Obstetric antiphospholipid syndrome (OAPS) manifests as an autoimmune disorder marked by pregnancy complications and the enduring existence of antiphospholipid antibodies (aPLs) [1]. Among aPLs, lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-$\beta$2-glycoprotein I antibodies (a$\beta$2GPI) are widely detected and included in antiphospholipid syndrome (APS) classification criteria [2]. APS predominantly affects women, with a female-to-male ratio of 3.5:1 in primary APS and 7:1 in secondary APS. The overall frequency of antiphospholipid antibodies (aPLs) associated with pregnancy morbidity was approximately 6% [3].

The reproductive challenges associated with OAPS encompass recurrent miscarriage, fetal demise, and premature birth resulting from conditions such as preeclampsia, eclampsia, or intrauterine growth restriction [2]. Treatment with low-dose aspirin (LDA) and/or low molecular weight heparin (LMWH) has improved the pregnancy outcomes of OAPS [2, 4, 5]. However, this treatment still fails in approximately 20% of OAPS patients [6, 7]. The incidence of adverse pregnancy outcomes (APOs) in OAPS is significantly higher than in healthy pregnant women [8]. Additional treatments to improve pregnancy outcomes include hydroxychloroquine (HCQ), low-dose prednisolone, and intravenous immunoglobulins (IVIG) [9], pravastatin [10], eculizumab [11], and certolizumab [12].

Identifying the risk factors related to APOs before or at the start of gestation could be a vital step for managing APS to prevent obstetric complications and establish optimal therapies. A systematic review and meta-analysis revealed that prior thrombosis, aPL profiles with double or triple positivity, and the presence of lupus anticoagulant are the foremost predictors of adverse pregnancy outcomes (APOs) [13]. However, the differences in the diagnostic criteria of APS and definition of APOs make the predictors vary from study to study. In order to predict pregnancy outcome and to provide obstetric management references, we investigated the risk factors for APOs in OAPS patients in a tertiary center.

In this study, we demonstrated that underlying autoimmune disease are positively associated with APOs. The use of LMWH and LMWH + LDA are negatively associated with APOs. Underlying autoimmune disease is a risk factor for APOs. Regular outpatient follow-up at the Department of Rheumatology and Immunology could be a protective factor for APOs.

Several studies have substantiated that expectant women with APS face a heightened risk of pregnancy complications [2, 23, 24]. These APS patients required careful risk assessment and medical management [9]. The first step in evaluating pregnant women with APS is to accurately determine their aPLs antibody status using standardized laboratory methods and threshold levels. Individuals with aPLs should be risk-stratified based on the presence of a high-risk aPLs profile, thrombosis and/or an adverse maternal history, and the coexistence of other autoimmune disease, such as systemic lupus erythematosus (SLE) [5, 9, 25]. Moreover, the evaluation of maternal-fetal risk should consider factors such as maternal age, obstetric history, the standard of medical care, and relevant associated risk factors [26].

Numerous previous studies have demonstrated that the presence of SLE and/or other autoimmune disease are risk factors for APOs [6, 7, 15, 20, 22, 27, 28]. Consistent with prior studies, our study found that underlying autoimmune disease was a risk factor for APOs in APS patients [7, 28]. The underlying autoimmune disease also has potential maternal and fetal complications. Controlling underlying autoimmune disease with certain medications is also an important part of treatment. Therefore, a detailed patient history, physical examination, and laboratory tests of autoantibodies should be performed before pregnancy.

APLs positivity was strongly associated with APOs in APS patients. In our study, the proportion of LA positivity was significantly higher in APO patients. In the PROMISSE (predictors of pregnancy outcome: biomarker in antiphospholipid antibody syndrome and systemic lupus erythematosus) study, 39% of LA-positive women had APOs, and the study also demonstrated that LA positive women were at the highest risk for APOs, and in the absence of LA, aCL, and a$\beta$2GPI did not predict APO [29]. LA positivity on its own is a high-risk factor in OAPS. Triple positivity for aPL is one of the described risk factors for an adverse obstetric outcome. Nevertheless, we did not observe a similar outcome, possibly due to the limited number of patients exhibiting triple positivity for aPL. We intend to enhance our research by increasing the sample size for future investigations.

Medical intervention for pregnant women with APS must be highlighted. Standardized treatment is important for pregnancy outcomes of APS patients and significantly impacts neonatal outcomes. In our study, APS patients taking LMWH alone or in combination with LDA were more likely to be APO-free. Early combined therapy with aspirin and LMWH could improve pregnancy outcomes and increase live birth rates [30]. As such, they are recommended as a standardized treatment for OAPS [9, 31, 32, 33, 34]. However, some people believe that the combination of aspirin and LMWH is not suitable for all pregnant women with antiphospholipid syndrome. Van Hoorn’s [35] study of preeclampsia and/or fetal growth restriction in pregnant women with APS who delivered before 34 weeks of gestation found that there was no significant difference in the effects of restricting aspirin alone or aspirin combined with LMWH, which was associated with gestational hypertensive disorders and/or fetal growth. There is currently no unified conclusion on how to treat pregnancies with antiphospholipid syndrome, which could be related to population characteristics and the specificity of the pathogenesis.

This study found an encouraging result: a significantly higher proportion of regular visits to the Departments of Rheumatology and Immunology in APS patients without APOs than in the control group. This was consistent with another Chinese APS cohort, and regular outpatient follow-up at the Department of Rheumatology was a protective factor for APOs [36]. It is recommended to check before pregnancy and during the first labor examination in the first trimester [37]. In the second trimester of pregnancy, abnormal uterine artery Doppler evaluation is highly predictive of adverse perinatal outcomes [38]. For mothers suffering from APS, regular visits allow rheumatologists to quickly identify potential complications, conduct appropriate treatments, and improve pregnancy outcomes.

This study also had certain limitations. First, it was a single-center retrospective cohort study, which had an admission bias. Second, only Chinese patients are included, which does not allow the results to be generalized. Third, the sample size may influence the results because few patients present some variables. However, we included a relatively large number of OAPS patients, which could also reflect the pregnancy outcomes and influencing factors of Chinese APS patients and provide a reference for further in-depth research.

Underlying autoimmune disease are associated with APOs. The use of LMWH and LMWH + LDA are negatively associated with APOs. Underlying autoimmune disease is a risk factor for APOs. Regular outpatient follow-up at the Department of Rheumatology and Immunology could be a protective factor for APOs.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

YKH, LH, JYJ, ZYS, LL, XWZ and CL conceived and designed the project. YKH and LH collected and input the clinical and laboratory data. YKH completed the statistical analyses. YKH and CL conducted table and figure predations. YKH and CL wrote the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript. All authors discussed the results and contributed to the final manuscript. All authors read and approved the final manuscript.

This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Peking University People’s Hospital (PKUPH; 2019PHB252). All patients signed written informed consents before participation in this study.

We would like to thank all the rheumatologists, gynecologists and patients that participated in this study.

This study was supported by the research project from the National Natural Science Foundation of China (No. 32200734, No. 2101000418); and Natural Science Foundation of Beijing Municipality (Grant No. 7192211), China International Medical Foundation (Grant No. Z-2018-40-2101) and the Peking University People’s Hospital Research and Development Funds Project (RDY2021-10; RDL2022-36).

The authors declare no conflict of interest.