CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Fertility Preservation for Pediatric and Adolescent Patients With Cancer: Medical and Ethical Considerations Sigal Klipstein, MD, FACOG,a,b Mary E. Fallat, MD, FAAP,c Stephanie Savelli, MD, FAAP,d COMMITTEE ON BIOETHICS, SECTION ON HEMATOLOGY/ONCOLOGY, SECTION ON SURGERY

Many cancers presenting in children and adolescents are curable with abstract surgery, chemotherapy, and/or radiotherapy. Potential adverse consequences of treatment include sterility, infertility, or subfertility as a result of gonad aDepartment of Obstetrics and Gynecology, Pritzker School of Medicine, removal, damage to germ cells as a result of adjuvant therapy, or damage to University of Chicago, Chicago, Illinois; bInVia Fertility Specialists, c the pituitary and hypothalamus or uterus as a result of irradiation. In recent Chicago, Illinois; Division of Pediatric Surgery, Hiram C. Polk Jr MD Department of Surgery, University of Louisville, Louisville, Kentucky; years, treatment of solid tumors and hematologic malignancies has been and dDivision of Pediatric Hematology/Oncology, Akron Children’s modified in an attempt to reduce damage to the gonadal axis. Simultaneously, Hospital, Akron, Ohio advances in assisted reproductive technology have led to new possibilities for Clinical reports from the American Academy of Pediatrics benefit from the prevention and treatment of infertility. This clinical report reviews the expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of medical aspects and ethical considerations that arise when considering Pediatrics may not reflect the views of the liaisons or the fertility preservation in pediatric and adolescent patients with cancer. organizations or government agencies that they represent. Dr Fallat conceptualized the initial manuscript and drafted, reviewed, and revised the updated manuscript; Drs Klipstein and Savelli drafted, reviewed, and revised the updated manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This document is copyrighted INTRODUCTION and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with Childhood cancer affects 1 of every 285 children younger than 20 years in the American Academy of Pediatrics. Any conflicts have been resolved the United States. Because of advances in treatment, survival has steadily through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any increased since the 1970s. With increasing survival rates, there are commercial involvement in the development of the content of this currently more than 375 000 survivors of childhood cancer in the United publication. 1,2 States, with 70% of them being 20 years or older. Improvements in The guidance in this report does not indicate an exclusive course of prognosis and survival have been observed for many childhood cancers, treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. including hematologic malignancies, Wilms tumor, malignant bone tumors, All clinical reports from the American Academy of Pediatrics and rhabdomyosarcomas. The relative 5-year survival rate for all fi 2 automatically expire 5 years after publication unless reaf rmed, childhood cancers combined is 83.8%. revised, or retired at or before that time. With the improved survival rate of children affected by childhood cancer DOI: https://doi.org/10.1542/peds.2019-3994 has come a growing population of adult survivors of childhood cancer who are or will be interested in having children. Past and contemporary To cite: Klipstein S, Fallat ME, Savelli S, AAP COMMITTEE ON treatments for childhood cancer, including chemotherapy, radiotherapy, BIOETHICS, AAP SECTION ON HEMATOLOGY/ONCOLOGY, AAP and hematopoietic stem cell transplant, can affect future fertility. In the SECTION ON SURGERY. Fertility Preservation for Pediatric current era, many children and adolescents who present with a new and Adolescent Patients With Cancer: Medical and Ethical Considerations. Pediatrics. 2020;145(3):e20193994 cancer diagnosis can benefit from fertility-preserving modalities initiated

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020:e20193994 FROM THE AMERICAN ACADEMY OF PEDIATRICS before cancer treatment. Individuals or other diseases requiring treatment pregnancy after 12 months or more of whose previous treatment of with gonadotoxic therapies to regular unprotected intercourse. childhood cancer led to infertility or understand the potential deleterious Earlier evaluation and treatment may sterility can often benefit from effects of the various treatments on be justified on the basis of medical fertility treatment options such as egg male and female fertility and to be history, such as anovulation or and sperm donation and gestational familiar with the American Society of erectile dysfunction. For women surrogacy. Clinical Oncology (ASCO) guidelines 35 years and older, a fertility for fertility preservation in children. evaluation is recommended after fi Although not speci cally addressed in Recognizing the risks associated with 6 months of unsuccessful attempts at this report, the same strategies of both radiation and chemotherapy, the conception.4 Although fertility fertility preservation apply to ASCO recommends that oncologists declines with age for both men and children facing gonadotoxic therapies (1) use established methods of women, this decline is much more for treatment of nonmalignant fertility preservation (semen profound in women. At age 40, half of diseases such as juvenile idiopathic cryopreservation and oocyte women will have trouble conceiving. arthritis and Fanconi anemia. cryopreservation) for postpubertal If in vitro fertilization (IVF) is Infertility resulting from the minor children, with patient assent as required, the chance of pregnancy per treatment of differences of sexual appropriate, and parent or guardian cycle is only 13.9% in women at age development and as a result of consent; (2) present information on 40 and under and 4% in women older hormonal or surgical gender- additional methods that are available than 42 years.5 For men at age 45, the fi af rming therapies for transgender for children but are still chance of achieving a pregnancy is individuals are beyond the scope of investigational; and (3) refer for much higher, and for these older men, this document. experimental protocols when the age of their female partner is the available.3 Establishing relationships most significant determinant of Although this document focuses on 6 adolescents and young adults under with centers and physicians who have outcome. The risk of infertility after the age of 18 years, many individuals expertise in counseling and treating cancer treatment depends on the type fi fi who received a cancer diagnosis in children who may bene t from of malignancy and its speci c childhood continue to be seen by fertility preservation will help treatment as well as the age of the their pediatric providers well into oncologists better streamline care individual both at the time of for their patients who are interested diagnosis and at the time that they adulthood. As such, these guidelines 7 are generalizable beyond the age of in fertility preservation. Oncologists wish to initiate a pregnancy. In men, majority and apply to decision- can refer families for consultation treatments can lead to a complete making for adult survivors of to discuss both the effects of therapy absence of spermatogenesis, childhood cancers as well. Complex and potential fertility preservation a decreased sperm count, or sexual ethical considerations arise when options in a timely manner, as dysfunction. In women, there can be counseling families confronting long as any delay will not negatively a complete depletion of viable egg a cancer diagnosis regarding fertility affect the success of their treatment. production or diminished ovarian preservation options. The difficulty of In so doing, they will prevent reserve, leading to subfertility and such decision-making is often missed opportunities for information a shortened fertile window. A compounded by the frequently and interventions related to fertility hysterectomy or insult to the uterus limited time available to make care. may lead to the inability to gestate a pregnancy. decisions that can affect fertility. The Recognizing that older adolescents differences between male and female and even young adults may develop reproductive physiology affect the cancers that fall under the umbrella NORMAL PHYSIOLOGY AND FERTILITY range of options available to boys and of childhood malignancies, this POTENTIAL girls. Options in adolescents who clinical report will include options have undergone puberty are broader Differences in the male and female that may be more appropriate for the reproductive systems influence than those in prepubertal children. patient who is older than 18 years The ideal time to consider fertility available options for fertility after but is still being cared for in cancer treatment.8,9 In general, there preservation is before the initiation of a children’s hospital. therapies that may decrease fertility is a lack of proven options for or cause sterility, but this sometimes preservation of fertility in is not possible. prepubertal boys and girls. The BACKGROUND process of spermatogenesis begins in It is important for physicians who Infertility is defined as the inability to the prepubertal boy, but the care for children who develop cancer achieve or sustain a successful production of mature sperm and

Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS steroidogenesis are functions of the infertility, a shortened reproductive by increased follicle-stimulating and adult testes.10 Spermarche (the window, or no compromise in fertility. luteinizing hormone concentrations, release of spermatozoa) is an early- to Many survivors of childhood cancer indicating decreasing gonadal – midpubertal event that precedes the with intact fertility worry about the function.34 36 ability to produce an ejaculate and is potential effects of previous cancer In a large cohort study, the St Jude associated with age-appropriate treatment on the health of their Lifetime Cohort Study, testicular gonadotropin production.11,12 There offspring.17 Reassuringly, decades of function was evaluated by using is a large variation in the stage of cumulative experience have shown a semen analysis. The investigators maturity among 13- to 18-year-old that naturally conceived biological performed a semen analysis on 214 males with respect to sperm children of survivors have no adult male survivors of childhood production. Once sperm are present, increased incidence of congenital – cancer, all of whom had received sperm quality in young boys, as malformations,18 22 genetic or – alkylating agents without determined by a semen analysis, does chromosomal anomalies,23 25 or radiotherapy. Azoospermia was noted not seem to be affected by patient cancer compared with sibling in 25%, oligospermia was noted in age. At this point, sperm can be controls and general population 28%, and normospermia was noted collected via masturbation, data.26–33 in 48%. Importantly, there was no electrostimulation, or surgical sperm identified threshold dose below extraction, and sperm can then be Risk of Infertility in the Male Patient which azoospermia did not occur or cryopreserved for future use. It is After Cancer Treatment one above which azoospermia was important to note that not all Male fertility can be affected by uniformly present.37 pediatric centers have impairment of spermatogenesis as electroejaculation equipment a result of gonadotoxic chemotherapy, Several large studies, including the available, and surgical extraction gonadotropin deficiency from central Childhood Cancer Survivor Study requires the expertise of a urologist nervous system–directed therapy, or (CCSS),38,39 have evaluated the experienced in this technique. Many functional abnormalities of fertility outcome of survivors of boys will, therefore, require referral genitourinary organs caused by spinal childhood cancer. The most recent to a reproductive urologist for these or pelvic surgery and/or cohort study included almost 11 000 services.13,14 radiotherapy. Deleterious effects on survivors not exposed to gonadal or testicular function have been cranial radiotherapy and more than In girls, oocyte production peaks in observed with alkylating agents, such 3900 sibling controls. On the basis of the fetus during midgestation, at as cyclophosphamide, as evidenced self-reported data, it was found that which time approximately 6 to 7 male survivors had a decreased million oogonia are present within likelihood of fathering a pregnancy the ovary. This number decreases to 2 compared with a sibling control TABLE 1 Alkylating Agents With Infertility Risk million at birth and to approximately group.40 This finding confirmed 15,16 300 000 at puberty. Once Alkylating Agents results from an earlier CCSS study menarche has been initiated, mature Classic alkylating agents showing that among male patients, oocytes develop, and monthly Busulfan risk factors for impaired fertility ovulation occurs. At this point, Carmustine (BCNU) Chlorambucil included increasing alkylating-agent fertility treatments can stimulate Cyclophosphamide exposures and higher testicular multiple eggs, which can be retrieved Ifosfamide radiation doses (Tables 1 and 2). from the ovary and cryopreserved for Lomustine (CCNU) These studies are important in later use. Mechlorethamine counseling because although Melphalan Procarbazine increasing chemotherapy and Thiotepa radiation doses are associated with RISK OF INFERTILITY AFTER TREATMENT Heavy metals a higher chance of infertility, there is Most children treated for cancer can Cisplatinum no dose so low as to guarantee the expect to be cured, although the Carboplatinum maintenance of fertility and no dose fi Nonclassical alkylators speci c chance of cure depends on Dacarbazine (DTIC) so high that infertility is certain risk factors at the time of diagnosis, Temozolomide to occur. including cancer type, stage, and Adapted from Children’s Oncology Group. Long-Term grade. Although permanent infertility Follow-Up Guidelines for Survivors of Childhood, Adoles- Risk of Infertility in the Female or sterility may occur after cancer cent, and Young Adult Cancers. Version 5.0. Monrovia, CA: Patient After Cancer Treatment Children’s Oncology Group; 2018:12–14. Available at: treatment, individuals may http://www.survivorshipguidelines.org/pdf/2018/COG_ Chemotherapy and tradiotherapy can experience temporary but reversible LTFU_Guidelines_v5.pdf. Accessed April 26, 2019. destroy ovarian follicles and

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020 3 TABLE 2 Childhood Cancer Therapy Affecting Reproductive Tissues Reproductive Effect Predisposing Therapy Modifying Factors Sex Both Altered pubertal timing (precocious, early, Hypothalamic-pituitary radiation Altered pubertal timing more common after low- rapid tempo), delayed puberty, dose radiation at 18–24 Gy, gonadotropin gonadotropin insufficiency or insufficiency more common after radiation at deficiency more than 30 Gy Female Acute ovarian failure (ovarian failure Alkylating-agent chemotherapy, radiation affecting Older age at treatment due at higher risk within 5 y of diagnosis), premature the female reproductive system (whole menopause (cessation of menses abdomen, pelvis, lumbosacral spine, total body), before age 40 y) oophorectomy Uterine vascular insufficiency, uterine Radiation affecting the uterus (whole abdomen, History of Wilms tumor and associated Müllerian growth impairment pelvis, lumbosacral spine, total body) anomalies Vaginal fibrosis or stenosis Radiation affecting the vagina History of hypogonadism (estrogen insufficiency), history of chronic graft-versus-host disease Sexual dysfunction, dyspareunia Pelvic surgery, hysterectomy, radiation affecting the History of hypogonadism (estrogen insufficiency) uterus or vagina Spontaneous abortion, neonatal death, Radiation affecting the uterus (whole abdomen, History of Wilms tumor and associated Müllerian premature labor, neonate with low pelvis, lumbosacral spine, total body) anomalies birth wt, fetal malposition Male Azoospermia oligospermia Alkylating-agent chemotherapy, radiation affecting Prepubertal status at treatment does not reduce the male reproductive system (pelvic, testicular, risk total body), orchiectomy (bilateral) Retrograde ejaculation, anejaculation Pelvic surgery (retroperitoneal node or tumor History of hypogonadism (androgen insufficiency) erectile dysfunction dissection, cystectomy, radical prostatectomy), radiation to pelvis, bladder, or spine See www.survivorshipguidelines.org for health risks to other organs and tissues resulting from treatment of childhood cancer. Adapted, with permission from Elsevier, from Hudson MM. Survivors of childhood cancer: coming of age. Hematol Oncol Clin North Am. 2008;22(2):218.

predispose female patients to Müllerian hormone (AMH) through its effects on the diminished ovarian reserve and concentrations to estimate ovarian hypothalamic-pituitary axis. Such premature ovarian failure. Premature reserve.44,45 Survivors of childhood infertility can be treated medically ovarian failure is defined as cancer often have lower AMH with stimulation of the ovaries or premature menopause occurring concentrations compared with testes with gonadotropins to induce 46,47 before age 40. This differs from a control group. Low AMH the maturation and release of diminished ovarian reserve, which concentrations can predispose to gametes. Radiation can affect the can lead to increased difficulty in diminished ovarian reserve and, uterus and vagina, and women achieving a pregnancy or to therefore, a higher risk of infertility as undergoing radiation to the uterus a shortened reproductive window well as earlier menopause. When are less likely to both conceive 48 despite regular menstrual periods. evaluated by treatment exposure a pregnancy and carry it to term. (alkylators only, alkylators and Direct pelvic radiotherapy, The deleterious effects of subdiaphragmatic radiation, or high- abdominal or spinal radiation, or chemotherapy are dependent on the dose alkylating therapy), all survivor scatter radiation can all affect the age of the patient at the time of groups had diminished ovarian ovaries. The oocyte median lethal therapy, the specific agents used, and surface area and AMH concentrations. dose for radiotherapy is less than cumulative dosing.41 Oocytes do not Ovarian reserve was worse when 2Gy.49 regenerate after birth, as opposed to survivors received a high dose versus spermatogenesis, which continues to a conventional dose of alkylating Several studies have been focused on occur from progenitor stem cells therapy. infertility and achievement of throughout a man’s life. Premature pregnancy in female survivors of ovarian failure is rare in survivors of Radiation has an effect on both the cancer. One CCSS cohort study found childhood cancer and was found to brain and the end organs. When the that the risk of nonsurgical have an incidence of 6% to 9% in brain is the target of irradiation, premature menopause was CCSS cohorts.42 Many women who do infertility can present as increased for survivors of childhood not have overt ovarian failure will hypothalamic amenorrhea. High-dose cancer.42 Survivors also had an have diminished ovarian reserve.43 cranial radiotherapy (35–40 Gy) can increased risk of clinical infertility Several studies have used anti- cause infertility via hypogonadism when compared with sibling

Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS controls. This risk was most PRESERVATION OF FERTILITY BEFORE either preserving fertility or speeding pronounced in the early TREATMENT IN THE PREPUBERTAL the recovery of spermatogenesis.3 reproductive years (#24 years), CHILD Animal studies suggest that testicular when fertility is high in a general Fertility preservation in the tissue cryopreservation, population. Increasing doses of prepubertal child is challenging. The autotransplantation, uterine radiation and alkylators majority of proposed treatment xenotransplantation, and in vitro were most strongly associated with modalities are thus far experimental maturation may be successful infertility. Promisingly, almost two- in nature and without proven efficacy. methods of fertility preservation, but thirds of survivors with clinical The one exception is gonadal most have yet to be tested in 56 infertility reported a pregnancy shielding or moving the gonads out of humans. Human spermatocytes during the study period, which the radiation field.51 Familiarity with have been matured in vitro to mature included both those achieving these options and the data spermatids, resulting in at least 1 57 pregnancy spontaneously and surrounding them can assist pregnancy. Testicular tissue those who underwent fertility physicians in treating and counseling cryopreservation has been reported, 50 treatment. Another CCSS cohort their patients with cancer. and ongoing clinical trials are being study analyzed only survivors who Furthermore, patients who wish to conducted to address prepubertal 58,59 had not received gonadal or cranial undergo prepubertal fertility fertility preservation in boys. radiotherapy to evaluate the effect preservation attempts may be best Oncologists can help their male of chemotherapeutic agents on served under an institutional review patients and their families by sharing pregnancy. Just as with male board (IRB)–approved clinical trial so with them information and options survivors, female survivors had that they can be carefully monitored regarding clinical trials to address a decreased likelihood of and their experience used to prepubertal fertility preservation. pregnancy and live birth compared determine if such therapies should Once testicular tissue has been with sibling controls. If a pregnancy continue to be offered in the future. cryopreserved, future options for its was not achieved by age 30, the use may include in vitro maturation likelihood of ever becoming Boys or germ cell transplant, which at this pregnant by age 45 was further time are theoretical in nature. Before puberty, methods available for reduced compared with siblings. As gonadal and gamete preservation in with previous studies, the most Girls the male patient are primarily deleterious chemotherapeutic Similar to prepubertal boys, most theoretical at the present time, with agents were the alkylating agents, fertility preservation modalities in the exception of shielding the testes including lomustine and prepubertal girls are experimental in or moving them out of the radiation cyclophosphamide.40 nature and are without adequate field.52,53 Most methods involve long-term outcomes data. The hormonal and other manipulations to exception is gonadal shielding and protect the testes from injury during oophoropexy. Shielding of the ovaries cancer treatment or involve OPTIONS FOR FERTILITY PRESERVATION during radiotherapy and preserving a testicular tissue sample. The options, burdens, and costs of oophoropexy to remove the ovaries Primordial sperm cells are fertility preservation differ for from the radiation field are strategies susceptible to toxicity at all stages of boys and girls. The availability of to preserve ovarian function during life. Gonad shielding can be used options also differs depending on treatment, although radiation scatter during radiotherapy but is only whether the child facing cancer is a concern despite best efforts to possible with selected radiation fields treatment is prepubertal or avoid radiation exposure.60–62 and anatomy and may increase the postpubertal and on the urgency Although ovarian transposition is risk of harboring malignant cells.3 with which treatment must be relatively effective for preserving the The gonad(s) can also be temporarily initiated. Some treatments are well endocrine function of the ovary (in relocated outside of the radiation established and have known 60% of cases), only approximately field to either the thigh or the efficacy and outcomes data, and 15% of patients treated with anterior abdominal wall.54,55 others are still experimental. It is transposition and wishing to become important to differentiate To date, no effective pharmacologic pregnant ever achieve this goal.60 Of between clinically accepted and intervention has been identified. note, the benefit of gonadal shielding experimental treatments when Gonadal protection through hormone is less effective if adjuvant counseling patients and families manipulation has been evaluated only chemotherapy with gonadotoxic regarding their fertility-preserving in small studies in patients with agents is required as part of the options. cancer and is uniformly ineffective in treatment regimen.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020 5 There are also potential means for leukemia cells in histologically PRESERVATION OF FERTILITY BEFORE preserving ovarian function in normal pretreatment ovarian tissue TREATMENT IN THE POSTPUBERTAL selected cases of reproductive tract specimens removed from patients ADOLESCENT malignancy, including more with leukemia and lymphoma before Once a male adolescent is able to conservative surgery for initiation of treatment, leading to the produce mature sperm or a female certain early-stage tumors and theoretical concern for reseeding the adolescent is able to be stimulated to choosing chemotherapeutic body with tumor cells after the provide mature oocytes, fertility 75,76 agents that have less gonadal autotransplant. In adults, more preservation options become more 60,63,64 toxicity. than 70 live births have been viable. The options for germ cell reported in women who preservation before treatment differ In prepubescent girls, the ovaries cryopreserved ovarian tissue, but depending on sex. cannot be stimulated to produce only when the tissue was harvested mature eggs. Ovarian tissue postpubertally.77–82 A potential Male Adolescents cryopreservation has been proposed confounder in the various case series as a method to preserve fertility in in which live births were reported is Sperm cryopreservation after this cohort of girls. In contrast to that in the majority of cases, some masturbation is the most established oocyte cryopreservation, ovarian native ovarian tissue was present in and effective method of fertility tissue cryopreservation (via removal addition to the autotransplanted preservation in male adolescents.71 of a portion of the ovary or unilateral ovarian tissue. It is possible that Whenever possible, sperm should be oophorectomy) is a process in which pregnancies occurred from oocytes collected before initiation of cancer normal, functioning ovarian tissue is obtained from the native ovarian therapy to prevent the risk that excised from the ovary and tissue and not from the transplanted sperm DNA integrity or sample 65–70 cryogenically stored. Currently, material.83 quality will be compromised. Sperm this technique is only available in can be collected at infertility centers certain parts of the United States as Until recently, all of the reports of or andrology laboratories and stored an open clinical trial to assess its successful births after autografts of either at these sites or at long-term efficacy and safety as a potential cryopreserved ovarian tissue in the storage facilities. Patients may be shy option for preservation of fertility in pediatric population were obtained or embarrassed at the prospect of prepubertal girls.71,72 Within this from adolescents who had already masturbation, such that a discussion context, it is the only method that can begun the pubertal transition. There of the available options is best be offered to prepubertal girls.73 This has now been at least 1 published conducted with the patient and his technique has been performed in report of a live birth after an legal guardian(s) in a comfortable and children as young as 2.7 years of age, autograft of cryopreserved ovarian accepting manner. It may be helpful and the chance of later restoring tissue in a prepubertal girl, who was to provide a space for the patient to fertility should theoretically be higher 9 years old at the time that her speak privately with a medical team because the ovarian cortex contains ovarian tissue was cryopreserved.84 member in the absence of the parent more primordial and primary follicles Before this, the youngest age at the or guardian to allow the adolescent to in younger children.73 Ideally, the time of ovarian tissue ask questions and address concerns. stored ovarian tissue is thawed and cryopreservation was 14 years, in Physicians may be instrumental in autotransplanted into the donor once a girl preparing to undergo guiding parents regarding approaches her treatment has been completed.74 a myeloablative conditioning regimen to effectively discuss sperm There are no data yet available as part of a hematopoietic stem cell cryopreservation with their regarding whether cryopreservation transplant performed for adolescent sons.86 One study of ovarian tissue in prepubertal girls homozygous sickle cell anemia. suggested that adolescent boys may can lead to pregnancy and delivery. Although she had not yet be more successful at masturbation if Given the potentially limited viability achieved menarche, there was a parent does not accompany them to of the autotransplanted tissue, this evidence that she had already the appointment.87 Underlying sperm procedure is more likely to restore started the pubertal transition on the quality may be poor in certain cancer reproductive endocrine function basis of existence of breast types, including testicular cancer, rather than result in preserving development.85 Given the unknown leukemia, and Hodgkin’s disease.88,89 fertility, unless the oocytes are efficacy of this technique, ovarian Nevertheless, recent progress in retrieved relatively soon after the tissue cryopreservation in andrology laboratories and with transplant. Studies using flow prepubertal girls is best assisted reproductive technology cytometric evaluation have confirmed performed under an IRB (ART) allows for successful freezing the presence of contaminating protocol. and future use of even a limited

Downloaded from www.aappublications.org/news by guest on September 29, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS number of sperm and even when the pregnancy rates by using previously invasive nature of the process. sperm quality is diminished.90 cryopreserved oocytes have been Although oocyte cryopreservation is reported to be as high as 50% in a medically viable option beginning Alternative methods of obtaining adult women cryopreserving their around the time of menarche, it is less sperm besides masturbation include oocytes but would be expected to be clear whether it should be routinely testicular aspiration or extraction, even better in young women and offered to young adolescents or to electroejaculation under sedation or adolescents.97 Such rates have been any minor. The process of oocyte anesthesia,91 or retrieval from obtained at fertility centers that are cryopreservation requires a postmasturbation urine sample.87 experienced with egg freezing, and approximately 10 days of monitoring Although fresh sperm samples may patients should be encouraged to with transvaginal ultrasonography result in higher success rates than freeze oocytes at centers with ample and blood tests, followed by frozen sperm, the success rate experience using this technology. The a transvaginal oocyte retrieval depends more on the sperm number of infants born from frozen performed under anesthesia. In some parameters at the time of production oocytes is increasing. Information on clinical situations, a delay of a week than on whether the sample was used the health outcomes of children born or more before initiating cancer fresh or was previously via this specific technique for fertility treatment may not be possible or may cryopreserved.92,93 With fair-quality preservation is limited but has overall compromise care such that oocyte frozen sperm samples, IVF is often been reassuring. No increases in cryopreservation may not be a viable recommended to achieve pregnancy chromosomal abnormalities, birth option. For many adolescents and rather than intrauterine insemination defects, or developmental deficits their parents or guardians, the because cycle success rates are much have been noted in the children born invasive nature of the ovarian higher and sperm are a limited from cryopreserved oocytes as stimulation process and retrieval may resource. In cases in which only a few compared with other standard ART prevent its acceptance on sperm are present, fertilization and procedures, such as IVF, and with psychological and emotional grounds. pregnancy can be achieved by – natural conception98 101; however, performing IVF with intracytoplasmic these data are not from patients who Women with hormonally sensitive sperm injection (ICSI). cryopreserved their oocytes after tumors who are interested in oocyte a cancer diagnosis. To date, it is not or embryo cryopreservation present Female Adolescents known whether success rates in this specific challenges because standard Although postpubertal female situation will mirror those achieved protocols for ovarian stimulation are adolescents historically had few after oocyte cryopreservation for associated with significant (albeit available options, this has changed other indications. Nevertheless, given temporary) elevations in estradiol over the past decade with the reassuring outcomes data for egg concentrations. Such elevations may improvements in oocyte freezing in other contexts and the lack theoretically increase the risk of cryopreservation. Oocyte of other options for many women tumor progression and spread.103 cryopreservation remains generally facing gonadotoxic therapies, the There has been a growing experience more invasive and expensive than American Society for Reproductive with the use of selective estrogen sperm harvesting. In October 2012, Medicine and the American College of receptor modulators and aromatase the American Society for Obstetricians and Gynecologists inhibitors during the stimulation Reproductive Medicine released support the use of oocyte portion of the cycle. Use of these a statement describing oocyte cryopreservation for women at risk agents has been shown to cryopreservation as no longer for losing ovarian reserve because of significantly reduce peak estradiol experimental and recommending that gonadotoxic exposures.102 This levels during ovarian stimulation to it be offered to adult patients facing technique requires controlled ovarian those more typical of a spontaneous the risk of infertility resulting from hyperstimulation with approximately ovulation during a normal menstrual chemotherapy and other gonadotoxic 10 days of subcutaneous period, thus theoretically decreasing therapies.94 Embryology laboratories gonadotropin hormone injections. the risk of stimulating hormonally are increasingly able to cryopreserve, Eggs are then retrieved from the sensitive tumors. Fortunately, this thaw, and fertilize mature oocytes, ovaries with transvaginal blunting of the hormones does not with success rates approaching or ultrasonography-guided needle have a negative effect on egg quality equaling those achieved with more aspiration performed under or cycle outcome. The lower estradiol traditional embryo freezing.94 This intravenous sedation. As mentioned concentrations in cycles using opens up a viable option for the previously, although medically viable, selective estrogen receptor postmenarcheal pediatric patient this technique has limitations in the modulators and aromatase inhibitors with cancer.95,96 Successful adolescent age group because of the do not appear to decrease the chance

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020 7 of achieving a pregnancy when the wish to consider parenting options fertility coverage because of resultant embryos are ultimately outside of adoption will require both mandates on insurance, and some transferred to the uterus.104,105 donation from a known or have recently begun mandating anonymous egg donor and the coverage of fertility Cryopreservation of embryos, in services of a gestational carrier. There preservation.113,114 The later use of which oocytes are fertilized with are significant costs associated with stored gametes may be covered under sperm from the woman’s male this mode of reproduction. Also, such fertility mandates.115 Legislative partner or with anonymous donor gestational surrogacy laws are efforts are underway in a number of sperm, was historically the only complex, differ among states, and states to address this issue.116 option available to postpubertal girls evolve over time. Because the cost burden on patients and young women wishing to or families can be expected to change preserve their fertility. As compared There has been speculation that over time and by geographic area, with oocyte cryopreservation, concomitant treatment with good counseling will require embryo cryopreservation is more gonadotropin-releasing hormone familiarity with current regional socially, emotionally, and ethically (GnRH) analogs may prevent ovarian data.117 Some patients may benefit complex because the patient needs failure induced by cancer therapy by from fertility preservation under the maturity to fully comprehend all protecting against chemotherapy- experimental protocols, and these aspects of the procedure, including induced follicle depletion. The studies should be considered when the fact that the eggs will be fertilized looking at this option to date were applicable and after appropriate with (usually anonymous) donor performed on adult women with 67 counseling has been provided. sperm. Given the success rate with breast cancer, and it is not clear oocyte cryopreservation, there is little whether these data are applicable to Sperm cryopreservation is need to consider fertilizing the eggs children. In adults, most studies a technique that has been used for before cryopreserving them, and evaluating GnRH analogs to prevent many years and has associated embryo cryopreservation should only ovarian failure have not benefits and a record of success that be used in rare circumstances, for demonstrated benefits,106–108 supports its widespread use in the example, when an older adolescent is although 1 recent randomized trial postadolescent male patient. The cost married or in a long-term committed revealed a significant reduction in of sperm cryopreservation after relationship. Even then, ovarian failure and an increased masturbation can total hundreds of cryopreserving oocytes opens up fertility rate in women receiving dollars a year, with additional costs more future options than GnRH analogs.109 These findings incurred if alternative methods, such cryopreserving embryos and cannot be applied to prepubertal as surgical sperm extraction, are should be encouraged when available girls, in whom the hypothalamic- needed to obtain sperm or for 3 and when the patient is of an pituitary-ovarian axis is still prolonged storage. When ready to be appropriate age and maturity level to quiescent.71 The 2018 ASCO used for reproduction, IVF and often undergo an ovarian stimulation guidelines acknowledge that there is ICSI may be needed to achieve procedure. conflicting evidence regarding the use pregnancy, especially given the often- limited quantities of sperm available. For women who have previously of GnRH analogs to protect fertility The relevant costs of IVF are undergone pelvic irradiation, there but suggest that in situations in which discussed later in this section. may be scarring or other proven fertility preservation methods postradiation effects to the uterus are not feasible, GnRH analogs may be In postmenarcheal female and vagina that preclude conception offered to patients, with the hope of adolescents, controlled ovarian or the ability to maintain a pregnancy. reducing chemotherapy-induced hyperstimulation for the purpose of fi 3 For girls who will be receiving pelvic ovarian insuf ciency. retrieving and cryopreserving oocytes irradiation and their families, is often not covered by insurance. The discussion of the future use of various components of such cycles a gestational surrogate may be COSTS OF FERTILITY PRESERVATION include (1) stimulating the ovaries warranted. If the ovaries remain The costs of fertility preservation are with daily subcutaneous injections functional after irradiation, it will be often not covered by insurance,110 over the course of 8 to 21 days and possible to retrieve eggs from them, especially given that insurance monitoring of the ovarian response fertilize them through IVF, and usually does not cover experimental with approximately 5 blood tests and transfer them into a gestational therapies, thus compounding the ultrasonographic examinations over carrier. When premature ovarian psychological distress with the the course of the stimulation; (2) the failure has occurred, women with economic impact of infertility.111,112 cost of gonadotropins to stimulate the uterine or vaginal compromise who Some states have comprehensive ovaries, medications to prevent early

Downloaded from www.aappublications.org/news by guest on September 29, 2021 8 FROM THE AMERICAN ACADEMY OF PEDIATRICS ovulation, and medications to blunt successful, the tissue would either conversations. Adolescents may the estrogen response in cases of need to be retransplanted into the benefit from the opportunity to speak hormonally sensitive malignancies; testes or some extratesticular one on one with their physician and/ (3) egg retrieval under anesthesia; (4) location, and/or sperm would need to or child psychologist or reproductive embryology and laboratory fees; and be extracted from the tissue after specialty surgeon in the absence of (5) cryopreservation of the oocytes. A sperm maturation. If sperm were to their parents. For adolescent girls typical oocyte cryopreservation cycle be extracted, then IVF and ICSI would who may benefit from oocyte can cost between $7000 and need to be used in the future to cryopreservation, a frank discussion – $14 000.118 121 Medications per egg obtain viable embryos. regarding their experience with retrieval cycle can cost between tampon use and intercourse should For prepubertal girls, the costs of $2000 and $7000, although currently, be undertaken because the ovarian tissue preservation can be some pharmacies and pharmaceutical monitoring that is required before separated into 3 parts: (1) the companies provide these medications retrieving the oocytes requires procedure to retrieve the tissue, at a discount or at no cost to patients multiple transvaginal generally laparoscopy and attendant with a cancer diagnosis. Storage fees ultrasonographic examinations. For anesthesia123; (2) ovarian tissue for cryopreserved oocytes are adolescent boys, a discussion of pathologic evaluation and freezing; approximately $350 to $600 per sexual experience and comfort with 3 and (3) the annual cost of ovarian year. When cryopreserved eggs are masturbation should occur. tissue storage. Laparoscopic ready to be used for reproduction, Recognizing that fertility preservation procedures, even in children, often there are additional costs associated may create both burdens and can be performed on an outpatient with thawing the eggs and fertilizing opportunities for patients and their basis, precluding an inpatient them with sperm as well as families, discussions regarding hospitalization cost.74 The cost of transferring the embryos back to the reproductive potential have, as their ovarian tissue freezing alone might be uterus. goal, the maximization of the child’s similar to that of freezing testicular future options and well-being. Women requiring an egg donor sperm after testicular dissection (see because of ovarian failure or previous discussion), incurring an Most often, a child will initially diminished ovarian reserve may incur annual cost for ovarian tissue storage present to the general pediatrician additional costs, particularly if they of several hundred dollars a year or and then be referred to a pediatric need to use eggs from an anonymous greater. Assuming recovery of the hematologist oncologist. Physicians egg donor, who is reimbursed for her patient after treatment, the costs will involved in cancer treatment should contribution. Women who require include tissue thawing and the be familiar with the ASCO guidelines a gestational surrogate because of an procedure for autotransplantation, for fertility preservation3 and be able inability to carry a pregnancy will subsequent medications, and to provide referral for consultation incur costs of both IVF and laboratory testing. Ovarian tissue and treatment to patients and gestational surrogacy, which often preservation remains experimental families who wish to seek these out. total in the tens of thousands of and is best performed at a specialized When possible, a child should be dollars. center and under IRB approval. In referred to a multidisciplinary team some cases, enrollment in such for a comprehensive approach to the Experimental fertility preservation studies does not incur a cost to the options may be covered under evaluation of options for fertility participants. fi a research protocol in some cases preservation for his or her speci c such that there may be no or minimal circumstances. This team can provide Counseling Families Regarding counseling regarding appropriate costs to the patient. The therapies Options for Fertility Preservation themselves can be expensive. Once treatments, their timing, and their they are no longer considered Counseling regarding fertility scope. The team may consist of the fi ’ experimental, the cost will be borne preservation options is the rst step patient s primary care physician, by the families of children using them in assisting families in navigating pediatric hematologist and oncologist, in the future to the extent that options for fertility preservation. This radiation oncologist, reproductive insurance does not provide coverage. counseling is best undertaken as endocrinologist, urologist specializing early as feasible after a cancer in male infertility, surgeon (if surgery For prepubertal boys, testicular tissue diagnosis is made and before the is part of the treatment), child-life or cryopreservation is a potentially initiation of any cancer treatment, if other integrative health specialist, costly option that has not yet proven possible. For preadolescents, it is and mental health professionals. to result in offspring in humans but appropriate for one or both parents Ethics consultants may be helpful has been successful in primates.122 If or guardians to be present for such when conflicts arise between medical

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020 9 professionals and the patient and appropriate for age) in offspring after the death of the family.124 Such a team approach developmentally appropriate individual who provided the allows families to obtain the language will help patients and their reproductive tissue. Posthumous information they require to make families understand the likelihood reproduction from gametes procured decisions regarding fertility that cancer treatment will in childhood should not occur if the preservation and allows those who permanently affect fertility. child does not survive beyond the age decide to pursue fertility preservation Reproductive endocrinologists and of majority. This is further discussed options to do so in an efficient urologists can be instrumental in below in the section on ethics. manner and maximizes the chance explaining the pre- and posttreatment Consent forms should designate that that fertility preservation options are options and may help alleviate these the disposition of reproductive tissue initiated before starting cancer anxieties.3 The downstream options will be delayed until the child reaches therapy. For prepubertal children, of adoption, egg and sperm donation, the age of majority or discarded if the consultation with and/or referral to and gestational surrogacy can be child does not survive to the age of a center performing testicular and discussed as well as the success rates, majority. Once the child becomes an ovarian cryopreservation under an costs, surgical risks, and experimental adult, he or she can make changes to IRB protocol is appropriate. The type, nature of specific ART options and the disposition of the reproductive stage, and severity of the cancer affect the acceptability of the option to tissue, including provisions for its the time frame during which decline the intervention.125,127 As posthumous use. Legal review of the decisions surrounding fertility part of this discussion, families and institutional consent process and preservation must be made. In some children (as appropriate for age) associated documentation can be cases, these decisions must be made should be made aware that cancer considered to preclude future emergently, whereas in other cases, treatments do not guarantee a loss of misunderstanding or the window for action is urgent but reproductive potential and that a misinterpretation of tissue or not emergent. In some circumstances, pregnancy can occur in sexually specimen disposition or disposal. lifesaving treatment will need to start active postpubertal adolescents and Because case law has evolved in the immediately and fertility young adults. The complexity and area of disposition of previously preservation options will not be impact of the various fertility collected embryos and gametes, available. Even when fertility preservation options may be which has not always strictly preservation is not possible because overwhelming to children and their enforced documentation in a consent of the need for treatment or other families. Whenever possible, the form, periodic review of the determinants, counseling regarding information should be conveyed program’s written consents by an the risks to fertility inherent in the incrementally over multiple visits. institutional attorney may be helpful. various treatment options will allow This will allow families the time to For this reason, involving an attorney patients and their families to cope internalize the various treatment as part of the team can be beneficial with the effects of cancer treatment. options and determine the optimal to families and medical personnel. course of action for their particular Once the child reaches the age of Counseling Regarding Expected situation. However, some clinical majority, he or she should issue new Outcomes After Fertility Preservation diagnoses do not allow for the luxury documentation regarding his or her Physicians have an important role in of time between identification of the wishes for future storage of counseling children and their cancer and implementation of previously collected reproductive caregivers regarding their future treatment, and fertility preservation material. reproductive options when faced with decisions must be made urgently. a cancer diagnosis. The option of It should also be disclosed that fertility preservation may be of great Dispositional Control of success rates are not guaranteed. comfort for patients and their families Cryopreserved Reproductive Tissue Even with successful collection and and may assist them in managing the The fertility specialist can play an freezing of eggs, sperm, and/or emotional trauma of the cancer important role in discussing the issue embryos, success rates will never be diagnosis,60 although the offer may of dispositional control of 100%; some children who go through also result in unrealistic reproductive tissue in the event of the the process of fertility preservation expectations.125 Most younger patient’s death or incapacity. Such will not ultimately be successful in patients with cancer have historically discussions best occur before the using their cryopreserved been left with significant anxieties collection of any reproductive tissue. reproductive tissue. Additionally, and insufficient information about Posthumous use of reproductive there are no guarantees that stored reproductive issues.126 Appropriate tissue is defined as the use of gametes embryos and gametes will be viable counseling of parents and patients (as or embryos in an attempt to create when ready for reproductive use or

Downloaded from www.aappublications.org/news by guest on September 29, 2021 10 FROM THE AMERICAN ACADEMY OF PEDIATRICS be free of neoplasia. Also, unexpected satisfied with only survivorship and needed consultations and decision- catastrophes, both natural and man- less concerned about reproductive making or may preclude the ability of made, can lead to unintended damage potential.130 In another study in the patient to provide more than 1 or to or destruction of reproductive which families were to recall 2 samples.87 Facilitating the tissue. discussions they had regarding andrology laboratory visit and fertility expectations after surviving delaying the initiation of Barriers to Receiving Counseling cancer, only about half of parents chemotherapy, if possible, are 2 Survey results of adult male and recalled receiving information on the approaches that might be used in female survivors of cancer of topic and nearly one-third expected appropriate cases to increase fertility reproductive age and studies normal fertility.131 options of survivors of cancer. Some evaluating oncology practice patterns situations are true medical Patients themselves are generally for discussing infertility have emergencies (eg, respiratory asking for this information and have suggested that a conversation with compromise from a mediastinal identified preservation of fertility as patients with cancer regarding the lymphoma) or are significantly urgent extremely important.17 Most men potential consequences of their to preclude even the short delay taking one survey responded that treatment on future fertility was required for an andrology they believed having experienced lacking in more than half of cases.3 laboratory visit. cancer increased the value they Pediatric oncologists admit that, placed on family closeness and would Currently available fertility despite their motivation to preserve make them better parents.132 For preservation options are not believed fertility in their patients and their men who desire children in the to compromise the success of cancer belief that all pubertal patients with future, lack of timely information is therapy or adversely affect cancer could benefit from a fertility the most common reason for not a survivor’s health.3 Other than consultation, they do not use the banking sperm. A survey of hereditary genetic syndromes, large ASCO fertility preservation adolescent patients with cancer registry studies have failed to guidelines3 and instead refer their revealed that 81% would want to demonstrate an increased risk of patients to fertility specialists only 19,23 128 undergo investigational or research- genetic abnormalities, congenital a minority of the time. Oncologists – based procedures to attempt to malformations,20 22 or cancers in the provide many different explanations maintain their fertility.133 Additional children of survivors of for not referring patients for fertility – data suggest that the process of cancer.26 30,32,33 Disclosing this preservation, including not fertility preservation, in and of itself, information to patients and families recognizing the importance of this may be therapeutic; for example, will provide reassurance of the issue, assuming that patients cannot young male survivors demonstrated potential value of fertility afford fertility preservation lower distress and enhanced coping preservation.137 For families with procedures, feeling emotionally with cancer treatment simply from hereditary conditions that are risk uncomfortable discussing the topic, the knowledge that they had stored factors for developing malignancies, or choosing not to refer the patient sperm.134,135 In addition, the long- the development of preimplantation because of a poor prognosis.73 term morbidity associated with genetic testing of embryos allows Additional barriers include beliefs infertility and interrupted couples to undergo IVF and screen that such discussions will add childbearing is not minor and persists their embryos for the hereditary additional stress to an overwhelmed well into adulthood.136 In addition to cancer syndrome for which their family or will violate provider or fertility preservation options, offspring is at risk. By electing not to family cultural taboos on issues of strategies to help survivors of cancer transfer affected embryos, the risk of sexuality. Even when counseling does identify and deal with unresolved transmitting cancer genes to their occur, family satisfaction with the grief about cancer-related infertility offspring is dramatically reduced. process is often lacking; in one study, are important health care This approach is supported by the only 30% of parents were satisfied interventions. American Academy of Pediatrics as with the fertility preservation well as by the Ethics Committee of the counseling they received regarding Despite its perceived importance, the American Society for Reproductive their children.129 In a survey study process is not easy for patients and Medicine for couples who wish to identifying reproductive concerns of families. Making an appointment with avoid having children with high-risk adolescent girls with cancer and their the andrology laboratory usually is cancers.138 parents, the concerns of the the responsibility of the patient and respective groups were not family. Chemotherapy induction may One difficulty in counseling either sex congruent. Parents incorrectly need to proceed expeditiously and regarding risks to future fertility is expected their daughters to be may not allow the luxury of time for that there are few absolutes, and the

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020 11 discussion should be focused on an open future for the child. At times, without a legal guardian present to a risk assessment. Some treatments there may be disagreements between help elucidate the adolescent’s have a high risk of infertility, a parent and child or between the feelings regarding such decisions. diminished ovarian reserve, sterility, family and the physicians regarding Such discussions should take place and/or premature ovarian failure. fertility preservation. Reasons for this regardless of the child’s sexual Other treatments are less likely to include the cultural or religious orientation because reproductive lead to the inability to have children. beliefs of the family or discomfort considerations remain the same as for The level of concern over the surrounding discussions of an any child. When conflicts between potential loss of fertility should be intimate nature with a child who has patient and family desires arise, addressed, and the spectrum of not yet or only just recently reached involving mental health professionals fertility options that are available to sexual maturity. Parents should be and/or an ethics consultant to work an individual should be presented. cognizant of their biases and work to through the contrasting desires is maximize options for their children. often helpful and should be ETHICAL CONSIDERATIONS Although they may not feel considered. completely comfortable with fertility Fertility preservation raises several preservation, it is important to Issues may arise with disposition of ethical issues, including the dilemma consider that the child will become an gametes (sperm, oocytes, embryos, or of counseling someone who has not adult who will make reproductive gonadal tissue) whether the child 110,143,144 yet reached adulthood, obtaining decisions regarding their fertility. lives or dies. Any procedure appropriate consent and/or performed has as its aim the 125,139 assent, managing When possible, after the child has preservation of a child’s reproductive disagreements between desires of the become an adult, he or she should future, and this should be discussed patient and his or her family, and have the broadest possible options as part of the consent and/or assent later use and disposition of from which to choose given the process. If the child survives, reproductive tissue that was acquired medical circumstances of his or her decisions surrounding disposition of before the age of assent. cancer diagnosis. The opportunity to the gametes should be delayed until A central ethical concern for children parent a biologically related child is after the child has reached the age of facing a cancer diagnosis whose an important option to attempt to majority. This stands in contrast to treatment may limit future fertility is preserve for the child. Recognizing organ donation, in which parents do that of supporting the right to an the limits of safety and current have control over donation decisions. open future.140 This encompasses technology, medical providers should The contrast between gamete and a set of moral rights children possess strive to discuss these options and organ donation stems from the that are derived from the autonomy help provide access to them. Special capacity of gametes to propagate the rights of adults. These rights protect circumstances might be posed by genome of the deceased. Posthumous children from having important specific religious beliefs or cultural gamete use in adults is ethically decisions made by others before they values that preclude either discussing complex. In minors who have not have had the ability to make them for or allowing ART or that prohibit survived to the age of majority, use of 110 themselves. The right to an open masturbation. The parent(s) or cryopreserved gametes is ethically future encompasses strategies that guardian(s) will most likely be impermissible. It is unethical for may safeguard a child’s future transferring their beliefs to the parents or legal guardians to arrange fertility.141 clinical situation, and these beliefs for gametes to be fertilized for the may or may not represent those of the purpose of reproduction. The only Of critical concern is the extent to child at the present time or in the individual ethically able to consent to which the minor child should be future. Individuals who will later the use of their gametes for involved in decisions surrounding his wish to have biologically related reproduction is the child who has or her care. Guidance on patient children may be adversely affected by reached the age of majority. Organs participation in decision-making and decisions that are made for them by and other tissues are donated for the assent should comply with their parents or guardians. In some purpose of saving a life or improving recommendations in the American cultures, a person’s status in their the health of another. Posthumous Academy of Pediatrics policy community may be culturally gamete donation does not serve statement “Informed Consent in dependent on their ability to either of these purposes. These issues Decision-making in Pediatric reproduce. It may be helpful, when are not unique, have precedent in Practice.”142 such options are presented to an case law, and need to be addressed by The patient’s family and physicians adolescent who is mature enough to any person agreeing to the should work together to help provide provide assent, to discuss them preservation of tissue or gametes.144

Downloaded from www.aappublications.org/news by guest on September 29, 2021 12 FROM THE AMERICAN ACADEMY OF PEDIATRICS Eggs, sperm, and testicular and age group are experimental at the 9. In considering actions to ovarian tissue obtained from a child present time. preserve a child’s fertility, ’ who does not survive into adulthood 4. When counseling families parents should consider a child s should be discarded. Because a child regarding fertility preservation, assent, the details of the or an adolescent who lacks capacity physicians should be clear as to procedure involved, and whether cannot give consent to have donated whether the treatments have such procedures are of proven gametes used for procreation and to proven efficacy or are utility or are experimental in avoid the risks inherent in the experimental in nature. nature. “ ” creation of a commemorative child, Experimental therapies should 10. Instructions concerning parents would not have discretion only be undertaken under IRB disposition of stored gametes or over the biological material of a child approval. gonadal tissue in the event of the who has died, and the gametes should ’ 5. Evaluation for candidacy for patient s death, unavailability, or be destroyed. This is consistent with fertility preservation should be other contingency should be recommendations made by the guided by an institutional formally recorded at the center American Society for Reproductive policy. Such policies should be where the gametes or tissue will Medicine and the European Society of informed by a team of specialists be stored and should include the Human Reproduction and patient if possible before 145,146 that may include a pediatric Embryology. collection of the tissue and/or oncologist, a specialist in germ cells. There should be reproductive medicine, another discussion between the a urologist with expertise patient and the physicians at the GUIDANCE FOR COUNSELING OF in male fertility, a radiation center where the reproductive PARENTS AND PATIENTS ABOUT oncologist, an ethics PRESERVATION OF FERTILITY OPTIONS tissue is stored about consultant, an expert in IN CHILDREN AND ADOLESCENTS WITH disposition of gametes after the reproductive law, and a mental CANCER child reaches the age of majority. health professional. 1. Physicians providing cancer Eggs, sperm, and testicular and treatment to children should be 6. Cryopreservation of sperm and ovarian tissue obtained from able to counsel patients and their oocytes should be offered a child who does not survive into families regarding the risk of whenever possible to adulthood should be discarded infertility and fertility postpubertal patients or families by the center preserving the preservation options. Although of adolescents, dependent on the reproductive tissue as per the there will be cases in which predicted gonadotoxicity of the consents signed at the time of cancer treatment must be prescribed treatment. cryopreservation. initiated emergently and fertility 7. Given the success that has been 11. When conflicts arise between the preservation will not be an achieved with cryopreservation parent and child regarding option, the impact of the of oocytes, embryo fertility preservation, all possible treatment on fertility should be cryopreservation should not be attempts should be made to discussed. considered in children. support an open future for the 2. When medically effective fertility Experience with oocyte child while respecting the ’ preservation options exist, cryopreservation is variable, and family s wishes. patients and their families should patients should be referred to fi be offered timely referral to fertility centers with signi cant LEAD AUTHORS centers and providers offering experience and success with this these options. This may include technique. Sigal Klipstein, MD, FACOG Mary E. Fallat, MD, FAAP delaying treatment to allow for 8. The option of ovarian tissue Stephanie Savelli, MD, FAAP fertility preservation to occur, as cryopreservation for female long as the delay does not children and adolescents and of compromise the success of the testicular tissue in male children COMMITTEE ON BIOETHICS, 2018–2019 cancer therapy. and adolescents is still Mary E. Fallat, MD, FAAP, Chairperson 3. Physicians who provide cancer considered experimental Aviva L. Katz, MD, FAAP treatment should be aware that and should be offered Robert C. Macauley, MD, FAAP Mark R. Mercurio, MD, FAAP only in selected institutions fertility preservation options are Margaret R. Moon, MD, FAAP limited in prepubertal children in the setting of a research Alexander L. Okun, MD, FAAP and that most treatments in this protocol. Kathryn L. Weise, MD, FAAP

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 145, number 3, March 2020 13 LIAISONS FORMER EXECUTIVE COMMITTEE MEMBERS ACKNOWLEDGMENTS Douglas S. Diekema, MD, MPH, FAAP – Jeffrey Hord, MD, FAAP, Immediate Past We acknowledge Dr Aviva Katz for American Board of Pediatrics Chair her insight and assistance throughout Sigal Klipstein, MD, FACOG – American the process of drafting this article. We College of Obstetricians and Gynecologists Kevin W. Coughlin, MD – Canadian Paediatric CONTRIBUTING MEMBERS also thank Dr Sarah Friebert and Dr Society Daniel M. Green for their drafting of Sarah Friebert, MD, FAAP Daniel M. Green, MD, FAAP the original document on which the current statement is based. LEGAL CONSULTANT STAFF Jessica W. Berg, JD, MPH Suzanne Kirkwood, MS ABBREVIATIONS AMH: anti-Müllerian hormone STAFF SECTION ON SURGERY EXECUTIVE ART: assisted reproductive COMMITTEE, 2012–2013 technology Florence Rivera Frederick J. Rescorla, MD, FAAP, Chairperson ASCO: American Society of Clinical Mary L. Brandt, MD, FAAP, Immediate Past Oncology Chairperson CCSS: Childhood Cancer Survivor SECTION ON HEMATOLOGY/ONCOLOGY Michael Caty, MD, FAAP Study – EXECUTIVE COMMITTEE, 2018 19 Kurt Heiss, MD, FAAP GnRH: gonadotropin-releasing George W. Holcomb, MD, FAAP Zora R. Rogers, MD, FAAP, Chairperson Rebecca L. Meyers, MD, FAAP hormone Carl Allen, MD, PhD, FAAP R. Lawrence Moss, MD, FAAP ICSI: intracytoplasmic sperm James Harper, MD, FAAP injection Jeffrey Lipton, MD, PhD, FAAP Cynthia Wetmore, MD, PhD, FAAP IRB: institutional review board STAFF Hope Wilson, MD, FAAP IVF: in vitro fertilization Amber Yates, MD, FAAP Vivian Thorne

Address correspondence to Sigal Klipstein, MD. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Fertility Preservation for Pediatric and Adolescent Patients With Cancer: Medical and Ethical Considerations Sigal Klipstein, Mary E. Fallat, Stephanie Savelli and COMMITTEE ON BIOETHICS, SECTION ON HEMATOLOGY/ONCOLOGY, SECTION ON SURGERY Pediatrics originally published online February 18, 2020;

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