Anti-phosphatidylserine, anti-cardiolipin, anti-β2 glycoprotein I and anti-prothrombin antibodies in recurrent miscarriage at 8–12 gestational weeks

Abstract

Objective

To investigate the association of antibodies to β2-glycoprotein I (anti-β2GPI), cardiolipin (ACA), phosphatidylserine (anti-PS) and prothrombin (anti-PT) with recurrent spontaneous miscarriage (RSM).

Study design

Case–control study involving 277 RSM cases and 288 controls: autoantibody levels were measured by ELISA. Differences between cases and controls were analyzed by nonparametric Mann–Whitney test, and logistic regression was used in analyzing the association of autoantibodies with RSM.

Results

Anti-PS IgG, ACA IgM and IgG, and anti-PT IgM were significantly associated with RSM risk, and differential antibody association was noted according to BMI and primary and secondary RSM. Higher prevalence of elevated anti-PS IgG was seen in cases, with the strongest risk above the 99th percentile. For ACA IgM, 28 cases (10.1%) and 5 controls (1.7%) were positive, with increasing OR for increasing cut-off points, which was significant at antibody titers >99th percentile. For ACA IgG, 101 cases (36.5%) and 13 controls (4.5%) were positive, with graded increase in OR for increasing cut-off points, which was significant at titers >90th percentile (maximal at titers >99th percentile). For anti-PT, 23 cases (12.0%) and 9 controls (6.1%) were positive, with increased OR at titers >90th percentile. Regression analyses confirmed the independent association of anti-PS IgG, ACA IgM and IgG with RSM, and significant RSM risk was associated with high anti-PS IgG (P < 0.001) and ACA IgM (P < 0.001) titers, and a dose-dependent increase in RSM risk was seen with progressively increased ACA IgG titers. No significant association existed between anti-PT IgM and RSM.

Conclusion

Elevated ACA IgM and IgG, and anti-PS IgG antibodies are positively associated with RSM.

Introduction

Anti-phospholipid antibodies (aPA) are a heterogeneous group of autoantibodies which target membrane phospholipids, such as phosphatidylserine (PS) and cardiolipin (CL), and phospholipid-binding proteins including β2-glycoprotein-I (β2GPI) and prothrombin (PT), among others [1], [2]. The presence of aPA is associated with characteristic manifestations, collectively grouped as the anti-phospholipid syndrome (APS) [1], a systemic auto-immune disease associated with recurrent arterial and venous thromboembolism and/or obstetric complications [1], [3]. The diagnosis of APS is based on laboratory and clinical findings [4]. The former include positivity for ≥1 aPA: lupus anticoagulant (LAC), anti-CL antibodies (ACA) or anti-β2GPI, while the latter include vascular thrombosis and/or pregnancy complications, including recurrent spontaneous miscarriage (RSM) [2], [3].

RSM is a reproductive problem with poorly understood etiology [5], which affects up to 1–2% of otherwise healthy women [5]. It is multifactorial in nature, and several factors are proposed to contribute to its pathogenesis. These include acquired/lifestyle factors (smoking, diet, obesity, oral contraceptive use) [6], [7], [8]; anatomic factors; endocrine factors; inherited predisposition (positive family history, skewed X-chromosome inactivation, HLA G); coagulation abnormalities such as protein S, protein C, or anti-thrombin III deficiencies [9]; and immunologic factors (altered cytokine production and APS) [10], [11], [12].

Previous studies have described an association between aPA and RSM [13], [14], [15], [16], with respect to anti-PS [16], [17], ACA [15], [16], anti-β2GPI [15], [16], [18], and anti-PT [17]. Other studies failed to demonstrate an association between anti-PS [18], [19], [20], [21], ACA [19], [20], and anti-β2GPI [16], [19], [20] and increased risk of RSM, while others suggested that anti-phosphatidylethanolamine, but not other aPA, is predictive of increased RSM risk [20]. Given the low number of subjects in most of these studies, their findings must be interpreted with caution. In our study, we examined the association of anti-PS, ACA, anti-β2GPI and anti-PT with RSM in 277 RSM cases and 288 age-matched multiparous control women.