Seminars in Fetal & Neonatal Medicine (2007) 12, 78e86

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s i n y

Postnatal nutrition and adult health programming

Josef Neu*, Nicholas Hauser, Martha Douglas-Escobar

Department of Pediatrics, University of Florida, College of Medicine, Division of Neurology,

Box J296, 1600 SW Archer Road, Room HD 513, Gainesville, FL 32610-0296, USA

KEYWORDS Summary The early postnatal interplay between nutrition, growth patterns, and metabolic
Epigenetics; and epigenetic phenomena is crucial in determining subsequent health; health that extends
Neonate; through the lifetime of the individual and very likely even into subsequent generations. Recent
Postnatal nutrition; research in the area of postnatal nutrition and its relationship to adult health, with an empha-
Premature infant; sis on the appropriate-for-gestational-age infant who is born prematurely and who undergoes
Programming growth delays, is presented. Select studies in animals, pertinent to understanding the mech-
anisms of how early postnatal under- and overnutrition might affect adult health and propaga-
te to subsequent generations, are reviewed. Scientifically based approaches to administering
postnatal nutrition designed to improve outcomes and areas where future investigations are
needed are presented.
ª 2006 Published by Elsevier Ltd.

Introduction A neo-Lamarckian concept has emerged, partially from

The idea that the metabolic syndrome results merely from
an interplay between an individual’s genetic inheritance
and dietary habits now appears to be an oversimplification.
Epidemiologic findings showing that infants born small are
prone to develop this syndrome have led to the ‘thrifty
phenotype’ or ‘fetal origins hypothesis’, the ‘predictive
adaptation with subsequent mismatch between early and
later environments hypothesis’ and the ‘developmental
origins of disease hypothesis’ (DOHAD).1e3 These closely re-
lated hypotheses have a common factor, the concept of
critical windows (such as fetal, early neonatal and puberty
periods) during which the individual is highly susceptible to
‘programming’ of adaptations for future stressful events.4
* Corresponding author. Tel.: þ1 352 392 4195; fax: þ1 352 846
3937.
E-mail address: neuj@peds.ufl.edu (J. Neu).
observations in animals and e more recently e with the
use of sophisticated molecular biological tools that supports
nutritional and several other environmental stimuli being
able to ‘program’ characteristics not only for the individu-
al’s lifetime but also for subsequent generations.
The literature about prenatal ‘fetal origins’ of adult
disease is vast and has been reviewed elsewhere.3,5 The
focus of this chapter is on the early postnatal interplay
between nutrition, growth, metabolic and epigenetic phe-
nomena, and subsequent health. The emphasis is on the
prematurely born appropriate-for-gestational-age (AGA)
infant who subsequently undergoes growth delays. We re-
view animal studies that are pertinent to understanding
how the mechanisms of early postnatal under- and overnu-
trition affect adult health and propagate to subsequent
generations, provide scientifically based approaches to
the administration of postnatal nutrition to improve out-
comes, and e finally e point to areas where future investi-
gations are needed.

1744-165X/$ - see front matter ª 2006 Published by Elsevier Ltd.

doi:10.1016/j.siny.2006.10.009
Postnatal nutrition and adult health programming
Current nutrition practices
Nutritional goals
One of the idealistic goals of premature infant nutrition has
been to maintain growth between the 10th and 90th
percentiles of the intrauterine growth velocity. However,
more meaningful goals than mere somatic growth are
emerging:
 maintenance of lean body mass and bone density
 prevention of complications (e.g. chronic lung disease,
necrotizing enterocolitis, and infection)
 optimization of neurodevelopment
 adult health.
To meet these goals, current nutritional practices need
to be thoroughly scrutinized in terms of both quantity and
quality (composition). It might not yet be possible to
customize intakes for each particular infant but we might
be able to improve nutritional guidelines for subgroups
(e.g. segmented by gestational age, weight for gestational
age, sex, pathology, etc.) to optimize adult health.
Very low birth-weight neonates
The history of neonatal intensive care is replete with
therapeutic misadventures.6 For example, in the 1960s,
when attempts to save small babies using intensive care be-
gan, nutrition (including glucose) was frequently withheld
for several days after birth, a practice that resulted in
significant morbidity and mortality. More recent attempts to
make nutritional intake in very low birth-weight (VLBW) in-
fants more physiologic, try to emulate the intake that these
infants would be receiving in utero.7 The use of total paren-
teral nutrition (TPN, i.e. carbohydrates, lipids and amino
acids) in premature infants attempts to mimic the nutri-
tional composition of the continuous fetus’ placental flux
2000
1500
Weight (grams)
Weight gain in < 25
week premature
1000 infants
500
24 w
Corrected gestational age (weeks)
Figure 1 Extrauterine growth delays in very low birth-weight premature infants. Adapted from Ehrenkranz et al (ref.9).
79
of nutrient to maintain energy metabolism and provision
of amino acids for. The fetus receives about 450 mL/day of
amniotic fluid through the gastrointestinal (GI) tract during
the last trimester of pregnancy.8 However, it is doubtful
that provision of such a volume to sick premature infants
will actually be safe or efficacious. After premature birth,
because of GI tract immaturity and the fear of developing
necrotizing enterocolitis, enteral intakes are delayed. Fre-
quently, nutrients are withheld at the times (usually the
first 2e3 weeks after birth) when the infant is most criti-
cally ill and nutritional requirements for meeting the met-
abolic demands of critical illness are highest. Despite the
safety and apparent efficacy of TPN, the common practice
for sick premature infants continues to involve slowly
advancing parenteral nutrition.
Concerns about early undernutrition,
overnutrition and catch-up growth
Enteral intakes and the delayed and slow advance of TPN in
premature babies frequently result in a significant deficit in
the amount of protein and lipid compared with the amount
the infant would have received in utero. This is at least
partially responsible for the growth delay evidenced by
the shift to the right in growth curve in the first several
weeks of life in these infants.9 In premature baby of less
than 31 weeks gestation, the cumulative deficits in energy
and protein intakes reach a mean deficit of approximately
800 kcal/kg and 23 g protein/kg by the end of the fifth post-
natal week.10 This postnatal growth delay, also referred as
extrauterine growth retardation (EUGR),11 has become
a concern not only because of the somatic growth deficits
but because of the association with irreversible long-term
neurodevelopmental delays and learning disabilities due
to prolonged catabolism during a highly vulnerable period
(Fig. 1).12 EUGR infants, but not those small for gestational
age (SGA) at birth, have an increased risk of adverse neuro-
developmental outcome at 24 months corrected age.13 SGA
P50 P10
Clear extrauterine
Ideal goal growth delay in < 25
of intra- week premature infant
uterine
growth
28 w 32 w 36 w
80
children who undergo catch-up growth have a neurodeve-
lopmental outcome that is comparable to AGA infants
with normal growth, whereas SGA infants with insufficient
catch-up growth are impaired in their motor development
as compared to SGA children who achieved substantial
catch-up growth. Conversely, the group of AGA children
who underwent extrauterine growth delays had signifi-
cantly poorer mental and motor function than AGA children
whose weight remained AGA at 9 and 24 months corrected
age. These results (summarized in Table 1) highlight the
importance of maintaining normal growth velocity in AGA
infants and catch-up growth in SGA infants born prema-
turely. Appropriate nutritional intervention to achieve an
in-utero growth pattern in AGA infants and catch-up growth
in SGA infants would appear to be justified.
Despite the data supporting improved neurodevelop-
ment when premature infants maintain normal growth
velocity, the issue of whether in-utero growth velocity
after preterm birth should be used as a template for growth
for the preterm infant remains a matter of debate. Recent
studies have highlighted neonatologists’ reluctance to
match in-utero nutritional intakes for premature infants,
despite strong suggestions that this approach is safe and
efficacious.14,15 One argument against this more ‘aggres-
sive’ approach is that several species of animals do poorly
in adulthood if they are provided high levels of nutrition
in early life.4,16 Evaluation of the long-term effects of early
nutrition in preterm infants suggests that there might be
detrimental consequences of early aggressive nutrition.
Singhal et al.17 measured fasting concentrations of 32e33
split proinsulin e a marker of insulin resistance e in adoles-
cents who were born preterm and who had participated in
randomized intervention trials of neonatal nutrition, and in
adolescents born at term. Fasting 32e33-split proinsulin
concentration was greater in adolescents who grew faster
in the first two postnatal weeks. Similar effects were
seen in flow-mediated endothelial vascular dilatation,
with the infants who had the lowest weight gain having
greater arterial distensibility when they reached their
teens.18 Unfortunately, these studies17,18 have been inter-
preted (probably mistakenly so) as a proof that catch-up
growth in the first 2 weeks of life predisposes premature in-
fants to adult disease and that they should therefore re-
ceive limited nutrition. These studies say little about the
composition (enteral or parenteral) of nutritional intake
in infants during this critical time (the first 2 weeks) and
Table 1 Summary of neurodevelopmental outcomes in appropriate-for-gestational-age (AGA) and small-for-gestational-age
(SGA) infants who attained adequate versus delayed extrauterine growth
Neurodevelomental Adequate
outcomes in subgroups catch-up growth
of VLBW premature infants
AGA Good neurodevelopmental
outcome
SGA Good neurodevelopmental
outcome (similar to AGA with
adequate catch-up growth)
VLBW, very low birth-weight.
J. Neu et al.
subsequent outcomes are likely to reflect factors other
than nutrition. Parenteral and enteral intake in sick prema-
ture infants during the first 2 weeks of life is extremely er-
ratic and weight gains during this period are related more
to fluid shifts than to actual increases in lean body mass
(non-water body mass). A large number of premature in-
fants weighing <1000 gat birth gain <100 g in the first
2 weeks and are still on parenteral nutrition at 2 weeks of
life, making it highly improbably that changes in weight
are due to excess of nutritional intake.
Catch-up growth
Although it appears that catch-up growth in term-born
infants with IUGR is associated with metabolic syndrome,19
other studies show that children who did not undergo
catch-up growth when they were infants also had evidence
of glucose intolerance.20 Thus it remains unclear whether
premature infants who suffered from EUGR and then under-
went catch-up growth actually have a propensity for in-
creased risk for metabolic syndrome due to their catch-up
growth or whether this is metabolic aberration associated
with being born preterm.
Visceral fateinsulin axis
Increased visceral adiposity in adults is recognized as
a marker for metabolic syndrome.21 Using whole-body MRI
in premature infants, Uthaya et al.22 showed a mean excess
of intra-abdominal fat that was greatest in the infants who
had previously required the greatest level of intensive care.
As this would predispose these infants to a greater risk of
metabolic syndrome, these findings seem to contradict
the speculation made in the studies showing increased pro-
pensity to metabolic syndrome in infants who grew
faster17,18; they suggest that early stress and not undernu-
trition or catch-up growth leads to a the deposition of a ma-
jor indicator of early metabolic syndrome, i.e., increased
abdominal visceral fat (Fig. 2).
Infants at low gestation have been found to have a state of
hypersecretion of growth hormone (GH) and associated
depressed serum concentrations of insulin-like growth factor
(IGF)-1 that is seen most commonly in extremely preterm
newborns (<28 weeks gestation), which persists for 3 months
after birth.23 This excess of GH is known to be associated with
Delayed extrauterine
growth (EUGR)
Decreased mental and
motor function
Decreased motor function
Postnatal nutrition and adult health programming
Sicker infants with
more intensive care
Stress and
increased cortisol
Increased intra-abdominal fat
altered leptin, adiponectin and
Proinflammatory mediators
Increased risk for
metabolic syndrome
Figure 2 Relationship of stress, hormones, and abdominal fat to subsequent risk for metabolic syndrome in sick premature babies.
insulin resistance and secondary hyperinsulinemia24 and
parallels the development of relative visceral adiposity as
observed by Uthaya and others.22
Studies in animals: early postnatal
nutrition and adult health
Because interpretation of epidemiologic studies of human
cohorts provides only associations rather than proof of
causality, and prospective studies in humans require long
observational periods, studies with animals are yielding
information about efficacy of early interventions and are
beginning to provide important information about mecha-
nisms of observed programming effects.
Pigs and baboons have been used as animal models for
the study of the long-term effects of pre- and/or postnatal
nutrition27,28 but are quite expensive and difficult to use.
The litter manipulation model in rodents has also been
used to study the long-term effects of postnatal under-
and overnutrition. In this model, pups are redistributed
shortly after birth to either small or large litters, resulting
in overnutrition or undernutrition during the suckling pe-
riod, respectively. McCance29 showed that rats undernour-
ished during the suckling period followed a permanently
diminished growth trajectory whereas those undernour-
ished after weaning compensated for the period of slowed
growth and resumed the growth trajectory of their normally
nourished littermates. This was one of the first studies to
suggest a programming effect by early postnatal nutrition.
A problem with the techniques used by McCance is that
the exact volume and nutrient composition the pups
receive from their mothers are difficult to control and
quantify. The artificial rearing technique, as described by
Hall,30 usually called the ‘pup in the cup’ model, partially
circumvents this problem. This model starts gastrostomy
feeds in rat pups at around 4 days of age. The pups receive
81
Premature < 28 weeks GA
Growth hormone
Low IGF-1
hypersecretion
Insulin resistance
Secondary hyperinsulinemia
a rat milk substitute formula that can be altered. Using this
technique, feeding a high-carbohydrate diet throughout
the suckling period resulted in several metabolic al-
terations that were seen on day 12.31 These included
increased insulin concentration, increased expression of
the gene-controlling insulin release (PDX1), and increased
hexokinase activity, demonstrating a short-term metabolic
response to early increased carbohydrate intake.
Moreover, despite provision of a normal chow diet after
weaning the metabolic abnormalities persisted at 100 days
of age. In addition to signs of glucose intolerance, animals
fed the high-carbohydrate diets developed obesity and at
100 days of life weighed approximately 140 g more than
their mother-fed controls. The high-carbohydrate diet
induced an up-regulation of several genes involved in the
glucose metabolism, including insulin, PI3K and GLUT-2
transporter gene. In the next generation, females who
were fed the carbohydrate-enriched diet during infancy
had progeny that continued to present the same metabolic
abnormalities (insulin resistance and obesity) as adults, de-
spite being fed a regular diet from birth.
Thus, early institution of a high-carbohydrate diet
appears to result in up-regulation of insulin resistance,
which disposes the animals to the development of meta-
bolic syndrome. In addition, from these studies, postnatal
perturbations in nutrition can be inferred to result in long-
term effects that can span generations. Whereas studies in
gastrostomy-fed infant rats might provide for evidence of
the possibility of metabolic programming by increased
carbohydrate intake, noting the clinical relevance of such
studies is also critical. These studies utilized a milk sub-
stitute enriched in carbohydrate by a percentage far
exceeding that common to formulas prescribed for catch-
up growth in premature infants. Moreover, the rat milk
substitute decreased lipid composition to provide for iso-
caloric intake with increased carbohydrate intake. Conse-
quently, long-term and generational effects observed in
82
these animals might be as much the result of low lipid
nutrition as they are the outcome of high-carbohydrate
intake. Nevertheless, the results are intriguing and merit
further evaluation.
Programming mechanisms
The normal development of a multicellular organism is
driven by genetic instructions acquired at conception. Yet
during the early critical period of life the body also has an
exquisite ability to respond to environmental situations that
program the individual for future responses to such stimuli.
These programming effects can be functional throughout
life and can be passed to future generations. Thus our
genetic constitution in terms of DNA nucleotide base pairing
appears to only be a part of what constitutes our phenotype.
Modern nutritional science supported by emerging molecu-
lar tools is beginning to support neo-Lamarckian concepts
that one’s environment might result in significant pheno-
typic and transgenerational effects. Within this framework,
early adaptation to certain quantities and types of nutrition
may permanently change the physiology and metabolism of
the organism and its progeny. Several adaptation mecha-
nisms have been proposed including apoptosis of progenitor
cells and epigenetic phenomena. We will expand upon
previously published mechanistic concepts32 by focusing
on early apoptotic and epigenetic mechanisms.
Apoptosis
One of the adaptations evident in animal models of early
nutritional stress is altered apoptotic homeostasis.25,26 Apo-
ptosis plays a central role in perinatal organogenesis and
growth in several organs, including the kidney and brain.
Gene expression of the apoptosis-related molecules Bcl-2
and Bax respond to multiple nutrient-related stimuli such
as paracrine growth factors. Bcl-2 is an anti-apoptosis pro-
tein that attenuates the effects of cytochrome c released
from mitochondria and counters the effects of the pro-
apoptosis protein Bax. Bcl-2 and Bax contribute to the sig-
naling pathways that activate caspase-3, which is necessary
for the chromatin condensation and DNA fragmentation that
characterize apoptosis.
Intrauterine growth retardation (IUGR) in rats is associ-
ated with the development of hypertension in adulthood33
and affects expression of Bcl-2 and Bax in a tissue-specific
manner. Fetal undernourishment has also been shown to
be capable of programming for adult morbidities such as
cardiovascular disease and hypertension through an apo-
ptotic pathway.24,33 In instances of fetal hypoxia, blood
flow is preferentially directed toward the brain and heart
and restricted from such organs as kidney. Studies in both
human and rat models have shown that offspring with
IUGR have smaller kidneys and decreased nephron number.
Nephrogenesis is an interesting case of organogenesis in
which rapid remodeling is required, and as such, apoptotic
pathways play an important role (Fig. 3).
As uteroplacental insufficiency affects 3e10% of preg-
nancies in Western societies, the effects of fetal undernu-
trition on pathways resulting in adult-onset disease are
serious. Nephrogenesis relies on proper regulation of
J. Neu et al.
apoptosis, and can therefore be altered by nutrition in-
sufficiencies that alter expression of factors such as p53.
Markers distinctive of an increase of renal apoptosis have
recently been found in IUGR pups.26
Whereas rat nephrogenesis commonly continues into the
first days of life, it is usually complete by week 36 of human
gestation. Thus it is likely that babies surviving in neonatal
intensive care units (down to 22 weeks gestation) are still
at risk for postnatal-nutrition-induced arrest of nephrogen-
esis through these apoptotic mechanisms. Elucidation of
the molecular basis underlying these mechanisms is likely
to lead to preventative strategies for a significant subset
of individuals with hypertension.
Epigenetic modifications
Although apoptotic mechanisms in IUGR fetuses can play
a role in development of adult illness, such a mechanism
does not fully explain the propagation of effects to sub-
sequent generations. A more subtle adaptation through
which the newborn might respond to altered nutrient
delivery involves epigenetics. Epigenetics encompasses
changes in the three-dimensional structure of chromatin
without affecting DNA sequence.34 These changes are heri-
table and relatively persistent. Two key determinants of
chromatin structure are DNA methylation and covalent mod-
ification of histone tails.
DNA methylation is associated with the formation of
heterochromatin and is therefore gene silencing. Histone
tails are modified by acetylation, methylation, phosphory-
lation, and ubiquitination at specific sites. The essentially
limitless combination of histone site-specific modification
has led several authors to speculate on the existence of
a ‘histone code’ or ‘nucleosome code’,35 which contains
detailed heritable genetic information that can turn gene
transcription on or off. Specific combinations of DNA meth-
ylation and histone tail modifications lead to the formation
of euchromatin or heterochromatin (Fig. 4). The three-
dimensional structure of euchromatin allows transcription
factor complex access to DNA and thereby permits subse-
quent transcription of select genes.
Evidence for ‘programming’ by
epigenetic mechanisms
Behavioral programming
It has been established that maternal behavior and stress
response during pregnancy can program the long-term
behavior and physiological function of offspring. Kapoor
and Matthews found that the male offspring of guinea pigs
exposed to stress displayed significantly more stress-
related behavior as adults, such as wall-seeking behavior in
an open-area environment.36 In addition, plasma cortisol levels
were significantly increased in response to challenge with
adrenocorticotrophic hormone (ACTH) and hypothalamice
pituitaryeadrenal axis function appeared to be pro-
grammed by the prenatal stress induction.37 Jarvis et al.
showed increased stress-response and abnormal maternal
behavior in female offspring of pigs.37 Sows exposed to
social mixing stress during the late gestation gave birth to
offspring that secreted higher levels of salivary cortisol in
Postnatal nutrition and adult health programming 83

Nephron

Bcl-2 p53 and Bax

Homeostasis Anti-apoptosis equilibrium Pro-apoptosis

Fetal
stress

Rat fetal hypoxia

Bcl-2
Anti-apoptosis
Blood flow to Relative renal p53 and Bax
the brain ischemia Pro-apoptosis
and heart

Activate caspase3

Kidney size
Adult rat DNA fragmentation
and number of
hypertension nephrons

Figure 3 Apoptotic changes in kidney with fetal stress in a rat model leading to adult hypertension.

response to social stress than did offspring of control sows.
Furthermore, female offspring of the stress-exposed
mothers exhibited abnormal maternal behavior (such as bit-
ing of piglets) after having themselves given birth.37
Moreover, postnatal maternal behavior has also been
shown to program adult physiology. Weaver et al. report
striking effects of varied levels of maternal behavior,
including arched-back nursing, licking and grooming
(ANLG), as shown in Table 2.38
These results support the epigenetic programming
hypothesis, and the cross-fostering studies support a
non-genomic transmission of stress-response associated
solely with postnatal maternal behavior.
Nutritional epigenetic programming
Multiple nutrition-sensitive signaling pathways communi-
cate conditions in the extracellular milieu to the nucleus
and can alter the chromatin structure. As a result, an early
significant nutritional stress can affect DNA methylation
and histone covalent modification, which subsequently
re-programs the cell’s response to further extracellular
signals. For example, it has been recently demonstrated

Epigenetic factors influence the behavior of genes

Acetylation
DNA methylation Histone tails modification Methylation
(gene-silencing or producing the ‘histonecode’
turning off genes) Phosphorylation
Ubiquination

Heterochromatin
Tightly Packed
chromatin
Changes in three-
dimensional chromatin
structure (without
changing DNA sequence):

Euchromatin
(genetically active)
Loosely packed
chromatin

Hereditary persistent
transcription of
selected genes

Figure 4 Euchromatin is associated with gene activity and is marked by decreased CpG dinucleotide methylation and increased
histone acetylation. Conversely, heterochromatin is associated by gene inactivation and is marked by increased CpG methylation
and decreased histone acetylation.
84
Table 2 Maternal behavior and adult offspring characteristics
ANLG maternal behavior and Offspring of high
adult offspring characteristics ANLG maternal
behavior
Hypothalamic-pituitary-adrenal Modest
(HPA) axis response to stress
Hippocampus glucocorticoid High
receptor (GR) expression
Glucocorticoid feedback sensitivity High
ANLG, arched back, nursing, licking and grooming.
that uteroplacental insufficiency in the IUGR rat have
hepatic DNA hypomethylation and histone H3 hyperacety-
lation that persist beyond the newborn period in associa-
tion with altered mRNA levels of several important
metabolic proteins.39
In a study investigating a possible nutrition-related
mechanism for observed prenatal and early postnatal pro-
gramming effects, Waterland and Jirtle40 demonstrated the
programming capabilities of epigenetic alterations utilizing
a yellow agouti (Avy) mouse model. The agouti gene is re-
sponsible for the yellow nature of otherwise black hair in
this mouse model; varied expression of the gene results in
a distribution of coat phenotype, ranging from yellow to
mottled to black. Virgin female a/a mice were fed either
a control diet or a diet supplemented with folic acid, vitamin
B12, choline chloride and anhydrous betaine, and were sub-
sequently mated with Avy/a males. As methyl donors and co-
factors are critical in the DNA methylation process, it was
hypothesized that dietary intervention would influence the
methylation pattern of the agouti gene in the offsprings.40
Nutrient supplementation did not affect litter size or
offspring body weight, but the color distribution of Avy/
a offspring was shifted toward a black coat in offspring of
dams fed the diet supplemented with methyl donors and
cofactors. DNA methylation of the agouti exon was signifi-
cantly increased in the offspring of supplemented dams.
Moreover, DNA collected from brain, liver, and kidney
(tissues representing all three germ layers), confirmed
overall increased gene methylation. The coat color distri-
butions persisted to adulthood. This data suggests nutri-
tional manipulations in the early embryo change lifetime
gene expression. Waterland et al. further evaluated post-
natal diet on CpG methylation of the insulin-like growth
factor 2 (IGF-2) locus in mice. A post-weaning diet including
methyl-deficient nutrients permanently affected expres-
sion of IGF-2, suggesting that a childhood diet could con-
tribute to IGF-2 loss of imprinting and expression in
humans41 as well as altered DNA methylation patterns.
Summary
In summary, although several molecular mechanisms are
likely to play a role in determining the effects of early
nutritional stresses on adult metabolism, both apoptosis
and epigenetic phenomena have been identified through
animal models as potentially relevant candidates. Unfortu-
nately, the specific mechanism through which certain
J. Neu et al.
Offspring of low Offspring of high ANLG Offspring of low ANLG
ANLG maternal maternal behavior, maternal behavior,
behavior cross-fostered cross-fostered with
with low ANLG mother high ANLG mother
High High Modest
Low Low High
Low Low High
nutrients trigger these pathways, and how they affect the
adult phenotype, are still in the early phases of
investigation.
Current clinical interventions
For healthy term infants, there appear to be no health-
related advantages for the use of formula over mother’s
milk. Moreover, the higher nutrient concentrations found in
the commercial formulas have been associated with met-
abolic syndrome in adulthood.42 Preliminary studies suggest
that infants fed breast milk have a lower incidence of obe-
sity and the effect on body mass index is suggestive.43 Sub-
stitution of lactose with other more glucose-dense
carbohydrates, such as glucose polymers or maltose, can
cause a higher glycemic index and adversely program the
infant’s metabolism by mechanisms similar to those
described for gastrostomy-fed rat pups receiving a high-
carbohydrate diet. However, experimental evidence for
this speculation is lacking.
In premature infants, it is likely that the biological
programming of prolonged early EUGR resulting from un-
dernutrition during a critical period might operate in the
same way as in an IUGR term-born infant because growth
retardation occurs at a similar stage of development. Thus
we have opportunities to institute preventative measures
for long-term benefits in low-gestation newborns. However,
several recent studies have provided neonatologists with an
apparent dilemma in nutritional management of premature
infants. Does subsequent neurodevelopment need to be
weighed against the risk of preventing metabolic syndrome
later in life?
In sick VLBW preterm infants, limiting early nutrition
might not only lead to devastating short-term conse-
quences, such as increased susceptibility to infection,
lack of organ growth (e.g. brain) during a critical period,
and pathologic bone fractures, but also to long-term
consequences such as poor neurodevelopment. Although
the data remain inconclusive, catch-up growth might be
associated with metabolic and cardiovascular risk later in
life. These findings have implications for the future adult
health of VLBW survivors if we attempt to aggressively
compensate for poor initial growth. Even though some
evidence suggests that higher intakes are associated with
evidence of type 2 diabetes and vascular abnormalities in
early adulthood, the complications of early undernutrition,
such as poor neurodevelopment, appears to outweigh these
Postnatal nutrition and adult health programming
metabolic problems. Overinterpretation and over-reaction
(such as markedly limiting nutrition in premature babies) to
studies17,18 suggesting that increased growth in the first
2 weeks of life is due to overnutrition and subsequently
leads to metabolic syndrome, need to be avoided. A very
important question is not whether the institution of early
postnatal nutrition should remain a mainstay in our therapy
for VLBW infants, but rather how can we best fine-tune
these regimens. As discussed in a recent review by Yeung,44
we should be fine-tuning the composition of the nutritional
intakes (e.g. high protein instead of carbohydrate or lipid)
so as to not cause long-term metabolic problems while
maintaining neurodevelopment.
Future directions
Nutritional composition (protein versus
carbohydrate)
It is common practice to enhance the nutrition of the
premature infants with commercial fortifiers containing
fatty acids of various chain lengths and glucose polymers or
starch derivatives. Evidence for the benefits of energy
intakes >120 kcal/kg/day in most preterm infants who do
not have morbidity association with increased energy de-
mand is lacking. Intakes of high non-protein energy pro-
mote weight gain due to gains in body fat rather than
lean body mass and this puts the infants at risk for long-
term adverse health outcomes. High carbohydrate intakes,
especially those with high glycemic indices increase insulin
demand and promote hyperinsulinemia. An alternative ap-
proach by correcting protein undernutrition might improve
insulin sensitivity. Supplementing protein intake in low
birthweight infants appears to benefit them in terms of
growth and also appears to be safe short term. The serum
IGF-1 concentration increases significantly with each even
small increases in protein-calorie intake.45 Increasing pro-
tein intake would, therefore, have potential for normaliz-
ing the growth-hormoneeIGF-1 axis and minimizing insulin
resistance, relative visceral adiposity and the long-term
risks in this population. Studies in both animals and human
prematures should be instituted, but it is likely that long-
term results will be seen more rapidly in studies in animals.
Thus use of the gastrostomy feeding model, as utilized by
Patel and Srinivasan,31 might be useful to compare compo-
sitional intakes and evaluate mechanisms that cannot be
evaluated in humans. Using this model, it has been demon-
strated that a very high carbohydrate intake in early life
can lead to short-term, long-term and transgenerational
metabolic abnormalities. This model also offers the op-
portunity for a comparative trial of isocaloric protein and
carbohydrate supplementation, with subsequent observa-
tion of short- and long-term as well as transgenerational
outcomes.
Modulation of inflammation with nutrients
Insulin resistance in premature infants might also be a result
of high concentrations of inflammatory mediators associ-
ated with a systemic inflammatory response (often derived
from the GI tract). Several interventions might be of benefit
85
and deserve exploration. These include early intake of
enteral nutrients,46 long-chain omega 3 fatty acids,47 gluta-
mine,48 probiotics,49 and/or microbial fermentation prod-
ucts such as butyrate,50 which strengthen the intestinal
barrier function and modulate inflammation.
Practice points
 Early postnatal life offers a ‘critical window’
during which too much or too little nutrition can
‘program’ the individual for subsequent health
that might even propagate to subsequent
generations.
 Premature infants who are appropriate for gesta-
tional age should not undergo purposeful growth
restriction to prevent subsequent adult metabolic
syndrome.
 The nutritional composition (e.g. carbohydrate
versus protein predominant intake; human milk
versus commercial formula) that is provided to in-
fants might be at least as important as total quan-
tity of nutrition in programming for future health.
 Stresses associated with neonatal intensive care
and prematurity are likely to play a role in producing
hormonal and inflammatory mediator imbalances
that lead to alterations in fat distribution, altered
regulation of genes associated with insulin resis-
tance, and subsequent development of metabolic
syndrome. Understanding the mechanisms of these
stress-induced metabolic aberrations may provide
targets for prevention with nutritional agents.
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