Antiphospholipid syndrome and recurrent miscarriages

Sixty percent of recurrent spontaneous abortions are unexplained. Antiphospholipid syndrome is a multisystem disease with the predominant features of venous and arterial thrombosis, recurrent pregnancy loss, foetal death and the presence of antiphospholipid antibodies. Many epidemiological studies focus on antiphospholipid autoantibodies syndrome (APS) as a cause of recurrent spontaneous abortion (RSA). It is found that 7-25% of RSA would have APS as the main risk factor. 'Association not being synonymous with cause', the proportion of abortions due to the APS is difficult to estimate for several reasons: definition of recurrent abortion is variable, the assays for antiphospholipid antibodies are not well standardised, inclusion of patients in the study group according to the antibodies titre is author dependent. Recent studies suggest association of antiphospholipid antibodies syndrome not only with recurrent abortions but also with infertility. New mechanisms are described by which antiphospholipid antibodies could cause placental thrombosis and infarction, acting directly on the surface anticoagulant expressed on trophoblastic cells. Only lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) assays are sufficiently standardised to be usable in routine. Testing for other antiphospholipid antibodies (aPLs) should remain investigational. Several treatments have been proposed: low doses of aspirin, low or immunosuppressive doses of corticosteroids, and preventive or effective dose of heparin, intravenous immunoglobulin.     

Obstetric antiphospholipid syndrome: an update on pathophysiology and management

Antiphospholipid antibodies (aPLs) are acquired antibodies directed against negatively charged phospholipids, a group of inner and outer cell membrane antigens found in mammals. Obstetric antiphospholipid antibody syndrome (APS) is diagnosed in the presence of certain clinical features in conjunction with positive laboratory findings. Although obstetric APS was originally reported in association with slow progressive thrombosis and infarction in the placenta, it is most often associated with a poor obstetric outcome. In fact, obstetric APS is one of the most commonly identified causes of recurrent pregnancy loss (RPL). Thus obstetric APS is distinguished from APS in other organ systems where the most common manifestation is thrombosis. Several pathophysiological mechanisms of action of aPLs have been described. The most common histopathological finding in early pregnancy loss has been defective endovascular decidual trophoblastic invasion. Treatment with heparin and aspirin is emerging as the therapy of choice, with ～75% of treated women with RPL and aPLs having a successful delivery compared with <50% without treatment. This review highlights the diagnostic challenges of obstetric APS, the obstetric complications associated with APS, proposed pathophysiological mechanisms of APS during pregnancy, and the management of women during and after pregnancy.     

Autoimmunity and pregnancy loss

Clinicians have recognized for several decades that certain autoimmune conditions, such as systemic lupus erythematosus (SLE), are associated with pregnancy loss. During the 1980s, investigations focused attention on fetal wastage in women with antiphospholipid antibodies and the antiphospholipid antibody syndrome (APS) was characterized. Its defining features include fetal wastage in the presence of significant levels of anticardiolipin antibodies. Since that time, interest in other autoimmune diatheses and various specific autoantibodies as possible causes of pregnancy loss has increased. Investigators have attempted to establish an association between recurrent pregnancy loss and the presence of a specific autoantibody or patterns of autoantibodies. Thus far, only modest evidence supports the concept that other autoantibodies are linked to, much less cause, pregnancy loss. In this review, we will define pregnancy loss in its various forms and discuss pregnancy loss in well-characterized autoimmune diseases such as SLE and APS. We will focus on the diagnosis and management of these conditions in women attempting to achieve successful pregnancies. Later we discuss the evidence concerning the less well defined association of antiphospholipid antibodies other than the lupus anticoagulant and anticardiolipin antibodies to recurrent pregnancy loss. We then outline the significance of antinuclear antibodies and antithyroid antibodies pertaining to adverse pregnancy outcome and conclude by summarizing and making some suggestions for further study.     

Antiphospholipid syndrome and pregnancy

The antiphospholipid antibody syndrome (APLS) is multisystem, autoimmune disease, which is characterized by: thrombosis, obstetrics complications and thrombocytopenia. The two most clinically significant antiphospholipid antibodies (APLa) that are associated with recurrent pregnancy loss and thrombosis are anticardiolipin antibodies (ACL) and lupus anticoagulant (LA). The laboratory diagnosis is based on the presence of moderate to high positive ACL and/or LA. The inhibitory effect of antiphospholipid antibodies /APLa/ on trophoblast intercellular fusion, hormone production and invasion may cause pregnancy loss. Once placentation is established their thrombogenic action leads to decreased placental perfusion and subsequent infarction. The APLa--mediated inhibition of trophoblastic invasion and APLa--mediated vasculopathy in the placental bed arteries result in abnormal uterine artery /UA/ Doppler waveforms. The association between APLa and high resistance index /RI/ and/or diastolic notch /DN/ in the Doppler waveforms is high predictive for adverse pregnancy outcome, including pre-eclampsia/eclampsia, intrauterine growth retardation, placental abruption, intrauterine fetal death. Maternal treatment and careful monitoring of fetal well-being are mandatory in the management of these high-risk pregnancies.     

抗磷脂综合征的围产期抗凝治疗

抗磷脂综合征(APS)是一组以弥漫性动静脉血栓形成、病理妊娠和持续性抗磷脂抗体阳性为特征的综合征。APS能增加复发性流产、早产、死产、子痫前期、胎儿生长受限等妊娠并发症的发生率。不利的妊娠结局和妊娠期血栓形成之间有关联。围产期APS的治疗主要是对症治疗、防止再次发生血栓和病理妊娠。低剂量阿司匹林和肝素能改善APS的妊娠结局。     

Testing for antiphospholipid antibodies: problems and solutions

The first aCL test was developed in 1983 and subsequently standardized. Although new and more specific tests have become available, the aCL ELISA and the LA tests are still the first choice to be used in diagnosis of APS. Newer tests such as the anti beta 2 GP1 ELISA and the APhL ELISA Kit (Louisville APL Diagnostics) use somewhat different antigens and likely provide a more specific (and possibly more reliable) diagnosis of APS while retaining good-to-excellent sensitivity. Other tests, such as ELISA for prothrombin antibodies and annexin V antibodies, are still undergoing development and will require standardization and extensive evaluation. We thank Dr Isabel Abreu and Dr Mittermeyer B. Santiago for performing some of the studies reported in this review.     

Antiphospholipid antibodies in high-risk pregnancy

Recently the connection of antiphospholipid antibodies (aPLs) presence with pregnancy loss and complications in pregnancy has been observed APLs related obstetric complications include: miscarriages after 10 weeks, IUGR, intrauterine foetal death, preeclampsia and severe preeclampsia. Our objective was to determine the aPLs prevalence in patients with recurrent pregnancy loss and/or complicated pregnancy. We examined 154 pregnant women aged 19-42 (average of 29.1) with recurrent pregnancy loss, current pregnancy complicated by preeclampsia and severe preeclampsia and/or IUGR, thrombotic episodes, thrombocytopenia or autoimmune disease. In all the patients anticardiolipin antibodies (aCL) were determined at least twice using ELISA and their coagulation system was tested including lupus anticoagulant (LA) test. In justified cases immunological examinations detecting connective tissue systemic diseases were conducted. Increased aCL titre was detected in 54 (34.4%) women. Statistically significant risk of increased aCL titre was observed in patients with autoimmunological diseases (RR = 4.3). Increased, but Statistically insignificant, risk of high aCL titre was observed in patients with venous thrombosis (RR = 2.45) as well as in patients with thrombocytopenia (RR = 2.45). LA prevailed significantly more often in patients with venous thrombosis episodes (RR = 6.33) and with autoimmunological diseases (RR = 17.4). Preterm deliveries were significantly more frequent in pregnant women with increased aCL titre and/or LA. Moreover, in this group foetal death and preterm stillbirth more often occurred. The above mentioned risks increased when aCL and LA coexisted. No relation between increased aPLs and miscarriage frequency was observed. CONCLUSIONS: 1) Increased aPLs titre prevail in multiparas with bad obstetrical anamnesis and with pathological course in present pregnancy, 2) increased aPLs titre prevail in patients with autoimmunological diseases, 3) increased aPLs titre are connected with pregnancy pathology manifested by frequent preterm deliveries and intrauterine foetal deaths.     

Antiphospholipid antibodies and pregnancy loss: a disorder of inflammation

The antiphospholipid syndrome (APS) is a leading cause of miscarriage and maternal and fetal morbidity. APS is characterized by thrombosis and pregnancy loss that occur in the presence of antiphospholipid (aPL) antibodies. Using a mouse model of APS induced by passive transfer of human aPL antibodies, we have shown that complement activation plays an essential and causative role in pregnancy loss and fetal growth restriction, and that blocking activation of the complement cascade rescues pregnancies. Conventional treatment for APS patients is sub-anticoagulant doses of heparin throughout pregnancy. Could heparin prevent pregnancy loss by inhibiting complement? In our experimental model of APS, heparin inhibits activation of complement on trophoblasts in vivo and in vitro, and anticoagulation in and of itself is not sufficient to prevent pregnancy complications. These studies underscore the importance of inflammation in fetal injury associated with aPL antibodies and raise the importance of developing and testing targeted complement inhibitory therapy for patients with APS.     

The obstetric antiphospholipid syndrome

The association of persistent presence of circulating antiphospholipid antibodies and thromboembolic events, (recurrent) pregnancy loss or both is termed antiphospholipid syndrome. Pregnancies in women with the syndrome should be regarded as at high-risk for complications. Optimal management consisting of close follow-up and pharmacological treatment can result in about 70-80% live births. Apart from the laboratory diagnosis of the syndrome and pathophysiology, this review will focus on treatment during pregnancy.     

Antiphospholipid Antibody Syndrome in Pregnancy

Objective: to provide an overview of the clinical significance of antiphospholipid antibodies (APLA) in pregnancy, dealing mainly with the diagnosis and management of patients with this disorder.Data Sources: sources were identified from a MEDLINE search of English language articles published from 1985 to 1995 (Keywords: lupus anticoagulant, anticardiolipin antibodies, antiphospholipid antibodies, and antiphospholipid antibody syndrome). Additional sources were identified from references cited in relevant research articles.Methods of Study Selection: thirty-six articles where selected, including publications that recorded the prevalence of commonly described antiphospholipid antibodies, clinical significance, laboratory testing, and management of pregnant women with this disorder. Almost all articles were based on case series, meta-analysis, and prospective trial. Management protocol was based on the findings and recommendations of prospective trials and clinical reviews.Results: lupus anticoagulant (LA) and anticardiolipin (ACL) antibodies belong to a heterogeneous group of antibodies directed against protein epitopes that form complexes with negatively charged phospholipids. The selected studies were reviewed critically and their conclusions were evaluated; the available literature indicates that these antiphospholipid antibodies are frequently found at low levels in otherwise healthy people. At higher levels, the presence of these antibodies is closely associated with the occurrence of arterial and venous thromboembolism, thrombocytopaenia, fetal loss, and a variety of other conditions in patients with and without systemic lupus erythematosus (SLE). This combination of significant antiphospholipid antibody levels with certain clinical sequelae defines the presence of antiphospholipid antibody syndrome (APLAS).Conclusions: screening for antiphospholipid antibodies in the prenatal population seems unwarranted. If investigations of women at risk for APLAS are positive, close maternal and fetal surveillance are required. Prophylactic treatment might be used in this select group of patients, although optimal therapy has yet to be defined. Even though knowledge of APLAS pathophysiology is limited, it is currently the guide to treatment options. All prenatal patients with APLAS should receive low dose acetylsalicylic acid (ASA) and either heparin or steroids. Heparin is suggested if there is a history of thrombosis or placental infarction, while steroids should be considered if APLAS is secondary to SLE, or if there is previous evidence of inflammation and complement activation. Defining optimal therapy will require a large multicentre prospective trial. A detailed management protocol is proposed.     

Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes

OBJECTIVE: Antiphospholipid syndrome is characterized by recurrent pregnancy loss, thrombosis, and antiphospholipid antibodies. However, some women with clinical features of antiphospholipid syndrome test negative for antiphospholipid antibodies ("antiphospholipid-like syndrome"). Women with antiphospholipid and antiphospholipid-like syndromes have serum immunoglobulin G that harms murine pregnancy, suggesting that the mechanisms of fetal death may be similar in both groups. The objective of our study was to determine whether patients with antiphospholipid and antiphospholipid-like syndromes share pathophysiology by comparing the histology of gestational tissues from these groups. METHODS: Placenta and abortion specimens were obtained from 44 pregnancies in 26 women with antiphospholipid syndrome and 37 pregnancies in 21 women with antiphospholipid-like syndrome. Of these, 16 pregnancies with antiphospholipid syndrome and 8 with antiphospholipid-like syndrome were treated with a variety of medications intended to improve pregnancy outcome. Placentas from 31 elective pregnancy terminations and 40 pregnancies complicated by idiopathic preterm delivery served as an additional control group. Twenty histologic parameters were systematically assessed by a single investigator who was blinded to the clinical status of the specimens. Histopathologic findings were compared among groups using multivariate logistic regression analysis. RESULTS: Antiphospholipid syndrome pregnancies included 15 spontaneous abortions, 13 fetal deaths, and 16 live births. Pregnancies in the antiphospholipid-like syndrome group resulted in 5 spontaneous abortions, 30 fetal deaths, and one live birth. Gestational tissues from antiphospholipid and antiphospholipid-like syndrome pregnancies were similar for every histologic feature tested. Decidua from women with both antiphospholipid and antiphospholipid-like syndromes had more necrosis, acute and chronic inflammation, and vascular thrombus compared to controls. Placental tissue from antiphospholipid and antiphospholipid-like syndrome pregnancies showed more infarction, intravascular fibrin deposition, syncytial knot formation, and fibrosis than controls. Histologic features were variable within groups. There were no histologic differences in tissues from live births and pregnancy losses, or in treated and untreated pregnancies. CONCLUSIONS: Placental histopathology is similar in antiphospholipid and antiphospholipid-like syndrome pregnancies, suggesting that these disorders may share pathophysiology. Histologic findings in women with APS are non-specific and may not differentiate between women with APS and APS-like syndromes.     

Antiphospholipid syndrome: Diagnosis and management in the obstetric patient

Antiphospholipid syndrome (APS) is a rare condition clinically characterized by thrombotic events or pregnancy complications and confirmed by one or more repeatedly positive antiphospholipid antibodies on two or more occasions at least 12 weeks apart. Several factors are thought to have roles in the pathogenesis of adverse obstetric events related to APS, including platelet and endothelial cell activation, complement activation, and ultimate activation of the thrombotic pathway. Despite standard treatment with a heparin agent and low-dose aspirin, 30% of women with definite APS cannot achieve a successful pregnancy outcome. Additional treatment options are still controversial, and prospective trials with appropriate controls are needed to investigate the efficiency of alternative treatments. In this chapter, we discuss diagnostic, clinical, and therapeutic approaches in the treatment of APS syndrome in pregnancy.     

Antiphospohlipid syndrome in obstetrics

Antiphospholipid syndrome is characterised by a variety of clinical and immunological manifestations. The clinical hallmarks of this syndrome are thrombosis and poor obstetric outcomes, including miscarriages, fetal loss and severe pre-eclampsia. The main antiphospholipid antibodies include lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I. The combination of aspirin and heparin is considered the standard of care for women with antiphospholipid syndrome and embryo-fetal losses; however, aspirin in monotherapy may have a place in women with recurrent early miscarriage. A good benefit-risk ratio of low-molecular-weight heparin in pregnancy thrombosis treatment has been reported. Warfarin must be avoided if possible throughout the first trimester of pregnancy. Adequate pregnancy management of women with antiphospholipid syndrome should include co-ordinated medical-obstetrical care, a close follow-up protocol and a good neonatal unit. Close blood pressure control and early detection of proteinuria, together with Doppler studies of the utero-placental circulation should be included in the management protocol.     

妊娠合并抗磷脂综合征13例临床分析

目的探讨妊娠合并抗磷脂综合征患者的孕期治疗与母儿结局。方法回顾性分析北京大学人民医院1990年1月至2013年7月妊娠合并抗磷脂综合征患者的临床资料。结果妊娠期共13例患者符合抗磷脂综合征的诊断。其中,按诊断时间分孕前诊断10例,孕期诊断3例;按类型分原发性抗磷脂综合征12例,继发性抗磷脂综合征1例。13例患者中3次以上胎停育或胎死宫内病史者8例。孕期治疗以小剂量阿司匹林治疗2例,以低分子肝素治疗3例,以小剂量阿司匹林联合强的松治疗3例,以小剂量阿司匹林联合低分子肝素治疗3例,由于血小板减少以糖皮质激素及丙种球蛋白治疗1例,单独丙种球蛋白1例。母儿结局：13例患者均获活产新生儿,围产死亡率0%。足月分娩11例,早产2例,平均体重（2 921.43±1326.6）g。胎儿宫内生长受限2例。重度子痫前期1例,妊娠高血压1例。结论孕期适当的干预治疗可改善妊娠合并抗磷脂综合征患者的妊娠结局,应重视并提高对妊娠期出现的抗磷脂综合征的及时诊断及必要的治疗。     

Treatment outcome in women suffering from recurrent miscarriages and antiphospholipid syndrome

OBJECTIVE: To evaluate the outcomes of treatment in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. MATERIALS AND METHODS: 148 observed women suffering from recurrent abortion with presence of lupus anticoagulant antibodies (LA) and/or high moderate concentration of anticardiolipin antibodies (ACA) have been divided randomly into followed three treated groups: I--56 patients treated by low-dose of acetylsalicylic acid (LDA, 75 mg daily); II--39 patients treated by low molecular weight heparin (applied in dose of 20 g daily); III--53 patients treated by LDA and low molecular weight heparin simultaneously. RESULTS: It has been affirmed that coincidental application of low-dose of acetylsalicylic acid and low molecular weight heparin statistically more often increase the percentage of successful pregnancy in comparison with application of low molecular weight heparin or acetylsalicylic acid alone. In the group where only low-dose of acetylsalicylic acid was applied the success of pregnancy equaled 89.3%, in the group where only low molecular weight heparin was applied the successful pregnancy equaled 81.1% and in the group with acetylsalicylic acid and low molecular weight heparin being applied together the successful pregnancy equaled 92.5%. In has simultaneously been affirmed that the percentage of pregnancy loss is statistically higher in the women suffering from isolated occurrence of lupus anticoagulant antibodies (21.2%) in comparison with the women suffering from occurrence of anticardiolipin antibodies (6.7%) and anticardiolipin antibodies with lupus anticoagulant antibodies simultaneously. CONCLUSION: 1. Simultaneous application of low-doses of acetylsalicylic acid and low molecular weight heparin seems to be the best solution in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. 2. The occurrence of anticardiolipin antibodies in the serum of blood in patients suffering from antiphospholipid syndrome is a better foretelling factor for the future pregnancy outcome than the occurrence of lupus anticoagulant antibodies.     

beta2-Glycoprotein 1 as a marker of antiphospholipid syndrome in women with recurrent pregnancy loss

OBJECTIVE: To determine if beta2-glycoprotein 1 (beta2-GP1) antibodies are a better marker of the antiphospholipid antibody syndrome (APS) in women with recurrent pregnancy loss (RPL). DESIGN: Evaluation and testing of sera from women with RPL. SETTING: A university-affiliated reproductive endocrinology practice. PATIENT(s): 90 women with RPL; 45 women met criteria for APS and 45 women met criteria for RPL without antiphospholipid antibodies (APA). Both groups were of similar age and had a similar history of RPL. INTERVENTION(s): Patient sera were obtained from women with RPL and were tested for APA and beta2-GP1. MAIN OUTCOME MEASURE(s): A standard antiphospholipid antibody assay was employed to detect the presence of immunoglobulin (Ig)G, IgM, and IgA antibodies in serum against cardiolipin, phosphatidyl inositol, phosphatidyl glycerol, phosphatidyl serine, and phosphatidyl ethanolamine. Samples were also assayed with a commercial beta2-GP1 assay for IgG antibodies. RESULT(s): Among the 45 women with APS, 10 (22.2%) had positive IgG antibodies for beta2-GP1. Only 1 woman (2.2%) of 45 was positive for beta2-GP1 among the control group of women with RPL but negative APA. There was no correlation noted among the beta2-GP1-positive patients for a specific phospholipid antibody or isotype. CONCLUSION(s): These data suggest that IgG beta2-GP1 antibodies are less sensitive than antiphospholipid antibodies for the diagnosis of APS.     

Antiphosphatidylethanolamine antibodies in recurrent early pregnancy loss and mid-to-late pregnancy loss

AIM: Associations have been reported between antiphospholipid antibodies (aPL), mainly anticardiolipin antibodies (aCL) and/or the lupus anticoagulant, and recurrent pregnancy losses (RPL). However, relatively few studies describing antiphosphatidylethanolamine antibodies (aPE) have been reported. We describe the prevalence of aPL to both cardiolipin and phosphatidylethanolamine in patients with RPL. METHODS: Patients with recurrent early pregnancy losses (n = 145) and mid-to-late pregnancy loss(es) (n = 26) were screened for aPE and aCL. RESULTS: In patients with recurrent early pregnancy losses, prevalence of immunoglobulin G (IgG) aPE (17.9%, P = 0.001) and immunoglobulin M (IgM) aPE (12.4%, P = 0.01) was significantly higher than in the control group. In patients with mid-to-late pregnancy loss(es), prevalence of IgM aPE (19.2%, P = 0.008) and IgG aCL (23.1%, P = 0.02) was significantly higher than in the control group. CONCLUSION: Our data suggest that aPE may be a risk factor in patients with mid-to-late pregnancy loss(es) as well as recurrent early pregnancy losses.     

妊娠合并抗磷脂综合征的诊治

抗磷脂综合征（antiphospholipid syndrome,APS）是一种由抗磷脂抗体引起的非炎症性自身免疫病。妊娠合并APS易发生早期反复自然流产,孕晚期胎死宫内,胎儿生长受限,血小板减少,子痫前期或子痫以及胎盘功能障碍等不良妊娠结局,严重危及母儿健康。临床上应充分重视妊娠合并APS的诊断和治疗。     

Catastrophic antiphospholipid syndrome in pregnancy,a diagnosis that should not be missed

Catastrophic antiphospholipid syndrome (CAPS) is an accelerated form of the antiphospholipid antibody syndrome resulting in multi-organ ischemia and failure. It is a rare and life-threatening condition that can be easily mistaken with hemolysis elevated liver enzymes low platelets syndrome, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. In order to make a diagnosis, it is required to have multi-organ thrombosis over 1 week affecting at least three organs or systems, and to have positive antiphospholipid antibody on two occasions (6 weeks apart), and histopathologic confirmation of small vessel occlusion. However, due to similarities in clinical and laboratory findings between CAPS and some other obstetric complications, potential misdiagnosis or delay in diagnosis are common, increasing the risk of adverse maternal and perinatal outcomes. In this review we summarized information presented in previous studies, focusing on CAPS related to pregnancy. We reviewed diagnostic criteria, differential diagnosis, and common presentation ranging from malaise, abdominal pain, dyspnea, hypertension, to altered mental status and seizures. We also discussed management in pregnancy and included a detailed algorithm with steps to take. Of note, the most significant reduction in mortality was seen in patients receiving triple therapy which will be discussed in this review.