IFPA Senior Award Lecture: Making sense of pre-eclampsia – Two placental causes of preeclampsia?
Introduction
Pre-eclampsia presents in highly variable ways. The classical sequence is pregnancy induced hypertension (PIH) first and proteinuria second, but the converse sequence occurs in a minority of cases [1]. Its crises, including eclampsia and the HELLP syndrome, may be unheralded, or only partially heralded by pregnancy induced hypertension alone or pregnancy induced proteinuria alone [1]. It is said that pre-eclampsia can only occur after 20 weeks but a well-documented case of eclampsia has been reported at 16 weeks [2]. For a condition that is said to originate in the placenta it is a paradox that severe cases can present suddenly, without warning, after delivery, when the placenta has been removed. A case of eclampsia as long as three weeks after delivery has been described [3].
It is well known that pre-eclampsia is associated with poor placentation and incomplete remodelling of the uteroplacental spiral arteries [4]. However the association is not specific. Poor placentation may occur with fetal growth restriction (FGR) without features of pre-eclampsia [5] or with partial features such as PIH. Poor placentation would be expected to cause FGR. However FGR is not a consistent feature of pre-eclampsia being confined largely to the early onset syndrome. In pre-eclampsia, at or beyond term, neonates are not growth restricted and may even be large for dates [6].
How can we make sense of this apparently inexplicable diversity? In this paper we present new concepts, which may help to address some of the problems.
The placental origins of pre-eclampsia have long been recognised and, after incomplete placentation was described, were formalised in the two stage model of the syndrome [7]. Poor remodelling of the spiral arteries (weeks 8–18 of gestation) leads to ischaemia re-perfusion injury and oxidative stress [8] of the chorionic villi. How the placental problem then extends to become a maternal problem has subsequently become clearer although a full explanation is still lacking.
It was first shown that uncomplicated pregnancy and pre-eclampsia are both associated with a low grade systemic (vascular) inflammatory response, which is more intense in pre-eclampsia. The role of the placenta was explained by the oxidative damage that it sustained. A generalised response to any form of cellular or tissue damage is inflammation [9], a hypothesis, which has been subsequently validated in many different contexts, not associated with pregnancy. In pre-eclampsia the maternal response to the oxidatively damaged placenta is what could have been predicted and what has been found. The precise nature of the stimulus has not been defined because it is not precise. By its very nature oxidative chemical damage may be heterogeneous. The systemic inflammatory response has massive and wide ranging consequences all of which are seen in pre-eclampsia [10]. Hence this model, at the time it was formulated, could explain more features of pre-eclampsia than any other.
Concepts were changed and extended by the later discovery of how angiogenic and antiangiogenic factors of placental origin could contribute to the pre-eclampsia syndrome [11]. This was a crucial development in that it not only specified precise factors secreted by syncytiotrophoblast – soluble vascular growth factor (VEGF) receptor-1 (sVEGFR-1 also known as sFLT1), soluble endoglin (sENG) and placental growth factor (PlGF) – but led to the discovery of potentially useful circulating diagnostic and predictive biomarkers of the syndrome. The typical but by no means consistent pattern (see below) of pre-eclampsia in the circulation is an excess of sVEGFR-1 and sENG, and lower PlGF. This is proposed to deprive endothelium of the support of VEGF, which specifically causes glomerular endotheliosis, a virtually pathognomonic lesion of pre-eclampsia [11]. The discovery was such a major step forward that, for some, it seemed that the problem of pre-eclampsia had been solved.
In this paper we suggest how pre-eclampsia may arise from placental causes other than poor placentation and propose that the angiogenic biomarkers of pre-eclampsia are better considered as markers of an integrated STB stress response.
Section snippets
Oxidative stress, cellular stress and the integrated stress response
The terminology that is used in this section is described in Table 1. In the two stage model oxidative stress is the primary placental problem causing pre-eclampsia. Oxidative stress is one of many forms of cellular stress listed in Table 2. In general, cell stress affects all cellular compartments, in which specific sensors detect the cellular damage rather than the stressful insult itself. Reactive oxygen species are the major second messengers for cellular stress response networks [12]. An
Biomarkers of pre-eclampsia and syncytiotrophoblast stress
Many studies have investigated maternal angiogenic imbalance in relation to syncytial proteins that are secreted during pre-eclampsia, as mentioned above. Soluble VEGFR-1 (sVEGFR-1) and soluble endoglin (sENG) are biomarkers that increase markedly in relation to the disorder. They are not the only ones: others that also increase include leptin, activin-A, CRH (corticotrophin releasing hormone), (reviewed in Ref. [10]), PP13 [26] and PAPP-A [27]. Placental growth factor (PlGF), on the other
Making sense of pre-eclampsia: intrinsic and extrinsic placental causes
Hence there is at least indirect evidence for a mechanism that could dysregulate placental perfusion in mature pregnancies without antecedent poor placentation in early pregnancy. This leads to our hypothesis that there are at least two placental causes of pre-eclampsia: the first is extrinsic to the placenta, affecting the uteroplacental circulation via incomplete spiral artery remodelling; the second is intrinsic with one or more processes associated with the size of the term placenta
Conflict of interest statement
The authors declare that they do not have any conflict of interest.
Acknowledgements
The authors are grateful for help and advice given by Professor T Mayhew, of Nottingham University, U.K.
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