Review
Trophoblast differentiation, fetal growth restriction and preeclampsia

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Abstract

The number of hypotheses trying to decipher the etiologies of preeclampsia and fetal growth restriction (FGR) is still increasing. However, for preeclampsia the actual knowledge we have is that the placenta is a prerequisite for the development of the syndrome. The recent years have seen a shift in understanding of the causes of preeclampsia from mostly focusing on the extravillous trophoblast towards the dysregulation of villous trophoblast development and maintenance. It seems as if a failure of the villous syncytiotrophoblast differentiation results in abnormal release of non-apoptotic fragments into maternal blood. In preeclampsia such necrotic or aponecrotic fragments can be found in maternal blood systemically and seem to be causative in the development of the inflammatory response of the mother. In cases with fetal growth restriction (FGR) extravillous trophoblast fails to adequately transform uterine spiral arteries. However, in FGR cases abnormal development of villous cytotrophoblast may have an impact on fetal nutrition without the induction of an inflammatory response of the mother.

It is still unclear why the villous trophoblast fails to achieve an adequate turnover both in preeclampsia and in FGR. However, the detection of new biomarkers for preeclampsia such as placental protein 13 (PP13) has helped in clarifying the issue of when the syndrome starts to develop. PP13 levels in maternal serum are significantly altered already at six to seven weeks of gestation in women subsequently developing preeclampsia. Thus, there needs to be a very early alteration of villous development in such placentas.

Herein the changes in villous trophoblast in preeclampsia and FGR are compared and differences between both scenarios are presented.

Section snippets

Trials to define preeclampsia

The exact etiology of the pathogenesis of preeclampsia is still unclear and remains a subject of extensive research even today. Although a multifactorial background is anticipated, it has become clear that the placenta rather than the fetus is a prerequisite for the development of the syndrome. Beside the crucial role of the placenta in the etiology of preeclampsia, the maternal response and susceptibility to placentally derived factors and proteins further modifies onset, severity and

Trophoblast differentiation

At about six days post conception (pc) when the morula develops into the blastocyst, trophoblast is the first cell lineage to differentiate during human embryonic development. During the next two weeks subsequent differentiation steps culminate in the formation of the two different populations of trophoblast, villous and the extravillous trophoblast [7].

Villous trophoblast with its two layers, villous cytotrophoblast and syncytiotrophoblast, already develops as soon as the first villi grow from

Serum markers to predict preeclampsia and FGR

As in other clinical sciences there is a general trend in obstetrics and perinatal medicine to focus on early predictive markers. Early prediction allows for setting up and planning appropriate management of pregnant women at high risk, even opening up the avenue for testing putative preventative measures to improve overall outcome. So far, putative therapies can only be started at the time of detection of clinical symptoms of preeclampsia and/or FGR [1], [2], [14], [15]. However, early

Placental origins of preeclampsia and FGR

The last decades have seen a variety of hypotheses that have been generated aiming to explain the placental origins of preeclampsia [34], [35], [36], [37] with most of them disappearing soon while a few are still discussed and are updated continuously [38]. Today it has become clear that preeclampsia does not originate in midgestation but rather the etiology needs to be located during very early stages of pregnancy [39]. The change in view also challenged one of the hypotheses that is still

Conclusions

The adaptations and updates of hypotheses to explain the etiology of FGR and preeclampsia continue. However, even after the update this hypothesis still clearly separates the origins of FGR and preeclampsia. It becomes obvious that the two syndromes are indeed different entities. Studies where preeclampsia cases with and without FGR are mixed will not help in elucidating the origins of both syndromes. Only a thorough analysis and comparison of both syndromes can decipher their similar but

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