Pregnant Women With Antiphospholipid Syndrome Still Lack Randomized Trial Evidence, Review Warns

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder in which antibodies against phospholipids drive some of the most feared complications of pregnancy: recurrent miscarriage, fetal loss, preeclampsia and fetal growth restriction. A new mini-review published in Frontiers in Lupus argues that the field is stuck in an evidence vacuum. Despite decades of clinical experience, the standard treatment—low-dose aspirin combined with low-molecular-weight heparin—still fails in roughly 20 to 30 percent of affected pregnancies, and the authors contend that no randomized controlled trials have been conducted specifically in OAPS since a handful of studies reported nearly two decades ago. Their conclusion is blunt: women are being treated on the basis of empirical practice, expert consensus and observational data, not rigorous experimental evidence.

The review, led by Christine Graversgaard Adams of the University of Southern Denmark and the Danish Centre for Expertise in Rheumatology, together with colleagues from Copenhagen and London, traces the scientific arc of the condition from its first description in the 1980s among patients with systemic lupus erythematosus to the 2023 ACR/EULAR classification criteria. That update introduced a weighted scoring system for pregnancy morbidity and excluded IgM antiphospholipid antibodies because of their limited clinical utility, sharpening the definition of research cohorts. Yet better classification has not translated into better trials. The authors systematically surveyed trial registries and found that most active interventional studies in antiphospholipid syndrome—testing biologics such as belimumab and rituximab, anticoagulants, and even CAR-T cell therapies—explicitly exclude pregnant women, even though reproductive outcomes are central to the disease burden.

The biology underlying OAPS helps explain why anticoagulation alone may not be enough. Antiphospholipid antibodies promote a pro-inflammatory endothelial environment, activate complement and trigger neutrophil extracellular trap formation. They also impair trophoblast invasion, angiogenesis and decidualisation, the processes that build a healthy placenta. The result is immune-mediated placental dysfunction rather than simple thrombosis, which means that thinning the blood addresses only part of the pathology. Current therapies, the review notes, insufficiently target this underlying immune-placental damage, and high-quality evidence for adjunctive or alternative treatments is sparse.

The cornerstone of care remains low-dose aspirin, typically 100 to 150 milligrams per day started before conception, plus low-molecular-weight heparin begun at conception and continued throughout pregnancy and for six weeks postpartum. A 2020 Cochrane review covering 11 trials found that the combination modestly increased live birth rates compared with aspirin alone, though effects on preeclampsia, pregnancy loss, preterm birth and intrauterine growth restriction were uncertain. Registry data from roughly 1,000 pregnancies indicate that heparin prevents the majority of recurrent fetal losses, with live birth rates of approximately 70 to 80 percent. Therapeutic-dose heparin is reserved for selected refractory cases or women with prior thrombotic disease, but no randomized trial has specifically evaluated its efficacy in OAPS, and extrapolation from studies of inherited thrombophilia cannot be assumed to apply.

Among the candidate add-on therapies, hydroxychloroquine has attracted the most attention. The drug inhibits prothrombotic and inflammatory pathways, enhances trophoblast function and endothelial integrity, suppresses complement activation and restores the anticoagulant activity of annexin A5. A systematic review of seven retrospective cohorts including more than 750 pregnancies reported a pooled live birth rate of 89.9 percent with hydroxychloroquine versus 73.9 percent without, an odds ratio of 2.66. Reflecting this rationale, the 2025 EULAR recommendations suggest adding the drug to standard care in refractory OAPS. But the trial record is sobering: of the randomized studies launched to test hydroxychloroquine in antiphospholipid antibody pregnancies—HIBISCUS, HYDROSAPL and HYPATIA—two were terminated prematurely, one was never launched, and only HYPATIA remains ongoing across multiple countries.

Glucocorticoids tell a cautionary tale. The only randomized trials evaluating steroids in OAPS date from the early 1990s, and they compared glucocorticoids with anticoagulation rather than testing them as an addition to modern standard care. Those trials found no improvement in maternal or fetal outcomes and hinted at obstetric complications. A more recent systematic review of 14 studies found a trend toward improved outcomes with non-fluorinated glucocorticoids, but treatment was associated with significantly increased risks of preeclampsia and gestational diabetes. The 2025 EULAR recommendations permit low-dose prednisolone in the first trimester of refractory cases but advise against routine use, and the review’s authors agree that careful risk-benefit assessment is essential.

Intravenous immunoglobulin has produced similarly mixed signals. A systematic review including two randomized trials of 118 antiphospholipid antibody-positive pregnancies found that IVIG was associated with significantly lower live birth rates than heparin plus aspirin. Small uncontrolled studies in refractory OAPS have reported high live birth rates when IVIG was combined with standard therapy, but these were heterogeneous and included concomitant treatments, limiting generalizability. Statins, particularly pravastatin, offer a mechanistically appealing option: small studies in women with OAPS complicated by preeclampsia or placental insufficiency showed that adding pravastatin increased nitric oxide levels, improved placental hemodynamics and prolonged gestation, with triple therapy extending gestational survival from a median of 23 days to 98 days compared with standard care alone. The evidence, however, remains limited to small uncontrolled series.

Biologics represent the newest frontier. The IMPACT trial recently investigated certolizumab pegol, a tumor necrosis factor blocker considered compatible with pregnancy, in women with high-risk APS and lupus anticoagulant, reporting improved outcomes including higher live birth rates, lower pregnancy morbidity and prolonged gestation compared with prior pregnancies. Eculizumab and rituximab have appeared in case reports and small series. These signals are promising but fragile: without randomized data, the safety and efficacy of biologic therapy in pregnancy remain uncertain, leaving what the authors call a critical evidence gap.

Is rigorous research in pregnant women feasible? The review points to successful randomized trials in other high-risk pregnancy populations—the High-Low study of heparin dosing, ALIFE 1 and 2 in recurrent miscarriage, TIPPS in thrombophilia, and ASPRE in preeclampsia prevention—as proof of concept. These trials succeeded through multicentre international collaboration, recruitment across numerous sites over several years, simple inclusion criteria, objective endpoints and pragmatic designs. Regulatory winds are also shifting: the European Medicines Agency and the U.S. Food and Drug Administration, along with the forthcoming ICH E21 guideline, increasingly encourage the inclusion of pregnant and lactating women in pre- and post-authorisation studies, provided robust safety strategies and ethical justifications are in place. Harmonisation between agencies remains incomplete, however, and large multicentre trials in pregnant populations continue to be slow, resource-intensive and logistically challenging.

The authors argue that rare diseases like OAPS may require innovative designs—adaptive, factorial or platform trials, and possibly synthetic controls or external data—accepting some increase in bias risk in exchange for feasibility. Progress, they conclude, will depend on standardised pregnancy outcome measures, international collaboration with coordinated leadership, and greater societal and regulatory recognition of the urgent need for research and funding. In the meantime, they caution that adjuvant therapies should be considered only in selected cases, never as routine treatment, and that decisions should be made through shared decision-making in which patients are told plainly about the lack of robust data. Until randomized trials are conducted in pregnant women with antiphospholipid antibodies, the women most affected by the disease will remain the population least studied by it.

Subject of Research: The evidence gaps and treatment options in obstetric antiphospholipid syndrome and the need for randomized controlled trials in pregnant women

Article Title: The urgent need for randomized controlled trials in pregnant women with antiphospholipid antibodies—protecting women through research

Article References: Adams, C. G., Rudnicki, J., Petersen, B. F., Jacobsen, S., & Schreiber, K. (2026). The urgent need for randomized controlled trials in pregnant women with antiphospholipid antibodies—protecting women through research. Frontiers in Lupus, 4, Article 1747204. https://doi.org/10.3389/flupu.2026.1747204

Image Credits: AI Generated

DOI: 10.3389/flupu.2026.1747204

Keywords: obstetric antiphospholipid syndrome, antiphospholipid antibodies, randomized controlled trials, pregnancy, low-dose aspirin, low-molecular-weight heparin, hydroxychloroquine, glucocorticoids, intravenous immunoglobulin, statins, biologics, EULAR recommendations