activation of placental hormones by pregnancy

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CHAPTER ONE

1.0 INTRODUCTIONThe establishment and maintenance of pregnancy in domestic animals requires interactions

between the developing conceptus and the maternal system (Fuller and Neal, 1983). These

interactions are essential for maintenance of the corpora lutea (CL), conceptus development and

placentation, regulation of uterine endometrial secretory activity, placental transport of nutrients

and gases, regulation of uterine blood flow, achievement of immunological "privilege" for the

conceptus, stimulation of development of the maternal mammary glands and various other

effects on the physiology and endocrinology of the maternal and conceptus systems (Fuller and

Neal, 1983).

Animal foetuses develop within a narrow growth trajectory that must balance the demands of the

foetus with the demands of the dam. If the foetus grows to be too large during pregnancy, a

difficult delivery is likely, putting the dam at risk during parturition, whereas being too small has

its own risks for the foetus too (Murphy et al., 2006). Understanding the endocrine factors

regulating these processes have been of tremendous impact in understanding how to cater for the

needs of the dams, likewise the developing zygotes (Gluckman and Pinal, 2002) as the

environment in which a foetus develops is critical for its survival and long-term health. The

regulation of normal foetal growth in livestock (and in humans too) involves many

multidirectional interactions between the dam (mother), the placenta, and foetus itself. Just as the

dam supplies nutrients and oxygen to the foetus via the placenta, the foetus in the same vein

influences the provision of maternal nutrients via the placental production of hormones that

regulate maternal metabolism (Murphy et al., 2006). Placental hormones are produced by one

genetic individual - the foetus, to act on the receptors of another genetic individual - the mother


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(Haig, 1993). The placenta is the site of exchange between mother and foetus and regulates

foetal growth via the production and metabolism of growth-regulating hormones such as Insulin-

like growth factors and glucocorticoids (Haig, 1993).

The placenta may respond to foetal endocrine signals to increase transport of maternal nutrients

by growth of the placenta, by activation of transport systems, and by production of placental

hormones to influence maternal physiology and even behavior. Endocrine regulation of foetal

growth involves interactions between the mother, placenta, and foetus, and these effects may

program long-term physiology (Murphy et al., 2006). This report therefore aims to review how

pregnancy activates placental hormones in the physiology of mammals.


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CHAPTER TWO

2.0 LITERATURE REVIEW

Ovulation is the culmination of numerous endocrinological and physiological events and usually

occurs between 30 and 45 hours, depending on the species of farm animal, after onset of oestrus

and the ovulatory surge of luteinizing hormone (LH), (Fuller and Neal, 1983). If ova are not

fertilized or if embryonic development is abnormal, the estrous cycle continues, seemingly

uninterrupted, to allow subsequent opportunities for mating and establishment of pregnancy. If

fertilization is achieved and embryonic development is normal, conceptus-maternal interactions

occur that result in - (i) maintenance of corpora lutea (CL) and production of progesterone, (ii)

continued development of the uterine endometrium, (iii) implantation and establishment of

conceptus membranes to allow nutrient partitioning, between the conceptus and maternal system

during pregnancy and (iv) parturition (Bauman and Currie, 1980).

The growth and development of the conceptus (embryo/foetus and associated extra-embryonic

membranes) in mammals unequivocally requires progesterone and placental hormone actions on

the uterus that regulate endometrial differentiation and function, pregnancy recognition

signalling, uterine receptivity for blastocyst (embryo) implantation, and conceptus-uterine

interactions (Carson et al., 2000; Gray et al., 2001; Paria et al., 2000). Hormones from the

conceptus act on the uterus in a paracrine manner to establish and maintain pregnancy.

Establishment of pregnancy involves maternal recognition of pregnancy and implantation.

Maternal recognition of pregnancy is a phrase coined by Roger Short in 1969, and is said to be

the physiological process whereby the conceptus signals its presence to the maternal system and

prolongs lifespan of the corpus luteum (CL). In most mammals, progesterone production by the

CL is required for successful pregnancy. Progesterone acts on the uterus to stimulate and


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maintain uterine functions that are permissive to early embryonic development, implantation,

placentation and successful foetal and placental development to term. Prolonged lifespan of the

CL is a characteristic feature of mammalian pregnancy in species with a gestation period that

exceeds the length of a normal oestrous or menstrual cycle, such as domestic animals, laboratory

rodents and humans. Maintenance of pregnancy requires reciprocal interactions between the

conceptus and endometrium (Wathes and Hammon, 1993). It is well established that gestagens

from the ovary and or placenta are necessary for the maintenance of pregnancy, and their levels

increase during pregnancy. The blood and urinary levels of oestrogen also increase with the

advance of pregnancy. Beside, nutrition plays an important role in the maintenance of pregnancy

either directly or indirectly mediating its action through the secretion of pregnancy hormones

(Handwerger and Freemark, 2000). Levels of gestagens and oestrogens which are the main

hormones involved in the regulation of pregnancy are maintained by adequate nutrition

(Catalano and Hollenbeck, 1992).

2.1 Establishment of Pregnancy

Domestic animals are spontaneous ovulators that undergo uterine-dependent oestrous cycles until

establishment of pregnancy. The oestrous cycle is dependent on the uterus, because it is the

source of the luteolysin, prostaglandin F2 (PGF). During the oestrous cycle, the endometrium

releases oxytocin-induced luteolytic pulses of PGF that result in functional and structural

regression of the ovarian CL, termed luteolysis (McCracken et al., 1999). After fertilization,

embryos spend a short period near or at the ampullary-isthmic junction of the oviduct before

entering the uterus at: 48 to 56 hours after ovulation in pigs (Dziuk, 1977); 72 to 96 hours after

onset of oestrus in cows (Robinson, 1977); 72 hours in ewes (Robertson, 1977) and about 144


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hours in the mare (Nishikawa and Hafez, 1974). Implantation of the fertilized egg into the

uterine decidua establishes a contact between the foetus, the placenta and the maternal

circulation. This contact between placenta and maternal circulation is crucial for the success of

pregnancy. Once pregnancy is established the decidua can be divided into three types, depending

upon anatomic location: (1) the decidua basalis, which underlies the site of implantation and

forms the maternal component of the placenta; (2) the decidua capsularis, which overlies the

gestational sac (this portion disappears in the later stages of pregnancy); and (3) the decidua vera,

which lines the remainder of the uterine cavity and becomes intimately approximated to the

chorion (Kliman, 2000). The decidua of pregnancy is associated with the foetal membranes and

is considered to be an endocrine organ. Hormones produced by the decidua can act on the

adjacent tissue (chorion and myometrium) or communicate with the foetus by means of the

amniotic fluid (Kliman, 2000).

Hormones from the conceptus act on the uterus in a paracrine manner to establish and maintain

pregnancy. Establishment of pregnancy involves maternal recognition of pregnancy and

implantation. Although, there is considerable variation in the process of implantation between

eutherian mammals, the end result is the same: the blastocyst becomes fixed in position and

forms a physical and functional contact with the uterus. In most mammals, progesterone

production by the CL is required for successful pregnancy (Challis et al., 2000).

2.2 The Placenta and Placentation

The placenta is the region of apposition between uterine lining and foetal membranes, where

metabolites are exchanged for sustaining pregnancy. It plays a critical role in providing an

environment that supports optimal foetal growth. It does this by providing the site of nutrient


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transfer from the mother to the foetus and waste secretion from the foetus to the mother, acting

as a barrier against pathogens and the maternal immune system, and as an active endocrine organ

capable of secreting hormones, growth factors, cytokines, and other bioactive products (Fletcher

and Weber, 2012). Placentation across all eutherian mammals is characterized by high

angiogenic activity and blood vessel growth. This is particularly the case for the site of placental

attachment.

Hormones are both growth stimulatory and growth inhibitory in utero (Fowden and Forhead,

2009). They act as environmental and maturational signals in regulating the proliferation and

differentiation of foetal tissues during late gestation, thereby ensuring that foetal development is

appropriate for the nutrient supply and optimal for survival at birth. They can also alter the

morphological and functional characteristics of the placenta, the main source of nutrients for

foetal growth (Vaughan et al., 2012). The main growth regulatory hormones are insulin, the

insulin-like growth factors (IGFs), the thyroid hormones, glucocorticoids and, possibly, leptin.

The mother is the supplier of oxygen and essential nutrients to the foetus via the placenta.

Maternal diet, caloric intake, and metabolic function each have an important role to play in

supplying nutrients to the foetus. In addition, alterations in maternal metabolism in response to

hormonal signals ensure a redirection of required nutrients to the placenta and mammary gland

(Picciano, 2003).

2.3 Maturation and functions of the placenta

As pregnancy advances, the relative numbers of trophoblasts increase as feto-maternal exchange

begins to dominate the placenta's secretory functions. Later, the placenta adapts its structure to

reflect its function such that near term, the villi consist mainly of foetal capillaries with sparse


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supporting stroma beyond that which is required to maintain its anatomic integrity. In contrast to

the early placental villus where trophoblasts are abundant as part of a continuous layer of basal

cytotrophoblasts, the term placenta's membranous interface between the foetal and maternal

circulation is extremely thin. Thus, as the gestation progresses toward term, the number of

cytotrophoblasts declines and the remaining syncytial layer becomes thin and barely visible. This

structural arrangement facilitates transport of compounds across the feto-maternal interface

(Ricketts et al., 1998).

2.3.1 Nutrition

The perfusion of the intravillus spaces of the placenta with maternal blood allows the transfer of

nutrients and oxygen from the mother to the foetus and the transfer of waste products and carbon

dioxideback from the foetus to the maternal blood supply. Nutrient transfer to the foetus occurs

via both active and passive transport. Active transport systems allow significantly different

plasma concentrations of various large molecules to be maintained on the maternal and foetal

sides of the placental barrier (Wright and Sibley, 2011).

2.3.2 Excretion

Waste products excreted from the foetus such as urea, uric acid, and creatinine are transferred to

the maternal blood by diffusion across the placenta (Wright and Sibley, 2011).

2.3.3 Immunity

Immunoglobulin-G antibodies can pass through the human placenta, thereby providing

protection to the foetus in utero (Sinister and Story, 1997), beginning very early in the
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gestational age. This passive immunity lingers for several months after birth, thus providing the

newborn with a carbon copy of the mother's long-term humoral immunity to see the newborn

through the crucial first months of extrauterine life. Furthermore, the placenta functions as a

selective maternal-foetal barrier against transmission ofmicrobes. However, insufficiency in this

function may still cause mother-to-child transmission of infectious diseases. Immunoglobulin-M

however, cannot cross the placenta, which is why some infections acquired during pregnancy can

be hazardous for the foetus (Pillitteri, 2009).

2.3.4 Endocrine functions

Placental hormones dominate the endocrine milieu of human pregnancy (Kliman 2000). This

remarkable organ not only provides the conduit for alimentation, gas exchange, and excretion for

the foetus, it also is a major endocrine organ, producing a plethora of protein (including

cytokines and growth factors) and steroid hormones, which it secretes in large quantities

primarily into the maternal circulation. Most hormones produced by the placenta are counterparts

to those produced in the non-pregnant adult. As placental hormones can bind to maternal

hormone receptors, they can be regarded as allocrine factors, that is, hormones produced by one

organism (the foetus) to act on the receptors of another (the mother) (Parker et al, 1986). In

general, placental hormones modify maternal homeostatic mechanisms to meet the nutritional,

metabolic, and physical demands of the rapidly growing foetus. Maternal targets cannot

discriminate between hormones of placental or maternal origin and as such, placental hormones

can readily influence maternal physiology. Thus, the placenta represents a secondary

neuroendocrine control center that tends to override the maternal system in favor of maintaining

the pregnant state and adjusting maternal homeostasis to support the developing foetus (Achache

and Revel, 2006).
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2.4 Hormones of the placenta

When pregnancy is established in mammals, physiological changes occur and production of

certain hormones are begun within the body of such mammal which are secreted in order to

provide growth-enabling environment for the foetus and to create a balance within the mother

within which it is.

2.4.1 Placental Gonadotropins

(a) Progesterone and Oestrogen

Progesterone is essential for endometrial differentiation and the establishment of pregnancy and

is produced exclusively by the corpus luteum (CL) during initial weeks of pregnancy. In non-

conceptive cycles, the CL usually regresses at about the second week after ovulation and the

subsequent decline in progesterone leads to menstruation. For pregnancy to be established, the

demise of the CL and the associated withdrawal of progesterone must be prevented (Mesiano,

1997).

Thus, one of the first endocrine interactions between the conceptus and the mother involves

signaling by the early embryo that pregnancy is occurring and that the functional life span of the

CL must be extended. This event is referred to as the maternal recognition of pregnancy and is

mediated by chorionic gonadotropin (CG) produced by the trophoblast cells (McDonald and

Wolfe, 2009). During the first 5 to 7 weeks of pregnancy progesterone is produced exclusively

by the CL in response to CG. Consequently, the ovaries are obligate organs for pregnancy

maintenance during this time, and abortion rapidly ensues if they are removed. However, after

weeks 6 to 7 of pregnancy the placenta begins producing large amounts of progesterone and at

around the same time progesterone production by the CL decreases. This transition in the source

of progesterone is referred to as the luteal-placental shift (Mesiano, 1997). Consequently,


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1997). Therefore, pregnancy can be detected before the first missed menstrual period. This has

clinical utility when it is important to determine the presence of pregnancy at an early stage. In

early pregnancy, there is an approximate doubling of levels every 2 to 3 days and concentrations

of hCG rise to peak values by 60 to 90 days of gestation. Thereafter, hCG levels decrease to a

plateau that persists during the remainder of the pregnancy. Maternal immunoassayable LH and

FSH levels are virtually undetectable throughout pregnancy. hCG also ensures that the corpus

luteum continues to secrete progesterone and oestrogen. Progesterone is very important during

pregnancy because, when its secretion decreases, the endometrial lining will slough off and

pregnancy will be lost. hCG suppresses the maternal immunologic response so that placenta is

not rejected (Zygmunt et al., 2002; Mesiano, 1997).

(c) Gonadotropin-Releasing Hormone

The human placenta produces gonadotropin-releasing hormone (GnRH), which is identical to

that produced by the hypothalamus (Mesiano, 1997). Levels of GnRH in the circulation of

pregnant women are highest in the first trimester and correlate closely with hCG levels. The

close relation between GnRH and hCG suggests a role for GnRH in regulating hCG production.

GnRH stimulates the production of both the and subunits of hCG in placental explants and

specific GnRH-binding sites are present in the human placenta. Thus, there appears to be

autoregulation of hCG production within the placenta. hCG also may influence placental

steroidogenesis, suggesting a complete internal regulatory system within the placenta. This

concept is further strengthened by the presence of other regulators of GnRH expression,

including inhibins and activins, in the human placenta (Mesiano, 1997, Mais et al., 1986).


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(d) Inhibins and Activins

Inhibin is a heterodimer composed of an subunit and one of two subunits, A orB. Inhibins

(A and B) derive their name from their ability to preferentially inhibit pituitary FSH

secretion. In contrast to inhibins, the homodimers A A and B B stimulate FSH production.

These compounds have been termed activins. Inhibins are produced by the human placenta; all

three subunits are expressed in the syncytiotrophoblast and the levels of expression do not

change with advancing gestation (Mesiano, 1997; Wongprasartsuket al., 1994; Marino et al.,

2003). Activin-A is also produced by the corpus luteum, decidua, and foetal membranes during

human pregnancy.The placenta also produces follistatin, the binding protein for activin. These

factors are secreted into the maternal and foetal circulations and amniotic fluid and their

production varies with stage of gestation. Although the exact function of the inhibin/activin

system in human pregnancy is not known, several studies indicate their involvement in the

pathogenesis of gestational diseases. Levels of inhibin-A and activin-A in the maternal

circulation can be indicative, albeit with relatively weak predictive value, of disorders such as

placental tumors, hypertensive disorders of pregnancy, intrauterine growth restriction, foetal

hypoxia, Down syndrome, foetal demise, preterm delivery, and intrauterine growth restriction

(Mesiano, 1997; Silva et al., 2004; Wongprasartsuket al., 1994; Marino et al., 2003).

2.4.2 Placental Somatotropins

(a) Human Placental Lactogen (hPL [Human Chorionic Somatomammotropin {hCS}]):

This hormone is lactogenic and has growth-promoting properties. It promotes mammary gland

growth in preparation forlactation in the mother. It also regulates maternal glucose, protein, and

fat levels so that this is always available to the foetus. hPL is a single-chain polypeptide of 191
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amino acids with two disulfide bridges and has a 96% homology with human growth hormone

(hGH) (Mesiano, 1997). It can be detected in the placenta from around day 18 of pregnancy and

in the maternal circulation by the third week of pregnancy. hPL is detectable in the serum and

urine in both normal and molar pregnancies, and it disappears rapidly from the serum and urine

after delivery of the placenta; it cannot be detected after the first postpartum day. After removal

of the placenta, the half-life of the disappearance of circulating hPL (in humans) is 9 to 15

minutes. Several studies have demonstrated changes in maternal hPL levels in response to

metabolic stress. Specifically, prolonged fasting at midgestation and insulin-induced

hypoglycemia raise maternal hPL concentrations. However, hPL levels do not change in

association with normal metabolic fluctuations during a typical 24-hour period (Mesiano, 1997;

Economides and Nicolaides, 1989; Murphy et al., 2006). Although extreme metabolic stress

influences hPL production, hPL expression does not appear to be modulated by metabolic status

within the normal range (Mesiano, 1997).

(b) Human Placental Growth Hormone (hPGH)

Two forms of hPGH have been identified, both of which are expressed in syncytiotrophoblast

cells (Mesiano, 1997). The smaller, 22-kDa form is almost identical to pituitary GH, differing by

only 13 amino acids. The larger 26-kDa hPGH is a splice variant that retains intron 4. The extent

of hPGH production is significantly less than that of hPL, and hPGH is not secreted into the

foetal compartment.During the course of human pregnancy, hPGH becomes the dominant GH,

and maternal pituitary GH production gradually declines. In the first trimester, pituitary GH is

measurable and secreted in a highly pulsatile manner. However, pituitary GH production

decreases progressively from about week 15 and by 30 weeks cannot be detected. (Mesiano,

1997; Mesiano and Jaffe, 1997).


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2.4.3 Placental Corticotropins

The human placenta expresses pro-opiomelanocortin (POMC) (Mesiano, 1997). In pituitary

corticotropes, this 31-kDa glycoprotein is the precursor for the adrenocorticotropic hormone

(ACTH)endorphin family of peptides. POMC is enzymatically cleaved into several peptide

hormones, including ACTH, -lipotrophic hormone (-LPH), -melanocyte stimulating hormone

(-MSH), and -endorphin (-EP). These neuroendocrine hormones play major roles in the

physiologic response to stress and the control of behavior. Each of these peptides, including full-

length POMC, has been detected in the human placenta (Phillips et al., 1996; Adams et al.,

1998).

(a) Adrenocorticotropic Hormone (ACTH)

Placental ACTH is structurally similar to pituitary ACTH. Under the paracrine influence of

placental CRH released from the juxtaposed cytotrophoblasts, placental ACTH is secreted by

syncytiocytotrophoblasts into the maternal circulation. Circulating maternal ACTH is increased

above non-pregnancy levels, but still remains within the normal range. Placental ACTH

stimulates an increase in circulating maternal free cortisol that is resistant to dexamethasone

suppression. Thus, relative hypercortisolism in pregnancy occurs despite high-normal ACTH

concentrations. This situation is possible due to two main differences in endocrine relationships

during pregnancy. First, the maternal response to exogenous Corticotropin Releasing Hormone

(CRH) is blunted. Second, a paradoxical relationship exists between placental CRH, ACTH, and

their end-organ product, cortisol; glucocorticoids augment placental CRH and ACTH secretion,

not suppress it. This positive feedback mechanism allows an increase in glucocorticoid secretion

in times of stress in excess of the amount necessary if the mother were not pregnant (Phillips et

al., 1996; Adams et al., 1998).


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(b) Corticotropin-Releasing Hormone

First identified in the hypothalamus, orticotropin-Releasing Hormone (CRH) is a 41amino acid

peptide that stimulates the expression and processing of POMC by pituitary corticotropes and, as

its name implies, the secretion of ACTH. The human placenta, fetal membranes, and decidua

also express CRH that is identical to that produced by the hypothalamus.Expression of placental

CRH (in humans) can be detected from the seventh week of pregnancy and increases

progressively until term. In the last 5 to 7 weeks of pregnancy, placental expression of CRH

increases more than 20-fold. Placental CRH is released mainly into the maternal compartment.

A binding protein (BP) for CRH also exists, and for most of pregnancy it is present in excess of

CRH in the maternal circulation. In vivo studies have shown that CRH responsiveness of the

maternal pituitary is markedly attenuated during pregnancy, and in vitro studies have shown that

CRH down-regulates expression of its receptor in pituitary corticotropes (Mesiano and Jaffe,

1997; French et al., 1999).

2.4.4 Thyrotropin-Releasing Hormone

A substance similar to the hypothalamic thyrotropin- releasing hormone (TRH) in now known to

exist in the human placenta (Banks et al., 1999). It stimulates pituitary thyrotropin thyroid-

stimulating hormone (TSH) release in the rat both in vitro and in vivo, but is not identical to

hypothalamic TRH (Banks et al., 1999; Mesiano, 1997).

2.4.5 Growth Factors and Cytokines

Many growth factors, cytokines, and their cognate receptors have been found in the human

placenta (Mesiano, 1997). These factors likely play a role in controlling the growth,


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development, and differentiated function of the placenta and foetus. In this regard the insulin-like

growth factors (IGFs) are notable. Studies in mice, using homologous recombination, have

shown that IGF-I and IGF-II are critical for placental and foetal growth. Disruption of placenta-

expressed IGF-II or overexpression of decidual IGFBP-1 (an IGF binding protein that inhibits

IGF action)leads to restriction of placental and foetal growth (Owens et al., 1994).

The size and ultimate health of the foetus depends greatly on the size of the placenta. Growth

factors that increase placenta size are an advantage to the foetus because they allow it to more

efficiently extract resources from the mother. Passage of paternal genes to the next generation is

favored if nutrient supply to the foetus is maximized. Maternal genes, on the other hand, not

only must survive to the next generation, but also must ensure that the current pregnancy does

not compromise the mothers future reproductive capacity. Maternal genes would therefore be

selected to counter and control the effects of paternally imprinted genes such as IGF-II.

Interestingly, Insulin-like growth factor binding protein-1 (IGFBP) is produced by the decidua, a

maternal tissue, and essentially all of the IGFBP-1 in amniotic fluid is maternally derived.Thus,

placental, and ultimately foetal, growth appears to be the net result of a balance between factors

that stimulate (e.g., IGF-II) and those that restrict (e,g., IGFBP-1) growth (Harding et al., 1985;

Owen et al., 1994).


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CHAPTER THREE

3.0 CONCLUSION

Together the mother, placenta, and fetus interact during pregnancy to modulate fetal growth. The

placenta is important in the production of growth hormones and corpus luteum-sustaining

hormones many of which are found only in trace amounts in the body of an animal in the

absence of pregnancy, but in significant amounts when pregnancy is established. Disturbances in

foetal growth regulation as coordinated by placental hormones can result in adverse outcomes for

the neonate, and these adverse outcomes may persist into adult life. It is therefore important to

understand the mechanisms regulating animal foetal growth, and particularly the role of mother,

placenta, and fetus in complicated pregnancies. As a result, a better outcome for the foetus may

be achieved, which may have long-term health benefits into maturity and hence, improved

reproductivity in animals, which consequentially leads to better animal production.


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