Which statement regarding the structure and function of the placenta is correct?

Philos Trans R Soc Lond B Biol Sci. 2015 Mar 5; 370(1663): 20140066.

Abstract

The placenta is arguably the most important organ of the body, but paradoxically the most poorly understood. During its transient existence, it performs actions that are later taken on by diverse separate organs, including the lungs, liver, gut, kidneys and endocrine glands. Its principal function is to supply the fetus, and in particular, the fetal brain, with oxygen and nutrients. The placenta is structurally adapted to achieve this, possessing a large surface area for exchange and a thin interhaemal membrane separating the maternal and fetal circulations. In addition, it adopts other strategies that are key to facilitating transfer, including remodelling of the maternal uterine arteries that supply the placenta to ensure optimal perfusion. Furthermore, placental hormones have profound effects on maternal metabolism, initially building up her energy reserves and then releasing these to support fetal growth in later pregnancy and lactation post-natally. Bipedalism has posed unique haemodynamic challenges to the placental circulation, as pressure applied to the vena cava by the pregnant uterus may compromise venous return to the heart. These challenges, along with the immune interactions involved in maternal arterial remodelling, may explain complications of pregnancy that are almost unique to the human, including pre-eclampsia. Such complications may represent a trade-off against the provision for a large fetal brain.

Keywords: placenta, fetal growth, pregnancy

1. Introduction

For the nine months of its intrauterine existence, the human fetus is totally reliant on the placenta, a transient extracorporeal organ that interfaces with the mother, to sustain and protect it. This dependency is reflected in the way that various societal groups consider the placenta as a twin or guardian angel, and venerate it as a sacred object [1,2]. Hence, the placenta is often accorded ritual burial, for in some beliefs the soul must be reunited with its placenta before being able to pass through to the afterlife.

What then is the placenta? The wide variety of morphological forms seen among mammals makes the organ hard to define, but the comparative placentologist Harland Mossman captured the essence by stating ‘The normal mammalian placenta is an apposition or fusion of the fetal membranes to the uterine mucosa for physiological exchange’ [3]. This definition rightly recognizes physiological exchange as the prime function of the placenta, but it fails to emphasize the other tasks the organ has to perform in order to achieve that function; for example, its remodelling of the uterine spiral arteries in early pregnancy to establish the maternal circulation, its endocrine activity that has a profound effect on maternal metabolism, and its metabolic role in providing protected substrates for the fetus. This review provides a brief overview of the development and function of the human placenta, so that its pivotal role in supporting fetal development, including the large brain, can be appreciated more fully in the context of the theory of pelvic constraint.

2. Structure and development of the human placenta

The placenta and associated extraembryonic membranes are formed from the zygote at the start of each pregnancy, and thus have the same genetic composition as the fetus. The two principal tissue sources are the trophectoderm that forms the wall of the blastocyst, and the underlying extraembryonic mesoderm. The trophectoderm differentiates into trophoblast, which in turn forms the epithelial covering of the placenta and also gives rise to the subpopulation of invasive extravillous trophoblast cells. The extraembryonic mesoderm forms the stromal core of the placenta, from which originate the fibroblasts, vascular network and resident macrophage population.

The mature placenta has been described in detail elsewhere [4,5], but is a roughly discoid organ, on average 22 cm in diameter, 2.5 cm thick at the centre and weighing approximately 500 g. Its surfaces are the chorionic plate that faces the fetus and to which the umbilical cord is attached, and the basal plate that abuts the maternal endometrium. Between these plates is a cavity, the intervillous space, into which 30–40 elaborately branched fetal villous trees project. Each villous tree arises from a stem villus attached to the deep surface of the chorionic plate, and branches repeatedly to create a globular lobule 1–3 cm in diameter. The centre of a lobule is located over the opening of a maternal spiral artery through the basal plate. Maternal blood released at these openings percolates between the villous branches before draining into openings of the uterine veins and exiting the placenta. Each lobule thus represents an independent maternal–fetal exchange unit.

The final branches of the villous trees are the terminal villi. These present a surface area of 12–14 m2 at term, and are richly vascularized by a fetal capillary network. The capillaries display local dilations, referred to as sinusoids, which bring the endothelium into close approximation to the covering of trophoblast. This is locally thinned, and the diffusion distance between the maternal and fetal circulations may be reduced to as little at 2–3 µm. The morphological resemblance of these structures, termed vasculosyncytial membranes, to the alveoli of the lung has led to the assumption that they are the principal sites of maternal–fetal exchange. Terminal villi are formed primarily from 20 weeks of gestation onwards, and elaboration of the villous trees continues until term [6].

The epithelial covering of the villous tree is the syncytiotrophoblast, a true multinucleated syncytium that presents no intercellular clefts to the intervillous space. This arrangement may assist in preventing the vertical transmission of pathogens from the maternal blood [7], but may also facilitate regional specializations of the syncytiotrophoblast. Because of its location, the syncytiotrophoblast is involved in many of the functions of the placenta, such as the synthesis and secretion of large quantities of steroid and peptide hormones, protection against xenobiotics and active transport. Hence, it has a high metabolic rate, and accounts for approximately 40% of the total oxygen consumption of the feto-placental unit [8]. Interposing such an active tissue between the maternal and fetal circulations potentially reduces the oxygen available for the fetus, and so the syncytiotrophoblast shows regional variations in thickness around the villous surface, being very thin and devoid of organelles at the site of vasculosyncytial membranes and thicker over non-vascular parts of the villous surface. Having no lateral cell boundaries may facilitate flow of the syncytioplasm, and so help to optimize oxygen supply to the fetus [9].

The syncytiotrophoblast is a highly polarized epithelium, bearing a dense covering of microvilli on its apical border. The projections provide a surface amplification factor of 5–7× for insertion of receptor and transporter proteins. At the base of each microvillus is a clathrin-coated pit, which is capable of forming a coated vesicle for the transport of macromolecules across the syncytiotrophoblast [10].

The syncytiotrophoblast is a terminally differentiated tissue, and its expansion during pregnancy is achieved by the fusion and incorporation of underlying mononuclear progenitor cytotrophoblast cells that rest on the underlying basement membrane. Fusion is a complex event that is still not fully understood, but involves exit of the progenitor from the cell cycle, the formation of gap junctions with the syncytiotrophoblast, externalization of phosphatidylserine and the expression of two endogenous retroviral proteins that entered the primate genome 25 and more than 40 million years ago [11,12].

3. Placental transport

The absence of intercellular junctions in the syncytiotrophoblast layer suggests that exchange must take place through the apical and basal plasma membranes, although there are two possible exceptions. First, the presence of water-filled transtrophoblastic channels has been postulated. The main evidence for such channels is that the human placenta is freely permeable to solutes of 1350–5200 daltons, whereas in the epitheliochorial placenta of the sheep diffusion is restricted to molecules of more than 400 daltons [13,14]. By measuring the transplacental flux of four permeants of different molecular sizes infused into patients prior to elective caesarean section, it was concluded that pores of different sizes must exist in the human syncytiotrophoblast [15]. However, the putative channels have never been visualized in the human [16], although this lack may reflect the complexity of the syncytioplasm and the limitations of current imaging techniques. Second, it is well recognized that there are small, scattered defects in the syncytiotrophoblastic surface of all human placentas, leading to deposition of fibrin plaques [17,18]. In this context, the plaques represent a possible route for the diffusion of hydrophilic molecules, whereas in broader terms they may also be potential portals for the ingress of maternal immune cells and the vertical transmission of pathogens. Immunohistochemical studies have localized transfer of alpha-fetoprotein to these sites [19], suggesting they may play a significant role physiologically.

Exchange across the intact placental membrane can occur through three main processes: diffusion, transporter-mediated mechanisms and endocytosis/exocytosis.

The rate of diffusion of an uncharged molecule is determined by Fick's law of diffusion, and so is proportional to the surface area for exchange, the diffusivity of the molecule in question and its concentration gradient, and inversely proportional to the diffusion distance between the circulations. Given the importance of these structural parameters, it is not unreasonable to assume that the requirements for diffusional exchange, and in particular oxygen exchange, are the principal drivers of placental architecture. Hence, the elaboration of terminal villi and vasculosyncytial membranes as gestation advances will increase the diffusing capacity of the organ. This view is supported by the fact that the specific theoretical diffusing capacity (ml per min per kPa per kg fetus) of the placenta for oxygen estimated stereologically remains constant across gestational age [20]. Furthermore, a reduction in the mean thickness of the villous membrane is observed in placentas from pregnancies at high altitude, enhancing the theoretical diffusing capacity [21].

In addition to these structural parameters, the exchange of charged molecules will be influenced by any electrical gradient existing between the maternal and fetal circulations. In the human, a small but significant potential difference of −2.7 ± 0.4 mV fetus negative has been measured in mid-gestation [22], reducing to zero or close to it at term [23]. A potential difference also operates across the microvillous membrane of the syncytiotrophoblast, decreasing between the early (median −32 mV) and late first trimester (median −24 mV), with a small subsequent fall to term (−21 mV). These data suggest that the driving force for cation flux into the syncytiotrophoblast decreases, and that for anions increases, as pregnancy advances.

Diffusion of small, relatively hydrophobic molecules, such as the respiratory gases, across the plasma membrane occurs rapidly. Hence, their flux depends more on the concentration gradient across the villous membrane than on its surface area or thickness. The concentration gradient, in turn, is determined in part by maternal and environmental factors, but is predominantly influenced by the rate of blood flow across the membrane. Hence, the exchange of such molecules is referred to as being ‘flow-limited’. Impairment of the uterine or umbilical circulations can therefore have a profound impact on the rate of fetal growth. By contrast, the concentration gradient for lipid insoluble (hydrophilic) molecules, such as glucose, that do not diffuse across plasma membranes so easily is often more stable. In this case, the structural parameters of the villous membrane are more significant, and exchange is said to be ‘membrane- or diffusion-limited’.

To aid the exchange of hydrophilic or charged molecules, transporter proteins may be inserted into the plasma membrane. Transporter proteins form a large and diverse family, but share common features such as substrate specificity, saturation kinetics and the ability to be competitively inhibited [24]. Transporter proteins may allow exchange down a concentration gradient at a faster rate than simple diffusion alone, often referred to as facilitated diffusion. The classic example in the placenta is the GLUT family of transporters handling glucose. Alternatively, they can enable exchange of molecules, such as amino acids, against a concentration gradient, referred to as active transport, which is an energy-dependent process. Expression of the genes encoding transporter proteins is, in part, under endocrine control, and leptin upregulates glucose and amino acid transporters, facilitating nutrient transfer [25]. In addition, one of the major benefits of transporter-mediated exchange is that under adverse conditions the rate can be modulated by altering the number of proteins inserted into the plasma membrane [26]. Thus, if the surface area for exchange is reduced experimentally in mice, or the mother is subjected to undernutrition, placental expression of certain amino acid transporters is increased, enhancing the flux [27,28]. Full details of the signalling pathways involved are not available at present, although experimental data implicate placental Igf2 [29].

Endocytosis is the process by which invaginations form at the apical cell surface, pinch off, and then move deeper into the cytoplasm. There, they may fuse with vesicles of the lysosomal pathway, or traverse the cell and fuse with the basal surface in the process of exocytosis. The former delivers nutrients for breakdown by proteolytic enzymes molecules and use by the cell, whereas the latter represents a transport pathway. Both are active in the syncytiotrophoblast of the human placenta [30,31]. During the first trimester, a number of proteins of maternal origin accumulate in the coelomic and amniotic fluids [32], whereas later in pregnancy, immunoglobulin G (IgG) crosses the placenta by this mechanism [24]. Specificity and the ability to avoid lysosomal degradation during the endocytosis phase may be provided by the presence of receptors for IgG in the microvillous membrane invaginations and vesicles.

4. Establishing the maternal–placental circulation

For effective transplacental exchange, there must be matched perfusion in the maternal and fetal placental circulations, especially for those hydrophobic molecules whose transfer is ‘flow-limited’. Establishing the maternal circulation to a haemochorial placenta, such as the human, where the maternal–fetal interface is represented by maternal blood bathing the trophoblast surface is a major haemodynamic challenge. It requires the trophoblast to tap into branches of the maternal uterine arteries that carry blood at a higher pressure than the fetus can ever generate. Hence, there is a danger that the fetal capillaries within the terminal villi will be compressed, impeding the umbilical circulation and preventing the formation of vasculosyncytial membranes [33]. Equally, the high velocity of maternal arterial blood flow can potentially cause mechanical damage to the delicate villous trees [34], with high shear rates also causing oxidative stress [35]. In many mammals, these dangers are avoided as there is either no or only limited invasion of the maternal tissues by the trophoblast, so-called epitheliochorial and endotheliochorial placentation respectively [36]. The trophoblast is simply apposed to the uterine epithelium or the underlying stromal matrix, and the maternal blood is retained within the uterine vascular network.

In all mammals, the uterine arteries undergo dilation during pregnancy in order to meet the metabolic demands of the feto-placental unit, and this is mediated by a combination of endocrine and local flow-dependent responses. In addition, in those species with a haemochorial placenta the final branches that deliver the blood to the placenta undergo considerable remodelling, resulting in their dilation as they approach the organ. In the human, data collected from pregnant hysterectomies near term indicate the diameter of the spiral arteries increases from approximately 0.5 mm at the endometrium/myometrium boundary to approximately 2.4 mm at their opening through the basal plate [37]. Mathematical modelling based on these dimensions predicts that as a consequence the velocity of maternal blood flow will reduce by an order of magnitude, from 2–3 m s−1 to approximately 10 cm s−1 [35].

The remodelling process involves the loss of smooth muscle cells from the walls of the spiral arteries, either through dedifferentiation or apoptosis, and their replacement by an inert, amorphous fibrinoid material [38,39]. The molecular mechanisms involved are still unclear, but it is now recognized that there is an initial phase of endocrine priming followed by a second phase that is dependent on the presence of extravillous trophoblast cells [40,41]. Extravillous trophoblast cells are most common during the first trimester of pregnancy, and arise from the tips of anchoring villi that attach the villous trees to the endometrium. The cells proliferate and then migrate away from the placenta, either down the lumens of the spiral arteries or through the endometrial stroma. Along the latter pathway, they interact with maternal immune cells, particularly the uterine natural killer (uNK) cells of the innate immune system. The uNK cells accumulate in the endometrium in the late secretory phase of the non-pregnant cycle, and are particularly numerous around the early implantation site. Despite their name, uNK cells do not engage in killing the migrating trophoblast cells. Rather, it is thought that upon appropriate stimulation they release proteases and cytokines that regulate trophoblast migration and mediate the arterial remodelling [42–44]. There is a carefully orchestrated dialogue between the two cell types involving polymorphic HLA-C ligands on the trophoblast and killer-cell immunoglobulin-like receptors (KIRs) on the uNK cells. Certain combinations of ligand and receptor are associated with an increased risk of complications of pregnancy, including miscarriage, pre-eclampsia and growth restriction [45].

Deficient remodelling of the spiral arteries has been associated with the ‘great obstetrical syndromes’ [46]. The mechanistic link is strongest in the case of pre-eclampsia, when the resultant malperfusion of the placenta is thought to cause oxidative stress [47]. Oxidative stress is able to stimulate the release of pro-inflammatory cytokines and angiogenic regulators from the syncytiotrophoblast, which in turn leads to activation of the maternal endothelium and hence the pre-eclamptic syndrome [48,49]. Recently, closely related endoplasmic reticulum stress has been identified in placentas from cases of early-onset pre-eclampsia [50], and also normotensive fetal growth restriction [51]. One of the consequences of endoplasmic reticulum stress is the suppression of protein translation, which in vitro leads to a reduction in cell proliferation rate. Hence, we speculate that placental endoplasmic reticulum stress is principally causally associated with growth restriction [52], although at high levels the same pathways can also contribute to activation of pro-inflammatory responses [53].

These stresses may be exacerbated in the human by the adoption of bipedalism, for in the upright position the pregnant uterus compresses the inferior vena cava against the lordosis of the lumbar vertebral column [54]. Such compression will reduce venous return to the heart and so compromise cardiac output. In addition, it will cause venous engorgement of the intervillous space, restricting arterial inflow and so potentially causing fluctuations in placental oxygenation. The effect is particularly marked when the mother is in the supine position [55], and fluctuations in oxygenation are a powerful stimulus for generation of placental oxidative stress [56].

5. Development of the fetal placental vascular tree

The placenta is one of the principal sites of vasculogenesis and angiogenesis, and in the space of nine months develops a vascular network over 500 km in length. Vasculogenesis starts with the differentiation in situ of haemangioblastic clusters within the mesenchymal core of early villi during the third week post-fertilization [57]. The clusters form cords of cells, usually located immediately beneath the trophoblastic basement membrane. Indeed, it is thought that their differentiation is induced by angiogenic growth factors secreted by the cytotrophoblast cells [58]. The cords gradually expand to form a network comprising endothelial cells linked by tight junctions, the molecular organization of which undergoes maturation with increasing gestational age [59]. Once a lumen is formed, haematopoietic stem cells delaminate from the inner surface of the clusters, and following further differentiation form a characteristic clump of tightly packed nucleated erythrocytes. These are not displaced until onset of the fetal placental circulation towards the end of the first trimester. The villous capillary network undergoes continued sprouting and remodelling throughout gestation [60], regulated most likely by angiogenic factors in response to changes in oxygen tension and mechanical stimuli such as shear stress and cyclic strain [57].

In the absence of an autonomic nerve supply to the placenta, vasomotor control of the fetal placental circulation is regulated by the local release of factors. The muscular arteries contained within the stem villi are thought to represent the principal resistance vessels within the placenta, and the gasotransmitters nitric oxide and carbon monoxide have been implicated in modulating their vasomotor tone [61,62]. Hydrogen sulfide has recently been demonstrated to be a potent vasodilator [63]. In this way, fetal blood flow within a lobule may be matched to maternal perfusion, ensuring maximal placental efficiency, although as yet there are no experimental data to support this suggestion.

6. Endocrine modulation of maternal metabolism

Glucose is the principal substrate for placental and fetal metabolism, and as discussed in §3, it crosses the placenta by facilitated diffusion. The flux to the fetus is thus critically dependent on the concentration gradient acting across the placenta as well as the density of transporter proteins in the trophoblastic membranes. Placental hormones modulate maternal metabolism in order to increase maternal blood glucose concentrations, and maximize transfer.

The placenta is a major endocrine organ, and placental hormones have diverse profound effects on maternal physiology and behaviour [64,65]. During early pregnancy, they drive an increase in food intake and energy storage, whereas towards term, they mobilize these reserves to support fetal growth and preparation for lactation [66,67]. The most important hormones in this respect are the family of closely related placental lactogens (hPL) and placental growth hormone (hGH) (96% amino acid sequence homology). Their importance for maternal–fetal allocation of resources is exemplified by the fact that evolution of the primates was associated with considerable duplication of the genes encoding these hormones [68]. This is in marked contrast to most genes that are involved in placental evolution, which are represented by single copies that have been recruited from other developmental systems [69]. In the human, there is a gene cluster on chromosome 17 that encodes five growth hormone-like proteins; hGH-N encoding pituitary growth hormone, hGH-V encoding placental growth hormone and hPL-A, hPL-B and hPL-L encoding placental lactogens. All except hGH-N are expressed in the syncytiotrophoblast, but most circulating hPLs originate from hPL-A and hPL-B.

Both progesterone and hPL are appetite stimulants, and maternal food intake increases by the end of the first trimester when the metabolic demands of the conceptus are still relatively low. The result is increased deposition of fat reserves, which represents a loss of the normal homeostatic mechanisms that regulate energy balance. Leptin secreted by adipose tissue normally feeds back on the hypothalamus to suppress intake, but pregnancy is a state of central leptin-resistance. During pregnancy, leptin is secreted in large quantities by the syncytiotrophoblast, regulated in part through human chorionic gonadotropin and 17β-oestradiol [25]. Expression levels correlate closely with maternal serum concentrations, peaking at the end of the second and during the early third trimesters. The hormone has local effects on placental transporter expression as well as central effects on appetite. Experimental data from rodent models indicate that placental lactogen and prolactin, secreted by the trophoblast and decidua, respectively, appear to mediate the central insensitivity [70]. These hormones also stimulate beta cell proliferation in the maternal pancreas during early pregnancy, increasing insulin concentrations and so again aiding fat deposition [67].

Later, in pregnancy, the mother develops insulin resistance, with an accompanying increase in lipolysis and in circulating triglycerides and free fatty acids. In the past, these changes have been attributed to placental lactogen and/or prolactin, but more recent evidence casts doubt on this assumption [66]. Instead, it appears that placental growth hormone may play a more important role. Placental growth hormone is secreted tonically by the syncytiotrophoblast, unlike the pituitary form that is secreted in a pulsatile fashion. The two variants differ in only 13 amino acids out of a total of 191, and the similarity is sufficient for the placenta to suppress maternal pituitary growth hormone production by mid-pregnancy. As its name suggests, it has strong growth promoting effects acting through GH receptors. Overexpression of the hormone in mice leads to a reduction in signalling through the insulin receptor secondary to altered expression of the p85 regulatory subunit of phosphatidylinositol 3-kinase [71]. Furthermore, there is a reduction in insulin-stimulated translocation of the transporter protein GLUT-4 to the plasma membrane of skeletal muscle, and a modest reduction in insulin receptors at the protein level. Collectively, these effects could explain the development of maternal insulin resistance.

Placental growth hormone is also an important regulator of insulin-like growth factor 1 [67,72]. Although this protein does not cross into the fetal circulation, it does have powerful effects on fetal growth. Maternal concentrations correlate with birthweight, and its actions are thought to be mediated through changes in maternal metabolism and nutrient partitioning, stimulation of placental morphogenesis, and an increase in maternal blood flow to the placenta [26,73].

7. Placental metabolism

Placentally induced changes in maternal blood flow, appetite and metabolism thus ensure a plentiful supply of nutrients to the placenta. However, the placenta has its own metabolic demands, and there is a danger that as it is interposed in the maternal–fetal nutrient pathway it may preferentially deplete the supply before it reaches the fetus. Indeed, it has been estimated that the placenta consumes 40% of the oxygen supplied to the feto-placental unit, with about one third supporting protein synthesis and another third supporting active transport and ionic pumping [8]. There are structural and metabolic aspects of the placenta that are likely to limit this potentially adverse effect. First, the formation of vasculosyncytial membranes ensures that there is only a minimal amount of syncytioplasm interposed between the maternal and fetal circulations. Mitochondria and other oxygen consuming organelles, such as the endoplasmic reticulum, are generally absent from these sites, and are concentrated in thicker areas of the syncytioplasm away from the fetal capillaries. By analogy with electrical circuitry, the formation of vasculosyncytial membranes places the metabolic demands of the placenta and fetus in parallel rather than in series as would be the case if the syncytiotrophoblast layer was uniformly thick over the villous surface.

Second, placental metabolism is heavily glycolytic even once the maternal circulation is established at the end of the first trimester [74]. Analysis of the coelomic fluid that is in communication with the placental tissues at 7–11 weeks of pregnancy showed evidence of anaerobic glycolysis, with a pH of 7.18 compared with 7.38 in the maternal serum, a lactate concentration of 0.6 compared with 0.3 mmol l−1, and a base excess of −7.8 mmol l−1 compared with −2.6 mmol l−1 [75]. Estimates based on placental tissues delivered at term and perfused in vitro suggest that 22% of the glucose consumed is converted to lactate even under conditions of high oxygenation [76]. Converting some of the glucose consumed to lactate rather than to carbon dioxide via the citric acid cycle may be beneficial for the fetus, for it is able to use lactate as a substrate, whereas the placenta is unable to do so. In this way, the placental metabolism may be setting aside resources for the fetus.

However, there are alternative means for regenerating the NAD+ necessary for maintaining glycolysis in early placental tissues besides fermentation to lactate. The phylogenetically ancient polyol pathways are highly active in the human early placenta, and sorbitol, inositol, erythritol, mannitol and ribitol are present in the coelomic fluid in high concentrations [77]. Many of the polyol pathways are closely integrated with the pentose phosphate pathway, which is important for the synthesis of nucleotides to support rapid cell proliferation. The pentose phosphate pathway also generates NADPH, which is essential for the regeneration of reduced glutathione and proper functioning of antioxidant defences. Hence, having a ready supply of glycolytic intermediates that can be diverted down these pathways will facilitate rapid growth of the placenta while conferring protection against free-radical-mediated damage.

Although glycolysis generates only a small fraction of the ATP per glucose molecule that can be achieved through oxidative phosphorylation, it may be beneficial in situations where resources are not limiting because it relies on simpler intracellular machinery [78]. Mitochondria are energetically costly to generate and maintain, and in view of the transient nature of the placenta, it may be more efficient to rely on glycolysis for much of energy production. Certainly, there is no shortage of glucose for the placental tissues during the first trimester as the endometrial secretions are carbohydrate rich and glycogen accumulates in the syncytioplasm [79,80].

This heavy reliance on aerobic glycolysis, also referred to as Warburg metabolism, will reduce the oxygen consumption of the trophoblast compared with what it would be if oxidative phosphorylation was more prevalent. Consequently, more oxygen is available for the fetus, along with protected resources, such as lactate.

8. The placenta as a selective barrier

The fetus requires its own unique microenvironment independent of maternal sex or stress hormones and environmental pollutants so that development of its neuroendocrine and gonadal systems is not compromised. Hence, the syncytiotrophoblast is equipped with a variety of enzymes and transporters that ensure the detoxification and efflux of xenobiotics, playing an equivalent role to hepatic cells in the adult. One of the best characterized examples is the enzyme 11-β-hydroxysteroid dehydrogenase 2 (11-βHSD2), which oxidizes maternal cortisol to the inactive metabolite cortisone. In this way, the placenta limits exposure to the potential harmful effects of maternal stress hormones, which when administered direct to the fetus causes reduced cell proliferation and growth restriction. The activity of placental 11-βHSD2 can be perturbed through reduced mRNA expression in pathological pregnancies associated with growth restriction [81,82], leading to hypercortisolaemia in the fetal circulation. This may impact adversely on the development of fetal organ systems, including the brain. It is notable that elevated levels of steroid hormones were recently found in the amniotic fluid of male babies who later developed autism, although whether the steroids were of maternal or fetal origin is unclear at present [83]. Sex-specific differences in placental 11-βHSD2 activity have been reported [84], and may potentially explain the increased risk of disorders, including autism, arising from developmental programming in males following adverse intrauterine experiences.

P-glycoprotein and members of the multidrug resistance protein family have been localized to the apical surface of the syncytiotrophoblast and to the endothelium of the villous capillaries at term [85]. These transporters mediate the ATP-dependent efflux of a wide range of anionic organic compounds, providing protection to the fetus against exposure to potentially noxious xenobiotics.

9. Conclusion

Fetal growth can only take place at a rate commensurate with that of the delivery of nutrients and oxygen by the placenta. There is now clear evidence that the placenta is not just a passive conduit from mother to fetus, but that it is able to respond to supply signals arising from the mother and demand signals emanating from the fetus [26,86]. The efficiency of placental exchange is governed by a complex interplay between placental growth, transporter protein expression, rates of placental blood flow, transmembrane concentration gradients and the metabolic demands of the placental tissues. This interplay is orchestrated by maternal, placental and fetal hormones, and under favourable conditions ensures an adequate supply to the fetus without overdepletion of maternal reserves. The relationship is best viewed as a dialogue to ensure mutual needs are met, rather than a conflict between two individuals. The haemochorial form of placentation displayed by the human provides the most intimate apposition of the maternal and fetal circulations of all the placental types, yet the evolutionary advantages are not immediately obvious. One benefit is that it is more freely permeable to hydrophilic solutes, which are thought to pass through water-filled transtrophoblastic channels. Although the great apes also share haemochorial placentation, trophoblast invasion is deepest in the human [87]. This is consistent with the theory that greater access to the maternal blood supply facilitates growth of our large fetal brain [88]. However, the deep invasion comes at a price, for it is associated with an increased risk of complications of pregnancy, such as pre-eclampsia [89]. Recent evidence shows these complications have, in part, an immunological basis [45], as explored in other contributions to this themed issue. Adoption of the upright posture may be another contributor, for it poses unique haemodynamic challenges to the placental circulations [90]. Hence, the interactions between bipedalism and human reproduction extend beyond the issue of pelvic constraint.

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