In conclusion, it seems feasible and safe to start total enteral feeding in stable VLBW infants born with birth weight greater than 1000–1200g. This approach can reduce the need of intravenous fluid or PN and its adverse consequences as well as decrease the length of hospital stay for these infants. A larger randomized trial is needed to ensure ETEF is not associated with increased risk of NEC in stable preterm infants with birth weight greater than 1000g and gestational age greater than 28 weeks. Furthermore, there is a need to explore whether ETEF regimen is feasible in extremely low birth weight infants.

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Early total enteral feeding in stable preterm
infants: a systematic review and meta-analysis
Belal Alshaikh, Dinesh Dharel, Kamran Yusuf & Nalini Singhal
To cite this article: Belal Alshaikh, Dinesh Dharel, Kamran Yusuf & Nalini Singhal (2019): Early
total enteral feeding in stable preterm infants: a systematic review and meta-analysis, The Journal
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2. REVIEW ARTICLE
Early total enteral feeding in stable preterm infants: a systematic review
and meta-analysis
Belal Alshaikh, Dinesh Dharel, Kamran Yusuf and Nalini Singhal
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
ABSTRACT
Objective: To evaluate safety and feasibility of early total enteral feeding (ETEF) in stable pre-
term infants.
Study design: Systematic review and meta-analysis of randomized trials comparing incidence of
necrotizing enterocolitis (NEC) and feeding intolerance between ETEF and slow rates of enteral
feed advancement.
Results: Four trials involving 393 very low birth weight (VLBW) infants with birth weight
>1000–1200 g were included. Meta-analyses did not show statistical difference in risks for NEC
(RR 0.87, 95% CI 0.19–3.98) and feeding intolerance (RR 0.78, 95% CI 0.39–1.59). ETEF resulted in
lower risk of late-onset sepsis (RR: 0.43, 95% CI: 0.30–0.61). Length of hospital stay was reduced
in ETEF (mean difference À1.31 days, 95% CI: À1.54 to À1.07).
Conclusions: ETEF appears to be safe and feasible in stable VLBW infants with birth weight
>1000–1200 g. A large randomized trial is needed to confirm benefits.
ARTICLE HISTORY
Received 23 November 2018
Revised 10 June 2019
Accepted 26 June 2019
KEYWORDS
Early feeding; feeding
intolerance; necrotizing
enterocolitis; preterm
infant; VLBW
Background
Enteral feeding is the preferred route for nutritional
support in preterm infants. However, fear of necrotiz-
ing enterocolitis (NEC) has perpetuated delayed initi-
ation and slow advancement of enteral feed volumes.
In most neonatal intensive care units (NICUs), initial
nutritional support of early preterm ( 336/7
weeks ges-
tation) and very low birth weight (VLBW) infants is
achieved by parenteral nutrition (PN) with delayed ini-
tiation and slow progress of enteral feeding. Prolonged
use of PN is associated with increased risk of infectious
and metabolic complications, increased length of hos-
pital stay, and adverse effects on growth and develop-
ment [1–3]. Delayed initiation of enteral feed is
associated with gastrointestinal atrophy, alteration of
gut microbiota, decreased gastrointestinal hormone
secretion, decreased motility, and decreased functional
adaptation of the gastrointestinal tract [4–7].
Improved understanding of fetal and preterm gastro-
intestinal functions along with increased recognition of
beneficial effects of early use of human milk have
encouraged neonatologists to try early total enteral
feeding (ETEF) regimen in stable early preterm infants to
optimize nutrition and shorten hospital stay [8]. In utero,
the fetus swallows around 250 ml/kg per day of amniotic
fluid [9], which contributes 10–14% of fetal nutritional
needs. This indicates clearly that the gastrointestinal tract
of preterm infants can handle a significantly higher vol-
ume than what neonatologists feed these infants in the
first few days of life [9]. Furthermore, osmolarity of
human milk (290–300 mOsm/L) is just slightly higher
than amniotic fluid (250–260 mOsm/L) [10,11].
Availability of donor human milk has made it possible to
feed early preterm infants larger human milk volume
until mother’s milk supply is sufficient.
Recent Cochrane reviews have suggested that
early enteral feeding and rapid advancement (up to
35 ml/kg/day) can be accomplished in preterm infants
without increasing the risk of NEC or death [12,13]
and can help achieve full enteral feeds 3–4.8 days
sooner [13]. However, studies included in these sys-
tematic reviews focus solely on different speeds of
enteral feed advancement in VLBW infants. Safety
and feasibility of rapid advancement regimens raises
the question whether ETEF (i.e. 50–80 ml/kg per day
from day of birth) is feasible, and if intravenous fluid
and/or PN can be avoided. There is no systematic
review evaluating the effects of ETEF in early pre-
term infants.
CONTACT Belal Alshaikh Belal.Alshaikh@albertahealthservices.ca Department of Pediatrics, Cumming School of Medicine, University of Calgary,
Calgary, AB, Canada
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2019.1637848

3. The objective of this review was to systematically
evaluate the feasibility of ETEF and to assess its effects
on risk of NEC, feeding intolerance, late-onset sepsis
and length of hospital stay in early preterm infants.
This is critically important for guiding feeding strat-
egies in the era of exclusive human milk use in
this population.
Methods
Criteria for considering studies for this review:
Types of studies: Controlled trials utilizing either
random or quasi-random participant allocation.
Types of participants: Enterally fed early pre-
term infants.
Types of interventions: Feeding initiated and
advanced to full enteral feed (minimum of 80% of
reference daily intake) from day of birth.
Types of outcome measures:
Primary outcome: Incidence of NEC (as defined by
the trial and in line with modified Bell’s staging crite-
ria) [14].
Secondary outcomes:
1. Incidence of feed intolerance (FI) (as defined
by trial).
2. Days to establish full enteral feeding.
3. Days to regain birth weight.
4. Incidence of late-onset sepsis (as determined by
culture of bacteria or fungus from blood, cerebro-
spinal fluid, urine, or from a normally sterile
body space).
5. Duration of hospital stay.
Search strategy
The literature search was performed in May 2019. This
meta-analysis has adopted the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines for systematic reviews and meta-
analysis [15]. Published randomized and quasi-random-
ized controlled trials (RCTs) of early (within 24 h of
birth) and total (at least 80% of total fluid intake is
given enteral) and NEC in early preterm infants were
identified using both manual and electronic search
strategies. Searches were limited to human infants but
were not limited by language. This search was applied
to MEDLINE (1966 to May 2019), EMBASE (1980 to
May 2019), CINAHL (1982 to May 2019), and the
Cochrane Central Register of Controlled Trials (2019).
The online metaRegister of Current Controlled Trials
was also searched for relevant ongoing clinical trials
(May 2019). Additional citations were sought by hand-
searching the reference list of retrieved articles and
abstracts of three major pediatric international meet-
ings (American Pediatric Society, the European Society
for Pediatric Research, and the Society for Pediatric
Research) published in the journal of Pediatric
Research (1985 to May 2019). A combination of text
words and exploded medical subject headings were
used to maximize the volume of literature retrieved.
The search was broken into three comprehensive
themes. The first theme was to identify the population
of interest using the Boolean search term “or” to
explode (search by subject heading) and map (search
by keyword) the medical subject headings “preterm
infants, or infants less than 37 weeks or 37 weeks
gestation or 36 ‘6/7’
weeks gestation”. We elected to
include all preterm infants in the search to capture all
potential preterm gestational age in literature. The
second theme was performed to identify relevant
intervention using the term “or” to explode and map
the medical subject headings “total feedà or exclusive
feedà or full feedà or rapid advanceà feedà or early
total feedà or early exclusive feedà or early full feedÃ
or total enteral feedà or exclusive enteral feedà or full
enteral feedà or early total feedà or total enteral nutri-
tion or exclusive enteral nutrition or early enteral
nutrition or full enteral nutrition”. The third theme was
created employing the recommended Cochrane
Collaboration’s high sensitive searching strategy to
identify relevant RCTs in Medline and Embase [16].
The three Boolean searches were then combined
using the Boolean term “and”. Outcome was not
specified in our search to capture all potential trials
evaluating the use of early total feed in neonates.
Study selection criteria
Three reviewer authors (BA, DD, KY) independently
searched for and assessed identified articles for eligi-
bility for this systematic review and meta-analysis.
Criteria for the inclusion and exclusion of studies were
based on the five components of the PICOD format:
(1) target population: preterm infants; (2) intervention:
early total feed or exclusive feed with rapid advance-
ment; (3) comparison: late feed start and slow feed
advancement; (4) outcome: NEC; (5) study design:
RCTs. Additionally, only studies with previously unpub-
lished outcome data (original data from an original
study) were included. Only trials in preterm (gesta-
tional age 37 weeks) were considered for this review.
2 B. ALSHAIKH ET AL.

4. All discrepancies encountered in the review process
were resolved by consensus.
Data extraction
Data extraction of retrieved studies was performed
independently by two reviewers (BA and DD) using a
standardized data collection form. Any discrepancies
in extracted data were resolved by consensus. The fol-
lowing data were collected: journal name, year of pub-
lication, country, single-center or multicenter status,
definitions adopted, inclusion and exclusion criteria,
details of study protocol, demographic data, duration
of follow-up, number of patients in intervention and
control arms, proportion of patients with the primary
or secondary outcomes of interest. The primary out-
come was the incidence of NEC as defined in individ-
ual trials and in line with Bell’s staging criteria [14].
The secondary outcome measures included incidence
of FI as defined in individual trials, time to establish
full enteral feeding, time to regain birth weight, inci-
dence of late-onset sepsis and length of hospital stay.
We also extracted information for key indicators of
study quality in clinical trials proposed by Egger et al.
[17,18] Authors of original studies were contacted via
email for missing information.
Assessment of trial quality
Two reviewers (BA and DD) independently assessed
the methodological quality of individual studies. Any
disagreements were resolved by discussion and con-
sensus. The methodological quality of the studies was
assessed using the following key criteria: method of
randomization, allocation concealment, blinding of
intervention, blinding of outcome, and whether all
outcomes of all infants enrolled in the trial were
reported. For each criterion, assessment was yes, no,
or not described. An overall quality score was deter-
mined for each study as described by Jadad et al. [19].
Data synthesis and analysis
Stata version 11 (Stata Corporation, College Station, TX)
was used for all statistical analysis. For categorical out-
comes, estimates for risk ratio (RR) together with the
corresponding 95% confidence intervals (CIs) and the
percentage weight contributed to the overall meta-ana-
lysis from each trial were calculated. Continuous out-
comes were analyzed using the weighted mean
difference along with 95% CIs. For each outcome of
interest, effect estimates were pooled assuming a fixed-
effect modeling approach and using the Mantel
Haenszel method for categorical variables and the
inverse variance method for continuous variables. If het-
erogeneity was observed, a random-effects model was
employed using the DerSimonian and Laird method.
Heterogeneity across RCTs was evaluated using both
the I2
and Q statistics; p .1 was defined to note statis-
tical significance in the analysis of heterogeneity. Lastly,
we assessed for potential evidence of publication bias
through visual inspection of Begg’s funnel plot and the
Egger test for funnel plot asymmetry.
Results
Study identification
Among the 230 citations identified after excluding the
duplicate titles, four randomized trials were eligible
(Figure 1).
Study characteristics
The number of infants in each study, criteria used for
the definition of ETEF and, feed volume advancement,
use of parenteral fluid or nutrition, primary and second-
ary outcomes, and duration of follow up are depicted in
Table 1. The methodological quality of included trials is
presented in Table 2. All studies were of moderate
methodological quality based on criteria that evaluates
allocation concealment, use of control arm, and com-
plete reporting of all outcomes for all patients. All four
studies had Jadad scores of 2–3 because they lacked
blinding for both intervention and outcome [20]. In all
studies, only hemodynamically stable preterm infants
with birth weight above 1000–1200g and below 1500 g
were eligible for inclusion (Table 1). All studies excluded
infants with major congenital anomalies, respiratory dis-
tress requiring mechanical ventilation, infants requiring
positive pressure ventilation during resuscitation at birth
and those with signs indicating possible birth asphyxia.
Infants needing nasal continuous positive airway pres-
sure (nCPAP), nasal prongs or hood oxygen were
included in studies by Sanghvi et al. [21] and Chetry
et al. [20]. Bora and Murthy [22] included only infants
with no respiratory distress and on room air while
Nangia et al. [23] included those with respiratory sup-
port limited to nasal prongs or hood oxygen. All studies
started feeding with 80 ml/kg per day. All studies
included small for gestation age (SGA) infants. Chetry
et al. [20] excluded infants who were severe SGA (less
than 3rd percentile on Fenton chart). Nangia et al. [23]
excluded infants who had absence or reversed end dia-
stolic flow on fetal ultrasound. Infants with
THE JOURNAL OF MATERNAL-FETAL NEONATAL MEDICINE 3

5. hypoglycemia were excluded from the study by Bora
and Murthy [22]. Infants who developed hypoglycemia
in the other three studies were treated according to spe-
cific protocol that allow use for intravenous bolus of
10% dextrose at 2ml/kg without changing the feeding
or fluid regimen unless the infant remained hypogly-
cemic on two consecutive blood sugar tests.
Definition of FI varied between the three studies.
Sanghvi et al. [21] and Chetry et al. [20] defined FI as
gastric residuals of 30% of the total feeds received
after the previous aspiration and/or associated with
vomiting or increased abdominal girth. Bora and
Murthy [22] defined FI as presence of one or more of
the followings: prefeed aspirate !50% of previous
feed volume, vomiting 3 times during any 24 h, any
episodes of bile or blood stained vomiting, abdominal
girth increase 2 cm between feeds, erythema of
abdominal wall, or gross blood in stool. Nangia et al.
[23] had a similar definition to Bora and Murthy [22]
except for prefeed aspirate of 25%, having recurrent
apnea (3 episodes in 1 h), and presence of occult
blood in stool. Definition of NEC was based on modi-
fied Bell’s staging criteria in all studies.
Quantitative data synthesis
The four studies contained data on 393 infants, among
whom 196 received ETEF and 197 received a feeding
regimen that involves gradual increase of enteral feed
along with intravenous dextrose 10%. All trials pro-
vided evidence of a similar relative risk for NEC
between infants on ETEF regimen and those on the
slow volume advancement regimen.
The overall pooled RR for FI using a random-effects
model was 0.78 (95% CI: 0.38–1.59) (Figure 2). There
was evidence of statistical heterogeneity between tri-
als (I2
¼ 54.1%; p values ¼ 0.09). Begg’s funnel plot
with pseudo 95% CIs to assess evidence of publication
bias was generated (Figure 3). The overall pooled RR
for late-onset sepsis using a fixed-effects model was
0.43 (95% CI: 0.30–0.61). There was no evidence of
statistical heterogeneity between trials (I2
¼ 37.3%;
p values ¼ 0.19). The pooled RR for developing NEC
using a fixed-effects model was 0.87 (95% CI:
0.19–3.98) with significant heterogeneity (I2
¼ 74.1%,
p values ¼ 0.049). Sanghvi et al. [21] and Chetry et al.
[20] had no NEC events in both arms of their trials;
therefore, these studies were excluded by Stata from
the analysis because standard error could not
be estimated.
The pooled estimate of the mean difference in time
to regain birth weight between the ETEF group and
control group using a random-effects model was –
1.15 days (95% CI: À1.86 to À0.45). There was signifi-
cant statistical heterogeneity between the trials
(I2
¼ 89.1% and p .001). The pooled estimate of the
Figure 1. Flowchart showing selection of studies for inclusion in the systematic review and meta-analysis.
4 B. ALSHAIKH ET AL.

6. mean difference between length of hospital stay in
ETEF and control groups using a random-effects
model was À1.35 days (95% CI: À2.57 to À0.13). The
test for heterogeneity was significant across trials
reporting (I2
¼ 96.1, p .001). Only two trials, Chetry
et al. [20] and Bora and Murthy [22], reported duration
to reach full enteral feeds. The pooled estimate for the
difference in duration to reach full enteral feeds utiliz-
ing a random-effects modeling approach was in favor
of ETEF À1.01 days (95% CI, À1.36 to À0.66) without
significant heterogeneity (I2
¼ 47.9%, p ¼ .17).
Discussion
This systematic review combines results from four
RCTs evaluating potential benefits of ETEF in stable
VLBW infants with birth weight greater than
1000–1200 g. Our results indicate that ETEF from birth
onward is feasible and well tolerated in this popula-
tion. In addition, this systematic review indicates that
ETEF is associated with lower rate of late-onset sepsis,
less time to reach full enteral feeds, less time to regain
birth weight and shorter duration in hospital stay.
This is the first systematic review and meta-analysis
looking at the feasibility, safety, and benefits of ETEF
in stable preterm infants. Our findings are also sup-
ported by cohort studies. A recent before and after
study to evaluate effectiveness of ETEF in stable pre-
term infants with birth weight 1000–1500 g indicated
safety as well as decreased incidence of sepsis and
NEC and shorter length of hospital stay [8]. Another
prospective observational study revealed that exclu-
sive enteral nutrition from birth is feasible in
30–33 weeks preterm infants and may reduce length
of hospital stay without increasing the risk of NEC
[24]. Nonetheless, this study has small sample size and
was mainly conducted to explore feasibility. Its results
were confounded by gestational age, as infants who
were totally enterally fed on first day after birth were
also of higher gestational age [24]. Mature infants are
anticipated to tolerate feeds better and to be dis-
charged earlier [24].
Potential benefits of ETEF include lesser need for
venous access such as peripheral intravenous (PIV)
catheter, umbilical vascular catheters (UVCs), and per-
ipherally inserted central catheters (PICCs). This can
explain the lower incidence of late-onset sepsis in
infants on the ETEF regimen. Skin puncture for PIV
and PICC catheter is painful and increases stress inten-
sity. Growing evidence suggests altered brain develop-
ment with repeated painful skin procedures in
preterm infants [25,26]. UVC provides painless venous
Table1.Characteristicsofstudiesreportingtheearlytotalenteralfeedinginearlypreterminfants.
Study
No.of
infants
Population
birth
weight(g)
Gestational
age(week)SGA(%)
Feedvolumestart
(ml/kg/d)
Typeoffeed
Feed
advance
(ml/kg/d)
Definition
offull
enteral
feed
(ml/kg/d)
Parenteral
fluidsinthe
intervention
group
Parenteral
fluidin
control
groupPrimaryoutcome
Secondary
outcomesFollow-upInterventionControl
Sanghvi2013461200–150028–3619.68030MOMor
preterm
formula
20180NoDextrose
10%
Timetoregain
birthweight
Lengthofhospital
stay.Incidence
ofNEC
andsepsis
Discharge
Chetry2014641000–150030–34All3rd
percentile
8020MOMor
preterm
formula
20180NoDextrose
10%
Timetoreach
full
enteralfeed
Feedintolerance,
incidenceof
NECandsepsis
Discharge
Bora20161031000–150062.18020MOMorDHM20150NoDextrose
10%
Feedintolerance
andNEC
Timetoreach
110kcal/kg/d,
timetoregain
birthweight
21daysor
discharge
Nangia20191801000–150028–3430.08020MOMor
preterm
formula
20–30150NoDextrose
10%
Timetoreach
full
enteralfeed
Feedintolerance,
incidenceof
NECandsepsis
Discharge
BW:birthweight;MOM:mother’sownmilk;DHM:donorhumanmilk;PN:parenteralnutrition.
THE JOURNAL OF MATERNAL-FETAL NEONATAL MEDICINE 5

7. access; however, it can cause life-threatening compli-
cations including central line-associated blood stream
infection [27]. None of the studies examined the fre-
quency of skin puncture for PIV access, or number of
inserted UVCs and PICC lines.
Although our systematic review provides details on
feasibility and potential benefits of ETEF in stable
VLBW infants with birth weight 1000–1200 g, several
limitations need to be considered. There were limited
availability of randomized trials to be included in the
meta-analysis. All studies in our systematic review had
small sample sizes and were not powered to detect
difference in incidence of NEC as a primary outcome.
NEC was rare outcome in the studies’ population. Two
of the studies, Sanghvi et al. [21] and Chetry et al.
[20], did not have any occurrence of NEC in either
arm. The overall sample size of the combined studies
was inadequate to estimate the difference in the
incidence of this rare but serious outcome.
Furthermore, the follow-up in all trials was until dis-
charge from NICU and any readmission to hospital or
long-term effect on growth and neurodevelopment
cannot be commented upon.
The trials included infants between 1000 and
1500 g with one, Sanghvi et al. [21], limited to
1200–1500 g. All studies included variable proportion
of SGA infants. Bora et al. [22] included infants born at
any gestational age as long as birth weight is under
1500 g. This resulted in having slightly more mature
and SGA infants in their study. The wide range of ges-
tational age may affect the generalizability of findings
to the less mature infants in the spectrum. A similar
situation applies to the inclusion of infants with vari-
able degree of respiratory support in the four studies.
Finally, the occurrences of hypoglycemia and the pro-
portion of babies in the ETEF regimen who received
Figure 2. Meta-analysis of incidence of feeding intolerance.
Table 2. Methodological quality of included trails.
Study
Single or
multicenter
Randomization
process
described
Allocation
concealment
Blinding
intervention
Blinding
outcome Controlled arm
Complete
follow-up Jadad scorea
Sanghvi Multicenter Yes Yes No No Yes Yes 3
Chetry Single center Not described Not described No No Yes Yes 2
Bora Single center Yes Yes No No Yes Yes 3
Nangia Single center Yes Yes No No Yes Yes 3
a
Jaded score range: 0–5.
6 B. ALSHAIKH ET AL.

8. intravenous fluid was not reported, which would have
been more informative in ascertaining safety of
this approach.
All the studies were conducted in low to middle
income country settings and it would be interesting
to investigate the feasibility and benefits of ETEF in
high income countries where PN and donor human
milk are standard of nutritional care in initial days of
life. The new trials should aim to enroll more infants,
preferably in multiple centers. Once proved feasible
and safe, the larger trials should aim for longer-term
growth and development as primary outcome. Cost-
effectiveness analysis of total enteral feeding against
conventional PN with gradual increment of enteral
nutrition can be an important addition to advocate for
best feeding approach for stable early preterm infants.
In conclusion, it seems feasible and safe to start
total enteral feeding in stable VLBW infants born with
birth weight greater than 1000–1200 g. This approach
can reduce the need of intravenous fluid or PN and its
adverse consequences as well as decrease the length
of hospital stay for these infants. A larger randomized
trial is needed to ensure ETEF is not associated with
increased risk of NEC in stable preterm infants with
birth weight greater than 1000 g and gestational age
greater than 28 weeks. Furthermore, there is a need
to explore whether ETEF regimen is feasible in
extremely low birth weight infants.
Disclosure statement
No potential conflict of interest was reported by the authors.
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