The Future of Preeclampsia Research

What does the future hold for preeclampsia research? 3D-printed placentas, of course. I speak to Professor Lana McClements about her groundbreaking work. And do you want to be part of a brand new study? Dr Bernadette Jenner tells us about the POPPY Study. And we meet mum Zoe, who knows first-hand the cost of severe early-onset preeclampsia.

Transcript

SPEAKER_03 0:20

Welcome back to Why the Hell Did I Get Preeclampsia? I'm aware that throughout this series I sound quite pessimistic about preeclampsia and the medical world. While funding and research is still lacking on this awful disease, there is sunlight. There are researchers who have made finding a cure or even treatment their life's work. And they are making advances. Meet Professor Lana McClements, a senior lecturer at the University of Technology Sydney and head of the Cardio Obstetrics Research Group. Since you can't safely test on a working human placenta, Lana has found an impressive workaround.

SPEAKER_00 1:10

Since arriving to Australia, I've been working and establishing my research program in Preclamcia mainly, and this latest one is all about um 3D bioprinting placenta, which is uh really cool because unlike with cancer, we can really go in and get a chunk of tissue of placental tissue and then analyze it and and you know investigate what treatments might work on it and and do like genetic analysis like they do with cancer. We we don't have uh the luxury because obviously uh collecting uh placental tissue during pregnancy through chorionic veloc sampling is very dangerous and is actually not can lead to um miscarriage. So it's not obviously done, um, and therefore we kind of what whichever placental tissue that we get, it's most from kind of term pregnancies, and that's a very different placental tissue because placenta grows and changes, and what it looks like in the first trimester is very different to what it looks like in the in the third trimester. So we've been trying to develop different models that could uh you know lead to um better understanding of what's causing all these kind of changes or um or or misfunctions in um placental cells and interaction between the different immune cells with the trophoblasts, which are the fetal cells, and then also the endothelial cells, which are the ones that that that you know supply placenta with the blood. We will call these things organoids, which are like little uh balls of cells, and they uh generally come from one cell, and then that cell divides and multiplies and differentiates into different types of cells. It's kind of like a stem cell type of trophoblast, and trophoblasts are like fetal cells that come from the fetus during the early development, um, and they form the placenta, and they're very very much responsible for forming the placenta, and if they're not functioning well early on in pregnancy, that can also induce periclampsia later on because placenta is not doing what it's supposed to do and it's not been developed in the correct way. So we are quite interested in the function of these particular cell types called trophoblasts. So when we bioprint them, what we do, we use this um rastrum bioprint bioprinter that is supplied from Inventia Life Sciences, which is a really cool technology. They make their own little matrices or bio inks that you can tune and adjust and modify according to the tissue that you want to mimic. So with Peri Clomster, we can actually identify some of these bioinks with a specific stiffness that are reflective of the tissue stiffness of the actual placenta. And then what it does, it prints these bio inks and then it prints cells and then bioinks again and cells on top, and then it keeps doing that until like little cushion-y construct is made, and within that cells start to divide and then make these little balls that are called organoids, and they look like a little placenta or mini placentas. We have been using them to understand uh this particular mechanism called FKVPL, what it does. We've tested some of the treatments as well, like metformin and aspirin. Um, we are focusing mainly on uh metformin, which is the anti-diabetic drug. Uh, it has been trialed now in in in South Africa in a clinical trial with severe periclampsia, showing some promising results. Um, in diabetic patients, it seems to reduce the risk of periclampsia compared to insulin. That could be linked to weight gain versus not as much of weight gain because the more weight gain occurs in pregnancy, the higher risk of periclampsia as well. Uh and then we're looking at kind of different repurposing some of the um use for those extra lobesicals from mesocamus stem cells, which are these little bubbles that are secreted by the cells and they call like contain all the really cool regenerative molecular cargo that could be delivered then to the cells that are struggling, like the placental cells, and give them all that little boost to actually work in a proper way. So, yeah, so we've we've been testing uh a few drugs um on on it to to kind of on these 3D biochromic placentas to kind of see how they um affect the growth of these organoids or the differentiation or the viability um and that sort of thing. So we're planning to do a lot more of that. We've been doing that and that's quite exciting, but we've been also equally developing this other model called placentona chip. These are these are little chips, like little um rectangular kind of devices that are very, very small. Um and what we do there again is quite similar to what we do with 3D bioprinting. We use these kind of gels um to mimic um the placental tissue rather than putting them on a plastic, uh, which is kind of what has been done, has been done for many, many, many years. And then we can add different cell types to the placental chip. So we were looking specifically between the interaction between these strophoblast and endothelial cells, but then what was really interesting is that we put collagen, which is kind of like a little gel that makes that environment more closer to like the human environment, and then we put endothelial cells in, which are the blood vessel cells. We actually put some inflammatory stresses in these placental chip and surrounding these cells, these jelly jelly cells, and we could find that that was also affecting how the cells behave and how good of a vasculature was formed or how much migration of these uh fetal trophy blood cells was happening across, too. Which are all the factors that can, if not done properly, or not uh if they don't function well, then they can lead to poor placentation and then eventually preclampsia. So, and then the finally the final one that I'm I'm I'm really proud of is our um point-of-care test that we developed uh for pre-clampsia based on uh the two biomarkers that we discovered. What was interesting that we found is that the ratio of these two biomarkers was increased at 20 weeks, and that was in women who didn't have any symptoms of preeclampsia. But then they proceeded later on to develop preclampsia. But once they developed preclampsia, the ratio of the two biomarkers of proteins actually went down. So it was kind of that from high to low, showing that something is happening with the body, body's trying to compensate for potentially placenta not working well and sending these signals. So we are thinking that when when you know the ratio goes from high to low, that's kind of where we can catch preclampsia. Uh that could potentially predict the risk of preclampsia at 20 weeks of gestation. So that's kind of a half halfway point. So it's too late potentially for the aspirin treatment, which is kind of has to be done at 16 weeks. But what it does allow potentially is closer monitoring. So if you in and the the the whole monitoring potentially of the blood pressure and the protein in the urine a lot sooner so that we can catch um the evolving disease, evolving preclampsia, and then potentially implement therapies uh and prevent complications because a lot of the uh you know individuals affected by preclampsia would have quite severe complications and be cospitalized and um they might may suffer strokes and you know things like that. So um we want to prevent that.

SPEAKER_03 8:51

As I've mentioned many times in recent episodes, the data needed to help researchers better understand precclamia is severely lacking. But there is one study that is hoping to change this. The Poppy study, led by Cambridge University, is hoping to get some concrete stats and facts when it comes to first-time mums and preeclampsia. I spoke to one of the study's lead researchers, Dr. Bernadette Jenner.

SPEAKER_02 9:22

So what we know from women who develop preclampsia, they have a longer term risk or increased risk of cardiovascular disease later on. And so the question that we really had is uh is it just the preclampsia alone that increases their risk, cardiovascular risk later on, or is there something before pregnancy in that preconception period that means they've they were always going to have a higher risk of developing that cardiovascular disease later on? And essentially the stress of pregnancy meant that they develop preocclampsia, but it's more that there was something happening beforehand. So we already know from what we call pilot data, so smaller numbers of women, that there are cardiovascular differences in women who develop preocclampsia and women who don't. And so, what we're hoping is that with more people we can develop kind of a stronger understanding of that and to really dig down and say, well, actually, this is this is the reason. Um so the Poppy study stands for preconception, so before pregnancy, it's postpartum, after pregnancy, cardiometabolic, so the study of basically your cardiovascular health in prima gravid pregnancy. So that's really important. So it's in a first pregnancy. And it is the largest UK preconception study. So the largest study that we are capturing people before they become pregnant and then monitoring them as they go into pregnancy. So a lot of studies before have looked at women as soon as they become pregnant, their positive pregnancy tests, have then said, if you get a positive pregnancy test or you're booked with a booking midwife, come see us, this is our study. But the Poppy study is trying to capture those people before they become pregnant because we know that before pregnancy, into pregnancy, there is huge cardiovascular changes in those first six to eight weeks. So as soon as your positive pregn um your pregnancy test is positive, there's already changes that have happened. So we need to know what your baseline is to see what these changes are. So the Poppy study, we're trying to recruit 3,500 women. So there's 3,000 women who are planning a pregnancy and 500 women who are not planning pregnancy in the next 18 months. Um, and so far we've recruited just over a thousand, which is fantastic, but we still have sort of two, two and a half thousand women to go. Um, and what we're hoping to find out is really the women who develop preclampsia or gestational hypertension, which is essentially just developing high blood pressure in pregnancy without the organ dysfunction that I mentioned, and also fetal growth restriction, so that's babies being born smaller than they're meant to be. Is there something we can pick up before they're pregnant that shows us that particular person is going to develop that? Because if we know that and we understand what's going on, then we have a way to try and treat it. So we've got six sites open at the moment, we've got three in London, and we've also got Glasgow, um, we've got Manchester, and then obviously here in Cambridge as well. Um, but our website, which is www.poppyuk.net, has got all of our sites on there. Um but equally, if you're want to email in and say, I live in X and I'm interested, where's the closest place for me? And if we find out that we're getting a lot of people in one particular place, then we can start thinking about whether having a site in that particular place is you know is beneficial to have that. But those are our six sites at the moment. So we see people before they become pregnant, and it can be in the kind of a year before they become pregnant. So often what we get is people say, Oh, well, I'm not I'm not going to be trying until December. Well, I'd much rather see you now, because we've had a couple occasions where people come and they're already pregnant. And if you're already pregnant, congratulations, but we can't have you in the study. Um, and so if somebody is thinking about pregnancy, or even if you know, not to be too typical, but if somebody's planning to get married and then have children afterwards, come see us beforehand. We can do all your baseline investigations, and then you've got a year to go off and try and get pregnant. And if you don't get pregnant in that year but you still want to be part of the study, we can re-enroll you and you can carry on with the study as well. When someone comes into the study and we do their baseline investigations, then we see them at six to eight weeks, eighteen to twenty two weeks, and 34 to 36 weeks. And then for a proportion of people, we will see them at 9 to 12 months after they deliver, and that's to try and capture all that information throughout pregnancy. When you come to see us, we do pretty much the same thing each time. So the first time you come to see us, we do very simple things like we take a bit of a medical history, we take blood pressure measurements, we take some bloods, we do a step test, we do some measures of sort of central blood pressure measures, and then in some sites, so like here in Cambridge, we can do echocardiograms as well. So that gives us a real very good idea of your baseline cardiovascular health. Um and then we do that all at the beginning to give us a good idea and understanding of what your baseline cardiovascular health is. We do the measures throughout pregnancy, and then after the end of pregnancy, for that subset of women at the 9 to 12 months, we again repeat the blood tests and repeat to see what the differences pregnancy has made. I think that is again the mystery of pre-clampsia. So we can say, you know, we know that there is a link with obesity, we know that there's a link if there is a higher blood pressure before pregnancy, or as I said, some of those inflammatory conditions. But because we don't know exactly what's changing, we are essentially guessing who is going to develop it. So it's not that everybody who's got a higher blood pressure before they're going to pregnancy develops preeclampsia. So, what is it about that person or that combination of things that means that they're more at risk? Um, but ideally, I said we try and get as many in now as possible. So, as I said, still recruiting are very much needing women to come into the study so that we can follow them, follow them up and see the outcomes. From the Poppy study, I think we can really understand the what we call the pathophysiology, so the the the mechanisms that happen of why somebody develops pre-clampsia. And what I would hope with that is two aspects. One, we can identify people earlier so that we can input preconception health, so before they even become pregnant, identifying people and saying, look, okay, we need to do XYZ to reduce your risk. Um, or that we at some stage would have a treatment for preoclampsia that isn't delivery. That would be the golden egg. Um, but that I think we've got is still a long way to go.

SPEAKER_03 16:00

As you've heard, it's not all bleak. There are people working on trying to understand preocclampsia and how to treat it and maybe one day even cure it. There's a long way to go, but I am filled with hope for what is possible in the future. Now it's time to talk to another mum, Zoe. Zoe had severe preoclampsia over 20 years ago. Again, this is a story of baby loss, so please take care of yourself if you decide to listen on.

SPEAKER_01 16:32

So um 1999 I was 35. Um, I was helping to run um a finance training business in London. Um Christmas Eve that year that I was pregnant. I had a change and test it that would take me the odds that I hadn't missed carried for six weeks. I was sort of naively expecting that it would be. Um three weeks later, about 24 weeks, I became a permanent resident in the course. Um and the first I knew of pre-campus was when my um very poorly bedside mannered consultants was at the end of my bed with a bunch of medical students. Didn't even introduce himself, picked my notes up and said she said medical students. This lady's got pre-campus and uh imagination she's probably going to be delivering her baby in the next three or four weeks. Um I think at that point my temperature, what we could do about it. But what we could do about it was essentially deliver the baby in sort of a world where you expect the medical profession, I guess, to have some control. Um was the big shock. Um what actually happened was they eat it out to uh around 29 weeks. Um by that date, my um protein was really at the top end of the scale. They took some advice um and decided to deliver at that point. To be honest, up to 28 weeks, they'd had a pediatric team on standby when we got to 29. They said they thought that um that would be okay. I'd had um whatever they gave at that point for the lungs, which is obviously not as sophisticated as it now is. Um I had a uh cesarian, um by cesarean, he was about three pounds two ounces. Um and ordinarily should have, you know, the odds were reasonably good. He was certainly bigger than some of the the babies in the neonate that did survive. Um but he was born on the 13th of June 2000. Um and on the 14th of June he um got an infection. He died in the early hours of the the 15th, um, because the infection wasn't survivable. Um so I was um left in the post-natal ward with people coming out going, it's a boy, and lots of happy people. And it was very difficult place to be. It took us a little while to find out that there was a sam frame, and uh, eventually the hospital moved us into it. Um a couple of the midwives and the registrar were amazing, and in fact, I still exchanged a card with one of the midwives who were fantastic at the time. Uh but baby loss is obviously not something that they particularly expect on the antenatal throat, post-natal wards, preocampus, my type of preocampus, very early onset preocampus is also not something they really came across. So they really struggled to deal with somebody that was basically a long-term statement. Long-term question, which you know, most people were just coming in and and and going out. Um turning up. But the mechanism you know, the the mechanisms were awful and some of the sensitivity was the week. Achievements and the the period afterwards, I got in touch with APEC, the pre-Eclumsy charity, to try and make sense of a bit of what had happened and why it might have happened and you know what the odds were of it happening again. And I had a pre-conception appointment with Professor Chris Redman, who at the time headed up Axel on Preocalcia and was the country's specialist, if you like, in preoccalpsia. And I went up to see him at Oxford, which is about an hour away from where we live. And he sort of said, Oh, you almost certainly will get preoclampsia again, you know, if you had it that badly that early, then you'll probably get it again. Um, but we can do stuff to manage, try and manage it. Uh, we might get you a bit further down the line, you can take low dose aspirin till we're in pregnancy, you know, we can do some stuff. So um I asked if he would take my care on. I did that. If I was your wife, where would you recommend I care? I have my next baby. Um, and so we went to Oxford um and the Silver Star unit there were fantastic, he was fantastic. When I was in the Silver Star unit, I was in a problem pregnancy unit at the Radcliffe, and that was very different, first of all, because everybody that was in there had some sort of problem. So you didn't feel like an alien, you felt like a member of a club. And whilst it wasn't very nice that everybody in there had some sort of problem, there was a sense of camaraderie. Being in the Silver Star was mentally good because everybody was super sensitive about your situation and understood how traumatizing it was. Um, and therefore, emotionally they dealt with it really well. And just silly things like you know, there was a butterfly on my nose, which meant that I'd previously had lost a baby. I ended up in hospital the first time about 29 weeks, which was around the time Jack had been born. I think my blood pressure was a bit all over the shop, and they sent me home again uh for a couple of weeks, and then I became a permanent resident in uh John Radcliffe at about 30, 31 weeks. And Maddy, who is now 24, was born on um the 7th of September, just short of 36 weeks, and I was just about to be 37 by the time that she was born. Uh we were a bit shocked, but she didn't need to go to special care. I wasn't really prepared to look after a baby. We had literally nothing. We had bought nothing. Uh she had a a silver star baby grow, and the day she was born, my husband went off to mother care and uh did a bit of shopping um because we hadn't wanted to to I guess tempt fate. Um and I I had not realised which um it's probably I guess naive, maybe a protection mechanism, how much Maddie being born would bring back the grief for Jack. I mean, you know, post delivery of hormones are all over the place anyway. But um so I kept calling the baby tea, and then there was a an awful moment fairly early doors where she seemed to stop breathing temporarily and we were like causing havoc on the ward. But uh yeah, so the end of the the pregnancy story was um obviously a happy one. Um it had taken a lot to get there. Um I'd spent a lot of time sitting on sofas doing nothing. It wasn't a very enjoyable pregnancy the second time round because you're sort of permanently waiting for the time when the protein's showing up in your urine and the blood pressure's going haywire. Um wasn't relaxed, I definitely wasn't a relaxed parent to start with for the first few months usually expecting that that something else was going to happen. Um but we decided, I mean I you know I could have gone on potentially to have other children, we decided that we would stick with our luck. Um I when I was on the Silver Star, somebody died, one of the mums died of Helt syndrome, and it was a very sobering moment because I think you're focused on the baby, looking after the baby. Certainly when I had Jack, my thought was entirely about him. It wasn't really about the damage that I could be doing to myself and my body. I wasn't expecting, you know, you don't I don't think in in today's world you embark on a pregnancy thinking you might not come out the other end of it. Most people don't even assume a baby, you know, that they'll they assume that there will be a baby at the end of it. Um so we decided we would uh take our luck and our blessings and uh not embark on any further pregnancies and take any more risks. Uh so I have a a lovely 24-year-old daughter and we have a couple of dogs and uh and we have a good life. But um preoclampsia robbed me of a relaxed pregnancy, it robbed me of an enjoyable period of time when my baby was small. It robbed me of a family of three, which was probably my intention in the beginning. It's when something happens in an instant that changes your life, you feel like you're never gonna be happy again and that you're never going to find normality again. And the reality is that we are all more resilient than we actually think we are, and that if at the time somebody said to you, Oh, you know, some good will come of this, you would probably want to something. But you can't choose what happens to you. You can find a way to pick what happens to you up and make it part of the fabric of your life, and that's all you can really do. And in the beginning, it takes all of your courage and energy to just stand up. After a little while you can face forward instead of looking backwards, and eventually you will find a way to move forward. And people talk I think language is a difficult thing. People talk about coming to terms with what happens to you. I don't think you ever come to terms with what happens to you. You find a way to carry it with you. Um there are still days 20 Jack Jack would have been 26 this year. There are still days 26 years on where something unexpected can completely flaw me. Fundamentally, I have a good and happy life. I, you know, I am happy. Uh Jack is a part of our story. Uh, and in that story we met lots of people who gave us huge amounts of support and courage. And I think uh that comes from surprising sources. Some of the people that you saw you were closest to you can't cope with your journey. And you really need to remember that that is about them and not you. And it isn't necessarily what you would choose, but other people who are probably completely unexpected will step up for you. Um and you just have to you know take it one step at a a time and look for the glimmers of light that are there.

SPEAKER_03 31:06

However, survival rates of commercial babies have experienced.