Although much research into mechanism of<unk>  has taken place, its exact pathogenesis remains uncertain.<unk>  is thought to result from an abnormal placenta, the removal of which ends the disease in most cases. During normal pregnancy, the placenta vascularizes to allow for the exchange of water, gases, and solutes, including nutrients and wastes, between maternal and fetal circulations. Abnormal development of the placenta leads to poor placental<unk> rfusion. The placenta of women with<unk>  is abnormal and characterized by poor trophoblastic invasion. It is thought that this results in oxidative stress, hypoxia, and the release of factors that promote endothelial dysfunction, inflammation, and other possible reactions. The clinical manifestations of<unk>  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<unk>  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 which are proangiogenic factors. Soluble endoglin (sEng) has also been shown to be elevated in women with<unk>  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 placentation involves a degree of maternal immune tolerance for a foreign placenta, 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<unk>  associated with shallow implantation, leading to downstream hypoxia and the appearance of maternal symptoms in response to upregulated sFlt-1 and sEng. Oxidative stress may also play an important part in the pathogenesis of<unk> . The main source 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 that causes endothelial cell damage. Abnormalities in the maternal immune system and insufficiency of gestational immune tolerance seem to play major roles in<unk> . One of the main differences found in<unk>  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<unk>  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<unk> . These findings have given rise to the hypothesis that<unk>  is a disease process by which a placental lesion such as hypoxia allows increased fetal material into the maternal circulation, that in turn leads to an immune response and endothelial damage, and that ultimately results in<unk>  and<unk> . One hypothesis for vulnerability to<unk>  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. 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<unk>  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 maternal and fetal fitness and survival because the fetus is invested in only its survival and fitness while the mother is invested in this and subsequent pregnancies. Another evolutionary hypothesis for vulnerability to<unk>  is the idea of ensuring pair-bonding between the mother and father and paternal investment in the fetus. Researchers posit that<unk>  is an adaptation for the mother to terminate investment in a fetus that might have an unavailable father, as determined by repeated semen exposure of the father to the mother. Various studies have shown that women who frequently had exposure to partners' semen before conception had a reduced risk of<unk> . Also, subsequent pregnancies by the same father had a reduced risk of<unk>  while subsequent pregnancies by a different father had a higher risk of developing<unk> . In normal early embryonic development, the outer epithelial layer contains cytotrophoblast cells, a stem cell type found in the trophoblast that later differentiates into the fetal placenta. These cells differentiate into many placental cells types, including extravillous trophoblast cells. Extravillous trophoblast cells are an invasive cell type which remodel the maternal spiral arteries by replacing the maternal epithelium and smooth muscle lining the spiral arteries causing artery dilation. This prevents maternal vasoconstriction in the spiral arteries and allows for continued blood and nutrient supply to the growing fetus with low resistance and high blood flow. In<unk> , abnormal expression of chromosome 19 microRNA cluster (C19MC) in placental cell lines reduces extravillus trophoblast migration. Specific microRNAs in this cluster which might cause abnormal spiral artery invasion include miR-520h, miR-520b, and 520c-3p. This impairs extravillus trophoblast cells invasion to the maternal spiral arteries, causing high resistance and low blood flow and low nutrient supply to the fetus. There is tentative evidence that vitamin supplementation can decrease the risk. Immune factors may also play a role.
Pre-eclampsia
Eclampsia
Early pregnancy bleeding
Hypertensive disease of pregnancy
Gestational hypertension
Gestational diabetes
Antepartum bleeding
Recurrent miscarriage