Originally posted by deerhart
In the long run, they are going to most likely find out that there are many causes to PE. PE is a symptom of something else going on in the body and a good analogy to it is a fever. A fever is the same response to a variety of different things.
Exactly. I want to hammer home this point, because it's critical to recognize that any theoretical explanation for PE is going to have to handle a multifactorial heterogeneous cause.
I would argue (obviously) that the best candidate to date is the idea that soluble factors are upregulated by the placenta in response to hypoxia and that those factors cause the downstream damage in order to benefit the fetus. Raising the mother's blood pressure means that more blood will be pumped across the placental interface, which grows a larger baby. These are likely adaptive responses to shallow implantation/hypoxia.
We know preeclampsia is related to:
chronic liver and kidney disease
diabetes, gestational or otherwise
living at a high altitude
living in a polluted valley
using barrier contraceptive methods
a history of preeclamptic pregnancies
and doubtless some others that I'm forgetting.
About a year ago I was looking at a slide of a 10 cm placenta from a delivery at 26 weeks. Multipara with 5 previous normal pregnancies, spontaneous labors, healthy babies. This was a emergency delivery at 26 weeks, following severe PE and HELLP syndrome.
The placenta had taken upon itself the task of going trisomy 16 in some of the lobes but not in others. The embryonic cell line was uncompromised, so the baby wasn't trisomy 16 and was one of those 480g babies who make it, after a rocky start. Trisomy 16 is highly compromised -- essentially none of the embryos make it out of the embryonic stage -- but only part of the placenta was compromised, so the pregnancy was able to be maintained for a significant length of time.
Definitely not related to dietary protein and calorie intake and a compromised blood volume thereby, you know?
The particularly compelling thing about the current understanding of the mechanism thought to underpin PE is that it can handle all of these risk factors. Either they're related to a hyperactive immune system, they cause you to become hypoxic, or they directly upregulate sFlt-1. And the best way I can explain the current understanding of the mechanism is this:
Current research suggests that the spiral arteries of the placenta do not appropriately establish an interface with the uterus in most cases of preeclampsia, failing to develop as broadly or as deeply as they would in normal placental invasion. This results in a shallowly implanted placenta, predisposing the pregnancy to early miscarriage or later preeclampsia. This shallow implantation compromises blood flow to the placenta, which eventually becomes hypoxic when the fetus begins to demand more exchanged nutrients and oxygen than the placenta can ferry. In response to this insufficiently oxygenated state, two known proteins are released by the placenta, soluble vascular factors which bind to proteins produced by the mother's body.
Occasionally preeclampsia is not associated with shallowly implanted placentae; in those women, it appears to be the case that either adequate oxygenation or perfusion cannot be maintained for some other reason (the eventual development of hypoxia results in the same downstream effects) or the placenta directly manufactures the proteins which are generally produced only by hypoxia regardless(trisomy 16).
And it's not just, well, *me* saying this. Here's just one review (note: typing "preeclampsia hypoxia" into the PubMed search engine returns 21 pages of results.)
It is now believed that preeclampsia is a two stage disease. In the first stage, a defective implantation and placentation, causes a reduction in uteroplacental perfusion and placental ischemia/hypoxia. Placental ischemia may promote the release of a variety of factors to the maternal circulation. In the second stage, these factors initiate a cascade of cellular and molecular events leading to endothelial and vascular dysfunction. The endothelial dysfunction leads to the clinically recognized symptoms of the syndrome, which include hypertension, proteinuria, thrombocytopenia and impaired liver function. Hypertension is mediated by various endothelial and non-endothelial regulatory factors that are altered in preeclampsia.
and here's another:
The pathophysiology of the disease involves impaired trophoblast invasion, abnormal genetic polymorphism, vascular endothelial cell activation, immune intolerance by the maternal immune system, but also an exaggeration of a systemic inflammatory process. Preeclampsia is one of the major causes of maternal and perinatal morbidities including preterm births and therefore merits ongoing intensive research. The inflammatory process is determined by immunogenetic and non-immunogenetic factors. While inflammation mostly appears to be related to immunogenic determinants such as HLA antigens, paternity, monocytes, proinflammatory cytokines and NK cells, also responses not directly related to the immune system have been observed such as related to hypoxia or agonistic autoantibodies directed against vasoconstrictive angiotensin II receptors.
Any explanation for preeclampsia is going to have to be able to handle the known data, including the studies showing that the population with the lowest quintile of urinary placental growth factor has a 29-fold increase in their risk of preeclampsia. (Soluble flt is an antagonist of placental growth factor.)
One of our researchers says our state of knowledge about preeclampsia is like our knowledge about blindness at the turn of the 20th century. Nowadays, no one would say that macular degeneration and retinopathy of prematurity were caused by the same condition even though they both caused blindness. Preeclampsia, too, is caused by multiple things *that lead to the same downstream symptoms.*
I can riff on this for hours so I'll stop now. [:D]