Effects of in utero conditions on adult feeding preferences

Abstract

The fetal or early origins of adult disease hypothesis states that environmental factors, particularly nutrition, act in early life to program the risks for chronic diseases in adult life. As eating habits can be linked to the development of several diseases including obesity, diabetes and cardiovascular disease, it could be proposed that persistent food preferences across the life-span in people who were exposed to an adverse fetal environment may partially explain their increased risk to develop metabolic disease later in life. In this paper, we grouped the clinical and
experimental evidence demonstrating that the fetal environment may impact the individual’s food preferences. In addition, we review the feeding preferences development and regulation (homeostatic and hedonic pathways, the role of taste/olfaction and the reward/pleasure), as well as propose mechanisms linking early life conditions to food preferences later in life. We review the evidence suggesting that in utero conditions are associated with the development of specific food preferences, which may be involved in the risk for later disease. This may have
implications in terms of public health and primary prevention during early ages.

Full text

Journal of Developmental Origins of Health and Disease (2012), 3(3), 140–152.
&Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012
doi:10.1017/S2040174412000062
REVIEW
Effects of in utero conditions on adult feeding
preferences
A. K. Portella
1
, E. Kajantie
2,3
, P. Hovi
2,3
, M. Desai
4
, M. G. Ross
4
, M. Z. Goldani
1
,
T. J. Roseboom
5
and P. P. Silveira
1
*
1
Nu
´cleo de Estudos da Sau
´de da Crianc¸a e do Adolescente (NESCA), Hospital de Clı
´
nicas de Porto Alegre, Faculdade de Medicina,
Universidade Federal do Rio Grande do Sul, Brazil
2
Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
3
Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland
4
Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA,
David Geffen School of Medicine at UCLA, Torrance, California, USA
5
Department of Clinical Epidemiology and Biostatistics and Department of Obstetrics and Gynaecology, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands
The fetal or early origins of adult disease hypothesis states that environmental factors, particularly nutrition, act in early life to program the risks
for chronic diseases in adult life. As eating habits can be linked to the development of several diseases including obesity, diabetes and
cardiovascular disease, it could be proposed that persistent food preferences across the life-span in people who were exposed to an adverse fetal
environment may partially explain their increased risk to develop metabolic disease later in life. In this paper, we grouped the clinical and
experimental evidence demonstrating that the fetal environment may impact the individual’s food preferences. In addition, we review the
feeding preferences development and regulation (homeostatic and hedonic pathways, the role of taste/olfaction and the reward/pleasure), as
well as propose mechanisms linking early life conditions to food preferences later in life. We review the evidence suggesting that in utero
conditions are associated with the development of specific food preferences, which may be involved in the risk for later disease. This may have
implications in terms of public health and primary prevention during early ages.
Received 15 August 2011; Revised 2 January 2012; Accepted 1 February 2012; First published online 6 March 2012
Key words: DOHaD, feeding preferences, fetal programming, thrifty behavior
Introduction
Developmental origins of adult disease – fetal
programming
The early life environment is now well recognized to con-
tribute importantly to health and disease predisposition later
in life. The fetal or early origins of adult disease hypothesis
stated that environmental factors, particularly nutrition, act in
early life to program the risks for chronic diseases in adult life.
In addition to the risks of adult obesity, hypertension,
1
and
type II diabetes,
2,3
infants small at birth are at increased risk
of atherogenic lipid profiles,
4,5
reduction of bone mass and
possibly bone mineral content,
6–9
differential stress respon-
ses,
10,11
less elastic arteries,
12
specific patterns of hormonal
secretion
13,14
and higher incidence of depression
11,15,16
in
adult life. Extensive studies in animal models have confirmed
that disease risk and behavior later in life can be influenced or
‘programmed’ dependent upon the fetal and early postnatal
environment.
Could food preferences also be programmed?
As eating habits can be linked to the development of several of
the diseases mentioned above,
17–20
it could be proposed that
persistent small nutrient imbalances across the life-span in
people who were small at birth may explain, in part, their
increased risk to develop metabolic disease later in life. In other
words, fetal adversity may drive the individual to prefer specific
foods during the life course, increasing their ingestion and
ultimately leading to disease. As such, a better understanding of
the mechanisms contributing to these imbalances is essential to
address the pathogenesis of the metabolic syndrome epidemic.
Although ‘hunger/appetite’ is a major determinant of caloric
intake, ingestive responses are significantly mediated by hedo-
nistic mechanisms (i.e. reward), food preferences and social
behavior. In this review, we synthesize clinical and experimental
evidence from independent research groups demonstrating
that the fetal environment may also affect the offspring’s food
preferences in adulthood and that programming of these
preferences may contribute to the development of metabolic
disturbances later in life. Other early life events also impact
food preferences in the offspring, such as early nutrition/
overfeeding,
21,22
maternal diet,
22
neonatal handling,
23
etc., but
the focus of this review lies on the fetal life events ability to
*Address for correspondence: P. P. Silveira, Departamento de Pediatria,
Faculdade de Medicina, Universidade Federal do Rio Grande do Sul. Ramiro
Barcelos, 2350, Largo Eduardo Zaccaro Faraco, 90035-903 Porto Alegre, Brazil.
(Email 00032386@ufrgs.br)

program the offspring food preferences. Prior reviews have
addressed the programming of appetite regulation.
24–28
Physiological, cellular and molecular basis of hedonic
feeding behavior
Essential to survival and homeostasis maintenance, feeding
behavior is finely regulated through an intricate and complex
mechanism. Basically, ingestive behavior may be divided into
several phases
29–32
:intheinitiation phase, the value of an
available food objective or the internal state attracts the
individual’s attention to feeding. Once the selective attention
is reached and the motivation to food ingestion is present, it
begins the procurement phase, which requires planning,
learning and memory, depending exclusively on cortical
cognitive processes. The consummatory phase begins when the
food is finally available and involves stereotypical behavioral
sequences, but also is characterized by the formation of
associations between the different sensorial characteristics of
the food. Thereafter, satiety mechanisms lead to the meal
termination, including the postabsorptive sensations and
storing of this information in the form of associative memory
for posterior comparison. Brain afferent systems regarding
food intake include external stimuli (visual, olfactory, audi-
tory and tactile information) and internal stimuli, which is
divided into pregastric (essentially taste), gastric (distention),
postgastric (or preabsorptive stimuli) and postabsorptive
stimuli (gastric hormonal release; nutrient, metabolites and
hormonal action at liver or brain receptors).
32
The individual
response to any of these stimuli could potentially be subjected
to developmental programming, as well as the learning
and reinforcement/extinction of the consequences of the
consummatory behavior.
Taste/olfaction
Research suggests that food preferences and behavior develop
early in infancy
33,34
and track further on until adult-
hood.
33,35,36
Taste bud development is observed at around
11 weeks gestation in humans.
37
Using radiographic techni-
ques on pregnant women, it was possible to demonstrate fetal
swallowing as early as 12 weeks gestation.
38
Early studies
describe that fetus can be induced to swallow amniotic fluid if
saccharine is introduced into the amniotic cavity
39
suggesting
that fetal taste buds are functional. Of note, maternal
hyperglycemia influences amniotic fluid glucose levels,
40
with
increased amniotic fluid glucose concentrations observed in
pregnant diabetics. Interestingly, researchers showed that
prenatal flavor experiences enhance the acceptance and
enjoyment of similarly flavored foods during weaning in
human babies.
41
Infants who had exposure to the flavor of
carrots in either amniotic fluid or breast milk exhibited fewer
negative facial expressions in response to that flavor than did
non-exposed control infants. Hence, it seems that the sensory
environment in which the fetus lives, the amniotic sac,
changes as a function of the food choices of the mother as
dietary flavors are transmitted and flavor the amniotic fluid.
42
Therefore, the pregnant female’s diet may be involved in the
programming of the offspring’s feeding behavior.
The development of food preferences continues when the
infant is exposed to maternal milk, itself containing a variety
of flavors dependent upon the foods ingested by the
mother.
43–45
From an early age it is possible to detect an early
attraction to sweet and salty tastes, which might later drive the
appetite for sweet and salty foods.
46
These varied flavor
exposures during the nursing period provide the infant with
opportunities to learn new flavors, which impacts on the
response to similarly flavored solid foods.
41
Whether mater-
nal food ingestion during pregnancy also influences offspring
food preferences is controversial. With weaning, several
factors promote the acceptance of solid foods, including
introduction of a variety of solid foods,
47,49
repeated exposure
to the specific food and previous breastfeeding experience;
48
in particular, when the foods consumed when the child was
being breastfed had the same flavor.
41
Infants exposed to a
variety of solid foods accept new foods more readily than do
infants exposed to a monotonous solid diet.
49
Besides repe-
ated exposure,
50
taste development is promoted by other
mechanisms such as flavor and nutrient learning. Parental
attitudes also play an important role in the development of
their child’s food preferences.
51
Later on and into adulthood,
food preferences are influenced by several other factors such
as personal experiences, cultural adaptations and perceived
health benefits.
51
The sensory and hedonic evaluation of the majority of the
food-related flavors is influenced by the olfactory perception.
Odor perception is initiated in the chemosensory olfactory
neurons in the nasal epithelium, where the chemical signal
is converted into electrical impulses. This information
is transmitted to the olfactory bulb, and decoded in the
olfactory cortex, leading to the perception of distinct
flavors.
52
Interestingly, even imagined odors can to some
extent induce changes in perceived taste intensity comparable
to those elicited by perceived odors.
53
Because there is no evidence for innate odor preferences,
most of our food preferences are probably acquired by
learning.
54,55
Food odors rated as pleasant have the ability to
stimulate appetite, as evidenced by increased ratings of hunger
following exposure to food-related odors,
56
as well as sti-
mulate other responses such as insulin release
57,58
and gastric
acid secretion.
59
At least partial olfactory, as well as taste,
sensory-specific satiety does not require food to enter the
gastrointestinal system, and does not depend on the ingestion
of calories.
60
Although children usually eat more of the foods
they like best in terms of taste,
61,62
the impact that taste
factors have on the food intakes of adults is much less clear,
for their taste preferences and aversions are not always direct
predictors of food consumption.
63–65
Therefore, the general
assumption that taste preferences predict food preferences
does not always hold true.
66
Effects of in utero conditions on adult feeding preferences 141

Reward/pleasure
The hypothalamus is the key brain structure involved in the
homeostatic food intake regulation. However, even in the
absence of hunger, the pleasure and reward sensations
associated to the food can also stimulate feeding behavior
(hedonic food intake). Thus, the perceived pleasantness of
foods can modulate food intake indirectly by influencing the
preference for certain foods. Among healthy individuals,
eating beyond homeostatic needs when facing caloric-rich
palatable foods evidences the fact that a significant proportion
of consumption is driven by pleasure, rather than energy
supply. The brain extracts information about quality, inten-
sity and hedonic value from gustatory neuronal responses;
thus all of these psychological attributes must be coded by the
neural activity in the taste pathways. Therefore, appetite for
specific foods and nutrients is under complex neuroregulatory
control. For instance, in animal studies, fat intake is increased
by opioids,
67–69
whereas carbohydrate intake is increased by
neuropeptide Y (NPY).
70
The forebrain plays a prominent role in the hedonic value
that the brain attaches to gustatory activity originating from the
oral cavity. The nucleus accumbens has been related to directive
behaviors and appetitive instrumental learning
71,72
and may
provide an interface between motivation and behavioral action.
Neuroimaging studies strongly support a role for central
dopamine in food reward processes. Studies in humans reveal
that food-related cues activate areas of the brain associated with
the processing of information related to the pleasurable features
of stimuli (i.e. the brain reward system), such as the ventral
tegmental area (VTA) and substantia nigra, amygdala and
orbitoprefrontal cortex
73,74
; these areas are either involved
in the synthesis and release of dopamine or are targets for
dopamine projections. Recent evidence suggest that dopam-
inergic neuronal activity in the VTA that projects to the nucleus
accumbens can be modulated by peripheral energy status signals
including leptin, insulin and ghrelin,
75–77
revealing the poten-
tial importance of the integration between the peripheral sig-
naling and the central mesolimbic system in food preference
regulation. Therefore, besides their well-known role in altered
regulation of appetite control in the field of developmental
programming when acting at the hypothalamic level,
24,28,78,79
these hormones also appear to modulate the pleasure associated
with the ingestion of palatable food and could be involved in
the programming of feeding preferences.
As a corollary to reward-mediated ingestion, studies in
humans demonstrate that emotional experience can lead to an
increase in food intake, especially sweets and calorie dense
foods.
80
Periods of workload are associated with a higher
consumption of calories and fat, especially in people who
practice dietary restraint.
81–83
Individual variation in the
hypothalamus–pituitary–adrenal (HPA) stress response
intensity correlates with the degree of stress influence on food
choices.
84
It has been proposed that glucocorticoids and
insulin stimulate the consumption of highly dense caloric
foods (‘comfort foods’), which in turn would protect the
HPA axis from potential dysfunction.
85
Intrauterine growth
restricted (IUGR) individuals are also reported to have an
increased adrenal response to acute stress,
11
a feature that
combined with their known insulin resistance could set the
stage for altered feeding behaviors, especially increased con-
sumption of palatable, ‘comfort’ foods.
Finally, the prefrontal cortex may be involved in the
conscious perception of some types of flavors
86
particularly in
the integration of the valuation and comparison processes
(coding of rewards relative to other available rewards, general
and specific satiety, temporal discounting and negative
valuations such as negative health consequences) that impact
food selection.
87
Obese children react to food stimuli with
increased prefrontal activation;
88
one could propose that
reduced inhibitory control may also be suggested as playing
a role in excessive feeding behavior. Infants who were
growth restricted have poorer executive functioning,
89,90
and
increased vulnerability to addictive disorders
91
and attention
deficit hyperactivity disorder,
92
therefore, alterations on brain
frontal regions could also play a role in their food choices.
Proposed mechanisms linking early life conditions to
food preferences later in life
A possible mechanism by which the early environment could
impact the individual’s food choices permanently is the
programming of the sensitivity to the reward (i.e. pleasure)
associated with the ingestion of a palatable food. In adult
rodents, prenatal protein malnutrition alters the response to
reward.
93
In addition, both leptin and insulin are associated
with a decrease in the response of the nucleus accumbens to
food cues.
94,95
Interestingly, several studies have shown that
cord leptin levels are diminished in small for gestational age
(SGA) infants,
96,97
increase during the catch-up growth
98
and
decrease again in adulthood in the context of an excess of
adipose tissue when corrected for body fat mass, gender and
fasting insulin,
99
suggesting an altered adipocyte function and
leptin resistance in these individuals. Low birth weight also is
related to impaired insulin secretion,
100,101
decreased glucose
tolerance in later life
13,102
and diabetes.
1,103
Besides the
potential implication of abnormal adipose/pancreatic tissue
development in the long-term metabolic consequences asso-
ciated with in utero undernutrition. Potentially, leptin/insulin
modulation of central dopamine is altered in SGA individuals,
leading to an altered reward response to food, consequent
increased palatable food ingestion and the development of
obesity. These alterations could make these individuals prone
to ‘food addiction’, a recent concept proposed by some
researchers. Although addictive behavior is generally associated
with drugs, alcohol or sexual behavior, it is becoming apparent
that certain food substances may cause similar physiological
and psychological reactions in vulnerable people.
104–106
Avena
et al.
107
classified sugar as an addictive substance because it
follows the typical addiction pathway that consists of bingeing,
108
142 A. K. Portella et al.

withdrawal,
109
craving
110
and cross-sensitization.
111
The
seeking behavior is motivated and reinforced not only by a
food’s positive effects but also the negative state or ‘antire-
ward’ that accompanies abstinence from its use,
112
ultimately
leading to obesity and related metabolic consequences.
In addition, peripheral hormones, within subsets of taste
cells and structures of the olfactory system, have also been
proposed as modulators of olfaction/taste perception.
Vasoactive intestinal peptide, cholecystokinin, leptin receptor
and NPY, are found within type II taste cells, whereas
glucagon-like peptide-1 is found in both type II and type III
taste cells. The interplay between these systems modulates not
only gustatory and olfactory function but also whole-body
physiological functions, such as metabolic control and energy
homeostasis.
113
Flavor–taste learning also involves brain
dopamine signaling.
114
Therefore, fetal adversities could
program the functioning of such systems modulating food
preferences (Fig. 1).
Evidences for the fetal programming of feeding behavior
Experimental (animal) studies
Animal studies have confirmed the potential for develop-
mental programming of obesity. Low birth weight sheep have
a higher relative fat mass as neonates compared with higher
birth weight offspring.
115
There is also evidence that a
maternal protein-restricted (50%) diet during pregnancy
programs offspring susceptibility to adult obesity in rats and
mice, with the difference apparent already by 7 days of
age.
116,117
Moderate (50%) and severe (70%) maternal
prenatal caloric restriction is also associated with greater fat
deposition in offspring when presented with a hypercaloric
or high-fat diet.
118,119
Importantly, animal studies have
consistently demonstrated increased caloric intake among low
birth weight offspring, a result in part of reduced anorexigenic
responses, neural pathways and neuronal signaling.
119–121
Several animal models aid in understanding the effects of
early life events upon behavioral and metabolic outcomes in
adulthood. A study using a low protein (LP) diet during
gestation describes specific food preferences for high-fat food
in both male and female adult offspring when compared with
the control animals. If offered at discrete periods during
gestation (early, mid and late gestation), the LP-diet programs
the offspring feeding behavior in a gender-specific and timing-
dependent manner, in which the females exposed to LP diet in
early gestation prefer to eat more carbohydrates over the other
macronutrients in adult life, as compared with controls.
122
Interestingly, the addition of high levels of folate to the LP diet
during gestation prevents the LP effects on offspring food
preferences, possibly a result of epigenetic effects.
123
However,
folate added to a normal protein diet also alters offspring’s
feeding behavior similarly to the LP diet exposure alone.
Therefore, it seems that the role for potential folate-influenced
DNA methylation in programming of food preference is likely
to be gene-specific rather than genome-wide.
Manipulation of the dietary fat content during pregnancy
also leads to altered offspring food preferences. Pups nursed by
dams fed low fat diet during pregnancy and lactation show an
increased preference for fat as compared with controls.
124
However, if the obesogenic diet is offered to the dams before
mating, it results in hyperphagia, decreased locomotor activity,
increased adiposity, endothelial dysfunction and hypertension
in the adult offspring.
125
Hyperphagia is also a consequence of
FOOD CHOICES
Peripheral sensation
(taste, olfaction, texture)
Judgement/value
(Prefrontal cortex)
Homeostatic regulation
(Hypothalamus)
Pleasure/Reward
(Mesolimbic system)
Socioeconimic status
Peripheral signalling (leptin, insulin, ghrelin, glucocorticoids, etc.)
Culture Exposure
Fig. 1. Brief schematic outlining the regulation of food preferences. Red – predominantly centrally mediated influences. Green –
predominantly peripherally mediated (adipose tissue, pancreas, gastrointestinal tract and hypothalamus–pituitary–adrenal axis) influences.
Blue – environmental influences. Fetal life adversities can affect any of the pathways, except for environmental factors (although they
could be a cause of fetal adversity).
Effects of in utero conditions on adult feeding preferences 143

prenatal nutritional disturbance. Subjecting pregnant rats to
severe food restriction (feeding 30% to 50% of ad libitum
intake) promotes profound intrauterine growth retardation in
their offspring
118,119
with decreased newborn plasma leptin
and increased ghrelin.
118
These growth-retarded pups become
hyperphagic, and when provided with a hypercaloric diet
from weaning, develop pronounced central adiposity.
119
Cross
fostering the IUGR offspring to dams receiving ad libitum
chow induces a rapid catch-up growth and results in increased
weight, percent body fat and plasma leptin levels.
118
In fetuses at term, the exposure of the pregnant rodent to
chronic stress reduces body, adrenal and pancreas weight as
well as plasma corticosterone and glucose levels.
126
Long-term
effects of this intervention include the induction of a rebound
and basal hyperphagia when the offspring is on chow diet,
with an exacerbated effect when put on a high-fat diet.
126,127
Moreover, these animals display hyperglycemia, glucose
intolerance and decreased basal leptin levels.
126
It has not
been determined whether the hyperphagia is mediated via
appetite or reward mechanisms.
These combined observations suggest that early life events
can lead to alterations in the feeding patterns of the adult
offspring. It is intriguing to note that, although the metabolic
disarrangements following these diverse interventions may be
very distinct depending on the type of model used, feeding
behavior (higher caloric consumption or specific food pre-
ferences) seems to be consistently found in the different
protocols.
Epidemiologic and clinical observations
The epidemiologic observations that inadequate availability
of nutrients to the fetus during gestation is associated with
altered feeding preferences in adult life come from popula-
tions throughout the world in mainly three different settings:
severe maternal undernutrition during a famine, intrauterine
growth retardation and severely preterm birth.
Severe maternal undernutrition (Famine studies)
The Dutch Famine Birth Cohort has provided evidence that
prenatal nutrition may affect dietary preferences later in
life.
128
During the final months of the World War II, there
was a period of extreme food shortage in the west of the
Netherlands, known as the ‘Dutch Famine’. The Dutch
famine birth cohort includes men and women who were born
around the time of the Dutch famine as term singletons
in one of the main hospitals of Amsterdam. In this study,
periods of 16 weeks were used to differentiate between per-
sons who were exposed in late gestation, mid-gestation and
early gestation. Persons born before and persons conceived
after the period of famine were used as the control group.
Food frequency of intake and physical activity and detailed
clinical examinations of cardiovascular and metabolic disease
were made at the ages of 50 and 58. Although the mean
percentage of protein, carbohydrate and fat in the diet did not
differ among the exposure groups, participants exposed to
famine in early gestation were more likely to consume a high-
fat diet (defined as the highest quartile of fat in the diet or
.39% of energy from fat). The relative risk of participants
with early exposure to famine consuming a high-fat diet
remained significantly higher even after adjustment for con-
founding factors. This finding may explain in part the finding
that the group of participants exposed to famine in early
gestation had more pronounced hypercholesterolemia and
hypertriglyceridemia than the other groups (after exclusion of
participants using lipid-lowering medication). Importantly,
offspring exposed to famine in early gestation had a two-fold
prevalence of coronary heart disease.
In another study,
129
involving a different sample of indi-
viduals exposed to the Dutch Famine during or immediately
preceding the pregnancy period was compared with a sample
of births from the previous or following year (1943 and 1947)
as hospital time controls and to same-sex siblings. Food
frequency and physical activity data was acquired using
questionnaires at a mean age of 58 years. Individuals exposed
to famine in the first half of gestation (i.e. week 20) had
higher reported absolute intakes of energy, fat and protein
and lower reported absolute intakes of carbohydrate than did
the controls. Using time controls as a comparison, gestational
famine exposure was associated with higher energy intake due
to higher fat density in the diet. In addition, lower levels of
physical activity were found in the exposed group. In sex-
stratified analyses, protein intakes were higher for exposed
men and lower for exposed women compared with unexposed
men and women, respectively. In a further comparison to
sibling controls, gestational famine exposure was still asso-
ciated with higher energy intake, higher fat density and
lower physical activity score. However, using a sex-stratified
analysis, energy intake was lower in exposed men and higher
in exposed women compared with their unexposed siblings.
Carbohydrate density was lower in individuals exposed to
famine at any point in gestation compared with their siblings,
and exposed and unexposed siblings did not differ in protein
intake. There was no evidence for heterogeneity by sex for any
macronutrient. Hence, independently of the control chosen
for interpretation of the study, these results confirm that there
is a specific food preference pattern associated with exposure
to undernutrition during gestation, with increased caloric
content mainly due to fat preference, as well as a diminished
propensity to physical exercise.
Intrauterine growth restriction
In a cross-sectional evaluation of a prospective, longitudinal
cohort of subjects born in the municipality of Ribeira
˜o Preto
(state of Sa
˜o Paulo, southeast of Brazil), it was investigated if
IUGR was associated with offspring macronutrient ingestion
and food preferences.
130
Food intake was measured by a food
frequency questionnaire and the data was shown in a carbo-
hydrate to protein ratio (preference). IUGR was determined
based on the birth weight ratio (BWR; the ratio between the
144 A. K. Portella et al.

newborn’s weight and the population’s sex-specific mean
birth weight for each gestational age). Individuals were clas-
sified as non-restricted (BWR >0.85), moderately restricted
(BWR ,0.85 and >0.75) and severely growth restricted
(BWR ,0.75). At the age of 24 years, offspring women born
severely growth restricted ate more carbohydrates than the
women born non-growth restricted, and this finding persisted
after adjustment for several confounders (maternal income,
smoking and schooling at the time of delivery, and partici-
pants’ smoking, schooling, current body mass index (BMI)
and physical activity). This effect was accompanied by a
decreased ingestion of protein. Rather than an absolute BWR
cut-off, regression analysis showed a continuous association
between growth restriction and adult carbohydrate to protein
ratio consumption, meaning that the more growth restricted
at birth (lower BWR), the more these women prefer to
eat carbohydrates over protein in adult life. The increased
carbohydrate to protein consumption was distributed across
different types of foods, and not associated with over or under
consumption of any one food. In addition to the carbohy-
drate preference, women born IUGR exhibited increased
waist to hip ratio (WHR), though the prevalence of
risk factors for metabolic syndrome (plasma fasting insulin,
glucose, high-density lipoprotein (HDL), triacylglycerol) did
not differ between the groups. Using the NCEP-ATP III
diagnostic criteria,
131
there were no differences in the pre-
valence of metabolic syndrome between the groups. As studies
were performed at 24 years of age, the increased WHR may
suggest a predisposition to subsequent metabolic syndrome,
which may be evident with follow-up. It is interesting to note
that protein ingestion seems to be more tightly controlled
than other macronutrients,
132
being set to around 15% of the
total calories. In this cohort, despite the fact that individuals
from the different groups eat protein at that percentage,
IUGR girls prefer comparatively less protein, and more
carbohydrates. This probably means that the set point of the
carbohydrate to protein ratio was changed to a different level
in this group. As carbohydrates are more effective in releasing
insulin (known for its anabolic actions), this may explain their
increased central adiposity, and could be interpreted as an
early sign of the thrifty phenotype.
Severely preterm birth
Another interesting model of an early adverse environment is
birth at very low birth weight (VLBW; ,1500 g) or very low
gestational age (VLGA; ,32 weeks), which comprise ,1%
to 1.5% of live births in countries with available statis-
tics.
133–134
Following birth, these infants experience a period
characterized by immaturity-related neonatal illness fre-
quently requiring neonatal intensive care, accompanied by
inadequate nutrition and slow growth, sometimes referred
to as ‘extrauterine growth restriction (EUGR)’. Moreover,
during infancy, VLGA infants frequently suffer from eating
difficulties including selective eating, which may be related
to neurodevelopmental impairments. A recent study in
6-year-olds born extremely preterm suggested that feeding
problems are present in those born most immature although
not solely explained by neurodevelopmental delay.
135
As
young adults, VLBW/VLGA offspring exhibit increased
cardiovascular risk factors such as higher blood pre-
ssure,
136,137
impaired glucose regulation
138
and lower rates of
leisure-time physical activity
139,140
as compared with their
counterparts born at term with normal birth weight. A
paradox is that adults born as small preterms are not more
obese but, if anything, tend to have on average a lower BMI
than those born at term.
138,141
Much of this difference is
attributable to lower lean body mass.
138
Although VLBW
adults have a higher basal metabolic rate per unit lean body
mass, their lower lean body mass results in a lower total basal
metabolic rate
142
and, accordingly, lower energy intake.
143
Although a preliminary report from the same cohort showed
no difference in energy-adjusted macronutrient intakes,
intakes of calcium and vitamin D were lower in VLBW
adults. This argues for the possibility of altered food pre-
ferences, although we are unaware of any published reports
on the analyses of intake and preference of specific foods in
this context. In general, although VLGA infants constitute a
promising model of early programming of food preferences, it
remains relatively understudied.
When comparing these studies, it is important to take into
account several facts. Firstly, Barbieri et al. evaluated the cohort
at 24 years of age, while the Dutch Famine studies evaluated
middle-aged individuals. It is known that food preferences vary
according to ageing,
46,144,145
and the apparent diversity in the
findings may simply reflect that these specific feeding
preferences in low birth weight subjects transit from high
carbohydrates to high fat as the individuals age. Moreover,
although all of these studies may reflect the effects of stress
exposure during fetal life, the Dutch Famine cohort was
exposed to both the nutritional and environmental (war
conditions) stress, while the Brazilian cohort was primarily
nutritional deprivation and stress exposure. As different types of
stress induce specific physiological responses,
146
one could
argue that different adverse events occurring in utero lead to
particular effects on feeding behavior later in life, depending on
the type of the insult (Fig. 2).
Specific food preferences may be involved in the
development of later disease
To date, several studies have shown that feeding preferences
during adulthood are related to physical health, impact the
risk for future disease and play a role in the prevention of
overweight. For example, rates of incident verified non-fatal
myocardial infarction, coronary death and diabetes are lower
among people following a general healthy eating pattern in
midlife (high consumption of fruit and vegetables, poly-
unsaturated oils and high-fiber bread and breakfast cereals and
a low consumption of red meats, saturated fats and refined
carbohydrate foods).
147
Large cohort studies point to the fact
Effects of in utero conditions on adult feeding preferences 145

that a western dietary pattern is associated with a substantially
increased risk for type 2 diabetes,
147–150
incident heart
failure,
151
coronary heart disease,
150,152
stroke,
153
chronic
obstructive pulmonary disease,
153
colon cancer,
154,155
altered
markers of inflammation and endothelial dysfunction
156
and
altered plasma biomarkers of cardiovascular disease risk and
obesity.
157
Although the issue is still debated,
158,159
asys-
tematic review of 37 published cohort studies showed that low
glycemic index and/or low glycemic load diets are associated
with a reduced risk of chronic diseases such as type 2 diabetes,
coronary heart disease, gallbladder disease and breast cancer,
suggesting that higher postprandial glycemia is a mechanism
for disease progression.
159
Whole-grain as well as fruits and vegetables intake have been
associated with lower risk of cardiovascular disease,
160–163
ischemic stroke
164
and hypertension,
165
improvements in
glycemic control,
166,167
and lower levels of inflammatory
biomarkers.
168
Dietary fiber may also affect fibrinolysis and
coagulation,
169,170
which may be important in the setting
of established atherosclerotic plaques. With regard to poly-
unsaturated fatty acid (PUFA) consumption, n-3 PUFAs from
both seafood and plant sources may reduce cardiovascular
risk,
171
whereas eating even limited quantities of fish may
reduce the risk of ischemic stroke in men.
172
Not simply the food choices, but feeding behavior per se is
also associated with human health. For instance, men eating
takeaway foods twice a week or more are significantly less likely
to meet the dietary recommendation for vegetables, fruits, dairy,
breads and cereals, and have a higher prevalence of moderate
abdominal obesity.
173
On the other hand, young adults who
report frequent food preparation have less frequent fast-food use
and are more likely to meet dietary objectives for different
macro and micronutrients.
174
Feeding frequency may also affect
health outcomes, as a high daily eating frequency is associated
with a healthy lifestyle and dietary pattern in both men and
women.
175
Finally, there is a well-known association between
television viewing and abdominal obesity in young adults,
whichispartiallyexplainedbyfoodandbeverageconsumption
while watching television.
175
While this review focuses on early programming of nutri-
ent intake and preferences, it is important to keep in mind
that the biological effects of specific nutrients also may be
programmed early in life. Not all people are equally sensitive
to health effects of specific nutrients. For example, lipid
responses to dietary interventions
176
and blood pressure
responses to alterations in salt intake
177
vary widely between
people, with genetic mechanisms explaining only a small
proportion of the differences.
178–180
Few human studies have
explored this area, although a study from Hertfordshire,
England, showed that among 59- to 71-year-old men, high
intakes of total and saturated fat were associated with reduced
HDL-cholesterol and HDL/LDL (low-density lipoprotein)
ratio only in men with low birth weight.
181
A Dutch study of
healthy adults showed a strong inverse correlation between
birth weight and salt sensitivity of blood pressure.
182
All of the above behaviors and preferences could potentially
be affected by early life events. Future studies may clarify the
particular behavioral facets of individuals exposed to specific
insults in order to identify their possible health risks.
Medical and public health implications
The worldwide rise in chronic diseases in children and ado-
lescents is challenging for the health assistance, financial
resources administration and biomedical research. These
disorders may be a consequence of a long process of epide-
miological and demographic transition, occurring during the
last century. The decrease in infant mortality and longer
life-span has created a new pattern of health and disease, in
which chronic and degenerative disorders have overcome
acute conditions and infectious diseases. In this scenario,
the identification of vulnerability and proposals for chronic
Newborns at 27
weeks of
gestational age
Newborns at 27
weeks of
gestational age
IUGR programs
the hedonic
response to
sweet food
3 years of
age
3 years of
age
IUGR girls are
impulsive
towards sweet
food
24 years of
age
24 years of
age
IUGR women
have a higher
preference for
carbohydrates
Adult life
Adult life
IUGR =
overweight,
metabolic
syndrome
Barker et al and
many others
Barbieri, Portella,
Silveira et al.,
2009130
Silveira et al.,
2012190
Ayres et al.,
2010192
50 years of
age
Individuals exposed
to undernutrition
during fetal life prefer
to eat more fat
Lussana et al.,
2008128
Fig. 2. Conceptual framework depicting the fetal programming of food preferences proposal. Human evidence of feeding preferences in
individuals exposed to fetal adversities suggests that the choices for specific types of foods at different times during the life course may play
an important role in the increased risk for disease largely described in these subjects. IUGR, intrauterine growth restricted.
146 A. K. Portella et al.

diseases prevention is of extreme significance and importance.
Knowledge about behavioral traits that could be linked to
specific health risks may alert health professionals to promote
early intervention and assistance.
Education, support and long-term follow-up may be
required to assist children exposed to fetal insults to make
lifestyle changes essential to a healthy lifestyle, such as wise
dietary choices. For instance, interventions that promote
reduced amount of added sugar and increased intake of
dietary fiber improve insulin action and reduce visceral adi-
pose tissue in youth.
183–187
The efficacy of these interventions
remains to be established for this population.
Importantly, prenatal care and preconception counseling is
critical for developing preventive strategies in terms of public
health. For instance, findings suggest that pre-pregnancy dietary
patterns may affect womens’ risk of developing gestational
diabetes mellitus.
188
A healthy diet before and during the
pregnancy promotes a better fetal environment, preventing
diseases in future generations. Women of reproductive ages,
especially those who are planning a pregnancy, should be
counseled to consume a well-balanced diet, and may be more
easily prone to engage in healthy life choices. We propose that a
prudent diet style before and during pregnancy affects the
newborn’s food preferences in a positive way, as well as its
future food choices in adulthood and is a promising new way of
preventing chronic degenerative disease in future generations.
This may be a transgenerational model of health programming.
Conclusions
In conclusion, evidence from experimental and clinical studies
demonstrate that early life events are linked to specific feeding
preferences in adulthood. Although these studies have some-
what divergent final findings, they consistently demonstrate that
a metabolic or environmental stress during gestation that
impacts fetal growth results in altered offspring adult feeding
behavior, with a preference for highly palatable, energy dense
foods (either rich in carbohydrates or fat or both). The chronic,
persistent alteration in feeding preferences in these individuals
likely starts in early life
189,190,192
and contributes to the devel-
opment of obesity and altered lipid profile reported in this
group.
128,130
This seems to be another facet of the ‘thrifty
phenotype’,
191
what could be called ‘thrifty behavior’. Future
studies are warranted to understand the mechanisms by which
specific insults lead to specific behavioral preferences, as well as
to establish the validity of preventive measures in humans.
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