ORIGINAL ARTICLE: HEPATOLOGY AND NUTRITION

Amino Acidbased Formula as a Rescue Strategy

in Feeding Very-Low-Birth-Weight Infants With
Intrauterine Growth Restriction
Francesco Raimondi, Anna Maria Spera, Maria Sellitto, Francesca Landolfo, and Letizia Capasso

ABSTRACT
impaired intestinal function (1,2). The preterm gut is further
Background and Aim: Very-low-birth-weight (VLBW) neonates may
affected by the adverse blood redistribution that occurs in fetuses
develop severe intolerance to standard preterm formula especially if they
with an IUGR. After birth, these infants frequently react to enteral
are associated with intrauterine growth restriction (IUGR). We tested the
feedings with abdominal distension, increasing volumes of gastric
hypothesis that these infants may tolerate an elemental, amino acidbased
residuals, and vomiting up to a full clinical picture of necrotizing
formula as a rescue feeding strategy.
enterocolitis (NEC). The longer they are kept on total parenteral
Methods: In a prospective, case-control pilot study, we enrolled VLBW
nutrition, however, the higher the risks of catheter-related infections
IUGR infants enterally fed with standard preterm formula (SPF) at daily
or thrombosis (3). Neonatologists are aware that human milk is
increments of 16 mL/kg. If gastric residuals accounted for >70% of milk
preferable to standard preterm formula (SPF) in fighting feeding
feed in the previous 24 hours, then feedings were temporarily withheld and
intolerance (4), although the former may not always be available.
then resumed with amino acid formula (AAF) increased at the same speed.
In this case, we speculate that an elemental, amino acid formula
Cases on AAF were compared to controls on SPF and with cases themselves
(AAF) may be equally tolerated by the intestine of the VLBW
while on SPF. Primary outcome was the time to reach full enteral feedings.
IUGR infant than SPF. Protein hydrolysis in preterm infant
Secondary outcomes were time on parenteral nutrition, time on central
formula has been shown to accelerate gastrointestinal transit and
venous catheter, and formula tolerability based on the amount of gastric
feeding advancement (5,6). Elemental formulas may even be more
residual volume.
beneficial given the anti-inflammatory properties demonstrated in
Results: Sixty-four infants (22 cases) were enrolled. Although during the
selected gastrointestinal illnesses (7,8).
total duration of nutrition, cases had worse primary and secondary outcomes,
AAF has few clinical indications in neonates (eg, severe
when on AAF, cases were comparable to controls in time to full enteral
cows milk intolerance) and its nutritional adequacy has been
feeding (14.4 vs 14 days), time on parenteral nutrition, and time on central
questioned in preterm newborns. Data on the safety and efficacy
venous catheter. Cases on AAF and controls had similar gastric residual
of AAF in feeding intolerant neonates are lacking.
volumes. At day 3 after AAF introduction, cases had a significantly reduced
We have conducted a prospective, pilot clinical trial in which
number (%) of gastric residual volume >5 mL/kg over total number
VLBW IUGR infants with severe feeding intolerance mandating
of feedings (5.6 vs 1.5%; P < 0.05) and the mean gastric residual
the discontinuation of enteral nutrition were rescued with AAF.
volume (2.7 vs 0.6 mL; P < 0.05) compared to themselves while on SPF.
Such infants were compared with controls who never developed
No difference was detected in weight at 21 and 28 days, in main serum
feeding intolerance for safety of the intervention.
parameters and outcome at discharge. Growth at 12 months of corrected age
was also comparable.
Conclusions: In our population of VLBW IUGR newborns with severe
METHODS
feeding intolerance, a short course on AAF was a safe and effective means of
This pilot study included all IUGR VLBW neonates born
nutritional rescue.
at the neonatal intensive care unit (NICU) of the University
Key Words: elemental formula, neonate, nutrition Federico II of Naples between January 2006 and June 2009
for whom maternal milk was not available. Exclusion criteria were
(JPGN 2012;54: 608612) major congenital malformations and anomalies that may interfere
with feeding, chromosomal abnormalities, severe sepsis, and
transfer to another hospital. The present study was approved by

V ery-low-birth-weight (VLBW) neonates with intrauterine

growth restriction (IUGR) often may have a severely
Received June 16, 2010; accepted December 12, 2011.
From the Department of Pediatrics, Division of Neonatology, Universita
degli Studi di Napoli Federico II, Naples, Italy.
Address correspondence and reprint requests to Francesco Raimondi,
Department of Pediatrics, Division of Neonatology, Universita
Federico II di Napoli, via Pansini 5, 80131 Naples, Italy (e-mail:
raimondi@unina.it).
The authors report no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3182483e8f
the local ethical committee and informed consent was obtained
from parents. Birth weight, gestational age, sex, type of birth,
antenatal steroids, and Score for Neonatal Acute Physiology
(SNAP)-II score were recorded.
According to the NICU protocol, enteral feeding (1 mL every
2 hours) was started for all of the infants on the second day of
life (nutrition period 1 [NP1] in Fig. 1). Feeding with SPF (Pre
Aptamil, Milupa, Friedrischsdorf, Germany) was advanced daily by
16 mL
kg1
day1 to 150 mL
kg1
day1. The gastric residual
volume was checked before each feeding. Feedings were withheld:
in cases of gastric residual volume, either 5 mL/kg or higher than the
scheduled feed; when >70% of milk feeds were not tolerated in
the previous 24 hours; in the presence of biliary or bloody gastric
residuals; in cases of abnormal abdominal examination (defined as

608 JPGN  Volume 54, Number 5, May 2012

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 JPGN  Volume 54, Number 5, May 2012
VLBW IUGR neonates = 67
Congenital malformations ?
No = 64
64 infants enrolled in the study and fed with daily increments (16 ml/ kg) of SPF
while on simultaneous i.v. nutrition
Developed feeding intolerance as defined?
No = 42 defined as controls
Kept on SPF while
weaning off pare nteral
nutrition
Full enteral feeding
FIGURE 1. Study flowchart.
abdominal distension, persistent visible bowel loops, absent bowel
sounds); and/or in cases of abnormal abdominal x-ray. The attend-
ing neonatologist performing the clinical evaluation was blind to
the purpose of the study. As soon as the residuals, the abdominal
examination, and/or x-ray returned to normal, feeding was resumed
with AAF (Neocate, Nutricia Italia, Milan, Italy) at the same speed
(NP2 in Fig. 1). Study endpoint was the achievement of full
enteral feeding (150 mL
kg1
day1) for all of the infants,
whether on SPF or AAF. When the latter neonates achieved full
enteral feeding, they were switched to SPF.
The primary outcome was time (days) to reach full enteral
feedings. Secondary outcomes were time (days) of parenteral
nutrition (central venous catheter and peripheral venous catheter),
time (days) on central venous catheter (umbilical vein and
percutaneous catheter), and formula tolerability based on 2 indexes
similar to those used by Mihatsch et al (5) to evaluate the tolerability
of an hydrolyzed formula in preterm neonates, that is, the number
(%) of gastric residual volume >5 mL/kg over the total number of
feedings and the mean gastric residual volume (residual/number
of feedings) calculated on day 3 before and after the introduction
of AAF. These indexes of formula tolerability were also used to
compare cases after 72 hours on AAF (ie, NP2) versus controls
(infants with a comparable gestational age 1 week and postnatal
age 1 week).
Additional data were recorded to evaluate the possibility
of undesired effects, that is, weight at 21 and 28 days of postnatal
age; serum parameters for all of the infants within 3 days after the
achievement of full enteral feeding when both groups were fed with
SPF (pH, urea, creatinine, albumin, total proteins, total calcium,
phosphorus, alkaline phosphatase); outcomes at discharge: death,
broncopulmonary dysplasia, intraventricular hemorrhage >28,
periventricular leukomalacia, retinopathy of prematurity >28,
NEC >28 diagnosed according to the modified Bell criteria (9);
growth at 12 months of corrected age: weight, length, and head
circumference.
Data Analysis
Infants on AAF were our case population and their data were
compared with that of both neonates who were always fed with SPF
and to themselves while on SPF. Parametric data are shown as mean
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Elemental Formula in VLBW Infants
Yes = 3 excluded from the study
Nutrition Period 1
(NP1)
Yes = 22 defined as cases
Started and progressing on AAF Nutrition Period 2
with daily increments (16 mL/kg) (NP2)
while weaning off parenteral nutrition
Full enteral feeding
and standard deviations and were analyzed with the Student t test;
nonparametric data were analyzed with the Mann-Whitney U test
and the x2 test with Yates correction. SPSS (SPSS Inc, Chicago, IL)
was used to analyze the data and a level of significance was set at
P < 0.05.
RESULTS
From January 2006 to June 2009, 130 IUGR VLBW
infants were admitted, 67 for whom no maternal milk was available.
Three neonates met the exclusion criteria (2 were diagnosed
as having early-onset sepsis and 1 as having esophageal
atresia); therefore, 64 were enrolled in the study with 22 cases
and 42 controls.
Table 1 shows the demographics of our population with no
difference between groups except for the SNAP-II score, higher in
the case group. This suggests that infants who later developed
prominent feeding intolerance had significant worse clinical con-
ditions at admission. AAF for cases was started at 7.52  306 days
of life. Table 2 summarizes the time to full enteral feeding and
on parenteral nutrition. Controls, who were kept on SPF for both
NP1 and NP2, show 1 figure for each outcome. For cases, NP1
(while on SPF) and NP2 (while on AAF) are reported separately.
Cases had a longer NP1 NP2 time needed to reach full enteral
nutrition, duration of parenteral nutrition, and central venous
access; however, NP 2 outcome times for cases were comparable
with NP1 NP2 in controls.
Table 3 shows a trend for lower gastric residual volumes in
cases compared with controls that did not reach statistical signifi-
cance; however, as shown in Table 4, the introduction of AAF
significantly and rapidly reduced the number (%) of gastric residual
volume >5 mL/kg and the mean gastric residual volume (residual/
number of feedings) after AAF introduction both calculated on
day 3.
No difference was recorded in weight at the postnatal age of
day 21 (1245  357 g for cases and 1383  347 g for controls) and
day 28 (1460  402 g for cases and 1444  345 g for controls).
Similarly, Table 5 demonstrates no difference between groups in
main blood parameters performed within 3 days after achieving full
enteral nutrition and switching to SPF (except for total protein
that was in any case within the normal range). Main outcomes at
discharge and growth parameters at 12 months of corrected age
609
 Raimondi et al JPGN  Volume 54, Number 5, May 2012

TABLE 1. Clinical characteristics of neonates TABLE 3. Secondary outcomes: formula tolerance in cases on
AAF versus controls on SPF
Cases Controls
Cases Controls
No. patients 22 42
Birth weight (mean  SD) 1060  283 1116  241 No. patients 22 42
GA (mean  SD) 31.5  2.7 32.3  2.1 No. (%) gastric residual 3/264 (1.1) 17/504 (3.3)
No. ELBW infants 10/22 (45%) 11/42 (26%) volume >5 mL/kg at 48 h
Use of antenatal steroids 86.3% 90.4% over total no. feedings
SNAP-II Score 25.1  22.2 12.5  17.6 Mean gastric residual 0.6  1.2 0.9  1.5
volume at 72 h, mL
ELBW extremely-low-birth-weight; GA gestational age; SD
standard deviation. AAF amino acid formula; SPF standard preterm formula.

P < 0.05 at Mann-Whitney U test.

were not different between groups as shown in Table 6. Once on full
enteral feedings, cases were switched back to SPF (at 23.6  15.6
days of life) without feeding intolerance of clinical significance.
DISCUSSION
Our results show that an elemental formula is a safe
nutritional alternative when rescuing VLBW IUGR neonates with
severe feeding intolerance. We also gained preliminary evidence
that AAF may ameliorate the clinical picture.
The role of growth retardation as an additional factor
hampering intestinal function in preterm neonates has been
suggested by several authors; however, Mihatsch et al (9) showed
that VLBW IUGR infants tolerated enteral feedings as well as
their AGA controls. Asphyxia may play a more important role in
deranging intestinal motility of the preterm infant, resulting in signs
and symptoms of feeding intolerance (10). Accordingly, neonates
in our population with a worse initial clinical presentation,
summarized by a higher SNAP-II score, became progressively
intolerant to SPF, requiring long-term parenteral nutrition. The
introduction of an amino acidbased formula was followed by a
rapid and significant improvement of enteral feeding indexes. When
considering nutrition on AAF, its tolerability and duration were
similar in cases and controls (Tables 2 and 3).
A fast achievement of full enteral feedings can be translated
into substantial savings mainly in infant exposure to the risks of
indwelling lines but also in human resources and cost for preparing
parenteral nutrition. Pharmacologic and nutritional approaches
have been launched to address this issue. Classic prokinetic drugs
have been used to fight feeding intolerance (11,12) with less fortune
than the antimicrobial erythromycin (13). The latter coordinates
via the motilin pathway the gastric and intestinal aboral motor
activity.
A hydrolyzed protein formula (HPF) has also been shown to
accelerate early feeding advancement in VLBW infants (14).
Tormo et al (15) showed that HPF induced higher motilin level
than intact protein formula. Also, protein hydrolysis may accelerate
gastrointestinal transit via a reduced B-casomorphin activity (16).
Given the paucity of data on the topic, it is not known
whether AAF can benefit the feeding intolerant VLBW neonate
via the same mechanisms. Because elemental diets are in use for
inflammatory bowel diseases (ie, cows milk protein intolerance,
Crohn disease), a speculation is that AAF may mitigate the gut
inflammation of a neonate with severe, pre-NEC, feeding intoler-
ance (7,8,17). Interestingly, macrolides have been found to down-
play intestinal inflammation in an experimental colitis model in the
rat (18). Also, unlike AAF, a significant amount of ingested protein
from SPF may escape absorption in the lumen of the small gut
and reach the colon, where an increased protein putrefaction by
the microbial flora may impair feeding tolerance. If proven, these
mechanisms may offset the higher osmolality of the AAF, which,
although well within the limits regarded as safe by the American
Academy of Pediatrics, is thought to hamper rather than facilitate
feeding progression (19).
Both AAF and HPF can be questioned for the long-term
nutritional adequacy in extremely preterm neonates. In 1995, Rigo
et al (20) showed that HPF were not equivalent to whole-protein
formulas in terms of nutritional efficiency for both preterm and term
infants, and more recently, concerns arose from the use of HPF as a
first-line nutrition for an average of 3 weeks in a general population
of VLBW infants (21,22). Unlike these studies, our intervention
focused on a select group of patients and a much shorter rescue trial.
AAF, while improving enteral feeding, caused no significant
difference in routine laboratory work at the time full enteral feeding
was reached and cases were switched back to SPF; also, both short-
and long-term growth were not impaired, although we cannot

TABLE 2. Primary outcomes

Cases Controls

No. patients 22 42
Days on parenteral nutrition (CVC PVC) 22.5  13.6 10.8  6.8
Days on parenteral nutrition (CVC PVC) with AAF 12.3  8.3
Days on central venous catheter 19.2  13.9 8.02  5.2
Days on central venous catheter with AAF 8  7.6
Days to full enteral feeding 23.6  15.6 14  6.8
Days to full enteral feeding with AAF 15.4  12.3
AAF amino acid formula; CVC central venous catheter; PVC peripheral venous catheter.

P < 0.05 at t test.

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 JPGN  Volume 54, Number 5, May 2012 Elemental Formula in VLBW Infants

TABLE 4. Secondary outcomes: formula tolerance in cases before and after AAF

Cases before AAF Cases after AAF

introduction introduction

No. patients 22 22
No. (%) gastric residual volume >5 mL/kg at 48 h over total no. feedings 14/248 (5.6) 3/264 (1.1)
Mean gastric residual volume at 72 h, mL 2.7  4.68 0.6  1.2
AAF amino acid formula.

P < 0.05 at x2 test;

P < 0.05 at Mann-Whitney U test.

TABLE 5. Main serum parameters in cases on AAF and controls on SPF

pH Urea Creatinine Albumin Total proteiny Ca P ALP

Cases (mean  SD) 7.38  0.06 10.3  3.8 0.3  0.09 3.06  0.2 4.3  0.3 9.4  1.1 5.5  0.8 330  141
Controls (mean  SD) 7.4  0.02 16.8  18.3 0.4  0.3 3.2  0.4 4.7  0.3 9.4  0.6 5.6  1.5 291  71
AAF amino acid formula; ALP alkaline phosphatase; SD standard deviation.

Serum parameters were obtained within 3 days after achieving full enteral nutrition. At that time both cases and controls were fed SPF.
y
P < 0.05.

TABLE 6. Outcomes at discharge and growth at 12 months of life

Outcomes at discharge Growth at 12 mo of life (percentile for corrected age)

Death BPD IVH > 2 PVL ROP > 2 NEC Weight, g Height, cm HC, percentile

Cases (%) 1/22 (4.5) 2/22 (9) 3/22 (13.6) 1/22 (4.5) 1/22 (4.5) 0/22 8936  728 (2550) 72.2  2 (2550) 45.2  1.1 (2550)
Controls (%) 2/42 (4.7) 1/42 (2.3) 0/42 0/42 1/42 (2.3) 0/42 8914  957 (2550) 72.5  2.4 (2550) 45.1  1 (2550)

BPD bronchopulmonary dysplasia; IVH intraventricular hemorrhage; NEC necrotizing enterocolitis; PVL periventricular leukomalacia; ROP retinopathy
of prematurity.

exclude that subclinical nutritional differences of individual
nutrients between groups may have occurred. In conclusion, this
pilot study showed that a short course on AAF is safe and associated
with improvement in feeding tolerance in VLBW IUGR infants;
however, a randomized trial is required to show whether AAF
improves feeding tolerance in contrast to SPF in such neonates
if human milk is not available. Such studies are highly warranted,
because new protein hydrolyzed formulas are targeted to the needs
of the preterm neonate (23) and severe feeding intolerance remains
a constant life threat for VLBW infants.
Acknowledgments: The authors thank Dr Luis Pereira da Silva
for expert advice and helpful suggestions. We are also indebted to
Dr Roberto Paludetto for constant supervision of the NICU clinical
activity while the study was ongoing. We acknowledge the help
of Mrs Shannon and Mr Charles Worthy, who carefully reviewed
the manuscript.
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