (12,22.5) 5.5 (5,7.5) < 0.0001
nutrition < 1000 g 19 10–49 (13,23) 7.5 5–16 (6.5,9.5) < 0.0001
1000–1500 g 16.5 7–35 (9,22) 5 3–10 (4,6) < 0.0001
Days of indwelling central line All infants 17.5 (10.5,25) 6 (4,8) < 0.0001
< 1000 g 19 0–56 (13,36) 7.5 2–16 (6,9.5) 0.0009
1000–1500 g 16.5 0–38 (0,24) 5 0–10 (2,7) 0.066
Highest base deficit week 1 All infants 7.2 (5,8.3) 7.2 (4.1,8.6) 0.90
< 1000 g 7.8 0–14.2 (7,8.4) 8.4 4.7–22.5 (7.4,10.2) 0.26
1000–1500 g 5 2.9–11.3 (4,7.7) 6 0.9–13.3 (2.4,7.8) 0.62
Highest BUN week 1 All infants 34 (27,43.5) 39 (28,49.5) 0.23
< 1000 g 38 16–55 (28,48) 38 22–95 (28.5,54) 0.75
1000–1500 g 29 12–48 (19,41) 40 16–59 (28,46) 0.089
Highest BUN on full feedings All infants 35 (27,43.5) 20 (16,25.5) < 0.0001
< 1000 g 38 17–66 (31,50) 22 17–60 (18.5,30.5) 0.0092
1000–1500 g 29 12–48 (19,41) 20 7–28 (13,22.5) 0.010
Number of abdominal films All infants 19 (11,33) 0.5 (0,2) < 0.0001
< 1000 g 29 4–59 (17,38) 2 0–5 (0.5,3.5) < 0.0001
1000–1500 g 14 1–26 (4,19) 0 0–5 (0,1.5) < 0.0001
Number of packed red blood All infants 2.5 (0.5,6.5) 0 (0,0.5) < 0.0001
cell transfusions < 1000 g 6 1–12 (2,11) 1 0–5 (0,4) 0.0015
1000–1500 g 0 0–3 (0,2) 0 0–1 (0,0) 0.011

BUN, blood urea nitrogen; DOL, day of life; IQR, interquartile range.

between 78–174 DOL at 12.9 g/kg/d. These small differences GV around minimum of 18 g/kg/d for infants <2 kg because
in GV are likely quite clinically significant when evaluated this has been correlated with improved neurodevelopmental
at a more detailed level by birth weight groupings. When outcomes.6 Intrauterine growth has been estimated to range
comparing weight categories, Horbar et al reported mean between mean of 12.2–18.6 g/kg/d from 24–33 weeks GA
GVs from birth to discharge for infants born 501–1000 g to (and weight < 2 kg).7 Our estimations of growth in the study
be between 13.4–13.6 g/kg/d.1 The median velocity for our group achieved the upper range of these goals. Growth
epoch 2 group of infants < 1000 g was 14.5 g/kg/d (and 15.3 from 2 kg to discharge remained appropriate, with standard
g/kg/d for infants < 750 g). Horbar et al also reported the growth goals for infants < 3 months being 25–35 g/d.7
mean GV for infants 1000–1500 g to range between 12.1– Analyzing trends in median head circumference
13.1 g/kg/d.1 Our epoch 2 group infants had a median GV percentiles at 36 weeks GA and at discharge remained
of 13.1 g/kg/d. statistically similar, except for the discharge percentile
We decided to analyze growth in more detail for epoch 2, between combined weight groups (25th vs 39th percentile,
given the different growth goals dependent on kilogram size. P = 0.0004). However, it remains notable that the epoch
Between first weight exceeding birth weight to first weight 1 infants either maintained or decreased in percentiles,
exceeding 2 kg, growth averaged 18.3 g/kg/d (median). From whereas epoch 2 infants maintained or increased across
the first weight of exceeding 2 kg until discharge, growth all groups. The incidence of high-grade IVH approached
averaged 31.7 g/d (median). Our goal is to provide average significance in the epoch 2 group of infants < 1000 g
Thoene et al 7

(P = 0.06) but not in any other weight category group. weighing as little as 750 g,14 but limited data is available
After re-analyzing head circumference size and percentiles for infants < 750 g. Our epoch 2 group had 4 infants born
for this weight category when excluding infants with weighing < 750 g (range 618–730 g). All infants began
high-grade IVH, results remained similar to initial results feedings on the first DOL. The range to achieve full enteral
at both 36 weeks and at discharge. The median growth feeding was 7–16 days of life, with median of 11 days. Birth
percentiles for head circumference were the 15th percentile weight was regained by median DOL 5. None of these
(control) vs the 15th percentile (study) at 36 weeks GA and infants developed NEC. This contrasts data by Viswanathan
the 15th percentile vs 30th percentile at discharge. There et al, who reported that a slow standardized enteral feeding
were no differences in the number of infants per group who protocol reduced the incidence of NEC in infants < 750 g.15
discharged with head circumferences plotting < the 10th Infants began enteral feedings at roughly 14 days of life and
percentile for age (13% control vs 6% study). In review of were then slowly advanced to full enteral feedings by 44–
epoch 2 infants, this baseline at birth was 13% of the group. 52 days of life.15 Based on our data, study infants < 750 g
We do not have baseline statistics on head size for epoch achieved enteral feedings earlier than the collective group of
2 group due to no data being previously collected on these epoch 1 infants (median of 22 days).
infants for this data point. Compared with percentages Attainment of full enteral feedings (defined as the infant
at 36 weeks GA, this discharge trend demonstrates a receiving a minimum of 150 mL/kg/d of preterm infant for-
decreased rate of small head circumference in epoch 2 mula, or breast milk fully fortified to 24 cal/oz using human
and an increased rate in epoch 1. These comparisons are milk fortifier and a protein modular) were also achieved
most prominent in the category of smallest infants born < faster by initiating milk fortification earlier. Rationale for
1000 g. Discharge rates of small head circumference was this is exemplified by Miller et al, who demonstrated that
22% in epoch 1 vs 0% in epoch 2. This is an important the transition from full PN to full EN was a determinant
consideration because sustaining or catching up in head of later growth failure.16 A partial reason for this was
growth has been linked to improved neurodevelopment the lower protein provision with decreasing supplemental
outcomes in infants born < 750 g,8 born < 1500 g,9 and PN use.16 Therefore, it is important to recognize that PN
born < 1500 g and weight-plotting < 10 percentile at birth.10 will be more limited with faster enteral advancement. This
supports early milk fortification because more nutrition
Rationale for Feeding Protocol Modifications is required from enteral feedings alongside supplemental
PN to meet overall nutrition goals for growth. Likewise,
and Assessing Clinical Outcomes past studies have demonstrated tolerance with early milk
Enteral feedings were initiated earlier in epoch 2 infants fortification at enteral volumes of 20 mL/kg/d or at first
(DOL 1 vs 4) and were achieved sooner (DOL 7 vs 22) feeding initiation.17,18 Furthermore, enteral protein goals
than epoch 1 infants. Available literature supports early for epoch 2 were slightly higher; the American Academy of
feeding introduction because low enteral volumes are well Pediatrics recommends a range of 3.8–4.4 g/kg/d for infants
tolerated, and late introduction of feedings does not reduce < 1000 g, followed by a recommended dose of 3.4–4.2 g/kg/d
NEC risk.11,12 Length of trophic enteral feedings before for infants 1000–1500 g.19,20 Safe upper end protein doses
advancement is not well defined, but evidence demonstrates are reported as 4.9 g/kg/d.21
that delayed feeding only contribute to a prolonged time to Incidence rates of BPD at 36 weeks GA remained sta-
achieve full enteral feedings while requiring longer PN use.13 tistically similar in our analysis between combined groups.
Our outcomes support this: the quicker advancement in the However, infants < 1000 g had a higher rate in epoch 2
epoch 2 group eliminated the prolonged need for PN and compared with control (92% vs 38%, P = 0.006). There
an indwelling central line for access (5.5 vs 17.5 days). Also are multiple factors to consider when assessing these differ-
unique is the significant decrease in abdominal X-rays to ences. Firstly, a higher portion of epoch 1 infants receiving
specifically assess for perceived feeding intolerance (average dexamethasone (81% vs 22%, P < 0.0001), which has been
of 19 vs 0.5 throughout hospitalization). Not only does linked to a lower risk of having chronic lung disease at
faster enteral advancement optimize nutrition, but it further 36 weeks GA.22 Secondly, epoch 2 infants experienced
reduces the risk of PN-associated complications. There were improved growth compared with epoch 1, which we would
no differences in NEC between groups, and there were expect would reduce incidence of BPD.
no cases of NEC in epoch 2 infants despite faster enteral There were no statistical differences in rates of ROP be-
feeding advancement. This concurs with a recent Cochrane tween groups (17% control vs 19% study). Dexamethasone
review, which demonstrates the ability of very low birth has been linked to higher rates of severe ROP, but this is not
weight infants to tolerate more rapid enteral advancement significant in survivors.22 One contributing factor among
of 30–40 ml/kg/d, further leading to a reduced time on multiple variables to consider in ROP development is an
PN without an increased risk for NEC.13 Additionally, an early adequate delivery of essential nutrients followed by
advancement of 30 ml/kg can still be utilized in infants sufficient early growth.23 Equations and models to identify
8 Nutrition in Clinical Practice 00(0)

infants at high risk for developing ROP include growth 3. Patel AL, Engstrom JL, Meier PP, Kimura RE. Accuracy of methods
analysis24 ; therefore, growth must be closely monitored for calculating postnatal growth velocity for extremely low birth weight
infants. Pediatrics 2005;116:1466–1473.
from a clinical standpoint to promote best outcomes.
4. Bartholomew J, Martin CR, Allred E, et al. Risk factors and correlates
of neonatal growth velocity in extremely low gestational age newborns:
Strength and Limitations the ELGAN Study. Neonatology 2013;104:298–304.
5. Stark AR, Carlo WA, Tyson JE; National Institute of Child Health
The primary strength of this study is that it analyzes and Human Development Neonatal Research Network, et al. Adverse
growth and feedings outcomes in very low birth weight effects of early dexamethasone in extremely-low-birth-weight infants.
National Institute of Child Health and Human Development Neonatal
infants cared for in a high level NICU. Our high inclusion
Research Network. N Engl J Med 2001;344:95–101.
encompasses various acuity levels and is more indicative 6. Ehrenkranz R, Dusick A, Vohr B, Wright L, Wrage, L, Poole W.
of a true population of NICU infants. Although we have Growth in the neonatal intensive care unit influences neurodevelop-
a standard protocol for feeding advancement, it may vary mental and growth outcomes of extremely low birth weight infants.
based on an infant’s unique clinical status. Again, this is Pediatrics 2006;117:1253–1261.
7. Corkins MR, Balint J, Bobo E, Plogsted S, Yaworski JA, eds.
more reflective of real life scenarios, further allowing our
The A.S.P.E.N. Pediatric Nutrition Suppport Core Curriculum. Silver
feeding methods to be highly applicable to other neonatal Spring, MD: American Society for Parenteral and Enteral Nutrition;
units. 2010.
Limitations of this study include that it is retrospective; 8. Claas M, de Vries L, Koopman C, et al. Postnatal growth of preterm
thus, there were limitations on data to be analyzed for epoch born children ࣘ 750g at birth. Early Hum Dev, 2011;87(7):495–
507.
1 insofar that it was previously collected. Evaluation of head
9. Sammallahti S, Pyhälä R, Lahti M, et al. Infant growth after preterm
circumference may vary among nursing staff due to differ- birth and neurocognitive abilities in young adulthood. Pediatrics
ences in measuring tape placement. Growth measurements 2014;165:1109–1115.
were unavailable for infants discharged prior to 36 weeks 10. Leppänen M, Lapinleimu H, Lind A; PIPARI Study Group, et al.
GA. Although many epoch 2 infants demonstrated catch- Antenatal and postnatal growth and 5-year cognitive outcome in very
preterm infants. Pediatrics 2014;133:63–70.
up growth for head size, it remains unknown if this led to
11. Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral
improved neurodevelopmental outcomes. fasting for very preterm or very low birth weight infants. Cochrane
Database Syst Rev 2013;3:CD000504.
Conclusions 12. Morgan J, Young L, McGuire W. Delayed introduction of progressive
enteral feeds to prevent necrotising enterocolitis in very low birth weight
Data from our current feeding practices with a progressive, infants. Cochrane Database Syst Rev 2014;12:CD001970.
standardized, and evidenced-based enteral feeding protocol 13. Morgan J, Young L, McGuire W. Slow advancement of enteral feed
volumes to prevent necrotising enterocolitis in very low birth weight
demonstrated that early introduction and rapid advance-
infants. Cochrane Database Syst Rev 2015;10:CD001241.
ment of enteral feedings are feasible in very low birth weight 14. Karagol BS, Zenciroglu A, Okumus N, Polin RA. Randomized con-
infants without an increased risk for NEC. This aggressive trolled trial of slow vs rapid enteral feeding advancements on the
feeding practice is associated with shorter duration of clinical outcomes of preterm infants with birth weight 750–1250 g.
central line access, less PN use, and improved weight gain JPEN J Parenter Enteral Nutr 2013;37:223–228.
15. Viswanathan S, McNelis K, Super D, Einstadter D, Groh-
and head growth.
Wargo S, Collin, M. Standardized slow enteral feeding protocol
and the incidence of necrotizing enterocolitis in extremely low
Statement of Authorship birth weight infants. JPEN J Parenter Enteral Nutr 2015;39:644–
654.
M. Thoene and A. Anderson-Berry equally contributed to the
16. Miller M, Vaidya R, Rastogi D, Bhutada A, Rastogi S. From parenteral
conception and design of the research. M. Thoene contributed
to enteral nutrition: a nutrition-based approach for evaluating postna-
to the acquisition of the data. E. Lyden contributed to the tal growth failure in preterm infants. JPEN J Parenter Enteral Nutr
analysis of the data. M. Thoene, E. Lyden, and A. Anderson- 2014;38:489–497.
Berry contributed to the interpretation of the data. M. Thoene 17. Shah SD, Dereddy N, Jones TL, Dhanireddy R, Talati AJ. Early
and A. Anderson-Berry drafted the manuscript. All authors versus delayed human milk fortification in very low birth weight
critically revised the manuscript, agree to be fully accountable infants: a randomized controlled trial. J Pediatr 2016;174:126–
for the integrity and accuracy of the work, and approved the 131.e1.
final manuscript. 18. Tillman S, Brandon DH, Silva SG. Evaluation of human milk fortifi-
cation from the time of the first feeding: effects on infants of less than
31 weeks gestational age. J Perinatol 2012;32:525–531.
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