So, our first presentation is titled Fertility in Contraception and Liver Disease Recommendations for Hepatic Adenoma, Cirrhosis, and Liver Transplant. Our speaker is our own Dr. Monica Sarkar from University of California, San Francisco. Okay, well I am delighted to be here to talk about fertility and contraception in women with liver disease. These are my disclosures. So today we're going to talk about why it's really important for us all as liver providers to be inquiring about women's reproductive intentions, and then we're going to be having a specific discussion about different major classes of contraceptives, and specifically their safety and efficacy in women with some key liver conditions, namely hepatic adenomas, cirrhosis, as well as transplant. So to put today's topic in context, it's important to recognize that the number of reproductive age women who have chronic liver disease is indeed rising. I'll mention this specifically regarding the contribution of NAFLD, so NAFLD is the most common chronic liver disease in North America and in many other countries, but what we've really seen is that among adults the most marked rise in incidence is among adults who are young, so less than 40 years of age. And this really parallels what we see in children and adolescents and appears to have implications for their reproductive health. So these are some data that we presented earlier in the meeting that really showed that there's been a nearly tripling of the prevalence of pregnancies in NAFLD, and this has kind of happened over the past 10 years. And it's similar to what we've seen also in Canadian data that we presented earlier in the meeting, where we've also seen a marked rise in the number of pregnancies among women who have NAFLD cirrhosis. So while we think of women who have cirrhosis as having impaired fertility, it's really important to keep in mind that that applies to women who have more severe decompensation. So these were data also presented earlier in the meeting that indicate that women who have compensated cirrhosis actually have similar if not higher rates of childbirth, but where you're really seeing marked impairment in fertility is among women who have decompensated disease. So this translates into what we see in the setting of liver transplant, where the majority of women who are listed for transplant, who are premenopausal, have secondary amenorrhea, meaning they had regular menstrual cycles, and as their liver disease progressed, those stopped. So it may not come to the minds of our patients or their providers that they have the potential to get pregnant following transplants, but it turns out that fertility is actually really rapidly restored following their operation. So these pregnancies usually come back about a year after transplant, but they can get pregnant as early as the first month. So while women who've had transplants with a multidisciplinary approach can have really healthy outcomes for their pregnancies, it's really those early pregnancies and unplanned pregnancies that carry the greatest risk to the mom, to the baby, and the graft. You can see here some data just showing much higher rates of acute cellular rejection, as well as lower birth rates in moms who've had those early pregnancies. So data on contraceptive counseling in the setting of chronic liver disease have really largely come from transplant populations. So this was a study that came out of Europe that was surveying women about five years after they had either a liver or kidney transplant, and these were sexually active reproductive age women, less of half of whom were using any contraception. And of those who were using contraception, the majority were using agents with a very high failure rate. So not surprisingly, over a third of the pregnancies that occurred were indeed unplanned. And survey data from the United States have also shown that about 60% of women have never been counseled about family planning contraception in either the pre or the post-transplant setting. And similarly, only about 50% of sexually active women are using contraception. And also, about 44% of these women didn't know that it was possible to actually conceive following their operation. So really highlighting the key role that we have as liver providers in educating our patients regarding the change in fertility and the possibility of pregnancy across severity of liver disease. So now I'm going to shift and talk about the three real main categories of contraceptive options. And in doing so, I'm going to be reflecting back to these CDC guidelines that really provide a spectrum of safety recommendations. And these range from one to four. One meaning no restriction in their use. Two meaning the benefits usually outweigh the benefits. Three is risks usually outweigh... The risks usually outweigh the benefits but are safer than unintended pregnancy. And then four means that that particular contraceptive agent is unacceptable because that's too high of a risk for that particular method. So first talking about combined hormonal contraception. So this includes both an estrogen and a progestin. And the failure rates of all forms of these combined hormonal contraceptives, including you can see the ring, the patch, the pill at the bottom of the screen, are about 9%. Now of any agent, this one is really the one that gives us most pause and has most safety concerns in the setting of chronic liver disease. Namely related to increased risk of thromboembolism in about one in a thousand women in the general population. Importantly, these are not associated with an increased risk of liver enzyme elevations as compared to placebo. Those data stemmed from older formulations with much higher estrogen doses. Although modern day contraception or combined hormonal contraception is still associated rarely with cholestatic liver injury. And associated rarely with stroke but more commonly associated with elevations in blood pressure and then interactions with the P450 systems. You have to be cognizant of other medications that they may be on. But no controlled studies in the setting of liver disease. So what does the CDC say? Well they say that if you have cirrhosis, as long as it's compensated, these agents can be used. But it's really among women who have decompensated disease where they confer their category four, so unacceptable. And that's similar for women who have hepatic adenomas. And as we know, adenomas are very responsive development and growth in response to estrogens. So our mainstay of managing women is to really stop their OCPs. And as we'll talk about in the panel discussion, pregnancies confers a particular risk in this setting for adenoma growth. Now when we look at combined hormonal contraceptive data in transplant, it's pretty limited. This is a series of kidney transplant recipients who had been using either the pill or the patch. They reported one episode of thrombophlebitis, one graft failure 10 years out. This is not clearly linked to the contraceptive agent itself. But about 35% of these women did need an increase in their blood pressure medications. In the setting of transplant, we also have data on a small group of women, 10 pill, six patch users who were followed for a year. One woman developed cholestasis, so she was receiving estrogen doses that were much higher than what would normally be available for contraceptive purposes. Hers was to treat heavy bleeding. And there were no associated issues with hypertension in the liver transplant recipients. Now when the CDC provides recommendations regarding contraceptive safety in transplant, they break it down. They break it down into whether a woman has uncomplicated graft function or complicated. They define complicated as acute or chronic graft failure or rejection. So they have no issues with the use of combined hormonal contraceptives if you've got normal graft function, but advise against this use if you have impaired graft function. Given the kind of nebulous terminology surrounding complicated graft function, we published our recommendations out of the Women's Health Community of Practice from AST, suggesting that in women who have had a transplant seat, the combined agents are reasonable if that is her preference. As long as she has a normal GFR, she has well-controlled blood pressure, no proteinuria that might increase her risk of clots, and similar as mentioned on the previous slide, no evidence of decompensated cirrhosis. So now moving on to the progestin-only methods. This is the second big class of agents. So this includes the mini-pill that you see at the top, the Depo-Provera injection, and then on the bottom, the subcutaneous implant. The progestin-only pill has the same failure rate as all those other combined hormonal contraceptives at around 9%. The pros are that it doesn't have the same associated increased risk in clot development or elevated blood pressure, but it really requires strict adherence. So women have to take it within the same one-hour window every day. The Depo-Provera injection is associated with a little bit lower failure rate. It's more convenient. She just gets an injection every three months. But the cons are that there was a black box warning issued by the FDA regarding increased risk of decrease in bone mineral density, so risk of adverse bone events. That did... They did... Women had resolution of their decrease in bone mineral density when they stopped the agent. But for those of us who take care of liver patients and transplant patients, there's still lingering concerns, as many of these women have underlying osteopenia, osteoporosis, and a setting of autoimmune disease transplant might be on long-term steroids. Now, the subcutaneous implant really has no major cons. It has the lowest failure rate of any method that we will mention today, no associated risk to the bone, and then there's no issues with adherence. You can have this placed and then come back three years later to have it replaced. So turning to what the CDC recommends, well, they say that if you have compensated cirrhosis, there's no restriction in using these progestin-only agents. But when it comes to decompensated disease, they provide a little bit more of a conservative recommendation with a Category 3, which is their same recommendation when it comes to hepatic adenomas. Yet, they'll say that there is no evidence available that these progestin-only agents actually increase the risk of adenoma development or growth. So what is the basis for this more conservative recommendation? Well, there were older data using higher-dose progestin agents that showed a very minimal fraction that was converted to estradiol, raising this concern that maybe these women could be exposed to estrogen, so the same concerns that one might have with traditional estrogen exposure. But it's important to keep in mind that those older formulations are not included in modern-day contraception. So we don't really have concerns, actually, in this context regarding estrogen exposure. And I work closely with, at UCSF, we have something called the Complex Contraception Clinic. And it's really a clinic for women who are medically complex, so our bariatric surgery patients, our transplant recipients. And in this context, these are particular agents that if you're seen in a Complex Contraception Clinic, we have no concerns or restrictions, regardless of your disease etiology or severity. Now, if you look towards their recommendations regarding solid organ transplant, the CDC also has no concerns regarding use of progesterone-only agents in that context. Now, for the last major group, these are the intrauterine devices. I'll kind of divide these down by the two flavors. The one is the hormonal agent, or levonorgestrel, and then the other is the copper. So both of these IUDs kind of act by creating a localized inflammation that make it inhospitable for pregnancy to occur. But the hormonal agent contains a very low dose of progestin, so this is also considered a progestin-only agent. It can last anywhere from three to five years, really depending on which particular option of the different levonorgestrel preparations you use. And the really nice thing about the hormonal IUD is that it lightens cramping, and it also really lightens or eliminates menstrual bleeding. So it's a great option for our patients who have chronic thrombocytopenia or chronic anemia. And it has a very low failure rate, so its failure rate is about 0.2%. Now for the copper IUD, this one is completely hormone-free, and it lasts much longer. So it can last for up to 10 years. The downside of the copper IUD is that it is associated with increase in menstrual cramping as well as menstrual bleeding. So not usually preferred by many of our patients, and I wouldn't recommend this for somebody who does suffer from chronic thrombocytopenia or anemia. It also does have a very low failure rate of about 0.8%. So if you turn to the CDC guidelines, they will say that use of the copper IUD has no restriction. So those can safely be used with compensated decompensated cirrhosis as well as hepatic adenomas. And then when it comes to use of a hormonal IUD, no restriction when it comes to women again with compensated disease, but we're still seeing that more conservative recommendation for women who have decompensated cirrhosis and women who have hepatic adenomas. And again, there's no data to support associated risk of IUDs in either one of those two contexts, and women who are seen in our complex contraceptive clinic at UCSF are freely encouraged to use the IUDs across severity of liver disease and indication if that's the method that she prefers. Now what about IUDs and transplants? There have been some historical concerns that really stemmed from a case report that was published back in 1981, and there were two adolescents who got pregnant while using an older formulation of the IUD. And the authors postulated that maybe that inflammatory reaction that you need for IUD efficacy is impaired if you have somebody who is immunosuppressed. But transplant immunosuppression, as you know, really acts primarily by T-cells, and that macrophage-driven activity is not affected by our IUDs. There's also the theory that maybe there are increased risks for pelvic inflammatory disease as they're immunosuppressed and they have a foreign body in place. And we now have really good, robust data from both transplant populations as well as HIV-infected individuals that indicate that risk of PID is no greater in women who are using IUDs as compared to those who are not. And this is consistent with kind of the comprehensive data that we have to date in more than 200 where you see the only unplanned pregnancies were those two case reports from 1981, and there have been no reports of pelvic inflammatory disease. So again, returning to what does the CDC say? Well, the CDC says that if a woman has normal graft function, she can have either type of IUD. But they are, again, more conservative when it comes to women who've had complicated graft function or graft impairments. And yet, they will go on to say that if a woman has an IUD in place, copper or hormonal, and she develops graft failure, it's safe to leave it in place as that is more dangerous. Unintended pregnancy is more dangerous than any theoretical risks, which hopefully I've dispelled in your mind. This is another one that we also feel freely comfortable using across severity of liver dysfunction including in transplant recipients. So in summary, the incidence of chronic liver disease in reproductive age women is rising. And family planning should be routinely assessed by liver providers. At the very least, what are her pregnancy intentions? Is she sexually active? And what is she using for contraception? And there are certain populations of women, as we'll discuss in subsequent lectures, that are at higher risk for having pregnancy complications, particularly when we think about women who have a liver transplant, who have cirrhosis, decompensated cirrhosis, or adenomas. And for those particular populations who wish to avoid an unplanned pregnancy, they should be encouraged to use methods with the lowest possible failure rate. When it comes to the combined hormonal contraceptive agents, these are safe as long as we're in the absence of decompensated cirrhosis, hepatic adenomas, or graft dysfunction. But you have to keep in mind that they still carry a failure rate of about 9%. Regarding the progestin-only agents, these are agents that we will use across severity of liver disease, albeit with some limitations with particular agents. Again, the challenges of the mini-pill, which requires very strict adherence, still has a failure rate of about 9%. And the Depo injection, which can be associated with a decrease in bone mineral density. But when it comes to the IUDs and the implants, these are the only agents when used alone that have very low failure rates of less than 1%. And these can be used across type of liver disease and across severity of liver dysfunction. And importantly, they don't rely on patient adherence. And I didn't talk too much about the adolescent populations, but the American College of Gastroenterology also recommends these long-acting agents as the most preferred agents for adolescent populations as well. So with that, I'll just put in a plug for an upcoming ASLD reproductive health guidance that should be out in 2020 that can provide you with some more specific formal recommendations on these aspects of managing women with chronic liver disease. For those of you who take care of transplant patients, I would direct you to the International Transplant Nurses Society. They have beautiful pamphlets that I routinely print out and give to my patients. And then for those of you who are also transplant providers, the American Society of Transplantation has dedicated webinars on family planning that include everything from contraception through pregnancy planning, as well as a transplant in 10 series of a short 10-minute snippet that can also give you these highlights. So thank you. Thank you, Dr. Sarkar, for a great review. We will open the floor for a few questions. Ashraf Malik from New Jersey. Dr. Sarkar, this is probably the best presentation I've seen in contraception in various liver disease patients. It's very thorough. It's really nice. Thank you. My question to you is a young patient with cirrhosis probably have just one episode of varicose bleed and now it's controlled, really doesn't have any other decompensation, normal synthetic function. Would you discourage to become pregnant? I'm sure this is not a good way to say it, but what would be your recommendation to somebody, young patient who probably had one episode of varicose bleed in terms of if she wants to get pregnant? So I will say that I, except for women who are actively on a teratogenic medication like Celset, I don't ever tell somebody they shouldn't get pregnant right now. It has to be a shared decision making. You have to come up with when is the most optimal time for you, if that is your wish, and provide them with the data on what are the risks of pregnancy and that's her choice to make. I know there's some scoring systems and Michael Hennigan is going to be coming up here for the next talk. He'll be talking about portal hypertension in pregnancy, so I'm going to let him address some of these questions. But if I have a woman who now has well-controlled disease, of course it's about removing the risk factor. Can you improve her disease anymore? How does her MELD score look? Are there other factors that we can look to prognosticate her risk? The biggest risk is surrounding variceal bleed, so I just want to be sure that's controlled beforehand that she gets screening during the early part of her second trimester. So it's really about optimizing her health, but I just really steer away from the language of telling somebody to telling women that they really can't get pregnant. I don't think that's our job. All right. Thank you. Tess McClure from Australia. I just have a question about counselling women about the implanon. Yeah, so I don't avoid it in patients who have thrombocytopenic. They can, it kind of depends on the severity because they can have kind of localized bruising when they're placing it. That may be less of an issue with IUD placement. Our providers at UCSF don't, they don't do any platelet correction before they place the IUDs in large parts. You know we're usually not seeing women with platelets under 20,000 coming in for these procedures. But yeah, you can have more bruising. It may be more uncomfortable in that setting. Sorry, I actually meant in terms of some women can get prolonged menstruation or total amenorrhea like with the implant. Yeah, so you can definitely have more irregular menses, but it shouldn't cause menorrhagia, so increase of menstrual bleeding. So in that context for women who are having thrombocytopenia or chronic anemia, it's really just the copper one that really increases your risk of menstrual bleeding. So that's one that I steer clear from. Thank you. We will take one more question. Elisa Kerman from Israel. What about estrogen-containing pills in cases of Wilson disease? As we know, estrogen may decrease the bile secretion of copper. Yeah, so with Wilson's disease, a lot of the data about contraceptive safety and concerns were very old data, including older formulations that had much higher estrogen doses. So at this time, I do the same counseling for my patients with Wilson's disease as if a woman doesn't have Wilson's disease. And really what's more important in my mind is does she have cirrhosis, does she have decompensated cirrhosis, and then of course if she would also have hepatic adenomas. But those are the factors that I check off in my mind, and it's not guided by her underlying diagnosis of Wilson's disease itself. And copper IUDs are also safe in the setting of Wilson's disease. Oh, yeah. Okay, so thank you.

fertility

contraception

liver disease

reproductive intentions

contraceptive options

family planning