Abstract
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 anti-cancer 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% [1]. At the same time, diagnoses of some malignant diseases have become more prevalent (e.g., breast and testicular cancer) [2]. 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.
Introduction
“Give me children or else I die.”
This quote is even more poignant when discussing the reproductive planning and options of a person who experiences iatrogenic infertility. Iatrogenic infertility is when necessary medical care may lead to infertility [1]. This would include among others cancer patients or cancer pre-vivors. For purposes of this chapter the term “pre-vivor” refers to one who does not yet have cancer but has an increased risk or predisposition to having cancer, such as an individual who is identified as having a BRCA1 or BRCA2 mutation. The imperative to have children is something that can be both psychological and biological and may be further exacerbated by one’s own confrontation of mortality. A 2015 study of female cancer patients found “A higher level of reproductive concerns is associated with greater odds of experiencing moderate to severe depression [2].” Recent scientific advances have made the once remote possibility of conception following cancer treatment more tangible, however, these advances are not without risks including legal and ethical risks.
Learning that one or one’s child has cancer or that one is at a greatly increased risk of developing cancer is life altering. Parents, patients and/or caregivers are bombarded with innumerable treatment decisions, many of which need to be made urgently with little time for deliberation. As such, meaningful discussion about fertility preservation often does not occur. In fact, a study published in the Clinical Journal of Oncology Nursing of nurses’ attitudes regarding fertility preservation revealed that “patients may be strongly focused on survival and their cure and may not want to think about other issues …” [3] According to a survey by Carlson, the vast majority of surveyed physicians discuss the potential for infertility with patients receiving cancer treatment, however, fewer than 25% responded that they made a referral to a reproductive specialist or provided educational information [4]. Even more striking in the Quinn survey was that only 38% of respondents knew that the American Society of Clinical Oncology (ASCO) has developed guidelines on fertility preservation [4]. Another study, published in the Journal of Clinical Oncology found that fewer than 25% of men bank sperm and the most common reason for not doing so was that the option was not made known to them [5]. Nearly one half of the men in the study had no recollection of any discussion about infertility before beginning their cancer treatment [5]. What is not clear is whether their lack of recollection is the result of not being provided with the information or the result of the stress and strain of having to cope with a cancer diagnosis and make immediate decisions directly impacting their cancer treatment. A literature review study by Deshpande, Braun and Meyer found that “Receiving counseling about the reproductive effects of cancer treatment and pursuing FP also was found to be associated with greater physical [Quality of Life] QOL and trends toward greater psychological QOL” [6]. Research does suggest, however, that more education of and communication with patients about potential infertility resulting from treatment as well as fertility preservation options is necessary as is more integration of care between oncologists and reproductive endocrinologists [6].
Advances in reproductive technology and oncology have made what was once impossible, possible, by allowing young cancer patients extended periods of survival and thus enabling them to contemplate a future with children. Cryopreservation of sperm has been an available option for men since the mid-twentieth century [7], but cryopreservation of oocytes has only become an option for women in the last decade or so and was only found to be a non-experimental treatment option in 2012 [8]. Unlike collection of sperm for cryopreservation collection of oocytes carries more risk and requires more time potentially delaying cancer treatment.
Numerous other treatments or experimental procedures are also available. According to ASCO, current options for fertility preservation in males include; sperm cryopreservation, gonadal shielding during radiation, testicular tissue cryopreservation and testicular suppression; for females: embryo cryopreservation, oocyte cryopreservation, ovarian cryopreservation and ovarian transposition are some of the available means of fertility preservation [9]. The availability of any given option, however, may be limited by a number of factors including age of the patient, risk of the procedure, prognosis of the patient as well as accessibility to and cost of the procedure. Each of these potential limitations has legal implications as well.
The majority of legal issues related to fertility preservation revolve around decision making of the patient or the patient’s guardian: informed consent for both adult and minor patients; participation in a research protocol or undergoing a more standard medical procedure; and future use and disposition of preserved gametes and/or reproductive tissue, including the potential necessity for female patients to utilize the services of a gestational surrogate. These issues are all related to the standard of care for the healthcare professional and thus raise questions of potential liability. Another significant legal issue that impacts patients, regardless of age or gender, is the question of insurance coverage. Legislation has been introduced in several states mandating insurance coverage for iatrogenic infertility and has met with some success as will be discussed later in the chapter. Here, each of these issues will be discussed for both adult and minor patients.
Informed Consent
Informed consent is the embodiment of respect for persons and reflects both a bioethical and a legal construct, applying to both treatment and research. The essential elements of informed consent are the same in both the treatment and research context and include: a discussion with one’s physician or investigator regarding the risks, benefits and alternatives to a particular treatment or protocol. Informed consent is not merely a signed document but rather an ongoing dialogue, the purpose of which recognizes “that adults are entitled to accept or reject health care interventions on the basis of their own personal values and in furtherance of their own personal goals.” [10].
For those unable or incapable of this level of self-determination, such as minors, parents, acting in the child’s best interest will be called upon to make such determinations. The sections that follow will discuss the issues of informed consent in both research and treatment for both adults and minors undergoing cancer treatment in which their future fertility might be compromised.
ASCO Guidelines
In 2006, ASCO recommended that:
As part of education and informed consent before cancer therapy, oncologists should address the possibility of infertility with patients treated during their reproductive years and be prepared to discuss possible fertility preservation options or refer appropriate and interested patients to reproductive specialists. [9]
This recommendation holds true today, with the 2018 ASCO Guidelines recognizing that:
People with cancer are interested in discussing fertility preservation. Health care providers caring for adult and pediatric patients with cancer (including medical oncologists, radiation oncologists, gynecologic oncologists, urologists, hematologists, pediatric oncologists, surgeons, and others) should address the possibility of infertility as early as possible before treatment starts. [11]
Unless this is part of the discussion between the physician and the patient or patient representative, no assumption should be made that the patient is aware of any potential impairment of his or her fertility let alone any measures that might be taken to preserve his or her fertility if warranted by the patient’s prognosis. Once made aware of this possibility, however, the patient should then be provided with information about what, if any, means might be available for preserving fertility and how any such interventions may or may not impact his or her cancer treatment. ASCO suggests that it is the role of the oncologist to “[a]nswer basic questions about whether fertility preservation options decrease the chance of successful cancer treatment, increase the risk of maternal or perinatal complications, or compromise the health of offspring.” [9] Referrals to reproductive medicine specialists and/or a mental health provider may also be necessary or advisable [9, 12].
Treatment – Adults
The legal principle of informed consent was solidified nearly 40 years ago by the United States Court of Appeals for the District of Columbia in the seminal informed consent case Canterbury v. Spence, which delineated what ought to be disclosed to patients. In that case the court held that:
True consent to what happens to one’s self is the informed exercise of a choice, and that entails an opportunity to evaluate knowledgeably the options available and the risks attendant upon each. The average patient has little or no understanding of the medical arts, and ordinarily has only his physician to whom he can look for enlightenment with which to reach an intelligent decision. From these almost axiomatic considerations springs the need, and in turn the requirement, of a reasonable divulgence by physician to patient to make such a decision possible. (Citations omitted) [13]
The ASCO and ASRM recommendations regarding elements to include in the informed consent process are in keeping with the principles set forth in Canterbury as that set forth the type of information that one would likely need in order to make an informed choice. Informing patients about potential risks to fertility of cancer treatment, followed by a discussion of fertility preservation options is the starting point. Patients need to also have information about how those options impact their treatment, the potential success of these options when the patient is seeking to reproduce, the cost of the procedures, whether the procedure is experimental and the risks such options may have to their own health as well as that of future offspring [9, 12, 14].
While little has currently been written about the information that should be provided to cancer pre-vivors regarding fertility preservation, many of these same issues merit consideration. A chapter, however, by Insogna and colleagues discusses some of the issues particular to fertility preservation in BRCA carriers [15]. For some pre-vivors, the option of fertility preservation is what will enable them to undertake prophylactic measures to reduce their heightened risk of cancer. For example, a young woman with a BRCA1 or BRCA2 mutation who has not yet had children, may be reluctant to remove her ovaries, a prophylactic surgery which could reduce her risk of ovarian cancer significantly [16]. However, if she becomes aware of fertility preservation options both in clinical practice and research, she may be more comfortable considering this option. As such, not only is it important for oncologists and reproductive endocrinologists to consider when, what and with whom to discuss fertility preservation options, it may also be important for geneticists and genetic counselors to be aware of fertility preservation options as well and to consider disclosing information about these options to both male and female patients who might benefit.
Given the depth and breadth of information that needs to be communicated, reliance on a multidisciplinary team may be the most efficient and expeditious means of communicating the information. Jeruss and Woodruff have recommended that institutions create a multidisciplinary board to aid in “identifying and communicating options for the fertility preservation in patients with cancer” [17]. Others also recommend involving clergy and theologians in any fertility preservation program [18]. Another approach taken by some programs is the engagement of a patient navigator. “In the hospital setting, an oncofertility patient navigator can help guide patients across institutional and disciplinary boundaries to assess their cancer treatment and infertility risk, seek consultation with reproductive endocrinologists, and discuss treatment options and costs.” [19] These are sound recommendations for patients and practitioners given the rapidly changing technology, the paucity of specific legal guidance, and the likely increase in patient demand as more individuals become aware of these options.
Treatment – Children
As mentioned above, parents are responsible for making medical decisions for their children. “The general rule seems to be that, unless there exists an emergency, which prevents any delay, or other exceptional circumstances, a surgeon who performs an operation upon a minor without the consent of his parents or guardian is guilty of a trespass and battery.” [20] This decision making authority is part and parcel of the constitutionally recognized right of parents to the care, control and custody of their children [21]. An historic rationale for giving parents this authority was based on the notion that if anything went wrong with the medical procedure, the parents would be responsible for raising the child and thus should make the decision with this awareness [22, 20]. Still another rationale for bestowing the obligation upon parents is that parents are in the best position to protect their child’s welfare and to consider what would be in the best interests of the child [23].
Under some circumstances, however, minors can make their own healthcare decisions, particularly around issues of reproduction. States have exceptions for emancipated minors, mature minors and for specific healthcare services [22]. For example, the US Supreme Court in a series of cases found that minors have a right to determine whether to bear or beget a child and decisions to do so should not be vetoed by another, however, some limitation is considered permissible [24, 25]. In addition, legislation exists which allows minors to make treatment decisions regarding sexually transmitted infections without parental consent or notification [26]; obtain information about contraception [27]; and to obtain medical treatment for alleged sexual assault without parental consent [28]. These statutes are in keeping with the general understanding that the right to reproduce is a fundamental one. Further supporting this is the recognition by most states that parents cannot make the decision to sterilize a minor without independent court review [29]. “Sterilization touches upon the individual’s right of privacy and the fundamental right to procreate.” [30] While parental failure to consent to the pursuit of fertility preservation likely is not the same deliberative process as consenting to the sterilization of one’s child, the consequence for the child might be the same and thus indicates the need for thoughtful consideration of the child’s future reproductive needs and wishes.
Even outside the context of reproductive health, the American Academy of Pediatrics asserts that healthcare decisions involving adolescents and older children should, to the greatest extent possible, involve the assent of the patient [23]. Assent is, in essence, a child’s willingness to accept the treatment after having had the treatment/procedures described to him or her in understandable terms appropriate for his or level of development [23]. A child’s unwillingness to assent should be given great weight [23] and in the context of research may, under some circumstances, be binding [31].
The American Academy of Pediatrics recognizes the importance of fertility and reproductive health in the pediatric population. In recent recommendations, the AAP stated that: “Given that numerous pediatric conditions and treatments impair reproductive capacity and sexual function, general pediatricians and pediatric medical subspecialists should provide ongoing counseling about these risks and potential management options as well as psychosocial support.” [32] In the context of cancer treatment parental decision making may be even more complex when parents are confronted with the option of fertility preservation.
In a Technical Report issued by the American Academy of Pediatrics in 2008, the authors acknowledged that for parents “the act of preserving a child’s life must take precedence over the preservation of the possibility of that child’s ability to have children, although the goals of each are intertwined.” [33] Legal and bioethics expert John Robertson supports parents’ decision to preserve their child’s fertility “as long as the minor assents and the intervention do not pose an undue risk.” [34] Dolin and colleagues reach a similar conclusion but considering the question from the perspective of the child. They assert that “[t]o the extent that the minor in question can rationally consider her options and express her preferences accordingly, that should be the end of the matter.” [29] In the event of a conflict between the wishes of parent and child, if the minor is above the age of 14 and deemed mature enough to give or refuse consent, there seems to be support to allow the minor to do so [5].
While many of the fertility preservation procedures available to adults are also available for children, not all are. This is, in part, due to psychosocial concerns. For example, in the past, “Adolescent girls have not been considered to be candidates for assisted reproductive technology, largely because of the psychosocial issues surrounding a delay in treatment and acquisition of donor sperm.” [17] Additionally, parents may, because of religious or cultural beliefs, be uncomfortable with some procedures such as cryopreservation of sperm collected through masturbation [33].
Because parents cannot always remove their own emotions and their own needs to contemplate what the child might desire when he or she becomes an adult, appointing a special advocate for the child or have an ethics committee or consultant review the decision may become necessary. The law tends to be reactive and not proactive and thus, little, if any legal guidance exists to dictate what should or should not be done to preserve the fertility of minors. Given the uncertainty, however, thoroughly discussing the issue with the child, if mature enough to understand, and with the child’s decision-makers is imperative especially in light of the fact that while “[i]mpaired future fertility is difficult for children to understand [it is] potentially traumatic to them as adults.” [9]
According to a recent survey, many of the practice guidelines for fertility preservation in minors and young adults are inconsistent and/or unclear [35]. How, what, why and when the discussion about fertility preservation should occur with minors and their parents will be somewhat case specific with consideration of a number of factors including but not limited to the age of the child; maturity of the child; family dynamic, particularly the nature of the relationship between the parent and the child; cultural and religious beliefs of the family; child’s prognosis; cost including whether insurance coverage is available; and availability and accessibility of any given fertility preservation option in the patient’s geographic area.
Research – Adults
Several fertility preservation techniques are still in the experimental phase and thus the elements of informed consent for research should be adhered to regardless of the funding source for such research. The goals of research and practice differ and thus must be reflected in the consent process. The goal of treatment is to benefit an individual patient whereas the goal of research is to contribute to generalizable knowledge [36]. Based on this distinction, more protections are required of human participants in research. One such protection includes Code of Federal Regulations’ requirement that research involving human subjects be reviewed by an Institutional Review Board (IRB) [37].
The role of the IRB is to determine that the risks to patients are minimized; that the benefits of participating in the research will outweigh the risks; that selection of participants is equitable and that informed consent is sought from the participant or his/her representative [38]. IRB review will include review of consent documents as well as the consent process to determine whether all of the consent elements required by the Regulations are satisfied. Section 46.116 sets forth the general requirements for informed consent which include among other things: an explanation of the purpose of the research and a description of the procedures; a description of the risks, benefits and alternatives; and a statement that participation is voluntary and that the participant is free to withdraw at any time without fear of compromising his/her medical care [39].
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