Placenta 30, Supplement A, Trophoblast Research, Vol.

23 (2009) S32–S37

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The Two Stage Model of Preeclampsia: Variations on the Theme
J.M. Roberts a, b, c, *, C.A. Hubel a, b
Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA
Department of Obstetrics Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA

a r t i c l e i n f o a b s t r a c t

Article history: The Two Stage Model of preeclampsia proposes that a poorly perfused placenta (Stage 1) produces
Accepted 14 November 2008 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 envi-
Keywords: ronmental) to result in Stage 2. Recent information indicates the necessity for modifications of this
Preeclampsia 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
Intrauterine growth restriction
Subtypes considered a toxin, we suggest that what is released may also be an appropriate signal from the fetal/
Cardiovascular disease placental unit to overcome reduced nutrient availability that cannot be tolerated by some women who
Metabolic syndrome develop preeclampsia. Further, it is evident that linkage is not likely to be one factor but several, different
Preterm birth 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
Ó 2009 Published by IFPA and Elsevier Ltd.

1. INTRODUCTION and environmental, modified by the physiological changes of
pregnancy were necessary to interact with reduced placental
Several years ago we extended a concept originally introduced perfusion to lead to the maternal abnormalities of preeclampsia
by Chris Redman and colleagues that it could be helpful to consider (Fig. 2). Many of these factors leading to the maternal syndrome
preeclampsia as a two stage disorder. The first stage was reduced were risk factors for cardiovascular disease in later life. The other
placental perfusion that led to the maternal syndrome, Stage 2 important component of the model was the linkage between
(Fig. 1). We further proposed that the reduced perfusion, posited as reduced perfusion and the maternal syndrome. Several placentally
secondary to failed remodeling of the maternal vessels supplying derived ‘‘toxins’’ were suggested, including cytokines [4], anti-
the intervillus space, was not sufficient to cause preeclampsia [1]. It angiogenic factors [5], syncytiotrophoblast microparticles (STBM)
was possible to identify evidence of reduced placental perfusion in [6] and formed blood products activated in the intervillus space [7].
women who had growth restricted babies unassociated with Oxidative stress was an attractive component as part of the linkage
maternal signs of preeclampsia [2]. Furthermore, in one third of [8]. Reactive oxygen species could be generated by the reduced
pregnancies complicated by preterm birth there was pathological perfusion of the placenta with consequent activation of monocytes
evidence of failed placental vascular remodeling [3]. This led to the and neutrophils [7] passing through the intervillus space. Oxidative
concept that maternal constitutional factors, genetic, behavioral 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.
* Corresponding author. Magee-Womens Research Institute, University of
Pittsburgh, 204 Craft Avenue, Pittsburgh, PA 15213-3180, USA. Tel.: þ1 412 641 1427;
Although still a useful model, some modifications are appro-
fax: þ1 412 641 1503. priate based upon current knowledge. First, it is now being
E-mail address: (J.M. Roberts). proposed that abnormal placentation is occurring before the stage

0143-4004/$ – see front matter Ó 2009 Published by IFPA and Elsevier Ltd.

Huppertz champions the concept that the placental abnor.M. It is also one linkage between the stages. Although somewhat placental perfusion (Stage 1). C. WHEN IS THE PLACENTAL ABNORMALITY OF PREECLAMPSIA INITIATED? It is also important to point out that it has not been established whether the markers released in the first trimester predict Dr. 2. is it possible remodeling should thus be modified given that abnormalities of that what is being produced by the poorly perfused placenta is not placentation appear to occur prior to this time. there is principally a ‘‘toxin’’ but rather the result of an adaptive fetal evidence of trophoblast invasion of spiral arteries as early as 6– response? Another question is whether there may be more than 8 weeks gestation that is disordered in preeclampsia [2]. This results in the release of factor(s) that leads to the circumstantial. J. 1. Huppertz of remodeling of the vessels supplying the intervillus space [9]. Can preeclampsia develop without abnormal implantation and failed vascular remodeling? 3. occur long before 12– 20 weeks of gestation when the deep invasion of trophoblast with remodeling of the placental bed vessels is thought to occur. would typically lead Evidence for the involvement of early placentation is largely the to the most severe placental dysfunction resulting in intrauterine abnormal release of placental proteins as early as the first trimester growth restriction (IUGR) with preeclampsia. ARE THERE DIFFERENT MARKERS FOR STAGE 1 AND STAGE 2? 2. Vol. Roberts. Trophoblast Research. the necessity of Stage 1 bed vascular remodeling occurring in later pregnancy. Hubel / Placenta 30. Finally. He posits. that the initial insults that lead to the clinical manifestations of preeclampsia. He suggests that the of pregnancy. Supplement A. 23 (2009) S32–S37 S33 the remodeling of the vessels supplying the placental site [9]. proposes that the early changes. Thus. behavioral or environmental. He proposes that trophoblast differentiation may be abnormal as early as the first trimester when these markers are measured. when present. . should be considered. 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. Preeclampsia: a two stage disorder: preeclampsia is initiated by reduced cytotrophoblast and syncytiotrophoblast. preeclampsia specifically as opposed to any disorder associated mality associated with preeclampsia occurs prior to completion of with abnormal implantation. Huppertz may be the root cause of both that are proposed to interact with Stage 1 to lead to preeclampsia abnormal implantation/placentation and the abnormal placental may also contribute to Stage 1. We possible that the placental aberrations in early pregnancy posited should also address the suggestion that the constitutional factors as important by Dr. concept that Stage 1 of preeclampsia begins at the time of vascular to distinguish markers of the two stages? Secondly.A. as the Two Stage Model would predict. However. Is it possible. Dr. that there are important differences in placentation prior to deep trophoblast invasion with vascular remodeling. the presence of these early markers clearly suggests maternal systemic pathophysiological changes (Stage 2). These are modified by the maternal patho- physiological changes of preeclampsia. The available data support the latter Fig. he posits abnormalities of either the differentiation of the morula to trophoblast or the slightly later differentiation of trophoblast to Fig. different in different women. based upon evidence of changes in the release of placental proteins in the first trimester [10–16].

In women with abnormal uterine artery velocimetry compared absence of this signal. these same amino acids are increased in the blood of growth pregnancy because of increased vascular resistance indicating restricted infants from preeclamptic pregnancies [28]. IUGR pregnancies for many markers (as well as blood pressures) are intermediate between normal and preeclamptic pregnancies. vating immune cells and transmitting oxidized lipids. as with the carbohydrate intolerance of diabetes mellitus. IS THE SAME FACTOR THE LINKAGE IN ALL studies we have rigidly defined IUGR pregnancies as neither having PREECLAMPTIC PREGNANCIES? an increase in blood pressure (no greater than 15 mm Hg diastolic or 30 mm Hg systolic) nor an absolute increase to either 140 mm Hg Implicit in the Two Stage Model is a common linker for the two systolic or 90 mm Hg diastolic. we failed remodeling of the vessels of the intervillus space [17]. Several of these markers are modifications to increase nutrient delivery. it is important that no such factor has ever fibronectin [23]. lower LDL cholesterol values than women whose pregnancies result These factors either cause abnormal vascular remodeling or equally in AGA infants [24]. C. This should be associated with blunting of to those without there is evidence of oxidative stress (reduced the normal fetal supply-related metabolic changes of pregnancy in circulating ascorbate) [19]. CAN STAGE 2 OF PREECLAMPSIA OCCUR IN THE ABSENCE OF availability and acting on the placenta to facilitate nutrient transfer. been shown to be present in all cases of preeclampsia. Furthermore. Trophoblast Research. dysfunction seems consistent as a common convergence point for early ways specifically in the development of Stage 2 of preeclampsia. we have demonstrated that women with growth restricted infants thase) [20]. several markers preceding preeclampsia but manifesting later than first of the metabolic changes of preeclampsia including increased trimester are not only increased prior to pregnancies that become triglycerides. Is it possible that larly has found the STBM are not increased in IUGR pregnancies there may be different linkages in different women? Endothelial [25]. growth restriction is accompanied by preeclampsia are consistent Are markers uniquely present in preeclampsia (with or without with the prediction by the model of a very different genesis of IUGR) and not in IUGR (in otherwise uncomplicated pregnancy) or growth restriction in these two settings. Consistent with this premise dimethylarginine (the endogenous inhibitor of nitric oxide syn. These markers are (AGA) infants. whereas associated with abnormal uterine artery velocimetry even with infants that are growth restricted in pregnancies without subsequent normal pregnancy outcomes. ings go on to have preeclampsia. Preeclampsia is defined arbitrarily at reduced nutrient delivery while IUGR in the absence of a maternal a given level of blood pressure and proteinuria. Evidence consistent with this We have discussed the fact that in the model as presented the hypothesis is that 70% of infants who are born of preeclamptic presence of abnormal placentation/reduced placental perfusion is mothers are not growth restricted. In addition. increased concentrations of asymmetric women destined to have IUGR infants. Hubel / Placenta 30. Second. Nonetheless.S34 J. First. Are there several ways to induce this endothelial dysfunction? Are antiangiogenic factors an 4. However. Roberts. It will be useful to inflammatory cytokines. making it possible syndrome reflects the absence of the signal.A. Also. In contrast to preeclampsia. Whether there are fetal/placental signals that present [10–16]. we have stages. The occurrence of Stage 2 requires . restricted infants from pregnancies with preeclampsia [29]. pathophysiological changes of preeclampsia. Uterine artery Doppler preeclampsia have reduced amino acid concentrations in their blood studies are proposed to be abnormal in the second trimester of [27]. In preeclamptic pregnan- other settings of abnormal placental bed perfusion? This is not an cies IUGR occurs when the signal is insufficient to overcome the easy question to answer. Oxidative stress is one proposed linker. and an increased prevalence of agonistic autoantibodies have lower plasma triglycerides than women with normally grown against the AT1 angiotensin receptor [21]. it is not surprising that in many studies the findings in factor to which a subset of women has an inappropriate response. In any case. this transport is not reduced in the placenta of similarly growth About half of women with abnormal uterine artery Doppler find. a linkage should seek an appropriately released fetal/placental Therefore. fatty acids. overcome this deficiency. excess syncytiotrophoblast fragments (STBM). Thus. Another possibility is that in a setting of examine the pathophysiology of preeclampsia from this perspective. cellular angiogenic factors. implies that. it components. low circulating amino acids when growth restriction is not these findings support the concept that poor placentation (Stage 1 accompanied by preeclampsia versus high amino acids when of the model) alone is not sufficient to cause preeclampsia. The Oxford group simi. 23 (2009) S32–S37 possibility [10–16]. acti. Perhaps the placental-to-maternal linkage is a factor(s) that modifies maternal metabolism to increase nutrient 6. or excess there are different subtypes of preeclampsia. as early as 18 weeks gestation women present regardless of whether the pregnancy proceeds to IUGR. as are SBTM and anti- found no increase in the antiangiogenic factor s-Flt [22]. preterm birth. The other half goes on to normal outcomes then IUGR without preeclampsia might develop as a result of the [18]. In our 5. In the studies in which IUGR pregnancies been the finding in a large series of placental bed biopsies where the (without clinically evident maternal complications) are also vast majority of women with preeclampsia have failed vascular examined the early abnormal placental protein release is also remodeling [26]. Supplement A. who will subsequently have infants of less than the 5th centile have preeclampsia or a normal outcome. WHAT IS THE PLACENTA RELEASING TO LEAD TO important precursor of the maternal syndrome in some women while PREECLAMPSIA? in others oxidative stress serves this role? This possibility has several very important implications.M. or leptin [24] with IUGR. Perhaps our search for that some women with IUGR also have a mild form of preeclampsia. This have shown that although System A amino transport is reduced in concept is supported by a few studies of placental bed biopsies in placentas from growth restricted pregnancies without preeclampsia. It is possible that those 70% of not always sufficient to result in the maternal changes of pregnancies do not have failed vascular remodeling but that has not preeclampsia (Stage 2). Finally. STAGE 1? (IS STAGE 1 NEITHER NECESSARY NOR SUFFICIENT?) Women who could not tolerate this modification would be much more likely to develop preeclampsia. these findings support the potential role of these path. women with abnormal uterine artery Doppler waveforms [18]. it suggests that not all cases of The factor linking the two stages of preeclampsia has usually preeclampsia will be avoided by the same preventive strategy been considered as a pathogen d increasing activated blood (certainly consistent with the results of large clinical trails). and insulin resistance are appropriate complicated by IUGR or preeclampsia. or pregnancies If preeclampsia results from the release of an appropriate signal complicated by IUGR. Furthermore. the fetal placental unit may release materials intended to preeclampsia is or is not associated with a putative linker. it is also evident that several of the increase nutrient availability is not yet proven. Vol. This raises two possibilities. reduced placental perfusion and subsequent reduced delivery of searching for commonalities in groups of subjects in whom nutrients. the findings in growth restricted infants of likely they are the result of reduced placental perfusion.

Thus. ARE STAGE 1 AND STAGE 2 COMPLETELY UNRELATED? who had previously been preeclamptic. preterm birth and IUGR. Similarly even women with early onset preeclampsia even without preeclampsia oxidative stress markers are slightly increased in normal pregnancy in a subsequent pregnancy [40]. very little contribution from the mother. Hubel / Placenta 30. in at least a subset of and fetus. Roberts. As the Furthermore. are woman. it seems quite likely that. In both of these cases the difference between normal but not second pregnancies. preeclampsia but preterm birth and pregnancies associated with sion to result in the development of preeclampsia in a particular abnormal implantation. Fig. reduced placental perfusion the generation of Stage 2 may require However. virtually all of the inflammatory associated with later life cardiovascular disease suggesting exten- changes of preeclampsia are present in normal pregnancy albeit to sive involvement of the maternal constitution [39]. with profoundly the infant or a long interpregnancy interval [37]. J. certain data are not compatible with this concept. Vol. preeclampsia of early onset is much more likely to be Oxford Group has emphasized. 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). not only interact with the insult(s) associated with reduced placental perfu. Supplement A. We found that there was an excess of pregnancy and preeclampsia is often not as pronounced as the the implantation related disorders. Triglycerides. We performed a lesser degree [31].A. 23 (2009) S32–S37 S35 predisposing maternal constitutional factors. the increased frequency of preeclampsia with nature of preeclampsia is consistent with varying degrees of barrier contraception [36]. This concept was increase the risk of developing the maternal preeclampsia supported by the reduced frequency of preeclampsia in women who syndrome (by adversely affecting the maternal response to reduced had been sexually active with the father of the baby for a prolonged placental perfusion) also act at the level of Stage 1 as mediators of time prior to conception [34] including exposure to paternal antigen poor implantation/placentation. abnormality was present in women who had preeclampsia in first nancy [32]. Likewise. The heterogeneous with oral sex [35]. there was increased endothelial dysfunction [41]. in difference between pregnancy and non-pregnancy. . Furthermore. C. develop preeclampsia with very little reduced perfusion. 3. We felt this was the explanation for the predominance of women with pregnancy abnormalities associated with abnormal preeclampsia in first pregnancies. placental abruption and infarction. followed women with yet another implantation disease. The exposure to paternal antigen implantation. cholesterol and When we first presented the model we believed that the sole inflammatory markers are higher at 15 weeks gestation in women contribution of the maternal constitution to preeclampsia was to who subsequently deliver preterm [42]. the same maternal constitutional factors that that occurred during pregnancy was protective. equally maternal constitutional and fetal/placental (B) or primarily maternal (C). most of the metabolic changes of a study in which we attempted to determine if the implantation preeclampsia are an exaggeration of the changes in normal preg. It is probably not too great a leap to conclude that in a mother gested that an immunological explanation was less likely in at least with an abundance of predisposing factors the changes of normal early onset preeclampsia. More recently Germain and coworkers pregnancy are enough to induce Stage 2 of preeclampsia. and found that. 3). Different contribution of fetal/placental factors and maternal constitution to Stage 2 of preeclampsia: the contribution of reduced placental perfusion. and when there was a different father for contribution from mother and infant [30].M. It can be primarily fetal/placental (A). recurrent miscarriage. Thus. fetal/placental ( ) or the maternal constitution (B) to result in the maternal pathophysiological changes of preeclampsia can vary. Trophoblast Research. Conversely. the woman likely to recur than preeclampsia occurring near term. as had been reported with women 7. Once again this observation sug- [33]. a difference with extensive predisposing constitutional sensitivity could not consistent with a purely immunological concept [38]. We posited that the abnormal placentation was most likely associated with an increased risk of cardiovascular death in later secondary to reduced immunological interactions between mother life [43]. In this setting almost any Preeclampsia delivering before 34 weeks gestation is much more woman would get preeclampsia (Fig.

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