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Antiphospholipid antibodies in early repeated abortions: a case-controlled study*
VoL 50, No.4, October 1988
FERTILITY AND STERILITY
Printed in U.S.A.
Copyright" 1988 The American Fertility Society
Antiphospholipid antibodies in early repeated abortions: a case-controlled study* Tiziano Barbui, M.D.t Sergio Cortelazzo, M.D.t Monica Galli, M.D.t Fabio Parazzini, M.D.:j:
Enrico Radici, M.D.§ Edoardo Rossi, M.D. II Guido Finazzi, M.D.t
Ospedali Riuniti, Bergamo, Istituti Clinici di Perfezionamento, and Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy
The relation among lupus anticoagulant (LAC), anticardiolipin antibodies (ACA), and repeated abortions was evaluated in a case-controlled study of 49 women with two or more unexplained spontaneous abortions (cases) compared with 141 control subjects, who had had one or more normal pregnancies and no previous spontaneous abortion. The women were admitted to the same hospital where the cases had been identified for acute conditions other than immunologic neoplastic, gynecologic or cardiovascular. LAC was detected in 7 out of 49 cases (14%, 95% confidence limits 8% to 26%) but in none of the 141 controls. Similarly, ACA were detected in four cases (8%, 95% confidence limits 0.3% to 30%) but no controls. These differences in frequency were statistically significant. These findings confirm that LAC and ACA are associated with a history of repeated abortions in clinically asymptomatic patients for immunologic conditions. Fertil Steril50:589, 1988
Lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA) are immunoglobulins IgG, IgM, or both that bind negatively charged phospholipids. They are properly termed antiphospholipid antibodies. 1 LAC is detected by its prolongation of phospholipid dependent coagulation tests, 2 whereas the presence of circulating ACA is demonstrable by immunoassay. 3 In the last few years, several reports have suggested an association between the presence of LAC and raised ACA levels and the following pathologic states: arterial and venous thrombosis, 1- 4 thromboReceived March 1, 1988; revised and accepted June 20, 1988. *This study was conducted in the framework of the Lombardy Region Health Projects contract 473, and of the CNR (Italian National Research Council) applied projects, "Preventive and Rehabilitative Medicine" contracts 85.00487.56 and 85.00549.56. t Divisione di Ematologia, Ospedali Riuniti. :j: Reprint requests: Fabio Parazzini, M.D., Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy. § Divisione di Ostetricia e Ginecologia, Ospedali Riuniti. II Centro Trasfusionale, Istituti Clinici di Perfezionamento. Vol. 50, No.4, October 1988
cytopenia, 5 livedo reticularis, 6 labile hypertension/ primary pulmonary hypertension, 8 neurologic disease,9 autoimmune disorders, 2•3 and recurrent fetal losses. 10 The clinical associations of these antibodies appear strong, but studies aimed at evaluating their prevalence and the related risks in various clinical situations are still lacking. With regard to the association between antiphospholipid antibodies and recurrent abortion, available data are generally based on small, uncontrolled clinical series, considering together women with and without clinical evidence of other concurrent immunologic disorders and without taking into account whether the fetal loss occurred in the first, second, or third trimester. Thus, we have designed a case-control study to assess the quantitative role of LAC and ACA exposure on the risk of "sine causa" early repeated abortions. MATERIALS AND METHODS
Since 1985, we have been conducting a case-control study on the association between habitual
Barbui et al.
Antiphospholipid antibodies and early abortions
589
abortion and lupus-like anticoagulant. Information on general socioeconomic characteristics and a detailed obstetric and reproductive history (previous full-term pregnancies, voluntary and spontaneous abortions, other reproductive failures such as intrauterine deaths in the third trimester) were collected from women without clinical evidence of systemic lupus erythematosus or other immunologic disorders who had had two or more pregnancies, at least two of which were consecutive unexplained spontaneous abortions (defined after an assessment of their general health, an hysterosalpingogram, a luteal-phase endometrial biopsy, a glucose tolerance test, a hormonal profile [three progesterone and prolactin assays in the luteal phase plus one 3,5,3 triiodothyronine, thyroxine, thyroid-stimulating hormone, and free thyroxine index assay] and the determination of maternal and paternal karyotype from peripheral leukocytes) and admitted between January 1985 and December 1986 to the "Ospedali Riuniti" of Bergamo. A total of 49 subjects (cases) met these criteria (median age 30, range 23 to 40 years). The control subjects were women who had had one or more normal pregnancies without previous spontaneous abortions, admitted to the same hospital where the cases had been identified for acute conditions other than immunologic, neoplastic, gynecologic, or cardiovascular. A total of 141 women (median age 33, range 20 to 43 years) were identified. They were admitted for traumatic conditions, nontraumatic orthopedic disorders (such as disc disorders), surgical conditions (such as acute appendicitis), and other illness such as ear, nose, and throat or teeth disorders. Lupus Anticoagulant Assay
Platelet-poor plasma (PPP) was prepared as previously described11 and immediately stored at -40oC until use. Pooled PPP of 20 normal individuals was used as reference. The presence of the lupus anticoagulant was confirmed when plasma gave a high activated partial thromboplastin time 12 (OD, Raritan, NJ) and Kaolin clotting time 13 not corrected by the addition of normal plasma at a ratio of 1:1. Tissue thromboplastin inhibition testi 4 was carried out by using a commercially available tissue thromboplastin (Simplastin, General Diagnostics, Morris Plains, NJ). The assay results were considered positive when the ratio of the patient's clotting time to the control clotting time was > 1.3. 590
Barbui et al.
Table 1 Distribution of 49 Cases with Unexplained Repeated Spontaneous Abortions and 141 Controls According to Age and Number of Pregnancies, 1983-87 Cases
Age (years) .,;29 30-34 ~35
Number of pregnancies 1 2 ~3
Controls
No.
%
No.
%
18 18 13
37 37 27
56 43 42
40 30 30
17 32
35 65
78 43 20
55 30 14
lgGACA
lgG ACA levels were measured with an enzymelinked immunosorbent assay according to Loizou et al. 15 All serum samples were run with 10 normal and 2 positive controls. Results were considered positive when the values were at least five standard deviations above the mean of normal controls. LAC and ACA were assayed at least 6 months after the last pregnancy. Data Analysis
The difference in frequency of positive LAC and ACA in cases and controls was assessed by Fisher's test.
RESULTS The distribution of cases with recurrent abortion and controls according to age and number of pregnancies is presented in Table 1. LAC was detected in 7 out of 49 cases (14%, 95% confidence limits ranging from 8% to 26%, based on Poisson's approximation), whereas 4 cases (all LAC positive) showed high lgG ACA levels (8%, 95% confidence limits 0.3% to 30%). In none of the 141 controls these antiphospholipid antibodies were detected. These differences in frequency were statistically significant (Table 2). No difference was found between the number of spontaneous abortions in the cases and the frequencyofpositivity of antiphospholipid antibodies (data not presented). Serologic markers consistent with a laboratory diagnosis of systemic lupus erythematosus· (SLE) were detected in two cases (both LAC and ACA positive) who, however, had no clinical signs or
Antiphospholipid antibodies and early abortions
Fertility and Sterility
Table 2 Distribution of 49 Cases with Unexplained Repeated Spontaneous Abortions and 141 Controls According to Lupus Anticoagulant (LAC) and Anticardiolipin Antibodies (ACA) Positivity, 1983-87 Cases
Controls
7 42
141
4c 45
141
LAC" Yes No ACAb Yes No
"Fisher's test LAG= P < 0.001. b Fisher's test ACA = P < 0.001. cAll LAC positive.
symptoms related of overt disease. The laboratory results were negative for SLE in the control group. Considering the role of LAC and ACA in repeated abortions in the absence of systemic lupus erythematosus, we restricted the analysis to the 4 7 SLE-negative cases: the statistically significant association was confirmed (Fisher's test= P < 0.05).
DISCUSSION
The present findings confirm the suggested association between lupus anticoagulant and anticardiolipin antibodies and spontaneous abortions. 10•16 In our series, 14% and 8% of unexplained habitual abortions had positive LAC and ACA, respectively. Selection bias could have slightly inflated these figures. In fact, women with repeated abortions and other clinical problems too could have been preferentially referred to the hospital. However, cases and controls were drawn from the same area, all the identified women entered the study, and no case had a history of major cardiovascular disease (such as myocardial infarction or cerebrovascular episodes) or immunologic tissue disorders. Further, LAC and ACA assays were performed at least 6 months after the last pregnancy~ An association between LAC and repeated pregnancy loss in otherwise totally asymptomatic patients has been recently reported. However, previous papers focused on the role of antiphospholipid antibodies in causing repeated abortions mainly in women with SLE. 10 In our study, ACA and LAC positivity was associated with repeated abortions even in the absence of serologic or clinical evidence of connective tissue disease. No case had a clear diagnosis of systemic lupus erythematosus according to commonly accepted criteria, 17 and only two Vol. 50, No.4, October 1988
had anti -deoxyribonucleic acid antibodies and no other hematologic or clinical disorders. Further, at variance with reported series considering early and late fetal loss together, our study analyzed only women with repeated early abortions. Our findings indicate that antiphospholipid antibodies are a relevant factor not only in late fetal losses but also in repeated abortions and may explain a considerable percentage of "sine causa" miscarriages. No conclusive estimate of relative risk of repeated abortions due to lupus anticoagulant and anticardiolipin antibodies could be made in this study because of the relatively small control group and the absence of LAC-ACA positivity in controls. However, a very high risk is confirmed by the observation that the prevalence oflupus anticoagulant in the general population, based on more than 4,500 tests carried out in the central laboratory of the same hospitals where cases and controls were identified, was 0.8% (4/4,639), an estimate largely comparable with previously published data on a Spanish population. 18 Although these prevalence figures should be considered with caution (age and sex were not taken into account and selection bias can be obviously hypothesized), they indicate that the risk of repeated abortions in women with lupus anticoagulant is several dozen times normal. The pathogenetic mechanism of this clinical event is poorly understood. It has been suggested that these antibodies may react with phospholipid antigen in the placental vessels, resulting in placental infarction and in reduced nutrient transport across the placenta. In addition, there is evidence that plasma containing lupus anticoagulant inhibits the production of prostacyclin by vascular tissue. Since prostacyclins have a physiologic role in pregnancy, their inhibition may have an adverse effect on pregnancy just in the first months. 19 Similarly the hypothetically different role of LAC or ACA in these mechanisms are not known, and both may in fact be merely only a serologic epiphenomenon of more general immunologic disorders. In conclusion, to our knowledge, these results provide the first estimate of prevalence of the antiphospholipid antibodies in habitual aborters and suggest a markedly elevated risk. The clinical implications are clear: the presence of these antiphospholipid antibodies should be sought in women with unexplained fetal loss. Acknowledgments. The authors thank Mrs. Maria Nigro and Mrs. Judy Baggot for editorial assistance.
Barbui et al. Antiphospholipid antibodies and early abortions
591
REFERENCES 1. Harris EN, Gharavi AE, Hughes GR: Anti-phospholipid antibodies. Clin Rheum Dis 11:591, 1985 2. Shapiro SS, Thiagarajan P: Lupus anticoagulants. Prog Hemost Thromb 6:263, 1982 3. Harris EN, Gharavi AE, Boey ML, Patel BM, MackworthYoung CG, Loizou S, Hugues GRV: Anticardiolipin antibodies: Detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 2:1211, 1983 4. Elias M, Eldor A: Thromboembolism in patients with the "lupus"-type circulating anticoagulant. Arch Intern Med 144:510, 1984 5. Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derne G, Hughes GRV: Thrombocytopenia in SLE and related autoimmune disorders: Association with anticardiolipin antibody. Br J Haematol59:227, 1985 6. Cosnes A, Perroud AM, Mathieu A, Jourdain C, Touraine R: Livedo reticularis et accidents vasculaires cerebraux. Ann Dermatol Venereol113:137, 1986 7. Jouquan J, Pennec Y, Mottier D, Youinou P, Cledes J, Leroy JP, Le Menn G: Accelerated hypertension associated with lupus anticoagulant and false-positive VDRL in systemic lupus erythematosus. Arthritis Rheum 29:147,1986 8. Asherson RA, Mackworth-Young CG, Boey ML, Hull RG, Saunders A, Gharavi AE, Hughes GRV: Pulmonary hypertension in systemic lupus erythematosus. Br Med J 287: 1024, 1983 9. Landi G, Calloni MV, Sabbadini GM, Mannucci MP, Candelise L: Recurrent ischemic attacks in two young adults with lupus anticoagulant. Stroke 14:377, 1983
592
Barbui et al.
10. Lubbe WF, Butler WS, Palmer SJ, Liggins GC: Lupus anticoagulant in pregnancy. Br J Obstet Gynaecol91:357, 1984 11. Cortellazzo S, Barbui T, Bassan R, Dini E: Abnormal aggregation and increased size of platelets in myeloproliferative disorders. Thromb Haemost 43:127, 1980 12. Green D, Hougie C, Kazmier FJ, Lechner K, Mannucci PM, Rizza CR, Sultan Y: Report of the working party on acquired inhibitors of coagulation: Studies of the "lupus" anticoagulant. Thromb Haemost 49:144, 1983 13. Exner T, Rickard KA, Kronenberg H: A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol40:143, 1978 14. Schleider MA, Nachman RL, Jaffe EA, Coleman M: A clinical study of the lupus anticoagulant. Blood 48:499, 1976 15. Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN: Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): Standardization and quantitation of results. Clin Exp Immunol 62:738, 1985 16. Lockshin MD, Druzin ML, Goei S, Qamar T, Magid MS, Jovanovic L, Ferenc M: Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Eng! J Med 313:152, 1985 17. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Tala! N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982 18. Duran-Suarez JR: Incidence of circulating anticoagulants in a normal population. Acta Haematol (Basel) 67:217, 1982 19. Feinstein DI: Lupus anticoagulant, thrombosis, and fetal loss. N Eng! J Med 313:1348, 1985
Antiphospholipid antibodies and early abortions
Fertility and Sterility
FERTILITY AND STERILITY
Printed in U.S.A.
Copyright" 1988 The American Fertility Society
Antiphospholipid antibodies in early repeated abortions: a case-controlled study* Tiziano Barbui, M.D.t Sergio Cortelazzo, M.D.t Monica Galli, M.D.t Fabio Parazzini, M.D.:j:
Enrico Radici, M.D.§ Edoardo Rossi, M.D. II Guido Finazzi, M.D.t
Ospedali Riuniti, Bergamo, Istituti Clinici di Perfezionamento, and Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy
The relation among lupus anticoagulant (LAC), anticardiolipin antibodies (ACA), and repeated abortions was evaluated in a case-controlled study of 49 women with two or more unexplained spontaneous abortions (cases) compared with 141 control subjects, who had had one or more normal pregnancies and no previous spontaneous abortion. The women were admitted to the same hospital where the cases had been identified for acute conditions other than immunologic neoplastic, gynecologic or cardiovascular. LAC was detected in 7 out of 49 cases (14%, 95% confidence limits 8% to 26%) but in none of the 141 controls. Similarly, ACA were detected in four cases (8%, 95% confidence limits 0.3% to 30%) but no controls. These differences in frequency were statistically significant. These findings confirm that LAC and ACA are associated with a history of repeated abortions in clinically asymptomatic patients for immunologic conditions. Fertil Steril50:589, 1988
Lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA) are immunoglobulins IgG, IgM, or both that bind negatively charged phospholipids. They are properly termed antiphospholipid antibodies. 1 LAC is detected by its prolongation of phospholipid dependent coagulation tests, 2 whereas the presence of circulating ACA is demonstrable by immunoassay. 3 In the last few years, several reports have suggested an association between the presence of LAC and raised ACA levels and the following pathologic states: arterial and venous thrombosis, 1- 4 thromboReceived March 1, 1988; revised and accepted June 20, 1988. *This study was conducted in the framework of the Lombardy Region Health Projects contract 473, and of the CNR (Italian National Research Council) applied projects, "Preventive and Rehabilitative Medicine" contracts 85.00487.56 and 85.00549.56. t Divisione di Ematologia, Ospedali Riuniti. :j: Reprint requests: Fabio Parazzini, M.D., Istituto di Ricerche Farmacologiche "Mario Negri," Via Eritrea 62, 20157 Milan, Italy. § Divisione di Ostetricia e Ginecologia, Ospedali Riuniti. II Centro Trasfusionale, Istituti Clinici di Perfezionamento. Vol. 50, No.4, October 1988
cytopenia, 5 livedo reticularis, 6 labile hypertension/ primary pulmonary hypertension, 8 neurologic disease,9 autoimmune disorders, 2•3 and recurrent fetal losses. 10 The clinical associations of these antibodies appear strong, but studies aimed at evaluating their prevalence and the related risks in various clinical situations are still lacking. With regard to the association between antiphospholipid antibodies and recurrent abortion, available data are generally based on small, uncontrolled clinical series, considering together women with and without clinical evidence of other concurrent immunologic disorders and without taking into account whether the fetal loss occurred in the first, second, or third trimester. Thus, we have designed a case-control study to assess the quantitative role of LAC and ACA exposure on the risk of "sine causa" early repeated abortions. MATERIALS AND METHODS
Since 1985, we have been conducting a case-control study on the association between habitual
Barbui et al.
Antiphospholipid antibodies and early abortions
589
abortion and lupus-like anticoagulant. Information on general socioeconomic characteristics and a detailed obstetric and reproductive history (previous full-term pregnancies, voluntary and spontaneous abortions, other reproductive failures such as intrauterine deaths in the third trimester) were collected from women without clinical evidence of systemic lupus erythematosus or other immunologic disorders who had had two or more pregnancies, at least two of which were consecutive unexplained spontaneous abortions (defined after an assessment of their general health, an hysterosalpingogram, a luteal-phase endometrial biopsy, a glucose tolerance test, a hormonal profile [three progesterone and prolactin assays in the luteal phase plus one 3,5,3 triiodothyronine, thyroxine, thyroid-stimulating hormone, and free thyroxine index assay] and the determination of maternal and paternal karyotype from peripheral leukocytes) and admitted between January 1985 and December 1986 to the "Ospedali Riuniti" of Bergamo. A total of 49 subjects (cases) met these criteria (median age 30, range 23 to 40 years). The control subjects were women who had had one or more normal pregnancies without previous spontaneous abortions, admitted to the same hospital where the cases had been identified for acute conditions other than immunologic, neoplastic, gynecologic, or cardiovascular. A total of 141 women (median age 33, range 20 to 43 years) were identified. They were admitted for traumatic conditions, nontraumatic orthopedic disorders (such as disc disorders), surgical conditions (such as acute appendicitis), and other illness such as ear, nose, and throat or teeth disorders. Lupus Anticoagulant Assay
Platelet-poor plasma (PPP) was prepared as previously described11 and immediately stored at -40oC until use. Pooled PPP of 20 normal individuals was used as reference. The presence of the lupus anticoagulant was confirmed when plasma gave a high activated partial thromboplastin time 12 (OD, Raritan, NJ) and Kaolin clotting time 13 not corrected by the addition of normal plasma at a ratio of 1:1. Tissue thromboplastin inhibition testi 4 was carried out by using a commercially available tissue thromboplastin (Simplastin, General Diagnostics, Morris Plains, NJ). The assay results were considered positive when the ratio of the patient's clotting time to the control clotting time was > 1.3. 590
Barbui et al.
Table 1 Distribution of 49 Cases with Unexplained Repeated Spontaneous Abortions and 141 Controls According to Age and Number of Pregnancies, 1983-87 Cases
Age (years) .,;29 30-34 ~35
Number of pregnancies 1 2 ~3
Controls
No.
%
No.
%
18 18 13
37 37 27
56 43 42
40 30 30
17 32
35 65
78 43 20
55 30 14
lgGACA
lgG ACA levels were measured with an enzymelinked immunosorbent assay according to Loizou et al. 15 All serum samples were run with 10 normal and 2 positive controls. Results were considered positive when the values were at least five standard deviations above the mean of normal controls. LAC and ACA were assayed at least 6 months after the last pregnancy. Data Analysis
The difference in frequency of positive LAC and ACA in cases and controls was assessed by Fisher's test.
RESULTS The distribution of cases with recurrent abortion and controls according to age and number of pregnancies is presented in Table 1. LAC was detected in 7 out of 49 cases (14%, 95% confidence limits ranging from 8% to 26%, based on Poisson's approximation), whereas 4 cases (all LAC positive) showed high lgG ACA levels (8%, 95% confidence limits 0.3% to 30%). In none of the 141 controls these antiphospholipid antibodies were detected. These differences in frequency were statistically significant (Table 2). No difference was found between the number of spontaneous abortions in the cases and the frequencyofpositivity of antiphospholipid antibodies (data not presented). Serologic markers consistent with a laboratory diagnosis of systemic lupus erythematosus· (SLE) were detected in two cases (both LAC and ACA positive) who, however, had no clinical signs or
Antiphospholipid antibodies and early abortions
Fertility and Sterility
Table 2 Distribution of 49 Cases with Unexplained Repeated Spontaneous Abortions and 141 Controls According to Lupus Anticoagulant (LAC) and Anticardiolipin Antibodies (ACA) Positivity, 1983-87 Cases
Controls
7 42
141
4c 45
141
LAC" Yes No ACAb Yes No
"Fisher's test LAG= P < 0.001. b Fisher's test ACA = P < 0.001. cAll LAC positive.
symptoms related of overt disease. The laboratory results were negative for SLE in the control group. Considering the role of LAC and ACA in repeated abortions in the absence of systemic lupus erythematosus, we restricted the analysis to the 4 7 SLE-negative cases: the statistically significant association was confirmed (Fisher's test= P < 0.05).
DISCUSSION
The present findings confirm the suggested association between lupus anticoagulant and anticardiolipin antibodies and spontaneous abortions. 10•16 In our series, 14% and 8% of unexplained habitual abortions had positive LAC and ACA, respectively. Selection bias could have slightly inflated these figures. In fact, women with repeated abortions and other clinical problems too could have been preferentially referred to the hospital. However, cases and controls were drawn from the same area, all the identified women entered the study, and no case had a history of major cardiovascular disease (such as myocardial infarction or cerebrovascular episodes) or immunologic tissue disorders. Further, LAC and ACA assays were performed at least 6 months after the last pregnancy~ An association between LAC and repeated pregnancy loss in otherwise totally asymptomatic patients has been recently reported. However, previous papers focused on the role of antiphospholipid antibodies in causing repeated abortions mainly in women with SLE. 10 In our study, ACA and LAC positivity was associated with repeated abortions even in the absence of serologic or clinical evidence of connective tissue disease. No case had a clear diagnosis of systemic lupus erythematosus according to commonly accepted criteria, 17 and only two Vol. 50, No.4, October 1988
had anti -deoxyribonucleic acid antibodies and no other hematologic or clinical disorders. Further, at variance with reported series considering early and late fetal loss together, our study analyzed only women with repeated early abortions. Our findings indicate that antiphospholipid antibodies are a relevant factor not only in late fetal losses but also in repeated abortions and may explain a considerable percentage of "sine causa" miscarriages. No conclusive estimate of relative risk of repeated abortions due to lupus anticoagulant and anticardiolipin antibodies could be made in this study because of the relatively small control group and the absence of LAC-ACA positivity in controls. However, a very high risk is confirmed by the observation that the prevalence oflupus anticoagulant in the general population, based on more than 4,500 tests carried out in the central laboratory of the same hospitals where cases and controls were identified, was 0.8% (4/4,639), an estimate largely comparable with previously published data on a Spanish population. 18 Although these prevalence figures should be considered with caution (age and sex were not taken into account and selection bias can be obviously hypothesized), they indicate that the risk of repeated abortions in women with lupus anticoagulant is several dozen times normal. The pathogenetic mechanism of this clinical event is poorly understood. It has been suggested that these antibodies may react with phospholipid antigen in the placental vessels, resulting in placental infarction and in reduced nutrient transport across the placenta. In addition, there is evidence that plasma containing lupus anticoagulant inhibits the production of prostacyclin by vascular tissue. Since prostacyclins have a physiologic role in pregnancy, their inhibition may have an adverse effect on pregnancy just in the first months. 19 Similarly the hypothetically different role of LAC or ACA in these mechanisms are not known, and both may in fact be merely only a serologic epiphenomenon of more general immunologic disorders. In conclusion, to our knowledge, these results provide the first estimate of prevalence of the antiphospholipid antibodies in habitual aborters and suggest a markedly elevated risk. The clinical implications are clear: the presence of these antiphospholipid antibodies should be sought in women with unexplained fetal loss. Acknowledgments. The authors thank Mrs. Maria Nigro and Mrs. Judy Baggot for editorial assistance.
Barbui et al. Antiphospholipid antibodies and early abortions
591
REFERENCES 1. Harris EN, Gharavi AE, Hughes GR: Anti-phospholipid antibodies. Clin Rheum Dis 11:591, 1985 2. Shapiro SS, Thiagarajan P: Lupus anticoagulants. Prog Hemost Thromb 6:263, 1982 3. Harris EN, Gharavi AE, Boey ML, Patel BM, MackworthYoung CG, Loizou S, Hugues GRV: Anticardiolipin antibodies: Detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 2:1211, 1983 4. Elias M, Eldor A: Thromboembolism in patients with the "lupus"-type circulating anticoagulant. Arch Intern Med 144:510, 1984 5. Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derne G, Hughes GRV: Thrombocytopenia in SLE and related autoimmune disorders: Association with anticardiolipin antibody. Br J Haematol59:227, 1985 6. Cosnes A, Perroud AM, Mathieu A, Jourdain C, Touraine R: Livedo reticularis et accidents vasculaires cerebraux. Ann Dermatol Venereol113:137, 1986 7. Jouquan J, Pennec Y, Mottier D, Youinou P, Cledes J, Leroy JP, Le Menn G: Accelerated hypertension associated with lupus anticoagulant and false-positive VDRL in systemic lupus erythematosus. Arthritis Rheum 29:147,1986 8. Asherson RA, Mackworth-Young CG, Boey ML, Hull RG, Saunders A, Gharavi AE, Hughes GRV: Pulmonary hypertension in systemic lupus erythematosus. Br Med J 287: 1024, 1983 9. Landi G, Calloni MV, Sabbadini GM, Mannucci MP, Candelise L: Recurrent ischemic attacks in two young adults with lupus anticoagulant. Stroke 14:377, 1983
592
Barbui et al.
10. Lubbe WF, Butler WS, Palmer SJ, Liggins GC: Lupus anticoagulant in pregnancy. Br J Obstet Gynaecol91:357, 1984 11. Cortellazzo S, Barbui T, Bassan R, Dini E: Abnormal aggregation and increased size of platelets in myeloproliferative disorders. Thromb Haemost 43:127, 1980 12. Green D, Hougie C, Kazmier FJ, Lechner K, Mannucci PM, Rizza CR, Sultan Y: Report of the working party on acquired inhibitors of coagulation: Studies of the "lupus" anticoagulant. Thromb Haemost 49:144, 1983 13. Exner T, Rickard KA, Kronenberg H: A sensitive test demonstrating lupus anticoagulant and its behavioural patterns. Br J Haematol40:143, 1978 14. Schleider MA, Nachman RL, Jaffe EA, Coleman M: A clinical study of the lupus anticoagulant. Blood 48:499, 1976 15. Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN: Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): Standardization and quantitation of results. Clin Exp Immunol 62:738, 1985 16. Lockshin MD, Druzin ML, Goei S, Qamar T, Magid MS, Jovanovic L, Ferenc M: Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Eng! J Med 313:152, 1985 17. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Tala! N, Winchester RJ: The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271, 1982 18. Duran-Suarez JR: Incidence of circulating anticoagulants in a normal population. Acta Haematol (Basel) 67:217, 1982 19. Feinstein DI: Lupus anticoagulant, thrombosis, and fetal loss. N Eng! J Med 313:1348, 1985
Antiphospholipid antibodies and early abortions
Fertility and Sterility