—  SHORT COURSE #06  —

Placental Development, Indications for and Methods of Examination

Section 2 - Circulatory Disorders

Phyllis C. Huettner, M.D.


Circulatory disorders of the placenta are common and are frequently clinically important for both the mother and the baby. It is important to keep in mind that the placenta has a dual circulation; disorders of the maternal circulation give rise to one set of abnormalities and clinical problems and disorders of the fetal circulation to another.

Maternal Circulatory Disorders

Case 1 : Massive Perivillous Fibrin Deposition

Massive Perivillous Fibrin Deposition
Some fibrin is seen normally in most placentas and is particularly common beneath the chorionic plate, around stem villi, and above the basal plate. This type of fibrin deposition is thought to be due to local stasis and eddy currents in these areas and may actually reflect good intraplacental blood flow, as this type of fibrin deposition is seen less commonly in placentas from abnormal pregnancies such as those complicated by preterm delivery and diabetes.

Large amounts of fibrinoid material can be appreciated grossly as firm white, yellow or brown plaques. These may be slightly granular or smooth. Often they are located in the periphery of the placenta where they fill in the angle where the fetal membranes meet the basal plate. Much less commonly the fibrinoid material forms thick white or grey strands that replace much of the placental parenchyma leaving only small pockets of interspersed red villous tissue.

Microscopically, the terminal villi are widely separated and enmeshed in an abundant amount of eosinophilic fibrinoid material that obliterates the intervillous space. In early lesions, the syncytiotrophoblast shows signs of degeneration and eventually disappears leaving behind a thickened trophoblastic basement membrane. The cytotrophoblast show a marked degree of proliferation and extends out into the perivillous fibrin. The villous stroma becomes progressively more fibrotic and eventually there is obliteration of fetal vessels.

In order to separate the normal amount of fibrin seen in the placenta from fibrin deposition that is likely to be clinically significant, Katzman and Genest have proposed some quantitative definitions. Transmural massive perivillous fibrin deposition (MFD) is defined as perivillous fibrinoid material that extends from the maternal to the fetal surface encasing greater than or equal to 50% of the villi on at least one slide. Borderline MFD is transmural or nearly transmural and encases 25% to 50% of the villi on at least one slide.

The differential diagnostic considerations include maternal floor infarct, placental infarct, fibrin associated with chronic villitis and fibrinoid deposition after fetal death with retained placenta. Maternal floor infarct has similar microscopic features, shares similar clinical features and often is associated with massive perivillous fibrin deposition. By definition, maternal floor infarct involves the villi near the maternal surface. Infarcts may be difficult to distinguish from perivillous fibrin deposition grossly, although they tend to be more sharply circumscribed and abut the maternal surface of the placenta. Microscopically, infarcts show collapse rather than expansion of the intervillous space, no thickening of the trophoblastic basement membrane, no cytotrophoblast hyperplasia, and necrosis rather than fibrosis of the villous stroma. Cases of fibrin deposition associated with chronic villitis usually have areas of active villits.

MFD, while quite rare, estimated to involve 0.28 to 0.5% of examined placentas, is an important lesion for pathologists to recognize because it is associated with an adverse fetal outcome. What is likely to be clinically significant is the location of the perivillous fibrin and the number of villi that are ischemic as a result of it. Redline and Patterson observed that perivillous fibrin that entrapped more than 20% of the terminal villi in the central basal portion of the placenta, which is thought to be the major nutrient-exchanging region, was significantly associated with intrauterine fetal growth retardation and low placental weight. Although not as carefully localized or quantitated, a study by Fuke et al also found a significant relationship between massive perivillous fibrin deposition and intrauterine growth retardation. These workers observed that the combination of intrauterine growth retardation and MFD could recur in subsequent pregnancies and could be prevented with anticoagulant therapy. Katzman and Genest reported a 31% incidence of IUGR in cases with MFD. About 14% of their cases had recurrent MFD or maternal floor infarct in subsequent 2nd or 3rd trimester placentas and 50% had increased perivillous fibrin or maternal floor infarct in 1st trimester placentas. Kumazaki et al found a significant relationship between MFD in the placentas of preterm infants and periventricular leukomalacia.

Maternal Floor Infarct
The term maternal floor infarct (MFI) is a misnomer in that no true infarction is seen. Grossly, the maternal surface of the placenta is covered by a thickened yellow plaque. Microscopically, there is heavy deposition of fibrin around the villi near the maternal surface of the placenta and in the decidua basalis. Often the perivillous fibrin extensively surrounds villi in the parenchyma of the placenta. The villi surrounded by fibrin eventually become ischemic. As mentioned above, there is significant overlap with MFD and these entities are not always clearly separated in the literature. Katzman and Genest have proposed a quantitative definition for classic MFI requiring that basal villi of the entire maternal floor be encased in perivillous fibrinoid greater than or equal to 3 mm in thickness on at least one slide.

In a large study of over 39,000 placentas, MFI, defined as involving at least one third of the maternal surface, was identified in about 1 in 200 cases. In other series it is much less common. Katzman and Genest found that many cases diagnosed as MFI represent MFD or other entities. MFI is an important disorder for pathologists to be aware of. It is associated with stillbirth in 13 to 50% of cases. Many of the liveborn infants, 24% to 100%, are growth retarded, many of them profoundly so. Preterm delivery occurs in 26% to 60% of cases. MFI in preterm infants has been shown to be an independent predictor of neurodevelopmental impairment. MFI can recur in subsequent pregnancies in as many as 12% to 78% of cases. It is very important that pathologists correctly diagnose maternal floor infarction so that these subsequent pregnancies can be carefully monitored. Maternal floor infarct often develops very rapidly in the third trimester but studies have shown that intervention at the first sign of trouble can result in successful outcomes in these subsequent pregnancies. For this reason pathologists should look for maternal floor infarct in all cases of growth retardation, preterm delivery and fetal death so that if found, subsequent pregnancies can be followed carefully.

The pathogenesis of MFI and MFD are likely related and will be considered together here. The material deposited in the intervillous space is composed of fibrin thought to be of maternal origin, other proteins from the coagulation cascade and extracellular matrix proteins that may have a fetal, placental or maternal origin. It is almost certainly the presence of this material in the intervillous space, interfering with nutrient exchange between mother and fetus, that causes the adverse effect on the fetus. What causes this material to be deposited is unclear. Many patients have coagulation abnormalities or autoimmune disorders such as anti-phospholipid antibodies. Some cases are associated with infection. It has recently been proposed that fetal disorders may contribute as MFI has been described in a fetus with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency and in only one of dizygous twins.

Subchorionic Fibrin
Plaques of subchorionic fibrin are seen in about 20% of placentas. On gross examination these appear as laminated white plaques that are roughly triangular with the broad base immediately beneath the chorionic plate. The area closest to the intervillous space may show fresh red clot.

Microscopically, subchorionic fibrin plaques are sharply demarcated from the surrounding tissue and contain no villi. They consist of laminated layers of fibrin with red cells at the junction with the intervillous space. The overlying chorionic plate shows no evidence of degeneration. The pathogenesis of this lesion is also thought to be secondary to stasis of maternal blood in the apex of the intervillous space. Most agree that subchorionic fibrin is of no clinical significance but Naeye has documented decreased subchorionic fibrin in conditions associated with decreased fetal movements and has suggested that fetal movements that strike the chorionic plate may play a role in the formation of subchorionic fibrin.

Infarct
Placental infarcts are common lesions seen in about 10% to 25% of placentas from normal pregnancies. Infarcts can vary in size and shape but are usually somewhat triangular with the broad edge abutting the basal plate. They are more commonly found in the peripheral regions of the placenta, where blood flow is les optimal. Recent infarcts are dark red, firm and granular. With age they become yellow and eventually white. Occasionally, central hemorrhage with cavitation is seen.

Microscopically, in early infarction the villi become crowded with narrowing of the intervillous space. The fetal vessels in the affected area are dilated and congested. The syncytiotrophoblast nuclei show signs of degeneration such as nuclear pyknosis and karyorrhexis. With time, the villous stroma and syncytiotrophoblast degenerate and eventually only "ghosts" of villi remain. The intervillous space no longer contains maternal red cells. Neutrophils and macrophages may be seen at the periphery of a longstanding infarct but no true organization occurs.

Like infarcts elsewhere in the body placental infarcts are caused by an interruption of the blood supply to a portion of the placenta. It is maternal blood, percolating in the intervillous space that supplies and nourishes the placenta. When this blood supply is cut off, the relatively well circumscribed area of villous tissue supplied by a particular maternal vessel or group of vessels undergoes infarction. This can occur because of vascular narrowing or occlusion of the vessel as in atherosis, with or without superimposed acute thrombosis, or because the supplying maternal vessel is physically separated from the placenta, as in retroplacental hematoma. Histologic sections of the decidua beneath an infarct may demonstrate these pathologic changes. Often the decidua is extensively necrotic indicating that the involved vessel is deep, near the myometrial-decidual junction. McDermott and Gillian have presented evidence that infarcts are also accompanied by a concomitant reduction in fetal blood flow to the villi in the infarcted area.

Extensive infarction, large infarcts (>3 cm), central infarcts, and infarcts in the first and second trimester are usually associated with significant underlying maternal disease. Preeclampsia represents a major risk factor for infarction. There is a strong relationship between the severity of preeclampsia and the extent of infarction. Increased rates of placental infarction have also been reported in a variety of thrombophilic conditions including factor V Leiden mutation heterozygosity, prothrombin gene variants, hyperhomocyteinemia, and antiphospholipid antibodies.

Extensive infarction may have serious consequences for the fetus including intrauterine fetal demise, hypoxia, and intrauterine growth retardation. It is thought that the normal placenta can withstand the loss of as much as 15 to 20% of the villous tissue without adversely affecting the fetus, but in conditions in which there is already low flow to the placenta, such as preeclampsia, even lesser degrees of infarction may be detrimental to the fetus. Extensive infarction in the placentas of preterm infants has been significantly associated with periventricular leukomalacia. High rates of infarction (85%) and low flow changes (55%) were also noted in a series of stillborn infants with ischemic cerebral injury. However, at least one study has found no correlation between placental infarcts and growth or neurodevelopmental abnormalities in the first year of life in growth restricted infants.

Retroplacental Hematoma
A retroplacental hematoma is a blood clot that lies between the basal plate of the placenta and the uterine wall and indents the overlying placental parenchyma. It may be large, covering most of the maternal surface, or small, best visualized on serial sections. A recent retroplacental hematoma will be soft and red and will easily separate from the placenta. An indentation, a disrupted maternal surface, a large amount of clot in the specimen container, the delivering physician's impression of the placenta when delivered or at the time of Cesarean section may all point to the diagnosis in the absence of adherent clot. Older hematomas are firm, brown and adherent. Sometimes the placental parenchyma overlying older hematomas is infarcted. Occasionally a hematoma may rupture and dissect into adjacent villous tissue. In a very recent retroplacental bleed there may be no clot adherent to the placenta and no deformation of the maternal surface.

Microscopically, early hematomas are composed of red cells while older ones contain varying amounts of fibrin, degenerated red cells, hemosiderin-laden macrophages and neutrophils. The overlying decidua may be necrotic. Villous stromal hemorrhage and villous edema may be seen adjacent to retroplacental hematoma, particularly when the hematoma occurs earlier in gestation (16 to 28 weeks).

Retroplacental hematoma is related to, but not synonymous with, the clinical syndrome of placental abruption (abruptio placentae). The features of this clinical syndrome include vaginal bleeding, increased uterine tone, uterine tenderness, diminished fetal heart tones and if severe, maternal hypovolemia, consumptive coagulopathy, and fetal death. The incidence of abruption is about 11.5/1000 deliveries. It is associated with a 20% to 40% fetal mortality rate and accounts for 10% of all stillbirths and 6% of all maternal deaths. The rate of placental abruption in the United States has increased in the last few decades.

Retroplacental hematoma and placental abruption share many of the same risk factors and a clear distinction between them has not always been made in the literature. In only about a third of the cases with a clinical diagnosis of abruption can a retroplacental hematoma be demonstrated on placental examination, probably because of the rapidity of development and subsequent delivery. Conversely, in only about a third of cases in which the pathologist identifies a retroplacental hematoma will the clinical syndrome of placental abruption have been diagnosed. These probably represent smaller, clinically insignificant hematomas.

Retroplacental hematomas are common, occurring in as many as 4.5% of placentas. The most consistently identified risk factors for retroplacental bleeding include preeclampsia with a three fold increase, abdominal trauma, cigarette smoking, both maternal and of male partner, a previous history of abruption, extremes of maternal age, multiparity, poor nutrition, low socioeconomic status, acute chorioamnionitis, severe fetal growth retardation, maternal thrombophilic conditions, and cocaine abuse.

The pathogenesis of retroplacental hematoma is not well understood. It is thought that in cases of preeclampsia the associated atherosis may weaken the vessels increasing the likelihood of rupture. Cigarette smoking and cocaine abuse may also damage vessels walls. Hyperhomocysteinemia and hereditary deficiencies in various factors involved in normal coagulation may also lead to thrombosis and possibly vascular damage.

The clinical significance of retroplacental hematoma is largely dependant on the size and the amount of placenta that is infarcted, keeping in mind that in a background of chronic uteroplacental ischemia, such as with preeclampsia, the functional reserve of the placenta will be exceeded with lesser degrees of infarction. Extensive retroplacental hematoma may result in fetal death and has been associated with periventricular leukomalacia in preterm infants.

Marginal Hematoma
Marginal hematoma is a crescent-shaped hematoma at the lateral edge of the placenta where the fetal membranes meet the edge of the placental disc. The blood clot may be adherent to the fetal membranes or extend as a thin layer over an adjacent area of maternal surface without indentation of this surface. Microscopically, marginal hematomas are composed of blood, fibrin and occasional neutrophils.

Fox reports that marginal hematomas are found in 1.9% of placentas. The bleeding is the result of rupture of uteroplacental veins at the margin during separation of the spongy and compact layers of the decidua. This occurs most commonly in patients with lateral placenta previa, or low lying placentas.

Intervillous Thrombohematoma
Intervillous thrombohematomas, are seen in from 3% to 50% of uncomplicated pregnancies and in up to 78% of pregnancies with complications. They are particularly common in the third trimester. Grossly, they are round to oval and may range in size from a few millimeters to 5 cm with a mean size of 1.5 cm. They are most often located midway between the basal plate and the chorionic plate but may abut the basal plate. Early intervillous thrombohematomas are dark red and soft. With age they become firmer and progressively more pale and laminated. Microscopically, intervillous thrombohematomas consist of degenerated red cells between lamina of fibrin. The lesion itself contains no villi but compressed or infarcted villi sometimes rim the periphery.

An immunohistochemical study utilizing antibody to fetal hemoglobin demonstrated that intervillous thrombohematomas contain both fetal and maternal blood. Careful histologic examination of villi from normal placentas has demonstrated breaks in the trophoblast overlying vasculosyncytial membranes often covered with a blob of fibrin in up to 60% of cases, providing a mechanism for entry of fetal blood into the intervillous space. The formation of a clot may serve a protective role in that it limits the amount of fetal hemorrhage and reduces the amount of potentially antigenic fetal blood that can enter the maternal circulation.

Intervillous thrombohematomas themselves are not the cause of increased fetal morbidity or mortality. Their significance is as a marker for fetal hemorrhage and entry of fetal blood into the maternal circulation. There is good correlation between the number of intervillous thrombohematomas and the degree of fetomaternal hemorrhage as measured by the Kleihauer-Betke test on maternal blood. Occasionally, fetal hemorrhage can be extensive and result in intrauterine demise or severe anemia. Although Rh isoimmunization is uncommon now thanks to the widespread use of Rhogam, fetomaternal hemorrhage may still sensitize a mother against uncommon and private fetal antigens with adverse consequences for subsequent pregnancies.

Subamniotic Hematoma
These are deep purple collections of liquid blood that pool between the amnion and the chorion. They are usually small and are thought to be the result of recent trauma to surface veins on the chorionic plate during delivery such as from umbilical cord traction. Since this occurs after delivery of the baby, they are not clinically significant for the infant. Occasionally subamniotic hematoma may be the result of laceration of a vessel at the time of amniocentesis. Careful examination of the vessels may localize the site of trauma. In this situation, there may be consequences for the infant.

Massive Subchorial Thrombosis
This condition, also known as massive subchorionic thrombohematoma or Breus' mole, is by definition a red thrombus measuring at least 1 cm in thickness situated immediately beneath the chorionic plate. Often the fetal plate shows bulging elevations where the thrombus protrudes into the amniotic cavity. Extension deep into the placental parenchyma may also be seen. Microscopically, massive subchorial thrombosis is composed of clotted red cells that separate the chorionic plate from the underlying villi over much of its area.

Massive subchorial thrombosis is quite rare, occurring in 0.53 per 1000 placentas from one large series. It is often associated with stillbirth and neonatal death although it is no longer thought to be secondary to fetal death as it once was. As many as 41% of cases have intrauterine growth restriction.

The pathogenesis of Breus' mole is uncertain. Some speculate that it is the result of sudden, marked stasis of maternal blood in the intervillous space such as could occur by obliteration of venous channels draining this space, but the cause of such obliteration is unknown. Others believe it is due to rupture of a large vessel on the chorionic plate or in a stem villus. It is thought that a large clot near the umbilical cord could impede flow through the cord resulting in growth restriction or death.

Fetal Circulatory Disorders

Case 2: Fetal Thrombotic Vasculopathy

Fetal Vascular Obstruction
Occlusion of vessels in the fetal circulatory system can involve vessels at any level - large umbilical cord vessels, their branches on the chorionic plate, or smaller fetal vessels within the chorionic villi. Remember that during gestation there is one continuous circulation between the fetus and the placenta. The term fetal vascular obstruction used in this discussion refers to thrombi or related lesions in the fetal portion of the placental circulation. It has become increasingly clear that thrombotic lesions in the placental part of this fetal circulation may be associated with, and could serve as a marker for, thrombotic or embolic lesions in the circulation of the fetus itself, sometimes with devastating consequences for the fetus. For this reason, it is important for pathologists to become familiar with the gross and microscopic appearance of fetal vascular obstructive lesions in the placenta.

On gross examination, areas of fetal vascular obstruction in the placenta form well circumscribed, pale areas with the same spongy consistency as the surrounding tissue. This contrasts with the increased firmess characteristic of infarcts, which may also be pale and well circumscribed. Microscopically, the affected villi are avascular and sharply demarcated from adjacent normal villi. There is an increased amount of bland stromal hyaline fibrosis. The villi are normally spaced within the intervillous space, not compact as would be seen in an infarct.

Redline et al recently proposed diagnostic terminology with precise, reproducible definitions for lesions of fetal vascular obstruction. The term uniformly avascular villi is used when three or more foci of two terminal villi show avascularity. Another form of fetal vascular obstruction that manifests in distal villi has been termed villous stromal-vascular karyorrhexis. This can be diagnosed when three or more foci of two or more terminal villi show karyorrhexis of fetal cells – endothelium, stromal cells or blood cell elements. Often the villi are hypovascular with degenerating capillaries and fragmented red cells. This lesion has been termed hemorrhagic endovasculitis in the past. It is now thought to represent part of the spectrum of changes in fetal vascular obstruction as both patterns coexist and both share the same predisposing risk factors and carry similar implications for the fetus. A third pattern termed villitis of unknown etiology (VUE) with obliterative fetal vasculopathy is diagnosed when VUE extends to stem villi and is associated with stem villus vasculitis and vascular occlusion with associated avascular villi in the downstream villi. All of these villous changes are considered severe when there are more than two foci that average 15 or more villi per focus per slide. It is recommended that the term fetal thrombotic vasculopathy be reserved for those cases in which the villous vascular obstruction is extensive.

Studies have shown that the thrombosed large vessel upstream from avascular terminal villi or villous stromal-vascular karyorrhexis can only be demonstrated in about 30% of cases when extensive avascular villi are present. The distal villous changes have been shown to be more sensitive and reproducible than large vessel lesions. A thrombus in a large vessel can be reliably diagnosed when two of three features are present: fibrin strands, glassy texture or endothelial adherence.

The main differential diagnostic consideration is with the villous changes associated with intrauterine fetal demise. The microscopic changes are the same but with intrauterine fetal demise, the process is generalized involving all villi and all vessels of a similar size to the same degree, in contrast to the sharply demarcated areas of avascularity in fetal vascular obstruction.

The pathogenesis fetal vascular obstruction in the placenta is usually related to stasis, hypercoagulability or vascular damage. There is an association with a variety of cord abnormalities including velamentous cord insertion, excessive cord twisting, nuchal cord, other encirclements, and very long cords. In these situations, clot may propagate downstream from an area of thrombosis in the cord or from the intramembranous segments of the cord vessels that are not protected by Wharton's jelly and therefore are prone to thrombosis. There is also an association with chorioamnionitis. The mediators of the inflammatory process trigger the coagulation cascade at several points. The incidence of thrombosis in the placental part of the fetal circulation is also increased in the placentas of diabetic mothers for reasons that are not well understood. There is some evidence that fetal vascular obstructive lesions in the fetal circulation of the placenta may be associated with abnormalities of fetal coagulation, but an inherited coagulopathy in the fetus probably acts as an additional factor tipping the balance towards thrombosis because a recent study found no increase in these lesions in infants known to harbor mutations in hereditary thrombophilic disorders.

Fetal vascular obstructive lesions in fetal circulation of the placenta may be associated with thrombotic lesions in the fetus itself or with fetal conditions such as cerebral palsy that may have thrombosis as part of its pathogenesis. Redline and Pappin, using avascular villi as a marker of this process, found that cases with extensive areas of avascular villi were significantly associated with fetal growth retardation, oligohydramnios in the absence of membrane rupture and acute and chronic monitoring abnormalities. In a subset of this group that was over 34 weeks, did not have malformations and did not have other major placental pathology, the presence of very large areas of avascular villi, diffuse platelet aggregates or intravascular fibrin strands was highly associated with major thrombotic events in the fetus. In a study of term, singleton infants with neonatal encephalopathy, McDonald et al found that fetal thrombotic vasculopathy, endothelial cushions and accelerated villous maturation were all independently and significantly associated with neonatal encephalopathy. Kraus has described a high rate of downstream avascular villi and thrombi in fetal placental vessels in a selected group of infants with cerebral palsy referred for the purpose of litigation. Redline et al, studying a similar population, also found extensive avascular villi in about 18% of term cases with long-term neurologic impairment. Potentially obstructing umbilical cord abnormalities were much more likely in infants with fetal thrombotic vasculopathy. In a study of 84 consecutive perinatal autopsies, Kraus found fetal vascular obstructive lesions in the placentas of 16 cases. The areas of fetal vascular obstructive lesions were extensive in the placentas of all cases and occupied 25 to 40% of the placenta in four cases. In these four cases, the extensive fetal vascular obstructive lesions were the only explanation for the fetal death. Six of these cases had thrombi in fetal organs including the brain, kidney and lungs. Eight of the mothers had an extensive work up for coagulopathy and five had one or more coagulation abnormalities. One study, analyzing placental tissue from cases of fetal thrombotic vasculopathy, found an increased incidence of factor V Leiden and prothrombin mutations in the fetal tissue, indicating that the fetus may have inherited a coagulopathy. In another series, however, there was no correlation between the presence of the most common hereditary thrombophilic mutations in the fetus and/or the mother and fetal avascular lesions in the placenta.

These findings indicate that fetal vascular obstructive lesions in the placenta, particularly if extensive, may be a reliable indicator of the potential for thrombi in the circulation of the fetus or newborn and may explain adverse perinatal outcome and some perinatal deaths. Prospective studies will be needed to determine the predictive value of fetal vascular obstructive lesions for various adverse fetal outcomes such as neurologic impairment. Further studies are also needed to determine the clinically significant amount of avascular villi, the appropriate work up for this finding, and what role, if any, there is for treatment in subsequent pregnancies.

Chorangiomas
Placental chorangioma is best considered a hamartomatous rather than neoplastic collection of fetal blood vessels of varying types. Large chorangiomas are uncommon, recognized grossly in 1 in 13,000 deliveries. About 1% of carefully sampled, microscopically examined placentas, however, will contain small chorangiomas.

Grossly, large nodules of firm red or gray-pink tissue may bulge from the fetal or maternal surfaces. The cut surface is homogeneous. Smaller lesions may be difficult to identify, grossly, however, especially in the unfixed placenta. Microscopically, they are composed predominantly of thin-walled, capillary-type vessels. Chorangiomas without many red cells will appear more cellular. Rarely, chorangiomas exhibit cytologic atypia and increased mitotic activity but biologic aggressiveness has not been reported.

Isolated small chorangiomas and most large ones are without clinical significance. Some large chorangiomas may, however, be associated with polyhydramnios, preterm delivery, antepartum bleeding, hydrops fetalis, anemia, thrombocytopenia, and cardiomegaly. One study has found a relationship between the size of the chorangioma and the presence of intrauterine growth retardation. Sometimes a large chorangioma or multiple small ones is the only explanation for growth retardation. Large chorangiomas are not usually associated with fetal anomalies although the incidence of hemangiomas elsewhere in the fetus is about six times that expected. Some have postulated that infantile hemangiomas may be of placental origin.

The fetal and neonatal mortality rate associated with large chorangiomas is as high as 40%. Occasionally chorangiomas recur in successive pregnancies. In these cases the chorangiomas are frequently multiple and the fetal outcome is often poor.

This vascular lesion may alter fetal hemodynamics in two ways. The tumor may act as a left to right shunt increasing the workload of the fetal heart culminating in heart failure. Alternatively, blood that has passed through the chorangioma which, if large, is not in contact with the maternal blood in the intervillous space, will be low in oxygen when returned to the fetus resulting in chronic hypoxia.

Various treatments for chorangiomas that are adversely affecting fetal hemodynamics have been described in the literature including ligation, laser, and injection of absolute alcohol into the feeding vessel or lesion and cordocentesis to treat the resulting anemia. These have been variably successful.

Chorangiosis and Chorangiomatosis
Chorangiosis is defined as the presence of more than 10 capillaries per terminal villus in 10 terminal villi in at least three different regions of the placenta. Care should be taken to distinguish this lesion from congestion. In fact, in many cases with true chorangiosis, the villi contain many more than 10 capillaries. The stem villi in this process do not show an increased number of capillaries. Each capillary is surrounded by a distinct basement membrane but not by smooth muscle actin positive pericytes.

Chorangiosis is found predominantly in placentas from gestations of at least 37 weeks. The prevalence of this finding is estimated to be about 5%. Associated placental findings include large placental size, delayed villous maturation, chronic villitis, lesions associated with acute and chronic placental ischemia and cord lesions. Associated clinical findings include maternal diabetes, congenital anomalies, delivery at high altitude, maternal anemia, maternal smoking and twin gestations.

The pathogenesis of chorangiosis is still not understood. One possibility is that capillary proliferation occurs in response to hypoxia or chronic inflammation. Another possibility is that the increased capillary proliferation is related to increased intramural pressure due to venous obstruction at the level of the umbilical cord or fetal heart. Still another possibility is that cytokines released from inflammatory cells, in cases with chronic villitis, trigger capillary proliferation.

Chorangiomatosis is a recently described, morphologically similar lesion. In contrast to chorangiosis in which the vessel proliferation occurs in the terminal villi, in chorangiomatosis, there is endothelial and perithelial proliferation in multiple stem villi and terminal villi. The lesion is not nodular and expansile like a chorangioma, however. A distinct basement membrane is not seen around each vessel but there is a uniform layer of SMA-positive pericytes around each capillary. Chorangiomatosis is thought to arise from the subtrophoblastic rim of connective tissue in immature stem villi. The pathogenesis is not known.

Chorangiomastosis is uncommon, occurring in about 1% of placentas and appears to be more closely related to chorangioma; these two lesions are commonly associated with each other. This lesion is most common between 32 and 36 weeks of gestation. It is associated with preeclampsia and multiple gestation but not with maternal diabetes. Diffuse, multifocal chorangiomatosis occurs at even earlier gestational ages and is associated with intrauterine growth retardation and congenital malformations.

References

Perivillous Fibrin:
  1. Fox H. Perivillous fibrin deposition in the human placenta. Am J Obstet Gynecol 1967; 98:245-51.

  2. Fuke Y, et al. Clinical significance and treatment of massive intervillous fibrin deposition associated with recurrent fetal growth retardation. Gynecol Obstet Invest 1994; 38:5-9.

  3. Katzman PJ and Genest DR . Maternal floor infarction and massive perivillous fibrin deposition: histological definitions, associations with intrauterine fetal growth restriction, and risk of recurrence. Pediatr Dev Pathol 2002; 5:159-164.

  4. Kumazaki K et al. Placental features in preterm infants with periventricular leukomalacia. Pediatrics 2002; 109:650-55.

  5. Redline RW, et al. Patterns of placental injury: correlations with gestational age, placental weight, and clinical diagnoses. Arch Pathol Lab Med 1994; 118:698-701.

  6. Sebire NJ et al. Placental massive perivillous fibrin deposition associated with antiphospholipid antibody syndrome. BJOG. 2002; 109:570-3.
Maternal Floor Infarct:
  1. Adams-Chapman I et al. Maternal floor infarction of the placenta: association with central nervous system injury and adverse neurodevelopmental outcome. J Perinatol 2002; 22:236-241.

  2. Andres RL, et al. The association of maternal floor infarction of the placenta with adverse perinatal outcome. Am J Obstet Gynecol 1990; 163:935-8.

  3. Bendon RW, et al. Maternal floor infarction in autoimmune disease: two cases. Ped Pathol Lab Med 1996; 16:293-7.

  4. Mandsager NT, et al. Maternal floor infarction of the placenta: prenatal diagnosis and clinical significance. Obstet Gynecol 1994; 83:750-4.

  5. Matern D, et al. Placental floor infarction complicating the pregnancy of a fetus with long-chain e-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Mol Genetics and Metab 2001; 72:265-9.

  6. Naeye RL. Maternal floor infarction. Hum Pathol 1985; 16:823-8.

  7. Redline RW. Maternal floor infarct and massive perivillous fibrin deposition: clinicopathologic entities in flux. Adv Anat Pathol 2002: 9:372-3.

  8. Redline RW et al. Discordancy for maternal floor infarction in dizygotic twin placentas. Hum Pathol 2003; 34:822-24.
Subchorionic Fibrin:
  1. Naeye RL. The clinical significance of absent subchorionic fibrin in the placenta. Am J Clin Pathol 1990; 94:196-8.
Infarct
  1. Becroft DMO et al. The epidemiology of placental infarction at term. Placenta 2002; 23:343-51.

  2. Becroft DMO et al. Placental infarcts, intervillous fibrin plaques and intervillous thrombi: incidences, coocurrences and epidemiological association. Ped Develop Pathol 2004;7: 26-34.

  3. Burke C and Tannenberg AE. Prenatal brain damage and placental infarction - an autopsy study. Devel Med Child Neurol 1995; 37:555-62.

  4. Fox H. White infarcts of the placenta. J Obstet Gynecol Br Comm 1963; 70:980-991.

  5. Fox H. The significance of placental infarction in perinatal morbidity and mortality. Biol Neonate 1967; 11:87-105.

  6. Gersell DG and Kraus FT (1994) in Blaustein's Pathology of the Female Genital Tract, 4th ed, ed. Robert J. Kurman, New York, Springer-Verlag.

  7. Gray PH et al. Placental pathology and neurodevelopment of the infant with intrauterine growth restriction. Develop Med and Child Neurol 1999; 41:16-20.

  8. Kumazaki K et al. Placental features in preterm infants with periventricular leukomalacia. Pediatrics 2002; 109:650-55.

  9. McDermott M, et al. Chronic reduction in fetal blood flow is associated with placental infarction. Placenta 1995; 16:165-70.

  10. Wallenburg HCS, et al. The pathogenesis of placental infarction I. A morphologic study in the human placenta. Am J Obstet Gynecol 1973; 116:835-40.
Retroplacental Hematoma:
  1. Ananth CV et al. Incidence of placental abruption in relation to cigarette smoking and hypertensive disorders during pregnancy: a meta-analysis of observational studies. Obstet Gynecol 1999;93: 622-8.

  2. Ananth CV et al. Placental abruption in the United States, 1979 through 2001: temporal trends and potential determinants. Am J Obstet Gynecol 2005;192:191-8.

  3. De Vries JIP et al. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynecol 1997; 104:1248-54.

  4. Fox H. (1997). Pathology of the Placenta. Major Problems in Pathology, Vol 7, 2nd edition, Philadelphia, W.B. Saunders.

  5. Goodijn-Wessel TAW et al. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Europ J Obstet Gynecol Repro Biol 1996; 66:23-29.

  6. Raymond EG, et al. Placental abruption: maternal risk factors and associated fetal conditions. ACTA Obstet Gynecol Scand 1993; 72:633-9.

  7. Saftlas F, et al. National trends in the incidence of abruptio placentae, 1979-1987. Obstet Gynecol 1991; 78:1081.

  8. Tikkanen M, et al. Clinical presentation and risk factors of placental abruption. Acta Obstet Gynecol 2006;85:700-705.

  9. Williams MA, et al. Risk factors for abruptio placentae. Am J Epidemiol 1991; 134:965-72.
Marginal Hematoma:
  1. Fox H (1997). Pathology of the Placenta. Major Problems in Pathology, Vol 7, 2nd edition Philadelphia, W.B. Saunders.
Intervillous Thrombi:
  1. Devi B, et al. Significance of placental pathology in transplacental haemorrhage. J Clin Pathol 1968; 21:322-31.

  2. Kaplan C, et al. Identification of erythrocytes in intervillous thrombi: a study using immunoperoxidase identification of hemoglobins. Hum Pathol 1982; 13:554-7.
Subamniotic Hematoma:
  1. Gersell DG and Kraus FT (1994) in Blaustein's Pathology of the Female Genital Tract, 4th ed, ed. Robert J. Kurman, New York, Springer-Verlag.
Massive Subchorial Thrombosis:
  1. Nishida N et al . Massive subchorionic hematoma (Breus' Mole) complicated by intrauterine growth retardation. J Nippon Med Sch 2001; 68:54-75.

  2. Redline RW. 1999. Disorders of the placental parenchyma In: Pathology of the Placenta 2nd Edition. Eds: Steven H. Lewis and Eugene Perrin. Churchill Livingstone, New York. P. 180.

  3. Shanklin DR, et al. Massive subchorial thrombohaematoma (Breus' mole). Br J Obstet Gynecol 1975; 82:476-87.
Fetal Thrombosis:
  1. Arias F, et al. Thrombophilia: A mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern-Fetal Med 1998; 7:277-286

  2. Ariel I et al. Placental pathology in fetal thrombophilia. . Hum Pathol 2004; 35:729-733.

  3. Dahms BB, et al. Severe perinatal liver disease associated with fetal thrombotic vasculopathy. Pediatr Dev Pathol 2002; 5:80-85.

  4. Gersell DJ. Selected vascular lesions of the placenta. Clin Lab Med 1995; 15:611-629.

  5. Heifetz SA. Thrombosis of the umbilical cord: analysis of 52 cases and literature review. Pediatric Pathol 1988; 8:37-54.

  6. Kraus FT. Placental thrombi and related problems. Sem Diagn Pathol 1993; 10:275-283.

  7. Kraus FT. Cerebral palsy and thrombi in placental vessels of the fetus: insights from litigation. Hum Pathol 1997; 28:246-8.

  8. Kraus FT et al. Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 1999; 30:759-69.

  9. McDermott M, et al. Trophoblast basement membrane haemosiderosis in the placental lesion of fetal artery thrombosis: a marker for disturbance of maternofetal transfer? Placenta 1995; 16:171-178.

  10. McDonald DGM et al. Placental fetal thrombotic vasculopathy is associated with neonatal encephalopathy. Hum Pathol 2004; 35:875-880.

  11. Rayne SC, et al. Placental thrombi and other vascular lesions: classification, morphology and clinical correlations. Path Res Pract 1993; 189:2-17.

  12. Redline RW, et al. Fetal vasculopathy: the clinical significance of extensive avascular villi. Hum Pathol 1995; 26:80-85.

  13. Redline RW, et al. Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med 1998; 122:1091-1098.

  14. Redline RW, et al. Placental lesions associated with cerebral palsy and neurologic impairment following term birth. Arch Pathol Lab Med 2000; 124:1785-1791.

  15. Redline RW, et al. Fetal vascular obstructive lesions: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol 2004; 7:443-452.

  16. Redline RW. Clinical and pathologic umbilical cord abnormalities in fetal thrombotic vasculopathy. Hum Pathol 2004;35:1494-8.

  17. Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J. Obstet Gynecol 2005;192:452-7.

  18. Thorarensen O, et al. Factor V Leiden mutation: An unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis. Ann Neurol 1997; 42:372-375.

  19. Vern TZ et al. Frequency of factor V (Leiden) and prothrombin G2021A in placentas and their relationship with placental lesions. Hum Pathol 2000; 31:1036-1043.
Placental Chorangiomas:
  1. Benirschke K. Recent trends in chorangiomas, especially those of multiple and recurrent chorangiomas. Pediatr Dev Pathol 1999; 2:264-269.

  2. Bhide A et al. Ultrasound-guided interstitial laser therapy for the treatment of placental chorioangioma. Obstet Gynecol 2003; 102:1189-91.

  3. Cash JB, et al. Placental chorioangiomas: presentation of a case with electron-microscopic and immunohistochemical studies. Am J Surg Path 1980; 4:87-92.

  4. Hamill N et al. Prenatal diagnosis and management of fetal anemia secondary to a large chorangioma. Obstet Gynecol 2003; 102:1185-1188.

  5. Lopez HBB et al. Chorioangioma of the placenta. Gynecol Obstet Invest 1989; 28:108-110.

  6. Mucitelli DR , et al. Chorangiomas of intermediate size and intrauterine growth retardation. Path Res Pract 1990; 186:455-8.

  7. North P et al. Are infantile hemangioma of placental origin? Ophthalmology 2002; 109:223-224.
Chorangiosis and Chorangiomatosis :
  1. Altshuler G. Chorangiosis: an important placental sign of neonatal morbidity and mortality. Arch Pathol Lab Med 1984; 108:71-74.

  2. Ogino S and Redline RW. Villous capillary lesions of the placenta: distinctions between chorangioma, chorangiomatosis, and chorangiosis. Hum Pathol 2000; 31:945-954.

  3. Redline RW. 1999. Disorders of the placental parenchyma In: Pathology of the Placenta 2nd Edition. Eds: Steven H. Lewis and Eugene Perrin. Churchill Livingstone, New York. P. 167-168.