Ep 57: Recurrent Pregnancy Loss with Dr. Mukherjee
Fertility Forward Episode 57:
There’s no difference between a pregnancy lost at six weeks than a pregnancy lost at 10 weeks, or later down the road. Any pregnancy loss, at any point, is damaging. It’s unexpected and carries weight, no matter where you are in your gestation. Our guest today is Dr. Tanmoy Mukherjee, a board-certified Gynecologist, and Reproductive Endocrinologist, and is the Associate Director of the Mount Sinai Division of Reproductive Endocrinology and co-director of Reproductive Medicine Associates of New York. He completed his residency at the Albert Einstein College of Medicine and completed his fellowship at Mount Sinai Hospital. The author of numerous journal articles and textbook chapters, Dr. Mukherjee is also the recipient of the prestigious Society of Reproductive Surgeons Award, for his extensive research in ovum donation and medical therapy for the treatment of infertility. In addition to his expertise in invitro fertilization, egg donation, and other assisted reproductive techniques, Dr. Mukherjee excels in a wide array of medical and surgical treatments for the management of endometriosis, uterine abnormalities, abnormal uterine bleeding, and abnormalities of the fallopian tubes. He has lectured and written extensively on the diagnosis and treatment of patients with recurrent spontaneous abortions. Today on the Fertility Forward Podcast, we are going to talk about the topic of recurrent pregnancy loss. Tune in today for a jammed-packed episode with Dr. Mukherjee to hear all about miscarriages, causes, statistics, and the mental health aspect thereof. There’s so much information and the discussion is filled with snippets and advice that you don’t want to miss out on. So, stay tuned and enjoy!
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 for medical professionals, mental health specialists, wellness experts, and patients, because knowledge is power and you are your own best advocate.
Dara: Dr. Tanmoy Mukherjee is a board certified gynecologist and reproductive endocrinologist is the Associate Director of Mount Sinai Division of Reproductive Endocrinology and co-director of Reproductive Medicine Associates of New York. He completed his residency at the Albert Einstein College of Medicine and completed his fellowship at Mount Sinai Hospital. The author of numerous journal articles and textbook chapters, Dr. Mukerjee is also the recipient of the prestigious Society of Reproductive Surgeons Award for his extensive research in ovum donation and medical therapy for the treatment of infertility. In addition to his expertise in IVF, egg donation, and other assisted reproductive techniques, Dr. Mukherjee excels in a wide array of medical and surgical treatments for the management of endometriosis, uterine abnormalities, abnormal uterine bleeding, and abnormalities of the fallopian tubes. He has lectured and written extensively on the diagnosis and treatment of patients with recurrent spontaneous abortions along with receiving countless awards and recognition. He has numerous television appearances that include the Fox News Channel’ Health Watch, and the Mike and Juliet Show. Wow, we are so excited to have you today and we are going to be speaking about recurrent pregnancy loss, a really hot topic.
Dr. Mukherjee: Well, Dara, thank you for that generous introduction. I think we should just end the show now.
Dara: I have to add, you know, a little insider information. I was a patient at RMA as many people on this podcast who are listening are well aware, but Dr. Mukherjee actually did some surgery on my fallopian tubes way back when about 11 years ago. So I am, I'm forever grateful for him operating on me.
Dr. Mukherjee: Thank you for that, Dara. Thank you so much for that.
Rena: I don’t think I knew that Dara. I don't think I
Dara: So I, I have, I have a special connection and a lot of admiration for him.
Dr. Mukherjee: Thank you to you both.It’s a pleasure working with you and I guess this is the new reality of us doing zoom in our separate domiciles or offices but nevertheless being able to communicate and talk about a topic that I think it's very important. You know recurrent pregnancy loss, it's unusual. Why? You know, because I get a lot of patients who come to my office, it's devastating. I mean, one of the first things I learned and I always took this lesson to heart back when I was a medical student, JJ Smith was my mentor. You know, aside from my family influence, he was the one I'm really excited to be going into the field. And he said, you know, there's no difference between a pregnancy that's lost at six weeks versus a pregnancy that's lost at 10 weeks, you know, and even later down the road, any pregnancy loss at any point is damaging and it's and it's unexpected. And it's just one of the worst moments that I think that you can experience. And the point that he was trying to make, I believe that there was a patient who had come to the clinic and had lost the pregnancy at six weeks and was told by some members of the staff. I don't remember who that it's okay. You can go ahead and start trying to conceive again, shortly. The pregnancy ended very early. Don't worry about it. Which is exactly the wrong thing to say because no matter where you are in your gestational age, losing a pregnancy is still akin to losing a child. You're no more aware, I believe, at six weeks than at 20 weeks, the baby's moving a little bit and you feel something. But still the feeling of being pregnant and the excitement that comes with looking forward to your delivery, looking forward to a pretty significant event in your life. That all, unfortunately, I think carries as much weight, no matter where you are in your gestation. So one of the things I learned early on is that you always have to be sympathetic and you have to be supportive because one of the biggest things is that tendency to blame yourself. Everybody who sits in front of me and relates that they had a loss, the first thing that goes through their heads, what did I do? What did I eat? What did I go, what did I lift? Who did I talk to? What, you know, should I have just stayed under my covers for the past, you know, eight weeks and this would not be happening to me. And it's important to make them understand that probably not, certainly not. I should say not probably not, certainly not. The vast majority of these pregnancy losses are chromosomal in nature. I'll talk about that in a bit. Anatomic in nature, structure of the uterus, general medical issues, medications so forth. So there are explanations for this. But I think the important thing to, you know, to, to lend support to is that it's not anything that they did. There's no element of blame here. It's a matter of figuring out what's going on, how frequently these miscarriages occur and what can be done about them. And I think that's another important thing. Most people don't realize just how frequently miscarriages happen. You know, it's censored data. When you get together with friends and family and, you know, Passover coming up or Easter or something like that, you're like, Oh, you get together and so-and-so's pregnant. Oh, my friend is pregnant and so forth, but that's because that's readily offered and it's a happy thing, but miscarriage has happened frequently and that's not offered up at the same rate. Oh yeah. I just had a miscarriage. How about you? It's like, no, that's not the normal conversation that you have around the table. So I think it's pretty important to let people know that the true miscarriage rate, I mean, certainly if you're in your thirties, can be anywhere from 20 to 30%. In the late, in your later thirties, that number can approach 30 to 40%. And certainly once you're in your forties, that number is as high as 50%. And the primary, primary driver of this is nothing that we can escape. It's age related. And you know, also younger people, even when you're in your twenties, miscarriage rates could be 15 to 20%. Human reproduction is inefficient. And as we get older, miscarriages increase, the good news is that even if you're talking about a 10, 20, 30% miscarriage rate, you're still talking about a 70, 80, 90% success rate. And ultimately, you know, once you have your evaluation and everything checks out, you will enjoy that success.
Rena: I just want to repeat one sentence you said there that I think will really resonate with people, which is human reproduction is inefficient.
Dr. Mukherjee: It’s hugely inefficient. And, you know, it's kind of a, I don't know if it's a joke or not, but you spend the first half of your life, not half, but the first two decades let’s say,not planning to get pregnant. And then when you realize what the true rate is of achieving a pregnancy, like what was I so worried about? And you know, it's a realization that I think is kind of bittersweet for some couples, but it's, it's important to know that even when you're young, if you're in your later twenties, let's say your per month pregnancy rate, maybe 28%, 30 to 35, that rate is about 25%. And the primary driver of those, I think, unexpectedly low numbers is that half of all eggs are chromosomally abnormal. Half of all sperm are chromosomally abnormal. So that per month pregnancy rate of 25% arises from, you know, the big picture, the inefficiency of chromosome health in the, in the gametes and the egg and sperm, and then the resulting healthy pregnancies happening with 25% of the time. So a lot of miscarriages, when I say the chromosomal in origin, it's the combining of the two genomes. The maternal genome with 46 chromosomes gets reduced. The oocyte with 23 chromosomes. Similarly with the sperm, the mature sperm only have 23 chromosome chromosomes. And once that sperm binds to the egg, those 46 chromosomes are reunited. But that's done through these delicate spindles in the oocyte that essentially grab onto the chromosomes of the sperm. And then another set grab on to the chromosomes that are in the oocyte. We combine them, then some shuffling goes on and everything. And with age, this egg, which you really have to think of as a little machine, it's kind of remarkable when you think about it, because everybody is born with all the eggs that are available to them. As you know, for example, the largest number of eggs are when you're in utero at 20 weeks, you have about 6 to 7 million eggs and that's the peak. And from that point on, there's a steady decline. At birth that number's down to 2 million and then when you start to menstruate that number’s around half a million, right? And during your entire reproductive life, let's say that you're fertile from 16 years of age until about 40 years of age, you only wind up using about 500 eggs at that initial mass at the start of your cycles of around 500,000. So talk about inefficiencies of scale. I mean, why, why are we built that way? Clearly there are biological and other pressures that kind of limit the number of children that are, are at a time, but I don't want to talk about that. But just to keep in mind that as you’re aging, as this process of egg loss goes up, the egg that you’re releasing, let's say when you're 30 years old, is literally 30 plus years old. And this machine, which has these spindles, is tasked with taking the chromosomes apart and recombine them, it becomes less efficient. Like any other machine over time, the efficiency with which this process can be done deteriorates and our bodies, certainly eggs are no exception to the rule. Same thing happens with sperm and then men keep making sperm. That process is relatively stable for the first five decades. But in the fifties, you start to accumulate abnormalities. Promatogenesis kind of feeds into this and makes pregnancy rates more difficult as well. So this primary miscarriage consideration is this event. In other words, if the resulting pregnancy doesn't have the requisite 46 chromosomes, you may almost think of it as nature's way of keeping this pregnancy from continuing any further. I mean, clearly there are some types of pregnancies with chromosomal abnormalities that, you know, go on for a full term and deliver down syndrome, being one. But down syndrome is, again, one of these issues where you have more than the necessary number of chromosomes. You expect two copies of the 21st chromosome. Three copies results in down syndrome. But you know, there are other more serious abnormalities of chromosomes. So keeping in mind, they're all in size order. So one all the way down to, you know, 22, 23.They're ranked by size. So you sell them, see abnormalities of the first chromosome because it's so big, it's got so much instruction set on it. You don't see trisomy one because there's so many abnormalities that pregnancy won't even attach and grow. Some abnormalities will allow attachment then the pregnancy fails. Some abnormalities, again, down syndrome, for example, they'll attach and grow and you have a child. But again, it's all a matter of the particular type of chromosomal abnormality that you have. And the other important thing is the different trimesters in pregnancy. These are far more common in the first trimester because when you think about what happens in those first 12 weeks of pregnancy, all of the organ systems differentiate. Right? First, you get your heart, which is interesting. The first thing that you see on the ultrasound, you see the heart, the flicker of the heartbeat, because that's the most important early structured form. But then when you get into week eight and nine, you have the central nervous system for me, skeletal structures forming at those critical junctures, if the chromosomal information is abnormal, you're going to get failure. That's why pregnancies commonly fail in that six to eight week period. And it's, you know, that's after the heartbeat is formed, then it's quite heartbreaking. But again, that is part of this of development. And that's when these bigger errors start to come into play.
Rena: So I wanna ask a question that so many of my patients ask me and grappled with, and that you kind of touched upon at the beginning, which is, you know, people blaming themselves. And did I lift something too heavy? Did I go over a bump in the road? Did I not get enough sleep? You know, isn't my fault. So is there anything concrete that somebody does beyond, let's say, you know, maybe, you know, consuming copious amounts of alcohol or drugs or anything, is there anything concrete somebody does that actually causes a miscarriage?
Dr. Mukherjee: Oh yeah. I mean, listen, if you're talking, let's go through those examples. Let's talk about trauma - hitting the pothole in the road. That's not going to do it. You have to, first of all, understand that we were engineered somewhat to deal with rather extreme situations but there wouldn’t be so many of us if reproduction were quite so frail or susceptible to the environment. The uterus, the pelvic anatomy is such that the uterus is shielded for that first trimester of pregnancy. And you should be able to tolerate minimal trauma and not expect to, you know, if you fall or you go over a bump in the road and you get jostled that you're going to be fine. What can cause harm if you get a blow to the pelvis, if you're struck in the pelvis, if you're in a motor vehicle accident where there was significant force that's transmitted, those are scenarios where miscarriages can occur because of blunt force trauma. And we're talking about levels of injury that are incapacitating. The other example was lifting something too heavy. That's very unusual. I mean, if you're talking about day to day activities of picking up a box or moving a chair or lifting a child or moving a dog out of the way, that's not going to do it. Now, if you go into the weight room and you're going to do squats, which I advise against, and you put a lot of abdominal pelvic pressure on board, I mean, that's a different story, but that's not a typical scenario. Your day-to-day activities and things that you would do 99% of the time, it's not going to induce a miscarriage.
Rena: What about eating or drinking or medications?
Dr. Mukherjee: Yeah, I mean listen: when, you know, when we have patients who initially present to us and we suggest, you know, lifestyle modifications or the oncoming pregnancy and clearly balanced diet is important. And of course, Dara can give you far more information on what exactly constitutes a balanced diet, but that's an important part. I do recommend vitamin supplementation, enough B12, folic acid, so forth. But the alcohol really you want to avoid because alcohol is an odd thing because it's a, it's a matter of when the alcohol is consumed, that it can have the most toxic effects on the developing nervous system. And in fact, you know, when patients in my practice are undergoing fertility therapy prior to pregnancy, I don't care. I'm okay with five to seven alcoholic beverages per week, no more than two in any given you don't want to binge or anything. Moderation of caffeine, you know, two to three, eight ounce cups of coffee a day. I'm saying, what about that?
Dara: You're very generous with that
Dr. Mukherjee: Yeah. There’s 2-300 milligrams of caffeine. You know, I'm talking about, I'm not talking about, you know, your you're,ventis or your grandes
Dara: Well that’s the thing - most people have ventis.
Dr. Mukherjee: Like I said, two to three, eight ounce cups of coffee. You know, the little styrofoam ones that they have next to the water cooler, that is not a problem at all. But once you're pregnant, clearly you want to, you want to stop consuming alcohol. I mean, you know, we're not talking about significant danger if you're five weeks and, Oh, I'm pregnant. I didn't realize that I had that glass of wine. Oh, this is going to happen. It's later when you're nine, 10, 11 weeks with a central nervous system is actively forming. That's where alcohol could have its most serious consequences. So again, when you're trying, I'm not that concerned. Once you are pregnant, clearly you want to stop drinking. Medications can have multiple effects. I'm sure that, you know, prior to you starting to conceive, you want to take a look, look at the medications that you're on and make sure there aren’t any category X medications or anything that needs to be monitored. The primary medications that I get concerned about are the skincare treatments, right? Noic acid and such because those can cause some fairly significant abnormalities in offspring. One of the other medications that's commonly used is spironolactone, which is, are used for excessive hair growth and can affect a male fetus. It can cause feminization. And so these are things that you want to have an ongoing discussion with your obstetrician about, clearly. And I'm sorry, Rena, I got sidetracked. What was the other part of the question?
Dara: No that was it! That was great!
Rena: Any kind of known causes of miscarriage. And so many people, as you know, you mentioned, blame themselves and,you know, it's not about, Oh, you reached for the can of soup in your kitchen pantry and that that caused a miscarriage. It's, you know, much more serious, as you said, a blunt force trauma.
Dr. Mukherjee: We’re talking significant injury. We’re talking significant injury that will usually result in an emergency room visit. So, you know, barring that, no, I wouldn't be concerned about those things.
Dara: But it's interesting. I, I remember clearly I had a chemical pregnancy with one of my IVF cycles and the first place I went to was I got a massage yesterday. It was the massage. And I remember Dr. Sandler right off the bat said, oftentimes when you have a miscarriage, it's a chromosomal abnormality and it’s your body telling you that it wouldn't have been successful.
Dr. Mukherjee: Right. Exactly. But you know, you have that loss and you're going to go back to the events of the past week. It's like, you know I had that extra cup of coffee. Or I had a massage or I went and I had, I played golf. I shouldn't have done that. I mean, these things really are not going...They’re way of rationalizing stuff. Very unfortunate event. We always look to explain, we always look to explain something, right? And then we latch onto the first thing that we do that's not typical in our behaviors. And we point to that and said, aha,
Rena: Well, we want a reason so then if we know, we'll say, okay, well this caused it so I won't repeat the pattern of behavior and therefore stop it from happening again.
Dr. Mukherjee: Right. Of course you want to, you want to be able to take control of that way too. Okay. I've identified it. I've had this loss. I want to move forward too, but you want to move forward with the right things. I mean, clearly when, you know, when you, when you, when I see somebody and they've had this loss, I need to go through a couple of things. In my head, the checklist is, okay. I know that age is a big cause of miscarriage. So I want to see not only how old you are, I mean, that's an independent predictor, very important prediction, but I want to see what your egg quality is for your age, because in some cases, you know, there could be some issues with egg quality that affect even younger women. So I want to make sure that I have a reasonable idea about how healthy eggs are. That's done in a nice, a there are good modalities now to look at that. The first one is an ultrasound. So the ultrasound lets me take a look at the ovaries because again, eggs matter. The ovaries are the warehouse of your eggs. So by looking at the size of the ovaries, we can get a quantitative idea of what your ovarian reserve is. And usually when you're in your thirties, you want to see the ovaries measure about two and a half centimeters by two and a half centimeters. And should be about four to six areas of falling collectivity on each ovary. That's reassuring. On top of that we do some blood work. You look at follicle-stimulating hormone. We look at anti-Mullerian hormone and other hormones as well, but these give me a qualitative sense of what's going on. For example, follicle-stimulating hormone, right? As long as you have a good group of healthy eggs, you don't have to work that hard to get the ovaries to make an egg. So your levels of follicle-stimulating hormone should be somewhere between 3 and 10, right? Or depending on the lab, sometimes they'll go up to 11 or 12, but that depends on your laboratory and your care provider will know what their normal reference ranges are. AMH is another hormone we look at. AMH is a little bit different. So every egg has these nursing cells called the granulosa. And the granulosa make AMH. So the more eggs, more granulosa the more AMH, right? So depending upon your age, you want to have certain levels. If you're over, if you're in your thirties, you want to have two or higher. The older you get that number drops and over 35 over one and a half. And so when you kind of put that gestalt together, if you will, of the age, FSH and AMH, an ultrasound, then you kind of get a nice comprehensive look at what's going on with egg quality. So that's the first thing you want to take a look at. Next thing you want to take a look at is the uterus, right? Because the uterus of course is where the pregnancy grows. And you want to make sure that structurally the uterus, which is a place for the embryo to attach and grow, that's going through its blood supply, deliver oxygen, deliver nutrients in developing pregnancy that it's unimpeded. So what are things that could impede the flow of oxygen and nutrition, growth supplies, if you will, to develop the embryo? Well, what is the shape of the uterus? Usually the uterus essentially has this nice triangular uterine cavity, but there are abnormalities of development where the uterine cavity is small. There are abnormalities with there's a little extra bit of tissue. And all of these things may not permit that embryo to attach and grow properly so your miscarriage rate’s going to increase. There could be fibroids, which are nodular growths of uterus. Very common. Fibroids are very common. 50% of women may have them, but most of the time, they're not going to cause a problem. The uterus is a nice bag if you will, of smooth muscle, but in, in the uterus, if you grow these hard nodules, if one enters the uterine cavity, for example, so it's sticking into the uterus, well then it’s acting like an IUD or uterine device. So that's going to keep pregnancies from attaching and growing as well. So you want to take a look at the architecture of the uterus to look for fibroids. You want to look at the shape of the uterus to make sure that it has an optimal configuration for successful implantation and growth. So again, it's a checklist, right? The first thing you do is you take a look at egg reserve and age structure of the uterus. Then you start looking at medical problems right?
Dara: Before that, I'm going to quickly interrupt. What about your fallopian tubes? Cause I know that was an issue on my case, and that was the surgery that you did for me, as you blocked off my fallopian tubes. Can that, could that also impair a healthy pregnancy?
Dr. Mukherjee: Great point. So one of the ways that we assess the uterus and we usually recommend this for miscarriage evaluation is a test called a hysterosalpingogram. So in that process, you put liquid into the uterus. It outlines the shape of the uterine cavity. Then that dye goes up and out through the fallopian tubes, right? Now, the fallopian tubes don't get enough credit and Dara, thank you for bringing it up. But these are very important structures that are on top of the uterine cavity and different parts of the fallopian tube are responsible for different important parts of reproduction. The end of the fallopian tube, they have these finger-like projections called fimbriae and they literally move close to the ovary. So after ovulation, when the egg is released, the fimbriae will mechanically pick up that egg and then transport it into the tube at the very end called the ampula. The end of the fallopian tube after intercourse the sperm actually populate the entire reproductive tract from the uterus, the cervix up into the fallopian tubes. And it's at the end of the fallopian tube where fertilization occurs. The sperm enters the egg at the end of the tube. After fertilization, the inside of the fallopian tube has these very fine projections, cilia, that essentially sweep this embryo back into the uterus and then deposit it to the uterine cavity after about five or six days. Now, if the fallopian tubes are occluded, they can get so blocked that they start to accumulate fluid. And that fluid, once it's accumulated, turns the fallopian tube into something called a hydrosalpinx or fluid filled tube. Now that fluid is problematic for a couple of reasons. One, it, it blocks the tube. So the tubes no longer function, but even if you get pregnant from the other side, because you have two fallopian tubes, two ovaries, and you can pick up an egg from either side. But if you get pregnant, let's say you get a, an embryo coming from your left fallopian tube and it's entering the uterus, if the right fallopian tube is filled with fluid, that fluid can actually leak into the uterus and mechanically wash out the embryo and for obvious reasons that is not going to lead to a pregnancy. And it increases your rate of miscarriage too, because if the pregnancy is attempting to grow and you have this constant irritation of the uterus with this fluid passing through, then you increase your miscarriage rates. So the fallopian tubes should be healthy and they should be free of fluid. If there are fluid, if there is fluid found in the fallopian tube, you may need to have surgery. We move that fallopian tube or try to open that fallopian tube and hope that the fluid doesn't recur. So that is a very important point there. So you want to make sure that the entire anatomy,
Dara: Sorry for the interruption. I just, you know
Dr. Mukherjee: No! Listen, I can sit here and I can talk for an hour, please ask me all the questions you want.
Dara: But I interrupted you because you said there were some other things that potentially can be a contributor.
Dr. Mukherjee: Right? So, you know, again, to be methodical. So you take a look at egg quality, you take a look at anatomy, uterine, and fallopian tube, and then you want to move on to general medical issues because your general health. And I think the first thing we should talk about is being overweight. Obesity in and of itself, unfortunately, if your BMI is over 40, for example, significantly affect your miscarriage. There are studies that suggest over 35 can affect your miscarriage rate and it’ll make it hard to get pregnant as well. So clearly Dara with, what are you thoughts on that?
Dara: No, I, I've seen a lot of that in terms of, of my patients and at least the research that I have read point in that direction. And so I think it's great. And I ended up working with a lot of patients who, who come to our clinic right off the bat if they have a BMI of above 35 cause I think it can, it can be helpful no matter what, but yes, because that could be a risk factor for miscarriages it's great that I get to meet with, with most of these people.
Dr. Mukherjee: And what, what kind of dietary recommendations do you usually make with patients who are still trying to conceive, but also attempting weight loss? I mean, how much weight can you, successfully safely lose? What rates are you looking for?
Dara: Well, I like to see about 10% weight loss of their, of their total weight of their overall weight. But it really should be customized from, from person to person. For me, I don't always like to focus on the numbers, even though numbers can, can be helpful, but that can also lead to unnecessary, you know, anxiety or stress. So I like to focus on what people should be including in their diet and, you know, the typical American diet is lacking in fiber and protein and vegetables, in adequate hydration coming from water and not from soda and, and juice. And that's often where I see the success with, with weight loss, but it's, it's less on, on the numbers even though I'm sure, you know, I know protocol says that, you know, if anyone wants to go through IVF at our clinic, they do have to have a BMI of below 40.
Rena: What about the reverse and being underweight and or malnourished?
Dara: I mean, I think that that definitely can play a role, especially with your hormone profile. I see a lot of hypothalamic amenorrhea, which can be related to, you know, excessive exercise, stress and, and under eating. And that's equally, I think, as important. And I like that you mentioned that Rena, cause I think that gets less attention.
Dr. Mukherjee: No, no. Yeah. That's a good point. Both of the extremes unfortunately are going to conspire to make it difficult to conceive. The primary issue with hypothalamic amenorrhea is getting pregnant in the first place. Not being able to ovulate, it kind of keeps you out of the game. Once you're pregnant with hypothalamic amenorrhea, miscarriage rates still are there. They're not quite as bad as the other extreme with a BMI over 40, but it's not... the harder part with hypothalamic amenorrhea is getting that successful, getting a successful ovulatory event. But anyway, when you think about overall medical problems, clearly nutrition, BMI figure into all of that. But, the next things that you really want to look at a thyroid control, I mean, there've been some recent articles that have suggested that the optimal thyroid hormone level should be some number between one and two which is very strict. The normal TSH thyroid stimulating hormone level is usually some number between 0.4 and 4 or 4.4, depending on the lab. And that's okay for your general health, but there are some studies. And I think that there's a lot of studies out there now that think that tighter control of your TSH levels are warranted to reduce your miscarriage rates and loss of pregnancy rates. How strict that should be? That, that's a little controversial. I'm actually okay with a TSH level between 1 and 3. I think getting it to two is a little much because TSH levels very dramatically. Looking at prolactin levels, looking at androgen levels to make sure that you don't have any underlying androgen abnormalities such as elevations in DHEA or testosterone. Those are all very important as well. So, you know, the, in general, the things that we're gonna look at, we're gonna look at egg, anatomy and general medical profile, making sure that you're in good health. In other words, miscarriage patients are different than fertility patients in the sense that we really want to make sure that you’re not only currently healthy, but that there, that we want to move you towards being a little bit more aware of what you are eating and what you are consuming, just to make sure that we're not overlooking anything. I was going somewhere with this...The one part of the evaluation that is always controversial, you know, because we have patients where all of this testing comes back as normal, everything's healthy and there's still a rate of pregnancy loss. And that's where we start to enter into areas of miscarriage testing and investigation that not a lot of providers are comfortable with because it's very hard to do research in these areas. What I'm talking about of course is the immunology of pregnancy. In other words, immune or inflammatory states that increase the rate of miscarriage. And part of the problem with this is that, you know, we're taught in our OB residencies that the uterus is a privileged space. That the placenta and the uterus act to kind of shield the developing pregnancy from outside influences. Right? But we do know that the state of pregnancy is a relative state of being immunocompromised. The immune system is turned down a little bit because the child's genetics are significantly different from mom. And you know, when you do an organ transplant, for example, the mother will reject the tissue. Why doesn’t the mother reject the child? The child is not the same genetic composition as the mother. There's different HLA profiles on every cell of the baby, but because the uterus does through a means we do not understand protect the child from the mother's immune system, we often feel that no matter what the immune system is not going to play a role in this carriage. And I think that's an oversimplification. Just because we don't understand how the, and we don't. There literally is no full understanding of the systems that protect the baby from the mother's immune system. And it's an ongoing area of investigation. And I think there's some work that's being done, but really it's hampered by the ability to do that kind, the kind of work that would need to be done in a pregnancy to assess the immune system. Clearly, you don't want to affect the pregnancy. So a lot of the testing that we do doesn't answer the question directly. But I do believe that after, you know, let's say two pregnancies and certainly a pregnancy where you know that the pregnancy was chromosomally normal, right? Pregnancy was chromosomally normal and that's one of the top reasons why pregnancy is miscarried, but you had another miscarriage now, what do you do? Well, we do rely on colleagues who are reproductive immunologists, and they will assess your immune system and they thankfully can provide therapies that at least 50 to 60% of these cases. So it is an area of miscarriage that is evolving. It's not well understood. And I think that there is a reluctance among a lot of very well-intentioned providers to minimize the impact of the immune system on reproduction. But I think personally, if I were going through the process, I would not want to be denied access to these services. I know that they're not very well tested. I know that they may not be effective, but I want to know. And it's, it's something that I think that, you know, as a practice, we are doing a better job of it. We have resources, thankfully in New York city, where if a patient has had, you know, chromosomally normal miscarriages, certainly on more than one occasion, then we have our colleagues in the reproductive immunology field who can assist at that point and, you know, suggest interventions that can make future pregnancy attempts more successful.
Rena: Hmm. I'm glad you brought that up. I think, you know, that's something that I think can be controversial. You know, I think that's a pretty hot button topic either really pro this treatment or they think it's, you know, kind of a farce, so I'm really glad you, you brought it up and,and you really are explaining sort of the benefits of it because I think it's, you know, kind of alternative and...
Dr. Mukherjee: I think despite Dara's very nice introduction with all the things that I've seen and done I think I know enough to know that there's a lot of, a lot of things yet that I don't understand. And so I welcome physicians who can help me in those areas. And even there, when you speak to them at length, I mean, they're also struggling to understand the science and, you know, explain some of these clinical scenarios. But I think that in the setting of miscarriage, which is really one of the most heartbreaking things we can deal with, you want to bring all your resources on board. So I don't see any reason to exclude a field of medicine that, while it may be controversial, there is no question - the immune system plays a huge role in successful pregnancy because there's no question about it. If the immune system attacks the baby it's done, but it doesn't in the majority of the cases. Why? I couldn't tell you. If I can't tell you, then I don't understand it well. So I need, you know, we need to figure it out
Dara: But I, I respect you. I respect the fact that you are open-minded and that you do have conversations with other people in different areas and that's, I think that's great.
Dr. Mukherjee: Listen, how else are you going to learn? You got to ask, you got to indulge in conversations. You have to go back and forth, listen to everything and, you know, try to consolidate that into your own practice. I mean, that's, that's what we do. We're professionals, we're all professionals. And we have to keep an open mind and, you know, dismissing things out of hand is, you know, not fair. You gotta have, you gotta understand it. You gotta look at it. Listen, there's things that we don't do. I mean, there's clearly things that we don't do, but, you know, we will investigate it. We'll ask the question, we'll ask why. Does it make biological sense? Has it been studied appropriately? Is it safe? Does it do harm? Does it not do harm? And you know, if the questions are answered appropriately, then we institute therapies and then we hope to help as many people as possible. That's the whole idea, this gig, right? You want to try to get as many healthy babies around this possible and happy families as a result.
Rena: I love that you brought that up. It's so when you were saying all that, I was thinking back to sending that it was never really solved for me when I was pregnant at about 25 weeks, I was hospitalized for a week. I was inpatient with this mystery infection and my body was attacking itself and, you know, they were monitoring. And the hope at that time was obviously that it wouldn't penetrate the placenta and thank God it didn't. And to this day they never diagnosed what it was. They have no idea. After a week I was released. But when you were saying all of that, I was like, wow, that's really crazy and you know, the body is just so mysterious.
Dr. Mukherjee: Well, it's a fascinating topic. And you know, of course I'm happy that we're not allowed to do that kind of research in pregnancy, but we're also limited in terms of how well you understand the scenario. Clearly nobody wants to be an experimental subject when they're, you know, 20, 30 weeks pregnant. That's obvious. But you know, that is, you know, it's an important area to investigate. The tools to investigate the immune system in pregnancy are evolving. If we can get better noninvasive tools, a better understanding of great, then ultimately we'll crack it. It's just that the amount of reliable data that you can get is limited. So it's a very slowly evolving field and, you know, medicine has always been conservative. We don't really move. We don't jump in any direction unless we have a calamity like this COVID nonsense. Species extinction clearly rises to that level and it makes us a little bit more open minded or closed minded, depending upon who's doing the talking. But, hopefully we'll figure all of this out soon.
Dara: There's two other things I wanted to, or a couple more things I wanted to kind of get your opinion on. The addition of progesterone - is it used around unexplained loss? And I know you mentioned it, we spoke about this briefly is low dose aspirin.
Dr. Mukherjee: So, you know, typically we do these evaluations at half the time, and I'm not talking about the reproductive immunology evaluation, but we'll take a look at egg quality. We'll take a look at the uterus. We'll take a look at your general medical health and find that everything's okay. Half the time we find that and if we find something we correct it. But what about the other half where we really don't get anything well, in that case, just because we haven't found anything doesn't mean there's nothing going on, right? So we usually use supportive interventions, right? And as you mentioned, one of them is baby aspirin. Why baby aspirin? Baby aspirin inhibits platelet activity. Platelets can cause clots to form. And they should that's what their job is. But if you get those clots forming in the interface between the attaching placenta and the uterine surface, then the flow of nutrients across that interface is diminished. So by giving a baby, I shouldn't say baby, the low-dose adult because you don't want to give aspirin to a baby, but low dose adult aspirin, 81 milligrams, you kind of want that platelet response and you hopefully will keep clots from forming. So one of the things that we recommend for empiric treatment, others, I don't know what's going on, but I'm going to try that. So baby low-dose aspirin. Progesterone. Progesterone is an important hormone in the maintenance of pregnancy, estrogen, not nearly as much. But progesterone is very important in the first trimester of pregnancy because it keeps the, it allows the implantation to occur. It continues sustained changes in the way the uterus functions to enable the pregnancy to burrow deeper, to provide more nutrition to the pregnancy and the pregnancy, ultimately, once the placenta is fully developed at around nine weeks or so is making all the progesterone it needs on its own. But in that critical period of time for implantation, which is, you know, about, six days after ovulation to nine weeks, supplemental progesterone therapy may be very helpful. Now progesterone therapy is easy. It's tablets or it's suppository, whatever is convenient. I usually recommend a suppository twice a day, but that's to make sure that you have adequate progesterone for that very important early part of pregnancy. So usually stop it at nine weeks.
Dara: I was going to say, is it not intramuscular anymore? Has it not been for a while?
Dr. Mukherjee: For IVF we do. For IVF we always go intramuscular progesterone but the reason is different because in IVF, we go into the ovaries and we puncture those follicles that ultimately we need to make that progesterone. So in most cases, you're not going to get enough progesterone. Some cases you are some cases you’re not. We're not gonna take any chances. Everybody gets intramuscular progesterone for an IVF cycle, but for a miscarriage cycles, the ovary’s left intact. It should be able to make a baseline amount because, you know, after you ovulate, the egg is released. What's left behind is a Corpus luteum and that's, what's making you progesterone and we'll leave that alone for natural pregnancies or, you know, with Clomid or Letrozole, we leave it alone. So it should be making some. We want to on top of that, provide additional support with either oral or vaginal progesterone. So usually I started with a positive pregnancy test. Some practitioners started earlier. You want to be careful because if you take progesterone too early, then it's the birth control pill. I mean, that's what the birth control pill is. It's just progesterone a little bit of estrogen to stabilize the uterine lining. So the timing of progesterone support, you don't want to take it for the first two weeks. It's going to, it's going to prevent implantation. So I'm a little hesitant to, unless the patient's really aware of where they are in their cycle. And even then I don't start it for a week after ovulation, but with a positive pregnancy test, I start progesterone. They've already been on a baby aspirin from the first time they, you know, we went over the plan. Additional folic acid is something that I recommend. As we all know folic acid is very important. And I think Dara you asked me about the difference between methyl folate and regular folic acid?
Dr. Mukherjee: For 90% of patients, regular folic acid is more than enough. So the reason that folic acid is important, well, methylation is something that happens in all of our cells. It's very important in turning on and off certain genes. Methylation is accomplished with this pathway folic acid cycle. MTHFR methyltetrahydrofolic reductase is an important enzyme in this pathway. So there are variants of this enzyme, some are more efficient than others. There are certain variants of that enzyme. If you have two bad copies and you, again, you need to have two bad copies of this enzyme. And the one that comes to mind is six, seven 17. If you have two bad copies of that, the enzyme is really inefficient. The vast majority of the time it's fine. And this cycle that occurs in our cells the folate cycle happens thousands of times a second. So even if you're not getting methyl folate, which is kind of one step ahead in the pathway for 90% of people taking regular folic acid it’s going to be more than fine. For that last 10%, you really want the methyl folate to skip that step because it's so inefficient, but that's very unusual. So I would say for the majority of patients taking regular folic acid is more than sufficient. So we recommend 800 micrograms of folic acid in addition to what's usually delivered in a women's one a day vitamin, which is what I recommend. So typically that's gonna have 400 micrograms of folic acid. We recommend if you're going to take regular folic acid, 800 micrograms on top of that, to give you 1.2 milligrams, or you could take a methylated folic acid, which is met next and you take that in addition to the multivitamin, because you need B12 to properly metabolize folic acid. And so people will just take the folic acid. You need to take the B12. So it's just easy to give them the vitamin. You got it all.
Dara: Thanks for explaining it. That's I think that makes it so much clearer because a lot of my patients are coming to me and asking and I'll be honest. My answer was like, it's better than just take a methylated folate, but you made a great point the last time we spoke is that it is much more expensive.
Dr. Mukherjee: It's very expensive and it's hard to get sometimes. You go to the pharmacy, but they're out of it. So I got to get my, I gotta get my metal folic acid, listen, just go, go buy your folate and then we'll get you that other prescription, when it comes around, you're going to be fine 90% of the time. Clearly it's, I don't want to put a patient in the position where they're not able to access something that in some, on some level they need. I leave, you know what I mean? They need to take a little bit of extra folate. I'm happy with that going to work 90% of the time, which is fine.
Rena: Okay. And I just have two more questions. So one is, okay, so say, you know, you're a patient, you have a miscarriage. And as we talked about at the beginning, the, you know, it's, it's one in four, depending on your age or stats can be anywhere from 20 to 50%. Okay. If you have one loss. When do you get to a point where you should, where it will be classified as recurrent pregnancy loss?
Dr. Mukherjee: It's a great question. I mean, believe it or not used to be three or more losses, which I think is cruel and unusual. I mean, clearly if you were in your thirties and you have one miscarriage, I want to see you. I want to make sure I may not do anything, but I'm going to test. I want to make sure that all of those things that are important are normal, and then I'm probably going to give you supportive therapy because low dose aspirin, little folic acid, a little bit of progesterone. There's no harm in that, right. If under my care you have another loss, right? Let's say, you came to me. You have another miscarriage. I test you. I give you supportive therapy. You have another one. And then I may want to talk to you about IVF. I may want to talk to you about looking at the embryos and screening them, making sure that their chromosomally normal, even before you get pregnant, that I can transfor normal embryo, chromosomally, normal embryo into the uterus. And hopefully I've taken one of these big causes of miscarriages off the table. Then let's say, I put that normal embryo in and you get to the heartbeat and you have the miscarry them. Then I'm going to reach out to my colleagues who are reproductive immunologist and say, okay, listen, I took chromosomal abnormalities off the table. We got pretty far in the pregnancy and I'm sorry to say, we've had another loss. Can you help me? So that's my progression with that. So, you know, anytime under my care, if there's a chromosomally normal loss, that's what I do. Prior to that if they're, if they're chromosomally abnormal, then we move to IVF to try to get normal embryos for them.
Rena: Okay. Thank you. I think that'll be so helpful. And then my other question that I just wanted to go back on, of course, from a mental health perspective, I was so happy to hear you really touch upon and be so empathic about the fact that, you know, whether you have a loss at anything, a chemical pregnancy to six weeks to 10 weeks, a loss is a lot. And you know, I know a lot of people sometimes think that, well, I was quote unquote only four weeks along. So, you know, my friend who had a loss at 12 weeks, they should be, they can be, you know, more sad than I can because it was so early. And, you know, I just want to, you know, say of course from a mental health perspective, there's no, there's a scale here. You know, loss is a loss and it's devastating, you know, from the moment you get a positive pregnancy test to when that's taken away. It doesn't matter if it's two weeks or 10 weeks or 20 weeks and either way it's extremely devastating,
Dr. Mukherjee: I learned that from the best. JJ Smith. That’s what he told me and he was right then and he’s right now and he’ll always be right on that point. You can’t minimize that. You’re only 4 weeks pregnant. So what? It’s devastating.
Dara: And Dara, I mean, I was so happy to not happy that you had the experience, but that you shared that you had chemical. And I had that as well. And I think that's something too, that's often overlooked. I don't know about you, but I often struggle with, you know, the same feelings and is that justifiable to say, well, I had a loss, you know, was it, I mean, medically speaking, a chemical is kind of different. But I feel like I went through this same roller coaster of emotions and devastation as, as a miscarriage and being told I was pregnant, you know, after doing fertility treatments for, for so long, and then that was taken away. And so I, I think too, for people that have had a chemical, they often feel not kind of validated in their feelings. And so to just say that that's a loss too.
Dara: It's nice that you said that. Yeah, I mean, I actually had this conversation last night with my children. I told them about my experience last night of all times and, and how it was heartbreaking, especially, you know, I told my parents and it was something that was kind of out there. And I think no matter when it is, it's heartbreaking. I just love that you said that, you know, of course the first place you think about is yourself and it was just so nice and reassuring to hear from doctors that, to remind us that, you know, it's almost always coming from something that's abnormal and that's a reason why there is a loss. You know, in some ways it can make it a little bit easier, but it's so interesting as as women, we, we blame ourselves. I'm sure men do too, but I can only speak for myself.
Dr. Mukherjee: That's just the way we're wired. We want to explain this. You know, we want to look into our own actions and say, okay, what did I do because that's your pregnancy, it’s your body and it’s like of course it must have been something I did. but that's just the way we think, which is unfortunate. We blame ourselves for things that, you know, we have no control over. That’s one of the things I try to teach my kids. Listen you got to break the world down into things that you can control and things that you can't control because spending all your energy on stuff that you can't control will drive you nuts.
Rena: I know Dara and I both believe that for sure. Well, this has been great. I'm really excited to get this episode out. I feel like, you know, these are conversations I have with patients all the time. And so I know this is going to be really so helpful and, you know, Dr. Mukherjee so grateful for you and your empathy, your kindness. I think, you know, it's and your openness to, you know, alternative medicines and therapies. I think our patients are so lucky to have you and really grateful to have your expertise and guidance.
Dr. Mukherjee: Thank you so much, Rena. Thank you so much for having me on your, on your podcast and putting up with me for an hour and Dara thank you for putting up with me as well.
Dara: Before you go we actually have one, one extra thing if you have a quick second. We always end our session with gratitude, what we're grateful for today at this very moment. I know you've have lots to be grateful for, but off the top of your head, what are you grateful for?
Mukherjee: I think given the current situation I’m grateful that my family and my friends are healthy god bless them. What more can I ask for given what we’ve all been going through. That's all I'm really grateful for today. Very grateful for actually.
Dara: That's a lot to be grateful for.
Dr. Mukherjee: Isn’t it? People take it for granted. At least the one thing we can learn from this is not to take that kind of stuff for granted. You know listening to my mom complain for an hour yesterday, kind of felt good. Like, alright.
Dara: What a good sign. Rena, what are you grateful for?
Rena: Yeah, I mean, just, you know, to piggyback on Dr. Mukherjee, health. I think that's really everything and, you know, I sort of shared snippets on here of, I've been going through some health stuff. And finally, yesterday I found out that most likely what's been going on with me and my immune system is a result of having COVID and my body has just been attacking itself, or I got COVID, literally a year ago tomorrow. But just really grateful to have at least some data and to have health because health is wealth, you know, without health, we are, we are nothing. And it is very, very difficult.
Dr. Mukherjee: Good luck with that, Rena. Hopefully we'll get some progress now that you have a handle on it. That'd be great.
Rena: I hope so. So yeah, health, I mean, without health, we are, it is a lot, a lot harder. Dara, what about you?
Dara: Bringing it back to Dr. Mukherjee, I am very grateful for your part in my fertility journey and really you, you played a, a big role in, in realizing that my mechanics weren’t working and, and helping figure it out. And also, you know, your openness. I, I really, I hear from your patients just, you are open to collaborating with other people and hearing other doctors and medical treatments and supplements out, whether you agree with it or not the fact that you are open-minded and are always, you know, doing the research and keeping abreast with, with all the information. I think it's great. It's a testament to, you know, why your patients adore you. And I'm thankful for that.
Dr. Mukherjee: Thank you so much. Thank you, Dara. Thank you for that. Thank you, Rena. Listen, it's always nice to be able to work with such a talented group of people. And I got to say, what's that statement they say? If you want to go fast, you go alone. If you want to go far, you go together.
Rena: Yes. I just heard that somewhere. Were we listening to the same thing?
Dr. Mukherjee: I hear it on and off. I'm not sure.
Rena: I think I heard it in a lecture for nutrition school, Dr. Mark said it.
Dr. Mukherjee: It’s true. A lot of very smart people to the left, to the right of us and we just got to keep an open mind so that we can take advantage of all the talent that's around us. And I'm always blessed to work with two incredibly talented practitioners, such as yourselves. It's great. When I send patients to you, I’m confident that they're getting the best advice that they can get.
Rena: I think it takes a village. And I think, you know, this last year has taught us anything it's that, you know, stronger together.
Dara: Thank you so much.
Dr. Mukherjee: Pleasure speaking with you both. Take care.
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 www.rmany.com and tune in next week for more Fertility Forward.