My name is Avi Stolovitz, and I'm a transplant hepatologist at Columbia University Irving Medical Center. On behalf of the ASLD and the Liver Transplantation and Surgery SIG, I would like to welcome you to today's webinar on reproductive health and liver transplant recipients. Today, you'll hear from three experts in the field of hepatology who specialize in the intersection between reproductive health, liver disease, and liver transplantation. The purpose of this webinar is to summarize current practice recommendations and data on post-liver transplant fertility, contraceptive use, as well as immunosuppression management in pregnant liver transplant recipients. Our experts will also provide an overview of maternal and fetal outcomes in liver transplant recipients. Finally, we'll end today's webinar with a question and answer session led by our moderator, Dr. Tatyana Kushner. So please use the question and answer function on Zoom to send us your questions, and we will try our best to address all of these at the end of the session. This activity will be offering CME credit as both a live activity and enduring material for one year. You will receive an email within the next day to complete an evaluation and receive your certificate, and you'll also have a chance to view the recording later. Financial disclosures of all panelists for this program have been reviewed, and you may find or list our financial disclosures on the ASLD website. Any potential conflicts of interest have been mitigated. So with that, I would like to hand it over to our moderator, Dr. Tatyana Kushner, a transplant hepatologist at Weill Cornell Medical Center to introduce our first speaker. Thank you so much, Avesh, and I'm really excited to be here with really an exceptional lineup of speakers on very exciting topics. So as you see here, we have three topics that we have speakers addressing, and then as Avesh mentioned, we'll follow up with a question and answer session. The three topics listed here are starting with fertility and contraceptive use and liver transplant recipients, which will be presented by Monica Sarkar. Then we'll move to immunosuppression and pregnant liver transplant recipients, which will be led by Carla Brady. And then finally, maternal and fetal outcomes in liver transplant recipients, which will be presented by Lisa Aschia. So without further ado, I will introduce our first speaker. So it's my pleasure to introduce a good friend and colleague, Monica Sarkar. Dr. Sarkar is a transplant hepatologist at UCSF, where she runs the Women's Liver Program there. Her NIH-funded work evaluates the influence of sex hormones on liver disease and metabolism in women. She's the former chair of the ASLD Women's Committee and current co-chair of the AST Women's Health Community of Practice. It's my pleasure to turn it over to Monica. Thanks so much. Thank you, Tatiana, for that lovely and kind introduction. Share, and then you can see my slides okay? Yes, we can, perfect. All right, perfect. So I'll be starting off today's session on fertility and contraception in liver transplant recipients. And these are my disclosures, nothing relevant to today's talk. And I think we need to first set the stage by understanding why contraception counseling and understanding safety and efficacy matters in our liver transplant population. So the first being that we are seeing indeed a rise in the number of deceased donor transplants that are occurring in young adults. So here from SRTR data from 2022, you can see the most marked rise in deceased donor transplant rates among young adults between the ages of 18 to 49. And 40% of all of these patients are female transplant recipients. And I think we all know that fertility is markedly impaired in the setting of end organ disease, chronic disease. This happens across many different subspecialties and conditions, and we are not immune from that. So when we see patients who have cirrhosis who progressed on to decompensation, we know that derangements happen at the level of the hypothalamus, where there's impairment in the pulsativity of gonadotropin-releasing hormone. That affects the pituitary, so there's impairment in the release of FSH and LH, which are very key for follicle development of the level of the ovaries, estradiol production, and really important for what we call the LH surge or the release of an egg. So needless to say, we oftentimes, as our patients are going into transplant, they will have impaired menses due to these metabolic and sex hormonal changes. But most of our patients, 75%, will have regular menstrual cycles by one year after transplant, though menses will happen much earlier. So even within the first week to two weeks after their operation, menstrual cycles will begin to resume and our patients can indeed get pregnant. But it's really these early and unintended pregnancies that confer the greatest risk to our population. So these are data that we recently published with Lisa Kossia, who we'll hear from in just a little bit from the Transplant Pregnancy Registry International. And we looked at about 565 pregnancies, about 39% of these were unintended. Those with unintended pregnancies were much more likely to be using mycophenolic acid products, which are highly teratogenic, have acute cellular rejection, babies with lower medium birth weight, and then a higher risk of graft loss at last follow-up. And then when we assess what our patients and our transplant providers know regarding sexual health knowledge and practice, we've identified some notable deficiencies. So these were data that we published back in 2020 at our own center at UCSF. And in this part of our survey, we assessed those who reported being sexually active within one year of their liver transplant. So that was 46 recipients. 41% of them were using any form of contraception. So meaning the majority of our patients were using no contraception, despite being sexually active during that very high risk period for pregnancy. And of those individuals who were using some form of contraception, over a third relied on high failure methods like condoms, rhythm withdrawal. So not surprisingly, over a third of these pregnancies that were reported in our cohort were indeed unplanned. And then when we asked some provider knowledge about what's safe and efficacious as far as contraceptive options go in our transplant recipients, 53% of our transplant providers thought that estrogens were unsafe, and 42% thought that IUDs were unsafe in transplant patients. So we'll be working on dispelling some of these myths in the subsequent slides. And we also asked our patients, how do you want to learn about pregnancy planning? What's safe for you when it comes to use of contraceptive agents in the post-transplant time period? And we offered many different modalities of learning about this information. These included videos in clinic, handouts, links to online resources. And as you can see, the single most favored modality by our patients to understand sexual and reproductive health was a discussion with their transplant provider, more so than providers in women's health who may be deemed real experts in this content area. So really emphasizing the role, the very important role that we as transplant providers have in at least initiating these discussions. So there are a breadth of different contraceptive options, but what I want to convey over the subsequent slides are some salient points for you to be able to understand and provide some real basic counseling when it comes to what is safe and can be used in our transplant population. And as I talk about these options, I'll break them down into three big categories. The first being combined hormonal contraception, so that includes an estrogen and a progestin, progestin-only agents, and then we'll finish up by talking about the IUDs. So when we think about combined hormonal contraception, this has an estrogen and a progestin. And as you can see, the three main types that, or formulations that these come in include the vaginal ring, the skin patch, as well as the pills. Risk of elevated liver enzymes is no greater than placebo. So with modern day preparations that have much lower doses of estradiol than those in the past. Safety concerns really are focused on risk of venous thromboembolism. And that risk is about three to nine out of 10,000 CHC users per year, but that's also compared to about five out of 10,000 non-CHC users. So absolute risk is low, but certainly higher and too high for us to routinely recommend these for certain higher risk populations, which we'll get into in a subsequent slide. Rare risk of cholestatic liver injury can occur, very rare risk of stroke, though we do more commonly see increase in blood pressure. So not a great agent for our patients who have poorly controlled blood pressure. And then we have to be aware of drug-drug interactions because these agents are metabolized by the P450 system. There are some data, some older pharmacologic data that suggests that these agents might raise the levels of calcineurin inhibitors. My recommendation is simply doing weekly monitoring of TAC, for example, for the first couple of weeks that they start these agents, but I have not, in my experience, actually had to modify drug levels based on that. Failure rates are around 9%, so that's decently high, although much lower than 18 to 22% that we see for condoms, Rhythm, or Wdraw, for example. And we have limited data in liver disease with no existing controlled studies. I will share with you data that we presented at ASLD last month from our own center. This included 74 reproductive age liver transplant recipients, and we looked at distinct contraceptive exposure windows of at least 90 days. Median time from transplant to contraception was just over three years. We had 35 users of combined hormonal contraceptives, 13 with a Depro-Provera shot, seven progestin-only pills. We'll talk about those in a moment, and then 41 IUT users. And we found no unintended pregnancies, venous thromboembolism events, stroke, or PID. Incident hypertension upon initiation of combined hormonal contraceptive use was also low at less than 6%. Now, because we have such limited data when it comes to contraceptive safety and efficacy in patients with liver disease and liver transplant, we do really rely on expert guidance. So here I've shown you the ASLD reproductive health guidance that was published in 2021, and I'll be talking about our recommendations on behalf of that. This past year, the CDC updated their own medical eligibility criteria for contraceptive use. So as I talk about the different categories, I'll let you know if and where there's some discrepancy with the CDC and ASLD RECs. So as we think about combined hormonal contraception, I do wanna talk about or let you know what's safe for cirrhosis as you're thinking about the pre to post-transplant journey. So as long as a patient has compensated cirrhosis, they have adequate function to be able to metabolize these agents, these are safe and acceptable for use at any time point over the course of their management of their liver disease. It's really those patients who progressed onto decompensation, our child's B, C cirrhosis, and whom we should avoid use of combined hormonal contraception. That is the same profile as we think about patients in the post-transplant setting. So as long as the patient doesn't have graft failure, we can comfortably use combined hormonal contraceptives. It's those patients who have progressed onto graft failure with recurrent decompensated cirrhosis and whom these agents should be avoided. Now, as we move on to think about progestin-only contraception, one option is the progestin-only pill or POPs. Failure rate also around 9%, so same as combined hormonal contraceptives. They don't have estradiol with the risk of VTE, hypertension, or stroke, so that's great, we don't have to worry about those side effects. They do usually require taking or use within the same three-hour window daily. So it could be a little bit more challenging for patients with adherence issues. But an important point is that the FDA approved the first ever over-the-counter contraceptive in the United States, and this is indeed a progestin-only pill, known as the OPIL. So given its incredibly safe safety profile, this can be picked up and taken by any of our transplant recipients, regardless of their graft function. Now, the subcutaneous implant is also a progestin-only contraceptive. Pros are it has the lowest failure rate of any agent that we have available on the market at only 0.05%. Also, no estrogen-related risks. We don't have to worry about adherence either. You just place it in the subcutaneous tissue under the arm, can stay in for three years, although it does require a dedicated provider visit for insertion of the device. And the last one in this bucket of the progestin-only contraception that I wanna mention is the DepoShot, or DMPA. Failure rate of around 6%. As a potential pro, some patients like that they have to, they only need to go in every three months for an ejection. But the cons are really more emerging health concerns. It has long had a black box warning against reversible bone loss, meaning once patients stop it, bone density returns to normal. We don't know how that plays out in patients who have underlying osteopenia, osteoporosis, who have, or risk for osteopenia, osteoporosis, such as our patients with cholestasis, cirrhosis, post-transplant steroid use. So for that reason, I think it's given many of us pause for routine recommendation in our patient population. And now there's more emerging data about VTE risk. So this was a meta-analysis that was published a couple of years ago, and it demonstrated an increase in VTE risk with Depo. And this was not observed for these other formulations of progestin-only contraceptives. Of note, these other two options that were associated with an increase of VTE use are higher dose that are used for other medical indications, like heavy menstrual bleeding, for example, so not contraceptive preparations. So DMPA is the only progestin-only contraceptive that confers that increase in VTE risk, and that relates to its unique activity on thrombin receptors. So how do we kind of summarize that when we're thinking about our patients with liver transplant? No restrictions when we think about progestin-only pills or the subcutaneous implant, regardless of graft function. DMPA, less favored for the reasons I mentioned before. The CDC comes down a little bit more strongly than the ASLD when it comes to graft failure, suggesting that risks may outweigh the benefits. All right, so now turning to the last big category of contraceptive options being the IUDs, or intrauterine devices. So I love this slide. I've modified it from Planned Parenthood, and it shows you the two main options, progestin-only, which is the hormonal IUD, and the copper. So when we use the word hormonal IUD, it refers to progestin-only agents. There's no such thing as an IUD that has estrogen. So for the progestin-only, depending on which one you use, it can last anywhere from three to seven years. It's low-dose progestin. One really advantageous aspect of this agent is it lightens menstrual bleeding and menstrual cramping. So particularly favorable for our patients who have underlying thrombocytopenia anemia. Copper can stay in much longer, up to 12 years. It's hormone-free, but it does increase menstrual bleeding. So less ideal for those patients who do have thrombocytopenia anemia. When we think about IUD efficacy and safety in transplant, there were two older case reports back in the late 70s that got published in 1981 that showed failure of these agents at preventing pregnancy. But subsequent to that, these older case reports with older device use, there have been no reports of unintended pregnancy. There's also been no reports of pelvic inflammatory disease. And that's important because historically there were myths regarding concerns with IUDs increasing the risk of pelvic inflammatory disease as a foreign body in immunocompromised patients. And we have really robust data from HIV-infected patients, other patients on long-term immunosuppression that demonstrate that PID risk is no higher than in patients without an IUD. So that myth has also been dispelled. So in the context of liver transplant, you can readily use combined hormonal contraceptives, progestin-only pills, a subcutaneous implant, or IUDs. DMPA are not contraindicated, but less favored as I mentioned. And it's really just those patients with graft failure and whom you should really avoid the estrogen-containing agents due to the potential for impaired metabolism and higher side effect profile, particularly when we think about hypertensive complications and VTE risk. I do wanna take a moment to comment on emergency contraception. As you're all aware, we're having growing restrictions in the ability to access pregnancy termination across the United States, which we anticipate is only gonna be worsening over time. So for many of our patients, including our adolescents, our patients with poorly controlled graft function who have unprotected sex, this may be the only modality or option for them to prevent an unplanned, unintended pregnancy. So use needs to be within three to five days of unprotected intercourse. Options include any IUD, so either the progestin-only or the copper. The nice thing about that is then you can just leave it in place to serve as long-term contraceptive. Olapristol is an option, or the levonorgestrel pill, also known as Plan B, which does not require a prescription. And it's safe regardless of liver function, graft function. So severity of graft failure does not play a role here. It's much more dangerous for these patients to have an unintended, undesired pregnancy. I did wanna share some new patient education materials. This was just launched on behalf of the Women's Health Community of Practice. We released this about a month ago, and this really summarizes for patients. It's a three-page brochure about the different options, the pros and cons as we're thinking about use in solid organ transplant. There's also a dedicated section here in this manual about emergency contraception and just thinking through what's safe and efficacious following your organ transplant. And then here's the blurb that we provide here in this contraceptive document on the different modalities for emergency contraception. So I'll stop there and turn it over to the next speaker. Thank you for your attention. Thank you so much, Monica. That was such an excellent, comprehensive overview. And just a reminder to everyone that you can please place any questions that you have in the Q&A box, and we will get to them hopefully at the end. But as questions come up, please feel free to enter them into the Q&A box. Okay, so we're shifting gears now from contraception to pregnancy, and I will introduce our next speaker, who is Carla Brady. She is a professor in the Division of Gastroenterology at Duke University Medical Center, having been a faculty member within the division since 2006. Additionally, she serves as the Vice Chair for Faculty Development for the Duke Department of Medicine. She's a transplant hepatologist with expertise in liver disease and liver transplantation from a women's health perspective, particularly at the intersection of reproductive health, liver disease, and liver transplantation. Dr. Brady has authored various manuscripts on liver disease and pregnancy and liver disease and menopause, including the first ASLD Practice Guidance on Reproductive Health and Liver Disease, which we just heard about. She's currently completing a term on the ASLD Governing Board as Secretary and has served in other roles within the ASLD, including service as Chair of the Inclusion and Diversity Committee and as a member of its Scientific Program Committee and Nominating Committee. So it's my pleasure to turn it over to Carla, who will be discussing immunosuppression in pregnant liver transplant recipients and the impact of immunosuppression medication on breastfeeding as well. All right. Thank you. Are you able to see my slides? We are, yes, perfect. It's not in slideshow view, but we see them. Perfect, thanks. They should be in slideshow view now. Perfect, yes. Great. Thank you for the opportunity to talk about this very important topic. I have no financial disclosures. And I'm going to start with talking about a very simple and foundational question, which is what is the recommended timing for pregnancy after liver transplantation? There have been published guideline statements regarding this. The AASLD has published guidance on this topic stating that pregnancy should be delayed until at least one year after transplant and with greater than or equal to six months of stable allograft function. And the American Society of Transplantation has also published a guidance statement on this topic stating that if a patient has adequate and stable graft function, is at low risk for opportunistic infections and is not taking teratogenic medications, then pregnancy could be attempted after at least one year post-transplant and as long as there are no concerns about any otherwise increased risks. And what I think is important to understand about these two guidance statements that will help the stage for today's portion of this discussion is the fact that this question is answered on the basis of whether or not allograft function is stable. And at the core of that is understanding how to manage immunosuppression to get to that point. So we're gonna first talk about the specifics of immunosuppression considerations for our pregnant liver transplant patients. And I'll be focusing my discussion about immunosuppression on our calcineurin inhibitors, our antiproliferative agents that we use such as azathioprine and mycophenolic acid products and the mTOR inhibitors, sirolimus and abirelimus. And I will also talk about corticosteroids, namely pretinazone. In immunosuppression management for solid organ transplantation, there have been emerging data about the use of bilaticept in this patient population. We do know that bilaticept is FDA approved for use in adult kidney transplant recipients who are EBV positive, and it can be used as a means of avoiding calcineurin inhibitor use. We don't really use it in liver transplantation, but there are some emerging data about the use of this medication in pregnancy and in breastfeeding suggesting outcomes similar to what have been observed in patients that are on calcineurin inhibitor based regimens. And there is a case report about the use of bilaticept in a liver transplant recipient who was pregnant suggesting favorable outcomes, but additional data are needed. So we won't talk more about this particular agent and we will stick to the others that I just mentioned. So in order to understand how immunosuppression is used in pregnancy and how effective it will be for solid organ transplant recipients and namely our liver patients who are pregnant, we need to understand that pregnancy physiology impacts the pharmacokinetics and pharmacodynamics of immunosuppression. In the context of pregnancy, we see increases in plasma volume and increased volume of distribution, as well as changes in protein binding and the increase in hepatic activity of cytochrome P450 proteins. And this can affect the volume or the concentration of the immunosuppression in our pregnant patients. We can see delays in gastric emptying and slower bowel transit, and that can affect absorption of immunosuppression medications. And we can also see increases in estimated GFR that can lead to changes in the excretion of the metabolites of these medications. And because of these changes, we can see reductions in whole blood concentrations of immunosuppression, namely our calcineurin inhibitors. And because of this, the optimal dose of calcineurin inhibitors in pregnancy is not actually known. And so there are guidance statements recommending monitoring of trough levels about every two to four weeks during pregnancy with dosing guided by liver test to help us estimate how well liver allograft function is in this setting and by trough levels. In terms of the specific immunosuppression recommendations that are made in pregnancy, it is acceptable for use of calcineurin inhibitors, corticosteroids, namely prednisone, and azathioprine to continue in pregnancy. Whereas expert guidance has recommended that there is discontinuation of use of mycophenolic acid products and mTOR inhibitors in the context of pregnancy. And I will talk about this more in the ensuing slides. In terms of calcineurin inhibitor use in pregnancy, there are data to suggest an association with preterm birth, fetal growth restriction, and low birth weight. And there are dose-related associations with expected side effects of CNIs, including hypertension, hyperglycemia, AKI, electrolyte abnormalities, and peripheral neuropathy. But overall, weighing risk and benefits, it's felt as though on the basis of published data that the use of CNIs in pregnancy is considered to be low risk and therefore acceptable. When it comes to use of MPAs, or mycophenolic acid products in pregnancy, we see an association with teratogenicity, and we can see an increase in first trimester spontaneous abortions in up to 50% of this patient population. And therefore, MPAs are contraindicated for use in pregnancy. There are recommendations to discontinue the use of MPAs six weeks prior to pregnancy. This is based upon expert guidance and our societal guidance statements. However, the manufacturers suggest discontinuation for up to 90 days. And if sexually active, patients should be using effective contraception while taking these products and for six weeks after stopping them. We have limited data about the use of mTOR inhibitors in pregnancy. There are case reports about this, and probably the largest series of reported data on this comes from the Transplant Pregnancy Registry International data. From these data, we have seen more reports of pregnancies conceived on sirolimus compared to everolimus, but overall, the outcomes do suggest outcomes that are similar to pregnancies conceived on calcineurin inhibitors, with miscarriage rates of less than 20%, live birth rates greater than 75%, and only three birth defects reported. There have been earlier concerns about a possible association with congenital defects and the birth defects that were seen in the pregnancy registry data are as I've listed on this slide. And because of the limitations about the data regarding the safety of this class of immunosuppression in pregnancy, it is not recommended for use in this circumstance. Regarding use of corticosteroids, namely prednisone in pregnancy, there are some conflicting data about risk regarding development of oral clefts. We may see some dose-dependent side effects that are typical of what we would expect with increasing doses of steroid therapy, even in non-pregnant patients. And there have been associations with preterm premature rupture of membranes and fetal growth restriction. But overall, again, weighing risk and benefits, it's felt as though corticosteroid use is thought to be acceptable for use in pregnancy. And actually, steroid use can be beneficial in this context because you could use this with a calcineurin inhibitor-based regimen to maintain adequate immunosuppression, thereby swapping out the mycophenolic acid product for prednisone. Azathioprine has also had an association with preterm birth and fetal growth restriction on the basis of prior published data, but it does not appear to be associated with teratogenicity and therefore, again, weighing risk and benefits, it is thought to be acceptable for use in pregnancy. And just like with steroid therapy, you could replace mycophenolic acid products with azathioprine in patients who are planning to conceive a pregnancy or those who are already pregnant. And just a word about immunosuppression and breastfeeding. Registry data have been showing increasing trends in the number of transplant recipients who breastfeed their infants. And in fact, there are strong recommendations from the American Academy of Pediatrics regarding breastfeeding in the first six months after a baby is born and up to two years thereafter if it is possible for the mother to continue breastfeeding. And therefore, with these strong recommendations, it is not surprising that we have been seeing increasing trends in the number of our transplant recipients who are making choices to breastfeed their infants. And data have shown favorable outcomes with breastfeeding and the setting of the same immunosuppression agents that we otherwise deem to be compatible with pregnancy. And so as you can see from this slide, based upon expert guidance, it is considered that calcineurin inhibitor use, corticosteroid use, and azathioprine are acceptable in the context of breastfeeding. Mycophenolic acid products are not advised to continue in the context of breastfeeding. This is not because of known data regarding negative outcomes specifically in the context of breastfeeding, but it's based upon an extrapolation of data regarding negative outcomes regarding pregnancy and use of mycophenolic acid products. So this is the reason why it has not been advised for use in breastfeeding. And because of limited data regarding the use of mTOR inhibitors in breastfeeding, just like in pregnancy, there are no expert guidance recommendations for using mTOR inhibitors in the context of breastfeeding. I would like to point your attention to a reference that can help to guide decisions about use of immunosuppression medications, and in fact, all medications in the context of breastfeeding. This is a database known as the Drugs and Lactation Database or more frequently referred to as LACT-MED. This functions very similarly to LiverTOX, which is a database that many of us use in order to determine if there's concern for drug-induced liver injury. With LACT-MED, if you go to this website, you can put in the medication that you have interest in understanding. It's whether or not it's safe for use in the context of breastfeeding, and it will bring up for you scientific data regarding any reports about outcomes of that drug in the context of breastfeeding, and then recommendations regarding whether or not it can be considered as safe for use in that context. And then a brief word about reproductive considerations for male transplant recipients. In general, it's felt as though there are no negative outcomes regarding pregnancies fathered by transplant recipients who are on calcineurin inhibitor-based regimens. However, given the fact that there is concerns for teratogenicity regarding pregnancies who are conceived by pregnant patients who are taking mycophenolic acid products, there are questions regarding whether or not there are negative outcomes regarding pregnancies fathered by male transplant recipients who are taking these agents. The manufacturer recommendations for mycophenolic acid use in these patients states that sexually active male patients and or their female partners are recommended to use effective contraception during the treatment of that male patient's allograft function, and for at least 90 days after cessation of treatment. However, there are pregnancy registry data as well as data published from institutional-based studies that suggest no increase in adverse pregnancy outcomes resulting from pregnancies fathered by male recipients taking MPAs. So I think more data are needed in order to determine what the actual guidance should be regarding this. And then regarding the use of mTOR inhibitors, in terms of its impact on fertility in men, there have been associations with decrease in sperm counts and motility as well as altered testosterone synthesis and impaired spermatogenesis. However, pregnancy registry data have suggested that regarding outcomes of pregnancies fathered by men who are taking mTOR inhibitors, those pregnancies are thought to have reasonably good outcomes, with only one miscarriage and three birth defects reported. And so therefore, more data are needed to understand whether or not there would be any concerns about the outcomes of these pregnancies. And so putting it all together, it's really important in terms of immunosuppression management to understand the timing of pregnancy post-liver transplant. We want to wait at least a minimum of one year post-transplant before thinking about conception of a pregnancy. We want to ensure stable liver allograft function and that the immunosuppression regimen is compatible with pregnancy. Those agents that are considered compatible with pregnancy and breastfeeding currently are calcineurin inhibitors, corticosteroids and azathioprine. And the immunosuppression agents that are recommended to be avoided in pregnancy are MPAs and mTOR inhibitors. And the actions that need to be taken in terms of reproductive health planning and transplant recipients need to include ongoing education about the importance of pregnancy planning. We need to identify the timing in which liver transplant recipients are interested in conceiving a pregnancy so we can enact plans that will help to ensure that they conceive pregnancies with the best possible outcomes. And with that timing, we need to ensure that we are employing immunosuppression management strategies that will support optimal pregnancy outcomes. And with that, I will conclude and thank you for your attention. Thank you so much, Carla. That was really an excellent overview and really encouraging to hear that as long as these discussions are had in a timely manner, that people can have healthy pregnancies, healthy outcomes on immunosuppression medication, but I think really emphasizing the importance of having these discussions early to make sure that things happen the way you hope that they will. All right, and so now we'll move to our last section and I will introduce Lisa Kassia. She has dedicated her career to the field of transplantation, including as a staff nurse transplant coordinator and has been with the Transplant Pregnancy Registry International or the TPRI for over 26 years and is currently the senior nurse research coordinator. Lisa is active in the transplant community, especially with the American Society of Transplantation as a past chair of the Women's Health Community of Practice and was elected as a counselor at large for the AST Board of Directors. She was also a past board member of the International Transplant Nurses Society. Lisa has authored numerous publications and has presented nationally and internationally on the topics of contraception and pregnancy after liver transplantation. So I will turn it over to Lisa to discuss maternal and fetal outcomes in liver transplant recipients. Thanks so much. Thank you so much, Tatiana, for that wonderful introduction and I'm very excited to present today. So let's just get right into it. The Transplant Pregnancy Registry International is one of the largest registry for solid organ transplant recipients reporting pregnancies and it was established in 1991 and we expanded in 2018 to include international participants as well and we do include all pregnancy outcomes. The methods are a retrospective cohort analysis and patients voluntarily self-report their information. We have questionnaires, telephone interviews, we look at medical records and then we're able to access obituaries and we really collect all patient reported information about their comorbidities, rejection, graft loss and long-term child health as well because we do call patients every two years to see how they're doing, their children are doing and their transplant. So we do collect information from all over the world. This is kind of our, we have about over 3,000 patients and someone from every continent. Overall, most of the patients are kidney recipients, that is the organ that is transplanted the most. However, the second largest is that of our liver recipients and it's really been encouraging over the years to see this group grow as well and that's where I'll be focusing, obviously, this presentation on today. I did wanna mention that we do collect information on male patients as well and we do not hear from them as much because they don't obviously think that they can be part of a pregnancy registry. So the majority of the information that I will be presenting today is from our annual report from 2022 and we will be updating this report with data from the end of 2024 and this is available upon request. So I'm happy to send this to any patients or any providers and any published information that we have, I will always send it when requested. So what do the outcomes look like? So I kept the kidney transplant outcomes on there as well so you can kind of get a comparison. I always like to say our liver patients actually do kind of the best with pregnancy after transplant and what you can see is that the liver recipients are much younger at their age at first transplant and we see a lot of patients who had their transplant as a child with years of immunosuppressive exposure going on to have babies much later in life and that is reflected in this transplant to conception interval as well, being almost double that of what we see in our kidney recipients. And I also think it's interesting to look at the conception range really from the time of the early liver transplant patients when they were receiving them in the mid 80s all the way to modern times we see pregnancies occurring. I think it's interesting to note the difference in hypertension between our kidney and liver recipients which you'll probably notice is reflected in the fetal outcomes as well. So less than like 21% of our liver recipients report using drugs to treat their hypertension during pregnancy. This percentage here is not gestational hypertension but just drug use for hypertension during pregnancy and that's similar to diabetes. This is just insulin use during pregnancy not gestational diabetes. And I think it's interesting to note that preeclampsia still occurs in a higher rate than we see in the general population but much less once again than our kidney recipients. And overall and across all recipients we really do not see a high rate of rejection. And I think this is reflected in graft loss within two years of pregnancy which is very low in our liver recipients. And what are the fetal outcomes look like? So overall the live birth rate is about 73% and this has been pretty stable across eras in the transplant pregnancy registry. As you can see the liver recipient offsprings are born a little bit closer to term almost 37 weeks. We see less prematurity and higher birth weights in our offspring as well. However, we still continue to see a high percentage of cesarean section births, despite several studies and long-term recommendation of a trial of labor prior to going right to cesarean section. So it's something, you know, to think about that we really don't want these patients who are immunosuppressed having another surgery if that could be prevented. And overall, the birth defect rate has been kind of in that general range of three to 5%, despite mycophenolate exposures in this group. So when we pull them out, we see a higher percentage, but when we kind of lump everything together, we see the birth defect rate being similar to that of the general population, and overall low percentage of neonatal deaths. So Monica had briefly shown this, but I just wanna get into this a little bit more because I feel like 40% of unintended pregnancies is really high for this high-risk population. And you can see that an unintended or unplanned pregnancy does have consequences for graft and birth outcomes. So as Monica mentioned, much higher use of mycophenolate. You can think if someone's not planning a pregnancy, they're gonna have that exposure when they become pregnant. We see a higher rates of acute cellular rejection. So patients might not have that nice stable transplant function we're looking for prior to a planned pregnancy, lower birth weights, and also graft loss, higher percentage and statistically significant in this group. So another outcome that we've looked at, which was recently also presented at AASLD is intracholestatic, ICP, intrahepatic cholestasis of pregnancy in our liver recipients. And we do see it reported at a much higher percentage in our liver recipients compared to the general population. And this group did consist of patients from 14 countries and the most identified as white and non-Hispanic. And the mean conception age was about 30. And what we also saw in this group, okay, slides are not going forward. Let's see here, here we go, is that there were other risk factors associated with ICP, including gestational diabetes and viral hepatitis as a cause of their liver transplant. So you can see here the odds ratio of the gestational diabetes and the viral hepatitis. However, the pregnancy number post liver transplant, so if they had more than one pregnancy, we did not see that, time from transplant to pregnancy, or if a cholestatic liver disease was their pre-liver transplant diagnosis. Additionally, ICP was associated with increased risk of adverse fetal outcomes and a huge increase in the liver transplant loss within two years of pregnancy, despite rejection after pregnancy not being increased risk. So it's really something that needs to be looked at. And patients that do have ICP during pregnancy really need that close follow-up postpartum. So in summary, we do see a high prevalence of ICP in the post liver transplant population. It is associated with diabetes and viral hepatitis as cause of liver transplant. And it's something to think about with increased risks of pregnancy, looking at bile acid testing and preemptive eryso use might be as strongly recommended in these patients. And really given that huge 22-fold increase risk of graft loss within two years, thinking about more invasive monitoring and really frequent LFT checks and lowering the threshold for biopsy in these postpartum patients. So I also wanted to show you some outcomes of IVF use in early liver transplant recipients. So we did a study looking at those that conceived naturally versus those who used in vitro fertilization in order to become pregnant. And in this group, you can see that the conception age was much higher in those that had IVF. However, successful pregnancy prior to transplant was no different. Either was graft function or graft loss after pregnancy and maternal mortality was similar. And overall, we did see more multiple gestations in the IVF cohort. However, overall birth outcomes were very similar between the two groups. Also similar were the neonatal outcomes, really no difference in gestational age, birth defects, and the majority were reported healthy at birth. There were about 5% of our liver patients using IVF. We didn't always ask this question. So some of our older participants might not have been asked this question, but we have gone back and asked it retrospectively as well for those patients that we can still reach. There was no difference in chronic hypertension, preeclampsia. However, there was a slightly higher, there was a higher percentage of diabetes in the IVF group, which might reflect that the age of the patients as well. And there was one maternal death in the IVF group and that was 24 years post-transplant and nine years postpartum. And the cause of death was unknown. We did look at graft survival compared with unassisted reproductive, you know, if they did not use any reproductive assistance, IVF, IUI, and then medication only. And there was no difference in the risk of allograft failure or mortality when comparing these pregnancies. So in summary, recipients of childbearing age should be counseled regarding the feasibility and timing of pregnancy after transplant. Overall, outcomes have been very favorable. If preconception, transplant function is good and stable with immunosuppression at maintenance doses. It is vital that women are aware of the potential for pregnancy. We really wanna have a planned pregnancy in these groups and really eliminate that fetal mycophenolate exposure. All pregnancies after transplant are considered high risk due to increased percentages of high blood pressure, preeclampsia, intrahepatic cholestasis of pregnancy and prematurity. And even though these percentages were less than our kidney recipients, they're still much higher than we see in the general population. And really the TPRI serves as a resource for recipients and their healthcare providers when making family planning decisions. And I just wanted to put our contact information here and we do send a small token of our appreciation to patients when they deliver. And thank you very much for your time. And I'm looking forward to our question and answer period as well. That was excellent. Thank you so much, Lisa. That was great and really just excellent to know that this registry exists and to put the word out there and that over time we're really collecting this real world data that can be so useful for patients and providers in counseling their patients. So we have a few minutes left for questions and I see there are some questions in the Q&A, but please feel free to add questions if you have any. And I think we'll start from the top with the questions in the Q&A. There was one actually, Monica, that I think you already addressed, but just for everyone to hear from you as well. The question that was asked was, is it generally safe to continue initiate CHCs in the immediate post-transplant period? And expanding on that, when should you be starting these CHCs and other contraceptive medications? How soon after should you really be thinking about this? Great. Thank you, Tatiana. And I think it was Ashina Singh who submitted that question. Thank you. Great question. So generally our patients who are going on to transplant have decompensated cirrhosis. So they're usually a population in whom combined hormonal contraceptives are not recommended, but that's not always the case. We have patients on them for other reasons. Patients have underlying compensated hep B with HCC is a smaller proportion of our reproductive age group. But for patients who are on CHCs and it's safe to do so, they can continue it through the transplant time course. ACOG, so American College of Obstetrics and Gynecology only advises holding combined hormonal contraceptive if there's anticipated prolonged immobility in a post-transplant period. I will say that there's also variability center to center how you plan for patients who are taking CHCs who are live donors. At our center, we do just advise that they stop them a month in advance. That is probably too restrictive, but we just need to make sure we're very protective and we don't want to have any undue concerns with clot risks happening in the initial post-transplant period. You would anticipate that they would be very active and up and at it and walking on post-op day zero to one, but there's always complications that can happen. So I think to be on the air on the safer side, that's what we do at our center when we have planned living donor live do, living donor liver transplants for our live donors, we recommend stopping a month in advance. And as far as initiating them for patients, like our live donors, for example, they can re-initiate that as soon as they're ready for discharge home. As I mentioned before, I do just recommend more routine, like weekly monitoring of calcineurin levels when somebody is re-initiating a CHC, but you would be doing that anyway in an initial post-transplant, post-operative patient. Great. Thank you. And no need, by the way, this didn't come up with the question, but there's no need to ever remove an implant, an IUD in the perioperative period. So they can go right on through transplant. So we, I have heard of cases, including at our own center where in live donors who were asked to have their IUD removed, that is completely unnecessary. So we definitely want to make sure that all patients who are on these long acting reversible contraceptives continue to take them through the perioperative period. Perfect, great. Thank you. And just to a little bit more, the question about drug interactions, on any of these medications that you are using in the post-transplant period, are there specific drug-drug interactions with immunosuppression medications and or other medications that may be used in the post-transplant period that you think about and worry about? It's really the calcineurin inhibitors. And then luckily we all at transplant centers have our transplant pharmacists on board. And so they'll review if there's any unusual medications, there's some kind of antipsychotic medications that can have more interactions with the P450 system that also can decrease the efficacy of these agents. The other way around is it, again, you may see some slight increase in calcineurin inhibitor levels on patients who are on CHCs, but we really want to be thoughtful about if there's any medications that patients are taking that can lower the efficacy of their contraceptive. So I always will just have, I mean, our transplant pharmacists are excellent at reviewing the meds anyway, but the calcineurin inhibitors are the ones that I think about, but otherwise, if there's anything unusual, have your team review it, have your pharmacist review it. Perfect, thank you. All right, so moving on to the next question. So there's another question about medications. And the question is, is there any new emerging data on mTOR inhibitors and fertility? And this Carla, I know you touched on it in male specifically, but anything specific in fertility for female individuals on mTOR inhibitors? There's some limited data that suggests that there may be some irregularities with ovulation in women and development of ovarian cysts. But overall, the data about fertility in women and men are pretty limited. And it's probably because we don't use the mTOR inhibitors quite as much to understand overall their impact on reproductive health. But overall, it has not been felt to play a significant role in altering fertility. Great, perfect, thank you. And then the next question is a very important one. So we touched on MMF, MPAs in different contexts in pregnancy and breastfeeding. So the question here is, do you ask MFM or OB to do anything extra in the course of gestation when patients on MMF MPA get pregnant? So to the point of unintended pregnancies that Lisa made that perhaps more of these individuals were exposed to MMF in early pregnancy, is there anything that should be done differently knowing that the exposure occurred? Interestingly, the Society for Maternal Fetal Medicine actually has its own set of guidelines regarding antenatal monitoring for these patients who conceive pregnancies as transplant patients. And so they do talk about increased surveillance testing after the initial anatomic survey and doing that with greater frequency across the time course of the pregnancy. So they have their own guidelines for that. That's not necessarily something that we as hepatologists would have to recommend, simply because they've already put that into their guidance and they implement that in practice. But it does sound that there is some recommendation for increased surveillance if there's a known exposure. Great, and then since we're on the MMF topic, so there's breastfeeding questions. So, I mean, is there any biologic plausibility to think that breastfeeding on an MMF or a male partner who had MMF and then that leads to conception? Is there any biologic plausibility to think that this would cause any issues? We don't have data to suggest that. And so the recommendation is really extrapolated from the teratogenicity data that we see in the context of pregnancy. What we need, I think, are more data to help us understand what we can observe regarding the outcomes of breastfeeding in these patients who are choosing to continue MPA use. So far, what's been published or reported with case series or observational data suggests that there aren't any increased risks, but I think we just need more scientific data to understand that into perhaps the recommendation. Right, and provide reassurance. I mean, Lisa, can you comment on that from the TPRI? Is there some data in terms of MMF and breastfeeding and male partners who are on MMF? So we've had, I think maybe two or three breastfeed on MMF, kind of three before we even knew about the teratogenicity. And we haven't seen any problems overall in breastfeeding. We have almost 70% of our patients choosing to breastfeed. What most providers do right now is leave them off of the MPA while they're breastfeeding and choose to put them back on it once they're finished or once breastfeeding is completed. And it is really, there is no data about men fathering children having problems on MPA and fathering children. That was the study that the TPRI did, and it was a study in Denmark as well, and that Carla had presented. And we have seen no difference in outcomes with male recipients on MPA and not. Yeah, thank you for clarifying. I mean, hopefully that will actually be reflected in guidance so that the unnecessary fears are assuaged. And Jess, I know we're out of time, but we have one last question in the Q&A that I wanted to address quickly. So the question is, do you encourage post-OLT patients to seek out preconception counseling with MFM prior to becoming pregnant, if no other prior obstetric issues? So does this automatically make it a high-risk pregnancy that they need MFM input? And I'll open it really to everyone to hear your thoughts. Maybe Monica, you can, oh, go ahead, Elizabeth. I feel like it's not gonna hurt to have an extra guidance and someone following the patient a little more closely. We've seen that some of these patients can have significant issues with ICP, potential rejection, and just having that comprehensive care is really, we suggest that it's interdisciplinary. Oh, obstetrics, transplant hepatology, pharmacology, you know, every discipline possible. And I guess your registry data demonstrated that, yes, many people do well, but they're still higher-risk pregnancies compared to the general, maybe better than the kidney patients, but still higher risk than the general. And Monica, what are your thoughts? Yeah, absolutely, they're high-risk. They should be seen by maternal-fetal medicine. And it doesn't mean that for some of my patients, they live three hours away in more rural area, but what we'll do is we could even get them for a video visit for MFM for like a one-time counseling. So those recommendations are conveyed to their local OB. So I recommend that every single one of my post-transplant patients is getting connected with MFM. And even if that's a one-time counseling so that they establish this multidisciplinary collaboration, the local OB can be calling the point person who's seen them one time, for example. So it doesn't mean they have to deliver at UCSF. They may deliver at their local center where it's more feasible for them, but at least that they understand that we're co-following the TAC levels and adjustments and providing very specific risk assessments for both maternal graft and fetal outcomes. Great, thank you. And Karla, your thoughts? I mean, issues that came, or topics that came up during this session is, mode of delivery was one, and it seems that many transplant recipients are going for C-section, and other things like higher risks of preeclampsia. Should they be on aspirin? So these kinds of considerations, I think, lend themselves to having important early discussions with MFM. So what are your thoughts about that as well? Absolutely. So it's fairly standard practice for me to have them connect with maternal fetal medicine. I work with the MFM team in close partnership anyway in management of patients with chronic liver disease who are seeking pregnancy or who have contraception questions, and also in the liver transplant population. So I agree with both Lisa and Monica that I think it's important for them to establish a connection with maternal fetal medicine as early as possible. For education, it's also for assurance for the patient to know that there is partnership available to help support their interest regarding pregnancy. And I think that it's helpful for them to be able to start that process early. We also use telemedicine frequently, and I can tell you that many of those consultations with MFM are telemedicine consultations that make things a little bit easier for the patients because we do, too, have a large catchment area that is not just across our state, but across our entire geographic space. So we have several patients who come from multiple states away for care, and I do think that it is important for them to hear from MFM at the larger tertiary care centers where there is expertise and partnership occurring between OBGYN through maternal fetal medicine and with the transplant program providers. Great, thank you. So I think we've all established that interdisciplinary management and actually early preconception counseling, if possible, is absolutely key in this population. So I realize we're over time, and I wanted to close out the session and really thank Avesh for bringing the session together and the SIG as well, and Carla, Lisa, and Monica for really excellent presentations. Thank you, everyone. Thank you.

reproductive health

liver transplant

fertility

contraception

immunosuppression

pregnancy outcomes

teratogenic medications

breastfeeding

Transplant Pregnancy Registry

maternal-fetal medicine