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ORIGINAL ARTICLE
Background/Objective: In this retrospective study, we intended to test whether early enteral feeding (EEF) of very low birth
weight (VLBW) preterm babies increases the risk of necrotizing enterocolitis (NEC) or not.
Subjects and Methods: Overall, 297 VLBW preterm babies admitted to the neonatal intensive care unit (NICU) between April
2003 and April 2006 were included. The study consisted of two periods: the first period was between April 2003 and October
2004, when babies were not fed enterally until they were extubated (167 preterm VLBWs). The second period was between
November 2004 and April 2006, when babies were fed even when they were intubated, starting preferably on the first day of life
(130 preterm VLBWs). Criteria for withholding enteral feeding in both periods were hypotension necessitating vasopressor agent
use, abdominal distention, abdominal tenderness and suspected or proven NEC. Possible risk factors for NEC were also
recorded.
Results: The overall incidence of NEC in VLBW preterm babies was 6.7% and did not differ between the two study periods: 7.2%
in the late and 6.2% in the EEF regimens. On logistic regression analysis, the most important risk factors associated with NEC
were sepsis (Po0.001) and blood culture positivity (Po0.001). The average daily weight gain was significantly higher in the
early fed babies (P 0.011).
Conclusions: The EEF of VLBW preterm babies does not increase the risk of NEC. Increased daily weight gain is an important
reason to feed these babies earlier.
European Journal of Clinical Nutrition (2009) 63, 580584; doi:10.1038/sj.ejcn.1602957; published online 28 November 2007
Keywords: prematurity; necrotizing enterocolitis; very low birth weight; enteral feeding; septicemia; neonatal intensive care unit
Introduction
Necrotizing enterocolitis (NEC) is the most common and
important gastrointestinal disease of the newborn that needs
emergency intervention . The incidence of NEC varies across
different neonatal units and periods, ranging from 1 to 22%
in very low birth weight (VLBW) infants (Lin and Stoll,
2006). In the latest NICHD neonatal network cohort (1999
2001), about 7% of VLBW babies developed proven NEC
(4stage II), with about half undergoing surgery (Guillet
et al., 2006). In this cohort, NEC rates were inversely related
to birth weight. Intestinal immaturity due to prematurity,
581
babies and whether early and late feeding policies have any
impact on daily weight gain, length of stay and mortality.
risk factors for NEC were also recorded, which were umbilical
vein catheterization, small for gestational age birth, polycythemia, partial exchange transfusion for polycythemia,
sepsis (clinical or blood culture proven), patent ductus
arteriozus and antenatal corticosteroid use (as a protective
factor).
Necrotizing enterocolitis was classified according to modified Bells staging criteria (Walsch and Klegman, 1986). Stage
Ia and Ib cases of NEC were treated with parenteral
antibiotics and bowel rest for 37 days. Stage II or greater
cases were treated with parenteral antibiotics and bowel rest
for 47 days.
Patent ductus arteriozus was diagnosed by echocardiogram
and treated with oral ibuprophen.
Partial exchange transfusion was performed in polycythemic babies whenever hypoglycemia and/or thrombocytopenia and/or poor signs of peripheral perfusion occurred and
when there was no other reason than polycythemia to
explain these signs.
llners
Clinical sepsis was diagnosed according to To
scoring system. Babies getting 10 points and higher were
diagnosed as clinical sepsis (Tollner, 1982). Every baby
diagnosed as clinical sepsis underwent sepsis work-up and
was treated with appropriate antibiotics.
According to the NICU protocol, none of the babies had
H2-receptor blocker therapy or corticosteroid use before 28
days of life during the whole study period.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS) for
Windows (SPSS Inc., Chicago, IL, USA), version 13.0, was
used for statistical analysis. Data were recorded as mean
values (s.d. and minimummaximum) and percentages. The
significance of mean differences between groups was
assessed by MannWhitney U-test.
Categorical variables were compared using the w2-test and
Fishers exact test.
Multivariate logistic regression analysis was used to
identify the risk factors associated with NEC. When NEC
was the dependent variable, the independent variables were
gestational age, birth weight, sex, polycythemia, partial
exchange transfusion, umbilical vein catheterization, small
for gestational age birth, positive blood culture, sepsis,
patent ductus arteriozus, antenatal corticosteroid use and
endotracheal intubation. Independent variables that had a Pvalue of o0.05 were retained into a regression model. The
results of logistic regression analyses were expressed as odds
ratios (OR) with 95% confidence intervals (CI). A P-value of
o0.05 was considered statistically significant.
Results
Clinical characteristics of the babies and risk factors for NEC
in early and late feeding periods are shown in Table 1. The
European Journal of Clinical Nutrition
582
Table 1 Clinical characteristics of the babies and risk factors for NEC in early and late feeding periods
Late feeding (n 167)
Birth weight (g)
Gestational age (weeks)
Female/male (%)
Antenatal corticosteroid use (%)
SGA birth (%)
Polycythemia (%)
Partial exchange transfusion (%)
Patent ductus arteriozus (%)
Respiratory distress syndrome (%)
Endotracheal intubation (%)
Umbilical vein catheterization (%)
Clinical sepsis (%)
Positive blood culture (%)
First enteral feeding (days)
Necrotizing enterocolitis (%)
Average weight gain (g day1)
Length of stay (day)
Death (%)
1130.5243.6
28.52.5
97/70
41
25
13
2
14
64
111
20
48
18
9.010.0
12
12.88.4
27.323.1
52
(4901495)
(2236)
(58.1/41.9)
(24.6)
(15.0)
(7.8)
(1.2)
(8.4)
(38.3)
(66.5)
(11.9)
(28.7)
(10.8)
(147)
(7.2)
(14, 40)
(1109)
(31.1)
1151.3236.5
29.32.7
66/64
31
26
16
6
17
44
82
105
52
27
4.44.6
8
16.310.9
31.825.5
34
(6001495)
(2236)
(50.8/49.2)
(23.8)
(20.0)
(12.3)
(4.6)
(13.1)
(33.8)
(63.1)
(80.8)
(40)
(20.8)
(123)
(6.2)
(13, 42)
(1147)
(26.1)
P-value
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
o0.001*
0.003*
0.03*
o0.001*
40.05
0.011*
40.05
40.05
average birth weight, gestational age, antenatal corticosteroid use, small for gestational age birth and babies diagnosed
with respiratory distress syndrome were similar in both
groups. Clinical characteristics of the patients with NEC,
according to early and late feeding regimens, are shown in
Table 2. Twenty (6.7%) patients during the study period were
diagnosed as NEC. None had gastrointestinal abnormalities.
Risk factors associated with NEC are shown in Table 3.
Following logistic regression analysis, the main risk factors
found to be associated with NEC were sepsis (OR: 5.5, 95%
CI: 1.225.7) and blood culture positivity (OR: 3, 95% CI:
1.18.1).
Discussion
In the present study, there was no difference in the incidence
of NEC between early and late enteral fed groups, both
including babies vulnerable to NEC, with similar average
gestational age and birth weight. The present finding that
EEF does not increase the risk of NEC was consistent with the
results of McClure (2001), Davey et al. (1994) and FlidelRimon et al. (2004), who recommend EEF of VLBW babies
and report positive outcomes with EEF. Enteral feedings
improve the activity of digestive enzymes, enhance the
activity of digestive hormones and increase the intestinal
blood flow and motility in preterms. Infants given early
trophic feeds were found to have better feeding tolerance,
improved growth, reduced length of hospitalization and
decreased likelihood of sepsis as compared with infants who
are not (McClure, 2001; Ziegler et al., 2002).
In the study of Flidel-Rimon et al., EEF starting at the
second or third day of life appeared to be associated with a
European Journal of Clinical Nutrition
583
Table 2 Clinical characteristics of patients with NEC
Late feeding (n 12)
1059.1251.9
28.73.3
9/3
2
3
3
4
10.610.4
7
1
4
5
5
12.24.3
40.026.0
38.3 26.3
42.4 28.4
7
(7201450)
(2334)
(75/25)
(16.7)
(25)
(25)
(33.3)
(337)
(58.3)
(8.3)
(33.3)
(41.7)
(41.7)
(618)
(883)
(880)
(1483)
(58.3)
Early feeding (n 8)
1095.0225.6
28.52.9
4/4
0
4
2
2
6.08.4
3
1
4
4
4
13.98.4
51.620.1
51.5 43.1
51.7 13.9
2
(8701470)
(2534)
(50/50)
(0)
(50)
(25)
(25)
(121)
(37.5)
(12.5)
(50)
(50)
(50.0)
(530)
(2182)
(2182)
(2565)
(25)
P-value
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
40.05
28.63.1
1073.5236.2
7/13
2
1
8
6
9
18
5
3
13
(2334)
(7201470)
(35/65)
(10)
(5)
(40)
(30)
(45)
(90)
(25)
(15)
(65)
(2236)
(4901495)
(46.6/53.4)
(8.3)
(1.8)
(35.4)
(16.2)
(10.8)
(41.1)
(9.4)
(22)
(54.1)
P-value
40.05
40.05
40.05
40.05
40.05
40.05
40.05
0.001*
o0.001*
40.05
40.05
40.05
584
were compared to no feedings, the relative risk for NEC was
1.16 (0.751.79) (Tyson and Kennedy, 2005). Contrarily,
the incidence of NEC did not increase in the EEF group
in our study. This result is also supported by the study by
Sisk et al. (2007), who fed 72% of 202 VLBW babies in
the first three days of life and 97% in the first week. An
enteral feeding of 50 ml per kg per day has been achieved
on an average of 11.2 days and 100 ml per kg per day on
16.3 days. Their overall NEC rate was 5%, similar to ours,
and still lower than the 7% NEC ratio of the NICHD
Neonatal Network data. We hope that other NICUs adopting
EEF protocols and publishing their results will provide
better information on EEF of VLBW babies in a positive or
negative way.
According to our results, the EEF of VLBW babies does not
increase the incidence of NEC. The superiority of BM over
formula on the incidence of infection in VLBW babies has
not been proved in systematic reviews (De Silva et al., 2004).
Contrarily, in a recent study, Sisk et al. (2007) have shown
that enteral feeding containing at least 50% human milk in
the first 14 days of life was associated with a sixfold decrease
in the risk of NEC.
In preterm babies in an intensive care unit, an abnormal
pattern of bowel colonization occurs when compared with
that of healthy term newborns. Bifidobacteria appears on the
11th day and is predominant in 20 days in breast-fed VLBW
infants. This is 4 days in term bread fed babies (Sakata et al.,
1985). Enteral feeding in the first 2 weeks with BM reduces
inflammation by promoting symbiotic bacterial colonization
and/or through other anti-inflammatory properties that it
possesses, and it may decrease the incidence of NEC (De Silva
et al., 2004). We conclude that EEF of VLBW babies should
not be withheld for fear of NEC, and BM would preferably be
the first feed to reach the vulnerable intestine.
Acknowledgements
kru
Ku
cu
ko
du
k, MD, for his support of
We thank Professor Su
all our scientific work and Eilon Shany, MD, for his
encouragement on early enteral feeding.
References
Davey AM, Wagner CL, Cox C, Kendig JW (1994). Feeding premature
infants while low umbilical artery catheters are in place: a
prospective, randomized trial. J Pediatr 124, 795799.
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