Extrauterine growth restriction (EUGR) is commonly seen in small

premature infants due to a lack of early aggressive nutrition that

results in energy and protein deficits during the first few days of life.
These deficits lead to early postnatal growth failure that continues at
discharge resulting in growth parameters being below the 10th
percentile, which is associated with poor neurodevelopmental
outcomes. Strong evidence supports an early aggressive nutrition
plan that includes early parenteral nutrition administration with 3–4 g
kg−1 day−1 of protein and minimal enteral feedings. This article
presents the current evidence surrounding early aggressive nutrition,
minimal enteral feedings, use of human milk and human milk
fortification and makes the argument for standardized practice to
improve nutrition in small premature infants.
Introduction
Premature birth continues to occur despite medical advancement in
the diagnosis, treatment and prevention of preterm labor. As a result,
the need for neonatal intensive care remains in high demand. The
demand for such care has led to major advances in technology and
life support measures leading to an improvement in the survival of the
smallest and most premature infants.[1] Although survival of small
premature infants has increased, these infants still experience a
number of morbidities at the time of hospital discharge. One of these
morbidities is postnatal growth failure or extrauterine growth restriction
(EUGR).
EUGR occurs when a premature infant's growth falls below the 10th
percentile in comparison to a normal fetus of the same gestational
age.[2]This type of postnatal growth failure is commonly seen in very
low birth weight (VLBW) (< 1500 g) and extremely low birth weight
(ELBW) (< 1000 g) infants. In fact, in 2001 the National Institute of
Child and Human Development (NICHD) Neonatal Research
Network[3] found that 97% of all VLBW and 99% of all ELBW infants
included in the study experienced EUGR by 36 weeks corrected
gestational age. In another study, Ehrenkranz and colleagues
assessed growth in VLBW infants and found that at the time of
discharge most of the infants born between 24 and 29 weeks
gestation failed to reach the median birth weight of their fetal
counterparts with the same postmenstrual age.[4] Extreme prematurity
and the associated critical illness seen in such small premature infants
often delay the initiation of early nutrition. Delaying early nutrition
results in nutrient deficits, which Embelton et al. estimate to be over
12 g/kg of protein and over 300 kcal/kg of energy during the first few
weeks of life.[5] These ongoing deficits were identified by Embelton et
al., to be directly related to poor growth and subsequent development
of EUGR.[5]
Early Aggressive Nutrition

Early aggressive nutrition is a nutritional approach aimed at preventing

the catabolic state that occurs during the first few days after birth in a
small premature infant.[15] This approach involves the administration of:
1) total parenteral nutrition (TPN) with a high level of amino acids,
usually 3–4 g kg−1day−1 within hours of birth, 2) Intralipids within the
first 24 hours of life usually at 0.5–1 g kg−1 day−1 with advancement to
3 g kg−1 day−1, and 3) Minimal enteral feedings at 10–20 ml
kg−1 day−1 are initiated within the first 1–2 days of life.
To date only three randomized controlled trials (RCT) have been
conducted to study the effects of early aggressive nutrition in small
premature infants. Wilson et al. studied 125 VLBW infants who were
randomized to receive a glucose only regimen with amino acids and
intralipids being added at 3 days of age and enteral feedings were
started once the infant was deemed stable (control group) or TPN with
amino acids and intralipids started at 12 hours of life and 48 hours of
life, respectively along with enteral feedings being started at 24 hours
of life (intervention group). Infants in the intervention group had
significantly higher energy intake, took less time to regain their birth
weight, and had a significant improvement in weight gain and linear
growth at hospital discharge.[16]

Early Administration of Amino Acids

The amount of amino acids administered in the early aggressive
nutrition RCTs varied dependent upon investigator and the year in
which the study was conducted. For example, the amount of protein
administered in the study by Wilson et al.[16] was 0.5 g kg−1 day−1 and
increased to a max of 2.5 g kg−1 day−1 whereas in the other two
studies[17.,18.] protein was started in the range of 2.8 to 3.8 g kg−1 day−1.
This same trend can be seen when reviewing the RCTs conducted on
the early use of amino acids in premature infants

Human Milk Fortification

Kuschel and Harding[38] conducted a systematic review of 13 RCTs

that evaluated human milk fortification versus no fortification. The
meta-analysis of the data showed human milk fortification with a multi-
component fortifier improves linear and head growth along with short-
term weight gain. The use of a fortifier was also found to have no
adverse effects and may possibly improve bone formation in
premature infants.
Recent findings regarding the use of early amino acids, discussed
earlier in this article, lead researchers to explore the addition of protein
to enteral feedings as a means to improve growth in small premature
infants. In a 2010 systematic review, Premji et al.[39] reviewed five
RCTs that examined lower enteral protein intake (< 3 g kg−1 day−1)
versus higher protein intake (> 3 g kg−1 day−1). Higher enteral protein
intake at 3–4 g kg−1 day−1 resulted in improved weight gain and an
increase in nitrogen accretion. Evidence presented in these
systematic reviews support human milk fortification with added
protein, fat, and mineral intake in order to meet the unique nutritional
needs of the premature infant and to promote adequate growth in
smaller premature infants.

Even though human milk is recommended as the gold standard for

enteral feedings in the premature infant, the protein, fat and mineral
content of human milk does not meet the nutritional needs of the
growing premature infant. In order to meet these needs, fortification is
necessary.
Miller et al.[40] confirms the systematic review findings in a more recent
RCT of 92 preterm infants who either received human milk fortified
with 1.4 g of protein/100 ml or the standard human milk fortifier with 1
g of protein/100 ml. The infants who received the human milk fortifier
with added protein had significantly better weight gain at the end of
the study. In a secondary analysis, the infants who received the higher
protein human milk fortifier were less likely to be at the 10th percentile
for length. The authors of the study concluded that a human milk
fortifier with added protein is needed to promote adequate growth in
premature infants.

1. Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a

serious problem in prematurely born neonates. Pediatrics. 2003;111:986–90.
2. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the
NICHD Neonatal Research Network: January 1995 through December
1996. Pediatrics. 2001;107:E1.
3. Ehrenkranz RA, Younes J, Lemons JA, et al. Longitudinal growth of hospitalized
very low birth weight infants. Pediatrics. 1999;104:280–9.
4. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation:
an inevitable consequence of current recommendations in preterm
infants? Pediatrics.2001;107:270–3.
5. De Curtis M, Rigo J. The nutrition of preterm infants. Early Hum
Dev. 2012;88:S5–7.
6. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge JA. Randomised
controlled trial of an aggressive nutritional regimen in sick very low birthweight
infants. Arch Dis Child Fetal Neonatal Ed. 1997;77:F4-F11.
7. Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Krouskop RW. Aggressive
early total parental nutrition in low birth weight infants. J Perinatol. 2004;24:482–
6.
8. Morgan C, McGowan P, Shakeel H, Hart AE, Turner MA. Postnatal head growth
in preterm infants: A randomized controlled parenteral nutrition
study. Pediatrics. 2014;130:e120–8.
9. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting
growth in preterm infants. Cochrane Database Syst
Rev. 2004, http://dx.doi.org/10.1002/14651858.CD000343.pub2. [Art No.
CD000343].
10. Premji SS, Fenton TR, Sauve RS. Higher versus lower protein intake in formula
fed low birth weight infants. Cochrane Database Syst
Rev. 2010, http://dx.doi.org/10.1002/14651858.CD003959.pub2. [Art No.
CD003959].
11. Miller J, Makrides M, Gibson RA, et al. Effect of increasing protein content of
human milk fortifier on growth in preterm infants born at b31 wk gestation: A
randomized controlled trial. Am J Clin Nutr. 2012;95:648–55.