What do families affected by Turner Syndrome think of ovarian tissue freezing in childhood?

Abstract

Ovarian tissue freezing (OTF), currently used to preserve fertility for girls and women with cancer, is beginning to be considered for conditions that cause ovarian insufficiency in childhood, such as Turner Syndrome (TS). This article addresses the gap in information on how women with TS and their families view OTF and the values that inform the decision to use it. It reports qualitative findings on the perceived benefits and challenges of OTF, using a purposive sample of 19 women with TS and 11 mothers of girls with TS in the UK, taken from a wider study on how reproductive choices are shaped by TS. It concludes by looking at ways to address the potential use of OTF with families. Most participants strongly supported the option of OTF. Perceived benefits included the potential for natural conception and a genetically-related child, and increasing the agency of women with TS. Perceived challenges included the invasive nature of tissue collection, the age it would need to be performed, and how girls and their family would be informed and supported. Some participants also identified the impact on a girl’s future fertility and the possibility that TS is heritable as barriers.

Keywords:

• Turner syndrome
• ovarian tissue cryopreservation
• reproductive preservation
• fertility

Introduction

The use of reproductive preservation (RP) technologies, especially egg freezing, has become widespread for both social and medical reasons. Although egg freezing may be suitable for adults and adolescents, only ovarian tissue freezing (OTF) can be performed in childhood. Most of the literature on OTF looks at its use with adults and adolescents with cancer; less attention has been paid to its use for girls and women with non-oncological diseases that cause premature ovarian insufficiency before puberty, such as Turner syndrome.

Turner syndrome (TS) is an X chromosome disorder affecting 1:2500 women; its main characteristics are short height and reduced fertility or infertility, but a range of physical and psychosocial signs are linked to the condition (Gravholt et al., 2017). In ‘classic’ TS (45,X), all cells have a missing X chromosome, while in mosaic TS, only some cells are affected. Girls with TS are often born with no ovaries, or their ovaries do not function by the time they reach puberty due to accelerated follicular atresia, which causes premature ovarian insufficiency at or before puberty; in adulthood, only 5% of women with TS can conceive naturally (Bernard et al., 2016; Mavridi et al., 2018). Fertility levels vary according to TS karyotype; while 40–50% of women have classic TS, the remaining women have mosaic TS, which is generally linked with a higher ovarian reserve, giving a possibility of natural conception for some (Cameron-Pimblett et al., 2017). Women with TS have successfully used egg donation to conceive and carry a pregnancy, but it tends to have a lower success rate compared with unaffected women of the same age (Calanchini et al., 2017). A woman with mosaic TS has given birth using her own frozen eggs (Strypstein et al., 2022). However, high rates of miscarriage, premature birth, stillbirth, and foetal anomaly mean the live birth rate is comparatively lower (Cauldwell et al., 2022; Hewitt et al., 2013). Heart and hypertension issues, both comorbidities associated with TS, can make pregnancy potentially riskier for those women who are affected (Cauldwell et al., 2022). Notably, there is a 2% risk of maternal mortality (Karnis et al., 2003).

Girls with TS are rarely fertile by the time they are old enough to undertake egg freezing, and their counselling and disease management needs are different (Condorelli & Demeestere, 2019; van der Coelen et al., 2022). Yet infertility can have a significant impact on the quality of life of women with TS (Falsey et al., 2022), and can be a barrier to forming intimate relationships (Gould et al., 2013), making it an issue of great importance to families affected by TS. Current guidelines on fertility preservation (FP) for women focus on options available to adults (ESHRE Guideline Group on Female Fertility Preservation, Anderson et al., 2020). The Turner Fertility expert panel recently published a consensus of international expert opinion on the use OTF for young girls with TS (Schleedoorn et al., 2020) but it does not explore the specific issues OTF raises for girls, women and their families and what might affect their decisions.

Prepubertal OTF is an innovative technique that provides the potential to preserve fertility for some girls with prepubertal ovarian failure. An ovary is removed and frozen, for reimplantation in later life; both procedures are performed with laparoscopy. Transplanting frozen tissue has enabled women to establish a menstrual cycle, avoiding the need for oestrogen supplementation, and to have a genetically-related child (Yasmin et al., 2018). An additional potential benefit is that, by transplanting their own ovarian tissue, women may avoid the increased risk of hypertension and pre-eclampsia linked to pregnancy with the use of donated eggs (Moreno-Sepulveda & Checa, 2019). However, little data is currently available on success rates which would ground decisions about whether OTF is feasible for girls with TS. The first live birth from frozen ovarian tissue was in 2004 (Donnez et al., 2004); the first live birth from prepubertal frozen tissue was in 2015 (Demeestere et al., 2015). Globally, there have been at least 130 live births from transplanted tissue recorded, but none to a woman with TS (Donnez & Dolmans, 2017).

OTF, like RP in general, is known to mitigate psychological distress in people whose fertility is at risk, whether through cancer or non-malignant conditions (Lotz et al., 2020). Transplantation has proven successful and OTF for adults is no longer considered experimental; however, the collection procedure is invasive and there are live birth rates of around 25% following transplantation (Donnez & Dolmans, 2017). A number of studies in different countries have demonstrated that ovarian tissue collection can be performed successfully in prepubertal girls with TS as young as 8 if they are diagnosed when they still have an ovarian reserve (Jadoul et al., 2010; Oktay et al., 2010); altogether 150 children and adolescents with TS have taken part in OTF studies (Jeve et al., 2019). A woman with TS had a live birth using ovarian tissue donated by her unaffected twin sister (Donnez et al., 2011). However, most girls who have had OTF are still in their early 20s and not ready for transplantation (Lotz et al., 2020). For this reason, there are no data so far showing whether transplantation could restore fertility in women with TS who have used their own frozen ovarian tissue.

Jeve et al. (2019) identifies three predominant concerns for girls with TS when considering OTF: there is no evidence so far of its efficacy in the context of TS; the availability of frozen tissue may encourage women to undertake high-risk pregnancies; and there is a higher risk of chromosomal anomalies in children conceived from ovarian tissue which is affected by TS (Bernard et al., 2016). There are also rare cases of familial TS (Burt et al., 2021), including cases which report women with a mosaic form of TS giving birth to a daughter with mosaic TS (Bahíllo-Curieses et al., 2016; Periquito et al., 2016; Portnoï et al., 2012). There is currently no evidence that classic TS is heritable; this evidence suggests that TS may be heritable in women with mosaic TS. Concerns about chromosomal anomalies and heritability could be addressed by using preimplantation genetic testing (Jeve et al., 2019). Currently OTF appears to be suitable only for a small subset of girls with mosaic TS who are diagnosed when they still have a sufficient ovarian reserve for freezing and transplantation to be feasible (Mamsen et al., 2019; Oktay & Bedoschi, 2019). This option is also uncertain since, between having OTF and the age at which they wish to have the tissue transplanted, an individual may develop TS-related health issues which could make it dangerous to undertake a pregnancy. For these reasons, some clinicians are concerned that OTF can give false hope to girls with TS who are not able to access it, or who may subsequently find that transplantation fails or cannot be used, risking psychological harm (Grynberg et al., 2016; van der Coelen, 2022).

An additional factor to consider is the cost. The procedure itself may be medically viable but if it is not publicly funded and patients and their families do not have the money to access it privately, this will present a barrier. Currently, OTF for fertility preservation is recommended only for cancer patients in the NICE Guidelines (National Institute for Health and Care Excellence, 2013) and even for this group, it is not consistently available across the UK (Abdallah et al., 2018, Latif et al., 2022).

OTF, and FP in general, have a positive impact on quality of life when used in both oncological and non-life-threatening conditions (La Rosa et al., 2020). They enable cancer patients to focus on their survival and future life (Bach et al., 2020; Hinkle et al., 2021). Including adolescents in discussions about FP can give them more of a sense of control over their situation (Barlevy et al., 2016; van der Coelen, 2022); a prerequisite for psychological satisfaction in adult women who undertook FP is that they were provided with genetic, medical and psychosocial counselling that gave them realistic expectations about the success rates of future treatment (Hewitt et al., 2013). Decision regret for those who have undertaken FP is very low, particularly where patients and families have been given high quality information and enough time to fully consider the choice, and there has been a shared decision making process as to what course of action to take (Jayasuriya et al., 2019; van der Coelen, 2022). In one survey study looking at OTF across a range of conditions that included TS (Lotz et al., 2020), most respondents had not yet had tissue transplanted, but were very satisfied they had undertaken OTF and would make the same decision again. A minority said that the cost would deter them from doing it again.

Interest is growing in whether prepubertal OTF is suitable for girls with TS, but few studies address patient views on this technology. This qualitative study explored the issues that women with TS and mothers of girls with TS consider to be important with respect to OTF, and its perceived benefits and disadvantages.

Materials and methods

Data presented in this paper were collected as part of ‘Reproductive decision-making, parenthood and the use of assisted conception: an exploratory study of the perceptions and experiences of women with Turner Syndrome’ (Fearon, 2020) undertaken between 2015 and 2020. This took a constructivist grounded theory approach (Charmaz, 2014), drawing on a purposive sample of 30 participants, 19 women with TS and 11 mothers of girls with TS.

Ethical approval was given by HLS Faculty Research Ethics Committee, De Montfort University (application no 1824).

Participants and recruitment

The sample was purposive and included women with TS of childbearing age who were planning to have, or already had a family (by any method), who were child free, or whose health, finances or another barrier had prevented them from having a family. It also included mothers who had a daughter with TS and had considered their daughter’s future family-building options.

Mothers of girls with TS were included in the wider study, firstly in order to explore views on reproductive options such as maternal egg freezing, where some mothers have frozen their eggs for their daughter’s use in later life, and OTF, where parents would need to give consent. Secondly, they tend to have a greater influence than fathers on their children’s reproductive choices and sexual behaviour (Beresford & Sloper, 2008 p82; Di Iorio et al., 1999; Swain et al., 2006), so could potentially influence their children’s family building choices in later life.

TS is a rare condition, so recruitment material was targeted widely, including flyers at patient group conferences, social media (a project Facebook page, patient group shares and retweets), websites (calls for participants on parenting and fertility sites; a project website) and paid advertising (Facebook; The Voice newspaper). Recruitment material and project information was also available in video format. Enquirers completed a screening survey asking for demographic data, parental status, type of TS, progress to date with reproductive decisions, and, if they had children, family-building method.

As TS is a syndrome, the reproductive options available to adult woman vary depending not only on age and access to treatment, but also an individual’s karyotype and medical risk (Jeve et al., 2019). The sample needed to reflect a range of experiences from women with TS, so screening enabled potential participants with classic and mosaic TS to be recruited in proportion to their numbers in the community.

Participant characteristics

Women with TS (n = 19) were aged between 21 and 60. Mothers (n = 11) were aged between 33 and 52 and their daughters ranged in age from 5 to 27. All participants who disclosed their ethnicity were white British or white Other. Eight participants with TS were married, five were engaged or had a long-term partner, and six were single. Five had children: three through egg donation, one through adoption, and one conceived naturally. Of the 14 participants with TS who did not have children, eight had chosen their family building method but not yet acted on it, for reasons of timing or finances. Three had no children for health reasons, two were still deciding what to do, and one was childfree.

Procedure

Data were collected using semi-structured, face-to-face photo elicitation interviews (Harper, 2003) at or near participants’ homes. Participants were asked to select three photographs to bring to the interview to use as a starting point, leading into further discussion about their experience and views on fertility, TS and family-building. They were then asked about any issues that had not been covered by the first part of the interview. Interviews lasted on average 1½ to 2 hours. Photo elicitation was chosen specifically to increase the agency of participants in discussing this sensitive subject (Liamputtong, 2007) as the process of selecting photographs enabled participants to plan what they wanted to say in advance of the interview.

TS is linked with a characteristic set of signs, some of which, such as anxiety or hearing impairment, could present a barrier to taking part (Gravholt et al., 2017). To support participation, a range of adjustments were planned into the interview design both for women with TS (detailed in Fearon, 2019) and for the whole sample, any of whom might have had a disability (Aidley & Fearon, 2021). Participants were invited to discuss in advance any adjustments they might need; none did so beforehand, but some did so as the interview started. In the interview, participants were asked for their views on OTF, which the researcher briefly described as a technique that involved removing and freezing an ovary from a girl with TS before puberty for transplantation in later life, which could potentially restore fertility.

Data analysis

Interview recordings were transcribed and analysed according to the principles of constructive grounded theory (Charmaz, 2014). Interviews were given interpretative codes in NVivo throughout the period of data collection. Data for the two groups were coded separately, sifted to select for a focus on reproduction, elaborated into categories using mind-mapping software, then refined into theoretical categories. For this article, the interpretative codes on OTF were extracted from both groups in the full study. The codes identified the range of participants’ perceptions about OTF, and were summarized into findings, which are presented below as a set of perceived benefits and risks.

Results

Infertility is reported as one of the most important issues affecting women with TS (Sutton et al., 2005) and participants were interested in hearing of any option that might support family building in adult life. Prepubertal OTF is considered an unproven technology in girls with TS due to the lack of outcomes data. Consequently, some participants did not know much about it and would need further information to make an informed decision. Several participants with TS mentioned that they could not have used OTF themselves as they did not have viable ovaries, or had streak ovaries removed, but most were unaware of whether they could have been eligible. Understanding who is eligible for treatment, and who is not, is a vital way to set expectations for girls and their families, particularly when the technology may raise hopes of a potential solution. Within this context, these are what participants described as the benefits and challenges of OTF.

The perceived benefits of OTF

Some women with TS commented that they had known at a young age that they wanted to be a mother, and even for a child, the diagnosis of infertility could be devastating.

If the option is there… and the more that they can make these things available, it gives hope to younger girls who are absolutely devastated at the thought of not being able to have a family, it gives them more options. [TSW18: woman with TS, early 30s, child free]

I think if I had been told that I couldn’t have had [children]… my desire for a family was pretty strong. Very strong. I would have probably wanted to give it a try. [TSW10: woman with TS, early 60s, 2 children via natural conception]

That meant, with reservations which are discussed below, most participants were strongly supportive of technology that enabled women to have the option to have a child, if it was feasible for them.

One of the major benefits of OTF expressed by both women with TS and mothers of girls with TS was its potential to enable women to have a ‘normal’ experience of conception and pregnancy. As girls with TS often grow up being visibly different from their peers due to their short height, the need to take growth hormone and puberty-inducing medication, and receiving an infertility diagnosis in childhood or at puberty, the prospect of a treatment which would enable her to fit in with her peers was very appealing.

I think that’s amazing! If the girl’s then got that option when she’s older, to try, I think that’s as close as she’s ever going to get to what a normal woman would do. [TSW9: woman with TS, late 20s, no children]

If only it had come sooner! [TSW6, woman with TS, early 50s, no children]

Another widely valued benefit of OTF was that it gave women the potential to have a biological child (and, as one participant mentioned, for their parents to become grandparents). This was seen as important because it mirrored normative family relationships.

I would bite someone’s hand off if it was offered because it would be their child and that’s what I would like her to have, that option. [TSM11: mother, mid-30s, 1 daughter aged 8]

Participants usually viewed intrafamilial donation, for example with eggs donated by a sister, as emotionally challenging and hard to manage, although they also understood the appeal of having a child genetically related to the mother. By comparison to this option, OTF was seen as a way to maintain family harmony by avoiding the emotional and social complexities of intrafamilial donation.

It’s more straightforward than having donor eggs from a family member, though, because it will be her own, the girl with Turners’ own tissue, own genes. [TSM10: mother, mid-40s, 1 daughter aged 8]

Several women with TS emphasized that it was important that women should have options to choose from, saying that there is a psychological benefit of having OTF, including that it would increase self-esteem and agency in adulthood.

I think the fact that you’ve got the option, that you’ve got the choice, is brilliant because then you can work out what’s best for you. [TSW12: woman with TS, late 40s, no children]

In summary, most participants strongly supported this option in principle, because it may give the option of natural conception and a genetically-related child.

The perceived challenges of OTF

The main concerns expressed by women with TS and mothers of girls with TS were the physical and emotional impact of the procedure on the child and the challenges that parents would face in explaining the need for the treatment and supporting her through it, particularly if she was very young when it was performed.

Even though she was only 5, she was still old enough to have some input into the conversation. You couldn’t do that with a three-year-old. [….] I think I’d have said no. [TSM7: mother, mid-40s, 1 daughter in her early 20s]

I think maybe at 4, understanding the intricacies of removing the ovaries and all that sort of thing, perhaps is a bit too much. If it was my child, I’d probably just say you know, ‘you’ve got a bit of a poorly tummy, you need to have an operation on this’, and then when she was older, explain to her exactly what it was. [TSW17: woman with TS, early 30s, no children]

Participants did not know the age when girls would need to have this intervention, and there was concern about them being ‘too young’, as well as doubts about whether a young child could really understand the implications. There were also concerns that a child might not wish to go through treatment at an age when it was feasible for her and would only become fully aware of the implications later.

I’d have probably felt, leave it be, at 10. I don’t know what I’d have done. What a difficult question, I don’t know. But I’m glad it’s there. It makes me happy now to know that [it’s] there. [TSW1: woman with TS, late 30s, no children]

Two participants, one woman with TS and one mother, suggested that in later life, women with TS might be unhappy that they had not had OTF in childhood if it had been medically appropriate for her.

I wouldn’t want my child resenting me for not giving her that chance, be able to be a mum. And then likewise if she decides no, then at least you know you’ve given her the chance. [TSW10: woman with TS, early 60s, 2 children via natural conception]

However, one mother said that it would be easier for a younger child to have OTF because she was more likely to accept her parents’ assurances that it needed to be done.

One mother mentioned her concern that OTF would be an additional task that could be too much to cope with on top of the daily challenges faced by a child who may already be dealing with growth hormone injections and treatment for other comorbidities, such as support for anxiety or neurocognitive issues. This could also affect the wider family, as the child would need support, preparation and aftercare.

My immediate feelings about it are that our daughter has a lot to deal with and that we have a lot to deal with because of Turner Syndrome, but on the other hand, maybe that’s just me being selfish, because kids can deal with a lot, can’t they, as long as you’re dealing with it as the parents. [TSM10: mother, mid-40s, 1 daughter under 10]

While it was considered a significant benefit to have ovarian tissue stored for potential reimplantation in adulthood, an option which women could freely use or decline if they wished, two women with TS commented that the existence of the eggs (and the investment that had gone into collecting and storing them) might produce pressure to use them.

One disadvantage, I would say, would be if you’ve had eggs or ovarian tissue frozen at an early age, you might feel under pressure to use those when you’re older and, actually, you [may] decide that you don’t really want to. [TSW2: woman with TS, late 20s, no children]

A further issue identified in the literature on OTF (eg Condorelli & Demeestere, 2019) is the unknown potential impact on the girl’s future fertility, which is likely to be reduced by removing one ovary. Although she did not see this as an absolute barrier to OTF, one mother commented that she was sceptical about the value of putting their daughter through invasive treatment that risked her future fertility without being sure there would be a benefit in later life.

It’s a decision that you’d be having to make, to preserve the ovarian function for the future, when actually they might have had their own ovarian function in the future anyway. So, you’re maybe halving the possibility of having an ovarian function in the future by taking out one. [TSM7: mother, mid-40s, 1 daughter aged 21]

A woman with TS also raised this point, commenting that if a girl had ovaries that were suitable for freezing, she would be more likely to be fertile in adulthood, and questioned whether OTF was needed. She suggested that, given the link between TS karyotype and potential success rates of OTF, girls and their families needed personalized information about the potential benefit in order to make an informed decision that took into account their child’s circumstances.

Two participants, both women with TS, mentioned the possibility that a child born from OTF might inherit TS.

I’m aware that TS is genetic in the sense that it can be passed onto a daughter and if I had a daughter, I wouldn’t want her to have faced some of the issues that I’ve faced in my life, health-wise or socially. [TSW17: woman with TS, early 30s, no children]

It is a sign of how well-informed participants in the TS patient groups tend to be, that there is awareness of this rare potential risk. Finally, no participants discussed pregnancy risk when talking about OTF.

Discussion

The present study explored participants level of knowledge about OTF and their initial reactions to a summary description of the procedure. While participants’ level of knowledge varied, and some had not heard of it, their observations and priorities are worth reporting for three reasons. Firstly, the findings reflect practical concerns that would need to be addressed by clinicians or clinic counsellors if this treatment became widely available. This includes information for girls and their families explaining what the technology is and what it can achieve, individually tailored to the girl’s karyotype so it is clear whether it is a suitable treatment for her. Secondly, there is little information on how the parents and wider family may manage the intervention itself. This study provides insights into how the family’s circumstances, the girl’s readiness, and potential demands on parents’ time, affect the feasibility and timing of undertaking treatment (Collin, 2013). Thirdly the findings provide a better understanding of the values that inform participants’ decision making process related to OTF, in the absence of customized, factual information. This is important: given there is currently no information about transplantation success rates, or whether OTF can restore fertility in women with TS and how for long, it is likely that the decisions of parents actively making this choice would rely on their values.

The response to the potential use of OTF in prepubertal girls with TS was broadly positive from both women with TS and mothers of girls with TS. In a setting where many families are actively looking for solutions to a diagnosis of future infertility, OTF can represent hope: it is particularly important to set expectations about who is eligible, and the success rates of OTF in later life. This is a challenge given the existing gaps in knowledge; further research in this area would support decision making for these families.

The findings that related to girls being ‘too young’ to understand OTF flagged the need for guidance for parents on how to have age-appropriate conversations about medical interventions, fertility and motherhood with girls with TS who may be eligible for OTF. Fertility is a topic that many parents (and some clinicians) find difficult to discuss, and guidance on how to address this painful topic could be useful.

No participants mentioned the cost, or challenges of accessing OTF. However, in the wider study, when discussing fertility options such as IVF, some women with TS said that private treatment was out of reach for them due to the cost, and some mothers with young children said that fertility treatment for their daughter was financially not possible or a low priority at that point in time. In a context where 2/3 of fertility treatments take place outside the NHS, finances are likely to be a high priority issue in practice.

Although it is difficult to clearly establish the benefits of OTF when outcomes data are unknown, it has been argued that cancer patients also used OTF despite a lack of evidence base, and their results have subsequently proven that it is a successful treatment for this group of patients (Jeve et al., 2019). Given the distress that infertility causes to women with TS and their families, and the willingness to consider the use of new technology, offering wider access to OTF to eligible girls could provide this evidence.

The feasibility of OTF also needs to be considered in the context of whether it is manageable at that point in time for the girl, her parents and the wider family. Prepubertal girls with TS may still be coming to terms with the diagnosis of TS and the understanding that her fertility is at risk, having daily growth hormone injections, and receiving educational support or other ongoing care. Parents of girls with TS support her and manage her treatment, a task which varies depending on how the individual girl has been affected. To some parents, for their daughter to undertake an expensive, unproven treatment may represent a difficult, emotional and unnecessary choice, particularly when the availability of egg donation means that women still have options when they are adults.

In conclusion, there are three ways in which the types of concerns that were reported around the use of OTF in prepubertal girls with TS could be mitigated. Firstly, by providing general information that is specific to the context of TS, in order to set expectations within the community. This could include: eligibility criteria; the ages when it would need to be done; clarity about where there is evidence and also a lack of evidence, such as success rates and familial links; information about health checks and other requirements prior to transplantation of frozen tissue in adulthood; and how OTF could be accessed and the associated costs. Secondly, by providing information that is specific to a girl’s individual karyotype and medical history, at a level that is age-appropriate. And thirdly, by ensuring that emotional support and psychosocial counselling is available to parents as well as to the girl herself.

Limitations

Although most participants had heard of OTF, nobody had used it, and some knew very little about it. Their responses may have been different, or more nuanced, if they had previously accessed information or had a discussion with a fertility counsellor. The inclusion of mothers of girls with TS, rather than fathers and partners, reflects their greater influence over decision making in this area, given the reproductive options that were being discussed. However, as couples usually make reproductive decisions together (Dudgeon & Inhorn, 2004), it is a limitation that no fathers or partners were included. All participants who disclosed their ethnicity were white, even though TS affects all ethnicities equally (Dotters-Katz et al., 2016); this lack of diversity means the findings may not represent a broad spectrum of views of girls and women with TS and their families. The women with TS in this study were more likely to be in a relationship than those in the wider community of women with TS (Gould et al., 2013; Sutton et al., 2005).

Acknowledgments

Many thanks to the participants, and the patient organizations, the Turner Syndrome Support Society and Ragdolls UK, for their support of this project. Thanks also to Dr Isabelle Demeestere and Professor Melanie Davies for their advice on TS heritability. This work was supported by a Mildred Blaxter Post-Doctoral Fellowship from the Foundation for the Sociology of Health and Illness.

Disclosure statement

No potential conflict of interest was reported by the author(s).