The impact of inflammation on pregnancy outcomes
File(s)
Author(s)
Howe, Laura
Type
Thesis
Abstract
Sepsis is the leading cause of direct maternal mortality in the UK, but also a leading concern worldwide. In the USA, severe maternal sepsis rates and the risk of sepsis-related death have doubled in the last decade. There appears to be an increased susceptibility to, and severity of, infections during pregnancy. However, the mechanisms behind the increased morbidity and mortality are not fully understood. Pregnancy is associated with acute physiological changes in most organ systems, in particular the cardiovascular and immune systems. In this thesis the haemodynamic response to infection and inflammation was investigated. It was hypothesised that there is an altered haemodynamic response to infection mediated by inflammatory pathways, and by targeting signalling pathways within the immune and cardiovascular systems maternal outcomes could be improved. In order to achieve to this, a murine model of endotoxaemia during pregnancy was employed to study the effects of inflammation on maternal haemodynamics, utilising a telemetric technique to monitor physiologic changes. Firstly, this model was used to demonstrate that inflammation in pregnancy can lead to marked hypotension and haemodynamic dysfunction that does not occur in non-pregnant controls. Supplementation with additional progesterone, a key hormone of pregnancy, did not exacerbate this hypotensive effect. Manipulation of the chemokine receptor CCR2 was able to reverse inflammation-induced hypotension in pregnancy, both by genetic knockout and pharmacological inhibition. Manipulation via genetic knockout of DDAH1, a component of the nitric oxide signalling pathway, whilst conferring an initial hypertension did not significantly impact the gestational haemodynamic profile. The marked fall in blood pressure in response to endotoxin may help to explain the greater susceptibility of pregnant women to sepsis. Maternal outcomes may be improved by modulating the immune response.
Version
Open Access
Date Issued
2015-09
Date Awarded
2016-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Johnson, Mark
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)