The Placenta: Unique Multifunctional “Tree of Life” for the Growing Fetus

Abstract: The Placenta: Unique Multifunctional “Tree of Life” for the Growing Fetus.

The article was designed as a retrospective overview of the scientific studies for distinguishing the role and the peculiarities of the placenta in feto–maternal interaction. The article focuses on representing, analyzing and comparing the basic overview of main issues and dilemmas, concerning normal and abnormal morphological aspects of the placenta and the umbilical cord. Fetoplacental Vascular Tree. Complexities and dilemmas interconnected with feto–maternal interaction were discussed with the following conclusions made. Informative pathological markers as the vital indicators of the emergencies were represented. The recommendations concerning preventive measures were given.

Introduction

Basically, trophoblast invasion is the vital constituent of first–trimester placental development and depends immensely on the invasion–promoting and inhibitory factors expressed at the maternal–fetal interface. The processes of embryo implantation and placentation involve the degradation and remodeling of extracellular matrix, cellular proliferation, apoptosis, and differentiation.

Implantation of the developing conceptus in the maternal uterus occurs by the end of the first week of pregnancy. Extra embryonic trophoblast of the blastocyst attaches to the endometrial epithelium at the embryonic pole [Knoth and Larsen, 1972; Lindenberg, 1991]. Upon attachment, the trophoblast proliferates rapidly and invades the uterine epithelium and underlying endometrial stroma. In the first trimester, the embryo attaches to the maternal decidua by intermediate (extravillous) trophoblast that streams off from the anchoring villi [Kurman et al., 1984; Kurman 1991]. The intermediate trophoblast invades maternal endometrial spiral arteries and dilates them in order to achieve a sufficient fetal blood supply. This process peaks during the 12^th week of pregnancy and declines rapidly thereafter. The placental villi are organized into two layers: an inner layer of mononuclear cytotrophoblast and an outer layer of multinuclear syncytiotrophoblast. The villi cover the vascular mesoderm, which contains fetal capillaries and mesenchymal cells.

Generally representing the issue, pregnancy is a homeostatic state whereby the maternal immune system is in close contact with semiallogeneic fetal tissues. It is known that the placenta acts as an immunological barrier between the mother and the fetus allowing two antigenically different organisms to tolerate one another. Considering that the fetus can survive despite the maternal immune system, pregnancy thus seems to be an immunological paradox. Nonetheless, complications of pregnancy may occur, such as Preeclampsia (PE) and miscarriage, which involve mechanisms that are incompletely understood at present.

Successful pregnancy depends on well–regulated Extravillous Trophoblast (EVT) invasion into the uterine decidua and moderate uterine spiral artery remodeling.

Early placental growth (8–10 week of gestation), characterized by extensive proliferation of stem cytotrophoblasts and differentiation to multinucleated Syncytotrophoblasts (STs) and invasive Cytotrophoblasts (iCT), is regulated by transcriptional activation as well as silencing of a variety of trophoblast–specific genes [Rossant and Cross, 2001].

The placental development begins with an extensive proliferation of stem cytotrophoblasts in hypoxic environment followed by differentiation into multinucleated Syncytotrophoblasts (STs) and invasive Cytotrophoblasts (iCT). This developmental transition of placenta is marked by downregulation and simultaneous activation of a plethora of genes, some of which are trophoblast specific and a few are imprinted [Banerjee et al., 2000].

Functional placenta establishment is of crucial importance for successful fetal development and pregnancy outcomes [Burton and Jauniaux, 2015]. During early placentation, trophoblast precursors differentiate into and highly invasive syncytiotrophoblasts and trophoblast subtypes [Pijnenborg et al., 2006]. The latter cell type, referred to as Extravillous Trophoblasts (EVTs), penetrate the maternal uterus, reaching as far as the inner third of the myometrium. Extravillous Trophoblasts (EVTs) physiologically interact with maternal immune cells, inducing elastolysis in the arterial wall and replacing the Endothelial Cells (ECs) lining the spiral arteries to achieve intraluminal vascular remodeling [Lyall, 2005; Harris, 2010].

Uterine spiral arteries play a vital role in supplying nutrients to the placenta and fetus, and for this purpose they are remodelled into highly dilated vessels by the action of invading trophoblast (physiological change). Knowledge of the mechanisms of these changes is relevant for a better understanding of pre–eclampsia and other pregnancy complications which show incomplete spiral artery remodelling. Controversies still abound concerning different steps in these physiological changes, and several of these disagreements should be highlighted, thereby suggesting directions for further research [Pijnenborg et al., 2006].

It is proved that in order to establish hemochorial placentation and to provide a progressive increase in blood supply to the growing fetus, the uterine spiral arteries must undergo considerable alterations [Lyall, 2005]. This process leads to an irreversible vasodilatation, ensuring that maximal blood flow is delivered to the materno–fetal interface at an optimal velocity for nutrient exchange. There is accumulating evidence that subtle changes in vascular structure precede Extravillous Trophoblasts (EVTs) colonisation; however, full physiological transformation is only achieved in the presence of trophoblast [Harris, 2010]. This physiological modification is thought to be brought about by the interaction of invasive cytotrophoblast with the spiral artery vessel wall [Lyall, 2005].

The uterine spiral arteries are completely transformed into a large–flow and low–resistance conduit, enabling adequate perfusion of the placenta by maternal blood. Aberrant Extravillous Trophoblasts (EVTs) function, superficial invasion, and reduced blood flow to the placenta are related to pregnancy complications like preeclampsia and intrauterine growth retardation [Avagliano et al., 2011; Lyall et al., 2013]. Thus, proper trophoblast–mediated uterine spiral artery remodeling is a fundamental condition for a healthy pregnancy, and an improved understanding of the multiple mechanisms of trophoblast invasion may provide therapeutic interventions for pregnancy complications.

1. The Placenta: Unique Multifunctional “Tree of Life” for the Growing Fetus

The placenta is a temporary multifunctional organ that performs the functions of several adult organs (the principal metabolic, respiratory, excretory, and endocrine organ) for the growing fetus, or, in other words, for the first 9 months of fetal life. The placenta is designed uniquely for exchange of oxygen, nutrients, antibodies, hormones, and waste products between the mother and fetus and may carry valuable information about the pregnancy. It maintains fetal homoeostasis by providing an immune interface between the maternal tissues and fetal allograft, transports nutrients and waste products between mother and fetus, and acts as the source of many peptide and steroid hormones that influence fetal, placental, and maternal metabolism and development. The placental barrier is a critical structure required to accomplish these functions; it separates the maternal blood in the intervillous space from the fetal blood in the vasculature in the core of the villi. The placental barrier is made up of different overlapping structures, including a maternal–facing syncytiotrophoblastic continuous layer with multiple apical microvilli, an endothelium that lines fetal capillaries and their underlying Basal Membranes (BM), as well as the connective tissue of the villi between them. The majority of maternofetal exchanges that significantly influence placental development and fetal growth are believed to occur at the terminal branches of the chorionic villi. An abnormal placental ultrastructure has been reported to be associated with various pregnancy’s complications, such as preeclampsia [Jones and Fox, 1980; de Luca Brunori et al., 2005; Dong–bao Chen and Wen Wang, 2013], Intrauterine Growth Retardation (IUGR) [van der Veen et al., 1983; Macara et al., 1996; Wawrzycka et al., 2002; Battistelli et al., 2005], Gestational Diabetes Mellitus (GDM) [Jones and Fox, 1976; Evemie Dubé et al., 2013; Heather et al., 2015], intrahepatic cholestasis of pregnancy [Costoya et al., 1980], lysosomal storage disorders [Fowler et al., 2007], metabolic storage diseases [Jones et al., 1990] and other pregnancy complications, suggesting that studying the placental ultrastructure could provide important evidence for understanding the physiopathology of pregnancy complications. Therefore, the investigation of placenta may provide valuable insights into placental functions and help identify molecular mechanisms that have both immediate and long–lasting effects on health of the fetus.

The tissue most involved in immunoregulation at the maternal–fetal interface is the placenta. It is comprised of cells of maternal as well as fetal origin, both of which express molecules (HLA–G by trophoblast and Fas Ligand (FasL)2 by maternal decidual cells) that play a role in fetomaternal tolerance [Guleria and Sayegh, 2007], in other words, the placenta is an immunologically privileged site.

However, because the placenta is a structurally complex organ composed of many cell types with different origins, it is necessary to obtain detailed information on the ultrastructure of each placental region to precisely classify abnormal placentation.

The placenta is a composite organ of trophectoderm–derived cells and cells that are derived from the Inner Cell Mass (ICM)/epiblast, and a minor component comes from the mother in the form of her blood. The Inner Cell Mass (ICM)/epiblast–derived components are the amnion, the umbilical cord, and the mesodermal components of the chorion. The amnion and chorion that line the amniotic cavity are incompletely fused, and together, they are called “reflected membranes;” the amnion and chorion that line the placental disk proper are called chorionic plate. The amnion is embryologically continuous with the epithelium of the umbilical cord, where it firmly fuses during development and cannot be dislodged. The amnion is composed of a layer of epithelial cells resting on a basement membrane over a thin layer of connective tissue. The chorion is juxtaposed with chorionic connective tissue and at term includes atrophied remnants of villi and associated fetal blood vessels. The chorion is interdigitated with maternal decidua and its associated blood vessels. The umbilical cord consists of an amniotic epithelium, two arteries, and one vein embedded in a matrix called Wharton’s Jelly. The villus parenchyma makes up most of the placenta and consists of 40–60 trophoblast villi. The trophoblastic villus is the functional unit of placenta where diffusion and active transport of nutrients and waste products takes place. The maternal side of villus parenchyma includes a thin basal plate corresponding to the maternofetal junction. The basal plate is made up of trophoblasts, interposed fibrinoid, and the endometrial components (stromal and fibroblast–like cells, as well as some macrophages, veins, and arteries).

2. Umbilical Cord: unique connection between the fetus and the placenta with multifunctional peculiarities

The placenta is a discoid reddish–brown structure attached to the uterine wall that binds the fetus to the mother via the umbilical cord. The umbilical cord forms the only connection between the placenta and the developing fetus. It is surrounded by the amnion, and normally contains a pair of umbilical arteries and an umbilical vein supported by loose connective tissue, the Wharton’s jelly. Wharton’s jelly is a special substance contained within the umbilical cord which serves to protect the vessels from trauma by acting as a cushion. A true umbilical knot develops when a fetus slips through a loop in the umbilical cord. The umbilical vessels carry blood to and from the fetus and placenta, and thus, are critical to the survival of the fetus [Karakecili et al., 2017].

The umbilical cord with its constituent tissues is vulnerable to a number of insults that may alter cord morphology, diminish cord flow, and ultimately compromise fetal nutrition. Thus, an investigation of the underlying mechanisms of the development of cord morphology and possible pathologies associated with it may provide insight regarding fetal growth in the intrauterine environment and have an impact on fetus development [Antoniou et al., 2011].

Being the principal connection between the fetus and the placenta, the umbilical cord provides the oxygen, nutrients and fluids necessary for fetus’s life in utero. The cord and its constituent tissues, an outer layer of amnion, porous Wharton jelly, two arteries, and one vein, are designed to provide and maintain the blood flow to the developing fetus. The outer amnion layer may regulate fluid pressure within the umbilical cord. The porous, fluid filled Wharton’s jelly likely acts to prevent compression of the vessels. Blood flow is regulated by smooth muscle surrounding the arteries that is intermingled with a collagen based Extracellular Matrix (ECM). Mechanosensory communication between cells and the Extracellular Matrix (ECM) may likely result in cords possessing abnormal physical dimensions, impaired hemodynamics, and altered composition within the umbilical cord tissues [Ferguson and Dodson, 2009].

Although it is established that the umbilical cord is one of the most vital components of the fetal anatomy, it should be highlighted with particular emphasis that is still one of the least–studied fetal structures, consequently, the researchers and clinicians should focus almost exclusively on its peculiarities and hidden complexities, closely interconnected with the extensive role of the umbilical cord in feto–maternal interaction. Understanding the essential peculiarities of the umbilical cord and its integrative role in feto–maternal interaction has vital implications for its developmental alterations which lead to the hidden complexities and negative consequences for developing fetus. Given that the umbilical cord is vulnerable to a number of abnormalities that may occur during pregnancy, labor, or delivery, it is important to investigate the underlying mechanisms of the development of the umbilical cord’s morphology and possible pathologies closely associated with it, because this may provide transparency into insight regarding fetal growth within the intrauterine environment and its impact on fetus’s life and on later life of the baby. For instance, some umbilical cord’s abnormalities predispose the fetus to stasis–induced vascular ectasia and thrombosis, thus leading to vascular obstruction and adverse neonatal outcome [Tantbirojn et al., 2009].

Modern embryology theories’ paradigms correlate with close scientific focus given to normal and abnormal morphological aspects of the umbilical cord. Some of the morphological aspects of the umbilical cord, such as its length, knots, insertion to the placenta, number of vessels, and twisting, have been associated with pathological consequences [Malpas and Symonds, 1966; Benirschke and Kaufmann, 1995; Heifetz, 1996; Ercal et al., 1996; Tantbirojn et al., 2009]. At term, the typical umbilical cord length is 55–60 cm [Heifetz, 1996], but it should be mentioned that basically there are two length abnormalities of the umbilical cord: particularly, there can be found abnormally long cords (70–130 cm) and abnormally short cords (30–40 cm) [Sarwono et al., 1991].

2.1. Morphological aspects of the umbilical cord: length of the umbilical cord in close focus

The length of the umbilical cord varies considerably. The factors controlling cord length have remained obscure and many studies have failed to demonstrate a correlation with several other fetal or maternal characteristics. Interestingly, studies involving the umbilical cord length’s abnormalities have emphasized that long or short umbilical cords can be the main cause of hematomas and thrombosis of cord vessels and the surface of the placenta, thus causing fetal hypoxia, damage to the central nervous system, or even fetal death [Benirschke, 1994; Yuan Zhang et al, 2011]. The risk of complications increased parallel with cord length. More detailed representation of the umbilical cord’s length correlation with the fetus’s pathologies were given by Benirschke K. (1994) in his study “Obstetrically important lesions of the umbilical cord”, where the umbilical cord’s length is an excessively essential indicator of the fetus’s well–being. Excessively long or short umbilical cords may be the cause of hematomas and thrombosis of cord vessels and the placental surface, thus causing fetal death and/or thrombocytopenia. In other cases, fetal hypoxia and central nervous system damage are possible outcomes. Thrombosis is also frequently induced by velamentous insertion of the cord, as are hemorrhages when the membranous vessels rupture during parturition. Entangling and knotting of the cord, especially of excessively long cords, may lead to similar lesions and fetal death. It was recognized recently that prolonged meconium exposure to the surface of the cord can cause partial necrosis of umbilical vessels and cord ulceration. The noxious moiety of meconium also causes contraction of the umbilical vessels, leading to fetal hypoperfusion and hypoxia. A structure at the fetal end of the cord and excessive spiralling of a very long umbilical cord are often present in cases of unexplained fetal demise, especially in early pregnancy. Less common abnormalities are obstruction of the circulation by amnionic bands and varices [Benirschke, 1994].

Consequently, the newborns with excessively long umbilical cords have a significantly higher likelihood of abnormalities on brain imaging and abnormal neurological follow–up in later life [Baergen et al., 2001]. Corresponding umbilical cord pathologic reports reviewed that excessively long umbilical cords were associated with fetal loss, long–term neurological complications, and fetal thrombotic vasculopathy [Taweevisit and Thorner, 2010]. Short umbilical cords were also significantly associated with certain pathologies. The presence of a short umbilical cord has been associated with antepartum abnormalities and risk factors for complications of labor and delivery. Being an informative pathological marker, the short umbilical cord indicates such complexities as congenital malformations, fetal distress and death within the first year of life [Krakowiak et al., 2004]. Several studies [Miller et al., 1981; Miller et al., 1982; Moessinger et al., 1982] have implicated a relationship between the presence of oligohydramnios during pregnancy and the subsequent development of a short umbilical cord. Miller et al. [Miller et al., 1981; Miller et al., 1982] hypothesized that the umbilical cord grows in response to tensile forces exerted on the cord by fetal movements. Previous studies of the association of short cords with malformation sequences and fetal problems have defined several groups of such sequences and problems among infants including stillborns and those who died shortly after birth due to multiple severe anomalies. These include ADAM sequence, cyllosomus/pleurosomus, acephalus–acardia, presumed primary defect of the umbilical cord and abdominal wall formation, schisis association, and reduced fetal movement [Miller et al., 1981; Grange et al., 1987]. Such anomalies are usually multisystem disorders, although they principally involve the central nervous system, limbs, and cardiovascular system or are associated with defects in the formation of the anterior abdominal wall. Intriguingly, but controversial results were received by Krakowiak et al. (2004), what makes the previous results the disputable issue: malformations of the central nervous system were not associated with the occurrence of short cords, and the association of musculoskeletal malformations was modest [Krakowiak et al., 2004].

It can be concluded that, multivariate analyses of the studies umbilical cords have shown that the pathogenesis of excessively long or short umbilical cords remains unclear and needs further investigation. One inclusive hypothesis to explain the ontogeny of the umbilical cord is the “stretch hypothesis,” which attributes the development of a long or short umbilical cord to intrauterine constraint [Miller et al., 1981; Miller et al., 1982].

2.2. Morphological aspects of the umbilical cord: knots of the umbilical cord in close focus

Less common but with potentially devastating consequences is the occurrence of umbilical cord knotting [Antoniou et al., 2011]. True knots of the umbilical cord arise from rotating movement of the fetus in uterus, mostly in the 1^stand 2^nd trimester of pregnancy (especially between the ninth and twenty–eighth weeks of gestation).

Numerous studies have presented the most essential factors and parameters that would be predictive for the occurrence of umbilical cord knotting, indicating that among the predisposing factors for umbilical cord knotting pathology occurrence are: a long umbilical cord, polyhydramnios, small fetus, excessive fetal movements and monoamniotic twin pregnancy [Heifetz, 1996; Maher and Conti, 1996; Sherer, 1997; Sherer and Anyaegbunam, 1997; Hershkovitz et al., 2001; Dias et al., 2010; Lewi 2010], but the clinical significance of true umbilical cord knots is unclear. Consequently, it needs transparent scientific investigation which would highlight the multifactorial causes, which would be the basis for further inclusive interpretation of the received results [Maher and Conti, 1996; Hershkovitz et al., 2001].

Umbilical cord knotting may be defined as entwining of a segment of umbilical cord, usually without obstructing fetal circulation and commonly result from fetal slippage through a loop of the cord [Hershkovitz et al., 2001]. The umbilical cord knots were associated with grand multiparity, chronic hypertension, hydramnios, cord prolapse, and cord around the neck [Hershkovitz et al., 2001]. When the true knot remains tight, it may impede the circulation of the fetus and may result to fetal death in utero especially in labor. The incidence of true knot of the umbilical cord is not only very low but it is often undiagnosed antenatally when present despite the availability of prenatal ultrasonography [Antoniou et al., 2011].

Umbilical cord knots in general can be classified as true or loose. The exclusion criteria of this classification are the following: true knots are identified with increased tension and thus with a higher risk for obstetric and neonatal outcome intervention, loose knots can tighten during pregnancy due to fetal movements, or during labour, leading to decreased blood flow in the cord [Scioscia et al., 2011]. It is essential that true knots should be distinguished from false knots, which are caused by the umbilical vein twisting around the artery, leading to localized thickening of Wharton’s jelly. A true knot, when untied, shows compression with a groove at the knot site, loss of Wharton’s jelly, and persistence of structural change after being untied [Srinivasan and Graves, 2006].

The list of risk factors for a true umbilical knot includes: multiple pregnancy including twins, a long umbilical cord, fetuses that are small for their gestational age, polyhydramnios, and monozygotic twins [Karakecili et al., 2017]. Many abnormalities have been observed in morphology and pathology of umbilical cords [Szczepanik and Wittich, 2007]. Risk factors include relatively large uterine size and fluid volume (hydramnios, polyhydramnios), which may lead to a true umbilical knot resulting from excessive and exaggerated fetal movements [Karakecili et al., 2017].

2.3. Morphological aspects of the umbilical cord: insertion to the placenta

Variations in the site of the umbilical cord insertion to the fetus and the placenta and its relationship with later development generally are categorized as placental insertions in the center, off the center, on the edge, or in the membranes. An insertion in the center of the placenta is more favorable compared to a marginal one that appears toward the edge of the plac2enta. The marginal insertion, which is most commonly referred to as velamentous insertion, is the insertion into the membranes. This type of insertion is associated with the worst outcomes. In a velamentous insertion, the veins traverse the membranes before they come together into the umbilical cord, and the umbilical cord inserts into the chorioamniotic membranes rather than on the placental mass [Antoniou et al., 2011].

2.4. Morphological aspects of the umbilical cord: number of vessels

The growth of the fetus mainly depends on the uterine and fetoplacental blood flows, which must be adequate to ensure exchanges between maternal and fetal compartments through the placental “barrier.” Fetoplacental vascularization is original in some respects and possesses its own morphologic, structural, and functional characteristics. One aspect of this originality is that placental and umbilical vessels lack autonomous innervation; consequently, regulation of fetoplacental vascular tone must depend on the balance between vasoconstrictive substances such as thromboxane A2, angiotensin, and Endothelins (ET) and vasodilator agents such as prostacyclin and Nitric Oxide (NO), which are either produced locally or conveyed to their site of action through the bloodstream [Corinne Cudeville et al., 2000].

The umbilical cord connects the fetus to the placenta. The umbilical cord achieves its final form by the 12t^h week of gestation and normally contains two arteries and a single vein, all embedded in mucous connective tissue––Wharton’s jelly, in other words [Spurway et al., 2012], within the umbilical cord are two arteries and one vein—thus, three vessels in total. The umbilical vein carries oxygenated blood from the placenta to the left portal vein in the fetal liver. The 2 umbilical arteries are continuous with the internal iliac arteries and carry deoxygenated blood from the fetus to the placenta. The two arteries send blood with waste products from the fetus to the placenta, and the umbilical vein sends oxygen and nutrient–enriched blood to the fetus from the placenta. Often, only two vessels are grossly visible: one artery and one vein [Antoniou et al., 2011].

The umbilical cord arteries and vein are unlike their counterparts in the remainder of the fetal body as the umbilical cord vein transports oxygenated blood to the fetal heart while the arteries return oxygen–depleted blood to the placenta [Spurway et al., 2012]. The walls of the umbilical cord artery lack an internal and external elastic lamina and the adventitia found in other arteries is replaced by mucous connective tissue. The umbilical cord vein has a thickened muscularis layer with intermingling circular, longitudinal and oblique smooth muscle fibres as well as an internal elastic lamina. Likewise, the umbilical vein exhibits an unusually thick muscularis, with intermingling circular, longitudinal, and obliquely disposed smooth muscle fibers. Furthermore, an internal elastic lamina is present, which serves to distinguish the vein from the accompanying arteries. Mucous connective tissue, a form of loose connective tissue, is characterized by its copious ground substance, rich in sulfated proteoglycan, which embeds a profusion of collagenous fibers [Bergman et al., 2012]. In most cases the umbilical arteries twist over the vein [Spurway et al., 2012].

2.4.Morphological aspects of the umbilical cord: the umbilical cord twisting [Umbilical cord torsions]

The cause of excessive umbilical cord twisting and stricture is unknown. The umbilical cord twist is an important feature of the umbilical cord. The umbilical cord is usually twisted on itself, with the number of turns ranging from a few to over 300 turns. The direction of this twist is usually left sided. Among the proposed reasons for this twisting are hemodynamic factors and fetal movements. Right sided twist is associated with the presence of a Single Umbilical Artery (SUA), congenital malformations, placenta praevia and stillbirths [Lacro et al., 1987].

A degree cord twisting is normal and may provide protection from compressive forces. Less spiraled cords are associated with an increased rate of complications [Strong et al., 1994]. Moderately twisted cords have been associated with a more favorable blood gas profile, less fetal entanglement, and better neonatal outcomes [Bender et al., 1978]. With excessive twisting, the protective effects are lost, and the risk of fetal hypoxia abounds. A normal degree of twisting can be differentiated from excessive, pathologic twisting by counting the number of twists and dividing by the cord length in centimeters. Using this method, an umbilical cord coiling index was developed which demonstrates an average of 0.2 twists/cm of cord length [Strong et al., 1994].

Umbilical cord complications are the most common cause for fetal demise in the third trimester [Larson et al., 1995]. Unfortunately, these complications are regarded as unpredictable and unpreventable and the consequences can be fatal for the fetus. Umbilical cord torsions can occur at any site of the umbilical cord. Umbilical cord torsions can either lead to chronic hypoxia with critically reduced blood flow, oligohydramnios and fetal growth retardation [Ben–Arie, 1995] or can acutely obstruct fetal–placental circulation with subsequent death. Furthermore, a multitude of torsions can occur without apparent sonographic signs of fetal retardation and that also in the case of multiple torsions intrauterine fetal death might be the first clinically apparent manifestation of this severe complication [Fleisch et al., 2008].

Conclusion

Implantation of the developing conceptus in the maternal uterus occurs by the end of the first week of pregnancy. Normal development and normal function of the placenta requires invasion of the maternal decidua by trophoblasts, followed by abundant and organized vascular growth. Extra embryonic trophoblast of the blastocyst attaches to the endometrial epithelium at the embryonic pole [Knoth and Larsen, 1972; Lindenberg, 1991].

The placenta is a critical organ during pregnancy, essential for the provision of an optimal intrauterine environment, with fetal survival, growth, and development relying on correct placental function. It must allow nutritional compounds and relevant hormones to pass into the fetal bloodstream and metabolic waste products to be cleared. It also acts as a semipermeable barrier to potentially harmful chemicals, both endogenous and exogenous.

The regulated growth of the placenta is critical for normal fetal growth and normal fetal development. Normal placental development relies upon the controlled invasion of fetal trophoblast into the spiral arteries in the maternal decidual tissue during the early stages of placentation. Inadequate trophoblast invasion and subsequent poor placental development is closely associated with disorders such as intrauterine growth retardation and maternal pre–eclampsia. Conversely, overexpression of the invasive phenotype by trophoblast may lead to a malignancy and choriocarcinoma.

A successful pregnancy is contingent on maternal tolerance of the immunologically foreign fetus. Prevalent diseases such as preeclampsia are thought to be due to an inappropriate immune response at the maternal–fetal interface. Despite intensive research, our understanding of the mechanisms that control trophoblast invasion in normal, let alone abnormal pregnancy, are still poorly understood. This is partly due to difficulties in obtaining “true” placental bed biopsies and most investigators have relied on in vitro models of trophoblast invasion. Clearly interpretation of such studies must be tempered with a degree of caution.

Both short and long umbilical cords have been associated with an increased risk of intrapartum complications [Rayburn et al., 1981]. The mechanisms and factors controlling umbilical cord length have remained incomprehensible and many studies have failed to demonstrate a strong correlation with several other fetal or maternal characteristics, consequently, there is no paradigm for exclusion criteria which can accurately determine this correlation. The risk of complications increased parallel with cord length. Both Excessively Long Umbilical Cord (ELUC) and Fetal Thrombotic Vasculopathy (FTV) have been associated with adverse perinatal outcomes, in particular, fetal loss and long–term neurological complications. The etiologies of these conditions are unclear and are likely multifactorial [Taweevisit, 2010].

The length of the cord is thought to reflect fetal movement in utero, often resulting in knotting. Reduced cord length is associated with constraint in utero, which is more likely to evoke intrauterine problems, with the fetus moving randomly within a confined space during pregnancy. Both short and long cords have been associated with hematomas and thrombosis of the cord vessels and the surface of the placenta, which could lead to damage of the fetal central nervous system and sometimes even fetal death. A knot can constrict the blood vessels and lead to fetal death. If the knot is loose, the fetal circulation is maintained, albeit at a diminished rate. The tightening knot can occlude the circulation between the placenta and fetus and therefore obstruct the circulation of food supply, leading to compromised feeding [Antoniou et al., 2011].

Intrauterine diagnosis of true knot of the umbilical cord can be a challenge for the obstetricians. Knots of the umbilical cord usually are not associated to an increased risk of obstetric intervention and neonatal outcomes because most of them are loose. It has been proved that true umbilical cord knots may be responsible for fetal compromise due to cord blood flow alternations. However, the loose umbilical cord knot may tighten during pregnancy due to fetal movements or during labor, leading to decreased umbilical blood flow and fetal distress, asphyxia and death. Thus, cautious and careful monitoring of pregnancy cases of true knot of the umbilical cord is recommended.

True umbilical cord knot is one of the abnormalities of the umbilical cord which is a rare occurrence. Constriction of a true knot of the umbilical cord may lead to obstruction of the fetal circulation and subsequent intrauterine death. Accurate and timely diagnosis of a true umbilical knot may reduce abrupt and unpredictable fetal distress. It should be emphasized that a true knot does not have a specific ultrasonographic image associated with it. Moreover, this pathology may be diagnosed in the presence of either normal or increased amniotic fluid volume. The alterations in the umbilical cord should be reviewed concerning anatomical abnormalities, disease, or chromosomal alterations using sonography, Doppler ultrasound, histology, and biomolecular and biochemical analyses.

The variance in cord characteristics (cord insertion and number of vessels) is predetermined by both shared and individually unique environmental factors, explain most of the variance in cord characteristics. The site of the placental implantation is thought to be important: The upper part of the uterus is the most favorable area for placental implantation, because it is rich in blood and therefore nutrients and oxygen. The lower part of the uterus, however, is not; thus, more risks are associated with a low implantation. However, certain conditions may predispose to a low implantation. Low implantations of placenta have a strong tendency to migrate upward toward the body and the base of the uterus, which can shift the cord toward a marginal or even velamentous cord insertion. It is believed that the occurrence of marginal cords, with no signs of genetic predispositions, is specific to the vascular supply and peculiarities of the uterus, including uterine scars, infections, or prior pregnancy complications [Antoniou et al., 2011].

The prevention of this complication is virtually impossible. The general consideration of umbilical cord complications as underlying cause for chronic intrauterine hypoxia with reduced fetal movements, growth retardation or oligohydramnios should be mandatory.

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The Placenta: Unique Multifunctional “Tree of Life” for the Growing Fetus

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