Chapter 10 Lesions of Villous Injury: Section B Maternal Floor Infarction/ Massive Fibrinoid Infiltration (MFI)

Fibrinoid

The pathologist looking at any placenta finds eosinophilic amorphous material in the intervillous space. Like a cave, some clings to the underside of the fetal surface with stalactite extensions toward the maternal surface, or mounds on the maternal floor like stalagmites or even forms columns from top to bottom (fig 1).

Other less cellular accumulations form shapes that mimic the pattern of villi (fig 2).

The amount of such eosinophilic material varies from placenta to placenta with no salient clinical correlation.

What is this eosinophilic amorphous material that is often called fibrinoid? Dr. Peter Kaufmann and associates, as well as others, have identified two separate forms using immunohistologic staining and electron microscopy¹. The first is a dense acellular type that they have designated as fibrinous fibrinoid. It contains fibrin, platelet fragments and likely fragments of degenerated syncytiotrophoblast^{2, 3}. It is usually found on the surfaces facing the intervillous blood flow. This is not notably different from a mural thrombus in an artery and it seems reasonable to refer to this simply as fibrin. If the fibrin is on the surface a villus, then it is designated perivillous fibrin (fig 3).

The second type of fibrinoid is a looser, less homogenous substance with cytotrophoblast embedded within it (fig 4).

Chemically the material is a type of extracellular matrix produced by the cytotrophoblast^4-9. There may be a layer of fibrin between this matrix and the intervillous blood flow, but fibrin is not integral to this type of fibrinoid. This can be called matrix type fibrinoid, but is simply cytotrophoblast proliferation with matrix secretion. The pathologist usually sees both types of fibrinoid together in intimate spatial relationships that beg for further explanation.

Fibrin deposition in the placenta is derived from blood. Blood clotting is the precipitation of insoluble, sticky fibrin from the cleavage of soluble fibrinogen by the enzyme thrombin. Numerous interacting factors including platelet degranulation regulate thrombin activity. Fibrin deposition is counteracted by the cleavage of fibrin by plasmin. In turn plasmin production is regulated by multiple factors. The basic biology of blood clotting is well understood in blood vessels in which patency is maintained by the endothelium. More than a century ago Virchow noted that fibrin deposition in blood vessels, that is thrombus formation, occurs in response to blood stasis, tissue injury and/or thrombophilia. The latter can be caused by stress notoriously after injury such as surgical procedures or be an innate condition such as genetic mutation. The reader can find the details in textbooks of hematology or pathology.

The intervillous space is in effect a blood vessel but instead of blood flowing into a smooth cylindrical channel it flows through a mass of projecting root-like villi and instead of having a lining of endothelium, it is lined by syncytiotrophoblast acting as the endothelium (among its many functions). Unlike the streamlined blood flow in most of the vascular system, the intervillous blood flow is a fountain of blood sprayed into a space filled with villous baffles. The monograph by Elizabeth Ramsey, Placental Vasculature and Circulation, gives a clear and cogent presentation of this flow¹⁰. This inherently turbulent and irregular blood flow provides an explanation for the normal presence of fibrin in the placenta. As in the vegetative fibrin deposition that forms on damaged heart valves (marantic endocarditis), turbulence creates eddies with areas of stasis and hypoxic injury favor fibrin formation. Some authors have proposed the interesting, but difficult to prove, hypothesis that the filling in by fibrin of this intervillous dead space helps streamline flow and improve perfusion efficiency¹¹. Under the microscope, perivillous fibrin can look remarkably in pattern like extensions and bridges between villi that mimic the normal villous architecture. As occurs in vitro, the fibrin is often resurfaced with syncytiotrophoblast completing the disguise^{3, 12}(fig 3). Could this pseudovillous pattern reflect conditions of stable flood flow in the intervillous space?

The initiating event in perivillous fibrin deposition is likely syncytiotrophoblast injury. Syncytium adjacent to fibrin deposition demonstrates morphological and biochemical evidence of injury usually with apoptosis, programmed cell death^13-16. There is evidence that hypoxia can initiate apoptosis in syncytiotrophoblast^17-19. In routine pathology, syncytiotrophoblast nuclei near or within the formation of perivillous fibrin demonstrate hyperchromatic irregular nuclei typical of apoptosis (fig 5).

If injury decreases antithrombogenic activity or exposes the basement membrane that underlies the synctiotrophoblast to the maternal blood, thrombin will be generated, and fibrin deposited.

A placental infarction provides a model of hypoxic placental injury that elucidates fibrin deposition (fig 6).

A true placental infarction occurs when the flow from a spiral artery is occluded and the overlying villi and intervillous space cease to have blood flow. The center of the infarction demonstrates collapse of the intervillous space and coagulation necrosis of villi, the morphologic features of anoxic cell death. An infarction becomes surrounded at its margin with villi trapped in perivillous fibrin. At the far periphery, villi demonstrate an increase in syncytial knots (piled up nuclei) and capillary syncytial membranes (thinned syncytium above fetal capillaries), both part of the adaptation of villi to ischemia that increases oxygen diffusion from mother to fetus. The reasonable assumption is that an infarction creates a gradient of hypoxia most severe at the center of the infarction. This assumption provides a simple paradigm for interpreting the morphologic response of the placenta to hypoxia. The most severe hypoxia/anoxia results in coagulation necrosis, an intermediate degree results in syncytial necrosis and pervillous fibrin deposition often with survival of Langhan’s cytotrophoblast that normally underlie and regenerate the syncytium, and the least hypoxic injury results in syncytial knot formation. This paradigm explains the deposition of fibrin in areas of poor perfusion around the periphery of the normal fountain of blood entering from the spiral artery as occurs beneath the fetal surface of the placenta. This does not imply that hypoxia is the only mechanism that induces syncytial injury and apoptosis.

 

Authors have theorized that fibrin can deposit on intact syncytiotrophoblast and cause hypoxic injury²⁰. The syncytiotrophoblast normally has strong plasminogen activity that upregulates in the presence of fibrin²¹. A potent thrombogenic stimulus could still overcome this activity and layer fibrin on intact syncytiotrophoblast. The appearance of such deposition is seen with laminated intervillous thrombi. However, perivillous fibrin deposition is not increased in mothers with inherited thrombophilia. Placentas from these affected mothers may have infarctions from spiral artery thrombi, but they do not have massively increased perivillous fibrinoid. I have not found convincing studies that show a benefit of maternal anticoagulation in preventing recurrence of massively increased perivillous fibrinoid ^{22, 23}. Subtle syncytial injury, for example a factor causing decreased plasminogen receptor, could lead to fibrin deposition that in turn causes hypoxia and necrosis of the syncytium resulting in the typical appearance of perivillous fibrinoid deposition on denuded basement membrane. The morphologist might have trouble telling the difference especially if apoptosis was being induced in surrounding nuclei.

The proliferation of cytotrophoblast and deposition of matrix may be a secondary process if syncytiotrophoblast dies, but cytotrophoblast survives. Released from syncytiotrophoblast relationships, the cells may revert to a different phenotype and lay down matrix much as they do at the interfaces of primary cytotrophblast with maternal tissue. In vitro, cytotrophoblast remain single cells at 1% oxygen, but form syncytium at 20%²⁴. The matrix is the glue that holds the placenta to the decidual stroma²⁵. Other cytotrophoblast cells in the intervillous space are likely residual from the original columns between lacuna of the developing placenta. Matrix in the placenta is always associated with cytotrophoblastic cells, but very often has a surface of fibrin. There are also intermediate forms in which villi encased in fibrin show a subtle proliferation of cytotrophoblast around there periphery (fig 7).

Cytotrophoblast proliferation and matrix secretion could be interpreted as the default program for cytotrophoblast freed from the villous architecture.

There are many unanswered questions about normal fibrinoid deposition. How can a focal area of syncytiotrophblast, which is a continuous cell sheet, be injured without broad damage? Why does perivillous fibrin take the geometrical form that it does? Why is more fibrin not deposited in placentas of mothers with thrombophilia? Is there such a thing as intravillous fibrinoid or this an illusion of syncytiotrophoblast “re-endothelializing” the surface of fibrin? The small punctuate intravillous fibrinoid described by Fox in cases of potential immune complex disease with both Rh sensitization and with anti-insulin antibodies could be a different and today uncommon entity²⁶. Is there cross talk between the syncytiotrophoblast and the fetal circulation? For example, stem villi often have perivillous fibrin instead of syncytiotrophoblast on the surface. This appears to be beneficial since high energy syncytiotrophoblast transport would not find fetal capillaries on the villous side to carry away the transported chemicals. Perhaps accumulation of these transported products leads to syncytiotrophblast degeneration. On the other hand, villi trapped in fibrin (or in an infarction) loose their fetal circulation, as if some transport product from syncytiotrophblast is needed to maintain the fetal circulation.

 

Bottom line: For practical descriptive purposes, the term “fibrinoid” in the placenta meets the need to describe focal accumulations of fibrin, cytotrophoblast proliferation and matrix deposition. Fibrinoid is understood to be composed of varying proportions of fibrin and matrix components. The most likely relationship between the components is that syncytiotrophoblast injury promotes fibrin deposition on the exposed villous surface. The underlying cytotrophoblast then proliferates and may produce matrix. In other cases, non-villous cytotrophoblast may proliferate and the exposed matrix will initiate fibrin deposition. In certain contexts, such as interpreting the pathophysiology, more precision may be had by referring directly to fibrin deposition or matrix proliferation.

 

Focal massive pervillous fibrinoid deposition

 

A curious phenomenon is the formation of a focal area of massive perivillous fibrinoid. This lesion has a superficial gross resemblance to placental infarction demonstrating a solid white to yellow mass lesion. The lesions can be grossly distinguished in that close inspection of an infarction shows villi in a collapsed intervillous space, but fibrinoid deposition shows a solid rubbery mass often with sponge like channels of blood flow (fig 8).

The massive fibrinoid deposition strangles encased villi that then undergo the same process of coagulation necrosis and loss of fetal circulation as in an infarction. Fox attempted to find any clinical correlation for these focal lesions, and did not find one²⁷.

Such a focal lesion is unlikely to be due to a circulating factor in maternal blood. Focal placental mosaicism can not be totally excluded, but has never been demonstrated. The sharply demarcated, varyingly sized, contiguous area often involves an extent supplied by multiple spiral arteries. Some small, often marginal, lesions show a small infarction buried within the fibrinoid shell. In such cases, the lesion appears to be a very exaggerated periphery of an old infarction. The relationship of focal massive perivillous fibrin deposition to diffuse massive perivillous fibrin remains unknown.

 

MFI: Massive perivillous fibrinoid infiltration/ maternal floor infarction of the placenta

 

This lesion or lesions has proved difficult to define. Infarction normally refers to occlusion of an end artery to a portion of tissue with subsequent ischemic necrosis (death) of that tissue, most notably occurring in the brain or heart, but also in the placenta. Maternal floor infarction then logically should refer to obstruction of blood flow of the arterial entrance to the intervillous space causing necrosis of the overlying placenta. Thickened fibrin or extravillous matrix at the interface of placenta and basal decidua could produce such an infarction. Microscopically, an infarction of the placenta would show collapse of the intervillous space with coagulation necrosis of the villi. A maternal floor infarction then should show fibrin or matrix thickening of the maternal surface with otherwise typical changes of infarction in the villi. It is moot whether such a lesion which I will call true maternal floor infarction occurs, but the term maternal floor infarction is not usually used in this sense. Instead it refers to extensive gross thickening of the maternal surface of the placenta with fibrin or matrix, often in the context of fetal growth retardation or death. Focal thickening of the maternal floor is common and not usually considered a pathological lesion. Diffuse deposition of fibrin/ matrix may be isolated to the maternal floor, but more commonly is associated with increased perivillous fibrin/matrix deposition throughout the placenta.

Maternal floor infarction was perhaps first introduced in the English published literature in the textbook by Benirschke and Driscoll who presented a case of a woman with nine recurrences of the lesion, each resulting in stillbirth. In a subsequent paper of 60 cases with Dr. Benirschke as an author, the definition of MFI was given as “ marked increase in fibrin deposition involving the decidual floor with villous encasement”²⁸. Others have tried to define the same lesion. Another study identified 25 patients as having maternal floor infarction based on “massive perivillous fibrin deposition proposed by Fox,” and elaborating “marked fibrin deposits among the villi when these deposits obliterated over three fourths of the intervillous space in all three sections”²². Another review of 80 placentas with MFI used the following definitions “ classic MFI (basal villi of the entire maternal floor encased by perivillous fibrinoid of > 3 mm thickness on at least one slide); transmural MFD (perivillous fibrinoid material extending from the maternal surface to the fetal surface, encasing >50% of the villi on at least one slide); borderline MFD (25%-50% villi on at least one slide encased by perivillous fibrinoid material in a transmural or nearly transmural, distribution)”²⁹. Of note, a single recurrence occurred in a mother who initially presented with transmural MFD, but recurred with maternal floor infarction. No matter how precise or vague the definitions, studies of the lesion have demonstrated correlations of MFI with intrauterine growth retardation, fetal death, and recurrence in subsequent pregnancies. The lesion may encompass functionally or biologically related entities, like an enclosure with zebras, horses, and camels, which will eventually be better defined by pathogenesis.

A diffuse increase in perivillous fibrinoid is a marker of significant pathology. In my files, I code the lesion MFI, an acronym that includes massive fibrinoid infiltration or maternal floor infarction. This preserves the acronym, but “infiltration” seems less accurate than “deposition”. The lesion presents on gross examination as a tactile resistance to compression of the placenta which is normally soft and flabby. The maternal surface often has a firm white convoluted pattern which on cut section may be continuous with diffuse increased fibrinoid or appear accentuated along the base (fig 9).

The pattern of parenchymal fibrin deposition varies. Some placentas have a diffusely granular network of fibrinoid placenta (fig 10).

Channels of open blood flow often appear embedded in the more confluent fibrinoid deposition. These channels may demonstrate laminated thrombi likely the result of slow flow and turbulence analogous to venous thrombi. Other placentas have a lumpy, coarsely irregular pattern that sometimes exaggerates the stalactite pattern that can be imagined to surround the jets of arterial inflow (fig 11).

There are rare cases that have increased fibrinoid confined to the placental floor with overlying ischemic infarction which could be considered true maternal floor infarction (fig 12).

These cases may have a different etiology from those with increased perivillous fibrinoid. Increased perivillous fibrinoid deposition is a continuum and likely, not all pathologists would agree on which placentas qualify for the diagnosis of MFI.

 

Under the microscope, massive increased perivillous fibrinoid in some cases shows a collapsed intervillous space and perivillous fibrin deposition showing the same features as in uncomplicated pregnancies, with apoptosis of syncytiotrophoblast, denuded villi with viable cytotrophoblast and matrix, and fibrin enmeshed sclerotic/ necrotic villi. The villi may appear necrotic or may have persistent or even somewhat proliferative cytotrophoblast beneath the fibrin (fig 13).

This pattern is often seen with the less confluent fibrin deposition. The same pattern can be seen in presumed ischemic areas of intervillous collapse and villous agglutination in placentas that are othwise normal from normal pregnancies. In a few placentas, often with the granular network of fibrin, there is a prominent proliferation of cytotrophobast surrounded by fibrin (or focally even without a fibrin surface)(fig 14).

This is the same appearance that may be seen on the floor of the placenta or in cytotrophoblastic “X-cell” collections in normal placentas.

The two patterns of coarse versus granular fibrinoid deposition could present ends of a spectrum of two different pathogenetic mechanism. The coarse deposition would result from processes such as stasis or turbulence that favors collapse of the intervillous space and fibrin deposition. The mechanism is analogous to the fibrinoid deposition around the periphery of a placental infarction. The granular distribution would be typical of a serum factor that would diffusely injure syncytiotrophoblast resulting not only in a more even distribution but in more cytotrophoblast proliferation following injury restricted to overlying syncytium. The cytotrophoblast normally replenishes the syncytium. The syncytium is extraordinarily metabolically active with high oxygen and glucose consumption which could make it vulnerable to toxic or metabolic injury. This mechanism was demonstrated experimentally by administering monoiodineacetate, an inhibitor of carbohydrate metabolism to pregnant guinea pigs which produced a lesion of syncytial destruction and fibrinoid (bundles of fibers on EM not identified immunologically) filling the labyrinth of the placenta in a description that could pass for MFI³⁰. A similar mechanism could underlie cases of MFI reported with long chain hydroxyacyl-coenzymes A dehydrogenase deficiency^{31, 32}. The one case of recurrence of MFI that I examined had the diffuse granular pattern in both placentas. One of the cases associated with autoimmune disease also had this pattern. Fibrinoid patterns falling in between would have different degrees of syncytial injury which would also be sensitive to regional blood flow. There is no proof that the dichotomy of fibrinoid patterns reflects different mechanisms, but this notion

Placentas with MFI show varying degrees of villitis and intervillositis. Villitis is common in placentas, but in some placentas areas with villitis correspond to those with perivillous fibrinoid. Even more striking and perhaps more common are placentas in which intervillositis appears to be directly part of the deposition of perivillous fibrinoid (Fig 21).

Whether the presence of the inflammatory cells, usually monocytes, but some neutrophils, is a cause of syncytiotrophoblast injury or a consequence of an immune/thrombogenic response can not be determined from the histology.

 

Over several years, I had received three placentas with the prenatal ultrasound diagnosis of complete replacement of the placenta by chorangioma that pathologically were consistent with my criteria for maternal floor infarction at that time, namely gross and microscopically increased perivillous fibrin that was not restricted to a single sector of the placenta. I suggested to our university maternal fetal medicine group that they review prenatal ultrasound examinations in placentas with the diagnosis of maternal floor infarction. They did and they agreed that there was a distinctive hyperechogenic ultrasonogrpahic appearance of the placenta in the three index infants, but not in 6 other cases diagnosed as maternal floor infarction. Looking prospectively for these ultrasound features, they correctly diagnosed maternal floor infarction in two pregnancies, one a recurrence. We published this case series ³³. Comparing the gross cut sections of the placentas in this study with and without an abnormal ultrasound pattern (Fig 15)

, equally varied patterns of fibrin deposition were present in both groups, so it was not the pathological pattern that determined ultrasound detection of the lesion. As a pathologist, I am surprised that the gross alterations of placental consistency and of intervillous blood flow are not always detectable by antenatal ultrasound. The only other published experience found 8 abnormal placentas with antenatal ultrasound from 12 cases with pathologically diagnosed MFI³⁴.

One ultrasonographic feature related to fibrin deposition is the presence of multiple subchorionic cysts (Fig 16).

Since subchorionic cysts appear to be due to secretion by cytotrophoblast trapped in subchorionic fibrin beneath the fetal surface, the association may not be accidental. A placental ultrasound correlation study found cysts in 3 of 34 placentas with maternal floor infarction³⁵. The cyst fluid has been demonstrated immunohistologically to contain major basic protein, the same as the toxic component in eosinophil granules^{36, 37}. Perhaps under certain conditions, cytotrophoblast differentiation morphs to that of trophoblast invasion of the maternal tissue with secretion of cytotoxic chemicals. Authors have suggested that this toxic fluid component could play a role in the pathology of MFI, but that role was not clarified³⁸. Another possible prenatal diagnostic clue favoring MFI is loss of bone density in the fetus. Most of my cases with body radiographs do not show obvious hypodensity of bone, but one had rachitic changes.

MFI has been associated retrospectively with varying incidences of fetal growth retardation and fetal death. The pathology suggests that MFI causes loss of function in enmeshed villi, maternal to fetal perfusion mismatch, and sometimes thrombosis of some intervillous space. The perfusion mismatch would occur because more blood from spiral artery flow is shunted to the remaining open intervillous space which has relatively few villi. Logically stillborn infants with MFI should be small for gestation unless the onset of MFI was very rapid, or the death was unrelated to the extant of loss of functional placenta.

Published studies have varying rates of stillbirths associated with MFI placentas from 17% (33/190) (using the definition: “diffuse, firm, pale thickening of the decidual basalis due to the heavy deposition of fibrin in the decidua basalis”)³⁹. to 40% (24/60)²⁸. The incidence of intrauterine growth retardation in MFI patients also varies from 31% (11/56)²⁹ to 54% (19 of 35 livebirths) ²⁸ to 92% (11 of 12 live and stillbirths)³³ to 100% (12/12). The association of MFI with growth retardation and fetal death appears significant, but in the larger picture it is an infrequent cause of either. The incidence varies from 0.5% (190/39,215) in the Perinatal Collaborative Study³⁹ with the most inclusive definition, to 0.03% in a different study (13/47,022)⁴⁰. The incidence of MFI and its complications in retrospective studies could have a selection bias in that patients with severe growth retardation or fetal death are more likely to be seen in tertiary centers and more likely to have their placentas sent to pathology. MFI is less likely to be diagnosed in uncomplicated pregnancies. In our study in which institutions send placentas from all deliveries for examination (see P.R.O.O.F study on web site) only 2 cases of MFI were diagnosed from 6,084 patients (0.03%). One was not small for gestation (assuming gestation was correct) and the other at 27 weeks gestation had no birth weight on the placental pathology history (patient not contacted for consent to the study). There is no quantitative study to answer how much fibrin or what pattern of fibrin deposition is needed to produce fetal compromise. Incidence of complications would also be affected by the definition of MFI used in the study. These same problems would also impact estimates of the incidence of MFI.

The increased risk of recurrence rate in subsequent pregnancies is clinically important. For the individual patient, this can be 100% (as in the nine recurrences in Benirschke and Driscoll). This striking reoccurrence makes a fetal genetic trait unlikely and is more consistent with an allo-immunization (similar to Rh antigen sensitization) or to a persistent maternal disease. The Collaborative Perinatal Study found that 50% of mothers with MFI had prior abortions or stillbirths compared to 27% of controls (P<.001). Most other series of cases report one or two reoccurrences, but the numbers of women followed in subsequent pregnancies is too low for statistical analysis. Given the very low incidence of MFI, it is astronomically unlikely that most recurrence was due to chance. Stillbirth from MFI may be prevented by careful observation of the fetus and placenta in subsequent pregnancies of affected mothers^{33, 41}.

Recurrence points to an underlying fetal or maternal condition causing MFI, but does not point to a specific etiology. Infrequently MFI is associated with other clinical disease that plausibly could cause the lesion. We reported mothers with autoimmune disease and MFI⁴². Both placentas had confluent deposition (one predominantly fibrin, the other matrix) and were fully developed before midgestation (Fig 17).

This pattern would be consistent with an antibody present from early gestation that could injure syncytiotrophoblast or interfere with surface anti-thrombotic proteins such as plasminogen activator. There are other reports of MFI associated with autoimmune disease. Maternal polymyositis has been associated with MFI ^43-46. A study of 22 MFI placentas reported 2 mothers with SLE²⁹. Conversely, a study of 42 patients with SLE reported two cases with perivillous fibrinoid change with growth retardation (the histological figure in the paper is not convincing for MFI). Both of these patients also had lupus anticoagulant/anticardiolipin antibodies. Three patients with anti-phospholipid syndrome were reported to have massive perivillous fibrin deposition⁴⁷. These cases could be due to an antibody other than the thrombophilic anti-phospholipid, in patients prone to develop autoantibodies, as in SLE. An autoimmune origin of a small percentage of cases of MFI is possible but unproven. The identification of antibodies to plausible antigens, such as urokinase plasminogen activator receptor, on the syncytiotrophoblastic surface would strengthen this hypothesis²¹

Discordance for MFI in dichorionic twins has been reported in which both twins were live born⁴⁸. I have seen this occurrence as well as cases in which the second smaller twin is stillbirth with MFI confined to his or her dichorionic placenta (Fig18).

This discordance for MFI should not be confused with increased intervillous fibrin that occurs with prolonged intrauterine retention following fetal death⁴⁹ (Fig 19).

 

In my experience, stillbirth associated with maternal thrombophilia, including anti-phospholipid syndrome, demonstrates multiple placental infarctions not MFI. The only possible exception was MFI in the placenta of a mother who had multiple sickle cell crises during her pregnancy (Fig 20).

The lack of association of thrombophilia with MFI is surprising. Plausibly, perivillous fibrin deposition can result from turbulent intervillous blood flow causing blood stasis and ischemic syncytiotrophoblastic injury resulting in fibrin precipitation. In a hypercoagulable state, this process could become exaggerated, increasing perivillous fibrin, which in turn creates more local turbulence, further increasing fibrin deposition until MFI results. In a study of 14 patients with prior MFI, 7 of 8 treated with anticoagulation had normal weight infants compared to 2 of 6 untreated²². However, the paper does not explicitly state that the untreated mothers had recurrent MFI. In 20 women with MFI there were no single nucleotide polymorphisms associated with genes in the coagulation system³⁴. A possible explanation for the lack of cases of MFI with thrombophilia is that the fetal losses occur in the first trimester at a time when the lesion is not well defined^{50, 51}. Anti-phospholipid syndrome fetal loss is often in the first trimester. A more likely explanation is that the placental anti-thrombin/ fibrin systems are sufficient to overcome those thrombophilias that are compatible with maternal survival.

Bottom line:

MFI is diagnosed grossly in the placenta by finding a firm parenchymal texture due to an increased amount of perivillous fibrinoid. There may be cases that are borderline, but this definition serves well in practice. Placentas with marked maternal fibrinoid confined to the basal plate may also be in the spectrum of MFI. Recognition of the lesion is important because of the association with growth retardation and stillbirth which may reoccur in subsequent pregnancies. Early delivery of the infant may be life saving, and in some cases MFI can be recognized on prenatal ultrasound.

There is likely more than one etiology for the lesion. There are different patterns most notably a diffuse pattern versus a coarsely distributed pattern sometimes appearing to accentuate the periphery of the spiral artery flow in the intervillous space. Both patterns may become virtually confluent. The amount of matrix proliferation also varies markedly among cases. The patterns suggest specific mechanisms, but the etiology of most cases remains obscure. There are potential associations with autoimmune disease, metabolic disease, and possibly certain thrombophilias (but not the commonly diagnosed forms). MFI may occur in one of dichorionic twins.

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