Recurrent Pregnancy Loss with guest Dr. Dana McQueen
Dr. Dana McQueen received her medical degree from UC Irvine, and residency in ObGyn at University of Chicago. She completed a one-year fellowship in recurrent pregnancy loss with Dr. Mary Stephenson, who is literally one of the most well-known recurrent pregnancy loss specialists in the country, if not the world. She completed her fellowship at Northwestern Feinberg School of Medicine in reproductive endocrinology and infertility. Now she’s at University of Chicago as an attending. I’m so excited to have Dr. McQueen on the show. You should take a look at her Instagram page, where she has some of the coolest and easiest to understand graphics related to fertility.
Dr. Aimee: Thank you, Dana, for coming on. Welcome. Tell us about what we’re doing and why we’re doing it.
Dr. Dana McQueen: Thank you so much for doing this. It’s a great opportunity for us to share our work at University of Chicago. I’m one of the attendings at University of Chicago, I see patients there clinically, but we are also doing research on recurrent pregnancy loss. I started this research with Dr. Stephenson when I was a resident, and then did her fellowship, like you said, for one year. I studied with her, learned all about recurrent miscarriage, continued to research on the topic, and then continued that work when I was in fellowship at Northwestern.
We’re really jumpstarting our program at University of Chicago and trying to create an RPL center where women can go, seek care, and also participate in research studies.
Dr. Aimee: What is considered recurrent pregnancy loss?
Dr. Dana McQueen: That’s actually a great question and a subject of debate. Some people consider miscarriage any pregnancy loss. Ectopic, a pregnancy in the uterus, a biochemical miscarriage, a stillbirth, those are all pregnancy losses. When we call something a recurrent pregnancy loss, we have to figure out which definition we’re going to use.
ASRM is sort of the governing society within the US, and their definition of recurrent pregnancy loss is two or more clinical miscarriages. What is a clinical miscarriage? It means that the pregnancy was in the uterus, it was either visualized, so you saw it on ultrasound. You could have seen an empty gestational sac or a yolk sac, or you got some kind of pathology diagnosis, so the p passed a tissue, they looked at it under the microscope and they saw pregnancy there.
ASRM defines recurrent pregnancy loss as two or more clinical miscarriages. If you go somewhere like Europe, ESHRE is going to define pregnancy loss as: two or more pregnancy losses at any time, any type of pregnancy loss, so biochemical pregnancy losses also count.
I tend to lean toward the ESHRE diagnosis criteria.
Dr. Aimee: Me too. I’m right there with you.
Dr. Dana McQueen: A loss is a loss. The reason I say that is because is if you have an early loss, a biochemical miscarriage, we know that still puts you at risk of having more subsequent miscarriages. It doesn’t matter if the loss was early or biochemical, it still puts you at risk of having more miscarriages, so it’s reasonable to start thinking about a workup. But technically, to meet the definition in the US, you have to have two losses that are documented.
Dr. Aimee: How do you know if it’s time for an evaluation? At what point would you say I should go see a doctor? Should you wait a year after that second loss and trying? What should people do?
Dr. Dana McQueen: I’m happy to see patients at any time. Sometimes people come just after one miscarriage and want to talk about what causes miscarriage and if there are any factors to improve their lifestyle that could be impacting the chances of success. Generally, we start thinking about a workup after two losses. I would argue that you could do it after two biochemical losses or after two clinical losses, but after two losses it’s reasonable to start thinking about a workup.
A study that was done looked at the cost of a workup and the cost-effectiveness of doing a workup after the second loss. They said that you could do chromosome testing on the miscarriage. If you have a miscarriage and you can do chromosome testing and it’s abnormal, that means we can explain the miscarriage, we know that this pregnancy loss happened because of a chromosome abnormality, and we can say you probably don’t need this whole million-dollar workup — it’s not a million dollars, but it is a large workup — if we know the cause of the miscarriage was a chromosome issue. If we get normal chromosomes back, then that pushes us down the track. We should definitely do a workup in this situation and figure out what’s going on, why is this happening to you.
I think the reality of it, though, is that most patients come to me with two losses and no chromosome testing, so you don’t really know if it was normal or abnormal, so you lean more toward starting a workup at that point because you don’t know what the cause was.
Dr. Aimee: I feel like people need to know that they can test their pregnancy tissue and learn about it. That’s the most valuable diagnostic testing you can do. Then people are told by really well-intentioned doctors, “You got pregnant, so it should be fine for you to try.” Then after a year, especially for patients in the Bay Area, most patients are starting their family in their 30s, and a lot of times in their late-30s, and that is precious time that they could be using to get a diagnosis and to figure out what’s going on.
Dr. Dana McQueen: Yes. I definitely wouldn’t want women to wait a year after getting pregnant to think that they have to meet some criteria for infertility or anything like that.
Dr. Aimee: Exactly.
Dr. Dana McQueen: I also say you can start trying again after your next normal period. If you have a miscarriage, you don’t have to wait three months, four months, six months to start trying again. I do usually do some kind of evaluation to make sure the miscarriage is complete, like a saline ultrasound to make sure the lining of the uterus is normal and there is no retained tissue, before I would have you try to get pregnant again. Right after that, you can start trying again. Don’t waste any time.
Dr. Aimee: Right. What is the workup? If I want everyone to listen and tune in, if I can share this information with them, what is the workup for people who are really interested? You’re going to get your paper and pen out, listen to Dr. McQueen. What is the workup from Dr. McQueen herself?
Dr. Dana McQueen: Sure. The initial workup is going to be the basic factors that we want to evaluate.
The first thing we’re going to see is if the uterus is normal. Is there some problem anatomically that is causing you to have recurrent losses?
One thing we think about is a septum inside the uterus. That’s a fibrous tissue band, it comes down in the middle of the uterus, divides the uterus into two parts. The fibrous tissue is not well vascularized, so there’s not a lot of blood supply there. If a pregnancy implants there, we think that pregnancy might lead to a miscarriage. We know that women who have septums have a high rate of miscarriage, of early losses.
We always want to evaluate the uterus, so what we do is a saline ultrasound or a hysteroscopy, those are the two options to evaluate the uterus. We look inside and say, “Is there a septum? Is there a big fibroid in the uterus that could cause a miscarriage? Is there a large polyp in the uterus that could lead to inflammation and possibly a miscarriage? Or is there retained tissue?”
One thing I commonly find is that if there is some little bit of placenta or something, it could be from your last full-term pregnancy, it could be from a miscarriage that you had a year or two ago, and it could be calcified, and I think that can cause this inflammation in the lining that can lead to more miscarriages, we think. So, cavity evaluation, anatomic evaluation is the first step.
The next thing that I think about is genetics. Are these miscarriages genetically abnormal, is that the reason that they’re happening? We know that as you age there are just errors that get made when you’re making an egg. Those errors increase exponentially as we age. So, we know that the chances of having an embryo that’s abnormal is increased. If we can test the pregnancy tissue — you can do that at the time of the miscarriage, but you can also test D&C specimens that happened years ago. We can send off these paraffin blocks that happened years ago, that are stored at your local hospital, and you can test them to see if the chromosomes are normal or abnormal. That can give you information to at least help you understand why this happened, why you had these losses.
The second genetic cause is that you could carry something called translocation. What that means is, everybody has 46 chromosomes in each cell, you could have two chromosomes that are kind of stuck together. A 13 and a 14 that instead of being separate are stuck together. Then what happens is when you pass those chromosomes down to your pregnancy, you actually pass the chromosomes down that are stuck together and you send an unbalanced number of chromosomes to the pregnancy. That just increases your risk of having miscarriages. If we can test that in advance, we can identify the embryos that are normal, usually with IVF, and the embryos that are abnormal, and then only transfer back the normal embryos to you.
So, looking for a genetic cause is the next sort of category.
Dr. Aimee: What percentage of people in general will have a translocation, in the general population?
Dr. Dana McQueen: We say it’s about 4% of women with recurrent miscarriage, but it’s going to be less than 1% of people in the general population. It’s not something that you need to be tested for in general or if you have infertility, but it’s something that we think about if people have recurrent losses, or two or more losses.
We actually test both partners. It’s one of the few things that we test in the male partner of a woman who has RPL or a couple that has RPL. We wish there were more male factors that we could identify, and I’m sure there are some. The carrier type on both partners is important, for sure.
Dr. Aimee: What about chronic endometritis? I know you talk a lot about that on your Instagram page and you have done a lot of research on that, so tell us about that.
Dr. Dana McQueen: Yes. Chronic endometritis was one of the research projects that I started as a resident and I continued it during fellowship, and I’m still working on it now.
Endometritis basically means an inflammation of the lining of the uterus. What we find with chronic endometritis is there are these inflammatory cells called plasma cells and they’re inside the lining, and we think they lead to sort of a hostile environment of inflammation. We know that it’s treatable, because when we give antibiotics for chronic endometritis, it resolves between 60–90% of the time on a woman’s second biopsy. It’s an inflammation, we know it’s treatable with antibiotics, and we’re trying to figure out why it’s happening.
Another cause is something inside the uterus, so a polyp, a fibroid, some structural cause for having an inflammation. Another thing we’ve found, and I’ve just submitted this paper recently, is that women who have retained pregnancy tissue have a very high rate of chronic endometritis. If we look at the surrounding endometrium of women with retained tissue, 60% of those women will have chronic endometritis. Women with RPL have been shown to have chronic endometritis.
I have a paper that’s under review, that’s very close to be accepted hopefully, where we’re looking at what is the definition of chronic endometritis and what is the true prevalence in women with recurrent miscarriage versus controls. We recruited two groups; one group that had recurrent miscarriage and one group is a control group of women just doing egg freezing for elective reasons or fertility preservation.
What we found is that when we use a strict definition of chronic endometritis, none of the women in the control group have it. Maybe they have a rare plasma cell, but none of them have what I would call endometrial stromal changes, which is like spindling of cells, inflammation, edema. None of them have any sign like that. Whereas women in the RPL group when we use this strict definition, 30% have chronic endometritis, so it’s a high prevalence.
It’s treatable, so it’s definitely something that I check for. It has not made it into the ASRM checkboxes yet, but we’re hoping that the next edition of ASRM’s recommendations includes a chronic endometritis evaluation.
Dr. Aimee: Do you think that everyone needs a repeat biopsy? Let’s say you’ve been diagnosed. Do you tend to do a repeat biopsy to make sure that it has been cured?
Dr. Dana McQueen: I always do one. It depends on what study you read and how likely you are to be cured with your treatment.
I think the first step now that I’ve seen that it’s so prevalent in women with retained tissue is that if you get a diagnosis of chronic endometritis, I recommend doing a hysteroscopy. Look for retained tissue, look for some cause for this chronic endometritis instead of just treating it with antibiotics.
Then I treat it with antibiotics. I usually do 14 days of Doxycycline, 100 BID. Other studies have done Ofloxacin and Flagyl. That has about a 90% cure rate, but Doxycycline has about a 60–70% cure rate. But these are pretty small studies. There’s really been no randomized control trial where we tried different antibiotics.
I know that it’s not a 100% cure rate, so I do want to make sure that the chronic endometritis is gone before women try to get pregnant.
Dr. Aimee: What about sperm DNA fragmentation, do you think that testing is important in people who have RPL?
Dr. Dana McQueen: That’s a really great question. I actually did a meta-analysis on this in fellowship. What that means is we pulled all the articles we could find and we did a systematic review. You search PubMed or different databases for every article that has been written on recurrent pregnancy loss and sperm DNA fragmentation. Once we did that, we took all that data and put it together to see if DNA fragmentation is truly associated with recurrent miscarriage.
It was. So, men who are partners of women with RPL had a significantly higher sperm DNA fragmentation than men who were partners with women who were fertile controls, who had children but had never had miscarriages.
So, it is associated. The question is what do we do with that information? I think that’s the next really big important research question. And does having high DNA fragmentation predict subsequent miscarriages? We know it seems like it’s associated, but the important thing that I always have to remember with research is that something that is associated doesn’t mean it’s causing the miscarriage. So, is there some factor that is causing both DNA fragmentation and miscarriages, or is it truly the DNA fragmentation that is causing the miscarriage?
It’s definitely something to look out for in future research to figure out what we do about it and does it cause subsequent losses.
Dr. Aimee: For people who are reading this and are curious on how to get a DNA fragmentation test ordered, how do you do that?
Dr. Dana McQueen: I usually use ReproSource. They actually have a great system. You can order it through your physician or they send you a home collection kit to do DNA fragmentation or do sperm analysis through them. That’s the group I usually use. I don’t know if you have another resource.
Dr. Aimee: No. They’re great, they’re awesome. If let’s say you see a doctor that is like, “I don’t believe in sperm DNA fragmentation, I don’t think it matters,” but you feel strongly that you should have that test, is that test something that you can order without a physician, or if you do it through ReproSource you have to have a physician’s order?
Dr. Dana McQueen: I don’t know the answer to that. Since I’m usually the one ordering it, I guess I do it myself. Do you know the answer?
Dr. Aimee: Unless things have changed, I think that is not direct-to-consumer. But there is a direct-to-consumer test, it’s SCSAdiagnostics.com. I use ReproSource as well, I think they do a great job. There are providers out there that patients think that this would be a helpful test for them and they want it and the doctor doesn’t believe in it. I think the science is definitely there that it could be a helpful tool.
Let’s say the sperm DNA is high. What kinds of things would you suggest they could do to improve it, to bring it down and make it better?
Dr. Dana McQueen: I think that’s a great question. That’s sort of what I was hinting at. If we find a group of men that have a male factor for RPL like elevated DNA fragmentation or we think there is a male cause for this RPL, what can they do for it?
Obviously, doing things like healthy diet, healthy lifestyle, don’t smoke, try to reduce oxidative stress in the body, because we think that the DNA fragmentation is happening because of oxidative stress. Frequent ejaculation has actually been shown to significantly reduce DNA fragmentation. It sounds a little odd to recommend frequent ejaculation, but we don’t want the sperm to have been there for a very long time and then use those sperm to get you pregnant, if that makes sense.
There are these new chips out there called microfluidic sorting chips that a company named ZyMōt is making. You can actually put the sperm in the chip and they’ve shown that the sperm that come out the other side have a significantly lower rate of sperm DNA fragmentation.
The other option, which sounds kind of intense, is doing a TESE, so actually doing a sperm extraction. When you do that, the sperm have not had to make their way out into the world, because they’ve been extracted, they have a lower DNA fragmentation than ejaculated sperm. Most men are not hoping to do that treatment option, but in the end, if you have very high DNA fragmentation and it was the only cause that we could find for recurrent miscarriage, it’s definitely something you might want to talk about.
Dr. Aimee: I think that’s right, most men would not want to sign up for that, that’s very true. I think for guys who have a really high DNA fragmentation you can run the sperm through this and then take that and send it for a DNA fragmentation test and see if in your particular case it came down enough, and then you would know if you would really need the TESE or not. That’s sometimes something that I do as well.
Dr. Dana McQueen: Yes.
Dr. Aimee: I want to go through the different treatments that are available for all of the different problems that you’ve just laid out very beautifully for us. Let’s just go through this.
The first one, septum, what do you do?
Dr. Dana McQueen: For a septum, I recommend removal. The way to do that is to do a hysteroscopy. That’s just a very small camera that goes through the cervix into the uterus, and then we use scissors and we cut out the septum. It’s a fairly simple procedure, but you do want to go to an expert who has done this many times.
Some septums can be very challenging, especially if it’s a complete septum. You could imagine, you go into one side of the uterus and you need to make your way over to the other side of the uterus, opening up, and that opening can be difficult. So, if you have a complete septum, I definitely recommend seeing a fertility specialist who does this quite a bit.
Dr. Aimee: What about polyps and fibroids?
Dr. Dana McQueen: Same thing, I definitely recommend removing polyps or fibroids. You can argue about what size of a polyp you would want to remove. In general, in someone who has recurrent miscarriage, if I find something in the cavity, I’m going to go after it. Usually, definitely over 1-centimeter sized polyp you’re going to want to remove. Those can be removed similarly to a septum, except that I usually use a little device called a MyoSure, where you put this little device in, it has a blade that kind of chops up the polyp or the fibroid and removes it.
I like doing that because I can see what I’m doing, I can watch it be removed, and I don’t have to do anything to the entire cavity. Especially for women who have recurrent miscarriages, I don’t want to do a large procedure where I’m going to put them at risk of further things like Asherman’s Syndrome or scar tissue. You want to do as limited amount of biopsy or removal as you can.
Dr. Aimee: There’s a lot online about blood thinners and recurrent pregnancy loss. What are those used for?
Dr. Dana McQueen: I don’t recommend using a routine blood thinner for all women who have recurrent miscarriage. The data is not there to support treating every patient with a blood thinner. But in women who have something called antiphospholipid antibody syndrome, I do recommend a blood thinner.
We didn’t talk about that. Antiphospholipid antibodies. There are three types; lupus anticoagulant, beta-2 glycoprotein1, and anticardiolipin. They all cause an increased risk of blood clots, outside of pregnancy or in pregnancy. Those are blood clots in your leg or your lung that can put you at risk during pregnancy.
The other thing that’s sort of interesting is they increase your risk of early miscarriage. We don’t even know if that is actually from a blood clot or because there’s beta-2 glycoprotein1 receptors actually on the trophoblast, which is the pregnancy itself. It’s interfering in some way with the way that your pregnancy implants and grows a placenta. We’ve found that women who take a blood thinner like Lovenox or Heparin and a low dose aspirin, 81 milligrams, that significantly lowers their risk of miscarriage in their next pregnancy.
I usually test women for all three of those antiphospholipid antibodies. If they’re elevated, you technically need to repeat that test 12 weeks later, which no one ever really wants to wait that long.
Dr. Aimee: No one wants to wait 12 weeks. No thank you. I’m going to repeat it in six weeks. I agree.
Dr. Dana McQueen: I’d repeat it somewhere between one month and then we also have a great rheumatologist at University of Chicago, Dr. Edens, so I also send all of those patients for a consult with a rheumatologist who talks about the long-term impacts of antiphospholipid antibodies and the chances of having Lupus, because that is related to having antiphospholipid antibodies. Not all women with positive APLS will have Lupus, but it’s a chance, so you want to check into it and make sure you’re not missing anything.
Then I will recommend doing low dose aspirin. I usually start that before you get pregnant. I say as soon as we diagnose it, start your low dose aspirin.
I usually wait to start the blood thinner until I know that their pregnancy test is positive and increasing. We get a beta glycoprotein level right after you get your positive home pregnancy test and then we do another one in two days. If it’s going up, that’s when I start the Lovenox.
Dr. Aimee: Got it. Is there a genetic component to that? If you’ve been diagnosed with that, is that something that you should tell your family members about?
Dr. Dana McQueen: That’s a great question. There are two types of what we call thrombophilias. Thrombophilias mean they have an increased risk of blood clotting. There are inherited thrombophilias, those are genetic. Then there’s acquired thrombophilias.
Antiphospholipid antibodies is an acquired thrombophilia, so you’ve gotten it sometime throughout your life, it’s an autoimmune disease, it’s not necessarily genetic. Whereas: Factor V Leiden, protein C, protein S, Antithrombin III, are inherited thrombophilias, and those you definitely want to tell your family members that you have because everybody is at risk of increased blood clotting.
Dr. Aimee: What about thyroid, how important is thyroid control and management, how does that play a role in RPL?
Dr. Dana McQueen: We’ve found that women who have elevated TSH have an increased risk of miscarriage, and women with antithyroid antibodies have an increased risk of miscarriage. I usually check TSH and antithyroid antibodies on everybody.
I don’t usually treat isolated thyroid antibodies, so if you just have a thyroid antibody but your TSH is completely normal, I would just say follow your thyroid closely, you’re at increased risk of having low thyroid in the future. An elevated TSH, I definitely will treat with a little dose of Levothyroxine or Synthroid.
My goal is to get your TSH level below 2.5. There is some debate about how low we should go. Some people say 4 is fine. The goal in pregnancy is 2.5. I want all of my patients to be pregnant very soon, so my goal is to get their TSH to a pregnancy level before pregnancy.
Dr. Aimee: When you say monitoring closely, what does that mean, how often are you checking their TSH levels?
Dr. Dana McQueen: I check it at least once a year in patients who are trying to get pregnant. Then, if elevated, I start thyroid medication and I usually check it in four weeks, even though that’s a little bit early for the thyroid medication to be working. Then we just follow it closely, and definitely check it when they get pregnant, with their first ultrasound.
Dr. Aimee: Okay. Do you give progesterone pretty routinely in patients who have RPL?
Dr. Dana McQueen: I do, yes. Progesterone has been shown to have some benefit in women with RPL. The exact dose, the exact duration, and the exact way to give it has not been well studied, so we don’t 100% know which progesterone is going to work the best, which way we should give it, but there is some evidence that it works for women with recurrent miscarriage.
What we think it’s doing is helping support the pregnancy. Maybe there’s a group of women that their ovaries are not making enough progesterone or it’s not working well at the level of the endometrium.
I usually do luteal progesterone. What that means is I have women do ovulation predictor kits at home, you measure your surge. Once you get your LH surge, I have you have intercourse to try to get pregnant, and then start your progesterone three days after your surge. I don’t want to start it before you surge because it could interfere with things, but three days later you start that.
The issue with progesterone is it can delay your next period, so it’s really important that you take a pregnancy test about 15 days after your surge. If it’s positive, you keep taking the progesterone. If it’s negative, you can stop, have a period, and then we start the whole thing all over again the next month.
Dr. Aimee: I think that’s the hard part, when you’ve been through so much and it’s so hard to check those pregnancy tests, people sometimes wait and think the lack of their period is because they’re pregnant. It just breaks my heart to say you have to check. A lot of people, if they have a hard time checking, I’m like, “Come in and we’ll do the blood test here. It’s okay.”
What kind of role does IVF play? A lot of times people think IVF can fix everything. What do you think about IVF and the role that it plays in women who have RPL?
Dr. Dana McQueen: That’s a great question. I would love if IVF was the solution to recurrent pregnancy loss. I love IVF, it’s easy to do. Unfortunately, it’s probably not the solution to all recurrent miscarriage.
We know that a certain group of pregnancy losses are chromosomal. Probably 60% of pregnancy losses are from a chromosome problem in the embryo. The benefit of IVF is that you can get a bunch of embryos, you can test their genetics, and you can put back only the ones that are chromosomally normal.
Women that could probably benefit from IVF are those who are in their late-30s to 40, who have a great AMH, so they have a great egg supply, and we know that they’re having miscarriages that are chromosomally abnormal. Now, that’s not based on a large study. That’s just sort of based on my intuition that if the miscarriages are caused by chromosome errors in this patient and this patient has enough eggs to do IVF, then that’s a reasonable group.
Where I don’t think it benefits is younger women who are having current losses, especially if those losses are chromosomally normal. If you’re having what we call euploid losses, IVF is not the solution. We know that the chromosomes were normal, so testing the chromosomes of embryos is probably not going to be helpful. It’s going to be looking at these other factors, making sure you don’t have chronic endometritis, making sure your thyroid is normal, and then doing close monitoring during pregnancy to figure out exactly what is going on.
Dr. Aimee: Right. All of our patients are VIP, they all have very important pregnancies. We provide this level of care that’s called TLC. Can you just describe to everyone what that means exactly?
Dr. Dana McQueen: Interestingly, TLC is a proven method of caring for women with recurrent pregnancy loss. There was a study done years ago that showed that women who had TLC did better and had better outcomes. Regardless, I think it’s important just for psychological health for our patients who are going through so much. What that means is I’m available to my patients all the time, I understand that this is stressful, I understand this is anxiety-provoking, and we’re going to work together to get you to a full term pregnancy.
Patients will take their home pregnancy test. Hopefully they get pregnant spontaneously. Sometimes patients are doing IVF or doing IUIs or something else, and we’re checking it. We have them come in for a beta right away, and then we repeat it two days later to make sure it’s going up appropriately. We check their progesterone to make sure that’s appropriate.
Then they come in for an early ultrasound. The first ultrasound I do is usually at five weeks and four days to six weeks, to make sure that the pregnancy is in the uterus, we’d look for that yolk sac. Then we do ultrasounds every week until the patient graduates.
I have had a couple of patients that say, “I really don’t want an ultrasound every week. Every time I come in for an ultrasound, it makes me anxious. I just want to assume everything is normal for a couple of weeks and then I’ll come back.” That’s fine. But for many women, it’s really hard to wait the whole week, so coming back every week is helpful, it’s reassuring because they’re growing normally.
The other thing we can do with that is diagnose the pregnancy loss if one happens early. We can identify it and we can intervene when it’s early, before you wait too long. Every week that you’re pregnant is another hope of having a baby, more planning that you’re doing, and I think that we want to know as soon as possible that this isn’t working so that we can intervene and get you started on your next pregnancy, hopefully.
Dr. Aimee: That’s exactly what I do. I feel like the more people hear that there are doctors just like us doing that, the more they can advocate for themselves and ask for the same. I hear all too often patients call and say, “I called and they said they won’t see me until I’m 10 weeks pregnant or 11 weeks pregnant,” and they’re refusing simple blood tests like HCG and progesterone levels, and they’re told that these things don’t matter. It’s just that they do, they actually do matter.
We have Dr. Dana McQueen from University of Chicago saying it matters, you guys. Take this show, send it to your doctor. We’re going to write up an article and transcribe it, and you can forward it to them. We’ll include all of the studies that Dr. McQueen is sharing with us tonight so that you guys can advocate for yourselves. I always tell people the more you know the better things will go. You just have to be knowledgeable about everything about your own health to get the care that you need.
I want to learn more about the research that you’re doing. There’s a lot of stuff going on and I feel like we need people like you to move this field forward. To say that this is exciting is really, obviously, not what I mean. It’s not exciting, but it’s really helpful to know that a lot of these answers are going to be answered by the work that you’re doing. Tell us about the research that you’re doing on chronic endometritis.
Dr. Dana McQueen: We have identified what we think is a good diagnostic criteria, the presence of a plasma cell in addition to these endometrial stromal changes. We’re writing up a paper that details out how we could use this diagnostic criteria in practice.
There’s a specific stain that we use called CV138, and we’re trying to identify which women would need that stain, because it is expensive and if we wanted to use this diagnostic criteria everywhere maybe we should just use that stain on women that have endometrial stromal cell changes and not other women. So, we’re trying to outline how a pathologist would evaluate tissue that they receive. It’s just not standardized everywhere. That paper is being reviewed and, hopefully, going through its second revision now.
We’re writing a paper about the retained pregnancy tissue in chronic endometritis, so that should be out soon. Hopefully, that will push providers into doing a hysteroscopy if they see endometritis, because we know now that it is related to retained tissue.
We’re also hoping to see if we can correlate the diagnosis with the next pregnancy outcome. What we have now is that chronic endometritis is associated with miscarriage or a history of miscarriage. We want to see with women who have untreated chronic endometritis what happens in their next pregnancy. Now, I feel like I can’t do that study.
Dr. Aimee: No, we cannot do that study.
Dr. Dana McQueen: I cannot treat women that have chronic endometritis, because I’ve been studying it for 10 years or whatever it is now. But there are a bunch of biopsies that have been done in the past that we have information about. Did those women go on to have pregnancy losses? Did those women go on to have live births? What I’m hoping to do is stain and understand these historical samples and look at their subsequent outcomes, so that’s the next study that we’re doing.
It is expensive to do research like this. We have to pay a pathologist to pull slides, cut slices of them, stain the tissue, and then we have to pay someone to actually look at it and understand if there is chronic endometritis there or if there is not. I have a pathology resident who has volunteered to do the study with me. She is going to switch over to OBGYN, we’ve convinced her, but she wants a research study to do in the interim, so she’s going to help us.
That’s our focus on the chronic endo side. Figuring out how we should diagnose it and does this diagnosis predict the next pregnancy outcome. Then I think, why is this chronic endometritis happening?
Is there a change of the microbiome in women who have chronic endometritis? Microbiome is the bacteria that live within us, they aren’t hostile, they aren’t causing infection, but they just exist and interact with our cells. We used to think that the lining of the uterus was sterile and had no bacteria at all. Now we’re learning that there’s a very ultra-low volume microbiome in the uterus. Is that microbiome disrupted in some way in the women that have chronic endometritis and that’s why it’s treatable with antibiotics, potentially?
There have been some early studies that suggest that women who have a low lactobacillus load — you should have a lot of lactobacillus in both the vagina and the uterus, over 90% of the bacteria should be lactobacillus — so, if there’s a lower number of lactobacillus, are those the women that have chronic endometritis? That is another study that I’d like to do, where we take biopsies, look at them pathologically, and then correlate that with the microbiome. There’s a great microbiome center at University of Chicago. There’s also one at Northwestern where I was before, and I think they’re going to keep looking at this also.
Dr. Aimee: People ask me all the time what my favorite probiotic is, and I don’t really have one. Do you have one that you recommend?
Dr. Dana McQueen: I have a couple that I rarely recommend. I don’t routinely use a vaginal probiotic. There is some interesting data coming out about vaginal probiotics. I know that there’s a new test, the ALICE test, that they’re looking at the microbiome of the uterus and I think generally recommending a probiotic to correct it.
I feel like the data is not quite there yet. I think that would be a great study to do, though, looking at should we be doing antibiotics for chronic endometritis in addition to a vaginal probiotic. I think that study is ripe for the picking and women would probably be willing to do a probiotic because it’s a pretty benign treatment.
Dr. Aimee: You can get them in a gummy bear now. They’re so easy to take.
Dr. Dana McQueen: Yes.
Dr. Aimee: You talked a little bit about sperm DNA fragmentation and research. For people who weren’t listening a little earlier on, tell us about the research related to that that you’re doing.
Dr. Dana McQueen: My main research for DNA fragmentation for sperm had been doing this meta-analysis where we put together a bunch of different studies, put all of those patients into one study and redid the calculations to see if sperm DNA fragmentation was significantly associated with miscarriage. If you weren’t listening earlier, what we found was that men who have had a history of recurrent pregnancy loss had a significantly higher sperm DNA fragmentation compared to men in a couple where they didn’t have a history of recurrent miscarriage or had a live birth.
The question is, first of all, why is this happening? What’s the exposure that is causing sperm DNA fragmentation? Then what is the pathology, how is it causing a miscarriage?
One theory that I had was that it was causing paternal aneuploidy. When you look at an embryo and you take a biopsy for preimplantation genetic testing, you can find out if you do certain type of analysis that Natera does, it’s one company that does this, they can tell you if the aneuploidy, or the abnormal chromosomes, were from the maternal side or the paternal side. When I was a fellow, I looked at 1,720 embryos that had been biopsied and sent to Natera for testing. Then we went through every single one — this is what research takes — and figured out was it a maternal aneuploidy, a paternal aneuploidy, or a combination of both.
What could predict paternal aneuploidy? My first question was is paternal aneuploidy associated with recurrent miscarriage, was this a cause for miscarriage? What we found is that isolated paternal aneuploidy wasn’t increased, but these mixed aneuploidies with both maternal and paternal, these complex aneuploidies were increased in women who had IVF for an indication of recurrent pregnancy loss versus women who had IVF for other indications.
Then we looked at all sorts of things related to paternal aneuploidy and not necessarily related to recurrent miscarriage. We looked at all of their sperm parameters and said if they had abnormal sperm, like morphology, motility, count, would that predict paternal aneuploidy? It didn’t. Then we tried to look at paternal age, and it didn’t really predict paternal aneuploidy.
This rate of paternal aneuploidy is really low, it’s 8% of embryos. The vast majority that are abnormal are, unfortunately, the maternal side.
A study that I just did and I’m submitting to ASRM next week was I thought maybe the paternal aneuploidy is actually caused by the egg. When sperm meet the egg, the chromatin or the DNA of the sperm is innate, it’s all packaged up, and the egg itself is the one that opens up the DNA, incorporates the paternal genome into the egg, so I thought maybe it’s an egg factor that causes increased paternal aneuploidy. I looked at female age and tried to see if egg quality, very high ages, women over a certain age (but I’m not going to list an age here) would increase the rate of paternal aneuploidy. Unfortunately, that was not associated.
As you can see, you have to do lots of research in order to find actually meaningful or interesting results, and there are a lot of roadblocks along the way and you have ideas that don’t work out. That’s why it’s interesting, it’s really stimulating to do this work and try to figure out what is causing infertility or miscarriage.
Dr. Aimee: I’ve heard that before, I’ve heard that theory that it’s the egg causing the abnormal cells, making it look like it’s a sperm issue when it’s not.
Dr. Dana McQueen: I thought it was an interesting idea and I definitely wanted to look at it, but it doesn’t seem to be true.
Dr. Aimee: I feel like you should be, “Mic drop, bam, I did it.” Now we all need to make sure people know about it.
Dr. Dana McQueen: Give women a break.
Dr. Aimee: Exactly. If you have a patient who has had recurrent pregnancy loss, at what point would you say, “At this time, I feel like IVF would be beneficial to you,” versus just trying naturally?
Dr. Dana McQueen: That’s a good question. I would say women who are late-30s who are having abnormal pregnancy losses. If we’re following you and you are having miscarriages that are chromosomally abnormal, if you did a D&C or you passed a pregnancy and we tested it and it was abnormal, that’s a woman that I think might benefit from IVF.
There haven’t been any randomized control trials — that’s sort of peak evidence — where we put women who had recurrent pregnancy loss into two groups, one that had IVF and one that didn’t. I don’t think in itself IVF would be helpful for recurrent miscarriage. The only part of IVF that I think would be helpful is the genetic testing of the embryos.
There’s also a group of women that say, “I just cannot have another miscarriage and I want to control this factor that I can control,” and then we have a discussion about it. The risk of miscarriage after an IVF and with PGT tested embryo is lower. There’s still a risk of miscarriage, it’s probably 8–10%, but it’s lower than if you get pregnant on your own.
There is a chance that you do IVF and you do genetic testing and you don’t get any embryos to transfer. I think that’s where people argue that IVF with PGT is not going to be helpful for RPL because maybe with RPL you get pregnant quickly and you have a high chance of success, whereas if you do IVF it’s going to take several months to get put into a cycle, you have to take your medications, and then you could come out with no embryos to transfer.
As long as you understand there’s that risk, it’s a patient-doctor discussion and I don’t ever say that you can’t do IVF or you can’t do PGT if that’s something that you want. Like I said, I love IVF.
Dr. Aimee: Right. I agree.
Dr. Dana McQueen: It’s just not for everybody.
Dr. Aimee: I know. Do you have time to answer some of the live chatted questions that people have asked?
Let’s go for it. There are a couple of really good questions. I’m going to lump this one with another question. Does low AMH increase chance of miscarriage? And another person asks does high FSH increase chance of chromosomally abnormal pregnancies and miscarriage?
Dr. Dana McQueen: That is a super great question. There has been a ton of research and questions about diminished ovarian reserve or low egg count (FSH is the marker of low egg count as well as AMH). Does that equal the egg quality? Does that decrease the chances of having a miscarriage?, the chances of having a chromosome problem with an embryo? They’re associated, but the association is not as strong as we would have thought it would be.
Mostly, egg quality is related to your age. As you age, AMH goes down and the chance of having chromosome problems and miscarriages goes up. I just looked at our data to see if AMH predicted maternal aneuploidy, so the same data set that we have that’s maternal and paternal, and it wasn’t significantly associated if you controlled for age. I think it’s mostly age that is causing miscarriages more than your AMH.
Dr. Aimee: Got it. Last two questions. Endometriosis versus endometritis, what’s the difference? Also, does endometriosis also increase your risk of miscarriage?
Dr. Dana McQueen: That’s also a great question. This is a common flip-flop that people make. Endometriosis is when the lining of the uterus, the endometrium, is located outside of the uterus, so it’s located in an ovary, in your pelvic wall, in your abdomen. It can cause scar tissue, it can cause infertility and inflammation. Endometritis is these plasma cells in the lining of the uterus, it’s either a subtle infection or a change in your microbiome, but it is definitely different than endometriosis.
Endometriosis has been associated with miscarriage. There’s this test called the Receptivadx that people are doing now that looks for endometriosis by doing a biopsy of the lining. What we’ve found is that there are changes in the lining inside your uterus even if you have endometriosis outside your uterus. So, it’s an interesting association and it’s definitely of ongoing research.
Dr. Aimee: Great. Last question. What if we have had two blighted ovums with genetically normal tested embryos, D&C tissue also tested, embryos still tested normal? Can you just share your general workup and evaluation and what you would do?
Dr. Dana McQueen: Yes. I think the first question is when they say that it was normal, what was the result? The most common result is going to be a 46XX result, which is female, and often that’s actually your own cells. So, they do a D&C and it gets a little bit of the lining of the uterus back and it comes back clinically normal.
What I would recommend doing is a reflex analysis to make sure that any kind of chromosome testing that shows a normal female is checked to make sure that it’s not maternal. What they do is they do a sample of you, a blood test or a cheek swab, to make sure that it’s not your cells. That will just give us a little bit more information.
Then I would say, yes, I would start doing an RPL workup on this patient. I would do a cavity evaluation. With two losses, I generally lean towards a saline ultrasound. I don’t know exactly where my cutoff is, but somewhere around three or four I started leaning more towards hysteroscopy just because I want to make sure I don’t miss anything in the uterus. I usually talk about both options with a patient, should we do an ultrasound and a hysteroscopy, or just stick with the saline?
At the time of the saline, I do an endometrial biopsy. I do it in the follicular phase, so we do it on cycle days 5 to 12. There can be plasma cells that enter the endometrial lining right before you have your period, so I wouldn’t want a misdiagnosed chronic endometritis by doing the biopsy too late in the cycle. Also, I’m hoping you’re going to get pregnant, so I don’t want to do a biopsy when you could be pregnant.
I will check your thyroid. We check prolactin, which we didn’t talk about, but it’s another hormone occasionally associated with miscarriage. I also check hemoglobin A1C, that looks for diabetes. If you have uncontrolled diabetes, it can increase your chance of miscarriage.
I very rarely discover someone with uncontrolled diabetes that didn’t know they had diabetes before, though. I often find uncontrolled hypothyroidism in patients that don’t have hypothyroidism, though. They might have fatigue, feel depressed, have weight gain, and then you find out their thyroid was the cause all the time.
Then I recommend antiphospholipid antibody testing to look for those autoimmune causes. Then I recommend a genetic evaluation for your carrier type for you and your partner.
Then we sit down again and we talk about all of those different things, then, based on all of these factors, we talk about what would be the right treatment for you, do we want to support your pregnancy with progesterone, do you need something to help you get pregnant. If you’re waiting six months between every miscarriage, this is just like torture, so you might need something to speed things up a little bit. Then how are we going to monitor you in your next pregnancy to make sure that you have the support you need.
Dr. Aimee: At what point would you treat someone’s A1C? Is there an A1C that you’re like this hemoglobin A1C might increase your risk of having miscarriages?
Dr. Dana McQueen: I think it’s probably a continuum. Definitely, if we see a prediabetic level of 5.7, I’m starting to say watch your diet, think about metformin, talk to your PCP. When you get to a 6.5, we’re worried about diabetes. I actually don’t want women to get pregnant until they’re hemoglobin A1C is less than 7.
I usually say I’ll help you get pregnant once it’s under 7, because sometimes our patients have a very high hemoglobin A1C, like 9. That’s really putting not just you at risk of having gestational diabetes, but also the pregnancy can have heart defects and other problems, not just recurrent miscarriage.
Dr. Aimee: Thank you, Dana, for everything.
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