Biologic Therapy Boosts Pregnancy Outcomes in High-Risk APS Patients
Landmark Clinical Trial Finds Certolizumab Significantly Improves Pregnancy Outcomes in Women with Antiphospholipid Syndrome
In a groundbreaking advancement for maternal-fetal medicine and autoimmune disease treatment, a phase 2 clinical trial co-led by Hospital for Special Surgery (HSS) and the University of Utah Health has demonstrated that certolizumab pegol, a tumor necrosis factor-alpha (TNF-α) inhibitor, significantly reduces the risk of serious adverse pregnancy outcomes in women with antiphospholipid syndrome (APS). The trial, known as the IMPACT Trial (IMProve Pregnancy in APS with Certolizumab Therapy), offers hope to a population of high-risk pregnant women who have long faced devastating pregnancy losses despite adherence to current standard treatments.
Published in the Annals of the Rheumatic Diseases on April 10, 2025, the study is the first clinical trial to evaluate the use of a biologic agent for the prevention of severe pregnancy complications in women with APS. The trial was co-led by Dr. Jane E. Salmon, a renowned rheumatologist and Collette Kean Research Chair at HSS, and Dr. D. Ware Branch, a leading obstetrician-gynecologist at the University of Utah Health.
APS and the Challenges of High-Risk Pregnancies
Antiphospholipid syndrome is a rare but serious autoimmune disorder that affects approximately 0.03–0.05% of the general population. It is characterized by the body’s immune system producing abnormal antibodies—most notably, antiphospholipid antibodies—that increase the risk of blood clots in arteries and veins. APS can occur on its own (primary APS) or alongside other autoimmune conditions, most commonly systemic lupus erythematosus (SLE).
The risk to pregnant women with APS is especially profound. The condition is associated with recurrent miscarriages, stillbirths, preeclampsia, and intrauterine growth restriction (IUGR), due largely to damage in the placenta caused by inflammation and clotting. Despite the widespread use of blood thinners like low molecular weight heparin and low-dose aspirin, outcomes remain poor for many women, particularly those who are positive for lupus anticoagulant (LA)—an autoantibody strongly linked to the most severe pregnancy complications in APS.
From Bench to Bedside: Translational Research Redefines the Role of Inflammation
The IMPACT trial is the culmination of over a decade of scientific inquiry and translational research led by Dr. Salmon and her colleagues. In preclinical studies using murine models of APS pregnancy, Dr. Salmon discovered that inflammation—not thrombosis—was the key driver of placental dysfunction and subsequent pregnancy loss. This insight was a major departure from the traditional understanding of APS as primarily a clotting disorder.
Her laboratory findings pointed to TNF-α, a pro-inflammatory cytokine involved in systemic inflammation, as a critical target. By inhibiting TNF-α in animal models, her team was able to prevent placental inflammation, restore normal fetal development, and reduce miscarriage rates. These findings laid the foundation for the IMPACT trial, in which certolizumab—a pegylated, Fc-free TNF-α inhibitor with limited placental transfer—was selected for evaluation in pregnant patients.
IMPACT Trial Design and Methodology
The IMPACT trial enrolled 51 pregnant women aged 18 to 40 years, all of whom had confirmed APS and were positive for lupus anticoagulant—placing them in the highest risk category for pregnancy complications. These participants were recruited from 16 U.S. states and one Canadian province, reflecting the study’s geographically inclusive design.
Each participant received certolizumab subcutaneously in addition to the standard-of-care treatment consisting of heparin and low-dose aspirin. The biologic therapy was initiated at eight weeks’ gestation—after confirmation of a viable pregnancy—and was discontinued at 28 weeks, a time point at which the placenta is typically fully developed and no longer as susceptible to inflammatory injury.
This protocol was intentionally crafted to maximize safety for both mother and fetus. Certolizumab, unlike many other TNF inhibitors, lacks the Fc region necessary for placental transfer, thereby limiting fetal exposure. The trial received regulatory clearance and ethical approval, marking a significant achievement given the historical challenges of conducting clinical trials in pregnant populations.
Transformative Outcomes for Mothers and Infants
The results of the trial were nothing short of extraordinary. Only 20% of certolizumab-treated pregnancies experienced severe complications, a dramatic improvement compared to the 69–79% complication rate reported in participants’ previous pregnancies—despite those being managed with heparin and aspirin alone.
The average gestational age at delivery among participants was 36.5 weeks, a near-term milestone that contrasts starkly with the 24-week average from their prior pregnancies. Perhaps most remarkable of all: 93% of participants in the IMPACT trial delivered healthy babies who survived to discharge. This outcome represents a massive leap from the mere 38% neonatal survival rate in their previous attempts at pregnancy.
Importantly, the therapy was well-tolerated. There were no reports of serious infections or lupus flares—a major concern when modulating immune responses during pregnancy.
A Paradigm Shift in Treating APS During Pregnancy
The IMPACT study supports a new clinical paradigm for the management of APS in pregnancy: one that shifts the focus from anticoagulation alone to the suppression of pathological inflammation within the placenta. The findings also underscore the importance of interdisciplinary collaboration, as the study brought together rheumatologists, obstetricians, immunologists, and maternal-fetal medicine specialists to address a complex clinical challenge.
“This study demonstrates what can be accomplished when stakeholders across government, industry, academia, and patient communities work together toward a shared goal,” said Dr. Salmon. “It’s a powerful example of how translational research can change lives.”
Dr. Salmon also highlighted the trial’s implications beyond APS, suggesting that the anti-inflammatory strategy could be relevant for more common obstetric disorders like preeclampsia—a condition that remains a leading cause of maternal and neonatal mortality worldwide.
“There is an urgent need for new therapies for preeclampsia, and our findings open the door to exploring TNF-α blockade in broader populations,” she added.
Toward Broader Adoption and Future Trials
The next step will involve larger, confirmatory phase 3 trials to evaluate certolizumab’s efficacy and safety in a broader patient population. If these findings are replicated, certolizumab could become the first biologic therapy approved specifically to prevent pregnancy complications in women with APS.
Regulatory pathways for such approvals may be shaped by the success of this trial, which managed to navigate the complex ethical and logistical barriers associated with studying novel agents in pregnancy.
“This study changes the conversation about what’s possible in pregnancy research,” said Dr. Branch. “We now have a model for how to design, fund, and execute high-quality trials that prioritize both maternal and fetal safety.”
In the interim, the rheumatology and maternal-fetal medicine communities are cautiously optimistic. The IMPACT trial offers renewed hope for thousands of women with APS who dream of starting or expanding their families without fear of repeated loss.
