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Formation of fetal cotyledons in the hemochorial placenta
Formation of fetal cotyledons in the hemochorial A theoretical
placenta
consideration
of the functional
implications
of such
an arrangement S. R.
M.
Chicago,
Illinois
REYNOLDS,
PH.D.,
D.Sc.
S I N c E the 1930’s man’s understanding of the maternal-fetal relationship has proceeded faster and with more certainty than in all the preceding years since 1774 when William HunteP3 studied the injected blood vessels of human placentas. There was much expert study of placental structure by skilled workers prior to the thirties. The definitive relationships were known, although some controversies existed. The works of Hertig and Rock,l’ Wislocki and Streeter,25 Amoroso,l Stieve,21 Spanner,‘O and Mossman14 could be cited as among those that are representative of the varied and developing views until a decade ago.ls The study of Hertig and RockI is basic to our present knowledge of placentogenesis of the hemochorial placenta. No justice is done by such brief reference as this, however, to a voluminous body of painstaking studies by scores of expert students of the subject. To review, or even state, the views held by investigators into the 1950’s would serve no
useful purpose here. Rather, the significant turning points-and there clearly are a number of such-may be mentioned with profit. Recent studies render it possible to state a current and accepted view of placental organization. However, having stated what the relationship between the maternal and fetal blood vessels are now known to be, tells us nothing of the mechanisms that determine how these structural relationships come into being. Enough is known of several areas of maternal and of fetal physiology pertaining to existing structures at various times of gestation to yield a comprehensible understanding of how and when the internal organization of the hemochorial placenta comes about. Even so, growth mechanisms including developmental differentiation that are part of early placentogenesis will remain unexplained, for proper understanding of these mechanisms carries one into molecular biology, problems of tissue differentiation, of vascularization, and of cytobiology which are being actively studied by developmental biologists today. The present analysis rests upon such basic and not-understood developmental processes. It accepts the currently recognized
the Department of Anatomy, University of Illinois College of Medicine. Aided by United States Public Health Service Grant HD 00975.
From
425
stage-by-stage sequence of development to the completion of the definitive placenta, usually stated to be achieved about the twentieth week of gestation in the human. This essay is concerned with two essential features of the fully developed placenta. One is the formative or molding processes by which the simpler structures of the early placenta become shaped into a definitive organ having a basic cotyledonary structure attached to both the chorioallantoic and the basal plates, respectively. The other is concerned with the existence and likely role of placental elements that are not parts of fetal cotyledons. Recognition of the existence of different types of villus-containing elements in the hemochorial placenta has been hinted in recent literature, but their functional role is defined theoretically by this study. This concept unifies and renders rational otherwise disparate and isolated observations of a morphologic and physiologic nature. Recent
historical
perspective
In 1953, Boe3 published a treatise that was It demonstrated unequivocally the unique. plexiform vascular network of small arteries, veins, and capillaries in stem villi, in anchoring villi, and of capillaries in free villi. For the first time, the development of a large cap,illary network has been visualized, growing and branching in syncytial buds as the and more numerous. villi become larger These free villi are found throughout the intervillous lake of blood. Such studies were amply confirmed and extended in injected specimens by Crawford,‘j and again recently by Alvarez? using fragments of living chorionic villi studied by phase contrast microscopy. All such studies require revision of the widely held concept that the ultimate fetal circulation in the hemochorial placenta possesses a simplex type of capillary network arranged to provide either countercurrent flow” or a random flow of fetal blood with respect to the circulation of maternal blood in the placenta. I5 The discovery of Bcre is not, in fact, vital to the main thesis of the present paper but it shows the value of look-
ing at “gross” relationships as well as microscopic and ultramicroscopic ones in order to comprehend the nature of placental development and function. The second breakthrough in recent years came through the work of Wilkin.Z3 First published in 1954, it became more widely known in 1958 with the publication of a chapter on placental morphogenesis in the volume, Le Placenta Humain.“& By the twentieth week of pregnancy, Wilkin found, at a time when the hemochorial placenta is commonly recognized to be definitively formed, the closest approximation to a structural functioning unit of the placenta was shown to be the fetal cotyledon. The term, “cotyledon,” in the sense Wilkin uses it in the human placenta, connotes a specialized fetal structure having the following essential characteristics. The cotyledon is supplied by a single fetal artery that originates as a vessel passing into the subchorial “space” from the chorioallantoic plate of the placenta (Fig. 1) . This primary artery (first order vessel) of a few millimeters to several centimeters in length divides into a few secondary arteries (second order vessels), that are arranged radially and more or less parallel to the chorioallantoic plate. The latter vessels curve downward and, descending, give rise to 20 to 40 blood vessels in as many stem, or anchoring, villi (third order vessels) .‘4 The third order structures of each cotyledon are arranged concentrically and radially on the basal plate of the placenta. Anchoring stems may be 2 cm. long at term. Venous drainage of villi in cotyledons follows the three orders of arteries in a reverse direction. Wilkin likens the arrangement of a cotyledon to a tambour. Free villi exist in various forms and places. Few are found on the first and second order vessels, although small growing “tufts” of growing free villi are seen. There are many tufts of free villi that arise along the third order vessels. At the site of the anchoring insertion in the basal plate of the stem villi, many give rise to continuing free villi in a recurrent direction, away from the basal plate and toward the chorioallantoic plate.
Volume 94 Number
Fetal
3
cotyledons
in hemochorial
placenta
427
__ CHORIOALLANTOIC PLATE
_- IST ORDER
VESSELS
- ZND. ORDER
VESSELS
--
3RD
ORDER
- SPIRAL -----
IMPLANTATION
ARTERY
MATERNAL BASAL
VESSELS
VEIN
PLATE
CROWN
Fig. 1. Schematic
diagram of the basic elements of the fetal cotyledon, as described by Wilkin. To this has been added the orifice of an endometrial spiral arteriole in the center of the implanted crown of the anchoring villi containing third order blood vessels. These give rise to numerous free villi and recurring villi, but the center of the “tambour” is relatively free of villi. Upon extension of the distance between chorioallantoic plate and basal plate, second order blood vessels, then first order blood vessels supplying the unit are pulled out of the chorioallantoic mesenchyme. The tambour constitutes a terminal glomus of arterial pressure which forces the maternal blood through the surrounding villi to the subchorial and true intervillous spaces, where the pressure is low (5 to 8 mm. Hg) .
These are the chandelier types of villi that SpannePO believed were the typical villi of the hemochorial placenta. Actually these villi, along with abundant free villi arising along the descending stem villi, make up a considerable portion of the total peripheral fetal vascular bed of the placenta. There is no evidence that the villi of adjacent cotyledons anastomose, although the terminal villi freely interlace unless a septum of the basal plate comes between two groups of cotyledons. All of the above observations have been fully confinned and extended by Crawford.7 Both Wilkinz4 and Crawford7 make a crucial observation
which
is clear
in the
figure
shown
by Wilkin (Fig. 3424) and by Crawford (Fig. 277). Crawford calls attention to the fact that the interior of each cotyledon is quite free
of villi
and
is essentially
hollow.
This
is
why Wilkin considered the cotyledon to be like a tambour. Crawford states, “The divisions in all cotyledons are so arranged that the peripheral or fringe region of the cotyledon is always on the outside. By contrast,
within the interior of the cotyledon the larger divisions are comparatiuely bare of small capillary-bearing branches” (italics supplied). The import of a relatively villus-free interior of the cotyledon appears to this writer to bear a necessary relationship to the morphogenesis of the cotyledon as well as to its function. Conditions cotyledon
governing formation
We are almost ready to ask, How is it that the definitive placenta, containing fetal cotyledons, is formed by the twentieth week of pregnancy? It will be helpful to take note in this respect of several features that Crawford has described in his careful and critical studies, for these clearly relate to the dynamics of cotyledonary formation. The number of fully formed cotyledons is small; about 10 are large, about 50 are of medium size, and the rest of the fetal elements, totaling up to about 150, are not cotyledons as described above. They are, in-
stead. unformed or rudimentary structurrs that do not appear to have been definitive11 described. Their very number should draw attention to them, and. indeed, in the case of Heyns,‘” they have. In a recent thesis txntitled Abdominal Decompuwion, an intriguing a.ccount is given of the rudimentary obviously residual structures of the chorion frondosum which do not become incorporated into fetal cotyledons. Heyns says, “A point of interest is the finding of visible filaments that run right across the placental space from chorionic to basal plate. One wondered what these were because they were too white and firm to be blood vessels. Microscopy showed them to be a core of homogenous material like umbilical cord, perhaps mesenchymc, carrying blood-vessels of up to 60 ,U diameter which were obviously arterioles. Further study showed that the villi seemed to bud off these columns.” These appear to be some of the major vascular units which give rise to free proliferating villi that R0e” and Crawford’ have shown so well, but they do not note, as does Heyns, that these are chiefly anchoring vessels like those of cotyledons but, nevertheless, independent of cotyledons ; that they are so numerous in relation to cotyledons as Crawford has found; and that they are, in a morphologic sense, terminal proliferations of umbilical vessels having passed into and through the chorioallantoic plate and on into the intervillous space, as so clearly described by Heyns. Physiologically, the entire fetal placental capillary bed consisting of rudimentary structures and cotyledons is under the same high distending blood pressure which results from resistance to umbilical vein flow by virtue of the sphincter in the ductus venosus and resistance to umbilical blood flow through tissues of the fetal liver.17, I8 The morphologic and functional consequences of such a distending pressure, familiar to obstetricians at cesarean section, will be referred to below. Crawford notes that the successive divisions of the umbilical arteries as they radiate and divide in the chorioallantoic plate govern the number and the size of cotyledons. In one type of placenta, the divisions axe
regular and dichotomous; extra arterial divisions do not obscure the basic pattern of blood vessel division. By contrast, the battledore placenta showx a large number of divisions’ of the umbilical arteries almost at once, with fewer arterial branches on the fetal side of the placenta. “It follows,” says Crawford, “that magistral cotyledons [in the battledore placentas] are generally larger and heavier” than in the other type of placenta in which arteries branch on the chorioallantoic part of the placenta. We set by this that conditions which relate to early development of the fetal cardiovascular system influence both the size and number of cotyledons. This developmental pattern is set in the early weeks of pregnancy. The manner by which the arteries of the chorioallantoic plate contribute to the formation of cotyledons will be described below. This latter process occurs sometime during the second or third month of pregnancy, as we shall see. Certainly, the number and size of arterial branches in the soft, mucopolysaccharidecontaining tissues of the chorioallantoic plate is one determining factor in the number of cotyledons that form. Other less evident fetal factors are capable of playing contributory roles. The arterial blood pressure in cotyledonary arteries, as well as in the arteries of the rudimentary anchoring villi described above, is high at term. An educated guess would place it at the level of 50 to 60 mm. Hg. The cotyledonary vein pressure is estimated by Dawes* to be about 15 mm. Hg, a figure close to the measurements made by Reynolds*” in umbilical veins of lambs (weighing 3 to 5.5 kilograms) near term. The high venous pressure is the result of resistance to flow of placental blood returning to the fetus through (a) the tissues of the liver. and/or (b) the ductus venosus which has a sphincter that controls blood flow through jt.17, 19 In short, the entire cotyledonary structure and fetal placental vascular bed is under a distending pressure from the back-pressure within it resulting in a gentle erectile action of all the placental tissues. The vascular distending mechanism serves to keep the cotyle-
Volume 94 Number 3
donary vessels patent and extended. So much for the present for the fetal conditions one must consider during the formative stages of cotyledonary development. We shall see their importance later on. The question of what relation, if any, the maternal circulation in the placenta bears to the fetal cotyledons has never been evaluated. The consensus one seems to derive from reading many papers dealing with the blood supply (endometrial spiral arterioles) to the basal plate of the placenta is that the distribution of arterioles exhibits a haphazard arrangement, except that there are none on maternal septa in the basal plate.15 One need refer only to the excellent recent papers of Ran~s.ey’~? l6 to obtain the best and most recent views dealing with a very large literature on the subject. There one finds that in the monkey (which has a hemochorial placenta) one animal has 17 arteries entering, and 37 veins draining and the 2 chorioallantoic placentas (one situated dorsally and one ventrally in the uterus). These vessel openings are fully verified by cineradiography in the monkey. All are not patent at one time. No one knows, however, how many cotyledons there are in the monkey. What of woman? Boyd4 has reported many arteries passing through the basal plate of the placenta at midpregnancy. He held at one time that there are some 180 to 320 at term. The number, he suggested, increases as pregnancy advances. According to Ramsey,15 Boyd now considers his original estimate as “appreciably too high.” It appears that the number of arterial entries into the intervillous space may approach the number of cotyledons that Crawford has observed. Is there a causal relationship between arteriolar openings and cotyledons? The fact that the inner aspect (e.g., inside) of the cotyledon lacks an abundance of free villi suggests that an endometrial spiral artery passes its rapidly moving stream under high arterial pressure into the center of a cotyledon from which it then would perfuse through the villous interstices and force villi within the tambour to be pushed toward the
Fetal
cotyledons
in hemochorial
placenta
429
outside periphery of the cotyledon, to resorb, or both. Following the paths of least resistance, maternal blood then courses toward venous orifices. Such paths may be rather direct or, passing to the subchorial lake, blood may move to nearby or somewhat distant venous orifices in the basal plate, in the septa of the basal plate, or at rare marginal lakes. Ramsey, Corner, and Donner16 in their recent paper discuss the flow of maternal blood in the intervillous space. “Blood,” they say, “is delivered to the intervillous space of monkey and human placentas under a maternal pressure somewhat higher than the pressure within the space itself. Slow lateral dispersion of blood occurs in consequence.” Pressures recorded by Hendricks9 in the human show such pressure differences within the intervillous space. The flow is referred to frequently in the literature as jets, but Ramsey points out that there is continuous flow from the arteries but of varying velocities. The term, “pulsatile flow,” would suit the physiologist better. RamseyI notes that the flow from an arterial orifice may be, at times, intermittent as a result of local or generalized uterine contraction. Most placentologists have not identified a maternal arterial opening at the center of the coronally attached anchoring villi of each cotyledon. Boe3 alone claimed in 1953 that basal plate arteries open primarily at the center of attachment of cotyledons, but he did not know the structural details of the fetal cotyledon, Blood would then flow into the cavities of the cotyledons. Neither he nor anyone else has attached developmental significance to this arrangement. The observation of Boe3 on this matter must be looked for again in both the monkey and the human. In the course of writing this essay, supporting evidence for this thesis has come to light. An early draft was sent to nine experts in the field,2 one of whom was Dr. Elizabeth Ramsey. She pointed out that the concept just cited would explain-and there is no other explanation known to us-what she and others had seen in cineangiographs of opaque
Fig. 2. For
legend
see
top of
facing
page.
Volume 94 Number 3
Fetal cotyledons in hemochorial placenta
431
Fig. 2. Serial angiographs following injection of x-ray opaque material retrograde into the femoral artery, and from there into a uterine artery contrast enhanced electronically (Logetroncis) . Rhesus monkey in midpregnancy (about the ninety-second day). Lateral view. (Serial pictures were taken at 1.5 second intervals for about 30 seconds by Dr. Elizabeth M. Ramsey and colleagues and made available by her and the Department of Embryology, Carnegie Institution of Washington.) The pictures here show: A, Filled myometrial arteries from which a number of filled spiral arterioles may be seen passing to the placenta. The ventrally implanted placenta is at the right. At several points, the dye is passing through arteriolar orifices in the basal plate of the placenta. At the top, two arterioles have a common opening (first demonstrated by Ramsey13; B, 3.0 seconds after A. Dye now appears as localized puffs of material at a number of points; C, 6.0 seconds after B and 9.0 seconds after A. Clear areas appear in center of contained puffs as dye-free blood penetrates these locally contained puffs. The absence of a “doughout” in top puff (presumed interior of a fetal cotyledon) would result from turbulence within the fetal cotyledon from two arteriolar jet streams of blood preventing clearing at the center of the contained puff of dye. Note the “dougnut” at bottom center. In addition to the cleared center, one can see about seven serrated indentations. These appear to be the innermost anchoring villi between which opaque medium filters from the cavity of the tambour to the outside of the cotyledon (see text). D, Same, 3 seconds after C and 12 seconds after A. The “holes” of the doughnuts are slightly longer than in C and the diameters of “doughnuts” are slightly larger than in C.
material entering the intervillous space from endometrial spiral arterioles.16 The first picture is that of a distinct “puR” of opaque material that retains its shape as it becomes larger and its center becomes less opaque before all the medium becomes dissipated. She referred to these as “doughnuts.” The point seems clear that while the first spurt of
opaque material is held to a confined space and not quickly dissipated, incoming blood without opaque material clears the center of the “puffs” (Figs. 2 and 3) . If it be true that the hollow cavity of each cotyledon receives pulsatile spurts of maternal blood, by what mechanism is this anatomical arrangement achieved? To find the answer, one must go back to the earliest time when this could come about. Consider the period of villous placental morphogenesis (Table I). This begins about 13 days after fertilization in the human.‘l It is preceded by a previllous period (days 6 to 13) which consists of prelacunar development (days 6 or 7 to day 9) and a lacunar period (days 9 to 13) in which connecting “lakes” of embryotrophe and venous blood
Fig. 3. Anterior-posterior view of same structures shown in lateral series described in Fig. 2 taken in another series of angiographs. Picture taken 6.0 seconds after injection of opaque substance into femoral artery. In this picture, the location of at least 10 fetal cotyledons can be identified. In at least four of these, the hollow centers already appear from opaque-free blood entering the site of the contained opaque dye, so clearing it. Suggestions of the “doughnuts” appear in several more areas. Compare with B and C in Fig. 2. The posteriorly implanted placenta is at the left, the ventral placenta, toward the right. (By Dr. Elizabeth M. Ramsey and colleagues and reproduced by courtesy of her and the Department of Embryology, Carnegie Institution of Washington.)
432
Reynolds
Table I. Hemorchorial Dap post ouulation
Basic stages placental development
placental of
l-6
Tubal and uterine transit cleavage-blastocyst formation
6
Implantation
7 to 8
Previllous
(,human
Key
(period)
mor$hologic-functional correlations
New
(period)
13-18
features
No fills
circulation
Sluggish circulation
likely
Chorionic villi form by cytotrophoblastic columns derived from chorionic vesicle; these are anchoring villi, unattached or branching villi as follows: (a)
Primary villi; 0.8 mm. long, 120 p thick. Cytotrophic cells continue to give rise to syncytium about them
(b)
Secondary villi; invasion by, and in situ formation of, extraembryonic mesoderm; (body stalk and its contents and amnion form) Tertiary villi; 2 to 2.7 mm. long, 400 p thick. Capillaries have delaminated from cytotrophoblast and then grow along with stroma and proliferate into capillary plexus. Umbilical arteries, veins spread through blastoderm (see Fig. 4) Villous capillaries tap these arteries and veins
18-21
Oxygen Fetal placental circulation established; still no maternal circulation of arteriovenous shunt variety, with arterioles entering the intervillous space 21 to 40
developmental
Prelacunar period; trophoblast proliferation-no maternal blood; cytotrophoblast gives rise to syncytium Lacunar period; endometrial veins tapped, maternal blood connecting lacunae; arterial capillaries tapped
Villous
i
1
9-10 11
13 to 40-50
morphogenesis
Chorion sum
frondo-
See Figs. 4 and 5. Multiple villi, having proliferating and ends of many anchored recurrent ends (“chandelier
anchored free villi vilii have type”‘)
Progressive trophoblast. forms
in cytoplate
relative decrease Chorioallantoic
Still from
tension
no circulation endometriul
low
in IVS
of maternal arterioles
blood
Volume 94 Number 3
Fetal
cotyledons
in hemochorial
placenta
433
Table I-Cont’d Days post ovulation 40-50
Basic stages placental development
of Key
morphologic-functional correlations
New
Cotyledon formation First phase
Second
Third
developmental
features
1. Cavitation. Trophoblast invasion opens spiral arterioles (40-60 in human; about 20 in rhesus). Further invasion stops. Jets of arteriole blood form localized hollows in chorion frondosum. Maternal circulation established. The anchoring villi contain third order fetal vessels. Pressure in cavities is 40-60 mm. Hg
phase
2. Crowning and Extension: Cavitation causes concentric orientation of anchored villi around each arteriolar spurt and cavitation. Maternal blood pressure in intervillous space separates chorioallantoic plate and basal plate, anchoring villi become extended and grow, but supplying vessels of anchored villi are pulled from chorioallantoic mesenchyme into intervillous space (sub-chorial lake begins to form) ; these vessels are second order fetal vessels) 3. Completion. Anchoring villi (third order vessels) and second order vessels are pulled as blood volume in IVS increases; main supplying vessel of each group of second order vessels supplying the anchored villi is pulled from chorioallantoic rnesenchyme forming the 1st order vessel of a fetal cotyledon
phase
4. Rudimentary cotyledons or anchoring villi (about 150) complete except for cavitation and crowning, fail to invade arteriole and form cavities. IVS pressure about them is about 5-8 mm. Hg 80-85 140 140
Definitive cotyledons about they are at 140 days Definitive
placenta
(a) (b) (c)
to 280
Septa
basal
plate
Septa
l/9
size,
IO-12 large cotyledons 40-50 small to medium cotyledons 140-150 rudimentary cotyledons, complete except for tambour, crown implantation and arteriolar jet to distend the cotyledon form
in basal
plate
5. Formed cotyledons are areas of high maternal IVS pressure; rudimentary ones are found in areas of low IVS pressure
Septa are folds plate resulting villi between allantoic plate, mary vessels. last half of stretched to ing fetus
or “puckers” in basal from pulls of inserted basal plate and choriothrough attached priUterus grows little in pregnancy, so it is accommodate the grow-
434
Reynolds
occur in the syncytiotrophoblast. During this period, maternal veins and arteriolar capillaries are tapped. l1 Maternal blood is in the lacunae, where it circulates sluggishly, at best. The period of villous proliferation and elaboration begins on day 13, as mentioned above and shown in Table I, and is generally held to continue to the end of the fourth month’l but according to Alvarez” and Crawford,’ it continues until term (Table I). At first, innumerable short, small chorionic villi (cytotrophoblastic columns) appear around the entire conceptus. These consist of a core of cytotrophoblastic tissue which gives rise to the surrounding syncytium.‘? They contain no blood vessels and are, by definition, primary villi. As extraembryonic mesoblast tissue migrates toward the villi from the blastoderm surrounding the extraembryonic coelomic cavity, the villi are only some 0.8 mm. long and about 120 microns thick. When filled with mesenchyme, secondary villi are said to exist; they, too, are still free of blood. Meanwhile, fetal blood vessels leave the body stalk of the embryo during the eighteenth to twenty-first days. They branch out within the tissues of the blastoderm around the extraembryonic coelomic cavity. As they ramify throughout the blastoderm, the capillary vessels which arise by angiogenesis in the secondary villi become connected with the fetal vessels that grow out from the body stalk. By this time, the villi are 2 to 2.7 mm. long and some 400 microns thick. The fetal blood vessels are now connected with the differentiated capillary plexus in the villi and so comprise the ultimate basic form of the tertiary villus. These anchoring villi of the chorion frondosum give rise to ever-proliferating free villi within the intervillous space; capillary blood vessels multiply within them.” This is the accepted view based upon the classic study of Hertig.” They constitute (a) the vascular precursors in the chorion frondosum of the future third order cotyledonary vesse!s, described by Wilkin and by Crawford and (b) the persisting, noncotyledonary stem villi, described by Crawford and by Heyns. The tertiary villi are anchored firmly by cytotrophoblastic cell col-
Fig. 4. Photograph of fresh human chorion frondosum surrounding the blastoderm of an embryo 7 weeks, 6 days menstrual age (probably about 42 days’ ovulation age). The origins of stems (anchoring) villi from the blastoderm are clearly visible, especially on the left side nearest insertion of umbilical cord. Each anchoring villus is covered with free villi, and is anchored in the deridua, only 5 small pieces of which (largest 20 x 45 mm.) were shelled out of the uterus as the concrptus was removed. The base area, which ultimately gives rise to the true placenta, orcupied about two fifths of the entire surface in the specimrn, the remainder being destined for atresia and to become chorion lacve between the amnion and the decidua capsularis as the growing conceptus presses upon it. The above description is based on original notes by Dr. C. H. Heuser. Note the dividing and splaying blood vessels derived from the umbilical vcssels as the former surround the coelomic cavity, throughout the blastoderm where they supply the blood vessels in the anchoring villi of the chorion frondosum. (Used by courtesy of The Department of Embryology, Carnegie Institution of Washington Specimen No. 8537. C-R = 19 mm.)
umns which break through the syncytial mass about the conceptus. The columns attach themselves firmly to maternal decidual tissue. From the sides of these anchored villi, free villi arise which become increasingly complex by virtue of further branching, as mentioned above. The anchoring villi may give rise to recurrent branching villi from the basal plate.
Vohne 94 Number 3
Fig. 5. Schematic drawing of early human embryo based on photographs and models showing origin of anchoring villi from embryonic blastoderm without abundance of free villi covering them, as seen in Fig. 4. Attachment to decidua is not shown. (Drawn by James F. Didusch. Used by courtesy of the Department of Embryology, Carnegie Institution of Washington. Carnegie Collection No. 836, 23 days’ ovulation age.)
So far so good. This is the line that ordinarily divides the embryologist from the placentologist. The former has not accounted for cotyledons and the placentologist accepts them as elements of the formed placenta. It is at this point that the theory of cotyledon formation, based on facts rooted on each side of this line, is presented as an essential guide to future investigators to make observations at this crucial point in order to understand much placental physiology and pathology. We know that forty or more days after fertilization, a multitude of anchoring (stem) and tertiary villi, each rich in free villi of the chorion frondosum, abundantly surrounds the developing conceptus (Figs. 4 and 5) . Gradually, as enlargement of the conceptus and uterus occurs, progressive changes in the fetal-maternal relationship take place. What are they? In the first place, the supply of maternal arterial blood to the intervillous space increases progressively as the uterus and its contents grow. Clearly, there is a first venous vascular breakthrough into the early lacunae (about day 9) ; other venous vascular break-
Fetal
cotyledons
in hemochorial
placenta
435
throughs follow. Later, capillaries are tapped. As the relative area of the chorion frondosum attached to the decidua capsularis diminishes because of ovum enlargement, resulting in the chorion laeve beneath the decidua capsular& the definitive placenta takes shape. Ultimately, by the end of pregnancy, there may be up to two hundred maternal arteries (very probably far fewer, predictably something of the order of 50 to 60) passing through the decidua basalis. How rapidly the increase of vascular openings into the intervillous space takes place is unknown. However, it is clear that the definitively formed placenta, as outlined above, exists by midpregnancy. Crawford shows formed cotyledons by the twelfth week. These are about half the size of 20 week cotyledons (two planes only, judged from photographs). Sometime between the fortieth and the eightieth days of pregnancy, therefore, the cotyledons are formed. The situation prior to cotyledon formation is that if a maternal arteriole opens up through the basal plate it should “spurt” into a mass of anchored tertiary villi of the chorion frondosum. This cannot help but cause local cavitation in the chorion frondosum. Since the spurt exerts force, it has the capacity to spread a group of villi about the vascular opening, and the surrounding anchored villi will become molded into a concentric, ringlike position (the couronne of Wilkin) . As a consequence, crowding, or forcing the growth of free villi along the stem villi toward the outer portion of the forming cotyledon should occur. It is possible that under pressure, resorption of villi within the cavity may take place. We have in this functional scheme, the potential for (a) the coronal attachment of villi and (b) the hollow tambour feature of cotyledons discovered by Wilkin and elaborated upon by Crawford. From what has been said, the opening of endometrial spiral arteries through the basal plate occurs after formative tissue differentiation of the placental elements is complete. Fetal angiogenesis is definitively complete and functioning and only requires that it be
436
Reynolds
molded by the shaping forces of maternal blood on the basic placental elements found in the chorion frondosum. There are other implications of the concept described above concerning placental morphogenesis which need consideration and study. Since the flow of arterial blood under pressure and in volume into the intervillous space by way of the cavities of cotyledons, the character of placental blood flow changes profoundly, Prior to this time, the circulation of maternal blood is by way of reflux venous flow and maternal capillary to maternal vein by way of lacunae, then the intervillous slow, at quite low space. I” It is relatively pressure and predictably sluggish and hypoxic. After direct entry of arteriolar blood, the elements of the arterial-venous shunt described by Burwell” are present. The internal cavity of each cotyledon must be considered to be a terminal arterial glonlus from which maternal blood escapes slowly into the intervillous space proper. Intervillous space blood pressure, oxygen tension and blood flow should increase substantially by enrichment with arterial blood, and in fact, they must do so in order to bring about the changes in maternal blood volume which do, in fact, occur as with a direct arteriovenous shunt. No one as yet has determined the earliest effects in the maternal organism of the placental arteriovenous shunt to its earliest moment of onset. In passing, it may be speculated-since theorizing on the basis of known related phenomena is one of the accepted methods of science- -that the placental tissue itself is invasive until the arterioles are tapped and that it ceases to be invasive after that time. Should such a hypothesis bear the test of objective measurement, it may be found by future investigators that anaerobic metabolic pathways in trophoblastic metabolism determine its invasiveness, and that elevation of the mean oxygen tension in the intervillous space evokes an aerobic pathway of metabolism in the trophoblast depriving it of its invasive quality. It is an intriguing possibility that the fetal placental tissue may exhibit the quality of invasiveness until its thirst for oxy-
February 1, 1966 Am. J. Obst. & Gynec.
gen is relieved, and that when it is, it beco’mes a passive tissue. The opening of 40 to 50 endometrial arterioles (the probable number present), one by one for a time, increases the quantity of maternal blood contained in the intervillous space, and the fully formed and functioning placenta is greatly thickened as the distance between the basal plate and the chorioallantoic plate becomes greater. This may be affirmed by observation at cesarean section. Such an increase will have consequences upon the fetal blood vessels that connect the two placental plates. At first, these are in anchoring villi, now arranged in a crowded circle of an implantation ring about each arteriolar orifice (couronne of Wilkin) and with a cavity formed within them about each spurting jet of blood. But how may one explain the development of the first and second order cotyledonary vessels? In the first place, the vascularity of the uterus increases as it grows.15 More blood is carried into the intervillous space until eventually a sustained pressure (during uterine diastole) of about 5 to 10 mm. Hg is maintained. Pressures at the jets within each cavity will be grea,ter, since endometrial arterioles become straightened out and 1arger.l” Pressure of blood in the subchorial lake forces the chorioallantoic and basal plates farther apart. The resulting pulling action on the anchored villi inserted in the basal plate is aided by fetal blood pressure within the placental blood vessels. Umbilical vein pressure contributes to extension of the anchored villous structures because of the blood pressure within them. The two forces, maternal intervillous space blood pressure, on one hand, and fetal cotyledonary blood pressure, on the other, can only combine (a) to extend the blood vessels by a pulling action on the anchored villi containing the third order cotyledonary vessels and (b) to pull arterial and venous fetal blood vessels in the blastoderm that connect the vessels in anchored villi of the cotyledon out of the soft, mucoid substance of the chorioallantoic plate. These form, in turn, the second order and first order blood vessels, respectively. Such
Volume Number
94 3
changes bring about completion of the cotyledonary vascular components of the placenta. The second order and first order vessels had their origin, therefore, in the dividing and splaying fetal blood vessels which divided dichotomously in the extraembryonic mesoderm as blood vessels grow out of the embryonic body stalk about the eighteenth day after fertilization. The ground work is laid, accordingly, at that early time for the ultimate cotyledonary differentiation that takes place weeks later. There are implications in the foregoing hypothesis which merit consideration. The growth rate of the uterus diminishes after the fourth month (evidenced by thinning of the uterine wall), while the fetus and amniotic fluid increase in size and amount, respectively. The cotyledons are now an integral, physical part of the basal plate. They are subjected, therefore, to pulls in different directions as the uterus is stretched. The cotyledons are attached by the first order blood vessels to the allantoic plate. The pulls between the two plates of the placenta must be accommodated by internal adjustments within the tissues to which the cotyledons are firmly attached. Clearly, stretching and growth of the uterus contribute to the displacement of the cotyledons by the forces to which they are subjected. Uneven pulls on the basal plate may be expected to buckle and fold it at some points. Such buckling undoubtedly is the basis of the origin of maternal septa in the basal plate. There is no other known concept or hypothesis to account for them at this time. The fetal cotyledons, once formed, are an integral part of the basal plate and the only mobility that exists between the chorioallantoic plate and the basal plate is imparted by the first order cotyledonary vessels. These, as mentioned above, may be 0.5 to 4 cm. in length. Unequal growth of the two plates of the placenta must of necessity cause multiple and varied lines of stress between them. This concept of dynamic force effecting a passive localized yielding of tissues in the basal plate accounts for the fact that septa form only between sites of attachment of fetal cotyle-
Fetal cotyledons
in hemochorial
placenfa
437
dons to the basal plate. They are devoid of openings of endometrial spiral arteries but do have venous openings to drain the intervillous space.l” Taken as a whole, the concept of the origin of fetal cotyledons from the elements of the chorion frondosum and the existence in mature placenta of elements of that structure which remain essentially as they were in chorion frondosum tells us that the functioning placenta, when fully formed, has some 50 localized regions in which maternal blood moves out slowly under high pressure, from the cavities of the cotyledons into other areas about free villi on rudimentary elements that are residual remnants of the chorion frondosum stems, where pressures are low. A key to the puzzle of fluid exchange between mother and fetus is the existence of high capillary blood pressure within the fetal placental capillaries. The cotyledons possess the potentiality for movement at high intracotyledonary pressure of water and dissolved solutes from maternal blood into fetal blood. The rudimentary structures of the early chorion, so well described by Heyns and counted by Crawford, on the other hand, are so situated that the same high fetal capillary blood pressure in them provides for movement of water in the opposite direction, from fetal blood to maternal blood. This is a partial equivalent of Mossmans’ principle of countercurrent flow as a factor in fluid exchange within the placenta. It is reasonable to say, therefore, that with respect to receiving water and some solutes the fetus transacts most of its business in one corner of the store, the cotyledons, and that for getting rid of water and some dissolved substances, this transaction takes place predominantly in other parts of the store. One area is for receiving, the other dispensing, so far as the fetus is concerned. All of the concepts set forth in this essay have much factual evidence to support them. Until each facet of the whole is subjected to the test of direct and critical examination, the flaws in the theory will not be seen. Meanwhile, with a conceptual framework in which to bring together the great multiplicity
438
Febluary 1, 1966 Am. J. Obst. & Gynrc.
Reynolds
of presently known facts of morphology, physiology, and pathology, it is possible to bring them together into a unified whole. Such is the purpose of this essay. Summary The principal stages of organogenesis of the hemochorial placenta are known in a descriptive sense. These are recognized, after implantation, as previllous, villous, and cotyledonary. The previllous stage is first without maternal blood but shortly, uterine veins, and later endometrial capillaries, are tapped and Iakes of maternal bIood and products of fetal tissue breakdown form embryotrophe in the syncytium. This material is believed to be a source of nourishment for embryonic tissues. When the conceptus becomes surrounded by an abundance of villi of cytotrophoblastic columns that give rise continuously to a covering layer of syncytial tissue, this is called the chorion frondosum. It has been seen as late as 45 days conception age in a human conceptus. No one knows now the nature (arterial, venous) of maternal blood flow about these early fetal tissues. However, by the eighty-fourth day, definitive hollow tambour-like fetal cotyledons exist and these become larger, in these dimensions, as gestation continues, To account for the transformation of chorion frondosum into fetal cotyledons (40 to 60 cotyledons altogether, and about 150 undeveloped rudimentary ones that are residual anchoring villi with numerous free villi from the chorion frondosum) the view is advanced in this essay that when endometrial spiral arterioles are tapped (sometime after the fortieth day) the local force of blood pressure causes organization of the local fetal cotyledons, and that this is essentially a hemodynamic molding process acting on the tissues
of the chorion frondosum. It involves (a! cavitation, (b) crowning and extension of anchoring villi, and (c) completion by dctlelofiment of the sup&&g vascular pattern out of the original blastoderm, now the chorioallantoic plate. Physiologic data from the literature (local blood pressure differences and oxygen tension differences within the intervillous space and cineangiography) are cited to support this functional concept of the last stages of definitive morphogenesis of the placenta. This theory raises questions concerning what metabolic factors limit trophoblastic invasiveness. It offers a solution by which physiologists may account for hydrostatic forces of a conventional sort in maternalfetal exchange of water and many dissolved substances since the cotyledons are local regions of high maternal blood pressure with respect to fetal blood pressure, and the noncotyledonary anchoring viIli are areas of low maternal blood pressure with respect to fetal blood pressure. Each cotyledon is a terminal arterial glomus from which blood filters slowly through the surrounding fetal villi into the intervillous space proper. Without such a concept one is confronted with the currently prevailing view of uptake of water by fetal blood into capillaries where pressure is high (15 mm. Hg or more) from regions where the pressure is commonly regarded as being low (intervillous space, 5 to 10 mm. Hg). The author is indebted to the following individuals, among others, for reviewing and criticizing helpfully an early draft of this paper sent to them in April, 1964: Dr. J. M. Crawford, Professor Arthur T. Hertig, Professor I. H. Kaiser, Professor Harlan W. Mossman, Dr. Elizabeth M. Ramsey, and Professor P. G. Wilkin.
4. Boyd, J. D.: In Vi&e,
REFERENCES
1. Amoroso, E. C., Marshall’s
physiology of reproduction, ed. 3, London 1952, Longmans, Green & Company, part 2, Chap. 15.
2. Alvarez, 3.
H.: Rev. obst. y ginec. latino-am.
20: I> 1962. Bse, F.: Acta obst. Suppl. 5, 1953.
et gynec.
scandinav.
32:
5. 6.
C. A., editor: Gestation: Transactions of the Second Conference, New York, 1956. Josiah Macy Jr. Foundation 17: 132, 1956. Burwell, C. 8: Bull. Johns Hopkins Hosp. 95: 115, 1954. Crawford, J. M.: J. Obst. & Gynaec. Brit. Emp. 66: 885, 1959.
Volume Number
7. 8. 9. 10. 11. 12.
13. 14. 15. 16.
17.
94 3
Crawford, J. M.: Am J. OBST. & GYNEC. 84: 1543, 1962. Dawes, G. S.: AM. J. OBST. & GYNEC. 76: 969, 1958. Hendricks, C. W.: AM. J. OBST. & GYNEC. 76: 969, 1958. Hertig, A. T., and J. Rock: Contrib. Embryol. 25: 37, 1935. Hertig, A. T., and J. Rock: Contrib. Embryol. 29: 127, 1941. Heyns, 0. S.: Abdominal decompression, Thesis, Witwatersrand University, Johannesburg, 1963, p. 69. Hunter, W.: The Anatomy of the Human Gravid Uterus Exhibited in Figures, 1774. Mossman, H. W.: Contrib. Embryol. 26: 129, 1937. Ramsey, E. M.: AM. J. OBST. & GYNEC. 84: 1649, 1962. Ramsey, E. M., Corner, G. W., Jr., and Donner, M. W.: AM. J. OBST. & GYNEC. 86: 213, 1963. Reynolds, S. R. M.: In Villee, C. A., editor:
Fetal cotyledons
18.
19. 20. 21. 22. 23. 24. 25.
in hemochorial
placenta
439
The placenta and fetal membranes, Baltimore, 1956, Williams & Wilkins Company, pp. 172173. Reynolds, S. R. M.: In Congenital heart disease, American Association Advances in Science. Washington. D. C.. 1960. D. 21. Reynolds, S. RI MI: Am,’ J. Physiol. 203: 655, 1963. Spanner, R. : Ztschr. Anat. u. Entwcklngsgesch. 105: 163, 1935. Stieve, H.: Ztschr. mikr.-anat. Forsch. 50: 163, 1935. Tao, T. W.: (See Hertig, A. T.:) Obst. & Gynec. 20: 859, 1962. Wilkin, P.: Gynec. et obst. 53: 239, 1954. Wilkin, P.: In Le placenta humain, Snoeck, J., editor: Paris. 1958. Masson et Cie. Wislocki, G. B., and Streeter, G. S.: Contrib. Embryol. 27: 1, 1938. 1853 West Polk Street Chicago 12, Illinois
placenta
consideration
of the functional
implications
of such
an arrangement S. R.
M.
Chicago,
Illinois
REYNOLDS,
PH.D.,
D.Sc.
S I N c E the 1930’s man’s understanding of the maternal-fetal relationship has proceeded faster and with more certainty than in all the preceding years since 1774 when William HunteP3 studied the injected blood vessels of human placentas. There was much expert study of placental structure by skilled workers prior to the thirties. The definitive relationships were known, although some controversies existed. The works of Hertig and Rock,l’ Wislocki and Streeter,25 Amoroso,l Stieve,21 Spanner,‘O and Mossman14 could be cited as among those that are representative of the varied and developing views until a decade ago.ls The study of Hertig and RockI is basic to our present knowledge of placentogenesis of the hemochorial placenta. No justice is done by such brief reference as this, however, to a voluminous body of painstaking studies by scores of expert students of the subject. To review, or even state, the views held by investigators into the 1950’s would serve no
useful purpose here. Rather, the significant turning points-and there clearly are a number of such-may be mentioned with profit. Recent studies render it possible to state a current and accepted view of placental organization. However, having stated what the relationship between the maternal and fetal blood vessels are now known to be, tells us nothing of the mechanisms that determine how these structural relationships come into being. Enough is known of several areas of maternal and of fetal physiology pertaining to existing structures at various times of gestation to yield a comprehensible understanding of how and when the internal organization of the hemochorial placenta comes about. Even so, growth mechanisms including developmental differentiation that are part of early placentogenesis will remain unexplained, for proper understanding of these mechanisms carries one into molecular biology, problems of tissue differentiation, of vascularization, and of cytobiology which are being actively studied by developmental biologists today. The present analysis rests upon such basic and not-understood developmental processes. It accepts the currently recognized
the Department of Anatomy, University of Illinois College of Medicine. Aided by United States Public Health Service Grant HD 00975.
From
425
stage-by-stage sequence of development to the completion of the definitive placenta, usually stated to be achieved about the twentieth week of gestation in the human. This essay is concerned with two essential features of the fully developed placenta. One is the formative or molding processes by which the simpler structures of the early placenta become shaped into a definitive organ having a basic cotyledonary structure attached to both the chorioallantoic and the basal plates, respectively. The other is concerned with the existence and likely role of placental elements that are not parts of fetal cotyledons. Recognition of the existence of different types of villus-containing elements in the hemochorial placenta has been hinted in recent literature, but their functional role is defined theoretically by this study. This concept unifies and renders rational otherwise disparate and isolated observations of a morphologic and physiologic nature. Recent
historical
perspective
In 1953, Boe3 published a treatise that was It demonstrated unequivocally the unique. plexiform vascular network of small arteries, veins, and capillaries in stem villi, in anchoring villi, and of capillaries in free villi. For the first time, the development of a large cap,illary network has been visualized, growing and branching in syncytial buds as the and more numerous. villi become larger These free villi are found throughout the intervillous lake of blood. Such studies were amply confirmed and extended in injected specimens by Crawford,‘j and again recently by Alvarez? using fragments of living chorionic villi studied by phase contrast microscopy. All such studies require revision of the widely held concept that the ultimate fetal circulation in the hemochorial placenta possesses a simplex type of capillary network arranged to provide either countercurrent flow” or a random flow of fetal blood with respect to the circulation of maternal blood in the placenta. I5 The discovery of Bcre is not, in fact, vital to the main thesis of the present paper but it shows the value of look-
ing at “gross” relationships as well as microscopic and ultramicroscopic ones in order to comprehend the nature of placental development and function. The second breakthrough in recent years came through the work of Wilkin.Z3 First published in 1954, it became more widely known in 1958 with the publication of a chapter on placental morphogenesis in the volume, Le Placenta Humain.“& By the twentieth week of pregnancy, Wilkin found, at a time when the hemochorial placenta is commonly recognized to be definitively formed, the closest approximation to a structural functioning unit of the placenta was shown to be the fetal cotyledon. The term, “cotyledon,” in the sense Wilkin uses it in the human placenta, connotes a specialized fetal structure having the following essential characteristics. The cotyledon is supplied by a single fetal artery that originates as a vessel passing into the subchorial “space” from the chorioallantoic plate of the placenta (Fig. 1) . This primary artery (first order vessel) of a few millimeters to several centimeters in length divides into a few secondary arteries (second order vessels), that are arranged radially and more or less parallel to the chorioallantoic plate. The latter vessels curve downward and, descending, give rise to 20 to 40 blood vessels in as many stem, or anchoring, villi (third order vessels) .‘4 The third order structures of each cotyledon are arranged concentrically and radially on the basal plate of the placenta. Anchoring stems may be 2 cm. long at term. Venous drainage of villi in cotyledons follows the three orders of arteries in a reverse direction. Wilkin likens the arrangement of a cotyledon to a tambour. Free villi exist in various forms and places. Few are found on the first and second order vessels, although small growing “tufts” of growing free villi are seen. There are many tufts of free villi that arise along the third order vessels. At the site of the anchoring insertion in the basal plate of the stem villi, many give rise to continuing free villi in a recurrent direction, away from the basal plate and toward the chorioallantoic plate.
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Fetal
3
cotyledons
in hemochorial
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427
__ CHORIOALLANTOIC PLATE
_- IST ORDER
VESSELS
- ZND. ORDER
VESSELS
--
3RD
ORDER
- SPIRAL -----
IMPLANTATION
ARTERY
MATERNAL BASAL
VESSELS
VEIN
PLATE
CROWN
Fig. 1. Schematic
diagram of the basic elements of the fetal cotyledon, as described by Wilkin. To this has been added the orifice of an endometrial spiral arteriole in the center of the implanted crown of the anchoring villi containing third order blood vessels. These give rise to numerous free villi and recurring villi, but the center of the “tambour” is relatively free of villi. Upon extension of the distance between chorioallantoic plate and basal plate, second order blood vessels, then first order blood vessels supplying the unit are pulled out of the chorioallantoic mesenchyme. The tambour constitutes a terminal glomus of arterial pressure which forces the maternal blood through the surrounding villi to the subchorial and true intervillous spaces, where the pressure is low (5 to 8 mm. Hg) .
These are the chandelier types of villi that SpannePO believed were the typical villi of the hemochorial placenta. Actually these villi, along with abundant free villi arising along the descending stem villi, make up a considerable portion of the total peripheral fetal vascular bed of the placenta. There is no evidence that the villi of adjacent cotyledons anastomose, although the terminal villi freely interlace unless a septum of the basal plate comes between two groups of cotyledons. All of the above observations have been fully confinned and extended by Crawford.7 Both Wilkinz4 and Crawford7 make a crucial observation
which
is clear
in the
figure
shown
by Wilkin (Fig. 3424) and by Crawford (Fig. 277). Crawford calls attention to the fact that the interior of each cotyledon is quite free
of villi
and
is essentially
hollow.
This
is
why Wilkin considered the cotyledon to be like a tambour. Crawford states, “The divisions in all cotyledons are so arranged that the peripheral or fringe region of the cotyledon is always on the outside. By contrast,
within the interior of the cotyledon the larger divisions are comparatiuely bare of small capillary-bearing branches” (italics supplied). The import of a relatively villus-free interior of the cotyledon appears to this writer to bear a necessary relationship to the morphogenesis of the cotyledon as well as to its function. Conditions cotyledon
governing formation
We are almost ready to ask, How is it that the definitive placenta, containing fetal cotyledons, is formed by the twentieth week of pregnancy? It will be helpful to take note in this respect of several features that Crawford has described in his careful and critical studies, for these clearly relate to the dynamics of cotyledonary formation. The number of fully formed cotyledons is small; about 10 are large, about 50 are of medium size, and the rest of the fetal elements, totaling up to about 150, are not cotyledons as described above. They are, in-
stead. unformed or rudimentary structurrs that do not appear to have been definitive11 described. Their very number should draw attention to them, and. indeed, in the case of Heyns,‘” they have. In a recent thesis txntitled Abdominal Decompuwion, an intriguing a.ccount is given of the rudimentary obviously residual structures of the chorion frondosum which do not become incorporated into fetal cotyledons. Heyns says, “A point of interest is the finding of visible filaments that run right across the placental space from chorionic to basal plate. One wondered what these were because they were too white and firm to be blood vessels. Microscopy showed them to be a core of homogenous material like umbilical cord, perhaps mesenchymc, carrying blood-vessels of up to 60 ,U diameter which were obviously arterioles. Further study showed that the villi seemed to bud off these columns.” These appear to be some of the major vascular units which give rise to free proliferating villi that R0e” and Crawford’ have shown so well, but they do not note, as does Heyns, that these are chiefly anchoring vessels like those of cotyledons but, nevertheless, independent of cotyledons ; that they are so numerous in relation to cotyledons as Crawford has found; and that they are, in a morphologic sense, terminal proliferations of umbilical vessels having passed into and through the chorioallantoic plate and on into the intervillous space, as so clearly described by Heyns. Physiologically, the entire fetal placental capillary bed consisting of rudimentary structures and cotyledons is under the same high distending blood pressure which results from resistance to umbilical vein flow by virtue of the sphincter in the ductus venosus and resistance to umbilical blood flow through tissues of the fetal liver.17, I8 The morphologic and functional consequences of such a distending pressure, familiar to obstetricians at cesarean section, will be referred to below. Crawford notes that the successive divisions of the umbilical arteries as they radiate and divide in the chorioallantoic plate govern the number and the size of cotyledons. In one type of placenta, the divisions axe
regular and dichotomous; extra arterial divisions do not obscure the basic pattern of blood vessel division. By contrast, the battledore placenta showx a large number of divisions’ of the umbilical arteries almost at once, with fewer arterial branches on the fetal side of the placenta. “It follows,” says Crawford, “that magistral cotyledons [in the battledore placentas] are generally larger and heavier” than in the other type of placenta in which arteries branch on the chorioallantoic part of the placenta. We set by this that conditions which relate to early development of the fetal cardiovascular system influence both the size and number of cotyledons. This developmental pattern is set in the early weeks of pregnancy. The manner by which the arteries of the chorioallantoic plate contribute to the formation of cotyledons will be described below. This latter process occurs sometime during the second or third month of pregnancy, as we shall see. Certainly, the number and size of arterial branches in the soft, mucopolysaccharidecontaining tissues of the chorioallantoic plate is one determining factor in the number of cotyledons that form. Other less evident fetal factors are capable of playing contributory roles. The arterial blood pressure in cotyledonary arteries, as well as in the arteries of the rudimentary anchoring villi described above, is high at term. An educated guess would place it at the level of 50 to 60 mm. Hg. The cotyledonary vein pressure is estimated by Dawes* to be about 15 mm. Hg, a figure close to the measurements made by Reynolds*” in umbilical veins of lambs (weighing 3 to 5.5 kilograms) near term. The high venous pressure is the result of resistance to flow of placental blood returning to the fetus through (a) the tissues of the liver. and/or (b) the ductus venosus which has a sphincter that controls blood flow through jt.17, 19 In short, the entire cotyledonary structure and fetal placental vascular bed is under a distending pressure from the back-pressure within it resulting in a gentle erectile action of all the placental tissues. The vascular distending mechanism serves to keep the cotyle-
Volume 94 Number 3
donary vessels patent and extended. So much for the present for the fetal conditions one must consider during the formative stages of cotyledonary development. We shall see their importance later on. The question of what relation, if any, the maternal circulation in the placenta bears to the fetal cotyledons has never been evaluated. The consensus one seems to derive from reading many papers dealing with the blood supply (endometrial spiral arterioles) to the basal plate of the placenta is that the distribution of arterioles exhibits a haphazard arrangement, except that there are none on maternal septa in the basal plate.15 One need refer only to the excellent recent papers of Ran~s.ey’~? l6 to obtain the best and most recent views dealing with a very large literature on the subject. There one finds that in the monkey (which has a hemochorial placenta) one animal has 17 arteries entering, and 37 veins draining and the 2 chorioallantoic placentas (one situated dorsally and one ventrally in the uterus). These vessel openings are fully verified by cineradiography in the monkey. All are not patent at one time. No one knows, however, how many cotyledons there are in the monkey. What of woman? Boyd4 has reported many arteries passing through the basal plate of the placenta at midpregnancy. He held at one time that there are some 180 to 320 at term. The number, he suggested, increases as pregnancy advances. According to Ramsey,15 Boyd now considers his original estimate as “appreciably too high.” It appears that the number of arterial entries into the intervillous space may approach the number of cotyledons that Crawford has observed. Is there a causal relationship between arteriolar openings and cotyledons? The fact that the inner aspect (e.g., inside) of the cotyledon lacks an abundance of free villi suggests that an endometrial spiral artery passes its rapidly moving stream under high arterial pressure into the center of a cotyledon from which it then would perfuse through the villous interstices and force villi within the tambour to be pushed toward the
Fetal
cotyledons
in hemochorial
placenta
429
outside periphery of the cotyledon, to resorb, or both. Following the paths of least resistance, maternal blood then courses toward venous orifices. Such paths may be rather direct or, passing to the subchorial lake, blood may move to nearby or somewhat distant venous orifices in the basal plate, in the septa of the basal plate, or at rare marginal lakes. Ramsey, Corner, and Donner16 in their recent paper discuss the flow of maternal blood in the intervillous space. “Blood,” they say, “is delivered to the intervillous space of monkey and human placentas under a maternal pressure somewhat higher than the pressure within the space itself. Slow lateral dispersion of blood occurs in consequence.” Pressures recorded by Hendricks9 in the human show such pressure differences within the intervillous space. The flow is referred to frequently in the literature as jets, but Ramsey points out that there is continuous flow from the arteries but of varying velocities. The term, “pulsatile flow,” would suit the physiologist better. RamseyI notes that the flow from an arterial orifice may be, at times, intermittent as a result of local or generalized uterine contraction. Most placentologists have not identified a maternal arterial opening at the center of the coronally attached anchoring villi of each cotyledon. Boe3 alone claimed in 1953 that basal plate arteries open primarily at the center of attachment of cotyledons, but he did not know the structural details of the fetal cotyledon, Blood would then flow into the cavities of the cotyledons. Neither he nor anyone else has attached developmental significance to this arrangement. The observation of Boe3 on this matter must be looked for again in both the monkey and the human. In the course of writing this essay, supporting evidence for this thesis has come to light. An early draft was sent to nine experts in the field,2 one of whom was Dr. Elizabeth Ramsey. She pointed out that the concept just cited would explain-and there is no other explanation known to us-what she and others had seen in cineangiographs of opaque
Fig. 2. For
legend
see
top of
facing
page.
Volume 94 Number 3
Fetal cotyledons in hemochorial placenta
431
Fig. 2. Serial angiographs following injection of x-ray opaque material retrograde into the femoral artery, and from there into a uterine artery contrast enhanced electronically (Logetroncis) . Rhesus monkey in midpregnancy (about the ninety-second day). Lateral view. (Serial pictures were taken at 1.5 second intervals for about 30 seconds by Dr. Elizabeth M. Ramsey and colleagues and made available by her and the Department of Embryology, Carnegie Institution of Washington.) The pictures here show: A, Filled myometrial arteries from which a number of filled spiral arterioles may be seen passing to the placenta. The ventrally implanted placenta is at the right. At several points, the dye is passing through arteriolar orifices in the basal plate of the placenta. At the top, two arterioles have a common opening (first demonstrated by Ramsey13; B, 3.0 seconds after A. Dye now appears as localized puffs of material at a number of points; C, 6.0 seconds after B and 9.0 seconds after A. Clear areas appear in center of contained puffs as dye-free blood penetrates these locally contained puffs. The absence of a “doughout” in top puff (presumed interior of a fetal cotyledon) would result from turbulence within the fetal cotyledon from two arteriolar jet streams of blood preventing clearing at the center of the contained puff of dye. Note the “dougnut” at bottom center. In addition to the cleared center, one can see about seven serrated indentations. These appear to be the innermost anchoring villi between which opaque medium filters from the cavity of the tambour to the outside of the cotyledon (see text). D, Same, 3 seconds after C and 12 seconds after A. The “holes” of the doughnuts are slightly longer than in C and the diameters of “doughnuts” are slightly larger than in C.
material entering the intervillous space from endometrial spiral arterioles.16 The first picture is that of a distinct “puR” of opaque material that retains its shape as it becomes larger and its center becomes less opaque before all the medium becomes dissipated. She referred to these as “doughnuts.” The point seems clear that while the first spurt of
opaque material is held to a confined space and not quickly dissipated, incoming blood without opaque material clears the center of the “puffs” (Figs. 2 and 3) . If it be true that the hollow cavity of each cotyledon receives pulsatile spurts of maternal blood, by what mechanism is this anatomical arrangement achieved? To find the answer, one must go back to the earliest time when this could come about. Consider the period of villous placental morphogenesis (Table I). This begins about 13 days after fertilization in the human.‘l It is preceded by a previllous period (days 6 to 13) which consists of prelacunar development (days 6 or 7 to day 9) and a lacunar period (days 9 to 13) in which connecting “lakes” of embryotrophe and venous blood
Fig. 3. Anterior-posterior view of same structures shown in lateral series described in Fig. 2 taken in another series of angiographs. Picture taken 6.0 seconds after injection of opaque substance into femoral artery. In this picture, the location of at least 10 fetal cotyledons can be identified. In at least four of these, the hollow centers already appear from opaque-free blood entering the site of the contained opaque dye, so clearing it. Suggestions of the “doughnuts” appear in several more areas. Compare with B and C in Fig. 2. The posteriorly implanted placenta is at the left, the ventral placenta, toward the right. (By Dr. Elizabeth M. Ramsey and colleagues and reproduced by courtesy of her and the Department of Embryology, Carnegie Institution of Washington.)
432
Reynolds
Table I. Hemorchorial Dap post ouulation
Basic stages placental development
placental of
l-6
Tubal and uterine transit cleavage-blastocyst formation
6
Implantation
7 to 8
Previllous
(,human
Key
(period)
mor$hologic-functional correlations
New
(period)
13-18
features
No fills
circulation
Sluggish circulation
likely
Chorionic villi form by cytotrophoblastic columns derived from chorionic vesicle; these are anchoring villi, unattached or branching villi as follows: (a)
Primary villi; 0.8 mm. long, 120 p thick. Cytotrophic cells continue to give rise to syncytium about them
(b)
Secondary villi; invasion by, and in situ formation of, extraembryonic mesoderm; (body stalk and its contents and amnion form) Tertiary villi; 2 to 2.7 mm. long, 400 p thick. Capillaries have delaminated from cytotrophoblast and then grow along with stroma and proliferate into capillary plexus. Umbilical arteries, veins spread through blastoderm (see Fig. 4) Villous capillaries tap these arteries and veins
18-21
Oxygen Fetal placental circulation established; still no maternal circulation of arteriovenous shunt variety, with arterioles entering the intervillous space 21 to 40
developmental
Prelacunar period; trophoblast proliferation-no maternal blood; cytotrophoblast gives rise to syncytium Lacunar period; endometrial veins tapped, maternal blood connecting lacunae; arterial capillaries tapped
Villous
i
1
9-10 11
13 to 40-50
morphogenesis
Chorion sum
frondo-
See Figs. 4 and 5. Multiple villi, having proliferating and ends of many anchored recurrent ends (“chandelier
anchored free villi vilii have type”‘)
Progressive trophoblast. forms
in cytoplate
relative decrease Chorioallantoic
Still from
tension
no circulation endometriul
low
in IVS
of maternal arterioles
blood
Volume 94 Number 3
Fetal
cotyledons
in hemochorial
placenta
433
Table I-Cont’d Days post ovulation 40-50
Basic stages placental development
of Key
morphologic-functional correlations
New
Cotyledon formation First phase
Second
Third
developmental
features
1. Cavitation. Trophoblast invasion opens spiral arterioles (40-60 in human; about 20 in rhesus). Further invasion stops. Jets of arteriole blood form localized hollows in chorion frondosum. Maternal circulation established. The anchoring villi contain third order fetal vessels. Pressure in cavities is 40-60 mm. Hg
phase
2. Crowning and Extension: Cavitation causes concentric orientation of anchored villi around each arteriolar spurt and cavitation. Maternal blood pressure in intervillous space separates chorioallantoic plate and basal plate, anchoring villi become extended and grow, but supplying vessels of anchored villi are pulled from chorioallantoic mesenchyme into intervillous space (sub-chorial lake begins to form) ; these vessels are second order fetal vessels) 3. Completion. Anchoring villi (third order vessels) and second order vessels are pulled as blood volume in IVS increases; main supplying vessel of each group of second order vessels supplying the anchored villi is pulled from chorioallantoic rnesenchyme forming the 1st order vessel of a fetal cotyledon
phase
4. Rudimentary cotyledons or anchoring villi (about 150) complete except for cavitation and crowning, fail to invade arteriole and form cavities. IVS pressure about them is about 5-8 mm. Hg 80-85 140 140
Definitive cotyledons about they are at 140 days Definitive
placenta
(a) (b) (c)
to 280
Septa
basal
plate
Septa
l/9
size,
IO-12 large cotyledons 40-50 small to medium cotyledons 140-150 rudimentary cotyledons, complete except for tambour, crown implantation and arteriolar jet to distend the cotyledon form
in basal
plate
5. Formed cotyledons are areas of high maternal IVS pressure; rudimentary ones are found in areas of low IVS pressure
Septa are folds plate resulting villi between allantoic plate, mary vessels. last half of stretched to ing fetus
or “puckers” in basal from pulls of inserted basal plate and choriothrough attached priUterus grows little in pregnancy, so it is accommodate the grow-
434
Reynolds
occur in the syncytiotrophoblast. During this period, maternal veins and arteriolar capillaries are tapped. l1 Maternal blood is in the lacunae, where it circulates sluggishly, at best. The period of villous proliferation and elaboration begins on day 13, as mentioned above and shown in Table I, and is generally held to continue to the end of the fourth month’l but according to Alvarez” and Crawford,’ it continues until term (Table I). At first, innumerable short, small chorionic villi (cytotrophoblastic columns) appear around the entire conceptus. These consist of a core of cytotrophoblastic tissue which gives rise to the surrounding syncytium.‘? They contain no blood vessels and are, by definition, primary villi. As extraembryonic mesoblast tissue migrates toward the villi from the blastoderm surrounding the extraembryonic coelomic cavity, the villi are only some 0.8 mm. long and about 120 microns thick. When filled with mesenchyme, secondary villi are said to exist; they, too, are still free of blood. Meanwhile, fetal blood vessels leave the body stalk of the embryo during the eighteenth to twenty-first days. They branch out within the tissues of the blastoderm around the extraembryonic coelomic cavity. As they ramify throughout the blastoderm, the capillary vessels which arise by angiogenesis in the secondary villi become connected with the fetal vessels that grow out from the body stalk. By this time, the villi are 2 to 2.7 mm. long and some 400 microns thick. The fetal blood vessels are now connected with the differentiated capillary plexus in the villi and so comprise the ultimate basic form of the tertiary villus. These anchoring villi of the chorion frondosum give rise to ever-proliferating free villi within the intervillous space; capillary blood vessels multiply within them.” This is the accepted view based upon the classic study of Hertig.” They constitute (a) the vascular precursors in the chorion frondosum of the future third order cotyledonary vesse!s, described by Wilkin and by Crawford and (b) the persisting, noncotyledonary stem villi, described by Crawford and by Heyns. The tertiary villi are anchored firmly by cytotrophoblastic cell col-
Fig. 4. Photograph of fresh human chorion frondosum surrounding the blastoderm of an embryo 7 weeks, 6 days menstrual age (probably about 42 days’ ovulation age). The origins of stems (anchoring) villi from the blastoderm are clearly visible, especially on the left side nearest insertion of umbilical cord. Each anchoring villus is covered with free villi, and is anchored in the deridua, only 5 small pieces of which (largest 20 x 45 mm.) were shelled out of the uterus as the concrptus was removed. The base area, which ultimately gives rise to the true placenta, orcupied about two fifths of the entire surface in the specimrn, the remainder being destined for atresia and to become chorion lacve between the amnion and the decidua capsularis as the growing conceptus presses upon it. The above description is based on original notes by Dr. C. H. Heuser. Note the dividing and splaying blood vessels derived from the umbilical vcssels as the former surround the coelomic cavity, throughout the blastoderm where they supply the blood vessels in the anchoring villi of the chorion frondosum. (Used by courtesy of The Department of Embryology, Carnegie Institution of Washington Specimen No. 8537. C-R = 19 mm.)
umns which break through the syncytial mass about the conceptus. The columns attach themselves firmly to maternal decidual tissue. From the sides of these anchored villi, free villi arise which become increasingly complex by virtue of further branching, as mentioned above. The anchoring villi may give rise to recurrent branching villi from the basal plate.
Vohne 94 Number 3
Fig. 5. Schematic drawing of early human embryo based on photographs and models showing origin of anchoring villi from embryonic blastoderm without abundance of free villi covering them, as seen in Fig. 4. Attachment to decidua is not shown. (Drawn by James F. Didusch. Used by courtesy of the Department of Embryology, Carnegie Institution of Washington. Carnegie Collection No. 836, 23 days’ ovulation age.)
So far so good. This is the line that ordinarily divides the embryologist from the placentologist. The former has not accounted for cotyledons and the placentologist accepts them as elements of the formed placenta. It is at this point that the theory of cotyledon formation, based on facts rooted on each side of this line, is presented as an essential guide to future investigators to make observations at this crucial point in order to understand much placental physiology and pathology. We know that forty or more days after fertilization, a multitude of anchoring (stem) and tertiary villi, each rich in free villi of the chorion frondosum, abundantly surrounds the developing conceptus (Figs. 4 and 5) . Gradually, as enlargement of the conceptus and uterus occurs, progressive changes in the fetal-maternal relationship take place. What are they? In the first place, the supply of maternal arterial blood to the intervillous space increases progressively as the uterus and its contents grow. Clearly, there is a first venous vascular breakthrough into the early lacunae (about day 9) ; other venous vascular break-
Fetal
cotyledons
in hemochorial
placenta
435
throughs follow. Later, capillaries are tapped. As the relative area of the chorion frondosum attached to the decidua capsularis diminishes because of ovum enlargement, resulting in the chorion laeve beneath the decidua capsular& the definitive placenta takes shape. Ultimately, by the end of pregnancy, there may be up to two hundred maternal arteries (very probably far fewer, predictably something of the order of 50 to 60) passing through the decidua basalis. How rapidly the increase of vascular openings into the intervillous space takes place is unknown. However, it is clear that the definitively formed placenta, as outlined above, exists by midpregnancy. Crawford shows formed cotyledons by the twelfth week. These are about half the size of 20 week cotyledons (two planes only, judged from photographs). Sometime between the fortieth and the eightieth days of pregnancy, therefore, the cotyledons are formed. The situation prior to cotyledon formation is that if a maternal arteriole opens up through the basal plate it should “spurt” into a mass of anchored tertiary villi of the chorion frondosum. This cannot help but cause local cavitation in the chorion frondosum. Since the spurt exerts force, it has the capacity to spread a group of villi about the vascular opening, and the surrounding anchored villi will become molded into a concentric, ringlike position (the couronne of Wilkin) . As a consequence, crowding, or forcing the growth of free villi along the stem villi toward the outer portion of the forming cotyledon should occur. It is possible that under pressure, resorption of villi within the cavity may take place. We have in this functional scheme, the potential for (a) the coronal attachment of villi and (b) the hollow tambour feature of cotyledons discovered by Wilkin and elaborated upon by Crawford. From what has been said, the opening of endometrial spiral arteries through the basal plate occurs after formative tissue differentiation of the placental elements is complete. Fetal angiogenesis is definitively complete and functioning and only requires that it be
436
Reynolds
molded by the shaping forces of maternal blood on the basic placental elements found in the chorion frondosum. There are other implications of the concept described above concerning placental morphogenesis which need consideration and study. Since the flow of arterial blood under pressure and in volume into the intervillous space by way of the cavities of cotyledons, the character of placental blood flow changes profoundly, Prior to this time, the circulation of maternal blood is by way of reflux venous flow and maternal capillary to maternal vein by way of lacunae, then the intervillous slow, at quite low space. I” It is relatively pressure and predictably sluggish and hypoxic. After direct entry of arteriolar blood, the elements of the arterial-venous shunt described by Burwell” are present. The internal cavity of each cotyledon must be considered to be a terminal arterial glonlus from which maternal blood escapes slowly into the intervillous space proper. Intervillous space blood pressure, oxygen tension and blood flow should increase substantially by enrichment with arterial blood, and in fact, they must do so in order to bring about the changes in maternal blood volume which do, in fact, occur as with a direct arteriovenous shunt. No one as yet has determined the earliest effects in the maternal organism of the placental arteriovenous shunt to its earliest moment of onset. In passing, it may be speculated-since theorizing on the basis of known related phenomena is one of the accepted methods of science- -that the placental tissue itself is invasive until the arterioles are tapped and that it ceases to be invasive after that time. Should such a hypothesis bear the test of objective measurement, it may be found by future investigators that anaerobic metabolic pathways in trophoblastic metabolism determine its invasiveness, and that elevation of the mean oxygen tension in the intervillous space evokes an aerobic pathway of metabolism in the trophoblast depriving it of its invasive quality. It is an intriguing possibility that the fetal placental tissue may exhibit the quality of invasiveness until its thirst for oxy-
February 1, 1966 Am. J. Obst. & Gynec.
gen is relieved, and that when it is, it beco’mes a passive tissue. The opening of 40 to 50 endometrial arterioles (the probable number present), one by one for a time, increases the quantity of maternal blood contained in the intervillous space, and the fully formed and functioning placenta is greatly thickened as the distance between the basal plate and the chorioallantoic plate becomes greater. This may be affirmed by observation at cesarean section. Such an increase will have consequences upon the fetal blood vessels that connect the two placental plates. At first, these are in anchoring villi, now arranged in a crowded circle of an implantation ring about each arteriolar orifice (couronne of Wilkin) and with a cavity formed within them about each spurting jet of blood. But how may one explain the development of the first and second order cotyledonary vessels? In the first place, the vascularity of the uterus increases as it grows.15 More blood is carried into the intervillous space until eventually a sustained pressure (during uterine diastole) of about 5 to 10 mm. Hg is maintained. Pressures at the jets within each cavity will be grea,ter, since endometrial arterioles become straightened out and 1arger.l” Pressure of blood in the subchorial lake forces the chorioallantoic and basal plates farther apart. The resulting pulling action on the anchored villi inserted in the basal plate is aided by fetal blood pressure within the placental blood vessels. Umbilical vein pressure contributes to extension of the anchored villous structures because of the blood pressure within them. The two forces, maternal intervillous space blood pressure, on one hand, and fetal cotyledonary blood pressure, on the other, can only combine (a) to extend the blood vessels by a pulling action on the anchored villi containing the third order cotyledonary vessels and (b) to pull arterial and venous fetal blood vessels in the blastoderm that connect the vessels in anchored villi of the cotyledon out of the soft, mucoid substance of the chorioallantoic plate. These form, in turn, the second order and first order blood vessels, respectively. Such
Volume Number
94 3
changes bring about completion of the cotyledonary vascular components of the placenta. The second order and first order vessels had their origin, therefore, in the dividing and splaying fetal blood vessels which divided dichotomously in the extraembryonic mesoderm as blood vessels grow out of the embryonic body stalk about the eighteenth day after fertilization. The ground work is laid, accordingly, at that early time for the ultimate cotyledonary differentiation that takes place weeks later. There are implications in the foregoing hypothesis which merit consideration. The growth rate of the uterus diminishes after the fourth month (evidenced by thinning of the uterine wall), while the fetus and amniotic fluid increase in size and amount, respectively. The cotyledons are now an integral, physical part of the basal plate. They are subjected, therefore, to pulls in different directions as the uterus is stretched. The cotyledons are attached by the first order blood vessels to the allantoic plate. The pulls between the two plates of the placenta must be accommodated by internal adjustments within the tissues to which the cotyledons are firmly attached. Clearly, stretching and growth of the uterus contribute to the displacement of the cotyledons by the forces to which they are subjected. Uneven pulls on the basal plate may be expected to buckle and fold it at some points. Such buckling undoubtedly is the basis of the origin of maternal septa in the basal plate. There is no other known concept or hypothesis to account for them at this time. The fetal cotyledons, once formed, are an integral part of the basal plate and the only mobility that exists between the chorioallantoic plate and the basal plate is imparted by the first order cotyledonary vessels. These, as mentioned above, may be 0.5 to 4 cm. in length. Unequal growth of the two plates of the placenta must of necessity cause multiple and varied lines of stress between them. This concept of dynamic force effecting a passive localized yielding of tissues in the basal plate accounts for the fact that septa form only between sites of attachment of fetal cotyle-
Fetal cotyledons
in hemochorial
placenfa
437
dons to the basal plate. They are devoid of openings of endometrial spiral arteries but do have venous openings to drain the intervillous space.l” Taken as a whole, the concept of the origin of fetal cotyledons from the elements of the chorion frondosum and the existence in mature placenta of elements of that structure which remain essentially as they were in chorion frondosum tells us that the functioning placenta, when fully formed, has some 50 localized regions in which maternal blood moves out slowly under high pressure, from the cavities of the cotyledons into other areas about free villi on rudimentary elements that are residual remnants of the chorion frondosum stems, where pressures are low. A key to the puzzle of fluid exchange between mother and fetus is the existence of high capillary blood pressure within the fetal placental capillaries. The cotyledons possess the potentiality for movement at high intracotyledonary pressure of water and dissolved solutes from maternal blood into fetal blood. The rudimentary structures of the early chorion, so well described by Heyns and counted by Crawford, on the other hand, are so situated that the same high fetal capillary blood pressure in them provides for movement of water in the opposite direction, from fetal blood to maternal blood. This is a partial equivalent of Mossmans’ principle of countercurrent flow as a factor in fluid exchange within the placenta. It is reasonable to say, therefore, that with respect to receiving water and some solutes the fetus transacts most of its business in one corner of the store, the cotyledons, and that for getting rid of water and some dissolved substances, this transaction takes place predominantly in other parts of the store. One area is for receiving, the other dispensing, so far as the fetus is concerned. All of the concepts set forth in this essay have much factual evidence to support them. Until each facet of the whole is subjected to the test of direct and critical examination, the flaws in the theory will not be seen. Meanwhile, with a conceptual framework in which to bring together the great multiplicity
438
Febluary 1, 1966 Am. J. Obst. & Gynrc.
Reynolds
of presently known facts of morphology, physiology, and pathology, it is possible to bring them together into a unified whole. Such is the purpose of this essay. Summary The principal stages of organogenesis of the hemochorial placenta are known in a descriptive sense. These are recognized, after implantation, as previllous, villous, and cotyledonary. The previllous stage is first without maternal blood but shortly, uterine veins, and later endometrial capillaries, are tapped and Iakes of maternal bIood and products of fetal tissue breakdown form embryotrophe in the syncytium. This material is believed to be a source of nourishment for embryonic tissues. When the conceptus becomes surrounded by an abundance of villi of cytotrophoblastic columns that give rise continuously to a covering layer of syncytial tissue, this is called the chorion frondosum. It has been seen as late as 45 days conception age in a human conceptus. No one knows now the nature (arterial, venous) of maternal blood flow about these early fetal tissues. However, by the eighty-fourth day, definitive hollow tambour-like fetal cotyledons exist and these become larger, in these dimensions, as gestation continues, To account for the transformation of chorion frondosum into fetal cotyledons (40 to 60 cotyledons altogether, and about 150 undeveloped rudimentary ones that are residual anchoring villi with numerous free villi from the chorion frondosum) the view is advanced in this essay that when endometrial spiral arterioles are tapped (sometime after the fortieth day) the local force of blood pressure causes organization of the local fetal cotyledons, and that this is essentially a hemodynamic molding process acting on the tissues
of the chorion frondosum. It involves (a! cavitation, (b) crowning and extension of anchoring villi, and (c) completion by dctlelofiment of the sup&&g vascular pattern out of the original blastoderm, now the chorioallantoic plate. Physiologic data from the literature (local blood pressure differences and oxygen tension differences within the intervillous space and cineangiography) are cited to support this functional concept of the last stages of definitive morphogenesis of the placenta. This theory raises questions concerning what metabolic factors limit trophoblastic invasiveness. It offers a solution by which physiologists may account for hydrostatic forces of a conventional sort in maternalfetal exchange of water and many dissolved substances since the cotyledons are local regions of high maternal blood pressure with respect to fetal blood pressure, and the noncotyledonary anchoring viIli are areas of low maternal blood pressure with respect to fetal blood pressure. Each cotyledon is a terminal arterial glomus from which blood filters slowly through the surrounding fetal villi into the intervillous space proper. Without such a concept one is confronted with the currently prevailing view of uptake of water by fetal blood into capillaries where pressure is high (15 mm. Hg or more) from regions where the pressure is commonly regarded as being low (intervillous space, 5 to 10 mm. Hg). The author is indebted to the following individuals, among others, for reviewing and criticizing helpfully an early draft of this paper sent to them in April, 1964: Dr. J. M. Crawford, Professor Arthur T. Hertig, Professor I. H. Kaiser, Professor Harlan W. Mossman, Dr. Elizabeth M. Ramsey, and Professor P. G. Wilkin.
4. Boyd, J. D.: In Vi&e,
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1. Amoroso, E. C., Marshall’s
physiology of reproduction, ed. 3, London 1952, Longmans, Green & Company, part 2, Chap. 15.
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20: I> 1962. Bse, F.: Acta obst. Suppl. 5, 1953.
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C. A., editor: Gestation: Transactions of the Second Conference, New York, 1956. Josiah Macy Jr. Foundation 17: 132, 1956. Burwell, C. 8: Bull. Johns Hopkins Hosp. 95: 115, 1954. Crawford, J. M.: J. Obst. & Gynaec. Brit. Emp. 66: 885, 1959.
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Crawford, J. M.: Am J. OBST. & GYNEC. 84: 1543, 1962. Dawes, G. S.: AM. J. OBST. & GYNEC. 76: 969, 1958. Hendricks, C. W.: AM. J. OBST. & GYNEC. 76: 969, 1958. Hertig, A. T., and J. Rock: Contrib. Embryol. 25: 37, 1935. Hertig, A. T., and J. Rock: Contrib. Embryol. 29: 127, 1941. Heyns, 0. S.: Abdominal decompression, Thesis, Witwatersrand University, Johannesburg, 1963, p. 69. Hunter, W.: The Anatomy of the Human Gravid Uterus Exhibited in Figures, 1774. Mossman, H. W.: Contrib. Embryol. 26: 129, 1937. Ramsey, E. M.: AM. J. OBST. & GYNEC. 84: 1649, 1962. Ramsey, E. M., Corner, G. W., Jr., and Donner, M. W.: AM. J. OBST. & GYNEC. 86: 213, 1963. Reynolds, S. R. M.: In Villee, C. A., editor:
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The placenta and fetal membranes, Baltimore, 1956, Williams & Wilkins Company, pp. 172173. Reynolds, S. R. M.: In Congenital heart disease, American Association Advances in Science. Washington. D. C.. 1960. D. 21. Reynolds, S. RI MI: Am,’ J. Physiol. 203: 655, 1963. Spanner, R. : Ztschr. Anat. u. Entwcklngsgesch. 105: 163, 1935. Stieve, H.: Ztschr. mikr.-anat. Forsch. 50: 163, 1935. Tao, T. W.: (See Hertig, A. T.:) Obst. & Gynec. 20: 859, 1962. Wilkin, P.: Gynec. et obst. 53: 239, 1954. Wilkin, P.: In Le placenta humain, Snoeck, J., editor: Paris. 1958. Masson et Cie. Wislocki, G. B., and Streeter, G. S.: Contrib. Embryol. 27: 1, 1938. 1853 West Polk Street Chicago 12, Illinois