Journal of Pediatric Gastroenterology and Nutrition

35:144148 August 2002 Lippincott Williams & Wilkins, Inc., Philadelphia

Early Feeding Advancement in Very Low-Birth-Weight Infants

With Intrauterine Growth Retardation and Increased Umbilical
Artery Resistance
*Walter Alexander Mihatsch, *Frank Pohlandt, *Axel Rainer Franz, and Felix Flock
*Departments of Pediatrics and Obstetrics, Ulm University, Ulm, Germany

ABSTRACT
Background: To investigate whether intrauterine growth retardation (birth weight <10th percentile), increased umbilical
artery resistance (resistance index >90th percentile measured
by Doppler velocimetry), or brain sparing (increased umbilical
artery resistance and decreased middle cerebral artery resistance index <5th percentile) were associated with early feeding
intolerance in very low-birth-weight (VLBW, <1,500 g) infants.
Methods: From July 1999 to December 2000, 124 inborn
VLBW infants were enrolled in a prospective trial evaluating
early enteral nutrition after a standardized feeding protocol
(daily feeding advancement, 16 mL/kg birth weight). Feeding
tolerance was assessed as the age at which full enteral feeds
(150 mL/kg daily) were achieved. Data are shown as median,
25th, and 75th percentiles.

Results: Full enteral feeds were achieved at 15 days (range,

1221 days) of age for all infants. Intrauterine growth retardation (full enteral feeding achieved at 14 days; range, 1221
days), increased umbilical artery resistance (full enteral feeding
achieved at 14 days; range, 1116 days), and brain sparing (full
enteral feeding achieved at 15 days; range, 1420 days) were
not associated with early feeding intolerance.
Conclusion: Very low-birth-weight infants with intrauterine
growth retardation, increased umbilical artery resistance, and
brain sparing tolerated enteral feeding as well as appropriatefor-gestational-age VLBW infants. JPGN 35:144148, 2002.
Key Words: Fetal Doppler velocimetryPremature infant
NutritionVery low-birth-weight infantBrain sparing
Intrauterine growth retardation. 2002 Lippincott Williams &
Wilkins, Inc.

Intrauterine growth retardation (IUGR, birth weight

<10th percentile) and increased umbilical artery resistance in growth retarded infants have been recognized as
significant risk factors for increased perinatal morbidity
and mortality (16). In preterm infants, an association
among gastrointestinal morbidity (e.g., delayed tolerance
of enteral feeding, abdominal distension, vomiting, and
necrotizing enterocolitis), IUGR, and increased umbilical artery resistance has been observed (712). However,
when birth weight and gestational age at delivery were
controlled for, increased umbilical artery resistance was
not an independent predictor of newborn morbidity
(13,14).

Very low-birth-weight infants (VLBW, <1,500 g) are

an extremely heterogeneous group of newborns and include those with very immature gestational age and those
who are more mature but extremely growth retarded.
Therefore, in this heterogeneous group of infants, it is
unclear to what extent IUGR and the results of fetal
Doppler flow velocimetry should be considered when
making decisions about enteral nutrition. Is it necessary
to develop special feeding protocols for various subgroups of VIBW infants?
The aim of the current study in VLBW infants was to
investigate whether IUGR, increased umbilical artery resistance, or fetal hemodynamic centralization with brain
sparing were independently associated with early feeding
intolerance in VLBW infants. We measured the age at
which full enteral feeding was achieved after a standardized feeding protocol.

This article accompanies an editorial. Please see Are

there beneficial effects of rapid introduction of enteral
feeding in very low birth-weight infants? Lafeber HN.
J Pediatr Gastroenterol Nutr 2002;35:137138.

METHODS
Study Population

Received August 29, 2001; accepted January 18, 2002.

Address correspondence and reprint requests to Dr. Walter A
Mihatsch, Universitts-Kinderklinik, 89070 Ulm, Germany (e-mail:
walter.mihatsch@medizin.uni-ulm.de).

From July 1999 until December 2000, all VLBW infants

admitted to the Division of Neonatology of the Ulm University
Childrens Hospital (tertiary referral center) were prospectively

144

DOI: 10.1097/01.MPG.0000016482.73596.5B

IUGR, DOPPLER VELOCIMETRY, AND FEEDING

enrolled in a study of early enteral feeding tolerance after following a new feeding protocol. The institutional ethics committee approved the study protocol. Exclusion criteria were
major congenital malformations and anomalies that may interfere with nourishing (e.g., hydrops). Eligibility was assessed
after the attending physician decided to initiate milk feeding.
Informed written parental consent was obtained. Initially, all
infants received parenteral nutrition, which was gradually decreased with increasing enteral intake.

Doppler Sonographic Examinations

Doppler velocimetry of the placental and fetal vessels was
performed within 1 week before delivery for the following
reasons: suspected fetal compromise, maternal hypertension,
antepartum hemorrhage, preterm labour, or prelabor rupture of
the membranes. Trained sonographers performed Doppler velocimetry using a GE Logic 500 (General Electric, 42655
Solingen, Germany), a Voluson 530D (Kretztechnik GmbH,
45768 Marl, Germany), or a Toshiba Powervision 6000
(Toshiba Medical Systems GmbH, 81241 Munich, Germany)
ultrasound device. Doppler velocimetry was performed using a
high-pass filter of 100 MHz or less, with the woman in a
semirecumbent position during fetal quiescence and fetal apnea. Umbilical artery Doppler studies were performed in a
midsegment of the umbilical cord. Increased umbilical artery
resistance was defined as a resistance index above the 90th
percentile for gestational age (15). Brain sparing was defined as
the combination of increased umbilical artery resistance with
resistance index of the medial cerebral arteries below the 5th
percentile (16,17). For every measurement, the resistance index
was calculated for three to five characteristic waveforms and
the median resistance index was recorded.
Gestational age was determined by the first day of the last
menstrual cycle and confirmed or corrected by the result of the
first sonographic investigation before the 10th week of gestation. Intrauterine growth retardation was defined as birth
weight below the 10th percentile for gestation (18). Suspected
early onset bacterial infection was defined as a C-reactive protein concentration >10 mg/L within the first 72 hours of life.

Feeding Protocol
Within the first hours of life, bolus gavage feeding of 5%
glucose, every 2 to 3 hours, was started at 16 mL/kg birth
weight daily. As soon as a sufficient amount of meconium had
been passed (19), bolus milk feeding was started at the discretion of the attending physician. Human milk feeding was encouraged. Human milk was fortified after full enteral feeds
(150 mL/kg birth weight daily) were achieved. Preterm infant
formula (Aptamil Prematil or Aptamil Prematil HA; Milupa
GmbH, Friedrichsdorf, Germany) was fed if human milk was
not available. The infants were fed every 2 (<1,250 g) or 3
(1,2511,500 g) hours, starting at 16 mL/kg birth weight daily.
Feedings were advanced every 24 hours by 16 mL/kg birth
weight whenever more than 50% of the calculated amount had
been given during the previous 24 hours. The gastric residual
volume was checked before each feeding. At a volume equal to
or less than 5 mL/kg, the scheduled feed was given; otherwise
the difference up to the scheduled amount was given (20). No
milk was fed if the gastric residual was more than 5 mL/kg and
the volume of the feed was equal to or less than the gastric
residual volume.

145

The color of the gastric residual (20); the subjective impression of those in charge; and clinical conditions such as hypotension, mild abdominal distension, infection, umbilical catheters in place, or indomethacin therapy did not cause a change
in the feeding strategy. However, with a sudden significant
increase in gastric residual volume, an abnormal abdominal
examination regardless of the gastric residuals, or if the infants
did not pass a sufficient amount of stool on a regular basis,
feedings were temporarily discontinued and a sepsis workup or
an abdominal radiograph were performed as appropriate. The
feedings were resumed as soon as the abdominal examination
was normal.
An abnormal abdominal examination was defined as follows: persistent palpable mass (meconium, predominantly in
the right lower quadrant); gross abdominal distension; persistent visible bowel loops without peristalsis; abdominal tenderness; decreased abdominal bowel sounds; sudden increment in
the abdominal girth (>2 cm); and blood in the stools. 5% Glucose glycerin enemas (10:1 mixture, 5 mL/kg) were administered twice daily until the infants passed spontaneously at least
one stool per day. After extubation or intubation, feedings were
withheld for 6 hours. Laxatives were not administered during
the study. Oral medications were not given until full enteral
feeds (150 mL/kg birth weight daily) were achieved.

Data Collection and Analysis

Demographic variables were recorded for all infants. The
study period covered the first 4 weeks of life. Feeding tolerance
was assessed as the age at which full enteral feeds (150 mL/kg
birth weight daily) were achieved. The cumulative intake of
any human milk from the beginning of milk feeding until full
enteral feeds were achieved was calculated and expressed as
percentage of the cumulative milk intake within this period of
time. Necrotizing enterocolitis was diagnosed according to the
Bell stages (21). Wilcoxon tests were used for categoric data
analysis, and forward selection multivariate logistic regression
analysis was used to determine the factors independently associated with the age at full feeds (level of significance was P <
0.05, Statistical Systems for Personal Computers Package, SAS
Institute, Cary, NC, U.S.A.). We made no correction for multiple testing. Data were presented as median, 25th, and 75th
percentile or as median and range as appropriate.

RESULTS
From July 1999 to December 2000, 150 VLBW infants were admitted. A total of 16 infants were excluded
for the following reasons: major malformations (n
10), severe hydrops (n 1), meconium plug syndrome
requiring laparotomy within the first week of life (n 2;
one infant with IUGR and one without IUGR), severe
sepsis (n 1, death on day 3), necrotizing enterocolitis
on the first day of life (n 1, clostridium difficile sepsis,
death on day 3), early transfer (day 3) to a regional
hospital (n 1). Eight of these 16 infants died within the
first 2 weeks of life. Two infants were not included for
no specific reason. Parents of 132 infants were approached, and informed written consent was obtained for
130 infants. Six infants were excluded because they were

J Pediatr Gastroenterol Nutr, Vol. 35, No. 2, August 2002

146

W. A. MIHATSCH ET AL.

transferred to regional hospitals in the first week of life,

before receiving full feeds. No participant withdrew.
Table 1 shows the clinical characteristics of the study
population. Appropriate-for-gestational-age (AGA) infants were less mature (P 0.007) but heavier (P
0.03) than infants with IUGR. For all infants, the age at
which feeds were started was 3 days (range, 25 days),
the time from initiation of milk feeds to full enteral feeds
was 11 days (range, 1016 days), and full enteral feeds
were obtained at 15 days (range, 1221 days). In two
infants, necrotizing enterocolitis developed (Bell stage
>2), both were AGA, and fetal Doppler velocimetry was
not available.
In 18 of the 35 infants with IUGR, length and head
circumference at birth also were below the 10th percentile for gestation (IUGR type 1), and in 17, only the birth
weight was below the 10th percentile (IUGR type 2).
However, we found no significant difference between
these two subgroups with regard to the age at which
feeds began: 4 days (range, 25 days) versus 3 days
(range, 24 days); P 0.49; IUGR type 1 versus type 2;
the time to achieve full feeds after initiation of milk
feeds, 11 days (range, 913 days) versus 10 days (range,
1012 days); P 0.98); and the age at full feeds, 14
days (range, 1219 days) versus 13 days (range, 1115
days); P 0.53).
We found no significant difference between infants
with IUGR and AGA infants in the age at starting feeds,
the time to achieve full feeds after initiation of milk
feeds, or the age at full feeds (Table 2). Doppler velocimetry had been performed in only 68 infants. Increased
umbilical artery resistance was found in 18 and brain
sparing in 10 infants. In infants with increased umbilical
artery resistance or brain sparing, milk feeding was initiated significantly later; however, we noted no significant difference in the time to achieve full feeds after
initiation of milk feeds and in the age at full feeds (Table
2). When birth weight and gestational age were con-

trolled for in a multivariate regression model to determine the factors significantly associated with the age of
full enteral feeds, neither IUGR, increased umbilical artery resistance, nor brain sparing proved to be significantly associated (Table 3).
DISCUSSION
These data confirmed previously reported findings
that variables such as birth weight probably are more
important predictors of postnatal morbidity than IUGR
and fetal Doppler flow (13,14). In VLBW infants,
growth status and maturity are inextricable confounded,
the most mature infants also being the most growth retarded. Gestational age and birth weight were associated
significantly with feeding tolerance, measured as the age
at full feeds, whereas IUGR, increased umbilical artery
resistance, and brain sparing did not show any significant
association (Tables 2 and 3). The detrimental effects of
poor growth status and poor Doppler blood flow on gastrointestinal function might have been blunted by maturity, confirming the findings of others who reported even
a misleading protective effect of IUGR against inhospital death in VLBW infants (22).
Although, the time until full feeds decreased with increasing gestational age and birth weight, only 32% of
the variation of the age at full feeds (Table 3, r2 0.32)
was determined by the clinical characteristics available
at the infants admission. Other criteria, for instance the
availability of human milk, the type of formula (hydrolyzed or nonhydrolyzed protein preterm infant formula),
nosocomial infections, or the feeding protocol itself,
might have been far more important. Nevertheless, based
on the presented data, we find no need to develop a
specific feeding protocol of extremely slow advancement
of feeds for the subgroups of VLBW infants with IUGR,
increased umbilical artery resistance, or brain sparing.

TABLE 1. Clinical characteristics

n
gestational age (wk)
Birth weight (g)
Length at birth (cm)
Head circumference at birth (cm)
Apgar 5 minutes
Apgar 10 minutes
Umbilical artery pH
Umbilical artery base deficit
Male (%)
Antenatal betamethasone
Suspected early onset bacterial infection
Less than 10% of human milk available
Necrotizing enterocolitis (Bell stage 2)

All infants

AGA infants

IUGR infants

124
28.2 (22.335.9)
890 (4201500)
35 (26.542.5)
25.1 (2031)
8 (210)
9 (310)
7.27 (6.767.46)
6.1 (22.2 to 1.1)
54 (44%)
111 (90%)
14 (11%)
83 (67%)
2 (2%)

89
27.1 (22.232.3)
940 (4201490)
35.5 (2842)
25 (2031)
8 (210)
9 (310)
7.28 (6.767.46)
6.5 (22.2 to 1.7)
38 (43%)
75 (86%)
12 (2.3%)
58 (66%)
2 (2%)

35
29.3 (24.135.9)*
780 (4501500)
33 (26.542.5)
25.2 (2031)
8 (210)
9 (310)
7.26 (6.957.46)
6 (18 to 1.1)
16 (46%)
36 (97%)
2 (0.5%)
25 (68%)
0 (0%)

Data is shown as median and range or n (%)

* P 0.007, P 0.03
AGA, appropriate for gestational age; IUGR, intrauterine growth retardation.

J Pediatr Gastroenterol Nutr, Vol. 35, No. 2, August 2002

IUGR, DOPPLER VELOCIMETRY, AND FEEDING

TABLE 2. Association between intrauterine growth, fetal
Doppler studies, and nutrition

N
IUGR

37

No IUGR
IUR

87
20

No IUR
BS

51
11

No BS

27

Age at starting
feeds (d)

Time to achieve full

feeds after starting
milk feeds (d)

Age at full
enteral
feeds (d)

4 (24)
P 0.65
3 (24)
4 (35)
P 0.02
3 (24)
4 (47)
P 0.05
3 (24)

11 (916)
P 0.23
12 (1016)
10 (913)
P 0.16
11 (1018)
10.5 (1014)
P 0.99
10 (917)

14 (1221)
P 0.60
15 (1221)
14 (1116)
P 0.80
14 (1121)
15 (1420)
P 0.53
13 (1121)

Data is sown as median (25th to 75th percentile).

IUGR, intrauterine growth retardation; IUR, increased umbilical artery resistance; BS, brain sparing.

The incidence of necrotizing enterocolitis (Bell stage

2) was too small (n 2) to draw sound conclusions.
The current study has some limitations. First, the attending physicians were aware of the clinical characteristics of the infants and may have had the intention to
slow down the feeding advancement in infants with
IUGR or increased umbilical artery resistance. In fact,
milk feedings were initiated significantly later in infants
with increased umbilical artery resistance and brain sparing. However, there was a standardized feeding protocol,
and the speed with which the feedings were advanced
was the same in all groups (Table 2).
The definition of IUGR did not consider height of the
parents, birth rank, maternal age, or pregravid weight
because these data were not available. Some of the infants who were defined as growth retarded in fact might
have been constitutionally small and therefore misclassified (23). However, we found no difference in feeding
tolerance between proportionally growth retarded
VLBW infants (IUGR type 1) who might have been
TABLE 3. Multiple regression model: variables determining
the age at full enteral feeds. Total goodness of fit of the
model r2 = 0.32
Variables included
in the model

P
value

Regression
coefficient b

Contribution
to r2

Constant
Gestational age (wks)
Birth weight (100 g)
Antenatal betamethasone

0.011
0.031
0.042

43.0
0.643
0.529
1.34

0.28
0.02
0.02

Variables excluded

P value

Increased umbilical artery resistance

Apgar score at 10 minutes
Brain sparing
Apgar score at 5 minutes
Apgar score at 1 minute
Umbilical artery pH
Intrauterine growth retardation

0.17
0.31
0.38
0.45
0.58
0.73
0.73

147

small from early on and disproportionally growth retarded VLBW infants who might have had poor placental
functioning during the second or third trimester of pregnancy (IUGR type 2).
More important, prenatal Doppler studies were available in only 55% of the infants studied. Because of the
routine obstetric management, prenatal Doppler studies
were performed only when fetal compromise was suspected and when there was enough time before delivery
to perform the studies. In addition, these Doppler studies
were obtained within the week before delivery, and the
length of time that fetal circulation was compromised
remained unknown.
Finally, the present feeding protocol anticipated problems with enteral feeding in all VLBW infants. Routine
enemas were given twice daily to all infants until they
began regular bowel movements. Five percent glucose
feeding was initiated within the first hours of life, but
milk was introduced only after the infants had started to
pass a sufficient amount of meconium (19). Although, no
effect of IUGR and increased umbilical artery resistance
on feeding tolerance was found at a rate of 16 mL/kg
birth weight daily, feeding intolerance may occur if intake is increased more rapidly.
CONCLUSION
Intrauterine growth retardation, increased umbilical
artery resistance index, and brain sparing were not independently associated with early feeding intolerance in
VLBW infants who were fed according to a standardized
feeding protocol, if birth weight and gestational age were
controlled for. Full enteral feeds were achieved at the
same postnatal age in VLBW infants with IUGR, increased umbilical artery resistance, or brain sparing as in
appropriate-for-gestational-age VLBW infants. Therefore, developing special feeding protocols for various
subgroups of VLBW infants is unnecessary.
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