Christine Graversgaard Adams1,2,3*
Jullie Rudnicki4Berit Fabricius Petersen2
Søren Jacobsen4
Karen Schreiber1,2,5
- 1Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
- 2Danish Centre for Expertise in Rheumatology (CeViG), Danish Hospital for Rheumatic Diseases, Sønderborg, Denmark
- 3Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
- 4Copenhagen Center for Autoimmune Connective Tissue Diseases (COPEACT), Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
- 5Thrombosis and Haemostasis, Guy's and St Thomas NHS Foundation Trust London, London, United Kingdom
Introduction: Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder associated with pregnancy morbidity, including recurrent pregnancy loss, preeclampsia and fetal growth restriction. Despite standard of care (SoC) with low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH), 20%–30% of pregnancies still result in adverse outcomes. The 2023 ACR/EULAR classification criteria have improved research standardisation, yet robust clinical evidence, including randomised controlled trials (RCTs), remains limited and current management largely relies on empirical practice and RCTs performed nearly two decades ago.
Methods: In this mini-review, with a particular focus on refractory OAPS, we summarise the quality of evidence and methodological limitations underpinning current therapeutic strategies. This included existing SoC and potential adjuvant treatments, such as hydroxychloroquine (HCQ), corticosteroids, statins, intravenous immunoglobulin (IVIG) and biologics.
Results: LDA and LMWH remain the cornerstone of OAPS care. Observational data suggest that HCQ may enhance live birth rates in refractory cases, while glucocorticoids offer limited benefit and pose maternal risks. Evidence for IVIG, statins, and biologics is sparse and primarily derived from small uncontrolled studies. With the exception of a few trials reported almost two decades ago, no RCTs have been conducted specifically in OAPS.
Discussion: Improved management of OAPS requires higher-quality evidence. Trials in other high-risk pregnancy populations demonstrate that RCTs are feasible. Progress will depend on standardised pregnancy outcome measures, international collaboration with coordinated leadership and increased societal and regulatory recognition of the urgent need for research and funding.
This mini-review synthesizes current knowledge on the treatment of refractory OAPS, identifies critical research gaps, and outlines key strategic elements needed to advance evidence-based care for this high-risk population.
Introduction
Antiphospholipid syndrome (APS) was first described in patients with systemic lupus erythematosus (SLE) in the 1980s, who also presented with thromboses and antibodies with reactivity against phospholipids (aPL). Formal classification criteria were introduced in 1998 (1) and most recently updated by ACR/EULAR in 2023 (2) to enhance specificity and more accurately define research cohorts. The 2023 update refined the classification of obstetric antiphospholipid syndrome (OAPS) by introducing a weighted scoring system for pregnancy morbidity and excluding IgM aPL due to their limited clinical utility. These revisions reflect an evolving understanding of distinct obstetric phenotypes and emphasises the importance of standardised outcome definitions in research.
OAPS primarily manifests as pregnancy complications, including recurrent early loss, fetal loss, preeclampsia and placental insufficiency. The pathogenesis involves immune-mediated placental dysfunction rather than thrombosis alone. aPL promote a pro-inflammatory endothelial environment, activate complement and trigger neutrophil extracellular trap formation. They also impair trophoblast invasion, angiogenesis and decidualisation, leading to defective placentation and and adverse pregnancy outcomes that define the condition (3).
Epidemiological data on OAPS are limited. Duarte-García et al. (4) reported an overall APS incidence of 2.1 per 100,000 persons per year and a prevalence of 50 per 100,000 based on a small number of incident cases, of which only 17% exhibited pregnancy morbidity. Prospective registry data, including APS ACTION (5) and EUROAPS (6), consistently demonstrate the despite strandard of care (SoC) with low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH), 20%–30% of women continue to experience pregnancy complications. Beyond medical morbidity, qualitative studies reveal substantial psychosocial burden among affected women (7).
Current therapies insufficiently target the underlying immune-placental pathology and high-quality evidence for adjunctive or alternative treatments is sparse. This mini-review focuses on refractory OAPS, summarising current management strategies, the evidence supporting emerging therapies, and key gaps that should guide future research, including the striking shortage of interventional trials in pregnant APS populations.
Current standard of care with low-dose aspirin and heparin
Low-dose aspirin (LDA) and heparin remain the cornerstone of treatment in obstetric APS, targeting both coagulation and inflammatory pathways (8).
LDA (100–150 mg/day) is typically initiated before conception, while LMWH is started at conception and continued throughout pregnancy and for 6 weeks postpartum to prevent fetal loss and maternal thrombosis.
Evidence from systematic reviews and registries demonstrates the benefit of this combination. A 2020 Cochrane review (9) including 11 trials up to June 2019 found that LDA combined with heparin modestly increased live birth rates compared with aspirin alone though the effects on preeclampsia, pregnancy loss, preterm birth and intrauterine growth restriction (IUGR) were uncertain. Registry data from 1,000 pregnancies indicate that LMWH prevent the majority of recurrent fetal losses, with live birth rates of approximately 70%–80% (10). Early initiation of LDA may further reduce the risk of early-onset preeclampsia, as shown in trials of high-risk pregnancies (11). According to the 2019 EULAR recommendations (12), women with a history of preterm birth due to severe preeclampsia or placental insufficiency may receive LDA alone or combined with prophylactic heparin.
Therapeutic-dose heparin is reserved for selected refractory cases or women with prior thrombotic APS. However, no randomised trials have specifically evaluated its efficacy in OAPS, and current practice is guided primarily by expert consensus. Extrapolation from studies in non-aPL thrombophilia cannot be assumed to apply to OAPS (13).
In the search to optimise pregnancy outcomes in women with OAPS, adjuvant therapies and their potential benefit in pregnancy have been assessed in retrospective and a few prospective clinical studies.
Additional treatment options to reduce pregnancy complications
Hydroxychloroquine
Hydroxychloroquine (HCQ) exerts several immunomodulatory effects relevant to OAPS, including inhibition of prothrombotic and inflammatory pathways, enhancement of trophoblast function and endothelial integrity, suppression of complement activation and modulation of T-cell responses. HCQ also restores annexin A5 anticoagulant activity (14). Together, these mechanisms may contribute to improved placental function and reduced obstetric morbidity. Reflecting this mechanistic rationale and accumulating observational evidence, the 2025 EULAR recommendations suggest adding HCQ to SoC in refractory OAPS.
Evidence from observational studies supports its benefit. A systematic review (15) of seven retrospective cohort including over 750 pregnancies reported a pooled live birth rate of 89.9% with HCQ vs. 73.9% without, corresponding to an odds ratio of 2.66 (95% CI: 1.44–4.91). Two of the included studies evaluated refractory APS and demonstrated improved outcomes with HCQ.
Another review (16) of 11 studies encompassing case reports, case series and cohort studies, concluded that HCQ may enhance live birth rates and maternal-neonatal outcomes when added to SoC, particularly in high-risk or refractory cases.
Several randomised controlled trials (RCTs) have been initiated to assess the efficacy of HCQ in aPL-pregnancies, including HIBISCUS, HYDROSAPL and HYPATIA (17–19). However, two trials were terminated prematurely, one was never launched, and only HYPATIA is currently ongoing across multiple countries.
In summary, mechanistic and observational data support HCQ as a promising adjunct in refractory OAPS, but robust RCT evidence remains lacking. Small sample sizes, heterogeneous diagnostic criteria and inconsistent definitions of refractory disease highlight the need for well-designed clinical trials to clarify its role in improving maternal and fetal outcomes.
Glucocorticoids
Glucocorticoids have historically been used in OAPS to suppress immune activation and inflammation at the maternal–fetal interface. The 2025 EULAR recommendations suggest that low-dose prednisolone during the first trimester may be considered in refractory cases, but routine use is not recommended due to maternal and fetal safety concerns.
A systematic review (20) of 14 studies, including case reports, series, one non-randomised clinical trial, one RCT and observational cohorts found a trend toward improved pregnancy outcomes with non-fluorinated glucocorticoid use (OR 0.509, 95% CI: 0.252–1.028; p = 0.06). However, treatment was associated with significantly increased risks of preeclampsia (OR 2.97, 95% CI: 1.36–6.45; p = 0.006) and gestational diabetes (OR 3.80, 95% CI: 1.79–8.07; p = 0.001) with a non-significant trend toward higher preterm birth.
The only RCTs evaluating glucocorticoids in OAPS date from the early 1990s (21–23), comparing glucocorticoids (with aspirin) to anticoagulation rather than addition to SoC. These trials reported no improvement in maternal or fetal outcomes and suggested potential obstetric complications.
In summary, low-dose prednisolone may benefit selected refractory cases, particularly in the first trimester, but overall evidence is limited. The increased risk of maternal complications necessitates careful risk-benefit assessment, and glucocorticoids should not be used routinely in OAPS pregnancies.
Intravenous immunoglobulin
Intravenous immunoglobulin G (IVIG) is used in autoimmune conditions to neutralise autoantibodies, including aPL, and modulate B-cell activity.
Evidence from RCTs and clinical studies is limited and inconsistent. In a systematic review (24) including two RCTs on 118 aPL-positive pregnancies (25, 26), IVIG was associated with significantly lower live birth rates compared with LMWH plus LDA [OR = 0.25, 95% CI (0.11–0.55), p = 0.0007]. A 2,000 pilot RCT (27) of 16 high-risk aPL pregnancies similarly showed no benefit of IVIG over SoC. Small uncontrolled studies in refractory OAPS reported high live birth rates with IVIG combined with LMWH plus LDA (28, 29), but these studies are heterogeneous and include concomitant therapies limiting generalizability. In summary, IVIG may be considered in highly selected refractory cases, but robust trials are required to clarify efficacy and safety.
Statins
Statins, particularly pravastatin, have been investigated as potential adjunct therapy in OAPS due to their effects on endothelial function and placental perfusion. Lefkou et al. (30, 31) studied pregnant women with OAPS and preeclampsia or placental insufficiency despite SoC. Adding pravastatin to SoC increased nitric oxide levels, improved placental hemodynamics, alleviated preeclampsia symptoms and enhanced fetal growth, resulting in live births close to term. In a small series, triple therapy (LMWH + LDA + pravastatin) improved maternal hypertension and proteinuria and prolonged gestational survival compared with SoC alone (median 98 vs. 23 days) and allowed delivery at a median of 36 weeks, with minimal neonatal complications.
Although these findings suggest a potential benefit, the evidence is limited to small uncontrolled studies. Larger controlled trials are required to confirm safety and efficacy before pravastatin can be recommended routinely in pregnancy.
Biologics
Evidence on biologic therapies in refractory or high-risk APS pregnancies is limited, primarly to case reports and small series remains sparse and mainly limited to case reports or small series (32). Investigated agents include eculizumab, rituximab and other biologics, with TNF-blockers generally considered pregnancy compatible (33). The IMPACT trial (34) recently investigated certolizumab pegol in pregnant women with high-risk APS and reported improved outcomes, including higher live birth rates, lower pregnancy morbidity and prolonged gestation compared with prior pregnancies. While these findings suggest biologics may offer a promising option when SoC is insufficient, robust RCTs are lacking, leaving a critical evidence gap regarding their safety and efficacy in pregnancy.
Interventional trials in OAPS
Only a few registered interventional studies explicitly include pregnant women with APS. These trials evaluate standard antithrombotic strategies, HCQ and isosorbide mononitrate (Table 1). In contrast, most registered studies systematically exclude pregnant participants, despite reproductive outcomes being central to the disease burden. These trials investigate biologics (belimumab, rituximab, daratumumab), anticoagulants (DOACs, clopidogrel) and advanced therapies such as CAR-T cells (Table 2). This situation underscores a significant evidence gap, where clinical practice in pregnant APS populations relies largely on observational data and expert consensus rather than interventional trial evidence.
Table 1. Interventional trials in APS populations with inclusion of pregnant women.
Table 2. Interventional trials in APS populations with exclusion of pregnant women.
Interventional studies and future directions
Recent regulatory initiatives from the European Medicines Agency and the U.S. Food and Drug Administration, as well as the forthcoming ICH E21 guideline (2025), increasingly encourage the inclusion of pregnant and lactating women in both pre- and post-authorisation studies, provided robust safety strategies and ethical justifications are in place. These initiatives signal a significant shift towards improved pregnancy research including the use of pregnancy exposure registries and standardised methodological recommendations. However, harmonisation between agencies remains incomplete, and large multicentre RCTs in pregnant populations continue to be slow, resource-intensive and logistically challenging. Consequently, the generation of high-quality evidence for interventions in pregnancy remains limited.
Successful RCTs in other pregnancy populations, such as the High-Low study (13), ALIFE 1 and 2 (35, 36), the TIPPS (37), and ASPRE (11), illustrate the scale and complexity required. These trials relied on multicentre, international collaboration, recruitment across numerous sites over several years, simple inclusion criteria, objective endpoints, pragmatic trial designs and skilled coordination to ensure protocol adherence and data quality.
RCTs remain the gold standard for driving changes in clinical practice. In rare diseases such as OAPS, however, traditional trial designs are often infeasible. Alternative approaches such as adaptive, factorial or platform trials, and the use of synthetic controls or external data may improve feasibility (38) but increase risk of bias and require sophisticated planning, transparent protocols and careful interpretation. Investigators face a trade-off between generating high-quality evidence through conventional RCTs and adopting pragmatic strategies that may compromise internal validity. Economic, ethical and regulatory constraints further complicate trial conduct. The current landscape highlights a critical need for innovative, collaborative and methodologically rigorous approaches to advance maternal and fetal outcomes in OAPS.
Management of obstetric APS remains guided by observational data and expert consensus rather than robust clinical trials. To move beyond empirical treatment, research should prioritise innovative trial designs, registry-embedded studies, harmonised outcome definitions, and mechanistic insights to inform rational combinations of anticoagulant and immunomodulatory therapies, ultimately improving maternal and fetal outcomes. Meanwhile adjuvant therapies should be considered in selected cases only and not as routine treatment, and the decision should be based on a shared-decision making process between patient and physician in which the lack of robust data for the choice of adjuvant therapies should be made. There is an urgent need for RCTs in pregnant patients with aPL or APS.
Author contributions
CA: Writing – review & editing, Writing – original draft, Visualization, Formal analysis, Data curation, Project administration, Methodology, Conceptualization. JR: Conceptualization, Writing – review & editing. BP: Conceptualization, Writing – review & editing. SJ: Supervision, Writing – review & editing. KS: Validation, Writing – review & editing, Project administration, Conceptualization, Supervision.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: antiphospholipid antibodies, obstetric APS, randomized controlled trials, refractory obstetrical APS, evidence gap
Citation: Adams CG, Rudnicki J, Petersen BF, Jacobsen S and Schreiber K (2026) The urgent need for randomized controlled trials in pregnant women with antiphospholipid antibodies—protecting women through research. Front. Lupus 4:1747204. doi: 10.3389/flupu.2026.1747204
Received: 15 November 2025; Revised: 15 November 2025;
Accepted: 14 January 2026;
Published: 4 February 2026.
Edited by:
Antonia Mazzucato-Puchner, Medical University of Vienna, AustriaReviewed by:
Aleksandra Djokovic, University Hospital Medical Center Bezanijska kosa, SerbiaCopyright: © 2026 Adams, Rudnicki, Petersen, Jacobsen and Schreiber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Christine Graversgaard Adams, Y2dyYXZlcnNnYWFyZEBkYW5za2dpZ3Rob3NwaXRhbC5kaw==