The role of complement components (C1q, C3a, MAC) activation in earlyand late-onset preeclampsia and fetal growth restriction

Introduction. Preeclampsia (PE) remains one of the leading causes for maternal and perinatal morbidity and mortality. Placental insufficiency associated with impaired trophoblast invasion, hypoperfusion, and inflammatory endothelial activation is considered a key link to developing PE. In recent years, an interest to assessing a role of the complement system, an important innate immunity component involved in maintaining maternal-fetal tolerance has been growing. An imbalance in complement system activation may lead to damage to the trophoblast, altered placental blood flow, and development of pregnancy complications, including early-onset and late-onset PE as well as fetal growth restriction (FGR). Studying the activity of individual complement components (C1q, C3a, MAC) in PE allows to clarify the immune mechanisms underlying placental dysfunction and identify potential diagnostic and prognostic markers. However, the contribution of individual complement arms in severe PE remains poorly understood, thereby justifying clinically significance for investigating their levels and activity.

Aim: to determine diagnostic and prognostic value for complement system components (C1q, C3a and MAC) in pregnant women with severe PE, by taking into consideration differences between early-onset and late-onset disease forms to be compared with healthy pregnant women in control group.

Materials and Methods. A single-center observational study with cross-sectional comparative analysis at the inclusion stage and subsequent collection of perinatal outcomes was conducted among pregnant women with severe PE and healthy pregnant women with physiological pregnancy. There were enrolled 120 pregnant women, matched for age and gestational age, divided into 4 groups: with early-onset PE, developing at ≤ 34 weeks of pregnancy (n = 56); with late-onset PE, developing after 34 weeks (n = 32); control group 1 – healthy pregnant women with physiological pregnancy at ≤ 34 weeks (n = 17); control group 2 – healthy pregnant women with physiological pregnancy at > 34 weeks (n = 15). The analysis of clinical and laboratory parameters was carried out, which included demographic data, obstetric history, obstetric complications, concomitant diseases, hemostasis parameters, general clinical laboratory parameters, perinatal data, immunological parameters of the complement system – levels of C1q, C3a and membrane attack complex (MAC, C5b–C9). The levels of complement system components were quantitated by enzyme-linked immunoassay.

Results. In severe PE, complement system hyperactivation occurs, manifested by increased C1q, C3a and MAC levels. Complement component C1q concentrations ≥ 250 ng/ml were associated with developing FGR risk (p < 0.008). The C3a component was elevated in FGR and impaired uteroplacental blood flow, as well as in early-onset and late-onset PE. C3a values ≥ 615 ng/ml had moderate predictive ability for FGR (p = 0.004) and for blood flow disorders (p = 0.048). The terminal component of the complement system, MAC (C5b–C9) was significantly elevated in late-onset РЕ and FGR, indicating pathway activation and damage to trophoblast cells. A MAC cut-off value of ≥ 2717 mAU/ml predicted FGR development with sensitivity of 61.0 % and specificity of 82.0 % (p = 0.009).

Conclusion. The changes identified in our study confirm that excessive complement activation and MAC formation play a significant role in developing placental insufficiency, PE, and FGR, and that quantitating C1q, C3a, and MAC levels can be used as an additional biomarker tool for predicting pregnancy complications.

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