The Prevalence of Antiphospholipid Antibodies in Women With Recurrent Spontaneous Abortion Women With Successful Pregnancies and Women Who Have Never Been Pregnant.
код для вставкиСкачать1231 THE PREVALENCE OF ANTIPHOSPHOLIPID ANTIBODIES IN WOMEN WITH RECURRENT SPONTANEOUS ABORTION, WOMEN WITH SUCCESSFUL PREGNANCIES, AND WOMEN WHO HAVE NEVER BEEN PREGNANT ANN L. PARKE, DANIEL WILSON, and DONALD MAIER Antibodies to negatively charged phospholipids are associated with a predisposition to both arterial and venous thrombosis, recurrent fetal wastage, and thrombocytopenia. These associations have been reported in patients who do not fulfill criteria for connective tissue diseases. In this study, we determined the prevalence of antiphospholipid antibodies in 81 women who had had recurrent spontaneous abortion (3 or more fetal losses), in 88 women whose pregnancies were successful, and in 64 women who had never been pregnant. Antiphospholipid antibodies were found in 16% of women with recurrent spontaneous abortion, and at a statistically greater prevalence than in women who had successful pregnancies (7 %) as well as those who had never been pregnant (3%). A false-positive VDRL and IgG anticardiolipin antibodies were more specific for fetal wastage than was either the lupus anticoagulant or IgM anticardiolipin antibodies. Antibodies to negatively charged phospholipids, measured as the biologically false-positive test From the Division of Rheumatic Diseases, Department of Medicine, and Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Connecticut School of Medicine, Farmington. Supported by NIH Multipurpose Arthritis Center grant AR-20621. Ann L. Parke, MBBS (FRCP): Associate Professor, Division of Rheumatic Diseases, Department of Medicine; Daniel Wilson, BA Biol: Research Assistant, Division of Rheumatic Diseases, Department of Medicine; Donald Maier, MD: Associate Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology. Address reprint requests to Ann L. Parke, MBBS (FRCP), University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. Submitted for publication December 26, 1990; accepted in revised form May 17, 1991. Arthritis and Rheumatism, Vol. 34, No. 10 (October 1991) for syphilis (VDRL), lupus anticoagulant (LAC), and anticardiolipin antibodies (aCL), are associated with a clinical syndrome having the predominant features of arterial and venous thrombosis, thrombocytopenia, and recurrent fetal wastage (1-5). The mechanisms for these associations are unknown, but it has been suggested that recurrent fetal wastage is a result of placental infarction (6). Anticardiolipin antibodies have been shown to be a predictor of fetal death in patients with systemic lupus erythematosus (SLE) (7). Some patients with antiphospholipid antibodies do not fulfill criteria for any well-defined connective tissue disease (8), and the significance of the presence of these antibodies in such patients is less certain (9). Previous studies addressing the prevalence of antiphospholipid antibodies in women who experience recurrent spontaneous abortion (RSA) have often lacked a control group and have involved only small numbers of patients (10-12). We designed this prospective study to determine the true prevalence of antiphospholipid antibodies in patients with RSA (3 or more fetal losses) compared with women who had successful pregnancies and with women who have never been pregnant. The latter group was added in an attempt to control for the possibility that pregnancy may induce the production of antiphospholipid antibodies. PATIENTS AND METHODS Two hundred thirty-three women were enrolled into the study: 81 with RSA, 88 with successful pregnancies, and 64 who had never been pregnant. Women with RSA had experienced a t least 3 fetal losses, and the total number of pregnancies for this group was approximately double that for PARKE ET AL 1232 the normal pregnancy group. Women with RSA were recruited from the infertility clinic at the University of Connecticut Health Center and from infertility clinics in the surrounding Hartford area. All consecutive women with RSA were studied, regardless of the results of their gynecologic evaluation. Control subjects were recruited from respondents to advertisements in the local press. Subjects taking any medication known to be associated with the induction of the lupus anticoagulant phenomenon and those taking oral contraceptives were excluded. Each subject completed a questionnaire detailing her full obstetric history, medical history, and current medical symptoms. Subjects with any features suggestive of a connective tissue disease were excluded, regardless of their study group. Blood (15 cc) was drawn from each patient and tested for LAC, VDRL reactivity, and aCL. The presence of a lupus anticoagulant was evaluated by a dilute tissue thromboplastin time using Organon Teknika (West Chester, PA) Simplastin Excel at 3 dilutions. Any ratio greater than 1.3 was taken as a positive result. Each patient also had the prothrombin time and partial thromboplastin time (PTT) measured. Patients found to have a prolonged PTT had a platelet neutralization procedure (13) as a check for the presence of LAC. A VDRL test was performed using antigen provided by the Connecticut state laboratory. A fluorescent treponema1 antibody (FTA) test was performed on all who had positive VDRL results to determine if the VDRL was truly or falsely positive. Anticardiolipin antibodies were detected using an enzyme-linked immunosorbent assay with cardiolipin antigen provided by Sigma (St. Louis, MO). Serum samples were diluted 1:100, run in triplicate, and run against blank control wells. This assay has been standardized using sera provided by St. Thomas’ Hospital (London, UK) and has been part of the Kingston Anti-Phospholipid Antibody Study (14). RESULTS Antiphospholipid antibodies were found in 16% of subjects with RSA, 7% of those with successful pregnancies, and 3% of those who had never been pregnant. These results confirm the findings of our previous small preliminary study, which showed that at least 10% of all subjects with RSA had antiphospholipid antibodies, and that some, especially those in whom no gynecologic cause of their recurrent fetal wastage could be found, had antiphospholipid antibodies and multiple laboratory abnormalities suggestive of subclinical autoimmune disease (15). Using Fisher’s exact test to determine the significance of the individual tests for antiphospholipid antibodies, it was determined that only the VDRL test result reached statistical significance when comparing RSA subjects with the 2 control groups: P = 0.02 versus normal pregnancy controls and P = 0.01 versus never-pregnant controls (Table 1). The prevalence of Table 1. Antiphospholipid antibodies in women with RSA, women with successful pregnancies, and women who have never been pregnant* Antibody test RSA group (n = 81) Successful pregnancy group (n = 88) Neverpregnant group (n = 64) LAC VDRL IgG aCL IgM aCL 4 7-F 6$ 4 4 1 0 2 0 1 0 1 * Values are the number positive. RSA = recurrent spontaneous abortion (3 or more fetal losses); LAC = lupus anticoagulant; aCL = anticardiolipin antibodies (IgG aCL normal <20 units; IgM aCL normal <7 units). t P = 0.02 versus successful pregnancy group and P = 0.01 versus never-pregnant group. $ P = 0.01 versus successful pregnancy group. IgG anticardiolipin was statistically significantly different only when comparing the 2 pregnancy groups (P = 0.01). The differences in results of the LAC test and the IgM aCL test failed to reach statistical significance. These findings suggest that of the current tests for antiphospholipid antibodies, the VDRL and IgG aCL tests appear to be more specific for fetal wastage. It is also important to note that only subjects in the RSA group had positive results on more than one test. Of the 13 RSA group subjects found to have antiphospholipid antibodies, 2 had 3 positive results and 4 had 2 positive results; thus, 46% of the patients with antiphospholipid antibodies had 2 or more positive results. Some of these patients with more than one positive result had the highest aCL levels found in the Table 2. Positive antiphospholipid antibody test results in women with recurrent spontaneous abortion* Patient no. 84 86 79 59 6 15 I&60 65 52 17 55 29 * LAC LAC VDRL IgG aCL IgM aCL Pos. Pos. Pos. Pos. - Pos. Pos. Pos. Pos . Pos . Pos. Pos. - 91 109 56 - - 11 23 - 44 38 60 30 16 - - = lupus anticoagulant; aCL = anticardiolipin antibodies (IgG aCL normal <20 units; IgM aCL normal <7 units). PREVALENCE OF ANTIPHOSPHOLIPID ANTIBODIES 1233 DISCUSSION - - -&_ __ 1: L I ':,rI; , ,, f I'i! N 1I , ,>,a, RSA (81) NORMAL PREGNANCY (88) NEVER PREGNANT 1641 Figure 1. Anticardiolipin antibodies in women with systemic lupus erythematosus (SLE), women with recurrent spontaneous abortion (RSA) (3 or more fetal losses), women with successful pregnancies, and women who have never been pregnant (n values shown in parentheses). Values are given in IgG phospholipid (GPL) units. Bars show the mean ? 2 SD; broken line marks cutoff point for normal results (5 SD from the normal mean). RSA group (Table 2), and repeated testing showed that these positive results were quite constant. The presence of both a positive VDRL and an IgG aCL conferred a relative risk of 4.29 for recurrent spontaneous abortion. Figure 1 compares IgG aCL levels in the 3 groups of study subjects with those in a group of female SLE patients. The data from the SLE patients were collected as part of a previous study and are included to show the similarity in the titers of IgG aCL found in subjects with RSA and in patients with SLE. Only SLE patients and RSA subjects had significantly elevated levels of IgG aCL. The lupus patients were 69 consecutive nonselected female patients who attend the lupus clinic at the University of Connecticut Health Center. All of these patients fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association [ARA]) criteria for SLE (16). The prevalence of antiphospholipid antibodies in women who experience recurrent spontaneous abortion has been studied previously, but many of those studies described small numbers of individuals, and some did not include control groups (9-11,17,18). These studies have produced discrepant results (17,18). In the present study, we have shown that antiphospholipid antibodies are more prevalent in women with RSA than in those who have successful pregnancies or in those who have never been pregnant. It was somewhat surprising that the LAC was not significantly more prevalent in the RSA group than in the 2 control groups, although it has been suggested that lupus anticoagulant is not as sensitive as anticardiolipin antibodies for predicting fetal wastage (7,19). Our test for the lupus anticoagulant (the dilute tissue thromboplastin time) is not one of the most sensitive tests for detecting lupus anticoagulants. Previous studies using kaolin clotting time showed that 8% of normal individuals have a lupus anticoagulant (20), whereas in our study, the test result was positive in only 3.3% of controls (5 of 152). It has been suggested that a biologically falsepositive VDRL result alone is insufficient laboratory evidence for the diagnosis of primary antiphospholipid antibody syndrome (21). A biologically false-positive test for syphilis is one criterion of the ARA revised criteria for the classification of SLE (16). However, patients who eventually develop SLE may have a biologically false-positive VDRL for years before any other markers of connective tissue disease develop (22). Our study shows that a biologically false-positive test for syphilis is a more specific marker for predicting fetal wastage than is the test for lupus anticoagulant. Indeed, we have a young patient whose only laboratory abnormality was a biologically false-positive VDRL. This patient was enrolled into the study because of a history of 3 fetal losses. She subsequently developed a right middle cerebral artery thrombosis at the age of 29, a classic clinical feature of the antiphospholipid antibody syndrome. It is therefore evident that in some cases, a biologically false-positive VDRL may be the only laboratory marker for the antiphospholipid antibody syndrome. Previous studies have suggested that the prevalence of a biologically false-positive test for syphilis (using the rapid plasma reagin [RPR] test) is no different in women experiencing fetal wastage than in women successfully completing pregnancy (21). Other PARKE ET AL 1234 studies are not consistent with these findings (23) but are consistent with the findings of our study, that a biologically false-positive test for syphilis confers significant risk for fetal wastage, especially if IgG aCL are present. There are many reasons for recurrent spontaneous abortion. Some gynecologic causes are easily corrected, but frequently, patients are not fully evaluated for fetal wastage until after they have experienced 3 fetal losses. This study evaluated all women with 3 fetal losses, regardless of their gynecologic findings. Even in these nonselected RSA subjects, there was a statistically significant difference in the prevalence of antiphospholipid antibodies compared with the 2 control groups. Our previous studies support the findings of other investigators and suggest that some women with unexplained RSA, i.e., women in whom no gynecologic cause for fetal wastage can be determined, have antiphospholipid antibodies and that these antibodies may be associated with numerous other laboratory markers suggestive of subclinical autoimmune disease (15,24). It is possible, therefore, that recurrent spontaneous abortion may be an early manifestation of autoimmune disease in some patients. Long-term followup of these women with antiphospholipid antibodies whose primary complaint is fetal wastage is necessary to determine if they remain clinically stable or progress to develop overt connective tissue disease, as has been demonstrated by studies of women with antibodies to various components of the extractable nuclear antigen (25). The relationship between SLE and the primary antiphospholipid antibody syndrome is not clear; however, some patients with the primary antiphospholipid antibody syndrome have close family members who do meet the ARA criteria for SLE (8,261. Several reports have suggested that fetal wastage can be reduced from more than 90% to approximately 30% in women with antiphospholipid antibodies, by using therapies aimed at inhibiting thrombosis and lowering the levels of these antiphospholipid antibodies (3,4). Such claims need to be substantiated by well-controlled, randomized studies. The fact that such studies have not been done are testament to the confusion that surrounds this syndrome. Whether these antibodies are an epiphenomenon associated with an underlying thrombotic diathesis or an early marker of a developing connective tissue disease remains to be determined. 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