Research in fertility preservation for children and adolescents receiving gonadotoxic chemotherapy has brought forth ethical and legal concerns that require special consideration. This article will discuss many of these issues and possible methods to safeguard the rights of these children.
Key Words
Research in fertility preservation for children and adolescents is complicated by unusual moral, ethical, and legal issues. In children who have not yet reached puberty, fertility preservation research involves cryopreservation of immature gonadal tissue and/or gametes (oocytes and spermatogonia), an experimental technology that should only be offered in the context of a research protocol. A recent review of the Fertile Hope database indicates that there are 103 centers in the United States with institutional review board-approved ovarian tissue cryopreservation protocols (
1
).Institutional review board regulations provide some degree of protection to children participating in these studies; however, these regulations are not structured to address many of the unusual circumstances of fertility preservation research. Further, precedent on the handling of these unique situations is difficult to find, and very little literature exists on the ethics and counseling of children involved in fertility preservation protocols. Although fertility preservation studies generally do not place children at great medical risks, the direct benefit to the child may be limited and thus make it difficult to justify study involvement. Religious prohibitions against the harvesting of gametes present another obstacle to participation. Although not unique to the pediatric population, decisions about the harvesting of gonadal tissue from children and adolescents ultimately falls to the parent, and we assume that the religious beliefs of the parent at the time of the harvest will reflect the beliefs of the child when he or she reaches maturity. We also assume that the parents' decision will consider the child's beliefs and not jeopardize the child's standing in their religious community. However, religious views often differ between parent and child, and may change over time, especially if the child survives a life-threatening disease such as cancer. As these decisions may have long-term implications for the child, they should be discussed before tissue harvesting. Finally, long-term disposition of the harvested tissue is a major concern with unique problems among underage children, particularly when the child does not survive into adulthood. This article will illustrate the importance of addressing these issues during the development and implementation of fertility preservation protocols, and in doing so will help identify areas of future focus for researchers, clinicians, and ethicists who deal in pediatric fertility preservation research.
What is fertility preservation?
The goal of fertility preservation research is to protect gonadal tissue from the adverse effect of chemotherapy, radiation, and other toxic exposures. In prepubertal girls, oocytes are immature and in vitro fertilization (IVF) techniques are not an option. However, ovarian tissue can be harvested, either as strips of ovarian tissue or as an entire ovary, and cryopreserved until pregnancy is desired. At the appropriate time, the tissue is surgically reimplanted with the belief that it will respond to hormones and produce mature oocytes. Because implanted ovarian tissue does not survive longer than 2 to 3 years (
2
), the tissue cannot be reimplanted until the patient desires pregnancy (3
). An alternative to tissue harvesting is the collection of immature oocytes, which are frozen and then matured at a later date in the lab using in vitro maturation. The oocytes would then be fertilized and implanted in the uterus as in any other IVF cycle. Success rates for both of these procedures are improving, but are still quite low.- Kazer R.
Ovarian tissue freezing for fertility preservation in women facing a fertility threatening medical diagnosis or treatment regimen: a study by the National Physicians Cooperative of the Oncofertility Consortium at Northwestern University.
Northwestern University, National Physicians Cooperative of the Oncofertility Consortium at Northwestern University, Division of Fertility Preservation Department of Obstetrics and Gynecology,
Evanston, IL2009
Techniques for fertility preservation in prepubertal boys are limited to tissue harvesting because semen collection is not feasible. As with ovarian tissue, testicular tissue is removed, frozen, and reimplanted at a later date, but the process is more complex in males than in females. Male tissue must not only survive the cryopreservation process, but the cellular mechanisms responsible for the generation and maturation of spermatogonia must survive cryopreservation. The use and success of these techniques in children is still being assessed (
4
).Informed consent
Until children reach their 18th birthday (or 21st birthday, depending on the state) or are declared emancipated minors, underage patients cannot legally provide informed consent; they can only assent to the procedure. Assent is an institutional review board requirement, even in young children who may be sexually naïve, and as with consent, assent is required before study participation. The consent/assent process requires that the patient is given information that a reasonable person would want to know, and in enough detail that a reasonable person would be able to understand the procedure. During assent, age-appropriate information about sexual reproduction is reviewed. This can be a major hurdle to study participation, as disclosure of this type of information may be objectionable to parents. Sensitivity to the parents' wishes is important, but disclosure is a necessary component of the assent process and cannot be circumvented. This information is best presented with a counselor, preferably a psychologist or psychiatrist with expertise in child development and who has worked with children facing life-threatening illnesses. The counselor can ensure that the information is age-appropriate and can help determine the child's level of understanding of protocol without causing undue stress to the child or parent. Having a counselor present during the consent process may reassure the parent and help limit objections about study participation.
Opponents of fertility preservation protocols have argued that these studies are ethically unsound (
5
) because they have no expectation of direct benefit to the child in the immediate future and may cause inadvertent harm. Benefits are only realized if the child survives into adulthood and chooses to reproduce. In addition, participation may inadvertently result in castration because of the loss of gonadal tissue during the harvest (6
), and may increase the possibility of early-onset gonadal failure. Although it is commonly felt that loss of a single ovary or testes has few negative effects on future fertility, evidence does exist that loss of ovarian tissue is associated with decreased ovarian reserve and an earlier age at menopause (7
). When loss of healthy gonadal tissue through surgery is compounded with loss of gonadal function because of toxic chemotherapy, the combined effect may deplete gonadal reserves enough to result in premature gonadal failure. Participants must be made aware of the possibility of premature gonadal failure, the need for close follow-up and the possibility of long-term hormonal therapy to ensure proper sexual development. Informed consent documents should include this information, and study participants must accept this risk and the possible social implications of delayed sexual development.Parental desires for future progeny may influence decision making (
8
), and may result in undue pressure to participate in these studies. Families are asked to make decisions about study participation when they are extremely vulnerable (9
), and they may have unrealistic expectations about the outcome (10
). If a parent believes the research protocol is their only possibility for future grandchildren, the child may be coerced into assenting without truly understanding the significance of participation, for example, the possible implications of premature gonadal failure or the religious “peril” of gamete donation. The family may view the protocol as the only avenue available for the child to have a “normal future,” and may make decisions based on the fear of possible infertility, without considering that infertility may not have as many negative effects on the child as the side effects of the treatment. Researchers should point out that not all children will become sterile after treatment, and participation should be viewed as a gamble (5
). Patients and parents should be advised that nonparticipation does not automatically sentence the child to a life without children, and that participation may not ensure future reproduction. Again, professional counseling should be available to all families to explore the nuances of participation as well as to resolve any dissention between family members. The researcher must determine the true wishes of the child so that no child is forced to participate based on the needs of the parent.Religious conflicts
Religious views often conflict with the goals of fertility preservation. Roman Catholics, Muslims, and Orthodox Jews do not believe in gamete collection from unmarried persons under any circumstances (
11
, 12
, 13
). Removal and storage of gametes may compromise the child's standing in the religious community, and any offspring resulting from the use of these gametes would be viewed as “illegitimate” in the eyes of the religious community. Special dispensation can be considered when the person is married, has proven infertility, and the collection is being used for procreation, but there are no such considerations with fertility preservation. The importance of religious opinions may vary among individual family members, which may be the source of considerable argument. Although all views must be respected, in the end, parental consent is required for participation. Input from religious leaders and experienced counselors should be sought whenever there is any disagreement to prevent long-standing resentment between children and their parents.Grazi R, Wolowelsky J. The use of cryopreserved sperm and pre-embryos in contemproary Jewish law and ethics. In: Jewish Law Available at: http://www.jlaw.com/Articles/semen.html, 2008.
Is fertility preservation a child's “right”?
The right of a child to participate in fertility preservation research is a murky subject, especially because this technology is still in its infancy. This becomes an issue when the child wants to participate and the parent refuses, and the child argues that it is his or her right to protect their future childbearing potential. Although this argument could be made with respect to nonexperimental procedures such sperm cryopreservation, in the context of a research protocol, this right is not recognized. Ovarian and testicular tissue cryopreservation in pediatric patients is an experimental procedure, and is therefore governed by federal regulations, which include the requirement for parental consent for underage participants. This regulation holds even when an underage child is able to understand the consequences of participation, and stems from the need to protect vulnerable population from unethical research as set out in the Belmont Report (
14
). Therefore, without parental consent, participation is not possible. Once fertility preservation techniques become standard of care, a child's right to demand treatment against parental advice should be reexamined, but that subject is beyond the scope of this article.The Belmont Report—Ethical Principles and Guidelines for the protection of human subjects of research. In. Vol. 2009 Available at; http://ohsr.od.nih.gov/guidelines/belmont.html: Department of Health, Education, and Welfare, 1979.
Disposition and posthumous use of gametes
Discussions about the disposition of gametes should the child die must be conducted at study entry and can be especially difficult. The ethical concerns surrounding this issue include the right of a parent to use a child's gametes to reproduce if the child dies before the age of 18, the age at which a child can legally declare their desire to reproduce. Although one can make a legal argument that an adult has shown a clear understanding and intent to procreate when they preserve and store gametes, the same cannot be said if the gametes were collected at an age when the child had a limited understanding of the process and implications of having children. If a child's gametes are used posthumously, this could violate the child's right to make independent decisions about childbearing and could be unethical. The use of a multistep consent process is a beginning toward addressing this issue. In this scenario, assent/consent for the initial tissue collection is given with the understanding that the tissue cannot be used for reproductive purposes until the child is an adult. Final consent is then given by the patient when the tissue is actually used, confirming the patients desire to have children.
This would seem to protect the child against unauthorized use; however, one must realize that consent documents are neither legally binding nor fool-proof. The “imperfect decision maker” (
15
) is one example of a legal loophole that has been successfully used to obtain posthumous gametes. In this scenario, the surviving party implies that the deceased declared their intent to reproduce but failed to communicate this decision to the clinic or researcher. The most infamous example of this argument occurred in California, where Pamela Reno's 19-year-old son was killed playing Russian Roulette. He had consented to be an organ donor, but his mother refused to allow harvesting of the organs unless the physicians also harvested sperm, which she planned to use to inseminate her son's childhood friend so she could have grandchildren (16
). Pamela argued that because her son had previously expressed a desire to have children, she was only fulfilling his wish. She was able to convince the courts of this argument and successfully obtain her son's sperm. Another example involves access to stored gametes. Here the surviving party argued that storage of gametes implied a decision to procreate, and that the decision remains in effect as long as it had not been specifically revoked (e.g., the gametes were destroyed) (15
). This argument has been used mainly by women to gain access to a deceased husband's sperm.Although defining reproductive tissue as property might help resolve some of these issues (
16
, 17
), most courts worldwide have been reluctant to rule on this matter. France and California have specifically ruled against granting property rights, whereas the British have avoided making any ruling (6
). The French argument was based on the opinion that “reproductive material was not inheritable nor an object of commerce” (6
). Other opposing arguments have posited that this action would “commodify” the body and demean human dignity (16
), thereby opening the door to the buying and selling of body parts. Those in favor of classifying gametes as property argue that viewing gametes in this manner would be protective and granting property rights would provide a unified approach when settling complicated issues around the status and disposition of human biologic material (16
).Clearly, consensus on this issue has not been reached. Guidelines from the American Society of Reproductive Medicine support the posthumous use of gametes only in cases where the decedent's wishes are well established and documented (
18
). The American Society of Reproductive Medicine also recommends against intergenerational gamete donation, such as daughters donating oocytes to mothers, because of concerns about parental coercion (19
). Although there are no published guidelines on the disposition of a child's gonadal tissue, looking at both position statements from the American Society of Reproductive Medicine would suggest that they would recommend against parental access to such tissue.Even if property rights were applied to gametes, this might not provide sufficient protection for children. Legally, a minor (with the exception of an emancipated minor) cannot own property until they are 18 years of age. Before that age, the parent owns the property and holds it in trust for the minor. In the event of the child's death, the parents would assume full ownership as the child's next of kin. If a multistage document had been used to protect the child, the protection would be lost if gametes were viewed as property because ownership of the tissue would pass to the parent after the death of the child. Clearly, reproductive law must be developed to restrict the use of any reproductive tissue for the purpose of creating independent life before the age where a child is able to provide legally recognized informed consent.
Conclusions
Fertility preservation research offers hope for future childbearing for many cancer patients who may otherwise be faced with infertility in later life. As cancer survival rates increase, the need to address quality-of-life issues such as fertility preservation becomes even more pressing. The ethical issues encountered in this research are unique from other areas of medical research. There is a distinct paucity of case law and few published ethical decisions that deal specifically with these or with any similar situations in the pediatric population, but the need for guidelines in this area is clearly growing. This article has highlighted the issues in pediatric fertility preservation research that must be addressed to protect a child's rights while ensuring ongoing research. By addressing these issues in a proactive manner, future adverse consequences may be avoided.
Acknowledgments
The author would like the thank Brad VanVoorhis and Ginny Ryan for their assistance in the preparation of this article.
References
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Article Info
Publication History
Published online: January 25, 2010
Accepted:
November 27,
2009
Received in revised form:
November 20,
2009
Received:
August 27,
2009
Footnotes
B.J.S. has nothing to disclose.
Identification
Copyright
© 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
