Different failures of placentation lead to preeclampsia or intrauterine growth retardation – a new concept

Aims: Some years ago it has been demonstrated that during the first trimester of pregnancy there is no flow of maternal blood cells into the intervillous space of the placenta. Only at the end of the first trimester the plugs of extravillous trophoblasts blocking spiral arteries are dislocated and open the flow of maternal blood towards the placenta. Only then higher oxygen levels can be detected in the placenta. In parallel, the last few years have witnessed an enormous increase in the knowledge of serum markers for preeclampsia, especially those showing significant alterations in their concentrations as early as in the mid first trimester. Hence, these alterations can be measured weeks before the onset of flow of maternal blood cells through the intervillous space.

Old hypothesis: The old hypothesis on the etiology of preeclampsia favors the failure of transforming spiral arteries resulting in a reduced diameter of the arteries, a reduced blood flow towards the placenta and thus hypoxia of the placenta. Since blood flow is only established at the beginning of the second trimester, such a failure in transformation can only be effective after onset of blood flow, i.e. at the beginning of the second trimester.

How can a failure that is effective only at the beginning of the second trimester lead to alterations of the release of proteins from the villous trophoblast already in mid first trimester?

New hypothesis: Here I hypothesize that an insult occurring very early during trophoblast development affects villous trophoblast differentiation and thus leads to preeclampsia. Due to alterations of villous trophoblast differentiation early in pregnancy, the turnover of villous trophoblast is disturbed and the release of apoptotic syncytial knots is no longer the main mechanism of disposal. Now other mechanisms take over such as necrosis and aponecrosis. The two mechanisms give rise to a necrotic and cellfree release of trophoblast material. Such subcellular trophoblast fragments can be detected in high numbers only in preeclampsia while in pure IUGR they are not elevated above normal levels. The trophoblastic fragments are small and thus can easily pass the lungs; therefore they can be detected in peripheral blood and may cause systemic alterations of the maternal endothelium and inflammatory system. Hence, preeclampsia is the result of a failure of villous trophoblast differentiation, which – on the placental side – ultimately leads to an abnormal release of trophoblast material into the maternal circulation.

Conclusion: Ultimately, preeclampsia is a syndrome of early placentation. An insult resulting in an aberrant development and differentiation of the villous syncytiotrophoblast causes an impaired maintenance of the placental barrier. This will subsequently lead to the release of necrotic and aponecrotic trophoblast fragments culminating in a systemic inflammatory response of the mother. By contrast, a failure of extravillous trophoblast invasion is correlated with the pathophysiology of IUGR. The new concept brought forward here clearly separates the origins of preeclampsia and IUGR and proposes alterations in different trophoblast differentiation pathways as origins for both syndromes.