Preeclampsia: An excessive maternal inflammatory response to pregnancy,☆☆,

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Abstract

The maternal syndrome of preeclampsia has previously been ascribed to generalized maternal endothelial cell dysfunction. In this review we suggest that the endothelial dysfunction is a part of a more generalized intravascular inflammatory reaction involving intravascular leukocytes as well as the clotting and complement systems. We provide evidence from our recent work and that of others that not only supports this proposal but indicates that such an inflammatory response is already well developed in normal pregnancy and that the differences between normal pregnancy and preeclampsia are less striking than those between the normal pregnant and nonpregnant states. From this we argue that preeclampsia arises when a universal maternal intravascular inflammatory response to pregnancy decompensates in particular cases, which may occur because either the stimulus or the maternal response is too strong. We conclude that there is no specific cause for the disorder, which can be better considered as the extreme end of the range of maternal adaptation to pregnancy. We propose that poor placentation is not the cause of preeclampsia but is a powerful predisposing factor. We predict that a single preeclampsia gene will not be found, nor will either a single specific predictive test or single preventive effective measure be devised. Aspects of the hypothesis are testable, and future work should allow its confirmation or refutation. (Am J Obstet Gynecol 1999;180:499-506.)

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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  • Cited by (0)

    Dr Sacks was supported by Action Research.

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