Scientists find cause of preeclampsia?

[joelle]

I just wanted to say thanks to you all for helping me understand this research (especially Caryn!). This has featured fairly prominently in the British press and it was only through this forum that I've really understood it, so thank you.

[jenprzygoda]

Thanks so much for all the info ladies. I am actually teaching redox reactions this week and have just finished enzymes with my AP Biology class. They all know about my experience with HELLP and I am using this study as a way to show them the 'real world' applications of what we are learning right now. These discussions have given me a lot to think about in my preparation for class tomorrow. My hope is that maybe one of my students will find this to be his or her calling and be the one to find a cause or better yet a cure for all those moms and babies out there!

[caryn]

A useful discussion here: http://www.nhs.uk/news/2010/10October/P ... mpsia.aspx

However, further research is needed to see whether oxidative changes in angiotensinogen would be sufficient to raise blood pressure in pre-eclampsia, and what triggers oxidative stress during pregnancy. At this stage it is not clear whether these changes to the ratio of oxidised-to-reduced angiotensinogen cause pre-eclampsia itself or simply a single symptom of pre-eclampsia. Further research is also required to understand how angiotensinogen regulates blood pressure before deciding whether it is a suitable target for new drugs.

While the results of this research are compelling, raised blood pressure is only one initial symptom of pre-eclampsia.

[caryn]

Also, I've sent email to the Medical Board asking for commentary on the significance of this finding. Many of them are at ISSHP in Melbourne (with Eleni) but I hope they will correct anything I've gotten wrong and let us know their takes.

[caryn]

All of the research being done on this is valuable, even the research that gives us the answer "Nope, that isn't it. Try again." That sort of answer lets science rule something *out*, which narrows the set of things to look at...

I can quite confidently say that this will not lead to any near-term cure. The obvious way to affect this mechanism is ACE inhibitors, and those cause birth defects. So they will have to try to a) invent a new drug based on what this tells them about the pathway to affect, b) get that drug successfully through human trials, and c) have that drug work for long enough to be worth using (48 hours, for steroid shots to take effect, is what we need right now.)

But because this is not the only thing going on in PE -- this just has to do with how to raise blood pressure, and probably doesn't affect placental abruption, or IUGR, or shallow implantation of the placenta, or liver enzymes, etc. -- it's likely that successfully targeting this pathway will slow but not stop the course of the disease.

If they can invent something from this that buys the 48 hours for steroids, that will be a *huge* advance, so I very much do hope that it is useful for that in the long run. But don't hold off on subsequent pregnancies waiting for a cure!

[ktsl123]

What I am wondering is do you think this is valuable enough information that will help with finding treatment or even a cure for preeclampsia?

[catherine]

What I think is interesting about this particular study is that the researchers were trying very hard to understand global mechanisms involved in causing hypertension, not specifically pre-eclampsia. So their research focus was on these quite well-understood effector molecules trying to figure out the biochemical interactions between them that ultimate lead to the disregulation of blood pressure. They observed the fixed ratio of oxidised v native protein in their samples and then wanted to know if this ratio was thrown off when a hypertensive episode occurred. Pretty hard to do with normal people experiencing a transient episode of hypertension I would imagine. However, pregnant women with preeclampsia are experiencing new-onset hypertension and in a relatively sustained fashion so they made the perfect population in which to examine this question. Furthermore, it's relatively easy to match them with nomotensive pregnant women of similar gestation for control purposes. Bonus, they were able to also examine stored serum from the babies delivered by the women. So while the implications for preeclampsia are interesting in that it reveals a mechanism by which hypertension can be triggered and maintained, the implications for those folks with hypertension generally are also important. So we're giving back to the world!!

With respect to the statistics question. They were comparing a fixed value for individual serum samples between two matched populations, or basically measuring the ratio for each sample (1 value/patient or control). That is relatively simple statistics (Student t-test) and the sample size under that circumstance did not need to be high when the difference was so different, even though they had to include the patient samples which didn't appear to have varied from the norm. Biology is variability demonstrated once again. Stats become much harder and more complex when you are trying to perform clinical studies/ outcomes etc.

[caryn]

Don't get me wrong; it's a really interesting article. But partly that's because it helps confirm multiple pathways by which things break in PE. Remember how filtering sflt-1 from maternal blood by dialysis bought a few weeks before delivery had to happen anyway, because it wasn't the only problem? If bp is rising not just because sFlt is upregulating production of angiotensinogen, but also because it is easier to break into constituent molecules once produced, then that opens up another pathway -- though yes, it is one that's been investigated a *lot* via antioxidant trials etc.

Angie, yeah, it points at a way to make a screening test, but will have to be further refined. I haven't checked the maths yet but it is possible to call something "statistically significant" even with a small sample size, if the analysis is strong enough. Since this is in a top top tier journal, I suspect the effect is there, maybe just not as useful as the popular articles want to say.

Kerisue, this is a full-text scientific paper, and yes, _Nature_ still charges for them, but we have a lot of posters who work for universities and can get copies for free because they have institutional access. Someone might well be able to share with you.

They took pics of the constituent atoms which is kinda cool -- the measurements are reported in angstroms. :)

[kerisue]

It says I have to pay $32 to read the article. Is that right?

[angieb]

So...it sounds like this is mostly stuff they already knew?

Also, thanks Caryn! I would be lost without you! :)

And thanks ktsl123 for posting this!

Also again, 24 pregnant women does not seem to be a large enough sample size, especially if there were 12 pre-eclamptics and they missed 4 of them, unless I'm misunderstanding or oversimplifying.