ASRM 2024 Abstract Submission is Open!

Menu
Close Close Icon

Fertility preservation and reproduction in patients facing gonadotoxic therapies: an Ethics Committee opinion (2018)


KEY POINTS

  • Clinicians should inform patients receiving potentially gonadotoxic therapies about options for fertility preservation and future reproduction prior to the initiation of such treatment. A collaborative multidisciplinary team approach is encouraged.
  • Established methods of fertility preservation include embryo cryopreservation for men and women, sperm cryopreservation in men, and oocyte cryopreservation in women.
  • Due to technological advances made in the past decade, oocyte cryopreservation has become a viable option prior to gonadotoxic therapy. It may be appropriate for women whether single or partnered, for postpubertal girls, and for those who have objections to embryo cryopreservation. Data on longterm follow-up are still limited.
  • Procedures such as cryopreservation of ovarian tissue in girls and women and testicular tissue in prepubescent males may be offered only in a research setting.
  • Data on the use of gonadotropinreleasing hormone analogs (GnRHa) for ovarian suppression have been conflicting; until definitive proof of efficacy is established, other fertility preservation options should be offered in addition to considering GnRHa treatment.
  • All available options should be offered and can be performed alone or in combination, often without causing significant delay to cancer treatment.
  • Concerns about the welfare of resulting offspring are not sufficient reasons to deny patients facing gonadotoxic treatments assistance in reproducing.
  • Parents may act to preserve the fertility of cancer patients who are minors and when the intervention is likely to provide potential benefits to the child. Assent of the child should be obtained if possible. Unless written instructions state otherwise, gametes should be discarded if the child does not survive to adulthood.
  • Instructions should be specified about the disposition of stored gametes, embryos, or gonadal tissue in the event of the patient's death, unavailability, or other contingency.
  • Preimplantation genetic testing (PGT) to avoid the birth of offspring with a high risk of inherited cancer is ethically acceptable.
Cancer patients survive at increasing rates, but successful treatment in younger patients often leads to reduced fertility. Also chemotherapy often is used for noncancerous conditions such as autoimmune diseases like systemic lupus erythematosus (SLE) and hematological diseases. If damage to reproductive organs from treatment is likely, cryopreservation of gametes, embryos, or gonadal tissue may help preserve fertility. Techniques for oocyte cryopreservation have seen dramatic improvement in the last decade with improved pregnancy outcomes; however, long-term data on outcomes are still limited. Techniques for cryopreservation of testicular and ovarian tissue are still experimental.

The intersection of gonadotoxic therapy and reproduction raises ethical issues for both cancer and fertility specialists, including issues of experimental vs established therapies, the ability of minors to give consent, the welfare of expected children, and posthumous reproduction (1). In some respects, gonadotoxic treatment-related infertility is not markedly different from other kinds of infertility. In other respects, however, the context of cancer gives rise to issues of patient and offspring welfare that do not arise in other infertility settings. This statement seeks to guide specialists who provide gonadotoxic therapy (oncologists, hematologists, rheumatologists, neurologists, etc.) and fertility specialists in attempts to preserve fertility and to aid patients in reproducing after gonadotoxic treatment.


INCREASED SURVIVAL AND REDUCED FERTILITY

Improvements in treating cancer have enabled many younger persons with cancer to survive (2). Five-year survival rates with testicular cancer, hematologic malignancies, breast cancer, and other cancers that strike young people may be 90% or greater. However, treatment of these cancers is often detrimental to both male and female reproductive function.

The testis is highly susceptible to the toxic effects of radiation and chemotherapy at all stages of life. Cytotoxic chemotherapy and radiotherapy may produce long-lasting or persistent damage to primordial sperm cells, leading to oligo- or azoospermia. The most common strategy to preserve fertility is cryopreservation of sperm before treatment for later use. Cryopreservation of testicular tissue from prepubescent males remains experimental (3).

Female fertility also may be impaired following surgery, chemotherapy, or radiotherapy treatment for cancer (4). Ovarian damage is drug- and dose-dependent and is related to age at the time of treatment, with progressively smaller doses producing ovarian failure as the patient's age increases. Total body, abdominal, or pelvic irradiation may cause ovarian and uterine damage, depending on radiation dose, fractionation schedule, and age at the time of treatment (5). An elevated serum follicle-stimulating hormone (FSH) level is the most traditional biochemical indicator of ovarian damage and failure. However, antimüullerian hormone (AMH) and antral follicle count (AFC) are now commonly used as other markers of ovarian aging (6–8).

Preservation of fertility in females is more complicated than in males. Conservative fertility-sparing treatment such as radical trachelectomy in cervical cancer, hormonal treatment of early endometrial cancer, and conservative surgical management of early-stage epithelial ovarian cancer may be possible for certain women with early invasive disease (9). Reducing the radiation dose to the ovary by shielding or surgically moving the ovaries from the field of radiation (i.e., oophoropexy) may preserve ovarian function (10). Suppression of folliculogenesis with GnRHa for fertility preservation has long been controversial (11, 12). Multiple randomized studies have been conducted as well as a dozen meta-analyses, which have presented conflicting data. Results have been limited by heterogeneous populations, different chemotherapy regimens, and variations in study endpoints. Recently, the first long-term analysis showed that GnRHa did not prevent primary ovarian insufficiency in lymphoma patients (13). However, a meta-analysis of all the randomized trials conducted in breast cancer patients showed efficacy of ovarian suppression in reducing premature ovarian failure and increasing pregnancy rate (14). The National Comprehensive Cancer Network (NCCN) guidelines were updated to acknowledge the use of GnRHa in preventing chemotherapy-induced ovarian failure in estrogen receptor-negative tumors (15), although the American Society of Clinical Oncology (ASCO) did not change its recommendation. If the cancer treatment can be delayed, it is possible to undergo ovarian stimulation and retrieve and cryopreserve eggs (both mature and immature) or produce embryos that can be frozen for later transfer to the patient or a gestational carrier. Ovarian tissue freezing prior to the initiation of gonadotoxic treatment is considered experimental by the ASRM Practice Committee, but over 87 live births have been reported worldwide (16). It is becoming a viable option for prepubertal girls for whom oocyte or embryo freezing is not an option, for women who either cannot delay treatment or for when hormonal treatments are contraindicated.


THE PATIENT'S DILEMMA: BALANCING CANCER AND FERTILITY

A diagnosis of cancer can be a life crisis for any person. Its impact varies with the type of cancer, treatment prospects, and the physical, emotional, and social resources of the patient. Younger persons face the additional potential loss of reproductive function and the opportunity to have children. Surveys of cancer patients reveal a very strong desire to be informed of available options for fertility preservation and future reproduction (17). At the same time that patients who wish to reproduce in the future (and their parents in cases involving minors) receive a diagnosis of cancer, they also must consider possible effects on fertility. To preserve fertility, they may need to accept changes in standard treatment protocols or undertake steps to preserve gametes or gonadal tissue that carry their own risks and uncertainties.

Men in these circumstances sometimes find producing a sperm sample highly stressful. Women have more options, but all are more intrusive. If there is time before treatment, a woman may undergo ovarian stimulation, oocyte retrieval, and oocyte or embryo cryopreservation. The approach of using oocytes to create embryos that can be cryopreserved indefinitely is an option only for women with male partners or women who are willing to use a sperm donor. Both embryo and oocyte cryopreservation require the woman to undergo an invasive procedure at or soon after the time of diagnosis and while she awaits definitive treatment for her cancer. In the future, laparoscopic ovarian biopsy with ovarian tissue cryopreservation may become established as a therapy to be offered routinely to patients.

If cancer survivors are not able to reproduce coitally, they may seek medical assistance, including the use of stored gametes or tissue. They also may consider donor gametes, gestational carrier, adoption, or not having children.


THE ROLE OF ONCOLOGISTS AND OTHER MEDICAL SPECIALISTS IN PRESERVING FERTILITY

Physicians treating younger patients for cancer and noncancerous conditions must be aware of the adverse effects of treatment on fertility and of ways to minimize those effects. Issues to be considered in choosing a treatment plan include the risk of gonadal failure and/or uterine damage with the proposed treatment program, the overall prognosis for the patient, the potential risks of delaying treatment, the impact of any future pregnancy upon the risk of cancer recurrence, and the impact of any required hormonal manipulation on the cancer itself. If gonadal toxicity is unavoidable, physicians also should be knowledgeable about options for fertility preservation and offer patients a referral to a fertility specialist. There can be great variability in how cancer treatments affect fertility and it may be difficult to predict with certainty an individual's risk; patients should be counseled about this uncertainty.

While many physicians treating cancer in younger patients are sensitive to these issues, oncologists traditionally have focused on providing the most effective treatments available to help prolong life. With the growing number of cancer survivors, much attention is now focused on their quality of life and the physical, psychological, social, and spiritual issues that they confront (18). A high quality of life for younger survivors may include the ability to have and raise a family. With such great improvements in survival rates for younger patients, oncologists also must pay attention to the impact of treatment on fertility and ways to preserve it. It is important that discussions about fertility preservation start as early as possible in the planning of cancer treatment. Fertility preservation can usually be completed in 2–3 weeks; if started promptly, it can often be done without a delay in cancer treatment.

Research has shown that patients desire their oncologists to be attentive to issues of fertility (19). If gonadal toxicity is likely, clinicians might not always inform patients of options for gamete, embryo, or gonadal tissue storage. In a recent study of male cancer patients, for example, only 29% of patients received fertility counseling and 11% attempted sperm banking (19). Another study showed that although 60% of oncologists reported an awareness of ASCO's guidelines for fertility preservation, less than 25% of the respondents said they follow them on a regular basis, distribute any type of educational materials, or refer patients for fertility-preservation discussions (20). In addition, some physicians raise the issue with adolescent patients in settings in which it may not be comfortable for the patient to discuss the matter (e.g., in the presence of parents). Reproductive endocrinologists should collaborate with oncologists, updating them regarding available technologies and facilitating consultations with patients newly diagnosed with cancer. To further these alliances, education about fertility preservation should be incorporated into training programs for oncology and reproductive endocrinology.

Fertility preservation is a core component of cancer care in younger persons with treatable cancers. This involves informing patients and/or their families of options, benefits, and risks, and referring them to fertility specialists, if appropriate. Unless patients are informed or properly referred before treatment, options for later reproduction may be lost. Fertility specialists, pediatric and adolescent gynecologists, and patient organizations should work with cancer specialists and cancer organizations to make certain that information is appropriately conveyed and options explained. Medical specialists who use gonadotoxic therapies to treat noncancerous conditions also must be aware of these fertility-preservation options and make appropriate resources available to their patients.


THE ROLE OF FERTILITY SPECIALISTS IN PRESERVING FERTILITY

Reproductive physicians play important roles in helping to preserve the reproductive capacities of young cancer patients. First, they are involved in developing and using procedures to preserve gametes, embryos, and gonadal tissue before treatment. Second, fertility specialists will assist cancer survivors in using preserved gametes and tissue or in providing other assistance in reproduction.

Having just been diagnosed with cancer or surviving the acute or extended phase of coping with cancer distinguishes the cancer patient from other fertility patients. Variations in type of cancer, time available until the onset of treatment, age, partner status, type and dosage of any chemotherapy and radiotherapy, and the risk of sterility with a given treatment regimen require that each case has its own treatment strategy. Consultation with the patient's oncologist is essential. A key issue at the time of treatment of the cancer is whether it is medically feasible to obtain gametes or gonadal tissue for storage and later use. Questions about the patient's health and prognosis also will arise when the patient is deciding later whether to reproduce. When a partner exists, he or she may be included in the discussion, but it is also advisable to discuss these issues with the patient individually.


PRESERVING GONADAL TISSUE, GAMETES, AND EMBRYOS: SAFETY AND EFFICACY OF PROCEDURES

The main role of fertility specialists with cancer patients is counseling and providing preservation of gametes, embryos, or gonadal tissue for use at a future time. The only established clinical option for preservation of male fertility is cryopreservation of spermatozoa obtained either via ejaculation or surgical sperm retrieval. The feasibility depends upon the sexual maturity of the patient. When it is not possible to obtain an ejaculate, sperm can be retrieved by epididymal aspiration or testicular biopsy in sexually mature men. Not infrequently, sperm produced by cancer patients at the time of diagnosis are of poor quality. With advances in assisted reproduction techniques, in particular intracytoplasmic sperm injection (ICSI), freezing of even one ejaculate before starting cancer treatment provides a plausible chance of having a biological child.

In most instances, preservation of sperm obtained by masturbation poses no particular ethical problem, but may not be allowed in some religious or cultural settings. Where ejaculation is not possible, questions also will arise about the permissibility and circumstances under which electroejaculation, testicular biopsy, testicular sperm extraction, or epididymal sperm aspiration may be appropriate.

Preserving ovarian function when chemotherapy or radiation to the ovaries cannot be avoided is more problematic. The most established strategy for preservation of female fertility is for a woman to undergo a cycle of in vitro fertilization (IVF) and create embryos for later use. This option is available only if there is time before treatment to undergo a cycle of stimulation to obtain oocytes and a safe method of ovarian stimulation exists. Willingness of spouse, partner, or patient to use donor sperm for this purpose also is necessary. When embryo cryopreservation is not feasible or desired, women who have the time and ability to undergo a stimulation cycle should be offered oocyte cryopreservation. Freezing ovarian tissue for later retransplantation or in vitro maturation of oocytes may still be offered with appropriate institutional review board (IRB) oversight when other more established options are not feasible.


Oocyte Cryopreservation

The option for postpubertal females who lack a male partner, do not wish to use donor sperm, or object to embryo cryopreservation is to undergo ovarian stimulation and oocyte retrieval to obtain oocytes that can be cryopreserved and warmed at a later time when the patient is ready to have offspring. Women with a partner also may wish to cryopreserve all or a portion of their oocytes unfertilized in the event that their current relationship dissolves. Oocyte cryopreservation, once deemed experimental due to the technical challenges associated with the size and structural complexity of oocytes, has now seen higher success in many programs as evidenced by recent literature. With the use of cryoprotectants and cryotools in combination with rapid cryopreservation techniques (vitrification) and fertilization with ICSI, multiple clinics have reported increasing pregnancy rates using cryopreserved and warmed oocytes (21, 22), including women who have had gonadotoxic therapy (23). In presenting the option of oocyte cryopreservation, the physician should clearly explain their practice's own experience with oocyte cryopreservation, including pregnancy rates.

The Italian registry of assisted reproductive technology (ART) is the most comprehensive assessment of children born from oocyte cryopreservation to date and shows no apparent increase in congenital anomalies in 2152 live births (24). The Practice Committee of the American Society for Reproductive Medicine, after reviewing available evidence, concluded that oocyte cryopreservation may be a viable alternative for those women with high potential for ovarian failure for whom embryo cryopreservation is not an option (25).


Ovarian Tissue Cryopreservation

At present, women who cannot delay treatment and undergo ovarian stimulation to create embryos or obtain oocytes for cryopreservation have limited options to preserve their fertility. Protocols do exist, however, for removing and cryopreserving ovarian cortical tissue; the ASRM Practice Committee considers this an experimental procedure. It is anticipated that ovarian tissue will be thawed and implanted after cancer treatment or that techniques for maturing oocytes in vitro will be developed in the future. Although ovarian tissue cryopreservation is still experimental, the technique is promising as a fertility-preservation option and there have been over 87 live births reported from cryopreserved ovarian tissue (16). Major problems include ischemic damage to the tissue pending transplant and revascularization and the theoretical possibility of reintroducing malignant tumor cells. If these and other problems are overcome, this technique may be used without delaying treatment or using hormones to stimulate the ovaries in patients healthy enough to undergo a laparoscopic ovarian biopsy or oophorectomy. Given the experimental state of this procedure, it should be offered only as part of an IRB-approved research protocol, with full disclosure of risks and uncertainty of benefits to the patient.


Issues in Minors with Cancer

The question of preserving fertility also will arise with minor patients, many of whom will not be competent to consent to such efforts. Ethical and legal norms require that procedures done on minors serve their best interests. If invasive procedures are necessary, minors who are able to understand the choice presented must give their assent (permission that is less than full consent). Accepted methods of preserving gonadal material for minors should be offered to parents in the informed consent process and also in accord with the American Academy of Pediatrics' statement on pediatric assent, according to which children should be involved in a developmentally appropriate manner in health-care decisions (26, 27). Investigational methods should be offered to parents only under an IRB-approved protocol.

Postpubertal males ordinarily will be capable of ejaculation and can provide sperm for storage. Care and tact should be taken in discussing this option with them, including discussions outside of the presence of their parents. If the children cannot ejaculate or are too young, then an epididymal sperm aspiration and testicular sperm extraction can be done with their assent and parental consent, as long as this is recognized as a safe and effective way of maintaining male fertility. At some point, testicular tissue cryopreservation in prepubertal males also may be feasible. Testicular tissue cryopreservation in prepubescent males is considered experimental and only should be performed under the auspices of IRB or surgical innovation committee oversight.

With females, the question of fertility preservation could arise first with postpubertal minors who would be capable of assent or objection. If a stimulation cycle may occur safely, they could assent to oocyte retrieval and cryopreservation to provide oocytes for storage. If ovarian tissue cryopreservation also becomes feasible, they could assent to laparoscopy to obtain ovarian tissue. If minors object to any of these alternatives, the procedures should not be done, despite parental wishes.

If ovarian tissue cryopreservation is shown to be safe and effective, efforts to preserve the fertility of prepubertal females also may be possible. As with older females, both parental consent and the child's assent to ovarian tissue cryopreservation procedures would be necessary. If the child is too young to give assent, parents may consent to removal of ovarian sections if the procedure is deemed to offer a potential benefit to the child. Although persons might differ on this question, reasonable persons could find that the parents' choice to preserve the child's fertility in this way is a reasonable one in light of the relatively limited intrusion (laparoscopic ovarian biopsy) that would be necessary.


Use of Experimental Procedures in Minors

The same requirements of minor assent, parental consent, and net benefit would apply to use of these procedures by minor children when the procedures are still experimental (28). Because their experimental use is beneficial for the minor patient, it might be done with his/her assent if developmentally appropriate or with the consent of the parents, only if an IRB finds that the expected benefits of future reproduction to the child outweigh the burdens of the procedure for obtaining gametes or gonadal tissue. If the child is postpubertal and there is time, then a controlled ovarian stimulation cycle could occur. If there is not time or the patient has not entered puberty, experimental ovarian cryopreservation might be offered as part of an IRB-approved protocol for preserving the fertility of younger female cancer patients with the assent of the patient and parental consent.


DIRECTIONS FOR DISPOSITION OF STORED GAMETES, EMBRYOS, AND GONADAL TISSUE

Persons whose gametes, embryos, or tissue are stored to preserve fertility or their legal guardians should give directions for disposition of that tissue in the future. This might be done best when the gametes, embryos, or gonadal tissue are removed or preserved, but directions can be given or amended at any later time that the patient wishes. For minors, directions should be updated by the gamete provider when they reach the age of majority.

As with directions for storing embryos, the patient should specify what should be done with stored gametes, embryos, or gonadal tissue if he/she dies or otherwise is unavailable; does not pay storage fees; or has abandoned the gametes, embryos, or gonadal tissue. Also important is that patients specify in writing in advance that they want those materials discarded or used in research, or whether they consent to use of them for posthumous reproduction and by whom. For minors, unless written instructions provide otherwise, gametes should be discarded if the minor does not survive to adulthood.


ASSISTING CANCER SURVIVORS TO REPRODUCE

Persons of reproductive age who survive cancer may seek to reproduce. Discussions about fertility should be incorporated into survivorship programs. If girls or women were not able to cryopreserve oocytes before treatment, they may consider doing this post-treatment if possible. Patients who have retained reproductive function may be able to conceive coitally. If they have diminished reproductive function, they may seek the help of fertility specialists. In some cases, they can make use of previously stored gametes, embryos, or gonadal tissue for that purpose. Other options that may be appropriate include donor gametes, donor embryos, gestational surrogacy, and adoption.

Apart from the risks posed by fertility treatment, physicians may be concerned about the risks posed by pregnancy on cancer recurrence. It is generally recommended that pregnancy be delayed until cancer treatment is concluded because of concerns over the impact of treatment on the fetus. The optimal timing of conception after cancer treatment may be uncertain for some patients.

Reproductive physicians treating cancer survivors should be cognizant of the patient's medical status, treatment plan, prognosis, and potential harmful effects of the therapy. Such effects may occur because of theoretic mutagenic effects secondary to previous cancer treatment, the reproductive techniques themselves, or the risk of heritable disease. They also may arise from psychosocial factors, such as the prospect of recurrence of cancer and a reduced lifespan or the posthumous use of gametes. Physicians alsomust disclose fully the accepted or experimental status of any procedures offered, as will be the case when cryopreserved ovarian tissue is used to reproduce.


Risks to Offspring from Reproduction

Providing medical assistance to cancer survivorsmay on occasion raise ethical issues about the impact of their reproduction on future children. One set of issues concerns whether resulting offspring are at a higher risk for congenital anomalies, chromosomal defects, or cancer because of previous treatment or the effects of the assisted reproductive technologies.

Studies that have examined pregnancy outcomes in cancer survivors have found no statistically significant increase in congenital malformations or malignant neoplasms in the resulting offspring (29). These studies, however, primarily evaluated women who conceived spontaneously many years after chemotherapy treatment. Patients should be counseled about the current state of knowledge about the risks of assisted reproductive techniques to the health of offspring.


Posthumous Use of Stored Reproductive Tissue

In some cases, persons who have stored gametes, embryos, or gonadal tissue will die before they have had an opportunity to use them. Patients, surviving spouses, or family might want to have the gametes or tissue used for reproduction, for donation to others, or for research. If this occurs, it could lead to the deceased person reproducing after death with his or her partner at the time of storage or with other recipients of their donated gametes or embryos.

A relevant question is whether the deceased had consented to posthumous use of his or her stored tissue or gametes in a consent form, advance directive, or another reliable indicator of consent before death. The legal system has recognized that the person's prior wishes about disposition of reproductive material is controlling after death. Instructions that all such material shall be destroyed or not used after death should be honored. Similarly, the law permits gametes and embryos to be used after death if the person has given such directions or if the partner or next of kin has dispositional control of them. Courts have also accepted that children born after posthumous conception or implantation are the legal offspring of the deceased if he or she gave instructions that gametes or embryos may be used after his or her death for reproduction (30, 31).

Until there is more experience with posthumous reproduction, a policy of allowing posthumous reproduction only when the deceased has specifically provided an advance directive and the surviving spouse or other designee agrees is a sound one (32). As a result, it is essential that programs storing gametes, embryos, or gonadal tissue for cancer patients inform patients of the options for disposition of those materials at a future time when the depositor is, due to death, incompetency, or unavailability, unable to consent
themselves to disposition. Whether offspring conceived or implanted posthumously will be recognized under the deceased's will or state inheritance laws will depend on the law of the state in which these events occur. Since legal decisions related to posthumous use of stored tissue or gametes may vary between jurisdictions, patients interested in pursuing this option should be advised to consult with knowledgeable legal counsel.


RISK OF POTENTIAL CANCER IN OFFSPRING

As previously noted, there do not appear to be major mutagenic effects in offspring born to patients successfully treated for cancer (29, 33). However, an additional concern can arise in patients with cancer-predisposing germline mutations. Some persons with heritable cancers want to reproduce only if they have reasonable assurance that their child would not have a high risk for their cancer and the burdens entailed in that risk.

Techniques for prenatal diagnosis and PGT provide a way for parents with heritable cancers to prevent transmission of that risk to offspring. Patients intent on minimizing the risk of transmitting cancer genes to offspring may be reluctant to use prenatal diagnosis and termination of pregnancy but would accept PGT for that purpose.

PGT is generally accepted to reduce the risk of the birth of a child with autosomal or X-linked diseases, such as cystic fibrosis, Tay-Sachs disease, sickle cell anemia, and fragile X syndrome. Unlike the early onset of these conditions, the risk of inheriting cancer might not eventuate until much later in the life of the child, and the gene for the disease may not be fully penetrant. While some persons would argue that the time of onset of disease or variation in risk for inherited cancer has enough ethical weight to justify treating those cases differently, this Committee believes that when the genetic risks are substantial and preimplantation tests for them exist, couples may ethically choose to test embryos to avoid having children with a high risk of those cancers (34).


CONCLUSIONS

Patients facing gonadotoxic treatments have important needs in preserving and exercising fertility that cancer and fertility specialists should try to protect. Oncologists should be encouraged to refer patients to a reproductive endocrinologist early in the planning of treatment. When damage to reproductive organs due to gonadotoxic treatment is unavoidable, health-care providers should inform patients of options for storing gametes, embryos, or gonadal tissue and refer them to fertility specialists who can provide or counsel them about those services. Counseling by a qualified mental-health professional and genetic counselor, when appropriate, also should be offered.

Fertility programs should counsel patients and survivors on the risks of gonadotoxic treatment on fertility and the options for and risks of preserving fertility and reproducing afterward. Fertility-preservation procedures that have not been shown to be safe and effective should be offered to patients only in an experimental setting under IRB oversight. Parents may act to preserve reproductive options of minor children undergoing gonadotoxic treatment as long as they seek the assent of a child able to provide it, the intervention does not pose undue risk, and the intervention offers a reasonable chance of net benefit to the child.

Concerns about the welfare of resulting offspring, whether due to an expected shortened lifespan of the parent or effects of cancer or infertility treatment (in the present state of knowledge) ordinarily are not a sufficient reason to deny cancer patients assistance in reproducing. Programs storing gametes, embryos, or gonadal tissue for cancer patients should request clear instructions about what should be done with stored materials in the event of the patient's death, unavailability, nonpayment of storage fees, or other contingency. Spouses or family members with legal rights to dispose of a deceased patient's stored gametes or other material should use them for posthumous reproduction only if the deceased had previously consented to such posthumous use.

Physicians should assess the likely impact on offspring of cancer treatments and fertility preservation and assisted reproduction procedures and inform patients accordingly. PGT to reduce the birth of offspring with a high risk of inherited cancer is ethically acceptable.


Acknowledgments:

This report was developed by the Ethics Committee of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. While this document reflects the views of members of that Committee, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment in all cases. This report was approved by the Ethics Committee of the American Society for Reproductive Medicine and the Board of Directors of the American Society for Reproductive Medicine.

This document was reviewed by ASRM members and their input was considered in the preparation of the final document. The following members of the ASRM Ethics Committee participated in the development of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest based on the relationships disclosed did not participate in the discussion or development of this document.

Judith Daar, J.D.; Jean Benward, M.S.W.; Lee Collins, J.D.; Joseph Davis, D.O.; Leslie Francis, Ph.D., J.D.; Elena Gates, M.D.; Elizabeth Ginsburg, M.D.; Susan Gitlin, Ph.D.; Sigal Klipstein, M.D.; Barbara Koenig, Ph.D.; Andrew La Barbera, Ph.D., H.C.L.D.; Laurence McCullough, Ph.D.; Richard Paulson, M.D.; Richard Reindollar, M.D.; Ginny Ryan, M.D.; Mark Sauer, M.D.; Rebecca Sokol, M.D., M.P.H.; Sean Tipton, M.A.; Lynn Westphal, M.D.; Julianne Zweifel, Ph.D.

REFERENCES

  1. Robertson JA. Cancer and fertility: ethical and legal challenges. J Natl Cancer Inst Monogr 2005;34:104–5.
  2. Surveillance, Epidemiology, and End Results Program. Cancer statistics and review 1975–2013. Available at: http://www.seer.cancer.gov; 2016.
  3. Faure A, Bouty A, O'Brien M, Throup J, Hutson J, Heloury Y. Testicular biopsy in prepubertal boys: a worthwhile minor surgical procedure? Nat Rev Urol 2016;13:141–50.
  4. Thomson AB, Critchley HO, Kelnar CJ, Wallace WH. Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Pract Res Clin Endocrinol Metab 2002;16:311–34.
  5. Critchley HO, Bath LE, Wallace WH. Radiation damage to the uterus— review of the effects of treatment of childhood cancer. Hum Fertil (Camb) 2002;5:61–6.
  6. Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009;30:465–93.
  7. Visser JA, de Jong FH, Laven JS, Themmen AP. Anti-Mullerian hormone: a new marker for ovarian function. Reproduction 2006;131:1–9.
  8. HI S. Measuring ovarian function in young cancer survivors. Minerva Endocrinol 2010;35:259–70.
  9. Plante M. Fertility preservation in the management of gynecologic cancers. Curr Opin Oncol 2000;12:497–507.
  10. Tulandi T, Al-Shahrani AA. Laparoscopic fertility preservation. Obstet Gynecol Clin North Am 2004;31:611–8.
  11. Blumenfeld Z. Gynaecologic concerns for young women exposed to gonadotoxic chemotherapy. Curr Opin Obstet Gynecol 2003;15:359–70.
  12. Oktay K, Sonmezer M. Gonadotropin-releasing hormone analogs in fertility preservation-lack of biological basis? Nat Clin Pract Endocrinol Metab 2008;4:488–9.
  13. Demeestrereor I, Brice P, Peccatori FA, Knetos A, Dupuis J, et al. No evidence for the benefit of gonadotropin-releasing hormone agonists in preserving ovarian function and fertility in lymphoma survivors treatmed with chemotherapy: final long-term report of a prospective randomized trial. J Clinic Oncol 2016;34:2568–74.
  14. Lambertini M, CeppiM, Pogio F, Peccatorini FA, Asim HA, et al. Ovarian suppression using luteinizing hormone-releasing hormone agonist during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies. Ann Oncol 2015;26:2408–19.
  15. National Comprehensive Cancer Network. National Comprehensive Cancer Network (NCCN) Guidelines. Available at: https://www.nccn.org/ professionals/physician_gls/default.aspx. Last accessed July 30, 2018.
  16. Gellert SE, Pors SE, Kristensen SG, Bay-Bjørn AM, Ernst E, Yding Andersen C. Transplantation of frozen-thawed ovarian tissue: an update on worldwide activity published in peer-reviewed papers and on the Danish cohort. J Assist Reprod Genet 2018;35:561–70.
  17. Schover LR, Brey K, Lichtin A, Lipshultz LI, Jeha S. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol 2002;20:1880–9.
  18. Centers for Disease Control. A national action plan for cancer survivorship: advancing public health strategies. Available at: http://www.cdc.gov/cancer/survivorship/what_cdc_is_doing/action_plan.htm. Accessed August 30, 2013.
  19. Grover NS, Deal AM, Wood WA, Mersereau JE. Young men with cancer experience low referral rates for fertility counseling and sperm banking. J Oncol Practice 2016;12:465–71.
  20. Quinn GP, Vadaparampil ST, Lee JH, Jacobsen PB, Bepler G, Lancaster J, et al. Physician referral for fertility preservation in oncology patients: a national study of practice behaviors. J Clin Oncol 2009;10:5952–7.
  21. Cobo A, Garcia-Velasco JA, Coello A, Domingo J, Pellicer A, Remohí J. Oocyte vitrification as an efficient option for elective fertility preservation. Fertil Steril 2016;105:755–64.
  22. Doyle JO, Richter KS, Lim J, Stillman RJ, Graham JR, Tucker MJ. Successful elective and medically indicated oocyte vitrification and warming for autologous in vitro fertilization, with predicted birth probabilities for fertility preservation according to number of cryopreserved oocytes and age at retrieval. Fertil Steril 2016;105:459–66.
  23. Druckenmiller A, Goldman KN, Labella PA, Fino ME, Bazzocchi A, Noyes N. Successful oocyte cryopreservation in reproductive-aged cancer survivors. Obstet Gynecol 2016;127:474–80.
  24. Levi-Setti PE, Borini A, Patrizio P, Bolli S, Vigilian V, De Luca R, Scaravelli G. ART results from frozen oocytes: data from the Italian ART registry (2005-2013). J Assist Reprod Genet 2016;33:123–8.
  25. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril 2013;99:37–43.
  26. Fallat ME, Hutter J, American Academy of Pediatrics Committee on Bioethics; American Academy of Pediatrics Section on Hematology/ Oncology; American Academy of Pediatrics Section on Surgery. Preservation of fertility in pediatric and adolescent patients with cancer. Pediatrics 2008;121:e1461–9.
  27. Bartholome WG. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995;96(5 Pt 1):981–2.
  28. Code of Federal Regulations, 2004. 45 CFR 46.401-408.
  29. Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstet Gynecol 2010;116:1171–83.
  30. Woodward v Commissioner of Social Security, 435 Mass. 536, 537–538, 760 N.E. 2d 257 (Mass Super Ct 2001).
  31. Gillett-Netting v Barnhart, 371 F.3d 593,599 (9th Cir 2004).
  32. Ethics Committee of the American Society for Reproductive Medicine. Posthumous collection and use of reproductive tissue: a committee opinion. Fertil Steril 2013;99:1842–5.
  33. Signorello LB, Mulvihill JJ, Green DM, Munro HM, Stovall M, Weathers RE. Congenital anomalies in the children of cancer survivors: a report from the childhood cancer survivor study. J Clin Oncol 2012;30:239–45.
  34. Ethics Committee of the American Society for Reproductive Medicine. Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion. Fertil Steril 2013;100:54–7.

Topic Resources

View more on the topic of fertility preservation
Document Icon

Planned oocyte cryopreservation to preserve future reproductive potential: an Ethics Committee opinion (2023)

Planned oocyte cryopreservation is an ethically permissible procedure that may help individuals avoid future infertility. View the Committee Opinion
Coding Icon

Z Codes Vs. Procedure Codes For Fertility Preservation Counseling

I am trying to understand better when to use the procreative management code vs the fertility preservation counseling and procedure codes. View the Answer
Coding Icon

Elective fertility preservation is ART

From an insurance standpoint, is fertility preservation is considered an assisted reproductive technology or would it be branched under other?  View the Answer
Coding Icon

Oocyte Preservation Consult

Our center performs oocyte preservation procedures for women looking to preserve their fertility. View the Answer
Coding Icon

Fertility Preservation Consult

What code are we supposed to use for counseling regarding fertility preservation for an individual with cancer... View the Answer
Coding Icon

Cycle Monitoring Fertility Preservation

If the patient is undergoing ultrasound tracking visits for fertility preservation, what I ICD-10 code do you use for the monitoring? View the Answer
Coding Icon

Coding For Ovarian Tissue Cryopreservation

Now that ASRM has removed the "experimental" designation from ovarian tissue cryopreservation what CPT code should be used instead of 0058T? View the Answer
Coding Icon

Fertility Preservation

A summary of codes for Fertility Preservation compiled by the ASRM Coding Committee. View the Coding Summary
Document Icon

Access to fertility services by transgender and nonbinary persons: an Ethics Committee opinion (2021)

The provision of fertility services to transgender individuals and the denial of access to fertility services is not justified. View the Committee Opinion
Document Icon

Reproductive and hormonal considerations in women at increased risk for hereditary gynecologic cancers: Society of Gynecologic Oncology and American Society for Reproductive Medicine Evidence-Based Review (2019)

Providers who care for women at risk for hereditary gynecologic cancers must consider the impact of these conditions. View the Joint Statement
Document Icon

Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion (2019)

Patients preparing to undergo gonadotoxic medical therapy, radiation therapy, or gonadectomy should be provided with prompt counseling regarding available options for fertility preservation for iatrogenic infertility. View the Committee Opinion
Membership Icon

Fertility Preservation Special Interest Group (FPSIG)

The FPSIG promotes knowledge on infertility induced by cancer therapy and other medical treatments. Learn more about FPSIG

Topic Resources

View more on the topic of cryopreservation
Document Icon

Planned oocyte cryopreservation to preserve future reproductive potential: an Ethics Committee opinion (2023)

Planned oocyte cryopreservation is an ethically permissible procedure that may help individuals avoid future infertility. View the Committee Opinion
Coding Icon

Coding for ovarian tissue cryopreservation

For Cryopreservation; Reproductive Tissue Ovarian- 0058T code is not being recognized. Is there an updated one being used or a replacement of this code? View the Answer
Coding Icon

Billing for cryopreservation procedures on different days

I understand that if cryopreservation of oocytes is performed on two separate dates of service, each date of service was billable. View the Answer
Coding Icon

Reimbursement for cost of donor egg

My wife and I are going through a fertility treatment process, and we have purchased a donor egg out-of-pocket from a donor bank.  View the Answer
Coding Icon

Coding for Ovarian tissue cryopreservation, experimental or not?

For Cryopreservation; Reproductive Tissue Ovarian- 0058T code is not being recognized. Is there an updated one being used or a replacement of this code? View the Answer
Coding Icon

Does the number of eggs being frozen matter?

There is currently only one CPT code for the cryopreservation of mature oocytes and embryos.  View the Answer
Coding Icon

Semen Freezing

We have a couple who are doing an IUI cycle. View the Answer
Coding Icon

Sperm Prep in Office vs. Lab

What are the codes for sperm washing when performed in the office vs in a CLIA certified lab? View the Answer
Coding Icon

Sperm Preparation IUI and IVF

What semen analysis codes apply to sperm preparation for IUI or IVF? View the Answer
Coding Icon

Reproductive Tissue Storage

What are the CPT codes for the Storage of Reproductive Cells/Tissues? View the Answer
Coding Icon

Office Testicular Aspiration

We are inquiring about a coding question for testicular aspirations.  View the Answer
Coding Icon

IVF Case Rates

What ICD-10 codes apply to case rates? View the Answer
Coding Icon

Oocyte Preservation Consult

Our center performs oocyte preservation procedures for women looking to preserve their fertility. View the Answer
Coding Icon

In Vitro Maturation

Have CPT codes been established for maturation in vitro? View the Answer
Coding Icon

Embryo Storage Fees For Multiple Cycles

We bill embryo storage 89342 for a year's storage.  View the Answer
Coding Icon

Embryo Freezing/Thawing

Our question refers to the CPT code 89258 “Cryopreservation; Embryo(s)” and 89352 “Thawing of Cryopreserved; Embryo”.  View the Answer
Coding Icon

Frozen Embryo Transport

What is the code for the cost of frozen embryo transport? View the Answer
Coding Icon

Gamete Thawing/Warming

Can patients be charged for each vial/straw of reproductive gametes or tissues thawed? View the Answer
Coding Icon

Billing For Cryopreservation Of Embryos Under The Male Partner

Can 89258 be billed under the male partner of a female patient? View the Answer
Coding Icon

Coding For Long-Term Storage Of Embryos

We have recently been contacted by a payer stating we have a patient whose plan will cover long-term storage of her embryos. View the Answer
Coding Icon

Coding For Ovarian Tissue Cryopreservation

Now that ASRM has removed the "experimental" designation from ovarian tissue cryopreservation what CPT code should be used instead of 0058T? View the Answer
Coding Icon

Cryopreservation/Vitrification Oocytes/Embryos

What are the correct codes for cryopreservation/Vitrification Oocytes/Embryos? View the Answer
Coding Icon

Cryopreservation/Vitrification Sperm/Testicular Tissues

What are the correct codes for the Cryopreservation/Vitrification of Sperm or testicular tissues? View the Answer
Videos Icon

Journal Club Global: Should everyone freeze oocytes by age 33?

Oocyte cryopreservation is one of the fastest growing areas of reproductive medicine. View the Video
Document Icon

Ethical issues in oocyte banking for nonautologous use: an Ethics Committee opinion (2021)

Medical guidelines applicable to women donating fresh oocytes should also apply to women donating oocytes to an oocyte bank. View the Committee Opinion
Document Icon

Evidence-based outcomes after oocyte cryopreservation for donor oocyte in vitro fertilization and planned oocyte cryopreservation: a guideline (2021)

A review of success rates, factors that may impact success rates, and  outcomes. View the Committee Opinion
Document Icon

Development of an emergency plan for in vitro fertilization programs: a committee opinion (2021)

All IVF programs and clinics should have a plan to protect fresh and cryopreserved human specimens (embryos, oocytes, sperm). View the Committee Opinion
Document Icon

Cryostorage of reproductive tissues in the in vitro fertilization laboratory: a committee opinion (2020)

This document is designed to assist IVF clinics in the management of cryopreserved reproductive tissues stored in cryogenic storage. View the Committee Opinion
Document Icon

Best practices of ASRM and ESHRE: a journey through reproductive medicine (2012)

ASRM and ESHRE are the two largest societies in the world whose members comprise the major experts and professionals working in reproductive medicine. View the Committee Joint Guideline

Topic Resources

View more on the topic of cancer and fertility
Coding Icon

Medication Administration

 Is CPT code 96402 applicable to a Depo-Lupron or Zoladex injection by nurse at REI practice, even if there is no diagnosis of cancer?  View the Answer
Coding Icon

Fertility Preservation Consult

What code are we supposed to use for counseling regarding fertility preservation for an individual with cancer... View the Answer
Coding Icon

D&C Under Ultrasound Guidance

What are the CPT codes and ICD-10 codes for coding a surgical case for a patient with history of Stage B adenocarcinoma of the cervix ... View the Answer
Coding Icon

Cycle Monitoring Fertility Preservation

If the patient is undergoing ultrasound tracking visits for fertility preservation, what I ICD-10 code do you use for the monitoring? View the Answer
Document Icon

Reproductive and hormonal considerations in women at increased risk for hereditary gynecologic cancers: Society of Gynecologic Oncology and American Society for Reproductive Medicine Evidence-Based Review (2019)

Providers who care for women at risk for hereditary gynecologic cancers must consider the impact of these conditions. View the Joint Statement
Document Icon

Best practices of ASRM and ESHRE: a journey through reproductive medicine (2012)

ASRM and ESHRE are the two largest societies in the world whose members comprise the major experts and professionals working in reproductive medicine. View the Committee Joint Guideline

Ethics Opinions

Ethics Committee Reports are drafted by the members of the ASRM Ethics Committee on the tough ethical dilemmas of reproductive medicine.
Ethics Committee teaser

Planned oocyte cryopreservation to preserve future reproductive potential: an Ethics Committee opinion (2023)

Planned oocyte cryopreservation is an ethically permissible procedure that may help individuals avoid future infertility.
Ethics Committee teaser

Ethical obligations in fertility treatment when intimate partners withhold information from each other: an Ethics Committee opinion (2024)

Clinicians should encourage disclosure between intimate partners but should maintain confidentiality where there is no harm to the partner and/or offspring.
Ethics Committee teaser

Ethical considerations for telemedical delivery of fertility care: an Ethics Committee opinion (2024)

Telemedicine has the potential to increase access to and decrease the cost of care.
Ethics Committee teaser

Misconduct in third-party assisted reproductive technology by participants and nonmedical professionals or entities: an Ethics Committee opinion (2023)

In some instances, it is ethically permissible for the physician to either disclose material information to the affected party or to decline to provide or continue to provide care.

More Resources

MAC 2021 teaser
ASRM Academy on the Go

ASRM MAC Tool 2021

The ASRM Müllerian Anomaly Classification 2021 (MAC2021) includes cervical and vaginal anomalies and standardize terminology within an interactive tool format.

View the MAC Tool
EMR Phrases teaser
Practice Guidance

EMR Shared Phrases/Template Library

This resource includes phrases shared by ASRM physician members to provide a template for individuals to create their own EMR phrases.

View the library
Practice Committee Documents teaser

ASRM Practice Documents

These guidelines have been developed by the ASRM Practice Committee to assist physicians with clinical decisions regarding the care of their patients.

View ASRM Practice Documents
Ethics Committee teaser

ASRM Ethics Opinions

Ethics Committee Reports are drafted by the members of the ASRM Ethics Committee on the tough ethical dilemmas of reproductive medicine.

View ASRM Ethics Opinions
Coding Corner general teaser
Practice Guidance

Coding Corner Q & A

The Coding Corner Q & A is a list of previously submitted and answered questions from ASRM members about coding. Answers are available to ASRM Members only.

View the Q & A
Covid-19 teaser
Practice Guidance

COVID-19 Resources

A compendium of ASRM resources concerning the Novel Corona virus (SARS-COV-2) and COVID-19.

View the resources
Couple looking at laptop for online patient education materials

Patient Resources

ReproductiveFacts.org provides a wide range of information related to reproductive health and infertility through patient education fact sheets, infographics, videos, and other resources.

View Website