F289

ORIGINAL ARTICLE

Early enteral feeding and nosocomial sepsis in very low

birthweight infants
O Flidel-Rimon, S Friedman, E Lev, A Juster-Reicher, M Amitay, E S Shinwell
...............................................................................................................................
Arch Dis Child Fetal Neonatal Ed 2004;89:F289F292. doi: 10.1136/adc.2002.021923

See end of article for

authors affiliations
.......................
Correspondence to:
Dr Shinwell, Department of
Neonatology, Kaplan
Medical Center, PO Box 1,
Rehovot, Israel;
[email protected]
Accepted 13 May 2003
.......................

Background: The interrelations between early enteral feeding, necrotising enterocolitis (NEC), and
nosocomial sepsis (NS) remain unclear.
Objective: To evaluate the effect of age at the introduction of enteral feeding on the incidence of NS and
NEC in very low birthweight (VLBW, 1500 g) infants.
Methods: Data were collected on the pattern of enteral feeding and perinatal and neonatal morbidity on
all VLBW infants born in one centre during 19952001. Enteral feeding was compared between infants
with and without NS and/or NEC.
Results: The study sample included 385 infants. Of these, 163 (42%) developed NS and 35 (9%)
developed NEC. Enteral feeding was started at a significantly earlier mean (SD) age in infants who did not
develop nosocomial sepsis (2.8 (2.6) v 4.8 (3.7) days, p = 0.0001). Enteral feeding was introduced at the
same age in babies who did or did not develop NEC (3.1 (2) v 3.7 (3) days, p = 0.28). Over the study
period, the mean annual age at the start of enteral feeding fell consistently, and this correlated with the
mean annual incidence of NS (r2 = 0.891, p = 0.007). Multiple logistic regression analysis showed age
at start of enteral feeding, respiratory distress syndrome, and birth weight to be the most significant
predictors of risk of NS (p = 0.0005, p = 0.024, p = 0.011).
Conclusions: Early enteral feeding was associated with a reduced risk of NS but no change in the risk of
NEC in VLBW infants. These findings support the use of early enteral feeding in this high risk population,
but this needs to be confirmed in a large randomised controlled trial.

arly introduction of enteral feeding in preterm infants is

associated with improved growth, better nitrogen
balance, and maintenance of the intestinal barrier.13
However, early feeding has been implicated in the pathogenesis of necrotising enterocolitis (NEC) and, accordingly,
initiation of enteral feeding is often delayed for several days
to weeks.4 5
The incidence of NEC in very low birthweight (VLBW)
infants is 512%, and up to 30% will have at least one episode
of nosocomial sepsis during their stay in the neonatal
intensive care unit (NICU).6 7
In studies of adults after injury, prospective randomised
controlled trials of enteral feeding versus parenteral nutrition
have shown significantly lower rates of infection when the
gut is fed.8 9 In addition, studies in animals have shown early
feeding to be associated with more rapid maturation of gut
associated immune function.10
In our unit, during recent years, we have gradually started
enteral feeding at an earlier age and progressed in larger daily
increments. Thus, the purpose of the study was to evaluate
the impact of this change on the rate of nosocomial sepsis
and NEC in VLBW infants.

METHODS
Setting
This study was conducted in the NICU at Kaplan Medical
Center, Rehovot, which is a 27 bed, inborn tertiary unit that
provides a full range of neonatal and surgical services. About
50005500 infants are delivered annually in the hospital.
To reduce the incidence of nosocomial sepsis, an infection
control task force was established during the study period.
The group recommended and enforced a range of measures
for infection control, such as strict hand washing, the use
of disposable gloves and gowns as required, closed airway
suction systems, improved antiseptic procedures, careful

isolation of infected infants, and shortened courses of

antibiotic treatment. In addition, as of December 1998, in
response to increased antibiotic resistance of Gram negative
bacteria, the empiric antibiotic treatment for suspected
nosocomial sepsis was changed from ceftazidime and
amikacin to piperacillin/tazobactam and amikacin.
Definitions
Sepsis with coagulase negative staphylococci was defined as
two positive blood cultures taken from two different
peripheral sites combined with appropriate clinical signs.
For other bacteria, a single positive blood culture was
considered sufficient. Nosocomial sepsis was defined as
appearing after 72 hours of age.
The severity of the initial disease was assessed using the
clinical risk index for babies (CRIB) score.11 NEC was graded
as described by Walsh and Kliegman.12 Intraventricular
haemorrhage was graded by the method of Papile et al,13
and retinopathy of prematurity according to the international
classification.14
Study protocol
A retrospective chart review of VLBW (, 1500 g) infants
born during 19952001 was performed. Data were collected
on the daily amounts of enteral and parenteral nutrition,
clinical course, and major morbidity during the NICU stay.
Enteral feeding was started as soon as the infants
condition was considered to be stable by the attending
neonatologist. None of the following was considered a
contraindication to enteral feeding: mechanical ventilation
(endotracheal or nasal), umbilical catheters, low Apgar
Abbreviations: CRIB, clinical risk index for babies; NEC, necrotising
enterocolitis; NICU, neonatal intensive care unit; RDS, respiratory
distress syndrome; VLBW, very low birthweight

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scores, small for gestational age, or polycythaemia. Criteria

for withholding feeds (attending level decision) were
suspected or proven NEC, feeding intolerance (large gastric
residuals, abdominal distension), and suspected sepsis.
Enteral feeds were begun with either breast milk or a
standard preterm formula, and, once the infant reached full
feeds, nutritional supplements were added (human milk
fortifier, polycose, MCT oil). Parenteral nutrition was begun
with glucose (46 mg/kg/min), protein, and lipid up to
3 g/kg/day each, and adjusted thereafter as required. In
general, the energy intake of full enteral feeding was in the
range 100140 kcal/kg/day and that of parenteral feeding
80110 kcal/kg/day.
Criteria for exclusion from the study included major
congenital malformations, death during the first 48 hours
of life (as usually the cause of death is not related to either
nosocomial sepsis or NEC), transfer to another unit before
discharge home, and missing records.
Statistical analysis
Amounts and day of introduction of enteral and parenteral
nutrition were compared between infants with and without
nosocomial sepsis, and those with and without NEC.
Categorical variables were compared using the x2 test. The
means of continuous variables were compared using
Students t test, and the data are presented as mean (SD).
Correlation between continuous variables was measured
using Pearsons correlation coefficient. The influence of
relevant confounding variables, identified by univariate
analysis, was assessed using multivariate logistic regression
analysis.
Bacteriological methods
Blood cultures were tested with a Bactec 9240 system
(Beckton Dickenson, Sparks, Maryland, USA) using standard
methods. Identification and antibiotic sensitivity testing of
the pathogens was performed by a Vitek system (bioMerieux
Vitek, Inc, Durham, Missouri, USA). Susceptibility results
were interpreted as sensitive, intermediate, or resistant to
each antibiotic according to National Committee for Clinical
Laboratory Standards guidelines.15

Flidel-Rimon, Friedman, Lev, et al

Enteral and parenteral nutrition

Enteral feeding was started at an earlier age in infants who
did not develop nosocomial sepsis (2.8 (2.6) days v 4.8
(3.7) days, p = 0.0001). They were free of intravenous access
earlier (10.9 (8.8) days v 23.7 (18.3) days, p = 0.0001) and
had fewer days on total parenteral nutrition than infants who
did develop nosocomial sepsis (8.3 (6) days v 20.6 (12) days,
p = 0.0001). The findings were similar for the subgroup of
extremely low birth weight (, 1000 g) infants and those
infants with RDS (table 2).
No difference was observed in the incidence of human milk
feeds in infants with or without nosocomial sepsis (32% v
25%, p = 0.28).
Multivariate analysis, including variables that were significant on univariate analysis (table 1), showed age at start
of enteral feeding, RDS, and birth weight to be the most
significant predictors of risk of nosocomial sepsis (p = 0.0005,
p = 0.024, p = 0.011).
Figure 1 shows the annual mean age at introduction of
enteral feeding and the incidence of nosocomial sepsis during
19952001. The correlation between these variables was
significant (r2 = 0.89, p = 0.007). In comparison, although
RDS and birth weight are predictors of nosocomial sepsis,
they did not change throughout the study period.
Enteral feeding and NEC
Enteral feeds were started at the same age in infants with
and without NEC: 3.1 (2) v 3.7 (3) days, p = 0.28. Similar
findings were noted in the subgroup of infants with birth
weight below 1000 g: 4.2 (2) v 4.6 (3) days, p = 0.68.
Morbidity
Infants who developed sepsis during their stay in the NICU
had significantly higher rates of morbiditychronic lung
disease (O2 at 36 weeks) (24% v 5%, p = 0.0001), retinopathy of prematurity (43% v 15%, p = 0.0001)and they
were discharged at an older age (80 (44) v 52 (29) days,
p = 0.0001). There was no difference between the groups in
rate of intraventricular haemorrhage (14% v 16%, p = 0.49)
or mortality (7.4% v 10.8%, p = 0.25)

RESULTS
Study population
During the years 19952001, a total of 440 VLBW infants
were admitted to the NICU. Fifty five were excluded because
of congenital malformations (n = 14), death before the age
of 48 hours (n = 24), transfer to or from another hospital
(n = 15), and missing records (n = 2). None of the VLBW
infants who were transferred to another unit or the two
infants with the missing records had either NEC or
documented sepsis during their stay in our NICU.
The study group included 385 VLBW infants, of whom 163
(42%) developed nosocomial sepsis and 35 (9%) developed
NEC. Thirty six infants died after the age of 48 hours.
Infants with nosocomial sepsis were of earlier gestational
age (28.5 (2.5) weeks v 30.1 (3.2) weeks, p = 0.0001) and
lower birth weight (1042 (260) v 1167 (292) g, p = 0.0001),
suffered more often from respiratory distress syndrome
(RDS) (72% v 47%, p = 0.0001) and chronic lung disease
(11% v 45%, p = 0.00001), and had higher CRIB scores (5.1
(4) v 3.4 (4), p = 0.0001). In addition, infants with
nosocomial sepsis received more surfactant, mechanical
ventilation, umbilical and peripheral catheters, and parenteral nutrition.
No significant differences in delivery type, Apgar scores,
sex, incidence of early onset sepsis, and the rate of multiple
pregnancies were detected between infants with and without
sepsis (table 1).

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Table 1 Descriptive data, morbidity, treatments, and

mortality in the nosocomial sepsis and control groups

Number
Birth weight (g)
Gestational age (weeks)
SGA
CRIB score
Apgar score (1 min)
Apgar score (5 min)
Male
Caesarean section
Singleton
Early sepsis
RDS
PDA
CLD
NEC
IVH (all grades)
Mechanical ventilation (days)
Surfactant (doses)
TPN (days)

Sepsis

No sepsis

p Value

162
1042 (260)
28.5 (2.5)
17%
5.1 (4)
6.2 (2.7)
8.5 (1.6)
51.5%
71%
58%
2%
72%
41%
45%
18%
14%
14.9 (16)
1.5 (0.8)
21 (12)

223
1167 (292)
30.1 (3.2)
31%
3.4 (4)
6.7 (2.7)
8.8 (1.5)
48.6%
71%
53%
3%
47%
22%
11%
7%
17%
6.3 (9.6)
1.2 (0.8)
8 (6)

0.0001*
0.0001*
0.007*
0.0001*
0.09*
0.16
0.58
0.93
0.8
0.3
0.00001*
0.001*
0.00001*
0.001*
0.49
0.0001*
0.003*
0.0001*

Values are mean (SD) or percentage.

*Variables included in multivariate analysis.
SGA, Small for gestational age; CRIB, clinical risk index for babies; RDS,
respiratory distress syndrome; PDA, patent ductus arteriosus; CLD,
chronic lung disease; NEC, necrotising enterocolitis; IVH, intraventricular
haemorrhage; TPN, total parenteral nutrition.

Early feeding in preterm infants

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Table 2 Age at start of enteral feeding in very (VLBW) and extremely low birthweight infants with and without nosocomial
sepsis and necrotising enterocolitis (NEC) and respiratory distress syndrome (RDS)

Birth weight ,1500 g

Birth weight ,1000 g
VLBW infants with RDS

Sepsis (days)

No sepsis (days)

p Value

NEC

No NEC

p Value

4.8 (3.7) n = 162

5.5 (3.7) n = 64
5.2 (3.5) n = 110

2.8 (2.6) n = 221

3.2 (2) n = 42
3.8 (3.3) n = 87

0.0001
0.001
0.006

3.1 (2) n = 32
4.2 (2) n = 13
2

3.7 (3) n = 322

4.6 (3) n = 93
2

0.28
0.68
2

(2)

(3)

(4)

Figure 1 Mean annual incidence of nosocomial sepsis, age at start of

enteral feeding, mean annual birth weight and incidence of respiratory
distress syndrome (RDS) 19952001.

DISCUSSION
In this study, early enteral feeding, starting at the second or
third day of life, appeared to be associated with a reduced risk
of nosocomial sepsis without incurring an increased risk of
NEC.
This study, when taken together with other recent work,
suggests that the potential benefit of less sepsis outweighs
the potential but unproven risk of NEC. In fact, there is
mounting evidence for the decreased significance of enteral
feeding in the pathogenesis of NEC. Rayyis et al16 compared
slow feeding advancement (15 ml/kg/day) with fast feeding
advancement (35 ml/kg/day) in VLBW infants and found no
difference in the incidence of NEC. Ostertag et al17 attempted
to determine the optimal time for initiating enteral feeds in
VLBW sick infants. They found no difference in the incidence
of NEC between early enteral feeding starting on day 1 of life
compared with day 7 of life. Davery et al18 compared early
(2 days) versus late (25 days) enteral feeding in VLBW
infants and likewise found no difference between the groups.
An alternative approach is to begin early trophic feeding, in
which only small volumes of 0.51 ml/kg/h are begun within
the first days of life and increased later when the infants
condition is considered stable. Trophic feeding combines an
attempt to overcome the lack of gastrointestinal stimulation
during total parenteral nutrition with minimal stress to the ill
infant.19 This has been tried successfully and without an
increase in the risk of intestinal complications.
Possible mechanisms involved in the decrease in the rate of
infection with early enteral feeding include:
(1) Prevention of gastrointestinal atrophy: animal studies
show that gastrointestinal atrophy develops within
two to three days of fasting even in those kept in

(5)

positive nitrogen balance. This appears to be because

enterocytes rely on the gastrointestinal luminal content
for nutrition.20
Intestinal bacterial contamination: the absence of enteral
feeding leads to an alteration in gut flora allowing the
overgrowth of enteropathogenic species.21 In addition,
Garcia-Lafuente et al22 showed that single-organism
colonisation of an isolated loop of rat intestine induced
changes in permeability that facilitate bacterial translocation into the bloodstream.
Early feeding allows decreased use of total parenteral
nutrition. Total parenteral nutrition has been shown to
have an immunosuppressive effect. Okada et al23 24 have
shown that when it is administered for more than two
weeks it impairs the phagocytosis and killing of
coagulase negative staphylococci, and that introduction
of small volumes of enteral feeding improved this
finding.
Earlier enteral feeding results in a decreased need for
intravenous devices and thus less insult to the skin and
less opportunity for the entry of pathogenic organisms.
Mucosal immunity: the source of most mucosal immunity in humans is from gut associated lymphoid tissue in
the Payers patches of the small intestine. Neonates are
born without any appreciable gut associated lymphoid
tissue, but it slowly increases to normal levels over the
first two years of life. There is evidence to suggest that
early feeding, particularly colostrum and human milk,
may promote the development of specific immune
function in association with the gut associated lymphoid
tissue.25 26 The possible significance of this mechanism in
preterm infants is as yet unclear.

Retrospective studies may point to correlations between

events and thus serve as the basis for hypotheses. Although
many factors, including infection control measures, may have
been important, this study appears to suggest that feeding
preterm infants earlier may help to reduce the risk of
infection. The multivariate analysis and correlation over time
between earlier feeding and less sepsis support this evidence.
However, large randomised trials are required to provide
conclusive evidence that it is safe and beneficial to start
enteral feeding early in preterm infants.
.....................

Authors affiliations
O Flidel-Rimon, S Friedman, A Juster-Reicher, M Amitay, E S Shinwell,
Department of Neonatology, Kaplan Medical Center, Rehovot, Israel
and The Hebrew University, Jerusalem, Israel
E Lev, Department of Pediatrics, Schneider Childrens Hospital, PetachTiqva, Israel

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