CHAPTER ONE 1.

0 INTRODUCTION

The 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

(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 Insulinlike 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.

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

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

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

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

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 dioxide back 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

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 of microbes. 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 nonconceptive 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,

removal of the ovaries after the ninth week has no impact on pregnancy. The placenta supplies progesterone for the remainder of pregnancy. While the placenta produces large amounts of progesterone, it has a limited capacity to synthesize cholesterol de novo. Maternal cholesterol in the form of low-density lipoprotein (LDL) cholesterol is the principal source of precursor for biosynthesis of progesterone during pregnancy, and oestrogen in concert with the foetal adrenal gland (Mesiano, 1997). (b) Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) is a 36- to 40-kDa glycoprotein hormone that is biologically and immunologically similar to pituitary luteinizing hormone (LH). It is produced by trophoblasts almost immediately after implantation (Zygmunt et al., 2002; Mesiano, 1997). As with LH and follicle-stimulating hormone (FSH), hCG is a heterodimer composed of an and subunit. The subunits of hCG, LH, and FSH are identical, whereas the subunits differ, conferring specificity to each hormone. Like LH, hCG is a potent luteotropin, and as such, it stimulates progesterone secretion by the CL. Importantly, hCG prolongs the functional life of the CL and converts the CL of the menstrual cycle into the CL of pregnancy, ensuring the production of progesterone necessary for the establishment of pregnancy. In an evolutionary context, this role may provide a basis for selection, as pregnancy will not ensue if the embryo is defective and cannot gain control of the CL. The capacity of the embryo to produce large amounts of hCG may represent a selective test of the embryos endocrine competence. Furthermore, the maternal level of resistance to the embryos efforts to control the CL would select embryos with more robust endocrine function (Zygmunt et al., 2002; Mesiano, 1997). In normal pregnancies, hCG is detectable 9 to 11 days after the mid-cycle LH peak, which is around 8 days after ovulation and only 1 day after implantation (Zygmunt et al., 2002; Mesiano,

10

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 or B. 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; Wongprasartsuk et 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; Wongprasartsuk et 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 for lactation 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

12

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 fulllength 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 thyroidstimulating 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 placentaexpressed 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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