Implantation and Placenta







  • Chapter Outline



  • Introduction 741



  • Anatomy and Embryology 741




    • Implantation and Early Pregnancy 741



    • Functional Unit of the Placenta 745




  • Examination of the Placenta 745




    • Umbilical Cord 745



    • Membranes 748



    • Meconium on Cord and Membranes 749



    • Architectural and Developmental Abnormalities 750




  • Microscopic Lesions of the Placenta 757




    • Placental Inflammation and Infection 757



    • Vascular Lesions 759



    • Non-Trophoblastic Tumors of the Placenta 764





Introduction


Interest in placental examination has increased in the last two decades, with more appreciation by obstetricians and neonatologists of the contribution the report can make to understanding adverse perinatal outcomes. Not every placenta need be examined, and a triage system is essential. Indications for examination are essentially any disease of the mother, and abnormality of pregnancy, labor, delivery, or the immediate postnatal period. Placental abnormalities should prompt at least macroscopic evaluation. In most institutions, this constitutes 10–15% of deliveries. Placental examination is an integral part of the fetal or perinatal autopsy and adds conclusive or important information in between one-third and two-thirds of such cases. While the delivery suite may be the ideal place to initiate microbiology and cytogenetic testing, full pathologic evaluation requires a laboratory-based grossing station with adequate photographic and other facilities. For those cases judged by the pathologist to only require gross examination, retention of formalin-fixed tissue can permit subsequent histologic examination in cases where an abnormality becomes apparent in neonatal life, rather than at birth. In addition to providing information to clinicians and parents, the placenta has been described as ‘an amazingly good defensive witness in “bad baby” lawsuits.’


In examining the placenta, the pathologist has the advantage of having the entire organ. Even so, many other variables must be taken into account to interpret the morphologic findings correctly. The gestational age may not be entirely accurate. Important data such as the infant’s weight, changes in growth patterns, and other biophysical parameters are not always provided. Even with these, the variable villous patterns can make clinical correlation difficult. Proper sampling of sections for histology is also important in order to avoid false conclusions.


This chapter aims to provide the pathologist with a structured approach to the placental features most commonly encountered in routine practice. Background information on morphogenesis is provided to assist in interpretation.




Anatomy and Embryology


Implantation and Early Pregnancy


Fertilization, cell division, formation of the morula, and later formation of a blastocyst are independent of maternal contact. The blastocyst reaches the uterus on day 3 after fertilization and implants by the end of day 7.


The process of implantation has three phases: muscular, adhesive, and invasive. The muscular phase concerns transport of the conceptus to the optimal site for implantation, which in humans is the mid to high posterior wall of the uterus in the mid-sagittal plane ( Figure 32.1 ). Implantation in different locations may be associated with different pathologies, e.g., fundal placentation shows an association with intrauterine growth retardation (IUGR). During the adhesive phase, the normally repulsive interactions between two epithelial surfaces (endometrium and trophoblast) are reversed. In the invasive phase, irregular projections of syncytiotrophoblast invade into the endometrium ( Figure 32.2 ). This phase lasts until approximately day 8 post conception and is called the prelacunar phase, based on the appearance of the blastocyst. At day 8 vacuoles appear in the syncytiotrophoblast, which become confluent to form lacunae. This change commences at the implantation pole and becomes confluent over the blastocyst by day 13. At this stage, the earliest forms of chorionic villi begin to form ( Figure 32.3 ) and the primary chorionic plate consists of a continuous layer of cytotrophoblast on the embryoblast side of the lacunae. Infiltration of the pillars of syncytiotropho­blast surrounding the lacunae by cytotrophoblast from the chorionic plate is followed by expansion of these pillars as extraembryonic mesenchyme follows cytotrophoblast. The outermost layer of trophoblast (the trophoblast shell) is formed by syncytiotrophoblast, and later by cytotrophoblast as well. Cytotrophoblast continues to invade endometrium and is seen as clusters of extratrophoblast (‘X’ cells) and trophoblastic giant cells in what will become the basal plate. The lacunar space becomes the intervillous space, and the embryologic development of villi proceeds during gestation. These developments are maximal at the deep aspect of the blastocyst and normally only this persists to form the true placenta (chorion frondosum). The remainder atrophies (chorion laeve) ( Figure 32.4 ).




Figure 32.1


Implantation (arrow) in early pregnancy.



Figure 32.2


Primitive trophoblast. Chorionic villi have not yet formed in the pregnancy of about 1 week’s duration.



Figure 32.3


(A) Day 14 conceptus as a tiny implant in superficial endometrium. (B) Detail of the earliest stage of chorionic villous formation.





Figure 32.4


Normal membrane in a third trimester placenta. (A) Amnion (A), parts of which include amnionic epithelium (AE), amnionic mesoderm (AM), and spongy level (S); the chorionic plate (C) is composed of chorionic mesoderm (CM) and trophoblast (T); beneath that is the maternal decidua (D). (B) Both the trophoblast and amnionic epithelium are markedly reactive for cytokeratin (CAM 5.2).


The cytotrophoblastic shell thins and is replaced by Nitabuch’s fibrin layer, which is composed of matrix-type fibrinoid and lies between the shell and the decidual boundaries. The fibrinoid between the shell and the intervillous space is called Rohr’s fibrinoid and is fibrin-type fibrinoid. The two are indistinguishable on routine H&E sections, but may be differentiated immunohistochemically using antibodies directed against oncofetal fibronectin for matrix-type fibrinoid and fibrin for fibrin-type fibrinoid.


The decidua is not merely the passive recipient of the conceptus, but plays an active role in successful placentation. Cytotrophoblastic cells stream out from the tips of the anchoring villi, penetrate the trophoblastic shell, and colonize the decidua and adjacent myometrium of the placental bed. These cells, which are reactive for human placental lactogen and cytokeratins, are called interstitial extravillous trophoblast. A subset of these called ‘intravascular extravillous cytotrophoblast’ invades and plugs the lumens of the decidual spiral arteries. The cells destroy the endothelium and the elastic and muscular tissues of the media, which are then replaced by fibrinoid material derived from fibrin and trophoblastic secretions. This produces large diameter vessels lacking intrinsic tone that allow a high-flow, low-pressure system to develop. Low oxygen tension may help control entry of cytotrophoblast into the S-phase of the cell cycle, while proliferation and high ambient oxygen tension may lead to an invasive phenotype. The higher oxygen tensions in the nontransformed spiral arteries may induce the expression of invasive integrins, a vascular adhesion molecule phenotype, and cessation of mitotic activity. This may explain why trophoblast only superficially invades the uterine veins. Trophoblast may switch to a noninvasive phenotype by becoming multinucleate.


Development in the first trimester takes place in a relatively hypoxic environment, and this is protective to the embryo. A trophoblast plug prevents maternal blood entering the intervillous space and early embryonic nutrition is provided by endometrial glands, perhaps facilitated by endoglandular trophoblast. The trophoblast plug is seen to be deficient in many early losses ( Figure 32.5 ). This results in the precocious onset of the maternal circulation, exposing the developing placenta to a higher oxygen concentration and to a higher arterial pressure. As spiral artery transformation is less effective peripherally, oxidative stress may be the mechanism by which villous regression occurs in the chorion laeve. Patterns of regression influence placental shape and cord insertion, and localized abnormalities of flow may result in a cord that was initially paracentral becoming marginal or velamentous. Noncentral cords are associated with lower birth weights, suggesting that their vasculature is less metabolically effective. Suboptimal or shallow implantation results in inadequate conversion of maternal spiral arterioles in the inner third of the myometrium. The resultant retention of vascular smooth muscle permits intermittent pulsatile contraction, resulting in mechanical and oxidative stress to the developing placenta.




Figure 32.5


A transforming spiral artery. Intravascular trophoblast and extravillous interstitial trophoblast are present.


Placental growth trajectories are established by the end of the first trimester, with cases of IUGR having smaller placentas than normal at 12 weeks, but similar growth after that. Villous development shows a major change from growth to differentiation at the end of the second trimester. Protrusions of trophoblast (trophoblast sprouts) into the lacunae are the forerunners of villi. Initially, the sprouts consist of syncytiotrophoblast, which are followed by cytotrophoblast and by connective tissue containing fetal capillaries. The villi thus formed are termed mesenchymal villi and are the precursors of all other villous types. While they are the dominant type in the first trimester, some trophoblast sprouting and mesenchymal villous development probably occurs up to term.


Immature intermediate villi (100–200 µm in size) are formed from mesenchymal villi and are primarily responsible for placental growth ( Figure 32.6 ). They have a complete trophoblastic mantle with many cytotrophoblastic cells present, but lack vasculosyncytial membranes. The syncytial nuclei are evenly dispersed without knots. They have a loose (reticular) stroma with abundant stromal channels containing Hofbauer cells. They are the dominant villous type seen in the second trimester and are transformed into stem villi when their production from mesenchymal villi decreases.




Figure 32.6


Immature intermediate villi with a reticular stroma.


Stem villi are defined by 50% or more of their stroma being compact and containing vessels with media or adventitia identifiable on light microscopy. They range in size from 80 to 1500 µm and connect the chorionic plate to the remaining distal villous tree. Some stem villi connect to the basal plate (anchoring villi). They have both an arterial and a venous circulation, which (depending on size) consist of either arteries and veins or arterioles and venules. The trophoblastic cover is predominantly syncytiotrophoblast and may be replaced with fibrinoid in the mature placenta. A perivascular capillary network is more prominent in less mature stem villi and reflects their origin from immature intermediate villi. The localization of myofibroblasts and smooth muscle cells in stem villi has been defined immunohistochemically and these cells may play a role in villous vascular regulation.


Mature intermediate villi ( Figure 32.7 ) are formed from the mesenchymal villi in the third trimester and give rise to the majority of terminal villi. They are 60–150 µm in diameter and contain capillaries, arterioles, and venules. The stroma is loose and the vessels constitute less than half the villous cross-sectional area. The syncytiotrophoblast has a uniform structure without vasculosyncytial membranes or knots. At term, mature intermediate villi make up one-fourth of the parenchyma.




Figure 32.7


Mature intermediate villi.


Terminal villi (40–60 µm) ( Figure 32.8 ) are the site of gaseous exchange and derive from the mature intermediate villi. They arise as capillary growths which, in exceeding that of parent mature intermediate villi, result in trophoblastic protrusions. The capillaries are dilated and constitute over 50% of the villus cross-sectional area. Optimal gas exchange requires the formation of vasculosyncytial membranes. The syncytiotrophoblast nuclei become pushed to one side so that only an attenuated layer of syncytiotrophoblastic cytoplasm remains applied to its basement membrane, which is itself applied to the capillary’s basement membrane. The capillaries are 3–5 mm long and each maintains its own nonbranching structure. They do not form a capillary network, but remain as long capillaries. In addition, the capillaries have varicosities where their diameters enlarge considerably. The exact functional significance of these varicosities is unknown, although a regulatory function where vascular deformation alters flow has been proposed. These villi appear at 27 weeks of gestation and increase in number until term, when they make up 40% of villi.




Figure 32.8


Normal terminal villi: over 50% of their area is capillary.


The placenta’s maternal surface is partitioned by septum formation. As collections of cytotrophoblast, the so-called ‘cell columns,’ anchor the decidua to the villi; their growth rates differ so that slow-growing ones tend to pull up the decidual basal plate, buckling it into the placental septa. These septa are incomplete and rarely reach the chorionic plate. They have no precise anatomic relationship to the functional units of the placenta.


Functional Unit of the Placenta


The placenta’s functional unit is variously known as the fetal lobule, fetal cotyledon, or fetal villous tree. At term, the normal placenta contains 40–60 lobules, each 2–4 cm in diameter. The central area receives the oxygenated blood from the maternal spiral arteries and shows an increased number of immature intermediate villi. The surrounding, more densely packed villi show a predominance of mature intermediate and terminal villi. This is the area where gas exchange is maximal, as the blood slowly percolates around small villi that have vasculosyncytial membranes. At the lobule’s periphery is the venous outflow area through which blood drains to the 50–200 maternal venous outlets. Despite the apparent continuity of the intervillous space, each lobule relies upon its own spiral artery. Thrombosis of that artery results in infarction in that lobule.




Anatomy and Embryology


Implantation and Early Pregnancy


Fertilization, cell division, formation of the morula, and later formation of a blastocyst are independent of maternal contact. The blastocyst reaches the uterus on day 3 after fertilization and implants by the end of day 7.


The process of implantation has three phases: muscular, adhesive, and invasive. The muscular phase concerns transport of the conceptus to the optimal site for implantation, which in humans is the mid to high posterior wall of the uterus in the mid-sagittal plane ( Figure 32.1 ). Implantation in different locations may be associated with different pathologies, e.g., fundal placentation shows an association with intrauterine growth retardation (IUGR). During the adhesive phase, the normally repulsive interactions between two epithelial surfaces (endometrium and trophoblast) are reversed. In the invasive phase, irregular projections of syncytiotrophoblast invade into the endometrium ( Figure 32.2 ). This phase lasts until approximately day 8 post conception and is called the prelacunar phase, based on the appearance of the blastocyst. At day 8 vacuoles appear in the syncytiotrophoblast, which become confluent to form lacunae. This change commences at the implantation pole and becomes confluent over the blastocyst by day 13. At this stage, the earliest forms of chorionic villi begin to form ( Figure 32.3 ) and the primary chorionic plate consists of a continuous layer of cytotrophoblast on the embryoblast side of the lacunae. Infiltration of the pillars of syncytiotropho­blast surrounding the lacunae by cytotrophoblast from the chorionic plate is followed by expansion of these pillars as extraembryonic mesenchyme follows cytotrophoblast. The outermost layer of trophoblast (the trophoblast shell) is formed by syncytiotrophoblast, and later by cytotrophoblast as well. Cytotrophoblast continues to invade endometrium and is seen as clusters of extratrophoblast (‘X’ cells) and trophoblastic giant cells in what will become the basal plate. The lacunar space becomes the intervillous space, and the embryologic development of villi proceeds during gestation. These developments are maximal at the deep aspect of the blastocyst and normally only this persists to form the true placenta (chorion frondosum). The remainder atrophies (chorion laeve) ( Figure 32.4 ).




Figure 32.1


Implantation (arrow) in early pregnancy.



Figure 32.2


Primitive trophoblast. Chorionic villi have not yet formed in the pregnancy of about 1 week’s duration.



Figure 32.3


(A) Day 14 conceptus as a tiny implant in superficial endometrium. (B) Detail of the earliest stage of chorionic villous formation.





Figure 32.4


Normal membrane in a third trimester placenta. (A) Amnion (A), parts of which include amnionic epithelium (AE), amnionic mesoderm (AM), and spongy level (S); the chorionic plate (C) is composed of chorionic mesoderm (CM) and trophoblast (T); beneath that is the maternal decidua (D). (B) Both the trophoblast and amnionic epithelium are markedly reactive for cytokeratin (CAM 5.2).


The cytotrophoblastic shell thins and is replaced by Nitabuch’s fibrin layer, which is composed of matrix-type fibrinoid and lies between the shell and the decidual boundaries. The fibrinoid between the shell and the intervillous space is called Rohr’s fibrinoid and is fibrin-type fibrinoid. The two are indistinguishable on routine H&E sections, but may be differentiated immunohistochemically using antibodies directed against oncofetal fibronectin for matrix-type fibrinoid and fibrin for fibrin-type fibrinoid.


The decidua is not merely the passive recipient of the conceptus, but plays an active role in successful placentation. Cytotrophoblastic cells stream out from the tips of the anchoring villi, penetrate the trophoblastic shell, and colonize the decidua and adjacent myometrium of the placental bed. These cells, which are reactive for human placental lactogen and cytokeratins, are called interstitial extravillous trophoblast. A subset of these called ‘intravascular extravillous cytotrophoblast’ invades and plugs the lumens of the decidual spiral arteries. The cells destroy the endothelium and the elastic and muscular tissues of the media, which are then replaced by fibrinoid material derived from fibrin and trophoblastic secretions. This produces large diameter vessels lacking intrinsic tone that allow a high-flow, low-pressure system to develop. Low oxygen tension may help control entry of cytotrophoblast into the S-phase of the cell cycle, while proliferation and high ambient oxygen tension may lead to an invasive phenotype. The higher oxygen tensions in the nontransformed spiral arteries may induce the expression of invasive integrins, a vascular adhesion molecule phenotype, and cessation of mitotic activity. This may explain why trophoblast only superficially invades the uterine veins. Trophoblast may switch to a noninvasive phenotype by becoming multinucleate.


Development in the first trimester takes place in a relatively hypoxic environment, and this is protective to the embryo. A trophoblast plug prevents maternal blood entering the intervillous space and early embryonic nutrition is provided by endometrial glands, perhaps facilitated by endoglandular trophoblast. The trophoblast plug is seen to be deficient in many early losses ( Figure 32.5 ). This results in the precocious onset of the maternal circulation, exposing the developing placenta to a higher oxygen concentration and to a higher arterial pressure. As spiral artery transformation is less effective peripherally, oxidative stress may be the mechanism by which villous regression occurs in the chorion laeve. Patterns of regression influence placental shape and cord insertion, and localized abnormalities of flow may result in a cord that was initially paracentral becoming marginal or velamentous. Noncentral cords are associated with lower birth weights, suggesting that their vasculature is less metabolically effective. Suboptimal or shallow implantation results in inadequate conversion of maternal spiral arterioles in the inner third of the myometrium. The resultant retention of vascular smooth muscle permits intermittent pulsatile contraction, resulting in mechanical and oxidative stress to the developing placenta.




Figure 32.5


A transforming spiral artery. Intravascular trophoblast and extravillous interstitial trophoblast are present.


Placental growth trajectories are established by the end of the first trimester, with cases of IUGR having smaller placentas than normal at 12 weeks, but similar growth after that. Villous development shows a major change from growth to differentiation at the end of the second trimester. Protrusions of trophoblast (trophoblast sprouts) into the lacunae are the forerunners of villi. Initially, the sprouts consist of syncytiotrophoblast, which are followed by cytotrophoblast and by connective tissue containing fetal capillaries. The villi thus formed are termed mesenchymal villi and are the precursors of all other villous types. While they are the dominant type in the first trimester, some trophoblast sprouting and mesenchymal villous development probably occurs up to term.


Immature intermediate villi (100–200 µm in size) are formed from mesenchymal villi and are primarily responsible for placental growth ( Figure 32.6 ). They have a complete trophoblastic mantle with many cytotrophoblastic cells present, but lack vasculosyncytial membranes. The syncytial nuclei are evenly dispersed without knots. They have a loose (reticular) stroma with abundant stromal channels containing Hofbauer cells. They are the dominant villous type seen in the second trimester and are transformed into stem villi when their production from mesenchymal villi decreases.




Figure 32.6


Immature intermediate villi with a reticular stroma.


Stem villi are defined by 50% or more of their stroma being compact and containing vessels with media or adventitia identifiable on light microscopy. They range in size from 80 to 1500 µm and connect the chorionic plate to the remaining distal villous tree. Some stem villi connect to the basal plate (anchoring villi). They have both an arterial and a venous circulation, which (depending on size) consist of either arteries and veins or arterioles and venules. The trophoblastic cover is predominantly syncytiotrophoblast and may be replaced with fibrinoid in the mature placenta. A perivascular capillary network is more prominent in less mature stem villi and reflects their origin from immature intermediate villi. The localization of myofibroblasts and smooth muscle cells in stem villi has been defined immunohistochemically and these cells may play a role in villous vascular regulation.


Mature intermediate villi ( Figure 32.7 ) are formed from the mesenchymal villi in the third trimester and give rise to the majority of terminal villi. They are 60–150 µm in diameter and contain capillaries, arterioles, and venules. The stroma is loose and the vessels constitute less than half the villous cross-sectional area. The syncytiotrophoblast has a uniform structure without vasculosyncytial membranes or knots. At term, mature intermediate villi make up one-fourth of the parenchyma.




Figure 32.7


Mature intermediate villi.


Terminal villi (40–60 µm) ( Figure 32.8 ) are the site of gaseous exchange and derive from the mature intermediate villi. They arise as capillary growths which, in exceeding that of parent mature intermediate villi, result in trophoblastic protrusions. The capillaries are dilated and constitute over 50% of the villus cross-sectional area. Optimal gas exchange requires the formation of vasculosyncytial membranes. The syncytiotrophoblast nuclei become pushed to one side so that only an attenuated layer of syncytiotrophoblastic cytoplasm remains applied to its basement membrane, which is itself applied to the capillary’s basement membrane. The capillaries are 3–5 mm long and each maintains its own nonbranching structure. They do not form a capillary network, but remain as long capillaries. In addition, the capillaries have varicosities where their diameters enlarge considerably. The exact functional significance of these varicosities is unknown, although a regulatory function where vascular deformation alters flow has been proposed. These villi appear at 27 weeks of gestation and increase in number until term, when they make up 40% of villi.




Figure 32.8


Normal terminal villi: over 50% of their area is capillary.


The placenta’s maternal surface is partitioned by septum formation. As collections of cytotrophoblast, the so-called ‘cell columns,’ anchor the decidua to the villi; their growth rates differ so that slow-growing ones tend to pull up the decidual basal plate, buckling it into the placental septa. These septa are incomplete and rarely reach the chorionic plate. They have no precise anatomic relationship to the functional units of the placenta.


Functional Unit of the Placenta


The placenta’s functional unit is variously known as the fetal lobule, fetal cotyledon, or fetal villous tree. At term, the normal placenta contains 40–60 lobules, each 2–4 cm in diameter. The central area receives the oxygenated blood from the maternal spiral arteries and shows an increased number of immature intermediate villi. The surrounding, more densely packed villi show a predominance of mature intermediate and terminal villi. This is the area where gas exchange is maximal, as the blood slowly percolates around small villi that have vasculosyncytial membranes. At the lobule’s periphery is the venous outflow area through which blood drains to the 50–200 maternal venous outlets. Despite the apparent continuity of the intervillous space, each lobule relies upon its own spiral artery. Thrombosis of that artery results in infarction in that lobule.




Implantation and Early Pregnancy


Fertilization, cell division, formation of the morula, and later formation of a blastocyst are independent of maternal contact. The blastocyst reaches the uterus on day 3 after fertilization and implants by the end of day 7.


The process of implantation has three phases: muscular, adhesive, and invasive. The muscular phase concerns transport of the conceptus to the optimal site for implantation, which in humans is the mid to high posterior wall of the uterus in the mid-sagittal plane ( Figure 32.1 ). Implantation in different locations may be associated with different pathologies, e.g., fundal placentation shows an association with intrauterine growth retardation (IUGR). During the adhesive phase, the normally repulsive interactions between two epithelial surfaces (endometrium and trophoblast) are reversed. In the invasive phase, irregular projections of syncytiotrophoblast invade into the endometrium ( Figure 32.2 ). This phase lasts until approximately day 8 post conception and is called the prelacunar phase, based on the appearance of the blastocyst. At day 8 vacuoles appear in the syncytiotrophoblast, which become confluent to form lacunae. This change commences at the implantation pole and becomes confluent over the blastocyst by day 13. At this stage, the earliest forms of chorionic villi begin to form ( Figure 32.3 ) and the primary chorionic plate consists of a continuous layer of cytotrophoblast on the embryoblast side of the lacunae. Infiltration of the pillars of syncytiotropho­blast surrounding the lacunae by cytotrophoblast from the chorionic plate is followed by expansion of these pillars as extraembryonic mesenchyme follows cytotrophoblast. The outermost layer of trophoblast (the trophoblast shell) is formed by syncytiotrophoblast, and later by cytotrophoblast as well. Cytotrophoblast continues to invade endometrium and is seen as clusters of extratrophoblast (‘X’ cells) and trophoblastic giant cells in what will become the basal plate. The lacunar space becomes the intervillous space, and the embryologic development of villi proceeds during gestation. These developments are maximal at the deep aspect of the blastocyst and normally only this persists to form the true placenta (chorion frondosum). The remainder atrophies (chorion laeve) ( Figure 32.4 ).




Figure 32.1


Implantation (arrow) in early pregnancy.



Figure 32.2


Primitive trophoblast. Chorionic villi have not yet formed in the pregnancy of about 1 week’s duration.



Figure 32.3


(A) Day 14 conceptus as a tiny implant in superficial endometrium. (B) Detail of the earliest stage of chorionic villous formation.





Figure 32.4


Normal membrane in a third trimester placenta. (A) Amnion (A), parts of which include amnionic epithelium (AE), amnionic mesoderm (AM), and spongy level (S); the chorionic plate (C) is composed of chorionic mesoderm (CM) and trophoblast (T); beneath that is the maternal decidua (D). (B) Both the trophoblast and amnionic epithelium are markedly reactive for cytokeratin (CAM 5.2).


The cytotrophoblastic shell thins and is replaced by Nitabuch’s fibrin layer, which is composed of matrix-type fibrinoid and lies between the shell and the decidual boundaries. The fibrinoid between the shell and the intervillous space is called Rohr’s fibrinoid and is fibrin-type fibrinoid. The two are indistinguishable on routine H&E sections, but may be differentiated immunohistochemically using antibodies directed against oncofetal fibronectin for matrix-type fibrinoid and fibrin for fibrin-type fibrinoid.


The decidua is not merely the passive recipient of the conceptus, but plays an active role in successful placentation. Cytotrophoblastic cells stream out from the tips of the anchoring villi, penetrate the trophoblastic shell, and colonize the decidua and adjacent myometrium of the placental bed. These cells, which are reactive for human placental lactogen and cytokeratins, are called interstitial extravillous trophoblast. A subset of these called ‘intravascular extravillous cytotrophoblast’ invades and plugs the lumens of the decidual spiral arteries. The cells destroy the endothelium and the elastic and muscular tissues of the media, which are then replaced by fibrinoid material derived from fibrin and trophoblastic secretions. This produces large diameter vessels lacking intrinsic tone that allow a high-flow, low-pressure system to develop. Low oxygen tension may help control entry of cytotrophoblast into the S-phase of the cell cycle, while proliferation and high ambient oxygen tension may lead to an invasive phenotype. The higher oxygen tensions in the nontransformed spiral arteries may induce the expression of invasive integrins, a vascular adhesion molecule phenotype, and cessation of mitotic activity. This may explain why trophoblast only superficially invades the uterine veins. Trophoblast may switch to a noninvasive phenotype by becoming multinucleate.


Development in the first trimester takes place in a relatively hypoxic environment, and this is protective to the embryo. A trophoblast plug prevents maternal blood entering the intervillous space and early embryonic nutrition is provided by endometrial glands, perhaps facilitated by endoglandular trophoblast. The trophoblast plug is seen to be deficient in many early losses ( Figure 32.5 ). This results in the precocious onset of the maternal circulation, exposing the developing placenta to a higher oxygen concentration and to a higher arterial pressure. As spiral artery transformation is less effective peripherally, oxidative stress may be the mechanism by which villous regression occurs in the chorion laeve. Patterns of regression influence placental shape and cord insertion, and localized abnormalities of flow may result in a cord that was initially paracentral becoming marginal or velamentous. Noncentral cords are associated with lower birth weights, suggesting that their vasculature is less metabolically effective. Suboptimal or shallow implantation results in inadequate conversion of maternal spiral arterioles in the inner third of the myometrium. The resultant retention of vascular smooth muscle permits intermittent pulsatile contraction, resulting in mechanical and oxidative stress to the developing placenta.




Figure 32.5


A transforming spiral artery. Intravascular trophoblast and extravillous interstitial trophoblast are present.


Placental growth trajectories are established by the end of the first trimester, with cases of IUGR having smaller placentas than normal at 12 weeks, but similar growth after that. Villous development shows a major change from growth to differentiation at the end of the second trimester. Protrusions of trophoblast (trophoblast sprouts) into the lacunae are the forerunners of villi. Initially, the sprouts consist of syncytiotrophoblast, which are followed by cytotrophoblast and by connective tissue containing fetal capillaries. The villi thus formed are termed mesenchymal villi and are the precursors of all other villous types. While they are the dominant type in the first trimester, some trophoblast sprouting and mesenchymal villous development probably occurs up to term.


Immature intermediate villi (100–200 µm in size) are formed from mesenchymal villi and are primarily responsible for placental growth ( Figure 32.6 ). They have a complete trophoblastic mantle with many cytotrophoblastic cells present, but lack vasculosyncytial membranes. The syncytial nuclei are evenly dispersed without knots. They have a loose (reticular) stroma with abundant stromal channels containing Hofbauer cells. They are the dominant villous type seen in the second trimester and are transformed into stem villi when their production from mesenchymal villi decreases.




Figure 32.6


Immature intermediate villi with a reticular stroma.


Stem villi are defined by 50% or more of their stroma being compact and containing vessels with media or adventitia identifiable on light microscopy. They range in size from 80 to 1500 µm and connect the chorionic plate to the remaining distal villous tree. Some stem villi connect to the basal plate (anchoring villi). They have both an arterial and a venous circulation, which (depending on size) consist of either arteries and veins or arterioles and venules. The trophoblastic cover is predominantly syncytiotrophoblast and may be replaced with fibrinoid in the mature placenta. A perivascular capillary network is more prominent in less mature stem villi and reflects their origin from immature intermediate villi. The localization of myofibroblasts and smooth muscle cells in stem villi has been defined immunohistochemically and these cells may play a role in villous vascular regulation.


Mature intermediate villi ( Figure 32.7 ) are formed from the mesenchymal villi in the third trimester and give rise to the majority of terminal villi. They are 60–150 µm in diameter and contain capillaries, arterioles, and venules. The stroma is loose and the vessels constitute less than half the villous cross-sectional area. The syncytiotrophoblast has a uniform structure without vasculosyncytial membranes or knots. At term, mature intermediate villi make up one-fourth of the parenchyma.




Figure 32.7


Mature intermediate villi.


Terminal villi (40–60 µm) ( Figure 32.8 ) are the site of gaseous exchange and derive from the mature intermediate villi. They arise as capillary growths which, in exceeding that of parent mature intermediate villi, result in trophoblastic protrusions. The capillaries are dilated and constitute over 50% of the villus cross-sectional area. Optimal gas exchange requires the formation of vasculosyncytial membranes. The syncytiotrophoblast nuclei become pushed to one side so that only an attenuated layer of syncytiotrophoblastic cytoplasm remains applied to its basement membrane, which is itself applied to the capillary’s basement membrane. The capillaries are 3–5 mm long and each maintains its own nonbranching structure. They do not form a capillary network, but remain as long capillaries. In addition, the capillaries have varicosities where their diameters enlarge considerably. The exact functional significance of these varicosities is unknown, although a regulatory function where vascular deformation alters flow has been proposed. These villi appear at 27 weeks of gestation and increase in number until term, when they make up 40% of villi.




Figure 32.8


Normal terminal villi: over 50% of their area is capillary.


The placenta’s maternal surface is partitioned by septum formation. As collections of cytotrophoblast, the so-called ‘cell columns,’ anchor the decidua to the villi; their growth rates differ so that slow-growing ones tend to pull up the decidual basal plate, buckling it into the placental septa. These septa are incomplete and rarely reach the chorionic plate. They have no precise anatomic relationship to the functional units of the placenta.




Functional Unit of the Placenta


The placenta’s functional unit is variously known as the fetal lobule, fetal cotyledon, or fetal villous tree. At term, the normal placenta contains 40–60 lobules, each 2–4 cm in diameter. The central area receives the oxygenated blood from the maternal spiral arteries and shows an increased number of immature intermediate villi. The surrounding, more densely packed villi show a predominance of mature intermediate and terminal villi. This is the area where gas exchange is maximal, as the blood slowly percolates around small villi that have vasculosyncytial membranes. At the lobule’s periphery is the venous outflow area through which blood drains to the 50–200 maternal venous outlets. Despite the apparent continuity of the intervillous space, each lobule relies upon its own spiral artery. Thrombosis of that artery results in infarction in that lobule.




Examination of the Placenta


Umbilical Cord


Abnormalities of the cord are associated with adverse outcomes and with stasis-induced abnormalities in the fetal vasculature. Cord length should be measured, but the possibility that sections of the cord may have been removed shortly after delivery should be excluded before a short cord is reported. The average cord length at term is 60 cm. Longer cords are associated with hypermotility and shorter ones with hypomotility. Neural tube defects and chromosomal abnormalities are sometimes the underlying cause of the latter. The lower limit for a normal cord varies, but seems to be around 35 cm and a short cord is associated with an increased risk of death in term infants. In an 18 year retrospective review, excessively long cords (≥70 cm) were associated with a range of gross and microscopic features, and with abnormal neurologic status in infants. Clinical or pathologic abnormalities of the cord were found in 70% of infants with fetal thrombotic vasculopathy. False knots (vascular loops) may be present ( Figure 32.9 ), but usually are of no clinical significance. The maximum diameter should be measured both, sonographically and pathologically; a thin cord (<8 mm) is associated with poor flow and growth restriction.




Figure 32.9


Umbilical cord with false knots (vascular loops).


True knots ( Figure 32.10 ) occur in approximately 1% of pregnancies. They are more likely to occur with a long cord, with polyhydramnios, and with male fetuses. The knots may be single or multiple. Chronic changes (grooving of the cord, edema, vascular congestion, or thrombosis) or their absence should be specifically commented on. The fetus with a long cord is less able to exert traction on the knot in utero . The effects of a knot are mediated by its tightening with traction, causing vascular compromise. This may happen at delivery, but then the chronic changes will be absent. Documentation of a true knot in utero is difficult, and a loose knot may be formed after intrauterine death. The lack of a difference in blood gas values between neonates with true knots and those without supports the interpretation that most knots are clinically insignificant. However, a true knot is more commonly associated with other cord problems including nuchal cord and cord prolapse, either of which may contribute to the observed increase in antepartum (but not intrapartum) stillbirths. Cord pathology is associated with fetal thrombotic vasculopathy. A feature to be sought in such cases is an increase in nucleated red blood cells, a finding that supports a conclusion of subacute hypoxic stress.




Figure 32.10


Umbilical cord with a single true knot.


Coiling of the cord is normal. It is greater at the fetal end and is variable throughout the length of the cord. A literature review has indicated 0.17 ± 0.009 spirals completed per centimeter. The 10th–90th percentile range is one per 3 cm to one per 14 cm on this basis. The mean coiling index (number of coils/length in cm) has varied from 0.13 to 0.28: the ‘mean of the means’ of the studies listed was 0.20. A long and/or hypercoiled cord ( Figure 32.11 ) will require a greater pressure gradient because of increased shear stresses. Both hypo- and hypercoiling of the cord are associated with a range of adverse pregnancy outcomes, including pregnancy loss and IUGR. The cord may show a stricture ( Figure 32.12 ). Stricture and/or hypercoiling was reported in 19% of fetal deaths and thrombosis of chorionic plate vessels was seen in 54% of these cases. Given the importance of the diagnosis, a thoughtful review of coiling has called for ‘a return to basic but critical mensuration.’




Figure 32.11


Long hypercoiled cord.



Figure 32.12


Stricture in umbilical cord.


The cord may insert centrally, eccentrically, and marginally or have a velamentous insertion. The last two are the most significant. In marginal insertion, the cord joins the disc at its edge. Cord insertion directly onto the membranes (velamentous insertion) ( Figure 32.13 ) occurs in approximately 1% of singleton deliveries. The vessels are at risk of compression and thrombosis, and rupture may lead to significant fetal blood loss and hypoxia. In addition to intrapartum events, velamentous insertion is associated with an increased risk of preterm delivery, low birth weight, and abnormalities of fetal heart rate. Vessels may be present in the membranes in up to 7% of placentas, but vasa previa (vessels in the membranes in advance of the presenting part) are less common (1 : 2500 deliveries). In addition to velamentous insertion, other risk factors for vasa previa include a bilobed or succenturiate placenta, a low-lying placenta, and multiple and IVF pregnancies. Prenatal diagnosis reduces the mortality rate, and screening of all twin pregnancies has been reported to be cost-effective. When examining a placenta where this has been queried clinically, a measurement of the length of the vessels in the membranes and a comment on whether they are intact or not is appropriate. We have found that marking a torn area with ink helps in microscopic evaluation.




Figure 32.13


Velamentous insertion, with vessels branching to run in the membranes.


In the third stage of labor, avulsion of the cord may occur due to traction and this may cause subamniotic hemorrhage. However, this form of hemorrhage may also occur where a central or eccentric insertion is furcate ( Figure 32.14 ), i.e., where cord vessels have lost their cover of Wharton’s jelly and have splayed out prior to inserting into the disc. In most cases fresh subamniotic hemorrhage is of no clinical significance. In some cases there may be hematomas of the cord without apparent explanation ( Figure 32.15 ).




Figure 32.14


Furcate (branched) insertion of umbilical cord.



Figure 32.15


Hematoma of umbilical cord.


The normal cord has three vessels—two umbilical arteries and one umbilical vein. A single umbilical artery, i.e., a two-vessel cord, occurs in 0.5–1% of deliveries ( Figure 32.16 ). As the arteries may fuse in the 5 cm before insertion into the placenta, further sections nearer the fetal end of the cord should be examined before a single artery is reported. One-third of cases of single umbilical artery are associated with other congenital abnormalities, including trisomy 18, and abnormalities of the heart, gastrointestinal and urinary tracts, and central nervous system. Isolated single umbilical artery is associated in some studies with increased preterm deliveries, growth restriction, and adverse outcomes. Other studies did not show a difference in perinatal outcome or long-term development.




Figure 32.16


Two-vessel umbilical cord.


Supernumerary vessels are rare and may be either arterial or venous. Tumors of the cord are also rare. Most are hemangiomas ( Figure 32.17 ) but occasional angiomyxomas and teratomas have been reported. The muscularis of cord vessels may be focally thin. Confirmation of a possible association with congenital malformations is needed, given the small numbers of cases reported. Grossly or sonographically visible cysts may develop from the vestigial remnants that are usually found as incidental microscopic findings. These remnants may be of the allantoic duct (possessing a flattened or transition cell-type epithelium; Figure 32.18A ) or omphalomesenteric duct (cuboidal epithelium with mucinous component; Figure 32.18B ).




Figure 32.17


Hemangioma of the cord.



Figure 32.18


(A, B) Normal findings in umbilical cord. (A) Allantoic duct (possessing a flattened or transition cell-type epithelium), residual urinary tract system. (B) Omphalomesenteric duct (cuboidal epithelium with mucinous component), residual digestive system.




The surface of the cord may appear edematous in some cases with acute inflammation. Traction and/or clamping should be excluded. An edematous cord with a reddish discoloration typically occurs with maceration.


Membranes


Acute chorioamnionitis is mainly caused by bacteria. It is the major cause of preterm birth, but it is still not clear if it is a cause or effect of either preterm rupture of membranes or preterm labor. While there are clinical guidelines for recognition of infected membranes histologic chorioamnionitis is a better surrogate of intra-amniotic infection. The severity of chorioamnionitis shows a direct correlation with proteomic signatures of inflammation. Organisms may or may not be cultured: group B Streptococcus and Escherichia coli are important causes of chorioamnionitis, with organisms such as Ureaplasma urealyticum frequently seen in mixed culture.


With early, mild acute inflammation, regardless of the organism, the membranes may be grossly normal or edematous. More advanced inflammation produces a milky opacity, altering the normal gray-purple color of the disc. There may be frank pus with an offensive odor. Meconium may obscure the alterations of the acute inflammatory infiltrate.


A section of membranes should be taken, extending from the rupture site to the margin of the disc and prepared for histologic examination as a roll. The yield is influenced by the extent of sampling, with increased yield up to four sections. Criteria for categorization of the maternal and fetal inflammatory responses as early, intermediate, or advanced, and grading of both as mild/moderate or severe have been published ( Figures 32.19 and 32.20 ). These are summarized in Table 32.1 . Severity of the maternal response is defined by the presence of subchorionic microabscesses, or three or more confluent polymorph bands, and in the fetal response as near-confluent bands. Amnionic inflammation is a better predictor of neonatal sepsis than funisitis in preterm gestations. The inflammatory pattern and the time taken to mount an inflammatory response may primarily reflect the virulence of the infecting organism. Organisms of low virulence (e.g., Ureaplasma , Mycoplasma , and anaerobes) may cause preterm labor, but not bacteremia in the neonate. They probably take days rather than hours to reach the placenta. Virulent organisms, e.g., group B Streptococcus , E. coli , and Listeria , can cause bacteremia and may reach the placenta in hours rather than days. However, membrane integrity, maternal immune status, and cytokine gene polymorphisms play a role. Gestational age is also of importance; chorionic vasculitis is less prevalent with increased gestational age. Data correlating chorioamnionitis with bacterial in situ hybridization suggest that organisms invade through a focal area of the membranes, proliferate in the amniotic fluid, and invade the membranes from there. The presence of acutely inflamed membranes should prompt a search for associated lesions, such as thrombi, and exclusion of coexistent pathology, such as retroplacental hemorrhage, where chorioamnionitis is more common.




Figure 32.19


Acute chorioamnionitis, stage 1 ( Table 32.1 ). The inflammation involves the trophoblast, but not the spongy layer of the amnion.



Figure 32.20


Acute chorioamnionitis, stage 3 ( Table 32.1 ). The inflammation pervades all structures and destroys the amnionic epithelium.


Table 32.1

Categorization of Inflammatory Responses in Acute Chorioamnionitis

Adapted from Redline et al.
































Response Stage Features
Maternal 1 PMN in subchorionic fibrin or membrane trophoblast
2 PMN in fibrous chorion and/or amnion
3 PMN karyorrhexis, necrosis of amnion
Fetal 1 PMN in umbilical vein or chorionic plate vessels
2 PMN in one or more umbilical arteries
3 PMN ± debris with perivasculitis

PMN, polymorphonuclear leukocytes.


In addition to bacteria, fungi and viruses may also cause infection via the ascending pathway. In Candida chorioamnionitis, numerous yellow-white spongy flecks stud the membranes and umbilical cord ( Figure 32.21 ).




Figure 32.21


(A, B) Candida funisitis. (A) Small white flecks are on the surface, which (B) microscopically are Candida organisms (arrows).




The clinical significance of chorioamnionitis and funisitis depends on gestational age and severity. Ascending infection is a major cause of preterm premature rupture of the membranes, which accounts for 30–40% of preterm births. Increasing stages of chorioamnionitis show a significant association with funisitis, preterm birth, and perinatal death. Funisitis has been directly linked with development of fetal germinal matrix hemorrhages, choroiditis with intraventricular hemorrhage, and periventricular leukomalacia. For term infants, there is an increased risk of sepsis following chorioamnionitis, but neurologic morbidity may be related to other complications of labor. In one study of very low birth weight infants, vascular thrombi associated with chorioamnionitis were felt to account for neurologic impairment. An association between chorioamnionitis and adverse developmental outcome has not been demonstrated in other studies on similar groups. Defining initiators of preterm birth (i.e., uteroplacental insufficiency vs inflammation) may be important in documenting their long-term effects and placental inflammation shows an association with poor neonatal growth.


Decidual necrosis manifests as a shaggy, cream-yellow area, usually present near the margin of the placental disc. Nodularity of the amnion may be due to either amnion nodosum or squamous metaplasia. Amnion nodosum is a consequence of oligohydramnios and presents as 1–3 mm nodules that may be relatively easily detached. Microscopy shows aggregates of amorphous and cellular debris ( Figure 32.22 ), and may include detached hair. With squamous metaplasia, which has no known clinical associations, the nodules are only detached with difficulty.




Figure 32.22


Amnion nodosum.


Abnormalities of the membranes may cause fetal malformation. Some may be fatal such as body stalk anomaly. Amniotic bands should be sought in the context of more restricted fetal abnormalities, including amputation, acral deformities, or even craniofacial abnormalities that may resemble neural tube defects. These bands are delicate strands of amnion and mesoderm whose effects may be predominantly or exclusively mechanical. They may be focal or extensive, and have been reported in Ehlers–Danlos syndrome and osteogenesis imperfecta.


Meconium on Cord and Membranes


Meconium-stained amniotic fluid is seen in 14% of deliveries, and is present in approximately 1% of deliveries at 32 weeks, compared with 100% at 42 weeks. Its passage at term may be physiologic, but is generally felt to reflect hypoxic stress in the fetus. We regard the presence of scanty macrophages with non-hemosiderin pigments as normal and physiologic: indeed, fetal defecation has been documented sonographically. More extensive meconium passage produces a green discoloration grossly. Meconium may reach superficial amnionic macrophages ( Figure 32.23 ) in 1 hour and chorionic macrophages in 3 hours. They may remain in the amnion or chorion for a week after the meconium is no longer visible in the amniotic fluid. Meconium acts as a vasoconstrictor on the fetoplacental vasculature, and may result in necrosis of smooth muscle cells of umbilical cord vessels ( Figure 32.24 ) or cause ulceration of the cord. The changes in muscle cells may mimic a vasculitis. The inflammation that meconium induces is maximal in the cord, but is less intense and more focal than that due to the vasculitis of chorioamnionitis. Documentation of its presence is important, as thick meconium is associated with adverse pregnancy outcome. If aspirated, meconium produces significant pneumonitis.




Figure 32.23


Meconium in a macrophage (arrow) is a light brown pigment usually less refractile than hemosiderin.



Figure 32.24


Meconium-induced vascular necrosis. Note the injured myocytes with a rounded hypereosinophilic appearance.


Architectural and Developmental Abnormalities


Extrachorial placentation is where the chorion laeve inserts at some distance inside, rather than at the rim of the placenta. The term ‘extrachorial’ implies that the edge of the placenta is uncovered except for fibrin and, sometimes, old clotted blood. If the transition is flat, the placenta is called ‘circummarginate’; if the edge is rolled up and folded over itself (‘plicated’), the placenta is then called ‘circumvallate.’


The circummarginate form ( Figure 32.25 ) has no known clinical associations. The circumvallate form ( Figure 32.26 ), however, is associated with threatened abortion, membrane rupture, and antepartum hemorrhage leading to prematurity, but not to an increase in perinatal mortality. Circumvallation is significantly associated with iron-laden macrophages in the membranes, termed ‘diffuse chorioamnionic hemosiderosism,’ suggesting that circumvallation may be caused by chronic peripheral separation of the placenta. Both types of extrachorial placentation are frequently partial and mixtures between the two and normal placentation are more frequently encountered.




Figure 32.25


Circummarginate placenta.



Figure 32.26


Circumvallate placenta. The membranes fold back upon themselves on the surface of the placenta.


A bilobed placenta has two nearly equal sized discs with the umbilical cord inserting between the two, either in a velamentous fashion or marginally on the larger disc. As discussed previously, inadequate blood flow leads to trophotropism and placentation on both the anterior and posterior endometrial surfaces. These placentas are associated with multiparity, older maternal age, previous history of infertility, assisted reproduction, retention, and abnormal adherence. The vessels between the two may thrombose or present as vasa previa. Higher orders of lobation are extremely rare.


Accessory (succenturiate) lobes are found in 6% of placentas and are areas of placental tissue joined by either an isthmus or velamentous vessels to the main disc ( Figure 32.27 ). If symptomatic, they may present as placenta previa with or without fetal hemorrhage or be retained in utero postpartum. Placenta membranacea arises when there is failure of villous regression to form a chorion laeve. Thus, an abnormally thin placenta comes to cover an unusually large area of the uterine lining. The entire conceptual sac is covered with villi and the placenta becomes, in addition, a placenta previa. The placenta on cut section is thinned from the normal 2.5 cm or 3 cm to perhaps 1 cm or less in the fixed state. This condition is sometimes associated with mid-trimester antepartum hemorrhage. It may also sometimes show undue adherence, but normal third-stage delivery usually occurs.




Figure 32.27


Succenturiate, or accessory, lobe of placenta.


A fenestrate placenta is one where a placental lobule appears to be missing. Careful inspection of the maternal aspect shows that the lobules surrounding the expected location of the missing lobule are smooth, and the featureless overlying chorion is smooth. A girdle or ring placenta is one with the membranes above and below the placental ring. They are rare in humans.


Placental Weight


Placental weight combined with length, breadth, and thickness has provided valuable epidemiologic information, and is part of the evidence for the fetal origins of adult disease. The placenta should be weighed trimmed of cord and membranes, with any adherent clot removed and weighed separately. Reference values for freshly delivered untrimmed placentas are also available.


Placental weight depends on the in utero environment, timing of cord clamping, storage interval, and fixation. The timing of umbilical cord clamping at delivery will either trap a considerable quantity of blood within the placenta if early, or lead to a relatively bloodless organ if delayed. The practice of placental examination in the unfixed state will be associated with fluid loss of variable extent, but it tends to increase with storage time. Formalin fixation of the placenta will result in a gain in weight of often 8–10%, and occasionally up to 15%. There is a trend for increasing placental weight during the past century, which is most likely due to improved nutritional status and environmental factors. Twin placental weights have a ratio of 1.69 above that of the same gestational age singletons. Racial and population differences exist. Recent figures for a North American population of both singletons and twins show a 50th percentile of approximately 675 g for singletons at term and are almost certainly not applicable to all patient cohorts. In this study, the placental to birth weight ratio at term for the 50th percentile was 0.19 for males and 0.20 for girls.


Placentas from infants with IUGR are often small, especially if multiple pathologies are present. Pre-eclamptic placentas tend to be small, as do those with fetal congenital anomalies, infection, and chromosomal abnormalities. Large placentas are found in women living at high altitude, those with diabetes mellitus, rhesus incompatibility, fetal hydrops, maternal and fetal anemia, and some chronic intrauterine infections, e.g., syphilis.


Fetal Surface of Placenta


The normal color of the fetal surface is a gray-purple color. Stripping the amnion allows more detailed inspection of the chorionic plate vessels. Normally, fetal arteries run over (i.e., uppermost on) veins. This is valuable to note grossly, as vessels may be difficult to distinguish histologically. Thrombi, which may appear grossly as thickened white areas of the vessel wall, may be subtle and only appreciated on close examination. Thrombi may be seen in arteries ( Figure 32.28 ) and veins ( Figure 32.29 ). Barium gelatin injection of the umbilical arteries is one definitive method to identify arteries ( Figure 32.30 ).




Figure 32.28


Arterial thrombus (arrow), visible on the fetal surface.



Figure 32.29


Thrombus in a chorionic plate vessel (arrow). The vessel is probably a vein.



Figure 32.30


Intra-arterial injection of barium gelatin distinguishes artery from vein.

(Courtesy of Dr. Peter Kelehan, National Maternity Hospital, Dublin, Ireland.)


Placental mesenchymal dysplasia shows aneurysmally dilated chorionic plate vessels ( Figure 32.31 ) and focally cystic stem villi with myxomatous stroma and cistern formation, but lacks the trophoblastic features of partial mole. Approximately one-third of cases are associated with Beckwith–Wiedemann syndrome. Most fetuses are female and there is a strong association with IUGR and fetal and neonatal death.




Figure 32.31


Mesenchymal dysplasia from a case of intrauterine death: aneurysmally dilated chorionic vessels are present.


Maternal Surface of the Placenta


The cotyledons of the placenta should be examined to ensure that the placenta is intact and complete. Evidence of old hemorrhage, manifest as foci of tan-colored granularity, should be sought, especially where there is a clinical history of pre-eclampsia or extensive or central infarction. The presence of hemorrhage and the percentage of the surface affected, its location (central or peripheral), and the presence or absence of cavitation should be noted. A wrinkled gyriform pattern is characteristic of maternal floor infarction. Thrombosed spiral arteries may be detected on examination of the basal plate.


Cut Surface


The placenta should be serially sectioned and examined at intervals of 1–2 cm. The parenchyma varies in color depending on the amount of maternal and fetal blood present. A degree of pallor is normal where the disc has been drained, e.g., following manual removal. A dramatic color change in an intact placenta, i.e., a ‘two-tone’ effect, may be seen in cases of retroplacental hemorrhage. Any lesions should be described as central (inner two-thirds of the disc) or peripheral and the percentage of the parenchyma affected estimated and recorded. Avascular villi may be more easily detected following formalin fixation ( Figure 32.32 ).




Figure 32.32


Full thickness region of avascular fetal villi appears pale upon fixation. A thrombosed vessel is also visible.


Infarction


The placenta requires both maternal and fetal blood flow for normal function. The spectrum of uteroplacental ischemia ranges from changes such as increased syncytial knots (discussed under microscopic findings) to infarction. Acute cessation of maternal blood flow results in a placental infarct. The placenta can withstand loss of a variable percentage, often given as one-third, of its tissue before this becomes clinically manifest. The clinical outcome will be influenced by how rapidly infarcts develop, and by the functional quality of the remaining parenchyma.


On cut section, an acute infarct is red and as it ages the color changes through brown, to tan, to off-white ( Figure 32.33 ). The consistency changes from firm to hard. Central infarcts and those occurring earlier in gestation are more likely to be significant, whereas peripheral infarction of 5–10% at term may be considered physiologic. The age of the infarct(s), location, percentage of parenchymal involvement, and presence of associated retroplacental hemorrhage should be noted.




Figure 32.33


Old infarction. The cavity was due to a hematoma that caused compression. The retroplacental nature of the hematoma cannot be appreciated from this section.


Histologically, the acute infarct is composed of nonviable villi with obliteration of the intervillous space. Aging lesions have ghost-like villi surrounded by fibrin ( Figures 32.34 and 32.35 ). Infarction is associated with IUGR, fetal hypoxia, and intrauterine fetal death. A reduction in fetal blood flow may sometimes precede infarction.




Figure 32.34


Infarct. The chorionic villi are ghost-like. No viable cells are present either in them or in the surrounding fibrin.



Figure 32.35


Infarct with ghost outlines of villi. As time passes, the outlines become less pronounced.


Perivillous Fibrin Deposition and Maternal Floor ‘Infarction’


Perivillous fibrin deposition is seen macroscopically as areas of firm gray-white waxy material. It may be focal or diffuse ( Figure 32.36 ). Histologically there is eosinophilic fibrin that separates villi ( Figure 32.37 ). There may be secondary infarction in larger lesions. Perivillous fibrin deposition is seen increasingly from 30 weeks’ gestational age, but is not unduly increased in post-term deliveries. It is less prominent where maternal blood flow is reduced, i.e., with pre-eclampsia, essential hypertension, and diabetes. With so-called maternal floor infarction there is an increase in basal plate fibrin that exceeds 3 mm thickness on at least one histologic slide ( Figures 32.38 and 32.39 ). Another pattern, massive perivillous fibrin deposition (≥25% of villi encased by fibrin on at least one slide), is more strongly associated with growth retardation than with maternal floor infarct. Recent studies have included the additional requirement of involvement of 25% or more of the disc macroscopically. It is associated with an increase in perinatal mortality and fetal growth restriction, and may recur in subsequent pregnancies. Maternal serum α-fetoprotein may be raised and PAPP-A reduced, and cases may be recognized clinically by the combination of IUGR, oligohydramnios, and increased placental echogenicity. Where a diffuse increase in perivillous fibrin is seen, chronic intervillositis should be actively excluded by searching for histiocytes: an immunostain for CD68 is helpful in this.




Figure 32.36


Perivillous fibrin deposition showing large waxy plaques.



Figure 32.37


Extensive perivillous fibrin around villi.



Figure 32.38


Maternal floor infarction: characteristic firm pale disc.



Figure 32.39


Maternal floor infarction: the basal plate is thickened by fibrin.


Subchorionic fibrin deposition results from changes in blood flow and eddy currents. It is usually laminated and roughly pyramidal in shape with its base at the chorionic plate. As it lacks (or has very few) enmeshed villi, placental function is not lost.


Hematoma


Retroplacental hematomas separate the placenta’s basal plate from the uterine wall, causing fetal anoxia and maternal hemorrhage. Retroplacental hemorrhage is found in 5% of placentas, and many small hemorrhages are clinically silent. Conversely, a dramatic abruption followed by rapid cesarean section may have no placental manifestations, and the diagnosis of abruption should be based on clinical criteria. A concealed retroplacental hematoma will indent the disc and cause compression infarction of the overlying parenchyma ( Figure 32.40 ). Small yellow flecks of decidua may be seen on the outer and inner surface of the hematoma. Acute lesions consist almost entirely of red blood cells, but with aging these degenerate and are replaced by fibrin. Neutrophils in the basal plate are found early (<4 hours) with the start of coagulative necrosis of villi following in the next 20 hours. Long-standing lesions may contain hemosiderin-laden macrophages.




Figure 32.40


Abruptio placentae with dramatic indentation of the parenchyma. The parenchyma is infarcted between the hemorrhage and the chorionic plate.


The following have been associated with retroplacental hematoma and abruption: pre-eclampsia, essential hypertension, obstruction of the inferior vena cava, folic acid deficiency, cigarette smoking, anticardiolipin antibodies, blunt abdominal trauma, and chorioamnionitis. An association with cocaine use may be overstated. A pregnancy with abruption carries a much higher risk for adverse perinatal outcome such as stillbirth and preterm delivery and increases the risk for recurrence in a subsequent pregnancy. The cause is likely to be multifactorial. The extent of the hematoma, the speed of onset, and the status of the uteroplacental vasculature all interact to determine outcome: the percentage of the maternal surface involved ranges from <20% to 100%.


A marginal hematoma is a collection of blood adjacent to the margin of the placenta with stripping of the chorion laeve, usually seen as a crescent around the placental periphery. It may be associated with antepartum hemorrhage.


Subchorial Thrombosis (Breus Mole)


Subchorial thromboses are found with both abortions and live term pregnancies ( Figure 32.41 ). The fetal surface shows numerous bosselations while the cut surface shows a laminated thrombus between the chorionic plate and the underlying villous tissue. Strands of stem villi may be found within the thrombus. Massive thrombosis defined as 1 cm or greater, measured following fixation, is associated with a poor outcome. These thrombi have been described in association with coagulation abnormalities including thrombophilia and anticoagulation, but the pathogenesis is not fully understood.




Figure 32.41


A 2 cm subchorionic hemorrhage. There was also abruption at the time of delivery of the premature infant.


Intervillous Thrombosis


Intervillous thrombi mark the site of fetal–maternal hemorrhage and consist of laminated blood clot comprising both fetal and maternal red cells. A rim of compressed and infarcted villi, which may be numerous, is found in about one-third of cases. Occasionally, these thrombi are found in cases of maternal–fetal rhesus incompatibility. A fresh thrombus, sometimes called a Kline’s hemorrhage, may appear on section as a hole in the villous parenchyma in which the blood is easily washed out. The pathogenesis probably lies in small disruptions in the villous capillaries.


Other Conditions


Calcification—occurring in areas of fibrin, rather than representing mineralization of villi—is common in the placentas of primigravidas, especially in those who deliver in the summer and autumn months. It is not more common in post-term placentas. Calcification occurring early preterm (i.e., less than 32 weeks) and detected sonographically is associated with an adverse outcome.


Septal cysts are collections of gelatinous gray fluid seen in placental septa. They occur more frequently with similar cysts in the membranes and may be a marker of chronic placental hypoxia.


Multiple Gestation


Multiple births occur normally in slightly under 1% of spontaneously conceived pregnancies and may be dizygotic or monozygotic ( Figure 32.42 ). Dizygotic twinning has a strong hereditary component on the maternal side. The frequency of dizygotic twinning and multiple gestations is substantially increased in women who have undergone artificial induction of ovulation with hormones.




Figure 32.42


Placental structure in twin pregnancy. The listed percentages are for each variant and total 100%.

(After Robboy SJ, Duggan M, Kurman R. The female reproductive system. In: Rubin E, Farber J, editors. Pathology. 3rd ed. Philadelphia: Lippincott; 1999. p. 962-1028.)


Separate placentas develop when two fertilized ova implant apart from one another. If the ova implant near one another, the two placentas show varying degrees of fusion and may appear as one. When the ova implant apart, there are discrete conceptuses, each placenta having its own amniotic sac. In the case of placental fusion, microscopic examination of the intervening membranes between the two fetuses shows two chorions and two amnions, i.e., a dichorionic diamniotic gestation ( Figure 32.43 ).




Figure 32.43


(A–C) Dichorionic diamniotic placenta. (A) Grossly, a low ridge is present at the junction of the two chorions; attempts to remove it expose the underlying villous parenchyma (B) . (C) Microscopically, a chorionic membrane separates two diamniotic fetuses, shown by the presence of trophoblast (arrow) between the two amnions.






The early division of a single fertilized ovum results in twins that are genetically identical and therefore of the same sex. If a single fertilized ovum divides within two days of fertilization, before the trophoblast has differentiated, two separate embryos develop, each with its own placenta and amniotic sac (dichorionic diamniotic twinning). Hence, scrutiny of the placenta cannot always distinguish between monozygotic and dizygotic twinning. If division occurs between days 3 and 8 after conception the trophoblast, but not the amniotic cavity, has already differentiated, and a single placenta with two amniotic sacs develops (monochorionic diamniotic twinning) ( Figure 32.44 ). A monochorionic monoamniotic placenta forms if division occurs between days 8 and 30 after conception, because the amniotic cavity has already developed ( Figure 32.45 ). Division at later periods results in conjoint twins.




Figure 32.44


(A, B) Monochorionic diamniotic placenta. (A) Grossly, both amnions can be separated and pulled toward their respective cords, leaving a clear chorionic surface below. (B) Microscopically, no trophoblastic layer is present between the two amnions.





Figure 32.45


Monochorionic monoamniotic placenta.


Each placenta should be clearly designated in the delivery ward (e.g., by one clamp on the cord of twin 1, two on that of twin 2, etc.). Chorionicity should be established prior to the removal of the cords and membranes. If both amnions can be separated and pulled toward their respective cords, leaving a clear chorionic surface below, the placenta is monochorionic ( Figure 32.44A ). In dichorionic placentation, a low ridge formed by the junction of the two chorions is present at this point ( Figure 32.43B ), and attempts to remove it will expose the underlying villous parenchyma. The contents of the membranes forming this ridge can be confirmed histologically, but this is usually unnecessary.


For practical purposes, a monochorionic placenta means the twins are monozygotic, or, in common parlance, ‘identical.’ In view of postzygotic events, the former term is preferable, especially as discordance for sex and karyotype can occur on occasion in monochorionic twins. However, it is still important to recognize that almost all monochorionic placentas are from monozygotic twins. Dichorionic placentas mean that there is a chance (approximately 10–15%) that the twins are monozygotic. Chorionicity, rather than zygosity, is the main determinant of fetal outcome. Monochorionic twins are at an increased risk of complications and adverse perinatal outcome compared with dichorionic twins. Growth discordance in twins is severe if ≥25% (calculated as a percentage of the larger twin’s weight). This occurs in less than 10% of twins. Peripheral cord insertion and avascular villi are associated with abnormal growth.


An important consequence of monochorionic placentation is that vascular anastomoses may be present and twin–twin transfusion syndrome may occur. Surface vessels may cross from one placenta to the other and form anastomoses ( Figure 32.46 ). These may be demonstrated by injection of air or gelatin, but their absence does not mean that significant vascular shunting did not occur in the parenchyma during intrauterine life. The rarity of twin–twin transfusion syndrome in monochorionic monoamniotic twins has been related to arterial–arterial anastomoses in almost 100% of these cases, in contrast to the greater frequency of veno-arterial anastomoses in monochorionic diamniotic twins. Diagnosis may be difficult and the entity may be under-recognized in monoamniotic twins if oligohydramnios in the donor and polyhydramnios in the recipient is a criterion. The placenta of the donor twin may be pale and bulky, with edematous villi and inconspicuous vessels, whereas that of the recipient may be congested ( Figure 32.47 ). Transfusion may be acute, but is usually chronic and the donor and the recipient may change with time. Even where both fetuses are available for autopsy, it may be difficult to be certain of the pattern of the condition. Twin–twin transfusion syndrome very rarely occurs in dichorionic twins. Endoscopic laser coagulation of anastomoses results in vascular thrombosis and necrosis of the underlying parenchyma. Other complications of twin pregnancy are acardia and fetus papyraceus. Acardia occurs where one twin lacks or has only rudimentary cardiac structures, but receives its blood supply from the other twin via vascular anastomoses. The term ‘twin-reversed arterial perfusion’ is sometimes used for this condition. The acardiac twin usually shows a variable degree of somatic organization, sometimes with only rudimentary structures, and the donor or ‘pump twin’ may develop cardiac failure and hydrops. The cord of the acardiac twin usually has a single umbilical artery. The placenta is most commonly monochorionic diamniotic.




Figure 32.46


Twin–twin superficial anastomosis.



Figure 32.47


Twin–twin transfusion syndrome with pale donor placenta and congested recipient placenta.


Fetus papyraceus occurs when one twin dies and becomes compressed, with some early losses appearing as thickened membranes. This occurs most commonly with triplets or more ( Figure 32.48 ). There are various etiologies, including twin–twin transfusion, cord accidents, and, less commonly, maternal trauma.




Figure 32.48


Fetus papyraceus. Two macerated fetuses (arrows) are each about 2 cm in length. This mother delivered three normal triplets.




Umbilical Cord


Abnormalities of the cord are associated with adverse outcomes and with stasis-induced abnormalities in the fetal vasculature. Cord length should be measured, but the possibility that sections of the cord may have been removed shortly after delivery should be excluded before a short cord is reported. The average cord length at term is 60 cm. Longer cords are associated with hypermotility and shorter ones with hypomotility. Neural tube defects and chromosomal abnormalities are sometimes the underlying cause of the latter. The lower limit for a normal cord varies, but seems to be around 35 cm and a short cord is associated with an increased risk of death in term infants. In an 18 year retrospective review, excessively long cords (≥70 cm) were associated with a range of gross and microscopic features, and with abnormal neurologic status in infants. Clinical or pathologic abnormalities of the cord were found in 70% of infants with fetal thrombotic vasculopathy. False knots (vascular loops) may be present ( Figure 32.9 ), but usually are of no clinical significance. The maximum diameter should be measured both, sonographically and pathologically; a thin cord (<8 mm) is associated with poor flow and growth restriction.




Figure 32.9


Umbilical cord with false knots (vascular loops).


True knots ( Figure 32.10 ) occur in approximately 1% of pregnancies. They are more likely to occur with a long cord, with polyhydramnios, and with male fetuses. The knots may be single or multiple. Chronic changes (grooving of the cord, edema, vascular congestion, or thrombosis) or their absence should be specifically commented on. The fetus with a long cord is less able to exert traction on the knot in utero . The effects of a knot are mediated by its tightening with traction, causing vascular compromise. This may happen at delivery, but then the chronic changes will be absent. Documentation of a true knot in utero is difficult, and a loose knot may be formed after intrauterine death. The lack of a difference in blood gas values between neonates with true knots and those without supports the interpretation that most knots are clinically insignificant. However, a true knot is more commonly associated with other cord problems including nuchal cord and cord prolapse, either of which may contribute to the observed increase in antepartum (but not intrapartum) stillbirths. Cord pathology is associated with fetal thrombotic vasculopathy. A feature to be sought in such cases is an increase in nucleated red blood cells, a finding that supports a conclusion of subacute hypoxic stress.




Figure 32.10


Umbilical cord with a single true knot.


Coiling of the cord is normal. It is greater at the fetal end and is variable throughout the length of the cord. A literature review has indicated 0.17 ± 0.009 spirals completed per centimeter. The 10th–90th percentile range is one per 3 cm to one per 14 cm on this basis. The mean coiling index (number of coils/length in cm) has varied from 0.13 to 0.28: the ‘mean of the means’ of the studies listed was 0.20. A long and/or hypercoiled cord ( Figure 32.11 ) will require a greater pressure gradient because of increased shear stresses. Both hypo- and hypercoiling of the cord are associated with a range of adverse pregnancy outcomes, including pregnancy loss and IUGR. The cord may show a stricture ( Figure 32.12 ). Stricture and/or hypercoiling was reported in 19% of fetal deaths and thrombosis of chorionic plate vessels was seen in 54% of these cases. Given the importance of the diagnosis, a thoughtful review of coiling has called for ‘a return to basic but critical mensuration.’




Figure 32.11


Long hypercoiled cord.



Figure 32.12


Stricture in umbilical cord.


The cord may insert centrally, eccentrically, and marginally or have a velamentous insertion. The last two are the most significant. In marginal insertion, the cord joins the disc at its edge. Cord insertion directly onto the membranes (velamentous insertion) ( Figure 32.13 ) occurs in approximately 1% of singleton deliveries. The vessels are at risk of compression and thrombosis, and rupture may lead to significant fetal blood loss and hypoxia. In addition to intrapartum events, velamentous insertion is associated with an increased risk of preterm delivery, low birth weight, and abnormalities of fetal heart rate. Vessels may be present in the membranes in up to 7% of placentas, but vasa previa (vessels in the membranes in advance of the presenting part) are less common (1 : 2500 deliveries). In addition to velamentous insertion, other risk factors for vasa previa include a bilobed or succenturiate placenta, a low-lying placenta, and multiple and IVF pregnancies. Prenatal diagnosis reduces the mortality rate, and screening of all twin pregnancies has been reported to be cost-effective. When examining a placenta where this has been queried clinically, a measurement of the length of the vessels in the membranes and a comment on whether they are intact or not is appropriate. We have found that marking a torn area with ink helps in microscopic evaluation.




Figure 32.13


Velamentous insertion, with vessels branching to run in the membranes.


In the third stage of labor, avulsion of the cord may occur due to traction and this may cause subamniotic hemorrhage. However, this form of hemorrhage may also occur where a central or eccentric insertion is furcate ( Figure 32.14 ), i.e., where cord vessels have lost their cover of Wharton’s jelly and have splayed out prior to inserting into the disc. In most cases fresh subamniotic hemorrhage is of no clinical significance. In some cases there may be hematomas of the cord without apparent explanation ( Figure 32.15 ).




Figure 32.14


Furcate (branched) insertion of umbilical cord.

Oct 5, 2019 | Posted by in GYNECOLOGY | Comments Off on Implantation and Placenta
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