Children diagnosed with cancer today can expect a greater than 85 % five-year survival, with many living to adulthood.1 Given improved survivorship, there have been recent multidisciplinary efforts to improve the quality of life for survivors of childhood cancer. An important, yet often overlooked, survivorship concern is future infertility and reproductive hormone dysfunction. Since many children will survive to their reproductive years, addressing the potential loss of fertility and reproductive hormone production following gonadotoxic treatment is a key to providing comprehensive cancer survivorship care. Women who were diagnosed with cancer when they were <21 years old had an increased risk of infertility when compared to sibling controls2; but over 75 % of young adults who are childless at the time of their diagnosis desire to parent in the future.3 Fertility-related psychological distress is prevalent from diagnosis to survivorship.4 In addition to infertility, gonadal dysfunction puts females at an increased risk of cardiovascular, bone and psychologic disorders.5,6 Currently this is a top unmet need in the survivorship period,7 but these conversations must start before therapy has begun. This has led the American Academy of Pediatrics,8 American Society of Clinical Oncology,9 Children’s Oncology Group (COG)10,11 and American Society of Reproductive Medicine (ASRM)12 to recommend discussions about fertility, irrespective of the risk profile, before treatment begins.

These recommendations have led to the formation of multidisciplinary oncofertility programs at many children’s hospitals providing comprehensive oncologic care.12 Increased risk of gonadal failure or infertility is dependent on both systemic and local therapy. Contributors to gonadotoxicity include alkylating chemotherapy, platinum-based chemotherapy, radiation exposure, hematopoietic stem cell transplant and surgical removal of gonads.13 The Best Practice Committee of the Pediatric Initiative Network of the Oncofertility Consortium developed a risk stratification model for future gonadal failure or infertility based on the contributors to gonadotoxicity.13 Although it is not possible to assign percentage chance of gonadal failure or infertility due to lack of studies with self-reported infertility, there are risk categories assigned (Table 1). It is using this model whereby oncofertility specialists provide counseling to patients and families about risk stratification and therefore potential fertility and hormonal preservation options.14

Currently, ovarian transposition and ovarian tissue cryopreservation (OTC) are the only fertility preservation (FP) options available to prepubertal female patients given their reproductive hormone immaturity and inability to stimulate for egg retrieval. The role of ovarian transposition is to surgically place the ovaries out of the planned radiation field to minimize the risk of premature ovarian insufficiency associated with direct gonadal radiation. Transposition does not protect the ovaries from the gonadotoxic effects of systemic therapy.15 Ovarian tissue cryopreservation is the only option available to prepubertal patients who will receive systemic therapy that will place them at high level of increased risk of infertility. Although the ASRM recently deemed OTC no longer experimental, pediatric oncofertility experts still advocate for OTC in prepubertal children to be carried out under an institutional review board (IRB) protocol given the uncertain outcomes in fertility restoration for prepubertal children.16,17

Postpubertal females may also undergo OTC, especially if they need to start therapy quickly, however, they can also participate in ovarian hormone stimulation with egg retrieval (OHS-ER). Additionally for certain post pubertal patients, both OHS-ER and OTC are acceptable FP options. OHS-ER can provide eggs for future embryo creation for in vitro fertilization (IVF). OTC can provide ovarian tissue for auto-transplantation for potential natural childbirth, as well as hormone restoration in the future. Egg retrieval and cryopreservation is standard of care and does not need to occur under an IRB.

Counseling for future fertility and hormone loss after therapy should occur before treatment begins, and ideally any interventions should also occur in this window.14,15 This can be difficult for some tumors where COG protocols mandate initiation of chemotherapy within 14 days of surgery or biopsy, but it can take some time to get the histology results.18 Initiation of chemotherapy is not a contraindication for future FP interventions, as the impact on fertility is related to the cumulative CED at each cycle.19 Thus, once the patient is referred to the pediatric oncology team or once the diagnosis has been made, counseling should ensue. Not all centers, however, have a formal oncofertility team. If this is the case, the center can use a web-based training,20 or a referral should be made to a center with a pediatric oncofertility team where consultations may be performed virtually so patients do not have to travel.21

Members of the oncofertility team who directly counsel patients and families could include an advanced practice provider, reproductive endocrinologist, an oncologist or surgeon, although it is likely best if neither is the patient’s primary oncologist or surgeon as this could be a conflict of interest if the patient qualifies for an experimental FP procedure. For hospitals with training programs in pediatric surgery, pediatric and adolescent gynecology and pediatric hematology/oncology, those trainees should participate in these counseling sessions.22,23 The provider performing the consultation should be knowledgeable speaking to the patient about the gonadotoxic risk of therapy, including the future hormonal and fertility implications; FP options available, as well as the outcomes; and financial concerns, including the cost of the procedure, tissue processing, long term storage and eventual use of the tissue, which may occur out of pocket. When speaking about options, the provider performing the consult must be clear which procedures are experimental (i.e. OTC), and which are not. Additionally, it should be mentioned that becoming a parent can be achieved beyond biological offspring, including adoption, surrogacy and donor egg or embryos. This perspective is important should patients/families not want to pursue FP, or if despite the FP procedure, the outcome is not successful.15 Through these discussions, FP should be seen to offer options for the child as a future adult.24

Counseling is a dynamic process and should be re-visited with every change in treatment. It is known that many patients regret deciding not to pursue FP and this is higher among those who believe it was either not discussed at all or mentioned too late.25 In sum, fertility discussions ought to be revisited throughout treatment and FP options considered should the therapy transition from a low to a high risk of gonadotoxicity.

OTC requires a surgical procedure to procure ovarian cortical tissue. While there is no standard operative technique, laparoscopic unilateral oophorectomy is the most frequently performed, has been shown to be a safe surgery with no delay in initiation of chemotherapy or radiation.26,27 When possible, surgery should be considered elective, and patients should be well enough from an overall clinical standpoint to undergo a same-day laparoscopic surgery.15 Additionally, FP procedures should be combined with other essential procedures such as central venous catheter placement, gastrostomy placement, bone marrow biopsy, or lumbar puncture to limit repeat exposure to general anesthesia.27

Some children are critically ill at the time of diagnosis or may have a large abdominopelvic mass that prohibits proceeding with laparoscopic surgery. In these cases, initiation of systemic therapy can be considered and oophorectomy delayed until the patient’s clinical status improves as long as they have not reached gonadotoxic levels of therapy. Upfront, sub-gonadotoxic levels of chemotherapy is no longer a contraindication to OTC and not only allows for safe surgery but also the potential of ovarian cortical tissue harvest at minimal residual disease.15,19,28, 29, 30 Once oophorectomy is deemed safe, patients are still a candidate for a laparoscopic approach since most oophorectomies are performed laparoscopically even after open abdominal surgery.31

There are technical aspects to consider when planning a laparoscopic oophorectomy for OTC for small, prepubertal children. First, their pelvis is small and provides limited working space for laparoscopic surgery. Trocar placement can vary depending on the size of the child, but a 5 mm camera is often helpful for good laparoscopic visualization and utilization of two 3 mm working instruments make dissection more feasible in the small pelvis. While either ovary may be taken, the surgeon should remove the ovary that will be in the radiation field, if applicable. Second, the mesovarium of prepubertal patients can be narrow which requires intentional exposure of the prepubertal ovary, mesovarium, and ipsilateral ovarian tube (Fig. 1). A 3 mm advanced energy device may be considered to facilitate careful division of the mesovarium. The ovary should be carefully extracted, without crushing the specimen, through a trocar site. The trocar site may need to be enlarged to allow for smooth removal of the ovary. Efforts should be made to protect the ipsilateral fallopian tube but if by doing so the ovarian cortical tissue is compromised a unilateral salpingo-oophorectomy can be considered.27

For postpubertal females who plan to undergo both OHS-ER and OTC, there are a few technical considerations as well. Some patients and families have asked about combining both options under one anesthesia. This option is not the standard recommendation since ideally the egg retrieval occurs in the reproductive endocrinology office with proximity to the andrology lab for egg freezing. If fewer eggs are retrieved than expected, the patient would have the option to undergo a second round of hormone stimulation and egg retrieval, if timing of medical therapy allowed for that. In addition, hormone stimulation of the ovary causes it to increase by ∼3–4x in size which makes the oophorectomy excision site larger than otherwise needed. This could result in increased post-operative pain which may change the outpatient nature of the surgery and slow recovery. The larger ovary size also causes cortical thinning which create cortical strips of higher number but decreased follicle density in each strip. This is expected to affect future use of the tissue such that more strips will likely be needed for autotransplantation. The best recommendation is to separate the procedures and perform OHS-ER first, followed by OTC once the ovary has returned to normal size. The entire process for both procedures requires about one month if no delays occur, which may be medically inadvisable in some patients.

The purpose of performing a laparoscopic oophorectomy for OTC is to preserve the possibility of restoring fertility and reproductive hormone function when the patient is ready to conceive or desires endogenous hormone function. Ovarian tissue transplantation (OTT) involves utilizing thawed ovarian tissue to reimplant in either an orthotopic or heterotopic position and is currently the only way this tissue can be used for fertility.32 Orthotopic transplantation is recommended as the primary choice for fertility restoration and involves surgical reimplantation of thawed ovarian cortical tissue on the remaining ovary or within a peritoneal bursa.28 Heterotopic transplantation of ovarian tissue into the subcutaneous tissues can be considered if intra-abdominal placement is prohibitive or if only hormone restoration is desired.33

Reproductive endocrine hormone function has been reported in 94 % of cases after orthotopic OTT and is often experienced within 4 to 5 months.29,34,35 The average lifespan of transplanted ovarian tissue has been reported from 1 to 7 years and grafts have been shown to support multiple pregnancies.36, 37, 38 For instances of short ovarian graft function or graft failure, additional thawed cortical strips, if available, can be transplanted to restore hormone function.34

Orthotopic OTT has resulted in over of 290 live births in patients who were postpubertal at the time of tissue procurement.12,29,38 Nearly half were achieved spontaneously with the remainder requiring assisted reproductive technology to conceive.28,29,39 Successful pregnancy after OTT was achieved 30 % to 37 % of the time with live birth rates ranging between 25 % to 35 %.28,29,35,40 The published pregnancy and live birth rates after OTT for patients aged 0–20 years at the time of their OTC are 69 % and 56 %, respectively.34 For these studies, the median age at the time of OTC was 19 years while the average age at reimplantation was 24 years.34 In a recent review that evaluated pregnancy outcomes using autologous transplantation of cryopreserved ovarian tissue, perinatal complication rates did not differ from that of the general pregnancy population, except for the incidence of preeclampsia which was suspected to be related to chemotherapy exposure, underlying medical condition and use of assisted reproductive techniques. The study also found that not receiving chemotherapy prior to OTC and natural conception were associated with lower perinatal complication rate.39

To date, there have been two reports of successful live births achieved from auto-transplantation of prepubertal ovarian cortical tissue.34,41 As mentioned, laparoscopic oophorectomy for OTC is considered a standard of care FP option in prepubertal patients, however many pediatric providers would advocate that it still occur under an IRB. OTT remains experimental in this group due to the small number of patients who have had live birth from prepubertal OTC and thus should only be offered under a research protocol.32 For postpubertal patients, OTT can be offered as part of standard clinical care.32

Although there is developing data as to the success of OTT, feasibility, live-birth and hormone restoration outcomes depend on the individual patient diagnosis, treatment history, and clinical condition. A group from Brussels has ongoing research in utilizing in vitro follicle maturation and options for evaluating ovarian tissue for possible presence of malignant cells prior to OTT.38 Research into non-autologous use of preserved ovarian tissue is underway, and a recent report documented successful allotransplant of ovarian cortical tissue requiring immunosuppression in a patient with Turner syndrome with resulting spontaneous pregnancy and live birth.42 Children who received high-dose pelvic radiation may not be candidates for OTT given the significant risk of pregnancy-related complications associated with uterine irradiation.28 However, patients may choose to build a family via use of their preserved tissue and a surrogate. For children who received chemotherapy prior to ovarian tissue harvest, ovarian follicle survival after transplant may be reduced. Rates of resumption of over-all ovarian function and pregnancy between patients who received chemotherapy and those who did not, did not vary significantly; although, those who received alkylating chemotherapy as part of their treatment had lower rates of pregnancy when compared to women who received non-alkylating chemotherapy.28 It is also important to counsel patients and families that family building options exist outside of FP procedures, which include adoption, surrogacy, and the use of donor sperm/eggs or embryos.15