Although much research into mechanism of preeclampsia has taken place, its exact pathogenesis remains uncertain. Preeclampsia is thought to result from an abnormal placenta, the removal of which ends the disease in most cases. During normal pregnancy, the placenta undergoes process of vascularization to allow for blood flow between the mother and fetus. Abnormal development of the placenta leads to poor placental perfusion. The placenta of women with preeclampsia is abnormal and characterized by poor trophoblastic invasion. It is thought that this results in oxidative stress, hypoxia, and release of factors that promote endothelial dysfunction, inflammation, and other possible reactions.

The cli⁮nical manifestations of preeclampsia are associated with general endothelial dysfunction, including vasoconstriction and end-organ ischemia. Implicit in this generalized endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors. Both circulating and placental levels of soluble fms-like tyrosine kinase-1 (sFlt-1) are higher in women with preeclampsia than in women with normal pregnancy. sFlt-1 is an anti-angiogenic protein that antagonizes vascular endothelial growth factor (VEGF) and placental growth factor (PIGF), both of with are proangiogenic factors. Soluble endoglin (sEng) has also been shown to be elevated in women with preeclampsia and has anti-angiogenic properties, much like sFlt-1 does.

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.

Oxidative stress is thought to play an important part in the pathogensis of pre-eclampsia. The main souce of reactive oxygen species (ROS) is the enzyme xanthine oxidase (XO) and this enzyme mainly occurs in the liver. One hypothesis is that the increased purine catabolism from placental hypoxia results in increased ROS production in the maternal liver and release into the maternal circulation causing endothelial cell damage.

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 Th 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.

One hypothesis for vulnerability to preeclampsia is the maternal-fetal conflict between the maternal organism and fetus. After the first trimester trophoblasts enter the spiral arteries of the mother to alter the spiral arteries and thereby gain more access to maternal nutrients. However, occasionally there is impaired trophoblast invasion that results in inadequate alterations to the uterine spiral arteries. It is hypothesized that the developing embryo releases biochemical signals that result in the woman developing hypertension and preeclampsia so that the fetus can benefit from a greater amount of maternal circulation of nutrients due to increased blood flow to the impaired placenta. This results in a conflict between the maternal organism’s Darwinian fitness and survival and the developing fetus because the fetus is invested in only its survival and fitness while the mother is invested in this pregnancy and subsequent potential pregnancies.

Another evolutionary hypothesis for vulnerability to preeclampsia is the idea of ensuring pair-bonding between the mother and father and paternal investment in the fetus. Researchers posit the idea that preeclampsia serves as an adaptation for the mother to terminate investment in a fetus that might have an unavailable paternal donor, as determined by repeated semen exposure of the paternal donor to the mother. Various studies have shown that women who frequently had exposure to partners’ semen before conception had a reduced risk of preeclampsia. Also, subsequent pregnancies by the same paternal donor had a reduced risk of preeclampsia while subsequent pregnancies by a different paternal donor had a higher risk of developing preeclampsia.

Prevention of eclampsia
Diagnostic criteria
Pathogenesis
Differential diagnosis