Post Reply FAQ Members Login

Is this the pathophysiology of preeclampsia?

The Preeclampsia Foundation does not necessarily endorse any research or news found in this forum, we just want to share what is out there. Please use your own discretion to evaluate any information you find here.

Is this the pathophysiology of preeclampsia?

Postby rodin » Sat Dec 17, 2011 10:44 am

by rodin (6 Posts), Sat Dec 17, 2011 10:44 am

:o Does this article explain the pathophysiology of preeclampsia? :?

Shortly summarized the hypothesis explained is:
Compression or kinking of the left renal vein --> activation of the Renin angiotensin system --> general arteriolar vasoconstriction --> organ and placenta hypoxemia --> vascular damage --> organ damage and preeclampsia symptoms.

http://philica.com/display_article.php?article_id=240

If this turns out to be right, pregnant women should probably be advised to sleep on there left side. :idea:
rodin
Registered User
 
Posts: 6
Joined: Sat Dec 17, 2011 12:51 pm

Re: Is this the pathophysiology of preeclampsia?

Postby blythe » Sat Dec 17, 2011 02:00 pm

by blythe (3060 Posts), Sat Dec 17, 2011 02:00 pm

Interesting article! I don't understand the physiology as well as some, but I don't think the author's hypothesis matches with the current research. Note also that no actual research has been done on positioning, and especially note at the bottom that this article has not been peer reviewed.

Avoiding sleeping flat on your back and sleeping on your left side as much as possible is already common advice in pregnancy
http://www.babycenter.com/404_whats-the ... cy_7608.bc
so my completely not-a-doc guess is that the author's hypothesis is probably incorrect - or at least incomplete.

I don't mean to be so negative ;) , this is an interesting article, I just have read a lot more articles that have different conclusions and have more research support! We love reading around here! If you'd like to read more about the biology of preeclampsia I'd recommend starting with

this thread:
http://www.preeclampsia.org/forum/viewt ... 12&t=16607
the articles in Caryn's profile:
http://www.preeclampsia.org/forum/membe ... ile&u=1465
pubmed for peer-reviewed articles:
http://www.ncbi.nlm.nih.gov/pubmed?term=preeclampsia

Please ask more questions and let us know what you find!
Heather, mom to
#1 7-18-03 - 5#8oz 37 weeks PE/PIH
#2 8-11-06 - 6#14oz 37 weeks PE/PIH
#3 9-10-09 - 5#10oz 37 weeks PE/PIH
blythe
Registered User
 
Posts: 3060
Joined: Sun Mar 21, 2004 10:24 am

Re: Is this the pathophysiology of preeclampsia?

Postby rodin » Sun Dec 18, 2011 12:44 am

by rodin (6 Posts), Sun Dec 18, 2011 12:44 am

I agree that this is still a hypothesis, which has not yet been peer reviewed and certainly should not be automatically accepted as correct.
However I find it is a logically sound new hypothesis. It is different from any current hypothesis on the pathophysiology of preeclampsia, but this isn't an argument against it. If you automatically assume a new hypothesis to be wrong, we would still think all stomach ulcers are caused by stress instead of H. pylori. We might even think the earth is flat...
rodin
Registered User
 
Posts: 6
Joined: Sat Dec 17, 2011 12:51 pm

Re: Is this the pathophysiology of preeclampsia?

Postby caryn » Sun Dec 18, 2011 03:28 pm

by caryn (10110 Posts), Sun Dec 18, 2011 03:28 pm

Careful - just being different and new doesn't make it a better hypothesis! Any new proposal for pathophysiology has to take into account the known evidence about this condition, which includes several phenomena you wouldn't be able to account for with simple kinking of the renal vein, like this: http://www.ncbi.nlm.nih.gov/pubmed/1729 ... stractPlus

There's also the problem of women who are advised to sleep on their left sides and who get preeclampsia anyway. *raises hand*

None of that is to suggest that we're locked into a particular explanation here, any more than we'd run with Newton over Einstein. It's just to point out that an explanation of preeclampsia has to account for many different phenomena, and activation of the renin-angiotensin system is just one of those.
Science! The articles you don't want to miss:
The Preeclampsia Puzzle (New Yorker) and Silent Struggle: A New Theory of Pregnancy (New York Times)
Looking for recent articles and studies? Lectures from researchers?
A chance to participate in research? For us on Facebook or Twitter?

Caryn, @carynjrogers, who is not a doctor and who talks about science stuff *way* too much
DS Oscar born by emergent C-section at 34 weeks for fetal indicators, due to severe PE
DD Bridget born by C-section after water broke at 39 weeks after a healthy pregnancy
User avatar
caryn
Forum Moderator
 
Posts: 10110
Joined: Fri Jun 25, 2004 06:36 am

Re: Is this the pathophysiology of preeclampsia?

Postby rodin » Sun Dec 18, 2011 04:27 pm

by rodin (6 Posts), Sun Dec 18, 2011 04:27 pm

If I understand you correctly, you are saying that the maternal immune system contributes to the development of pre-eclampsia and that this can't be explained by a compression of the renal vein.
When we look at the mechanism
(Activated RAS --> vasoconstriction --> organ and placenta hypoxemia --> vascular damage --> symptoms)
the influence of the maternal immune system comes in at the stage of vascular damage.

For instance look at this article:
http://www.ncbi.nlm.nih.gov/pmc/article ... ool=pubmed
When you look at figure 1: you see how a cascade of inflammatory effects could follow the placental ischemia. This placental ischemia could be the result of vasoconstriction secondary to angiotensin II. Differences in the maternal immune system could in this way (because they influence the inflammatory response) be a risk factor for preeclampsia.

In this article
http://ajprenal.physiology.org/content/288/4/F614.long
the author states: Convincing evidence of the elevation of angiotensin II in preeclampsia does not exist despite the fact that much of vascular pathogenesis appears to be due to angiotensin type I (AT1) receptor activation. Vascular maladaptation with increased vasomotor tone, endothelial dysfunction, and increased sensitivity to angiotensin II and norepinephrine in manifest preeclampsia may be explained on the basis of angiotensin II-mediated mechanisms.
This hypothesis explains where this elevated angiotensin comes from.

I'm not suggesting everything is clarified now, but I'm saying that this hypothesis could be compatible with the known immune reactions in preeclampsia.

There's also the problem of women who are advised to sleep on their left sides and who get preeclampsia anyway. *raises hand*
Women would develop preeclampsia when there is a "long enough" compression of a renal vein. The anatomy of the women, her body position or maybe even the movement of the unborn baby might be of influence on the compressing a renal vein. There is no guaranty that even continues lying on the left side would protect against preeclampsia in all women.
rodin
Registered User
 
Posts: 6
Joined: Sat Dec 17, 2011 12:51 pm

Re: Is this the pathophysiology of preeclampsia?

Postby caryn » Sun Dec 18, 2011 05:02 pm

by caryn (10110 Posts), Sun Dec 18, 2011 05:02 pm

Nope; the primary immune conflict happens at implantation and compromises the depth of implantation of the placenta. KIR-AA/HLA-C conflicts happen at the initial stages of spiral artery remodeling by the trophoblast: http://www.ncbi.nlm.nih.gov/pubmed/21873457 and result in less broadening of the interface at the placental interchange: http://www.ncbi.nlm.nih.gov/pubmed/21743843 (pull the datasets.) http://www.nature.com/nri/journal/v2/n9 ... 86_F2.html is a picture of the inadequate depth of implantation of those trophoblast.

There is certainly *also* an inflammatory response following hypoxia, but that's not the initial problem! :D

With respect to compression of the renal artery - the obvious way to test this would be to randomize populations, and that's a problem, since women are going to know which side they're sleeping on and be able to use Google to find out that the conventional recommendation is to sleep on the left because it relieves the compression of the main artery supplying the placenta. That said, we could try stenting animal models - though animal models are *horrible* for preeclampsia research since it's a human disease. (No one would even entertain stenting human women, especially in the absence of a predictive test.) So if those options are out, that leaves looking to see if advising women to sleep on the left side or use bedrest is in anyway advantageous to prolonging delivery, and the data here are shoddy. I'd be interested to see a randomized controlled trial of bedrest vs. activity (again, this is unblindable.)

There are a *lot* of therapies compatible (in this broad sense) with the known immune reactions in preeclampsia, but without hard data... *shrug*
Science! The articles you don't want to miss:
The Preeclampsia Puzzle (New Yorker) and Silent Struggle: A New Theory of Pregnancy (New York Times)
Looking for recent articles and studies? Lectures from researchers?
A chance to participate in research? For us on Facebook or Twitter?

Caryn, @carynjrogers, who is not a doctor and who talks about science stuff *way* too much
DS Oscar born by emergent C-section at 34 weeks for fetal indicators, due to severe PE
DD Bridget born by C-section after water broke at 39 weeks after a healthy pregnancy
User avatar
caryn
Forum Moderator
 
Posts: 10110
Joined: Fri Jun 25, 2004 06:36 am

Re: Is this the pathophysiology of preeclampsia?

Postby caryn » Sun Dec 18, 2011 05:20 pm

by caryn (10110 Posts), Sun Dec 18, 2011 05:20 pm

I just remembered this article, which might make more sense than what I type in a hurry between Christmas parties! :D

http://www.preeclampsia.org/component/l ... ember-2010

"The invading placental trophoblast cells intermingle with maternal immune cells in the uterine lining. Trophoblast express not only maternal but also paternal genes and these will be different or “foreign” to the mother. Maternal immune cells can recognize these “foreign” fetal molecules and are thought to regulate the implantation process, allowing sufficient but not excessive invasion of the placenta. In the preeclamptic pregnancy this interactive process goes wrong and there is inadequate modification of the blood vessels which can lead to “starvation” of the placenta and subsequently triggering of the preeclamptic syndrome later in gestation in the mother..."
Science! The articles you don't want to miss:
The Preeclampsia Puzzle (New Yorker) and Silent Struggle: A New Theory of Pregnancy (New York Times)
Looking for recent articles and studies? Lectures from researchers?
A chance to participate in research? For us on Facebook or Twitter?

Caryn, @carynjrogers, who is not a doctor and who talks about science stuff *way* too much
DS Oscar born by emergent C-section at 34 weeks for fetal indicators, due to severe PE
DD Bridget born by C-section after water broke at 39 weeks after a healthy pregnancy
User avatar
caryn
Forum Moderator
 
Posts: 10110
Joined: Fri Jun 25, 2004 06:36 am

Re: Is this the pathophysiology of preeclampsia?

Postby rodin » Thu Dec 22, 2011 08:01 am

by rodin (6 Posts), Thu Dec 22, 2011 08:01 am

Dear Caryn,
I have taken some time to read the articles you have referred to. In them I have found:
- Evidence that the invading placental trophoblast cells express HLA (Human Leukocyte Antigen) family known as HLA-C.
- Evidence that the maternal receptors that recognize and interact with HLA-C are the KIR family (Killer Immunoglobulin-like Receptors).
- Evidence that genetic differences and combinations in two gene families (HLA and KIR) are a risk factor for preeclampsia.
- Evidence that during early pregnancy, trophoblast cells, invade into the uterus and tap into the mother’s blood supply to sustain the growing baby.
- The hypothesis that initial or primary failure of the placenta to implant correctly into the uterus or womb causes insufficient blood supply to the unborn baby and could cause preeclampsia.
- The hypothesis that sometimes the combination of these genes (HLA and KIR) from mother and baby could result in inadequate invasion and lead to preeclampsia.

I would have to agree with you that when there is evidence of failure of the placenta to implant normally in very early stages of the pregnancy in PE, this would be an important argument against the renal vein compression hypothesis. (Or, at least it would mean renal compression is not involved in all “forms” of preeclampsia) However, I didn’t find this evidence.

An alternative is not impossible: The placenta keeps on growing during a normal pregnancy. When a normal developing placenta and unborn baby are confronted with vasoconstrictive spinal arteries and arteriole and are deprived of oxygen, this could lead to damage and cell death in the placenta. Because of be increased possibility for exudation the contact between placental trophoblast cells with maternal leukocytes could then take place. In the end this could account for the placental changes observed in preeclampsia.

I agree with you that new studies on left side sleeping have methodological difficulties. Double blind is impossible and randomization difficult. An option would be to take a large enough population of pregnant women and study the effect of advising left side sleeping on the incidence of preeclampsia. If this results in a clear drop in incidence this could become an treatment option.
There already have been studies in the past that had encouraging results in al small population of women at risk of preeclampsia. http://www.ncbi.nlm.nih.gov/pubmed/6846433

The renal compression hypothesis itself could be confirmed by studying the renal vein diameter, RAS reaction and blood pressure in reaction on different women body positions. But read the references of the article, a lot of evidence is already available. There is for instance a clear dilatation of the left renal vein in preeclampsia. (Just before it crosses between the aorta and the superior mesenteric artery.)
http://www.ncbi.nlm.nih.gov/pubmed/11243294
This would be difficult to explain without the renal vein compression hypthesis.
Stenting could become an option in women in which the renal vein blockage is clearly visualized.

Finally, as you state preeclampsia is very much a human disease. This is (in my opinion) because animals do not tend to sleep on their back.
rodin
Registered User
 
Posts: 6
Joined: Sat Dec 17, 2011 12:51 pm

Re: Is this the pathophysiology of preeclampsia?

Postby caryn » Thu Dec 22, 2011 10:58 am

by caryn (10110 Posts), Thu Dec 22, 2011 10:58 am

If you're going to reject the (literally hundreds - the articles I linked are only the tip of the iceberg) of studies that have found deranged and shallow placentation in preeclampsia patients, then I suppose you'll need to find some current studies showing that modifying sleeping position affects preeclampsia rates in humans. This still would not explain why preeclamptic placentas initially develop so differently from the placentas from normal pregnancies, from the first trimester.

You might also be interested in the studies linked from my .sig file, which are work nailing down the production of soluble flt by the placenta as a consequence of shallow implantation and subsequent hypoxia.

The rollover test has been abandoned IIRC (notice the publication date of 1983) - because it *didn't* pan out in later work.

There are ways to compromise the endothelium that don't involve compression or kinking of the renal artery - like binding all the free VEGF. There is strong support in the research literature for an upregulation of soluble flt before arterial compromise, which is why the diagnostic tests in developments pick up preeeclampsia early in the third trimester before the onset of any maternal symptoms.

The women posting here would like nothing more than a therapy for preeclampsia.
Science! The articles you don't want to miss:
The Preeclampsia Puzzle (New Yorker) and Silent Struggle: A New Theory of Pregnancy (New York Times)
Looking for recent articles and studies? Lectures from researchers?
A chance to participate in research? For us on Facebook or Twitter?

Caryn, @carynjrogers, who is not a doctor and who talks about science stuff *way* too much
DS Oscar born by emergent C-section at 34 weeks for fetal indicators, due to severe PE
DD Bridget born by C-section after water broke at 39 weeks after a healthy pregnancy
User avatar
caryn
Forum Moderator
 
Posts: 10110
Joined: Fri Jun 25, 2004 06:36 am

Re: Is this the pathophysiology of preeclampsia?

Postby rodin » Thu Dec 22, 2011 04:03 pm

by rodin (6 Posts), Thu Dec 22, 2011 04:03 pm

I'm not rejecting the studies that have found deranged and shallow placentation in preeclampsia patients. I'm suggesting that this shallow placentation is secondary to apoptosis of placental cytotrophoblasts.
The only recent study of left side sleeping I'm aware of is on the association between maternal sleep practices and risk of late stillbirth. http://www.ncbi.nlm.nih.gov/pubmed/21673002
Last edited by rodin on Fri Jan 06, 2012 12:49 am, edited 1 time in total.
rodin
Registered User
 
Posts: 6
Joined: Sat Dec 17, 2011 12:51 pm

Next

Return to Announcements and Preeclampsia in the News

Who is online

Users browsing this forum: mamc2003 and 2 guests