Journal Club Global: Clinical Evaluation and Management of Chronic Endometritis and Its Impact on Fertility

F&S Reviews is proud to partner once again with the Johns Hopkins Fellowship to discuss a recently published article by Dr. Michael Strug et al., titled "Unveiling the Silver Lining: A Narrative Review of Clinical Evaluation and Management of Chronic Endometritis and Its Impact on Fertility."

Discussants:

• Johns Hopkins REI Fellowship with Pardis Hosseinzadeh, MD
• Dana McQueen, MD

• Michael R. Strug, DO, PhD
• Ruth B. Lathi, MD
• Lindsay A. Hartup, MD

• Anne Steiner, MD, Editor in Chief F&S Reviews
• Blake Evans, DO, Media Editor F&S Reviews

1. What are the different type of scientific review articles?
2. How is chronic endometritis defined in the literature?
3. What are the limitations in the literature on diagnosing and treating chronic endometritis?
4. Who should be screened for chronic endometritis during fertility treatments?
5. How or should chronic endometritis be treated?

All right, everyone, we're going to go ahead and get started. Welcome to FNS Reviews Journal Club Global. I'm your host, Dr. Blake Evans, Media Editor for FNS Reviews, and I'll be co-hosting today's session with Editor-in-Chief Dr. Anne Steiner.

Welcome, Anne. Today, we have a fantastic panel that's joining us, and we'll be discussing quite the hot topic. The title of the article we'll be discussing is Unveiling the Silver Lining, a Narrative Review of Clinical Evaluation and Management of Chronic Endometritis and its Impact on Fertility.

We're joined today by some of the authors of this paper, Dr. Ruth Lathi from the REI Division at Stanford. Welcome, Dr. Lathi. Thanks for having us.

Absolutely. We also have Dr. Michael Strug, who's also with the REI Division at Stanford. Welcome, Dr. Strug.

And we have Dr. Lindsay Hartup, who's from the Department of OBGYN at the University of Texas, San Antonio. Welcome, Dr. Hartup. Thank you.

Thanks, everyone, for joining. And so, we also are joined by our expert panelist who has had an extensive amount of publications regarding this topic, Dr. Dana McQueen of RMA San Francisco. Welcome, Dana.

And lastly, but certainly not least, our hosting REI Fellowship Program. We'll be reviewing this manuscript. Dr. Pardis Hosseinzadeh and Dr. Valerie Baker, some of the Johns Hopkins REI faculty, are joined by their wonderful REI Fellows.

Welcome to the Johns Hopkins Program, and thank you so much for joining us. Before we get started on our discussion today, Dr. Steiner is going to review a few highlights, excuse me, a few highlights of some important aspects of our journal FNS Reviews. So, I'll turn it over to you now, Anne.

Thanks so much, Dr. Evans, for that introduction. So, FNS Reviews, as you know, is ASRM's review journal, which is SCOPUS indexed, and we will be getting an impact factor in June of 2025. Just so you're aware, our vision is to make sure that we're an authoritative resource for clinicians, scientists, learners, people like you on this webinar today, such that you can really advance our readers' understanding of a facet of human reproduction.

And how do we see our, what is our mission and our goal, and what are we looking for in our review articles published in FNS Reviews? Well, we're not looking at a specific type of review. We do publish both systematic reviews and narrative reviews. We also publish things like scoping reviews and umbrella reviews.

And for those of you that aren't familiar with or are less familiar with these types of reviews, the article we'll be discussing today is a narrative review. A systematic review is a little bit more formulaic in its approach. It does require a question and a systematic search, and subsequently assessment of the quality of the papers.

A scoping review, for those of you who are not familiar with that, tends to take on a more larger topic and with a goal of perhaps describing the literature out there and perhaps deficits in areas of research or opportunities for research. And then an umbrella review, which I find fascinating, is basically a review of reviews. So it basically looks at systematic reviews on a topic and summarizes the reviews out there.

You may have heard of a meta-analysis. That would fall under systematic review. So after a systematic review, a meta-analysis combines the data and to provide us a single answer.

But the type of review is not what defines the quality. And so what I want to talk to you today about is about quality of review articles. And because we are looking for quality at F&S Reviews, and as I would like to stress, is this is a good example of a high quality paper that we publish in F&S Reviews.

What makes something quality? Well, it's going to be comprehensive, meaning it's going to make sure you're covering the breadth of the literature out there. And whether this is done by doing a systematic search, or whether it is just being thorough and making sure that you're looking for not only the positives, but also the negative literature out there. We want to make sure the review is impartial.

Obviously, there is the potential people may have conflicts of interest, but it's important that they recognize those conflicts as they're addressing the subject. We're certainly not looking for opinion articles. Now, it's important after you've gathered all this information, whether it's systematically or through a narrative review, that it must be readable for our readership.

Nothing worse than picking up a review article that's just a bunch of facts pulled together. And so, I think that's what's so nicely done with this article. Although it's comprehensive, it's impartial, it's also incredibly readable.

It has a take-home point. It has a conclusion. It has paragraphs.

It has an outline. It has tables and figures. Because in the end, what we want is something that people, we want to advance the reader's understanding of the topic.

And finally, we want to make sure that the review article advances our knowledge. So, it really needs to be novel and or have a premise. If there are 10 other papers out there or 10 other articles on this topic, how does your review article advance our knowledge? Does it take a new approach? Does it answer different questions? Does it have a different analysis or assessment of quality? So, I'd like to point out, as I've mentioned multiple times here today, that this is a good example of a high-quality paper that we obviously would love, that we love in F&S Reviews.

If you have an idea and think you could write as quality of an article as this, which I'm sure you can, those listening today, please submit a pre-submission proposal to F&S Reviews. You can find out how to do that by going to our website, Fertstertreviews.org. Fertstertreviews.org, not too hard to remember. And you can find information on how to submit a pre-submission proposal.

It's very easy. And we provide you with some feedback and guidance on recommendations on conducting your review. And if you are asked to ever do review a review article, it means if you're asked to do a critical review of one of our review articles for F&S Reviews, please know that on our website, we also have instructions and a little PowerPoint presentation going over to critically analyze a review article.

So, that's all I've got today. And I appreciate you all giving me a little bit of time to talk about our great journal F&S Reviews. And I'll turn it back over to you, Dr. Evans.

Thank you, Dr. Steiner. Well, without further ado, we're going to turn it over to the Johns Hopkins REI Fellowship. And if you all go ahead and just introduce yourself, and then we'll go ahead and move forward with the review of this paper.

All right. Hi, everyone. It's truly a pleasure to host this journal session tonight.

It is an incredibly relevant topic. And I'm excited for this discussion ahead. Before we get started, I would like to introduce my wonderful co-host, Dr. Valerie Baker.

It's an honor to have her here tonight. And I'd like to introduce our fantastic team of fellows and our rotating resident. Let's start with our rotating resident, Dr. Sebastian Gerasi, and our first-year fellow, Dr. Bronwyn Bedrick, our first-year fellow, Dr. Daniel Jackman, our third-year fellow, Dr. Katie Schmeck, second-year fellow, Dr. Abigail Combs, and our third-year fellow, Dr. Anita Madison.

Fellows, the floor is yours. We can't wait to hear your presentation. Chronic endometritis is a challenging and controversial diagnosis that impacts women at key points in their reproductive lives.

In this review article, the authors tackle this issue head-on by defining when and which populations we should be screening for chronic endometritis, when and how to treat them, and also looking at diagnostic guidelines. The diagnosis of chronic endometritis has historically been made by the presence of plasma cells in the functional layer of the endometrium. The limitation of relying solely on plasma cell infiltrates for this diagnosis was raised 70 years ago and continues to be an today.

The authors provide more specific guidelines to improve diagnostic accuracy and study comparability. The authors recommend standardizing biopsy timing to the late follicular and early luteal phase. The number, frequency, and density of plasma cells needed for diagnosis has not been validated, but the authors recommend the following schema, none, one to two, greater or equal to three, and clusters per tissue section.

The authors also discuss secondary features such as stromal edema can be useful in helping making the diagnosis of chronic endometritis. Additionally, the use of immunohistochemistry with CD138 staining can increase the diagnostic rate of chronic endometritis from H&E staining alone from 10 to over 50%. However, CD138 staining is nonspecific, and so the authors suggest that using it can help target key areas to examine with the H&E staining for plasma cells.

Evaluating the prevalence of chronic endometritis is challenging. This is because making the diagnosis requires an invasive approach with an endometrial biopsy. Endometrial biopsies are also more commonly performed on patients with gynecologic or fertility-related conditions, which introduces bias when determining disease prevalence.

Lastly, there are discordant diagnostic criteria that are used to make this diagnosis. Although diagnostic criteria vary, the authors recommend using a stricter criteria of greater than or equal to three plasma cells per tissue section or greater than or equal to two plasma cells per 10 high-powered field to establish a diagnosis. Factors contributing to chronic endometritis include both microbial and non-microbial or intrauterine pathologies.

Symptoms are variable, ranging from asymptomatic to menstrual irregularities, vaginal discharge, pelvic pain, and most prevalent, bleeding. The gold standard for diagnosis is an endometrial biopsy with histological analysis for plasma cells. However, hysteroscopic fetus can aid a diagnosis, and these include hyperemia, edema, and micropolyps.

Molecular testing using real-time PCR shows potential for identifying pathogens involved and as a treatment, as a guide to treatment. Some studies also suggest that a loss of lactobacillus dominance in the microbiome may correlate with reduced pregnancy rates, making microbiome testing a promising area of research. For treatment, the authors state that the data support a bacterial etiology of chronic endometritis and support the role of antibiotic treatment in patients at a threshold number of plasma cells.

Clinical outcomes appear improved when a negative test of cure is achieved compared to those who were treated but did not have a test of cure. Multiple regimens have been utilized. However, studies are limited by heterogeneity in patient population, diagnosis, test of cure, and lack of randomized control trials.

Recommendations based on expert opinion are when chronic endometritis is diagnosed on histologic criteria, positive findings should be treated initially with doxycycline. Test of cure biopsies should be performed and, if persistent, treat with a combined course of ciprofloxacetametronidazole. Third-line treatment options are limited, but amoxicillin clavulanate can be considered.

At this point, the authors go on to apply what has been discussed so far to specific populations in the infertility group. The authors recommend testing for and treatment of patients with unexplained recurrent pregnancy loss and endometriosis. The best evidence exists for patients with recurrent pregnancy loss who seem to have a higher prevalence of chronic endometritis, and it seems that treatment may be correlated with improved outcomes.

In patients with endometriosis, the authors also recommend testing and treatment because of the overlapping symptoms and the evidence that there's a higher prevalence in this group. So, in patients with abnormal uterine bleeding or chronic pelvic pain, they especially recommend. The authors do not recommend testing and treatment in patients with infertility that are seeking treatment or patients with recurrent implantation failure.

This is because the studies are small, heterogeneous, and the results are mixed. And for this reason, they do not recommend testing. They do not recommend for or against testing in these groups.

In conclusion, the authors summarize their recommendations in Figure 1 and acknowledge key limitations, including the lack of a large, multi-centered, randomized control trials. They also highlight another limitation to the study being the lack of specific diagnostic criteria and variability of timing of endometrial sampling. Despite these limitations, this study highlights important findings, which is that the presence of endometrial plasma cells is linked to poor outcomes in select populations and resolving chronic endometritis with antibiotics appear to improve pregnancy outcomes.

The authors emphasize the need for future large, randomized studies to refine diagnostic criteria and validate treatment efficacy. These studies should also focus on evaluating plasma cell identification methods, determining clinically significant thresholds, and defining optimal antibiotic recommendations. With that, our fellows have some questions that we have for our wonderful panel and we're hoping to stump our wonderful panelists.

One of the first questions that we thought of was, after doing this review article, in your day-to-day practice, what are the actual clinical situations in which you do screen for chronic endometritis? First off, kudos to all of you. It's not easy to summarize all of that in such a short period of time. You did awesome.

To answer your question, really, you kind of highlighted who I would screen in my practice because practicing in REI, we mostly see patients that have infertility, recurrent pregnancy loss, recurrent implantation failure, and some endometriosis. First off, anybody who is symptomatic, as we discussed, I would screen them if they're having abnormal bleeding, and also patients who have potentially even pelvic pain, spotting, those types of things. You want to rule out other etiologies like chlamydia, gonorrhea, all of the other things that could potentially cause those symptoms first, but in the absence of those features, this could be considered.

I use it primarily for patients who have recurrent pregnancy loss. I do consider it for recurrent implantation failure. Esri guidelines actually say that there's some moderate data to support this as well for screening for RIF, and those patients are really challenging as well, so looking for any answers.

Those are the main folks that I'm screening. Certainly do not screen infertility patients that are undergoing IVF. That's not beneficial.

I don't screen unexplained infertility, and I wouldn't upfront screen all patients with endometriosis. Another question that we had is, is there a role for empiric treatment of chronic endometritis, and if so, in what clinical scenarios would this be considered, if any? I guess we can just take turns on this. Common question we get asked, and I want to echo Dr. Strug's kudos to your excellent review.

I was like, oh, we did say that, didn't we? Great job. So the rationale behind not treating empirically, so I guess your question is, are we going to treat every patient with RPL, or are we going to just screen them first? I think that one, that's over-treating. Secondly, we also know that endometritis and other forms of inflammation are really a balance of good and bad bacteria, and if you don't have overgrowth of bad bacteria, you might be harming your beneficial bacteria load as well, so I don't like treating without having a confirmed diagnosis.

I think also from a patient perspective, having an answer and knowing what they're doing is also a little bit more satisfying, so we really do push for the biopsy to stratify who we'll treat, but back to the question about who do you screen? I think if a patient is really hesitant to do the biopsy because of discomfort or delays or other things, you can look at your patient and her history and her symptoms and make a judgment. Is this likely to be an endometrial cause of her infertility or recurrent pregnancy loss, or is it more likely to be aneuploidy or something else? So I do look at how many miscarriages she's had as well as whether the miscarriages are euploid or aneuploid, so for patients with three or more or repeated euploid, that makes more sense to me that it be endometrial, and those are the ones who I really encourage to undergo the gold standard or what we have now as a gold standard to investigate. Sorry, just to piggyback on that a little bit, back to treating empirically, one of the points that we tried to make in this article is most of the studies evaluating a benefit clinically, seeing improved live birth rate, seeing reduced miscarriage rates, most of those were seen in the setting of a negative test of cure.

Patients who have persistent chronic endometritis, where you're repeating biopsies and they still have it, those patients were poorer prognosis, and so you won't really figure out who you're benefiting if you're just treating everybody, and in addition to antibiotic stewardship, which we all learned in medical school and all that, so another consideration. As a side note, I was just going to add, you know, definitely the main reason I biopsy is because I'm looking for test of cure information, so I want to know where I started and where I'm ending, and seeing if it's improving helps me understand what's going on with the disease, so I always do a biopsy before and then test of cure. I also would comment that I like them to have a period before the test of cure is done, because then they're shedding their lining, you're giving them a chance to, like, take time to get better, and then the other point about which patients to screen, if you're going to highlight which patients with RPL might be higher risk, I think those who had a late loss have a higher risk of having chronic endometritis, and we found that, and then women who've had retained pregnancy tissue will have a higher rate of chronic endometritis, because it's kind of a chicken-and-the-egg question, right? Like, is this causing miscarriages, or is chronic endometritis caused by having miscarriages, and I think there probably is a big component of it being caused by having a miscarriage, and then it persists and lingers and maybe causes poor pregnancy outcomes.

That's a very good point, and kind of, like, leading to our next question. So, Dr. McQueen, you said that you want them to have at least one period to shed the lining, but is there, like, a specific time that you guys recommend to do a test of cure, or would just one period be sufficient? So, for my practice, what I do is one period. So, usually, I'm doing the biopsy at the saline, so we do a saline to look for retained pregnancy tissue or any issues, scar tissue, do an endometrial biopsy at that time, and it's late follicular, and then treat, so get your results back hopefully quickly, treat before the next period, have a period, and then late follicular, again, do another biopsy.

I've also sometimes, in patients who are doing IVF also, do the biopsy at the VOR, or sorry, we call it a VOR, at the egg retrieval, because that's a time when they're under anesthesia, and so anytime you can do these things when someone isn't uncomfortable is helpful. And are you doing a saline sonogram for all losses, or just when there's a fetal pole present, or at what point are you doing a saline sonogram in these RPL patients? I always do a saline sonogram to evaluate the cavity. Even in biochemical pregnancy losses, you could have polyps or other etiologies in the uterus that are going to cause a higher risk.

We found that polyps do increase the risk of chronic endometritis too, and so maybe that's part of this correlation with abnormal uterine bleeding, that you're having polyp causing that bleeding, and then chronic endo present because of the inflammation, but I always do a saline. There are some patients where I'll go directly to hystroscopy, and those are the ones I mentioned earlier, maybe the late losses, known retrained pregnancy tissue before, multiple DNCs, but usually just a saline. And I don't know if there is an answer for this, but when recurrence is seen, usually in what interval that recurrence is to be expected, because the pregnancy doesn't usually necessarily happen in the following cycle following stopping the antibiotics, and is there a certain timeline that you should get worried and re-biopsy these patients? I don't know what Ruth does, but I usually biopsy if they have another loss, if they have another clinical loss.

Yeah, I don't think we have data on that. It's a judgment call for sure. Yeah, I kind of wrap it into when we would be doing another cavity evaluation anyway, one to two years after a birth, after a change in status.

I think it's pretty durable for some period of time, but patients who are predisposed to endometritis, again, back to our theory of this could be a dysbiosis or there's an association there that I do think that there are some patients who it will come back on, so about one every year or if there's a change in status. Thank you. This is always something that is challenging for us to diagnose, as you mentioned in your article.

Are there any other secondary histologic characteristics that aid in the diagnosis of chronic endometritis when you have an equivocal case? Dr. McQueen? Yeah, so we're going to be, we're at conflict with our diagnostic technique, I think. No, I'm joking, but so yes, there are some endometrial signs of chronic endometritis in the pathology literature. It'll be like spindling of the endometrial cells, edema, and these are things that the pathologists do notice, and we did a study where we looked at, you know, controls and the rate of chronic endometritis in women doing egg freezing, and you did a biopsy at their egg retrieval, and we found that controls do have plasma cells occasionally, but the controls never had plasma cells with endometrial stromal cell changes, and so like if we use these criteria, that two or more plasma cells per high power field that they mentioned in their paper, if we use that in controls, we would have a 26 or 27 percent rate of chronic endometritis in our controls, so two or seven of the 26 women, so it's a high rate of pulse positives potentially if you don't look at the endometrial stromal cells.

I guess the downside is a lot of our pathology labs don't report this, and so you have to be working with a lab who's willing to evaluate the endometrium for stromal cell changes and comment on it in your pathology report. So I just want to speak a bit to the diagnostic criteria and how we came to this because that was just brought up, and that this, you know, when I was reviewing the articles, it forced me to kind of take a step back and think about how do we even design a test, and how like, and if you read this article through Lew et al., it was from 2018 published in FNS, and that was a big driver for how we came to this criteria because of how this study was designed, and they specifically stated your goal in a control healthy population should be that a disease is no more than five percent of the population, and so they took that number and they applied that to a series of healthy control patients, and they actually did timed luteal biopsies, and based off of some of the data from Stanford, we found that there were lower levels of plasma cells in the luteal phase because depending on what phase of the cycle you're looking at, there's going to be plasma cells, and especially during the menstrual phase, never look during that phase because there's lots of plasma cells around, and so if you're looking at a control population in perfectly timed biopsies, they looked at different criteria and defined sort of you see this many plasma cells in 10 per 10 high power fields per whole section or per unit area was the third criteria that they used, and ultimately they set the bar to what was five percent, and that's where we came to that conclusion. They found that it was two per 10 high power field or three per section, and then there was one for the unit area, but that's less standardized and probably not as realistic to use because you're not measuring the area when you're looking at a slide, so that was how we came to this conclusion based off of setting this threshold, and personally, I think that we should have reset the whole bar from there and use this criteria moving forward for designing all of our studies looking at prevalence in different populations, and that's unfortunately I don't see that a lot of people have used this criteria, but I would urge people in addition to needing randomized control trials consider using this criteria when you're designing studies in the future because it seems like at least it has more validated rationale for using this versus the other studies did not necessarily describe it.

Do you think there should be different criteria for the follicular phase biopsy than the luteal? So, I think we had 25 percent positive if you use this, right, and then eight percent positive if we said five plasma cells, so maybe in the follicular phase we should be looking for a larger number. It seems so silly to have two different, you know, numbers, but no, that's a great point, and I thought you might, somebody might ask that, but yeah, exactly. I think that there probably needs to be defined criteria in the follicular phase.

There's probably a higher level of baseline plasma cells in that time period. Absolutely, so what we are hearing is that the presence of plasma cells are kind of like essential, and if you are seeing those secondary characteristics of like spindle-shaped endometrial cells, stromal edema, without the presence of the plasma cells, you would not call this chronic endometritis or retreat, right? I seem to see a uniform nod, so I think so. We do get that in our, you know, reports a lot, and that creates a, this clinical dilemma of someone with recurrent pregnancy loss, and now we have this pathology, so are we treating, not treating? It's a sure decision-making that happens there with the patient.

Are they using CD138? Because if your pathologists aren't using it, they could have spindling and edema and be missing plasma cells. I know, I think it was Cornell or somewhere, some places the pathologists have not been using certain markers to stain. What are they using in your laboratory? I believe our pathology unit uses an HNA staining, and they do not use CD138.

Yeah, so if I were at your location, I would treat if they saw spindling and edema, because I think they're probably missing some of the plasma cells with HNA. Great insight. Thank you.

All right, I'm asking about who you treat. I thought the studies about patients with endometriosis and the prevalence of chronic endometritis were interesting, and unfortunately, you know, these were from hysterectomies, so what about patients who have an endometrioma on an ultrasound or evidence of adenomyosis on an MRI? Do you think about sampling those patients and treating? Personally, I don't. I was going to let someone else speak, but personally, I don't really screen those patients.

I did think it was kind of neat from a teleologic standpoint. They talk about uterine contractility differences in the setting of chronic endometritis being off, and that's also been proposed as a mechanism for retrograde menstruation and endometriosis, but as you mentioned, it was hysterectomy specimens, and so these patients are clearly going to be a different group of patients than we're going to be seeing in our clinic. For me, it's still an area of active research.

The overlap or the correlation between endometritis and endometriosis is what I'm really curious about. I think we need a little more data at this point. It does make some sense, but I'm not sure how to reconcile that without some more data, so I think let's keep an eye on the literature on that one.

I had a really interesting lecture, was it just yesterday, about where they were talking about this overlap, and it really piqued my interest, so maybe that can be our next review. What does an endometrial assessment look like in a patient with endometriosis? You heard it, fellows. Spoon-fed two fellows.

There you go. I'm going to schedule journal club for two months from now. We'll reassess.

We're ready for the pre-submission proposal. Pass it our way. Yeah, we are on standby.

Excellent. All right, let's go to the next question from our fellows. Actually, let me pause there.

We do have a question from the audience, so anyone can answer here. The question says, what do you think about the role for screening in patients with secondary infertility? You all briefly touched on this earlier. This individual is saying they've been diagnosing this a lot in patients with this population.

Did you all have experience with this? Go ahead. Who was talking? I was just saying, I haven't been screening in secondary infertility. It's an interesting question.

I think if you've got a pregnancy history and ask them a lot of questions about their delivery, maybe you could get a hint at, okay, this person had a retained placenta, and then she had to have a DNC later. She had strange spotting after her delivery. Maybe those patients would be higher risk.

It's an interesting question, but I don't know. Have you guys been doing any screening on secondary? Go ahead. That's exactly what I was going to say, Dana.

I have a low threshold to screen if they have a prior infection or any symptoms. Choreo, retained placenta, any kind of instrumentation, even a history of endometritis, I often will screen them at the time of cavity eval. No data on it, but I agree with the audience member who said you might see it sometimes.

I think it's helpful to rule it out. How about patients with a history of STDs? We recommend HSGs for patients who've had STD history several years ago. Is there some underlying issue to be suspicious of endometritis in these patients from your perspective? One of the papers that we reviewed during this, they looked at cultures for, in general, bacterial and also for viral cultures as well, and the ones that you have to run PCR because you can't even culture them sometimes, which I think chlamydia and gonorrhea fit into that category.

They found that actually, surprisingly, I think one of the studies, there was only one patient who had chlamydia and no patients that had gonorrhea in the subset of patients who had chronic endometritis. To me, that actually suggests that these are probably separate conditions and there's not a lot of overlap. Excellent.

All right, let's go to our next question from our fellowship. Okay. In the article, it was mentioned that removing intrauterine pathology, like during a hysteroscopy, such as for retained prostate conception, would be enough, sufficient to not do any treatment or not need to do antibiotics.

Would you recommend repeating a biopsy, maybe like with the next cycle, to see if they have chronic endometritis after such situation? That's challenging. Whenever I get those path reports and it says like possible polyp and some plasma cells, you're kind of like, should I treat? And I'd be interested to hear what Dr. McQueen does in that scenario, because I really agree. It's kind of like that chicken or egg scenario you were talking about, where one may be coming from the other, and especially in the setting of retained products, where that's foreign tissue, it causes inflammation.

You can get buildup, theoretically, of plasma cells in that setting. I don't typically do that, but if other people do, I could be convinced to start screening. It's a good question.

I'm not at the point where I'm not treating after you remove the pathology. I don't think we have any evidence or any good studies where you take out the pathology, do a biopsy in a month and show that it's treated, right? Once I see a study where removing the pathology treats it, then maybe that would stop me, but usually I do treat still and then re-biopsy. One area I'm not really treating is when it says rare plasma cell, so like one plasma cell.

I'm not treating that. I think it needs to be several plasma cells, I guess two in this diagnostic routine. I just had a question along the line of the sexually transmitted diseases that Dr. Evans was mentioning.

In cases that you see like recurrence of endometritis or persistence of endometritis, is there any role for screening or treating the partner due to conditions such as undiagnosed mycoplasma, urea, plasma, things like that? That's a data-free zone as well. I occasionally, if I come across a highly recurrent case that doesn't respond to antibiotics or it will just keep coming back, that's something I might try with just that shared decision of we're not sure where this is coming from, but that's something we can consider. That's what I do in my practice.

I'm curious what others do. Can you check for mycoplasma, urea, plasma? What are the things that you check in the partner? I just treat with doxy. I assume urea, plasma and treat without culture.

It's a hard culture to do and just real tricky, so not perfect, but doxy covers a number of things and most of them wipes out a lot of your first line suspicions. I think I can think of maybe like two cases I treated the partner when I really have a persistent case and I can't get rid of, but very rarely. I don't think it's caused by sexual transmission.

A couple of other questions from our audience here, some of which were partially answered, but we'll see what you all think. If doing hysteroscopy for retained products of conception and the pathology showed three plasma cells, is this something that you all recommend treating in this setting? I think you're going to see a lot of plasma cells in patients with retained products. I would lean towards allowing a cycle or two even and then re-biopsy after the acute inflammation is gone.

To be honest, in this situation, I'm trying to prevent chronic endometritis from forming, so I typically do treat with a week of doxy at least, and then do a biopsy exactly like this in a couple months to see if they have chronic endo. But I'm worried that in the setting of retained proteins of tissue, you're going to get chronic endometritis. Before we circle back to our Hopkins fellows, this is a great question too.

If one of our attendees had a question to add a tip on achieving sufficient endometrial bias with sample tissue at the time of a saline sonogram, it seems that the PIPEL refills quickly with saline. So I guess I would ask with that, do you biopsy before with the possible risk of having a bunch of false findings and things floating around in the saline or what are your recommendations in that regard if you're doing both at the same time? Personally, I use the PIPEL sort of to remove the fluid and then get a sample once the fluid is removed. I do the same thing during hysteroscopy, so I'll drain the fluid and actually watch the fluid drain with the hysteroscope, and then I'll go in and do the biopsy after that.

Takes a couple passes, unfortunately, for the patient. Yeah. Great tips.

All right. Back to our fellowship, did you all have any more questions for our panels before we start to wrap up? Oh, I have one. I have one more.

So we do some office hysteroscopy here, and I've been, you know, I was really, this is the first I've seen the information on hysteroscopy and evidence on hysteroscopy of chronic endometritis. Do you recommend or has anyone thought about the value of directed biopsy given that it's not always like universal hyperemia or biopsy of like the micropolyps? Or do you think, you know, blind biopsy is just as good? I'll usually go with a blind biopsy in my practice. If there's a larger polyp, we'll grab that and take it, but micropolyps are just hard to capture.

Yeah, I agree. I had a patient today with a lot of micropolyps. They're really kind of all over.

And so I actually was using a hysteroscope. I came out, did an in vitro biopsy, went back in, they were all gone. I got a great sample.

I didn't have to do much else. So I think you get a pretty good sample just with a biopsy. And we have a question from our editor-in-chief.

Anne, did you want to ask your question or do you want me to ask it for them? Well, I'll follow up. This follows up on the question. If that woman that Dr. McQueen, you mentioned had multiple micropolyps, let's say she had hyperemia and you're like, this is definitely chronic endometritis.

The biopsy comes back negative. Do you treat? Good question. I mean, I haven't started her on treatment today.

I was waiting for the biopsy to come back. I think I probably wouldn't treat, but it's a good question. I don't diagnose by hysteroscopy, but in Europe, really the push is to diagnose by hysteroscopy and not use the biopsy as a finding.

I mean, I've been doing hysteroscopy for a few years now and haven't found the, maybe my eyes aren't as good as the people in Europe, but haven't found a good correlation. I see this all the time where I'm like, this one looks like she's got it and they don't. I wonder sometimes if it's just cycle phase or other, if we're too close to the menses or something like that.

We often do our hysteroscopies while people are on agestin or birth control pills and that can cause the lighting maybe to look a little bit different. I generally go with the PATH, but I have CD138 in my clinic. When we send a PATH, we have a good pathology look at it, so I trust it.

If you're in a place where your pathologist is not doing CD138, then maybe going with the European route and treating based on suspicion and visual appearance might be a better choice. We've had really good luck with our pathologists and we trust their results. You mentioned earlier about the CD138 not being specific.

When you have CD138 staining on a plasma cell, you can tell that it's a plasma cell. You can see the nucleus. You can see the shape.

It will stain other things, but I think the pathologists can recognize if it's a plasma cell or not. I think partnering with your pathology department and trying to get them to add this and showing them the data in this review article would be great. I think they would be willing to partner with you.

Make them be part of a study. They might do it for that reason. We're laughing because that's exactly what we did.

I sent this article to our pathologists last year because I think it's been underappreciated just given the confusion in the literature about diagnosis and the value of treating. Your article is what helped us to at least have that dialogue with our pathologists. I would imagine a lot of people in practice nationally don't have the same resources that some of you who've done research in this area have.

We still need to take care of our patients and need to think about how to do these workarounds when you don't have that quality of pathology available to you. I'm not a pathologist by any means, but I have learned that they're using the CD138 more so to identify the areas. They're seeing there's more staining in this region and then they go and look at the H&E where they can actually identify those plasma cells in that region as well.

It's more of a tool to assist with the H&E where it might otherwise be missed. I do have a question for the group, though, since we're discussing different diagnostic methodologies. We've talked about biopsy.

We've talked about hysteroscopy. We haven't really spoken much about the microbiome testing or the bacterial testing. How many of you all are doing that? Is anybody using that for routine screening up front, like instead of even doing any biopsy routine? Well, I guess you're doing a biopsy when you collect it, but is anybody doing that routinely and what has your success? I don't do it routinely.

I've done some Alzheimer's tests before for cases of persistent chronic amyotritis. I've treated it. I'm not getting a response and maybe I can get some specific pathogen.

There is evidence that this is a dysbiosis and there's changes in the lactobacilli levels in patients with chronic amyotritis. There is definitely something there, but for screening, I just use plasma cells. Kind of in line with that, one of our attendees had asked about the Receptiva test.

This might be similar to what you're asking, Michael, but they had asked about, given that the pathologist may have different criteria and varying familiarity with the CD138 staining as well as potential inconsistencies in interpretation when using CD138, do we find the Receptiva testing to be helpful in clinical decision-making? Does anyone use that test here? I don't think it's been valid. I've studied BCL6 a little bit and I don't think it's been validated for chronic amyotritis, but it is a marker of inflammation, so perhaps there's some overlap there, but I'm not aware that there's a correlation. The Receptiva test, you can add on a CD138.

If your lab is not doing CD138 and you want this test done, you can send it off. I don't know if Receptiva will allow you not to order a BCL6 and just test for chronic amyotritis, but you can definitely add on the CD138 if you want to. We're doing that in cases of repeated implantation failure in IVF.

I haven't really been doing it for RPL patients. I will point out there is a lovely article in FNS Reviews on these testing options, including Receptiva and Alice and Emma by Dr. Devine. If anybody would like to, there's a great review article on this.

A shameless plug. Excellent. Any other questions from our fellowship? No.

All of our questions were answered. Thank you so much. Excellent.

Awesome. Well, I'm curious, Dana. I know you and I have talked briefly about this in the past, but as of right now, our ASRM criteria for RPL evaluation do not have any of this that we've discussed, so what are your all's thoughts on that? I know last time we talked, Dana, I think you mentioned it was possibly in the works.

What do you all think about it? Dr. Lathi and I have reviewed, I think Mike was involved too, in looking at new guidelines for the RPL guideline for ASRM. It's not out yet, so I don't know. Ruth, do you have an update? I believe we'll put something.

I've been told it's coming. There is a soft recommendation to say to consider it from the ASRM. Not a mandated test at this point in the new guideline.

We'll see. It's still under review if there's going to be any additional changes. I think that the guideline committee felt that without RCT, that treatment, that it was not strong enough data to have it be a standard of care required test, but we definitely have it in there in the consider bucket.

Excellent. Well, before we wrap things up, any last comments from our panelists to everyone? This has been great. I've learned a lot.

I really appreciate you all's time. So, if anyone has any last comments or anything, then that would be great. Well, I want to thank FNS Reviews for giving us the opportunity to write this review and get it out there.

I think it was a really fun exercise. Dr. Strug was a fellow at the time. He has now graduated, but we also were able to involve a resident, Dr. Hartup, who's here.

She was really instrumental in helping us work with this. So, it was great learning for all of us. It allowed us to kind of work on multiple levels and all learn from each other on this.

So, it's a great opportunity to involve trainees and learn a little something along the way. So, really encourage you all to look around at a topic that seems that it's a little ambiguous and roll up your sleeves and give it a shot. That's actually what we'd also like to thank the authors because this is obviously a very difficult topic and yet one that we need to deal with on a day-to-day basis, even though the evidence is imperfect.

So, really appreciate that you've synthesized this. You were clear on where the limitations were, but still really helped us guide clinical care. So, thank you for taking it on.

Also, thank you to Dr. Hosseinzadeh, our Associate Fellowship Director here at Hopkins, who really organized things on our end. Thank you for having us. Yeah, absolutely.

So, on behalf of F&S Reviews, really appreciate everyone's time. Really, I learned a lot. And for the residents and fellows at Hopkins, great job.

If you want to hear me try and fumble through massive reviews every month on the podcast, then you can listen on the F&S Unplugged podcast. Maybe I'm going to have you guys join me because you guys nailed it, did an awesome job. And you did it in about 10% of the time that I do on the podcast, so that was great.

But anyways, thanks again to everyone. We really appreciate it. As always, I recommend everyone to read the article in its entirety.

There's a lot more information in there that's really helpful, good graphs, good tables. So, on that, everyone have a great night, and until next time, everyone have a good one.