Abstract
Background
Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age and is often associated with adverse pregnancy outcomes (APOs). Antiphospholipid antibodies (aPLs) are known risk factors for APOs in the general population, and the prevalence of aPLs is higher in patients with SLE than healthy women.
Objective
This study aimed to investigate the impacts of aPLs and different aPLs profiles on pregnancy outcomes in patients with SLE.
Study design
This study analysed data from a single-centre SLE cohort in China. aPLs profiles, including anticardiolipin antibodies (aCL) IgG/IgM, anti-β2 glycoprotein I (anti-β2GPI) antibodies IgG/IgM and lupus anticoagulant (LA), were measured. APOs were defined as prefetal death, fetal death, pre-eclampsia with severe features occurring before 34 weeks of gestation and placental insufficiency with severe features occurring before 34 weeks of gestation.
Results
The study comprised 441 singleton pregnancies occurring in 410 patients with SLE and 78 (17.9%) were positive for aPLs. Seventy-one (16.1%) patients developed APOs and 391 (88.7%) patients succeeded in giving a live birth. Patients with positive aPLs experienced APOs more frequently (29.5% vs 13.2%), with an OR of 2.56 (95% CI 1.38 to 4.65, p=0.002). aPLs were also associated with higher risks of fetal death (OR 3.87, 95% CI 1.17 to 12.19, p=0.021) and failure of live birth (OR 2.54, 95% CI 1.22 to 5.15, p=0.011). Analysis on the aPLs profiles revealed that aCL IgG (OR 3.02, 95% CI 1.44 to 6.15, p=0.003), anti-β2GPI IgG antibodies (OR 2.60, 95% CI 1.13 to 5.72, p=0.020) and LA (OR 2.85, 95% CI 1.44 to 5.56, p=0.002) increased the risks of APOs significantly, but aCL IgM and anti-β2GPI IgM antibodies did not. Further analysis demonstrated that LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies was the highest-risk profile, increasing the incidences of APOs with an OR of 3.98 (95% CI 1.66 to 9.35, p=0.002), while the other combinations of aPLs positivity did not (OR 1.82, 95% CI 0.81 to 3.81, p=0.128).
Conclusion
This study demonstrated the adverse effects of aPLs in patients with SLE regarding the pregnancy outcomes, and different aPLs profiles displayed distinct impacts. This highlights the importance of risk stratification when managing pregnancy among patients with SLE, putting more focus on those with positive aPLs, especially those positive for LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies.
Keywords: Systemic Lupus Erythematosus; Antiphospholipid Antibodies; Outcome Assessment, Health Care
WHAT IS ALREADY KNOWN ON THIS TOPIC
Antiphospholipid antibodies (aPLs) are established risk factors for adverse pregnancy outcomes (APOs) in the general population and are more prevalent in patients with systemic lupus erythematosus (SLE); however, the specific impact of different aPLs profiles on pregnancy outcomes in patients with SLE has not been systematically investigated.
WHAT THIS STUDY ADDS
In this SLE cohort, aPLs positivity significantly increased the risk of APOs.
Analysis on the aPLs profiles revealed that anticardiolipin antibodies (aCL) IgG, anti-β2 glycoprotein I (anti-β2GPI) IgG antibodies and lupus anticoagulant (LA) displayed significant impacts on the incidence of APOs, but aCL IgM and anti-β2GPI IgM antibodies did not.
Crucially, the combination of LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies was identified as the highest-risk profile.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings highlight the need for risk stratification in managing pregnancies in patients with SLE, moving beyond a simple positive/negative aPLs classification.
Clinicians should focus more on patients with LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies to potentially improve pregnancy outcomes.
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women of childbearing age. While fertility is typically preserved in SLE,1 accumulating evidence suggests that patients with SLE are prone to unfavourable pregnancy outcomes compared with the general population. This is characterised by a lower rate of live birth and a higher incidence of adverse pregnancy outcomes (APOs), such as fetal growth restriction, preterm delivery and gestational hypertension.2–6 Several risk factors for APOs in SLE have been identified, which included active disease, proteinuria, thrombocytopenia, high glucocorticoid dose and lack of hydroxychloroquine treatment.7–10 However, few studies up to now systemically investigated the impacts of antiphospholipid antibodies (aPLs) on pregnancy outcomes among patients with SLE.
aPLs represent a group of autoantibodies, primarily comprising anticardiolipin antibodies (aCL), anti-β2 glycoprotein I (anti-β2GPI) antibodies and lupus anticoagulant (LA). In the general population, aPLs are recognised as a risk factor for APOs.11 Notably, the prevalence of aPLs is significantly higher in patients with SLE than healthy individuals, with a proportion of 25%–40%.12 Studies have revealed that aPLs could impact the clinical manifestations of patients with SLE from many aspects, such as the severity and prognosis of thrombocytopenia, the development of future atherosclerotic cardiovascular disease and the presence of cardiac valve lesions.13–15 In terms of the relationships between aPLs and pregnancy outcomes in SLE, researchers have made many attempts. Possibly interfered by the heterogeneity of study populations, sample sizes, definitions of APOs and measurements of aPLs across the studies, the conclusions were controversial.16–20 Moreover, data have proven that patients with different aPLs profiles displayed distinct pregnancy outcomes,11 21 while this association has not been thoroughly explored in SLE.
This study, which analysed data of the Peking Union Medical College Hospital (PUMCH) SLE cohort in China, sought to delineate the impacts of aPLs on pregnancy outcomes in patients with SLE and to evaluate the specific effects of different aPLs profiles. This study aimed to provide better instructions for the pregnancy management of patients with SLE.
Materials and methods
Data source and study population
This was a single-centre cohort study conducted at the Department of Rheumatology and Clinical Immunology, PUMCH from January 2013 to January 2024. Consecutive patients with SLE were registered. All patients fulfilled the revised 1997 American College of Rheumatology (ACR) criteria, 2012 Systemic Lupus International Collaborating Clinics criteria or 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR criteria. This study analysed data on pregnancies occurring during this period. The inclusion criteria were: (1) have singleton intrauterine pregnancy; (2) have undergone a minimum of two antiphospholipid antibody tests 12 weeks apart before conception; (3) have follow-ups from 3 months before conception to the first trimester of pregnancy and (4) have recorded pregnancy outcomes. Patients who had an elective termination of pregnancy were excluded from the study.
Data collection
This study collected data on demographics, obstetric history, clinical manifestations, SLE activity, autoantibody profiles, therapeutics and pregnancy outcomes. Demographic information included age at conception, body mass index (BMI), history of chronic hypertension, age at SLE diagnosis and duration of SLE. The obstetric history comprised gravidity, parity and previous APOs. APOs were defined as having at least one of the following manifestations: (1) prefetal death, defined as pregnancy loss before 10 weeks 0 days of gestation that was not explained by chromosomal abnormalities, anatomic malformation or congenital infection; (2) fetal death, defined as pregnancy loss between 10 weeks 0 days of gestation and 33 weeks 6 days of gestation that was not explained by chromosomal abnormalities, anatomic malformation, congenital infection, pre-eclampsia or placental insufficiency; (3) pre-eclampsia with severe features before 34 weeks 0 days of gestation and (4) placental insufficiency with severe features before 34 weeks 0 days of gestation, defined as intrauterine fetal growth restriction (estimated fetal weight or postnatal birth weight less than the 10th percentile for gestational age in the absence of fetal-neonatal syndromes or genetic conditions) with one or more of the following severe features: abnormal or non-reassuring fetal surveillance tests, abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxaemia, oligohydramnios, severe intrauterine fetal growth restriction (estimated fetal weight or postnatal birth weight less than the 3rd percentile for gestational age) and maternal vascular malperfusion on placental histology. Clinical manifestations including mucocutaneous lesions, arthritis, serositis, lupus nephritis, neuropsychiatric lupus, haematological involvement and thrombosis were defined as positive if they had ever been present before conception. The patients meeting the 2006 Sydney revised classification criteria at baseline were diagnosed as secondary antiphospholipid syndrome (APS).22 The activity of SLE at conception was assessed by SLE Disease Activity Index 2000 (SLEDAI-2K). The autoantibodies assessed in this study included anti-double-stranded DNA (dsDNA) antibodies, anti-Smith (Sm) antibodies, anti-ribonucleoprotein (RNP) antibodies, anti-Sjögren’s syndrome-related antigen A (SSA) antibodies, anti-Sjögren’s syndrome-related antigen B (SSB) antibodies and anti-ribosomal P protein (rRNP) antibodies. The anti-dsDNA antibodies were detected by immunofluorescence test using Crithidia luciliae as substrate. The medications at baseline, such as glucocorticoids, immunosuppressants, low-dose aspirin and low-molecular-weight heparin, were retrieved. The baseline period was defined as the 3 months before conception to the first trimester of pregnancy. Finally, the primary outcome focused by this study was composite APOs. The secondary outcomes were live birth, failure of live birth, gestational week at delivery, birth weight, delivery method and each type of APOs. The failure of live birth was defined as any pregnancy that did not result in a liveborn neonate, encompassing prefetal death, fetal death, neonatal death and therapeutic abortion occurring at any time during gestation.
Detection of antiphospholipid antibodies
Five aPLs isotypes were detected in this study, including aCL IgG antibodies, aCL IgM antibodies, anti-β2GPI IgG antibodies, anti-β2GPI IgM antibodies and LA. The measurements of aPLs followed the Scientific and Standardization Committee for LA/aPLs of the International Society on Thrombosis and Haemostasis (ISTH) guideline.23 The plasma sample for tests was collected before anticoagulation therapy if feasible. For patients on anticoagulation therapy, the heparin neutraliser used in the test reagents could quench unfractionated heparin and low-molecular-weight heparin to some level. The activated partial thromboplastin time-based assay (aPTT) and the dilute Russell viper venom time (dRVVT) methods were conducted to detect LA. The LA positivity was defined as an aPTT ratio of >1.20 or a dRVVT ratio of >1.20. ELISA (Euroimmun, Lübeck, Germany; EA 1632–9601 G) was adopted to measure aCL and anti-β2GPI antibodies. Following the instructions of the manufacturer, the positivity of aCL or anti-β2GPI antibodies was defined as titres exceeding 20 U/mL for both IgG and IgM. The medium titres were defined as values between 40 and 79 U/mL, and the high titres were defined as values of ≥80 U/mL. According to the 2006 Sydney criteria,22 aPLs were defined as positive if at least one aPL isotype was detected on two or more occasions at least 12 weeks apart. According to the 2019 EULAR recommendations,24 high-risk aPLs profile was defined as meeting at least one of the following criteria: (1) LA positivity; (2) persistent high titres of aCL or anti-β2GPI antibodies; (3) double positivity, namely any combination of LA, aCL and anti-β2GPI antibodies and (4) triple positivity. If none of the criteria above was fulfilled, the aPLs profile would be defined as low risk.
Statistical analysis
Continuous variables were presented as mean with SD or median with IQR when appropriate. Categorical variables were presented as absolute values with percentages. The χ2 test, Fisher’s exact test, unpaired t-test or Mann-Whitney U test were employed to compare variables between groups categorised by the aPLs status when appropriate. Multivariate logistic regression analysis was used to calculate the OR of aPLs and aPLs isotypes for different outcomes, adjusting for the generally recognised predictive factors of pregnancy outcomes, including APO history, lupus nephritis, baseline clinical activity, glucocorticoid use at a prednisone dose of >7.5 mg/day at conception and non-use of hydroxychloroquine. For sensitivity analysis, the use of low-dose aspirin and the use of low-molecular-weight heparin were adjusted additionally. Results were presented as OR and 95% CIs. The time to APOs was compared between the two groups with the Kaplan-Meier method. The HR with a 95% CI was calculated using Cox regression analysis. The above statistical analyses were performed with R (V.4.3.1), with a two-tailed p value of <0.050 denoting statistical significance unless stated otherwise.
Results
Baseline characteristics of participants
A total of 441 singleton pregnancies occurring in 410 patients with SLE between January 2013 and January 2024 were finally included in the analysis. Among them, 78 (17.9%) pregnancies occurred in patients positive for aPLs, while 363 (82.1%) were negative. Table 1 summarises the baseline characteristics, clinical manifestations, autoantibody profiles and medications of patients categorised based on the aPLs status. Overall, the average maternal age at conception was 30.80 (3.94) years. 182 (41.3%) pregnancies were primigravida and 354 pregnancies (80.3%) were primipara. Among patients who were multigravida, 100 (38.6%) had experienced APOs before, with a significantly higher incidence among those with positive aPLs (56.1% vs 33.7%, p=0.003). As for clinical manifestations, patients with SLE who were positive for aPLs displayed an increased prevalence of thrombosis history (7.7% vs 1.4%, p=0.004), but were less likely to have mucocutaneous lesions (56.4% vs 75.2%, p=0.001) or lupus nephritis (25.6% vs 44.1%, p=0.004). Among 31 patients diagnosed APS, nine had thrombotic APS and 22 had obstetric APS. The disease activity at conception assessed by SLEDAI-2K was generally comparable between the two groups, but thrombocytopenia (14.1% vs 3.0%, p<0.001) occurred more frequently in the group positive for aPLs. When it comes to autoantibodies, patients with positive aPLs were less frequently positive for anti-Sm antibodies (13.0% vs 25.6%, p=0.027) and anti-RNP antibodies (28.6% vs 41.9%, p=0.040). The two groups exhibited similar profiles regarding the use of glucocorticoids and immunosuppressants, but the patients tested positive for aPLs were more likely to be administered low-dose aspirin (88.5% vs 47.7%, p<0.001) and low-molecular-weight heparin (48.7% vs 8.8%, p<0.001).
Table 1. The baseline characteristics of 441 singleton pregnancies occurring in patients with systemic lupus erythematosus, 78 with and 363 without aPLs positivity.
| Total (n=441) | aPLs positive (n=78) | aPLs negative (n=363) | P value | |
|---|---|---|---|---|
| Age at conception (years), mean (SD) | 30.80 (3.94) | 30.92 (4.55) | 30.77 (3.80) | 0.761 |
| Age at conception >35 years of age, n (%) | 73 (16.6) | 14 (17.9) | 59 (16.3) | 0.843 |
| BMI (kg/m2), median (IQR) | 21.26 (19.75, 23.88) | 22.03 (20.55, 24.98) | 20.96 (19.63, 23.83) | 0.024* |
| Chronic hypertension, n (%) | 17 (3.9) | 5 (6.4) | 12 (3.3) | 0.333 |
| Age at diagnosis (years), mean (SD) | 23.40 (5.32) | 23.20 (5.62) | 23.45 (5.26) | 0.711 |
| Disease duration (years), median (IQR) | 6.76 (3.90, 10.46) | 6.85 (4.05, 10.54) | 6.75 (3.77, 10.36) | 0.714 |
| Obstetric history, n (%) | ||||
| Primigravida | 182 (41.3) | 21 (26.9) | 161 (44.4) | 0.007* |
| Primipara | 354 (80.3) | 61 (78.2) | 293 (80.7) | 0.727 |
| Adverse pregnancy outcome history | 100 (38.6) | 32 (56.1) | 68 (33.7) | 0.003* |
| Clinical manifestations, n (%) | ||||
| Mucocutaneous lesions | 317 (71.9) | 44 (56.4) | 273 (75.2) | 0.001* |
| Arthritis | 215 (48.8) | 33 (42.3) | 182 (50.1) | 0.258 |
| Serositis | 43 (9.8) | 7 (9.0) | 36 (9.9) | 0.965 |
| Lupus nephritis | 180 (40.8) | 20 (25.6) | 160 (44.1) | 0.004* |
| Neuropsychiatric lupus | 27 (6.1) | 3 (3.8) | 24 (6.6) | 0.507 |
| Haematological involvement | 252 (57.1) | 48 (61.5) | 204 (56.2) | 0.460 |
| Thrombosis | 11 (2.5) | 6 (7.7) | 5 (1.4) | 0.004* |
| Diagnosed APS | 31 (7.0) | 31 (39.7) | / | / |
| Thrombotic APS | 9 (2.0) | 9 (11.5) | / | / |
| Obstetric APS | 22 (5.0) | 22 (28.2) | / | / |
| Disease activity at conception | ||||
| SLEDAI-2K, median (IQR) | 2.00 (0.00, 2.00) | 2.00 (0.00, 2.00) | 2.00 (0.00, 2.00) | 0.636 |
| Clinical SLEDAI-2K score >0, n (%) | 46 (10.4) | 12 (15.4) | 34 (9.4) | 0.170 |
| 24-hour UPro >0.5 g, n (%) | 12 (2.7) | 2 (2.6) | 10 (2.8) | 1.000 |
| Leukocytopenia, n (%) | 7 (1.6) | 2 (2.6) | 5 (1.4) | 0.794 |
| Thrombocytopenia, n (%) | 22 (5.0) | 11 (14.1) | 11 (3.0) | <0.001* |
| Hypocomplementaemia, n (%) | 132 (29.9) | 23 (29.5) | 109 (30.0) | 1.000 |
| Autoantibody profiles, n (%) | ||||
| Anti-dsDNA antibodies | 180 (40.8) | 28 (35.9) | 152 (41.9) | 0.397 |
| Anti-Sm antibodies | 102 (23.3) | 10 (13.0) | 92 (25.6) | 0.027* |
| Anti-RNP antibodies | 173 (39.6) | 22 (28.6) | 151 (41.9) | 0.040* |
| Anti-SSA antibodies | 267 (61.1) | 41 (53.2) | 226 (62.8) | 0.153 |
| Anti-SSB antibodies | 69 (15.8) | 9 (11.7) | 60 (16.7) | 0.360 |
| Anti-rRNP antibodies | 108 (24.7) | 18 (23.4) | 90 (25.0) | 0.877 |
| Medications at baseline, n (%) | ||||
| Glucocorticoids (prednisone mg/day), median (IQR) | 5.00 (2.50, 10.00) | 7.50 (5.00, 10.00) | 5.00 (2.50, 10.00) | 0.151 |
| Glucocorticoid dose equivalent to >7.5 mg/day of prednisone | 141 (32.0) | 27 (34.6) | 114 (31.4) | 0.676 |
| Hydroxychloroquine | 421 (95.5) | 75 (96.2) | 346 (95.3) | 0.982 |
| Azathioprine | 51 (11.6) | 12 (15.4) | 39 (10.7) | 0.333 |
| Ciclosporin A | 16 (3.6) | 3 (3.8) | 13 (3.6) | 1.000 |
| Tacrolimus | 111 (25.2) | 20 (25.6) | 91 (25.1) | 1.000 |
| Low-dose aspirin | 242 (54.9) | 69 (88.5) | 173 (47.7) | <0.001* |
| Low-molecular-weight heparin | 70 (15.9) | 38 (48.7) | 32 (8.8) | <0.001* |
*Statistically significant result (p<0.05).
anti-RNP, antiribonucleoprotein; anti-rRNP, anti-ribosomal P protein; anti-Sm, anti-Smith; anti-SSA, anti-Sjögren’s syndrome-related antigen A; anti-SSB, anti-Sjögren’s syndrome-related antigen B; aPLs, antiphospholipid antibodies; APS, antiphospholipid syndrome; BMI, body mass index; dsDNA, double-stranded DNA; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; UPro, urinary protein.
Antiphospholipid antibodies profiles and pregnancy outcomes
Figure 1 presents the aPLs profiles of the cohort. Among the 78 pregnancies with positive aPLs, 49 (62.8%) were positive for aCL, among which 45 (57.7%) were aCL IgG and 14 (17.9%) were aCL IgM. Anti-β2GPI antibodies comprised 56.4% (n=44), with 33 (42.3%) accounting for IgG and 27 (34.6%) accounting for IgM, respectively. Fifty-five (70.5%) patients were positive for LA (figure 1A). Then, 12 (15.4%) patients had a low-risk aPLs profile, while 66 (84.6%) had a high-risk aPLs profile (figure 1B). As for the number of positive aPLs, 33 (42.3%) patients were single positive, 20 (25.6%) were double positive and 25 (32.1%) were triple positive (figure 1B).
Figure 1. The distribution of antiphospholipid antibodies (aPLs) isotypes in the cohort. (A) Venn diagram shows the distribution of aPLs, which was displayed as anticardiolipin antibody (aCL) IgG, aCL IgM, anti-β2 glycoprotein I (anti-β2GPI) antibodies IgG, anti-β2GPI antibodies IgM and lupus anticoagulant (LA). (B) Donut plot shows the distribution of aPLs divided by risk levels and the number of positive aPLs. The high-risk aPLs profile is defined as meeting at least one of the following criteria: (1) LA positivity; (2) persistent high titres of aCL or anti-β2GPI antibodies; (3) double positivity, namely any combination of LA, aCL antibodies and anti-β2GPI antibodies and (4) triple positivity.
As displayed in table 2, APOs occurred more frequently among the patients with positive aPLs (29.5% vs 13.2%, p=0.001). For each type of APOs, the incidences of fetal death (7.7% vs 2.5%, p=0.050) and placental insufficiency (14.1% vs 6.6%, p=0.047) were significantly elevated among patients with positive aPLs. The risks of prefetal death (6.4% vs 3.9%, p=0.484) and pre-eclampsia (6.4% vs 3.0%, p=0.265) were numerically increased. Then, the patients tested positive for aPLs were less likely to give a live birth than the other group (80.8% vs 90.4%, p=0.026). The gestational week at delivery, birth weight and the ratio of caesarean section were generally comparable between the two groups.
Table 2. Outcomes of 441 singleton pregnancies occurring in patients with systemic lupus erythematosus, 78 with and 363 without aPLs positivity.
| Total (n=441) | aPLs positive (n=78) | aPLs negative (n=363) | P value | |
|---|---|---|---|---|
| Adverse pregnancy outcomes, n (%) | 71 (16.1) | 23 (29.5) | 48 (13.2) | 0.001* |
| Prefetal death | 19 (4.3) | 5 (6.4) | 14 (3.9) | 0.484 |
| Fetal death | 15 (3.4) | 6 (7.7) | 9 (2.5) | 0.050* |
| Pre-eclampsia | 16 (3.6) | 5 (6.4) | 11 (3.0) | 0.265 |
| Placental insufficiency | 35 (7.9) | 11 (14.1) | 24 (6.6) | 0.047* |
| Live birth, n (%) | 391 (88.7) | 63 (80.8) | 328 (90.4) | 0.026* |
| Gestational week at delivery, median (IQR) | 38.29 (37.14, 38.86) | 38.14 (37.14, 38.57) | 38.29 (37.29, 38.89) | 0.091 |
| Birth weight (g), median (IQR) | 2920.00 (2630.00, 3190.00) | 2840.00 (2640.00, 3117.50) | 2930.00 (2620.00, 3230.00) | 0.335 |
| Caesarean section, n (%) | 265 (67.9) | 45 (72.6) | 220 (67.1) | 0.482 |
Statistically significant result (p<0.05).
aPLs, antiphospholipid antibodies.
The impacts of aPLs on pregnancy outcomes
To identify the impacts of aPLs on pregnancy outcomes, Cox regression analysis was conducted, showing that patients with positive aPLs experienced APOs more frequently, with an HR of 2.43 (95% CI 1.48 to 3.99, p<0.001; figure 2). In the meantime, multivariate logistics regression analysis was performed (figure 3A), adjusting for the generally recognised predictive factors of pregnancy outcomes, including APO history, lupus nephritis, baseline clinical activity, glucocorticoid use at a prednisone dose of >7.5 mg/day at conception and non-use of hydroxychloroquine.7–10 After adjusting the covariates, the values of OR of aPLs positivity for APOs and failure of live birth were 2.56 (95% CI 1.38 to 4.65, p=0.002) and 2.54 (95% CI 1.22 to 5.15, p=0.011), respectively (figure 3A). For each type of APOs, aPLs displayed significant impacts on fetal death (OR 3.87, 95% CI 1.17 to 12.19, p=0.021), but not on prefetal death (OR 1.77, 95% CI 0.53 to 5.06, p=0.313), pre-eclampsia (OR 1.96, 95% CI 0.56 to 6.10, p=0.262) and placental insufficiency (OR 1.89, 95% CI 0.82 to 4.14, p=0.121).
Figure 2. Kaplan-Meier plot of the free of adverse pregnancy outcomes (APOs) probability in pregnancies occuring in patients with systemic lupus erythematosus (SLE) impacted by antiphospholipid antibodies (aPLs).
Figure 3. Forest plots showing the OR of antiphospholipid antibodies (aPLs) after adjusting the covariates for different pregnancy outcomes among patients with systemic lupus erythematosus (SLE). (A) The covariates adjusted were adverse pregnancy outcome history, lupus nephritis, baseline clinical activity, glucocorticoid use at a prednisone dose of >7.5 mg/day at conception and non-use of hydroxychloroquine. (B) In addition to the covariates adjusted in (A), the use of low-dose aspirin and the use of low-molecular-weight heparin were also adjusted.
For sensitivity analysis, in addition to the covariates mentioned above, the use of low-dose aspirin and the use of low-molecular-weight heparin were adjusted additionally (figure 3B). The values of OR of APOs (from 2.56 to 2.63), fetal death (from 3.87 to 4.78) and failure of live birth (from 2.54 to 3.19) all increased slightly.
The impacts of aPLs profiles on pregnancy outcomes
When it comes to the aPLs isotypes (figure 4A), aCL IgG (OR 3.02, 95% CI 1.44 to 6.15, p=0.003), anti-β2GPI IgG antibodies (OR 2.60, 95% CI 1.13 to 5.72, p=0.020) and LA (OR 2.85, 95% CI 1.44 to 5.56, p=0.002) showed statistically significant effects on APOs, while aCL IgM (OR 1.93, 95% CI 0.49 to 6.30, p=0.302) and anti-β2GPI IgM antibodies (OR 1.78, 95% CI 0.65 to 4.36, p=0.229) did not. Then, the titres of aPLs did not appear to be associated with the incidence of APOs, regardless of whether aCL, anti-β2GPI antibodies, the IgG isotypes of aPLs or the IgM isotypes of aPLs were evaluated. As for the risk levels of aPLs stratified based on the 2019 EULAR recommendations, high-risk aPLs profile increased the risk of APOs significantly (OR 2.89, 95% CI 1.51 to 5.44, p=0.001), while the low-risk profile did not (OR 0.96, 95% CI 0.14 to 3.90, p=0.963). Finally, the adverse effects of aPLs on APOs could not be adequately discriminated based solely on the number of positive aPLs, and the values of OR of single, double and triple positivity were 1.88 (95% CI 0.78 to 4.24, p=0.140), 2.42 (95% CI 0.81 to 6.44, p=0.090) and 2.31 (95% CI 0.86 to 5.83, p=0.083), respectively.
Figure 4. Forest plots showing the OR of different antiphospholipid antibodies (aPLs) profiles after adjusting the covariates for adverse pregnancy outcomes (APOs) among patients with systemic lupus erythematosus (SLE). (A) Forest plot shows the OR of different aPLs isotypes, titres of aPLs isotypes, risk levels and the number of positive aPLs for APOs among SLE. (B) Forest plot shows the OR stratified by the positivity of lupus anticoagulant (LA), anticardiolipin antibodies (aCL)/anti-β2 glycoprotein I antibodies (anti-β2GPI antibodies) IgG and aCL/anti-β2GPI antibodies IgM. The covariates adjusted were APO history, lupus nephritis, baseline clinical activity, glucocorticoid use at a prednisone dose of >7.5 mg/day at conception and non-use of hydroxychloroquine.
As LA and the IgG isotypes of aPLs were shown to have the most significant impacts on APOs, the further risk stratification was conducted based on the positivity of LA, IgG isotypes of aPLs and IgM isotypes of aPLs. In the multivariate logistic regression analysis (figure 4B), patients with positive LA plus IgG isotypes of aPLs showed the highest risks of APOs (OR 3.98, 95% CI 1.66 to 9.35, p=0.002). Then, patients with positive LA and negative IgG isotypes (OR 1.92, 95% CI 0.65 to 5.04, p=0.204) and patients with positive IgG isotypes and negative LA (OR 2.13, 95% CI 0.57 to 6.55, p=0.214) had numerically increased risks of APOs. The sole positivity of IgM isotypes seemed not to impact the incidence of APOs (OR 0.96, 95% CI 0.05 to 6.18, p=0.972). Cox regression analysis showed similar results (figure 5). Compared to patients with negative aPLs, the positivity of LA plus IgG isotypes of aPLs (group 1) impacted the occurrence of APOs significantly (HR 3.23, 95% CI 1.72 to 6.09, p<0.001), while the other combinations of aPLs positivity did not (HR 1.91, 95% CI 0.99 to 3.67, p=0.054).
Figure 5. Kaplan-Meier plot of the free of adverse pregnancy outcomes (APOs) probability in pregnancies occuring in patients with systemic lupus erythematosus (SLE) impacted by lupus anticoagulant (LA) and IgG isotypes of anticardiolipin antibodies (aCL)/anti-β2 glycoprotein I antibodies (anti-β2GPI antibodies). Group 1 represents patients who are positive for LA and IgG isotypes of aCL/anti-β2GPI antibodies. Group 2 represents patients with other forms of aPLs positivity excluding those in group 1.
Discussion
Patients with SLE are usually more susceptible to unfavourable pregnancy outcomes. The studies in general population have delineated that aPLs is a risk factor for APOs and different aPLs profiles displayed various effects. However, the role of aPLs, especially the role of different aPLs profiles, on pregnancy outcomes in patients with SLE remains unclear. In this single-centre Chinese SLE cohort, based on data from 441 pregnancies occurring in 410 patients collected between January 2013 and January 2024, we have revealed that aPLs was an independent risk factor for the occurrence of APOs in SLE. Furthermore, LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies showed the most significant impact.
The prevalence of aPLs positivity in our cohort was lower than that reported in other studies of the general SLE population,12 but was comparable to that reported in other studies of pregnant patients with SLE.16 Such results indicate that patients with SLE who are positive for aPLs may be more cautious with pregnancy, possibly leading to the underestimation of the adverse effects of aPLs. Then, the impacts of aPLs on pregnancy outcomes in patients with SLE were seldom investigated in previous studies and the results were generally controversial. One study, consistent with our results, indicated a strong association between aPLs and APOs,16 while other two have reported no significant relationship.17 19 These discrepancies may be attributed to differences in study populations, definitions of APOs and measurements of aPLs. Generally, the detection methods of aPLs were scarcely reported in previous studies, which might introduce much variability in results interpretation.25 Our study adopted standardised aPLs testing following the ISTH guideline. Also, the measurement and interpretation of aPLs was conducted in a single centre. These increased the reliability of our results. Then, the adverse effects of LA on pregnancy outcomes observed in our study were consistently recognised by previous publications.16 17 20 26 The results further highlight the importance of LA positivity. Additionally, the importance of IgG isotypes of aPLs was recognised by this study, which had not been characterised before. As for the further risk stratification, previous studies seldom attempted. Our analysis revealed that LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies showed the most significant impact.
The mechanisms how aPLs mediated APOs have been investigated before, demonstrating a variety of adverse effects on trophoblast cells. First, one ex vivo study suggested that serum from patients with positive aPLs could inhibit placental growth and induce trophoblastic apoptosis.27 Next, the fusion of cytotrophoblast cells was found to be inhibited by anti-β2GPI antibodies via toll-like receptor 4 (TLR4), and blocking TLR4 could restore the fusion.28 As for trophoblast cell migration, anti-β2GPI antibodies could downregulate trophoblast IL-6 secretion, and then diminish STAT3 activation, finally leading to the prohibition of cell migration.29 Then, the secretion of trophoblast angiogenic factor was perturbed by anti-β2GPI antibodies, displayed as an elevated level of vascular endothelial growth factor, placenta growth factor and soluble endoglin, which may interfere with vascular development and remodelling.30 Also, the impacts of aPLs on human chorionic gonadotropin secretion have been proven in several studies, which may result in the defective placentation.28 31 Finally, aPLs could activate the complement system and promote complement deposition in the placenta, contributing to placenta injuries such as deciduitis, villous infarcts and decidual vasculopathy.32–34 It should be noticed that many mechanistic studies have primarily focused on anti-β2GPI antibodies, as β2GPI is expressed on trophoblast cells.35 Our analysis indicated that the IgG isotypes of aPLs and LA displayed more significant adverse effects. Therefore, how they mediate APOs need to be further studied in the future.
To date, high-quality clinical evidence remains lacking for the clinical management of patients with SLE who are positive for aPLs. One observational study (n=49) indicated that low-dose aspirin might decrease the risk of fetal growth restriction.36 On the contrary, one randomised controlled trial with a small sample size (n=19) and one observational study with 139 pregnancies did not recognise the benefits of low-dose aspirin among patients with SLE who are positive for aPLs.37 38 The guidelines generally recommend low-dose aspirin for these patients.7–9 24 In our cohort, nearly 90% of the patients with SLE who are positive for aPLs were taking low-dose aspirin; therefore, it was not feasible to investigate whether such treatment would improve the prognosis. As for the anticoagulation therapy, several mechanistic studies have verified that heparin fails to reverse the pathogenic effects of aPLs on trophoblast cells,29 30 and anticoagulation therapy is not recommended by current guidelines. Whether this therapy could provide benefits to patients with SLE who are positive for aPLs in terms of APOs and live birth needs to be further investigated.
This study has some limitations. First, pregnancy outcomes of some individuals were lacking, resulting in missing data that might introduce some bias. Then, detailed information of neonates was not recorded in the cohort, limiting a deeper investigation into the impacts of aPLs on neonatal conditions. Finally, the cohort exclusively included Chinese participants and was conducted in a single centre, and the generalisability of the conclusions beyond the Chinese population requires further validation.
Conclusions
Our study demonstrated that patients with SLE who are positive for aPLs, especially those with LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies have an increased risk of APOs. The findings of this study highlight the importance of risk stratification and individualised management among patients with SLE who are positive for aPLs, putting more focus on those with LA plus IgG isotypes of aCL and/or anti-β2GPI antibodies, to achieve favourable pregnancy outcomes.
Acknowledgements
We thank all CHOPARD co-authors for their assistance with case collection.
Footnotes
Funding: This study was supported by the Chinese National Key Technology R&D Programme, Ministry of Science and Technology (2021YFC2501300), the National Natural Science Foundation of China (32441090, 92574108), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2025-I2M-XHZY-001, 2025-I2M-XHJC-005), the National High Level Hospital Clinical Research Funding (2025-PUMCH-C-026), the Beijing High-Level Innovation and Entrepreneurship Talent Support Programme for Young Top Talent Projects (G202521084) and the Peking Union Medical College Hospital Talent Cultivation Programme (Category B, UGG10647).
Data availability free text: Data supporting this study are not publicly available because the data are under analysis for an ongoing study. Please contact the corresponding authors for data requests, subject to ethical, legal or commercial considerations.
Patient consent for publication: Not applicable.
Ethics approval: This study was approved by the institutional review board (IRB) of Peking Union Medical College Hospital (approval no. I-23PJ1007). Participants provided informed consent before taking part in the study.
Provenance and peer review: Not commissioned; externally peer reviewed.
Collaborators: Chinese Research Committee of Pregnancy and Reproduction in Autoimmune Rheumatic Diseases (CHOPARD).
Data availability statement
Data are available on reasonable request.
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Associated Data
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Data Availability Statement
Data are available on reasonable request.