Objective Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies.
Methods The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit.
Results APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12–15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12–15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12–15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013).
Conclusion In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.
- systemic lupus erythematosus
- antiphospholipid syndrome
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Handling editor Tore K Kvien
Contributors All authors made substantial contributions to study design or acquisition, analysis or interpretation of data. MYK, JES, JPB wrote the manuscript and all authors contributed to revising it critically for important intellectual content. All authors have read and approved the final manuscript. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work have been appropriately investigated and resolved.
Funding Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number RO1 AR49772 (PROMISSE Study, MYK, MMG, EK, CAL, MP, DWB, MDL, LRS, JTM, TFP, AS, JPB, JES), Mary Kirkland Center for Lupus Research (JES, MDL) and NIH AR43727, AR69572 (MP).
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests DWB reports serving on the UCB Pharmaceuticals Advisory Board; JES has received an investigator-initiated grant from UCB Pharmaceuticals and consulting fees from Alnylam and Alexion.
Ethics approval The Institutional Review Board at each study site.
Provenance and peer review Not commissioned; externally peer reviewed.
Presented at Preliminary data included in this publication were reported in an abstract at the American College of Rheumatology (ACR) Meeting in 2015.