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So our next session is going to begin with Professor Alex Hazel and Alex is a professor of obstetrics at University of Manchester and a consultant obstetrician at Manchester University NHS Foundation Trust. He's the director of the Tommy Stillbirth Research Center. And as such, he's given clinical advice and guidance to obstetricians in Northern Ireland, looking after couples experiencing stillbirth. And one of those um colleagues is going to be part of his presentation today. Um His research focuses on the placenta and his talk today is entitled Chronic Histiocytic Interval, asciis and other recurrent placental lesions. Perfect. So, hi, everyone. My name is Kiara Daly. I'm a consultant at the Ulster Hospital. And thank you to Alex for inviting me to present a local case of chronic histiocytic intervillositis and how we managed a subsequent pregnancy. I'm very happy and delighted to welcome the patient at the center of the case to join us at the conference today to hear the presentation and the expert discussion. So this is how it came about. I was contacted by email um through our bereavement midwives uh that the patient was coming to book on the Fourth of May and that she would be 12 weeks pregnant. At that time, Missus C had suffered a fetal loss previously at um 21 weeks gestation of BBS and then had had a five week miscarriage. Following that at her debrief, a medication regime had been proposed and she had questions about the medication and about care for the condition. So I hadn't managed chronic histiocytic intervillositis case before and I wanted to um get more about the background on the patient and then seek an expert opinion. So, um a 37 year old para naught plus two and in 2021 had a 21 week fetal loss. She had attended with vaginal bleeding and ruptured membranes. And subsequently, there was no fetal heartbeat, swabs were positive for group B strep and this was also isolated in a midstream specimen of urine. She underwent medical management and delivered a baby boy whose birth weight was on the 93rd centile. The postmortem came back with chronic histiocytic intervillositis and high grade fetal vascular malformation around this time. Um we were coming out of the COVID pandemic and COVID was still circulating um which has been linked to chi I however, all investigations of postmortem and for the mom were negative for COVID-19. A subsequent thrombophilia screen had also been negative and then um there was a five week uh miscarriage in 2022 with regards to other history BMI was normal at 24 nonsmoker and no other really significant past medical history. So M BBS is post mortem placenta, weight was around the 10th centile. Um The histological examination did show uh patchy chronic histiocytic interval, asciis of the high grade fetal vascular mal perfusion uh which were thought to be the likely cause of um fetal loss. And it just detailed that it was a rare condition. It usually represents a host versus graft reaction that has been linked to COVID-19 but that this was negative in this case. Um And that it's associated with um intrauterine death recurrent loss, fetal growth restriction. Its estimated recurrence is 70 to 100%. So, having looked at this, I decided and the patient previously requested expert opinion. And so having spoken to a colleague, I emailed um Professor Hazel and um I had advice that they're very, he was very responsive to um taking advice. And even that evening after the email, I had a response. Um and he was advising that the treatment regime they're looking at is aspirin 100 and 50 mg at night, low molecular weight heparin and a prophylactic dose prednisoLONE, 20 mg once a day, hydroxychloroquine, an antimalarial 200 mg twice a day. And these should start from six weeks then to do a uterine artery Doppler fetal size and placental morphology at 17 weeks. And if that was normal, weaning down the prednisoLONE by 5 mg per day a week at a time, if all is going well to scan really every three weeks. Um And then every two weeks from 34 weeks and offer birth from 38 weeks, I had read um the paper by Prof Heel. Um and it hadn't showed a significant difference but um positive a trend towards um an advantage with the regime. And actually, he had now treated over 60 pregnancies with only three per outcomes. So that provided more reassurance for continuing with the drug regime and also to refer for consultation um and that we could have a joint team's appointment. So um for the sea booking visit, I was actually on leave that day, but I did a prebooking telephone conversation to relay this information in advance because we were already at around 1112 weeks of pregnancy and we discussed the plan as per prof heel. Um looking at the medications, the evidence for the potential side effects. I worked with the maternity pharmacist to have the medications available at the booking clinic for collection and then we would meet them face to face um at 14 weeks. So at the booking visit, um dates were in keeping with scan, we went ahead with the plan as per prof and additionally added folic acid and progesterone twice a day. And this was because it wasn't clear from the previous loss whether cervical incompetence was a factor as well. So we added that in with cervical lengths every two weeks. We planned a fetal medicine referral at the 17 weeks and a glucose tolerance test um as that has been associated with fetal vascular malperfusion. Um I also completed an extra contractual referral form and this was sent to um the S PPG who came back a week later to say that's fine to send any invoicing for this rare condition to them. So, in the antenatal clinic visits, MRS C was seen every two weeks really because we were doing the cervical lengths initially. And additionally, because um my clinic is alternate weeks. Um It was important to provide the continuity of care and particularly for this um woman to have um regular follow up. So all was going well, cervical lengths were long. Um A fetal medicine review, placental morphology was normal and we weaned down the prednisoLONE. Um The anomaly scan was normal by 22 weeks, we had stopped prednisoLONE. A swab test was treated um for yeast. And then at 24 weeks, we had a teams meeting with pros and this was really very useful to um discuss the woman's questions and just to have reassurance more about using the medication regime, we discussed that we had started the medications at 12 weeks. Um But the recommendation had been six weeks and overall, this was felt unlikely to have made any significant difference to outcome that yes, the treatment is experimental overall. But more research is coming to show positivity for it that we'd stop prednisoLONE at 17 weeks as placental transfer to baby can occur. Um but hydroxychlor chloroquine would continue in the background um for immune modulation that a recent systematic review on hydroxychloroquine in pregnancy had shown that it appears to be safe. And just to remember to use SPF when using it as there's a risk of photosensitivity that it was safe and we would recommend continue with vaccines in pregnancy. The normal growth of baby at this stage is reassuring. However, baby s's growth was actually on the 93rd centile um with Chi I, um although the placenta was on the 10th centile, we discussed that Chi in this case, had been patchy on the placenta that not all of the placenta sampled during testing. So this would still be a significant finding that there was no COVID placentitis. And additionally, that if growth was slowing, that wouldn't, we wouldn't be overly reassured by any normal Doppler and there would probably be more of a preference towards delivering. Um but to contact with any concerns. So aiming for a delivery between 37 and 38 weeks, the fall was normal and to send the placenta for histopathology in the third trimester growth was normal. Progesterone was stopped. Um At 26 weeks, baby was transverse. Um The first um complaint with reduced movements occurred less in 10 but then came back to normal. And um our CG advice was was given at 28 weeks, baby was breached, growth was normal. There was just a mild elevation in liver function which subsequently returned to normal. And we planned and discussed mode of delivery which is going to be by elective cesarean birth at 37 weeks and three days. The baby was noted to have increased growth velocity going from the 50th up to 80th cent high. But with normal, like her at 34 weeks, growth had really increased again to greater than the 95th centile. A repeat lupus tolerance test was negative at 35 weeks, there was a second um episode of reduced movements but um assessment with CTG was all normal. At 36 weeks, um growth had went from the 95th just down to the 90th, but again, a healthy environment. So at this stage, I just planned for one extra review in E ou as we're coming up to the due date. At that review, the CTG was normal. The Doppler actually showed a low P I and ri but normal like her um and no um high resistance in the placenta Mrs C had started to have tightenings 1 to 2 and 10. And overall at this stage, we decided to go ahead and expedite birth that evening. The um we could not facilitate delivery due to work load. Um So we planned for it really in the morning time, it was reviewed by the overnight registrar with the tightenings. These were short able to breathe through. There was a repeat Doppler which was entirely normal and CTG was normal. Um And we went ahead with planned for delivery in the morning. So the next day, um delivery by Cesarean baby girl extended breech um good size baby 97.7 centile. It was normal. Apgars. Um Postnatally, the baby was well had a, an ultrasound because of breech position was normal. There was a sacral dimple that was followed up. Um But that again, um was all normal on follow up and the placenta was sent for histopathology. So, what did we find no recurrence of chronic histiocytic intervillositis. Um There was some focally increased in side knots and a stage one basal plate, myometrial fibers. The knots can reflect a degree of oxidative stress but probably not clinically significant. Given that the baby was very well grown with a normal placental weight, there was variable villous maturation um but no diffuse villous maturation. And um the the myometrial fibers can be associated with placenta accreta, but there was no um history or anything relevant for accreta in this case. So overall, we found no recurrence of chi. Um we found a large baby with negative um glucose tolerance test and having discussed it again, we felt that in subsequent pregnancy we would still follow the same management regime. Thank you. Thank you so much um carer. Um And oh, there we go. So um one of the things um that um that has actually been really helpful. We just reflecting on the first session about having specialist services is that um instead of seeing one in 5000 to 1 in 10,000 cases, which is the incidence of c we got referred loads of people that various had various complexities of history. And we began to see more and more of the, and you see patterns because, you know, if you think most of what we do in medicine and clinically is pattern recognition, um and you've got to have the people lined up in front of you to be able to see the patterns because if they're all just distributed amongst a great big sea of people who have pregnancy loss, you just never see them. Um And we established um our pregnancy after last clinic about um 12 years ago now. Um and um we got a handful of people who had two or three losses late in pregnancy, had devastating pregnancy histories and they all had c now one of the sad things that unified them is in their first one or two losses. They'd encountered people who the, the pathology reports quite clearly said they had chi but um they had been told that, don't worry, lightning can't start twice if you take nothing else in this talk today. If you see C on a placenta pathology report, do not say to the patient that lightning can't strike twice because it has an extraordinarily high chance of recurrence and it will strike twice. So what is C well in the good tradition of medical nomenclature. The the cells that are involved histiocytes and macrophages are two words for exactly the same thing. Um So histiocytic just means it involves macrophages. So you can see it's macrophages in the intervillar space are here because they can be quite difficult to see. Here are your placental villa. They're like roots of a tree and then you've got your Intervillar space, that space you where the maternal blood is. And in Chr, you can see here this is a CD 68 stain. It stains at macrophages that Intervillar space is absolutely obliterated by macrophages. Um Now, um we know it's very strongly treated with stillbirth um with miscarriage. So particularly second trimester, miscarriage, um fetal growth restriction and or whether the placenta has forgotten to hide, we just don't know. And it's a very difficult thing to work out. But you can see there's a whole variety of different things that have been reported in C. So there's increased complement deposition which is related to antibody immune response. You can have more fibrin that isn't a universal finding. Um But you can have more um t cells and other immune cells that then just stimulate this response. So you have a breakdown in immune tolerance. The only important take home message is that if you have a breakdown in immune tolerance, you will have that in every single pregnancy, it will just keep happening. You don't have a breakdown in immune tolerance in one pregnancy and then it's all, it's a bit like, you know, if you've become sensit to Teresa disease, you don't just have an TD in that pregnancy and then you're all right after that, it's, it's there. So we think there's this, that was our hypothesis. So, what we then did is um, to try and actually put some numbers to that. And so we, you can see here, um, macrophages have got a stain called CD 68 and in the middle bar in the index c pregnant, you can see there's way more macrophages in chi than there is in healthy normal pregnancies. And then in subsequent pregnancies with treatment, they fall back down to baseline. Um Fibrin is a bit more variable. You see quite a lot of fibrin in just normal healthy pregnancies. You have to be very careful with perilous fibrin. You can see there is more of it here in the middle and the subsequent pregnancy, it falls back down to the same medium before. But you can see it's very varied. There are also more T cells in CD. Um and more fox P three cells, the T regulatory cells. There we go. Now, when we want it to try and get a treatment. So we've characterized what it looks like in, in vivo and said, you know, there's more macrophages. So we then started scratching our heads and well, what do we give mums? What could we treat this? With. And so we were very lucky that we had a specialist antenatal clinic for women who had lupus and autoimmune disease. So we spoke to our rheumatology colleagues and they said, you know, this sounds a lot like active lupus and we know that active lupus has bad outcomes in pregnancy. And so they said, if I were you, I'd give these women the drugs that we give to women who have active lupus. And we thought, well, that sounds good because you've obviously given that to those women in pregnancy, they've had babies. Let's try that. So then we went into the lab. Now, um I've spent a sad amount of my life culturing bits of placental tissue in laboratories. Um It keeps me out of mischief. Um But it's a useful way to give us some preliminary evidence about what a drug does to the placenta. Does it do what we want? Um So there's lots and lots of grass here, but essentially, um what we're able to see is if you produce an insult into the placenta. Uh but then you give hydroxychloroquine. Um Actually, what we saw was that the synthetic trophoblast layer, the outside of the placenta that transfers all the nutrients to the baby was more likely to be intact. Um And there were fewer um apoptotic it when we induced apasis. Oh, sorry, when you induced hydroxychloroquine reduced that background back down to background levels. And in addition, hydroxychloroquine also, um actually slightly increased um anti anti inflammatory interleukin 10. So it seemed to be doing something to our placental tissue in the lab. So we thought, OK, that's um that's encouraging. So we then tried giving um er more hydroxychloroquine to mums who had ch I, so if you look over here on this now, if you ever publish in frontier in medicine, they make you do graphs in completely mad colors to help people that are visually impaired um and like stripes and all sorts like this journal policy. So I haven't sort of had a like hallucinogenic moment on the left hand side of the slide. Um So the first thing so in the index pregnancies, these are the mums who had initially been referred to us with Chi. And you can see that actually some of these mums were already on aspirin and some of them were already on aspirin and low molecular heparin I am. And when we were beginning to see what happened in subsequent pregnancies, you can see there were some mums because it was experimental said I don't want any treatment at all because I don't want to be in in your mad experiment. Professor Hazel, which is absolutely fine. Some had aspirin, some had aspirin and low molecular heparin. Some had aspirin hydroxychloroquine and low electro heparin. And then the stripy bit that looks like a, a sort of school tie is the sort of quadruple therapy where they had aspirin hydroxychloroquine la electro heparin and prednisoLONE, which is the combination that carer just told you about. Um So what we found um is that so overall, about two thirds of our, of subsequent pregnancies were treated with one im immunomodulatory agent say prednisoLONE or hydroxychloroquine. Um And you can see on the left hand column here c was associated with significant pathology. Only 11% of infants were live born when we diagnosed c in the placenta. And that's very consistent with other prior samples, mostly stillbirths, some terminations of pregnancy and then some neonatal deaths and the neonatal deaths were often in babies that didn't attain a survivable birth weight. Um We had uh thankfully much higher rates of live births in the subsequent pregnancies. And by the time you get to second subsequent pregnancy, everybody had, had um a live birth. Um In particular, the rates of fetal growth restriction also decreased. Um Interestingly what we, what we saw was when you had immunomodulatory treatment, there was much either the severity of the chi got less or it disappeared entirely, but only when you had immunomodulatory treatment. Um It well, much more frequently. So um and where the severity of the lesions got better, the live birth rate went up. So what we now need to do is to do this on our up to date cohort um cause we've now almost doubled these numbers and I think we would get a much clearer picture now. Oh, that was this has done it in the wrong order. So then what we wanted to do was to look at inflammatory markers. So we looked at serum from pregnant women who were treated after C um and serum from healthy pregnant women to try and understand whether we can get a test to under to help us see about the severity of CH I. So there were some inflammatory markers. So interleukin eight, interleukin 31 um interleukin 21 and oh, which one was that one? Interleukin 21? Sorry, in 22 and in 21 were different. So interleukin eight is a pro inflammatory cytokine that's made in macrophages. So it kind of makes sense that in the subsequent pregnancy that goes up a little bit interestingly in all of these subsequent pregnancies, actually, the other markers all fell and they have various different roles. But it could well be that actually it's the treatment that's reducing um that phenotype clearly because we can't diagnose chi I in the index pregnancy, we can't get the blood tests. We really, really want to get which are the mums who are affected, but we don't know they're affected until the pathologists told us. So we can't, we'd have to take a lot of blood off. A lot of people. Um to get that there are studies that propose that placental alkaline phosphatase might be a good marker. So we're all used to seeing alkaline phosphatase levels in pregnancy that are above those, you know, normally comes back high on the normal range. So there's different isoforms in pregnancy. It's largely high because of the placental isoform. But also because bone turnover is higher when you're pregnant, actually seeing your bone isoforms higher as well. So we didn't actually see any evidence, any relationship at all between placental alkaline phosphatase and outcome or the degree of macrophage infiltration. So you can see actually the levels of placental alkaline phosphatase in controls and c pregnancies were identical. They go up as you get more placental mass. So as pregnancy continues and there was no relationship with the CD 68. So I'm afraid, although there's some nice ideas on the internet, I don't think placental alkaline phosphatase is going to help us. So, um I'm now just gonna leave ci behind just a little bit and just think a bit about subsequent pregnancies in general. So, um this was a report from from Rainbow Clinic where we looked at 266 months in which we had the um initial, all of the information, including the placental pathology from the index loss. And then we knew what the outcome was in their subsequent pregnancy. So we had 266 women, a quarter of them had an adverse outcome. And that is consistent across pretty much across every study of subsequent pregnancy that I've read in high income countries. The risk factors for having an increased risk of adverse outcome were women who had pre existing medical conditions, women who continued to smoke which was really rare. Um Interestingly, however, we chose to classify the stillbirth or the gestation of stillbirth did not alter the risk of what happened in a subsequent pregnancy at all. But what did alter the risk of recurrence was what's going on in the placenta? So, actually, we, we really have got to prioritize getting placental tissue and I would extend that to mid trimester losses as well. Um because things like c tends to be a mid trimester, early third trimester loss phenomenon. If we're not sending tissue, that's f for a 1516 week loss, you're not gonna see it. The lesions that we saw were recurrent with stillbirth were maternal vascular malperfusion, fetal vascular malperfusion and chorioamnionitis. So there's obviously different causes there, but they are all recurrent and you can just see in terms of overlap, all of the lesions at the bottom had a significant proportion where they occurred in both the index and the subsequent pregnancy. So it was not a universal thing. It doesn't mean it's definitely going to happen again. But there's a high proportion where you see the lesions in both. So what we've been trying to do in Manchester is to try and decode the placentas a bit. And I'm trying to put together this clinical placental pathology tool so that when we read a pathology report and there's the features in the left hand column, we then group them together into clinically useful categories. We can then think about what other additional investigations we need to do. We can tell the mum and family how likely it is to come back and what we might do. So this example is maternal vascular malperfusion. So you might see a small placenta infarcts, distal vous hyperplasia, excessive syncytial knots. And these are all beautifully artistic terms. I think that to us, mere clinicians are usually pretty meaningless, um particularly syncytial knots, which are a favorite little placental feature of mine because they're not a knot, they're just a group of dead nuclei. There's nothing knotty about them really. It's just what somebody called them once and it's stuck. So the key thing is it's maternal vascular malperfusion. So you can tell the mum that this is because there's less blood flow from your side of the placenta. What we need to do is to see that you haven't got a thrombophilia. There's a reasonably high chance it could recur. We want to give you some aspirin 100 and 50 mg once a day at night. And if you've got a thrombophilia, we're gonna give you low molecular heparin. So these are just some examples. There's a great big infarct and loads of perillus fibrin. This is another infarct here. Um This is exaggerated since or knots. They, they are these little purple blobs of lots of nuclei and uh V UE is something that again, have people seen V UE on a report? So people, there's people think that this is immune. I think it probably isn't actually. So this is macrophages in the placental villi. And do you remember, I said one of the jobs of macrophages is to clean up when there's been a toxic insult and all the cells are dying. I think this is the, this is the placenta trying to right itself. So if you kill the placenta because you make it hypoxic, it tries to sort itself out and it sorts itself out with macrophages. So that's what I think is going on there. So, again, thrombophilia screen, make sure that it's um uh we check all of those things again, quite likely to recur, we would only give aspirin 100 and 50 mgs once a day for this and low electrolyte heparin if there is a thrombophilia. So they don't need um they don't need um uh any sort of immunomodulatory drugs. And then lastly massive perilous fibrin deposition, which is like like maternal vascular malperfusion on steroids. It's just the whole of the intervillous space has just become a great big blob of fibrin um quite strongly associated with maternal antiphospholipid antibody syndrome. So you should always check them a very high risk of recurrence. And in these mums, we do give aspirin and low electrolyte heparin even if they test negative. Um and that's massive perils fibrin deposition here with the villa and they're just sort of floating in a sea of pink fibrin. So um I think hopefully, um one of the take home messages from this is that we must ensure that we send the placenta after a perinatal death. Um ideally try and take the results we're getting from the pathologist and make sure we get a clinic, a pathological correlation and the really good pathologists will help us with that. And I think that actually the pathology reports that carer showed us were really super helpful in that regard. C is one example of a highly recurrent placental condition. One of the things that makes it unique is it requires some form of anti inflammatory treatment. Um We know that other things like Vue um and maternal vascular malperfusion also recur but they don't need anti inflammatory medication. And I think one of the challenges, this is more of a challenge than a place where I chose to leave the talk is how can we get better information than we have now? Because it's really hard I think to what we really want is lovely, randomized controlled trial evidence that we can have that enables um us to counsel women really well. And at the moment, I have to preface all of my because I'm an honest human being, I preface all of my consultations with, it might be nothing to do with this medication. It might be something to do with the medication. This at the moment is the best thing that I think we've got available, but I might be wrong and there's absolutely no, you know, sadly, there have been three months with whom it hasn't worked and they must have a different, something else about their immune system that those drugs aren't working. It's really hard because there are other people out there in the bigger world who will say this is absolutely what you should have. Um, and we can't be that absolute, it's a really dangerous game to be playing. So I think one of the things that would be really interesting to, to, to think about in the rest of the meeting as well is how do we get the sort of level of evidence in these really high risk pregnancies that we want? It's a really tricky. It's not a, it's not an easy answer. Um, I just really wanted to very quickly. Um, thank Chloe, who was my phd student and now post do who's led most of the chi work. Um, Ian, who was my phd supervisor, but a great, um, reproductive immunologist and placental biologist. Um, he sadly passed away at the beginning in August 2022 and Christopher Reeves, he did all the placental alkaline phosphatase work. Um, so thank you very much, um, for your attention. Did that go off for a reason? Ok. Fantastic. Thank you very much to, uh, Kira to Alex and to Rachel. I think we can all agree. Those were two really fascinating uh talks from two very different angles. Um I personally, I, I'm a bit aware, I'm standing close to you and I'm a doctor and you obviously have. But um I think there's such a role for this. I think it's a fantastic, fantastic thing. And as you said, and II said earlier, so much of this is not complex, it is compassion, it's continuity of care, it's taking time to listen to people and, and thank you for sharing that with us. It was really, really helpful, Alex, could I ask you? And is Kira still here? Do you want to come back up to the front? Um We do have a few questions. Um If you don't mind, I'm gonna go to the online audience first and then we'll um give an opportunity for uh our audience to ask in the room. So, um Alex, thank you for your talk and for seeing some women from Northern Ireland from Kevin Black and I often see F BM and placental histopathology, but the pathologist often suggests this is sporadic with low recurrence risk. Did you say it does tend to recur? Um So we do see a recurrence of EFM. Um Now, one of the problems with fetal vascular malperfusion. So, um so if you imagine your fetal vascular tree, um fetal vascular malperfusion is this side of the fetal vascular tree is, is not there anymore. And one of the challenges of that is that can come about because the baby's died. Because when obviously, when the baby's died, the fetal circulation collapses. And then if there's an interval, actually, those capillaries regress. So you get those sort of appearances of fetal vasal perfusion, you can get them with prolonged in utero retention. Um And then there's a list about as long as my arm of other things that are associated with it. So it's actually probably the least specific of any placental lesion in terms of its cause because I haven't the faintest idea about what to do with it. Um I usually give them aspirin and Vitamin D because I give everybody aspirin and Vitamin D who's got a placental problem. Um because they're things that make the placenta healthier and in my sort of do no harm. Yeah. Um List of things they're things that are very unlikely to do harm. Um Say um th that um I was surprised by that recurrence risk, but I think probably within the list of things that as long as my arm, there are things in there that might recur, but there are other things that won't. So it's hard to counsel. So perhaps safer to assume that it does and can, right? And also the British side of hematology advises against thrombophilia testing. Do you feel it should be tested for all stillbirths or only with certain findings suggest in your clinical pathology tool? So, what we've tried to do in, in, in the way that we've approached it. I think your idea of having a, an investigation. So, is a really, really good idea is to say, get the placenta first because what you really don't want is to get a spurious positive. You know, you, you've got Factor Five Leiden Heterozygote. Well, we know there's gonna be, that's gonna be a pro proportion of our mums get the placenta first. If the placenta is clearly got maternal vascular malperfusion, then I would argue that any thrombophilic lesion is sitting on a causal pathway to generate that lesion. If you had a bright sparkly clean placenta, that was absolutely fit, you know, fine and not the explanation of why the baby died and you turned up some antiphospholipid antibodies. You're then kind of where does that fit? Yeah. So what I would do is get the placenta first A N test, right? And that also avoids having. So the other thing that we tend to see a lot of is we did a thrombophilia screen at the time of loss. The protein S is always low because they were pregnant at the time of or very shortly after being pregnant. So the protein is always low. So then you end up repeating it anyway. Yeah. So my advice would be don't do your thrombophilia screen until you've seen your placenta. That's brilliant. Thank you. Aisle Thompson online has said as a district General obstetrician and gynecologist, should we be thinking about starting the treatment for women in future pregnancies who have had c in their index pregnancy, despite the experimental nature of treatment at present, should we be contacting you for advice and treatment every time prior to considering starting this treatment? I think, because it's experimental, I think it's really important. Um You know, it's not rocket science, it's not drugs that are really kind of out there. Um But I think it's important to, to work together. I would, you know, I'm a bit of a workaholic. So I'm a really bad example, but there's myself and David Williams who um probably have the greatest experience in the UK seeing mums with Chi, we don't need to see the mums as carer very nicely illustrate, you know, we need to see them face to face. Um but we can help support and advise you so you're not out there on a limb. Um And I think that's really helpful for them as, as well as the staff. So we heard it here. First folks, we can all ask him for advice. Um G Chili who has asked, when would you advise starting HQ in women with first trimester, early second trimester losses as it's relatively slow acting, we suggest consider at least six weeks before conception. Yeah. So basically asked me exactly the same question before. I'm afraid this comes down to what I reckon we good practice point if it was in a guideline because it takes 8 to 10 weeks to get stable levels of hydroxychloroquine in my head. If you've got a loss before 14 weeks, I treat pre conceptual. If you've got a loss after that, I treat from a really early scan, say do an early scan at six weeks, you can see it in future on pregnancy ben start. So that, that's my dividing life. So because I'm stupider than you. Um II tend to arbitrarily say 33 months, preconception with hydroxychloroquine because mostly minor first trimester. So yeah, that's a bit of a relief. Um Fatima Koma. Um do women attending the clinic, Rachel um during their first visit, get any advice around nutrition from the nurses? Yeah, so it's part of the lifestyle. Um So nutrition but also um healthy weight and um yeah, as I mentioned alcohol, smoking as well. So yeah, all of it comes into one. Yeah. So yes, you can't do that on a standard 15 minutes Gyne appointment. Can you definitely not? No? Brilliant, great to hear. Um So those are all our online questions. Are there any questions in the room that anybody would like to ask at this stage? And we'll fire the microphones around to you. So there's uh Yep. Fantastic. So, Rachel's working your way quickly. Hi, I'm Leslie. I'm an early pregnancy nurse in the Ulster Hospital. I just wanted to know how many staff you have Rachel that are looking after your recurrent pregnancy last clinic or is it just you? So it's just me running the clinic. Um but cause it's based in the early pregnancy unit, they get involved. So they'll help me with regard to especially the scanning element because I work as a matron as well. And we've got four sites for the hospital. I can be at other sites. So they will help me with the scanning and obviously they get to meet them and then we give the continuity, the numbers we've got are quite big because we're quite a big unit. So just to give you an idea, we see about 1200 emergencies a month come through. So I've got 11 CNS S 16 nurses, staff, nurses running the unit and but it is a 24 7 unit um just to give it context. But yeah, I'm very lucky. We, we started 19 years ago and there were two of us um that learned to scan and you know, used to support the doctors mainly that was our job. And then as time has gone on, we've grown, grown it to the point now where the early pregnancy unit itself, the nurses see 90% of all the patients through to discharge. So yeah, it's a very satisfying role. Thank you. Fantastic. The other, we could just put our hands up again, folks and, and give our names and our units that would be really helpful. Thank you very much for the wonderful presentations. My name is Felicity. I'm working in school of midwifery here in Queens. So I have first one question for Professor Hazel and one for Rachel. So my question to you um is in relation to the Chloroquine, the Hydro um the Chloroquine. How does it work? Because actually, I was quite fascinated when we were talking about that. So in terms of helping women, so maybe I finished the question and then, and then the question, the second question then goes to Rachel. Rachel. Thanks. Also um the work you do, you, you mentioned compassion, continuity and so on, which is really very helpful for women. But how do you actually look after yourself? Because it has to get to a point. Maybe it doesn't where you, where you are taking everything in, you are listening to them history counseling, like people breaking down in front of you. How do you look after yourself? Thank you. They're two quite different questions. Aren't pleased you got your one. So um hydroxychloroquine has di different modes of action. But the thing that we think is most important is that it is a toll like receptor antagonist. Um And essentially in any, any immune response is a bit like a party. One macrophage tells another macrophage, it should come and enjoy time in the intervillous space and then it just grows and grows and grows and they talk to each other by toll like receptors. So what we think is essentially what we're doing is we're stopping them talking to each other. So, even if one or two of them kind of float there, um, they're not able to then summon the rest of them. So, a bit like a teenage party, you're sort of limiting the damage by there being fewer of them there where you don't want them. Wait. That's brilliant. How do you, how do you follow that, Rachel? I love that. Thank you for your question. I'd like to think anybody that comes into our profession comes in because they care and you want to look after people. And I think I'd started as a nurse. So obviously did a lot of palliative care during nursing. And then in midwifery just naturally migrated to looking after women going through their stillbirths. So it almost became like a natural order of things going into it, having that passion for looking after people through a heartbreaking time. I think compassion fatigue is a real thing. I think we've seen it everywhere after COVID in healthcare. But I think having a very trusted team around you knowing that we can call each other when we're having a bad day and someone else can come in and support. We have a in our unit, what we call case cafes where we get together as a team and we will bring a case if we want to talk about it, debrief. And interestingly more medics turn up to that because I think sometimes we underestimate how much it affects, especially the consultants. We recently had a case where a 13 year old had a ovarian torsion. So nothing to do with early pregnancy. It was a go case. But this consultant found it really, really difficult because her daughter was the same age and it was a very traumatic case. And so she came and sought counseling off the nurses in this, in this safe environment because she recognized she wasn't ok. So I think that's important. And I think ultimately, for me, it's trying to enjoy life outside of work. So a weekend in Belfast is just great. I love the combined analogies of KS cafes and like receptor parties never happen. Could I just add to that? Just to say, I think absolutely agree with everything you said within Rainbow Clinic. We've actually just had a doctoral psychology student and we brought her in to actually do more psychology stuff with the patients, but once a month after clinic, she just done a staff session and it's absolutely been brilliant. And I think it can be really hard. You're quite right, carrying around all of these loads and not low risk pregnancies and sometimes you're making big decisions or helping people make big decisions. And that feels like a big responsibility. So actually having an ability to share that I think is a really essential part of the service. Yeah. For them. Yeah. Were there? Yeah, absolutely. And were there any other questions in the audience, I think? Oh, Yes, my goodness. Hi, thank you very much, Francis Stuart. I'm a consultant in the Northern Trust. Can I ask, um, what do you do about, um, say a successful pregnancy where the placenta has been sent and you find an incidental finding? Maybe you don't see chi in a successful pregnancy. I don't know enough about it, but the other kind of malperfusion abnormalities that you saw. And how long do you keep the aspirin going for? What gestation? So we would keep the, I'll do the second bit first. It's easy. So if I start aspirin, I tend to either do it, the trials do various different things. So I would do it to at least 36 weeks because that's the minimum, that trials have done it now because I'm largely seeing people in pregnancies after loss. It's quite difficult not to get sucked into being a little bit superstitious. So we end up normally stopping it 48 hours before any planned birth because they don't want to stop it. And I, I don't want to stop it either really. So, um I'd love to say that was evidence based, but it's not remotely evidence based at all. Um Yeah, so that's when we would stop it the first bit I think, depends on the significance of the abnormality. We know there was a really helpful paper from the Cambridge group that looked at, they just took, I think it was about 1000 placentas just completely indiscriminately. And they showed these are all live births, but they showed, you know, chorioamnionitis is present in at least 25 30% of term births, maternal vascular malperfusion is present. The problem is our definition of unhealthy birth is pretty rubbish actually. Um, so if you're born on the 20th percentile and it all, you know, you cried and all of that was fine. What if you were supposed to be on the 80th percentile? We have no idea. Now, I guess in Ireland it's a bit different because you've been scanning people. Whereas over the other side of the RC where we're still using tape measures for low risk women, we just don't know. So I would argue if you had, you know, we would only normally send a placenta if we thought there was an indication. So let's say a baby came out on it. You know, it went to Nick or a term admission to Nick on the 20th centile and it came back with significant maternal vascular malperfusion. I think I would, on the basis of that, I would recommend aspirin in another pregnancy purely because we just, you know, we have no idea where that baby was supposed to be. And so it, it comes back to what I do no harm. The thing we're giving is pretty low risk in terms of its ability to be harmful. Um But the consequences of missing it and having another percent with MV could be more significant. No, no. So with the, I don't often give many things preconceptually. And my understanding of the aspirin data was that actually, if you give it periconceptually, it doesn't improve outcome over and above starting it from an early scan, I realize I'm in a room of people who are probably better equipped to know the answer to that. But yes. So I tend to mainly also because if I'm giving la electro heparin as well, I don't think many of my gynecological colleagues would forgive me to give forgiving heparin to someone who had a chewable pregnancy. So I like to have a scan that says it's in the uterus before I give them anything that might make them bleed thing. I wanted to ask Rachel, how do you manage the patient? Who all her tests are, are negative? And um but she's had two losses and, and has done reading et cetera and is keen for treatment. I mean, do you treat those patients with medication or what, how do you manage those or do you wait for the third? So we follow the recommendations which is we will test after two miscarriages and if those investigations come back normal, we would treat exactly as if somebody had lost 345 pregnancies. So we don't do any empirical treatment. Everything we do will be research based. One of the things we learned very early on is you start doing empirical treatment and then you bring in a research study a year later and patients talk. So even if your patients who don't, aren't there from a year ago, they will, they will know somebody who knows somebody who's come in and they will say, but you gave that person this and you and you just find your clinic loses its credibility. So we don't do any empirical treatment. We literally will just do research studies. Um And it's just about explaining to them um why we don't give it. And I think as long as it's explained, they, they do understand they're not stupid women, you know, they, they get it. In fact, most of them are probably more well read than we are when they come. Yeah. Um but it's just being honest with them. Um and then being aware of um the risks and why we don't do what we do. And it is difficult because at the minute you have got some units that will give out medicine like smarties. And I think it is hard and I don't criticize those clinics because to sit there and say to a woman, sorry, there's nothing I can do I can give you is incredibly hard and sometimes it's easier to give somebody something. It's going to make them feel a bit better, but it is a little bit of what you fancy. Does you good? Is that scientific? So it's about being honest, giving that supportive care. We do follow the guidelines So we have got a form of a progesterone, for example. So if a lady has got bleeding, then all the early pregnancy nurses have got a PGD, but it's very specific, they've got to fit the criteria. So, previous miscarriage and they're bleeding in that pregnancy because you do get a lot of ladies coming in, printing out leaflets to look after our pregnancies after unknown stillbirth. And it's because we've got a tendency to over treat people. So we chuck the kitchen sink at them because for two reasons, firstly, we've had to tell them that we don't know why the baby died. So we can't do anything functionally about. You know, we can't say well, if we do this and that isn't happening, your baby's not gonna die. Um And so, you know, we get people, I think the record, we've got the National Rainbow Clinic study running at the moment. I think the record is 147 appointments, which is really quite impressive for an appointment for like a 40 well, not even a 40 week pregnancy. I am. So um I think we should make across the board a really strong argument to say this service a stops us doing things we shouldn't do and improves outcomes by allowing us to focus treatments appropriately and that improves what we do. So I think there is something that we could do about trying to make because let's face it. I mean, perinatal pathology has got a bit of an image problem, hasn't it? It's not the most joyous of topics. Um I think actually, rather than it being sort of viewed as a, we're gonna tell you why your baby died or why you miscarried. A how we're going to have a successful outcome next time and try to reframe that in a much more positive light I think would make it potentially a more attractive specialty. I think also the other thing that's happening in the UK is that we're trying to have more focused post mortem so that if we get to a point where there's a clear cause we don't kind of keep going for the sake of keeping going. Um So, you know, if you've got an IUGR baby with Chr and a placenta, you know, you don't really need to go and look at that baby's brain because you know, it's not going to tell you anything else you didn't know already. So I think actually that those two things I hope would make a difference. Um And also to value the guys that we have um and use them because they are really, really, you know, they are our only tool out there um uh to help us guide and for subsequent pregnancies. Thank you. So, answer to your question, there's a few things I think that are needed. It's recognition of early pregnancy and recurrent miscarriage. So if you already look at the rcog and the ATM may run and the recognition for early pregnancy isn't there and how we're pushing for that. I think it's not even there at medic level. And as we know, nursing tends to follow after medic training and with regard to nursing, I was lucky that I had people that would listen. I think one of the biggest problems we have in nursing and midwifery is our leadership and recognition of what we do and the pay that goes with it because I think that you can have people, you know, the fact that people are online and sitting in here today shows how dedicated and how much you want to engage in this service, helping women. But, you know, II can guarantee that there's probably not even a couple of you that are above an eight, a pay grade. So, you know, the job doesn't go with the money. And I think until that happens, you can't really get people engaging and doing what they need to do because they're not getting the recognition for it. And I was lucky in the way that I just kept pushing and pushing, which is just my personality. But also when I got to matron level, I could then make the change as well. So I remember going into my position and my CNS were a six and I was like, there's no way they should be a six, there should be at least a seven. And if I start doing MS there should be at least an eight B and I remember someone saying to me, but then that means they're a higher band than you. And I'm like, yeah, well, they do more advanced skills than me. So they should be higher than me. And many directors of nurses will say to me, oh, that's not how we do things. I'm like, why, why isn't that how we do things? So, you know, it's, it's having people brave in the room and online that want to go and apply for these jobs that are stressful and are hard. But actually you go and make the difference for your team. I put their job description in four times and on the fourth time because he kept coming back. No, kept coming back. No. And I said, right, if it, if it comes back, no, this time, I'm resigning because you're not listening to me and then it came back with the banding that they needed. And I've got a happy workforce. But again, you've got to have a manager that's got, he's got a dog with a bone and keeps keeps going at it because that unfortunately seems to be the way the NHS works. Same with Apu The reason I wanted to go to a and became the first nurse to chair it again was I wanted to see the changes. Not because, and I do love doctors honestly, but I'm very aware that 90 per cent of the work that goes on in these units are run by nurses and midwives and they need that recognition. So, one of the things we've done with a, with the RCN and if any of you haven't seen it, there's a CNS in early pregnancy book that we launched about four years ago. And that's that list. All the schools that the AP and the RCN fail early pregnancy miscarriage nurses and midwives need to have. I've had about 12 hospitals feedback that they actually use that to rewrite their job description and they all got high abandon. Now it's little things like that, that we just, that's why we need people in the national positions to keep pushing it forward. I would absolutely love more and more people to come and join me with this crusade I'm on because at the end of the day, what you do is invaluable but no to the cloning then. No, I don't think II, my husband would say you definitely don't want more. Thank you, everybody. That was fantastic question. Thank you very much.