ESHRE guideline: female fertility preservation.

The field of fertility preservation (FP) has grown hugely in the last two decades, driven by the increasing recognition of the importance of potential loss of fertility as a very important effect of the treatment of cancer and other serious diseases, and the development of the enabling technologies of oocyte vitrification and ovarian tissue cryopreservation for subsequent autografting. This has led to the widespread, though uneven, provision of FP for many women and young girls. The very rapid development of this field in clinical practice, yet with limited data on outcomes, has led to the need for the evaluation of the underpinning evidence and the development of guidelines to assist practitioners in its safe and effective implementation. The guideline focuses on FP options for four populations: (i) post pubertal women diagnosed with cancer undergoing gonadotoxic treatments; (ii) post pubertal women with benign diseases undergoing gonadotoxic treatments or with conditions associated with premature loss of fertility, e.g. Turner syndrome; (iii) transgender men (assigned female at birth); and (iv) women considering oocyte cryopreservation for age-related fertility loss. In all these four populations, the guideline also provides recommendations regarding patient selection to ensure safe and effective care, including during future pregnancy. While it is recognized that this does not comprehensively include all those requiring FP (notably men, prepubertal girls and boys and transgender women), it was decided to limit the scope to focus primarily on adult women.

The current document summarizes all the key questions and the recommendations from the guideline ‘Female Fertility Preservation’. Further background information and the supporting evidence for each recommendation can be found in the full version of the guideline available at https://www.eshre.eu/FFPguideline . A team approach to care for women undergoing FP is advocated in the guideline. To support implementation, the following suggestions were formulated ( Figure 1 ). Model of care for patients eligible for fertility preservation (FP) . There should be agreement within an FP service for who is responsible for all issues, including agreement on referral pathways, availability of standard forms for diagnosis, intended therapy, time intervals and a check whether FP counselling has been offered and has taken place. For FP treatment, a member of the FP team should be responsible for discussing any proposed treatment with the clinical care team before treatment initiation. Documentation and registration should be organized; all relevant medical information should be documented in the patients’ medical records, all patients undergoing FP should have been counselled about the legal and financial consequences and must have given written informed consent and accurate supporting documentation, especially about the gametes/embryos/tissue stored, is essential as storage may last for many years. A direct link between the clinical care team and the FP team, preferably in multidisciplinary team meetings, is recommended. In addition, identification of a key individual (the ‘coordinator’) in clinical care teams is advisable to facilitate patients of reproductive age meeting with the FP team. Psychological support/counselling should be available to all patients considering FP, and specific support for particular patient groups may be required. Expanding access to FP options is also important in the organization of FP care. The guideline group advocates improving (i) public awareness of fertility and of factors that may have negative effects on it; (ii) oncologists’ awareness of FP options; (iii) referral pathways; and (iv) availability of different FP procedures. With regard to these items, specific attention should be given to FP care for specific patient groups, such as adolescents and transgender men. The key organizational features for establishing an FP program are summarized in Figure 2 . Checklist for a high-quality fertility preservation (FP) program . With regard to availability of FP interventions and storage of reproductive material, a survey was conducted to collect national legislative information in European countries, while recognizing that this is a constantly changing area. It was concluded that FP is available in most but not all European countries; thus, specialists should be aware of their national legislative and regulatory situation. This generally supportive legislative environment applies to patients with cancer and benign diseases, and mostly to transgender men. Provision of financial support is less widespread. This may reflect the rapidly developing nature of some FP procedures, and the ongoing change in their status from experimental towards being part of established care. With regards to the duration of storage of reproductive materials, regulations are very variable across Europe. Some countries also have different storage regulations for different materials. While a duration of storage is often applied, this may be supplemented by an upper age limit for use. Given the young age at which FP may occur, the often short allowable duration of storage (5–10 years in many countries) is inappropriate, and legislation should focus more on a maximum age of use. The full guideline includes a table of decision aids that are currently available for FP interventions. A checklist for clinicians to cover the information needs of patients undergoing FP counselling (for the four different indications) is included as Supplementary data I . The multidisciplinary FP team counselling FP patients should be aware that maladaptive psychological processes and past psychopathology are risk factors for psychological distress during FP decision. It is recommended that patients at risk are referred for psychological support when needed. A checklist for patient assessment and selection for FP is presented in Figure 3 . Checklist for patients’ assessment and selection for fertility preservation (FP) interventions (adapted from Wallace et al. ( 2012 )) . An overview of factors that increase the risk of gonadotoxicity, and of factors where evidence is not yet available in presented in Figure 4 . Summary of factors to be considered when estimating the risk of gonadotoxicity . Fertility can be preserved through several procedures, including cryopreservation of oocytes, embryos or ovarian tissue, and potentially medical and surgical methods of protection (see Figure 5 ). Since the development of vitrification, oocyte cryopreservation is the method of choice for women undergoing treatment for age-related fertility loss, and for most women undergoing FP for medical indications. Embryo cryopreservation is even more widely available and long-established part of assisted reproduction, but the necessity for joint legal ownership with the male partner is an important consideration that may result in difficulties later on. Ovarian tissue cryopreservation (OTC) is an important option either through choice, or if there is insufficient time for ovarian stimulation. In vitro oocyte maturation (IVM) can also be considered, and in some cases, there may be a possibility of combining different approaches. Schematic overview of the options for female fertility preservation (FP) . Adapted from ( Anderson et al ., 2015 ) . Protection of the ovary against the effects of treatment would be an ideal approach. Options include GnRH agonists (mostly investigated in women with breast cancer) and ovarian transposition in women scheduled for pelvic radiotherapy. Information on patient re-assessment before attempting pregnancy (with or without the use of stored material) is summarized in Figure 6 . With regards to pre-conception counselling, a checklist was prepared outlining the reproductive options after FP for cancer patients and for transgender men ( Supplementary data II ). Patient re-assessment before attempting pregnancy (with or without the use of stored material) . With regards to obstetric outcomes after oocyte cryopreservation for age-related fertility loss, it has been shown that there are risks of due to older age at pregnancy, which increase after the age of 45 ( Aoyama et al. , 2019 ). More research is needed on the number of women who return to use their frozen oocytes, pregnancy complications, and live birth rates in these women. To increase the spectrum of FP options, innovative technologies and novel in vitro avenues are continually being developed. This includes technologies involving transplantation into the patient, such as transplantation of the whole ovary after cryopreservation and procedures to optimize the use of transplanted ovarian cortex tissue, such as in vitro activation, processes to reduce ischaemia by promoting revascularization, techniques to eliminate residual malignant cells, methods for transplantation of follicles isolated from ovarian cortex tissue as bioprosthetic ovaries, and methods for transplantation of isolated cells into the remaining (gonadotoxic-exposed) ovary. Another line of research focuses on technologies that do not involve transplantation, such as in vitro matured oocytes from cultured ovarian cortex tissue, in vitro matured oocytes from primordial follicles isolated from ovarian cortex tissue and in vitro matured oocytes from cells isolated from the ovary. In addition, research is conducted in the use of in vitro matured oocytes from induced pluripotent stem cells ( in vitro gametogenesis) or from mesenchymal stromal cells. Treatments to prevent gonadotoxic-induced POI have been recently reviewed ( Spears et al. , 2019 ). Regarding future FP interventions, the GDG formulated the following conclusion: It is important to stress that emerging technologies, however promising, need to be followed by rigorous clinical trials, ensuring internationally accepted standards, to demonstrate efficacy and safety before they can be offered as medical treatment. Moreover, a scientific-medical consensus is required regarding safety and functional criteria that needs to be achieved before considering clinical use of in vitro -derived human oocytes. In this regard, a societal debate on the ethical issues and what emerging technologies may be considered acceptable for human reproductive purposes is recommended.

The guideline was developed according to a well-documented methodology that is universal to ESHRE guidelines ( Vermeulen et al., 2017 ) . The guideline development group (GDG) was composed of past and present members of the coordination of the Special Interest groups (SIGs) Fertility Preservation and Quality and Safety in ART, with representation of other SIGs (SIG Psychology and counselling, and SIG Ethics and law), and addition of experts in the field, including oncologists, a scientist, and patient representatives. In short, 21 key questions were formulated by the GDG, of which 7 were answered as narrative questions, and 14 as PICO (Patient, Intervention, Comparison, Outcome) questions. For each PICO question, databases (PUBMED/MEDLINE and the Cochrane library) were searched from inception to 1 November 2019, limited to studies written in English. From the literature searches, studies were selected based on the PICO questions, assessed for quality and summarized in evidence tables. GDG meetings were organized where the evidence and draft recommendations were presented by the assigned GDG member and discussed until consensus was reached within the group. Each recommendation was labelled as strong or weak and a grade was assigned based on the strength of the supporting evidence (High ⊕⊕⊕⊕, Moderate ⊕⊕⊕◯, Low ⊕⊕◯◯, Very low ⊕◯◯◯). Good practice points (GPPs) based on clinical expertise were added where relevant to clarify the recommendations or to provide further practical advice. ‘Research only’ recommendations were also made, and those interventions should be applied only within the context of research, with appropriate precautions and ethical approval. Strong recommendations should be used as a recommendation to be applied for most patients, while weak recommendations require discussion and shared decision-making. For the narrative questions, a similar literature search was conducted. Collected data were summarized in a narrative summary and conclusions were formulated. The guideline draft and an invitation to participate in the stakeholder review were published on the ESHRE website between 6 May and 17 June 2020. All comments were processed by the GDG, either by adapting the content of the guideline and/or by replying to the reviewer. The review process was summarized in the review report which is published on the ESHRE website ( www.eshre.eu/Guidelines ). Overall, 71.5% of the 231 comments resulted in an adaptation or correction in the guideline text. This guideline will be considered for update 4 years after publication, with an intermediate assessment of the need for updating 2 years after publication.

The current paper summarizes the 78 recommendations on information provision and support, pre-FP assessment, FP interventions and after treatment care from the ESHRE Guideline on ‘Female Fertility Preservation’. This Guideline covers all aspects of FP on four different patient populations, specifically cancer patients, patients with benign diseases, transgender men and women requesting FP for age-related fertility loss, and was written by a multidisciplinary group with gynaecologists and fertility specialists, oncologists, a psychologist, a bioethicist, an embryologist, a scientist, and patient representatives. According to the World Health Organization, individuals and couples have the right to decide the number, timing and spacing of their children ( https://www.who.int/news-room/fact-sheets/detail/infertility ). FP can be considered one option in preventing infertility and an important part of realizing the right to have a family. The importance of FP has also been demonstrated at the start of the COVID-19 pandemic, when ESHRE recommended not starting fertility treatments with the exception of treatments for FP. It has been shown that although most fertility treatments were suspended, FP interventions were continued in most centres throughout Europe ( Vermeulen et al. , 2020 ). Notwithstanding the importance and relevance of FP, research data on many aspects are scarce. As a basis for the current guideline, a broad and formal literature review was conducted. Few relevant RCTs have been performed, with evidence for most interventions deriving from case series. Research gaps were detected in several areas, and these are documented in a list of recommendations for further research ( Supplementary data III ). Although the literature searches focused on the four patient populations separately, most studies included in the guideline reported on women with cancer, mostly breast cancer, with very few studies on FP in benign diseases, and even fewer on FP in transgender men and in women requesting FP for age-related fertility loss. For the latter patient groups, most reports focus on feasibility, acceptability and ethical considerations, rather than efficacy, efficiency and safety. To advance the field of female FP, more research is needed on the efficacy and safety of both established and newer techniques with a focus on achievement of live birth, but also on patient preferences and indications for FP. Indeed, one key aspect of the provision of FP is the need to widen access, while offering it to appropriately selected patients with a relevant indication. The variable provision of FP interventions deprives some women from having a family. However, applying FP to all patients undergoing gonadotoxic treatment, even with limited gonadotoxicity, will result in large amounts of stored but unused reproductive cells and tissue, creating unnecessary burden and costs for some patients involved and for health services. The risk of gonadotoxicity can be estimated or quantified in those patients receiving specific treatments that have been studied in sufficient detail, albeit generally with ovarian reserve testing which has very limited value for predicting future fertility. For many patients, the risk and benefits of FP interventions require multidisciplinary discussion and decision-making with regards to FP. New targeted treatments in oncology including immunotherapy largely have unknown gonadotoxicity ( Lambertini et al. , 2020 ). Providing appropriate information to patients and supporting their decision-making is crucial, both on whether to proceed with FP, and when it has become time to attempt pregnancy. Patient information leaflets summarizing the guideline’s most relevant information for patients are available and can be used as a template, and links to decision aids are provided. Despite the limitations of guidelines in general, and the limitations in the evidence supporting the current guideline, the guideline group is confident that this document will help best practice in female FP.

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