Our next speaker is Dr. Christina Doligalski, who has a very interesting practice. She's a solid organ transplant clinical pharmacist practitioner from University of North Carolina Chapel Hill. She will be covering pregnancy and transplant recipient, pre-conception care, maternal as well as fetal outcomes. All right. Wonderful. Thank you so much and thank you to the association for this opportunity to speak to you today. I have no disclosures other than that I am a pharmacist speaking to you about these items. So if you are like me and like we've spoken about previously, seeing a female of child-bearing age come into clinic after transplant is almost like seeing a unicorn sometimes. But in reality, about 13% of our patients undergoing liver transplant or who have undergone liver transplant are either of child-bearing age or will be coming into that and will be wanting to think about pregnancy at some point in their lifetime. So what data do we have for pregnancy after transplantation? Well, of course, we have many single center retrospective reports, but most of the data and what I'm going to spend a good amount of time presenting on comes through registry data. So we have the Transplant Pregnancy Registry International in the United States and then the ERA, EDTA and the UK Transplant Registries in Europe. Now the National Transplant Pregnancy Registry, which is now the Transplant Pregnancy Registry International was established in 1991. It tracks female transplant recipients who become pregnant as well as male transplant recipients who father children. So from that data and their most recent report that we see, we have about 1,700 female transplant recipients who have gone on to have a total of around 3,000 pregnancies. Of course, the majority of the data, as we would expect, is going to come from our kidney transplant recipients, but we see around 600 pregnancies that have been reported to this registry in our liver transplant recipients. Not unsurprisingly, we see that the most common underlying etiology for liver transplant in this population that becomes pregnant are those with autoimmune hepatitis, biliary atresia, PSC, as well as medication toxicity in alpha 1, with our viral etiologies being much less common. Before we go into the risk associated with pregnancy in our liver transplant recipients who become pregnant, I think it's really important to understand what baseline risk looks like, and I'm presenting this from the U.S. data that we have. But we see that in a general U.S. population, the risk of a major birth defect is anywhere between 2 and 4 percent, and the miscarriage rate in recognized pregnancies is 15 to 20 percent. Now, of course, that rate would go up significantly if we included unrecognized pregnancies as well. The live birth rate is around 65 percent, and then preeclampsia occurs in around 3 to 4 percent of our women, with prematurity happening around 9 percent, and then that very early preterm birth being very rare at 2 to 3 percent. The C-section rate in the U.S. is around 32 percent, but we know that that has been declining as more efforts have been made to decrease how often we have C-sections happening. So when we look at our data in our transplant recipients, we see that for the 304 women in the transplant pregnancy registry data who received a liver transplant and then went on to conceive, they were around the age of 21 when they received their transplant, and then conceived almost 8 years later. So these are generally older women after their transplant who are wanting to conceive. So I think that, again, the focus on talking about conception and family planning, not only early after transplant, but then as their course progresses, is really important. You can see that we have about 10 years of follow-up on average for these patients, and about a quarter of them had had a pregnancy prior to their transplant. Now focusing in on some of the outcomes that we see from the transplant pregnancy registry and focusing in on liver transplant specifically, and as a nice comparison, our kidney and KP data, we see that the majority of our patients are maintained on Tercrolimus as their primary immunosuppressant with around a third on cyclosporine. Very minimal azathioprine exposure compared to our other abdominal counterparts, most likely given the overall decreased need for immunosuppression in our liver transplant recipients. We do, however, see a very high rate of preeclampsia and hypertension occurring across the board, less so in liver transplant, but significantly higher than what we see in the general population. Importantly, rejection during pregnancy and graft loss following pregnancy is around 4% higher in our liver transplant recipients than in kidney. However, we don't see that concern for a significant increase in graft loss within two years following pregnancy in those liver transplant recipients. Switching gears to our fetal outcomes, we see that we have a live birth rate of around 72%, so increase from what we see in the general population, however, a much higher rate of prematurity, early prematurity, cesarean section, and then low birth weight infants. So I mentioned the planned and unplanned pregnancy risk factor earlier. We see that in planned versus unplanned pregnancies, and this is liver transplant specifically, that there was a much higher rate of mycophenolate use in our unplanned pregnancies, as expected, around 12%, and a higher rate of termination, around 6% compared to 1% in our planned pregnancies. Importantly, rejection occurred more frequently in our unplanned pregnancies, rejection both during pregnancy as well as postpartum, and this... We did not see in this particular cohort a change in graft loss within two years between planned and unplanned, but we'll talk a little bit more about that in a minute. But age absolutely makes a difference in this cohort. Younger transplant recipients were much more likely to have an unplanned pregnancy, so only 37% of those women between the ages of 18 and 25 had a planned pregnancy compared to planned rates of around 60 to 70% in our over 25-year-old women. We see a higher rate of rejection both during and postpartum in our younger recipients, so almost 10% rate of rejection compared to 3% in our older women, and then a higher rate of graft loss in those younger transplant recipients. So it seems like really that the highest risk population are those young unplanned pregnancies, as expected. Of course, cholestasis of pregnancy is an important consideration. This affects approximately 1% of our general population and per what we see in registry reports looks like it's about seven-fold higher risk in our liver transplant recipients. We see that cholestasis of pregnancy is associated with a higher rate of prematurity, a lower birth weight, and a much higher newborn complication rate than what we see in those that do not develop it. From the report, so this was 30 cases out of the transplant pregnancy registry, the cholestasis of pregnancy resolved upon delivery and there were no long-term poor outcomes from the mother that were reported. UK data that was recently published showed that some predictors of pregnancy outcomes in liver transplant recipients included poor renal function and we see a decremental effect from this with decreasing renal function associated with even continued poor outcomes and that prednisone use in the mother was associated with a much higher infection rate than what we see in those who were not maintained on prednisone. Similarly, predictors of graft loss have been assessed out of the transplant pregnancy registry. I put the kidney data on here to show you that it seems fairly consistent that rejection during or in the three months after pregnancy carries a significantly increased risk for graft loss following pregnancy at odds ratios of anywhere between 10 and 14. We see that age at conception and gestational age were protective factors for our liver transplant recipients. So I say all of that to present that adequate immunosuppression in these patients is critical to maintain good maternal outcomes after pregnancy. So talking about that medication management. For many of the folks that I work with and many of the pharmacists that I talk to when they ask me what medications can I use in pregnancy, this is the list that we get. We all feel comfortable with these, right? Unfortunately we've got to step out of that comfort zone a little bit when we start talking about this patient population. And so when we're talking about immunosuppression, we're really striking this balance between allograft function and then our fetal drug exposure, the adverse drug events that we expect from immunosuppression, and then any peripartum complications that we need to consider. Now when we think about medications, I always like to think about it through the entire spectrum of what is pregnancy going to do to my medications from absorption to distribution, metabolism, and ultimately to elimination so that I can better prepare and manage my patient's medications. We know that pregnancy causes a reduction in gastric emptying and intestinal motility, so we're going to have slower medication exposure and may potentially exacerbate pre-existing gastroparesis. We also see changes in gastric pH, which may affect our acid labile medications. As was presented earlier, we know that there are a lot of homeostatic and cardiovascular changes that occur during pregnancy. And so if the dotted line here is our normal function, we see that total body water increases throughout pregnancy. We have a similar increase in red blood cell count, however this is to a lesser degree than the total body water, creating a dilutional anemia. Cardiac output increases dramatically. And then systemic vascular resistance decreases during the first and second trimester and then increases to just above normal during the third trimester. And then finally, as any woman who has ever been pregnant in this audience can attest to as albumin drops off during that third trimester, countering with your significant increase in total body water, you get a significant amount of edema that can develop. So these are all important characteristics because we know many medications are going to be either bound to albumin, serum albumin, or when we start talking about some of our main immunosuppressants, potentially are bound to red blood cells as well. And so we need to take that into account when we think about medication exposure. Similarly to our cardiovascular system, we see significant changes in hepatic metabolism and our CYP450 systems. And so many of our isoenzymes increase throughout pregnancy, including 2C9, 3A4, importantly we'll talk about in a little bit, 2A6, as well as... and then 1A2 is our one main drug isoenzyme that we know of that decreases during pregnancy. And so again, looking at what are medications, how they are metabolized, and what we can anticipate occurring throughout the course of pregnancy. Biliary elimination during pregnancy is largely unchanged. However, we do see around a 50 to 60% increase in GFR during pregnancy. Of note, that GFR declines back to normal within the three to four weeks preceding birth. We do not know or don't have a good sense about the effect of pregnancy on our tubular secretion and reabsorption in some of our transporters, such as P-glycoprotein. Some other considerations to take into effect, of course we know that pregnancy is going to cause some degree of mild proteinuria. The placenta is going to produce some alkaline phosphatase. And then from a cardiovascular perspective, with that large increase in cardiac output and total body water, we're going to have increased JVD heart rate in the development of an S3. And so these are all normal physiologic things that we're going to be seeing that could compound what we see in our pregnant transplant recipients. Now I would be a terrible pharmacist if I got up here and did not talk about compliance. So it is reported in the literature that anywhere between 40 and 60% of pregnant women are non-compliant or non-adherent with their medications. There are many reasons for this, including concerns for safety for their developing baby, nausea, vomiting, hormonal or mood changes, and then unintentional non-compliance that comes with life getting really busy as you get ready for a new baby. So I always try and remind myself that the biggest difference in the pharmacokinetics of a medication is whether or not someone took it in the first place. So moving into our immunosuppressants and what we need to think about as we're managing these transplant recipients, cyclosporine, our kind of oldie goldie immunosuppressant, will have a slower rate of GI absorption. So a later C-max, but overall exposure stays the same. We know that there's mild binding to red blood cells, but that probably does not affect total concentrations as much as we're going to see with Tercrolimus. And we have that increased CYP3A4 activity, so we know we're going to need to increase doses as pregnancy progresses. There have been no identified patterns of fetal malformation or harm out of registry data with cyclosporine, and in the old FDA category, it is a pregnancy category C. Tercrolimus, similarly, we have a slower rate of absorption. So our T-max is going to be later, but our overall AUC will be no different. Tercrolimus is predominantly bound to red blood cells, and then it raises this very important question of, we monitor whole blood concentrations. We are not monitoring free drug concentrations. There's not a great way to do that, but we have more drug potentially bound to red blood cells, and so how much drug do we actually have free and available to cause an effect? We don't really know when it comes to this situation. We do know that we have increased CYP3A4 activity, so our doses are going to need to be increased as pregnancy progresses. Similarly, to cyclosporine, we have no identified patterns of fetal malformations or harm with Tercrolimus. Now, azathioprine is a nice medication from the perspective of there are not a lot of pharmacokinetic changes that we need to anticipate or be concerned about. It is in the old FDA system labeled as a pregnancy category D, and that's based off some animal teratogenicity that was seen with skeletal and visceral defects. We know azathioprine readily crosses the placenta. However, the fetal liver has low fetal methylation and oxidation activity, and so it cannot rapidly convert azathioprine into 6-mercaptopurine, and so interestingly, at least in the observational data that we have, there is no pattern of fetal harm or malformation that's been associated with azathioprine, at least in these registry reports, kind of conflicting with what we see with animal data. We do know that there is immunosuppression and lower white blood cell counts that's seen in babies that are born to moms who are on azathioprine therapy. And then prednisone, similarly to azathioprine, has no major pharmacokinetic considerations. It does require glucuronidation, and we aren't quite sure exactly what the effect of pregnancy is on glucuronidation. As far as fetal issues or fetal concerns, it is, in the old system, a pregnancy category C with a D in the first trimester, and that was because of an increased risk of oral facial clefts that was seen in prednisone use across many disease states, not just transplantation, with a four- to five-fold increased risk of isolated cleft lip or cleft palate. Now very quickly, we have minimal data for our mTOR inhibitors in transplant... in transplant pregnant... pregnant transplant recipients with around 20 pregnancies with sirolimus and four pregnancies with everolimus. Many of these were unplanned pregnancies. There was no identified pattern, but this is a very small cohort for us to know. Very similarly, with the mTOR inhibitors, we're going to have some of the same pharmacokinetic concerns that we do with circrolimus when... with sirolimus and everolimus given its metabolism... metabolism through CYP3A4. There are three pregnancy case reports out there with bilaticept use. Again, this is all just incredibly limited data for what we would need to do. If we do have a pregnant transplant recipient on bilaticept, we, of course, need to make sure that we're adjusting the doses appropriately as weight increases during pregnancy. And hopefully we all know that we should not be using mycophenolate during pregnancy. There's anywhere between a 50% and 80% risk of spontaneous abortions and that's associated with early use during the first trimester. So these women really should not be on mycophenolate if they are trying to conceive. And then there are congenital malformations as well. There's the Mycophenolate RIMS program that requires patient education and routine testing, although that is not mandated as to what that testing should be. Interestingly, there was an assessment done to see if the total exposure or dose of mycophenolate affected the risk for spontaneous abortion or defects. And we see that there was no difference in the doses that were given and the risks for those outcomes. So even low dose does not appear to be safe. So in conclusion, successful pregnancy following liver transplant is possible with acceptable maternal and fetal outcomes. Adequate immunosuppression is really critical to avoid postpartum graft loss. Many physiologic changes occur during pregnancy that affect the pharmacokinetics and the pharmacodynamics of the medications that we're using. An elective reporting of pregnancies to our international registries is really critical to optimize maternal and fetal outcomes as we move forward. And with that, I will answer any questions if we have time. Thank you. Thanks for the great review. We will take a couple questions, if any. I have one question for you, Christine. It's a fantastic talk. Thanks so much for joining the program. So one is about what to do with Tercrolimus. So is your personal recommendation to increase the dose as someone is conceiving, or do you just respond to ALT levels and then monitor them over the course of the pregnancy and adjust accordingly? Yeah. So I think my approach in these situations when I've managed these patients has been to just monitor much more frequently. We have had, of course, those handful of folks who are hard to keep track of, and in those situations, if I know that they are going into a period where they may not follow up with us, I may be a little more aggressive with my dose increases so that if they don't follow up for two or three weeks, that they're probably okay. Thanks. Thank you. According to the consideration regarding immunosuppressive regimen, what should be your recommendation for planned pregnancies? For planned pregnancies, I feel very comfortable with either Tercrolimus or Cyclosporine as our backbone of immunosuppression. If a patient is maintained on monotherapy going into transplant, I think that it's acceptable to maintain them on monotherapy while you ensure that they have adequate drug levels throughout pregnancy. I also feel very comfortable with low doses of prednisone use during pregnancy. You know, I know that there's that first trimester, Category D, but I think that the risk of graft loss or rejection during pregnancy outweighs the potential risk that we would see with those birth defects. And so, of course, stopping mycophenolate, the recommendation is six weeks before conception and getting someone transitioned over to an appropriate regimen. Hi. Ashna Singh from Henry Ford. I have two questions. One to follow up on what Dr. Sarkar had just asked you about the Tercrolimus levels. Most of our patients are not on monotherapy and especially not our younger post-transplant patients for obvious reasons. So do you ever consider adding an immunomodulator in addition to the Tercrolimus? And then obviously adjusting the level of K. Absolutely. You know, so in non-liver transplant recipients and, you know, I've taken care of a couple of lung transplant recipients. I feel absolutely comfortable using a calcineurin inhibitor, using azathioprine at routine doses and using prednisone to maintain immunosuppression in those patients. And the second question is, what do you do to counsel patients postpartum in regards to breastfeeding? Oh, that's such a great question. It's one of my favorite topics. So, you know, I think that everyone is very anxious about breastfeeding, but when you think about mother's systemic exposure that then gets into breast milk, how much gets into breast milk, and then a child has to then drink that and then what their systemic exposure is, I think many women have chosen to...that the benefit of breastfeeding and all of those benefits outweigh the risk of potential exposure. And you even see that in the trends and data that almost 60% of transplant recipients are now breastfeeding. So, I think it...and you can look at the ratio that crosses the placenta to help guide you on whether or not a medication is generally safe during breastfeeding. I'll just do one quick follow-up comment to that, is that there's a really wonderful resource that's maintained by the NIH. It's called LactMed, so lactmed.gov. And you can just type in any medication, including any immunosuppression. It will tell you the quantity that will end up in breast milk, and it will give you more mechanism of action. And it will specifically provide you with their clinical recommendation regarding safety in nursing. Go ahead. Sally Bell-Melbourne. Just a comment about the steroids, because in fact there's been a rerun of the Otis registry, and the rerun of the data has a lot more patients in it and doesn't show the same link to cleft palate and cleft defects. So, I think there's less concern about that. And the second comment is that... Thank you for that. ...there's now some data from the IBD literature looking at azathioprine levels in pregnancies, suggesting that they probably do go down in the third trimester, which is something worth...and you can now do levels quite easily. So, you can monitor that throughout pregnancy. Okay. Thank you so much. Thank you. All right.

Dr. Christina Doligalski

solid organ transplant

pregnancy in liver transplant recipients

Transplant Pregnancy Registry International

immunosuppression

medication management during pregnancy