Chronic Endometritis & IVF: Could Silent Uterine Inflammation Affect Implantation or Miscarriage?

Could chronic endometritis—silent inflammation in the uterine lining—affect IVF implantation, miscarriage, or embryo-transfer success?

In this episode of Taco Bout Fertility Tuesday, Dr. Mark Amols explains what chronic endometritis is, what it is not, and when it may actually be worth investigating.

We break down CD138 biopsies, hysteroscopy, cultures, EMMA, ALICE, and vaginal microbiome testing—and why these tests are not interchangeable. We also discuss antibiotics before embryo transfer, what ASRM says about routine antibiotic use, and why finding bacterial DNA does not automatically mean treatment will improve live-birth rates.

The takeaway: chronic endometritis can be real and treatable in the right patient, but not every borderline result explains infertility, miscarriage, or a failed IVF transfer.

Thanks for tuning in to another episode of 'Taco Bout Fertility Tuesday' with Dr. Mark Amols. If you found this episode insightful, please share it with friends and family who might benefit from our discussion. Remember, your feedback is invaluable to us – leave us a review on Apple Podcasts, Spotify, or your preferred listening platform.

Stay connected with us for updates and fertility tips – follow us on Facebook. For more resources and information, visit our website at www.NewDirectionFertility.com.

Have a question or a topic you'd like us to cover? We'd love to hear from you! Reach out to us at TBFT@NewDirectionFertility.com.

Join us next Tuesday for more discussions on fertility, where we blend medical expertise with a touch of humor to make complex topics accessible and engaging. Until then, keep the conversation going and remember: understanding your fertility is a journey we're on together.

Transcript

>> Dr. Mark Amols: 0:00

Today we talk about chronic endometritis, the possible silent inflammation in the uterus that may be affecting implantation, miscarriage, and fertility treatment. I'm Dr. Mark Amols, and this is Taco 'Bout Fertility Tuesday. Could there be a silent infection in your uterus keeping you from getting pregnant? Well, that sounds scary. It also sounds like the kind of thing that can lead the Internet to turn it into a everyone needs this test immediately type of thing. But, before we hit the pause button, let's talk about this a little bit more. Let's talk about what chronic endometritis is, how it might affect your fertility, when testing may make sense, and why the different tests you hear about do not always answer the same question. First off, chronic endometritis is not endometriosis. Endometriosis is tissue similar to the uterine lining growing on the outside of the uterus. Chronic endometritis is inflammation inside the lining of the uterus itself. And it's not usually the severe infection most people picture when they hear the word infection. We're not typically talking about eye fever, severe pelvic pain, or someone looking obviously sick. Chronic endometritis is usually a low grade inflammation. Many people have it and have no symptoms at all. And this is the big idea for today. Chronic endometritis may be real. It may even matter. It may even be treatable. But a positive test is not automatically the smoking gun for infertility, failed IVF or miscarriages. And that distinction matters because fertility medicine has enough expensive rabbit holes already. We only need another one. Without actually asking, is the rabbit really there? So what is chronic endometritis? Well, the hallmark of chronic endometritis is the presence of plasma cells in the endometrial stroma. That means inside the tissue. And this tissue is the supporting tissue of the uterine lining. Plasma cells are immune cells. They show up when there are inflammation and other inflammatory processes going on. Now, why would that matter for fertility? Well, implantation is not just an embryo landing in the uterus like a plane at an airport. The uterine lining first must become receptive. It has to respond properly to progesterone, and it has to have the right balance of immune signaling. It has to allow the embryo to implant and then support early placental development. Well, chronic inflammation can interfere with some of those processes. For example, it may alter decidualization, which is a transformation of the lining to help support the implanted embryo. It may affect immune signaling, local blood flow, and the overall uterine environment. So the biology makes sense. But. And this is an important but, finding inflammation after a failed transfer or miscarriage does not prove that the inflammation caused a bad outcome. A person may have a polyp retained tissue after a pregnancy, adhesions, a fibroid near the cavity, or another uterine issue that both causes inflammation and affects fertility. Sometimes the inflammation may be the signal that and not the entire explanation. And that is why we should not tell every patient with one or two plasma cells, ah, we've solved your infertility, because that's not true. Sure, we found something important, and maybe we found a major clue. But a clue is not always the culprit. So if everyone shouldn't be evaluated, what should make us think about chronic endometritis? I think testing becomes more reasonable when there's a pattern or another reason to be suspicious. For example, recurrent pregnancy loss or repeated implantation failure, particularly after transferring good quality or euploid embryos. Maybe things like persistent irregular bleeding or prolonged spotting or bleeding between periods or an unusual discharge. Maybe it's a hysteroscopy showing micro polyps, edema, patchy redness, or strawberry appearance in the lining. Basically any abnormality in the uterine cavity, such as polyps, retained tissue and adhesions. These are the situations where you start to say, maybe there's more going on in this lining. But this does not mean that chronic endometritis testing should be automatic before every IVF cycle. What about after one failed euploid embryo transfer? Well, usually not one failed transfer. Yeah, frustrating. But it's not proof that there's something unusual hiding in the uterus. Even a genetically normal embryo does not implant 100% of the time. Now, the goal is not to ignore chronic endometritis. The goal is to use testing where it has a reasonable chance of changing a decision. And this is where things get a bit confusing, because people hear endometrial test, microbiome test, maybe infection test, and they assume they're interchangeable, but they are not. A hysteroscopy looks inside the uterine cavity. It can identify things like polyps, adhesions, retained tissue, and visual changes that can raise suspicion of chronic endometritis. But hysteroscopy alone does not prove it. A traditional endometrial biopsy looks at the tissue itself. And a CD138 staining is an additional pathology stain that helps identify plasma cells. That is probably the most established test for chronic endometritis because it looks for the inflammatory cell that defines the condition. Now, a culture attempts to grow bacteria, and if it grows something meaningful, it may help direct antibiotic treatment. But culture misses bacteria that do not grow well in the lab, and they can be affected by contamination. Then you have tests like Alice and Emma. Alice looks for DNA from selected bacteria that are associated with chronic endometritis, whereas Emma looks at targeted bacterial profiles and compares it to what the company considers a more favorable endometrial microbial pattern, often with a lot of emphasis on Lactobacillus. And then there are vaginal microbiome tests which take a sample from the vagina. So here's the simple

version. CD138 test asks: 6:31

Are plasma cells, which are inflammatory, present in the uterine lining?

The ALICE test asks: 6:37

Is DNA from certain bacteria

present? The EMMA test asks: 6:40

Does the bacterial profile look favorable according to this assay? And the vaginal swab says, what's happening in the vagina? Now, those questions may be related, but they are not the same question. CD138 is probably the test most physicians think of when they're evaluating chronic endometritis. And it's useful because plasma cells can be hard to identify on the standard pathology slide. So CD138 makes them easier to see. But there's a problem. There is no universal agreed upon cutoff for what counts as positive. Is one plasma cell enough? 2, 5, 10? What about a certain number per microscopic field? A certain number across the entire sample? And different studies use different definitions. Different pathologists may interpret borderline cases differently. A biopsy is a very small sample of a very large organ. So timing of the cycle, tissue quality and how the specimen is processed can affect the answer. One systematic review gives us a useful but not final anchor. Using a threshold of at least five plasma cells across ten high power fields. Chronic endometritis was associated with a higher miscarriage rate, but lower level findings. Fewer than five cells per 10 fields did not reliably predict worse pregnancy outcomes. Now, that does not make the five cells the magical universal line. The studies were heterogeneous and the live birth difference was not statistically clear. But it does support a practical point. A few scattered plasma cells may not mean the same thing as substantial inflammation throughout the sample. So CD138 is good at finding plasma cells. The harder question is whether the number it finds is enough to explain a fertility problem. And this is especially important when someone gets a borderline result. A tiny number of plasma cells may not carry the same meaning as more substantial inflammation. And that's why I would be cautious about turning a very mild finding into a six month antibiotic adventure. Now, when it comes to EMMA and ALICE, they're very interesting tests. The technology is very impressive. But technology and proven clinical value are not automatically the same thing. These molecular tests look for bacterial DNA, and to be specific, they look for a very specific portion of DNA that is found in these bacteria. This is how they're able to distinguish between human cells and bacterial cells. This also allows them to detect organisms that might not grow in a culture, and that can be useful information. But finding bacterial DNA does not necessarily mean there is an active infection. It doesn't even mean that the bacteria are alive. It does not necessarily mean that those bacteria caused infertility. And it definitely does not automatically mean that that taking antibiotics will improve the chances of a live birth. Another challenge is that the uterus is a low biomass environment. In plain English, that means there's not much bacterial material compared with places like the vagina, the mouth or the gut. When you are trying to measure a tiny signal, contamination matters more. A little DNA from the vagina, cervix, the catheter, the collection device, maybe even lab reagents or the processing environment can potentially influence the results. That does not mean the tests are worthless. It means we have to be honest about what they can and cannot tell us right now. A, molecular test can be incredibly good at detecting bacterial DNA and still not tell us whether treating the DNA helps someone take home a baby. That is the gap. Now, let's talk about something many patients see in transfer instructions. Antibiotics before embryo transfer. Why do clinics do that? Usually the thought process is one of three things. First, maybe there's a low-level cervicouterine infection that we're not detecting. Second, maybe bacteria could be carried upward during the transfer process on the catheter. Or third, maybe antibiotics are a low risk way to cover a possible problem before putting a very valuable embryo inside the uterus. That logic is understandable. It's not absurd. And studies have shown that antibiotics can reduce bacteria culture from embryo transfer catheters. So there may be less detectable bacterial contamination at the time of the transfer. But the key question is not can we reduce bacteria on the catheter? The key question is, does it lead to more healthy babies? And this is not just my interpretation. ASRM's Embryo Transfer Guidelines concluded that there is fair evidence from the available randomized trial that amoxicillin-clavulanate given around embryo transfer does not improve pregnancy rates because there is not additional evidence showing a benefit. ASRM does not recommend routine prophylactic antibiotics at embryo transfer to improve outcomes. Now, for a patient with a ah, known infection, suspected significant chronic endometritis, or another specific indication, antibiotics may be entirely appropriate. But routine coverage for every transfer has not been shown to improve IVF success. And it's true antibiotics are not completely harmless. They do cause things like GI symptoms, yeast infections and disruption of normal bacteria, such as in the vagina or in the bowels. Now that being said, do we still do it? Of course we do, because just like you, we want to do everything possible to help improve your chances. And the small risk of creating symptoms or even bacterial resistance is low compared to the thought that you won't get pregnant due to a mild case of endometritis. It doesn't make it right, but it's just the difference between science and medicine. Now if you noticed recently there are a lot of tests coming out looking at the vaginal microbiome, but the vagina is so far away from the uterus, does it really matter? Well, the simple answer is yes, because they're connected and the vaginal microbiome can absolutely matter for vaginal health. Bacterial vaginosis, sexually transmitted infections, cervicitis, and recurrent vaginal symptoms deserve appropriate evaluation and treatment. And some studies show that vaginal bacterial patterns are associated with IVF outcomes and early pregnancy outcomes. But a vaginal swab is not the same as sampling the uterine lining. Although the vaginal and endometrial environments overlap, they are not identical. A vaginal test may give us useful clues. It may help us diagnose bacterial vaginosis or another real clinical issue. But it is not yet a, validated shortcut for saying your uterine lining has chronic endometritis or you need antibiotics before transfer. The best patient friendly explanation is the vaginal microbiome may give us clues about the reproductive tract, but there is not yet a reliable window into whether the uterine lining is inflamed. Now, when chronic endometritis is convincingly diagnosed, treatment often includes antibiotics, commonly doxycycline, although regimens vary. If there is a polyp, retained tissue adhesions or another structural issue that needs attention too. Sometimes the best treatment is not simply antibiotics. It might be removing the thing that is continuing to irritate the lining. The most interesting data, are often from studies showing that patients whose chronic endometritis resolves do better than patients whose inflammation persists. But be careful how we interpret that. It may mean treatment worked. It also may mean the people who persistently had inflammation had a different or more difficult underlying problem. What it does not prove is that every borderline result needs antibiotics or repeat antibiotics or probiotics or another biopsy or then a second molecular test for good measure. For someone with clear chronic endometritis and an upcoming embryo transfer, repeating a biopsy after treatment may be reasonable, especially when the original finding was significant. And the transfer decision depends on whether inflammation has resolved. For a patient with one rare plasma cell and no other warning signs, the value of chasing the result is much less clear. Just, so you know, there's a lot of research ongoing in this area. Researchers are studying the normal endometrial microbiome and how to collect samples without contamination, whether vaginal and uterine bacteria profiles meaningfully correlate, and whether antibiotics, probiotics, or other treatments can even improve the outcomes in selected patients. But the studies we really need are pretty straightforward. We need a standardized definition of chronic endometritis, what number of plasma cells actually predict worse outcomes. We need randomized trials in clearly defined groups, such as patients with recurrent embryo transfer failures with euploid embryos. We need to compare testing versus no testing. We need to compare targeted treatment versus placebo or usual care. And most importantly, we need live birth as the endpoint. Not just did the bacterial pattern improve, not just did the repeat test turn negative, and not just did we get a positive pregnancy test. This time. Those things may be interesting, but the outcomes patients care about is the healthy baby. So where do we land? Chronic endometritis is not fake. It can be a real and potentially treatable issue, particularly in the right clinical situation, such as recurrent implantation failure, recurrent loss, suspicious bleeding, abnormal hysteroscopy, or structural uterine finding. But it's not a universal explanation for every failed transfer, every miscarriage, or every unexplained infertility diagnosis. CD138 is an inflammation test. ALICE is a bacterial DNA test. EMMA is a microbiome profile test. A vaginal swab is useful in the right setting, but it's not the same as a uterine diagnosis. And routine antibiotics before every embryo transfer may make theoretical sense and feel good, but we still have not seen convincing proof that it improved the outcome that matters most. The responsible middle ground is to look for chronic endometritis in the right patient, understand what each test actually measures, treat clear disease thoughtfully, and resist the urge to turn every subtle lab finding into a fertility diagnosis. If you've had repeated losses, repeated failed transfers or unusual bleeding, or you've been told you have a positive CD138, EMMA, or ALICE test, ask your physician a simple question. What exactly did the test find and how confident are you that it matters? For me? And how would treatment change my chances of a live birth? That conversation is much better than simply asking should I take antibiotics? In a future episode, I really like to sit down with the company that makes these tests so you can have a deep understanding of their test and hopefully at that future time will have more research studies helping guide us on what to do with that information. And if this episode helped you understand the tests you have been offered, or maybe think of someone who's in fertility treatment right now, send this to them. And if you haven't already and you like this podcast, give us a five star review on your favorite medium and tell your friends about us. As always, I greatly appreciate everyone listening to this and I look forward to talking to you again next week on Taco'Bout Fertility Tuesday.