Preeclampsia: An excessive maternal inflammatory response to pregnancy☆,☆☆,★
Section snippets
The components of the inflammatory response
Inflammatory responses are nonspecific and stimulated by any form of tissue injury as well as by immune activation. They encompass activation not only of the nonadaptive effectors of immune reactions, monocytes and granulocytes, but of the complement and clotting systems.14 Most inflammatory responses are localized to an area of injury, but in some instances they can spread to involve the entire vascular compartment, as in generalized sepsis.
Central to the processes of inflammation is a
Systemic inflammatory changes during preeclampsia
In addition to endothelial dysfunction there is substantial published evidence that there is systemic activation of maternal inflammatory cell responses in preeclampsia. Both granulocytes16, 17, 18 and monocytes19, 20 are activated. There is increased release of the proinflammatory cytokine tumor necrosis factor α and its 2 soluble receptors, interleukin 68 and soluble phospholipase A2 —an important mediator of inflammatory reactions21, 22—into the circulation. It is well known that the
Hypothesis
Central to our hypothesis is that the intravascular inflammatory response is not an epiphenomenon but is in fact the cause of the clinical syndrome of preeclampsia. This cannot be proved. Although the concept of endothelial dysfunction as a primary part of the pathogenesis of preeclampsia is widely accepted there is no stringent proof that this is true either; nevertheless, the circumstantial evidence is compelling and widely accepted. We simply extended the idea by proposing that the
Predictions arising from the hypothesis
The first prediction is that the placenta, directly or indirectly, generates one or more signals that excite generalized inflammatory reactions in the mother. This signal becomes larger as the placenta grows, such as with advancing gestation or in the presence of multiple pregnancy, or for reasons unrelated to placental size with severe intrauterine growth restriction, underlying uteroplacental circulatory insufficiency, and placental oxidative stress. The nature of the possible signals is
Unresolved problems
The question remains about the factors that generate the preponderance of preeclampsia among first pregnancies. Does this determine the maternal inflammatory response in late pregnancy or act at an earlier stage; for example, is it among the factors involved with deficient placentation? A clue here may be that of partner specificity. It may be that primipaternity, not primiparity, is the key issue with a longer duration of preconceptual cohabitation (vaginal exposure to paternal antigens)
Implications of the hypothesis
No hypothesis about pathogenesis is useful unless it can be tested. If the hypothesis were to be confirmed, its consequences would be profound. The first and major implication is that preeclampsia is not a separate, distinct abnormality of pregnancy but rather represents an extension of changes wrought by pregnancy. The problem is not preeclampsia, but pregnancy itself. The second implication is that no single cause will be found for preeclampsia, as previously suggested by others.48 Different
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