Good afternoon to everyone. It is somewhat queer to meet you in this way, but nevertheless, I am happy that the ASLD provided us with the opportunity to meet via web, despite the fact that I would have to drink a lot of coffee to stay awake as it is almost midnight in my country. If not in this way, the only possible choice would have been to skip our meeting and this, of course, would have been a great pity. This year, our session of the Women's Health Programme is devoted to a very relevant topic, the evolving management of liver disease in pregnancy. The relationship between liver disease and pregnancy has great clinical impact. Although severe liver disease in pregnancy is rare, pregnancy-related liver disease is the most frequent cause of liver dysfunction during pregnancy and the source of a lot of worries for the mother-to-be. In some instances, liver disease in pregnancy can represent a trait to the survival of mother and child. Furthermore, it is not always easy, at the onset of symptom liporitis or signs like jaundice, to distinguish between a severe condition and a bothering but harmless situation. Our speakers will examine the impact of liver disease on course of pregnancy and conversely that of pregnancy of liver disease. They will also focus on viral-related conditions. HPV and especially HCV infection have been associated with impaired fertility, increased mixed carriage rate and fewer live births. Viral-related conditions have become much more manageable thanks to the latest generation of antiviral drugs. However, they still represent a cause for concern for the mother and sometimes for their doctors. The last talk will specifically address the problem determined by liver transplant in pregnancy. Liver transplants usually restore reproductive function that women have lost because of cirrhosis. Women regain the possibility of becoming pregnant again. This has clear implications as about 30% of liver transplant recipients are women and about 10% of them are of childbearing age. This means that a potentially high number of women could ask their doctor for advice on whether and how to become pregnant. Our learning objectives are therefore to understand and discuss the impact of liver disease on course of pregnancy, to review the possible influence of pregnancy on liver disease and to outline the specific problem determined by liver transplantation in pregnancy. We start now with the first lecture on Cholestatic Liver Disease in Pregnancy, presented by Cynthia Lely. Thank you. Hello, thank you for attending the Women's Health Programme at the Liver Meeting 2020. I'd like to thank ASLD and the course organisers, Drs. Hernandez and Villa, for inviting me to present today. My presentation is entitled Cholestatic Liver Disease in Pregnancy. My name is Cynthia Lely. I am Professor of Clinical Medicine at the University of Miami and these are my disclosures. Today I plan to discuss how chronic cholestatic liver diseases behave in pregnancy. Here I am referring to primary biliary cholangitis and primary sclerosing cholangitis. Then we'll discuss the cholestatic disease presenting in pregnancy, which is intrahepatic cholestasis of pregnancy. And finally, we'll review the general management of pruritus in pregnancy. Starting with the chronic cholestatic liver diseases, let's discuss what we know about primary biliary cholangitis in pregnancy. Well, PBC is an immune-mediated disease that causes inflammation and destruction of the small bio-ducts and which, if left untreated, progresses to biliary cirrhosis. It affects predominantly females, roughly one for every 1,000 women over the age of 40, with mean age at presentation in the mid-50s. Even though most women are older at the time of diagnosis, 25% are of childbearing age and a third of all cases are first diagnosed during pregnancy. Furthermore, fertility does not seem to be affected based on case control studies. Diagnosis of PBC requires the presence of two out of three of these criteria. Unexplained elevation of alkaline phosphatase, positive anti-mitochondrial antibody, or presence of PBC-specific ANA, or histology showing destructive cholangitis. You need two out of three. However, during pregnancy, if you suspect a diagnosis but you don't have two criteria, you're not going to rush and do a liver biopsy. We can make a presumptive diagnosis, treat as such, and then reassess after delivery and determine do we really need a liver biopsy or not. We will not biopsy during pregnancy to make this diagnosis. Now, the course of PBC in pregnancy has been described in small case series like this one, where nine pregnancies in six patients are described. Here are labs from prior to conception to 12 weeks postpartum. Notice that there is a trend towards improvement in liver chemistries, specifically ALT and alkaline phosphatase during pregnancy, with a subsequent rebound during the postpartum period. And likewise, there is a decrease in titers of the anti-mitochondrial antibody, sometimes with disappearance of titers, and then later reappearing in the postpartum. Clinically, we see that itching can be a problem. It may worsen or appear de novo during pregnancy in about half of the women. In this study from Toronto with 50 pregnancies in 32 women, a biochemical flare was described in 30% during pregnancy and in 72% during postpartum period, consistent with previous reports. Here, although there was no relationship between flare and age at conception or preconception biochemical activity, it was observed that patients who had been on treatment with ursodeoxycholic acid for more than 12 months did not have a flare-up during pregnancy. How about the course of pregnancy in patients with PBC? This slide shows the collective experience reported in several studies. Overall, pregnancy is successful and well-tolerated. Live birth rates are up to 76%. Preterm delivery, however, seems to be increased and is reported in 6% to 33%. Fetal and neonatal complications may be slightly increased. And there is no teratogenicity associated with UDCA use. Talking about treatment, the first-line therapy in primary biliary cholangitis is ursodeoxycholic acid, 13 to 15 milligrams per kilo per day. For those who are incomplete responders or intolerant to UDCA, second-line therapy is available with obetecholic acid, which is the only that is approved by the FDA, and with fibrates, which are offered as an off-label therapy. During pregnancy, however, things are a little bit more complicated. Urso has excellent safety profile. It's not associated with adverse events in pregnancy or breastfeeding. However, data for obetecholic acid and fibrates are scarce. There's no human data on obetecholic acid, although no teratogenicity or postnatal abnormalities have been noted in animal studies. Fibrates, on the other hand, affected maternal reproductive outcomes at high doses in animal models. And fibrates pass into the breast milk. Therefore, neither OCA nor fibrates are recommended during pregnancy or lactation. Moving on to primary sclerosing cholangitis, this is another immune-mediated disease that affects both small and large bio-ducts, causing inflammation and fibrosis of the ducts and eventually leading to biliary cirrhosis. Clinical presentation and disease progression are extremely variable. Different from PBC, two-thirds of patients with PSC are males, typically presenting in the mid-30s or 40s. And an association with inflammatory bowel disease is striking, observed in up to 85% of patients. Well, even though two-thirds of the patients are male, we still have 30 to 40% of patients being female, and many are in reproductive age. The association with IBD is important because studies evaluating outcomes in pregnancy should definitely adjust for that variable. Fertility does not seem to be impaired, even if patients have inflammatory bowel disease, although prior pelvic surgery does affect fertility and fecundity. The course of PSC during pregnancy is less defined and more variable. Providers can also worsen or appear de novo. There is no consistent pattern of liver test abnormality during pregnancy or postpartum, but the disease doesn't seem to acutely worsen, and there is no increase in the frequency of cholangitis. IBD can worsen during pregnancy. One interesting point, which we actually also observe with PBC, is that when itching worsens and bio-acid levels rise, it may become unclear whether a patient also has ICP. One very recent study from the UK evaluated 61 pregnant women over a period of 20 years. 27 had PBC and 34 had PSC. I'd like to focus on laboratory changes from conception to delivery with attention to bio-acid levels. Note that results are provided in median and interquartile range, so you can't fully appreciate how high these bio-acid levels reached. The authors specified that 14 patients had bio-acid levels greater than 40, and 5 had levels greater than 100 micromoles per liter. They observed a correlation between serum bio-acid levels at delivery and gestational age, with higher levels correlating with earlier delivery. No surprise there. ALT levels also correlated with gestational age. Importantly, the preterm delivery in this population was 27%, compared to 7.3% observed in the general population. In terms of the course of pregnancy in patients with PSC, the outcomes are generally favorable. Live birth rate is around 84%. Fetal loss is not really associated with liver disease or with activity of the liver disease, but may be associated with activity of the inflammatory bowel disease. The preterm and c-section delivery rates are also increased. When UDCA is used, the liver enzymes tend to remain more stable, but there is no impact on maternal or fetal outcomes. The largest study on this topic is a population-based study from Sweden, including 229 single-term births from women with PSC, 13 of whom were diagnosed with PSC during pregnancy. 35% of these women also had IBD. Here, the authors found 3.6-fold increase in the rate of preterm delivery and 2.2-fold increase in the risk of c-sections, regardless of presence of IBD. Again, there was no increase in congenital malformations or stillbirth rates. Let's switch gears now to discuss a cholestatic disease that presents during pregnancy, namely intrahepatic cholestasis of pregnancy. ICP is described as a reversible cause of cholestasis occurring in genetically predisposed individuals, usually late in pregnancy. There is great geographical variation, with higher prevalence noticed in the Araucanian Indians in Chile, as well as in Sweden and Baltic countries. The overall prevalence is 0.4 to 10% in Europe. Many risk factors have been described in ICP. In addition to these genetic mutations, seropositivity for hepatitis C, seasonal onset during the winter, multiple gestations, older age at conception, low selenium and low vitamin D levels have also been associated with ICP. This relationship between hep C and ICP is not well explained, and it may be related to downregulation in bioacid transporters. But it is very clear that moms with ICP are more likely to have hepatitis C virus before or after pregnancy, and more likely to have higher viral loads compared to non-ICP moms. Clinically, ICP is characterized by intense pruritus, usually presenting in the late second or third trimester. Cases have been described as early as seven weeks, usually associated with marked increase in serum estrogen levels, as in the ovarian hyperstimulation syndrome, for instance. These patients with early onset ICP tend to have a worse clinical course. Palms and soles are more frequently involved with the pruritus, and although there is no rash preceding the pruritus, excoriations and prurigo nodularis may appear later. Bioacid levels are typically greater than 10 micromoles per liter, and transaminase elevation can be seen with levels varying between 2 and 30 times the upper limit of normal. The itching usually precedes this enzyme elevation. Jaundice can occur, but it's uncommon. Choluria and E. coli are also uncommon. The pruritus and enzyme elevation typically resolve within two to three weeks of delivery, but ICP can recur in future pregnancies. Once again, I'd like to call your attention to the association with hepatitis C virus and with other hepatobiliary diseases. This table shows the mutations that have been associated with ICP, and you can appreciate that most involve bioacid transporters. On the first column, you see classic mutations ATP8B1, ABCB11, ABCB4, ABCC2, NR1, NH4, and FGF19, all of these associated with high bioacid levels. Focusing now on the last column on the right, you see the clinical spectrum that has been associated with each of these mutations, thus the association with other hepatobiliary diseases that we see in ICP. Among these, there are the PFIX, BRX, DILI, the low-phospholipid-associated cholelithiasis, and others. In terms of pathophysiology, the reduction in bioacid excretion leads to increased levels of bioacids crossing the placenta. This, in turn, is associated with a number of effects. Increased sensitivity and expression of oocytocin receptors in the myometrium, placental anoxia due to the vasoconstrictive effect of bioacids, impaired cardiomyocyte function, reduced lung surfactant, and high meconium passage associated with bioacid-induced increased fetal gut motility. The severity of symptoms has been associated with the concentration of progesterone, which mediates itching through TGR5-dependent pathway, and autotaxin activity or levels of lyophosphatidic acid. And they mediate itching through the LPA5 receptor, phospholipase D, TRPA1, and TRPV1 signaling. And what is the maternal fetal prognosis? Well, in general, it is quite favorable, especially the maternal prognosis. Even though there is an increased risk of preterm delivery, meconium stained, amniotic fluid, and stillbirth, the risk of fetal demise is actually really low. It is only increased significantly for patients whose serum bioacid levels is greater than 100. And keep in mind that 80% of women with ICP have serum bioacid levels between 10 and 40, therefore with much better prognosis. Treatment of ICP definitely involves a multidisciplinary approach, including maternal fetal specialists, a neonatologist, and a hepatologist. Delivery is recommended at 36 to 37 weeks gestation, or at the time of diagnosis if it happens after 37 weeks of gestation. Genetic testing should be considered for the more severe cases. The primary goal, of course, is to reduce serum levels of bioacids, to reduce pruritus, prolong pregnancy, and reduce fetal risks. Thus far, UDCA has been the first-line therapy for the management of pruritus in ICP, and for quite a long time has been taught to improve prognosis. But let's dig in a little bit more into some recent data on the role of UDCA. Previous studies suggested that UDCA could not only improve itching, but also improve liver chemistries and possibly improve fetal outcomes. The largest previous trial had only 84 participants. The PEACHES trial, published in 2019, is the largest randomized control trial in this field, and included 605 women, and a total of 1,000 women. In this study, use of UDCA made no difference in the primary outcome, even if you restricted the analysis only to patients whose bioacid levels were greater than 40. The study also showed that the use of UDCA did not make a difference in the primary outcome. The study also showed that the use of UDCA did not make a difference in the primary outcome. Only to patients whose bioacid levels were greater than 40. They didn't have enough subjects with bioacid levels greater than 100 to perform a further sub-analysis in that subgroup. Maternal itching was lower with UDCA, but the mean reduction was minimal, and it was unclear whether that was clinically significant. A meta-analysis that was just published now in 2020, and incorporated this data from 2019, was unable to find the benefit of UDCA in reducing the rates of stillbirth. UDCA use was associated with a slight increase in gestational age by about half a week. Finally, I would like now to focus on the management of pruritus in pregnancy. This is the most common dermatologic complaint during pregnancy, but not all that glitters is gold. Focusing on the algorithm on the right, it's important to determine whether or not there is a rash associated with the itching. If a rash is present, then we take into consideration the timing during pregnancy and whether or not there is tria and what are the areas involved by the rash. Your differential will be predominantly polymorphic eruption of pregnancy, pantheoid distationis, or atopic eruption of pregnancy. However, if no rash is present, we think of a systemic disease including hepatic renal dysfunction, malignancy, drug reactions, and of course, ICP. The meta-analysis I just shared with you before also evaluated the role of UDCA in controlling itching. Two studies were included that used a numeric rate scale of 0 to 100. Indeed, UDCA was associated with improvement in itching, although very mild. In a scale of 0 to 100, the improvement was of about 6.7 points. For patients with PBC or PSE who have new or worse itching during pregnancy, and for those patients with ICP who don't respond well to UDCA, the following drugs can be tried. Cholestyramine at 4 to 16 grams daily in divided doses, rifampin 300 to 600 milligrams a day, SAMe at 1,000 or 1,200 milligrams a day, and antihistaminics, keeping in mind that chlorphenidramine and diphenidramine are the first-line agents in pregnancy, with loratadine and cetirizine being second-line agents. To conclude, my take-home message with respect to PBC and PBC is that fertility is probably not affected. The course of PBC may improve during pregnancy, and flare-ups can occur in the postpartum. PSE, on the other hand, is more unpredictable, but significant worsening is not commonly seen. There's no increase in cholangitis. Pruritus may exacerbate or appear de novo. We do see an increased rate of preterm and c-section delivery for both diseases, and importantly, UDCA use is safe during pregnancy and lactation. As far as ICP, a multidisciplinary approach is definitely needed, and early delivery is recommended at 36 to 37 weeks. We should monitor bioassay levels, knowing that risk of stillbirth is significantly higher for those with bioassay levels greater than 100. UDCA seems to be effective in reducing pruritus, but does not seem to affect fetal outcomes. Genetic testing is recommended for the most severe cases. Test for hepatitis C virus, monitor for other hepatobiliary diseases. And with that, I'm going to conclude, and I thank you for your attention. Hi, good evening. My name is Jennifer Fleming, and I'll be presenting today on cirrhosis in pregnancy, risk stratification, and management. And I'd like to thank everybody for attending today, and especially the organizing committee for the invitation to present. So I'm an associate professor of medicine at Queen's University in Kingston, Ontario, Canada. These are my disclosures, nothing relevant to what I'll be discussing today. So first I'd like to start off with a case of a 34-year-old female with NAFLD cirrhosis who comes for routine follow-up in your clinic. She had biopsy-proven NAFLD cirrhosis diagnosed two years ago after evaluation for chronically elevated liver enzymes. She had a screening EGT at the time of diagnosis which showed no varices, and she's had no decompensation events. She was recently seen by her primary care provider for family planning discussions, and during their conversation, she was told that contraception was contraindicated given her underlying cirrhosis, that she was unlikely to become pregnant, and that if she did get pregnant, she would be high risk for poor outcomes. And so she comes into the clinic to see you, and she has many questions. She wants to know what are the chances that I can actually become pregnant. If I don't want to be pregnant, do I need contraception, and if so, what is safe for me to use? What are the chances that something bad will happen to myself or my baby? Will my liver get sicker if I become pregnant, and will I need another endoscopy? So knowing that, this is the outline of the talk that I'm going to be presenting today. First, I'll be discussing the epidemiology of pregnancy in women with cirrhosis, and then turning to evidence that we have on the outcomes of pregnant women with cirrhosis, focusing on maternal, infant, and liver-related outcomes. We'll then discuss evidence that will help us to identify women at risk of peripartum complications, and discuss the role of GI and hepatology in the management of pregnant women with cirrhosis, with specific attention paid to screening for varices and variceal prophylaxis. So cirrhosis in women of childbearing age is increasing. In North America and the United States, mortality secondary to cirrhosis increased between 2009 and 2016, most in those aged 24 to 35, and more so in women than in men. And it's also been shown that NAFLD is driving liver transplantation rates in those under the age of 40. In Canada, the highest increase in new diagnoses of cirrhosis over the past 20 years has been in women born after 1980. And further cirrhosis incidents in those under the age of 18 in Ontario during the same period increased by almost 140%. This is data that I'll be presenting at this year's liver meeting, looking at the projection of cirrhosis incidents in women after the year 2040, and just wanted to highlight that in those women born after 1980, there is an expected increase of over 125% over the next 20 years. Therefore, not surprisingly, given that changing epidemiology of cirrhosis in women of childbearing age, pregnancy in women with cirrhosis is also increasing, although historically considered to be a rare event due to hormonal related disturbances and low prevalence of cirrhosis in this age group previously. More recent data has suggested that the number of women with cirrhosis having children is on the rise. This has been seen in the United States using data from the National Inpatient Sample, where there was an average increase of pregnant women with cirrhosis by 8% per year between 1993 and 2005. Data recently from Sweden showed that the number of deliveries of children to women with cirrhosis increased over almost 10 year period. And our recent study using data from Ontario, Canada, showed that the incidence of childbirth in women with cirrhosis increased almost eightfold between the years 2000 and 2016. Using our data from Ontario, we then looked at the rate of childbirth in women with cirrhosis compared to the general population, and we stratified this based on decompensation status. Within the general population of women matched for age and SES, the number of deliveries was 46 per thousand person years. If you had compensated cirrhosis, the rate of childbirth was actually higher to the general population by 17%, once accounting for parity, SES, and comorbid illness. However, if you had a history of decompensated cirrhosis, your rate of childbirth was 33% less. We also looked at the rate of childbirth in women with cirrhosis versus the general population stratified by cirrhosis etiology. And here at the bottom is the reference group of the general population without cirrhosis, and you can see that in women with hepatitis B, NAFLD, genetic causes, and autoimmune liver disease, the rate of childbirth was comparable or somewhat higher, whereas the rate in women with underlying hepatitis C or alcohol-related cirrhosis was lower. So what are some explanations for the higher rate of childbirth in women with compensated cirrhosis? Well, it has been shown that women with chronic diseases in general have low use of highly effective contraception, and within the liver population, pregnancies in women with cirrhosis and with chronic liver diseases post-transplantation have pregnancies which are frequently unplanned. Also, there may be fear of the use of contraception in women with chronic liver diseases by providers, as well as the potential perception that pregnancy may not be possible. And therefore, discussions regarding contraception in women with cirrhosis is important. And I want to draw your attention to the recent ASLD guidelines regarding options for contraception in women with cirrhosis. It will depend on whether they have compensated or decompensated disease. In women with compensated cirrhosis, it is recommended that they can choose any number of effective contraceptive therapies, while if you have decompensated liver disease, it is recommended to avoid combined hormonal oral contraceptive pills. Now switching to looking at outcomes in pregnant women with cirrhosis. So first, before we go into detail, I just wanted to highlight that there's been a changing in the demographics of women with cirrhosis who become pregnant. On the left-hand side here is data from the UK cohort between 1984 and 2009, where the age at conception was 29 years, and the most common cause of underlying liver disease was autoimmune or genetic causes. However, this is our more recent contemporary data from Ontario between 2000 and 2017, suggesting that in a contemporary population, the majority of women who are pregnant with cirrhosis have underlying NAFLD and are slightly older than previous with an average age of conception at 31 years. I also wanted to highlight that in 17% of women who are pregnant with cirrhosis had their first diagnosis of cirrhosis made during their pregnancy, highlighting that cirrhosis can be a silent condition and that the time of family planning or pregnancy may be the first time that these women become aware of their underlying liver disease. So when we talk about outcomes of pregnancy and cirrhosis, I've divided it up into maternal and infant outcomes. As they are generally grouped together, maternal outcomes refer to such things as gestational diabetes, preterm delivery, intrapedic cholestasis of pregnancy, whereas infant-related outcomes relate to large or small for gestational age, respiratory distress, or infant mortality. And typically, these peripartum outcomes are evaluated up to six weeks postpartum. However, in pregnant women with cirrhosis, we're also interested in liver-related outcomes such as variceal hemorrhage, ascites, and mortality. And depending on the study that you look up, the follow-up time for these outcomes are variable. Over the next few slides, what I'll be doing is I'll be highlighting the literature on what we understand about the outcomes in pregnant women with cirrhosis when we compare them to pregnant women without cirrhosis. I want to highlight that these study bases vary, as well as whether or not these studies had multivariate confounder adjustment, and the follow-up times are different. I also wanted to highlight that what I will be displaying are difference in proportions of these outcomes in women with cirrhosis compared to without cirrhosis. And I've signified with the red arrows if there was a significant difference on a statistical test in women with cirrhosis versus without. First, we'll look at maternal outcomes. These are five contemporary studies that I've chosen to review, published between the years 2010 and 2020. As you can see, they vary in their region, some being from the United States, one from Canada, one from Sweden, and one from Egypt. And I've highlighted whether or not there was any confounder adjustment in these outcomes. The first two outcomes that I would like to highlight are preterm birth and cesarean section, because for the majority of the studies, there was an association between cirrhosis and preterm birth and c-section compared to women without cirrhosis. For hypertensive complications, which refer to eclampsia, preeclampsia, and gestational hypertension, there was an association with cirrhosis in the three studies without confounder adjustment, and the two population-based studies, which adjusted for things such as diabetes, baseline hypertension, there was no association seen between cirrhosis. Postpartum hemorrhage has been variable in whether or not it's associated with cirrhosis. In our study from Ontario, we found an association between cirrhosis and induction of labor, as well as peripheral infections. However, no studies have found a strong association between cirrhosis and the development of gestational diabetes. I wanted to pay particular attention to cirrhosis and intrapartic cholestasis of pregnancy, as this is something that we deal with as hepatologists. The original association between chronic liver disease and ICP had originally been shown in women with HCV, but this has also been extended to women with multiple different types of chronic liver disease and cirrhosis. There was a case control study from Sweden, which showed that in women with intrapartic cholestasis, that the hazard ratio for cirrhosis was greater than five. And in our recent study from Ontario, where we looked at women with cirrhosis who are pregnant compared to women in the general population, 5% had ICP versus 0.5% for an adjusted risk ratio of over 10. We then stratified this to look at the etiology of liver disease and the association with ICP, and compared to NAFLD, the risk of ICP was higher with individuals with autoimmune liver disease and alcohol-related liver disease. Now shifting to infant outcomes, again using the five studies that I had presented for the maternal outcomes previously. First, I wanted to highlight the association of cirrhosis and neonatal death. Although the majority of the studies have shown an association, if you look at the absolute difference, it's relatively small. And in our study from Ontario, after adjustment for confounding, we did not find an association between cirrhosis and neonatal death in women with compensated cirrhosis. Depending on the study population you look at, large and small for gestational age have been associated with cirrhosis, as well as respiratory distress. However, meconium aspiration, neonatal jaundice, and stillbirth have not been found to be higher in women with cirrhosis. How can we predict some peripartum outcomes in pregnant women with chronic liver diseases? This is a heterogeneous population from the UK, which included pregnant women with both chronic liver disease and cirrhosis. And they looked at biochemical liver-related scores, including the ALBI score and the APRI score. And with respect to the ALBI score, it cut off of minus 2.7. This had an ROC of 0.74 for a gestation carrying to greater than 37 weeks, whereas the APRI score that cut off of 0.84 had an ROC of 0.74 at live birth. And both of these scores were superior to the MELD score in predicting these peripartum outcomes. And finally, moving on to liver-related outcomes. Historically, data had suggested that a high proportion of women with cirrhosis who were pregnant had liver-related events, most commonly variceal hemorrhage, which was originally shown in the 1980s to occur in up to 30% of pregnancies, as well as other hepatic decompensation events. And most concerningly, some reports had shown that death occurred in up to 10% of pregnancies. This is a graph looking at liver-related outcomes in pregnant women with cirrhosis. There's no comparator group here, but I just wanted to highlight that there is differences in the follow-up time based on all of these studies. And the single-center study from Egypt I've put on the right side is their outcomes have higher event rates than all other studies. When looking at variceal bleeding, the majority of studies would suggest that this is less than 5%. And other decompensation events have been shown to be between 1% to 10% for a total liver outcome event rate of between 10% to 15%. Liver transplantation is rare. And reassuringly, in more contemporary cohorts, death associated with pregnancy in women with cirrhosis is much less frequent, likely less than 2%. There's always been a concern that pregnancy in and of itself could worsen underlying liver disease. This is a study from the UK which looked at liver-related scores before conception and then after pregnancy to see if there was any difference. And looking at the APRI-LB MELD and MELD-sodium, there was no difference in these liver-related scores, either pre- or postpartum. Similarly, in our cohort in Ontario, we presented this at the liver meeting last year, where we matched pregnant women with cirrhosis to non-pregnant women with cirrhosis and then looked at the outcomes of decompensation, transplantation, or death up to one year postpartum. And in women who were pregnant, these events were tenfold less than women that were not pregnant. Again, suggesting that pregnancy in and of itself does not appear to necessarily worsen the natural history of chronic liver disease. How can we predict liver-related outcomes in women with cirrhosis? Again, the cohort from the UK showed that a MELD score greater than 10 at the time of conception had a sensitivity of 83% and specificity of 83% for a liver-related outcome. And this was similar when they looked at the UK ELD score. In our cohort from Ontario, we showed that if you had a history of preconception, hepatic decompensation, that a liver-related event up to one year postpartum occurred in 13%. However, if you had compensated disease at the time of pregnancy, a liver-related event was approximately 1%. So finally, what is the role of the GI and the hepatologists in the management of pregnant women with cirrhosis? Well, first and foremost, it's the participation in the multidisciplinary management of these women in conjunction with primary care, high-risk obstetrics, and social work. And in North America and the UK, there is the emergence of combined hepatology and obstetrics clinics because of the increase in the need for this service in women with chronic liver disease. And I think most importantly, preconception counseling regarding the evidence on the safety of contraception, as well as the risk of maternal, infant, and liver-related outcomes are important as a hepatologist. And it's been recently shown in the UK that preconception counseling occurred in only 15% of pregnancies in women with chronic liver disease, highlighting a need in women of childbearing age. We also participate in the management of the underlying liver disease etiology, whether that be autoimmune liver disease, viral hepatitis, alcohol-related disease, or NAFLD, which some of my co-presenters will be discussing in further detail today. And I wanted to highlight, since variceal hemorrhage is the most common liver-related event that occurs in pregnancy, we have a role in variceal screening and prophylaxis in these women. Both in the cohort from Ontario, as well as the UK, it showed that endoscopies performed at the time of pregnancy were very rare and occurred in less than 10% of women with cirrhosis. However, they showed with the advent of preconception counseling that they were able to improve the EGD rate to approximately 60%. This is a schema from the recent ASLD guidelines on how to perform screening and prophylaxis in women either contemplating pregnancy or who are pregnant. If variceal screening was performed within one year prior to conception, then there's no need to repeat the endoscopy during pregnancy, and you can use the findings at that endoscopy to suggest prophylaxis. With small varices, that could be the consideration of non-selective beta blockade. And if medium or large varices are present, then beta blockade or banned ligation can be considered. However, if variceal screening was not performed within one year of conception, and the woman is pregnant, then it's suggested that you defer EGD until the second trimester of pregnancy, and then base your prophylaxis recommendations on the endoscopy findings. And I think also important to note that propofol, midazolam, fentanyl, and meperidine are all acceptable forms of sedation in pregnant with cirrhosis. However, it's recommended that there is consultation with your MFM colleagues pre-procedure to make these decisions. Finally, what happens if a woman with cirrhosis does have a variceal bleed? Well, the management is very similar to the non-pregnant state with the use of octreotide, PPI, cephalosporins, and endoscopy. Where it's available, turdlypressin is suggested to be avoided. And in refractory bleeding or in women with bleeding gastric varices, there are case reports where TIPS has performed with success in women who are pregnant. So finally, I'd like to return to our case, our 34-year-old female with naphthalocirrhosis who comes in for routine follow-up. She asked, what are the chances I can become pregnant? Well, I think the evidence would suggest that if you have compensated disease, your rate of childbirth is similar or actually higher to the general population. However, you have decompensated disease, the rate of childbirth is 33% lower, but importantly, it's still possible. If I don't want to become pregnant, do I need contraception? And if so, what is safe to use? Well, contraception is recommended and is safe for women regardless of their decompensation status who do not wish to become pregnant. And those with compensated disease, all options are acceptable. Whereas in decompensated disease, it's recommended to avoid combination hormonal OCPs. What are the chances that something bad will happen to myself or my baby? Well, I think I've shown that maternal and fetal outcomes are associated with cirrhosis, especially for preterm birth, large and small gestational age, intrapedic cholestasis of pregnancy and C-section. I've also suggested that evidence shows a potential association with neonatal mortality. However, if you compare that risk to the general population, it's still relatively low. Will my liver get sicker if I become pregnant? Well, if you have compensated disease, the risk is probably about 1%. However, if you have a MELD score greater than 10 or a history of decompensation, the event rate can be as high as 10 to 15%. Although reassuringly, more contemporary data would suggest maternal mortality is less than 2%. And finally, will I need another endoscopy? Well, that depends on whether the patient is pregnant and when the last EGD was performed. If there was no endoscopy performed less than one year from conception, then use that EGD findings to decide on prophylaxis. Whereas if the individual is pregnant and the last EGD was greater than one year pre-conception, then it's recommended to defer the endoscopy until the second trimester. So the key takeaway points from this talk are that pregnancy in women with cirrhosis is possible and that the majority will have excellent outcomes and that GI and hepatology have an important role in educating patients and other healthcare professionals regarding decisions around family planning and outcomes. And the involvement of multidisciplinary teams will be key to improving maternal and infant liver-related outcomes into the future. Thank you, and I'm happy to take any questions. I'm delighted to be with you today, and I want to thank the organizers for the opportunity to participate in the Women's Health Program. I'll be addressing hepatitis B and C in pregnancy, evolving treatment practices. I'm Nora Turo from the University of Southern California, and these are my disclosures. Pregnancy offers unique opportunity for us to identify women who have hepatitis B and C and ensure that they get linked to a provider who can give them both care during pregnancy for their viral hepatitis as well as afterwards. In the course of my talk, I'm going to be touching on the unique aspects of managing women who are pregnant who have these infections and specifically address effects of pregnancy on the course of viral hepatitis, the effects of the viral infection on pregnancy outcomes, and most importantly, I'll be addressing mother-child transmission. So, mother-child transmission can occur intrauterine or interpartum, peripartum or postpartum, as shown in this figure. In the case of hepatitis B and C, the period of greatest risk is peripartum. The infant is exposed to infected blood at the time of delivery, and we know that viremia in the mother is an important risk factor. But highlighted by this figure is that intrauterine or intrapartum infections can also occur. The precision in the estimates of how frequently that occur are not great, but you can see that it definitely is a notable proportion, and the potential mechanisms are intraamniotic bleeding related to procedures such as chorionic villus sampling or amniocentesis or could be related to dysfunction of the placenta. So, it's important to acknowledge that that's another risk period. Also shown in this figure is that postpartum is not a risk period, really very rare that we see transmission from mother to child during this period, so that's very reassuring. So, I'm going to talk about each virus in turn around these three elements. So, starting with chronic hepatitis B, just to set the stage, 4.5 million women with chronic hepatitis B give birth annually in the U.S. and Europe. The majority of pregnant women with chronic hepatitis B are foreign born. In the U.S., we may be seeing an increase in cases related to an increasing proportion of reproductive-aged women who are using injection drugs related to opioid epidemic. That's evolving data. But shown on the right is how the number of HBV-positive women who are delivering has increased from 1988 to 2011. This graphic shows the average percent change. You can see the percent change has been greatest among women over the age of 30, but is also increasing those 20 to 29, potentially representing both women who immigrate, who are foreign born, as well as this emerging epidemic potentially related to drug use. What are the risks to the mothers who have chronic hepatitis B in terms of pregnancy risks? There are some data suggesting there may be a higher risk of intraparticular states of pregnancy and gestational diabetes, and I've shown you two recently published meta-analyses looking at these two pregnancy outcomes. You can see that for intraparticular states of pregnancy, there's an adjusted odds of 1.68 and for gestational diabetes, an adjusted odds of 1.47. Both of those are significant, so maybe something that we have to be watchful for in our patients with chronic hepatitis B. Now, not all of these studies are adjusted for other potential confounders that could account for these increased prevalence of these pregnancy complications, but nonetheless, women with chronic hepatitis B seem to have higher rates than non-chronic hepatitis B patients. There's also some data suggesting there may be some additional outcomes that are seen more often in women with chronic hepatitis B. This data is less solid with less consistency across studies, but there has been reports of preterm labor, premature rupture of membranes in large for gestational age infants that have been seen more frequently in women with chronic hepatitis B than those who do not have that infection. Mother-to-child transmission is really front and center in terms of our therapeutic focus. We recognize that the maternal viral load is an important risk factor for mother-to-child transmission. This is shown very nicely on this graphic, which shows the maternal viral load on the X-axis and the risk of transmission on the Y-axis. You can see that to the left of the red line, those women with a viral load under 5.3 log IUs per ml or less than 200,000 have a negligible risk of mother-to-child transmission, and you really only see it in women who have viral loads that are higher. Now, there are parts of the world where viral loads are not easy to come by and serological tests need to be relied upon. There's a very nice systematic review that looked at whether e-antigen was a reasonable alternative to HPV DNA levels greater than 5.3 log per IU per ml, and indeed it was shown that it's got good sensitivity and specificity in identifying women who have high viral loads. So an alternative not to be used in the U.S. where we have access to HPV DNA testing, but really in more resource-constrained settings. So for those women who have a viral load over 200,000 IUs per ml, antiviral therapy in the last trimester is recommended. These are the guidance statements. Initially, the ASLD came out with this recommendation in 2016 and in 2018 updated it to indicate that TDF was the preferred antiviral drug and specifically highlighting that there were insufficient data on TAF to recommend its use in pregnancy. Very recently, the WHO also endorsed the use of antiviral therapy for women with viral loads over 200,000 and also that TDF be the drug of choice beginning prophylaxis at week 28 of pregnancy until the time of birth. Here is a meta-analysis very recent that focuses on tenofovir-DF and very robustly shows, I think, that the risk is significantly reduced. In every study it was reduced. The magnitude in this meta-analysis was an 84% reduction over no treatment. TDF is preferred over lamibidin and talbibidin, even though those two drugs are safe in pregnancy, but tenofovir-DF was preferred because of the concerns for drug resistance with short exposures in the mothers. Now there is a very minor variability across the guidelines in terms of how we use antivirals in women during pregnancy and I highlight in the bold here where they do differ. You'll see that the apposal guidance continues to suggest that talbibidin could be a drug that can be used and they also have a higher threshold for initiation of antiviral therapy. The other difference here is that the easel recommends a treatment with antivirals at an earlier time in the pregnancy, week 24 to 28, and that's a focus of a slide that I'll get to in just a moment. Notice that all of them recommend stopping at delivery or up to 12 weeks postpartum. Breastfeeding is not contraindicated and c-section should be done for obstetrical indications only, not as a means to reduce mother-to-child transmission. Now in addition to the maternal antiviral therapy, the other pillar of preventing mother-to-child transmission is immunoprophylaxis and is shown in the box on the right. The recommendation is to give HBIG in the first dose of vaccine within 12 hours of delivery. There's actually very nice data that shows that if you give it even within four hours, that the risk of mother-child transmission is very low, even if maternal antiviral therapy is not used. But just highlighting that earlier is better in terms of maximizing the prevention of infection in the infant. The other thing to note is that in some resource-constrained areas, HBIG is not available. In fact, it can be even difficult to get vaccine. But in some areas, vaccine alone is given to the infants and there is now some discussion about whether in that scenario, extending maternal antiviral therapy for a few months postpartum might be beneficial in further reducing risk of mother-to-child transmission. That remains to be established, but an important area for further investigation. It is noteworthy that there are still great challenges on a global basis of delivering vaccine to mothers who are giving birth, many of whom are in remote areas or even doing home delivery. So this is an important area for continued focus in our elimination efforts. Coming back to this issue of when to start the antiviral therapy, as I mentioned, the ASLB guidance recommends in general that you start at weeks 28 to 30. But there are some situations in which it's recommended that earlier start of treatment should be considered and that's highlighted in this figure. It's shown here that if you have a patient who has a second trimester prenatal invasive test, has a high risk of preterm labor or has an HBV DNA level that's greater than or equal to eight logs, that that's a scenario in which you should start your tenofovir earlier. And earlier means at the beginning of the second trimester. So that's a more nuanced and I think important adjustment to the approach of using antiviral therapy in pregnant women. Turning to the effect that pregnancy has on the course of hepatitis B, this very nice prospective study looked at 158 women during pregnancy and postpartum, of which 22% started on antiviral therapy during that time. Shown on the left are e-antigen negative patients, on the right e-antigen positive patients. The time zero indicates delivery and you can see that ALT levels tended to be quite stable during pregnancy, increased modestly postpartum. But ALT flares defined by levels greater than five times upper limit of normal were very infrequent, 3.4% during pregnancy and 4.3% after pregnancy. With most of the flares occurring in the context of withdrawal of prophylactic antigen, in the context of withdrawal of prophylactic antivirals was 17.1% of the ALT flares occurring during that time, none of which were severe with elevations of bilirubin or with clinical decompensation. But because of the recognition of this period of time of being one when flares can occur, the AASLD guidance indicates that you should monitor ALT and HBV DNA levels for six months postpartum or after cessation of antivirals. Turning to chronic hepatitis C in pregnancy, the prevalence varies by country and by risk profiles and I've shown on the left some rates across the globe to give you a sense of how it does vary. In the United States, the prevalence of maternal HIV infection has increased 161% from 2009 to 2017 related to the opioid epidemic. And you can see in the graphic of the United States that it's very variable by region with the highest rates in the Appalachia region. Currently, it's estimated 4.7 cases per thousand live births. With this recognition of more women being infected with hepatitis C, AASLD and IDSA recommend universal screening for hepatitis C with each pregnancy. This is a window of opportunity to identify women who are infected and we know that risk-based screening misses many cases because providers don't ask and patients don't tell. Including HCV in routine screening is also easy given that we already have universal screening for HIV and HPV and there are very nice data showing that universal screening in pregnancy is cost-effective in the United States. Why do we need to find the women and know about them as they come into pregnancy? During that time, it's because there's a higher rate of pregnancy complications and as we'll discuss, some risk for mother-to-child transmission. But in terms of the pregnancy complications, maternal outcomes including an increased risk of intraparticular pregnancy and gestational diabetes have been identified. I'll review ICP in more detail. And important neonatal outcomes have also been seen at higher rates in women with HCV including preterm delivery, intrauterine growth restriction, low birth weight, admission to NICU and mechanical ventilation. With all of these studies, it's difficult to ascertain whether the association is related to HCV per se and this is particularly with respect to the adverse fetal outcomes or due to potential confounders meaning comorbidities such as injection drug use in the population being studied. Nonetheless, they're a group at higher risk for pregnancy complications. Regarding the intraparticular states of pregnancy, what's striking about this is the magnitude of the association. Here's a meta-analysis of studies, three studies from Europe. They found a pooled odds that indicates a 20-fold higher rate or risk of ICP and HCV positive versus HCV negative women. There's a proposed mechanism related to the downregulation by HCV of a MRP, a transporter within the liver, which is exacerbated in the setting of high estrogen or progesterone levels, so theoretically a reason why there may be an association. Regardless, the main issue is that there's a higher risk of adverse fetal outcome with ICP, so recognizing and providing appropriate therapy for this condition is imperative. And importantly, in the new AASLD guidance on reproductive health, that guidance recommends that all women with ICP should be screened for hepatitis C. What about mother-to-child transmission as shown in this table, which is reflecting three large meta-analyses? First of all, only HCV viremic women are at risk for transmitting, and unlike hepatitis B, the level of HCV RNA in the mother, we've not identified a specific threshold thus far, so all women who are viremic need to be considered at risk. Overall, the risk of child transmission is 4-6%, higher if HIV co-infection is present, up to 10-11%. There are both antepartum and peripartum factors that can be modified in order to reduce risk. In the antepartum phase, it's recommended that, if possible, to avoid invasive perinatal testing, but if it's necessary, is to avoid placental contact in order to minimize any risk of child transmission. And then at the time of delivery, avoidance of internal fetal monitoring and avoidance of rupture of membranes beyond six hours are recommended based on associations which show a higher associated odds in women with those factors. Note that mode of delivery and breastfeeding are not associated with risk of HCV transmission, so important messages to communicate to both patients and to their obstetricians. Well, we've talked a lot about the role of antiviral therapy in hepatitis B, what about in hepatitis C? While an attractive idea, none of the current DAAs are approved for use in pregnancy, though it must be admitted that they have favorable safety profile based on animal studies. But the drugs would be predicted to cross the placenta and to be excreted into the breast milk, so both the developing fetus and infant would be at risk for exposure. There are very limited data from a single phase one trial and some real-world reports, most of those reports due to accidental exposures with women conceiving while on treatment. There have been no birth defects or adverse outcomes that have been associated with exposure to the DAAs, but the numbers, as you can see, are very small. In the one U.S. study, it's a phase one trial of soft lidiposphere. They started treatment at week 23, gestation, and continued it for 12 weeks. They saw no safety concerns, no mother-child transmission, and no alteration of the PK of the drugs related to pregnancy. While these are encouraging early results, clearly more studies are needed. And then finally, what about the infants born to the HCV-infected mothers? There is a five percent risk of transmission. AASLD HCV guidance recommends that all infants be tested for anti-HCV at 18 months of age or later, with that time point selected to ensure that maternal antibody is not what's being detected. We don't do very well in terms of the follow-up of infants, and that's shown in the two studies on this slide. On the left, a study from Philadelphia in which among the 568 women giving birth, only 16 percent of the children had appropriate testing. And on the right, in a University of Pittsburgh study, they found that 30 percent of the infants underwent appropriate screening. So lack of follow-up testing represents a missed opportunity, clearly something of importance so that we can ensure that infants are identified and that they get access to treatment when they are children, since we now have therapies available for them, at least after the age of three. So the takeaways. All women should be screened for hepatitis B and C during pregnancy, an important opportunity to identify both infected women so we can manage them better during pregnancy and also ensure that they're linked with ongoing care. Chronic hepatitis B, TDF, is the pervert antiviral used to achieve an HPV DNA level less than 200,000 at the time of delivery, starting earlier in the second trimester if there's a very high viral load, risk of preterm labor or interpartum procedures that are planned. ALT flares are most frequent after antiviral therapy stops, so we need to monitor for ALT flares for a period of up to six months after delivery or after antiviral therapy stopped. Chronic hepatitis C, recognize that ICP is more frequent in the setting of ICP, should test for hepatitis C. Mother-to-child transmission is low and reduced by optimal obstetric management. Antiviral therapy during pregnancy not currently recommended. We need more safety data. And this, of course, I think emphasizes the importance of treating all reproductive-aged women so that hopefully they'll be without virus by the time they conceive. And follow-up of infants is essential for us to prevent infection or if it occurs, to ensure that they get appropriate care. Thank you very much. Greetings, and welcome to this talk, which is entitled Pregnancy and Liver Transplant Recipients, Management and Outcomes. I am Dr. Carla Brady, an associate professor in the Division of Gastroenterology at Duke University. I am a transplant hepatologist with a specialized focus on the management of liver disease and liver transplant-related care in pregnants. I have no disclosures. I will begin this talk with a brief discussion on issues of fertility among our female patients with liver disease and those who have undergone liver transplantation. And I will discuss some epidemiological data to help set the stage for an understanding of the importance of reproductive care in women who have undergone liver transplantation. End-stage liver disease can lead to disruptions in the hypothalamic-pituitary-gonadal system that decrease fertility due to decreased ovulation in amenorrhea in women and oligospermia and impotence in men. However, in the setting of liver transplantation, fertility is restored, often very rapidly, as corrections of abnormalities in the hypothalamic-gonadal axis occur on average about two to six months post-transplant. Of note, there are reports of ovulation occurring as early as the first month post-transplant. The first successful pregnancy in a liver transplant recipient was reported over 40 years ago in 1978. In recent years, we have observed increasing rates of chronic liver disease and cirrhosis in women of reproductive age. Data from the nationwide inpatient sample of the Health Care Cost and Utilization Project were used to examine pregnancy outcomes in women between 1998 and 2014. During that time period, researchers were able to identify 1,165 births among women, and they observed that births across that time period increased. Much of what is known about pregnancy outcomes comes from registry data. The largest registry is the Transplant Pregnancy Registry International, or TPR, also formally known as the National Transplantation Pregnancy Registry. This was established in 1991 and has actively collected data on pregnancy outcomes in transplant recipients in North America, with extension of registry enrollment to international transplant recipients as of 2016. Its most recent annual report was issued in September of 2019, and at that time had data on thousands of pregnancies in female recipients and pregnancies fathered by male recipients. Data from this registry will be included in this talk. Important data from the TPR has revealed that about 40% of pregnancies in liver transplant recipients are unplanned. This is much higher than the rate of mistimed or unwanted pregnancies in the general population. Unplanned pregnancies in liver transplant patients tend to occur in younger recipients, and the time from transplant to conception of pregnancy is shorter in those with unplanned pregnancies. Other data have demonstrated that the rates of pregnancies in recipients who are less than one year post-transplant is 10 to 11%. These data are significant in that the timing of pregnancy post-liver transplant can influence outcomes. What are the known outcomes of pregnancy in liver transplant patients? Maternal and fetal complications in liver transplant recipients are higher than those in the general population. Preconception diabetes is common in liver transplant recipients, and the incidence of gestational diabetes mellitus is about 7 to 10%. Registry data have demonstrated higher rates of gestational diabetes mellitus with tacrolimus-based immunosuppression compared to cyclosporine-based immunosuppression, and providers have advocated for earlier glucose tolerance testing and aggressive glycemic control to lessen risk associated with gestational diabetes, which include fetal macrosomia, preeclampsia, and cesarean delivery. Hypertensive disorders are also more common in pregnant liver transplant recipients. Hypertensive disorders in pregnancy include a spectrum of chronic hypertension, gestational hypertension, and preeclampsia. Many studies on pregnancy outcomes in liver transplant recipients do not distinguish between these individual disorders along the spectrum of hypertensive disease in pregnancy. However, recent data have shown rates of hypertensive disorders as high as 36%. Registry data have demonstrated a preeclampsia rate of 20%. The increased incidence is likely due to vasoconstriction from calcineurin inhibitors and altered renal function. The Transplant Pregnancy Registry has reported a liver allograft rejection rate of 4.4% in pregnant women, with graft loss occurring in 3% within two years of delivery. Other data have demonstrated much higher rates of acute rejection in pregnant women who conceived at one year or earlier post-transplant, and across studies, postpartum rejection appears to occur in up to 10%. This underscores the importance of ensuring stable liver allograft function before pregnancy. Interestingly, pooled data on the live birth rate in pregnancies conceived in liver transplant recipients is 75%, which is higher than live birth rate in the general population. However, rates of preterm deliveries, low birth weight, and C-section are higher in the liver transplant population compared to the general population. Stillbirths and ectopic pregnancy rates in liver transplant recipients are low, and miscarriage rates approach that of the general population. The most recent TPR report examined potential differences in outcomes among pregnancies that were planned compared to pregnancies that were unplanned. Among the listed outcomes on this slide, trends were seen in increased rates of C-section, hypertension, gestational diabetes, acute rejection, and graft loss among unplanned pregnancies compared to planned pregnancies. However, the only statistically significant difference among outcomes in this table is the significantly higher rate of termination of pregnancy in unplanned pregnancies compared to planned pregnancies. We have reviewed epidemiology data and data on outcomes of pregnancies in liver transplant recipients. How do we manage these patients' liver allograft function in the setting of pregnancy? Calcineurin inhibitors are the primary immunosuppression for liver transplant patients. Although there have been early reports of an association of calcineurin inhibitors with intrauterine growth restriction, hypertension, preeclampsia, and premature rupture of membranes, calcineurin inhibitors can be taken in pregnancy and during lactation. Mycophenolic acid products are associated with a significant risk of miscarriage and birth defects and are thus contraindicated in pregnancy and are not advised for use during lactation. Safety data on mTOR inhibitors are limited and thus not recommended in pregnancy or lactation. Although there are reports of potential adverse events associated with prednisone and azathioprine use in this setting, it is believed that the wealth of data from transplant and non-transplant disciplines indicates that both of these drugs can be used in pregnancy and lactation. In cases of patients needing to discontinue mycophenolate due to interest in pregnancy, a conversion to azathioprine with or without uptitration of prednisone dosing would be a good alternative to mycophenolate. The optimal dosing for calcineurin inhibitors in pregnant liver transplant patients is not known. Kidney transplant data suggests a 20 to 25 percent increase in dosing of calcineurin inhibitors in pregnancy. There are a number of physiologic changes in pregnancy that influence metabolism of tacrolimus, including increases in CYP3A activity and pregnancy-related altered volume of distribution, weight gain, increased total body water, increased glomerular filtration rates, and increased activity of renal transporters. There are also decreases in hemoglobin and albumin. These factors affect tacrolimus binding and can reduce whole blood concentrations of tacrolimus trough levels. Trough levels adjust for whole blood concentration, but the unbound concentration of tacrolimus is the active form of the drug and remains unchanged in pregnancy. Thus, trough goals for tacrolimus should be established based on medical and allograft function history, the use of other medications, and the possible impact of the unbound concentrations on the patient's health and course of pregnancy. Since mycophenolic acid products are contraindicated in pregnancy, a mycophenolate risk evaluation and mitigation strategies, or RIMS, program has been designed to provide provider and patient education and collect data on mycophenolate use in patients of reproductive age. Recommendations from this program include the need to document a negative pregnancy test within one week of starting mycophenolate. Effective contraception should be used with mycophenolate as listed on this slide. Note that these acceptable forms of contraception involve singular options of intrauterine devices, tubal ligation, or sterilization of partner vasectomy, but other commonly used forms of contraception, such as pills or barrier methods, must involve the use of these forms of contraception in combination. It must be emphasized that mycophenolate should be discontinued at least six weeks before attempts to conceive pregnancy. In terms of male reproductive considerations, animal data have demonstrated decreased sperm counts and motility with calcineurin inhibitor use, but these outcomes have not been seen in humans. There have also been concerns about possible impaired spermatogenesis, decreased sperm counts and motility, and lower free testosterone levels with sirolimus use. There are no clear human data on the effect of mycophenolic acid products on gonadal function or fertility. However, FDA labeling recommends contraception for sexually active male patients and or female partners during mycophenolic acid use in the male patient and for 90 days after discontinuation of mycophenolic acid. There are additional recommendations for avoidance of sperm donation for at least 90 days after discontinuation of mycophenolic acid. Collectively, these data and recommendations demonstrate that the timing of conception post-liver transplant is paramount to ensure transition to immunosuppression regimens that are compatible with pregnancy and to minimize the risk to the mother, fetus, and allograft. Timely reproductive counseling can address several modifiable factors that will allow patients of reproductive age to achieve their family goals safely. However, there are barriers to reproductive counseling in liver transplant patients, and such counseling often occurs less commonly than needed. A recently published single-center study examined patient and transplant provider perceptions of reproductive counseling and contraception practices in the liver transplant setting using survey data. In this study, only 37% of liver transplant patients received any reproductive health counseling, although 65% of these patients believed that reproductive health counseling is important. Among the study population, 82% of post-liver transplant patients received counseling, and among transplant recipients, only 41% used contraception in the first year post-liver transplant. 64% of transplant providers conducted counseling, and nearly all providers expressed interest in greater education on reproductive counseling, which along with prioritization of other medical issues and time constraints are barriers to reproductive counseling. However, reproductive care should be a priority in the overall care of the liver transplant patients of reproductive age. Multidisciplinary linkage with obstetricians, gynecologists, and primary care providers can enhance transplant provider education and facilitate distribution of time so as to minimize the concerns about time constraints in transplant care. Such reproductive care includes contraception management, which should be conducted in concert with obstetricians, gynecologists, and primary care. The U.S. Medical Eligibility Criteria for Contraception Use provides recommendations for use of specific contraceptive methods in persons who have certain medical conditions, and its companion document, the U.S. Selected Practice Recommendations for Contraceptive Use, provides recommendations for management questions about contraceptive use. The U.S. Medical Eligibility Criteria for Contraceptive Use ranks recommendations about contraception based on a numeric system as outlined on this slide, in which a rank of one indicates no restriction in use and four indicates that use is unacceptable due to health risk. In general, it is believed that combined hormonal contraceptives can be used in patients who have undergone solid organ transplantation as long as allograft function is stable, but graft failure or rejection are contraindications to use of combined hormonal contraceptives. I will point out on this slide that combined hormonal contraceptives can be used in cases of cholestasis, although a history of prior cholestasis with such use predicts risk for subsequent cholestasis. Progestin-only pills, depo-medroxyprogesterone acetate, and implants can be used in solid organ transplant recipients and in those with liver disease with the exception of decompensated cirrhosis. In summary, I offer the following key points which are a part of the recently published AASLD Reproductive Health Guidance Statement. Calcineurin inhibitors, azathioprine, and steroids are acceptable for use in pregnancy and lactation. Mycophenolic acid products are contraindicated in pregnancy and lactation, and contraceptive agents with low failure rates should be used. mTOR inhibitors are not recommended in pregnancy and lactation due to lack of safety data. Pregnancy should be delayed until at least one year after transplant and with at least six months or longer of stable allograft function. More frequent monitoring of graft function during and in the postpartum period is recommended. Thank you for your attention. Women's Health Program Closing Remarks. The scientific agenda of this meeting has brought together local and international experts to discuss important aspects of reproductive health management in patients with chronic liver disease. The Women's Health Program reviewed expert recommendations on the diagnostic workup and management of cholestatic liver diseases occurring in pregnancy. This program provided key information related to the prevention and management of complications occurring during pregnancy amongst cirrhotic women. The Women's Health Program provided clinical evidence supporting all preventive efforts aimed at reducing mother-to-child transmission of hepatitis C and hepatitis B infection. Our experts showed available data on the use of antiviral agents prior to conception, during pregnancy, and during lactation. The Women's Health Program delivered recommendations in the management of reproductive health issues in transplant recipients. It addressed conception and pregnancy among transplant patients and offered a review of maternal, fetal, and graft outcomes among these patients.

Liver Meeting 2020

Women's Health Program

Liver disease management

Pregnancy

Maternal health

Fetal health

Severe liver disease

Pregnancy-related liver issues

Viral-related conditions

Liver transplants

Cholestatic liver diseases

Risk stratification