Obstetric Antiphospholipid Syndrome: Insights on the Diagnosis, Treatment, and Hot Issues

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder associated with various pathological pregnancies, such as recurrent miscarriage, stillbirth, severe pre-eclampsia and severe placental insufficiency. The persistent presence of antiphospholipid antibodies (aPLs) is the most important laboratory characteristic of OAPS. OAPS severely affects the reproductive health of women of childbearing age in China. Reports indicate that approximately 9.6% stillbirths, 11.5% severe pre-eclampsia, and 54% recurrent miscarriages are associated with OAPS or aPLs. However, the pathogenesis of OAPS remains unclear. Previously, thrombosis at the maternal-fetal interface (MFI) was considered the main mechanism of OAPS-related pathological pregnancies. Consequently, the use of low molecular weight heparin and aspirin throughout pregnancy was recommended to improve outcomes in OAPS patient. In recent years, many studies have found that thrombosis in MFI is uncommon, but various inflammatory factors are significantly increased in the MFI of OAPS patients. Based on these findings, some clinicians have started using anti-inflammatory treatments for OAPS, which have preliminarily improved the pregnancy outcomes. Nevertheless, there is no consensus on these second-line treatments of OAPS. Another troubling issue is the clinical diagnosis of OAPS. Similar to other autoimmune diseases, there are only classification criteria for OAPS, and clinical diagnosis of OAPS depends on the clinicians' experience. The present classification criteria of OAPS were established for clinical and basic research purposes, not for patient clinical management. In clinical practice, many patients with both positive aPLs and pathological pregnancy histories do not meet the strict OAPS criteria. This has led to widespread issues of incorrect diagnosis and treatment. Timely and accurate diagnosis of OAPS is crucial for effective treatment. In this article, we reviewed the epidemiological research progress on OAPS and summarized its classification principles, including: 1) the persistent presence of aPLs in circulation; 2) manifestations of OAPS, excluding other possible causes. For the first point, accurate assessment of aPLs is crucial; for the latter, previous studies regarded only placenta-related pregnancy complications as characteristic manifestations of OAPS. However, recent studies have indicated that adverse pregnancy outcomes related to trophoblast damage, such as recurrent miscarriage and stillbirth, also need to be considered in OAPS. We also discussed several key issues in the diagnosis and treatment of OAPS. First, we addressed the definition of non-standard OAPS and offered our opinion on defining non-standard OAPS within the framework of the 2023 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) APS criteria. Then, we discussed the advantages and disadvantages of different aPL testing methods, emphasizing that harmonizing results across platforms and establishing specific reference values are keys to resolving controversies in aPL testing results. We also introduced the application of non-criteria aPLs, especially anti-phosphatidylserine/prothrombin antibody (aPS/PT) and anti-β2 glycoprotein Ⅰ domain Ⅰ antibody (aβ2GPⅠDⅠ). Additionally, we discussed aPL-based OAPS risk classification strategies. Finally, we proposed potential treatment methods for refractory OAPS. The goal is to provide a reference for the clinical management of OAPS.