Elsevier

Placenta

Volume 30, Supplement, March 2009, Pages 32-37
Placenta

The Two Stage Model of Preeclampsia: Variations on the Theme

https://doi.org/10.1016/j.placenta.2008.11.009Get rights and content

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.

Introduction

Several years ago we extended a concept originally introduced by Chris Redman and colleagues that it could be helpful to consider preeclampsia as a two stage disorder. The first stage was reduced placental perfusion that led to the maternal syndrome, Stage 2 (Fig. 1). We further proposed that the reduced perfusion, posited as secondary to failed remodeling of the maternal vessels supplying the intervillus space, was not sufficient to cause preeclampsia [1]. It was possible to identify evidence of reduced placental perfusion in women who had growth restricted babies unassociated with maternal signs of preeclampsia [2]. Furthermore, in one third of pregnancies complicated by preterm birth there was pathological evidence of failed placental vascular remodeling [3]. This led to the concept that maternal constitutional factors, genetic, behavioral and environmental, modified by the physiological changes of pregnancy were necessary to interact with reduced placental perfusion to lead to the maternal abnormalities of preeclampsia (Fig. 2). Many of these factors leading to the maternal syndrome were risk factors for cardiovascular disease in later life. The other important component of the model was the linkage between reduced perfusion and the maternal syndrome. Several placentally derived “toxins” were suggested, including cytokines [4], antiangiogenic factors [5], syncytiotrophoblast microparticles (STBM) [6] and formed blood products activated in the intervillus space [7]. Oxidative stress was an attractive component as part of the linkage [8]. Reactive oxygen species could be generated by the reduced perfusion of the placenta with consequent activation of monocytes and neutrophils [7] passing through the intervillus space. Oxidative stress would also stimulate release of cytokines, antiangiogenic factors, microparticles and other potential linkers, many of whose systemic effects would also be mediated by oxidative stress.

Although still a useful model, some modifications are appropriate based upon current knowledge. First, it is now being proposed that abnormal placentation is occurring before the stage of remodeling of the vessels supplying the intervillus space [9]. Evidence for the involvement of early placentation is largely the abnormal release of placental proteins as early as the first trimester of pregnancy. Is it possible, as the Two Stage Model would predict, to distinguish markers of the two stages? Secondly, is it possible that what is being produced by the poorly perfused placenta is not principally a “toxin” but rather the result of an adaptive fetal response? Another question is whether there may be more than one linkage between the stages, different in different women. We should also address the suggestion that the constitutional factors that are proposed to interact with Stage 1 to lead to preeclampsia may also contribute to Stage 1. Finally, the necessity of Stage 1 should be considered. Can preeclampsia develop without abnormal implantation and failed vascular remodeling?

Section snippets

When is the placental abnormality of preeclampsia initiated?

Dr. Huppertz champions the concept that the placental abnormality associated with preeclampsia occurs prior to completion of the remodeling of the vessels supplying the placental site [9]. He posits, based upon evidence of changes in the release of placental proteins in the first trimester [10], [11], [12], [13], [14], [15], [16], that the initial insults that lead to the clinical manifestations of preeclampsia, occur long before 12– 20 weeks of gestation when the deep invasion of trophoblast

Are there different markers for Stage 1 and Stage 2?

It is also important to point out that it has not been established whether the markers released in the first trimester predict preeclampsia specifically as opposed to any disorder associated with abnormal implantation. The available data support the latter possibility [10], [11], [12], [13], [14], [15], [16]. In the studies in which IUGR pregnancies (without clinically evident maternal complications) are also examined the early abnormal placental protein release is also present [10], [11], [12]

What is the placenta releasing to lead to preeclampsia?

The factor linking the two stages of preeclampsia has usually been considered as a pathogen — increasing activated blood components, excess syncytiotrophoblast fragments (STBM), activating immune cells and transmitting oxidized lipids, or excess inflammatory cytokines. Another possibility is that in a setting of reduced placental perfusion and subsequent reduced delivery of nutrients, the fetal placental unit may release materials intended to overcome this deficiency. Perhaps the

Is the same factor the linkage in all preeclamptic pregnancies?

Implicit in the Two Stage Model is a common linker for the two stages. Oxidative stress is one proposed linker, as are SBTM and antiangiogenic factors. However, it is important that no such factor has ever been shown to be present in all cases of preeclampsia. Is it possible that there may be different linkages in different women? Endothelial dysfunction seems consistent as a common convergence point for early pathophysiological changes of preeclampsia. Are there several ways to induce this

Can Stage 2 of preeclampsia occur in the absence of Stage 1? (Is Stage 1 neither necessary nor sufficient?)

We have discussed the fact that in the model as presented the presence of abnormal placentation/reduced placental perfusion is not always sufficient to result in the maternal changes of preeclampsia (Stage 2). The occurrence of Stage 2 requires predisposing maternal constitutional factors. The heterogeneous nature of preeclampsia is consistent with varying degrees of contribution from mother and infant [30]. Thus, with profoundly reduced placental perfusion the generation of Stage 2 may require

Are Stage 1 and Stage 2 completely unrelated?

When we first presented the model we believed that the sole contribution of the maternal constitution to preeclampsia was to interact with the insult(s) associated with reduced placental perfusion to result in the development of preeclampsia in a particular woman. We posited that the abnormal placentation was most likely secondary to reduced immunological interactions between mother and fetus. We felt this was the explanation for the predominance of preeclampsia in first pregnancies. The

Summary

The modifications of the Two Stage Model have important implications (Fig. 4). Evidence that placentation is abnormal earlier in pregnancy may provide a better opportunity for therapeutic interventions to prevent Stage 2. Evidence that not all pregnancies associated with abnormal implantation (as least as measured by uterine artery Doppler and placental markers) have abnormal pregnancy outcomes suggests a search for what is different in these pregnancies. The possibility that the factors

Conflict of interest

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

Acknowledgements

This work was supported by NIH PO1 HD30367.

References (43)

  • E. Shibata et al.

    Placental system a amino acid transport is reduced in pregnancies with small for gestational age (sga) infants but not in preeclampsia with sga infants

    Placenta

    (2008)
  • R.B. Ness et al.

    Heterogeneous causes constituting the single syndrome of preeclampsia: a hypothesis and its implications

    American Journal of Obstetrics and Gynecology

    (1996)
  • G.P. Sacks et al.

    Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis

    American Journal Of Obstetrics and Gynecology

    (1998)
  • P.Y. Robillard et al.

    Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception

    Lancet

    (1994)
  • C.A. Koelman et al.

    Correlation between oral sex and a low incidence of preeclampsia: a role for soluble hla in seminal fluid?

    Journal of Reproductive Immunology

    (2000)
  • J.I. Einarsson et al.

    Sperm exposure and development of preeclampsia

    American Journal of Obstetrics & Gynecology

    (2003)
  • B.M. Sibai et al.

    Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis

    American Journal of Obstetrics and Gynecology

    (1991)
  • J. Roberts

    Pre-eclampsia a two-stage disorder: what is the linkage? Are there directed fetal/placental signals?

  • T.Y. Khong et al.

    Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants

    British Journal of Obstetrics and Gynaecology

    (1986)
  • E.J.I. Schipper et al.

    Tnf-receptor levels in preeclampsia – results of a longitudinal study in high-risk women

    Journal of Maternal-Fetal & Neonatal Medicine

    (2005)
  • S.E. Maynard et al.

    Soluble fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia

    Pediatric Research

    (2005)
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