So I'd really like to thank the Society for inviting me to speak at this session. It's a really fantastic initiative and I'm so delighted to be here. These are my disclosures. So it's appropriate, it's Sunday evening and this is usually when I'd be sitting down for my dinner and this is usually the phone call I get from the emergency room. And it's a patient who has come to the emergency room, she's just miscarried and she's got a variceal bleed and it turns out that she actually has undiagnosed chronic liver disease. Worse still, we get her on some treatment and her life is a little bit chaotic. She comes back having been lost to follow-up. This time, 18 weeks pregnant, again, not having really much to take care of, failure of care in many respects, not taking her meds, her albumin is low, her clotting is high. So this is the scenario that makes us all nervous and it's trying to avoid this that I'll be talking about. So what I'm going to focus on in the course of my talk are physiology, outcomes of cirrhosis and pregnancy, review some data, also review data in relation to non-cirrhotic portal hypertension, butchiari, talk a little bit about management of bleeding and then the optimal paradigms for management. Now as you've heard, many women of reproductive age with chronic liver disease, you assume they will not become pregnant mainly because of the reduction in LH and FSH, reduction in estrogens and blunting of pituitary responses. And that indeed is true, but even women on the transplant waiting list, 40% of them will still have menstruation. And indeed, if you're dealing with women with cholestatic liver disease, 20% of them will have amenorrhea, 80% will still be having periods. So there is potential even in women with moderately severe liver disease to become pregnant. And actually, something that's really not discussed amongst hepatologists in the literature, the sexual activity reduces with severity of cirrhosis or certainly interest in sexual activity and relationships. So women who are on the waiting list for transplantation are unlikely to be having sexual activity even at relatively low MELD scores. Of course nobody asks anybody over 55 whether they're having sex at all. However, for women with cirrhosis, what we can absolutely say is that the rates of pregnancy in cirrhosis are increasing. This is a population-based study from Sweden, from the Karolinska, and indeed over a period of 15 years, absolutely these rates are going up. Not so much data from the United States, but this is data I will come back to, a review from 1993 to 2005, hospitalizations for women with cirrhosis in pregnancy. Estimated numbers based on 350 admissions over this time, the rates are certainly going up. When compared to a normal population, a four-fold increase in admissions to hospital during pregnancy. The trouble with the data is that it's murky. And whilst there is population-based data, there are very few series of women with cirrhosis or indeed chronic cirrhosis who are having or indeed chronic liver disease becoming pregnant. But this is our own practice over a 35-year period at King's College Hospital. The numbers of women each five years in terms of era, the numbers with both cirrhosis and chronic liver disease without cirrhosis are going up on a five-yearly basis. So just to review some of the pathophysiology of portal hypertension and the impact upon pregnancy. We know that pregnancy mimics the cirrhotic state. So no surprise in pregnancy then, plasma volume, blood volume increases by 40 to 50 percent. Cardiac output increases. Peripheral vasodilatation, palmar erythema, a drop in vascular peripheral resistance, and of course, azagus flow increased because of compression in the IVC. And all of this adds to the risk of bleeding in pregnancy. So the risk factors for bleeding in pregnancy generally, we know that if you have previously bled from varices or have been decompensated previously, a greater likelihood. If you scope people, again, standard general hepatology, looking at the red signs, undiagnosed varices implying that if you have not looked after patients and screened them in the pregnancy, of course, they're at a greater likelihood of having a variceal bleed. And of course, underlying cirrhosis, portal hypertension. And adding to this is the whole issue of procoagulation in pregnancy. So we see women presenting with butchiari syndrome, portal vein thrombosis during pregnancy as a consequence of these changes in procoagulant factors. When you're doing a high-risk pregnancy clinic with women who are actually pregnant, your obstetrician is going to say to you, what are you going to do about preventing preeclampsia? Because guess what? Many of these women that you will be dealing with, the women with non-alcohol related fatty liver disease with undiagnosed or diagnosed cirrhosis, diabetes, type 2 diabetes, women with autoimmune liver disease, in particular, the group that are most likely to be fertile, wanting to have children, are at increased risk of developing hypertension-related disease in pregnancy. Because they will say to you, what about putting these women on aspirin? And the rationale from an obstetric standpoint, and I know we're not at an obstetric meeting, but using aspirin from week 11 or 12 in pregnancy, 75 or 150 milligrams a day, improves the outcomes, reduces the likelihood of complications, and reduces cost. So we're all frightened because of these data that are now almost more than 50 years old. This is what we have grown up on. Data from Sheila Sherlock and some other larger series, 36 pregnancies where the maternal mortality was reported at 10%, rates of variceal hemorrhage at 30%, rates of decompensation 50%, but still a live birth rate of 66%. So what I'm going to focus on now is reviewing outcomes of cirrhosis in pregnancy, and indeed from 2000, there isn't that much in the literature, and the literature is bedeviled by the fact that there are only three or four studies. It's a mix of studies which are population-based. One study from Egypt on patients with hepatitis B and C, the Rashid study, and what I would say is that actually, in terms of the outcomes, you have to be very careful in interpreting these. It's a huge range, and of course, patients are looked after in slightly different ways depending on your location of care. So studies from the United Kingdom, or indeed from the US, over the last 20 years are showing much less in the way of decompensation, less in the way of variceal bleeding, less in the way of ascites, and indeed, it is the Egyptian study now that shows this rate of death of almost 8%. This is the US-based study from Shaheen from less than 10 years ago. We can expect women with cirrhosis to have a low risk of death if they are looked after properly, and the key is to look after them properly. Surge rates, of course, are self-reported. We, as hepatologists, don't hear about the majority of early fetal losses, but actually, what we encounter is women who lose and still are at risk of losing pregnancies through stillbirths or intrauterine deaths, and in our series, and indeed the Rashid series from Egypt, it runs still at around 5%. What is also clear is the risk of growth restriction and prematurity. In all series of cirrhosis approximately a quarter of our kids are premature, and this is the Egyptian study. Looking more closely at the etiology of liver disease and cirrhosis, what is absolutely clear is that it doesn't really matter what cause of liver disease is. The rates of complications are statistically similar. However, in terms of in-hospital mortality, where alcohol or indeed viral hepatitis is still an issue, there seems to be a slightly increased signal for in-hospital mortality for these women, and indeed I was slightly shocked this morning to hear that hepatitis C is not universally screened for in pregnancy in this country, so I think this is something that the society needs to really focus on. But what is very clear is that from this U.S. population-based study, maternal death rates are much less than they were, 1.8%. Fetal death rates are 5.9% in cirrhotic patients, but the rates of preterm labour and growth restriction are not inconsequential. Of course, no surprise, the rates of cesarean section are higher, but that's a decision to be made in a multidisciplinary way based on the presence of viruses, and of course more women with cirrhosis are likely to be admitted to hospital prior to their delivery for liver-related issues. But what is actually quite reassuring, and I apologize for the busyness of this slide, this is a data on 100 women with cirrhosis from Sweden. Actually, the maternal mortality rate was zero, which is really reassuring. Of course, you have to understand that the types of patients are likely to be viral hepatitis, viral compensated liver disease. So the guidelines tell us, and these are really the most current guidelines, endoscopy in pregnancy, all women with cirrhosis or suspected portal hypertension should undergo screening upper endoscopy for esophageal viruses in the second trimester. Endoscopy is safe, and we'll talk about medication subsequently. But of course, that's looking after things when something has already happened. You want to be doing a pre-pregnancy endoscopy so you can inform people of where they are and modify risks accordingly. We have been interested in scoring systems. MELD score, I'll bring your attention particularly to this. This was one of the things that we were most interested in. You would say women with a MELD score of 10 and cirrhosis really are not at major risk of anything, but what the message here is that even women with relatively well-preserved synthetic function have significant issues and significant risk in terms of liver-related adverse events for the mother in pregnancy. U-KELD is essentially a MELD sodium, and again, significant differences. A higher U-KELD score means that they're more likely to be heading towards transplantation. So watch the MELD score and calculate accordingly. We have expanded our data based on looking at a range of women with cirrhosis and chronic liver disease and have categorized them accordingly. What's quite interesting is that actually if you look at the predictors of live birth, and you need larger numbers to be able to look at this, simple things are still the most relevant in counseling our women who are intending to become pregnant. Albumin levels, bilirubin levels, these seem to be the things in multivariate analysis that come across more importantly. What I would encourage people to think about is looking at these non-invasive scores, the ratio between albumin and bilirubin ALBI score designed primarily to look at decompensation or risk of decompensation in the context of managing HCC. APRI score, these parameters along with MELD and MELD-sodium are very important in terms of defining the risk of live birth. And indeed, the ALBI score is probably the most sensitive and specific in terms of prognosticating. If you categorize the grade of ALBI, which can go into three separate categories, the more severe or the more severe your ALBI grade, the less likely you are to bring that pregnancy to term. And indeed, you can see with well-preserved liver synthetic function, that relationship between albumin and bilirubin gets you almost a 70% chance of it going to term. But as those parameters change, the likelihood of coming to term decreases significantly. Also, APRI, the relationship between transaminase activity and platelets, again categorized, you can look at the APRI score and potentially predict gestational length. But again, we think about APRI levels being high above, well above one. Actually, it's at relatively lower cutoffs that the sensitivity seems to be important. So if you screen patients endoscopically, what might you find? This is 39 pregnancies and cirrhosis from the same series over a 35-year period. So not a lot of inconsistency in practice over years. But what I would bring your attention to, less than 50% will not have varices on that second trimester endoscopy, but actually more than 50% will have esophageal and gastric varices. And of course, if you have counseling pre-pregnancy, you're more likely to undergo an endoscopy. You'll get better care. Now, not to forget about splenic artery aneurysms in pregnancy, something that typically you see in older women in particular, but actually catastrophic in the context of pregnancy, because this is when they tend to present in rupture, 70% in the third trimester. Size greater than 2.5 centimeters seems to be somewhat predictive. And typically, these present with left upper quadrant pain, present with a herald bleed. They're stable for a day or two and then a catastrophic bleed. So often you will have time. And think about this in young women who have had liver disease in childhood with big spleens. These are the ones that typically present. I'm going to focus on non-cirrhotic portal hypertension. Just bring your attention to the outcomes with portal vein thrombosis. Again, high levels of platelets seem to predict poorer outcomes, more prevalence of thrombotic events. But actually, if you have isolated portal vein thrombosis, either intra or extrahepatic, many women will get to term and deliver in a very easily way. In contrast, if you have non-cirrhotic portal hypertension, hepatoportal sclerosis, some of the more unusual things, it's more difficult to manage in pregnancy. Fetal outcome is certainly reduced, as is the rate of preterm delivery. And the majority of these women end up delivering by cesarean section. For Bud Kiari, again, I would contrast this with portal vein thrombosis and look at the outcomes in terms of fetal losses. Higher rates of fetal loss in the first 20 weeks, 30 weeks of pregnancy. And again, this delivery between 32 and 36 weeks, in contrast to women with portal vein thrombosis who are more likely to go to term. And again, what's also interesting is that in the Bud Kiari women, they're more likely to have bleeding from other sources, not just varices, and also at risk of thrombotic events. Focusing on endoscopy, you'll be familiar with this, even though the FDA has changed the categorization, it's still very useful. Propofol, very safe. Pethidine, lignocaine, and naloxone. In Europe, a lot of midazolam is used, and it still seems to be pretty safe. In terms of anticoagulation, if you have women on warfarin or DOACs, get them converted to heparin. Although, again, in the Bud Kiaris, the risk of heparin-induced thrombocytopenia seems to be higher. If you screen someone in the second trimester, and they have new varices, what do you do? Band or beta blockade? Well, beta blockers, they're relatively safe. Atenolol, which we don't tend to use, seems to be the most problematic in terms of neonatal bradycardia and so forth. Charleypress in the U.S., not used, and certainly has definite activity in terms of uterine contraction and blood flow to the uterus. Octreotide is safe, and avoids ciprofloxacin and the other quinolones as antibiotic therapy. Just a word about tips. This seems to be safe in pregnancy as a salvage procedure. There's a group of five patients published from Seattle, and this seems to be really quite safe if need be. So to summarize and conclude, if you have women who are intending to get pregnant with cirrhosis, what do they worry about? They worry about deterioration in health, death, pregnancy loss, medication side effects, and the risk of passing their disease on. It's all about preparation, calculating the risk scores, and having a plan. Thank you very much. So I think we have a few minutes for a couple of questions, if there's any that are out in the audience. Yeah. Go ahead. Hi. I'm Vaishali Patel. I'm a hepatologist from VCU. So say someone has varices. You put them on propranolol and you want to withdraw it before delivery. Do you recommend C-section or do you go to normal delivery? Because do you worry about them bleeding in the second phase of labor? So in real terms, the risk of bleeding in the second term or the second phase of labor is really small. And if you look at the Egyptian study, there were six deaths or six bleeds at that point. The rest of the literature, it doesn't seem to be as big a problem. However, of course, you're guided by how big the varices are in the second trimester, whether or not you're going to go and ban them. And of course, women spontaneously go into labor anyway. So most of the time, you don't have that option of stopping the beta blockers unless you're going to induce them, in which case you have that potential option. So for high-risk varices, do you recommend C-section? So I think that is a discussion with the patient and the obstetrician. And yes, I think for women that have very low platelet counts, cesarean section is more manageable. So it was not completely clear to me what you advise when you find varices in mid-term large varices. Do you give beta blocker or banding? So I think that's for individual hepatologists. The guidelines are comfortable around banding or indeed beta blockade. I certainly, if I'm faced with big varices, will have a low threshold to band. Not everybody feels the same way. It depends on your comfort level. But I certainly faced with big varices in pregnancy, will band them and put the patient on beta blockers. I agree. I do both. For gastric varices, bleeding, what do you do? You do isochrale or what treatment do you do in pregnancy? So again, I would treat gastric varices in exactly the same way as you treat them in the non-pregnant state. The risk of death is substantially higher. Histoacryl is really the best. And go back and retreat the varices two weeks later and keep going until you try and eradicate or solidify the varics. So Dr. Henning, you mentioned that the proportion of pregnant patient with cirrhosis has been increasing in the last decade. And what are some of the variables accounting for that? So I think in the United Kingdom, we have universal screening for hepatitis B and C and HIV. So we're identifying people at a greater frequency. Of course, as Dr. Sarkar has shown, rates of NASH are going up. The other thing is that we have many kids who have had childhood liver disease, biliary atresia, allergy ill. They're all coming through and they want to have families. So they are the ones that are more of a challenge, I think, than common garden, parenchymal liver disease. I will follow up on the first question. So I'll make a comment and ask a suggestion. In terms of caesarean section, because the one concern is, you know, etabdominal or medical varices. So I think the indication should be based on obstetrician. The obstetrician is key. And I think what I'm always impressed with is that obstetricians are more likely to suggest normal delivery rather than a section. And I'm always surprised at the risks they're willing to take. But obviously, going into pelvic varices, very troublesome. Thank you.

pregnancy

cirrhosis

risk management

varices

multidisciplinary care

treatment options