Inflammation and pre-eclampsia
Introduction
Pre-eclampsia is a widespread and potentially dangerous disorder of the second half of pregnancy. It is characterised by polymorphic, maternal systemic disturbances and clinical features. However, pre-eclampsia is currently impossible to predict or prevent as its precise causes are unknown. The signs that are used for clinical screening are new hypertension and proteinuria, which regress after delivery, but there is no specific diagnostic feature that, on its own, allows unequivocal recognition.
It seems clear that pre-eclampsia originates in the placenta as the presence of a placenta is necessary to cause the disorder.1 A fetus is not required as pre-eclampsia can occur with hydatidiform mole, a complication of pregnancy characterised by dysregulated trophoblast proliferation without a fetus. Furthermore, the only cure for pre-eclampsia is delivery, which removes the placenta. However, the placenta does not need to be abnormal to induce pre-eclampsia.
The disease constitutes a spectrum that includes so-called ‘maternal’ and ‘placental’ pre-eclampsia.2 With placental pre-eclampsia, there is an abnormal placenta in a normal woman. With maternal pre-eclampsia, there is a normal placenta within a woman who suffers from a pre-existing problem, such as cardiovascular disease or diabetes. In practice, many women with pre-eclampsia have both types in varying degrees.
The placental problem is principally one of oxidative stress, resulting from a poorly developed uteroplacental blood supply. The maternal problem results from a systemic inflammatory response that involves the entire inflammatory network of the circulation, including the endothelium. While the first stage (placental) is difficult to detect clinically, the second (maternal) stage is the clinical syndrome. The sequence of events has been highlighted by the two stage hypothesis for pre-eclampsia (Fig. 1).1
Section snippets
Innate and adaptive immunity
Inflammatory (innate) responses evolved before adaptive immune responses. The innate system responds quickly to stimuli and is relatively non-specific, while the adaptive system develops slowly but has a precise mode of action as it delivers antigen-specific responses with immunological ‘memory’. The innate system can interact with the adaptive immune system but does not require this interaction to function, whereas, the adaptive system cannot function without signals from the innate system.
Systemic inflammatory responses
A systemic inflammatory response differs from local inflammatory responses, which are confined to specific tissues. Rather, a systemic response is diffuse, involving all cells and protein systems within the blood and, by secondary extension, affecting inflammatory networks outside the circulation in target organs.
The primary inflammatory cells are the phagocytes (monocytes and granulocytes), dendritic cells and NK cells. Endothelial cells are involved and produce a range of pro-inflammatory
Systemic inflammatory response and pregnancy
Normal pregnancy is characterised by a mild systemic inflammatory response, which becomes apparent during the luteal phase of the menstrual cycle before implantation occurs and develops as pregnancy progresses. In pre-eclampsia, a similar response occurs, but is of greater intensity.10
During normal pregnancy, the mild inflammatory changes do not indicate illness. Rather, many physiological features of pregnancy are indicators of the associated acute phase response, such as increased plasma
Conclusions
Pregnancy is a systemic inflammatory stress for women, particularly during the second half of gestation, to which both endocrine and placental factors probably contribute. The placental stimulus may comprise sFlt-1 and/or debris released into the maternal circulation from the syncytiotrophoblast, signalling danger to the maternal innate immune system. Pre-eclampsia ensues when the threshold for sustaining homeostasis is reached and excessive involvement of maternal endothelial integrity occurs.
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