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Pregnancy, embryo-fetal development and nutrition: physiology around fetal

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DOI: 10.7243/2055-091X-2-1

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 Journal of Histology & Histopathology
ISSN 2055-091X | Volume 2 | Article 1

Review Open Access

Pregnancy, embryo-fetal development and nutrition:

physiology around fetal programming
Giuseppe Musumeci1*, Paola Castrogiovanni1, Francesca Maria Trovato2, Rosalba Parenti3, Marta Anna Szychlinska1 and Rosa Imbesi1

*Correspondence: g.musumeci@unict.it
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1
Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine,
University of Catania, Catania, Italy.
2
Department of Medical and Pediatric Sciences, Internal Medicine Division, University of Catania, Catania, Italy.
3
Department of Biomedical and Biotechnological Sciences, Physiology Section, School of Medicine, University of Catania,
Catania, Italy.

Abstract
The purpose of this brief narrative review is to highlight the role of nutrition during the gestation period. We
focused on the possible effects of imbalance of some nutrients in normal course of pregnancy and embryonic
development. We discussed about changes in nutritional and/or hormonal embryonic microenvironment,
which represent the basis of a phenomenon known as “fetal programming”. We strongly believe that the
understanding of these events can be a valuable tool in order to prevent the onset of disorders and diseases in
postnatal life.
Keywords: Infant feeding, malnutrition, nutritional support, nutritional surveillance, pregnancy

Introduction maternal undernutrition, due to reduced caloric intake, there is

Experimental observations clearly indicate that during pregnancy, a proportional increase in catabolic activity of maternal tissues
the pre-implantation phase is the period of the greatest vulne that results in the release into the maternal-fetal circulation
rability for the future embryo in relation to several endogenous of many amino acids, vitamins and minerals, which are able
and/or exogenous factors, including those nutritional ones [1-3]. to balance the insufficient “diet” of the fetus. Instead, when
In mice, the nutritional stress, during the pre-implantation we consider the selective essential micronutrients during the
phase, is often responsible of blastocyst death and pregnancy embryo-fetal development, the insufficient intake of some of
block [4]. Reduction, deprivation or imbalance of nutrients in them is clearly associated with some malformation syndromes,
the very early stages of pregnancy, before implantation, results such as neural tube birth defects related to insufficient amounts
not only in an obvious impaired somatic development at birth of folic acid and vitamins C, B6 and B12 [11,12]. The purpose
[5,6], but also in the profound alterations of endocrine and of this brief narrative review is to emphasize the importance
metabolic functions [7] and, often, in the impaired maturation of nutrition before and during pregnancy, as the mother is
of reproductive system in postnatal life [8]. In addition, obser- the source of all the molecular elements that help to regulate
vations from clinical, epidemiological and experimental studies growth and development of the embryo until birth.
in vivo and in vitro, showed that different nutrients seem to be
able to influence both the normal course of pregnancy and the Review
embryo-fetal development in different animal species, including Nutritional deficiencies in preconception period
humans (Figure 1) [1-3]. Experimental results showed that Sexual reproduction is a phenomenon that begins before ferti-
undernutrition during pregnancy significantly reduces the lization. It can be realized thanks to the existence of the germ
number of infants in mice, by increasing the phenomenon of line and the subsequent gametogenesis, which takes place
fetal resorption and neonatal mortality [9]; in sheep, it defers during the puberty. The literature provides more and more
intrauterine development of the fetus [10] and in rats, it reduces information about the consequences of nutritional deficiencies
the weight of pups at birth [8] (Table 1). In case of a severe in parental germ cells, even before the fertilization of the egg

© 2015 Musumeci et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Musumeci et al. Journal of Histology & Histopathology 2015,
http://www.hoajonline.com/journals/pdf/2055-091X-2-1.pdf doi: 10.7243/2055-091X-2-1

cell [13-15]. Recently, it has been shown that damage to

Fetal gene expression DNA in spermatocytes of adults, as a result of micronutrient
deficiencies, can significantly increase the risk of congenital
Fetal endocrine milieu malformations and even carcinogenesis in descendants [16,17].
Fetal nutritional needs Some substances such as cigarette smoking and alcohol can
maternal availability aggravate deficiencies of crucial nutrients such as folate, zinc,
vitamins C, E and A [11,12]. A condition of undernutrition
Placental vascular resistance during the folliculogenesis, a phase characterized by active
angiogenesis and protein synthesis, results in a poor quality of
Evolutionary the oocyte [18]. Therefore, both in the preconception period
adaptations and in the earliest stages of embryonic development, the
nutritional deficiencies and/or nutrient-gene interactions may
be responsible for changes or complications of reproductive
process.

Number and types fo cells Vascular and cardiovascular factors

structure of organs Complications of reproductive process become more seri-
Hormonal feedback ous if mediated by vascular and cardiovascular factors [19].
Metabolic activity Deficient or abnormal development of placenta and of its
vascularization, both in the early stages of pregnancy and
in the perinatal period, may also play a substantial role in
the control of normal embryonic development [19,20]. In
Long-term effects this case, many congenital defects are also related, at least
in part, to the vascular damage of embryonic tissues [20]. A
Figure 1. Diagram of interrelations between fetal development
and long-term effects on its body.
possible cardiovascular disease in the pregnant women, is
often associated with a significant increase of the incidence
of body weight reduction in infants [19]. This is related to the
Table 1. Effects of micronutrients intake on female reproductive reduction of blood flow to the uterus and the consequent
activity. reduction in the supply of oxygen and nutrients into the
Supplements Significant effects embryo-fetal circulation (Figure 2) [19].
Calcium Reduction of symptoms related to PMS
Endocrine and paracrine factors
Reduction of the preeclampsia effects in
high-risk pregnancy
A general or selective deficiency of essential nutrients is not
the only cause of potential congenital defects. During embry-
The maternal intake of calcium improves
bone mineral component of the newborn onic tissue growth and differentiation, a number of important
Reduction in the incidence of hip fractures
from osteoporosis
Folic acid Prevention of the incidence of NTDs in Periconceptional period: determination of fetus needs-
the fetus Trajectory of fetal growth
Folic Acid+Zinc+ Prevention of the incidence of NTDs
multivitamin preparations and other birth defects
Early pregnancy: scenery of maternal-placental
Prevention of preterm birth nutritional capacity-size placenta and uterus-placental
Prevention of a low birth weight blood flow
Multivitamins Reduction of the risk of premature
birth and the consequences of hypo-
weight at birth Late Pregnancy: modulation of effective nutritional capacity
Daily diet and placental transport
Minimization of the risk of fetal death
and increase the plasma concentra-
tions of immune cells in HIV-positive
pregnant Adaptation of fetus if its nutritional needs exceed the
capacity of maternal-placental contribution-
Vitamin A/b-carotene Reduction of maternal mortality Cardiovascular disease and NIDDM programming
Vitamins C and E Reductionof the risk of preeclampsia
Figure 2. Effects of maternal nutrition on fetal development
PMS: Premestrual Syndrome; NTDs: Neural tube defects; and its programming. NIDDM: non-insulin dependent
HIV: Human immunodeficiency virus diabetes.

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Musumeci et al. Journal of Histology & Histopathology 2015,
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endocrine and paracrine factors, whose action is crucial in the an important role in the regulation of nutrient metabolism
control of reproductive processes, are involved [3]. Among (especially in the later stages of pregnancy). Instead, in the
these, a crucial role, not only during embryonic development immediate neonatal life they promote the use of energy for
but also in the course of postnatal life, is played by insulin growth and for the final differentiation of various tissues, es-
and insulin-like growth factors (IGFs), which are considered, pecially those of musculo-skeletal and nervous systems, and
as amply demonstrated in the experimental animal, the most their progressive adaptation to extrauterine environment [26].
potent regulators of cell proliferation, apoptosis (especially Moreover, IGF-I is important for some essential functions such
programmed apoptosis), oogenesis, embryogenesis and ovar- as the increase of protein synthesis and, at the same time, the
ian secretion (Table 2) [2,3,16]. The role played by serotonin in limitation of catabolic process [29]. Alterations in the regula-
the diet of pregnant rats has been shown in recent data from tion of nutrients in prenatal life may be responsible for the
onset of short or long-term endocrine-metabolic disorders
such as postnatal insulin resistance, diabetes type 1, obesity
Table 2. Effects on fetal and placental weight in mice in the last
stages of gestation according to the distribution of genes that and disorders in puberty [7,30]. This is the pathophysiologi-
control the bioavailability of IGFs. cal basis for numerous and detailed clinical studies on adults
% of normal weight
[31-33]. These studies start to highlight the mechanisms
that are able to establish a link between the various critical
Gene target Effects Fetus Placenta
moments of the embryo-fetal development, which are also
Igf1 Absence of IGF-I in 60 100
represented by a rapid cell proliferation, and the eventual
tissues and plasma
Igf2 Absence of IGF-II 60 75 diseases of postnatal life.
reduction of placental
Placental PO Igf2 IGF-II 75 65 Fetal programming and immune system
normal fetal IGF-II Nutritional or/and hormonal changes in the embryo-fetal
IGF-Type I No response from the 45 100
microenvironment, can alter the fetal genomic expression
receptors for the IGFs
Receptor (IGFIr) IGF1r -- -- and exert permanent effects on a wide range of physiological
processes [34]. This phenomenon is known as “fetal program-
IGF-Type 2 No clearance of IGF-II 140 140 ming” (Table 3). Results from recent researches confirmed that
Receptor (Igf2r) Increase of plasmatic -- -- maternal-fetal malnutrition (both hypo- and hyper-nutrition)
IGF-II
exerts a suppressive effect on the immune response of both
H19 No suppression of 130 140
maternal IGF-II mother and fetus, with inevitable consequences on the deve-
Increase of tissue opment of the immune system of the latter [35,36]. Hyponutrition,
IGF-II in fact, evokes a significant hypotrophy of both primary and
Igf2 eH19 Increase of tissue and 200 230 secondary lymphoid organs. Also hyper-nutrition, especially if
plasmatic IGF-II
characterized by the abundance of fat, may have a suppressive
effect on the immune response [29,35]. The consequences of
literature [16,21-24]. Our recent studies showed that deficiency
or absence of L-tryptophan (L-Tp), the precursor of serotonin Table 3. Tissues and systems for which there is evidence, in
(5-HT), could be responsible for altered growth and possible humans, of fetal programming.
alterations in sexual development of descendants of pregnant Tissue/systems Examples of programming
rats fed with L-Tp free diet [8]. Even the excess of L-Tp in diet Cardiovascular Vascular compliance
of pregnant rats, showed adverse effects on their descendants system Thickness of the wall of the left ventricle
[25], in particular on muscle tissue development. Indeed, this
Endothelial function
amino acid has been shown to limit the production of IGF-I by
Respiratory system Volume of each lung
the liver [26], therefore, we could hypothesize the existence
Endocrine system Hypothalamic-pituitary-adrenocortical axis
of a real 5HT/growth hormone (GH)/IGF-I axis [27]. In humans,
there are numerous clinical observations in pregnancy, which Insulin metabolism of glucose
may confirm these experimental conclusions. It is known that GH-IGF-I axis
IGF-I significantly influences the secretion of ovarian steroids Hypothalamic-pituitary-gonadal axis
(estrogen and progesterone) in human ovary [28]. Nucleo- Musculo-skeletal Insulin resistance
system Glycolysis during exercise
tides such as cyclic adenosine monophosphate (cAMP) and
guanosine monophosphate (GMP), as intracellular second Bone Bone mineral content
messengers, may be responsible for mediation or control Kidney Renin-angiotensin system
of the pituitary gonadotropic cells, with obvious effects on Liver Cholesterol metabolism
ovarian function, and in particular on folliculogenesis. During Synthesis of fibrinogen and factor VII
the intrauterine life, in particular IGF-I, but also IGF-II, play Immune system Thyroid autoimmunity

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Musumeci et al. Journal of Histology & Histopathology 2015,
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malnutrition are more severe if present in particular stages restrict the provision of maternal-fetal nutrient and oxygen
of life. Malnutrition during pregnancy is a serious risk for the supply to the fetus (Figure 3). So much has been already done,
development of the immune defense of the fetus, both in the but further studies are needed to understand how the fetus
intrauterine life and in the postnatal one, when the infant is no adapts to the limited supply of nutrients from mother, how
longer protected by the maternal defenses [37]. Malnutrition
during weaning and in early childhood may result in lasting
effects that can affect important aspects of the entire postnatal Fetal Composition of Dietary and Utero-placental Placental
life, such as the somatic and stature growth and defense aga- genome mother’s body metabolic status blood flow transport
inst infectious diseases [35]. The gastro-intestinal immune
system develops mainly on the basis of the reports that it
contracts with the world of bacteria [38] and the development Fetal nutritional needs>maternal nutritional intake: fetal
of bacterial flora begins from the moment of birth and con- undernutrition

tinues, especially in humans, with a particular sequence of

bacterial strains, that change with different stages of infant Hypoxemia Metabolic changes Endocrine changes
nutrition, from breast feeding to weaning [39]. The principle Redistribution of Reduced glucose oxidation Insulin and IGF-1
of succession of bacterial micro flora varies in different species blood flow Increased amino acid and loctate reduction
of mammals [40]. In the human fetus, it begins with coliform oxidation
bacteria and enterococci, and it is subsequently followed by
bifid bacterium [41]. Some specific nutrients also seem to Disproportionate fetal growth
Fetal programming
act as crucial co-factors in the immune response expression
[35]. Moreover, the bacterial flora intervenes directly on the Figure 3. Diagram explaining the maternal regulation of the
development and embryo-fetal programming.
digestive function, and for this reason it acts as indirect supplier
of nutrients in the gastro-intestinal tract [38]. This, in turn,
has an impact on the development of the intestine immune these adaptations influence body structure and physiology,
system [37]. This has significant consequences for production and by which molecular mechanisms, nutrients and hor-
of: immunoglobulin A (IgA), receptor mfolecules of the major mones can alter the gene expression. We believe that, for the
histocompatibility complex (MHC) and intraepithelial lymp- improvement of the pregnancy outcomes, the promotion of
hocytes [42] (Table 4). healthy growth and development, the reduction of the risk
of chronic diseases and the slowing down of the metabolic
Table 4. Effects of micronutrient intake on the immune response decline associated with aging, it is necessary to develop dietary
in pregnant women. strategies to optimize the nutrition not only during the preg-
Supplement Significant effects nancy, but already at the time in which it is planned, through
Multivitamins In healthy woman and in elderly they improve the intake of adequate micronutrients, of complementary
the response to delayed-type hypersensitivity test foods and also by the promotion of breast feeding.
(DHT): keep the number of T-helper cells; reduce
morbidity from infectious diseases; increase the List of abbreviations
antibody titer in influenza vaccination. 5-HT: Serotonin
Vitamin E Increase DTH; promotes the proliferation of cAMP: Cyclic adenosine monophosphate
immunocytes; improves the antibody titer in GH: Growth hormone
the vaccination against hepatitis B; increases the GMP: Guanosine monophosphate
production of IL-2; reduces the production of IgA: Immunoglobulin A
MPEG2. IGFs: Insulin-like growth factors
Vitamin C Improves the response to the test of delayed-type L-Tp: L-tryptophan
hypersensitivity (DTH). MHC: Major histocompatibility complex
b-carotene Block the UV-induced immunosuppression in Competing interests
both young and old patients; improves the The authors declare that they have no competing interests.
function of NK cells
Authors’ contributions
DTH: delayed-hypersensitivity skin-test; IL-2: Interleukin-2
Authors’ contributions GM PC FMT RP MAS RI
Research concept and design ✓ ✓ -- -- ✓ ✓
Conclusions Collection and/or assembly of data ✓ ✓ ✓ ✓ ✓ --
What has been observed clinically in humans, has also been Data analysis and interpretation ✓ ✓ ✓ ✓ ✓ --
confirmed by experimentation on animals, and this allows Writing the article ✓ -- -- -- ✓ ✓
us to use this new knowledge to reduce the onset of many Critical revision of the article ✓ ✓ ✓ ✓ ✓ ✓
diseases. Therefore, it is necessary to understand and know Final approval of article ✓ ✓ ✓ ✓ ✓ ✓
both factors that determine fetal growth and conditions that Statistical analysis -- -- -- ✓ ✓ ✓

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Musumeci et al. Journal of Histology & Histopathology 2015,
http://www.hoajonline.com/journals/pdf/2055-091X-2-1.pdf doi: 10.7243/2055-091X-2-1

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Citation:
Musumeci G, Castrogiovanni P, Trovato FM, Parenti R,
Szychlinska MA and Imbesi R. Pregnancy, embryo-fetal
development and nutrition: physiology around fetal
programming. J Histol Histopathol. 2015; 2:1.
http://dx.doi.org/10.7243/2055-091X-2-1

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