Placental abruption

Interlesional Relationships and Perinatal Outcomes

* Background and Objective.-Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration of fetal-placental blood vessels that has been associated with perinatal morbidity and mortality and abnormalities of growth and development. Clinicopathologic conditions that are often identified in pregnancies with HEV-affected placentas include villitis of unknown etiology, chorionic vessel thrombi, villous erythroblastosis, meconium staining, and maternal hypertension. The clinical implications of HEV are often disputed. This case-control study assesses the clinical relevance of HEV in placentas of viable infants and examines the interplay of coexistent intraplacental lesions.

Methods.-We reviewed clinical records and slides from 104 livebirths with placentas affected by HEV above a specified severity level (cases) and 104 matched livebirths with placentas that were not affected by HEV (controls). We evaluated incidences of perinatal complications with increasing HEV severity indices in placentas with and without coexistent lesions. Interlesional relationships were established by matching HEV severity indices with severity indices of coexistent lesions. Hemorrhagic endovasculitis was subcategorized into active, bland, and healed forms and clustered capillary lesions (hemorrhagic villitis).

Results.-Lesions that were frequently coexistent in HEV-affected placentas included villitis of unknown etiology, chorionic thrombi, villous fibrosis, erythroblastosis, and primary infarcts. Compared with the control group, the case group had higher incidences of abnormal fetal heart rate tracings (P

Conclusions.-Severe forms of HEV can occur in placentas of livebirths. The severity of HEV and associated lesions and the presence of hemorrhagic villitis have important clinical implications. Interlesional relationships between HEV and thrombotic, chronic inflammatory, and chronic vaso-occlusive lesions exist. Pregnancies with HEV-- affected placentas with or without coexistent lesions are at risk for perinatal complications. (Arch Pathol Lab Med. 2002;126:157-164)

Hemorrhagic endovasculitis (HEV) is a vasodisruptive alteration of fetal-placental blood vessels first described in 1980.1 Studies carried out in subsequent years have shown associations between this lesion and stillbirth, intrauterine growth restriction (IUGR), and neurologic impairment in liveborn children evaluated at 5 years of age.2-6 Light microscopic criteria for the diagnosis of HEV include disruption or nonexudative necrosis of the vessel wall with hemorrhage, erythrocyte fragmentation, and intravascular nucleocytoplasmic debris (Figure 1).

It has become apparent that HEV most often occurs in concert with other placental abnormalities including chronic villitis of unknown etiology, fetal-placental vessel thrombi, villous fibrosis, erythroblastosis, and meconium staining of the chorioamnionic membrane.2,3,5,7 Thus far, maternal hypertension has been the only maternal cofactor identified2,3,8,9 Hemorrhagic endovasculitis has been recurrent in some patients. Risk factors for recurrence include coexistent villitis of unknown etiology, clinical hypertension, and placental lesions reflecting hypertensive maternal vessel disease.10

This case-control study of livebirths with and without placental HEV was intended to assess the clinical relevance of this lesion in placentas of viable infants. Additionally, to achieve a better understanding of the nature, pathogenesis, and role in pregnancy outcome of placental HEV, we evaluated the clinical implications of increasing degrees of severity and examined the interplay of coexistent intraplacental lesions.

MATERIALS AND METHODS

Case and control placentas were selected from 10 820 specimens referred to the Michigan Placental Tissue Registry (MPTR), a statewide referral center, between January 1, 1990, and December 30, 1996. Of these referrals, 8886 were from liveborn infants. Hemorrhagic endovasculitis was identified in 987 (11.1%) of these placentas. Most specimens are referred by physicians for consultation on pregnancies in which there has been some complication of the pregnancy, labor, or delivery or a birth abnormality. A form containing clinical and other relevant information accompanies each referred specimen. The methods used for examining and reporting MPTR referrals are published.11 Cases were selected from livebirths with a placenta that exhibited HEV at or above a specified level of severity. The methods used for assessing the extent and severity of microscopic placental lesions are published.10,12 Briefly, the MPTR protocol includes processing 5 sections of parenchymal tissue from both singleton and twin placentas for examination. The extent of a lesion refers to the number of sections exhibiting the lesion; thus, extent scores range from 0 to 5. Severity is assessed by the number of affected areas per slide visualized using the lOx objective, ranging from 1 (focal) to 3 (diffuse). An extent-severity index is calculated by multiplying the extent score by the average severity score. With 5 sections of parenchymal tissue, extent-severity indices range from 0 to 15. Extent-severity indices were calculated in this manner for HEV and villitis of unknown etiology. Because of the nature and distribution of lesions other than HEV and villitis of unknown etiology, extent scores only were used with a range of 0 to 5. These scores were equated with extent-severity indices by multiplying the extent score by 3.

One hundred four placentas from livebirths with an HEV severity index of 4 or higher (cases) were matched as closely as possible by gestational age and time and place of birth with 104 placentas from livebirths without HEV (controls). One single disk twin placenta (case) was included with an appropriately matched twin control. Thus, a total of 208 placentas and 210 infants were evaluated. All referrals (1990-1996) were initially examined by 1 of 3 board-certified pathologists. For quality assurance, 10% of all referrals were reexamined by a second pathologist. All slides from case and control groups were rereviewed by one author (C.M.S.). Slides were evaluated to determine the presence and extent-severity index of HEV, villitis of unknown etiology, fetal-- placental vessel thrombi, villous fibrosis, and erythroblastosis (nucleated red blood cells within chorionic and/or umbilical vessels), and the presence of lesions indicative of maternal hypertension, including primary infarcts, changes described by Tenney and Parker,13 decidual atheromatosis, decidual thrombi, and ischemic decidual necrosis. Morphologic criteria for the diagnosis of these histologic lesions are published."4 Villous fibrosis was documented when 5 or more adjacent villi exhibited fibrous stromal replacement. Hemorrhagic endovasculitis was subclassified as to form by designating active-vasodestructive (Figure 1), bland (Figure 2), and healed forms.10 Peripheral clustered capillary lesions were classified as hemorrhagic villitis15 (Figure 3). Histologic criteria for subclassified forms of HEV are listed in Table 1.

Placental reports and clinical history forms were assessed for all maternal, fetal, placental, cord, and membrane abnormalities as indexed in the MPTR manual of coded diagnoses (unpublished data). Perinatal outcome was based on histories of fetal distress, abnormal fetal heart rate tracings, and IUGR. Fetal growth for single births was assessed using the Colorado Intrauterine Growth Chart.16 Intrauterine growth for twins was assessed using growth curves of expected weights for twins as established by the University of Illinois Perinatal Network.17 Birth weights were available for 86 case and 85 control infants. Infants whose birth weights were below the 10th percentile of expected weight for their gestational age were considered to have IUGR.

Differences between cases and controls for all categorical and categorized numerical variables were analyzed for significance using X^sub 2^ tests. P

RESULTS

The mean gestational age was 37.3 weeks for infants in the case group and 38 weeks for infants in the control group, with an overall average gestational age for both groups of 37.6 weeks. Significant differences between case and control groups were evident with specific parenchymal placental lesions, other placental abnormalities, and fetal perinatal complications. Parenchymal lesions occurring with significantly greater frequency in HEV-affected (case) placentas than in non-HEV-affected (control) placentas included villitis of unknown etiology, fetal-placental vessel thrombi, villous fibrosis, and primary infarcts (Figure 5). Higher incidences of other abnormalities including erythroblastosis and meconium staining were also present in the case group (Figure 5) as was clinical oligohydramnios (P

Hemorrhagic endovasculitis extent-severity indices ranged between 4 and 14, with a mean index of 6. Nineteen of 104 case placentas (18.3%) had extent-severity indices of 10 or higher (Figure 4). Increasing extent-severity indices for HEV and other lesions were associated with higher rates of 1 or more perinatal complications (Table 2). There were significant correlations between increasing extent-severity indices for HEV and increasing extent-severity indices for villitis of unknown etiology, fetal-placental vessel thrombi, villous fibrosis, and erythroblastosis (Figure 4 and Table 3). Increasing extent-severity indices of HEV were associated with higher rates of fetal distress and IUGR with or without coexistent lesions (Table 4).

Noticeable and/or significant negative associations between case and control groups included acute inflammatory responses of the chorioamnionic membrane and umbilical cord and retroplacental hemorrhage and abruption. We did not find a significant difference in the incidence of clinical maternal hypertension between cases and controls.

COMMENT

Since its description in 1980, placental HEV has stimulated debate and diversity of opinion as to its nature and clinical relevance.18-20 Controversy of this sort can be expected as current understanding of the morphology, pathogenesis, and clinical significance of many placental abnormalities lags far behind that of the more familiar visceral organs. Confusion surrounding the diagnosis of HEV may stem from a lack of acquaintance with published criteria for this diagnosis or merely from failure on the part of the examiner to recognize the characteristic microscopic features of the lesion21 (Figures 1 and 3 and Table 1). Overlap between bland forms of HEV (Figure 2) and vascular changes considered to be retrogressive, following fetal death and cessation of fetal circulation, may add to this confusion.20,22 Contrariwise, the often dramatic changes in blood vessels exhibiting vasodestructive forms of HEV (Figures 1 and 3) and the potential for widespread vascular damage in some affected placentas would indicate that a significant pathologic process is involved.

Cases selected for this study were those in which the HEV severity index was at or above a designated level. We felt that compared with placentas with focal lesions, placentas with well-established HEV would more reliably reflect associated events. Control placentas were those referred for similar reasons as cases (see "Materials and Methods"). Thus, control placentas were in most instances associated with some clinical or pathologic abnormality. The salient difference between case and control groups was the presence versus the absence of HEV. Differences in incidences of other placental lesions between case and control groups were used to establish associations between HEV and coexistent lesions. Differences in incidences of perinatal complications between case and control groups were used to indicate differences in clinical outcome pointing to clinical relevance.

Associated Lesions

It is apparent from this study that in placentas of livebirths, HEV rarely occurs by itself but instead exists as part of a pattern of coexistent lesions similar to that identified in previous analyses of HEV3,8 Because insight into the pathogenesis of this process may evolve through examination of the nature of these coexistent lesions, we present a brief summation of their salient features and potential interrelationships) with HEV

Chronic Villitis of Unknown Etiology.--Chronic villitis of unknown etiology is an inflammatory response that affects parenchymal placental villi to a variable degree in 7% to 13% of examined placentas.23,24 Clinically, villitis of unknown etiology has been associated with IUGR and in some instances with stillbirth.23 Theories relevant to its etiology include responses to an as yet unidentified infectious agent or to an altered fetal-maternal immune interaction, possibly of graft versus host type.24 Activated intravascular coagulation has been described in areas of villitis.25 An obliterative endovasculitis may result from intravillous inflammation involving chorionic vessel walls.26 These features found in association with villitis of unknown etiology may relate to clinicopathologic events surrounding HEV including IUGR, thrombosis, and villous scarring.

Chorionic Vessel Thrombi.-Considerable attention has recently been given to the process of thrombosis within the fetal-placental circulation.20,27-29 Studies suggest that thrombi within fetal-placental vessels are often associated with thrombi and/or thromboembolic events in other fetal organs.19,28,29 The cause or causes of thrombosis within fetal-placental blood vessels are often unknown.19,20 Thrombogenic events such as stasis, vascular injury, infection, and inflammation may be involved.28,29 An association between villitis of unknown etiology and fetal-placental vessel thrombi is apparent.20,25,27 Heritable disorders of coagulation such as protein S or C or factor V Leiden deficiencies have been advocated as potential causes of fetal-placental vessel thrombi.29 The disruptive alterations of blood vessels occurring with HEV are likely associated with thrombus formation.3,15 The concurrent occurrence of thrombosis with nonexudative necrosis of vessel walls and erythrocyte fragmentation has supported the concept that HEV is a thrombotic microangiopathy similar to the glomerulopathy of the hemolytic uremic syndrome and other microangiopathic hemolytic conditions.1,3,15,19 Conversely, it has been suggested that HEV might be a consequence of a proximally thrombosed chorionic vessel.30 It is difficult to demonstrate a chain of events with standard histologic techniques; however, the vasodisruptive nature of HEV is acceptably thrombogenic, and a vicious cycle involving vessel wall necrosis and thrombosis may occur once this process is under way,

Thrombosis within the fetal-placental circulation is not a simplistic event. Different types of thrombi are described including (1) formed intraluminal thrombi (thromboemboli); (2) fibrin (fibrinoid) deposits within vessel walls, which may or may not propagate into vessel lumina 20-31; and (3) platelet-fibrin complexes that form within vessels with a disrupted wall or a lumen bridged by endothelial or myointimal cells that facilitate deposition of thrombus material and potential thrombus formation. 15 Vessels so affected may have additional alterations that fulfill the criteria for the diagnosis of HEV Thrombi resulting from all of these mechanisms were classified as fetal-placental vessel thrombi in this study.

Villous Fibrosis.-Replacement of villous stroma by fibrous tissue is considered to be an end result of occlusion of fetal-placental blood flow.22 This process can involve the entire placenta as with prolonged intrauterine fetal death or a segment of villous tissue after occlusion of a primary, secondary, or tertiary chorionic vessel. Fibrous replacement of the villous stroma is assumed to take at least a week or more to develop after cessation of fetal circulation.22 Identification of segmental areas of villous scarring is therefore useful for establishing the time of adverse intrauterine events leading to circulatory occlusion. Villous fibrosis has been associated with perinatal and neonatal abnormalities.211,32 In some instances, such complications are not the result of scarred villi themselves; rather, the fibrotic villi are indicative of other processes or events that adversely affect fetal-placental blood flow.30 Currently recognized causes for fetal-placental circulatory occlusion, in addition to fetal death in utero, include fetal-placental vessel thrombi, obliterative endovasculitis occurring with villitis of unknown etiology and other villous inflammations,26 and vaso-occlusive forms of HEV.10 Redline and Pappin 20 found clinicopathologic complications associated with pregnancies in which placentas exhibited multifocal areas of villous fibrosis. These complications were similar to those identified in this study of HEV, including IUGR, acute and chronic monitoring abnormalities, oligohydramnios, chronic villitis, and meconium staining. These authors included fetal-placental vessel thrombi and HEV along with villous fibrosis under the general heading of "fetal thrombotic vasculopathy" and emphasized a relationship between the extent of villous fibrosis and clinical outcome. Thrombi were identified in 17 of 29 of their study cases. The incidence or extent of placental HEV was not documented.

Primary Infarcts.-Discrete areas of ischemic villous necrosis (primary infarcts) reflect obstruction to maternal-- placental blood flow. These lesions often occur with hypertensive maternal vessel disease and in pregnancies with growth-retarded infants.30 Primary infarcts may occur in the absence of clinical hypertension.14 This may in part explain our finding of significantly higher incidences of primary infarcts in HEV-affected placentas versus nonHEV-affected placentas despite the absence of a noticeable difference in clinical hypertension between these 2 groups. Studies evaluating the potential for recurrent HEV have shown higher rates of recurrence and subsequent stillbirth when initial HEV-affected placentas also exhibit infarcts and other hypertensive-type maternal vascular lesions.10 This association suggests that the coexistence of abnormalities of both fetal- and maternal-placental circulations may have a synergistic effect that potentiates adverse clinical outcomes.10

Erythroblastosis.-Erythroblastosis in the context of this study included placentas of any gestational age in which nucleated red blood cells were identified within fetal-placental or umbilical blood vessels. Although we categorized this finding as a placental abnormality rather than a parenchymal lesion, we included circulating erythroblasts with parenchymal lesions for purposes of data analysis within this study. An increased number of erythroblasts within the placental circulation of second and third trimester gestations has been correlated with tissue hypoxia.30 The pathogenesis of increased circulating erythroblasts in HEV-affected placentas may involve fetal blood loss from hemorrhage into damaged vessel walls and the surrounding villous stroma.33 Hemorrhage into the intervillous space (fetal-maternal hemorrhage) from affected vessels near the villous surface may also occur.3 15,34 Additionally, fragmentation of erythrocytes probably alters their functional capacity. These hemorrhagic and hemolytic events would result in tissue hypoxia that would, in turn, stimulate erythropoiesis.

Likewise, meconium staining of the chorioamnionic membrane and chorionic plate may be an indicator of fetal jeopardy, possibly associated with tissue hypoxia.19 Although not all studies have been in agreement on this concept,30 it is reasonable to assume that both meconium and the presence of erythroblasts in placentas late in pregnancy reflect adverse intrauterine events.

The higher incidence of oligohydramnios in cases versus controls may be related to a recognized association between oligohydramnios and IUGR.35

Clinical Outcome and Increasing Severity

In addition to previously recognized neonatal and developmental abnormalities associated with placental HEV, data from this study of livebirths identifies additional HEV-associated clinical events that are detectable in the preparturient period.

Incidences of perinatal complications rose with increasing severity indices of HEV and all frequently coexistent lesions (Table 2). We found this "dose-response" association between all 3 outcome variables (abnormal fetal heart rate tracings, fetal distress, and IUGR) and HEV, fetal-placental vessel thrombi, and villous fibrosis (Table 2). Villitis of unknown etiology and primary infarcts were related to 1 outcome variable only (IUGR), and erythroblastosis was related only to fetal distress (Table 2). These findings correlate with established, presumably chronic associations between villitis of unknown etiology and primary infarcts with IUGR.23,30 The association between erythroblastosis and fetal distress might indicate a relationship between circulating erythroblasts, tissue hypoxia, and fetal jeopardy nearer the time of delivery. Higher incidences of fetal distress and IUGR occurring with higher HEV severity indices did not appear related to the presence of other placental lesions (Table 4). This finding may or may not imply differences of clinical relevance between HEV and these coexistent lesions.

Interlesional Relationships

The question of how HEV and associated coexistent placental lesions relate to one another is an important one. We felt that by comparing severity indices between HEV and each associated lesion on a case-by-case basis (Figure 4), potential interlesional relationships might surface (ie, closely related trends of severity between lesions would imply some type of interlesional interplay). From the data presented in Table 3, it appears that a close interlesional association exists between HEV and villitis of unknown etiology, fetal-placental vessel thrombi, villous fibrosis, and erythroblastosis. The lack of a similar association between HEV and primary infarcts may relate to the fact that villitis of unknown etiology, fetal-placental vessel thrombi, villous fibrosis, and erythroblastosis constitute abnormalities of fetal-placental tissue and/or blood flow, whereas primary infarcts reflect abnormal maternal-placental perfusion.

HEV Forms

In hopes of clarifying issues of confusion involving the diagnosis and clinical relevance of HEV, we subclassified this lesion into 3 forms based in large part on the microscopic appearance of HEV activity within affected vessels' (Table 1 and Figures 1 through 3). Data from this study indicate that in livebirths, active-vasodestructive and active/healed lesions are most prevalent. Bland lesions were infrequent and occurred only in combination with active forms (Table 5). This finding agrees with the results of a previous study that included both liveborn and stillborn infants; in that study, livebirths exhibited active or active/healed HEV forms, whereas stillbirths had considerably higher incidences of the bland form of HEV10 Healed forms of HEV imply, as does villous fibrosis, a chronicity of adverse intrauterine events.

Approximately half of the 104 HEV case placentas exhibited clustered vasodestructive capillary lesions (hemorrhagic villitis) (Figure 3 and Table 6). Higher incidences of perinatal complications were present in HEV-affected placentas with hemorrhagic villitis than in those with HEV alone (Table 6). This finding suggests that this form of HEV may be the most clinically significant. The pattern of related complications in placentas with hemorrhagic villitis involved abnormal fetal heart rate tracings and fetal distress but not IUGR. This pattern suggests that hemorrhagic villitis reflects an acute rather than a chronic process, possibly occurring near the time of delivery.

Pathogenesis

Although a distinct etiologic agent or clear-cut chain of events leading to these hemorrhagic and vasodisruptive alterations of chorionic blood vessels has not yet surfaced, it seems reasonable to suspect endothelial cell injury as a possible initiating event. Control of the coagulation process and blood vessel tone normally exerted by intact endothelium is altered after injury.36 This alteration results in accelerated coagulation and a more rigid vessel wall. The ensuing intraluminal deposition of platelets and fibrin results in a mesh capable of entrapping and shearing erythrocytes.37 A more rigid vessel wall would facilitate mural disruption and necrosis, allowing diapedesis of erythrocytes and furthering formation of schistocytes and hemorrhage.38

Basic to these events is the question of what might be causing endothelial cell injury in HEV-affected placentas. Established causes for endothelial injury in tissues include hemodynamic instability, circulating immune complexes, toxins, and hypoxia 36 Hemodynamic instability leading to turbulent blood flow and subsequent endothelial cell damage is highly probable within the voluminous network of blood vessels comprising the fetal-placental circulation. Immune complexes resulting from fetal-maternal antigen incompatibility, commensal or pathogenic infectious agents, and toxins of environmental or infectious origin might alter the endothelium directly.15 Hemorrhagic endovasculitis-like lesions induced experimentally by Silver et al38 in tissue culture have been explained on the basis of hypoxia and vascular smooth muscle contraction leading to necrosis of the vessel wall. These authors found ultrastructural evidence of altered endothelial and smooth muscle cells within chorionic vessels exhibiting HEV-like lesions. Additionally, we observed ultrastructural evidence for endothelial and smooth muscle cell injury in chorionic vessels of formalin-fixed HEV-affected human placentas.3,15 This information supports the concept that endothelial cell injury is fundamental to the pathogenesis of placental HEV

From this study we make the following conclusions about placental HEV in liveborn infants:

1. REV may be widespread and associated with significant incidences of complications identifiable in the perinatal period.

2. Vasodestructive forms of REV are the most prevalent forms.

3. The severity of REV and associated lesions and the presence of hemorrhagic villitis appear to have important clinical implications.

4. A distinct set of coexistent parenchymal lesions occurs. These lesions reflect chronic inflammatory, thrombotic, and vaso-occlusive events of both fetal and maternal circulations. Their nature implies chronicity of adverse intrauterine events in many affected pregnancies.

5. Pregnancies with REV-affected placentas, with or without coexistent lesions, are at risk for perinatal complications.

6. Significant interlesional relationships are apparent between HEV and coexistent lesions that reflect abnormalities of placental tissue or fetal-placental blood flow. The precise mechanism of interplay and role of each lesion in pregnancy outcome remains to be determined.

Follow-up evaluation of the growth and development of liveborn infants with HEV-affected placentas and followup of outcome and placental status of subsequent pregnancies are necessary to further assess the long-term clinical relevance of this lesion.

We are grateful to Kathleen M. Foley-Geiger, PhD, and Julie Van Raalte, BS, for their advice and assistance with this study.

References

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C. Maureen Sander, MD; Dennis Gilliland, PhD; Cheryl Akers, MS; Ann McGrath, DVM; Tarek A. Bismar, MD; Laura A. Swart-Hills, BS

Accepted for publication October 5, 2001.

From the Division of Human Pathology, College of Medicine (Drs Sander and McGrath and Ms Swart-Hills), Department of Statistics & Probability (Dr Gilliland), and Department of Microbiology & Molecular Genetics (Ms Akers), Michigan State University, East Lansing, Mich, and the Department of Pathology & Immunology, Lauren V. Ackerman Surgical Pathology Laboratory, Washington University Medical Center, St Louis, Mo (Dr Bismar).

Presented in part at the United States and Canadian Academy of Pathology Annual Meeting, Boston, Mass, March 2, 1998, and in part at the American Society of Clinical Pathologists/College of American Pathologists Spring Meeting, Los Angeles, Calif, April 5 and 6, 1998.

Reprints: C. Maureen Sander, MD, Division of Human Pathology, A630 East Fee Hall, Michigan State University, East Lansing, MI 488241313 (e-mail: sander@msu.edu).

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