Chapter 9 Placental Perfusion: Section D Placental Infarction

What is a placental infarction?


The cessation of blood flow in an end artery leads to death of the tissue supplied by that artery. This is the fundamental concept of an infarction. Obstruction of an end artery results in loss of blood flow to some volume of an organ. The consequent loss of tissue respiration leads to anaerobic metabolism in the cells which increases metabolic acids such as lactate and pyruvate which make the cell acidotic. This acidosis releases the enzymes from cell organelles, the lysosomes, which contain digestive enzymes, lysozymes. These enzymes digest the nucleic acids, proteins, and other substances in the cell. This digestion produces characteristic gross and microscopic change that can be seen by the naked eye and on routine hematoxlyin and eosin stained microscope slides. This change is called coagulation necrosis and microscopically shows progressive loss of nuclear basophilia (blue color) and a brighter, more homogenous pink color of the cell cytoplasm (Wigglesworth 1964; Fox 1967). Coagulation necrosis takes hours to become visible by routine microscopy, but the process begins with the obstruction of blood flow.

In the heart, these end arteries are branches of the coronary arteries. In the uterus, they are branches of the radial arteries called spiral arteries which supply the endometrium and the placenta. The direct evidence that the spiral arteries are end arteries was established by Dr. Elizabeth Ramsey in eloquent angiographic studies done by vascular dye injection and sequential radiographs in monkeys(Ramsey and Donner 1980). Monkey placentas are virtually identical to human placenta except they typically are bilobed instead of a single disk. The spiral arteries appear as fountains shooting into the intervillous space, supplying a distinctly shaped volume of placenta that resembles the characteristic shape of a placental infarction. Interestingly, the arteries appear to perfuse in separate intervals, and not all the arteries at once.

An infarction may be smaller than the volume of organ normally circulated by an end artery because a portion of that volume may become circulated by collateral blood vessels after the end artery is occluded. The size of the infarction in both the heart and placenta depends in part on the extent of this collateral circulation. In the heart, this collateral circulation comes from small vessels that have anastomosed (fused with) vessels that supply the infarcted tissue. When flow in the end artery stops, the pressure gradient allows some flow from these anastomotic vessels into the territory of the occluded end artery. In the placenta, the collateral circulation comes from an open pattern of intervillous blood flow. While strong collateral flow may make an infarction smaller, a lack of collateral flow would not be expected to make an infarction larger than the volume supplied by an end artery. Placental infarctions larger than the expected spiral artery volume are often due to premature placental separation which separate spiral arteries from the placenta over a contiguous area. However, the disruption of normal flow in the continuous intervillous space could have spatially more complex consequences than that in solid tissues perfused by vessels.

What does a placental infarction look like?


A placental infarction results in loss of blood in the intervillous space. The villi become compressed against each other forming a solid mass that can be recognized by a solid feel, and a more compact appearance. On close inspection, the villous architecture remains discernable. Infarctions can vary from a deeper red color compared to the surrounding placenta to brown, tan, yellow and white as they age(Wigglesworth 1964; Fox 1967; Wentworth 1967) (ppt.infgross). Microscopically, the tissue shows the touching of villi from collapse of the intervillous space and the progression of coagulation necrosis (ppt.infmicro). The size and shape of a placental infarction tends to be ovoid with a maximum diameter 1 to 3 cm with the base on the maternal surface of the placenta, although the shape can be more irregular. There is usually some undermining of the base and top and sometimes the infarction appears to float between both surfaces. The shape appears to reflect the circulation of a spiral artery as demonstrated by angiography in the monkey placenta, but flow from surrounding spiral arteries may modify the volume that becomes infarcted. Most often, the microscopic sections shows some viable maternal floor chorion and decidua beneath the infarction (ppt infarct base).

What lesions might be confused with an infarction?

There are three other lesions that overlap with infarction. These lesions like infarction can be easily palpated within the soft placental parenchyma. First is focal massive perivillous fibrinoid deposition which may have a small infarction deep within it, but the predominant pathology is the expansion of the intervillous space with fibrinoid. Grossly the fibrinoid has a more wedge shaped appearance, and a more rubbery consistency than infarction. Close inspection shows a pattern of solid material often with sponge like intervillous blood spaces. Villi trapped in this fibrinoid, undergo coagulation necrosis and the progressive changes seen with infarction. The intervillous space however is not collapsed. This lesion and the composition and genesis of fibrinoid is discussed in the chapter on massive fibrinoid deposition.

A retroplacental hematoma or hemorrhage when partial can disrupt the utero-placental blood supply usually over a contiguous area of multiple spiral arteries. A partial separation usually demonstrates some physical evidence of a hematoma beneath the placenta. The area is usually larger than that of an infarction which results from occlusion of a single spiral artery. The villi above the separation undergo the same changes of coagulative necrosis as does an infarction. Unlike an infarction, the basal plate is necrotic and often there is evidence of decidual hemorrhage. This entity is discussed in the chapter on placental separation/ abruption.

Laminated intervillous thrombi often trap individual villi depriving them of oxygen. The entrapped villi undergo coagulation necrosis in a sequence similar to infarction. The typical intervillous thrombus is usually pyramidal, not usually oriented against the placental floor, and the predominant lesion is clearly the laminated thrombus. This lesion is discussed in the chapter on fetal hemorrhage.

There is a variant appearance of infarction in which the typical infarction has a central hematoma (ppt.infhem). In this lesion, the intervillous blood is not well laminated, and the rim of necrotic villi is not entrapped in thrombus but a separate rim of collapsed intervillous space. This central hemorrhage is mentioned in passing in descriptions of infarctions (Wigglesworth 1964; Wallenburg, Stolte et al. 1973) an many infarctions do have a small central hemorrhage that extends from the spiral artery. One hypothesis to explain these hematomas proposes that the occlusion of the spiral artery that caused the infarction is overcome and new blood flow hemorrhages into the infarction. In the brain, this is the classic explanation of hemorrhage into infarctions, so called red infarcts. However it is also possible that the lesion begins as a small retroplacental hematoma that ruptures into the placental parenchyma. Hemorrhage from the decidual spiral artery seem unlikely since the pressure must be very close to the perfusion pressure of the intervillous space above it, but smaller decidual arterioles or occlusion of decidual veins might initiate a small focus of decidual hemorrhage. This intraplacental hematoma has been well described on prenatal ultrasound(Fitzgerald, Shannon et al. 2011). I proposed that the lesion be distinguished from other infarctions with a specific name, infarction hematoma, in order to separate it from the usual infarction(Bendon 2011). This lesion can be seen in placenta mixed with ordinary infarctions and like other infarctions can occur in patients with toxemia. This overlap does not prove that the infarction hematoma does not have a clinical or etiologic specificity different from infarction. At least a couple patients in my experience have had recurrence of this lesion in subsequent pregnancies.

An unusual form of infarction occurs by obstruction of blood flow in the intervillous space during sickle cell crisis in the mother. I have seen these small infarctions in the parenchyma that are not related to spiral artery occlusion but to more distal occlusion in the intervillous space by fibrin and sickled red cells (ppt .infss). These appeared as small pale lesions floating in the parenchyma of the placenta.

Occlusion of the fetal circulation of the placenta is not an infarction. This occlusion causes villous changes but not the necrosis of the villi since the vitality of the villi depends on the maternal, not the fetal, circulation. The area of involved placenta becomes pale, but the texture remains normal.

I and colleagues have also encountered a lesion that appeared as a mirror image of multiple infarctions in a case of maternal hypotension(Bendon and Cantor 2007)(ppt.infinv). We reasoned that a sudden loss of blood pressure reduced the spiral artery blood flow of the intervillous space with the result that the outer portions of that circulation became infarcted. A more gradual decrease in spiral artery perfusion might increase ischemic adaptation or syncytiotrophoblast injury with fibrinoid deposition, but not caused infarction. This inverted infarction pattern would only be detectable if the fetus is delivered long enough after the hypotension for coagulation necrosis to become evident.


What happens to a placental infarction over time?


Initially infarction in the heart and placenta follow a similar course with coagulation necrosis followed by acute inflammation at the margins of the infarction(ppt.infage). After that stage, the paths diverge. The heart, like most organs, repairs infarctions by a process of scar formation, technically termed organization. Organization removes dead tissue and replaces it with new blood vessels and myofibroblasts the produce collagen fibers. Eventually, the new vessels are removed, and the myofibroblasts contract and collagen fibers form a denser tough mass that pulls together the margins of healthy tissue. The discovery of this process is entertainingly explored in the book The Healing Hand by Guido Majno. This process of scar formation is used to time a myocardial infarction after the first couple days(Mallory, White et al. 1939). The placenta does not scar. The placenta does not remove the dead tissue, but leaves it in a mummified state (sometimes referred to as ghosted) and therefore can not replace the dead tissue with new vessels and myofibroblasts. Over time the placental infarction margins undergo change. The outer villous layer of syncytiotrophoblast undergoes necrosis but the underlying stem cells of cytotrophoblast proliferate and secrete a tissue matrix that mixes with fibrin forming a border of fibrinoid walling off the infarction(Carter, Vellios et al. 1963; Wentworth 1967). Outside this layer the villi often show increased syncytial knots associated with decreased maternal blood flow.

How old is the infarction?: To the pathologist looking at samples fixed in time, there does appear to be a clear and logical progression of both placental and myocardial infarction even though the progression is different in each organ, but such a progression can not determine the absolute, only the relative, timing of events. To estimate that absolute timing for the heart, investigators compared the histological features with the interval from the onset of chest pain until the time of the patient’s death(Mallory, White et al. 1939). A placental infarction does not cause maternal pain, so there is no similar time of reference. Placental abruption causes an infarction of the overlying placenta by separating it from the uterine blood supply. This is discussed in the chapter on retroplacental hemorrhage/ placental separation. Extensive placental abruption may result in hemorrhage into the uterine wall and pain. The limitation of using onset of this pain to time infarction is that the infant is usually delivered shortly after the onset of pain. Not all placental separations cause pain, but they can infarct a large enough area of placenta to cause fetal death. By using criteria for estimating the length of time the infant has been dead in utero, and assuming the infant died at the time of the separation, a rough timing of infarctions can be constructed(Bendon 2011). This technique has a wide margin of error, but may be the best that can be estimated directly from the placenta.

Because the placenta has wide anatomic variation among species, experimental studies in animals other than primates are probably not helpful in human pathology. Fortunately, there is one experimental study of the repair process of placental infarction in the monkey. This study was performed by ligation of individual utero-placental arteries in pregnancy rhesus monkeys, and examination of the placenta at later intervals(Wallenburg, Hutchinson et al. 1973). In spontaneous deliveries all but one placenta was consumed by the mother preventing examination, but 18 other placentas were recovered by hysterotomy or hysterectomy. The four placentas less than 16 hours of age had no lesions. One placenta at 23 hours of age, and 2 at 48 hours of age demonstrated infarctions. Eight placentas 8 to 70 days post ligation also had infarcts. The youngest infarction (23 hours) was red in color and demonstrated some syncytial necrosis and blurring of cell detail. The older lesions were yellow white and better demarcated grossly. Microscopically there was evidence of stromal necrosis and a border of polymorphonuclear leukocytes around the lesion. The lesions older than 8 days had complete villous necrosis and a border of fibrinoid.

There is one other way to estimate the age of an infarction that is most useful for infarctions older than those dated by comparison with the monkey study or stillbirths from placental abruption. After an infarction, the shape of the dead villi is fixed. If the infarcted villi’s shape is that of a much younger gestation placenta, then the infarction occurred that much earlier in gestation. One source of error is that decreased utero-placental blood flow causes premature maturation of the villi surrounding the infarction. This could make the villi appear younger in comparison to the surrounding villi, but still they provide evidence that the infarction occurred at an earlier gestation. (ppt. infgest)

What does the timing of infarctions tell us? :

Knowing when infarctions occurred provides possible clues to the mechanism. If all the infarctions in a placenta are the same age, then likely there was some triggering event, such as a sudden increase in coaguability of the blood. Infarctions that occur throughout gestation are compatible with an ongoing disease process. Given that extensive infarctions can cause fetal harm, knowing when they occur in a given disease potentially can help decision making.

Can the presence or extent of placental infarctions by diagnosed before delivery of the placenta?

Prenatal ultrasound has been used to identify pathologically proven infarctions(Jauniaux and Campbell 1991). It may be difficult in some cases to distinguish infarctions from other solid lesions like intervillous thrombi or focal massive fibrinoid deposition. There is a group of creative investigators at the University of Toronto who are actively exploring this area(Proctor, Whittle et al. 2010). Another potential test for infarction would be to measure chemicals lost by the dying placental villi in the maternal blood, analogous to the measurement of release of myocardial cell chemicals into the patient’s serum. The trophoblast microvilli have numerous unique surface components such transferrins and plasminogen activators that are potential candidates as markers of infarction. One less obvious marker may already have been inadvertently used, maternal alpha feto protein. This substance has a function in fetal blood similar to albumin in more mature blood, and therefore is plentiful. It has been measured in maternal blood as a screening test for neural tube defects in the fetus. During a placental infarction, there could be leakage of fetal blood from the affected villi. Elevations in the second trimester have identified infants with severe intrauterine growth retardation, although this finding was not directly correlated with placental pathology(Hamilton, Abdalla et al. 1985).


What causes thrombus to form in a spiral artery?


The usual assumption is that a placental infarction is caused by a thrombus in a spiral artery. A thrombus is the end result of precipitation of fibrin fibers from flowing blood to create a tight net capable of stopping blood flow. If a tube of blood simply sits, it will clot, that is the soluble precursor of fibrin, fibrinogen, will precipitate and cross link and form a weak gel. A thrombus occurs by continuous accumulation of more fibrin from flowing blood. Whether a thrombus forms in a blood vessel is a dynamic balance between the factors that lead to thrombus formation and those opposed, including those that lyse, that is digest, the thrombus. The balance depends on the blood platelets, the blood clotting factors, and the endothelial cell lining of the vessel. The factors favoring thrombus formation have been summarized by the one of the founders of modern pathology, Virchow, as hypercoaguability (thrombophilia), stasis and vessel injury.

What is thrombophilia?

One can imagine the evolutionary pressure on the coagulability of blood. If we are injured, we want our vessels to form thrombi to prevent more serious hemorrhage. On the other hand, we want blood to continue flowing to our organs to keep them alive even in some cases when there is injury. Not surprisingly trauma including surgery increases our coagulability. Pregnancy, which invariably results in blood loss with separation of the placenta, also increases maternal coagulability by increasing clotting factors in the blood. Not surprisingly there are a number of genetic alleles in the population that make some people more coagulable, that is more thromobphilic, than others. Some pathologic antibodies directed against self antigens such as phospholipids and proteins that bind them, can also cause thrombophilia. The good side is those with thrombophila may better survive trauma, the bad side is they may form thrombi inappropriately for example from stasis in leg veins. These thrombi can then break loose and travel (embolize) to the lung with harmful consequence. Genetic or acquired thrombophilia may contribute to the pathological formation of thrombi in the spiral arteries and hence to placental infarctions.


What might cause spiral artery injury?

In myocardial infarction, the etiology of coronary artery thrombus is usually the rupture of an atherosclerotic plaque. This would qualify as an injury to the vessel, basically removing the protective function of the endothelium and releasing substances favoring thrombus formation. The superficial spiral arteries are normally shed with menstruation and regrow each month, so they would not be subject to chronic vascular disease like atherosclerosis. Even the deeper spiral arteries in women of reproductive age do not show significant atherosclerosis. Instead the vascular injury in the spiral arteries arises from the very adaptation of the vessels to support the pregnancy with placental blood flow. There is a normal non-gravid baseline blood flow through the endometrial lining of the uterus that the placenta taps into, but this flow must be increased eight to ten fold to supply the observed blood flow of the mature placenta. As a simplistic model, the simplest way to increase blood flow is to lower resistance especially by increasing the radius of the vessels since this increases flow to the second power of the radial increase, tripling the diameter increases blood flow 9 times, about the volume of flow that the placenta needs. This simple model ignores turbulence, and the complex branching with serial versus parallel resistance of the vessels.

The adaptive widening of the spiral arteries has been demonstrated, most eloquently in the pregnant monkey uterus, but with some minor differences, has been confirmed in the human uterus(Ramsey and Donner 1980). The widening of the vessels is accomplished first by the penetration of trophoblastic cells into the endometrium, and later into the superficial myometrium (muscle layer). These cells secrete substances that result in the death of the vascular smooth muscle, the muscle whose tone normally regulates the vascular diameter. The vessels that undergo this change initially are the spiral arteries that normally supply the endometrium and are shed each month with menstruation, but deeper permanent vessels are also successfully stripped of vascular muscle as these fetal trophoblastic cells invade more deeply into the uterus. An observer looking at this tissue invasion can not help but wonder if some of the genes needed for a successful malignancy do not have their origin in genes for implantation.

If this destructive widening of the spiral arteries happened at a pace that allowed the endothelium lining the vessel to grow over the expanding internal surface, then presumably the destruction of the vascular smooth muscle might not have any impact on thrombus formation. The process however is not so simple. The vessels early in placental development had opened into the intervillous space and the endothelium and cytotrophoblast at the base of the placenta became continuous. Following destruction of the spiral artery muscle, fetal cytotrophoblastic cells enter the lumen of the vessel and lift up and replace the endothelial cells. The cytotrophoblast, like the syncytiotrophoblast covering the villi, can function as an endothelium in the prevention of blood clotting. In midtrimester curettings this fetal cytotrophoblast lining of maternal arteries can be identified by the high cuboidal appearance of the cells compared to the typical flattened appearance of endothelium. If this process of vascular invasion was altered, the possibility exists that the basement membrane beneath the endothelium would be exposed to the flowing blood. Exposure of the underlying basement membrane is a normal part of initiating thrombosis with trauma to a vessel. Similarly exposure during cytotrophoblastic remodeling of the spiral arteries could lead to thromboisis.

In toxemia, if portions of the spiral artery remained or became lined by endothelium, then that lining would become injured by the sFLT-1 protein etc, and potentially become thrombogenic as underlying basement membrane became exposed, even without an error in remodeling.


Is there a role for stasis in spiral artery thrombus formation?


Stasis would not seem to be a significant factor in spiral arteries given the high flow of utero-placental blood. However, stasis can occur in the eddies behind turbulent flow. The varying diameter of the remodeled spiral arteries, their helical shape and increased blood viscosity could all contribute to turbulence, that might initiate thrombosis.

Summary: Thus, the potential ingredients for spiral artery thrombus exist, but it is another problem entirely to demonstrate that a particular mechanism of thrombus formation occurred in an individual patient. It is not even possible to know if the infarction was caused by a thrombus, or by non-thrombotic occlusion of the vessel perhaps from collapse of the weakened artery or from plugging of the lumen by invasive cytotrophoblast. Even in toxemia, the mechanism of placental infarction is not known although abnormal remodeling and endothelial injury are likely to be involved (see question about diseases associated with placental infarction). A better understanding of the mechanisms of placental infarction might better direct interventions to prevent them.


Are there direct observations of spiral artery thrombi causing placental infarction?


Some authors report finding thrombi in decidual arteries underlying placental infarction(Fox 1967; Wallenburg, Stolte et al. 1973). I think it is difficult to discern if these are causative thrombi or simply clotted blood from a deeper thrombus. The base of the placental typically shows a shallow layer of decidua still attached to the chorionic plate of the placenta. If a deeper portion of the spiral artery held the inciting thrombus, back flow into the large spiral arteries from other blood in the intervillous space could create clot within the superficial portions of the vessel. A curious but common observation is that the decidua beneath an infarction of the placenta is frequently still viable. The decidua above an infarcted villi caused by placental separation is invariably necrotic since the base is also separated from its blood supply. This suggests the location of the thrombus with an infarction is superficial to the take off of the basal arteries that supply the basal decidua.

The best opportunity to understand the mechanism of spiral artery thrombus is the direct examination of the uterus with the infarcted placenta in situ. Fortunately for the mothers, such specimens are rare. One such specimen was reported from a hysterectomy performed at 31 weeks of gestation from a mother with essential hypertension and superimposed toxemia, three days after fetal death (Brosens and Renaer 1972). Two infarctions are illustrated, and the vessels beneath them are described as being thrombosed at the myometrial decidual junction with hyalinization and foam cells and other mononuclear cells in the vascular wall, but without evidence of trophoblast remodeling. The authors comment that the vessels should have had cytotrophoblast invasion. The artery appearance is that of acute atherosis that will be discussed in the section on infarction and toxemia. The large autopsy series of mothers with toxemia presented in a monograph did not consider placental infarctions and spiral artery pathology in any detail. The authors state“ We have not made a detailed histological investigation of the placenta in toxaemia, and the following brief notes are based almost entirely on the literature” (Sheehan and Lynch 1973) P678.

The report of the uterus discussed above also describes endometrial biopsies taken from mothers with toxemia. The biopsies will not always be from the actual placental bed, and there is little hope of correlating them with the location of placental infarctions. Placental bed biopsies have been a productive approach for investigators over many years, but they are a poor tool for studying infarction. Routine histology and molecular localization techniques applied to the rare hysterectomy with the attached placenta may yield a better understanding of placental infarction in the future.

I and colleagues reported on the findings including the uterus with attached infarcted placenta in a mother who presented with an intrauterine death, and while waiting overnight in the hospital for induction the next morning, died of overwhelming disseminated thrombi in her organs(Bendon, Wilson et al. 1987). (ppt: infarcts in situ)

What effect does a placental infarction have on the fetus?


In both the heart and placenta the extent of tissue infarcted is proportionate to the loss of organ function. Both organs have some reserve before failure occurs. However, even a small infarction in the heart can cause death by interfering with the heart rhythm. In the placenta, there is no epidemiologic evidence that a small infarction compromises the fetus. The lack of effect is surprising. Unlike heart muscle, the placental villi are supplied by a separate circulation supplied by the fetus. The deoxygenated blood arriving from the baby is not able to maintain the viability of the villi. If the fetus continued to circulate the dead villi, returning blood would not only be deoxygenated, but could potentially carry harmful material such as potassium and lactic acid from the dying villi.


How is the fetus protected from circulation of the infarcted villi?


In a myocardial infarction, the dead tissue first appears paler than the surrounding tissue. In contrast, a recent placental infarction is much redder than the surrounding tissue. The redness is because the fetal vessels are markedly dilated, and under the microscope appear distended with blood compared to surrounding vessels in the viable villi. This appearance could be due to one of two hemodynamic mechanisms, either increased blood flow in dilated vessels or no blood flow but dilatation due to venous obstruction.

In the first mechanism, the surface chorionic vessels that supply the villous stem vessels would simply continue to perfuse the villi in the area of infarction. The hypoxic vessels which normally have thick smooth muscle would dilate because of hypoxic injury to the muscle, and flow in the capillary beds of the villi would increase, turning the villi a deeper than normal red. In a sense, the infarcted villi would steal fetal chorionic blood flow from the viable villi exacerbating the effect of the infarction. Since there are several hundred stem villi, a few of them being non-functional might not be too great a stress on a fetus with an otherwise healthy placenta. In a fetus with already compromised placental respiration this lowering of returned oxygen and delivery of harmful metabolites might cause fetal injury.

In the second mechanism, constriction of the proximal vein of the stem villous would stop flow into the villus, although the arterial pressure would still expand the hypoxic vessels and capillaries. There are two observations supporting this second mechanism as the more likely. The most convincing evidence is the progressive pallor of the villi as an infarction ages. Under the microscope the red blood cells in the vessel lose their hemoglobin, as if they were suffering the same infarction to coagulation changes that the rest of the villous tissue in undergoing. Clearly, this would not happen if the red cells were just passing through during perfusion of the villus. The mechanism of this venous occlusion is not obvious in the histologic sections. Thrombi in the vessels of the infarcted villi are distinctly rare, leaving vascular constriction as the most likely mechanism to stop blood flow. Some vessels in the stem villi, that is the larger conducting villi, do show intact red cells in areas that otherwise have been reduced to ghosts. It is possible that there is some shunting between villi as some portion of villi from a fetal stem vessel (the end artery to a branch of the villus tree) would not necessarily be infarcted. Unlike some animals such as the sheep, humans do not match the inflow of maternal blood to the fetal placental villous units.

Villous venous constriction is a surprisingly plausible mechanism of stopping blood flow. Early in my career, I was at a conference in which the maternal fetal medicine speaker affirmed that the placental did not regulate its own blood supply. This assertion seemed very improbable. Both the arteries and the veins in the trunks and stems of the villi are extremely muscular. So much so, that histologically the veins and arteries can not be distinguished. It would be a waste of energy and nutrients if this vascular muscle did not have a function. The normal function is likely matching villous blood flow to intervillous blood flow similar to matching pulmonary blood flow to ventilation. Dr. Ramsey’s monkey placental angiograms demonstrated that the blood flow in the intervillous space was constantly changing as different spiral arteries squirted on and off. Only rapid changes in villous blood flow could match this erratic perfusion. If the intervillous perfusion were to stop, is it possible that the venous muscle in the effected villous stems would stay completely constricted? There is precedent in the simple fact that after the infant is delivered, the umbilical arteries constrict and stay constricted in the umbilicus until the stump is shed. Interestingly a similar mechanism might underlie a vexing phenomenon that occurs with attempted in utero cardiac surgery in fetal lambs (personal communication). After the bypass surgery, the vascular resistance in the placenta has become so high that it can not be reperfused by the lambs heart. The vasoconstriction behind this phenomenon appears due to vasopressin release, a powerful peptide that causes vascular muscle constriction. This is not totally analogous to placental infarction because it is the cessation of fetal blood flow that triggers the constriction, but it demonstrates that the mechanism of permanent vascular constriction can occur in the placenta itself, not just in the umbilical cord.

The second piece of evidence for decreased blood flow in the villus comes from Dr. R. A. Bartholomew and colleagues who argued wrongly that placental infarction caused eclampsia/preeclampsia(Bartholomew, Colvin et al. 1961). However, their observations are relevant. In their own words “Rapid venous placental sphincter spasm apparently accounts for fulminating eclampsia and abruption placentae. Slower sphincter spasm is more in keeping with pre-eclampsia, which may extend over a more prolonged but progressive course, terminating in eclampsia or abruption placentae. In these conditions, syncytial necrosis results from sphincter blockage of placental vein circulation, distention of villus capillaries, enlargement of villi, and deficient intervillous circulation.” (page 288). Few would agree with this formulation today, but their observations of the placental veins overlying infarction might be correct. Disappointingly, the illustration of the sphincter even in an original paper copy of the journal is unclear, but the captions states “ Placental vein sphincter, recognized externally by sharply localized constriction in vein. Sphincter exhibits a central thick core of smooth circular muscle fiber cut transversely and a thin layer of longitudinal smooth muscle fibers adjoining the blood stream. Obviously, it is possible that contraction of this sphincter induced by spasmodic agent could readily obstruct exit of blood from its corresponding placental unit and produce the villous changes resulting in necrosis and thrombosis locally and distally” (page 282). If his observations are accurate, he was describing the mechanism by which the fetal/placental unit avoids shunting blood through necrotic villi. I have not been successful in identifying such a sphincter looking at the fetal surface of the placenta, but in the broader sense of a permanent constriction of veins leading from anoxic villi, the concept provides the best explanation of the dilated vessels in an acute infarction.


What are the functional effects of multiple placental infarctions?


There is no question that placental respiration and nutrient exchange have some reserve, but in the extreme case, there is point of placental loss for which these reserves are not sufficient. One outcome of such compromise is growth retardation. Decreased utero-placental blood flow leads to villous remodeling with thinning of the villi over the fetal capillaries that improves respiration over nutrient transport. An infarction simply eliminates a portion of placental function without the chance for at least short term adaptation to the loss. How much placenta can be lost safely may not be fixed amount. A placenta in a resting uterus does not have to provide the same additional respiratory function as a placenta during contractions or a placenta undergoing premature separation. Infarctions that occur at different times could allow the placenta to adapt by growth compared to the same volume of infarction occurring simultaneously. Placental infarctions occurring in the context of more generalized utero-placental ischemia may be more damaging than those with otherwise normal placental perfusion. The loss of placental function from multiple infarctions is associated with stillbirth (intrauterine death) and growth restriction (Wigglesworth 1964; Naeye 1977; Burke, Tannenberg et al. 1997; Gray, O’Callaghan et al. 1999; Schjetlein, Abdelnoor et al. 1999; Becroft, Thompson et al. 2004). Infants with placental infarctions and growth retardation or intrauterine death also have an increased incidence of toxemia (Naeye 1977; Salafia, Vogel et al. 1992; Kovo, Schreiber et al. 2010).

Infarctions may also be associated with intrauterine brain injury. A postmortem study of 37 stillborn infants found placental infarctions in 24(Burke, Tannenberg et al. 1997). There was histological evidence of brain injury, predominantly white matter necrosis or astrocytosis in 26 of 27 infants dying at greater than 26 weeks of gestation, but 11 mothers had preeclampsia and 8 were twins. The individual cases were not presented but the conclusion is that infarctions might be associated with brain injury. Another study of brains from stillborn infants by the same author found that of 46 placentas with infarctions, 39 had cerebral ischemic lesions. In 17 placentas, the infarctions were estimated to involve more than 10 % of the placenta(Burke and Tannenberg 1995). Another study of 98 brains from infants dying within 1 hour of birth found a significant association of infarctions, including abruptions, with white matter necrosis/gliosis (7 of 27 brains with the lesion) and of neuronal necrosis (3 of 6 brains with the lesion)(Grafe 1994). These studies have not shown a clear relationship between brain injury and the extent of infarction or the extent of utero-placental ischemia. The very fact that the infants died suggests that there may have been additional factors such as abruption or cord compression. Because the infants were dead, the clinical significance of the histological brain lesions is unknown. In a study of 68 living small for gestation infants, placental infarctions were significantly associated with the small infant size, but the infants showed no abnormalities on neuro-behavioral testing at one month of age(Gray, O’Callaghan et al. 1999). The authors of this study suggest that superimposed asphyxia on the growth retarded fetus may be necessary to alter neural development.

Sorting out the risk factors and the mechanisms of brain injury is complex and will be approached in more detail in the chapter on fetal asphyxia. Studies, for example from percutaneous sampling of umbilical cord blood, demonstrate that some growth retarded infants are hypoxic/acidotic(Nicolaides, Economides et al. 1989). These infants are plausibly at risk of brain injury or death from further asphyxia or even gradually increasing acidosis from hypoxia. What is not well documented is the quantitative significance of infarctions in producing intrauterine hypoxia and acidosis. The Collaborative Perinatal Study of the National Institute of Neurological and Communicative Disorders and Stroke followed more than 56,000 pregnancies from 1959-1966, following children’s development until age 7. The placental pathology for this study has been reported in multiple articles by Dr. Richard Naeye who summarized the data in two monographs, the most recent of entitled Disorders of the Placenta, Fetus and Neonate, Diagnosis and Clinical Significance(Naeye 1992). The main conclusions of the study relating to placental infarction was that finding 4 or more gross infarctions (1281 cases) or an infarction larger than 3 cm (1663 cases) significantly correlated at P<.001 with preeclampsia, growth retardation, and stillbirth. Neurologic abnormalities, primarily mild retardation, correlated with both lesions at lower .05, .01 significance.

The association of stillbirth with placental infarction is not proof that the infarctions per se caused the fetal death. As with brain injury, there may be multiple related factors. Most authors conclude that the greater extent of the infarctions, the higher risk of stillbirth (Wigglesworth 1964; Fox 1967). The perinatal collaborative study arbitrarily attributed stillbirth to infarctions “when 25% or more of the placenta was involved by infarcts and there was no other ready explanation of death.”(Naeye 1977) In my own experience, stillbirth is not common in toxemia, unless there are multiple placental infarctions or a placental abruption. I have also autopsied stillborn infants in which the placental infarctions were due to maternal thrombophilia in which there was no evidence of utero-placental ischemia apart from the multiple infarctions. The role of infarctions as a predictor or cause of fetal morbidity and mortality is not completely resolved.

What diseases are associated with placental infarctions?


The most often confirmed association of placenta infarctions is with the clinical condition of peripheral edema and hypertension variously called toxemia, pre-eclampsia/eclampsia, gestosis, and pregnancy induced hypertension among other synonyms(Wentworth 1967; Naeye 1977; Salafia, Vogel et al. 1992). Since modern molecular techniques demonstrated the placental toxin(s) originating in the placenta (such as the FLTs 1 protein) for simplicity I will call the disease by its old name, toxemia. Not all observers however found the association(Shanklin 1959). Among the potential problems in recognizing the association is that only the minority of women with toxemia show placental infarctions although with severe pre-eclampsia the percentage with infarctions may approach 50%. Early studies were also “contaminated” by lesions that were not infarctions in the sense of this chapter. A simplified précis of the toxemia follows: A failure of trophoblast remodeling of endometrial vessels causes decreased placental perfusion. The placenta responds with chemical signals, such as s FLT-1 that blocks the effects of endothelial growth factor. The latter is required not just for growth but also maintenance of endothelial function. The endothelium as a consequence leaks which causes tissue edema and proteinuria. The loss of serum increases the hematocrit which increases delivery of oxygen to the placenta. The endothelial injury also exposed the myometrium to signals for vasoconstriction which elevated blood pressure which can also increase placental blood flow. The villi of the placenta also adapt by forming more capillary syncytial membranes which favor oxygen diffusion over active trophoblastic transport to the fetus. Unfortunately, these adaptations may lead to significant secondary pathology in the mother and may not succeed in preventing hypoxia of the fetus. Since endothelial injury favors thrombi formation in vessels, logic would expect widespread thrombus formation in maternal vessels. This does not happen, and the mechanism of placental infarction and abruption must have a different explanation, perhaps harking back to the original failure of the trophoblast remodeling of the spiral arteries. The placental infarctions in toxemia characteristically occurred at different times from each other. This suggests an almost random process that might indeed occur during the progressive deepening of trophoblastic invasion of the endometrial arteries.

There is another potential cause of thrombosis in toxemia. There is direct injury to the spiral arteries in the decidua in some patients which does not occur in other parts of the body. It is usually seen in the spiral arteries beneath the membranes, a location without trophoblast remodeling. The lesion may also be found occasionally beneath the placenta apparently in arteries that did not have trophoblastic remodeling. This injury, designated as acute atherosis, shows a smudged appearance of necrotic media (fibrinoid necrosis) and foam cells in the wall of the vessel. This type of injury could occur in vessels deep to the placenta that have not been altered by trophoblast invasion. The mechanism of acute atherosis in the fetal membranes remains an enigma. Are there local factors triggered by toxemia that only occur in the decidua? Is the renin produced in the membranes activating angiotensinogen? Whatever the mechanism, it is focal even in the decidua and occurs in a minority of patients with toxemia. The observable acute atherosis in the fetal membranes shed at delivery has not been proven to correlate with an increased incidence of placental infarctions. Without more direct evidence, the mechanism of placental infarction in toxemia remains unknown.

Despite papers often showing a strong association between placental infarctions and toxemia, my personal experience is that most placentas from patients with mild toxemia, having normal birth weight infants and usually term deliveries do not show infarctions. The incidence is much higher with severe toxemia and with toxemia and fetal growth retardation.

Do inherited or acquired thrombophilias cause placental infarctions?

Since thrombophilia is one of the factors favoring thrombus formation, given other potential factors such as vascular injury, thrombophilia would be expected to increase the risk of thrombi in the spiral arteries. A cohort study found a significant 10 fold increase in infarctions exceeding 10% of the placenta from mothers with the Leiden mutation (10 of 24 placentas) compared to controls(Dizon-Townson, Meline et al. 1997). The placenta was examined by a perinatologist not a pathologist, but histological confirmation was obtained. I did not find prospective studies of the placenta in mothers with thrombophilia in uncomplicated pregnancies, but in my practice, placentas from mothers with known inherited thrombophilias usually do not have placental lesions. Some of these mothers may have had some form of anticoagulation. I looked at 10 placentas from mothers followed prospectively that had anti-cardiolipin antibodies and they did not have infarctions, but the cases were a mix of IgG and IgM antibodies and most did not have a proven thrombophilia(Bendon, Hayden et al. 1990). The placentas were sectioned using a motorized meat slicer that gave thin uniform sections of unfixed placenta. This technique proved very sensitive to finding infarctions. There is probably little justification for large prospective studies if finding an infarction has little clinical significance.

Most studies have started with complicated pregnancies and then looked for the incidence of thrombophilia in those pregnancies. A study of 68 mothers with similar severe pregnancy complications (severe toxemia, fetal growth retardation, placental abruption or fetal death) found that 32 women had a variety of inherited thromobophilias. The placentas from thrombophilic mothers showed an increase in single infarctions (23/32 compared to 14/36) and of multiple infarctions of the placenta (14/32 compared to 5/36)compared to the mothers with the same complications without thrombophilia(Many, Schreiber et al. 2001). The mothers were not selected for thrombophilia, but the 47% percent incidence of thrombophilia is much higher than the normal population incidence of thrombophilia. Another study that selected patients with pregnancy complications and placental lesions found a high incidence of fetal thrombotic vasculopathy associated with maternal thrombophilia. Increased thrombi in fetal vessel would be expected to associate with fetal thrombophilia, but also with maternal thrombophilia since the mother is likely to carry at least one gene for the same thrombophilia. Three of the 13 cases in that study not only had fetal thrombotic vasculopathy and maternal thrombophilia, but also multiple placental infarctions (Arias, Romero et al. 1998). Another study looked at stillborn infants and found 9 had maternal thrombophilia compared to 8 without thrombophilia (Alonso, Soto et al. 2002). Four of the mothers with thrombophilia compared to none without thrombophilia had multiple placental infarctions (P=.05). A study that looked 165 placentas with a either placental infarctions and a small infant or a clinical and placental evidence of abruption found an increased incidence of the C677T mutation in methyltetrahydrofolate reductase gene (12% versus 5% in controls)(van der Molen, Arends et al. 2000).

Case reports can not show an epidemiologic correlation between a test and an outcome, but they can provide insight based on logical inferences of mechanism that can’t be obtained by epidemiological methods. I autopsied of a woman who suffered a fetal death then died the evening of admission to the hospital before her planned induction of labor(Bendon, Wilson et al. 1987) (ACA1ppt). The placenta showed multiple acute infarctions. These showed changes consistent with the timing of fetal death approximately 24 hours before maternal death. The infarctions seemed to be approximately of the same age. The mother demonstrated wide spread small arteriolar fibrin thrombi including in the heart, brain and kidney. The uterus showed similar thrombi in arterioles not invaded by trophoblast. However, beneath the placental infarctions, there was thrombus in the superficial spiral artery that showed reaction unlike the widespread fibrin thombi. This thrombus had the appearance of the thrombi seen in sickle cell crisis even though the mother had only sickle cell trait. Postmortem serum demonstrated an anti-cardiolipin antibody, a marker of acquired thrombophilia usually with a paradoxical lupus-anticoagulant. She had histologic chronic pericarditis and a compatible history and her serum demonstrated an anti-double stranded DNA together suggestive of systemic lupus erythematosis. We hypothesized that the anti-cardiolipin antibodies caused a thrombophilia that resulted in placental infarctions which caused fetal death that in turn triggered, perhaps from thrombogenic material from the infarcted placenta, a disseminated coagulopathy, Degas syndrome. There were many unanswered questions such as the role of the sickle cell trait, and the roles of autoantibodies in creating a coagulopathy. The cause of fetal death is even unclear since the infarctions involved less than 50% of the placenta, and the mother may have been chronically hypoxic. The case did show the superficial level of the spiral artery thrombus that caused the lesion. There were no deeper thombi in the underlying uterus. The case also demonstrated the complex nature of cause and effect in thrombosis. I have seen a case of an 18 week gestation fetal death with placental infarctions associated with an anti-cardiolipin antibody but complicated by marantic endocarditis (thrombi on the heart valves)(ACA2ppt. ). The anti-cardiolipin antibody does not directly cause the thrombophilia. This patient most likely had an unusually severe thrombophilia causing both placental infarctions and marantic endocarditis rather than a concentration of emboli from the heart valves to the placenta, but I had no way to prove that. There are other case reports with similar findings in mothers with antibody mediated thrombophilia(Silver, Laxer et al. 1992).

The bottom line is that thrombophilia can be associated with placental infarctions in some circumstances, but there were no studies showing a substantial risk of placental infarctions in uncomplicated pregnancies.

Can infarctions cause toxemia?

Could infarctions cause toxemia? The villi bordering an infarction show the same ischemic changes seen in toxemia. If these affected villi produce the same signals found in generalized utero-placental ischemia, then with enough infarctions, the end result might be clinical toxemia. However, dead villi do not secrete reactive peptides, so this mechanism would occur only in exceptional cases with many infarctions and extensive border areas.   A more likely relationship is that patients with thrombophilia and toxemia are more likely to have infarctions than those with normal coagulation and toxemia. This interpretation is consistent with the studies a higher incidence of infarctions in complicated pregnancies with thrombophilia. One such study that evaluated 101 women with early-onset severe toxemia for thrombophilia did find a much higher incidence of thrombophilia than in general population incidence(Dekker, de Vries et al. 1995). The placentas were not examined. If the observation is true, then a reasonable hypothesis is that spiral artery thrombus formation adds to the other factors causing placental ischemia producing earlier toxemic symptoms.


            Are there other less established associations with infarction?

One paper has proposed an association of placental infarctions with obesity, but this study was based on ICD-9 codes and I doubt that the incidence of infarction is valid(Becker, Vermeulen et al. 2008). Studies looking at placental lesions and cocaine abuse have not found an association with placental infarction, only with placental abruption(Gilbert, Lafferty et al. 1990; Mooney, Boggess et al. 1998; Cejtin, Young et al. 1999).Cigarette smoking may also have an association with placental abruption, and with marginal placental infarctions, but this is not well established(Naeye, Harkness et al. 1977). It is conceivable that like the susceptibility to Buerger’s disease, infarctions may only be associated with smoking in a small subpopulation. Cigarettes, cocaine or other vasoconstrictive drugs can temporarily reduce spiral artery blood supply, but they would more likely effect all arteries equally making isolated infarctions unlikely.






Alonso, A., I. Soto, et al. (2002). “Acquired and inherited thrombophilia in women with unexplained fetal losses.” Am J Obstet Gynecol 187(5): 1337-1342



Arias, F., R. Romero, et al. (1998). “Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta.” J Matern Fetal Med 7(6): 277-286.Thirteen patients were selected to have their coagulation parameters evaluated based on an abnormal placental examination which in itself had been performed because of a pregnancy complication. Most of these infants had fetal thrombotic vasculopathy suggesting a highly selected group, and not surprisingly there was a correlation with maternal thrombophilia. Three of the cases however also had multiple infarctions with fetal thrombotic vasculopathy and genetic thrombophilia.



Bartholomew, R. A., E. D. Colvin, et al. (1961). “Criteria by which toxemia of pregnancy may be diagnosed from unlabeled formalin-fixed placentas.” Am J Obstet Gynecol 82: 277-290.A study of placentas that had prolonged fixation reported that a characteristic pattern in toxemia was extensive acute infarction called “early E” and late “E”. In the illustrations these are extensive and most consistent with acute placental separation. The author mentions abruption and also intra-partum toxemia and fetal death, but the direct clinical correlation with each example placenta is not stated. “D” infarctions appear to be older true infarctions, while other designations are for different ages of intervillous thrombus. The author argues that the cause of the “E” infarctions is constriction of the venous sphincters of the chrorionic surface veins which leads to villous congestion and obliteration of the intervillous space which causes infarctions. The observation raises a still unanswered point. Is the congestion seen in an acute infarction due to ischemic vasodilatation of the villous vessels or could it be due to a reactive constriction of the umbilical surface veins that matches perfusion to intervillous “ventilation”?



Becker, T., M. J. Vermeulen, et al. (2008). “Maternal obesity and the risk of placental vascular disease.” J Obstet Gynaecol Can 30(12): 1132-1136.A retrospective study of 386,323 singleton pregnancies examined obesity and diabetes with placental abruption or infarction as an outcome variable based on ICD-9 codes on the hospital chart. The lowest weight group of patients had fewer infarctions and abruptions, but the authors note that the diagnosis of these placental lesions was not validated.




Becroft, D. M., J. M. Thompson, et al. (2004). “Placental Infarcts, Intervillous Fibrin Plaques, and Intervillous Thrombi: Incidences, Cooccurrences, and Epidemiological Associations.” Pediatr Dev Pathol.A study of small for gestational age infants in New Zealand found statistically significant correlations of intervillous thrombi and plaques of intervillous fibrin deposition with placental infarctions in the same placenta. The thrombi and the fibrin deposits as in other studies did not correlate with growth retardation or gestational hypertension even though infarctions did. The authors did not fully explain this disconnection, but did suggest the connection could be related to a common tendency to thrombophilia. The authors also note frequent reclassification of the gross diagnosis of the three lesions based on the more definitive microscopic findings. The study does distinguish marginal from central lesions and correlations between lesions were not always present for all locations. The authors also point out that the fibrin plaques may have a more complicated morphology with an intervillous laminated fibrin component.



Bendon, R. W. (2011). “Nosology: infarction hematoma, a placental infarction encasing a hematoma.” Hum Pathol



Bendon, R. W. (2011). “Review of autopsies of stillborn infants with retroplacental hematoma or hemorrhage.” Pediatr Dev Pathol 14(1): 10-15



Bendon, R. W. and D. B. Cantor (2007). “Stillbirth due to placental hypoperfusion after salpingo-oophorectomy for an ovarian cyst.” Obstet Gynecol 110(2 Pt 2): 482-484



Bendon, R. W., L. E. Hayden, et al. (1990). “Prenatal screening for anticardiolipin antibody.” Am J Perinatol 7(3): 245-250



Bendon, R. W., J. Wilson, et al. (1987). “A maternal death due to thrombotic disease associated with anticardiolipin antibody.” Arch Pathol Lab Med 111(4): 370-372



Brosens, I. and M. Renaer (1972). “On the pathogenesis of placental infarcts in pre-eclampsia.” J Obstet Gynaecol Br Commonw 79(9): 794-799.One paper reports on the direct observation of placental infarctions in situ in a gravid hysterectomy specimen removed 3 days after the intrauterine death at 31 weeks of gestation from a mother with essential hypertension with superimposed severe preeclampsia. They found hyalinization of arteries at the decidual myometrial junction with occlusive thrombi. Lipid macrophages and other mononuclear inflammation were present. These vessels did not show the normal trophoblastic invasion. In 12 of 13 placental bed biopsies from mother with preeclampsia and placental infarctions, normal trophoblast invasion was absent in the similar vessels. The authors suggest that low flow to the intervillous space preceded the occlusion of the vessels.



Burke, C. J. and A. E. Tannenberg (1995). “Prenatal brain damage and placental infarction–an autopsy study.” Dev Med Child Neurol 37(6): 555-562.A study of the pathology of 175 stillborn brains and 165 corresponding placentas found that 70 brains had some form of cerebral ischemic injury (40 white matter astrocytosis based on Rourkes’ H&E criteria, 5 with white matter necrosis, 8 with gray matter ischemia, and 17 with astrocytosis identified only with GFAP immunostaining). Forty six placentas had infarctions, excluding small marginal lesions, and 39 of these were associated with cerebral ischemic lesions. Those without cerebral lesions were often too macerated or too immature to evaluate. In 17 of the placentas infarction was estimated to involve more than 10% of the placenta.



Burke, C. J., A. E. Tannenberg, et al. (1997). “Ischaemic cerebral injury, intrauterine growth retardation, and placental infarction.” Dev Med Child Neurol 39(11): 726-730.A postmortem study of 37 infants less than the 3rd percentile in weight for gestation, but without malformation or infection, demonstrated a strong correlation with placental infarction 26 of 36 placentas10. Histological evidence of ischemic injury was present in 31 cases of which 24 had infarctions. 26 of the 27 stillbirths > 26 weeks of gestation had cerebral ischemia. Eleven mothers had preeclampsia, and 8 cases were twins. The brain lesions were primarily white matter necrosis and or astrocytosis. Three cases had gray matter necrosis (2 hippocampal, 1basal ganglia). The histologic criteria were not illustrated.



Carter, J. E., F. Vellios, et al. (1963). “Histologic Classification and Incidence of Circulatory Lesions of the Human Placenta, with a Review of the Literature.” Am J Clin Pathol 40: 375-378.A histological study of gross lesions of the cut placenta in 650 specimens proposed a novel classification based on the relationship of villi to the intervillous space. The villi were convergent (that is the intervillous space was collapsed) were infarctions. The villi are divergent with intervillous thrombi which pushes them apart. There were three static lesions that kept the villous intervillous relationship unchanged, namely fetal thrombotic disease, encasement of villi by fibrinoid, and severance of decidual veins and arterioles (premature separation). While the terminology never became accepted the concept is still true and useful.



Cejtin, H. E., S. A. Young, et al. (1999). “Effects of cocaine on the placenta.” Pediatr Dev Pathol 2(2): 143-147



Dekker, G. A., J. I. de Vries, et al. (1995). “Underlying disorders associated with severe early-onset preeclampsia.” Am J Obstet Gynecol 173(4): 1042-1048



Dizon-Townson, D. S., L. Meline, et al. (1997). “Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction.” Am J Obstet Gynecol 177(2): 402-405



Fitzgerald, B., P. Shannon, et al. (2011). “Rounded intraplacental haematomas due to decidual vasculopathy have a distinctive morphology.” J Clin Pathol 64(8): 729-732



Fox, H. (1967). “The significance of placental infarction in perinatal morbidity and mortality.” Biol Neonat 11(1): 87-105.A study of 715 placentas which focused on infarctions included 679 live born, and 36 stillborn infants(Fox 1967). The pregnancies were further subdivided into 50 uncomplictated except for gestation > 42 weeks, 64 were uncomplicated except for delivery <38 weeks,   21 were > 38 weeks with “non-toxemic ante-partum hemorrhage. Pre-eclampsia was present in 159, and essential hypertension in 50. Diabetes was present in 48 and Rh immunization in 105. Twelve uncomplicated term pregnancies had infants with a birth weight below 2,500g. The extent of infarction was graded grossly as 0, + for less than 5%, ++ 5-10% and +++ as >10%. Infarctions were not increased except in the group with pre-eclampsia. The study demonstrated “a marked increase in the incidence and degree of placental infarction with increasing severity of the toxemic process…””No correlation could be found between the incidence of placental infarction and the duration of toxaemic symptoms and signs.” In this group there was also a significant correlation of ++ infarction and birth weight less than 2727g. Fetal death was increased in the +++ group, 7 deaths of 10 +++placentas, compared to 19 deaths /509 placentas without infarctions. In 15 stillbirths with otherwise uncomplicated pregnancies only one had extensive placental infarction. The paper also presents descriptions of the aging of infarctions both grossly and microscopically. As the mechanism of the infarction 14% were over retroplacental hematoma, and nearly 50% had a thrombosis of an arteriole beneath the infarction. Others had an area of decidual necrosis under the infarction and over one third had no obvious cause.



Gilbert, W. M., C. M. Lafferty, et al. (1990). “Lack of specific placental abnormality associated with cocaine use.” Am J Obstet Gynecol 163(3): 998-999



Grafe, M. R. (1994). “The correlation of prenatal brain damage with placental pathology.” J Neuropathol Exp Neurol 53(4): 407-415



Gray, P. H., M. J. O’Callaghan, et al. (1999). “Placental pathology and neurodevelopment of the infant with intrauterine growth restriction.” Dev Med Child Neurol 41(1): 16-20.A study of placentas from 68 infants below standard deviations of birth weight for gestation compared to 65 matched control cases found a significant association overall of placental infarction and increased syncytial knots with IUGR. They did not include isolated marginal infarctions as positive. There were no correlations with infant outcome measures including neuro-behavioral tests at one month of age. Only one infant had an Apgar score below 7 at one month. The authors’ suggest that superimposed asphyxia on the growth retarded fetus may be necessary to alter neural development. Of the 68 placentas, 30 were normal, 9 had infarctions, 9 had infarctions and increased syncytial knots, 9 had increased syncytial knots and 11 had miscellaneous unrelated lesions. The analysis was stratified by normal or abnormal placenta. No assessment of the percentage of placenta infarcted was made.



Hamilton, M. P., H. I. Abdalla, et al. (1985). “Significance of raised maternal serum alpha-fetoprotein in singleton pregnancies with normally formed fetuses.” Obstet Gynecol 65(4): 465-470



Jauniaux, E. and S. Campbell (1991). “Antenatal diagnosis of placental infarcts by ultrasonography.” J Clin Ultrasound 19(1): 58-61



Kovo, M., L. Schreiber, et al. (2010). “Placental vascular lesion differences in pregnancy-induced hypertension and normotensive fetal growth restriction.” Am J Obstet Gynecol 202(6): 561 e561-565.A study comparing the placental pathology in women with pregnancy induced hypertension, non-hypertensive growth retardation, and both hypertension and growth retardation found a significant increase in maternal villous lesions in the latter combined group. However, maternal villous pathology included “increased syncytial knots, villous agglutination, increased intervillous fibrin deposition and villous infarctions”. Thus, the data can not separate out the significance of placental infarction. The study did confirm the association of non-hypertensive fetal growth retardation with chronic villitis.



Mallory, G., P. White, et al. (1939). “The speed of healing of myocardial infarction A study of pathological anatomy in seventy-two cases.” Am Heart J 18(6): 647-671



Many, A., L. Schreiber, et al. (2001). “Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia.” Obstet Gynecol 98(6): 1041-1044



Mooney, E. E., K. A. Boggess, et al. (1998). “Placental pathology in patients using cocaine: an observational study.” Obstet Gynecol 91(6): 925-929



Naeye, R. L. (1977). “Placental infarction leading to fetal or neonatal death. A prospective study.” Obstet Gynecol 50(5): 583-588.A study of 53,518 pregnancies found 107 stillbirth and 17 neonatal deaths due to infarction of at least 25% of the placenta[6]. Using a χ2 test, these deaths were associated predominately with factors related to hypertension, and pregnancy induced hypertension. Because associations among findings are not analyzed, independent associations are difficult to discern. The associations of hypertension in pregnancy, proteinuria, low fetal weights, primigravidity, and high hematocrit are all part of pregnancy induced hypertension. Prior fetal losses also correlate, but it is not clear if this is due to recurrent pregnancy associated hypertension or a separate group. An association with employment correlated with decreased prenatal visits. Whether the decreased visits resulted in delayed recognition of pregnancy induced hypertension and delayed delivery is not clear. The author states that the association with low pre-pregnancy weight is evidence of a role for poor nutrition. However, weight is not separated from the association with primigravidas. The microscopic placental findings were based on 31,494 placentas examined by four trained technicians. There is no explanation of how training and consistency of diagnosis were established. An increase in some of the microscopic findings points to pregnancy induced hypertension as the basis for the association, such as with acute atherosis of decidual arteries. The absolute numbers of cases involved in the different clinical features are not included, so the positive association with active glomerulonephritis may be based on very few cases. The number of deaths due to infarctions increased with gestational age. A finding that would be interesting to associate with degree of fetal growth retardation as well as the onset of symptoms of pregnancy associated hypertension. Cases of death due to abruption were excluded, but abruption was significantly associated with death with infarctions. Abruption is associated with pregnancy associated hypertension, but how the cases were selected was not clear. Were only abruptions without infarctions excluded? Sadly, this incredible database from the Collaborative Perinatal Project along with the microscope slides was not saved in a manner that would allow reanalysis in the present.



Naeye, R. L. (1992). Disorders of the Placenta, Fetus and Neonate, Diagnosis and Clinical Significance. St. Louis, Mosby Year Book.



Naeye, R. L., W. L. Harkness, et al. (1977). “Abruptio placentae and perinatal death: a prospective study.” Am J Obstet Gynecol 128(7): 740-746



Nicolaides, K. H., D. L. Economides, et al. (1989). “Blood gases, pH, and lactate in appropriate- and small-for-gestational-age fetuses.” Am J Obstet Gynecol 161(4): 996-1001



Proctor, L. K., W. L. Whittle, et al. (2010). “Pathologic basis of echogenic cystic lesions in the human placenta: role of ultrasound-guided wire localization.” Placenta 31(12): 1111-1115



Ramsey, E. M. and M. W. Donner (1980). Placental vasculature and circulation. Philadelphia, W. B. Saunders Company Ltd.



Salafia, C., C. Vogel, et al. (1992). “Preterm Delivery – Correlations of Fetal Growth and Placental Pathology.” American Journal of Perinatology 9: 190-193.The correlation of placental pathology with growth parameters in premature infants stratified by preterm labor (238 placentas), premature rupture of membranes (175), pre-eclampsia(18), non-hypertensive abruption(13), and placenta previa(22) found a statistical association of infarctions with pre-eclampsia (11 of 18). The association of infarctions with low birth weight appeared to be secondary to the association with preeclampsia. No correlation of fetal growth with quantity of infarction was found, but the details are not reported.



Schjetlein, R., M. Abdelnoor, et al. (1999). “Hemostatic variables as independent predictors for fetal growth retardation in preeclampsia.” Acta Obstet Gynecol Scand 78(3): 191-197.A study of 200 women with preeclampsia in Norway found that placental infarctions were a significant predictor of fetal growth retardation in both a logistic regression and a multivariate linear model. The diagnosis of placental infarction was based on the macroscopic report of the midwife.



Shanklin, D. R. (1959). “The human placenta with especial reference to infarction and toxemia.” Obstet Gynecol 13(3): 325-336



Sheehan, H. L. and J. B. Lynch (1973). Pathology of Toxaemia of Pregnancy. Baltimore, The William and Wilkins Company.



Silver, M., R. Laxer, et al. (1992). “Association of Fetal Heart Block and Massive Placental Infarction Due to Maternal Autoantibodies.” Pediatric Pathology 12: 131-139



van der Molen, E. F., G. E. Arends, et al. (2000). “A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy.” Am J Obstet Gynecol 182(5): 1258-1263



Wallenburg, H. C., D. L. Hutchinson, et al. (1973). “The pathogenesis of placental infarction. II. An experimental study in the rhesus monkey placenta.” Am J Obstet Gynecol 116(6): 841-846.An experimental study of infarction was achieved by ligation of individual utero-placental arteries in pregnancy rhesus monkeys, and examination of the placenta at later intervals. In spontaneous deliveries all but one placenta was consumed by the mother preventing examination, but 18 other placentas were recovered by hysterotomy or hysterectomy. The four placentas less than 16 hours of age had no lesions. One placenta at 23 hours of age, and 2 at 48 hours of age demonstrated infarctions. Eight placentas 8 to 70 days post ligation also had infarcts. Two placentas in this duration group did not have infarcts and infarcts were also absent in a 28 hours placenta. A sham operated placenta at 69 days did not have infarctions. The youngest infarction (23 hours) was red in color and demonstrated some syncytial necrosis and blurring of cell detail. The older lesions were yellow white and better demarcated grossly. Microscopically there was evidence of stromal necrosis and a border of polymorphonuclear leukocytes around the lesion. The lesions older than 8 days had complete villous necrosis and a border of fibrinoid. In one case lacking an infarction, the authors saw a second utero-placental branch artery supplying the same area.



Wallenburg, H. C., L. A. Stolte, et al. (1973). “The pathogenesis of placental infarction. I. A morphologic study in the human placenta.” Am J Obstet Gynecol 116(6): 835-840.A microscopic study of 536 infarctions infarctions fixed in formalin from 345 placentas found 9 recent infarctions, 58 with mixed stages and the rest with intermediate or older infarctions. Seventeen of the infarctions were serially sectioned. The authors’ observations failed to find thrombus in the fetal stem vessels, but found thrombosis in most of the spiral arteries in those infarctions in which the artery was present, including in 14 of the serially sectioned cases. From the illustrations, it is not totally clear how the authors distinguished clot from thrombus. The authors comment that thrombus at the decidual myometrial junction would result in extensive decidual necrosis and these thrombi would usually be present in the placenta. They comment that “ The center of the lesion is always less compact than the periphery and frequently contained a cavity with a thrombus, especially in the older stages.”



Wentworth, P. (1967). “Placental infarction and toxemia of pregnancy.” Am J Obstet Gynecol 99(3): 318-326.A study, using a technique of thin sections (400 microns) of the whole placenta, found 9 recent and 42 older infarctions in 679 cases, with 8 of the recent and 8 older infarctions found in 12 cases of severe toxemia. This study uses the term red infarct to refer to recent infarctions, and group white through brown infarctions as true infarctions. They also note the reparative cytotrophoblast around the edges of infarctions. All five stillbirths from the toxemia group demonstrated recent infarctions and 4 had remote infarctions as well, but there is only passing mention of a role for retroplacental hemorrhage.



Wigglesworth, J. S. (1964). “Morphological Variations in the Insufficient Placenta.” J Obstet Gynaecol Br Commonw 71: 871-884.A correlation of gross pathological lesions with the microscopy of the same areas compared 48 normal term placentas with those from various abnormal pregnancies including 52 with pre-eclampsia and eclampsia. The author distinguished infarctions from intervillous thrombi and increased intervillous fibrin deposition microscopically, he did not do so in the tabulations which showed 19 normal placentas having infarctions, although at an estimated <5% of the volume. The pre-eclamptic patients had 17 placentas with <5% infarctions, but also 17% with >5% infarctions. The author comments that many of the pre-eclamptic placentas had a central hematoma in the infarction that he attributes to rupture of the spiral artery proximal to a thrombosis. He includes infarction over a retroplacental hematoma in the same group. The author looked at many descriptive microscopic features noting the features of coagulation necrosis in the infarction but also the surrounding villous changes both cytotrophoblast proliferation and increasing syncytial degeneration with knots and increased cytotrophoblast. He argues that infarctions are an extreme of decreased utero-placental blood flow and imply an overall decrease in the intervillous blood flow that can no longer provide collateral blood flow to areas of spiral artery thrombus. He noted a correlation of increased percentage of infarction with low birth weight and that 7 of 8 placentas with more than 30% infarction were from stillbirths. Some low birth weight for gestation infants had no evidence of infarction or villous changes. He recommends the term “utero-placental circulatory insufficiency” over “placental insufficiency” to emphasize that the placental morphological changes are secondary in cases of with infarctions. He also recommends correlating the gross pathology of the spiral artery remnants attached to the placental base with the overlying pathology. He presents three recurrent cases of placental pathology, one of which is that of massive perivillous fibrinoid deposition.





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