What is the process and evidence for attempting fertility preservation prepubertally?

Attempting to preserve fertility in a prepubertal child requires a number of steps. First, the tissue must be safely harvested from the child’s ovary or testis. For girls, this may involve the removal of a whole ovary. For boys, only a piece of testicular tissue needs to be removed. The surgery to retrieve the tissue involves small but real risks, including bleeding, infection, scarring, damage to surrounding structures and the risks associated with the general anaesthetic. This latter risk can be minimised if the surgery can be done at the same time as the child is having a general anaesthetic for another element of his or her treatment,14 although this is not possible for all patients. With appropriate clinical selection of patients, the chance of a major complication is usually very low.

This tissue then needs to be frozen and stored by an appropriate facility (such as an In Vitro Fertilisation clinic) until the child is an adult. If he or she wants to become a genetic parent, the next step is for the tissue to be grafted back into the body. The tissue then needs to function to produce gametes. (Research is being done to mature the ovarian tissue in vitro, and produce gametes without reimplantation into the patient’s body; this would be useful for cancers like leukaemia where the reproductive tissue could have malignant contamination, such that reintroduction of the tissue would reintroduce the malignancy into the patient’s body.)15 16 The final steps would be for the gametes to be fertilised either naturally or via IVF, producing a pregnancy, which is then carried to term, resulting in a live birth.

For both males and females, the retrieval procedure has been found to be safe.17 18 For females, there is some evidence that ovarian tissue can be collected from a prepubertal girl, frozen, then be reimplanted and begin functioning. The level of function is enough to induce puberty and menstruation.19 There has been one reported case of a live birth.11 For prepubertal boys, fewer steps in the process have been demonstrated; however, success is considered possible within the lifetime of a boy who might have tissue collected today.12

Existing ethical guidance for clinicians

The guidance offered by professional bodies to clinicians about fertility preservation for prepubertal patients is varied and vague. The relevant peak international bodies recommend discussion of the impact of gonadotoxic therapy on fertility with all patients—including paediatric patients and their families—prior to treatment.5 20 21 Discussion of cancer treatment’s impact on fertility is required as part of standard of care, but the guidelines are less clear in relation to discussing possible fertility preservation procedures where these lack proven efficacy. Generally, American guidelines recommend that procedures that do not have established efficacy, such as ovarian tissue cryopreservation in girls or testicular tissue cryopreservation in boys, only be offered under ethically approved research protocols.5 20 UK guidelines have recently recommended that a lower age limit not be used for cryopreservation for cancer patients21; however, the options recommended do not include procedures that could be undertaken on prepubertal patients.

Professional guidelines are therefore far from definitive in relation to the ethics of offering prepubertal fertility preservation. They do not address the fundamental ethical question facing clinicians: under what circumstances would it be ethically appropriate to offer fertility preservation for a prepubertal patient? Rather, their statements tend to be too vague to guide individual clinicians and centres and/or to focus on the need for research ethics oversight of these procedures.

As such, it is not surprising that there is significant variation between clinicians and centres in relation to whether and how fertility discussions are approached with different types of paediatric patients with cancer, including prepubertal patients.22 There is a lack of definitive data about current practice, but anecdotally few Australian hospitals offer fertility preservation procedures to prepubertal females and only one to prepubertal males. Global numbers are similarly unclear but look to be small; a recent international survey indicates 26 hospitals offering ovarian tissue cryopreservation to girls aged 0–11 years and 16 hospitals offering testicular tissue cryopreservation to boys aged 0–11 years.23 The ‘Edinburgh criteria’ developed by Wallace and colleagues constitute one published approach to offering ovarian tissue cryopreservation, including to prepubertal patients.24 This set of criteria exclude patients who have had previous gonadotoxic therapy. They also require that the patient is at high (>50%) risk of infertility from her treatment. The substantial variation in practice internationally and within institutions reflects, in part, the ethical uncertainty about the status of prepubertal fertility preservation procedures.

Ethical concerns in practice

Our clinical ethics service was recently approached by clinicians for ethics support around the issue of surgery aimed at fertility preservation for prepubertal children. Coming from the perspective of evidence-based medicine, clinicians were concerned about offering a procedure that lacked proven efficacy. Was it burdening the child without justification? However, there were also worries about failing to offer a potentially beneficial procedure: attempting fertility preservation is low risk for many children, is an area of rapidly progressing research and relates to becoming a genetic parent, which is important to many cancer survivors.4 5

A process of routine referral for clinical ethics case consultation was instituted. Each time fertility preservation was being considered for a prepubertal patient, the case was referred for a clinical ethics discussion. The clinical ethics case consultation process at our hospital uses a multidisciplinary collaborative model that has been described in detail elsewhere.25 In a series of clinical ethics case consultations, the burdens and benefits associated with attempting fertility preservation for specific prepubertal children were explored with the treating clinicians. The following discussion draws on our experience of providing these clinical ethics case consultations.

The need for an individual risk–benefit assessment

In our view, these benefits justify offering the procedure in cases where the surgery is low risk, and the potential benefits are not further reduced by some additional feature of the child’s situation. The potential benefits of the procedure are sufficient that children should not be excluded from accessing fertility preservation surgery in situations where the potential burdens are absent or mitigated. Some of the potential burdens (such as delay to treatment or creating false hope) can be addressed with appropriate organisational systems and support for clinicians to ensure good parental understanding of the procedure. Some of the burdens will not apply to specific children (such as increased risks of surgery because of comorbidities or lesser benefit because of previous gonadotoxic therapy). Thus, we suggest that it is sometimes ethically justifiable for doctors to offer fertility preservation for prepubertal patients. Although the degree of benefit is low, so too is the degree of burden in many cases. When the medical team judges that this low-benefit/low-burden situation applies, the procedure is ethically permissible but not ethically required; it is the parents’ decision to make.

This is not to suggest that parents ought to be abandoned to solo decision making in this area, without information, guidance and recommendations from the child’s healthcare team. Of course, the decision making process around fertility preservation in prepubertal children will include the clinicians and the parents (and the child, in a developmentally appropriate way). Parents generally want to share decision making with clinicians, although role preferences are individual and situation specific. The key point is that when attempting fertility preservation is low benefit/low burden, parents may justifiably choose either to pursue or to decline the procedure.

A clinical ethics process to support clinicians navigating the ethical complexity of prepubertal fertility preservation

Given that the procedure will be ethically justifiable in some cases and not others, the key challenge for clinicians lies in assessing whether each specific case is one in which offering fertility preservation is ethically justifiable. We suggest that there is an important role here for clinical ethics support. Clinical ethics review is best suited to the individualised case assessment that is necessary in this area. Research ethics processes are necessary too but these focus on the research protocol at a much more general level. Exclusive reliance on research ethics processes does not allow the individualised ethical assessment that is necessary in relation to prepubertal fertility preservation procedures. (A very important feature of the research ethics protocol is collection of outcome data, but this can also be achieved by participation in a clinical registry.) Clinical ethics review enables consideration and promotion of each individual child’s interests, rather than relying on an overall ethical assessment of a scientific protocol.

We have developed a process of clinical ethics oversight for prepubertal fertility preservation surgical procedures at the Royal Children’s Hospital, Melbourne (as one part of a comprehensive approach to governance of paediatric fertility preservation at this hospital). The aim is to ensure that ethical reflection is built into the care pathway for each individual child in this situation. Rather than requiring that patients access the procedure only as part of a research protocol, we have developed a clinical ethics process that focuses on assessing potential burdens and benefits associated with the procedure for each individual patient.

The process began with routine referral to clinical ethics for prepubertal patients for whom fertility preservation was being considered and has since evolved into a clinician-led process using a checklist of questions (box 2). This framework aims to distinguish cases that are ethically straightforward from those that are more ethically complicated. After a series of clinical ethics case consultations, we noticed that the same potential concerns were being explored in each discussion. We captured these into a list that we began to use in our case discussions of individual children in order to ensure that the discussions were comprehensive. We also continued to create space for any other concerns to be discussed, beyond those included on the list. Clinicians now use the framework of questions themselves in a written format to work through the potential ethical issues for a specific child. This continues to be supported by the clinical ethics team; an ethicist reviews the written responses. The option remains for a full clinical ethics case discussion if the ethicist, clinician or family remains uncertain about the case.

This list of questions is an example of an inductively derived checklist that highlights ethically relevant considerations. The checklist does the work of stimulating and capturing ethical deliberation but without reducing the ethical concerns to a ‘tickbox’ or procedural checklist. In this way, it represents a tool for promoting ethical literacy for clinicians involved in this area of work.