Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by clinical manifestations, including thrombotic events and/or obstetric complications, and it is accompanied by the presence of antiphospholipid antibodies (aPLs) (1). The 2006 Sydney International Consensus provides an extensive overview of adverse obstetric outcomes linked to recurrent first-trimester miscarriage, fetal loss, stillbirth, early and severe pre-eclampsia, or preterm birth (before 34 weeks of gestation) (2). In patients with a history of thrombosis, these complications are classified as obstetric APS (OAPS) and are primarily attributed to placental dysfunction (3). This is partly due to the detrimental effects of aPLs throughout the stages from implantation and placentation to delivery (4).

Recent research has indicated that placental inflammatory responses, including complement activation and subsequent endothelial damage in patients with OAPS, may impair the invasive function of placental trophoblasts (5). Additionally, the formation of neutrophil extracellular traps (6), release of interleukin-8 (7), upregulation of the target of rapamycin complex on endothelial cells (8), and an imbalance in angiogenic factors (9) do not culminate in thrombosis. While the administration of glucocorticoids appears promising in mitigating inflammatory response (10), the current gold standard in clinical treatment remains the combination of low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH) (11). This treatment regimen has significantly increased the rate of successful deliveries in patients with OAPS; however, potential maternal placental pathology and effects on the offspring cannot be ruled out, due to the persistence of aPLs.

However, whether this treatment fully normalizes the course of pregnancy and eliminates risks for both the mother and neonate remains a subject of inquiry. A focus solely on live birth may overlook significant maternal and neonatal morbidity that persists despite treatment. For instance, some reports suggest an association between OAPS and adverse outcomes such as fetal growth restriction, preterm birth, and placental pathology even in treated pregnancies (9). Furthermore, a notable proportion of patients with clinical features highly suggestive of OAPS tested negative for the criteria OAPS (C-OAPS), a category often referred to as seronegative or non-criteria OAPS (NC-OAPS) (12), presenting a diagnostic and management challenge. According to the 2023 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria for antiphospholipid syndrome, these patients are likely to be classified into an under-recognized group. Although the new standards significantly enhance specificity and introduce a more detailed clinical and laboratory stratification weighting system, their strict inclusion criteria—requiring a cumulative score of at least 3 in both clinical and laboratory domains—may result in the exclusion of some patients with typical obstetric clinical manifestations whose laboratory tests do not meet the threshold from the classification (13).

Given these considerations, this study was conducted to systematically evaluate the pregnancy characteristics and outcomes in a cohort of OAPS patients who achieved a live birth following standard treatment. We aimed to retrospectively analyze and compare basic maternal characteristics, laboratory parameters, and perinatal outcomes between these treated OAPS patients and matched healthy controls. The objective of this study was to assess the potential persistent effects of OAPS on pregnancy and to provide a detailed clinical profile that may inform future management strategies and research directions.

A total of 1,024 women were included in this study: 256 OAPS cases and 768 healthy controls (HCs). The OAPS group was divided into 166 patients in the typical OAPS group and 90 patients in the atypical NC-OAPS group, according to the Sydney Classification Criteria. All of the participating women had delivered successfully following treatment during the most recent pregnancy in the hospital. We also randomly selected 768 healthy pregnant women admitted to the obstetrics department during the same period, who were matched at a 1:3 ratio to the OAPS group based on the time of delivery and age.

Compared to the HC group, the most salient clinical manifestation in the OAPS group was pathological pregnancy, particularly a history of preterm labor, stillbirth, and miscarriages, all of which were significantly more frequent than in the HC group. The underlying causes of pathological pregnancy may involve activating endothelial cells, monocytes, and platelets by aPLs, leading to a procoagulant state. This process may be further exacerbated by the direct action of the placental trophoblast, resulting in trophoblast cell destruction and apoptosis. This process can lead to a cascade of adverse outcomes, including reduction of hormones such as human chorionic gonadotropin, diminished capacity of trophoblast cells to invade and implant in the uterus, and suppression of trophoblast cell proliferation. These alterations may hinder the embryo’s attachment to the uterus and progression of the pregnancy (16). Although the standard treatment regimen of low-dose aspirin combined with low-molecular-weight heparin significantly improved the live birth rate in patients with OAPS (17), our research found that, even after standard treatment, OAPS mothers and fetuses still face a series of significant residual risks, including a hypercoagulable state of the mother, unique placental pathological changes, and adverse neonatal outcomes. This finding indicates that the current therapy has limitations in correcting the fundamental pathophysiological mechanisms of OAPS, highlighting the urgency of assessing its impact on pregnancy quality beyond the live birth rate.

Key laboratory findings from this study delineate distinct hematological and biochemical profiles in OAPS patients compared to healthy controls. The OAPS group exhibited a significantly higher incidence of abnormalities in activated partial thromboplastin time (APTT) and prothrombin time (PT), yet a lower incidence of abnormal prothrombin activity (PTA). This apparent prolonged conventional coagulation time alongside a lower rate of reduced PTA likely reflects the therapeutic effect of low-molecular-weight heparin (LMWH) (18). The observed alterations in these coagulation parameters are consistent with the documented pharmacologic profile of LMWH calcium, as previously reported (19). LMWH, primarily through the inhibition of factor Xa, can induce a modest prolongation of APTT and PT, representing a predictable and intended anticoagulant state rather than a marker of bleeding risk (20). Concurrently, the significant elevations in the mean values and abnormality rates of D-dimer and fibrin degradation products (FDP) in the OAPS group provide direct laboratory evidence of ongoing fibrin formation and degradation, indicating a persistent hypercoagulable state with secondary fibrinolysis. Furthermore, the observed increase in total bile acid (TBA) levels suggests the presence of intrahepatic cholestasis in a subset of patients, which may compound obstetric risks. The higher incidence of red blood cell (RBC) and hemoglobin (HB) abnormalities is consistent with the greater prevalence of anemia observed in the OAPS cohort, implying a potential impact of the disease on hematopoiesis or erythrocyte stability. Collectively, these laboratory findings define a distinct hematological profile in OAPS, characterized by a treated prothrombotic phenotype and associated systemic involvement, underscoring the need for comprehensive monitoring.

The observed lower incidence of intrauterine distress in the OAPS group can be logically explained by its standardized clinical management. The implementation of intensified antenatal surveillance in these high-risk pregnancies facilitated timely detection of complications, leading to earlier elective delivery and thereby reducing the incidence of frank distress. In addition, a comprehensive review of the extant literature indicates that the effects of OAPS on fetal and neonatal outcomes primarily encompass birth weight, fetal death, preterm delivery, FGR, and fetal acidosis (21). In this study, the birth weight of neonates in the OAPS group was significantly lower than that in the HC group. However, there was no statistically significant difference in the proportion of low birth weight. Additionally, the OAPS group exhibited a higher proportion of preterm births than the HC group. Previous research found that 127 patients with OAPS were at risk of preterm labor, and the incidence of “spontaneous preterm labor” was 16.5% (22). Consequently, the occurrence of preterm labor in pregnancies affected by OAPS encompasses two distinct categories: (1) medically indicated preterm labor associated with pre-eclampsia or fetal factors and (2) a latent predisposition to preterm labor. The underlying predisposition to preterm labor is well-documented. Furthermore, the study noted that neonatal infections and hyperbilirubinemia were more prevalent in the OAPS group than in the HC group. Previous research has indicated that preterm infants are more susceptible to diseases and hyperbilirubinemia compared to term infants (23). To further investigate this observation, a subgroup analysis was conducted. Crucially, the subgroup analysis confirmed that this elevated risk remained significant even after accounting for prematurity, as the infection rate was also considerably higher in term neonates from the OAPS group. This suggests that the predisposition to infection is not solely a consequence of preterm birth but is intrinsically linked to the OAPS condition itself. We propose that the altered intrauterine environment in OAPS—characterized by a persistent placental inflammatory state and immune dysregulation (24)—may impair fetal immune system programming or function, increasing susceptibility to postnatal infection. These findings underscore that the ramifications of OAPS transcend the endpoint of live birth, warranting a shift in clinical focus from merely “securing fetal survival” to “safeguarding neonatal health.” This necessitates closer collaboration between obstetricians and neonatologists to optimize perinatal management from pregnancy into the postpartum period.

Given these persistent challenges in management, the recent introduction of the ACR/EULAR 2023 classification criteria for APS marks a significant step forward. These updated criteria refine the original Sydney standards by incorporating a weighted scoring system and expanded serological markers, thereby enhancing specificity for research (13). However, it is important to distinguish between classification criteria, designed to ensure cohort homogeneity, and the broader clinical spectrum of the disease. The stringent nature of such criteria may inevitably exclude some patients with highly suggestive clinical presentations—a group often identified as NC-OAPS. Our study found that there was no significant difference between the NC-OAPS group and the C-OAPS group, not only in obstetric history but also in terms of maternal complications, comorbidities, and outcomes (Tables 2–4). This key finding demonstrates that patients in the NC-OAPS group experience a clinical burden of disease comparable to that of patients who meet the formal criteria. By intentionally including NC-OAPS patients, our study aims to characterize the outcomes and pathophysiological features across the entire clinical phenotype managed as OAPS, thus providing insights that may inform future diagnostic and therapeutic strategies.

For patients diagnosed with OAPS, particularly those with recurrent pregnancy loss, combination therapy with low-dose aspirin and low-molecular-weight heparin remains the cornerstone of management and is effective in improving live birth rates (25). However, our findings underscore that this standard regimen does not fully eliminate significant residual risks, including maternal hypercoagulability, placental pathology, and adverse neonatal outcomes. Therefore, meticulous monitoring for maternal and neonatal complications is imperative, and management must be highly individualized. Future care for OAPS necessitates a paradigm shift, extending beyond anticoagulation. A proactive, multidisciplinary approach—involving obstetricians, rheumatologists, and often neonatologists—is essential throughout the pre-pregnancy, antenatal, and postpartum periods. The overarching goal must transition from merely “ensuring survival” to comprehensively “optimizing health.” Achieving this requires a dual strategy: advancing interventions to target fundamental pathophysiological mechanisms earlier in the disease course and deepening clinical vigilance toward placental function and long-term neonatal wellbeing. This redefined focus should guide the next generation of research and clinical innovation in OAPS.

This study, focusing on OAPS patients who achieved successful delivery, shows that despite standard treatment with low-dose aspirin and LMWH, these women continue to exhibit a distinct and complex clinical profile. Key findings include a persistent maternal hypercoagulable state, evidenced by elevated D-dimer and FDP and an increased risk of adverse neonatal outcomes, such as lower birth weight, preterm delivery, and a heightened susceptibility to neonatal infection and hyperbilirubinemia. These findings collectively indicate that the central clinical challenge in OAPS is shifting from achieving live birth to safeguarding the quality of pregnancy and neonatal health. Consequently, a paradigm shift in management is warranted—extending beyond current anticoagulation strategies to embrace a proactive, multidisciplinary approach focused on pre-pregnancy counseling, intensified placental and fetal surveillance, and long-term neonatal care, with the ultimate goal of optimizing overall maternal and offspring health outcomes.

Several limitations of this study should be acknowledged. First, its retrospective and single-center design may introduce selection bias and limit the generalizability of the findings. The sample size, though substantial, may still be insufficient to detect significant differences in rarer complications. Second, the study population consisted of patients who ultimately achieved a successful delivery, which may not fully represent the entire spectrum of OAPS severity, particularly those with the majority of refractory cases. Furthermore, the absence of detailed placental histopathological analysis for all participants limits our ability to correlate clinical outcomes with specific underlying placental lesions. Third, the subgroup analyses based on antibody profiles were limited by small sample sizes, which may have obscured statistically significant differences and precluded a more robust comparison. Finally, potential unmeasured confounding factors, despite our matching efforts, could have influenced the observed associations. Future prospective, multi-center studies with larger cohorts and systematic placental examination are needed to validate these findings and further elucidate the pathophysiological mechanisms linking OAPS to adverse outcomes.