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Establishment of a Pediatric Ovarian and Testicular Cryopreservation Program for Malignant and Non-Malignant Conditions: The Mayo Clinic Experience

Published:April 25, 2021DOI:https://doi.org/10.1016/j.jpag.2021.04.006

      ABSTRACT

      Study Objectives

      To describe the structure of a pediatric fertility preservation (FP) program and to share safety and patient satisfaction data.

      Design

      The FP program operates under prospective research protocols approved by the Mayo Clinic Institutional Review Board (IRB).

      Setting

      The FP program is a multidisciplinary effort between pediatric gynecology, reproductive endocrinology, pediatric urology, pediatric surgery, and laboratory medicine.

      Participants

      The FP program enrolls patients between 0-17 years of age who have been diagnosed with a fertility-threatening condition and/or are scheduled to undergo gonadotoxic treatment.

      Interventions

      FP is offered in the form of ovarian tissue cryopreservation (OTC) and testicular (TTC) tissue cryopreservation.

      Main Outcome Measures

      The outcome measures are the safety of the procedure and results of patient surveys conducted by phone using a standard list of questions to assess attitudes towards FP.

      Results

      To date, we have enrolled 38 OTC and 37 TTC patients. The median age (range) of OTC and TTC patients was 11 years (0.83-17 years) and 10 years (0.92-17 years) at the time of enrollment, respectively. Childhood cancers currently represent 88% of the fertility-threatening diagnoses. Meanwhile, patients with non-malignant conditions include those with gender dysphoria, aplastic anemia, and Turner's syndrome. To date, no serious adverse events (SAEs) have been reported following surgery. According to n = 34 one-year follow-ups, 100% of parents felt that FP was a good decision.

      Conclusion

      Consistent with the literature, our data suggests FP is safe and improves the quality of care provided to pediatric patients for their fertility-threatening diagnoses and/or treatments.

      Trial Registration

      NCT02872532, NCT02646384.

      Key Words

      Introduction

      In 2018, it was estimated that 10,590 children under the age of 15 years would be diagnosed with cancer in the United States, and that approximately 85% of these children would be long-term survivors.
      • Siegel RL
      • Miller KD
      • Jemal A
      Cancer statistics, 2018.
      Thus, long-term survivorship issues have emerged as a result of late effects of cancer treatment.
      • Robison LL
      • Hudson MM
      Survivors of childhood and adolescent cancer: life-long risks and responsibilities.
      Impaired fertility represents one of these challenges, with 8-12% of female survivors
      • Geenen MM
      • Cardous-Ubbink MC
      • Kremer LC
      • et al.
      Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.
      and ∼33% of male survivors
      • Rendtorff R
      • et al.
      Hormone and sperm analyses after chemo- and radiotherapy in childhood and adolescence.
      suffering fertility impairment. To address this, guidelines regarding fertility preservation (FP) were published by several medical societies including the American Society of Clinical Oncology (ASCO)
      • Lee SJ
      • et al.
      American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.
      • Loren AW
      • et al.
      Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update.
      • Oktay K
      • et al.
      Fertility preservation in patients with cancer: ASCO clinical practice guideline update.
      and the American Academy of Pediatrics (AAP).
      • Fallat ME
      • Hutter J
      American Academy of Pediatrics Committee on, B.American Academy of Pediatrics Section on, H. O.American Academy of Pediatrics Section on, S
      Preservation of fertility in pediatric and adolescent patients with cancer.
      In men and some pubertal boys, cryobanking of semen before the initiation of treatment is standard practice, allowing for future in vitro fertilization (IVF).
      Practice Committee of the American Society for Reproductive Medicine
      Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.
      In women and post-pubertal girls, particularly after menarche, cryopreservation of embryos and mature oocytes represent standard clinical practice. Occasionally, peri-pubertal girls can also be included in this cohort, depending on the degree to which they have mature oocytes present. However, these methods can delay initiation of cancer treatment and sometimes adversely affect the cancer trajectory.
      • Coyne K
      • et al.
      Challenges and considerations in optimizing ovarian stimulation protocols in oncofertility patients.
      In the pre-pubertal setting and in circumstances in which cancer treatment cannot be delayed, FP remains a challenge. Ovarian tissue cryopreservation (OTC) and testicular tissue cryopreservation (TTC) are currently the only FP options available to pre-pubertal children.
      Practice Committee of the American Society for Reproductive Medicine
      Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.
      ,
      • Woodruff TK
      Pediatric and Adolescent Oncofertility: Best Practices and Emerging Technologies.
      In addition to orthotopic transplantation of the cryopreserved tissue, in vitro maturation (IVM) of immature oocytes obtained during the OTC procedure and subsequent IVF using these matured oocytes are also being investigated.
      • Fadini R
      • et al.
      Embryo transfer following in vitro maturation and cryopreservation of oocytes recovered from antral follicles during conservative surgery for ovarian cancer.
      In over 95% of OTC cases involving women or pubertal girls, re-implantation has restored ovarian function for an average period of 4-5 years,
      • Donnez J
      • Dolmans MM
      • Diaz C
      • et al.
      Ovarian cortex transplantation: time to move on from experimental studies to open clinical application.
      ,
      • Donnez J
      • Dolmans MM
      Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice.
      and orthotopic transplantation has led to more than 130 live births as of 2017.
      • Donnez J
      • Dolmans MM
      Fertility preservation in women.
      • Oktay K
      Evidence for limiting ovarian tissue harvesting for the purpose of transplantation to women younger than 40 years of age.
      • Donnez J
      • et al.
      Livebirth after orthotopic transplantation of cryopreserved ovarian tissue.
      • Meirow D
      • et al.
      Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy.
      • Ernst E
      • Bergholdt S
      • Jorgensen JS
      • et al.
      The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue.
      • Sanchez-Serrano M
      • et al.
      Twins born after transplantation of ovarian cortical tissue and oocyte vitrification.
      • Roux C
      • et al.
      Live birth after ovarian tissue autograft in a patient with sickle cell disease treated by allogeneic bone marrow transplantation.
      • Donnez J
      • et al.
      Children born after autotransplantation of cryopreserved ovarian tissue. a review of 13 live births.
      • Donnez J
      • et al.
      Pregnancy and live birth after autotransplantation of frozen-thawed ovarian tissue in a patient with metastatic disease undergoing chemotherapy and hematopoietic stem cell transplantation.
      • Dittrich R
      • et al.
      Live birth after ovarian tissue autotransplantation following overnight transportation before cryopreservation.
      • Donnez J
      • et al.
      Fertility preservation for age-related fertility decline.
      • Van der Ven H
      • et al.
      Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.
      • Meirow D
      • et al.
      Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria.
      • Dunlop CE
      • et al.
      Re-implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function, natural conception and successful pregnancy after haematopoietic stem cell transplantation for Wilms tumour.
      • Rodriguez-Wallberg KA
      • et al.
      Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries–compilation of 20 years of multicenter experience.
      • Jensen AK
      • et al.
      86 Successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children.
      Based on these findings, the American Society for Reproductive Medicine (ASRM) no longer considers OTC experimental in either the pre-pubertal or pubertal setting as of December 2019.
      Practice Committee of the American Society for Reproductive Medicine
      Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.
      In pre-pubertal males, TTC is the sole FP option currently available. Due to the relatively novel nature of testicular tissue cryopreservation, there have been no live births using this tissue in humans. Thus, TTC is still considered experimental by the ASRM.
      Practice Committee of the American Society for Reproductive Medicine
      Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.
      However, reports of functional sperm and/or healthy offspring in other mammalian species,
      • Brinster RL
      • Avarbock MR
      Germline transmission of donor haplotype following spermatogonial transplantation.
      • Ogawa T
      • Dobrinski I
      • Avarbock MR
      • et al.
      Transplantation of male germ line stem cells restores fertility in infertile mice.
      • Hamra FK
      • et al.
      Production of transgenic rats by lentiviral transduction of male germ-line stem cells.
      • Honaramooz A
      • et al.
      Fertility and germline transmission of donor haplotype following germ cell transplantation in immunocompetent goats.
      • Herrid M
      • et al.
      Irradiation enhances the efficiency of testicular germ cell transplantation in sheep.
      • Hermann BP
      • et al.
      Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.
      • Schlatt S
      • Honaramooz A
      • Boiani M
      • et al.
      Progeny from sperm obtained after ectopic grafting of neonatal mouse testes.
      • Honaramooz A
      • Li MW
      • Penedo MC
      • et al.
      Accelerated maturation of primate testis by xenografting into mice.
      • Liu Z
      • et al.
      Generation of macaques with sperm derived from juvenile monkey testicular xenografts.
      • Kaneko H
      • et al.
      Generation of live piglets for the first time using sperm retrieved from immature testicular tissue cryopreserved and grafted into nude mice.
      • Fayomi AP
      • et al.
      Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring.
      combined with advancements in tissue-based technologies,
      • Gassei K
      • Orwig KE
      Experimental methods to preserve male fertility and treat male factor infertility.

      Gassei K, Cannon GM, Meacham LR, et al: In: Gosiengfiao YC, Woodruff TK, eds. Pediatric and Adolescent Oncofertility. New York: Springer; 2017:119-142

      • Medrano JV
      • et al.
      Basic and clinical approaches for fertility preservation and restoration in cancer patients.
      • Del Vento F
      • et al.
      Tissue engineering to improve immature testicular tissue and cell transplantation outcomes: one step closer to fertility restoration for prepubertal boys exposed to gonadotoxic treatments.
      • Onofre J
      • Baert Y
      • Faes K
      • et al.
      Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in fertility preservation.
      show promise.
      Despite guidelines that address the need for FP, retrospective analyses show that childhood cancer patients do not receive routine FP counseling. In a cross-sectional survey of ∼2700 adult childhood cancer survivors, 50% reported that they were not counseled on infertility risks.
      • Hohmann C
      • et al.
      Patient counselling on the risk of infertility and its impact on childhood cancer survivors: results from a national survey.
      This is in part due to low referral rates among pediatric oncology providers who are either unfamiliar with FP or do not have access to an established FP program. For example, a 2010 survey of 167 pediatric oncologists revealed that only 5-6% of respondents offered FP more than than 50% of the time, and a 2018 meta-analysis of oncology provider surveys found inadequate facilities, absence of guidelines, and poor interdisciplinary communication to be extrinsic barriers to routine FP counseling and program development.
      • Panagiotopoulou N
      • Ghuman N
      • Sandher R
      • et al.
      Barriers and facilitators towards fertility preservation care for cancer patients: a meta-synthesis.
      Similarly, patients facing non-malignant fertility-threatening diagnoses and/or treatment are not regularly offered FP. For example, one study found that only 12% (13/105) of transgender adolescents presenting to a pediatric transgender clinic were provided a formal FP consult prior to beginning hormone therapy,
      • Chen D
      • Simons L
      • Johnson EK
      • et al.
      Fertility preservation for transgender adolescents.
      despite the ASRM recommending such.
      Ethics Committee of the American Society for Reproductive Medicine: Access to fertility services by transgender persons: an Ethics Committee opinion.
      To address the need for FP in the childhood cancer setting and beyond, we began offering OTC and TTC to patients in 2016. We aimed to overcome the above-mentioned barriers by creating a formal FP program that is operating centrally through the Mayo Clinic Children's Center and is a collaborative effort between multiple specialties including pediatric gynecology, reproductive endocrinology, pediatric urology, and laboratory medicine.

      Materials and Methods

      The Mayo Clinical Pediatric Fertility Preservation Program (MC-FP) has operated under the approval of the Mayo Clinic Institutional Review Board since 2016. TTC patients were consented under Institutional Review Board (IRB) #15-004891, and OTC patients were consented under IRB #14-010037 in accordance with all institutional, state, and federal regulations. Informed consent was obtained from the parent or legal guardian of all pediatric patients. Informed assent was obtained from all pediatric patients aged 13-17 years in addition to informed consent from their parent or legal guardian. The MC-FP continues to enroll patients.
      The MC-FP is designed to benefit patients with indications for which the use of fertility preservation may be of benefit. These include, but are not limited to oncologic/hematologic, renal, and rheumatologic diseases requiring therapy with gonadotoxic agents; genetic or autoimmune causes of premature gonadal failure; and diseases requiring stem cell transplants, as well as transgender patients. Patients are eligible if they are ≤17 years of age and have a diagnosis of a medical condition (eg, Turner syndrome) or use of treatment(s) (eg, chemotherapy, radiation) expected to result in permanent diminished or complete loss of subsequent ovarian/testicular function. To be considered for TTC, patients must be in the high-risk category for prolonged azoospermia (≥80% and/or summed alkylating agent dose score ≥3 and/or cyclophosphamide equivalent dose ≥7500 mg/m2). To be considered for OTC, patients must be in the moderate-to high-risk category for gonadotoxicity.
      • Appiah Leslie A.
      • Green Daniel M.
      Fertility Risk with Cancer Therapy.
      Patients with existing permanent diminished or complete loss of ovarian/testicular function are also considered for program eligibility. The main eligibility criteria are summarized in Table 1.
      Table 1Major inclusion and exclusion criteria for the Mayo Clinical Pediatric Fertility Preservation Program.
      Major inclusion criteria
      1Be 0-17 years of age
      2
      • A
        Be scheduled to undergo surgery, chemotherapy, drug treatment, and/or radiation for the treatment or prevention of a medical condition or malignancy with risk of causing permanent and complete loss of subsequent gonadal function. Due to the complexity of different treatment regimens, patient risk stratification is at the discretion of the investigators.
      • B
        Or, have a medical condition or malignancy that requires removal of all or part of one or both gonads.
      • C
        Or, have a medical condition (genetic or autoimmune) that results in decline in fertility.
      • D
        Or, have a newly diagnosed or recurrent disease affecting fertility. Those who were not enrolled at the time of initial diagnosis (ie, patients with recurrent disease) are eligible if they have not previously received therapy that is viewed as likely to result in complete and permanent loss of gonadal function.
      3
      • A
        Have two gonads if undergoing elective removal of a gonad for fertility preservation only. Note: removal of both gonads will limit fertility preservation options.
      • B
        Or, have one gonad but limited potential for future fertility due to underlying condition, malignancy, prior surgery, or previous injury and no other fertility preservation methods are available except for tissue cryopreservation.
      Major exclusion criteria
      1Diagnosed with psychological, psychiatric, or other condition that prevents giving fully informed consent.
      2Diagnosed with an underlying medical condition that significantly increases risk of complications from anesthesia and surgery.
      3Previously received gonadotoxic chemotherapy or radiation therapy that is thought to have resulted in impairment of testicular function.

      Patient Referral

      Patients are identified by pediatric oncology (if oncologic indication) or other providers in disciplines in which fertility potential may be affected (eg, the gender clinic or the rheumatology/nephrology clinic). These patients are then referred to a specialist in pediatric gynecology, reproductive endocrinology, or pediatric urology for an FP consult, if deemed moderate to high risk for gonadotoxicity or reduced fertility potential. This provider acts as the central MC-FP program navigator for the patient. Prior to the consult, the referring provider assesses the patient's eligibility for FP against the study's inclusion and exclusion criteria (Table 1). In cases in which impaired ovarian/testicular function is suspected due to prior treatment, the provider will coordinate testing of ovarian/testicular function. In the ovarian setting, this may manifest via testing of follicle-stimulating hormone (FSH). In some cases, an anti-Müllerian hormone (AMH) concentration or ovarian ultrasound may be required to better identify ovarian reserve. In the testicular setting, this may include blood tests for FSH, luteinizing hormone (LH), and/or total testosterone. Baseline (pre-FP) laboratory values are summarized in Supplementary Table S1.

      Fertility Preservation Counseling

      The provider (a pediatric gynecologist, reproductive endocrinologist, or pediatric urologist) counsels the patient and their family on FP. In cases of childhood cancer, the provider begins by explaining the significant improvement in survival rates, highlighting impaired fertility as a medical late effect that can arise due to the treatment that the patient is about to receive. In other cases, the provider outlines the gonadotoxicity risks of the patient's fertility-threatening treatment(s) or diagnosis. Next, the paucity of current FP options for pre-pubertal males and pre-pubertal females is explained, and OTC/TTC is presented as an option.
      The remainder of the consult is spent discussing OTC/TTC, including the surgical approaches, costs, potential risks, and potential future benefits. The possibilities of both improved fertility and hormone replacement therapy are discussed as potential benefits of tissue cryopreservation. For TTC, the provider emphasizes the experimental nature of this approach. Patients undergoing OTC/TTC in our program may agree to donate 20% of their tissue to research, and this is explained to the patient. Other topics of discussion include costs, mandatory infectious disease testing to comply with Food and Drug Adminstration (FDA) regulations, and next steps. The provider then refers the patient to a clinical research coordinator (CRC) for research consent and pediatric surgery/urology for a surgical consult. Refusal to participate in the study did not affect their care at the Mayo Clinic.

      Informed Research Consent

      Informed consent was obtained from the parent or legal guardian of all pediatric patients, and informed assent was obtained from all patients aged 13-17 years.

      Surgery

      Whenever possible, the surgery to remove ovarian or testicular tissue is coordinated with other surgical procedures to mitigate risks from anesthesia and to reduce costs for the patient. OTC via laparoscopy is performed under general anesthesia using standard laparoscopy techniques. Once two grossly normal ovaries are identified, part or all of one ovary is removed from the peritoneal cavity through one of the port sites. The remaining ovary is left intact to allow for the potential resumption of ovarian function and reproductive capacity after all treatment is completed.
      TTC may be performed via wedge resection of one testis or simple orchiectomy. Wedge resection is presented to the patient as the preferred option, and simple orchiectomy is presented in rare cases, such as those with testicular volume of <1 cc.

      Post-surgery

      A segment of each ovarian or testicular specimen is sent to the Mayo Clinic Anatomic Pathology Department to assess for contamination by malignant cells. This report is used to counsel patients on the likelihood that the tissue obtained could be used for future fertility restoration.
      The remaining tissue is sent to the Mayo Clinic In-Vitro Fertilization (IVF) Laboratory for processing and cryopreservation.

      Tissue Processing

      Although a small portion of the ovary or testicle is reviewed by pathology for verification of healthy tissue and absence of malignant cells, the remaining whole ovary or testicle is transported on ice (5-8°C) to the IVF Lab. The tissue is processed using the National Physicians Cooperative of the Oncofertility Consortium's protocol for tissue slow-freezing, thawing, labeling, and testing
      National Physicians Cooperative of the Oncofertility Consortium
      Ovarian tissue freezing, thawing, labeling, and testing.
      (Supplementary Figs. S1 and S2).

      Patient Follow-up

      In addition to routine postoperative check-ups, a study team member contacts the patient's family by telephone one week post-surgery to assess for any adverse events as a result of the procedure, and annually by telephone thereafter.
      At the annual follow-ups, the study team asks the parent/legal guardian for updates on their child's diagnosis, overall health, and whether their child's scheduled treatment has been completed. In the TTC group, the parent/legal guardian is asked whether their child has reached puberty and whether their primary care physician has commented on their child's physical development. The parent/legal guardian of OTC patients are asked details regarding their child's pubertal and menarchal status. Following this assessment of the child's health and physical development, the study team discusses parental knowledge and attitudes regarding OTC/TTC one year post-procedure using a standard survey created for the purposes of the study (Supplementary Table S2).
      All pre-pubescent patients are monitored for hormonal deficiency after their indicated clinical therapy to ensure adequate sex hormone production through anthropomorphic measurements, growth velocity curves, and Tanner staging. These follow-ups are part of the patient's clinically indicated surveillance and are not provided as part of the study.

      Results

      As of November 2020, we have enrolled 38 OTC and 37 TTC patients in the MC-FP program. The median age (range) of OTC and TTC patients was 11 years (0.83-17 years) and 10 years (0.92-17 years) at the time of enrollment, respectively (Table 2). In regard to physical development, 73% (27/37) of TTC and 53% (20/38) of OTC patients are classified as Tanner Stage I, while 11% (4/37) of TTC and 37% (14/38) of OTC patients are classified as Tanner Stage V, respectively (Fig. 1). This is because that semen cryobanking was not an option for some pubertal TTC patients due to factors including cancer-related pain, religious background, and the participant's comfort level with providing a semen sample. Although embryo or mature oocyte cryopreservation was available to the Tanner Stage V OTC patients, their cancer therapy could not be delayed for the several weeks required by these FP approaches. The FSH median (IQR) of OTC and TTC patients was 3.3 IU/L (2.7-6.0 IU/L) and 2.5 IU/L (0.9-3.0 IU/L), respectively. All baseline (pre-FP) laboratory test results are summarized in Supplementary Table S1.
      Table 2MC-FP program participant demographics and fertility-threatening diagnoses at time of enrollment.
      Median age, yr (range)RaceEthnicityDiagnosis
      OTC, n = 3811 (0.83-17)Asian: 1

      Black/African American: 3

      White: 31

      Unknown/not reported: 3
      Hispanic/Latino: 4

      Not Hispanic/Latino: 33

      Unknown/not reported: 1
      Muscoskeletal malignancies: 47% (18/38)

      Hematologic malignancies: 32% (12/38)

      Genitourinary malignancies: 8% (3/38)

      Neurologic malignancies: 8% (3/38)

      Genetic syndrome: 3% (1/38)

      Non-malignant hematologic condition: 3% (1/38)
      TTC, n = 3710 (0.92-17)Black/African American: 2

      White: 34

      Unknown/not reported: 1
      Hispanic/Latino: 1

      Not Hispanic/Latino: 35

      Unknown/not reported: 1
      Hematologic malignancies: 46% (17/37)

      Muscoskeletal malignancies: 30% (11/37)

      Germ cell malignancies: 3% (1/37)

      Neurologic malignancy: 3% (1/37)

      Gender dysphoria (trans females): 11% (4/37)

      Non-malignant hematologic condition: 3% (1/37)

      Acute gonadal injury: 3% (1/37)

      Genetic syndrome: 3% (1/37)
      MC-FP, Mayo Clinic Fertility Preservation; OTC, ovarian tissue cryopreservation; TTC, testicular tissue cryopreservation.
      Fig 1
      Fig. 1Tanner Stages of enrolled fertility preservation patients. Blue bars denote ovarian tissue cryopreservation (OTC) patients; orange bars denote testicular tissue cryopreservation (TTC) patients. UNK, unknown.
      Among TTC patients, the most common diagnoses were hematologic malignancies (46%), whereas among OTC patients, musculoskeletal malignancies were the most common diagnoses (47%). Overall, childhood cancers represented 88% (66/75) of the fertility-threatening diagnoses in this group, whereas other indications requiring gonadotoxic treatments, such as aplastic anemia, were much less frequent (Table 2).
      Across both groups combined, chemotherapy with or without radiation represented 37% (28/75) and 47% (35/75) of fertility-threatening treatments, respectively. Overall, 96% (72/75) of patients were prescribed a fertility-threatening treatment, whereas only 4% (3/75) of patients were diagnosed with a condition that resulted in impaired reproductive potential.
      Nine patients had the following non-malignant diagnoses requiring FP: gender dysphoria (trans females) (n = 4), aplastic anemia (n = 2), testicular torsion/concern for atrophy (n = 1), Turner syndrome (n = 1), and 46 XY disorders of sexual development (DSD) (n = 1). Six of nine patients did have the presence of germ cells with the potential preservation of future fertility. The remaining patients did not have viable germ cells noted (Table 3).
      Table 3OTC and TTC patients with non-malignant fertility-threatening diagnoses.
      DiagnosisAge, yr (Tanner stage)ProcedureOutcome
      Aplastic anemia6 (I)OophorectomyTissue cryopreserved
      Aplastic anemia8 (I)Testicular biopsyTissue cryopreserved
      Gender dysphoria (trans female)13 (III)Testicular biopsyTissue cryopreserved and mature sperm seen (2 twitching and 3 non-motile sperm seen in 40 HPFs)
      Gender dysphoria (trans female)10 (I)Testicular biopsyTissue cryopreserved and mature sperm seen (2 twitching and 23 non-motile in 10 HPFs)
      Gender dysphoria (trans female)16 (IV)Testicular biopsyTissue cryopreserved and mature sperm seen (3 twitching and 12 non-motile in 12 HPFs)
      Gender dysphoria (trans female)14 (II)Testicular biopsyTissue cryopreserved. No mature sperm seen.
      Turner syndrome5 (I)OophorectomyPathology reported extremely small gonads with no follicles in tissue.
      Testicular torsion/concern for atrophy13 (IV)Bilateral orchiectomyNo mature sperm seen (poor-quality tissue likely due to torsion).
      46 XY DSD12 (I)Bilateral testicular biopsyTissue was atrophic. No viable tissue stored.
      DSD, disorders of sexual development; HPF, high-power field; OTC, ovarian tissue cryopreservation; TTC, testicular tissue cryopreservation.
      No serious adverse events (SAEs) were reported following surgery to remove ovarian/testicular tissue. Adverse events (AEs) were reported in 26% (10/38) and 8% (3/37) of OTC and TTC cases, respectively. The most frequent adverse event reported was moderate-to-severe lingering pain at the site of incision in 18% (7/38) of OTC and 8% (3/37) of TTC patients. In 19% of cases (14/75), additional pain medications aside from acetaminophen/ibuprofen were required for pain management. Two OTC patients presented with superficial erythema at the site of incision.
      In all, 22 TTC and 12 OTC patients have completed their first annual follow-up. Overall, 100% of parents/legal guardians felt that the OTC/TTC procedure was a good decision. Parents/legal guardians reported high levels of satisfaction with the manner in which the information was presented to them. Specifically, parents/legal guardians were asked to comment on the thoroughness of the discussion; 100% of parents/legal guardians stated that they felt well informed prior to making a decision. A small proportion (6%, 2/34) of parents/legal guardians reported feeling overwhelmed with having to make a decision regarding fertility preservation in addition to decisions pertaining to their child's primary diagnosis. However, all parents/legal guardians appreciated the time-sensitive nature of the decision and were glad that they were counseled on fertility preservation. Of the parents/legal guardians, 100% would recommend the FP program to a friend if they were faced with the need to make a similar decision.
      Of parents/legal guardians, 100% reported that having this option for their child's future was the most positive aspect of the decision. When asked what the most difficult aspect of the decision was, fear of medical complications was cited as the most frequent concern (23%, 8/34), whereas 35% (12/34) of parents/legal guardians had no concerns or difficulties in making the decision. Other concerns among parents/legal guardians included the cost of the procedure (15%, 5/34), the chance that OTC/TTC would be successful in restoring their child's fertility (12%, 4/34), and difficulty having a conversation regarding fertility with their young children (9%, 3/34) (Table 4).
      Table 4Patient or Parent/Guardian attitudes regarding fertility preservation (data collected from 34 one-year post-procedure follow-up surveys).
      Survey QuestionResponse
      How are you feeling about the decision to store tissue?
      • OTC/TTC was a good decision (100%, 34/34)
      Could you please share the most difficult aspect of making this decision for you/your family?
      • Not a difficult decision/no concerns (23%, 8/34)
      • Fear of medical complications/risks/pain (35%, 12/34)
      • Cost (15%, 5/34)
      • Chances of future success (12%, 4/34)
      • Difficult explaining FP to child (9%, 3/34)
      • Overwhelmed by cancer diagnosis (6%, 2/34)
      FP, fertility preservation.

      Discussion

      Since its launch in 2016, the Mayo Clinical Pediatric Fertility Preservation Program has been able to offer safe and highly accepted ovarian and testicular cryopreservation procedures to children facing fertility-threatening diagnoses and/or treatment. The lack of any serious adverse events highlights the minimal risk posed by OTC and TTC procedures, and which is further mitigated by pairing the procurement of ovarian/testicular tissue with another clinically indicated procedure such as central line placement. Furthermore, this also helps to reduce cost to the patient and to increase the likelihood of the patient's insurance covering the cost of the procedure. All patients thus far have had their insurance cover the entire expense of the procedure, and it is likely that cost would be prohibitive if insurance did not cover these costs.
      With 43% of patients (32/75) being from out of state and a consistent year-to-year increase in patient accrual (Supplementary Fig. S3), awareness of the MC-FP program appears to be rising within the national setting. Furthermore, the MC-FP program's unique multidisciplinary approach enables the inclusion of patients outside of the childhood cancer setting (Table 2).
      This being said, our data suggest that childhood cancers represent the most common threat to future fertility among children. Given the frequency of diminished future fertility among these young cancer patients,
      • Geenen MM
      • Cardous-Ubbink MC
      • Kremer LC
      • et al.
      Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.
      ,
      • Rendtorff R
      • et al.
      Hormone and sperm analyses after chemo- and radiotherapy in childhood and adolescence.
      FP programs should be designed with these patients in mind and in a manner in which FP can be routinely integrated into their existing standard of care. The recent de-classification of ovarian tissue cryopreservation as experimental by the ASRM
      Practice Committee of the American Society for Reproductive Medicine
      Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.
      marks an important step forward, and studies like ours provide an FP program framework for other institutions interested in offering FP.
      Although childhood cancer patients comprise the majority of patients enrolled in the MC-FP, participation by children who are facing non-malignant, fertility-threatening diagnoses and/or treatment is growing. This demonstrates that there are a wide range of patients that may benefit from FP, such as patients with genetic syndromes, non-malignant hematologic disease, and transgender children beginning hormone therapy. However, based on our study, individual results are largely dependent on the subject's age, underlying diagnosis, and pubertal status. This is exhibited by six of nine patients in our cohort having evidence of viable cells for future use (Table 3).
      It has already been shown that although most cancer survivors believe that it is important to have discussions surrounding fertility,
      • Tam S
      • et al.
      Improving access to standardized fertility preservation information for older adolescents and young adults with cancer: using a user-centered approach with young adult patients, survivors, and partners to refine fertility knowledge transfer.
      few families feel that they have received adequate information regarding FP.
      • Oosterhuis BE
      • Goodwin T
      • Kiernan M
      • et al.
      Concerns about infertility risks among pediatric oncology patients and their parents.
      Furthermore, it has also been demonstrated that interest in FP increases with implementation of a FP program.
      • Vu JV
      • Llarena NC
      • Estevez SL
      • et al.
      Oncofertility program implementation increases access to fertility preservation options and assisted reproductive procedures for breast cancer patients.
      Notably, the feedback collected from the parents/legal guardians of our patients supports these notions. Although some parents/legal guardians expressed feeling overwhelmed at the time, all parents/legal guardians were glad that they had received FP counseling and felt grateful for being able to potentially restore their child's reproductive potential in the future (Table 4). These survey responses also suggest that FP improved family perspectives on the quality of comprehensive cancer care that their child received.
      Interestingly, cost was not a major limiting factor for parents/legal guardians making a decision about FP (Table 4). Although cost to the patient for the procedure varied depending on insurance coverage, only 15% (5/34) of parents/legal guardians felt that cost was the main factor influencing their decision to proceed. Given that patients were also responsible for annual storage fees ($250 per year) after the first year, these data suggest that families are willing to incur additional medical expenses in order to have access to FP, further highlighting the value of FP to families.
      Our results also demonstrate and support the concept that patients and families are willing to discuss FP after being counseled on the gonadotoxic effects of their diagnosis and/or therapy, even in the midst of decision-making surrounding their diagnosis and treatment. Our findings are consistent with studies showing that although patients and families feel overwhelmed immediately after a cancer diagnosis, the majority also feel that the most appropriate time to discuss fertility is immediately following a diagnosis, prior to beginning gonadotoxic treatment, when the chances of preserving fertility are the highest.
      • Ginsberg JP
      • et al.
      Sperm banking for adolescent and young adult cancer patients: sperm quality, patient, and parent perspectives.
      • Nieman CL
      • et al.
      Fertility preservation and adolescent cancer patients: lessons from adult survivors of childhood cancer and their parents.
      • Crawshaw MA
      • Glaser AW
      • Hale JP
      • et al.
      Young males' experiences of sperm banking following a cancer diagnosis–a qualitative study.
      • Crawshaw MA
      • Glaser AW
      • Hale JP
      • et al.
      Male and female experiences of having fertility matters raised alongside a cancer diagnosis during the teenage and young adult years.
      These findings highlight an important factor in the FP process: namely, the multidisciplinary team. Multiple studies demonstrate that the counseling provider's comfort level, knowledge, and overall ability to discuss FP have a marked impact on FP outcomes.
      • Panagiotopoulou N
      • Ghuman N
      • Sandher R
      • et al.
      Barriers and facilitators towards fertility preservation care for cancer patients: a meta-synthesis.
      ,
      • Kohler TS
      • et al.
      Results from the Survey for Preservation of Adolescent Reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer.
      Our data underscore the importance of referring patients to a team that is adequately trained in FP counseling in order to provide consistent and high-quality FP counseling. leading to the most favorable outcomes for the patient and the institution.
      Overall, access to fertility preservation has improved following the establishment of the MC-FP program. A retrospective analysis from our group on the pediatric oncology practice at the Mayo Clinic showed that patient−provider discussions of impaired fertility significantly increased after the establishment of our program, as did the incidence rates for fertility preservation consults and incidence of fertility preservation options by patients.
      • Behl S
      • et al.
      Consult and procedure incidence outcomes following establishment of a fertility preservation program for children with cancer.
      Since its inception in 2016, the MC-FP has faced challenges and limitations. For instance, the need for continued provider education and training of new staff on the study protocol is an ongoing challenge. This is particularly challenging in non-oncologic settings for fertility preservation, such as in transgender medicine, and in the treatment of genetic syndromes, nephrological, or rheumatologic conditions. Efforts to improve awareness regarding the FP program within these areas among providers and patients are ongoing. In addition, because institutional financial resources are limited, the MC-FP providers do not have protected time for program maintenance and development. To address these challenges, the program now has dedicated nursing and study coordinator staff to support the program. In addition, to ensure high referral rates even in the absence of complete FP training for new providers, efforts are underway to make FP consults an “opt-out” option within the pediatric oncology electronic documentation workflow. This will allow for consistent documentation of FP discussions and FP referrals for those patients who are eligible for fertility preservation.

      Conclusion

      From childhood cancer survivorship studies, it is clear that the experience of infertility is a key survivorship issue but is not routinely discussed prior to treatment. Access to FP among patients with non-malignant fertility-threatening diagnoses and/or treatment is even lower, including transgender children on hormone therapy and patients with fertility-impairing genetic syndromes.
      Herein, we have described the structure, workflow, and early results from the Mayo Clinic Fertility Preservation Program. The MC-FP program has been providing OTC and TTC to pediatric patients since 2016. Our program is able to offer this procedure to children who would not otherwise have options to protect future reproductive potential, particularly children facing non-malignant fertility-threatening diagnoses and/or treatment. Consistent with the literature, our data suggest that FP is safe and is associated with unanimously high patient and family satisfaction. With growing enrollment numbers and patients from across the United States, the MC-FP program hopes to continue providing FP to pediatric patients in a safe, affordable, and high-quality manner.

      Author contributions

      A.C., C.F.G., Z.K., and Y.Z. designed the study. V.B.J. and S.B. acquired the data, performed data analysis, interpreted the data, drafted the manuscript, and prepared the final version of the manuscript. All authors discussed the results, contributed to and approved the final manuscript, and have agreed to be personally accountable for all and any part of the work.

      Acknowledgments

      We thank all members of Pediatric Hematology/Oncology, Pediatric Endocrinology, Pediatric Surgery, Urology, Obstetrics and Gynecology, Pediatrics, and the In Vitro Fertilization Lab at Mayo Clinic Rochester for their ongoing support in the success of this program including Julia H. Byrne, Adriana M. Delgado, Jolene R. Fredrickson, Terri M. Galanits, Dr. Patricio C. Gargollo, M.D., Anthony G. Krenik, Kari L. Lampat, Hannah Lechner, and Dr. D. Dean Potter, M.D. Study data were recorded and managed using the Research Electronic Data Capture system
      • Harris PA
      • et al.
      Research Electronic Data Capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support.
      .

      Appendix. Supplementary materials

      • Fig. S1. (A) Pediatric ovary, processing post-surgery. The ovary is bisected, and the outer cortex of approximately 1 mm thickness is dissected away from the inner medulla using a sterile #10 scalpel blade and tweezers. (B) Controlled-rate freezing machine..

      • Fig. S2. (A) Pediatric testicular tissue, processing post-surgery. The tissue is weighed, and the tubules are teased apart using sterile scissors and tweezers. (B) Stereomicroscope image of adult testicular tubules.

      References

        • Siegel RL
        • Miller KD
        • Jemal A
        Cancer statistics, 2018.
        CA Cancer J Clin. 2018; 68: 7
        • Robison LL
        • Hudson MM
        Survivors of childhood and adolescent cancer: life-long risks and responsibilities.
        Nat Rev Cancer. 2014; 14: 61
        • Geenen MM
        • Cardous-Ubbink MC
        • Kremer LC
        • et al.
        Medical assessment of adverse health outcomes in long-term survivors of childhood cancer.
        JAMA. 2007; 297: 2705
        • Rendtorff R
        • et al.
        Hormone and sperm analyses after chemo- and radiotherapy in childhood and adolescence.
        Klin Padiatr. 2010; 222: 145
        • Lee SJ
        • et al.
        American Society of Clinical Oncology recommendations on fertility preservation in cancer patients.
        J Clin Oncol. 2006; 24: 2917
        • Loren AW
        • et al.
        Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update.
        J Clin Oncol. 2013; 31: 2500
        • Oktay K
        • et al.
        Fertility preservation in patients with cancer: ASCO clinical practice guideline update.
        J Clin Oncol. 2018; 36: 1994
        • Fallat ME
        • Hutter J
        • American Academy of Pediatrics Committee on, B.
        • American Academy of Pediatrics Section on, H. O.
        • American Academy of Pediatrics Section on, S
        Preservation of fertility in pediatric and adolescent patients with cancer.
        Pediatrics. 2008; 121: 1461
        • Practice Committee of the American Society for Reproductive Medicine
        Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.
        Fertil Steril. 2019; 112: 1022
        • Coyne K
        • et al.
        Challenges and considerations in optimizing ovarian stimulation protocols in oncofertility patients.
        Front Public Health. 2014; 2: 246
        • Woodruff TK
        Pediatric and Adolescent Oncofertility: Best Practices and Emerging Technologies.
        Springer, New York2017
        • Fadini R
        • et al.
        Embryo transfer following in vitro maturation and cryopreservation of oocytes recovered from antral follicles during conservative surgery for ovarian cancer.
        J Assist Reprod Genet. 2012; 29: 779
        • Donnez J
        • Dolmans MM
        • Diaz C
        • et al.
        Ovarian cortex transplantation: time to move on from experimental studies to open clinical application.
        Fertil Steril. 2015; 104: 1097
        • Donnez J
        • Dolmans MM
        Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice.
        J Assist Reprod Genet. 2015; 32: 1167
        • Donnez J
        • Dolmans MM
        Fertility preservation in women.
        N Engl J Med. 2017; 377: 1657
        • Oktay K
        Evidence for limiting ovarian tissue harvesting for the purpose of transplantation to women younger than 40 years of age.
        J Clin Endocrinol Metab. 2002; 87: 1907
        • Donnez J
        • et al.
        Livebirth after orthotopic transplantation of cryopreserved ovarian tissue.
        Lancet. 2004; 364: 1405
        • Meirow D
        • et al.
        Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy.
        N Engl J Med. 2005; 353: 318
        • Ernst E
        • Bergholdt S
        • Jorgensen JS
        • et al.
        The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue.
        Hum Reprod. 2010; 25: 1280
        • Sanchez-Serrano M
        • et al.
        Twins born after transplantation of ovarian cortical tissue and oocyte vitrification.
        Fertil Steril. 2010; 93: 211
        • Roux C
        • et al.
        Live birth after ovarian tissue autograft in a patient with sickle cell disease treated by allogeneic bone marrow transplantation.
        Fertil Steril. 2010; 93: 2413
        • Donnez J
        • et al.
        Children born after autotransplantation of cryopreserved ovarian tissue. a review of 13 live births.
        Ann Med. 2011; 43: 437
        • Donnez J
        • et al.
        Pregnancy and live birth after autotransplantation of frozen-thawed ovarian tissue in a patient with metastatic disease undergoing chemotherapy and hematopoietic stem cell transplantation.
        Fertil Steril. 2011; 95: 1787
        • Dittrich R
        • et al.
        Live birth after ovarian tissue autotransplantation following overnight transportation before cryopreservation.
        Fertil Steril. 2012; 97: 387
        • Donnez J
        • et al.
        Fertility preservation for age-related fertility decline.
        Lancet. 2015; 385: 506
        • Van der Ven H
        • et al.
        Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.
        Hum Reprod. 2016; 31: 2031
        • Meirow D
        • et al.
        Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria.
        Fertil Steril. 2016; 106: 467
        • Dunlop CE
        • et al.
        Re-implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function, natural conception and successful pregnancy after haematopoietic stem cell transplantation for Wilms tumour.
        J Assist Reprod Genet. 2016; 33: 1615
        • Rodriguez-Wallberg KA
        • et al.
        Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries–compilation of 20 years of multicenter experience.
        Acta Obstet Gynecol Scand. 2016; 95: 1015
        • Jensen AK
        • et al.
        86 Successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children.
        J Assist Reprod Genet. 2017; 34: 325
        • Brinster RL
        • Avarbock MR
        Germline transmission of donor haplotype following spermatogonial transplantation.
        Proc Natl Acad Sci U S A. 1994; 91: 11303
        • Ogawa T
        • Dobrinski I
        • Avarbock MR
        • et al.
        Transplantation of male germ line stem cells restores fertility in infertile mice.
        Nat Med. 2000; 6: 29
        • Hamra FK
        • et al.
        Production of transgenic rats by lentiviral transduction of male germ-line stem cells.
        Proc Natl Acad Sci U S A. 2002; 99: 14931
        • Honaramooz A
        • et al.
        Fertility and germline transmission of donor haplotype following germ cell transplantation in immunocompetent goats.
        Biol Reprod. 2003; 69: 1260
        • Herrid M
        • et al.
        Irradiation enhances the efficiency of testicular germ cell transplantation in sheep.
        Biol Reprod. 2009; 81: 898
        • Hermann BP
        • et al.
        Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.
        Cell Stem Cell. 2012; 11: 715
        • Schlatt S
        • Honaramooz A
        • Boiani M
        • et al.
        Progeny from sperm obtained after ectopic grafting of neonatal mouse testes.
        Biol Reprod. 2003; 68: 2331
        • Honaramooz A
        • Li MW
        • Penedo MC
        • et al.
        Accelerated maturation of primate testis by xenografting into mice.
        Biol Reprod. 2004; 70: 1500
        • Liu Z
        • et al.
        Generation of macaques with sperm derived from juvenile monkey testicular xenografts.
        Cell Res. 2016; 26: 139
        • Kaneko H
        • et al.
        Generation of live piglets for the first time using sperm retrieved from immature testicular tissue cryopreserved and grafted into nude mice.
        PLoS One. 2013; 8: e70989
        • Fayomi AP
        • et al.
        Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring.
        Science. 2019; 363: 1314
        • Gassei K
        • Orwig KE
        Experimental methods to preserve male fertility and treat male factor infertility.
        Fertil Steril. 2016; 105: 256
      1. Gassei K, Cannon GM, Meacham LR, et al: In: Gosiengfiao YC, Woodruff TK, eds. Pediatric and Adolescent Oncofertility. New York: Springer; 2017:119-142

        • Medrano JV
        • et al.
        Basic and clinical approaches for fertility preservation and restoration in cancer patients.
        Trends Biotechnol. 2018; 36: 199
        • Del Vento F
        • et al.
        Tissue engineering to improve immature testicular tissue and cell transplantation outcomes: one step closer to fertility restoration for prepubertal boys exposed to gonadotoxic treatments.
        Int J Mol Sci. 2018; : 19
        • Onofre J
        • Baert Y
        • Faes K
        • et al.
        Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in fertility preservation.
        Hum Reprod Update. 2016; 22: 744
        • Hohmann C
        • et al.
        Patient counselling on the risk of infertility and its impact on childhood cancer survivors: results from a national survey.
        J Psychosoc Oncol. 2011; 29: 274
        • Panagiotopoulou N
        • Ghuman N
        • Sandher R
        • et al.
        Barriers and facilitators towards fertility preservation care for cancer patients: a meta-synthesis.
        Eur J Cancer Care (Engl). 2018; : 27
        • Chen D
        • Simons L
        • Johnson EK
        • et al.
        Fertility preservation for transgender adolescents.
        J Adolesc Health. 2017; 61: 120
      2. Ethics Committee of the American Society for Reproductive Medicine: Access to fertility services by transgender persons: an Ethics Committee opinion.
        Fertil Steril. 2015; 104: 1111
        • Appiah Leslie A.
        • Green Daniel M.
        Fertility Risk with Cancer Therapy.
        in: Woodruff Teresa K. Gosiengfiao Yasmin C. Pediatric and Adolescent Oncofertility. Springer International Publishing, 2017: 1-16
        • National Physicians Cooperative of the Oncofertility Consortium
        Ovarian tissue freezing, thawing, labeling, and testing.
        2017 (Available at:) (Access Year: 2021)
        • Tam S
        • et al.
        Improving access to standardized fertility preservation information for older adolescents and young adults with cancer: using a user-centered approach with young adult patients, survivors, and partners to refine fertility knowledge transfer.
        J Cancer Educ. 2018; 33: 528
        • Oosterhuis BE
        • Goodwin T
        • Kiernan M
        • et al.
        Concerns about infertility risks among pediatric oncology patients and their parents.
        Pediatr Blood Cancer. 2008; 50: 85
        • Vu JV
        • Llarena NC
        • Estevez SL
        • et al.
        Oncofertility program implementation increases access to fertility preservation options and assisted reproductive procedures for breast cancer patients.
        J Surg Oncol. 2017; 115: 116
        • Ginsberg JP
        • et al.
        Sperm banking for adolescent and young adult cancer patients: sperm quality, patient, and parent perspectives.
        Pediatr Blood Cancer. 2008; 50: 594
        • Nieman CL
        • et al.
        Fertility preservation and adolescent cancer patients: lessons from adult survivors of childhood cancer and their parents.
        Cancer Treat Res. 2007; 138: 201
        • Crawshaw MA
        • Glaser AW
        • Hale JP
        • et al.
        Young males' experiences of sperm banking following a cancer diagnosis–a qualitative study.
        Hum Fertil (Camb). 2008; 11: 238
        • Crawshaw MA
        • Glaser AW
        • Hale JP
        • et al.
        Male and female experiences of having fertility matters raised alongside a cancer diagnosis during the teenage and young adult years.
        Eur J Cancer Care (Engl). 2009; 18: 381
        • Kohler TS
        • et al.
        Results from the Survey for Preservation of Adolescent Reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer.
        J Assist Reprod Genet. 2011; 28: 269
        • Behl S
        • et al.
        Consult and procedure incidence outcomes following establishment of a fertility preservation program for children with cancer.
        J Assist Reprod Genet. 2021; 38: 495
        • Harris PA
        • et al.
        Research Electronic Data Capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support.
        J Biomed Inform. 2009; 42: 377