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BIOLOGY OF REPRODUCTION 83, 325–331 (2010)
Published online before print 5 May 2010.
DOI 10.1095/biolreprod.110.084517
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Maternal Undernutrition Influences Placental-Fetal Development1
Louiza Belkacemi,2,3 D. Michael Nelson,4 Mina Desai,3 and Michael G. Ross3
Department of Obstetrics and Gynecology,3 Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute
at Harbor-UCLA, and David Geffen School of Medicine at UCLA, Torrance, California
Department of Obstetrics and Gynecology,4 Washington University School of Medicine, St. Louis, Missouri
Maternal nutrition during pregnancy has a pivotal role in the
regulation of placental-fetal development and thereby affects
the lifelong health and productivity of offspring. Suboptimal
maternal nutrition yields low birth weight, with substantial
effect on the short-term morbidity of the newborn. The placenta
is the organ through which gases, nutrients, and wastes are
exchanged between the maternal-fetal circulations. The size,
morphology, and nutrient transfer capacity of the placenta
determine the prenatal growth trajectory of the fetus to
influence birth weight. Transplacental exchange depends on
uterine, placental, and umbilical blood flow. Most important,
maternal nutrition influences factors associated not only with
placental homeostasis but also with optimal fetal development.
This review associates fetal growth with maternal nutrition
during pregnancy, placental growth and vascular development,
and placental nutrient transport.
MUN AND PLACENTAL DEVELOPMENT
The placenta of mammals is a highly efficient multifunctional organ that integrates signals from both mother and fetus
to match fetal demand with the maternal substrate supply of
nutrients and gases, while ensuring that fetal waste products are
transferred back to the mother. Altered placental structure and
function (reflected by weight, morphology, vascular development, and transport function for amino acids, glucose, and fatty
acids) may contribute to altered nutrient supply.
fetus, IUGR, placenta, programming, undernutrition
INTRODUCTION
Effects on Placental Weight
An optimal maternal nutrient supply has a critical role in
placental-fetal growth and development. Maternal suboptimal
nutrition during pregnancy results in intrauterine growth
restriction (IUGR) and newborns with low birth weight.
Intrauterine growth restriction is associated with increased
perinatal morbidity and mortality, and newborns with low birth
weight have increased risk for development of adult metabolic
syndrome [1, 2]. Adverse effects of maternal undernutrition
(MUN) have generally focused on the reduced maternal
nutrient supply to the fetus. Few studies [3–8] highlight the
crucial role of the placenta on the ensuing phenotype.
The placenta forms the interface between the maternal-fetal
circulations and as such is critical for fetal nutrition and
oxygenation. In turn, the placental supply of nutrients to the
fetus depends on its size, morphology, blood supply, and
Placental weight is correlated with dietary intake in
mammalian pregnancies. Although the effect of global MUN
on placental weight is unequivocal, the timing, duration, and
etiology of nutritional restriction can each differently affect
placental mass. A frequently cited example of this premise is
the effect of timing and duration of limited nutrient intake
during the Dutch Famine of 1944–1945 [9]. Women subjected
to starvation in their third trimester of pregnancy had light
placentas and newborns with low birth weight but an unaltered
placental weight:birth weight ratio compared with nonstarved
women. In contrast, exposure to famine only during the first
trimester of pregnancy enhanced placental weight at delivery,
although without any effect on newborn weight compared with
control women. These results suggest that human placental
adaptation in early pregnancy can overcome environmental
stressors so that fetal nutrition is maintained in late gestation.
Similar to humans, global MUN during early to mid
pregnancy in sheep increased the placental weight:fetal weight
ratio by enhancing placental weight at term without altering
fetal weight [10]. Conversely, a 50% MUN during the second
half of rat pregnancy yielded a decrease in the placental
weight:fetal weight ratio [11], implying that MUN irreversibly
affects placental weight when nutrient deprivation coincides
with the time when fetal nutrient demand is maximal.
An important question is whether global MUN or
deprivation of a selected nutrient component is the insult that
1
Supported by a Los Angeles Biomedical Research Institute Seed Grant.
Correspondence: Louiza Belkacemi, Department of Obstetrics and
Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical
Research Institute at Harbor-UCLA, and David Geffen School of
Medicine at UCLA, Torrance, CA 90502. FAX: 310 222 4131;
e-mail: [email protected]
2
Received: 2 March 2010.
First decision: 28 March 2010.
Accepted: 27 April 2010.
Ó 2010 by the Society for the Study of Reproduction, Inc.
eISSN: 1529-7268 http://www.biolreprod.org
ISSN: 0006-3363
325
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transporter abundance. During normal pregnancy, the placenta
undergoes a variety of physiological changes, regulated by
angiogenic factors, hormones, and nutrient-related genes, to
maximize efficiency for an ever-increasing demand for
nutrients. Perturbations in the maternal environment following
MUN may adversely alter these changes.
This review discusses the influence of MUN during
pregnancy on placental development and nutrient transfer. It
also describes the subsequent effects on fetal development.
ABSTRACT
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BELKACEMI ET AL.
induces the change in growth trajectories of the placenta and
fetus. Notably, selective protein deprivation is a key factor in
the dietary alteration of placental weight:fetal weight ratios.
Protein restriction with 9% vs. 18% casein in the diet
throughout pregnancy in the rat yielded heavier placentas and
reduced fetal growth in late gestation [12]. The placental
overgrowth compensates for the reduced protein availability in
early gestation to maintain normal fetal weight in earlier
gestation, but such compensation is insufficient to maintain
fetal growth near parturition. Normal or even excess fetal
growth occurs in rats exposed to protein deprivation in early
gestation, with midgestation restoration of normal nutrition [4].
Collectively, these data suggest that an adaptive response in the
placenta enhances transfer of substrates from mother to fetus,
improves efficiency of substrate utilization, or both when the
supply of amino acids is limited. The placenta compensates to
minimize fetal growth restriction. However, placental function
is not always improved with increases in weight because the
histomorphology of the placenta ultimately determines placental function.
Changes in Histomorphology
Alterations in Vasculogenesis and Angiogenesis
Vasculogenesis is de novo formation of blood vessels from
mesoderm precursor cells, and angiogenesis is creation of new
vessels from a preexisting blood supply. Both processes are
critical to the maternal-fetal exchange. Vascular endothelial
growth factor (VEGF) and angiopoietin proteins [21, 22] are
critical to these processes. Angiopoietin proteins contribute to
the formation of mature blood vessels, but their role in MUN
placentas is unknown to date.
Insult induces compromise in placental vasculogenesis and
angiogenesis and impairs exchange between the maternal-fetal
circulations [4, 23], ultimately resulting in IUGR fetuses. For
example, ewes fed with 60% global nutrient intake beginning
on Day 50 of gestation had increased placental vascularity,
reduced VEGF receptor expression in placentomes, and
nutrient transfer deficiency [24]. The greater placentome
vascularity in the feed-restricted ewes had no effect on VEGF
mRNA expression, suggesting that other factors were essential
in the overall process of angiogenesis; for example, the
angiopoietin proteins may have a role in modulating VEGF
function [25].
Endothelium-derived nitric oxide (NO) is a mediator of
angiogenesis and has a role in modulating vascular resistance
[26]. VEGF stimulates the release of NO and upregulates the
expression of NO synthetase. A critical role for NO during
human pregnancy is suggested by investigations of fetuses with
IUGR [27]. The importance of NO was also demonstrated in
pigs fed a protein-restricted diet for up to 60 days of gestation.
The animals showed decreased placental arginine (a common
substrate for NO), less NO synthesis, and reduced NO
synthetase activity compared with pigs fed a normal protein
diet [28]. These changes are likely one mechanism for placental
vascular dysfunction that results in reduced placental-fetal
growth in the protein-deficient offspring.
Collectively, these results underscore that typical features of
nutrient restriction models include some level of placental
vascular and angiogenesis dysfunction during pregnancy. This
is summarized in two studies [29, 30] of low dietary protein
intake.
Modifications of Nutrient Transfer Capacity
Fetal nutrient availability results from several elements.
These include the interrelationships of maternal food intake,
availability of nutrients in the maternal circulation, and ability
of the placenta to efficiently transport substrates to the fetal
circulation.
Global maternal nutritional status affects transporters in the
placenta, thereby influencing the rate of nutrient delivery
through the placenta. For example, rats fed a 50% global
MUN during the last week of gestation experienced decreased
glucose levels in maternal plasma [31]. The maternal-fetal
glucose concentration gradient (which drives facilitative glucose
diffusion across the placenta) is also reduced, and glucose
transporter 3 (solute carrier family 2 [facilitated glucose
transporter] member 3 [SLC2A3, previously called GLUT3])
expression is substantially decreased, suggesting a mechanism
for placental glucose transport dysfunction. Although glucose
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The histomorphology and ultrastructure of the placenta
change throughout normal gestation and in response to
maternal nutritional manipulations [13]. In mammals, the
placenta develops a large surface:volume ratio, forming highly
branched structures with advancing pregnancy. Trophoblast
provides the covering surface and is positioned to mediate
critical steps in hormone production and immune protection of
the fetus. Invasive trophoblasts also facilitate an increase in
maternal vascular blood flow into the placenta [14]. In
primates, the zone of exchange is represented by a single layer
of syncytial trophoblast and an underlying layer of mononucleated cytotrophoblasts [15]. In rodents, this zone (labyrinth
zone) is formed by a mononucleated trophoblast layer with two
syncytiotrophoblast layers that serve as the structural basis of
the placental barrier between the maternal-fetal blood. In
ruminants, placental mononucleate trophoblasts form the
majority of the interface and are primarily involved in nutrient
exchange [16]. In pig, the labyrinth zone contains fetal
capillaries and maternal blood sinuses and provides the means
for exchange between the two circulations, as well as an
interlobium that is composed of syncytiotrophoblast and
maternal blood sinuses and is the site where much of the
metabolic activity occurs [17].
Alterations of exchange surface area, barrier thickness, and
cell composition of the different gestational ages of the
placenta may all affect placental transport capacity [18].
Notably, MUN that results in human IUGR generates placentas
with a reduced surface area for exchange in villi and a lowervolume density of trophoblasts [19]. These structural alterations in the placenta are mirrored in the guinea pig that is
exposed to global MUN compared with control diets. The
nutrient-deprived gestations exhibited placentas with surface
area for exchange that were diminished by up to 70% due to
reduced development of the labyrinth, while barrier thickness
was increased by 40% in late gestation [20]. These histopathological changes predispose to reduced nutrient transfer to the
fetus. Our work in which rats were exposed to MUN
demonstrated enhanced apoptosis occurring in both the
junctional and labyrinthine zones of the placenta [11].
Moreover, MUN affected to a greater degree the placenta
located in the midhorn compared with proximal uterine horn
positions. The marked effect of MUN on midhorn placentas
may indicate a potential compounding effect of reduced
maternal vascularity, decreased oxygen supply, or other factors
that are regionally distributed along the uterine horn. Reflecting
the complexity of the phenotype that results from exogenous
insults, these findings suggest that two insults may interact in
the same animal to accentuate the morbidity associated with
growth restriction.
MATERNAL UNDERNUTRITION AND PLACENTAL-FETAL DEVELOPMENT
stimulates SLC2A expression [48]. Interestingly, fetal cortisol
infusion in sheep increased placental glucose consumption and
reduced placental delivery of glucose to the fetus [49].
Glucocorticoid treatment changed placental handling and fetal
delivery of lactate and selected amino acids [50]. Whether or
not glucocorticoids affect amino acid transporters in the
placenta is still not fully known. Based on an in vitro study
[51] using BeWo cells, glucocorticoids can alter placental
solute carrier family 38 member 2 (SLC38A2, previously
called sodium-coupled neutral amino acid transporter 2
[SNAT2]) by altering the localization of SLC38A2 and
changing protein and mRNA expression.
Imprinted placental genes, expressed in a manner that is
parent-of-origin specific, can also regulate nutrient transport
capacity of the placenta. For instance, mice exposed to
restriction of dietary intake to 80% of controls from Day 3 of
pregnancy showed a significant decrease in an imprinted
placental Igf2 transcript [52]. Deletion of a placenta-specific
transcript (P0) from the Igf2 gene, which is expressed only in
the mouse labyrinthine trophoblast, decreased placental
growth, limited nutrient transfer, and reduced fetal growth
[53]. These data offer a mechanism by which the Igf2 gene may
affect placental structure and function during maternal food
restriction. It remains to be determined whether MUN, fetal
nutrient demands, or other environmental signals act on the
placental-specific promoter in the Igf2 gene to change its
imprint status, promoter usage, or expression from the active
allele.
In summary, suboptimal placental growth and development
following MUN yields growth-restricted fetuses. As discussed
in the next section, those fetuses have altered fetal physiology
in utero, resulting in newborn abnormalities with increased
long-term effects well into adulthood.
MUN AND FETAL DEVELOPMENT
Maternal diet affects fetal growth directly by determining
the amount of nutrients available, indirectly by affecting the
fetal endocrine system, and epigenetically by modulating gene
activity. Nutritional insults during critical periods of gestation
may thereby have a permanent effect on progeny throughout
postnatal life and beyond.
Nutrient Levels and Fetal Growth
Reduction of nutrient availability during gestation decreases
fetal growth in both humans and animals [4]. MUN in pregnant
women may result from low intake of dietary nutrients due to a
limited supply of food or because of severe nausea and
vomiting that persists long after the usual first-trimester effects
[54]. Short interpregnancy intervals also result in maternal
nutritional depletion at the outset of pregnancy, whereas
pregnant teenage mothers compete with their own fetuses for
nutrients. Infants with low birth weight babies and preterm
deliveries in adolescent pregnancies were more than twice as
common as in adult pregnancies, and neonatal mortality in
adolescent pregnancies was almost three times higher than that
for adult pregnancies [55]. In pregnant rat dams, a 5% protein
reduction yielded offspring that were significantly smaller than
pups born to 20% protein-fed controls [36]. Although maternal
serum amino acid levels were maintained in the rat dams fed
low-protein diets, fetomaternal serum amino acid ratios were
reduced, suggesting diminished nutrient transfer to the fetus.
Therefore, maternal protein deprivation in rats decreases the
activity of Na þ-dependent neutral amino acid transport
mediated by system A but not system alanine-serine-cysteine
transporter [36]. A decrease in placental amino acid but not
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represents the principal metabolic fuel during gestation, specific
effects of maternal dietary glucose restriction on placental-fetal
development have not been extensively studied to date.
Placental transport of amino acids is pivotal for fetal
development and is affected by the activity and location of
amino acid transporter systems. In humans, reduced circulating
concentrations of essential amino acids (such as leucine and
lysine) are observed in growth-restricted human fetuses [32–
34], implying that there is a global alteration of placental amino
acid transport activity in IUGR. In animal models, rats fed a
6% casein low-protein diet from Day 5 of gestation showed
27% reduced transfer of nonmetabolizable amino acid C-a
amino isobutyric acid from the maternal-fetal circulations
compared with well-fed controls [35]. In addition, rats fed a 5%
casein diet exhibited reduced placental system A transporter
(Na þ-dependent neutral amino acid uptake) activity for neutral
amino acids at term compared with dams pair-fed a control
20% casein diet [36]. Maternal protein restriction in rats
resulted in downregulated placental nutrient transport before
the onset of fetal growth restriction, suggesting that a reduced
placental supply of amino acids is a causal factor for IUGR and
not simply a consequence of this malady [37].
Adequate placental transport of fatty acids to the fetus is
crucial for normal fetal development and growth because fatty
acids have multiple roles as cell membrane components, energy
sources, and precursors to cellular signaling molecules.
Intrauterine growth restriction placentas showed disrupted lipid
metabolism and altered microvillous plasma membrane lipid
hydrolase activities; both affected the flux of essential fatty
acids and preformed long-chain polyunsaturated fatty acids to
the human fetus [38]. Undernourished women exhibited a
relative placental deficiency of essential fatty acids, and this
suggests a lower source of placental membrane fluidity and
subnormal content of essential fatty acids in their offspring
[39]. Placentas from pregnancies with IUGR also have
decreased levels of arachidonic acid and docosahexaenoic acid
[40], and fetuses affected by IUGR exhibit proportions of both
these fatty acids that are lower than control proportions relative
to their linoleic acid (LA) and aLA precursors [41].
Taken together, these studies demonstrate the pivotal role of
fetal nutrient availability. Adequate transplacental exchange of
multiple nutrients is needed to sustain normal fetal growth.
A number of factors have a critical role in the regulation of
placental nutrient transport to the fetus. These include NO,
glucocorticoids, and imprinted genes.
Nitric oxide is an angiogenic factor [42]; as such, decreased
concentrations of NO synthesis can impair placental-fetal blood
flow [43] to limit transfer of nutrients. For example, sheep
exposed to 50% global MUN between Embryonic Day (E) 28
and E78 of gestation had levels of NO that were lower than
those of controls in maternal-fetal plasma when measured at
E78 [44].
Glucocorticoids affect placental expression of glucose
transporters (SLC2A1 and SLC2A3) in a dose- and timedependent manner in both human [45] and rat [46] placentas.
Therefore, a single injection of glucocorticoids at E16 reduced
placental SLC2A1 and SLC2A3 abundance in rat and results in
IUGR [45]. Long-term glucocorticoid exposure from E15 to
term in the rat was also associated with IUGR, despite a
doubling in placental expression of SLC2As in late gestation
[46]. Concomitant downregulation of both SLC2A1 and
SLC2A3 following a single injection of glucocorticoid may
reflect an immediate attempt to increase fetal glucose supply to
attenuate potential fetal hypoglycemia [46]. In contrast,
upregulation of the SLC2As following long-term glucocorticoid exposure may be due to placental hypoxia [47] that
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glucose transport precedes IUGR [36, 37], and this reduced
amino acid supply likely contributes to the fetal growth
reduction, rather than being a consequence of the disorder.
Modulation of Hormone Secretion
Effects of Epigenetic Influences
Maternal nutrition during pregnancy can program adult
disease susceptibility through epigenetic changes of the fetal
genome [77] that affect the adult genotype and phenotype. The
epigenetic changes result from mechanisms unrelated to the
DNA sequence. Availability of amino acids and micronutrients
may alter DNA methylation or modify histones. For example, a
deficiency of amino acids in cultured mouse embryos resulted
in reduced genomic DNA methylation and aberrant expression
of the normally silent paternal H19 allele, an imprinted gene
[78]. Moreover, rat dams fed a low-protein diet generally
developed hypermethylation of cytosine and adenosine residues in DNA of the fetal liver [79]. However, rat dams fed low
protein showed hypomethylation of the nuclear receptor
peroxisome proliferator-activated receptor alpha (Ppara) and
the glucocorticoid receptor (Nr3c1, previously called Gr) in the
liver of their offspring [80]. These changes in the epigenetic
regulation of hepatic Ppara and Nr3c1 expression may
contribute to adult-onset hypertension and to impaired fat and
carbohydrate metabolism. Therefore, epigenetic modifications
represent a molecular mechanism by which maternal nutrition
influences fetal programming, postnatal disease susceptibility,
and genomic imprinting. Whether subsequent interventions can
reverse in utero epigenetic effects remains to be discovered.
Impact of Intrauterine Programming on Offspring
Low birth weight is a major consequence of MUN in both
humans and animals [81, 82]. Human newborns with low birth
weight are more likely than newborns with average birth
weight to develop insulin resistance, type 2 diabetes mellitus,
and hypertension in adult life [2]. In addition, infants exposed
to IUGR are at high risk for physical and mental impairments
in later life [83]. MUN results in precocious maturation of the
fetal hypothalamic pituitary axis, and these effects are
associated with a delay, if not a permanent deficit, in cognitive
processes [84] and school performance of affected children
[85]. Adverse effects are similarly observed in undernourished
newborn animals. Growth restriction in prenatally undernourished pigs was accompanied by increased adiposity of the
newborn and maldevelopment of offspring skeletal muscle and
liver. Moreover, IUGR newborns exhibited altered thermogenesis, glucose levels, and cholesterol homeostasis at birth, while
insulin action was adversely affected later in life [86]. Rats
exposed to 50% MUN in the last half of pregnancy had reduced
fetal and newborn weights [11, 87, 88], with poor remodeling
of vasculature, a contributing factor to subsequent hypertension
[89]. The liver of IUGR rat offspring increased expression of
peroxisome proliferator-activated receptor gamma coactivator
1, a regulator of mRNA expression for glucose-6-phosphatase
and other gluconeogenic enzymes, suggesting that the
alteration in hepatic glucose production resulted from changes
in intracellular signaling. In adulthood, these rats developed
obesity, with increased adipocyte differentiation, adipocyte
hypertrophy, and upregulation of lipogenic genes. Moreover,
the Pparg gene produces an adipogenic transcription factor that
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Normal pregnancy entails substantial production of hormones in the maternal, placental, and fetal compartments.
Secretion of these hormones can be affected by MUN and can
thereby affect fetal development. Glucocorticoids, insulin-like
growth factors (IGFs), and leptin have important regulatory
roles in fetal development and homeostasis.
Glucocorticoids are essential for maturation of fetal tissues
so that the organs they form can cope with extrauterine life [56,
57]. However, excessive exposure to endogenous glucocorticoids in utero reduced fetal growth and predisposed to anxiety
disorders in adult rats [58]. Moreover, maternal global nutrient
restriction during late gestation in rats induced overexposure to
glucocorticoids in the fetus and disturbed the hypothalamopituitary adrenal axis in the newborn [59]. Consequently, the rat
offspring has an altered ‘‘set point’’ for negative feedback,
giving rise to higher basal secretion of adrenal corticosterone.
The increase in basal corticosterone levels in the newborn rat
accelerates the appearance of age-related neural and cognitive
deficits, including atrophy of dendritic processes and cell
death.
Insulin-like growth factors are a family of hormones acting
in autocrine, paracrine, and endocrine fashions to modulate
growth [60]. The IGF ligands (IGF1 and IGF2) are regulated
by a family of proteins known as the IGF-binding proteins
(IGFBPs), and these interactions control fetal growth. In
pregnant women, the concentration of IGFBP1 was negatively
correlated with birth weight [61]. In sheep, MUN during
periconceptual and gestational periods altered the IGF system
to reduce fetal insulin, IGF1, and IGFBP3 levels, while
enhancing IGFBP2 [62]. Alterations in the IGF cascade have a
role in compromised fetal growth [62] and in fetal programming (see Note Added in Proof ). For example, a reduction in
plasma IGF1 is caused by MUN in pigs, and this yielded
altered proportions of muscle fibers in the offspring [63].
Conversely, in ovine gestation, an increase in IGF1 plasma
concentrations was associated with increased muscle mass and
myofiber hypertrophy [64]. In MUN pigs, maternal-circulating
IGF2 levels were positively associated with fetal weight [65]
and inversely correlated with fetal IGF2 compared with agematched controls [66], suggesting a crucial role for IGF2 in
fetal growth. Taken together, these studies imply that IGFs are
important for development both before and after birth.
Leptin is a satiety factor that has a key role in the regulation
of energy homeostasis in adults and likely has a role in fetuses
as well. In humans, growth-restricted newborn plasma leptin
concentrations are low; however, these concentrations increased in infants by age 1 year [67]. The enhanced plasma
leptin in infants was correlated with weight gain and an
increase in subcutaneous tissue [68]. Whether this increase in
plasma leptin is related to changes in leptin transport,
metabolism, or clearance is unknown to date. The low levels
of leptin in the growth-restricted fetuses enhanced development
of appetite stimulatory pathways (e.g., increased NPY mRNA
expression) and suppressed development of anorexigenic
inhibitory pathways [69]. Offspring born with IUGR among
sheep [70–73] and rodents [74–76] showed resistance to the
anorexigenic effects of leptin as adults, which suggests in utero
programming as a source of obesity in adults. The findings
among humans and in animal models indicate that undernu-
trition in utero programs leptin dysregulation to yield
subsequent obesity.
Collectively, these studies suggest that alteration in fetal
hormones following MUN emerges as a major contributor to
suboptimal fetal growth and development. Programmed
changes induced by altered fetal hormone activity in utero
can thus affect newborns and eventually yield disordered
responses in adults.
MATERNAL UNDERNUTRITION AND PLACENTAL-FETAL DEVELOPMENT
is significantly increased in both newborns and adults [90] and
promotes adipocyte differentiation and lipid storage [91, 92].
Therefore, the abnormal activation of adipocytes in the IUGR
may contribute to the development of subsequent obesity.
Collectively, these studies show that suboptimal maternal
nutrition not only affects fetal growth but also influences longterm outcomes of the affected offspring.
SUMMARY
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NOTE ADDED IN PROOF
28.
Additional information regarding fetal programming can be
found in an article by Gallaher et al., 1998 [94].
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Maternal nutrition during pregnancy is an important
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nutritional setting and include decreases or increases in
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MUN can also affect fetal growth and organ development
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