There Are More Drugs for Erectile Dysfunction

Why have there been more drugs developed for erectile dysfunction than for anything that can happen in pregnancy? This episode explores the funding gaps and regulatory history that have left preeclampsia so poorly understood. we hear from Rita, a scientist who lost her daughter Freya to it.

Transcript

SPEAKER_02 0:20

Welcome back to Why the Hell Did I Get Preclampsia? When I started on the journey to find out why my placenta failed at the last hurdle, I was so angry about the lack of information out there on this disease. When you are diagnosed with other serious conditions like cancer or diabetes, it feels like doctors have this wealth of knowledge that they are confident they know what to do to fix you. Well, it doesn't feel like that with preoclampsia. With the many mothers I have met, the experience seems to be the same. You are often met with a bewildered medical team, misdiagnosis, and one inevitable only treatment, delivering your baby. But it's truly not the doctor's fault. They are only working with the information they've got, which is mostly nothing. The scientific world has been aware of preoclampsia since ancient Greece. It's a very common condition, suspected in around 80,000 pregnancies a year in the UK, more than the number of women diagnosed with breast cancer. And it seems that people are barely aware of it. I feel this frustration from all the researchers and experts I've spoken to. Dr. Francis Conti Ransden from last week's episode speaks quite passionately about this.

SPEAKER_03 1:43

Running clinical trials is a super expensive, and if you don't choose the right endpoint and you get a negative result, you know, so like there's m the amount of money that it takes both to develop and test and to get drugs but also innovations into healthcare is a very, very challenging path. And pharma companies are one of the few kind of entities in the world that have the money to take on that kind of work. That is the kind of money that you know the majority of people will never be near in their life. I include that, I include I include myself in that group. So, you know, you need to have ex incredible amounts of money to make these things move. And I think the problem is that in women's health, and then in maternity in particular, we have we just we really lack data and evidence, and that's a reflection of the funding landscape for the last you know 80 years because women's health has been, hasn't been a priority, and pre-eclampsy, like I said, is one example of that. But there are lots and lots and lots of others, like endometriosis is another, you know, another one, diagnostic times terrible, treatment options really, really limited. Um, PCOS, we just put women on the pill. You know, there's so many things that I do in my day-to-day clinical practice which are so unsatisfactory, and I think about you know, my oncology colleagues who are like genotyping everyone, and they know that the the tumor cell uh genes and they're they're developing all these new medicines all the time, you know. So there are new medicines in oncology, it's like it's a huge pipeline. In women's health, there have been two in in pregnancy, two drugs in 50 years. There have been more drugs for erectile dysfunction than the whole of or anything that can happen to you in pregnancy, just to give you a flavour of the mismatch, and I think that's why it's so challenging because the problems are vast, the unanswered questions. You know, there's tons of them, but actually the money to make to move things forward is is incredibly, incredibly limited. And again, that's one of the reasons why I've started to take on a more commercial role because I'd like to really make difference. I need money, you know, it's all very well trying to research stuff, and obviously you do get grant funding, but um, it's uh, you know, it really feels like to be able to move things forward in a different way, you you you need to have you need to be the one who's holding the purse strings because that's who gets to decide what what what gets progressed. Uh, and and and I think there is change, you know, the Gates Foundation are doing amazing work in women's health. There have been lots of calls on pre-eclampsia in the last couple of years. Melinda Gates, Pivotal, she started, you know, putting calls out specifically for women's health. So people are starting to do this, but it's gonna take time to undo the last 80 years about who has been, what have been the focuses. Um, you know, it's a it's a very long road.

SPEAKER_02 4:38

One of the biggest hurdles facing researchers is a big one. How do you test new treatments on pregnant women without hurting their baby? In the 60s, Western Europe learned the hard way about what medications can do to a fetus. Fermidamide was a terrifying tragedy and scandal. A medicine that was meant to treat morning sickness caused babies to be born with severe deformities, such as missing limbs and brain damage. Thank God my nan turned down this drug when she was pregnant with my dad. The world of fetal medicine never really recovered, and this is a topic Dr. Natalie De Petro-Mager has extensively studied.

SPEAKER_01 5:17

I'm Natalie DePetro-Mager. I am a pharmacist and a maternal and child health epidemiologist. So there are good historical reasons why it was decided to exclude women from the early phases of clinical trials. So the two major turning points were drugs that had been used and given to women during pregnancy that were found later to have very serious adverse events. So one of these was thalidomide. Through that experience of that drug being on the market and taken by so many people, it strengthened a lot of regulations, especially in the US for the FDA. It strengthened requiring that clinical trials have a higher bar to show safety and efficacy of a drug before it could get approved and on the market. And it also led in the late 70s to FDA coming out and saying that women of childbearing potential should not be involved in the earliest phases of clinical research until we knew more about that molecule and what impact it might have. The second drug that I don't know is talked about as much is known as DES. And that was a product that was given to women to prevent miscarriage as well as other health conditions. And with DES, the issue was very much delayed, where it was found that the children and even sometimes grandchildren of women who received DES while pregnant went on to develop cancers or other health conditions. So it had this delayed effect of this in utero exposure, but not realizing until the children became adults themselves that these effects were happening. So DES and thalytomide came together, you know, these historical um happenings, you know, caused regulators to think, well, we need to be more careful and protect a potential vulnerable population of the fetus, of their exposures to these medications. So as I mentioned, in 1977, FDA issued their regulations indicating that women of childbearing potential should not be included in the earliest phases of research. So this is those phase one, phase two trials, and they had a very strict narrow view of reproductive potential. Even if women were abstinent, didn't have a partner, had a sterile partner, were on birth control, they weren't eligible if they were at all capable of becoming pregnant. Now that ruling had an unintended consequence of because of saying that it wasn't safe to look at women in the earliest stages of research, many pharmaceutical companies and others in research took a very conservative view and felt that women should not be included in other phases of research as well. So really, FDA did not intend for the consequences to be that women weren't at all involved in clinical trials. And then, you know, frankly, there were lawsuits and a lot of legal liability, and so sponsors were also not sure if it financially made sense to include women in clinical trials. I also think at that time there was less understanding of the potential differences between men and women and how they might metabolize drugs, what their outcome to the drug may be. And so we call it the male norm, just this assumption that studying the male body would give you an answer that would also be applicable for the female body. And we have found in time that that is not the case. Over time it was recognized that this effect or this unintended consequence really meant we didn't have a lot of answers about women's health, especially for very common diseases like cardiovascular disease, where large studies were done with tens of thousands of people and no women were enrolled. So that outcry led to the pendulum swinging the other way, such that in their early 90s, FDA came out and said, now you must include women in clinical trials. And if you don't, you have to have a very good justification. But unfortunately, some of that unintended consequence still remains.

SPEAKER_02 9:24

I know I sound very cynical and judgmental about the medical and pharma world. While the issue of being sued and funding play a big part, I know there are genuine concerns about the safety of women and their babies.

SPEAKER_01 9:37

The first tenet of medicine is always do no harm. We don't want to hurt people with our interventions or the medications that we recommend. And that extends, I think, not just from clinicians to the pharmaceutical industry because they don't want to be developing drugs that are potentially harmful, um, that are gonna harm people. I mean, we're all in the business of trying to improve people's health and help them lead healthier and longer lives. And so I do think that, yes, I mentioned, you know, lawsuits earlier. That wasn't, I would say, the main driving force of excluding women from clinical trials. I think it was this felt of a duty or obligation that, you know, we are doing this, we're trying to create new drugs to help people. And we don't want to be inadvertently harming people in the process. You know, their main goal is to protect the public health. And at that point, that's how they felt it was best done. On the one side, as we've discussed, you are potentially exposing her and her baby to something that we don't know much about at this point in time. So there could be harmful effects that we aren't aware of. But yet the flip side of that argument is well, once the drug is approved and on the market, it will be prescribed widely to a broad number of people who were never studied in the clinical trials, and likely pregnant women will take the drug at that point. And so is it ethical that potentially thousands or millions of pregnant people could be taking this drug that was never studied? So when a drug gets approved and on the market, the the studies don't stop there. The pharmaceutical company, the FDA, other regulatory bodies will collect safety data about the drugs that are reported, whether that's from patients, clinicians, anytime there's an adverse event for a drug, there's an opportunity to report that. And those data are collected and analyzed. And that's why over time you'll see the side effect profile of a drug change, or even sometimes a drug be removed from the market because it's found from the post-marketing data that there are adverse events that are of concern. So we do have information about drug use in pregnancy, mainly though, through that post-marketing data. Over the years, there have been advocacy groups that have advocated that pregnant women should be involved in clinical trials. You know, there are some groups that do believe that it is, you know, although those individuals are putting themselves out on out there, you know, with potential unknown effects. Again, some people believe it's better to have that contained in an environment of a clinical trial to better understand that information before that drug is out and able to be prescribed to a much wider group of people. But yes, it does take those individuals being willing to be in that clinical trial in order to be even able to capture that data in the first place.

SPEAKER_02 12:18

Now it's time to meet another mum, Rita. A doctor and researcher whose experience with preeclampsia has possibly changed her field of research and career. I want to warn listeners that Rita's story is one of baby loss. A really devastating thing to talk about, but very important. Remember, preeclampsia is a leading cause of infant fatality, and it isn't something we can shy away from. So please take care of yourself if you decide to listen on.

SPEAKER_00 12:52

So my name is Rita, and I am originally Italian, but I moved a little bit around from my country because of my job. So I am an assistant professor in chemical biology. The field I worked on was always cancer. And yeah, I worked in active research to try to understand like new mechanisms of cancer and trying to get like uh wrapping up our mind around this sort of terrible disease. I am now in London. Um was in London a few years ago, um and then I mean I moved to the Netherlands, then I came back. So I uh got pregnant when I was I mean I actually found out that I was pregnant my 37th birthday. I also had a journey of infertility, uh so it was like around two years journey of infertility, and uh we were very happy. Um and I have to say, like mainly maybe this is like when you have a journey of infertility. Like when you have a journey of infertility, the discovering that you are pregnant looks like the end of the painful uh part path. But yeah, I realized now that that that's just the beginning actually of another path. Oh, because of the experiences of my sisters, of my friends around me, I I have never known someone who had lost a baby. I mean, yes, miscarriages, I had a miscarriage myself before the Freya's pregnancy. It felt always like you know, you go over the three months, and if you go over the milestone of the three months, uh then it's fine. I mean, you know, you get the viability, the baby will survive in any way. So yeah, I had this weird uh I would say stupid confidence, uh, I I say now. Uh but yeah, it was uh it was a normal pregnancy, nice pregnancy, um, well, all the yeah, all the symptoms of the first trimester. I had strong nausea, and um yeah, it was it was tough the first four months, but uh yeah, everything everything went went okay, everything went fine. I would say until I was around 26-27 weeks pregnant, where um I started to realize that I was putting on a lot of weight. And um I didn't really ask myself what's going on here because um yeah, I also felt okay. This is I mean, I am very careful and I am a big um I have big hypochondria, so like I also decided to not ask myself many things. But then I really realized it was around like Christmas and uh New Year's Eve. I really realized that I I wouldn't fit in in my shoes even, so my feet were very swollen, and um it was also kind of you know something to be expected uh at the last part of the pregnancy. I was always doing a full-time job still standing up every day, so I was like, okay, this is normal, but but then at night I would go home, I would put my feet over the on the pillow, and then nothing would change. In the morning I would wake up and my feet were still uh like as swollen. So I started thinking something is not right here. And I had my midwife appointment uh at the beginning of January, and they measured my pressure, and my blood pressure was around 140-90, something like that. So below the threshold that the clinicians used to indicate and diagnose preclampsia. So I was saying, yeah, I am just very swollen, I have this pressure. Do you think that there is something going on? And I was told, no, there is nothing, it's completely fine. Your pressure is is is okay, you are swollen, but everything is okay, don't worry. And um, yeah, I remember I was very, very bad this this this week. I felt like very heavy, headaches, um very nauseous, and it was weird to have again nausea at the end of the pregnancy. And yeah, I mean at one point I I had put I think 10 kilos in like 10 days, so I was like, this is not normal because I'm not eating that much, and I was seeing myself just growing and being swollen, like also the eyelids were swollen at one point. So when I went again at the midwife, I was like, listen, I think something is not right. I I explicitly asked, Is this there a possibility that this could be preclampsia? And she told me, no, really, because like you have the blood pressure and the blood pressure is way low than uh than than what we consider that. You are at like at that point I was around 31 weeks of pregnancy, and she said it's okay to have it a little bit higher than normal because my blood pressure normally is around 165-70, and then I was saying 140-90 is a pretty high for me. That day I didn't give up. There was something inside myself that was like, something is not right, I feel it. So I asked explicitly to have the urine test to check the protein levels. I still remember the words of the midwife. She told me, uh, I am doing this for yourself more than for me, because I am not worried, but I see that you are worried and you um I will do it for you. And you know, we are talking about literally a urine test, like a a strip test. And uh yeah, I remember it was it was an evening, and uh yeah, my husband was with me having to go to a singing lesson actually, and it was on in late, and then I said, Yeah, don't worry, go to the singing lesson, I will do this test, and then see you. Oh then I did the I did the test, gave the urine sample, and then the midwife came back so pale in the face, and she tells me, Oh my god, your urine levels are very high, they are like close to hundreds, and normally you would have like you will need 35 to be diagnosed with preclampsia. And I had no words at that point, and then yeah, she sent me directly to the hospital, of course. So then I went to the hospital, and and yeah, at the hospital then they said okay, it will be good to have that you will have a 24 um sample urine urine sample to test, like the um the pre-clampsia. I had these, so I went back home that night, but after the 24 hours urine samples, they said yes, you have preclampsia. After five days, like the um the disease like proceeded very very fast. And the the most worrying thing I had was like my vision really changed. So, in order to prevent seizures, I was I was put on magnesium sulfate. And I was telling my husband, I mean, why they not just give me this magnesium sulfate? Why why are they doing this big deal? Like, what can it be? This magnesium sulfide sulfate. And then, yeah, well, when they gave me, then I realized what was it like? It was like in the beginning, 10 grams in 20 minutes, like my body was on fire, literally, like it's such a bad feeling, like such a unique bad feeling, like my tongue was boiling, and it was so weird. I spent like one week in the hospital where I was constantly pushing to deliver. Uh, I was like, really, I want to deliver because I was really bad, strong headaches, uh vomiting constantly, uh, the magnesium was giving me so much nausea. So it was like very, very, very, very hard days, difficult days, and then I was asking. Of course, the baby was completely fine, monitored every second, she was moving like crazy in my belly, and um yeah, I mean I was always told, well, we have to wait at least 37 weeks. Uh so then the baby's not premature, and you know, we we avoid other risks. But at one point I was like, listen, I mean, I don't think that 36 weeks, five days is very different from 37. At this point, I really can't take it anymore. And I mean, they kind of listened to me in a way, uh, but they took like the long turn, they started already uh inducing me for the delivery. I I put the first balloon like on Thursday morning early, and uh it was Saturday, and I was still like that. So having mild contractions, this balloon in my uterus, but nothing was happening. Uh in the meantime, I was like really degrading. I told them, please, you really have to make me deliver because I am done, and they decided to give me morphine to kind of help with headaches and an anti-emetic to stop the vomit. And then they said, first time, first thing in the morning on the Sunday, we will give we will start giving you oxytocin to really induce the delivery. Freya was completely fine also after the morphine administration, which also was another worry for the baby. And yeah, they started giving me the oxytocin, and uh I vomited like I think the day of my labor and delivery I vomited 50 times. Um, and yeah, I mean I started the I started basically my labor, they broke my waters, and um there was a moment of fear already at the when they broke my water. I had a lot of water, and that was a funny moment because, like, all the doctors were like wet for my water, so they had to change their clothes. Um, but then the doctor could not feel the heartbeat of Freya immediately. Uh, but then it was just he told me it may have been like just a shock that she had in losing the water, but then they found it, they also put like a probe on uh on her head. What they were noticing from the beginning on is that Freya was reacting a lot to the contractions of my uterus. Um, so every time my uterus will contract, uh, her heartbeat will go down. And uh yeah, I did this for uh nine hours basically. Uh I was really really bad at one point, so I asked for having an epidural because I I really was very bad. Um at the epidural, but uh they could not increase the oxytocin dose because of the early decelerations that Freya was showing, so they didn't want to put her under pressure more. I was like, I don't like this up and down over heartbeat, uh, although they were telling me everything was fine. I was literally almost fainting, so I was like, I really have to deliver now. Now, if it's not possible naturally, please do a c-section because I I can't anymore. So then she agreed to do the c-section because it was my wish, and um, we literally went to the c-section room like very very relaxed, very slowly. Everyone was really relaxed, my husband was with me. Um yeah, they they immediately cut me open and uh yeah, they showed me Freya after um 10 minutes. Um they showed me her face. I remember to have seen her face, like she was kind of a little bit grumpy, and I immediately said, Oh, this is my daughter because it's my same expression. Uh, I realized immediately that she didn't cry. Uh, but I wasn't so worried at that point because they have told me that normally babies that are born a little bit earlier, and for with C-section, they need a little bit of help to breathe. So I didn't really, I wasn't scared about that, also because I clearly saw like a a little like her grumpy face, so she was she was alive, you know. I could see that. And uh yeah, what happened after that? Uh it's just a still a big blur in my mind. Um Freya lived 38 minutes. Um 38 minutes that were terrible because I was there and they were stitching me, removing the placenta and everything. Uh, I was in a Dutch hospital, all the doctors were speaking Dutch, and I was not understanding what was going on. And uh yeah, I mean Freya was born in very poor conditions already. Um they gave her oxygen and she took a breath and her heart went up. But and there was a one point where I asked my husband what was going on and is that so he could understand them, and he told me, Oh, they are bringing her to the neonatal world because she started breathing and their heart is beating, and I relaxed a bit. Uh, but then something went wrong. Something went wrong. The doctors uh kept coming, like more and more and more in the room. Uh also the doctor that uh that was taking care of my anesthesia was helping them to reanimate Freya, and at one point my anesthesia went off, and then I started feeling all the pain, and I had to call. I I scrammed and I called the doctor, and she ran back to give me one more dose of anesthesia. And yeah, all I remember is just uh being me on this uh on this bed and seeing like doctors trying to reanimate her during doing like chest pressures, compression, and um yeah, it's um doctor came and told us that she didn't make it. Um yeah, and at the same time I I was losing a lot of blood, so they had to really stitch me very fast. Um and yeah, I mean after that it's a big Yeah, I had 24 hours of um shock. I don't remember anything. I I don't know, it must have been a mechanism of the brain to defend you from from what happened. Uh I regret so much that I didn't hold her when she was just dead and she was still at work. I feel very guilty and a bad mother for that. But yeah, something in my brain didn't work in that moment. There is believe me, I have we have tried to find so many answers and ask so many questions to many doctors, many tests. We we gave the permission to to look at their organs and do all the possible tests that could have done, and nothing came out of it. Freya was perfect. Um the only thing that they found out was that she had gasped in the uterus before because some cells that are normally present in the amniotic liquid were found in her lungs. Why she gasped it's not known. My placenta at the moment of the delivery and the umbilical cord showed perfect transmissions of gas and everything. So the most plausible explanation is an acute cord compression that can be fatal for a baby. Um the only the only thing that keeps me going is the will of trying to avoid these things in the future, if they can be avoided. And yes, as a scientist, I feel the responsibility of pushing this field. Immediately after the death of Freya, I knew that uh I was always very passionate about science and research and trying to find solutions and answers. I could not accept I had a lot of guilt in the beginning towards myself because I was thinking, how is it possible that I am this person and I do not have answers now for what happened to my own daughter? And I started thinking what could have been wrong, and you know that there are thousand things that could have been wrong, and of course, we don't know. The only thing that I knew is that I was um diagnosed with pre-clampsia in the previous 10 weeks before the the end of the term. Um I started reading about that and I was um so surprised how little is known about it. And it's not that people do not ask questions about it or they do not want to um to study this because there are many people actually, many scientists that are looking for that. It's more about like how the research funds are allocated. And um, yes, of course, the majority go to cancer because it's it's still a big relevant societal problem, but I realize that pre-clampsia and in general women's health, it's not a um less common um field where research is needed. Um, like literally, there are many women that develop preclampsia in their uh in their pregnancy, they do not have any risk factors, nobody in their family had it before, and you are basically told you are having this terrible disease, which will bring you to have high blood pressure, uh organ failure, uh, potential death of yourself and your child, uh, increased risk of cardiovascular diseases in the future. And basically, you are not told why you have that, if you could have done something to avoid it. Uh, there are many countries they don't not even check if you are a risk of this disease. This is like also in my experience. I I honestly and I feel sometimes also ashamed about that. I did not even know what pre-eclamcia was. I mean, I studied science since 20 years now, and I have never heard about that. And never heard like from also other women pregnant around me the fear of getting this disease. It was always just like you have your feet swollen, that's it. And since I I had it myself, I still didn't realize what was it. And when you see what this disease does to yourself, it's like it's so bad. And the all that the doctor can tell you is like this is a disease of the placenta, okay. But they don't know what's going on, they really do not know, they have no idea. Like, you know, yes, I I am planning if I manage to start working in this field, because also, of course, the academic world is very difficult and complicated. Everyone tells mihas, like my husband, uh, like it's you know, where are you finding the strength? And and yeah, we are not strong at all, we are pretty destroyed, but you have to go on, like that's no choice, right? At one point you have to decide if I have to go on, I have to go on with you know with dignity and in a way. So is this mean means being strong? Maybe yes, and I'm glad I am finding the strength. But if you ask me how I am, I am I am pretty destroyed, you know. So yeah, it's very difficult. It's just very difficult to navigate this this journey.

SPEAKER_02 33:10

I want to thank Rita for her bravery in telling hers and Freya's story. I truly believe she will become a world leader in preeclampsia research. Next episode, I'm going to be looking at the future of preeclampsia research and treatment. Are we any closer to a cure? For more information and support on preeclampsia, please reach out to charities such as APEC, also known as Action on Preclampsia. Their free helpline offers advice and support. Why the hell did I get preeclampsia is produced and edited by me, Imogen Lafree Ling. Music and vocals are by Rebecca Green.