The two stage model of preeclampsia: variations on the theme

Abstract

The Two Stage Model of preeclampsia proposes that a poorly perfused placenta (Stage 1) produces factor(s) leading to the clinical manifestations of preeclampsia (Stage 2). Stage 1 is not sufficient to cause the maternal syndrome but interacts with maternal constitutional factors (genetic, behavioral or environmental) to result in Stage 2. Recent information indicates the necessity for modifications of this model. It is apparent that changes relevant to preeclampsia and other implantation disorders can be detected in the first trimester, long before the failed vascular remodeling necessary to reduce placental perfusion is completed. In addition, although the factor(s) released from the placenta has usually been considered a toxin, we suggest that what is released may also be an appropriate signal from the fetal/placental unit to overcome reduced nutrient availability that cannot be tolerated by some women who develop preeclampsia. Further, it is evident that linkage is not likely to be one factor but several, different for different women. Also although the initial model limited the role of maternal constitutional factors to the genesis of Stage 2, this does not appear to be the case. It is evident that the factors increasing risk for preeclampsia are also associated with abnormal implantation. These several modifications have important implications. An earlier origin for Stage 1, which appears to be recognizable by altered concentrations of placental products, could allow earlier intervention. The possibility of a fetal placental factor increasing nutrient availability could provide novel therapeutic options. Different linkages and preeclampsia subtypes could direct specific preventive treatments for different women while the role of maternal constitutional factors to affect placentation provides targets for prepregnancy therapy. The modified Two Stage Model provides a useful guide towards investigating pathophysiology and guiding therapy.

Figure 1

Preeclampsia: a two stage disorder: Preeclampsia is initiated by reduced placental perfusion (Stage 1). This results in the release of factor(s) that leads to the maternal systemic pathophysiological changes (Stage 2).

Figure 2

Maternal fetal interactions in the pathogenesis of preeclampsia: This version of the Two Stage Model emphasizes that reduced placental perfusion (Stage 1) is not sufficient to cause preeclampsia but requires interaction with maternal constitutional factors that may be genetic, behavioral or environmental. These are modified by the maternal pathophysiological changes of preeclampsia.

Figure 3

Different contribution of fetal/placental factors and maternal constitution to Stage 2 of preeclampsia: The contribution of reduced placental perfusion, fetal/placental () or the maternal constitution () to result in the maternal pathophysiological changes of preeclampsia can vary. It can be primarily fetal/placental (A), equally maternal constitutional and fetal/placental (B) or primarily maternal (C). It is a reasonable extension that some women with exquisite sensitivity to fetal/placental function could respond to the normal physiological changes of pregnancy (D).

Figure 4

Revised maternal fetal interactions in the pathogenesis of preeclampsia: The original Two Stage Model presented in Figures 1 and 2 is revised to indicate that abnormal placentation (that occurs in the first trimester) is the important contributor to Stage 1. Further, appropriate signals from the fetal/placental unit in response to abnormal placentation () modify maternal physiology, which cannot be tolerated by women resulting in preeclampsia. The same maternal constitutional changes that interact with abnormal placentation can also stimulate abnormal placentation (). Also the linkage between Stage 1 and Stage 2 is likely secondary to many factors (several 305 arrows compared to one in the original model).