Building a Family after Transplant

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Building a Family after Transplant

May 3, 2023

Presenter: Suneeta Senapati, MD, MSCE , Hospital of the University of Pennsylvania

Presentation is 37 minutes long, plus 12 minutes of Questions & Answers

Summary: A third of patients who undergo a stem cell transplant are either pediatric, adolescent or young adult patients for whom fertility after transplant can be a major concern. A variety of fertility preservation options prior to transplant, and assisted reproduction options after transplant, may enable a stem cell transplant recipient to build a family after transplant.

Highlights:

• The high-dose chemotherapy (also called the conditioning regimen) that is given to patients prior to transplant can cause germ cell loss in the ovaries and the testes, limiting future reproductive options.
• Prior to transplant, if a male patient has gone through puberty, sperm cryopreservation from an ejaculatory sample is the standard of care to preserve fertility options.
• For female patients, the options for fertility preservation before transplant include oocyte or embryo cryopreservation, ovarian tissue cryopreservation, and medical therapy with gonadotropin-releasing hormone agonist.

Key Points:

(03:43): Factors that impact fertility after transplant include the underlying disease being treated, the type and dose of the conditioning regimen, the patient's age, whether that patient has gone through puberty, and, for female patients who have already gone through puberty, their baseline ovarian reserve prior to transplant.  

(06:17): The number pregnancies that have occurred after a stem cell transplant is unclear. Data is not routinely collected from patients about pregnancies after a stem cell transplant.

(07:33): Several studies have reported an increased risk of cesarean delivery, preterm birth, and low birth weight in those who conceived after stem cell transplant. There does not appear to be a difference in the rate of miscarriage, pregnancy-induced hypertension, or birth defects.

(11:23): Factors that determine whether a female can undergo fertility preservation before transplant include their age, whether or not the patient has gone through puberty, the type of disease and treatment plans, whether the patient is currently partnered or not, the available window of time before starting transplant treatment, and the health status of the patient.

(12:13): Oocyte and embryo cryopreservation are routinely available around the world for female patients who have initiated puberty before transplant, and who wish to preserve their family building options after transplant.

(18:56): Oocyte and embryo banking procedures ideally should be completed prior to initiation of high-dose chemotherapy prior to transplant.

(19:47): Generally speaking, the process of ovarian stimulation is considered low risk. However, there are some specific risks that patients need to consider.

(22:58): Ovarian tissue cryopreservation is different than ovarian stimulation and is another option female patients can consider prior to transplant to preserve fertility options.

(30:08): Females can also consider gonadotropin-releasing hormones agonist treatment, or GnRH therapy, prior to transplant to preserve ovarian function after transplant. This is considered experimental and remains controversial.

(32:23): For patients who did not have the opportunity to undergo fertility preservation prior to transplant, there are several options for family building after transplant including donor gametes, either donor eggs or donor sperm, donor embryos, either carried to term by the patient or a gestational carrier, and adoption.

Transcript of Presentation:

(00:00): [Marsha Seligman]: Hello, everyone. Welcome to the workshop Building a Family after Transplant. My name is Marsha Seligman, and I will be your moderator for the workshop.

(00:08):  It is my pleasure to introduce today's speaker, Dr. Suneeta Senapati. Dr. Senapati is an assistant professor at the University of Pennsylvania Perelman School of Medicine. She practices reproductive endocrinology and infertility at Penn Fertility Care, where she's the director of third-party reproduction and co-director of female fertility preservation.

(00:33): Dr. Senapati's research focuses on pregnancy and long-term maternal child health outcomes after assisted reproductive technologies. Additionally, she has clinical and research expertise in epigenetics, endometriosis, fibroids, and fertility preservation. Please, join me in welcoming Dr. Senapati.

(00:56): [Dr. Suneeta Senapati]: Learning Objectives. I’d like to thank the organizers of this symposium for the opportunity to speak about this subject that is very near and dear to my heart. My goal in the next hour is to get you thinking, no matter what your specific frame of reference is, whether it's as a healthcare professional, a patient, a family member, or support person of someone who's been through the transplant process, about what fertility and family building can look like after transplant, to really understand the scope of what can now be done, the gaps that we have in the science, and to really improve awareness and access to care for patients after transplant.

(01:33): At the end of this hour, I hope that you'll be able to describe the unique reproductive concerns for patients after bone marrow and stem cell transplant, to be able to identify methods of fertility preservation prior to transplant, and to understand alternative options for family building after transplant.

(01:56): This audience is no stranger to the trends in bone marrow transplant and hematopoietic stem cell transplants over time. What we've seen is that the number of patients undergoing transplant continues to rise, as is evidenced by this graph that's been adapted from the Center for International Blood and Marrow Transplant Research Group.

(02:18): A third of patients who undergo a stem cell transplant are either pediatric, adolescent or young adult patients for whom fertility after transplant can become a major concern. This graph depicts trends in both allogeneic and autologous transplant over a 40-year span. Importantly, if you look at the age distribution of the patients who are receiving transplants, we see that a third of these patients are either pediatric, adolescent, or in the young adult age group. The blue pie piece is those that are under 18 years, the orange, those that are 18 to 39 years. As more of these patients receive curative therapies, and their care shifts from acute care to managing life after treatment, fertility and family building become a major concern for many of these patients and their families.

(03:00): The high-dose chemotherapy, called the conditioning regimen, given to patients prior to transplant can cause germ cell loss in the ovaries and the testes, limiting future reproductive options.  What are the challenges that patients face if they're considering or are after transplant? While some patients getting ready for transplant have already received chemotherapy, the majority that are getting ready for transplant are about to undergo a conditioning regimen that involves high doses of chemotherapeutic agents. These conditioning regimens given prior to transplant can cause germ cell loss in the ovaries and the testes. Germ cells are the precursors of eggs and sperm. When these cells are exposed to these types of chemotherapy, the chemo can cause these cells to die off, limiting future reproductive options.

(03:43): Factors that impact fertility after transplant include the underlying disease being treated, the type and dose of the conditioning regimen, the patient's age, whether that patient has gone through puberty, and, for female patients who have already gone through puberty, their baseline ovarian reserve prior to transplant.  We will discuss fertility preservation treatment prior to starting that conditioning regimen for bone marrow transplant. Advances in reproductive medicine have made fertility preservation options a possibility for some, in order to increase the chances of having biological children later in life. However, some of the most effective methods of fertility preservation require a two-to-three-week span of time to complete before the body is exposed to those conditioning regimens. Given the short time span between completion of chemo and moving to transplant, patients are often balancing the acute effects of disease and their treatments while trying to make very complex decisions about future quality of life issues, including fertility.

(04:29): It's important to note that while we know that conditioning regimens used for transplant can impact fertility, the extent to which that effect occurs and the options available for fertility preservation can vary from patient to patient. Some of the factors that impact fertility after transplant include the underlying disease being treated, the type and dose of the conditioning regimen, the patient's age, whether that patient has gone through puberty, and, for female patients who have already gone through puberty, their baseline ovarian reserve prior to transplant.

(05:07): An important component of the female fertility story has to do with this concept of the ovarian reserve and oocyte pool, or the group of eggs that a female patient is born with. This graph shows how the follicle pool is expected to change. On the X axis, we have time, and on the Y axis, we have the number of follicles or eggs. Females are born with the greatest number of eggs that they will ever have, that's about 1 million eggs, and the process of follicular atresia or loss of eggs is ongoing, even at birth. At puberty, there are about 300,000 eggs, that number slowly goes down over time until menopause or the final menstrual period.

(05:53): This oocyte pool can be altered iatrogenically or by the things that we do in medicine with certain types of chemotherapy or radiation, directed at the pelvis. We know that in patients that go through systemic chemotherapy and pelvic radiation, the decline in fertility begins earlier and the rate of decline can be faster.

(06:17): How do the effects of transplant translate to chances of pregnancy after transplant? There have been a few retrospective cohort studies that have looked at this and they've suggested that fewer than 5% of transplanted individuals report having children after transplantation. But the reality is that the data are very sparse, as there's no established reporting guidelines to accurately capture pregnancy and fertility after transplant.

(06:45): The type of conditioning regimen does seem to matter, as most of the reported cases are from patients who have received cyclophosphamide conditioning alone as opposed to regimens that include Busulfan or total body irradiation. There has been a subtle shift to use more non-myeloablative or reduced intensity conditioning regimens in some pediatric patients. It's possible that we could see an increased number of pregnancies without assistance in the future. In fact, pregnancy was recently reported within the first two years after transplantation in a woman who had been transplanted at 19 years of age, after reduced intensity conditioning.

(07:33): Importantly, when considering pregnancy after transplant, patients should be aware that they may be at greater risk than those who have not undergone transplant. Specifically, several studies have reported an increased risk of cesarean delivery, preterm birth, and low birth weight in those who conceived after transplant. There does not appear to be a difference in the rate of miscarriage, pregnancy-induced hypertension, or birth defects.

(08:01): I encourage patients to talk to their hematology or oncology teams and consult with maternal fetal medicine and the high-risk obstetricians, before pursuing family building so that they can understand their individual risk and have a plan for surveillance during pregnancy if needed. A multidisciplinary approach to care is usually best for some of these more complex cases.

(08:25): Given what is known about transplant, and the potential effects on fertility and future family building, the American Society for Clinical Oncology has recommended that all adult patients and all parents of pediatric patients who may be receiving the gonadotoxic therapy, receive information about the risk of infertility based on age prior treatment, planned conditioning regimen, the availability of fertility preservation techniques, as well as the timeline for each technique.

(08:59): What do those fertility preservation treatments available before transplant actually look like? They are different for male and female patients. We'll start with male patients. If a male patient has gone through puberty, sperm cryopreservation from an ejaculatory sample is the standard of care. There are tools including vibratory or electro ejaculatory stimulation that can be utilized if needed. Testicular tissue cryopreservation may be an alternative for male patients who haven't gone through puberty yet. This does require a surgical procedure and is typically performed by a pediatric surgeon or a urologist with training in this area. While sperm cryopreservation from ejaculatory specimens has been around for a long time and there's a lot of good pregnancy data to support its utility, there's still very limited data on pregnancy after testicular tissue cryopreservation.

(09:55): For female patients, the options for fertility preservation are different. These can include oocyte cryopreservation, embryo cryopreservation in those presenting with a partner or planning to use a sperm donor, ovarian tissue cryopreservation, and medical therapy with gonadotropin-releasing hormone agonist. There have been incredible advances in technologies available for fertility preservation over the past couple decades. This slide presents an overview of assistive reproductive technologies available to females. Post-pubertal females may undergo traditional ovarian stimulation and extract eggs to fertilize them and bank embryos or bank mature eggs. Alternatively, immature eggs can be retrieved after no, or limited, stimulation and grown in vitro and then frozen. Another option is surgery to access ovarian tissue from the ovarian cortex, or the outer covering that contains the eggs. Beyond embryo banking, methods for collecting and preserving eggs from follicles and tissue are really becoming more successful. These advancements are particularly important in children and adolescents who may not be great candidates for embryo banking.

(11:23): Factors to consider for females considering fertility preservation before transplant. When we meet with female patients who are considering fertility preservation, there are a number of factors to consider in discerning which treatment is right for them. These include age, whether or not the patient has gone through puberty, the type of disease and treatment plans, whether the patient is currently partnered or not, the available window of time before starting transplant treatment, the health status of the patient, and the personal desires of that patient in terms of the importance of using their own eggs or sperm for family building in the future, versus the willingness to consider using donor eggs or donor sperm in the future. This is ultimately a balance of risks, cost, and may also consider the chances of utilization and success in the future.

(12:13): Oocyte and embryo cryopreservation are widely and routinely available around the country as well as around the world for female patients who have initiated puberty. This process involves ovarian simulation, which is a two-week course of medications, to help the ovaries produce a group of mature eggs followed by a surgical procedure, oocyte retrieval. The day of the oocyte retrieval, oocytes or eggs can then be frozen, or they can be fertilized with sperm to form early embryos. Embryos are then developed in embryo culture and an in vitro fertilization laboratory over the course of five to six days and then embryos can be frozen.

(13:01): This very busy slide is a schematic of what we use every day during our office visits with patients to explain the ovarian stimulation and in vitro fertilization process. I often tell patients that when they're going through fertility preservation, they're really doing the first half of the IVF (in vitro fertilization) process. The second half will occur when they come back to use eggs or embryos, they have frozen.

(13:25): The first phase of this process involves patients getting medications to stimulate the ovaries and get multiple mature eggs to grow on the surface of the ovaries. We typically will start this process with the onset of a menstrual cycle, although in some cases, if time is of the essence, we'll just start as soon as we see the patient after baseline ultrasound and blood work. In the typical menstrual cycle, a group of immature eggs sits on the surface of the ovary, one mature egg develops and is released by the ovary. With the ovarian stimulation process, we give high doses of hormones that are the same hormones the female brain makes naturally to stimulate the ovary each month to send much higher doses than what the body usually makes.

(14:09): Those medications are usually self-administered by injections at home in the evening. There are typically two medicines that are given to stimulate the ovaries, and then one injection is given to prevent ovulation or prevent the ovaries from releasing the eggs until we're ready to go in and retrieve them at the time of surgery. During the weeks that the patients are taking these medications, they come into the office every two to three days for vaginal ultrasounds and laboratory testing to monitor development. Once we determine that the eggs are ready, the patients will take a third set of injections, called trigger shots, that are very carefully timed, such that 36 hours later an egg retrieval has been performed.

(14:59): During the oocyte or egg retrieval, we use vaginal ultrasound to guide a needle through the vagina into the ovary and drain fluid from follicles we see on the surface of the ovary. So, this picture on the left is an example of an ultrasound view of an ovary during the egg retrieval process. These follicles are fluid-filled sacs that appear as dark black circles on the ultrasound, and each follicle theoretically contains an egg. These eggs are microscopic, so we can't actually see them via ultrasound, but we can use the sizes of the follicles to determine how the ovaries are responding to the hormonal medications used and to guide retrieval of the actual eggs. With this surgery, there's no incision, everything is typically done through the vagina with the needle aspiration technique.

(15:48): This picture on the right is one of my colleagues, Dr. Kalra, in a mock setup that we use for teaching how egg retrievals are done. These procedures are typically done in an ambulatory surgical facility, meaning they're usually done in an operating room with anesthesia, but often done offsite from the main actual hospital. After the eggs are obtained, they're evaluated for maturity and they can either be cryopreserved (frozen), or they can be inseminated with sperm to form embryos. If fertilization is successful, then embryos will be monitored in the laboratory and frozen five to seven days later at the blastocyst stage.

(16:31): Some patients pursuing this technology may have a genetic disorder. For example, for patients with sickle cell anemia, there is the option to do pre-implantation genetic testing for specific genetic disorders at the level of the embryo. This testing usually requires building a test that is specific to a given individual mutation and can take some time, usually about six to eight weeks to develop that test before it can be applied to the embryo.

(17:04): When eggs are obtained from the oocyte retrieval procedure, they're taken to the embryology laboratory, which in most facilities is on site, in the same place that the retrieval is occurring. In our practice, our embryology lab is directly attached to the operating room where we do the egg retrieval. There, the embryologist takes fluid from the follicles, and they look under the microscope to look for eggs. So, the picture in the top left is what the oocytes can look like when they come out. They're typically surrounded by a bunch of supporting or cumulus cells. If we are freezing eggs, then those outer cells are removed to assess for maturity before determining if an egg can be frozen.

(17:44): This picture in the top middle is an example of an immature egg, or what's called a germinal vesicle. The picture in the top right is an example of a mature egg. What we're looking for is this little bleb of tissue right next to the egg called a polar body, the presence of which tells us that this egg is mature. If a patient has elected to freeze embryos, the eggs and sperm can be put together either by a conventional insemination or a process called intracytoplasmic sperm injection or ICSI. This is where we look under the microscope, select a single sperm, load it into a very tiny catheter and push it into the egg to help with fertilization.

(18:27): After allowing the resulting embryo to grow and develop in the IVF (in vitro insemination) laboratory over the course of the next five to six days, it can form a blastocyst, which is a multicellular early embryo. This blastocyst can then be cryopreserved or frozen for future use. Some facilities will keep their eggs or embryos on site in their IVF laboratories, or they can be shipped to long-term facilities, or to different locations across the country.

(18:56): Oocyte and embryo banking procedures ideally should be completed prior to initiation of gonadotoxic therapies. Sometimes we will see patients who have already received some chemotherapy and are undergoing this treatment prior to transplant. So, we counsel those patients that prior chemotherapy may decrease the number of retrievable eggs. In fact, if this is attempted within two to three months of the last round of chemo, there is a risk that no eggs may be retrieved at the time of retrieval.

(19:29): There's also some concerns that if follicles were recently exposed to chemotherapy, there may be a risk of abnormal oocytes. This mostly comes from animal studies at this stage, and there's very limited human data to confirm or refute that.

(19:47): Generally speaking, the process of ovarian stimulation is considered low risk. However, there are some specific risks we discuss with patients. One is the risk of ovarian hyperstimulation syndrome. This is a phenomenon that can occur about three to five days after the egg retrieval. Patients can experience fluid shifts, and fluid can accumulate in spaces where it's not supposed to be; in the abdomen or around the lung spaces, and they can also be at high risk for electrolyte imbalances and blood clots. The incidence of this is very low, about 5% overall, and there are methods that we can use to try to decrease this risk, including using a medicine called leuprolide (Lupron®) for the actual trigger shot.

(20:33): As the ovaries respond to medications, they also become physically much larger and they're at an increased risk of twisting on their blood supply, something called ovarian torsion. This is also very rare and occurs in less than one percent of patients after ovarian stimulation. But if it does occur, it is something that can be a surgical emergency requiring another procedure. All surgeries come with the risks of bleeding and infection, and with these procedures it's usually considered less than 1% overall.

(21:06): While this is not exactly a risk, one of the greatest barriers to fertility preservation is access to care and cost. While insurance coverage for fertility services are improving, at this time, it's not universally covered in the United States. Costs can range anywhere from $7,000 to $20,000 and upwards, depending upon the extent of treatment as well as geographically, where someone is accessing care.

(21:36): I mentioned that both egg and embryo cryopreservation are becoming more widely accepted. Embryo cryopreservation has been around for much longer than egg cryopreservation. However, there have been several randomized clinical trials that have been performed that demonstrate that fresh and frozen oocytes, in general, seem to have fairly similar outcomes.

(22:03): Many of these studies were initially done in egg donors, so young patients with good ovarian reserve. Some of the later studies were also done in the infertility population. You can see that, in these patients, the mean age at egg retrieval is a little different across some of these randomized controlled trials, and implantation rate and clinical pregnancy rate per embryo transfer did differ as a result of that, largely probably due to the impact of age.

(22:36): One of the things we talk to all patients about is this concept that each egg has reproductive potential, but we really want a group of eggs to maximize the chances of pregnancy, because the clinical pregnancy rate per egg that's thawed can range between about four and 6% overall.

(22:58): Ovarian tissue cryopreservation is another option, and while in some places it is still considered experimental, it is now considered an acceptable alternative for fertility preservation. This process does not require ovarian stimulation and therefore there's a very minimal potential delay in treatment. Also, there's no partner needed in this situation, and importantly, this is the only option that's available to female patients who have not gone through puberty yet. If a female patient has not gone through puberty, her body will not respond to the medications needed for ovarian stimulation for egg or embryo banking. So, ovarian tissue cryopreservation is a viable alternative.

(23:49): This process requires surgical removal of ovarian tissue, which is typically done as an outpatient procedure. This can either be done by removing ovarian cortical tissue or removing a whole ovary. When the ovarian cortical tissue is removed, that involves doing a laparoscopy, so a surgery with small incisions in the abdomen using long instruments to access the ovary, and then the outer covering or the cortical tissue of the ovary is removed, divided into small strips, and frozen. Again, this could be considered, if time does not allow for ovarian stimulation in prepubertal girls, or in those who have already initiated chemotherapy fairly recently, because, as I mentioned, some of those patients may not respond well to the ovarian stimulation process.

(24:47): This slide is an example of pictures that were taken from an ovarian tissue cryopreservation case. The picture in the upper left demonstrates an ovary that's being grasped with the one instrument, and then laparoscopic scissors are being used to dissect a portion of the ovarian cortex away from the ovary. Then this tissue is removed from the body, and it can then be frozen. This particular case was done by one of my partners at The University of Pennsylvania, Dr. Clarisa Gracia.

(25:22): As I mentioned before, once removed, this tissue can be cut into very small strips and cryopreserved. Then when someone comes back to utilize the tissue in the future, that tissue is thawed, and it can then be sutured either to the ovary or to other locations inside the body. The thought is that the tissue would then resume function that is similar to that at the time at which it was frozen.

(25:52): Orthotopic transplantation or essentially putting the tissue on the same type of tissue from which it was derived seems to be the most successful. So, this is often done either onto the ovary it was removed, from, the other ovary or contralateral ovary, or sometimes in the ovarian fossa, which is a little pocket where the ovary sits inside the abdomen.

(26:18): There is a lot of variation in terms of how long it can take to see a resumption of function and how long this function will last. Some of the early studies suggested that the average time in resumption of menstrual cycles is about 4.7 months, and that duration of function can last for anywhere from nine months to several years. At this point, it's very difficult to determine for a given individual where they fall along that spectrum. We often will counsel patients that if ovarian tissue cryopreservation is performed, usually within about six months we'll know if it's working. Then sometimes those patients will undergo additional fertility treatments to stimulate ovaries, harvest eggs, recognizing that ovarian function may not last for the full duration of time that we would otherwise expect. The average age of menopause is typically around 51, so this is definitely still a shorter time window of ovarian function overall.

(27:27): Important to discuss is that there is some theoretical concern about reintroduction of malignant cells into a patient who may be in remission, and this is particularly a concern for certain types of hematologic illnesses, leukemias or tumors with ovarian involvement. There is an option, potentially, to do testing of the tissue for tumor cells via real time PCR for certain tumor types. However, this has not been universally done for all patients. This is a technology that has resulted in live births around the world. To date, there are approximately 200 live births that have been reported, and in general the live birth rate is about 29%. So, a little bit lower than what we had talked about with oocyte cryopreservation, but still a potentially very viable option.

(28:29): Other things to be aware of in terms of ovarian tissue cryopreservation risk: this procedure usually requires a laparoscopy. So, there are surgical risks including bleeding, infection, damage to surrounding structures, the risk of anesthesia, and the risk of blood clots. Some centers will, instead of removing a portion of the ovarian tissue, remove the entire ovary, and there have been mixed views about whether one versus the other is appropriate in pediatric patients. However, overall, it is reassuring that for most patients, even if an entire ovary is removed, that doesn't seem to be significantly impacting optimal ovarian function.

(29:16): There was a multi-site study that looked at patients who were undergoing ovarian tissue cryopreservation and compared those who were going through tissue cryopreservation and transplants versus transplant alone. They saw no clinical differences in the rates of complications of patients who underwent the tissue cryopreservation prior to transplant. And the percentage of patients that experienced premature ovarian insufficiency with ovarian removal was 65% versus 45% in those who went through the transplant alone. Again, this is fairly recent data and there probably will be more groups that report on this as time goes on. But, overall, this data suggests that both may be viable options.

(30:08): The last fertility preservation option to discuss is gonadotropin-releasing hormones agonist treatment, or GnRH therapy. This is considered off-label use of this medication for ovarian protection prior to and throughout the duration of chemotherapy. The thought is that this medication can decrease ovarian activity and may reduce damage to the pool of immature oocytes. This is given via a depot injection, meaning it's given as an injection that then lasts for about a month. The medicine that is commonly used for this is leuprolide acetate, given as a 3.75 milligram dose as an intramuscular injection. This can also be given as three months dosing at a slightly higher dose. Some people will get the three months right off the bat, others may get a one-month dose, and if tolerating the side effects, then will get the longer dose depending upon the duration of chemotherapy anticipated.

(31:15): There have been several randomized clinical trials that have demonstrated mixed results in terms of preservation of ovarian function. Many of these have been in older patients with other types of treatments that they have undergone. So, there was one meta-analysis that was performed in patients with Hodgkin's lymphoma that showed no benefit. This included two randomized controlled trials and two observational trials. There was also another meta-analysis that was performed in the breast cancer patients that showed a significant reduction in chemotherapy-induced ovarian insufficiency, and a relatively high number of pregnancies across seven randomized control trials. So, the jury is still out in terms of efficacy, but this may be a good option for those who cannot undergo ovarian tissue cryopreservation or oocyte cryopreservation.

(32:16): Importantly, pregnancy data has not been uniformly reported after agonist treatments, and there's very limited data in the pediatric population as well. This is considered experimental and does remain controversial.

(32:23): What about patients who did not have the opportunity to undergo fertility preservation prior to transplant? What are their options for family building? There are certainly options that involve the use of assisted reproductive technologies. This can include donor gametes, either donor eggs or donor sperm, donor embryo, and in some patients, if the issue is that they themselves cannot carry a pregnancy due to risk, then there is the option of using a gestational carrier, and certainly adoption can also be an alternative.

(33:10): Third-party reproduction has been around for quite some time. When we think about the timeline of assisted reproductive technologies in general, the first baby that was born from IVF was in 1978, and the first time someone did a compensated surrogacy agreement was in 1980. The first baby that was born from egg donation was in 1983, and then artificial insemination with surrogacy was in 1984.

(33:37): The first gestational carrier pregnancy, so to understand the difference, gestational carrier is when the person who is carrying a pregnancy in which the eggs and sperm are not from her, that was established in 1985. Since then, there have been a lot of state, federal and international regulations that have changed whether gestational surrogacy is an option. In the US, there are some places where we can do this safely.

(34:11): To explain the donor egg process, with donor egg, a woman gives her eggs to another woman to allow that recipient to have a baby. There are also other scenarios, including male couples who may be building their family using both an egg donor and a gestational carrier. This can involve utilizing a non-identified egg donor or a directed or a known egg donor. It does not require the recipient to have a normal menstrual cycle. Even if they have stopped cycling, you can still carry a pregnancy safely. It involves a synchronized cycle with an egg donor as she goes through ovarian stimulation. Or there are also several frozen donor egg banks around the country now that already have eggs frozen from donors that went through stimulation, and those eggs can be purchased to then thawed and utilized. This compensation structure can be variable, as is insurance coverage regarding this.

(35:13): I also mentioned donor embryos. In the current practice of IVF, some patients may create more embryos than they need, and these extra embryos may be cryopreserved or frozen so that they could be transferred later. If the embryos are not used, then the patients have the option to donate those embryos to another patient or back to a practice to help someone else achieve a pregnancy. Again, this does not require the recipients have a normal menstrual cycle. This is an extremely limited resource, because it is dependent on the altruism of patients that are going through fertility treatments. We can see variable success rates based on the characteristics of those that are donating the eggs.

(35:58): Finally, gestational carrier. This can be considered when there's a concern that it may be medically unsafe for a patient to carry a pregnancy. It can involve the use of previously cryopreserved oocytes or embryos, or potentially donor eggs or embryos. The availability of this process can differ by state and by country. This is an example that's taken from the Creative Family Connections group, that basically shows that there is a very wide distribution of availability of this service, with the green states being states where this is allowed, red states being states that this is not permitted.

(36:43): Great strides have been made to expand reproductive options to patients with cancer and other fertility threatening conditions. While there's limited data in pediatric and adolescent populations to inform care, the available data are very encouraging. There's more work that's needed to study and improve the safety, efficacy, and availability of these techniques for patients after transplant. That's something that I hope to continue in my work, so that as time goes on, there will be more and more options that are available to patients. With that, I'd like to thank the symposium and I'll take any questions at this time.

Question and Answer Session

(37:28): [Marsha Seligman]: Thank you, Dr. Senapati, for this excellent presentation. We will now begin the question-and-answer session. "If I already have an embryo frozen, is it too late to have genetic testing?"

(37:42): [Dr. Suneeta Senapati]: There is the option of thawing an embryo and doing a biopsy of that embryo for genetic testing. The reasons for genetic testing can differ. If we're looking for a specific genetic mutation, that usually requires some additional samples from the patient, and the patient's partner to derive a test that is very specific to the genetic mutation that they're looking for. When these biopsies are done, they're done on a very small number of cells, usually about five to 10 cells from the embryo, and their biopsy is usually taken from the part of the embryo that becomes the placenta for supporting structures. But the short answer is yes, it can be done if the embryos were already cryopreserved. It will require an extra step of thawing the embryos, doing the testing, refreezing the embryos, so that we can wait to get the test results before planning for an embryo transfer.

(38:49): [Marsha Seligman]: "Is it possible to remove the leukemia gene before implanting a preserved embryo?"

(38:55): [Dr. Suneeta Senapati]: At this point, we don't have the technology available to do gene editing at an embryo level. It is possible to test an embryo to see if that particular embryo has the genetic disorder of concern. So, in terms of thinking about how different genetic disorders are transmitted, it would depend on whether the mode of transmission is such that we think that half of the embryos could be affected, or a quarter of the embryos may be affected. That's based on the genetics of the condition involved. At this stage, once that embryo actually has that gene, we don't have the technology yet to remove the gene from that embryo, but that may be something that comes in the future.

(39:52): [Marsha Seligman]: The next question: "I received my BMT five months ago and had conditioning of chemo plus 1,350 gray of total body irradiation. Prior to BMT, I had my eggs frozen. What are my risks and what are my chances to have a successful pregnancy in the future?"

(40:13): [Dr. Suneeta Senapati]:  I think after bone marrow transplant, the first thing to assess is whether ovarian function has been permanently impacted. It can take about a year after exposure to the initial chemotherapy and radiation to really assess if there has been any resumption of ovarian function. If there has been, there is the possibility that one could carry a pregnancy or get pregnant on one's own. However, as I mentioned before, in general, the chances of getting pregnant on your own after total body irradiation can be very, very low.

(40:54): When someone is about a year out from their treatment, assuming that their oncology and care teams have deemed that the disease is in remission and you're healthy, then yes, pregnancy can be achieved. Some of the main risks include, some patients, after going through bone marrow transplant, can have different organ systems that have been impacted by graft-versus-host disease or other conditions. So, first and foremost, we usually recommend a general assessment of health and recommend an assessment with our high-risk obstetrician colleagues to understand each individual's unique risk to carrying a pregnancy.

(41:40): If it's determined that one could carry a pregnancy without any issue, then typically you would work with a reproductive endocrinologist to have those eggs thawed put together with sperm and culture. The chances of success are based on a variety of factors, some related to the age at which someone cryopreserved the eggs, but also factors related to the patient's partner. Is there any other kind of gynecologic issues at play? But in general, if someone goes through egg freezing under the age of 35, then the chances of success can be very good, in the range of about 50% per embryo transfer, and cumulative success can be higher. It can take multiple tries to achieve a pregnancy.

(42:31): Either way, the pregnancy would be monitored very closely. As I mentioned earlier in the talk, there is a higher risk of cesarean delivery, low birth weight, and preterm labor. So, those are conditions that would be monitored for during pregnancy, but it is possible to carry a pregnancy after a bone marrow transplant.

(42:52): [Marsha Seligman]: "My son had his transplant when he was six and is sterile. We have heard this is because the stem cells that create the sperm were killed off. Is there any hope in the future that stem cell therapy will be able to recreate that ability?"

(43:12): [Dr. Suneeta Senapati]: This is an area where there's been a lot of research to understand whether we can we take stem cells and create the precursors of gametes to eggs and sperm. At this point, it is still in the research arena, so there hasn't been any clinical applicability. But as stem cell technology is developed, I think that there is a possibility. At this point that's still one of the many things that we need to figure out in the reproductive medicine community.

(43:52): [Marsha Seligman]: "Does fertility ever come back after an allogeneic stem cell transplant?"

(43:58): [Dr. Suneeta Senapati]: It can, but it is rare. A lot of this has to do with the conditioning treatments that are given prior to the actual transplant. Most of the time, what we recommend is a reassessment a year out from transplant to see if there's been any resumption of ovarian function. In patients with premature ovarian insufficiency, talking about female patients, we usually will say there's about a five to 10% chance that someone could have a random ovulatory event, even if it seems that their ovaries are not functioning normally. It's possible, and that's where we see in the literature, there have been case reports and a few retrospective cohorts that have described pregnancies after bone marrow transplant. In most of those cohorts, it's been in about the 5% or lower range.

(44:58): What we don't know yet is, in younger patients or patients that have received some of the conditioning regimens that are reduced intensity, whether there may be more reproductive potential there. I think time will tell, as those patients grow to reproductive age, whether that may change things a bit. But there's no question that the best options possible are to try to preserve fertility before transplant and then after transplant, if ovarian function has not resumed, then pursuing third-party reproduction options or adoption, maybe alternatives to family building.

(45:48): [Marsha Seligman]: "What fertility treatments are available for men?"

(45:53): [Dr. Suneeta Senapati]: For male patients, when we talk about fertility preservation, we usually talk about the sperm cryopreservation or the testicular tissue cryopreservation. Those are the two that are typically recommended. When sperm is cryopreserved, in the future, it can be used in a female partner to achieve a pregnancy via intrauterine insemination of sperm. Essentially, a sperm sample is thawed and, around the time that that female partner is ovulating, a sample of sperm can be placed directly inside the uterus or that's called intrauterine insemination, or IUI.

(46:36): Sperm that has been previously cryopreserved can also be utilized in the setting of in vitro fertilization. That same process that I mentioned for female fertility preservation can be used in a couple who had frozen sperm prior to cancer treatment to then utilize for family building in the future. For same sex male couples, typically, if one partner had previously gone through fertility preservation treatment, that sperm could then be utilized with an egg donor and a gestational carrier in the future. If we had a situation where a given male patient had gone through transplant and did not have the opportunity to go through fertility preservation, then oftentimes we'll talk to patients about using donor sperm to build their families in the future.

(47:32): [Marsha Seligman]:  Our last question. Are there any specific grants available for BMT couples who are adopting?

(47:41): [Dr. Suneeta Senapati]: Historically, it has been challenging for patients who have gone through different types of gonadotoxic therapy to adopt but, in general, some adoption agencies are becoming more friendly to that process. Grants are few and far between, but a couple of resources that I usually recommend to patients to look at include the Alliance for Fertility Preservation, and there are individual foundations like the Expect Miracles Foundation, and the Worth the Wait Charity, who will give grants to patients that are going through different types of cancer treatments. Some of them can cover expenses related to adoption as well as some of the other medical services related to family building. So, I can't say that there's one in particular that we recommend across the board, but, as awareness is increasing, this is an issue that's really important to patients. My hope is that more and more opportunities will be available.

(48:53): [Marsha Seligman]: Thank you so much. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Senapati for a very helpful and informative presentation. Thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way. Enjoy the rest of the symposium.