One of the consequences of cancer therapies, including radiation and chemotherapy, is gonadotoxicity. As effective treatments have rendered a number of malignancies curable, or have delivered long-term survival, post-treatment fertility has emerged as an important consideration for patients and their healthcare providers. Unfortunately, there are currently no definitive ways to limit the injurious effects of these treatments on gonadal function, other than shielding the gonads from direct exposure to ionizing radiation. Suppression of gonadotropin secretion may have a protective effect in some populations and with certain treatment regimens (e.g., alkylating agents), but the general efficacy of this intervention for preserving fertility remains uncertain.
Fertility preservation is a new subfield of reproductive medicine aimed at preserving the potential for genetic parenthood in adults or children at risk of sterility before undergoing anticancer treatments. Modern and powerful chemo- and radiotherapy protocols are either curing or significantly extending the survival for many young patients with cancer. Five-year survival rates for Caucasian and Hispanic American women have increased for Hodgkin’s lymphoma from 86 to 98% in the quarter century before the year 2000 and for breast cancer from 78 to 91% . At the same time, diagnoses of some malignant diseases have become more prevalent (e.g., breast and testicular cancer) . The net effect has been an increase in patients of reproductive age (and pre pubertal) at risk of sterilization or early menopause by the effects of ionizing radiation or alkylating agents such as cyclophosphamide and platinum-based drugs .
As a result of this progress, quality of life issues after cancer are emerging. Included in this quality of life rubric is the possibility of protecting fertility from the toxicity of these efficacious but noxious treatments. Many strategies have been devised to pursue fertility preservation (Table 38.1) . Embryo and oocyte freezing are well established but are not always applicable options; for example, women requiring immediate treatment or for young pre pubertal girls. Other techniques like ovarian tissue or whole ovary freezing are still considered experimental and require research approvals (IRB) and specific consents. For men the option of semen cryopreservation before chemo/radiotherapy is well established, while testicular tissue freezing or spermatogonial harvesting and freezing for later use with transplantation or with xenografting or in vitro spermatogenesis, are highly experimental.
Both therapeutic and experimental techniques require an informed consent. In presenting the option of therapies, women and men have the right to know their options concerning fertility preservation and the risks and costs involved. Consent to therapy may require involving a surrogate decision-maker in the case of young children or mentally impaired persons. Providing thorough informed consent in recruiting persons to participate in research is the foundation of the ethical conduct of research. It is based on three components: adequate, comprehensible information; a competent decision-maker; and a voluntary decision process. Research should also be reviewed and approved by Institutional Review Boards. Patients have the right to know what will happen if they or any children that are created are injured or disabled in terms of health insurance and compensation. Unfortunately, much of the existing literature on informed consent using reproductive technology has focused on information disclosure with an eye toward minimizing professional liability. Those involved in using experimental techniques must focus not simply on disclosure but on comprehension. The use of quizzes and documenting responses to questions after are effective tools to assist in documenting that patients understand the experimental or innovative nature of some modes of fertility preservation.
From an ethical viewpoint, a key reason for pursuing fertility protection is to restore personal autonomy to those who may lose ability to conceive . However, many of the technologies are innovative and experimental, making it difficult to design clinical trials on how to provide a proper informed consent and insure respect for autonomy. Who to include or exclude in trials of innovative techniques and how best to recruit them? The presentation of risk information is complicated by the fact that both the adult and their offspring may be involved. A core principle of medical ethics is to do no harm. If ovarian tissue or testicular tissue cryopreservation is to be tested, then the level of risk that can be tolerated should require essential careful animal studies and close oversight of research by review committees. It is reasonable in the absence of grant funds to seek reimbursement from patients to cover the expenses of the research, but there should be no charge for clinical fees until the experimental options have been proved safe and effective.
Ideally the decision about who is candidate for fertility preservation should be provided by a team including a medical oncologist, reproductive endocrinologist, a pathologist and a psychologist, all guided by written protocols which can be shared with patients . Patients should not be given false or exaggerated hopes, and alternative plans including no intervention with the prospect of adoption or childlessness should also be part of the discussion. Equity or ownership interests in novel technologies utilized in research must be disclosed to potential subjects.
Impaired future fertility after exposure to cancer therapies must be considered even for children.
This risk however, may be difficult for children to conceptualize, but potentially traumatic to them as adults. Unfortunately, the modalities that are available to children to preserve their fertility are limited by their sexual immaturity and are experimental.
For boys who cannot produce mature sperm, harvesting and cryopreservation of testicular tissue or stem cells (spermatogonia) with the hope of future autologous transplantation or in vitro maturation represents potential methods of fertility preservation. For girls, isolation and cryopreservation of ovarian cortical strips/primordial follicles followed by future retransplant or in vitro maturation of gametes when fertility is desired as a possible option. Extensive research is still required to refine these modalities in order to safely offer them to patients as therapies . Future use of Assisted Reproductive Technologies (ARTs) with gametes produced in vitro must be scrutinized based on efficacy and safety and they must be subjected to rigorous ethical deliberation by independent review committees before they can be offered. The modalities involved in fertility preservation of young children are no exception to these rules. In addition to ensuring that the basis for offering the intervention is scientifically sound, the execution of the intervention must be deemed ethically sound. This determination requires that the intervention in question be evaluated within an ethical framework that considers it in terms of beneficence, respect for persons (autonomy) and justice . It can be argued that fertility preservation aimed at children is ethical because it prevents morbidity (both reproductive and psychosocial) and it safeguards their reproductive autonomy . However, the main ethical question is the process involved in achieving fertility preservation and the techniques required. The answer is found in an exploration of the potential risks of the intervention to the patient and his or her progeny, the special situation of children as research subjects and patients, and the potential abuse of the technologies [6, 7]. Programs must make every effort to minimize financial barriers to access for children and to work with patient advocacy groups to seek coverage for children and families who cannot afford to participate in fertility treatment or research.
Children represent a unique and vulnerable population with respect to medical research. They have diminished autonomy and capacity to understand risks and benefits of research objectives and lack the ability to provide consent for research studies. As a result, they require special protection against potential violation of their rights that may occur during research investigations [5, 8]. Until very recently, institutional attitudes impeded significant participation by children in medical research for fear of exploitation . This attitude was attributed to several historical episodes of the unethical targeting of children as medical research subjects. Ethical guidelines to protect children as research subjects were outlined with the publication of the Belmont report in 1979, generated by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Children should not be exploited to participate in pediatric research, nor should they be deprived of the benefits research has to offer because of their vulnerable status. Research involved in childhood fertility preservation should be conducted on patients who could experience personal benefit from the research, eliminating the prospect of exploitation for the gain of others .
With respect to childhood fertility preservation, proper attainment of informed consent from a legally authorized representative (i.e., parent or guardian) and of childhood assent must be ensured [5, 8]. Assent – the active affirmation by the research subject – can be obtained from incompetent minors and it should be obtained from children whenever possible. While the benefits of gamete cryopreservation are promising they are largely unquantifiable because human data on the survival of gametes after the freeze-thaw-transplant process is limited. Until more data becomes available we cannot tell patients what percentage of gametes will survive and what the probability of conception is, and we must not provide them with false hope. Alternatives to gamete cryopreservation should be discussed and patients should be given the option of no intervention . Barriers to the consent process for fertility preservation interventions may develop. While parents may be competent to consent for their children, the scenario is very complex clinically and emotionally. It has been suggested that to overcome some of the practical obstacles involved in the consent process, it should be performed in stages [9, 10]. If a two-stage process is adopted, the issues of gonadal harvesting/storage and gamete manipulation can be handled as two separate topics at distinct time points. The decision to harvest gametes would be made at the time of cancer diagnosis and consent for the procedure would be left to parents/guardians. The decision of whether to use the gametes after they have been isolated can then be made at a future point by the child when they reach adulthood. At such a point in time, the young patient would be better able to express personal preferences about the handling of the tissue based on an enhanced capacity to understand the ramifications of the possible medical interventions available at that time.
Cancer survivors who did not preserve fertility and became sterile after chemo or radiotherapy may agree to the use of donor gametes (oocytes or spermatozoa). The pre-eminent ethical issues here are: (1) Should couples resorting to the use of donor gametes be obliged to disclose such use to their children once they reach the age of understanding? [11, 12]; (2) Should the utilization of donor gametes follow policies analogous to those governing disclosure to children that are adopted? ; (3) What will be the welfare of a child if he or she “finds out” that a gamete donor participated in his or her creation and this was kept as a secret? (4) Should a woman’s age and life expectancy factor into a clinic policy concerning access to services? (5) How hard should a clinic try to establish what parenting arrangements have been made in the event of the death (or cancer recurrence) of the would-be mother or father, since little is known about the capacity for post-cancer women to parent infants and toddlers?
Without clear guidelines the ethical propriety of the technologically driven options for parenting after cancer (with donor gametes), becomes a matter of the marketplace.
Mandating disclosure by a couple is problematic on a number of fronts and the claim that the practice of gamete donation is similar to adoption is not obvious . With gamete donation, one of the parents is the biological parent, while the other is the social parent; with adoption, both parents are social parents. With gamete donation the child’s mother, whether biological or not, carries the pregnancy with all the accompanying psychological interplay. In the case of a donor egg, to ask such a mother (and she is a mother under any definition of motherhood) to tell the child that technically she is not the mother because she is not genetically related may strain the bond between mother and child .
Certainly, the pre-eminent concern is the welfare of the child . However, the benefits accruing to a child from disclosure are difficult to assess and still remain open to many interpretations. In debates about child welfare with adoptions, researchers and policy makers have not yet provided a clear consensus on what is the best interest of the child . In addition to considerations of child welfare, one must address the impact on the other participants in the process, including the donor, the couple and the healthcare providers. A donor must be willing to donate his sperm or her oocytes knowing that later he or she can be identified; the couple must agree in revealing the origin of the gametes to their offspring; the providers must restrict reproductive services only to couples who agree in writing to disclosure. Without uniform requirements for the collection and maintenance of records, the usefulness of revealing information is not clear.
To force fertility specialists to participate in implementing disclosure is ethically problematic as well. Including acquiescence to disclosure as part of screening criteria or recruitment to protocols may unjustly interject social factors into criteria for program acceptance. It may also encourage desperate couples to lie if they disagree. Since relationships vary greatly with background, ethnic origin and attitudes of both the male and female partners, it would not be unreasonable for a healthcare provider to raise the issue of informing offspring of his or her genetic background at the time of the use of donor gametes is considered by a couple. To do more than to raise the issue and present known data on the potential psychological and health ramifications of disclosure and non-disclosure, could violate the privacy of the couple’s relationship and interfere with their ability to decide. Programs that use donor gametes should, however, prepare policies on how to handle in future requests of information from children of donor gametes. They may choose to disclose only non-identifying information when the requesting party has reached 18 years of age, or they may disclose more based on the particular willingness of donors to remove more of their information from anonymity . In countries where the identification of the donor is required by law, such as the Netherlands, Sweden and the United Kingdom, the pool of sperm donors has substantially decreased, and many clinics have ceased using this option. Despite this concern, legislation in the United States enacted in April 2005 imposed mandatory disclosure for donor sperm. As a result of donor’s unwillingness to be identified, there has been a marked reduction in the frequency of donor inseminations.
A BBC survey in September 2006 found that 90% of UK sperm donors were recruited in just 10 of 87 licensed clinics for donor insemination and that after the removal of donor anonymity, the cost for purchasing sperm rose very substantially; about an eightfold increase. Between 2004 and 2006 there was a 30% reduction in patients requiring donor insemination but a much larger, about 45%, reduction in the number of treatment cycles using donor sperm (www.geneticsandsociety.org/search).
Current advances in understanding the genetic mutations responsible for many cancers (examples are the BRCA 1–2, Lynch mutations), has created new indications for pre-implantation genetic diagnosis (PGD). In these cases, there are no ethical objections. The ethical ramifications of PGD are essentially related to the issue of requesting embryo biopsy for non-medical indications such as family balancing (also known as gender selection) and HLA matching (also known as designer babies). Simply stated, is it permissible to select embryos based on HLA compatibility? And if not, what are the moral justifications to deny it? Is it morally justified to create embryos and then transfer only the ones HLA matched with an existing sibling, so to design a perfect tissue-donor? The medical reasons clearly offset the moral arguments of gender selection for the prevention of gender-specific genetic disorders (e.g., Hemophilia [XLR], muscular dystrophy or incontinentia pigmenti [XLD]). But in the absence of clear medical indications like embryo screening for family balancing, the moral arguments to deny this service become stronger. Using procreation and reproductive technologies as a means to save another sibling’s life could be seen as exploitation. Creating a child (savior) whose own value and identity could later be affected by the act of being an organ donor for their sibling requires a full psychological evaluation of the requesting families and the risks of instrumentation and exploitation. Currently, only a minority of couples seems to give importance to the sex of their children and even less seems to be willing to use the service of pre-conception sex selection for non-medical reasons . It is important however to follow ethical guidelines for both HLA-matching and for gender selection requests, the fates of the non-HLA-matched embryos and of the embryos of the undesired gender.