Placenta
Volume 30, Supplement , Pages 19-25, March 2009

Evolution of Factors Affecting Placental Oxygen Transfer

  • A.M. Carter

      Affiliations

    • Corresponding Author InformationTel.: +45 6550 3716; fax: +45 6613 3479.

Department of Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark

Accepted 10 November 2008. published online 15 December 2008.

Article Outline

Abstract 

A review is given of the factors determining placental oxygen transfer and the oxygen supply to the fetus. In the case of continuous variables, such as the rate of placental blood flow, it is not possible to trace evolutionary trends. Discontinuous variables, for which we can define character states, are more amenable to analysis. This is exemplified by factors contributing, respectively, to blood oxygen affinity and placental diffusing capacity. Comparative genomics has given fresh insight into the evolution of the beta-globin gene complex. In higher primates, duplication of an embryonic gene yielded HBG-T2, a gene that is expressed in the fetus and confers high oxygen affinity on its haemoglobin. A separate event in ruminants involved duplication of an adult gene, again resulting in a fetally expressed variant (HBB-T3) that conveys high oxygen affinity. In rodents and lagomorphs, where fetal and adult haemoglobin are not different, developmental regulation of 2, 3-diphosphoglycerate ensures the high oxygen affinity of fetal blood. Oxygen diffusing capacity is dependent on diffusion distance, which may vary with the type of interhaemal barrier. It has been shown that epitheliochorial placentation is a derived state and that the common ancestor of placental mammals probably had a placenta of the endotheliochorial type. Where evolutionary trends are implied for mammals as a whole or within orders such as primates they often accompany a switch in reproductive strategy that is manifested in a change of newborn state from poorly developed (altricial) to well developed (precocial).

Keywords: Beta-globin genes, Blood oxygen capacity, Endotheliochorial placentation, Epitheliochorial placentation, Haemochorial placentation, Haemoglobin oxygen affinity, Phylogeny, Placental diffusing capacity, Umbilical blood flow, Uterine blood flow

 

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1. Introduction 

It is self evident that each of type of placenta is designed to meet the oxygen requirements of the fetus that it serves. There is nonetheless reason to think that optimisation of placental gas exchange has followed a different course in different orders or families of placental mammals. This review will explore the factors that determine placental oxygen transfer and discuss how some of them have evolved. It will become apparent that for continuous variables, such as the rate of placental blood flow, we are as yet unable to trace evolutionary trends. Discontinuous variables, for which we can define character states, are more amenable to analysis. This will be exemplified with blood oxygen affinity, which revolves around evolution of the beta-globin gene, and placental diffusing capacity, which depends in part on the structure of the interhaemal barrier.

The focus will be on oxygen supply to the fetus near term of pregnancy. The placenta plays a different role during embryonic development up to and including organogenesis. The events of this period need to take place in a low oxygen environment [1]. Molecules such as embryonic haemoglobins are designed as much to protect cells from high PO2 levels as for oxygen delivery to tissues [2], [3]. Embryonic development occupies a greater part of gestation in a mouse than in a guinea pig. Murine rodents have adopted a reproductive strategy that leads to delivery of poorly developed or altricial young. This pattern is found in most small mammals; it implies a short gestation and usually is associated with a large litter size [4]. The alternative strategy, found in all large mammals, leads to delivery of well developed or precocial young. This requires a much longer gestation period and a smaller litter size. The human newborn is sometimes characterised as secondarily altricial because a baby is rather well developed at birth yet still entirely dependent on parental care [5].

Short gestations leading to delivery of altricial young typically have a growth spurt in the last few days of gestation. Evolution of the alternative strategy with a longer gestation and larger, precocial neonates may well require more complex adaptations to ensure an adequate oxygen supply. In a concluding section it will be discussed if there is evidence to support this prediction.

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2. Oxygen delivery and oxygen consumption 

The placenta facilitates gaseous exchange between the maternal and fetal circulations. The principal factors affecting placental exchange of oxygen have been reviewed extensively [6], [7], [8], [9], [10] and are summarised in Table 1. Oxygen delivery to the gravid uterus depends on the rate of uterine blood flow and the oxygen content ([O2]) of maternal arterial blood:

Since arterial blood is almost fully saturated, its oxygen content will depend on the haemoglobin concentration. This falls slightly during human pregnancy due to the volume expansion that is among the physiological adaptations to pregnancy [11].

Table 1. Principal factors affecting oxygen exchange across the placenta.
ParameterDescription
Maternal placental blood flowOxygen delivery to the placenta is the product of blood flow and the oxygen concentration in arterial blood
Oxygen capacity of maternal bloodDetermined by the haemoglobin concentration
Oxygen affinity of maternal bloodUsually expressed as the PO2 at which haemoglobin is 50% saturated (P50)
Fetal placental blood flowOxygen delivery to the fetus is the product of umbilical blood flow and the oxygen concentration in umbilical venous blood
Oxygen capacity of fetal bloodFetal blood often has a higher haemoglobin concentration and thus a greater oxygen capacity
Oxygen affinity of fetal bloodIn most mammals fetal blood has a greater affinity for oxygen than maternal blood
Direction of blood flowCountercurrent flow of maternal and fetal blood allows for the most efficient extraction of oxygen and occurs in the placentas of some but not all mammals
Oxygen diffusing capacity of the placentaA complex function it is in part dependent on diffusion distance, i.e. the thickness of the interhaemal barrier
Placental oxygen consumptionPlacenta is metabolically active and its oxygen consumption may equal or even exceed that of the fetus

In steady state, oxygen uptake corresponds to the combined oxygen consumptions of the fetus, placenta and uterine wall. It is found by:

An equivalent set of equations defines oxygen delivery to and uptake by the fetus.

Despite the adaptations discussed below, oxygen saturation in umbilical venous blood will be 80% or less. In most cases this is compensated by a higher haemoglobin concentration in fetal blood and thus a greater oxygen capacity. It should be noted that fetal oxygen uptake will be smaller than uterine oxygen uptake, the difference representing oxygen use by the uterus and placenta [12]. This is far from negligible. At term, oxygen consumption by the human or ovine placenta accounts for 40% of oxygen uptake by the gravid uterus [13], [14], [15]. At mid-pregnancy in sheep, where fetal oxygen consumption is smaller, uterine and placental oxygen uptake accounts for more than 80% of the total [16].

Rates of uterine and umbilical blood flow have been reliably determined in only a handful of species. To compare these values it is necessary to correct for fetal size. Rather more information is available on the haemoglobin content of maternal and fetal blood [17]. In both cases we end with a set of overlapping values that do not lend themselves to meaningful analysis in an evolutionary context. It is at best possible to compare closely related species such as the laboratory mouse (Mus musculus) and the Northeast African spiny mouse (Acomys cahirinus); the latter is a murine rodent that delivers precocial young [18].

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3. Blood oxygen affinity 

In most species examined, the oxygen affinity of fetal blood exceeds that of maternal blood and this facilitates placental oxygen transfer. In human pregnancy, if maternal and fetal bloods equilibrate at a PO2 of 30mm Hg, maternal haemoglobin will be about 50% saturated, whilst fetal haemoglobin will have achieved an oxygen saturation of about 80% [6]. This explains why fetal blood is quite highly saturated even at the low PO2 levels found in the umbilical vein. A common measure of oxygen affinity is the P50, the PO2 for 50% oxygen saturation. Values are available across a broad range of species [17], [19]. Once again they overlap quite closely and are difficult to analyse. However, the mechanisms underlying the high oxygen affinity of fetal blood differ and they tell quite an interesting story.

In adults each haemoglobin molecule is a tetramer composed of two alpha and two beta chains attached to a heme moiety. In mammals there are multiple isoforms of both chains, in each case determined by a cassette of genes. Here we shall deal only with the beta-globin genes, one of which finds expression as the gamma chain found in human fetal haemoglobin. The nomenclature of these genes has been changed recently [20]; for convenience the previous symbols are given in brackets.

The genome of the duck-billed platypus (Ornithorhyncus anatinus) [21] has been helpful in sorting out the evolution of beta-globins [22] (Fig. 1). There is a single beta-globin gene in amphibians and in the sauropsids, extant members of which include crocodiles and birds. This gene has undergone a series of duplication events that in eutherian mammals resulted in a cassette of five genes: HBE (epsilon), HBG (gamma), HBH (eta), HBD (delta) and HBB (beta) [23]. The HBE gene is highly conserved, expressed earliest in development and confers a high affinity for oxygen. The HBH gene was lost in three of the four major mammalian lineages, including that leading to the primates (Euarchontoglires).

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  • Fig. 1 

    Evolution of the beta-globin gene in vertebrates. In this hypothesis an ancestral gene was duplicated after amniotes diverged from mammals. One of the products (HBW, ω-globin) is found in extant monotremes and marsupials but was lost in other lineages. A further duplication in the common ancestor of marsupials and mammals resulted in embryonic (HBE, ɛ-globin) and adult (HBB, β-globin) forms. Further duplications in placental mammals gave rise, respectively, to globins expressed in the fetus (HBG, γ-globin) and adult (HBD, δ-globin). This resulted in a cassette of four genes. From ref. [22]. Copyright (2008) National Academy of Sciences, U.S.A.

3.1. Evolution of beta-globins in primates 

These genes are developmentally regulated. They are lined up on the same chromosome with a locus control region upstream [24]. The closer a gene is to the control region, the earlier it is expressed. Thus the HBE gene is expressed early in embryonic development. In the hypothetical primate ancestor, the next gene along was HBG [24], [25]. It too was expressed in the embryo. This is still the case in strepsirrhine primates (lemurs and lorises) such as the bush baby (Otolemur sp.). In the line leading to higher primates, however, the HBG gene was duplicated, yielding HBG-T1 (γ1-globin) and HBG-T2 (γ2-globin). The latter was initially silent but later acquired expression in both platyrrhine and catarrhine primates. The distance between the locus control region and HBG-T2 was now sufficient to allow expression of this gene in the fetus as the gamma chain found in fetal haemoglobin. It is a nice example of evolution leading to more efficient placental gas exchange.

To understand why the gamma chain confers greater oxygen affinity on haemoglobin, it must be recognised that the molecule has four principal ligands [26]. These are oxygen, carbon dioxide, hydrogen ion and 2, 3-diphosphoglycerate or DPG. When one of these ligands binds to haemoglobin, it decreases the molecule's affinity for the other three. This is the basis of the Bohr Effect that makes gas exchange in tissues so efficient. As haemoglobin binds carbon dioxide, its affinity for oxygen decreases and oxygen is offloaded. The opposite occurs in the lungs. Indeed, in the placenta, where fetal blood offloads carbon dioxide to maternal blood, there is a double Bohr Effect [6]. Oxygen affinity is also decreased by the binding to haemoglobin of DPG. The point about the gamma chain is that it has very low innate affinity for DPG and a correspondingly high affinity for oxygen [27].

3.2. Developmental regulation of blood oxygen affinity in rodents and lagomorphs 

Most common laboratory mammals are either rodents or lagomorphs. Together these two orders form the monophyletic clade Glires, which is the sister group to Primates [28]. Apart from tree shrews and colugos, they are our closest relatives. They do not, however, have a fetal haemoglobin. They do have an HBG gene, but it is close to the locus control region, so only expressed in the embryo. Throughout the major part of pregnancy the haemoglobin in fetal blood is identical to that in maternal blood [29].

Yet there is a difference in oxygen affinity. In rabbits the P50 value is 20mmHg in fetal blood against 29mmHg in maternal blood. The reason is that fetal red cells have an exceedingly low content of DPG, <1μmol/g Hb compared to 27μmol/g Hb in maternal red cells [29]. In the absence of this ligand, the haemoglobin molecule has a higher affinity for oxygen. A similar pattern can be discerned in the mouse [30].

Thus rabbits and rodents have evolved a different strategy than primates. Studies in rats show developmental regulation of two key enzymes involved in the metabolism of DPG [31]. Diphosphoglyceromutase converts 1,3-DPG to 2,3-DPG and this enzyme activity is absent in fetal red cells. In contrast pyruvate kinase activity, which promotes breakdown of 2,3-DPG, is tenfold higher. The situation is similar in rabbits, where the high pyruvate kinase activity is associated with a discrete fetal isozyme [32].

3.3. Evolution of beta-globins in ruminants 

Fetal expression of HBG was not present in the common ancestor of rodents, lagomorphs and primates, but was evolved on the line leading to higher primates. A fetal haemoglobin with high oxygen affinity has been separately evolved in ruminants following duplication of the HBB gene. (The HBG gene was lost in the lineage leading to Superorder Laurasiatheria, which includes ruminants [23]). As described for the domestic goat (Capra hircus), the original four gene set was duplicated and then there was a second duplication of one of the resultant sets [33]. As a result, there are three HBB genes, all homologues of the human beta gene, one of which (HBB-T3) is expressed in the fetus. It is not known how developmental regulation of these genes occurs. However, it is clear that HBB-T3 codes for a beta chain that confers a high innate affinity for oxygen. In the yak (Bos grunniens) fetal haemoglobin accounts for over 40% of total haemoglobin well into adult life [34]. Since yaks live at an elevation of 3000–6000m above sea level, this is seen as an adaptation to the hypoxic conditions at high altitude. The observation is consistent with the view that developmental regulation of the beta-globin genes is dependent on oxygen tension mediated by hypoxia-inducible transcription factors (e.g. ref. [35]).

The high oxygen affinity of ruminant fetal haemoglobin has nothing to do with DPG. Indeed, it has been known for some time that ruminant haemoglobins have very low affinity for DPG [36]. Interestingly, the DPG content of the bovine fetal erythrocyte is six times the adult value, yet the fetal blood still has higher oxygen affinity [37].

Although less well researched, it seems unlikely that a fetal beta-globin gene is present in non-ruminant families of Order Cetartiodactyla (artiodactyls and whales). In the domestic pig (Sus scrofa), for example, there is but a single HBB gene [23] and the higher oxygen affinity of fetal blood is achieved by lowering the DPG content of the erythrocytes, much as in rodents and lagomorphs [38]. The latter mechanism seems to be widespread. In addition to the pig, it has been described for the Weddell seal (Leptonychotes weddellii) [39].

In summary, we know of three mechanisms that were evolved to provide fetal blood with a high oxygen affinity (Table 2). In higher primates an HBG gene was moved away from the locus control region and expressed in the fetus rather than the embryo. In ruminants there was a duplication of the HBB gene to give a fetal haemoglobin with high intrinsic affinity for oxygen. Finally, in rats and rabbits the DPG concentration of the erythrocytes was brought under developmental regulation.

Table 2. Beta-globin genes expressed in fetus and mother of selected species and corresponding blood oxygen affinities.
SpeciesRabbitBush babyRhesus monkeyHumanGoat
Fetally expressed beta-globin genesHBBHBD, HBBHBG-T2HBG-T2HBB-T3
Maternally expressed beta-globin genesHBBHBD, HBBHBBHBBHBB-T1, HBB-T2
Fetal P50 (mmHg)20n/a162219
Maternal P50 (mmHg)29n/a272630

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4. Vascular architecture 

Efficiency of gas exchange is to some extent dependent on the vascular architecture of the placenta. In the labyrinth of hystricognath rodents, such as the guinea pig or capybara (Hydrochoeris hydrochaeris), maternal blood flows in trophoblastic channels that run parallel to fetal capillaries [40]. This arrangement enables the placenta to act as a countercurrent exchanger. There are no known instances of placentas with mainly concurrent flow. Cross current flow does occur, however, as in the placenta of the sheep [41] and in villous placentas, such as those of higher primates. As shown by Metcalfe et al. [6], this does not make a substantial difference unless placental diffusing capacity is high relative to the transport capacity of the blood. Transport capacity is a rather complex function but factors in oxygen affinity, oxygen capacity and blood flow [6]. Analyses that factor in permeability and the ratio between fetal and maternal blood flow rates also tend to downplay the importance of vascular architecture for placental exchange [42].

In labyrinthine placentas, a pattern of predominantly countercurrent flow with cross current components would seem to be ubiquitous. It can be exemplified by the lesser hedgehog tenrec (Echinops telfairi) [43]. There is certainly a greater cross current component in the cotyledons of the sheep than in the labyrinth of the capybara, but once more we encounter a continuous variable that is not well suited to phylogenetic analysis.

An interesting question is why many primate placentas are of the villous type. This likely is an adaptation allowing for greater volume flow and thus a higher rate of oxygen delivery. It is achieved at the expense of a large cross current component. However, as already remarked, the disadvantage of cross current flow is less apparent when the transport capacity of the blood is high.

As early remarked by Wislocki [44] and Starck [45], a stage intermediate between a labyrinthine and a villous placenta is found in the flying lemurs or colugos (Order Dermoptera). This is interesting because the order is closely related to primates [46]. There certainly is a progression among haplorrhine primates. The tarsier placenta is more labyrinthine than villous [47]. In platyrrhine monkeys connections persist between the villi, which form a trabecular network, not unlike that of the tarsier placenta [44], [47]. Branched villi and a more or less continuous intervillous space are found only at a late stage of fetal development in platyrrhine monkeys. In catarrhine monkeys, on the other hand, arborescent villi are present from a very early stage, as they are in the human placenta.

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5. Placental diffusing capacity 

Placental factors of importance for fetal oxygen supply include oxygen consumption by the placenta itself. This has been reliably measured only in ruminants [13], [16] and recently in human pregnancy [15]. Thus there are not enough data for phylogenetic analysis. The other placental factor of importance to oxygen transfer is the diffusing capacity. This can be determined experimentally by measuring diffusing capacity for carbon monoxide [48]. Data is available for several species [7], but still they represent a small sample. However, some of the factors determining diffusing capacity are more amenable to analysis. Disregarding diffusion within the blood, the oxygen diffusing capacity of the “membrane” (Dm) in mol s−1 Pa−1 is given by the equation:

Thus it is directly proportional to surface area in m2 (A), the diffusion coefficient of oxygen in the membranes in m2 s−1 (d) and the solubility of oxygen in the membranes in mol m−3 tissue Pa−1 (α) and inversely proportional to the mean diffusion distance in m (x) [49].

5.1. Placental surface area 

Measuring the surface area of a placenta presents challenges similar to measuring the coastline of a country. Nonetheless, an approximation was attempted by Baur [50], who related total surface area to the volume of the fetus and placenta. He found that diffuse placentas such as those of the horse (Equus caballus) or llama (Lama glama) had a smaller surface area per tissue volume than any of the cotyledonary, discoidal or zonary placentas that he examined. It is remarkable that there were differences within the same order between ruminants and non-ruminants. Recently Klisch and Mess [51] showed that a diffuse, epitheliochorial placenta was likely present in the common ancestor of Cetartiodactyla (artiodactyls and whales). They further noted that development of the cotyledonary placenta could be related to diminished glucose availability associated with the evolution of fore stomach fermentation and they discussed this in terms of the viviparity-driven conflict hypothesis. As shown by Martin [52], the evidence overall indicates that equivalent energy resources can be transmitted across a diffuse placenta despite the fact that the available surface area is smaller.

5.2. Diffusion distance and the interhaemal barrier 

Oxygen diffusing capacity is inversely proportional to diffusion distance. That is one reason we continue to be fascinated by the number of cell layers in the placenta. According to whether the trophoblast is apposed to uterine epithelium, the endothelium of maternal vessels, or directly to maternal blood, placentas are classified as, respectively, epitheliochorial, endotheliochorial or haemochorial [53]. Of course, it can be argued that this classification is of limited functional significance, since extensive thinning of the tissues reduces the diffusion distance between fetal and maternal blood even in placentas of the epitheliochorial type [53].

On the other hand, here is a character that breaks down into discrete states and is amenable to cladistic analysis. We can ask, for example, whether there was an orderly progression from epitheliochorial placentation, through the endotheliochorial type to the haemochorial type, with progressive loss of tissue layers. In several recent papers this matter has been approached by mapping character states on to existing trees (Fig. 2). The trees chosen were those generated by molecular phylogenetics, i.e. by statistical analysis of nucleotide sequences from mitochondrial and nuclear genes [28], [54], [55], [56].

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  • Fig. 2 

    Evolution of the interhaemal barrier in eutherian mammals. Red branches indicate clades with epitheliochorial placentation, yellow branches those with endotheliochorial placentation, and blue branches those with haemochorial placentation. The black line indicates an unresolved situation. In this interpretation, which is supported by other recent studies, epitheliochorial placentation is found to be a derived state. Tree adapted from Douady et al. [71] with character coding from Mess and Carter [60].

One of the first results to emerge [57] was that epitheliochorial placentation in living mammals must be regarded as a derived state. This had been argued by previous authors [53], [58], [59] and was confirmed in several subsequent papers [52], [60], [61], [62]. In fact this type of interhaemal barrier has been evolved twice, once in the lower primates (lemurs and lorises) and once in the line leading to perissodactyls (e.g. horses), artiodactyls and pangolins. This latter group are all large mammals that have long gestation periods, small litters and precocial young.

There is less agreement about whether the common ancestor of living eutherian mammals (i.e. crown placentals) had an endotheliochorial or haemochorial placenta. One study [61] concluded that haemochorial placentation was the primitive type, but their statistical analysis has been strongly criticised [52], because they failed to recognise that a transition from epitheliochorial to haemochorial placentation, in either direction, necessarily counts as two steps. Reanalysis of their data suggests that endotheliochorial placentation is the primitive type [52]. This was also the result achieved in an independent analysis [60].

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6. Reproductive strategies and placental evolution 

Although we are far from understanding what drives placental evolution, several of the trends discussed in this review can be linked to a change in reproductive strategy involving lengthier gestation and more highly developed young. It is far from obvious what advantage accrues to horses, antelopes or pangolins from having epitheliochorial placentation. One recent suggestion is that it allows a much different immunological relationship between mother and fetus somewhat akin to that of a commensal parasite in the gut [63]. Despite the interdigitation that occurs between maternal and fetal cell membranes at their interface (e.g. ref. [64]), it would seem that the total exchange area is smaller, at least in the diffuse type of placenta [50]. This must be compensated by more efficient transport mechanisms that are presumed to involve active transport [52]. The oxygen supply, on the other hand, is secured by thinning of the interhaemal membrane. The capillaries on either surface deeply indent the uterine epithelium and the trophoblast. Connective tissue cells are not found in these interhaemal regions [53].

In the evolutionary transition to epitheliochorial placentation, retention of the uterine epithelium would have meant an initial increase in the diffusion distance for oxygen in comparison to more invasive placental forms. The emergence of large mammals during the Caenozoic era has been linked to the increase in ambient oxygen during this time [65]. The initial disadvantage of epitheliochorial placentation for diffusion processes may have been countered by the increase in ambient oxygen in the Eocene, allowing the evolutionary experiment of epitheliochorial placentation [62].

Evolution of beta-globin genes, yielding a fetal haemoglobin of high oxygen affinity, also occurred within this group of large mammals. It was possibly limited to the ruminants. At the present time data is missing for critical groups, but this may be remedied in the context of comparative genomics, as whole genome sequences now can be interrogated for the presence of different members of the beta-globin gene cluster [23].

The evolution in developmental regulation of the beta-globin gene cluster in primates, leading to fetal expression of the HBG gene, was a separate event. It too occurred within an order where evolution is characterised by increasing body size and lengthening gestation, albeit leading to a human newborn that reverted to dependence on parental care. Another trend in primates was from a labyrinthine placenta through a trabecular form to a placenta with branching villi and an intervillous space. The purpose is seen to be an increase in maternal placental blood flow and ultimately a higher rate of oxygen delivery to the fetus. The deep trophoblast invasion that occurs in great apes was part of the same design [66].

Finally, a change in reproductive strategy occurred within rodents, with the hystricognath forms in particular going in for longer gestations, smaller litters and precocial young. This infraorder appeared in the Eocene and underwent an extensive radiation in the Miocene. They were able to capitalise upon the emergence of grasslands for which they were well adapted in a number of ways [67]. It is notable that they did not evolve a fetal haemoglobin and retained a haemochorial and labyrinthine placenta [40]. What they did do was to fold the labyrinth, thus increasing the exchange area while keeping the placenta quite compact [68]. The resultant lobulated appearance of the placenta, when seen in cross section, is considered a defining feature of the hystricognath placenta [69].

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7. Conclusion 

Many of the factors regulating fetal oxygen supply, including the oxygen capacity (haemoglobin concentration) of fetal and maternal blood and rates of blood flow in the two circulations, are continuous variables difficult to analyse in a phylogenetic framework. Others require complex physiological measurements that have been made in few species; an example is the oxygen consumption of the placenta itself. There are also adaptations too widespread to carry a phylogenetic signal. For instance, in all labyrinthine placentas examined, the fetal and maternal blood vessels and/or channels are arranged so that fetal and maternal blood flows in roughly opposite directions. Thus it is just occasionally that we encounter characters with discrete states. The evolution of the beta-globin gene cluster to yield fetally expressed haemoglobins of high oxygen affinity is the most instructive example to date. It is possible to make statements about the evolution of the placental barrier, but unlikely that this was driven by the need to supply more oxygen to the fetus. It is rather the case that there are secondary compensations, such as extensive indentation of the epithelia by the capillaries in epitheliochorial placentas. Overall it is more likely that placental evolution has been driven by conflict between maternal and paternal genes [70] than by fine tuning of the factors determining fetal oxygen supply.

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8. Conflict of interest 

The author does not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in the paper.

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Acknowledgements 

The views here expressed are those of the author but it is a pleasure to mention stimulating discussions with Kevin L. Campbell, Allen C. Enders, Robert D. Martin, Andrea Mess and Peter Vogel.

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PII: S0143-4004(08)00379-2

doi:10.1016/j.placenta.2008.11.006

Placenta
Volume 30, Supplement , Pages 19-25, March 2009

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