Introduction

Pediatric fertility preservation is an emerging field that is beginning to be applied to expanded groups of patients. This article discusses the current state of fertility preservation for pediatric patients, including eligible patient populations, available techniques and ethical considerations.

Who: Which Children Are Eligible for Fertility Preservation?

Pediatric patients who are facing fertility threatening treatments or diagnoses are all potential candidates for experimental or established fertility preservation options (Table 1).

Relevant populations include oncology patients who are receiving chemotherapy with a cyclophosphamide equivalent dose >8,000 mg/m², radiation to the pelvis or hypothalamus, and those undergoing stem cell transplant. Patients with nononcologic diagnoses including sickle cell anemia or thalassemia who are undergoing stem cell transplant, and patients with rheumatological disease who are being treated with cyclophosphamide are also candidates. Children with differences of sex development (DSD) who are undergoing prophylactic gonadectomy due to tumor risk are potentially eligible. Finally, fertility preservation techniques are applicable to transgender children who are receiving gender-affirming treatments that suppress endogenous gonadal function, including pubertal suppression, testosterone or estrogen. Pediatric patients preparing to undergo gonadotoxic medical therapy, radiation or gonadectomy should be counseled on options for fertility preservation and risk of iatrogenic infertility before initiating these therapies.

What: What Are the Current Options for Pediatric Fertility/Preservation?

Available tissue- or gamete-saving options for pediatric patients depend on patient pubertal status and gamete type. For patients who are receiving pelvic radiation, options for preservation of native tissue should be considered (eg testicular transposition to thigh pouch for groin/contralateral testicular radiation or ovarian shielding). The optimal strategy and timing of fertility preservation technique depends upon age, current gonadal function, reason for risk of infertility and severity of underlying condition. Whenever possible, pediatric fertility preservation should be handled by programs associated with an experienced assisted reproductive technology program capable of providing embryo, oocyte, sperm, and ovarian (OTC) and testicular tissue cryopreservation (TTC).

In 2020, the American Society for Reproductive Medicine officially recognized prepubertal OTC as the only fertility preservation option for prepubertal girls since ovarian stimulation and in vitro fertilization are not options.¹ This opinion was based on several decades of clinical experience under research protocols. Though OTC is no longer considered experimental, and hormonal restoration data are promising, the ability to use the tissue to produce a biological child is far from guaranteed. The first live birth resulting from prepubertal OTC was reported in 2015.² Between 2004 and 2018, 70 cases of cryopreserved ovarian tissue autotransplantation were reported in women who had OTC at age 14 years or older, with 94% return of menses, 50% with at least 1 pregnancy and a 41.6% delivery rate.³

Prepubertal TTC is still considered experimental. For this option, a wedge biopsy is taken from 1 testis and stored in liquid nitrogen. Experimental options for future tissue maturation and use include transplantation of spermatogonial stem cells, auto- or xenografting, and testicular organ culture. Nonhuman primate studies demonstrate feasibility of grafting, with return of spermatogenesis with 1 successful birth reported after ectopic grafting, sperm retrieval and intracytoplasmic sperm injection.⁴ Prepubertal testicular tissue and DSD gonadal tissue cryopreservation (GTC) are available as experimental therapies under research protocols.

For peri- and postpubertal patients, mature egg and sperm preservation afford the highest likelihood of successful fertility preservation. Therefore, mature gamete retrieval should be prioritized over tissue preservation for patients who are at least Tanner stage 3 and able to complete the necessary procedures. For egg preservation, patients must undergo ovarian stimulation. For sperm, samples are either obtained via manual collection or microsurgical testicular sperm extraction and testicular sperm cryopreservation when semen emission is not feasible.

Why (or Why Not): What Are the Ethical Considerations?

The concept of pediatric fertility preservation brings up multiple ethical issues that may influence families’ decisions about whether to pursue fertility preservation for their child.⁵ The most relevant options for many children with fertility-threatening conditions either are experimental without successful human live births (TTC, GTC for DSD) or have limited data about expected birth rates from tissue frozen prepubertally (OTC). The uncertainty about whether the tissue will ever produce a biological child generates concern about false hope. Cost of fertility preservation procedures and storage is another consideration that may lead to inequity in which children pursue fertility preservation. Cost varies by circumstance and insurance coverage, but tissue processing and cryopreservation is ∼$,1000/patient, with surgical costs typically bundled with other oncologic care performed under the same anesthetic. Storage is not usually covered by insurance, and commercial sperm and testicular tissue storage fees are $300 per year, with price reduction for long-term storage and sliding scale discounts based on income available.⁶ For some patients, it is not logistically possible to combine procedures (or no additional procedures are needed to treat their disease), such that risk of an additional anesthetic/surgical procedure is a consideration. Tissue ownership is another key ethical issue’disposition of preserved gametes in the event of death should be discussed at the time of fertility preservation consultation.¹ Concerns about parental proxy decision making and patient assent are also important to consider, as the decision to preserve tissue or gametes is about future quality of life, not immediate disease course or survival. Clinicians must also be aware of the potential for genetic transmission of cancer predisposition syndrome, or DSD, and counsel patients considering fertility preservation accordingly. Finally, for DSD, separate ethical issues exist around timing of gonadectomy and whether gonadectomy should be performed at all, such that that decision for gonadectomy and the decision for experimental GTC should be distinguished from one another in discussions with families.

Pediatric Fertility Preservation: Takeaways

Fertility preservation is an option for many pediatric patients with fertility-threatening diagnoses and treatments. Key takeaway points are summarized in Table 2.