Female Fertility Preservation PSP protocol

Purpose of the PSP and background

The purpose of this protocol is to clearly set out the aims, objectives and commitments of the Female Fertility Preservation Priority Setting Partnership (PSP) in line with James Lind Alliance (JLA) principles.  The Protocol is a JLA requirement and will be published on the PSP’s page of the JLA website. The Steering Group will review the Protocol as needed and any updated version will be sent to the JLA. 

The JLA is a non-profit making initiative, established in 2004.  It brings patients, carers and clinicians together in PSPs.  These PSPs identify and prioritise the evidence uncertainties, or ‘unanswered questions’, that they agree are the most important for research in their topic area.  Traditionally PSPs have focused on uncertainties about the effects of treatments, but some PSPs have chosen to broaden their scope beyond that.  The aim of a PSP is to help ensure that those who fund health research are aware of what really matters to patients, carers and clinicians.  The National Institute for Health and Care Research (NIHR) coordinates the infrastructure of the JLA to oversee the processes for PSPs, based at the NIHR Coordinating Centre, University of Southampton.  

The Female Fertility Preservation Priority Setting Partnership (PRESERVE) group is a clinician researcher led project to establish a Priority Setting Partnerships (PSPs) in fertility preservation in individuals assigned female at birth. This will bring together clinicians and those with lived experience on an equal footing to identify evidence gaps that are important to both groups. By identifying evidence gaps, PRESERVE will improve clinical practice and outcomes for women requiring fertility preservation.

Problem

In recent years, there has been an increase in the incidence of cancer among adolescents, particularly in the United Kingdom, where the rate has surged by 24% over the past three decades. This rise is especially notable among young females, with approximately 1,200 new female cancer cases being diagnosed annually. Remarkable advancements in research have undoubtedly contributed to improved diagnostic techniques and treatment options, resulting in reduced mortality rates among young cancer patients. However, the long-term consequences of gonadotoxic treatments, including infertility, pose significant challenges for cancer survivors. Gonadotoxic treatments not only target cancer cells but can also damage reproductive tissues, leading to infertility and hormonal imbalances, causing infertility as well as premature menopause. Unfortunately, the focus of treatment is often primarily on survival, with less attention given to the reproductive system and the quality of life after cancer. Preservation of fertility serves as an insurance policy, offering a limited window of opportunity to preserve the option of having children in the future.

Furthermore, while there is a plethora of data on fertility preservation in young girls and women undergoing gonadotoxic treatment for malignant diseases, research on FP in non-malignant conditions remains considerably limited. These non-malignant conditions encompass various benign haematological, autoimmune, and genetic disorders, as well as numerous benign gynaecological conditions that can potentially impact ovarian reserve and reproductive potential. This could be due to various pathogenic mechanisms or as a consequence of medical or surgical interventions.

In addition to the medical necessity of FP for cancer patients, there is a growing trend among young girls and women to delay motherhood for personal reasons. Factors such as career aspirations, lack of a long-term partner, or simply not feeling ready to become mothers can significantly impact women later in life when conceiving becomes more challenging. Elective fertility preservation usually through oocyte cryopreservation has provided such females with the opportunity to preserve the option of having children in the future.

As for fertility preservation techniques, various options are available including embryo, oocyte and ovarian tissue cryopreservation, ovarian transposition, as well as pharmacological protection using gonadotropin-releasing hormone (GnRHa). As our understanding of this subject progresses rapidly, there's an urgent need to pinpoint priority questions that will drive future research, ensuring it's most beneficial to those it serves. Specifically, within non-malignant conditions, there's a noticeable increase in offering fertility preservation (FP) options to affected women. However, given the limited research, particularly in its early stages, it's crucial to focus on key inquiries. By doing so, we can bridge existing knowledge gaps and pave the way for impactful research that truly meets the needs of patients.

Gaps in the evidence

A PSP to establish shared priorities for research is a powerful tool to ensure that research is pertinent and addresses critical gaps in the evidence. However, consultation with women who have lived experience of FP and their clinicians, to establish research priorities in female fertility, has not yet occurred. This step is critical to ensure that research questions address priority areas for patients, and to establish a dialogue between clinicians, researchers, and patients about future research. 

Similar initiatives in other areas of women's health research have demonstrated the effectiveness of involving patients in setting research priorities. The top 10 female FP research priorities, identified through this inclusive process, will inform future research, and enable the responsive allocation of resources to improve the health and well-being of women requiring FP. Funding bodies, such as the National Institute for Health and Care Research (NIHR), allocate specific funds for research addressing leading priorities identified through PSPs. Lastly, the setting of research priorities also directly aligns with the Women's Health Strategy for England. The strategy emphasises the significance of addressing 'fertility' related issues as a crucial aspect of women's health across her life course.

Aims, objectives and scope of the PSP

Aim:

We want to understand the questions that people with lived experience and health care professionals have about preservation of fertility in females. This includes healthcare professionals looking after individuals who have needed fertility preservation for reasons including cancer, non-malignant conditions requiring gonadotoxic treatments, transmen who have undergone or want to undergo gender reassignment or for social reason. Patient groups are to include teenage and young adolescent and individuals of reproductive age assigned female at birth. 

Objectives of the PSP are to:

• Work with those with lived experience and clinicians to identify uncertainties about fertility preservation options.
• To include as wide as possible range of voices, including (in no specific order) individuals requiring gonadotoxic treatment, those with premature ovarian insufficiency, endometriosis, ethnic minority and culturally and linguistically diverse groups LGBQTI+ (particularly Trans and those with infertility caused because of medical treatment).
• To agree by consensus a prioritised list of those uncertainties, for future research.
• To publicise the PSP process and results.
• To take the PSP results to research commissioning bodies to be considered for future funding.

In scope for the PSP are the following: 

Population of interest

Those who underwent FP and those at risk of needing it and are to include:

• Individuals assigned female at birth who underwent any fertility preservation technique (embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, GnRH analogues or ovarian transposition). 
• Women or young girls (prepubescent) requiring gonadotoxic treatment – their parents/care-givers.
• Women with premature ovarian insufficiency including those at risk and those with experience.
• Women with non-cancer conditions that can impair fertility such as endometriosis, Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH) and Turner syndrome. 
• Women undergoing FP due to personal reasons or who have considered it.
• Transmen who have had medical interventions (such as bilateral salpingo-oophorectomy as part of gender reassignment).

The scope is international, primarily Europe, UK and the USA but all international contributions will be accepted if in English.

The PSP will exclude from its scope questions not asked in English, personal clinical questions, and questions about access to services in specific geographical locations which are not generalisable. 

The Steering Group is responsible for discussing what implications the scope of the PSP will have for the evidence-checking stage of the process.  Resources and expertise will be put in place to do this evidence checking.

The Steering Group

The Steering Group (SG) includes lived experience representatives and healthcare professionals, as individuals or representatives from a relevant group. The SG is a working group, contributing to the running of the PSP, ensuring timely delivery and adherence to the JLA principles of transparency, inclusion, equality and use of existing evidence. The SG ensures that the process is documented, open and transparent and adheres to the survey responses and evidence review. 

The JLA Adviser supports and guides the PSP, ensuring fair and transparent processes with equal input from all groups. The Adviser provides advice and materials for use of the JLA methodology, survey design, documentation, tools, data management, and communications and chairs the SG meetings. 

Engagement of those with lived experience is fundamental to the process of PSP and lived experience members will be actively engaged at all stages. Our global SG comprises approximately 20 people. At present we have 4 members that either have lived experience or are patient representatives. The aim is to have at least a quarter of the SG representing individuals with lived experience. The SG also includes healthcare professionals across relevant disciplines such as gynaecology (including paediatric and adolescent gynaecology), reproductive biology, oncology, endocrinology, paediatrics, specialist nurses).

Hajra Khattak leads the SG and is an Academic Clinical Lecturer with a PhD in female fertility preservation techniques and is currently also leading the first Core Outcome Set in female fertility preservation research and we will draw on these networks for PRESERVE. The SG will complete the JLA interests and privacy declarations. 

An experienced JLA Adviser (Caroline Magee) and information specialist (Kristina Staley) is part of the SG. The SG will meet every 1-3 months, depending on the stage and needs of the PSP.

The Female Fertility Preservation PSP will be led and managed by a Steering Group including the following:

Lived experience or patient support group representatives: 

• Danya Kaye
• Lauren Shute 
• Zainab Garba-Sani
• Daisy O’Leary Pye
• Sarah Markham
• Farzana Kausir
• Georgina Jones Cancer Fertility and Me
• Yvonne O’Meara, ROI Psychosocial Oncologist; Systemic Psychotherapist, Women’s Cancer Survivorship Research Coordinator 

Clinical representatives: 

• Hajra Khattak (PSP Leader), NIHR Academic Clinical Lecturer (Assistant Professor) in Reproductive Health, Honorary Specialist Registrar in Obstetrics and Gynaecology, University College London Hospital and University College London
• Jemma Barash (PSP Coordinator), University College London Hospital and University College London
• Jessica Mascarenhas (PSP Coordinator), Academic Foundation Doctor, University Sussex NHS foundation trust
• Ephia Yasmin, Consultant Gynaecologist and a subspecialist in Reproductive Medicine and Surgery, Honorary Associate Professor, University College London Hospital and University College London
• Melanie Davies, Professor of Gynaecology, Consultant Gynaecologist and a subspecialist in Reproductive Medicine and Surgery, University College London Hospital and University College London
• Zachary Nash, Clinical Research Fellow Gynaecology, University College London Hospital and University College London
• Richard Anderson, Consultant Gynaecologist and Professor of Clinical Reproductive Science, The Centre for Reproductive Health, Edinburgh
• Mahmoud Salama, REI Clinical scientist, Director of the Oncofertility Consortium and Assistant Professor, Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University
• Julia Kopeika, Consultant Gynaecologist and a subspecialist in Reproductive Medicine and Surgery, Clinical Lead for the Fertility Preservation Service at Assisted Conception Unit at Guy’s and St Thomas’.
• Maxine Semple, Senior Clinical Embryologist, Lead for Ovarian Tissue Cryopreservation Service and Lead Clinical Scientist, Guy’s and St Thomas’ and King’s College London
• Dusko Ilic, Professor of Stem Cell Science, King’s College London
• Christiani Amorim, Professor of Reproductive Physiopathology, Director of Research Pole in Reproductive Physiopathology, Brussels, Belgium.
• Kirsten Macklon, Consultant Gynaecologist, Oncofertility specialist, Fertility Clinic, Copenhagen, Denmark.
• Stine Kristensen, Reproductive Biologist and Senior Scientist, Head of the Laboratory of Reproductive Biology at the University Hospital of Copenhagen, Denmark.
• Mike Rimmer, Clinical lecturer and Obstetrics and Gynaecology Trainee, University of Edinburgh

The Partnership and the priority setting process will be supported and guided by:

The James Lind Alliance (JLA) advisor: Caroline Magee

Information Specialist: Kristina Staley, TwoCan Associates

The Steering Group will agree the resources, including time and expertise that they will be able to contribute to each stage of the process, with input and advice from the JLA Adviser. 

Partners

Relevant organisations and groups will be invited to be involved with the PSP as partners. Partners will commit to supporting the PSP, promoting the process, and encouraging their represented groups or members to participate. Partners represent the following groups:

• People who have lived experienced of fertility preservation method(s)
• Health and social care professionals with experience of caring for those requiring fertility preservation. 

Confirmed Partner Organisations: 

• BFS Fertility Preservation UK
• Cancer Fertility and Me
• Wellbeing of Women, UK
• ESHRE FP Special Interest Group
• Turner Syndrome Support Society
• The Oncofertility Consortium 

Exclusion criteria:

Some organisations may be judged by the Steering Group to have conflicts of interest.  These may be perceived to potentially cause unacceptable bias.  As this is likely to affect the ultimate validity of the findings of the PSP, those organisations will not be invited to participate.  It is possible, however, that interested parties may participate in a purely observational capacity when the Steering Group considers it may be helpful.

The methods the PSP will use

This section describes a schedule of proposed steps through which the PSP aims to meet its objectives.  The process is iterative and dependent on the active participation and contribution of different groups.  The methods used in any step will be agreed through consultation between the SG members, guided by the PSP’s aims and objectives.  More details of the method are in the guidebook section of the JLA website.

A period of 18 months will be given to complete this exercise (which may be revised by the Steering Group if required).

Awareness raising 

The PSP will raise awareness of the project among lived experience and clinician communities, to secure support and participation. 

Awareness raising has several key objectives:

• to present the proposed plan for the Female Fertility Preservation PSP
• to generate support for the process
• to encourage participation in the process
• to initiate discussion, answer questions and address concerns.

The SG and partners will raise awareness of the PSP amongst communities, through the media and via the PRESERVE website in order to secure support and participation. The SG will create a short video targeting potential participants to explain the PSP purpose and process, an approach effectively used by other PSPs. The survey will be launched through social and mainstream media, using our partner organisations and SG networks to disseminate the survey. The headline message will be: 

“Do you want to shape the future of fertility preservation research?”

Identifying evidence uncertainties (unanswered questions)

The Female Fertility Preservation PSP will gather uncertainties (unanswered questions) from patients, carers, clinicians and scientists. 

The SG will design the survey with guidance from the JLA, JLA Adviser, Information Specialist and previous successful PSPs. Lived experience members will be engaged at all stages. Steering Group members will contribute to the survey design and development. 

The survey will target:

1. Those with lived experience: Women who have experienced fertility preservation (any method). These will be targeted through our extensive SG and partner networks and through social media groups. 
2. The Female Fertility Preservation PSP recognises that the following groups may require additional consideration:
   1. Patients with a previous cancer diagnosis 
   2. Patients with premature ovarian insufficiency 
   3. LGBQTI+ (and particularly trans) individuals 
   4. Ethnic minority and culturally and linguistically diverse groups
   5. Patient with infertility because of medical treatment 

The survey will cover three areas:

1. Demographic information including age, ethnicity, sexual orientation and gender, reason of fertility preservation if already undergone it (e.g. previous gonadotoxic treatment, elective FP) 
2. Respondent group (lived experience, HCP, researcher), recognising that respondents may identify in more than one group (e.g. HCP and seeking or previously sought FP).

3. The key unanswered questions for fertility preservation research by asking:

   “Please list up to 3 questions about female fertility preservation that you would like to see answered by research.”

Participants can provide up to 3 responses. Participants can choose to provide their contact details to receive information or be involved in future stages of the PSP.  This helps with disseminating and targeting recruitment to the final consensus workshop. Participant names and contact details will not be linked to their survey responses.

We will widely disseminate the survey using contacts from our SG, partners, social media, consumer groups, targeted communication, and advocacy groups. Our partners are well placed to promote and disseminate the survey. 

The survey will be live for 8 weeks. We will check for saturation after 6 weeks and monitor responses for any new questions/topics. At saturation or after 3000 responses the survey will close. Otherwise, we may extend the open for a few more weeks with additional promotion through our partners and social media, or targeted promotion.

Existing sources of evidence uncertainties may also be searched.

Organising and summarising the responses

We anticipate responses to be a mix of specific questions, personal stories and themes or issues. Survey responses are rarely formed as research questions but will contain a question or issue that is important to the respondent.

The review methodology is a qualitative, interpretative, and iterative exercise conducted by an independent JLA Information Specialist, Kristina Staley (KS).  The responses will be read, categorised and summarised by KS, with the support of the SG.  Similar or duplicate responses will be combined where appropriate into summary questions.  Out-of-scope and ‘answered’ responses will be compiled separately.  The aim is to develop a manageable number of summary questions for the first stage of prioritisation, aiming for 50-60 questions. 

The SG provides governance, ensuring that the original responses are interpreted fairly, checking those identified as out-of-scope, and checking singleton questions to determine if they stand alone or should be merged with another question. The summary questions should include a balance of responses from diverse groups. The SG will also ensure that the summary questions are clear, accessible and unambiguous.  A focus group may be formed and consulted to support this review of responses. The JLA Adviser will observe to ensure accountability and transparency.

The analysis will result in a list of in-scope summary questions. These are not framed as research questions, as this may make them too technical for a non-research audience. They are framed as researchable questions that capture the themes and topics that people have suggested in their responses.

These summary questions will be checked against the evidence to determine whether they have already been adequately answered in published research. We will search PubMed for RCT, systematic reviews and clinical guidelines to establish whether high-quality evidence already exists to answer the questions identified in the survey. The search will be extensive and include websites of national organisations, professional societies, and guidelines databases. Clinical trials.gov will be searched for relevant trials in progress. The Cochrane Library and PROSPERO database will be searched for completed or in progress systematic reviews. The Turning Research Into Practice (TRIP) and PubMed databases will be searched for evidence-based guidelines and systematic reviews. When the evidence is uncertain (“borderline questions) will be discussed amongst the Steering Group and Focus Groups to determine whether these questions are already ‘answered’ or ‘unanswered’. Level of evidence will be graded using the updated Grading of Recommendations, assessment, development and evaluations (GRADE) approach. 

The summary questions that are verified as being unanswered form the long-list for the first stage of prioritisation. 

The SG will consider how to deal with the responses that have already been answered and those considered out of scope. This may include sign-posting to available sources of information or support. 

Both the original survey responses and summary questions will be published on the JLA website at the end of the PSP. An audit trail is maintained for transparency showing how the summary questions have been developed, including the original responses, the respondent group, and other demographics. The responses should be anonymous, but are checked for any inadvertent personal information. Full anonymity will be maintained throughout. 

The PSP will complete the JLA Question Verification Form, to document the process used to verify the uncertainty of the questions, before starting prioritisation. This will be published on the JLA website, to enable researchers and other stakeholders to understand how the PSP has decided that its questions are unanswered, and any limitations of this.

Prioritisation – initial and final stages 

There are usually two stages of prioritisation. 

Initial prioritisation by individuals

Initial prioritisation is the stage where the long-list of questions is reduced to a shorter list that can be taken to the final priority setting workshop.   

Based on similar PSP (Contraception (.PDF)) we anticipate that the long list will contain around 50-60 unanswered summary questions. 

We will target the same stakeholder groups as the first survey. We aim to involve as many people as possible, including those who did not contribute to the first consultation. Participants will be asked to select the Top 10 questions that are most important to them. The results will be analysed and balanced by group, to avoid skewing the results if there are unequal numbers of participants in each stakeholder group. Where the interim prioritisation does not produce a clear cut off point, the SG may decide which marginal questions should be taken forward, also considering the balance of themes/topics. The interim prioritisation allows the long list of 50+ summary questions to be reduced to a short list of up to 20. These will be reviewed by the steering group and taken to the final priority setting consensus workshop. 

Consensus workshop

The aim of the final stage of the PSP is to prioritise through consensus the identified unanswered questions about female fertility preservation. This will involve input from the priority population and HCPs. 

The final priority setting process will be a full day workshop facilitated by the JLA and held in mid- 2025. The JLA Adviser (Caroline Magee) will attend in person and chair the workshop. With guidance from the JLA and input from the Steering Group, around 30 people with lived experience and HCPs will be recruited to participate in a day of discussion and ranking, to determine the top 10 questions for research.

The meeting is planned to be a hybrid (including online participants) to facilitate participation by those outside of the UK who are unable to attend in person, this hybrid model has been used for other PSPs. Participants will equally represent each stakeholder group and include diverse experiences. All participants will declare their interests. The SG will advise on any adaptations to ensure the process is inclusive and accessible. The workshop will follow the standard JLA priority setting approach, drawing on Nominal Group Technique. This involves participants being provided with the shortlist of questions, which they review and rank for themselves in advance of the workshop. Through a series of small and large group sessions at the workshop, the questions will then be ranked by consensus discussion, facilitated by JLA Advisers.

Dissemination of results

The Steering Group will identify audiences with which it wants to engage when disseminating the results of the priority setting process, such as researchers, funders, and lived experience communities. They will need to determine how best to communicate the results to these groups.  Previous PSPs’ outputs have included academic papers, lay reports, infographics, conference presentations and videos for social media. 

It should be noted that the priorities will all be published and made available for research. Those that did not make the Top 10 will not be abandoned. The priorities are not worded as research questions. The Steering Group should discuss how they will work with researchers and funders to establish how to address the priorities and to work out what the research questions are that will address the issues that people have prioritised. The dissemination of the results of the PSP will be led by Hajra Khattak and Jemma Barash. 

The JLA encourages PSPs to report back about any activities that have come about because of the PSP, including funded research and the JLA will be kept updated.

The Top 10 will be launched at the European Society of Human Reproduction and Embryology (ESHRE) in 2025 where healthcare professionals discuss the most recent scientific and research developments in the field of reproductive medicine and surgery. 

The SG will identify the key audiences who should be aware of the Top 10 including researchers, funders, patient and advocacy groups, conference presentations, social media. Steering group and partners will disseminate amongst networks (#femalefertilitypreservation10). We anticipate that our findings will be published in high-impact journals. 

We will work with global funding bodies and advocacy groups to promote the value of supporting research questions prioritised.

Agreement of the Steering Group

The Female Fertility Preservation PSP Steering Group agreed the content and direction of this Protocol on 11th July 2024.