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Early Path Medical Consultation Services
Pathology Services Working for Safer Pregnancies

Abstract

Disorders of the decidua and maternal vasculature in obstetric compromise including preeclampsia.
Carolyn M. Salafia, M.D., Robert Pijnenborg, Ph.D.

A successful pregnancy requires the conceptus to have (1) a normal developmental program; (2) a normal fetoplacental vasculature which allows nutrient transport via the villous trophoblast to the fetus and, (3) a normal maternal vasculature which enables nutrient transport to the intervillous blood space at a volume adequate for fetal needs, and with flow characteristics which permit normal placental growth and development. In complicated pregnancies, "normal" uteroplacental vascular adaptation takes place only partially within any one vessel, and/or not to the maximum depth, and/or in a more limited total number of placental bed arteries. The wide range of pregnancy compromise which has been associated with poor uteroplacental vascular conversion- from first trimester pregnancy loss to prematurity and late fetal growth restriction- most likely reflects different combinations of these potential problems, with different strengths of deleterious influences, with different times of onset in gestation. These combinations have been associated with (and may be causally related to) early pregnancy loss, IUGR at term, and every clinical manifestation of obstetric compromise in between.

TEXT

The most obvious property of the future uteroplacental arteries is their peculiar shape, hence the term "curling arteries" (coined by their discoverer, William Hunter, 1774) or "spiral arteries" as they are presently known. Since they are involved with extensive changes during the menstrual cycle they are one of the most labile vascular systems in the human body. They arise from the radial arteries at the inner third of the myometrium, while the radials themselves branch from the arcuate system. Small basal arteries arise from the radials and nourish the basal layer of the endometrium, facilitating tissue regeneration after shedding at menstruation or delivery. Basal arteries are generally considered to be relatively unresponsive to hormonal stimuli, although in our view they cannot be considered to be completely inert. Finally, along the endometrial segments of the spiral arteries minor side branches arise, which are the same caliber as the basal arteries, but seem to supply more superficial tissue layers. Our main focus is on the spiral arteries, which represent the future uteroplacental arteries.

Histological variation occurs along the length of the vessels: within the endometrium, segments situated close to the endometrial-myometrial junction show a more defined muscular coat compared with the higher, superficial parts, while the most solid wall structure is found within the myometrial segments. The apparent shift in muscular coat structure from myometrial to endometrial segments is also reflected in the gradual disappearance of elastica in the spiral arteries when they enter the endometrium. The deeper segments of the spiral arteries will play an important role during pregnancy. As far as these myometrial parts are concerned, Robertson and Manning pointed out the frequent presence of split and reduplicated elastic lamellae in spiral arteries of multiparous women in which pregnancy-associated changes had not completely been resolved postpartum.

Gestational modifications of the uterine vascular anatomy

A dramatic feature of uteroplacental vasculature during pregnancy is the invasion of spiral arteries by extravillous trophoblast, leading to marked changes in vascular architecture that are essential for successful pregnancy. Trophoblast invasion proceeds in two different pathways: interstitial and endovascular. Both, of course, are ultimately derived from the proliferating tips of the anchoring villi, and it can be assumed that the distal ends of spiral arteries (which possess a relatively undifferentiated wall structure) or the small venules are easily penetrated by "interstitial" trophoblast that then become "endovascular" and begin to migrate retrograde along the vascular lumen. While interstitial trophoblastic cells will fuse to form multinuclear giant cells at the end of their itinerary, the endovascular trophoblast remain mononuclear as they are buried in an amorphous acidophilic "fibrinoid" material.

An outline of vascular anatomy during the first weeks of gestation is provided by Harris and Ramsey , but detailed histological descriptions are not available for this early period. At 8 weeks vascular changes are well established in the decidua, resulting in a vessel wall composed of "fibrinoid" with embedded trophoblastic cells. It is, therefore, assumed that invasion and endovascular migration begin soon after implantation. Histological descriptions of this period show degenerative changes in vessel wall structure including disruption of the medial smooth muscle layers and fragmentation of elastic tissue prior to the appearance of endovascular trophoblast. These changes have been related to the presence of interstitial trophoblast. The end result of these processes is a "physiological change" of the spiral arteries that replaces the original musculo-elastic tunica media by mononuclear trophoblast embedded in fibrinoid. A physiologically changed artery has undergone a marked increase in diameter, permitting the change from a high resistance/low capacitance circuit to a high capacitance system, able to carry large volumes of blood to the intervillous space. Moreover, the absence of musculo-elastic tissue should prevent the spiral arteries from responding to vasoactive stimuli, thereby protecting the fetus from undesired fluctuations in maternal blood supply. A commonly held opinion is that the media is destroyed by the invading endovascular trophoblast: according to our data this vascular layer disintegrates prior to the trophoblast invasion wave, and this disintegration is probably caused by the interstitial trophoblast. Hamilton and Boyd describe marked vascular alterations as the spiral arteries "approach the trophoblastic shell", including marked endothelial hypertrophy disrupting the normal smooth contour of the vessel lumen, and increasing attenuation of the media to the point that the lining endothelium is surrounded only by a layer of reticular or collagen fibers. The exploration of non-trophoblast dependent (and potentially pre-implantation) uterine vascular changes may permit improved therapy for in vitro fertilization that may increase the chance of successful pregnancy.

The degenerative changes in the vessel wall are effected by a loss of the normal medial organization. In other words, while individual (actin-positive) smooth muscle cells may still be present, the functional capacity of a well-organized muscular tissue has been lost. In many converted vessels thickened intimal cushions may appear, which probably result from local tissue repair. These intimae contain so-called myofibroblasts, which are ?-actin positive, but do not contribute to any contractile function of the blood vessel at that stage of development. This feature is not to be viewed as pathological. During normal pregnancy the majority (i.e. over 90 %) of the vessels have undergone the physiological conversion at term, while at 16-18 weeks only one third of the arteries has been invaded. During the intervening period the remainder of the vessels is invaded in normal pregnancy; failure to complete the later stages of conversion may underlie a wide range of obstetric pathology (see below).

Vascular changes are restricted to the arteries, while the veins do not seem to be involved. In the very superficial layers of the placental bed, facing the intervillous space, the very distal venous segments may show replacement of endothelium by trophoblast, outgrowths from the syncytiotrophoblastic covering of the placental floor and is therefore not to be considered as extravillous trophoblast. However, some interstitial trophoblastic cells appear to attach to venules from the outside, leading to occasional insertion of isolated trophoblastic cells in the endothelial layer of the vessel, but the significance of this process is not clear (Pijnenborg R et al, unpublished observations, 1996). The different behavior of trophoblast versus arteries and veins has suggested that physical (hemodynamic) flow-stress may be important to induce retrograde trophoblast migration in blood vessels.

Uteroplacental vascular pathology - an overview

In complicated pregnancies, "normal" uteroplacental vascular adaptation takes place only partially within any one vessel, and/or not to the maximum depth, and/or in a more limited total number of placental bed arteries. The wide range of pregnancy compromise which has been associated with poor uteroplacental vascular conversion- from first trimester pregnancy loss to prematurity and late fetal growth restriction- most likely reflects different combinations of these potential problems, with different strengths of deleterious influences, with different times of onset in gestation. These combinations have been associated with (and may be causally related to) early pregnancy loss, IUGR at term, and every clinical manifestation of obstetric compromise in between.

Uteroplacental vascular pathology : The placental bed

Placental bed biopsy specimens are not easy to obtain, and their interpretation may be even more complicated than placental histopathologic examination. However, given the recent increased appreciation of the role of uteroplacental vascular pathology in obstetric compromise, the placental bed biopsy may become a less rare specimen, especially at university centers. Also, since the endometrial segments available for review in the basal plate of delivered placentas represent the end-vascular distributions of these myometrial arteries and can show identical lesions, an understanding of this deeper anatomy and physiology can aid in the understanding of basal plate uteroplacental vascular lesions.

The most outstanding of uteroplacental defects is the complete or partial absence of physiological conversion of spiral arteries. Restriction of trophoblastic invasion and associated physiological change has been documented most extensively in preeclampsia. The classical view is that the second wave of endovascular trophoblast invasion that proceeds in the myometrial segments of the spiral arteries from about 15 weeks, does not occur in patients who will develop preeclampsia. Direct observations within the critical time period, from late first throughout the second trimester, are lacking. Only one observation on a hysterectomy-specimen at 15-18 weeks with complete absence of endovascular trophoblast in the myometrial spiral arteries has been reported, but of course it is impossible to tell whether or not this woman would have developed preeclampsia later in her pregnancy. There is no evidence of restricted interstitial invasion in preeclampsia as indicated by often high numbers of interstitial trophoblast in the myometrium, and therefore a failure to induce early disruption of spiral artery walls prior to the arrival of endovascular trophoblast cannot be implied. Lack of physiological conversion is not only apparent in the myometrial segments of spiral arteries, but also in the decidual parts of some of the vessels, so that a proportion of spiral arteries completely fail to undergo trophoblast invasion and physiological change. Since unconverted vessels retain high resistance/low capacitance properties, the effect on maternal blood supply to the placenta may be dramatic. Non-invaded arteries may retain a normal arterial structure, but may also show a disorganized muscular coat or, at least in hypertensive cases, medial hyperplasia. Such non-converted vessels may subsequently be prone to atherotic lesions, characterized by fibrinoid necrosis, infiltrating leukocytes and macrophages, and lipid-containing foam cells. Although the presence of trophoblast has often been regarded to protect an artery from developing atherotic lesions, remnants of trophoblastic cells are occasionally observed in such vessels. Atherotic vessels often end up into areas of decidual necrosis, and may be associated with placental infarction.

Defects in endovascular trophoblast invasion not only occur in preeclampsia, but also in other hypertensive conditions of pregnancy. In various conditions trophoblast invasion and physiological changes may be partial or isolated, rather than occurring along the whole circumference of the vessel. Restricted trophoblast invasion also occurs in miscarriage and intrauterine growth retardation. Therefore, limitation of trophoblast invasion is associated with defective placentation, but cannot be viewed as specific for preeclampsia or pregnancy-induced hypertension. Endovascular trophoblast invasion and associated conversion of spiral arteries is not an all or none phenomenon, but may show different degrees within normal and abnormal cases, with the balance tipping to a more complete invasion in normal pregnancy.

There may be differences in the three- dimensional architecture and size of placental bed arteries in preeclampsia. Computer assisted morphometry has demonstrated that, at least in certain cases, preeclamptic spiral and basal arteries of the placental bed can be more tortuous and/or densely distributed than normal placental bed arteries. Intrinsic differences in anatomical distribution and caliber of placental bed arteries may be an anatomic basis for some cases of familial preeclampsia. Alternatively, the altered three-dimensional distribution of placental bed arteries may develop because of abnormal growth of the preeclamptic placenta. Normal placental expansion in the early trimesters deforms the placental bed arteries. Failure of normal placental implantation and placental growth may fail to stretch the placental bed sufficiently, leading to a tortuous and hemodynamically vulnerable architecture. We speculate that endothelial damage in preeclampsia may be caused by effects of shear forces in these small caliber and tortuous arteries. Further study is necessary to determine whether different demographic groups cases of preeclampsia will have similar or different features, and what three-dimensional architecture will be found in cases of spontaneous preterm birth with uteroplacental vascular pathology. One mental image of the anatomy of placental bed arteries may not suffice to categorize the vasculature of the placental bed in pathologic conditions.

Uteroplacental vascular pathology: The placental basal plate

In the everyday clinical setting, principal questions include:

1. Is there histologic evidence of uteroplacental vascular pathology?

2. Is the pathology (in the most general of terms) "acute" as compared to "chronic"?

3. Is there associated placental damage that may have impaired placental function (and fetal well-being)?

These questions can generally be answered by careful and thoughtful examination of the delivered placenta without placental bed biopsy. While lesions of the end-vascular distribution of the uteroplacental circulation (in the basal plate) may not accurately represent the myometrial pathology, biopsy of the placental bed (of necessity) provides only a small and focal sample of the placental bed, within which there is a great deal of regional variation. Placental bed biopsies are therefore difficult to interpret except when procured by an experienced operator. Uteroplacental arteries are generally easily seen in the basal plate of the delivered placenta. Samples from these end-vascular samples should be available for review whenever the question of uteroplacental vascular insufficiency is clinically relevant. Four or five en face slices of the basal plate (which can all fit into a single cassette) may include the distal (basal plate) segments of several different uteroplacental arteries, located at different sites in the placental bed, and improving on the view of the uteroplacental vasculature provided by a placental bed biopsy. Variation in uteroplacental vascular anatomy and pathology implies also that one section of the placental villi may not be representative of placental function. Identification of failure of uteroplacental vascular adaptation, fibrinoid necrosis/atherosis, persistence of endovascular trophoblasts, thrombosis, and chronic vasculitis in the basal plate may shed light on the nature and mechanisms of uteroplacental vascular pathology. Clinically, this information has proved useful in the selection of appropriate therapy in subsequent pregnancies.

In the basal plate or the placental bed, uteroplacental arteries with absent, incomplete or failed adaptation have variable persistence of vascular muscle and elastic lamina. This leads to increased uterine vascular resistance, decreased capacitance, and decreased total blood flow to the placenta. Doppler and isotope studies in the human suggest uteroplacental flow is decreased to 50-70% of normal, which may explain the often-associated fetal IUGR. While trophoblast vascular conversion of the deeper/myometrial spiral arteries continues well into the second and even the early third trimester, endovascular trophoblast in the superficial endometrial (basal plate) uteroplacental arteries after the early midtrimester may reflect a disturbance in the normal process of uteroplacental vascular conversion. Fibrinoid necrosis of the vessel wall with mural foamy cells ("atherosis") is accompanied by dense lipoprotein(a) deposition within the vascular wall, clearly reflecting a vascular pathology akin to that seen in atherosclerosis. Other common uteroplacental arterial lesions are thrombosis and chronic vasculitis. In cases of preeclampsia, Redline and Patterson explored the hypothesis that there is a generalized maturation defect in the extravillous trophoblast that leads to increased accumulation of trophoblast in the superficial layers of the implantation site- rather than a normal process of progressive invasion through the endometrium to the myometrium. They were able to distinguish increased thickness of basal cytotrophoblast and increased cytotrophoblast proliferation (by immunostaining with proliferating cell nuclear antigen) in preeclamptic placentas studied from 24-40 weeks compared to cases at term. It is unlikely that trophoblast "pile-up" at the placental-decidual interface reflects an intrinsic invasive defect, since placental bed biopsies in preeclampsia show normal interstitial trophoblast invasion even at that deep level (and an apparently selective defect in vascular invasion). Cytotrophoblast have been demonstrated to proliferate in conditions of low oxygen tension; the basal plate findings are more likely an additional histologic marker of generally poor uteroplacental perfusion that can be assessed in the delivered placenta.

Uteroplacental thrombosis is required at the time of placental separation during parturition to protect the mother from exsanguination. On the other hand, uteroplacental thromboses cannot occur during gestation without risk to placental- and fetal- well-being. In our experience, single thrombotic lesions in the uteroplacental arteries that occlude <50% of the lumen, and which are not accompanied by villous evidence of abnormal uteroplacental perfusion are common at term. However, the uterine vasculature appears to be particularly susceptible to thrombosis, possibly because its endothelium is normally eroded, and basement membranes and decidual stromal collagen normally exposed to circulating maternal platelets, for up to at least 24 weeks. As a central player in clinically significant allograft rejection, coagulation, not surprisingly, has been also implicated in the pathogenesis of obstetric compromise, including antiphospholipid antibody related fetal death, and preeclampsia. The characteristic pathology of pregnancy loss in these conditions, uteroplacental thrombosis and placental infarction, is not pathognomonic of a positive test for lupus anticoagulant as opposed to cardiolipin antibody. It is likely that our serologic investigations of gestation-associated coagulopathy do not test for critical (but as yet unidentified) antibodies; on the other hand, coagulation is a non-specific response to a wide variety of pathologic stimuli and would not likely be uniquely associated with any one clinical or laboratory test abnormality. Failed regrowth of the maternal endothelium over the converted uteroplacental vascular wall of fibrinoid material and embedded trophoblasts- and protracted exposure of the maternal vascular wall to the maternal circulation- has been identified in preeclampsia. Potential targets for pathologic coagulation include the (maternal) uteroplacental vasculature, the basal plate (including Nitabuch's fibrin), the intervillous space, the villous (syncytiotrophoblast) surface, and the fetoplacental vasculature. It has been our clinical (and unfortunately anecdotal) experience that maternal anticoagulant therapy is most effective when the maternal vasculature is the target of pathologic coagulopathy, and is specifically not effective when coagulation is initiated on the villous trophoblast surface or within the fetoplacental vasculature.

If uteroplacental vascular damage is part of the pathophysiology of obstetric compromise, molecular markers which have been localized to areas of vascular injury (such as lipoprotein(a)) might be found in the uteroplacental vasculature. In support of this speculation, Berg et al reported a patient with serum lipoprotein(a) level >99th centile for her population who delivered 3 consecutive very low birth weight infants with placentas described as "small and ischemic". Meekins et al have demonstrated that lipoprotein(a) deposition in the placental bed spiral arteries is increased in preeclamptic cases over normotensive controls, and is directly related to the severity of histologic disruption of nonconverted spiral arteries. These observations have recently been expanded to include placental basal plate arteries from consecutive births in March- June, 1995 in normal term births, term preeclampsia, preterm preeclampsia, spontaneous preterm birth, and post partum curettage and peripartum hysterectomy samples. Results of this study are presented in Table 1. If we consider the hematoxylin and eosin histology of normal uteroplacental involution, the similarity to atherosclerosis becomes clearer. Normal uteroplacental vascular involution is accompanied by thrombosis, leukocytic infiltration of the vascular wall, and apparent proliferation and/or migration of endothelia and vascular smooth muscle. Similar changes can be seen to a lesser degree in the basal plate at term; similar changes in the vascular microenvironment are induced in atherosclerosis. A significant role of lipoprotein(a) in processes related to uteroplacental vascular wall damage would explain the recent clinical observation of homocysteinuria in patients with preeclampsia. Harpel and Borth have recently identified that sulfhydryl-containing compounds (including homocysteine) increase the affinity between lipoprotein(a) and fibrin. The up to 84 fold increase in affinity seen in the presence of homocysteine may explain the increased prevalence of vascular pathology, placental ischemia and preeclampsia in patients with homocysteinuria. Interestingly, homocysteine has been studied as a marker of atherosclerotic vascular processes.

Placental effects of abnormal uteroplacental perfusion

Endovascular trophoblast invasion has been considered to serve the "purpose" of establishing, from the earliest days of gestation, a maternal circulation providing the conceptus with nutrients. This circulation was conceived originally as a sluggish capillary derived blood pool, which evolves with trophoblast remodeling of the spiral arteries into a high-volume, low-resistance circuit. Hustin and Schaaps have challenged this theory based on their failure to identify intervillous circulation both on direct visualization of the intervillous space and in perfused hysterectomy specimens, in which they demonstrated occlusion of the uteroplacental circulation by trophoblastic plugs until the twelfth week of pregnancy. They speculated that these trophoblastic plugs protect the young conceptus from the force of maternal arterial blood flow until implantation is well-established. Since then, it has been proposed that precocious initiation of maternal arterial perfusion of the intervillous space may be responsible for early pregnancy loss. The issue of whether the entire period of embryogenesis occurs without any direct contact with the maternal circulation has not been resolved. A cogent rebuttal has suggested that fixation artifact and intervillous flow rates (below the current limits of Doppler resolution) may explain most of the observations. The issue of whether most or all of embryogenesis occurs in the absence of contact with the maternal circulation awaits final resolution.

When uteroplacental vascular lesions are present, the resultant disturbance in resistance, capacitance and increased fragility of the vasculature predisposes to "uteroplacental vascular accidents" such as placental infarcts or abruption. When uteroplacental arteries are occluded, intervillous flow ceases, the intervillous space collapses, and villi become compressed and undergo ischemic necrosis (an infarct). The gross appearance of placental infarcts varies with the age of the infarct; older lesions, in which blood is more extensively degraded, may appear tan to pink-tan. More recent lesions may be the same color as the adjacent non-infarcted placenta, but simply have a firm feel- consistent with the collapse of intervillous space. The boundaries of an infarct, with the compressed villi, often can be clearly demarcated by the naked eye. Older lesions are characterized histologically by complete loss of nuclear detail. Central infarcts are believed to be more significant to the fetus, given the greater dependence of the fetus on the central, most healthy area of villous parenchyma. The author personally grossed 500 consecutive placentas from uncomplicated term deliveries in a community hospital; 10% of placenta had an infarct. Ninety per cent of that 10% (9 out of 10 lesions) were located at the placental margin; ninety per cent of that 10% (9 out of 10 lesions) were less than 1 cm3 in dimension. Therefore we consider placentas with more than one infarct, infarcts located centrally, and infarcts of greater than 1 cm3 dimension to be outside of the range of normal. These types of lesions only rarely compromise the more than 50% of the placenta required for "placental insufficiency" based on estimated of placental reserve. However, they reflect an abnormal uteroplacental vascular environment because the 40-60 placental functional units are served by 100-150 uteroplacental vessels, providing a redundancy of perfusion (collateral flow) which should prevent placental infarct. The presence of an infarct therefore means that collateral flow in the intervillous space must be so poor as to fail to protect the placental parenchyma if a single uteroplacental vessel becomes occluded or otherwise compromised. As a corollary, in placentas with central, large, and/or multifocal infarcts, viable villi most commonly show evidence of chronic and diffuse uteroplacental malperfusion. Central, large, and/or multifocal infarcts generally do not occur in the context of non-infarcted placental villi with normal syncytial knotting, no cytotrophoblast proliferation, normal (non fibrotic) villous stroma and well-developed terminal villous capillary networks.

Abruption is essentially a hemorrhagic infarct. In abruption, the placenta is forcibly separated from the uterine wall by retroplacental hemorrhage from abnormal uteroplacental vessels. Placental compression by a retroplacental hematoma increases fetal blood volume and may be associated with villous stromal hemorrhage. In some settings, villous stromal hemorrhage may develop as an effect of placental trauma, essentially a bruise. Villous stromal hemorrhage may also be a precursor or associated lesion underlying fetomaternal transfusion. In our experience, in cases of feto-maternal blood group compatibility (where preformed maternal antibodies to fetal blood do not exist), an acute abruption which is clinically stabilized may be followed by fetal decompensation due to a chronic fetomaternal transfusion and severe fetal anemia, which may lead to fetal death. Separation from the uterine lining precludes effective blood flow to the involved placental area, acutely reducing fetoplacental oxygen availability. Endothelial damage due to hypoxia, complicated by increased intravascular volume (due to placental compression) may explain the common correlate of extensive visceral and germinal matrix hemorrhages in abruption. Basal intervillous thrombi are primarily maternal blood; these lesions may be very mild forms of abruption-type pathology.

The potential for mechanical factors to remodel and in effect deform the evolving intraplacental vasculature cannot be underestimated. Intraluminal direction and volume of fetoplacental flow is a major determinant of arterial as opposed to venous differentiation of the placental vasculature. Recently Burton and co-workers have confirmed the mechanical effect of both intraplacental and maternal perfusion pressures and on villous capillary growth. Increasing intraplacental perfusion pressure from 40 mm Hg to 100 mm Hg resulted in more proliferating endothelial nuclei suggesting that mechanical factors affect villous angiogenesis and the formation of terminal villi. Similarly, if a sufficiently high pressure is generated in the intervillous space, the elastic and deformable placental capillaries may be compressed.

In addition to these "large-scale" placental lesions, chronically abnormal uteroplacental vascular perfusion may impair the growth and development of the placenta, or alternatively, lead to diffuse villous lesions which cannot be identified grossly. Scarred, shrunken, fibrotic and hypovascular villi, with reduced number and/or caliber of placental capillaries, have been proposed to result from destruction of growing villous capillaries by abnormal uteroplacental flow. Such capillary damage may lead to fetomaternal hemorrhage. Given the uteroplacental vascular pathology common in hypertensive pregnancies, it is not surprising that fetomaternal hemorrhages in the midtrimester are more frequent in hypertensive pregnancies. "Tenney-Parker" changes of the terminal villi, an increase in syncytial nuclear clumping and basophilia, are common in cases of chronic uteroplacental malperfusion. However, it is commonly forgotten that these syncytial histologic features accompany abnormal placental perfusion of either maternal or fetal origin. It is common experience that avascular villi (villi devascularized from intraplacental vascular lesions) will have excess syncytial knotting compared to their normally vascularized neighbors. Experimentally, ligation of a fetal artery in the monkey placenta appeared to result in creased syncytial knotting in the villi so rendered avascular.

The small size of placentas delivered in the context of long-standing poor uteroplacental perfusion has been taken to imply that chronic placental nutritional deprivation may impair terminal villous arborization. This is supported by the microscopic impression of increased intervillous volume and decreased villous parenchymal volume. In these cases, there may be a primary failure to develop adequate placental mass, rather than its destruction by abnormal perfusion patterns. Either way, the total villous capillary bed will be reduced. Essentially, this produces an anatomy analogous to the emphysematous lung, with parallel compromise of placental respiratory sufficiency. Just as significant to the fetus is the potential for increased placental resistance and increased cardiac work, since 500 ml/minute of fetal cardiac output is directed to the placenta An indirect reflection of umbilical-placental resistance is the umbilical systolic/diastolic (S/D) ratio. The S/D ratio approaches infinity, and end diastolic flow in the umbilical artery may be negative when the placental capillary bed is reduced by more than 50%. A reduction in the total fetoplacental capillary bed will necessitate a like reduction in fetoplacental volume. This may lead to reduced fetal glomerular filtration rate and oligohydramnios. Arabin and Laurini have related histologic evidence of uteroplacental ischemia to abnormal umbilical artery Doppler velocimetry. Perfusion of the placenta at abnormally low oxygen tension is associated with increased basal perfusion pressure, consistent with placental vaso-constriction. Chronic vaso-constriction (and increased intraluminal pressure) could lead to vascular obliteration via progressive mural hyperplasia. Increased intraluminal pressure could predispose to endothelial damage and luminal obliteration via lesions of the "hemorrhagic endovasculitis" type.

Chronic inflammatory decidual pathology

A few decidual lymphocytes are normally present in the basal plate decidua and the extraplacental membranes. One component of the normal decidual leukocyte population, the large granular lymphocytes, have been suggested to play a major role in the limitation of trophoblastic penetration of maternal tissues. In uncomplicated term pregnancies, clustering of maternal lymphocytes near anchoring villi, and even sparse infiltration- with preservation of the anchoring villous structure- are common. Chronic destructive anchoring villitis is more common, in our experience in complicated gestations, especially in the context of fetal growth restriction or maternal preeclampsia. The inciting stimulus to this response is unknown, but has been suggested to indicate underlying maternal-placental immunopathology, and to be more common in patients with poor reproductive outcome. We will only - and briefly- discuss chronic inflammation of maternal spiral and/or uetroplacental vessels. Chronic uteroplacental vasculitis is significantly more common in early euploid pregnancy loss than aneuploid pregnancy loss, and is among the lesions associated with low birth weight infants. Causal relationships among elevated levels of antiphospholipid antibodies, chronic uteroplacental vasculitis and poor pregnancy outcome have been proposed. It is speculated that antiphospholipid antibodies directly induce pregnancy failure via induction of deleterious cellular immune responses, rather than by initiation of coagulation.

Decidual hemosiderin

Decidual hemosiderin deposition indicates that decidual bleeding has occurred 24-48 hours prior to delivery. In a recent study, decidual hemosiderin- in either extraplacental or basal plate decidua-was found significantly more frequently in preterm as compared to term deliveries. Decidual hemosiderin was associated with increased likelihood of preterm delivery for indications of preeclampsia or non-hypertensive abruption, was not related to clinical bleeding within 72 hours of delivery. Basal plate hemosiderosis was associated with a significantly increased incidence of villous infarct (p<0.0001), uteroplacental vessels with absent physiologic change (p<0.003), increased numbers of circulating nucleated erythrocytes (p<0.0007), uteroplacental vascular thrombosis (p<0.0001), and villous fibrosis and hypovascularity (each p<0.0001). Preterm delivery for whatever indication appears to be commonly associated with subclinical decidual bleeding. Such bleeding in the basal plate is related to other histologic evidence of chronic uteroplacental vascular pathology. Decidual hemosiderin has also been described to be more prevalent in cases with numerous avascular villi.

Basal plate myofibers

Basal myofibers can be observed in the basal plate of the delivered placenta. We studied the distribution of this histologic features in term and preterm, and according to the clinical indication for preterm delivery. Forty-four of 457 (9.6%) of preterm placentas had basal plate myofibers, compared with one of 108 (0.9%) term controls (p<0.001). Uteroplacental vessels with abnormal physiologic changes (incomplete or absent conversion) were more frequent and placental weights were lower in cases with basal plate myometrial fibers. In 35 of the 44 cases (80%), a focus of basal myometrial fibers was adjacent to a basal spiral vessel; in 20 of the 35 foci (57%), the spiral artery lacked physiologic changes, and two additional foci showed thrombosed uteroplacental vessels. Therefore in 63% of foci of basal plate myometrial fibers, the adjacent basal plate vessel was abnormal. The distribution of basal plate myometrial fibers did not differ among the different causes of preterm delivery represented in the study population (PROM, preterm labor, preeclampsia, and non-hypertensive abruption). Zhou et al have speculated that local uterine hypoxia may be a stimulus to deeper myometrial invasion. We hypothesize that our foci of basal plate myometrial fibers, the majority of which were adjacent to pathologic uteroplacental vessels, represent local abnormalities of depth of cytotrophoblast invasion.

Table 1.
Distribution of lipoprotein(a) immunoreactivity in uteroplacental vessels of the placental bed and basal plate.

	# (%) Lipoprotein(a) reactive uteroplacental or spiral arteries	p value	OR (95% C.I.)
Placental bed biopsy
Normotensive	2/69 (3%)
Preeclampsia	71/179 (40%)	<0.0001*	22 (5-134)
Basal plate
Normal term	14/35 (40%)
Term preeclampsia	20/21 (95%)	0.0001#	30 (3.5-670)
Preterm preeclampsia	10/10 (100%)	0.003#	150 (N/A)
Spontaneous prematurity	49/56 (88%)	<0.0001#	10.5 (3-34)
Remote post partum implantation site	65/70 (93%)	0.0001#	19.5 (6-72)
Massive peripartum hemorrhage	0/40 (0%)	<0.0001@	>1000 (N/A)

* significance compared to normotensive placental bed biopsies
# significance compared to normal term basal plate
@ significance compared to involuting implantation sites.

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