BACKGROUND: Preeclampsia is a deadly pregnancy complication, killing >500,000 babies and 76,000 mothers each year. There is no cure, current management of symptoms utilises treatments with limited effectiveness. Complement pathway overactivation and elevated systemic C5 levels are postulated contributors to preeclampsia pathogenesis. Targeting complement overactivation has been proposed as a treatment strategy. Here we determine placental C5 levels in preeclampsia, and if C5 inhibition via eculizumab (biologic therapy), mitigates placental and vascular dysfunction that drives disease.
METHODS: Placental C5 mRNA expression was examined in healthy placentas collected from: first trimester surgical terminations (7-11 weeks), preterm (24-30 weeks), and term (38-39 weeks) caesarean deliveries, as well as preterm (<34 weeks) and term (>37 weeks) preeclampsia and gestation-matched controls (qPCR). Placental tissue explants collected from term healthy and preeclamptic pregnancies were treated with 125-1000nM eculizumab for 48h. Inflammatory mediators interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF) and anti-angiogenic factor soluble fms-like tyrosine kinase (sFLT-1) protein secretion was measured via ELISA/Luminex. Human omental arteries from term, healthy pregnancies were treated with preeclamptic serum ± 1000nM eculizumab, and vasoconstriction response measured via wire myography.
RESULTS: Placental C5 expression was reduced at term (n=10-15/group) compared to preterm gestations. Placental C5 was downregulated in cases of preterm preeclampsia and fetal growth restriction compared to preterm controls, but upregulated in term preeclampsia compared to term controls (n=10-25/group). Inhibiting C5 with eculizumab in healthy term and preeclampsia placenta did not alter secretion of IL-1β, IL-6, TNF or sFLT-1. Preliminary studies (n=2) suggest that eculizumab does not reduce vasoconstriction induced by preeclamptic serum.
CONCLUSION: Placental C5 is dysregulated distinctly in preterm and term preeclampsia. Blocking placental C5 via eculizumab did not mitigate release of inflammatory or anti-angiogenic molecules, nor affect vasoconstriction. Further studies are underway to test the potential of other biologics targeting key inflammatory molecules elevated in preeclampsia.