Advances in fertility preservation and pregnancy care for transplant patients

Abstract

Fertility preservation and pregnancymanagement are critical considerations for patients undergoing organtransplantation. Innovations in assisted reproductive technologies, hormonalmodulation, and personalized medicine have expanded options for these patients, who face unique challenges due to immunosuppressive therapy and organ functionconcerns. This mini-review explores advancements in cryopreservationtechniques, pre-conception counseling, and multidisciplinary strategies forsafe pregnancies post-transplantation. Emphasis is placed on balancing maternalhealth, graft function, and fetal outcomes. The integration of reproductive andtransplant medicine is paving the way for improved quality of life andreproductive autonomy for this patient population.

Key Words: Fertility preservation; Pregnancy management; Organ transplantation; Cryopreservation; Assisted reproductive technology; Immunosuppressive therapy; Reproductive health

Core Tip: Fertility preservation and pregnancy management in transplant patients require an inter disciplinary approach integrating advancements in reproductive medicine and transplant care. Innovations such as cryopreservation, personalized immunosuppressive protocols, and pre-conception counseling have significantly improved outcomes. Addressing unique challenges like graft function and fetal health, these strategies offer transplant recipients the opportunity to achieve parenthood safely. Continued research and collaboration are essential to refine care models and enhance reproductive autonomy in this population.

INTRODUCTION

Since the first human-to-human organ transplantation was performed in the 20^th century, a lot of research has been done. Despite the low successful rate of organ transplantations in the early years, in contemporary times, recipients have years of normal life[1]. The number of transplants worldwide is increasing. The Global Observatory of Donation and Transplantation database shows an almost tripled number of transplantations in Europe and the Americas between 2000 and 2023[2]. Thus, the number of reproductive-age recipients also increases. According to the Health Resources & Services Administration, the majority of the patients on the waiting list for organ transplantation are aged between 50 and 64 years old (nearly 60%). Still, the proportion of those of reproductive age (18-49) is more than 33%. In addition, 2.8% are at child and adolescent age, and if transplanted successfully, they are likely to survive to adulthood[3].

Transplant patients are prescribed certain medicines for a long time or even a lifetime, including immunosuppressive drugs, to prevent rejection of the graft. These medications could affect their fertility in several ways: Change in hormonal levels or damaging the gonadal cells and make natural conception harder or even no possible; teratogenicity due to maternal exposure during pregnancy or paternal exposure before conception; certain pregnancy complications like miscarriage, eclampsia, preeclampsia, preterm birth, and requirement of Cesarean delivery[4-6].

There are also ethical challenges for fertility preservation, achievement, and management of successful pregnancy among individuals who have undergone organ transplantation. Pregnancy in transplant women could increase the risk of graft rejection during pregnancy or postpartum and may make them eligible for re-transplantation. In addition, there is a risk for the fetus, especially when the pregnancies are unintended, and the medicines received by both parents are not adapted[7].

Alongside the psychosocial challenges before, during, and after transplantation, fertility preservation, conception, pregnancy, and birth add additional burdens to the patients[8]. Fertility treatment causes psychological distress to the couples involved in it. Thus, emotional support could address these new needs[9].

Recent innovations in fertility preservation and pregnancy management in transplant patients could help toman age these concerns. They could be applied in the pre-conception period to decrease the damage of immunosuppressive treatment on gonadal tissue. Modern approaches could be used for assisted conception, pregnancy management, and outcomes. Lowering the risks for the mothers and fetuses will also add ethical and psychological challenges. This review comprehensively describes the recent innovations and strategies in fertility preservation and pregnancy management, specifically for transplant patients.

SEARCH STRATEGY

To identify relevant studies on the topic, a comprehensive literature search was conducted across the following databases: PubMed, Scopus, Web of Science, and Embase. The search included a combination of Medical Subject Headings (MeSH) and free-text keywords, systematically organized using Boolean operators to maximize retrieval of pertinent research.

The search query was constructed to address three key components: The population of interest, the innovative interventions, and the focus on pregnancy management. For the population, terms such as "transplant patients," "organ transplantation," and "solid organ transplant recipients" were used. For interventions, terms included "fertility preservation," "ovarian tissue cryopreservation," "testicular tissue cryopreservation," and "innovative reproductive techniques." The pregnancy management component was explored using terms such as "pregnancy management," "pregnancy outcomes," "maternal-fetal medicine," and "high-risk pregnancy care."

A representative search string was as follows: ("transplant patients" OR "organ transplantation" OR" solid organ transplant recipients") AND ("fertility preservation" OR "ovarian tissue cryopreservation" OR" testicular tissue cryopreservation" OR "innovative reproductive techniques") AND ("pregnancy management" OR "pregnancy outcomes" OR "maternal-fetal medicine" OR "high-risk pregnancy care").

Filters were applied to focus on relevant studies, including clinical trials, systematic reviews, guidelines, narrative reviews, case reports and original articles published in the last decades to capture recent advancements (from 2000 up to date). Each database's specific syntax and filters were tailored accordingly, with MeSH terms prioritized in PubMed and subject headings emphasized in Scopus and Web of Science. Additionally, the reference lists of key articles were manually screened to identify further relevant studies. The inclusion criteria focused on studies discussing innovative reproductive and pregnancy managements strategies specifically for transplant patients. Exclusion criteria omitted studies unrelated to the target population or lacking innovation in fertility preservation and pregnancy care.

The process of identification, screening and selection of papers to include is presented in Figure 1.

Figure 1 Identification, screening and selection of papers included in the review.

FERTILITY PRESERVATION TECHNIQUES

Fertility preservation techniques are important for transplant patients who are often subjected to high doses of chemotherapy or immuno-suppression that are damaging to the reproductive system. The main established approaches to fertility preservation are as follows: Ovarian tissue cryopreservation, oocyte cryopreservation, in vitro fertilization (IVF) and sperm cryopreservation.

OVARIAN TISSUE AND OOCYTECRYOPRESERVATION

Ovarian tissue cryopreservation involves surgically removing ovarian tissue, which is then frozen for future use. The tissue can later be reimplanted to restore the natural hormone production and potentially fertility, which can provide a significant option for prepubertal girls and patients who cannot delay their treatments for other fertility preservation methods. Oocyte cryopreservation, in contrast, involves stimulating the ovaries, retrieving mature eggs, and freezing them. According to recent observations, the outcome of live births from these procedures has improved due to new freezing techniques such as vitrification, which eliminates crystals, hence improving survival rates after thawing[10,11]. There are still questions about the application of ovarian tissue cryopreservation as it is still mostly in the experimental stage. However, it has been used in several high-risk cases, including patients diagnosed with Turner's syndrome, which indicates potential use in the transplant population[10].

IVF

IVF is another common fertility preservation method, which is particularly appropriate for patients who are undergoing less invasive transplant series or have a good ovarian reserve. The process requires the patient to be given medication to stimulate the ovaries to produce multiple eggs, collected and fertilized in the laboratory, and the fertilized embryos are cryopreserved. In the case of transplant patients, in particular, those without aggressive treatments but with plans for them soon, IVF presents a viable solution for fertility preservation with proven advantages and success rates[12].

Modern approaches include 3D culture systems for in vitro maturation that better approximate the ovarian natural environment and utilize tissue engineering scaffolds, organ-on-chip models and others that are appropriate when there are problems such as primary ovarian insufficiency, ovarian cancer, etc.[13].

SPERM CRYOPRESERVATION

Sperm cryopreservation is widely used for male patients, especially pre-transplant, as the process is very straightforward and involves minimal intervention. The protocol typically includes sperm collection and freezing, which can be done very fast and with high post-thaw viability. Sperm preservation has shown high efficacy in terms of successful future fertilization, with protocols optimized to improve outcomes even after prolonged freezing periods[14]. This technique provides are liable fertility preservation option for men who may face gonadotoxic treatments as part of their transplant procedures.

EMERGING AND EXPERIMENTAL TECHNIQUES

The new emerging techniques in fertility preservation aim to widen the options for those patients who, due to particular medical considerations or other circumstances, cannot benefit from traditional methods. This category involves follicular activation and culture, testicular tissue preservation, and a few experimental applications in gene therapy and regenerative medicine.

Follicular activation and culture

Follicular activation and culture involve the stimulation of dormant follicles to mature in vitro, offering the potential for patients with reduced ovarian reserve or those who may not be candidates for oocyte retrieval before transplant. The main focus of this technique is activating the primordial follicles in ovarian tissue through targeted molecular signaling pathways and culturing these follicles in a lab environment to allow maturation. Studies show that in vitro follicular activation may significantly enhance fertility options for transplant patients by increasing the availability of viable eggs, even in cases with minimal ovarian reserve[15]. These methods are still in the experimenting stage, but they represent promising avenues for expanding fertility options in challenging medical cases.

Testicular tissue preservation

For prepubertal males who lack mature sperm for standard cryopreservation, testicular tissue preservation presents an appealing solution. The technique itself involves cryopreserving immature testicular tissue with spermatogonia stem cells, which can later be used to restore spermatogenesis after reimplantation or in vitro maturation. Early-stage studies on animal models have demonstrated success in creating viable sperm from preserved testicular tissue. The current ongoing research aims to translate these findings to human applications[16]. If successfully implemented, testicular tissue preservation could significantly expand fertility preservation options for young male transplant patients.

Gene therapy and regenerative medicine

The application of gene editing and regenerative medicine in fertility preservation holds potential for patients with severe reproductive damage due to high-risk transplants or treatments. Contemporary gene editing techniques like CRISPR and stem cell-based regenerative therapies are being explored to repair or regenerate damaged reproductive tissues. For example, approaches based on stem cells could potentially restore ovarian or testicular function by generating new gametes or supporting tissue. At the same time, gene editing could address specific genetic or epigenetic issues affecting fertility. While these technologies are still largely theoretical in the context of human fertility preservation, early-stage research suggests they could play a significant role in future fertility strategies for transplant patients with extensive reproductive challenges[12].

Table 1 presents the advantages and limitations of fertility preservation techniques for transplant patients[17-22].

Table 1 Innovations in fertility preservation and pregnancy management for transplant patients, along with their successes and limitations/challenges.

Innovation	Successes	Limitations/challenges	Ref.
Oocyte cryopreservation	Successful long-term storage of oocytes before transplant procedures	Potential risk of ovarian failure due to immunosuppressive therapy	[17]
	Offers female transplant patients the possibility of future fertility options	Limited knowledge of the effects of cryopreservation on oocyte quality post-transplant
Embryo cryopreservation	High success rates of pregnancy post-transplant when embryos are used after fertilization	Ethical concerns and challenges with donor sperm/eggs
	Suitable for patients undergoing fertility treatment before transplantation	Requires hormonal stimulation, which may not be possible for all transplant patients due to their medical conditions
Testicular tissue cryopreservation	Success in preserving fertility in male transplant patients	Limited access and expertise in cryopreservation of testicular tissue
	Potential to preserve the ability for future sperm retrieval even after the transplant	Uncertainty of long-term success in fertility restoration
IVF	Allows transplant patients to use their gametes or preserved embryos to conceive	IVF may not be feasible for all patients due to immunosuppressive therapy or health complications
Hormonal manipulation during pregnancy	Modifies immunosuppressive therapy to reduce risks during pregnancy, leading to successful pregnancies	Risk of graft rejection or complications in maintaining immune balance
	Tailored immunosuppression protocols can enhance pregnancy outcomes for transplant patients	Hormonal therapies can have side effects that complicate pregnancy
Genetic counseling	Helps patients understand the risks of inherited diseases or the effects of transplantation on offspring	Limited access to specialized genetic counseling in some regions
	Provides a clear understanding of pregnancy and fertility options for transplant patients	Emotional and psychological challenges for patients in dealing with possible outcomes
Pre-implantation genetic testing	Identifies genetic disorders in embryos, reducing the risk of inherited conditions in offspring	High cost and limited availability of testing
	Helps to choose the healthiest embryos, which is crucial in transplant patients with compromised health	Ethical concerns surrounding genetic screening and selection
Pregnancy monitoring post-transplant	Advanced monitoring technologies help track graft function and fetal development simultaneously	The increased complexity of monitoring, especially in immunosuppressed patients, may increase medical burden
	Early intervention and personalized care plans can improve pregnancy outcomes for transplant patients	Risk of complications, including organ rejection and infection, remains a challenge

IVF: In vitro fertilization.

COMPARATIVE EFFICACY AND LIMITATIONS

There are strengths and weaknesses in each approach to fertility preservation relative to the benefit for transplant patients. The methods are well-practiced and often successful-ovarian tissue and oocyte cryopreservation, IVF, and sperm freezing-commonly restore fertility through protocols that have been established over decades. New methods, including the activation of dormant follicles, testicular tissue preservation, and gene therapies, offer new perspectives. Those still-experimental methods, though, are stymied by technical roadblocks and a patchwork of regulations. They seem more promising yet are not currently as consistently effective as tried-and-true methods[10,12].

PREGNANCY MANAGEMENT FOR TRANSPLANT PATIENTS AND PRE-CONCEPTION COUNSELING ANDMULTIDISCIPLINARY CARE

Assessment and risk analysis

Transplant candidates interested in pregnancy should undergo comprehensive pre-conception health screening and risk stratification. This usually includes assessing transplantation organ health and function, checking current drugs, and looking for any concomitant health disorders that could be potentially dangerous. As an example given by Turkyilmaz et al[23], kidney transplant patients will routinely perform renal function tests to assess the compatibility of the kidney to the physiological challenge of pregnancy, and liver transplant patients may need supplementary liver function tests. Pre-conception evaluations enable patients and clinicians to appreciate better the possible risks encountered so that they can take appropriate steps in advance to prepare optimally for the unique challenges of post-transplant pregnancy.

Multidisciplinary teams

Multidisciplinary team participation is essential for caring for transplant patients during pregnancy. This team comprises specialists in high-risk pregnancy (OB-GYNs), nephrologists and immunologists, and sometimes cardiologists or hepatologists if required. Each expert brings their expertise to develop an optimized, personalized care plan. For example, immunologists try to configure immunosuppressive agents to avoid allograft rejection while preserving the pregnancy. Adjunctive communication between these experts is critical to look ahead and predict and manage potential complications, thus improving chances of successful mother and baby outcomes, as noted by Chandra et al[24].

Patient education and counseling

Education and counseling are key to giving transplant patients a voice to make informed pregnancy decisions. By causing them to receive pre-conception counseling, patients learn the risks, required lifestyle changes, and the need for drug adherence. These sessions deal with the main topics, e.g., identification of symptoms, preeclampsia, gestational diabetes, infection risk, etc. Physicians may promote a partnership in which the patients are actively involved in their treatment by educating and accustoming them with the knowledge and techniques for caring for themselves throughout pregnancy, as demonstrated by Carretto et al[25].

MEDICATION ADJUSTMENTS ANDMONITORING

Immunosuppressive therapy

Changing immunosuppressive therapy is critical in pregnancy care for transplant recipients as immunosuppressive therapy is critical in preventing organ rejection but may be a risk to fetal development. Drugs, e.g., mycophenolate mofetil, are generally avoided during pregnancy because they pose teratogenic risks, and safer agents (e.g., azathioprine) are commonly substituted[26]. During pregnancy, doses may need to be modified due to physiological changes in drug metabolism and distribution. Careful balancing is necessary to deliver enough immunosuppression to protect the graft while reducing possible harm to the fetus. However, no approved protocols exist, and no comparison between the various immunosuppression medications suggests a strategy regarding the level adjustment.

Monitoring protocols

Close monitoring of maternal and fetal health is essential. Protocols typically involve routine ultrasounds to evaluate fetal growth, amniotic/hydrops, and placental compromise, as well as routine laboratory tests to monitor organ function and immune suppressive therapy levels. This vigilance is noted in the study conducted by Kittleson et al[27], who identified and treated early manifestations of complications such as preeclampsia, anemia, or impaired organ function and thus allowed early intervention. Monitoring procedures are often individualized to the patient's clinical state and the type of transplant provided to anticipate and address particular needs during pregnancy.

Preventive measures

Preventive measures focus on managing common complications such as hypertension, gestational diabetes, and infections. Lifestyle changes, such as diet and physical exercise, are recommended to keep blood pressure and glucose within normal range. Vaccination and infection screening are also essential protective measures since susceptible patients with a weakened immune system (i.e., immunosuppressed patients) are more likely to develop serious infections. Also, constant monitoring for any evidence of graft rejection continues to be very important, as noted by Marzec et al[28]. Since the immune response can still change due to the influence of pregnancy, which might increase the risk.

SPECIAL CONSIDERATIONS FOR DIFFERENTORGANS

Transplantation organs should be taken into account individually to manage pregnancy. For instance, renal transplant recipients require careful renal function monitoring as pregnancy is an extrinsic stress on the kidneys. Liver transplant recipients can be subjected to more frequent liver enzyme testing to detect early hepatocellular dysfunction. In contrast, patients undergoing cardiac transplantation carry with them their own cardiac risk and particular cardiovascular requirements that must be explored with particular investigations and, possibly, a continuation of the drug control regime to ensure good cardiac health, as reviewed by Misra et al[29]. These personalized care approaches are tailored to address the unique risk associated with subtypes of transplant to achieve better maternal and infant outcomes.

We also have to mention uterus transplantation in this regard. Itis an entirely different kind of transplantation than the solid organ transplantations that we discuss in this review, as this allows for improving fertility. It was shown that appropriate donor and recipient selection is time-consuming and needs careful preparation. Thrombosis, infection, vaginal stricture, prenatal problems, and graft failure are among the issues that have been reported in the recipient. Although it happens often, graft rejection seldom ever results in graft removal. Although the majority of embryo transfers are successful, patients who have received uterine transplants have experienced repeated implantation failures. Although preterm delivery rates are high, they seem to decline; more information is required, especially long-term outcome statistics. In conclusion, absolute uterine factor infertility, for which there were no prior effective treatment options, is now being treated via uterus transplantation. It is critical that reproductive health[30].

OUTCOMES AND COMPLICATIONS

Fertility and pregnancy outcomes

Many transplant patients can now achieve pregnancy safely with live birth rates comparable with the general population in the presence of carefully focused care, as seen in the paper by Kallapur et al[26]. Additionally, Chandra et al[24] suggested that kidney and liver transplant recipients can achieve positive pregnancy results. Still, there is a nominally greater risk of preterm outcome due to the complexity of pregnancy in light of immunosuppression and underlying disease. So far, improved monitoring and medical interventions have enabled pregnancy in transplant recipients to be considered safer, yet close integration with medical providers is still necessary.

Dyulgerova-nikolova et al[31] recently presented results from their experience with oocyte cryopreservation and consequent fertility treatment. The retrospective analysis of 296 women who had oocyte freezing procedures for non-medical(social) reasons, medical conditions (oncological treatment) and oocyte donation for ten years period demonstrated that 190 women with 221 procedures vitrified their oocytes for future use (only 9.47% of them had medical conditions). In the period, 46 (24.2%) women who stored their gametes in our cryobank claimed them for assisted reproduction, leading to nine clinical pregnancies registered and 10 children born.

Complications and risks

Even when advances are made, transplant recipients remain at risk of some complications, such as preeclampsia, graft rejection, and Cesarean section. Preeclampsia is a frequent complication in transplant recipients. Still, it probably results from underlying conditions and immunosuppressive treatment. It is often a candidate for early intervention for the benefit of both mother and child, as mentioned by Kothari et al[32]. Graft rejection, despite the minimization through proper medical management, is not unexpected in patients with major physiological changes following pregnancy but continues to be a question. Medical indications, however, lead to a tendency to perform Cesarean delivery with higher proportions within all groups of transplant donors and recipients. Preventing these risks requires a multidisciplinary cooperative effort with regular monitoring and adherence to individually adjusted medical guidelines to achieve excellent maternal and neonatal pregnancy outcomes.

ETHICAL AND PSYCHOSOCIAL CONSIDERATIONS

There are potentially competitive interests between healthcare providers, transplant patients, and their offspring. Pregnancy and delivery for transplant patients are risky not only for the mothers and the graft but also for the off spring[33]. Thus, patients should be informed of all the underlying risks. The decision should be taken together with their physician, discussing all the pros and cons. Moreover, transplant patients should be informed about the risks of unplanned pregnancies and the need for medication adjustment before conception. This is essential for the mothers and also for the fathers, as their fertility could also be affected. Furthermore, teratogenicity could also arise from paternal immunosuppressive exposure before conception[34,35].

The timing of pregnancy counseling is also important. It should start before the transplantation procedure and cover all aspects of fertility preservation, contraception if needed, conception and fertility treatment, pregnancy, and parenthood. A shared-decision approach is recommended in collaboration between physicians and patients[33].

The need for transplantation, the waiting time before the transplantation, the transplantation procedure itself and consecutive treatment, and all the risks for patients' health and graft rejection predispose a lot of stress[36]. In addition to this, fertility preservation, treatment, pregnancy, and parenthood add additional physiological load to these patients. Fertility preservation is accompanied by stressors like lack of time before the preservation procedure or uncertainty about the procedure's efficacy, and the related psychological distress affects patients' quality of life[26]. Stress and anxiety frequently accompany fertility treatment and influence couples' well-being, but the reported results are controversial. However, psychological counseling and emotional support are associated with better adjustment to the treatment procedure and its outcome[37,38]. Psychological support also copes with the stress during fertility preservation[39]. Moreover, integrating mental health professionals in fertility preservation or treatment shows promising results[40].

We must also acknowledge that the mental health of transplanted patients deteriorates independently of the reproduction status: Depression, anxiety, etc., are concomitant conditions that require management[41-43].

Family and Social Support networks could also help in coping with the emotional and practical challenges of fertility preservation and pregnancy in transplant patients. There is evidence that low social support during pregnancy leads to a higher risk of depression, anxiety, and self-harm[44]. Moreover, socials support interactions decrease stress levels among couples who underwent IVF and improve their well-being[45].

FUTURE DIRECTIONS AND RESEARCH GAPS

Transplant patients face various challenges when it comes to preserving their fertility. Time is one of them, as urgent manipulation is often a priority. Sometimes, there is no possibility for comprehensive fertility planning. Financial constraints are also challenging and can limit access to different fertility preservation methods. Emotional state can also complicate decision-making about fertility and reproduction. This is because the results of transplantation are unpredictable, which in turn leads to thoughts of uncertainty related to the possibility of infertility.

Although transplantation improves patient survival, they often experience subfertility as a consequence of toxic medical therapy[46]. For some patients, fertility preservation measures and the use of assisted reproductive technologies (ART) help preserve fertility. The main goal of ART is to achieve a healthy pregnancy with minimal complications for both the mother and the off spring[47].

A multidisciplinary team is needed to address the medical, psychosocial, and ethical issues associated with infertile transplant patients. Possible complications should also be anticipated, and protocols and prevention strategies should be followed to avoid them[48,49]. Individual and specific factors should be taken into account when it comes to preserving fertility. Cryopreservation of sperm in men and cryopreservation of eggs or embryos in women are some of the preferred options offered to patients interested in preserving fertility. Cryopreservation of ovarian and/or testicular tissue and hormonal stimulation offer patients the opportunity to manage infertility but are not always appropriate for all transplant patients due to their medical condition[50].

Further research efforts on the subsequent risk of infertility in transplant patients, as well as the safety of fertility preservation strategies, should be a priority. Patients must be informed and guided to utilize the available options for fertility preservation. Poor coordination between doctors and health departments leads to patients being ignorant about the procedures and uncertainty about the financial aspects of the procedure's possibilities. The obstacles we face prevent the proper implementation of good practices and should be overcome to improve patient care. Additionally, there is a need for larger, multicenter studies to validate findings and explore the long-term effects of fertility preservation techniques on transplant patients.

CONCLUSION

Innovations in fertility preservation and pregnancy management are transforming outcomes for transplant patients, offering hope for family-building while preserving long-term health. Advances in ART, tailored immunosuppressive regimens, and interdisciplinary care have made pregnancy safer for both mother and child. Future efforts should focus on optimizing protocols, enhancing access to reproductive care, and addressing ethical concerns related to this specialized population. By integrating cutting-edge technologies with patient-centered care, healthcare providers can better support transplant patients in achieving their reproductive goals, marking significant progress in this dynamic and evolving field.