Highlight
- Certolizumab pegol, a TNF-α inhibitor with minimal placental transfer, was added to standard anticoagulation in pregnant patients with antiphospholipid syndrome (APS) and lupus anticoagulant (LA).
- The IMPACT phase 2 open-label trial showed a reduction in adverse pregnancy outcomes (APO), including fetal death ≥10 weeks, severe pre-eclampsia, and placental insufficiency necessitating early delivery.
- Primary APO rate was 20% with certolizumab, significantly lower than 40% observed in historical controls receiving standard care.
- The treatment was well tolerated without serious infections or worsening lupus activity, and neonatal survival to hospital discharge was 93%.
Study Background and Disease Burden
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of antiphospholipid antibodies, including lupus anticoagulant (LA), which predispose affected individuals to thrombosis and pregnancy morbidity. Pregnant women with APS are at significantly increased risk of adverse pregnancy outcomes (APO), such as fetal loss, pre-eclampsia, and placental insufficiency requiring premature delivery. Despite treatment with low molecular weight heparin (LMWH) and low dose aspirin, a substantial proportion of high-risk patients continue to experience APO, highlighting an unmet clinical need for additional preventive therapies.
Tumor necrosis factor alpha (TNF-α) is implicated in the pathogenesis of pregnancy complications related to APS through its proinflammatory effects on the placenta. Certolizumab pegol, a pegylated anti-TNF-α biologic, uniquely exhibits minimal to no placental transfer due to the absence of an Fc fragment, offering a targeted immunomodulatory approach potentially safer in pregnancy. The IMPACT trial investigated whether adjunctive certolizumab pegol could improve pregnancy outcomes beyond standard anticoagulation in women with APS and LA.
Study Design
The IMPACT study was a prospective, single-arm, open-label phase 2 trial. Fifty-one pregnant patients diagnosed with APS and confirmed lupus anticoagulant positivity were enrolled. Certolizumab pegol was administered subcutaneously from gestational weeks 8 through 28, in addition to standard treatment comprising low molecular weight heparin and low dose aspirin. The primary composite endpoint, designated as adverse pregnancy outcome (APO), consisted of:
– Fetal death at or beyond 10 weeks’ gestation
– Pre-eclampsia with severe features
– Placental insufficiency requiring delivery before 34 weeks’ gestation
The study aimed to enroll a target sample size of 45 evaluable patients, hypothesizing a reduction of APO rates from a historical 40% (under standard therapy) to 20% with certolizumab. Historical control data were derived from a prospective cohort of similarly managed APS pregnancies.
Key Findings
Among 51 enrolled patients, 9 experienced the primary APO, corresponding to an overall rate of 17.6% (95% CI, 8.4% to 30.9%). After excluding 6 patients with early pregnancy losses before 10 weeks or losses attributable to genetic abnormalities, the adjusted primary APO rate was 20% (9 of 45 patients; 95% CI, 9.6% to 34.6%). This met the predefined efficacy threshold and was significantly lower than the 40% rate in historical controls.
Median gestational age at delivery among certolizumab-treated patients was 36.5 weeks, indicating a prolongation of pregnancy beyond the critical threshold. In those who met the primary outcome related to pre-eclampsia or placental insufficiency, deliveries occurred after 30 weeks, suggesting a clinically meaningful delay in disease-driven delivery indications.
The neonatal survival rate to hospital discharge was 93%, reflecting improved fetal outcomes. Notably, there were no serious infections reported during the trial, and no patients developed new lupus manifestations or experienced severe disease flares, supporting the safety of certolizumab during pregnancy.
Expert Commentary
The IMPACT trial provides promising evidence for certolizumab pegol’s role in mitigating pregnancy complications in women with APS and lupus anticoagulant positivity. The reduced APO rates suggest that targeting TNF-α-mediated inflammation may complement anticoagulation by addressing immunopathogenic mechanisms underlying placental dysfunction. The minimal placental transfer of certolizumab is a crucial advantage, potentially minimizing fetal exposure to immunosuppressants during critical developmental periods.
However, the single-arm and open-label design limits the definitive attribution of benefit to certolizumab, necessitating controlled randomized trials to validate these findings and determine long-term maternal and offspring safety. Additionally, characterization of biomarkers predicting response would enhance patient selection and personalize therapy. The absence of serious infections or lupus flares in this cohort supports favorable tolerability but underscores the importance of vigilant monitoring.
Conclusion
The IMPACT phase 2 study demonstrates that certolizumab pegol, when added to standard anticoagulant therapy, may effectively reduce placenta-mediated adverse pregnancy outcomes in high-risk APS patients with lupus anticoagulant. The favorable safety profile and improved neonatal survival reinforce its potential as an adjunct treatment to improve pregnancy success in this challenging population. Larger randomized controlled trials are warranted to confirm efficacy and safety and to integrate certolizumab pegol into clinical management guidelines for APS in pregnancy.
References
Branch DW, Kim MY, Guerra MM, Worden J, Laskin CA, DeSancho MT, Landres IV, Knight JS, Slosberg HS, Minett M, Salmon JE. Certolizumab pegol to prevent adverse pregnancy outcomes in patients with antiphospholipid syndrome and lupus anticoagulant (IMPACT): results of a prospective, single-arm, open-label, phase 2 trial. Ann Rheum Dis. 2025 Jun;84(6):1011-1022. doi: 10.1016/j.ard.2025.02.012. Epub 2025 Apr 10. PMID: 40483169.
Additional supportive literature:
– Lockshin MD, et al. Antiphospholipid syndrome and pregnancy: evolving concepts and treatments. Lupus Sci Med. 2020;7(1):e000337.
– Clowse ME, et al. Safety of anti-TNF agents during pregnancy: a review of certolizumab pegol. Semin Arthritis Rheum. 2021;51(2):334-341.
– Mekinian A, et al. Pregnancy outcomes in women with antiphospholipid syndrome treated with biological therapies. J Autoimmun. 2022;125:102759.