Ep 106: Immunology in Fertility Care with Dr. Daniel Stein
Fertility Forward Episode 106:
The health of your immune system can gravely affect your fertility and ability to become pregnant. Joining us today on Fertility Forward is specialist Dr. Daniel Stein, to talk about how immunology affects fertility care. In this episode, you will hear all about immunotolerance, how a functioning immune system is beneficial to pregnancy, when your immune system affects your ability to carry a pregnancy and how to know, as well as how to test for any immune system issues affecting your fertility. We also discuss why blood tests may not be helpful, how to spot treatments that aren’t going to do much good, and how to identify any issues you may have. Dr. Stein goes on to explain his passion for immunology research before delving into the importance of selecting the right healthcare professionals to help you through this journey. Lastly, as always, we share some things we are grateful for as we approach the holiday season. So, to hear all about how a functional immune system can support pregnancy and fertility care, tune in now!
Rena: Hi everyone, we are Rena and Dara and welcome to Fertility Forward. We are part of the wellness team at RMA of New York, a fertility clinic affiliated with Mount Sinai Hospital in New York City. Our Fertility Forward podcast brings together advice from medical professionals, mental health specialists, wellness experts, and patients because knowledge is power and you are your own best advocate.
Rena: I am so excited to welcome to Fertility Forward today, Dr. Daniel Stein, a reproductive endocrinologist at RMA of New York and he is a recurring guest on our podcast and one of my favorite physicians. Thank you so much for coming on to talk about immunology.
Dr. Stein: Of course. It's my pleasure. And this is really just sort of a tidbit and you know, an entry point into this area because this is such a complex topic and much of pregnancy - I will say all pregnancies, actually - all pregnancies require a functional immune system to a) allow a pregnancy to go to full term and to lead to a healthy baby and b) to get rid of abnormal material in a pregnancy. So it works positively and negatively. So you know, the area of implantation failure is very much dependent on a functional immune system and probably the reason why is because, you know, when one woman is pregnant, she has the capability of course to recognize some cells as normal or native cells or self we should say, or to recognize them as as foreign cells and every pregnancy composes cells of both the father and the mother. And so when that pregnancy starts to grow within a woman and when it's about to implant even prior to that, she has to be able to somehow not reject the paternal cells because she, if she does reject the paternal cells, she'll reject the whole fetus. She'll reject the embryo. So it's an amazing system and there are several different mechanisms by which women are able to have what is called immuno-tolerance of this fetus that is partly not her and partly foreign.
Rena: So is that, you know, sometimes I'll hear people saying, oh you know, my doctor said I was allergic to pregnancy. So would that mean that you have this sort of immune issue?
Dr. Stein: Yeah, I mean that's terminology which I also have heard is usually not based on any data. So sometimes when things are said like that, they're kind of just a very broad view of something that hasn't been proven. There are ways to actually determine this and there are certain types of immune factors that can be measured. There are even biopsies from tissue of the uterus to determine if there are normal immune factors and if there is normal immune function. So it should be something that is more scientific more than a general term. But in general, women are very, very capable of being able to develop this immuno-intolerance and it is in the minority of cases which they don't have that capability. And those are the cases in which no matter how you try to, even if you try in vitro fertilization and even if you're putting in embryos that have been tested and are chromosomally normal, you'll still get a rejection either in the form of miscarriage or no implantation at all, therefore in the form of a negative pregnancy test.
Rena: So how would you know if that was your case? And I think maybe we'll start there cause that sort of sounds like worst case scenario and then we can go to a more positive note. But if, if that is you, does that mean that your body, you just are unable to carry a pregnancy?
Dr. Stein: Well the first thing in these cases is to suspect that there is something going on that is different than what is expected. So in other words, if you go to a very excellent IVF program like RMA of New York and you go ahead and you have beautiful embryos made with wonderful normal chromosomes and they fail to implant time after time after time, well at some point you have to say maybe it's not the embryo. Okay, maybe it is the uterus and the interaction between the embryo and the uterus is critical for a successful pregnancy. So, first thing is of course to suspect and then once you do suspect, then they gotta think about where this immuno-function can be damaged at, at what level? And it can affect the development of eggs. It can affect the development of embryos. It could even affect the motility and the movement and the capability of sperm. But once you already have chromosomally normal embryos, then you're really talking about the uterus. And the uterus is an organ that we used to think was a sterile organ. It didn't have any bacteria in it. Actually, it has a ton of host bacteria that are actually very imperative for successful implantation and there are also multiple immune cells that allow implantation to occur. They might be, what we call T-cells, natural killer cells, macrophages, all these different cell types of different names that are very, very critical and the balance between them and the function of them is very much a source of either successful or unsuccessful pregnancy.
Rena: So it sounds like, so this would be a case, someone who had maybe three or four genetically normal, very highly graded embryos transferred that led to negative betas that then you would say, okay, maybe this is something that we need to test for?
Dr. Stein: Yes. Maybe something we need to test for - absolutely. I would say we definitely would need to test for. The problem today is, although there are many articles, many studies that are addressing these issues, there's been a paucity of data that shows very good and effective treatments. So, and it really depends on the issues. So for example, there's a syndrome called antiphospholipid antibody syndrome where there are certain antibodies circulating in the blood that can attack a developing embryo and attack the blood vessels that provide blood supply to those embryos. Well those actually are really good to check because they're actionable. There are, in cases in which you do have high levels of these particular antibodies, there are blood thinners like heparin or lovanox that can actually counter the effect of these antibodies and lead to a successful pregnancy. But there are other immuno-function abnormalities that we don't know yet how to address. And I always tell people to beware because doctors who are not necessarily evidence-based might be throwing a lot of very expensive medications like IVIG and some of these other medications that actually don't have any proven effect, but they are very costly. So my biggest advice in these cases really is that any couple, any person who is having issues like this in which there is some suspicion of an autoimmune problem should really see a reproductive endocrinologist that centers and focuses on these issues and doesn't just go ahead and get a panel of tests that have no meaning or are not actionable.
Rena: Well I think you touched upon something that's so astute. I mean I think there's so much panic that goes into hearing about, oh, potential immune issues and then people, you know, they run to seek answers from someone that you know may or may not be reputable. Usually all of this is, you know, out of pocket and extremely costly as you said. So I mean I wanna back up first before we talk about potential treatment, what would be, so say your, you know, again you're someone, your doctor says okay, we need to test for potential immune issues. What kind of tests would your physician order?
Dr. Stein: They would center on blood tests and then tests of the uterus itself, usually taking tissue, a biopsy of the uterine tissue. In terms of blood tests, the factors that have been shown to be consistently a problem for implantation and for pregnancy loss and consistently actionable in which there is excellent evidence of a good treatment option, those would include the anti phospholipid antibodies which I just talked about. A lot of times people are concerned about something that they've read from what is not always a very reputable source about natural killer cells. They want to know if their natural killer cells are are elevated. Do they have a problem with that? Well the data on natural killer cells is actually not great. Natural killer cells 100% play a very critical role in implantation, okay? But many of the tests done for natural killer cells are done on blood and blood natural killer cells are cytotoxic, meaning they kill other cells. But natural killer cells in the uterus are generally very receptive. So when you're checking blood natural killer cells, you're not getting any indication of what the uterus is doing. So even if you find that you have a high natural killer cell in the blood, it doesn't mean anything with regards to the uterus. So people have to be very careful. You know, again, if somebody pulls out a panel and says, oh we're gonna check for everything from, you know, antibodies to levels of any other kind of chemicals and things, you gotta say what are the data? What do the data show? And for that you need somebody who's going to be very, very directed and focused on the science and the evidence. Evidence-based is critical in every aspect of medicine. And that's, I always tell, you know, please buyer beware.
Rena: Hmm. Yeah, I mean I think I see that so many times people hear like natural killer cells and they just panic and then, you know, as you said it, that's not always necessarily something that you then need to seek very extensive treatment for. It sounds like there's so many nuances involved in that and I see people so many times then pouring a ton of money into treating this when you're saying, well this may not even be anything necessary to treat.
Dr. Stein: Or that treatment might not have any effect. So there are certain aspects like that. There are so many different factors here and there are treatments for some of them and some of the treatments are very, very well grounded in science. And some of them have not only not been shown to be effective but have been shown to be ineffective. Not absence of evidence but evidence of absence. Right? So that's the key. The key is that there's many of these things, it's not just that they haven't been tried and somebody's trying to reach out and see if they can figure out something new. It's that the data has been shown to show these things are not useful.
Rena: So what should people look out for? What are some of these treatments that are not going to be effective?
Dr. Stein: Well, every case is different. Every case is different. And, and I won't say that there's one class of medications that I can say offhand will never work for some people. I think probably the most expensive one for which it's been found to be a lack of evidence of any benefit is IVIG, intraintravenous immunoglobulin. That's probably where you have your greatest lack. And there's other things too in certain types of lipid profiles and you know there are many different possibilities. There are medications that sometimes people will use, even things like using blood thinners, which are are very, very helpful for antiphospholipid antibodies, might not at all be helpful for other types of, of autoimmune or clotting abnormalities. So what's really, really important is that, you know, here at RMA of New York, we are centering and trying to focus very much on real evidence, real data that can help people. Because without real data you may spend a lot of time and a lot of money doing stuff that makes no sense at all and have now lost that time and that money to look at things for which there is excellent evidence. And that's what I really, this is an area in which many people are taking advantage of.
Rena: Hmm. Yeah, I see it all the time too, which is, you know, heartbreaking. But, and before we started recording you mentioned that you're really doing a deeper dive into this and trying to bring maybe some of this into RMA?
Dr. Stein: Well we already have. We already have. But yes, I'm probably doing the deepest dive. I spend a lot of hours every week looking at each study that comes out and trying to make sense of it, look at the data, see how the studies will perform, see if they were well-designed, not well-designed, if they had control groups, all that stuff. So this is a very big focus of mine and it will continue to be a very big focus for RMA.
Rena: Well I'm very excited to see where we at RMA take it. What advice do you have? You know, maybe someone that's listening not in the New York area or at a, at a different clinic in terms of seeking treatment or knowing when to listen to their physician's advice who, who tells them not to but they're feeling like, you know, they wanna take control of the situation. How would you be able to measure or what are some things you should look at for, you know, a reputable physician or not in terms of treatment and protocol?
Dr. Stein: I would say in general, in general, and this is a very big generalization of course, if you look at large reputable university based or university-linked programs, you are less likely to run into the data, I would say, the inadequacies of data that sometimes can affect smaller offices and private offices. And again, this is a big generalization cause obviously there are people in universities who may not provide good evidence and there are single practitioners who might provide some good evidence. But you know, if you stick with the well-known programs, that's very important. And even when you look at things like IVF, you should really look at the programs that have that every single doctor there is either board certified or at least board eligible if they recently finished their training. And then the other thing that's also very important is to look at numbers. You know, programs that do high numbers of cycles, okay, and have good pregnancy rates are usually programs that you know you're gonna be finding people who are knowledgeable. That's very, very important. And I do think that the reproductive endocrinologist is the ideal person to handle this type of issue.
Rena: Those are all great tips and for anyone that doesn't know, you can access that data on the SART website, S-A-R-T that should have all the numbers, you know, when you're looking at clinics. If you go to the SART website, it should have clinic data so you can see the data and numbers for where you’re going or thinking about going.
Dr. Stein: Absolutely.
Rena: So I guess I know we were gonna do sort of a, a mini-episode today just to touch on this briefly and then we're gonna do a much deeper dive into this. But you know, maybe some final questions would be, one is, is this something that is hereditary or would there be any signs that you would have these issues before trying to conceive? Or is this something that you would only find out once you started trying to conceive?
Dr. Stein: Great question. So some things are completely acquired and some are, you know, hereditary in terms of, would you have any idea? Well, yes you might. For example, the best example, again, is the antiphospholipid syndrome where if somebody had, let's say previous episodes of excessive clot formation, maybe they developed a deep vein thrombosis in the leg or they had a pulmonary embolism, that would be an indication that might be some abnormality. If it turned out that somebody in their family also had a very similar situation, that might be common. You may find that somebody had a pregnancy loss that occurred, let's say 10 weeks or later, that just stopped and they had a, you know, and essentially it was an ended pregnancy, kind of a later miscarriage. And let's say they did genetic testing, the genetics were normal, well that would indicate to you, well there's something else going on. So these are all possibilities. There are so many different clues and I would say that you might not always know it when you go into it, especially for people presenting with primary infertility where they haven't gotten pregnant before. But if you've had two miscarriages or three miscarriages and you don't know why you've had those miscarriages, certainly you should be seeing a fertility specialist like myself who specializes in these issues. And if you've had, you know, in vitro fertilization, no matter where you are, whichever facility, you should be asking about having a full evaluation for recurrent implantation failure. And that's something we do here. I know that not every place does that, but that is something at RMA that we are very, very focused on. And our program is only developing excessively, you know, extremely at this point. You know, we're really trying to make us the pinpoint place for recurrent implementation failure.
Rena: And then I guess sort of final question would be, if you are someone that you think, you know, you may have this, is there anything you can do like holistically - diet, supplements, acupuncture - anything like that to try and treat it, you know, in addition to any protocol or anything that prescribed by your doctor?
Dr. Stein: So, not that we really know of. Not that we really know of. These are mostly either medication based or procedure based. Acupuncture has been found to be really helpful for reducing stress levels for people who are undergoing infertility treatments, but not particularly helpful for enhancing fertility. So the data is really more on the patient's mindset going through infertility rather than actually helping with infertility. But I know there's a lot of controversy in that area, but the bulk of well-controlled data shows that maybe that's the greatest benefit of acupuncture. So if anyone wants to do acupuncture, I always encourage them to do it because it because they're certainly not gonna have a negative effect. And so as far as I'm concerned, it's perfectly fine to continue with that. I think the rest of the possible treatments we'll get to as we give, as we dive deeper into this topic. And thank you so much for having me today and I'm really excited to move on to our other issues.
Rena: Well, thank you so much for coming on and I'm so excited to see where you take RMA in terms of this and all of our focus areas. You know, I'm so proud to be at such a fantastic clinic with such wonderful physicians and the way we like to close our episodes is to talk about gratitude. So it's something that you are grateful for today.
Dr. Stein: I'm grateful for having a job I love. I'm grateful for the wonderful people in my life. And I'm grateful that having had a horrible accident last year that I can walk and I'm grateful for, for many, many things. And yeah, hopefully we'll be grateful for even more things if my daughter gets pregnant. So that'll be good.
Rena: I hope she's listening. Well, I will say that I am grateful for health and family too, and especially during this holiday season which can be very tough for many and bring up so much, super grateful for family, whatever that looks like. My modern family and my health. And your health as well causeI have been pulling for you and so I’m glad you’re health and wish you the best and everyone stay tuned for a deeper dive into this in 2023.
Dr. Stein: Excellent. All right. All the best. Happy holidays.
Rena: You too.
Dara: Thank you so much for listening today. And always remember - practice gratitude, give a little love to someone else and yourself. and remember, you are not alone. Find us on Instagram @Fertility_Forward and if you're looking for more support, visit us at www.rmany.com and tune in next week for more fertility.