Investigating the role of complement in the pathogenesis of pre-eclampsia in previously healthy pregnant women, and in high-risk groups.

Blakey, Hannah ORCID: 0000-0003-4979-5599 (2024). Investigating the role of complement in the pathogenesis of pre-eclampsia in previously healthy pregnant women, and in high-risk groups. University of Birmingham. M.D.

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Abstract

Pre-eclampsia (PE) is a leading cause of obstetric morbidity and mortality. Certain groups of women, including those with chronic kidney disease (CKD) and those of sub-Saharan African (SSA) ethnicity, are at particularly high risk. There remains no definitive treatment other than expedited delivery of baby and placenta. Previous studies suggest a role for complement dysregulation in the pathogenesis of PE, but results are often conflicting, and it remains unclear whether changes in circulating complement concentrations reflect a general heightened inflammatory state in PE or are directly associated with placental complement-mediated injury.
This thesis tested the hypothesis that PE is associated with excessive complement activation within placental tissue, with concurrent complement activation within the maternal and fetal circulation, and that groups with a high prevalence of PE, and of PE with severe features (women with CKD and women of SSA ethnicity) would exhibit a greater degree of systemic complement activation. Three arms of research were conducted, and I report:
• In a cohort of previously healthy women, PE was associated with significant placental complement deposition, associated with concurrent changes in maternal and fetal circulating complement markers (reduced maternal properdin and C4, and elevated maternal and fetal Ba). Placental C4d deposition was strongly correlated with maternal properdin and C4, suggesting that those patients with the most excessive changes in circulating markers of complement activation also have the greatest extent of placental complement-mediated damage.
• There was no evidence of excessive complement activation in the maternal circulation in superimposed PE in a cohort of women with CKD. However, raised Ba levels were associated with adverse pregnancy outcomes in women with CKD.
• There was no evidence of excessive complement activation in PE in a Ghanaian cohort of women of SSA ethnicity when compared to healthy pregnant controls. However, pregnant women of SSA ethnicity did have significantly elevated levels of C5b-9, serum free light chains, and immunoglobulin G, when compared to the UK-recruited cohorts; suggestive of a baseline elevated inflammatory state.
The results suggest that inhibition of complement activation is a potential therapeutic target for certain groups of women with PE. However, PE is a heterogenous syndrome and additional pathophysiological mechanisms may contribute to the development of disease in women with CKD and women of SSA ethnicity.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):