Placental pathology in systemic lupus erythematosus: A prospective study

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Placental pathology in systemic lupus erythematosus: A prospective study Margret S. Magid, MD,a Cynthia Kaplan, MD,e Lisa R. Sammaritano, MD,c Margaret Peterson, PhD,d Maurice L. Druzin, MD,b and Michael D. Lockshin, MDc New York, New York OBJECTIVES: Systemic lupus erythematosus and antiphospholipid antibody, often identified in patients with systemic lupus erythematosus, are associated with poor pregnancy outcome. This study distinguishes between the effect of each of these factors on gestational outcome and placental pathologic conditions in pregnant patients with systemic lupus erythematosus. STUDY DESIGN: Thirty-seven pregnancies and 40 placentas from 33 women with systemic lupus erythematosus were studied prospectively. RESULTS: Systemic lupus erythematosus alone, but not systemic lupus erythematosus activity, was associated with increased spontaneous abortions, preterm gestations, and fetal growth restriction. Placental correlates were ischemic-hypoxic change, decidual vasculopathy, decidual and fetal thrombi, chronic villitis, and decreased placental weight. Extensive infarction and fetal death were important antiphospholipid antibody–related findings. CONCLUSIONS: Decidual vasculopathy/coagulopathy appears to mediate the antiphospholipid antibody–related and much of the systemic lupus erythematosus–related deleterious effect on the placenta and gestational outcome. The presence of antiphospholipid antibody largely, but not invariably, predicts fetal death. Antiphospholipid antibody–independent chronic villitis may represent a second mechanism of systemic lupus erythematosus–related change. (Am J Obstet Gynecol 1998;179:226-34.)

Key words: Placenta, systemic lupus erythematosus, anticardiolipin antibody, pregnancy

Systemic lupus erythematosus is associated with poor pregnancy outcome, including increased rate of stillbirth, fetal growth restriction, and prematurity.1 Antiphospholipid antibodies, which include anticardiolipin antibody and lupus anticoagulant, are found in 30% to 40% of patients with systemic lupus erythematosus.1 The antiphospholipid antibody syndrome consists of recurrent venous or arterial thromboses, fetal loss, or thrombocytopenia in the presence of anticardiolipin antibody. Antiphospholipid antibody, both in the setting of systemic lupus erythematosus and as an isolated serologic finding, has been associated with the complications previously attributed to “lupus” pregnancies.2 Thromboses or other abnormalities of the maternal blood supply to the placenta are thought to mediate systemic lupus eryFrom the Departments of Pathologya and Obstetrics and Gynecology,b the Division of Rheumatic Diseasec and the Department of Biomechanics and Biomaterials,d Hospital for Special Surgery, New York Hospital–Cornell Medical Center, and the Department of Pathology, University Hospital, State University of New York at Stony Brook.e Supported in part by grant No. AR32929 from the National Institutes of Health. Received for publication August 11, 1997; revised October 3, 1997; accepted December 31, 1997. Reprint requests: Margret S. Magid, MD, Department of Pathology, Mount Sinai Medical Center, Box 1194, One Gustave L. Levy Place, New York, NY 10029. Copyright © 1998 by Mosby Inc. 0002-9378/98 $5.00 + 0 6/1/88525


thematosus–related or antiphospholipid antibody–related fetal loss.3, 4 The placental pathologic condition associated with systemic lupus erythematosus and/or antiphospholipid antibody has been studied in case reports and small series over the past 20 years. Studies report an increased incidence of small placentas, infarction, decidual hemorrhage, and decidual vasculopathy3-13; however, the separate roles that systemic lupus erythematosus and antiphospholipid antibody play in contributing to placental dysfunction and poor pregnancy outcome have not yet been explained. To delineate and distinguish the placental pathologic condition and pregnancy outcome resulting from systemic lupus erythematosus and antiphospholipid antibody, we present a prospective study of a large series of patients with systemic lupus erythematosus in whom the serologic status of antiphospholipid antibody was known. Material and methods Study population. The study population consisted of 33 women who were being followed up clinically for a pregestational diagnosis of systemic lupus erythematosus according to the most recent American College of Rheumatology criteria.14 The placentas were selected without regard to status of disease, which ranged from asymptomatic to severely symptomatic at the onset of pregnancy. The placentas are all those available from pa-

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Table I. Clinical characteristics of mothers with systemic lupus erythematosus and their pregnancies Study population No. of patients No. of pregnancies Age (y, average) Race White Hispanic Black Asian Unknown Primiparous No. of multiparous patients with prior spontaneous abortions Active lupus during pregnancy Antiphospholipid antibody present during pregnancy Extractable nuclear antibody Preeclampsia Chronic hypertension Prednisone therapy Aspirin therapy

All pregnant patients with systemic lupus erythematosus

33 37 31 (range 22-39)

109 139 30 (range 19-41) (9 unknown)

24 4 3 1 1 13 (39%) 14/20 (70%) (range of abortions per patient 1-5; average losses per patient 2) 16 (43%) 20 (54%) (7 low level [30 GPL]; 1 LAC only) 13/32 (41%) (Ro 7; La 1, RNP 3, SmRNP 1; RoSmRNP 1)

68 16 16 9 – 43 (39%) 42/66 (64%) (range of abortions per patient 1-5; average losses per patient 1.97) –* 40/100 (40%) (40 unknown)

7 (19%) 3 (8%) 27 (73%) 16 (43%)

48/115 (42%) (24 unknown) (Ro 19; LA 5, RNP 10; SmRNP 7; RoSmRNP 1; RoLa 1; RoLaRNP 1; RoRNP 4) 17 (12%)† –* 68/131 (52%) (8 unknown) –*

LAC, Lupus anticoagulant. *Information unavailable. †This represents a minimum number. Preeclampsia was not systematically recorded.

tients with lupus erythematosus during the study period (July 1983 through July 1989). For comparison, clinical data on all 139 lupus pregnancies seen during the same time period are also presented (Tables I and II). A total of 37 pregnancies was followed prospectively, with four women undergoing two consecutive pregnancies. There were three twin gestations. Patient evaluation. Prospective evaluation of the pregnant patients began at the first visit after pregnancy had been confirmed. Antiphospholipid antibody status was evaluated by a standard enzyme-linked immunosorbent assay test for anticardiolipin antibody. The antibody was classified as to immunoglobulin isotype and quantified by IgG phospholipid antibody (GPL) and IgM phospholipid antibody (MPL) units. We used prolonged activated partial thromboplastin time, which persisted despite mixing with normal plasma, to screen for lupus anticoagulant. Antinuclear antibody was detected with the human Hep 2 cell line. Anti-double-stranded deoxyribonucleic acid antibodies were evaluated by the Farr technique. The presence of extractable nuclear antigens was determined early in the study by the Mancini radial immunodiffusion technique and later by enzyme-linked immunosorbent assay. Lupus activity was based on the physician’s global assessment by use of signs, symptoms, and laboratory data. Although grading was semiquantitative (ie, none, mild, modest, severe) because of small numbers, any lupus activity was considered a “yes” for the

purposes of this analysis. Therapy included daily prednisone (varying doses), given for the presence of either lupus activity or antiphospholipid antibody, and low-dose aspirin (80 to 100 mg/day), given prophylactically for antiphospholipid antibody. Therapy varied according to clinical need. Management of pregnancy. Patients were followed up in regular obstetric visits. Preeclampsia was defined as hypertension plus proteinuria and/or generalized edema, separated from exacerbation of lupus disease activity (lupus flare) by clinical and serologic evaluation. Beginning in the gestational week 25, pregnancies were monitored by weekly nonstress tests, followed by contraction stress tests if indicated. A patient with repeatedly abnormal tests was hospitalized and monitored daily. Fetuses of 28 to 30 weeks’ gestation or older with continued evidence of distress were treated with betamethasone and delivered by cesarean section. Neonatal and fetal weights were compared with published controls.15, 16 Intrauterine growth restriction (small for gestational age) was defined as less than the 10th percentile in weight for gestational age. Placental pathologic conditions. A total of 39 placentas (including two separate twin placentas and one fused twin placenta, which was subsequently separated into two vascular distributions) was collected within 2 hours after delivery. The placentas were examined grossly as per accepted procedures.11 Sections for microscopic study,

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Table II. Gestational and fetal results for all systemic lupus erythematosus and by antiphospholipid antibody status Study population

Total pregnancies No. of fetuses/infants Prior spontaneous abortions in multiparous women Mean gestational age (wk) Preterm (2 SD below mean Infarction (>20%) Ischemic-hypoxic change Any Diffuse, moderate or marked Diffuse, mild/moderate/marked Decidual vasculopathy Decidual thrombi Fetal thrombi Chronic villitis of implied unknown etiology Perivillous fibrin

Statistical Statistical significance All systemic significance of of antiphospholipid lupus Antiphospholipid antiphospholipid Antiphospholipid antibody positive Control erythematosus antibody negative antibody negative antibody positive vs antiphospholipid (%) (%) (%) vs control (%) antibody negative

16 2 .005. *Low statistical power because of small number of cases.

controls. Placental weight of the systemic lupus erythematosus group was at least 1 SD less than the expected mean for gestation in more than half of placentas, and more than 2 SD less than the mean in nearly one third of the placentas. Seven placentas (18%) had extensive infarction involving more than 20% of the volume (Fig 1). Ischemic-hypoxic change was noted in almost all placentas and was moderate or marked in almost one third of the placentas (Fig 2). Six of 35 placentas (17%) with adequate blood vessels showed decidual vasculopathy (Fig 3). Only one of these patients was considered to have concurrent preeclampsia. Decidual vasculitis was not identified. Fresh decidual thrombi were increased in incidence (32%). Thrombi in fetal stem villous vessels were present in 22% of placentas. In every case only one blood vessel was involved and thrombi were recent. No associated increase in focal villous fibrosis or atrophy occurred. The overall incidence of chronic villitis of implied unknown etiology (Fig 4) was increased (28%) compared with controls, but in most of these cases (82%) was focal and mild. Perivillous fibrin was relatively increased for gestation in 65%. The incidence of numerous other lesions, including retroplacental hematoma, decidual hemorrhage, decidual plasma cell infiltration, chorioamnionitis, focal villous immaturity, villous edema, and nucleated red blood cells, was not elevated. The incidence of decidual necrosis and decidual chronic inflammation was decreased in the systemic lupus erythematosus placentas compared with controls. Systemic lupus erythematosus versus antiphospholipid antibody effects. The abnormal placental findings were further segregated by antiphospholipid antibody status, and the differences were analyzed (Table III). Antiphospholipid antibody negative placentas (n = 19)

reflect the effect of systemic lupus erythematosus without the contribution of antiphospholipid antibody. These are compared statistically with the control population. Antiphospholipid antibody positive placentas (n = 21) have been compared with the antiphospholipid antibody negative placentas to evaluate the supplementary effects of antiphospholipid antibody positivity in this systemic lupus erythematosus population. Antiphospholipid antibody negative systemic lupus erythematosus increased the incidences of ischemic-hypoxic change, decidual thrombi, chronic villitis of implied unknown etiology, decidual vasculopathy, fetal thrombi, and decreased placental weight compared with controls. The first 3 factors were statistically significant. Presence of clinical lupus activity was studied as an independent variable against the abnormal placental findings and was found to have no statistically significant correlation. All 7 placentas with extensive infarction were from antiphospholipid antibody positive patients. Antiphospholipid antibody positivity resulted in an incremental effect on low placental weight, ischemic-hypoxic change of high grade, and decidual vasculopathy. The incidences of decidual thrombi, fetal thrombi, chronic villitis of implied unknown etiology, and perivillous fibrin were either the same or lower in the antiphospholipid antibody positive group than in the antiphospholipid antibody negative group. The positive antiphospholipid associations were not statistically significant when analyzed by GPL or MPL units or by immunoglobulin isotype. Table IV summarizes the clinical and placental abnormalities associated with antiphospholipid antibody negative systemic lupus erythematosus and antiphospholipid antibody positive systemic lupus erythematosus pregnan-

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Fig 1. Extensive placental infarction. Numerous recent and old infarcts replace approximately 60% of the volume of this 22 weeks’ gestation placenta.

cies. Lack of statistical significance (P > .005) for many of these variables reflects the small number of cases and indicates the need for further study. Associations between variables other than antiphospholipid antibody. Table V lists the significant relationships observed between various clinical and pathologic variables in the entire group. All cases of decidual vasculopathy were associated with decidual thrombi; however, the converse was not true. When the two entities coexisted, thrombi were sometimes identified in or adjacent to vessels showing vasculopathy; however, more often the two lesions were widely separated. Vasculopathy was not statistically associated (P > .005) with chronic villitis of implied unknown etiology, fetal thrombi, decreased fetal weight, ischemic-hypoxic change, fetal death, perivillous fibrin, or decidual chronic inflammation, necrosis, or plasma cell infiltration. Five of the 6 fetal deaths were associated with extensively infarcted placentas (P = .0002). The relationship between infarction and prematurity was also statistically significant (P < .001). Although 70% of placentas 31 weeks’ gestation showed >20% infarction. Although infarction was associated with decidual vasculopathy, it was not significantly related to the presence of decidual thrombi. Aside from its association with decidual vasculopathy, decidual thrombi showed no statistically significant associations with other abnormal placental findings or unfavorable gestational outcomes. The highest incidence of chronic villitis of implied unknown etiology in these placentas occurred in gestations of 31 to 36 weeks and was associated with small placentas. No significant relationship was found with clinical

Fig 2. Ischemic-hypoxic changes. The placental villi from this 25-week gestation are smaller than normal (“acceleration of maturation”) and show increased syncytial knots. (Original magnification ×25.)

Table IV. Summary of clinically distinct risk profiles of systemic lupus erythematosus patients with and without antiphospholipid antibody Antiphospholipid antibody negative systemic lupus erythematosus risks (increased risk over controls)

Antiphospholipid antibody positive systemic lupus erythematosus risks (increased risk over antiphospholipid antibody negative systemic lupus erythematosus)

Clinical Abortions Prematurity Fetal growth restriction

Clinical Abortions Prematurity Fetal growth restriction Fetal death

Placental Decreased weight Ischemic-hypoxic change Decidual vasculopathy Decidual thrombi Fetal thrombi Chronic villitis

Placental Decreased weight Ischemic-hypoxic change Decidual vasculopathy Extensive infarction

lupus activity, maternal extractable nuclear antigens, decidual vasculopathy, low fetal weight, ischemic-hypoxic change, or perivillous fibrin. Chronic inflammation in the decidua was not significantly related to any other variable. Low placental weight was directly related to restricted fetal growth but was not significantly related to decidual thrombi, perivillous fibrin, or fetal death. Low fetal weight was not significantly associated with antiphospholipid antibody, chronic villitis of implied unknown etiology, decidual vasculopathy, or ischemic-hypoxic change.

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Fig 3. Decidual vasculopathy. Decidual blood vessels with fibrinoid change and scattered foamy intimal cells (atherosis). (Original magnification ×50.)

Fig 4. Chronic villitis. Villi are infiltrated by lymphocytes and other mononuclear cells and show decreased vascularity and fibrosis. (Original magnification ×50.)

Table V. Highly correlated associations between variables other than antiphospholipid antibody Variable Decidual vasculopathy vs

Extensive infarction vs

Chronic villitis vs Low placental weight (of unknown etiology) vs SGA vs

Preterm gestation vs

Systemic lupus erythematosus activity vs

Associations Decidual thrombi* Preterm gestation Extensive infarction Decidual hemorrhage Fetal death* Preterm gestation* Small for gestational age Decidual vasculopathy Increasing gestation Low placental weight Small for gestational age Chronic villitis Preterm gestation Extensive infarction Low placental weight Fetal thrombi Extensive infarction* Decidual vasculopathy Ischemic-hypoxic change Small for gestational age Decidual hemorrhage

Statistical significance P = .0002 P = .007 P = .02 P = .02 P = .0002 P < .001 P < .01 P = .02 P = .01 P = .03 P = .03 P = .03 P < .01 P < .01 P = .03 P = .04 P < .001 P = .007 P < .01 P < .01 P = .02

Comment: Because of missing values or low number of cases, the power is low in many analyses. All P values < .05 are provided. *Statistically significant relationship (P < .005).

Comment Previous studies of systemic lupus erythematosus pregnancies failed either to identify antiphospholipid antibody status or to distinguish between the effects of systemic lupus erythematosus and antiphospholipid antibody. In this study antiphospholipid antibody status was known for all patients. An extensive literature describes the adverse effects of systemic lupus erythematosus and antiphospholipid antibody on pregnancy, measured by spontaneous abortion, fetal death, preterm delivery, and fetal growth restriction.1, 2 Studies attempting to identify placental lesions

have described abnormalities of placental vasculature and coagulation, including extensive infarction,5, 6, 8-13 decidual vasculopathy,5-9, 11, 12 abruptio placentae,6, 11, 12 and decidual thrombi.9, 11 Less common are inflammatory lesions of decidua and villi, including decidual chronic inflammation,5, 11 decidual vasculitis,5, 11, 12 and chronic villitis of implied unknown etiology.7, 11, 12 Decreased placental weight2, 11 is a common end point. Several mechanisms have been proposed. Immunoglobulin and complement deposition in the walls of decidual blood vessels suggests that maternal autoantibodies and immune complexes are important.6, 7 Erlendsson

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et al5 proposed a T-lymphocyte–mediated inflammatory reaction. Antitrophoblast antibodies have been described.10 Decidual thrombosis mediated specifically by antiphospholipid antibody has been implicated in humans1, 4, 9 and in experimental models.3 The mechanism by which antiphospholipid antibodies induce vascular occlusion is still controversial. Antiphospholipid antibody may interfere with formation of prostaglandin or its release from the vessel walls.8 Antiphospholipid antibodies bind to the placenta20 and may induce deficiency of the placental tissue anticoagulant, annexin-V (placental anticoagulant protein I).21 La Rosa et al.22 suggested that a phospholipid binding serum glycoprotein, β2-glycoprotein I, binds antiphospholipid antibody on the trophoblast surface, enabling it to effect local injury. Our findings indicate that systemic lupus erythematosus alone, regardless of antiphospholipid antibody, is associated with decreased placental weight, ischemic hypoxic change, decidual vasculopathy and thrombi, fetal thrombi, and chronic villitis of implied unknown etiology (Table IV). Systemic lupus erythematosus activity did not correlate with these findings. Labarrere et al7 similarly had been unable to demonstrate an association between lupus activity and histologic findings. The studied placentas are not fully representative of all systemic lupus erythematosus pregnancies because studied patients had poorer prior obstetric histories, more frequent antiphospholipid antibody, more prednisone use, and fewer fetal deaths than did all systemic lupus erythematosus patients (Table II). The differences likely reflect the clinicians’ aggressive management of the pregnancies and vigor in obtaining placentas for special study. These differences do not invalidate the within-group comparisons we make. The effects of low-dose aspirin and steroid on placental morphology in healthy mothers is unknown. Study of treated patients with prior vascular pathologic conditions failed to demonstrate significant changes in histologic findings with aspirin therapy, despite some improvement in outcome.23 Prednisone therapy might explain why our patients with systemic lupus erythematosus had less decidual chronic inflammation and decidual necrosis than the controls. Antiphospholipid antibodies were associated with ischemic-hypoxic change, extensive infarction, and fetal death. These relationships did not correlate significantly with antibody level or immunoglobulin class. Out et al.4 were unable to find any statistical relationship between antiphospholipid antibody isotype or level and placental pathology. Decidual thrombi showed no increased incidence with antiphospholipid antibody. Decidual vasculopathy (absence of physiologic change and/or fibrinoid change and atherosis) in our study is a systemic lupus erythematosus–related phenomenon. A potential difficulty in evaluating decidual vascular abnor-

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malities is that the vascular lesion of preeclampsia may be impossible to distinguish from that of lupus,11 and the clinical manifestations of preeclampsia may be confused with lupus flares. To avoid this problem we established strict criteria for the clinical diagnosis of preeclampsia. A common theme, regardless of antiphospholipid antibody status, is decreased placental weight. The only placental variable associated with decreased weight was chronic villitis of implied unknown etiology. Although a small percentage of otherwise normal placentas will contain evidence of chronic villitis of implied unknown etiology,24 the percentage of placentas showing this histologic finding in our study was more than three times the control population. Chronic villitis of implied unknown etiology appears to be a systemic lupus erythematosus–related, antiphospholipid antibody–independent variable, previously observed in systemic lupus erythematosus patients by Labarrere et al.7 Chronic villitis of implied unknown etiology is a late gestational occurrence. In our study population chronic villitis of implied unknown etiology occurred most frequently between 31 and 36 weeks’ gestation, earlier than the lesion’s typical distribution. It has been suggested that chronic villitis of implied unknown etiology is an immunologic lesion24 mediated by maternal inflammatory cells. An alternative explanation is that chronic villitis of implied unknown etiology reflects infection by as yet unidentifiable pathogens25 to which systemic lupus erythematosus patients may have a heightened susceptibility. Our findings suggest two possible mechanisms for systemic lupus erythematosus and/or antiphospholipid antibody placental injury. The first is a decidual vasculopathy/coagulopathy. Extensive infarction in the antiphospholipid antibody positive group supports an occlusive mechanism. Decidual vascular injury, when severe, occurs relatively early in gestation, causing extensive infarction and interruption of pregnancy by death or early delivery. Our inability to demonstrate a significant relationship between antiphospholipid antibody and vascular lesions may reflect the limitations of the study—the optimal material for assessing decidual vasculopathy is decidual bed curettings, which were unavailable. Our results confirm that in lupus the presence of antiphospholipid antibody largely predicts fetal death.2 However, the role of antiphospholipid antibody is not invariable. Although no patient with systemic lupus erythematosus without antiphospholipid antibody had extensive infarction or fetal death, the presence of antiphospholipid antibody, even in high levels, did not invariably predict adverse gestational outcome. Conversely, prematurity, growth restriction, and small placentas occurred in the absence of antiphospholipid antibody. The second possible mechanism is antiphospholipid antibody–independent immunologic or infectious injury accompanying chronic villitis of implied unknown etiology. This appears

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to be of later onset than vascular events and/or of lower grade effect, eventually resulting in deficient placental function or fetal distress. Although chronic villitis of implied unknown etiology appears to be a more specifically systemic lupus erythematosus–related change, its incidence is not related to either clinical evidence of systemic lupus erythematosus activity or particular lupus autoantibodies. REFERENCES

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