Low Preconception Complement Levels Are Associated with Adverse Pregnancy Outcomes in a Multicenter Study of 260 Pregnancies in 197 Women with Antiphospholipid Syndrome or Carriers of Antiphospholipid Antibodies

Abstract

Antiphospholipid antibodies (aPL) can induce fetal loss in experimental animal models. Human studies did find hypocomplementemia associated with pregnancy complications in patients with antiphospholipid syndrome (APS), but these results are not unanimously confirmed. To investigate if the detection of low C3/C4 could be considered a risk factor for adverse pregnancy outcomes (APO) in APS and aPL carriers’ pregnancies we performed a multicenter study including 503 pregnancies from 11 Italian and 1 Russian centers. Data in women with APS and asymptomatic carriers with persistently positive aPL and preconception complement levels were available for 260 pregnancies. In pregnancies with low preconception C3/C4, a significantly higher prevalence of pregnancy losses was observed (p = 0.008). A subgroup analysis focusing on triple aPL-positive patients found that preconception low C3 and/or C4 levels were associated with an increased rate of pregnancy loss (p = 0.05). Our findings confirm that decreased complement levels before pregnancy are associated with increased risk of APO. This has been seen only in women with triple aPL positivity, indeed single or double positivity does not show this trend. Complement levels are cheap and easy to be measured therefore they could represent a useful aid to identify patients at increased risk of pregnancy loss.

Antiphospholipid Antibody Assays in 2021: Looking for a Predictive Value in Addition to a Diagnostic One

“…Medium/high titers of aPL detectable by solid-phase assays (i.e., aCL and anti-β2GPI) or the positivity for two or three laboratory assays confer a higher risk for both vascular and obstetric events than low titer aPL or positivity in a single test only ( 5 , 6 ). Preliminary studies raised the issue of whether abnormalities in serum complement levels can be predictive for a poor pregnancy outcome, but confirmatory studies are still needed and to be extended to vascular APS ( 7 , 8 ). So, aPL are emerging as a risk factor, and their high likelihood ratio/predictive value is becoming more and more important.…”

The mosaic of autoimmunity – Finally discussing in person. The 13th international congress on autoimmunity 2022 (AUTO13) Athens

“…Based on that, Lini and colleagues studied the effect of hydroxychloroquine (HCQ) administration in aPL pregnant carriers and APS pregnant women. The results showed that treatment with HCQ on top of the traditional treatment of low dose aspiring (LDA) and low molecular weight heparin (LMWH) in women with triple aPL positivity and compliment consumption had significantly better pregnancy outcome compared to patients taking LDA and LMWH without HCQ [ 51 ]. In terms of therapeutic implications, the use of complement pathway inhibitors, specifically targeting the C5a receptor pathway, in the treatment of ANCA-associated vasculitis (AAV) was presented by Tervaert.…”

“…Furthermore, there was no difference established in anti-C1q and anti-FH between control pregnancies and women with preeclampsia [ 170 ]. Antiphospholipid antibodies (aPL) are well-established factors that might lead to adverse pregnancy outcomes (APO) by which anti-thyroperoxidase antibodies (aTPO) may act as a risk factor [ 51 , 171 ]. Lini and colleagues searched for the contributory role of aTPO in aPL positive pregnant women.…”

Beyond Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome: The Relevance of Complement From Pathogenesis to Pregnancy Outcome in Other Systemic Rheumatologic Diseases

“…Furthermore, pregnant women with SLE and APS display higher serum levels of complement degradation products compared to healthy expectant mothers ( Kim et al, 2018 ; Scambi et al, 2019 ). Despite the progressively raising bulk of evidence, available data on C3 and C4 as predictors of adverse obstetric outcome in lupus and APS are not consistent, not yet allowing to draw definite conclusions about the clinical relevance of complement monitoring throughout pregnancy progression in these settings ( Chighizola et al, 2020 ; Nalli et al, 2021 ). Of note, in SLE even the association between complement levels during pregnancy and disease flare is questioned, due to the physiologic fluctuation of complement levels during gestation.…”