Thank you. Hello everyone and welcome to FNS Journal Club Global. I'm your host Blake Evans, an REI out of the University of Oklahoma, and I'm the media editor for FNS Reviews.
So FNS Reviews is proud to again partner with the Stanford REI Fellowship Program. Thank you all very much for joining today. And we're going to be having an important discussion on an article entitled The Evidence Practice Gap in Immunotherapy for Recurrent Pregnancy Loss.
And before we dive into our discussion, I want to take just a brief moment and put a plug in as to why someone or one of you all out there should consider submission to FNS Reviews. So our journal is part of the FNS family. We're one of the sister journals for FNS, and we publish systematic reviews, meta-analyses, comprehensive reviews, as well as critical analytic reviews of published literature.
We consider review articles as well that inform clinical practice based on emerging and also established evidence from clinical research and also reviews that advance our understanding of human reproduction, as well as contemporary studies in the reproductive sciences. This is a particularly great journal, I will say, for REI fellow physicians to submit as you all are inevitably doing deep dives on literature, patient presentations, and you may have questions as you're going through that process as to what data exists or may not exist on a certain topic, and that can prompt a review article to submit. So all right, back to the journal club.
We have a very special journal club today. I'm honored to be with several very incredible physicians and scientists to discuss this article and also to help advance and continually improve patient outcomes. So before we dive into the summary of our article with the Stanford REI Fellowship Program, I want to give a very special thanks to a couple of our authors who are in Copenhagen, a completely different time zone than most of us here.
So it is approaching late hours of the evening for them, so we really appreciate you being here with us today, and so we can't thank you enough. So in just a moment, I'm going to have the Stanford REI Fellowship Program introduce themselves and then summarize the article, but first I want to just go around the screen, if you will, and have our discussants introduce themselves, and if you all don't mind giving your name, your title, and where you work at. So we'll start with Kilian.
Yes, hi. Good afternoon or evening. My name is Kilian Wamstein.
I'm a consultant and clinical associate professor at the University of Copenhagen and Copenhagen University Hospital in Hvidovre. Next on my screen is Ruth, so we'll go with you next, Ruth. Hi, Blake.
I'm Ruth Lottie from Stanford. I'm the division director and I guess professor, so thanks for having us. Yeah, thanks for joining.
All right, next I have Ida. Hello, everyone. I'm a medical doctor and a PhD student doing research at Copenhagen University Hospital in Hvidovre with Kilian, who is my co-supervisor.
Excellent. Thank you so much for joining, and so now we'll go to our fellowship program. If you all want to go ahead and just introduce yourselves.
I'm Arjen Korsiet. I'm one of the third-year REI fellows here. Anthony Bui, I'm a second-year fellow.
I'm Lucy Akadinova. I am fellowship program director and practicing REI, clinical professor. Hi, I'm Brenda Bouvan.
I'm a clinical assistant professor and also the associate program director for the fellowship. Hi, everyone. I'm Wendy Zhang.
I'm the first-year fellow at Stanford, and for those listening in, I don't know if you noticed the orange to honor in the U.S. the National Infertility Awareness Week. Yes, very ironically timed. We didn't plan this to be during Infertility Awareness Week, but it worked out perfect, so thank you for that special plug.
So, all right, I will let you all go ahead and start with your review. Perfect. Hello, everyone, and thank you, Dr. Evans, for your introduction.
We're grateful to be invited to discuss this very important review. So, to motivate this conversation, as we know, up to 45 percent of early pregnancy losses remain unexplained after evaluation, and therefore, there is strong recognition of the need to identify treatments to prevent early pregnancy loss. We know that successful pregnancy requires an immunologic balance between the mother and the semi-allergenic fetus.
As such, there's been ample study of the possible immunologic mechanisms underlying recurrent pregnancy loss. Furthermore, we know that immune perturbations may also be a precursor for chronic inflammatory diseases later in life. However, there remains a striking gap between the immunologic theories of recurrent pregnancy loss and the clinical transition into evidence-based treatments.
Recent guidelines from the American Society for Reproductive Immunology, while providing recommendations for various immunotherapies, acknowledge that these treatments remain controversial and backed by limited evidence. There continues to be a lack of validated immunologic biomarkers as well for RPL and a lack of immunomodulatory treatments that are proven by high-quality randomized trials. And so, I'll start by briefly summarizing some of the knowledge that we have to date regarding the role of immune cells in early pregnancy and the perturbations that have previously been described in the setting of recurrent pregnancy loss.
Among the most studied immune cells, when it comes to early pregnancy and RPL, include natural killer cells and CD4 T-cell derivatives. With natural killer cells, they can be further subclassified to peripheral and uterine cells. Peripheral natural killer cells are mostly cytotoxic in function, whereas uterine natural killer cells have been shown to play critical roles in spiral artery remodeling, trophoblast regulation, and decentralization support.
When it comes to CD4 plus T-cell derivatives, relevant T-cells that have been studied in the RPL setting include T regulatory cells and Th17 cells. T regulatory cells have been shown to suppress uterine natural killer cell cytotoxicity via cytokine release, and in turn, the natural killer cells promote differentiation of the CD4 plus precursor cells towards the T regulatory cells and away from the Th17 cells, which are known to be inflammatory. And so, you can kind of see they kind of act synergistically in cycle.
Similarly, Th1 and Th2 cells are thought to have also emerged as a potential contributor towards recurrent pregnancy loss. In similar ways, Th1 cells are pro-inflammatory, whereas Th2 cells are anti-inflammatory. Aside from the natural killer cells and the T-cells, other immune markers that have been explored include autoantibodies, such as antinuclear antibodies, as well as thyroid peroxidase antibodies.
Additionally, as well as HLA compatibility or theory of excessive sharing of HLA alleles between the partners, although these roles are much less well-defined. And so, many of the treatments that we will review today have some basis in immune modulation, with the biological plausibility often derived from the proposed effects specifically on these cell types. And so, the purpose of this paper was to review the current evidence of the immunomodulatory treatments for RPL.
And so, this was a systematic literature search, prioritizing systematic reviews and meta-analyses and randomized controlled trials, with particular attention to studies that have used immune markers as inclusion criteria. We will review the evidence behind these interventions as possible treatments for RPL. All right, and we'll first discuss the most commonly prescribed off-label treatment for RPL that's immunologic, and that's corticosteroids.
So, corticosteroids are an effective treatment for autoimmune conditions in general, and they are relatively low cost compared to some of the other treatments we'll talk about today. And although they do promote regulatory T-cell differentiation, you know, their nonspecific immunosuppression could theoretically be detrimental rather than beneficial in RPL. And as it will become a common theme when discussing the other treatments today, you know, the evidence behind corticosteroid use in RPL is really insufficient.
You know, the authors discuss the heterogeneity of the studies that investigated corticosteroid use in RPL. You know, there's different patient selection criteria. There's different doses and timing of when corticosteroids are administered.
Most often, they're used in combination therapy with other treatments rather than in isolation. And there's also different outcome measures between different studies. And there are really only two studies that they highlight, one prospective, one RCT, that, you know, looked at adding a corticosteroid with live birth as an outcome for this population.
And neither study individually showed a statistically significant outcome. And the overall sample sizes were really too small to kind of derive any meaningful results that are broadly applicable. It is also worth emphasizing that, you know, corticosteroid use in the periconception period is really not safe.
You know, there's well-documented adverse effects on maternal health and fetal development with the use of high-dose steroids in the periconception period. And so, in summary, it's really, you know, unclear whether steroids benefit people with RPL. And if they do, which specific people with RPL they would benefit.
But it is clear, you know, that their use can cause maternal and fetal harm. And that's why, really, they're not recommended to be used for RPL. And then I do want to discuss another intervention that is also probably very familiar to most, which is intravenous immunoglobulin, so IVIG.
The mechanism by which it works is pretty broad immunomodulating effect, including its suppression of autoantibodies, it modifies cytokine production, and then also expands regulatory T lymphocytes. It, interestingly enough, represents the only immunologic treatment that the ESHRI guideline considers for treatment of patients with unexplained RPL, particularly those with four or more losses. And in terms of the studies, there have been multiple systematic reviews and meta-analyses, excuse me, in the past few decades, looking at IVIG.
One that's really highlighted in the review is a double-blind RCT of 102 women. And this includes four or more unexplained pregnancy losses. And they found an over two-fold odds ratio of live birth when given in high doses in early pregnancy.
If you look at men analyses that really appropriately restricted to placebo-controlled studies, then mixed results were found. It is worthwhile to note that in a subgroup analysis, though, they did find significant benefit in women with six or more pregnancy losses, so higher order losses. I really appreciate that authors looked into specific populations within the context of IVIG.
With regards to IVF in observational data, there was some suggestion that IVIG could be beneficial. With secondary RPL, there was no significant benefit noted. And then with positive immunologic biomarkers, it was found to increase odds of live birth in women with three or more losses with the presence of biomarkers.
Some of those could be elevated NK, elevated Th1 to Th2 ratio, and then a diagnosis of autoimmune disorders. And this supports the American Society of Reproductive Immunology guideline that was put out in 2025, that perhaps this would be appropriate for patients with high-risk immune RPL. So, the evidence seems to support the use of preconception IVIG in specific subpopulations, particularly patients with multiple unexplained losses, like we mentioned.
The jury is still out, though, on biomarker positive population. I do really want to highlight the fact that there were quite a few limitations in terms of heterogeneity and the dosing of IVIG that was noted in prior studies, and then also the timing of initiation, whether it is before pregnancy or in early pregnancy, in addition to the continuation duration, whether it was initiated throughout pregnancy or terminated at some point in the pregnancy. And it's also really important to note that there's a huge cost on the scale of tens of thousands of dollars for this intervention that's not been well demonstrated.
And there are also some risks, preterm birth, fetal growth restriction, and congenital abnormality. The next intervention that I want to highlight is the LIT, lymphocytic immunotherapy. The mechanism behind that is, first, it's an allogeneic lymphocyte therapeutic from either the male partner or a third-party donor to induce maternal immune tolerance.
Theoretically, the thought is it prevents the rejection from the semi-allogeneic fetus. I do want to note that in the United States, our Food and Drug Administration, or FDA, did suspend the use of LIT, and the authors did highlight this. And it was suspended in 2001 due to concerns about safety and also efficacy.
So it's really reserved for research use. In terms of the evidence and the studies behind LIT, in 2014, there was a concurrent systematic review that included multiple immunotherapies. So they weren't specifically only looking at third-party donor LIT or partner, but they also included others.
And they found that in patients with unexplained RPL and at least three pregnancy losses. So you get a sense of the heterogeneity in terms of inclusion criteria amongst the studies. They found no benefit.
And a more recent meta-analysis did find significant benefit for LIT with actually a life birth rate of 65% compared to 45% in their placebo or no treatment group. Similar to the theme that you'll hear through multiple discussions is that there is limitation in the heterogeneity of the control group. Some of the control groups had steroids on board.
Others had no placebo group. And then one study that I really appreciate that the authors mentioned, the intervention group included only pregnant women who received paternal LIT and developed antibodies. So then if they did not develop antibodies, then they were put in the control group, which one would argue they received the LIT, the intervention, right? So probably not the most appropriate intervention control group differentiation.
Looking at specific populations. So there are studies that looked at RPL stratified by ANA status or anti-TPO status. And even though the studies observed improved outcomes for both of, regardless of antibody status, it is really notable to that ANA negative and anti-TPO antibodies patients did confer better outcomes with LIT.
The caveat is that these were unblinded and had no control groups. In terms of the risk, congenital abnormalities were also noted, fetal growth restriction, and then a specific one to LIT was neonatal alloimmune thrombocytopenia. So LIT is not quite ready for prime time in the absence of more rigorous double-binded RCTs.
All right. So moving on, a treatment approach that has been of heightened interest as of late is calcineurin inhibitors. These drugs work by blocking the calcineurin signaling pathway, which in immune cells leads to reduction of TH1 cytokines.
Remember going back to these being inflammatory and thereby reducing natural killer cell cytotoxicity. Examples of these medications include tacrolimus and cytosporine. With tacrolimus, specific mechanisms in pregnancy have also been described, including suppression of natural killer cell degranulation, promotion of TH1 to T regulatory cells, and suppression of TH17 differentiation.
There have been several studies that have showed improved implantation and live birth rates in patients with RPL or RIF, actually, specifically in the setting of elevated TH1-TH2 ratio. In a randomized study, Lewitt et al. found that treatment with tacrolimus significantly improves live birth rates in patients with primary RPL with increased TH1-TH2 ratio who have failed other treatments.
A 2023 systematic review in meta-analysis, which included eight studies spanning 1,042 women, found that calcineurin inhibitors significantly increased clinical pregnancy rate and live birth rate and decreased pregnancy loss rate. However, the analysis was limited, as was with many of these analyses, by heterogeneous inclusion criteria. Regarding safety, evidence for safety derives largely from the transplant patient population, specifically in tacrolimus-treated women who have had successful pregnancies.
While women treated with calcineurin inhibitors report increased rates of maternal, perinatal morbidity and mortality, the data does reflect pregnancy outcomes in a critically ill group of patients, and so it's hard to tease out the harms conferred by the intervention versus the patient baseline risk. Generally, these medications are thought to be acceptable for use in pregnancy in select cases. However, at this time, these treatments are not endorsed by ASHRAE or ASRM due to lack of evidence and are currently limited to specialty centers that perform the Th1 to Th2 ratio testing.
I'll now discuss the use of aspirin and heparin. These therapies are pretty commonly used in the setting of recurrent pregnancy loss, either alone or in combination. Their use is best described in recurrent pregnancy loss in a setting of antiphospholipid syndrome, as we all know.
The primary mechanisms of action of aspirin are thought to be irreversible COX-1 acetylation, resulting in reduced thromboxane A2, and therefore reduced platelet aggregation and vasoconstriction, as well as counteraction of direct platelet activation in the setting of antiphospholipid syndrome. With heparin, several mechanisms have been described, including anticoagulation through binding of antithrombin 3, as well as complement inhibition via the inhibition of C5-convertase, which has been shown to be the mechanism in the setting of antiphospholipid syndrome. Regarding the evidence supporting the use of these interventions in RPL, Rye et al.
established that combination therapy is superior to aspirin alone in improving live birth rates, specifically in the setting of antiphospholipid syndrome. Several subsequent randomized studies, most notably the SPIN trial in 2010 and the ALOP2 trial in 2022, explored the use of combination aspirin and heparin in non-antiphospholipid syndrome RPL and actually found no difference between combo treatment compared to either aspirin alone or placebo. And then three recent meta-analyses found that treatment of women with unexplained RPL with heparin, with or without aspirin, did not seem to show improved live birth rates.
However, there's some emergent evidence, much newer evidence, that anticoagulation may benefit some immunologically defined subgroups of patients. Specifically, there's an observational study that found benefit from aspirin with unfractionated heparin in women with RPL with anti-Beta-2 glycoprotein and HLA-DR antibodies, which further highlights the need for us to identify biomarkers for selection of treatment-responsive populations. Definitely, yeah.
And next one is a household name as well. This is hydroxychloroquine. It's a medication developed for malaria in the 1950s and made somewhat infamous by the COVID pandemic.
In terms of the mechanism, it's pretty diverse in terms of the immunomodulatory effect, both on the innate and adaptive immune system. There's also an antithrombotic effect that may play a role in endothelial dysfunction. There have been quite a few systematic reviews that did suggest benefit in women with RPL and APLS, so antiphospholipid syndrome, but the evidence is very limited and mixed for unexplained RPL, so specifically RPL with APLS.
Recent data from the French FALCO registry, so that was a registry investigating the causes of recurrent miscarriage, did find limited efficacy for patients with immune-mediated RPL. There are notably two ongoing RCTs investigating hydroxychloroquine in RPL, though one was actually prematurely terminated due to two fetal adverse events of polydactyly. The primary findings were actually presented at the 2025 Esri conference, as the authors noted, and the investigators did conclude that there was sufficient power to demonstrate lack of efficacy.
So for hydroxychloroquine, even though it's quite safe, it's affordable, and very well tolerated by patients, as the current evidence stands. It really should be reserved for malaria, prophylaxis, autoimmune diseases, maintenance, and pregnancy, but not quite for RPL. And there's a few more less common interventions that the authors highlighted in the paper that we'll briefly go over as well.
The first of those is granulocyte colony stimulating factor, or GCSF for short, which is a cytokine that's in the placenta and the decidua that kind of regulates granulocyte proliferation and may also inference trophoblastic growth. And so because of these properties, you know, there have been several studies looking at whether the use of GCSF is actually beneficial in unexplained RPL. And once again, you know, heterogeneity in study design kind of makes it challenging to derive any kind of broadly applicable conclusions from the data.
The authors do describe how some RCTs did show statistically significant higher live birth rates when using GCSF, while others did not. And this discrepancy is likely due to a number of factors, including how many prior losses these RPL patients had, how much GCSF was given, when it was given, and how it was given. There's one meta-analysis that they highlight that conducted the subgroup analysis that seemed to indicate that intrauterine administration of GCSF was actually more effective than subcutaneous administration in reducing miscarriage rates specifically.
And so, and while we don't really know about any safety issues when it comes to the use of GCSF in the RPL population, we don't also really know how to best administer it and which specific patients without unexplained RPL would benefit from it. And so, and this uncertainty is kind of particularly relevant given the significant cost that's associated with the use of GCSF off-label. Next is TNF-alpha inhibitors.
So, TNF-alpha is a pro-inflammatory cytokine. So, its inhibitor is, you know, is a treatment used in various autoimmune conditions. And the use of this class of medication has been investigated in RPL, but really never as a monotherapy as the authors highlight.
You know, there's multiple studies that have used a TNF-alpha inhibitor, but have always kind of included other treatments in the intervention group, like aspirin, heparin, and or steroids. And so, you know, while some of these studies have shown significantly higher live birth rates in intervention groups with combination therapy, it's really impossible to determine whether any of that benefit came from the addition of a TNF-alpha inhibitor or not. Conversely, you know, studies that have looked at the safety of TNF-alpha inhibitor use in pregnancy for other autoimmune conditions have shown an association with increased rates of birth defects, preterm birth, growth restriction, and even pregnancy loss.
So, we really have no idea whether TNF inhibitors really work in the RPL population or provide any benefits. And there seems to be some concern that it can cause harm, so they're really not recommended to be used. And there are a few more experimental treatments that are also discussed by the authors that fall in that bucket of we really don't know, and more data is needed.
There are several emerging immunomodulatory therapeutics under investigation. One of them is belimumab. It's a B-cell monoclonal antibody, and in our sister field of GYN oncology, we know that monoclonal antibodies are getting a lot of press and a lot of attention, like embryolizumab with GYN malignancy.
In a 2025 observational study, so not a randomized trial, 100 women with RPL and B lymphocytic dysfunction, so specifically that's their inclusion criteria, did have some promising results, but there have been yet no randomized trials. The other one that's mentioned is also interlipid infusion. There were promising animal studies, and then there was a recent meta-analysis of RCTs grouping recurrent implantation failure patients and RPL together, given that individually the groups didn't have sufficient power to evaluate them separately, but grouped together they did find improved pregnancy outcomes combined.
It is really important to note also that one of the RCTs included that actually specifically focused on RPL patients was retracted, and also the adverse events and the risk of the medication is quite significant with the risk of acute kidney failure and cardiac arrest. So really in summary, with regards to previously discussed immunotherapies, specifically in the RPL population, there's really promising mechanistic rationale, and I love the way that the authors phrase that, and there's a lot of biologic plausibility about that, but right now there's insufficient rigorous evidence to guide and support the routine clinical use, and I really highly encourage the readers, if nothing else, to really take a good look at Table 1. It's such a wealth of information, and it so beautifully summarizes all the therapeutics that we just discussed, including the mechanisms in action, evidence, key studies, safety, costs, guidelines, and the consensus recommendations. So it really is a one-stop shop in terms of learning about the immunotherapies of RPL, so I really appreciate the authors for putting that together.
And so to wrap up, there is really a substantial lack of evidence regarding the management of unexplained RPL using immunologic treatments, and as the authors highlight, there is a very great need for an intervention, driven both by patients who are suffering with RPL and by clinicians who may feel lost on how to best help them. You know, despite decades of using and studying immunologic treatments in RPL, we're still stymied by the central issue that we don't really have any immunologic markers with enough sensitivity and specificity for use in RPL, apart from antiphospholipid syndrome. You know, and the lack of reliable markers means that we're really unable to identify which patients with RPL would benefit from immunologic treatments.
And thus, you know, the studies we designed to investigate these treatments either have very broad patient selection, which makes it less likely to see an effect, or they have considerable heterogeneity in how they selectively choose patients, and the more selected that they are, the smaller the sample size is and the harder it is to detect an effect if there is one. And so, apart from the lack of reliable biomarkers, you know, another limitation we face is that most studies begin their immunologic intervention at the time of pregnancy confirmation. But there is a good amount of biologic plausibility that if an intervention is effective in treating RPL, that effect may be noticeable, you know, before conception or at least at the time of implantation and placentation.
But comparative data between preconception and post-conception initiation of immunologic treatments is really lacking. And finally, there's the issue of cost and ethics. You know, we touched on how some of these treatments can be extremely expensive.
And, you know, for the most part, we don't really know if they work or who they work for. And so, like you said, some of them cost a lot of money, and some have significant safety concerns as well with their use. And some treatments like IVIG are actually globally in short supply.
And so, you know, our off-label use of them actually could be preventing somebody whose life depends on it from being able to access that medication. And so, even though the psychological burden of RPL is so high, you know, we as physicians and providers, you know, we must still prioritize non-maleficence in how we practice. And the authors ultimately conclude that because of these limitations and the lack of quality evidence supporting their use, immunotherapy for RPL should only be offered through clinical trials.
And they do mention a path forward, you know, which is an application of precision medicine and multi-omics to both the discovery of biomarkers and the targeted therapy for unexplained RPL. And so, with that, we'll hand it back to Dr. Evans and the authors. Awesome.
Thank you all so much. That's, as you all well know, a heavy lift to summarize such a complex topic. And as fellows, I'm sure you can appreciate the even heavier lift to write the paper.
So, we have the luxury of having the authors. As you all kept saying, the authors say this, the authors say that. Well, we've got a few of them here with us.
So, we're going to take advantage of that. And our fellows have prepared some questions. And so, if you guys, let's just start with the first one that's on the list and hear from our authors.
I do have several questions that the audience has been typing in. We'll do our absolute best to get to some of those. But we're going to start with our fellows' questions first.
So, the first question that we were hoping to discuss is, you know, given how central this issue is of the lack of reliable biomarkers to base patient selection on for trials, you know, how do we choose which patients to offer any of these immunologic treatments to? Because clearly, they are being used off-label, you know, not that frequently in some cases. So, if it is going to be used before we have adequate evidence, you know, how do we choose who to give it to? That was a really difficult question. We are actually looking into doing an LCT ourself, and we have been discussing it for so long.
There are, as we also highlighted, and as you presented before, and thank you so much for the really, really impressive presentation of the article, there are some biomarkers which could be promising, but we still find it really, really difficult. So, I'm actually not sure still how to choose patients. We're considering looking at the autoimmune diseases, the presence of autoantibodies, but we're still not, yeah, we're still not sure.
Do you have any suggestions, Kilian? I think it's partly actually in the article, right? That's why we came out with this whole idea of actually also biobanking and doing multiomic studies and all this, because we don't really know what to look at. And so, I think actually the most important part would be, now you've mentioned it several times, that we do have super heterogeneous cohorts when looking at that. So, even if you did an RCT in just a well-defined three losses, let's say they are consecutive and you have a cutoff for a biochemical loss and go from there, then you would probably do a better RCT than most of the RCTs that are out there.
To be completely honest, still based on very clinical criteria, if you then also for the outcome collect the pregnancy tissue or do an IPT testing for the product of conception, then you even lift it to another level, because at least then we know more about the outcome and about the patients included. And I mean, what we have as a biomarker then on the other side, I think that's actually almost the next story. Ruth, do you have something to add to that? I think, right, this is a challenge.
In my practice and in a lot of the ways I think about patients with repeat pregnancy loss, what we're calling unexplained is really missing half the story. So, I would really do whatever we could to isolate this to euploid pregnancy loss. So, whenever possible, we obviously know that immune therapy will not prevent an aneuploid loss.
And so, there are some patients where we have that information. What can we do to reduce euploid pregnancy loss and kind of enrich our patient population for those at highest risk for euploid pregnancy loss? And ultimately, it is somewhat those patients who have had one or more euploid loss in the past. So, that would be in the absence of reliable biomarkers, that's the outcome we're trying to prevent.
So, maybe that is the population we should start focusing on. That's just one approach. Absent the miscarriage genetic testing, you know, I agree with what some of the previous more successful studies have shown, which is that looking just purely at number of losses is kind of a surrogate marker of euploidy, because some really elegant studies have shown that separate from age, which is obviously a risk for aneuploidy, when controlling for age, as the number of losses increases, the likelihood that that loss is euploid also starts to increase.
So, again, targeting what we're trying to prevent with this therapy, we are trying to prevent euploid pregnancy loss. So, at any way, we could focus and design our studies around enriching our outcomes for that outcome, powering our studies to that outcome, and looking at those patients based on any factors that we have that are most risk for euploid loss. And that ties really nicely into the next question about kind of study design and how should we prioritize as a field, right? And Kilian touched upon this, and I acknowledge that this is also not an easy question to answer, not a softball question.
The need, and the authors highlighted this, the need for both development of reliable biomarkers for patient selection is just as important as the need for high-quality randomized controlled trials for immunotherapy. So, being mindful of funding limitations, resource allocation, what should we prioritize? Development of reliable biomarkers or immunotherapies? And you can't answer both. Yes, you can somehow, and that again comes a little bit into, I mean, if you have a well-defined cohort, right, and you do agree on a treatment you want to try in that cohort, and you do integrate this with the biobanking, with the methods we have now, we can actually test hundreds of proteins at the same time, right? It's not that you have to use them for inclusion, but you can also do that, that you collect the samples and do analysis upon these samples after you've included on your well-restricted inclusion criteria.
And that's, I think, the way to move forward, because it is difficult enough to actually collect these cohorts and to include the patients. I mean, the second trial on Plaquenil, that's a study from us, and we agreed on, or the protocol is set up on four losses, four or more losses, and that actually kind of diminishes the amount of patients you can include that you have in your clinic, right? And that actually makes it very hard to include. So I think the first, most important part is actually to define your patient population, and then the biomarker, we've been talking about biomarkers for the whole past of publishing about reproductive immunology, so I think the most important part would be to have your study cohort set up.
Yeah, I think the biomarkers are critical. Right now, the best marker we have is number of losses, and it doesn't feel good as a clinician to say, oh, you haven't had enough losses to be eligible for this treatment. Imagine feeling that as a patient.
We don't like to say that. Well, whoa, I have to have four losses before I have it. But I also would love a biomarker that would help differentiate high risk from low risk for miscarriage, because one of the mainstays of the counseling of a patient with recurrent pregnancy loss is that many patients with lower number of losses have an excellent prognosis without any of these therapies.
And if we had a way to tell someone that based on these biomarkers, you are not eligible because your odds are so good without them, we can't beat your odds with any treatment we have, that is also very empowering. We know that you don't need it. That's as important as knowing that you do need it.
And so for me, picking the right patients, giving more individualized prognostic information to patients, you do have a good prognosis of success without these treatments, is a really important part of what we do. Selecting who does need it, but also selecting who doesn't need it, and who will have a high chance of success without any of these treatments. So that's the other side of it, that there are people who don't need these as well.
So I'm curious, because a lot of the word that's been used commonly in today's discussion is heterogeneity. And not only the studies involving all these biomarkers and possible tests, but there's heterogeneity in what physicians are recommending patients to do as well, which makes it difficult to counsel a patient who has talked to multiple providers as well. So how do you all grapple with that and handle the patient who's really insistent on wanting to do certain interventions that just don't really have the data to support it and may in fact be dangerous? Probably easier in Denmark than here, or maybe not.
We might have more heterogeneity. I'm hoping that our bioinformatics colleagues will be able to help us sort through this heterogeneity a little bit better, sort of the nature's randomization protocol, which is that randomly people get treatments A or B without any rationale at all. And if we can leverage our EMRs or our big data that we have, is there any hints that we can glean by using, you know, kind of this large unselected EMR data? So that's sort of a call to action if there is somebody out there who is good with, you know, building that algorithm, looking at messy data, cutting through the variants and the heterogeneity.
There are statistical ways to do this. And in some other fields, you know, prematurity or, you know, other complex disorders and outcomes, we have been able to glean some hints from just dissecting this out in the machine learning, you know, bioinformatics approach with that messy data. So I really hope that, you know, not that I want people to be, you know, guinea pigs, but I hope that if we can learn from, you know, the nature's randomness that happens in a field of well-meaning doctors and patients who are willing to try anything to get pregnant and have a baby, that maybe there will be some way to distill that data down to have some learning points.
On the theme of study design, we wanted to ask the authors, you know, when we're implementing these immunotherapies and hoping and looking forward to the randomized controlled trials on the horizon, would you suggest focusing more on implementation timing in the preconception or the post-conception window? Well, I think that's a tough one. But because, of course, when you focus on the preconception as well, you do also treat for a relatively long time in patients trying to conceive. There are some data in the IVIG data, for example, where you kind of, especially in the IVF patients, of course, it's easier, right? Because, you know, when the transfer happens, so they get some infusions before the transfer.
So that's kind of an easier window of opportunity there. But, I mean, there have been discussions about progesterone as well, like when to start progesterone. If you would do it in an RPO cohort, would you do it with a positive pregnancy test? Would you do it in the luteal phase to support that if you have a luteal phase defect there? And I think it kind of goes down to the same question.
What are we actually expecting as being the issue here? Is it implantation or is it the pregnancy development that goes on after that? And the other thing is, which drug are we talking about? So we do know from hydroxychloroquine that it does need some time until you have kind of the right levels, which we don't have in other treatments. So I think there's kind of this balancing on what are we actually looking at, and you can't just say it always has to be pre-implantation. And the cost, right? The cost matters as well.
Of course. And that's why progesterone and baby aspirin is easy to try. They are not expensive, but IVIG or other medications are more toxic.
Exactly. And same goes for prednisolone, right? That's why it's so widely used. I mean, that's what we see at least from the private market as well.
Nearly every patient coming in from private has heparin, prednisolone, and aspirin on his list. There were a lot of questions from the audience specifically about IVIG. So something that I personally, I wouldn't even know how to go about getting it.
So that goes to show I never discussed it in my practice, but there was questions about the specific congenital anomalies that came across. Do you all recall what those were? There were questions about that and also the dosing of the IVIG administration. I'm not sure if you have the information from your study.
I actually don't recall. I just... For the IVIG dosage, just to quickly answer that question. In the double blind RCT that was highlighted for unexplained pregnancy loss and then four more unexplained, they used high dose IVIG.
So 400 milligrams per kilogram per day for five days and repeated treatment. No, but I think they asked what kind of malformations, right? Those questions were asked. Okay.
I mean, I saw one of the studies, they saw a lot more malformations in the group receiving IVIG, but the authors stated that it was because these were probably someone who was lost in the placebo group, would have been lost in the placebo group. So it was not, they argued that it was not the IVIG, but a fetus that for some way, IVIG could save it, but yeah. So it's difficult to say, but I don't recall the exact malformations.
I think you can find it. I also just want to put it to mind that the studies finding the meta analysis you were referring to before, where they use biomarkers to identify patients to include and that showed there was a significant improve in the BR with IVIG, they didn't include the randomized control trials, but observational studies just to, yeah. And also just to mention, I mean, all the things we've discussed about heterogeneity, but also about small sample sizes, right? In all these groups.
So all the discussions about anomalies and malformation and everything, I think we have to be very careful about that. Because they are underpowered for the primary outcome they are measuring, but they are for sure underpowered for the secondary outcome of malformations and safety. So I think that's really, really important to keep in mind.
Yeah, absolutely. That's a great point. All right, fellas, what was the next question you all had on your list? You guys had a great list of questions.
We have many more. Yeah. So obviously, you know, halfway through fellowship, and I have some perspective on this myself, but I'll ask the experienced folks in the room.
For purposes of determining efficacy, we know that it's best to use a treatment in isolation. But for the purposes of improving outcomes, and Dr. Lahti, I know you alluded to this earlier, patients are just desperate to try anything and everything that we would offer to them. Well, we often almost always, especially in reviewing these manuscripts, see that these treatments are always nearly given in combination with each other.
How would we suggest balancing this? And maybe not saying discipline being the right word, but how do we kind of, you know, tailor our need to better understand these therapies and how they work and how they work isolated from another versus meeting the needs of our patients, knowing what the data is? I just think it's actually, I wouldn't recommend to offer them a mix of many different treatments, if you have no studies showing that could actually improve the outcome. So if you have no evidence at all, I think that's a great argument saying that then maybe I would try one of the most promising candidates, and then we can actually learn from it. Because if you treat with one treatment option, and you record the data outcome, and you actually see the live birth rates, and maybe we can combine with other data sources and actually gain more knowledge.
And I think that the argument that they're desperate to try everything. I have also met these patients who received like seven different drugs, but we still don't know if any of them work, and they could probably have severe side effects. And some of them could even cause a loss.
So I think we should be careful with giving them many different things we think theoretically could improve the outcome without referring to any previous data would be my view. Yeah, and I think also, I mean, it's they are desperate, and they would do everything. But I think if you take the time, explain what it's about, why you do this, and then I think they are, or that's what I see in our clinic every day, that then they are also willing to participate in those studies.
I think the biggest issue is actually that people are not taking the time actually explaining what it is all about. What are the odds? What are the chances? Just as Ruth said, also, what are the chances of getting pregnant with a healthy healthy kid, because they sit in your practice, and they would probably guess that they have a chance of 5% for a healthy baby. And that is definitely not the case.
And once you kind of get into that discussion, and say, but you do have also an RCT, because these RCTs are usually placebo controlled, right? So they have a 50-50 chance of actually getting nothing, right? So I think that's actually this desperate part. That's something that we can actually switch into a motivational part also for them to participate in studies. And that's a great thing if you consider other specialties in medicine, that we actually have patients that are so willing to participate in studies.
Yeah, very good point. So we have time for maybe one, maybe two more questions, if you guys want to prioritize which ones you want to ask our authors before we run out of time today. I can ask a question.
And just a reminder, we are talking about unexplained RPL. When we think it's euploid loss or it's confirmed euploid loss, no antiphospholipid syndrome, uterus is great, hormones are great, no genetic issue, right? So given the lack of evidence in almost any of these directions that we are trying to do for evaluation treatment of unexplained RPL, what do you guys and probably I would want answer from everyone, personally think we should focus on in terms of treatment. If there will be one treatment you have money and resources and time to focus on, what would you choose? Right now, we are changing a lot of patients to receive treatment with tacrolimus, but again, we still don't know much about the drug, but we try to study more to actually follow the patients and to compare them with patients receiving other kinds of treatments or no treatments to learn more.
So hopefully we'll learn more from that source. But that's also because I don't think we have many other good candidates right now. Yeah.
And I think it's important. So I've worked in Germany and Austria and now I'm in Denmark and Denmark has a way more restrictive medical system. So that makes it, as Ruth said earlier, makes it sometimes even a little bit easier because you just also cannot offer everything.
But at the same time, I do think that it's also okay to tell patients that there is no evidence to do something and to inform them, get them on board. And we do not have to have to treat every unexplained RPL patients with a relatively good prognosis, right? I think it's also about, just like I said, about explaining and then basically I think what you can do in a study, do it. And I wouldn't start with the most difficult, most expensive drug, which is why we chose to get a little bit more used to tacrolimus.
But we come from a clinic now here in Copenhagen that has kind of a history of giving IVIG and we almost completely stopped with that. So I think there is also a transition, the more and more we know about euploidy that was very, very difficult to find out earlier and that we're getting better and better in actually having in our patients and having more things in our hand. Yeah.
If you just had three previous pregnancy losses, most often you're just followed with tender love and care. And that can also mean a lot for the patients because they're actually met, they're followed and they're taken care of. And as Julian said, most of these patients will have a baby in the next pregnancy, even without treatment, medical treatment.
I would say if there's time, if I had one treatment to study more or better, I think I would probably dig into progesterone actually. Progesterone is nature's immunomodulin. It is what a woman's body is making to prepare her body for pregnancy.
And it does have immune properties. So studying that further, what's the optimal route, timing, doses, are there people who do and don't respond to progesterone? So I think there's more to be done with progesterone itself. And that's something that we know is safe.
The heterogeneity is the timing and the route and the dosage that we've seen. Maybe we just haven't quite optimized that for every patient or individualized it for every patient. And I think the other thing that I would love to see is that there's a lot of ways to decrease inflammation in the body.
Are there lifestyle factors, environmental toxins, diet, and other ways to reduce inflammation other than these really powerful immunosuppressants that have many off-target effects? So I don't know. That's where in my practice where I focus a lot of my time and energy on the tender loving care, using what we know works, keep counseling with confidence and support, and ensuring that those patients that do have a good prognosis know it and are supported without fear to try again. And then really isolating those highest risk patients for these potentially harmful, expensive, and off-label treatments.
And I think that's actually a very nice point. And I think that should also kind of be the bottom line for this whole RPL discussion, that in the end, it's a lot about meeting the patient and getting them into the clinic, explaining about the risk factors in general, and not kind of throwing medicine at them all the time. Not everyone has to go out and receive a medication, actually, but if they received advice, I think that's already a lot.
Yeah, absolutely. Very well said. I was about to ask if you all had any closing remarks, but you kind of segued into that for me, Kilian.
So the other authors or participants, any other closing remarks? This is a very, as you all know, very hot topic. We could talk on this subject for a very long time. I really, really appreciate the many questions sent to us from the audience.
I wish we could address all of them. As I'm talking, they're still coming in. So I'm sorry we couldn't get to all of them.
But with the time that we're allotted, just wanted to ask if you guys had any other closing remarks before we wrap up today. I just appreciate the collaboration across the globe. Thank you guys for meeting us on our time zone this time.
I guess we owe you a midnight meeting on our time. But thank you so much. And for all the work that you're doing in your center, look forward to seeing the outcome of your studies.
Thank you very much, Ruth. Thank you. Yeah, absolutely.
Have a nice day. Yeah. And to our fellows, thank you so much for summarizing very nicely and eloquently.
Again, as Ruth said, thank you all so much for joining us. And despite the time zone being with us today, I'm sure you can see my very bright and sunny background behind me. So I'm sure it looks a little different where you're at now.
But we appreciate it. Thank you for everyone who's attended. This is probably one of the most highest attended journal club globals that I've seen.
It's almost 170 participants. So that's really great. But anyways, hope you guys have a great rest of your day.
And we'll talk to you all soon. Thank you. Bye.
Bye.
