Pre-eclampsia - Pathogenesis

Pathogenesis

Although much research into the etiology and mechanism of pre-eclampsia has taken place, its exact pathogenesis remains uncertain. Some studies support notions of inadequate blood supply to the placenta making it release particular hormones or chemical agents that, in mothers predisposed to the condition, leads to damage of the endothelium (lining of blood vessels), alterations in metabolism, inflammation, and other possible reactions.

Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th₁ responses and the production of IFN-γ. The origin of IFN-γ is not clearly identified and could be the natural killer cells of the uterus, the placental dendritic cells modulating responses of T helper cells, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. It has been documented that fetal cells such as fetal erythroblasts as well as cell-free fetal DNA are increased in the maternal circulation in women who develop pre-eclampsia. These findings have given rise to the hypothesis that pre-eclampsia is a disease process by which a placental lesion such as hypoxia allows increased fetal material into maternal circulation that leads to an immune response and endothelial damage ultimately resulting in pre-eclampsia and eclampsia.

Some studies suggest that hypoxia resulting from inadequate perfusion upregulates sFlt-1, a VEGF and PlGF antagonist, leading to a damaged maternal endothelium and restriction of placental growth. In addition, endoglin, a TGF-beta antagonist, is elevated in pregnant women who develop pre-eclampsia. Soluble endoglin is likely upregulated by the placenta in response to an upregulation of cell-surface endoglin produced by the maternal immune system, although there is also the potential that sEng is produced by the maternal endothelium. Levels of both sFlt-1 and sEng increase as severity of disease increases, with levels of sEng surpassing levels of sFlt-1 in HELLP syndrome cases. Recent data indicate that Gadd45a stress signaling regulates elevated sFlt-1 expression in pre-eclampsia.

Both sFlt-1 and sEng are upregulated in all pregnant women to some extent, supporting the idea that hypertensive disease in pregnancy is a normal pregnancy adaptation gone awry. As natural killer cells are intimately involved in placentation and as placentation involves a degree of maternal immune tolerance for a foreign placenta which requires maternal resources for its support, it is not surprising that the maternal immune system might respond more negatively to the arrival of some placentae under certain circumstances, such as a placenta which is more invasive than normal. Initial maternal rejection of the placental cytotrophoblasts may be the cause of the inadequately remodeled spiral arteries in those cases of pre-eclampsia associated with shallow implantation, leading to downstream hypoxia and the appearance of maternal symptoms in response to upregulated sFlt-1 and sEng.