Infertility and Immunology: Dr. Geneviève Genest

Can infertility be treated successfully? Why does recurring infertility happen? One out of six Canadian couples experience fertility problems. While many become parents thanks to artificial insemination and in vitro fertilization, the usual treatments don't seem to work for some. Dr. Geneviève Genest, immunologist and researcher at the Montreal General Hospital (MUHC) is on a mission to find out why. Along the way, she is helping a majority of couples who visit her clinic –one that is unique in Canada- get pregnant and have the family the always dreamed of. 

Annie DeMelt speaks with Dr. Genest about why the immune system matters in pregnancy; and how certain blood molecules, such as immunoglobulin, can be a game changer for some couples. 

Transcript

Dr. Genest: In all of the patients that we see in clinic for reproductive failure, it's only a certain percentage that are going to have a problem with the immune system that's causing their reproductive failure. So if you're able to have a blood test to tell the couple, look, here's your problem, here's a treatment, that's great. Or this is not your problem, it's not worth trying these treatments. Let's try some other options. That's even better. So just being able to tease out those different patients, for me, is the future of what we're trying to do.

Annie DeMelt: Hello, I'm Annie DeMelt and welcome to the Code Life Interviews, a podcast about innovation in health care brought to you by the Montreal General Hospital Foundation. Today we're going to be talking about some really promising and fascinating advances in reproductive medicine. We know that one out of six Canadian couples experience fertility problems, and fortunately, many do become parents thanks to artificial insemination and in vitro fertilization. However, there are some couples for whom this doesn't work. The treatments don't seem to work, for some unknown reason. It is still unexplained. And that's where our guest today comes in. Dr. Genevieve Genest is an immunologist and a researcher at the Montreal General Hospital, and her mission is to help patients become parents. Now, she runs a clinic that is doing some groundbreaking work that is unique in the country. And at the same time, she is trying to make some key findings that can help reach more patients in the future. Dr. Genest, thank you so much for being with us today.

Dr. Genest: Thanks for having me.

Annie DeMelt: So I want to start with the perspective of the patients that are coming to you. Typically, where are they in their journey when they finally reach out to you, email or first visit? Where are they in their journey?

Dr. Genest: They're pretty much at the end of the road. So the patients that I see in my clinic really are the patients for whom reproductive technology has not worked. So they've had a long journey in either IVF, in the fertility world, where they've done multiple IVF cycles, multiple embryo transfers and nothing has stuck. Or I'll see patients with recurrent pregnancy loss, you know, patients that have had multiple miscarriages that we still can't figure out, and for whom all of the usual investigations that we do are completely negative. So I'll usually get the patients that are really at the end of their reproductive rope, if you will, and for whom their physicians say, look, I don't know what to do. Let's go see elsewhere.

Annie DeMelt: Okay. And you said reproductive rope. And emotional rope, I imagine, as well, right?

Dr. Genest: Oh, yeah. That's a whole other ball game. You know, the infertility in itself or just recurrent miscarriages, has a huge emotional toll on the couple. Not just the woman, but the couple. And that's something that's not exactly talked about in society. So if you're not experiencing that as a patient, you can't possibly know what it is. You know, it's this roller coaster of ups and downs and grief and isolation. So yeah, when patients do come to see me, they're pretty much at the end of their emotional ropes as well.

Annie DeMelt: And as you said, in the case of the patients that you are seeing, that you're treating, there's also that unknown. There's no explanation. So, you know, as an immunologist, what's the theory as to what's happening with these patients for whom in-vitro or artificial insemination hasn't worked?

Dr. Genest: Actually, that's a great question. So just as a little bit of background: for pregnancy to happen, you need a permissive immune system. So your uterus actually has its own immune system that it recruits at each menstrual cycle. And that immune system is very useful because it helps recognize the embryo, it helps the embryo implant into the endometrium, and it helps that embryo form a placenta while at the same time telling the rest of the body not to attack whatever's growing inside the uterus. So it's actually an immunologic miracle that we can reproduce. So it's logical to assume that for certain patients that have unexplained reproductive failure that there might be a problem in the immune environment that that embryo is growing into. The only problem is that right now we don't have any diagnostic tests for these patients. So it's a diagnosis of exclusion, meaning that if we still have a patient that has failed multiple different trials for reproduction or multiple different medications and for whom all of the medical workup is completely negative, that's when we start suspecting that there might be an underlying immune problem.

Annie DeMelt: And you've referred to it as a black box. I thought that was an interesting way of looking at it because you can't really investigate easily. So again, you're left with these all of these questions. So, you know, I want to go to the part where where you started making certain connections and you do have a personal connection to this, which allowed you to really interestingly think outside the box, perhaps, and lead you to what you're doing today. So can you tell us a little bit about that.

Dr. Genest: Yeah, sure.

Annie DeMelt: That path during your your residency?

Dr. Genest: Sure. I actually started as a resident in internal medicine, and I was very interested in the immune system. I had a bachelor's degree in the immune system. I thought I might want to work with HIV or something. And then I started my residency in allergy immunology, and I think it was the second month of my residency, I was working with Dr. Phil Gold. At that point I myself had had probably three miscarriages and we had seen a patient who had maybe five, six, seven miscarriages. I can't remember. I was wondering why this patient was referred to an allergy immunology clinic for her miscarriages. And Dr. Gold said, Oh, don't worry, give her this blood product called intravenous immunoglobulin. She'll get pregnant in no time. And sure enough, he was completely right. And from that point on, I was completely fascinated. You know, why on earth would this blood product that we use for so many different indications actually work for someone with recurrent pregnancy loss? And are there other molecules that we might be able to use for such patients as well? And I became really interested and invested with these patients that are having such a hard time becoming pregnant and experiencing the joy of parenthood. So for me, it was a personal calling, but scientifically exceedingly interesting as well because there's so much things to do.

Annie DeMelt: He told you use the immunoglobin globulin, right? Is that something that was being done, sort of through kind of trial and error or instinct almost? Where were they at that point?

Dr. Genest: There were a few publications on intravenous immunoglobulin where they were using it kind of as an off label to try and get certain women pregnant with the thinking that intravenous immunoglobulin kind of re-establishes the immune homeostasis that you need to be able to tolerate the implantation of an embryo. So there were a few publications, but very murky literature. I mean, it'll work for some patients and it won't work for others. But trying to figure out exactly which patients for whom it will work and which patients for whom it won't work is exactly what interests me.

Annie DeMelt: You began, in your own research, eventually treating patients with this immunoglobulin. What was it like having Dr. Phil Gold, who's really quite renowned, as an immunologist in cancer research and medicine, as your mentor? How did he guide you along to to make it less sort of... Get away from the murky literature and a little bit better defined?

Dr. Genest: Dr. Gold is not the kind of person who's going to tell you what to do. He's just going to encourage you in whichever path you do decide to take. So I remember at the beginning we were going to talk about this new clinic that we were trying to get off the ground. He would come with me at every single presentation to all the fertility clinics, all of the obstetrics and gynecology clinics across Quebec. And he was just letting me talk about this clinic, talk about reproductive immunology. He was helping me publish. He was helping me get the patients. He was helping me get support from the Montreal General Hospital Foundation. So he set up everything so that I would be okay and that I could flourish in that type of environment. So he got me started on the clinic. He also got me a lot of support to be able to do my PhD. So I'm doing my PhD right now so I can become an independent clinician scientist. And this is exactly what I want to research, why certain patients reject their pregnancies. So Dr. Gold really was able to mentor me through all of that without overshadowing anything. He was just encouraging whichever tangent I took and kind of bringing me back if I was going too much one way that wouldn't necessarily be good.

Annie DeMelt: At the clinic that you are leading now, how did you start treating patients and what was the success rate? Because I believe there was a really great initial success rate and which continues to be not only promising... It's the results now, right? Patients and couples are becoming parents. How did that evolve?

Dr. Genest: Well, what we did at the beginning is we really took the worst case scenarios. So the patients with multiple miscarriages, the patients with multiple recurrent implantation failures. So that's failure to implant an embryo after an IVF process. And we decided to treat those patients with intravenous immunoglobulin. And then what we did was a retrospective review of our cohort every single year to see: are we doing better than what would be naturally expected from these patients, given the amount of reproductive failures that they've had in the past. And what we were seeing with intravenous immunoglobulin, with the first usage of it, we were having 60% live births. And that's a trend that continued over about a period of five, six years until the pandemic hit.

Annie DeMelt: Right.

Dr. Genest: And then the pandemic hit. And the problem is that intravenous immunoglobulin is a blood product. And with the paucity of blood donors during that time, we weren't able to offer intravenous immunoglobulin off label. The government was concentrating their resources, and rightly so, on patients that absolutely required it for survival. So there was this two year period where we couldn't treat our patients with that molecule. At which point we started looking elsewhere. So we started looking into the literature. We started looking at other research that was being done elsewhere, and we were able to find different molecules. So for example, hydroxychloroquine, prednisone, different protocols that were used in different clinics to try to improve these patients outcomes, which we did. So we have an at least, and this is as of yesterday, looking back into our two year data... We have at least a 50% ongoing pregnancy rate with those molecules.

Annie DeMelt: And are these people that you wouldn't necessarily treat with immunoglobulin or is it just another sort of tool in your arsenal? How do you see that?

Dr. Genest: Now it's another tool in our arsenal. So we've actually lobbied the government for the last year to get intravenous immunoglobulin back for very select women. And we were able to get that. Just one of the criteria to be able to access intravenous immunoglobulin now is to have failed one of the therapies that we've been using for the last two years in clinic, because then that really means that you've tried absolutely everything. You really don't have any other options. And that's when we try intravenous immunoglobulin.

Annie DeMelt: For everybody else, these other molecules might be an option?

Dr. Genest: Yeah. Well, you also have to keep in mind that... Say, for example, you're taking recurrent pregnancy loss. The natural history of recurrent pregnancy loss, even after three pregnancy losses, your chances of a live birth at the next pregnancy are upwards of 70%, which is pretty good. So even if we do nothing and we do watchful waiting or we give a little bit of progesterone, maybe some baby aspirin, most of the time you will have a live birth. So the patients that we're really looking at are those who are in trouble, you know, five, six, seven miscarriages. Those patients are the ones that we have to specifically select for maybe thinking outside the box.

Annie DeMelt: The diagnostic test. We were talking about this in a pre-interview, but.. So basically right now you have the problem, which is the fertility problem. You have a bunch of different potential solutions that seem to be working quite well, and it's making that connection, right? It's the test. It's who needs what, personalizing the care. So how do you go about figuring that out, trying to create a diagnostic test right now?

Dr. Genest: So that's a great question because clinically it's a lot of guesswork. I will have a specific patient that will have a specific medical history and you kind of guess that the right molecule is for her depending on her history. But that's not good medicine. The ideal is really having a diagnostic test and being able to put the patient in a box saying, okay, this is your problem, here's the best molecule for you. So as you say, personalization of medical treatment. So what we're doing right now in clinic is several things. So first off, every single patient that walks into a clinic is part of a registry, which means that we document each treatment, each outcome, and we document any side effects of the treatment. So that's the first step in trying to figure out which treatment is the best for which patient. And then we're also looking into developing biomarkers. So blood tests, for example. So right now, before and after treatment, we're taking bloods and we're freezing that blood for an eventual research that will let us figure out how patients that respond to specific medications are immunologically different than patients who are able to have kids. So we're really trying to find the needle in the haystack and trying to figure out that magic bullet. What is our biomarker, What can predict response to these medications or what can even diagnose these patients with immune mediated reproductive failure?

Annie DeMelt: And is that really the key for you? Is this sort of... Is the blood test, the diagnostic blood test that would allow you to know what's going on with each different patient or couple?

Dr. Genest: Absolutely. I think it's a must because in all of the patients that we see in clinic for reproductive failure, it's only a certain percentage that are going to have a problem with the immune system that's causing their reproductive failure. So if you're able to have a blood test to tell the couple, look, here's your problem, here's the treatment, that's great. Or, this is not your problem, it's not worth trying these treatments. Let's try some other options. That's even better. So just being able to tease out those different patients, for me, is the future of what we're trying to do.

Annie DeMelt: It's not all of the patients that come to you that you're going to be able to help.

Dr. Genest: Exactly. Because, again, you're hypothesizing that there's a problem with the immune system for these patients. So you have this large population of patients that is not able to become pregnant. But again, only a certain percentage of them will have a problem with the immune system. So it's not every single patient that you treat with these immune modulating drugs that will get a baby. And, you know, there are side effects to certain of these drugs and there are... not not long term side effects. But some patients will not feel good. They can have consequences with these medications. So trying to figure out which patients are best-suited for which medications and which medication would be most effective for which couple is really key.

Annie DeMelt: And you know, we talked again about the the whole emotional side of it. You're on this journey. You know, you said at the beginning of the interview, oftentimes people are coming to you, you know, kind of at the end of the line, they're already sort of worn out emotionally, physically. How would it help for them to have that test? Sort of a simple yes or no answer, basically.

Dr. Genest: Exactly. I think, probably one of the worst things that happens to a couple is not being able to figure out why they can't have a baby. Because if you can project yourself as a couple, if you've chosen that person, you project yourself as having a family, as being parents, as watching your children grow. And everyone around you is is doing that. They're posting on Facebook. They're putting pictures everywhere. They're talking about their kids. And you're still, you know, two, three, four, five years later and you're still not able to have children. People keep asking you, when are you going to get pregnant? You know, when when am I going to get grandbabies? All these questions, it's very difficult for a couple. So when you're faced with a bunch of doctors who are, like, I'm sorry, I have no idea what's going on, that is exceedingly frustrating. And it's very isolating as well because you have no one to turn to and you have no one to talk to about what's going on. So if at least you're able to give an explanation to these couples, even if you're not giving them a baby, if you're not allowing them to have a baby. Just telling them, here's a medical diagnosis, it's going to be impossible for you to have children with this X diagnosis. Try finding other ways or, you know, this is your problem. We can help you with this problem. That can be tremendously helpful.

Annie DeMelt: In the meantime, you have your clinic. People are coming to you from all over the country, right? Because it's such a unique... What you're offering is so unique. And I guess for now, while you try to to make that connection and to personalize a test, you're still sort of forging ahead and helping people get pregnant. Right? So are you are you still enjoying the same sort of success rate as initially, with the 60%? Basically, what's happening at the clinic right now?

Dr. Genest: We're actually doing pretty good. So I'd say we're having minimum 50% live birth rate. It's not necessarily the first pregnancy or the first embryo transfer that we treat, but we do learn while we're going so we can eliminate a few diagnostics or at least eliminate one molecule that doesn't work. And we'll usually be able to help couples get pregnant. There's a few extremes where we'll say, Look, we've tried everything. We can't do anything. Go towards gestational carrier, egg donation, adoption. But I'd say that's a minority of patients in the clinic. Most of them will be able to get pregnant. 

Annie DeMelt: I'd like to know: what do you need right now in terms of support in order to be able to help even more people? There's a research element, obviously. There's the clinical care element. How can people support you, essentially?

Dr. Genest: Several ways. In terms of being able to do what we do at a larger scale, it's especially administrative support. So, you know, having a dedicated, even part time secretary for the clinic, who knows what these patients are going through, who knows that it's important to book a patient when she's pregnant. To be able to follow up with appointments. To be able to be a hub for these patients when they need access to their doctor. We need a research, at least part time research nurse to help us enter all of the data, keep track of all the patients, make sure that everyone's doing okay. That all of their blood tests are done at the right time. Emailing the patients, because there's a lot of back and forth with the patients. You know, we're giving medications that are off label, so we have to make sure to have that close contact with patients. So right now everyone has my email, which is a little problematic. And eventually have a full time research coordinator to really help us with all of the blood testing, all of the tracking of the patients, making sure that all of the samples get to the lab, all of those samples are processed. So there's a lot of things to get set up. We're doing it slowly. But having a little bit more resources would probably help us help a lot more patients. And then lastly, we do have a fellowship program where we're able to train other residents who'd want to be doing this as their their job later on. So we do actually have someone from Quebec who's currently training in the program now, who's eventually going to be "me", but in Quebec City. So it's really just having that infrastructure to support research at both sites and support patient care at both sites as well.

Annie DeMelt: Eventually they'll be able to take what you're doing at the Montreal General Hospital and bring it to patients across the province.

Dr. Genest: Across the country, exactly. We're expecting an increase in terms of trainees that are interested in the program from across Canada, at the very least. I'm not taking anyone outside of Canada for now just because it's too much. So we are expecting a steady increase of people from across Canada coming to train in our centre at the Montreal General Hospital and this novel clinic. And bring that knowledge elsewhere to be able to form this collaborative network around the country where we're really forging guidelines and standards of practice with these patient populations.

Annie DeMelt: So your face is lighting up as you as you say this, right? Clearly, you're very enthusiastic about this element of this. You know, and I saw when we were zooming a couple of days ago, there's pictures of patients and their babies on your wall. How... Again, you were emotionally invested at the beginning. Does it continue to be like that today? Do you have relationships with these couples, with these patients that feel really personal and that keep you going, that motivate you, essentially?

Dr. Genest: Well, absolutely. I mean, the couple is kind of inviting you into their personal life. And it's probably the most personal that you're ever going to get with a patient. It's making babies. And even if you spend half an hour with the patient explaining what the immune system does or explaining how we can treat or how we can investigate. Just that time invested in that relationship is very meaningful. So you get really attached to these patients and these patients get really attached to you. So, I'll get Christmas cards every year from patients who show, just, the pictures of their kids. I think I was giving you the example which really touched me. I think it was about a month ago when I left on vacation. I guess I must have told one patient who told someone on social media. It kind of made the whole circle. And, I had patients who were emailing me "happy vacation" and were emailing me pictures of their kids on the beach. So you develop these very human connections that last for a long time. I remember all of my patients kids names. I remember their stories. It's very gratifying when they do get that pregnancy and you're able to get them through that pregnancy and get them to have their kid because you know that you've just created life and you've just created a family forever. And that's very cool.

Annie DeMelt: All right. Thank you so much for what you're doing. So many people clearly appreciate you very much. And thank you for joining this Code Life interview presented by the Montreal General Hospital Foundation. And if you want to find out more about Dr. Genest's clinic, about her research, as well as other initiatives, really interesting initiatives that are supported by the generosity of donors, you can visit the foundation's website codelife.ca. Of course. Don't forget to follow us on social media and subscribe to the podcast for more Code Life interviews. Thank you very much and see you next time.