Chapter 12 As the zygote undergoes cleavage, it moves along the uterine tube and enters the uterus. The developing embryo, suspended in tubal fluid, is transported by a combination of ciliary and muscular action and takes up to three days to reach the uterus in most mammals. The nutritional requirements of the conceptus are supplied initially by its own yolk and by the secretions of the maternal reproductive tract. The zygote is protected from maternal cellular defences by the zona pellucida, which is immunologically inert as it does not express major histocompatibility complex antigens. Because the embryo is enclosed within an intact zona pellucida, implantation cannot occur as it moves through the uterine tube. On reaching the uterus, the blastocyst hatches from the zona pellucida and remains free for a short period in the uterine lumen. During this time, it receives nourishment from secretions of the uterine glands. Subsequently, the developing embryo attaches to the uterine mucosa, a process referred to as implantation. The term implantation is used to describe the attachment of the developing embryo to the endometrium. This process, which occurs in three stages in domestic animals, is gradual, with apposition of the blastocyst or foetal membranes to the uterine epithelium followed by adhesion. Depending on the species, the final stage may involve firm attachment or actual invasion of the endometrium. As an embryo remains relatively independent of maternal influences prior to implantation, it can be grown to the blastocyst stage in vitro. However, from the time of implantation onwards, the viability of the conceptus is greatly influenced by maternal factors, with embryonic survival dependent on hormonal and immunological adaptation of the dam to pregnancy. The intervals between fertilisation and implantation in humans and different species of animals are presented in Table 12.1. The form of implantation differs from one species to another. In primates and guinea pigs, the blastocyst burrows through the uterine epithelium to the uterine stroma where the embryo develops. This form of implantation is referred to as interstitial implantation (Fig 12.1A and B). In rodents, implantation involves the blastocyst becoming lodged in a uterine cleft with proliferation of the surrounding uterine mucosa. This form of implantation is known as eccentric implantation (Fig 12.1C). In horses, cattle, sheep, pigs, dogs, cats and rabbits, the fluid‐filled sacs surrounding the embryo expand so that the extra‐embryonic membranes become apposed to the endometrium and attach to it. This form of implantation, the most common form of attachment in mammals, is referred to as centric or superficial implantation (Fig 12.1D). In animals with either interstitial or eccentric implantation, these three stages of attachment occur within a short time interval and it is possible to estimate accurately the time of implantation. With centric or superficial implantation, the stages of attachment extend over a longer time period than in interstitial implantation and wide variation has been reported for the time of implantation in ruminants and horses. Table 12.1 The interval between fertilisation and implantation in humans and in selected domestic animals. Figure 12.1 Cross‐sections through pregnant uteri showing forms of implantation. A. Interstitial, anti‐mesometrial implantation. B. Interstitial, mesometrial implantation. C. Eccentric, anti‐mesometrial implantation. D. Centric or superficial implantation. In eccentric or interstitial implantation, the site of blastocyst attachment is described by relating its position in the uterus to its peritoneal suspension, the mesometrium. When the blastocyst implants in the endometrium on the same side as the attachment of the mesometrium, this is referred to as mesometrial implantation (Fig 12.1B). When implantation occurs at a site opposite to the attachment of the mesometrium, this is referred to as anti‐mesometrial implantation (Fig 12.1A). The orientation of the blastocyst is similarly described by relating the position of the inner cell mass to the mesometrium (Fig 12.2). Figure 12.2 Cross‐sections through pregnant uteri showing orientation of blastocyst at time of implantation. A. Mesometrial orientation of inner cell mass. B. Anti‐mesometrial orientation of inner cell mass. After reaching the uterus, blastocysts move to their implantation sites. In cattle and sheep, when a single oocyte is fertilised, the blastocyst attaches to the middle or upper third of the uterine horn adjacent to the ovulating ovary. In sheep, when two blastocysts are derived from one ovary, one blastocyst usually migrates to the contralateral horn, where it becomes implanted. As intra‐uterine migration is rare in cattle, when twins arise from ovulation involving one ovary, both embryos usually develop in the same horn. In mares, ultrasonography has demonstrated that, irrespective of which ovary ovulates, the blastocyst migrates between the left and right uterine horns from the 11th to the 17th day. After this time, mobility ceases and the blastocyst implants in either the left or right horn close to the body of the uterus. In polytocous animals, those producing litters, the blastocysts are evenly spaced within the uterine horns. Although the underlying mechanism responsible for the spacing of implanting blastocysts is unclear, oestrogen produced by the developing blastocyst is considered to have an important role in embryo spacing. Implantation requires cooperative interaction between the dam and the blastocyst. The high levels of oestrogen produced during the follicular stage of the oestrous cycle cause proliferation of the endometrium and, in addition, progesterone produced during the luteal stage renders the endometrium receptive to the blastocyst. In all mammals, progesterone is essential for both the establishment and maintenance of pregnancy. For maintenance of pregnancy in domestic mammals, continued functioning of the cyclical corpus luteum is a requirement and this is achieved through the production of anti‐luteolysin by the conceptus which inhibits the production of luteolytic uterine secretions. This response to the presence of the conceptus is referred to as maternal recognition of pregnancy. While the basic strategy is to maintain and prolong the cyclical corpus luteum by inhibiting or reducing the secretion of prostaglandin F2α (PGF2α), the factors which control the process show species variation. In species in which the life span of the corpus luteum is similar in pregnant and non‐pregnant animals, recognition of pregnancy may occur by different means. In a number of species, there is an unusually long delay between the entry of the blastocyst into the uterus and the time at which implantation occurs. In these species, the blastocyst enters a period of decreased cell division and metabolic quiescence, referred to as diapause, a state characterised by decreased protein and nucleic acid synthesis and a decline in carbon dioxide output. In mink and ferrets, the interval is comparatively short, usually a matter of weeks, whereas in roe deer, bears, badgers and seals, the interval may be substantially longer, up to four months in some instances. Delayed implantation increases the probability that offspring are born at a time of year favourable for survival. Although there is limited information on the underlying mechanisms which operate in delayed implantation, both uterine and hypothalamic factors are implicated. When blastocyst development is slowed as a consequence of seasonal influences, this type of diapause is referred to as seasonal or obligative delayed implantation. In addition to those animals in which delayed implantation is a normal occurrence, a similar but shorter delay may occur in certain species of rodents and insectivores. The delay in implantation in these species is attributed to the influence of stress factors, such as lactation, which inhibit implantation. If rodents become pregnant during a post‐partum oestrus, blastocyst implantation is delayed until weaning occurs. This delay is influenced by litter size. With a litter size of one or two, implantation is not delayed, whereas with six or more offspring there may be a delay of up to six days. This mechanism, which ensures that the dam does not have to support two litters contemporaneously, is referred to as facultative or lactational delayed implantation. Implantation and subsequent embryonic development in an extra‐uterine location is referred to as ectopic pregnancy. Sites of abnormal implantation include the ovary, the uterine tube and the peritoneal cavity. Ectopic pregnancy, which occurs more frequently in humans than in domestic animals, usually leads to death of the embryo or foetus and may be accompanied by severe maternal haemorrhage and sometimes death. In the absence of infectious diseases, and despite optimal nutrition, early embryonic mortality is a frequent occurrence in all domestic species. Most of these early embryonic deaths, which occur around the time of maternal recognition of pregnancy or the time of implantation, are attributed to defective interaction between the conceptus and the dam. Survival of the developing embryo depends on the establishment of a placenta, the formation of which, in turn, depends on cooperative interactions between the blastocyst and the uterus. These interactions are affected by complex factors, which involve adequate hormonal stimulation of the endometrium, environmental stimuli and the nutritional status of the mother. Factors which may contribute to early embryonic mortality are hormonal imbalance, maternal rejection and chromosomal abnormalities in the developing embryo. These factors are considered in greater detail in Chapter 13. When the blastocyst reaches the uterus, it is initially sustained by uterine secretions and, after a short delay, it attaches to the endometrium with the subsequent formation of a placenta. This complex structure allows selective exchange of nutrients, gases and waste products. It also functions as a site of hormone production. Based on the relationship between foetal membranes and maternal tissue, two basic types of placentae are recognised, choriovitelline and chorioallantoic. When the fused vascular choriovitelline membranes become attached to the endometrium, the resulting placenta is known as a choriovitelline or yolk sac placenta. This type of placentation is commonly encountered in marsupials. When the chorioallantoic membrane becomes attached to the endometrium, the resulting placenta is referred to as a chorioallantoic placenta. While this is the definitive form of placentation in higher mammals, it may be preceded by and co‐exist with a temporary choriovitelline placenta (Fig 12.3). Figure 12.3 Components of a choriovitelline placenta and chorioallantoic placenta. In higher mammals, the yolk sac is formed early in development, usually while the blastocyst is still unattached in the uterine cavity. In most mammals, the endoderm of the early yolk sac combines with the trophoblastic layer of the blastocyst forming a bilaminar yolk sac. When the vascular mesoderm becomes interposed between the chorion and the endoderm, the bilaminar structure becomes a trilaminar yolk sac which functions as the embryonic component of the choriovitelline placenta (Fig 12.3). While the choriovitelline placenta persists as the definitive placenta in most marsupials, among domestic mammals it exists only as an early temporary structure, losing its exchange function when the extra‐embryonic coelom extends into the mesoderm of the trilaminar yolk sac, separating the mesoderm into splanchnic and somatic layers. As these changes take place rapidly in cattle, sheep and pigs, this yolk sac placenta functions for only a short period of time. In dogs and cats, the choriovitelline placenta functions up to the 21st day of pregnancy, whereas in horses it functions up to the eighth week of pregnancy. The choriovitelline placenta does not establish an extensive and intimate contact with the endometrium. The embryonic component of a chorioallantoic placenta is formed by the attachment and fusion of the outer wall of the expanding allantoic sac with the adjacent chorion (Fig 12.3). This is the definitive form of placentation which occurs in higher mammals and it is characterised by an extensive area of contact between the embryonic placental component and the endometrium. Increased surface contact is achieved through folding of the chorioallantois and the endometrial surface, formation of chorionic villi and the establishment of chorionic labyrinths. Chorioallantoic placentae can be classified according to their shapes and the relationship of the extra‐embryonic membranes to the endometrium. Formation of chorionic villi, their distribution on the surface of the chorionic sac and their relationship with the endometrium are used to define some placental characteristics. Placental morphology and areas of chorionic villous attachment can be described as diffuse, cotyledonary, zonary or discoidal. Diffuse placentation, which occurs in horses and pigs, is characterised by uniform distribution of villi on the outer surface of the chorion (Fig 12.4A). In cotyledonary placentation, which occurs in ruminants, chorionic villi are restricted to defined areas referred to as cotyledons, which are distributed over the surface of the chorionic sac (Fig 12.4B). Zonary placentation, which occurs in domestic carnivores, is characterised by chorionic villi which are confined to a girdle‐like structure around the middle of the chorionic sac (Fig 12.4C). In discoidal placentation, which occurs in humans, monkeys and rodents, villi are restricted to disc‐shaped areas on the chorionic sac (Fig 12.4D). Figure 12.4 Classification of placentae based on the shape and the distribution of attachment sites of the chorion to the endometrium. A. Diffuse form of placentation which occurs in horses and pigs. B. Cotyledonary form of placentation which occurs in ruminants. C. Zonary form of placentation which occurs in carnivores. D. Discoidal form of placentation which occurs in humans, monkeys and rodents. The degree of contact between foetal tissue and endometrium varies and may involve merely the loose apposition of these two tissues, termed apposed placentation, or their intimate fusion, termed conjoined placentation. With an apposed placenta, fusion of the maternal and foetal tissue does not occur and separation is easily achieved at parturition without damage to the uterine mucosa. This form of placentation is termed non‐deciduate. In conjoined placentation, an intimate connection is formed between maternal and embryonic tissue and, at birth, some maternal tissue is lost with the foetal tissue. This type of placentation is termed deciduate. The placentae of horses, ruminants and pigs are described as apposed and non‐deciduate; in humans, dogs, cats and rodents, they are conjoined and deciduate. Based on the number of tissue layers interposed between the foetal and maternal bloodstream, four basic types of placentation can be described. In the simplest form, maternal endothelium, maternal connective tissue, maternal uterine epithelium, foetal (chorionic) epithelium, foetal connective tissue and foetal endothelium separate the maternal blood and foetal blood. In the most complex form, the maternal layers are successively broken down until the chorionic epithelium (trophoblast) comes in direct contact with the maternal blood supply. By using the name of the maternal tissue which is contiguous with the chorion, the following types of placentation, based on histological features, can be described: epitheliochorial, synepitheliochorial, endotheliochorial and haemochorial (Fig 12.5). Figure 12.5 Classification of placentae based on the number of tissue layers interposed between foetal and maternal blood. A. Epitheliochorial. B. Synepitheliochorial. C. Endotheliochorial. D. Haemochorial. In epitheliochorial placentation, the endometrial epithelium remains intact and is apposed to the chorionic epithelium (Fig 12.5A). This class of placentation occurs in horses, donkeys and pigs. The term ‘syndesmochorial’, which describes removal of uterine epithelium leaving the chorion in contact with maternal connective tissue, was formerly used to describe the histological form of placentation in ruminants. Electron microscope studies, however, have demonstrated that an attenuated layer of combined maternal and foetal epithelium persists in ruminant placentae. Consequently, the term ‘syndesmochorial’ has been replaced by the term ‘synepitheliochorial’ (Fig 12.5B). The prefix ‘syn’ implies a union of foetal and maternal cells in the cryptal epithelium. In endotheliochorial placentation, the uterine epithelium and connective tissue are removed and the chorionic epithelium comes in direct contact with the endometrial capillaries (Fig 12.5C). Placentae of this type are found in dogs, cats and elephants. With haemochorial placentation, the maternal endothelium is removed and chorionic epithelium comes in direct contact with maternal blood (Fig 12.5D). This type of placentation is found in some rodents and in higher primates. A current classification of placentation, based on histological features, is presented in Table 12.2. The functional efficiency of placentae is not directly related to the number of tissue layers interposed between foetal and maternal circulations. Table 12.2 Description and histological classification of placentae of domestic animals, rodents and primates. Foetal layers are listed in accordance with their position relative to the maternal circulation. Localised accumulations of maternal blood occur between the chorion and endometrium in the placentae of carnivores and ungulates. These areas are referred to by various names including haematomata, haemophagous organs, green border and brown border. These blood‐filled spaces are considered to be a source of iron for the foetus. Despite the extensive use of the term ‘haematoma’ in the literature relating to these structures, it is an inappropriate description as it more correctly describes a pathological accumulation of extravasated blood. The folded columnar epithelium of the trophoblast, which is in direct contact with the accumulated blood, possesses microvilli which enhance uptake of red blood cells and other nutrients. It is reported that these columnar cells engulf maternal red blood cells which are utilised as a source of iron by the developing embryo. The breakdown products of haemoglobin account for the green and brown colouration of canine and feline haemophagous organs, respectively. The relative prominence and gross appearance of placental haemophagous organs show species variation. The nutritional material supplied to the embryo from the circulating maternal blood is referred to as haemotrophe. Products absorbed by the embryo from the endometrium are known as histotrophe.
Forms of implantation and placentation
Implantation
Animal
Time (days)
Rodents
5 to 6
Humans
6 to 7
Rabbits
7 to 8
Cats
12 to 14
Pigs
12 to 16
Dogs
14 to 18
Sheep
14 to 18
Cattle
17 to 35
Horses
17 to 56 
In utero spacing and embryo orientation
Endocrine control of implantation
Delayed implantation
Ectopic pregnancy
Embryonic mortality
Placentation in mammals
Choriovitelline placenta
Chorioallantoic placenta
Classification of chorioallantoic placentation
Histological classification of placentation
Classification
Cows
Sheep
Pigs
Horses
Dogs
Cats
Humans/primates
Rodents
Implantation
Interstitial
X
Eccentric
X
Centric (superficial)
X
X
X
X
X
X
Placentation
Chorioallantoic
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Deciduate (Conjoined)
X
X
X
X
Non‐deciduate (Apposed)
X
X
X
X
Epitheliochorial
X
X
Synepitheliochorial
X
X
Endotheliochorial
X
X
Haemochorial
X
X
Placental haemophagous organs
Haemotrophe and histotrophe
Implantation and placentation in pigs
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