Evolution of the mammalian placenta revealed
by phylogenetic analysis
Derek E. Wildman†‡§, Caoyi Chen‡, Offer Erez†§, Lawrence I. Grossman‡, Morris Goodman‡¶?, and Roberto Romero†‡
†Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
¶Department of Anatomy and Cell Biology and‡Center for Molecular Medicine and Genetics, Wayne State University School of Medicine,
540 East Canfield Avenue, Detroit, MI 48201; and§Department of Obstetrics and Gynecology, Wayne State University School of Medicine and
Hutzel Women’s Hospital, Detroit, MI 48201
Contributed by Morris Goodman, January 3, 2006
The placenta is essential for the success of therian mammalian
reproduction. Intense selective pressure has shaped changes in
placental anatomy and function during mammalian cladogenesis.
Here we challenge the view that the hemochorial placenta is a
derived feature in haplorhine primates. Using phylogenetic and
statistical analyses of molecular and morphological data, we dem-
onstrate that the ancestral eutherian mammalian placenta had the
distinctive features of (i) hemochorial placental interface, (ii) a
discoid shape, and (iii) a labyrinthine maternofetal interdigitation.
These results reveal that the first eutherians had a deeply invasive
placenta and imply that the major role of the placenta in sustaining
pregnancy and promoting gestational development existed
throughout the eutherian lineage that descended to humans from
the last common ancestor of placental mammals. The ancestral
state reconstructions demonstrate both clade-specific patterns of
placentation and specific cases of convergent evolution within
individual eutherian clades. Determining the mammalian pattern
of change in placental morphology is important for understanding
the evolutionary pressures faced by these lineages. The effects of
selection pressures on the efficiency of placentation may stem
embryos per pregnancy, uterine shape, and maternal body consti-
tution. The influence of these factors on placental development
needs further investigation.
discoid shape ? Eutheria ? hemochorial ? maternofetal interdigitation ?
eutherian mammals reveal the pattern of evolution for the
structural characteristics of eutherian placentation. The mam-
malian chorioallantoic placenta is essential for the growth and
development of the embryo and fetus and distinguishes euther-
ian mammals from other organisms (1).
Placental morphology is characterized by five major features (2).
Three have been extensively studied (descriptions of their mor-
phology have been presented in Supporting Text, which is published
as supporting information on the PNAS web site): (i) the definitive
type of placental interface (called placental barrier by others, e.g.,
epitheliochorial, endotheliochorial, and hemochorial); (ii) fetoma-
ternal interdigitation (e.g., folded, lamellar, villous, trabecular, and
zonary, and discoidal). The other features have been studied to a
much lesser degree: (iv) fetomaternal blood flow interrelations
(e.g., concurrent, countercurrent, crosscurrent, and multivillous)
and (v) neonatal?placental weight ratio. This basic scheme of
placental morphology has been in use for nearly a century, and,
although much more sophisticated tissue analysis methods are
useful for understanding placental anatomy (2–4).
Analysis of placental functional morphology and physiology
has focused mainly on two parameters: (i) the extent of the
fetomaternal contact (according to the shape and interdigitation
of the placenta) (5) and (ii) the amount of maternal–fetal
ecent advances in the understanding of mammalian phylog-
eny combined with studies of comparative placentation in
exchange (e.g., nutrient and gas exchange, hormonal actions,
etc.) according to the type of placental interface and fetoma-
ternal blood flow interrelation (4–8).
Molecular phylogenetic studies reconstruct four major placental
mammalian groups (i.e., clades): Afrotheria (elephants, sirenians,
hyraxes, aardvarks, elephant shrews, tenrecs, and golden moles);
Xenartha (armadillos, sloths, and anteaters); Laurasiatheria (car-
nivores, pangolins, bats, soricid shrews, moles, hedgehogs, cetar-
tiodactyls, and perrisodactyls), and Euarchontaglires (primates,
rodents, rabbits, treeshrews, and flying lemurs) (9). Clades Laur-
asiatheria and Euarchontaglires group together to form Boreouth-
eria. Although most published molecular studies support a sister-
group relationship between Laurasiatheria and Euarchontaglires,
disputes exist as to the relationships among Boreoeutheria, Afroth-
eria, and Xenartha (10–13). In reconstructing character state
evolution, we employ each of the three sister groupings for these
major eutherian clades. Our aim is to use the molecular evidence
placenta first evolved and subsequently shaped the development of
primate embryos and fetuses.
Multiple topologies inferred (Fig. 1) from the molecular data set
were evaluated because of the inability of these data to resolve
Conflict of interest statement: No conflicts declared.
Abbreviation: P.L., proportional likelihood.
?To whom correspondence should be addressed. E-mail: email@example.com.
© 2006 by The National Academy of Sciences of the USA
groups. Four major superordinal placental (i.e., eutherian) mammalian clades
are supported by molecular data (9, 13). These clades are the Afrotheria,
Xenartha, Euarchontaglires, and Laurasiatheria. All studies also support the
(Boreoeutheria). The phylogenetic branching order at the root of the tree is
three clades (i.e., Notolegia). (B) Depiction of the Xenartha as sister to the
remaining three clades. A third choice in which Boreoeutheria is sister to a
clade that consists of Xenartha and Afrotheria is not supported by parsimony
analysis (Table 1).
Phylogenetic relationships among major placental mammalian
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February 28, 2006 ?
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the order of initial branching events within Eutheria (10–13).
Table 1 shows that the molecular data set has statistically
indistinguishable (when ambiguous characters are excluded)
parsimony and likelihood scores when Xenartha is the sister
clade to all other placental groups (i.e., Epitheria) or when
Afrotheria is the sister clade to other placental mammals (i.e.,
Notolegia). The Afrotheria ? Notolegia tree has the optimal
maximum likelihood score. The parsimony score for the tree in
which Boreoeutheria is sister to a clade made up of Afrotheria
? Xenartha is significantly longer and was not considered in
Evolution of the Mammalian Placental Interface.Thehypothesesthat
taxa with hemochorial, endotheliochorial, and epitheliochorial pla-
centas comprise monophyletic groups was rejected whether each
state was considered individually or in concert with the others
(parsimony, P ? 0.0001; likelihood, P ? 0.01; Table 1).
Parsimony and likelihood ancestral states were recon-
structed for the two statistically equivalent tree topologies
(i.e., Afrotheria or Xenartha as sister to other eutherians). The
parsimony reconstructions according to both tree topologies
unambiguously infer the hemochorial placenta as the ancestral
state for eutherian mammals. The Markov model reconstruc-
tions define the hemochorial placental interface as the most
likely ancestral eutherian placental type both when Afrotheria
is the sister to other taxa [proportional likelihood (P.L.) ?
0.75; Table 2] and when Xenartha is the sister to other taxa
(P.L. ? 0.87; Table 2); however, only the Xenartha model
reaches statistical significance.
These analyses indicate that at least 11 character state changes
Table 1. Morphological hypotheses tested with DNA sequence data
Parsimony tests Likelihood tests
Templeton Winning sites
£ Rank sums†
Murphy et al. (8)
tree (Fig. 1A)
?0.2281 0.8196 880.8791 211,110.54(best)——
41,973 211,119.66 9.10.13 0.66
A significant result indicates the rejection of the stated hypothesis. Tests were conducted by using PAUP*. KH, Kishino-Hasegawa; SH, Shimodaira-Hasegawa.
£, number of steps in the phylogenetic tree.
†The Wilcoxon signed-ranks test statistic is the smaller of the absolute values of the two rank sums.
‡Approximate probability of getting a more extreme test statistic under the null hypothesis of no difference between the two trees (two-tailed test).
§P ? 0.05.
¶The difference between the maximum likelihood tree ?In L and the alternative hypothesis ?In L.
Table 2. Evolution of the primate placental morphology from the most recent common eutherian ancestor
Crown nodeParsimonyP.L. 1a* P.L. 1b†
Parsimony P.L. 1a*P.L. 1b†
Parsimony P.L. 1a*P.L. 1b†
*Afrotheria ? Notolegia.
†Xenartha ? Epitheria.
www.pnas.org?cgi?doi?10.1073?pnas.0511344103 Wildman et al.
(most parsimonious reconstruction) are required to describe the
evolution of the placental interface (Fig. 2A). Within the Afroth-
eria, three evolutionary events are reconstructed: (i) a transition
from the hemochorial to endotheliochorial placenta occurred
in the aardvark, Orycteropus afer]; (ii) a transition from the
hemochorial to epitheliochorial state may have occurred in the
dugong, Dugong dugon. There is no change within the sampled
(see Materials and Methods for details of reconstruction methodology). Taxon names and branching order are identical in all panels of the figure. Only the
Afrotheria ? Notolegia tree (i.e., 9) is shown. The data for all tree topologies examined is available as supporting information. (A) The placental interface
describes the degree of invasiveness of fetal (i.e., placental) tissue into maternal tissue, with epitheliochorial being least invasive and hemochorial being most
invasive. (B) The shape of the contact zone between fetal and uterine tissues. (C) The form of interdigitation between fetal and maternal tissues. Parsimony and
Markov model likelihood reconstructions were constructed by using the data file available as supporting information.
Wildman et al. PNAS ?
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members of Xenartha in our study (all are hemochorial). Within
Euarchontaglires two changes are observed: (i) a transition from
hemo- to endotheliochorial placentation in the tree shrew and
(ii) a transition from the hemo- to epitheliochorial state in
strepsirrhine primates (Fig. 3).
The placental interface state is equivocal on the stem laur-
asiatherian and stem scrotiferan (Laurasatheria less eulipo-
typhlans, i.e., moles, soricid shrews, and hedgehogs) lineages. An
epitheliochorial placental interface is inferred as present on the
stem Ferungulata (Scrotifera less bats) lineage. Within Ferun-
gulata the carnivore stem lineage evolved an endotheliochorial
interface. The evolution of placental interface types within
Yangochirpotera (i.e., most microbats) remains unclear.
Evolution of Placental Shape. Phylogenetic estimations of the
ancestral placental shape suggest this character had a minimum
of seven state changes during eutherian evolution (Fig. 2B). A
discoid placenta is clearly ancestral for Eutheria (and probably
for Metatheria ? Eutheria) and is still maintained in most
Transitions of this character state have occurred in afrotherians
(change to zonary), in ferungulates (most change to diffuse), and
in euarchontans. An expanded primate data set (see Data Sets
1 and 2, which are published as supporting information on the
PNAS web site) shows that this feature has changed additionally
within the order (e.g., bidiscoid placentas are found among New
World platyrrhine monkeys).
Evolution of Maternal–Fetal Interdigitation. The topology that de-
picts a branching between Afrotheria and other placentals
reconstructs a labyrinthine maternofetal interdigitation (P.L. ?
0.99). However, when Xenartha is the sister to other eutherians
the ancestral character state for Eutheria cannot be differenti-
ated (the P.L. values are distributed as follows: labyrinthine
ancestor, 0.39; trabecular ancestor, 0.39; folded ancestor, 0.19).
The possibility that the ancestral eutherian state is either villous
or lamellar is rejected. From these two models we can learn that
the villous and lamellar forms of interdigitation emerged later
during eutherian evolution. The villous type of blood flow
exchange from mother to fetus has evolved at least three times
independently during the descent of placental mammals from a
eutherian most recent common ancestor (Fig. 2C). Changes
occurred in the dugong (labyrinthine to villous) and in the stem
primates (labyrinthine to villous). As in the previous characters,
most change occurred in the laurasiatherians with transitions
to folded (pig) and lamellar (carnivores).
Primate Placental Evolution. The hemochorial and discoid placen-
tas found in humans represent ancient mammalian character
states that emerged well before the origin of primates (Fig. 3).
The epitheliochorial and diffuse placenta of strepsirrhine pri-
mates are shared derived features that evolved on the strepsir-
rhine stem lineage. Strepsirrhines and catarrhines (Old World
monkeys, apes, and humans) have villous maternofetal interdig-
itation, but tarsiers and New World monkeys have trabecular
interdigitation. Ancestral state reconstructions for this character
are equivocal at the crown primate, crown haplorhine, and crown
anthropoid nodes (see Data Set 2). The presence of a villous
interdigitation on the crown primate node is supported by two
lines of evidence. (i) The P.L. for this state is highest (P.L. ?
0.48) for villous in comparison to trabecular (P.L. ? 0.25). (ii)
The strepsirrhine maternal placental interface and shape are
synapomorphies for the clade. The fact they share a villous
interdigitation with the catarrhines suggests that the villous
form is ancestral and that the trabecular form has evolved twice
in primate evolution on the tarsier and New World monkey
Phylogenetic reconstructions demonstrate that the placenta of
the ancestral eutherian mammal had a hemochorial placental
interface with a discoid shape and a labyrinthine interdigitation.
The change from labyrinthine to other forms of interdigitation
occurred later during evolution in multiple clades (including
primates). These findings challenge the traditional Haeckelian
view of eutherian placentation in which the hemochorial pla-
centa evolved from a placenta in which the fetal tissue had a
more shallow contact with maternal tissue (14).
human placental morphology is an advanced, derived state. This
perspective was accepted by Le Gros Clark (16) and expanded by
Luckett (17, 18) and is widely accepted today. However, the idea
that the hemochorial placenta is the ancestral primate state is not
that the strepsirrhine placental interface is secondarily derived.
Recently it has been suggested that a hemochorial placental inter-
face is a possible ancestral state among eutherians (10, 20); how-
ever, the current study is the first, to our knowledge, to test this
hypothesis and provide evidence to support it.
The relationship between the types of placental shape and
maternal placental interface suggests that selection pressures con-
strain the evolution of these features such that the presence of one
Our findings demonstrate that an association between discoid
shape and hemochorial interface had begun as early as the time of
the last common ancestor of eutherian mammals. Changes in
placental shape along the lineages of the phylogenetic tree usually
were accompanied by changes in the maternal placental interface.
Villous maternal–fetal interdigitation evolved concomitantly
in the primates and in Ferungulata. Within the latter clade,
perrisodactyls, cetartiodactyls, and pholidatans (pangolins, i.e.,
scaly anteaters) have the villous form of interdigitation. The
lamellar interdigitation seen in carnivores is derived in that
group. The fact that haplorhine primates and ferungulates have
different placental shapes and maternal–fetal interfaces, yet
have the same fetal maternal interdigitation, raises questions
reconstructions of internal nodes are shown for the placental interface char-
acter (see Materials and Methods for details of reconstruction methodology).
Parsimony and Markov model likelihood reconstructions were constructed by
using the data file available as supporting information. Strep., Strepsirrhine;
NWM, New World monkeys; OWM, Old World monkeys.
The evolution of the placental interface in primates. Parsimony
www.pnas.org?cgi?doi?10.1073?pnas.0511344103Wildman et al.
concerning the selective advantage of maintaining this form of
interdigitation in these clades.
Reviewing the reproductive features of clades with a villous
type of inderdigitation reveals that many of the species have
single offspring and relatively long gestation (between 8 and 18
months). Possibly villous interdigitation imposes less metabolic
demand on the mother than labyrinthine interdigitation, thereby
enabling her to sustain a longer gestation. In humans, exchange
between villous trophoblast and maternal blood is not fully
functional until the end of the first trimester (21), and the
diabetogenic effect of pregnancy (a state of relative insulin
resistance relating to increased fetal glucose transport) becomes
effective toward the end of second trimester until delivery
(22–26). Human placental lactogens are trophoblast-secreted
(27) members of the growth hormone family (28) that play a role
in inducing the diabetogenetic effect (29–31) of pregnancy (26,
32, 33). Placental lactogens have evolved independently at least
three times during mammalian evolution (34, 35). The increased
concentration of placental lactogens in the maternal circulation
results in the increased fetal utilization of maternal resources,
and therefore maternal–fetal conflict can occur (36, 37). In
rodents (with a labyrinthine type of fetomaternal interdigita-
tion), placental lactogens are secreted throughout pregnancy
(type I during the first half and type II through the second half
of their pregnancy) (38, 39). Conversely, in primates and rumi-
nants (with a villous type of fetomaternal interdigitation) pla-
cental lactogens are secreted mainly during the second half of
pregnancy (27, 40, 41). This observation implies that during their
short gestation rodent fetuses use maternal resources to a much
greater extent than do the fetuses of primates and ruminants.
This finding coincides with our hypothesis that the evolution of
the villous type of maternal–fetal interdigitation represents an
evolutionary compromise that helps sustain longer pregnancies
without depleting maternal resources to the point of starving the
mother. This compromise resolves the maternal–fetal conflict.
However, pathologic processes that interfere with this adapta-
tion may result in the development of pregnancy complications
(e.g., preterm delivery, intrauterine growth restriction, and
stillbirth) (42). Therefore, the success of pregnancy involves
maintaining the balance between maternal and fetal demands.
That intimate contact between fetal and maternal blood was
established in the last common ancestor of the crown group of
Eutheria gives credence to the hypothesis that successful preg-
nancy requires appropriate allorecognition and tolerance at the
maternal–fetal interface. The comparison of the immunological
diversity of different mammalian clades (with different placental
shape, interface, and interdigitation) can provide a framework
for understanding whether there is an association between
maternofetal immunological recognition during pregnancy and
the characteristics of the placenta.
morphology that challenges the view that has existed for over a
century. Our proposed view, which is based on our current
understanding of the phylogenetic relationships among mam-
malian orders and within primates, suggests that the last
common eutherian ancestor possessed a discoid, hemochorial
placenta. The villous type of placental interdigitation is derived
from the ancestral state.
Materials and Methods
Data Composition. Mammalian phylogenetic trees were analyzed
by using molecular data (9). Character state distributions were
obtained from the literature (2, 4). The molecular data set
consists of 44 taxa with at least one representative per
eutherian order (n ? 1 for Carnivora, Cetartiodactyla, Chi-
roptera, Eulipotyphla, Lagomorpha, Macroscelidea, Perriso-
dactyla, Pilosa, Primates, and Rodentia). A marsupial dipr-
odontian and an opossum served as representative members of
the metatherian outgroup. Three morphological characters
and their states (in parentheses) were examined for the data
set: (i) placental interface (epitheliochorial, endotheliocho-
rial, and hemochorial). The hemochorial character state is
subdivided into three character states (hemomonochorial,
hemodichorial, and hemotrichorial). We performed a suba-
nalysis given these three states. No difference was found
whether the state was subdivided or not; therefore, we con-
ducted our analysis with solely a hemochorial placental inter-
face. (ii) Placental shape (diffuse cotylydon, zonary, bidiscoid,
and discoid). (iii) Type of maternal–fetal interdigitation
(folded, lamellar, villous, trabecular, and labyrinthine). De-
tailed descriptions of these character states are available (2);
data currently available on the description of fetomaternal
blood flow interrelation and neonatal?placental weight ratio
are insufficient for statistical and phylogenetic analyses. The
morphological data set is available as a taxon by character (n ?
44) matrix in Data Set 3, which is published as supporting
information on the PNAS web site.
Phylogenetic Analyses. Extrapolating from methods used by
Losos et al. (43), parsimony and likelihood scores for the
molecular data were calculated according to a variety of tree
topologies, including those previously published (9–12), as
well as the most parsimonious topological constraint trees in
which placental interface character state status was used as the
constraining factor. Four constraint trees were analyzed: (i) a
monophyly constraint consisting of all taxa with epitheliocho-
rial placental interface; (ii) a monophyly constraint consisting
of all taxa with endotheliochorial placental interface; (iii) a
monophyly constraint consisting of all taxa with hemochorial
placental interface; (iv) three monophyly constraints consist-
ing of all taxa with epitheliochorial, endotheliochorial, and
hemochorial placental interfaces. Statistical analysis was con-
ducted to compare these trees (44–46). Tests using parsimony
included the Templeton and the winning-sites tests. The
likelihood tests were the Kishino–Hasegawa and the Shimo-
daira–Hasegawa procedures. Optimal trees, depicting three
commonly recognized topologies among superordinal clades
(Afrotheria, Laurasiatheria, Xenartha, and Euarchontaglires),
were compared with trees with topological constraints based
on morphological character states.
Character state evolution was reconstructed by using two
methods: (i) maximum-likelihood-based discrete Markov k-state
approach (44). Parsimony analyses considered character state
transformations unordered. The likelihood-based Markov k-
state 1 model does not consider any particular state plesiomor-
phic at the root of the tree, and a character state can change to
any other state on any branch of the tree with equal probability.
We report P.L. values of states scaled so that the sum of all states
is 1. We used a decision threshold of 2.0 in MESQUITE (45) for
as were presented in the molecular phylogenetic tree; however,
this was not always possible. Only one macroscelidean was
included in the morphological analysis; also, two sirenians were
included because they may differ so greatly in placental mor-
phology (4). An expanded primate data set was also analyzed
given an estimate of phylogenetic relationships within the order
(48). This data set is also included in Data Set 1.
We thank Drs. Joaquin Santolaya-Forgas, Juan C. Opazo, James
Schuttle, and Monica Uddin for insightful comments and discussion. Dr.
Mark Springer (University of California, Riverside, CA) graciously
provided the alignment files of the molecular data. This research was
supported in part by the Intramural Research Program of the National
Institute of Child Health and Human Development, National Institutes
of Health, Department of Health and Human Services.
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