Ms. F and Mr. G are trying to have a child. They have been having sexual intercourse approximately three times a week for the past year, and daily around the time when Ms. F thinks she is ovulating. They are both 38 years old. Ms. F has had regular menstrual cycles up to the last three months, in which she has had only two. They are worried they have delayed starting a family too long and will not be able to afford the expensive fertility treatment they may require at Ms. F’s age. They have questions regarding the success of in vitro fertilization and the possibility of having twins or triplets.
Assisted reproduction enables the deliberate manipulation of the processes and materials of human reproduction outside of sexual intercourse. In describing the practices that constitute assisted reproduction, it must be understood that all such practices are embedded with ethical issues, whether standard therapies such as ovulation induction (Messinis, 2005), insemination with donor sperm (Daniels et al., 2006), and in vitro fertilization (IVF) (Steptoe and Edwards, 1978); emerging practices such as pre-implantation genetic diagnosis (PGD) (Handyside, 1990; Nisker and Gore-Langton, 1995); or practices prohibited under law in many countries, such as the purchase or bartering of oocytes (Gurmankin, 2001; Nisker, 1996, 1997, 2001).
Ovulation induction through clomiphene citrate has been practiced for over 30 years (Messinis, 2005). This oral therapeutic strategy can assist 50–80% of women with ovulatory dysfunction become pregnant, depending on the etiology of their disorder (with the exception of premature ovarian failure) (Messinis, 2005). Aromatase inhibitors are new oral ovulation induction agents (Casper and Mitwally, 2006; Holzer et al., 2006). When these are unsuccessful in inducing ovulation, menotropins (also referred to as gonadotropins) may be used (Messinis, 2005). This is a much riskier strategy, with side effects including ovarian hyperstimulation syndrome (Budev et al., 2005) and the creation of high-order multiple pregnancies (Barrett and Bocking, 2000a, b).
Provision of sperm, by other than the woman’s partner, was one of the earliest forms of assisted reproduction and has been encompassed in medical practice for 50 years (Daniels et al., 2006). Sperm donation is a common practice when a woman’s partner has sperm of low count or quality or carries a communicable disease, when she is in a lesbian relationship, or if she is single. Oocytes may be provided to women who no longer have an “ovarian reserve,” because of their advanced age (Pastor et al., 2005) or having undergone cancer treatment (Byrne et al., 1999; Nisker et al., 2006).
Menotropin ovarian stimulation create multiple oocytes for IVF (Abramov et al., 1999). When the oocytes reach approximately 2 cm in diameter, they are matured with human chorionic gonadotropin and approximately 36 hours later are removed through transvaginal ultrasonographic-guided needles (Yuzpe et al., 1989). The oocytes are placed in Petri dishes under strict sterile conditions, sperm is added, and if fertilization occurs, the embryos are microscopically observed for two days (up to four days if the plan is to transfer blastocysts) (Blake et al., 2002). Embryos are then transferred to the uterus (Min et al., 2006) (one or two embryos preferred, but often more in older women), and the remaining embryos are cryopreserved for transfer in non-treatment cycles (Trounson and Mohr, 1983). Cryopreserved embryos no longer required for reproductive purposes are usually donated to research (Nisker and White, 2005) or discarded. They may, however, be donated to another couple, although this rarely occurs for a number of reasons, including parental fear of allowing a child for another couple that is genetically related to their own (Newton et al., 2003; Nachtigall et al., 2005). Pregnancy rates for IVF exceed 25% per cycle for women/couples whose infertility etiology may be blocked Fallopian tubes, endometriosis, sperm problems (with intracytoplasmic sperm injection) (Van Steirteghem et al., 1994) or unexplained. They become higher following the transfer of cryopreserved embryos (Alsalili et al., 1995; Mishell, 2001). The risks of IVF are in both the menotropin stimulation (Abramov et al., 1999; Buckett et al., 2005) and the surgery (Alsalili et al., 1995). There are also risks to the child and family unit, such as those owing to multiple births (Barrett and Bocking, 2000a, b).
Gestational agreements (Rodgers et al., 1997; Ber, 2000) are often used in conjunction with assisted reproduction practices (Mykitiuk and Wallrap, 2002; Rivard and Hunter, 2005). Although the more common type of gestational agreement occurs when the gestational carrier is impregnated with the sperm of the partner of a woman who, because of medical problems, cannot gestate her own embryo/fetus, gestational agreements may also include those in which the embryo’s genetic make-up has resulted from an oocyte other than that of the gestational carrier, sperm other than that of the man for whom the embryo/fetus is being gestated, or both (Rodgers et al., 1997).
A relatively new area relates to the genetic scrutiny of embryos by PGD (Handyside et al., 1990; Nisker and Gore-Langton, 1995), or most recently, preimplantation genetic haplotyping (PGH) (Renwick et al., 2006). The embryos or polar bodies (Verlinsky et al., 1990) are assessed genetically through polymerase chain reaction (Mullis and Faloona, 1987) or fluorescent in situ hybridization (Delhanty et al., 1993). Genetic determinations of an embryo through PGD may be used not only to implant embryos to avoid a specific genetic characteristic but also to implant embryos with particular characteristics, for example embryos of a specific histocompatibility in a savior sibling scenario (Pennings et al., 2002), embryos that will result in a child who is deaf (Levy, 2002) or who has Duchene’s dwarfism (Nunes, 2006).
Assisted reproduction enables subfertile heterosexual couples, single women, and women in lesbian relationships to have children. In addition, individuals and couples who carry genetic conditions may wish to use assisted reproduction in order to avoid passing (or to deliberately pass) these conditions on to their children. Thus, assisted reproduction is important for both medical and social indications.
Assisted reproduction is increasingly important as many women delay having a child until they have employment and financial security. Delay in becoming pregnant predisposes a woman not only to deplete her ovarian reserve but also to develop other etiologies of infertility, such as endometriosis or tubal occlusion, as well as lengthening her exposure to environmental toxins (Younglai et al., 2002), an under-researched area (Royal Commission on New Reproductive Technologies, 1993).
Assisted reproduction is also increasingly important as more women are surviving cancer treatment, including leukemias in girls and adolescents, lymphomas, and breast cancer (Nisker et al., 2006). Women who have received chemotherapy, for example, may have a dramatic decrease in the number of ovarian Follicles that remain, and thus the normal attrition rate frequently causes these women to develop ovarian failure in their thirties (Sklar et al., 2006).
Commercialization and commodification of gametes, and commercial gestational agreements, offend a number of ethical precepts including respect for human integrity and dignity through the non-commodification and non-commercialization of the person, her or his bodily parts, tissues, substances and processes; protection of vulnerable persons from coercion or inducement; and respect for the patient–physician relationship by avoiding a conflict of interest between the two parties (Royal Commission on New Reproductive Technologies, 1993; Nisker and White, 2005).
“Donation” is an ethically charged term in that, until the 1990s, in most countries, “donors” of sperm and oocytes have been paid in the range of $100 for sperm and between $1500 and $5000 for oocyte donation (Nisker, 1996, 1997, 2001; Gurmankin, 2001). In addition, oocyte “donors” are almost always economically disadvantaged women who either sell their eggs to support their family or pay tuition, or who barter half of their oocytes in order to undergo an IVF cycle (Royal Commission on New Reproductive Technologies, 1993; Nisker, 1996, 1997, 2001; Mykitiuk and Wallrap, 2002). The ethical problems of these practices is reflected in their prohibition by law in most Western European countries such as France, the UK, and Germany, as well as Australia, New Zealand, and Canada, amongst other countries (see the list of relevant legislation at the end of the chapter). In some of these countries, sperm donors may be offered reimbursement of expenses, and occasionally compensation for their time (Daniels et al., 2006).
Free and informed choice requires that the patient must be informed about the benefits and risks of treatment, alternative courses of action, and the consequences of not having the treatment (Mykitiuk and Wallrap, 2002). This includes the provision of sufficient information for the patient to be able to both understand and appreciate the chances of having a child for that particular patient in that particular infertility clinic, including clarification of the meaning of success rates (as to biochemical pregnancy or live birth), and the specific risks of treatment inherent for that patient (in general and in that particular clinic). Patients should also be informed about the potential for multiple births to have physical and cognitive consequences for children, as well as social consequences for them and their families and financial costs (Barrett and Bocking, 2000a,b; Elster, 2000; Mykitiuk and Wallrap, 2002; Adamson and Baker, 2004).
A free choice process is difficult to ensure for sisters and close friends of infertile women who have been asked to become oocyte “donors” or gestational carriers for them (Rodgers et al., 1997; Ber, 2000). These women have indicated that they would feel that they were a bad sister or a bad friend if they did not comply with the request. Further, even in the best-case scenarios for altruistic oocyte donation or gestational agreements, ethical problems remain.
Informed choice is particularly difficult for those who are soon to undergo cancer treatment (Nisker et al., 2006). In the case of girls and adolescent women, a substitute decision maker, usually a parent or guardian, may base their decision on the belief that the child will want to be a mother. As with adult women, decision making is also complicated by the fact that delaying cancer treatment in order to retrieve and cryopreserve oocytes (or for adult women to possibly undergo IVF to freeze embryos) may be problematic to the success of the cancer treatment. Finally, although encouraging, the success of new techniques such as oocyte vitrification (Lucena et al., 2006) and in vitro maturation (Rao and Tan, 2005) requires further study.
Free and informed choice for research purposes may also be complex in that it is difficult for a woman undergoing fertility treatment not to agree to a request by her physician to participate in research, as she may perceive that the research must be important to the physician or it would not have been offered, and that a negative decision may compromise her clinical care (Sherwin, 1992, 1998; Kenny, 1994; Nisker and White, 2005). Particularly regarding stem cell research, women who “volunteered” to undergo IVF to provide eggs may be coerced (Cyranoski, 2004; Nisker and White, 2005; Chang, 2006).
Access to assisted reproduction is constrained in some jurisdictions by financial considerations and other eligibility criteria. Without public funding, access to IVF is generally limited to economically advantaged women/couples. In most countries where a publicly funded healthcare system exists, access to infertility treatment, including IVF and intracytoplasmic sperm injection, is provided. In some countries, such as Australia, IVF is publicly funded for the number of cycles it takes for the woman to complete her family, while in most Western European countries and Israel, some restrictions are placed on the maximum number of cycles or the maximum number of children for which publicly funded IVF is available (Birenbaum-Carmeli, 2004). Canada is an exception among countries with publicly funded healthcare systems in that no public funding is provided for IVF and corollary therapies, with the exception of the province of Ontario, where IVF is provided for blocked Fallopian tubes only (Mykitiuk and Wallrap, 2002; Nisker, 2004).
Access may also be restricted by the eligibility criteria used by physicians and clinics. Although the access criteria typically center on the potential benefits and risks to the health and safety of participants based on medical factors, including the condition of infertility and the participant’s age, some physicians and clinics use non-medical criteria. These may include a woman’s or couple’s ability to parent, which may be perceived to be limited by physical or cognitive disability (Gurmankin et al., 2005), low income (Gurmankin et al., 2005), marital status (Vandervort, 2006), and sexual orientation (Mykitiuk and Wallrap, 2002; Peterson, 2005). Individuals and couples may also face barriers to access based on race and ethnicity (Mykitiuk and Wallrap, 2002; Gurmankin et al., 2005). These non-medical barriers to access are ethically suspect, often relying on discriminatory personal or social prejudices and may be subject to human rights challenges (Mykitiuk and Wallrap, 2002).
Assisted reproduction is now used to determine the potential characteristics of children (Mykitiuk et al., 2006) through PGD (Handyside et al., 1990; Nisker and Gore-Langton, 1995) and PGH (Renwick et al., 2006). Focus on genetic characteristics of an embryo has been used not only to avoid a specific genetic characteristic but also to enhance the chance a child will have a particular characteristic (Pennings et al., 2002). To a limited degree, couples have for more than 10 years purchased sperm from genius sperm banks and oocytes from “Ron’s Angels” to enhance the chances of an “intelligent” or conventionally “beautiful” child (Nisker and Gore-Langton, 1995; Nisker, 2002). The use of these strategies, as well as PGD and PGH for such purposes, raises ethical issues about the proper use of medical technology and the physician’s role in providing enhancement rather than therapeutic benefits (Nisker, 2002). The use of PGD to avoid specific genetic conditions and diseases is also considered by some to be ethically problematic, resting on discriminatory ideas of disability and difference (Parens and Asch, 1999; Shakespeare, 1999; Taylor and Mykitiuk, 2001; Mykitiuk, 2002a). Also morally complex is the use of PGD to detect embryos of a specific histocompatibility in order to produce a savior sibling for an existing child (Pennings et al., 2002). The potential use of PGD to ascertain embryos that will result in a child who is deaf (Levy, 2002) or who has Duchene’s dwarfism (Nunes, 2006) is also ethically problematic.
Assisted reproduction also makes possible the creation of novel social arrangements: postmortem insemination, virgin births, postmenopausal pregnancy, multiple parents, anonymous genetic parents, and embryos conceived at one time being born at different times or to different people (Mykitiuk, 2002b). The use of assisted reproduction, therefore, has implications for kinship and also the understanding of the legal, social, and emotional bonds created by heredity and the consequences presumed to ensue from processes of conception and birth (Mykitiuk, 2002b). Social factors include the inappropriate continuation of a male-dominant work ethic that sees women as less valuable employees if they want to become pregnant. This coerces women to delay pregnancy and risk infertility rather than create an obstacle to career advancement or employment.
Western European countries, such as France, Sweden, the UK, and Germany, as well as Australia, New Zealand, Canada, and Israel, have enacted legislation governing assisted reproduction (see the legislation listed at the end of this chapter). However, in many jurisdictions, including the USA and eastern Europe, these practices remain largely unregulated by law. “Reproductive tourism” can result when patients and clinicians are prohibited by law from accessing certain practices in their own jurisdiction (Storrow, 2005).
The law generally sets out prohibited practices, usually enforceable through criminal sanctions (e.g., payment for gestational arrangements and oocytes in most jurisdictions) and provides a regulatory framework within which permissible practices must be carried out (e.g., the storage, handling, and use of reproductive materials, and a registry of gamete donors). In addition, national legislation may establish a regulatory or oversight body whose responsibility it is to license, inspect, and monitor all human reproduction clinics. Further, domestic human rights legislation may prohibit discrimination: for example, a single or disabled woman, or lesbian couple being denied access to IVF or donor conception for non-medical reasons.
In most countries where legislation regarding assisted reproduction exists, it is illegal to create an embryo for research purposes (e.g., Canada, France, Germany, and Sweden; see legislation at the end of this chapter). By contrast, in the UK, it is legal to create an embryo for research if legal consent has been given, provided one is licensed to do so (Human Fertilization and Embryology Act, 1990). However, in some countries, such as Canada, France, and Australia, research can be performed on embryos that were created for reproductive purposes but are no longer required for this purpose, pursuant to a license and with consent of the embryo donor. In most countries with legislation, there are also prohibitions on reproductive cloning, ectogenesis, and germ-line modification. For more on issues related to stem cell research and therapeutic cloning, see Chs. 21 and 31.
Professional practice policies are developed in order to set the standard of care by which clinicians should practice in order to provide optimal therapeutic outcome and minimum risk to their patients. As policies impact not only patients, clinicians, and researchers but also social relationships and institutions, good policy making must involve voices and perspectives of all parties who are affected by that policy, as well as those of the general public. In the development of such policies, it should be appreciated that women more than men are affected by assisted reproductive practices (Royal Commission on New Reproductive Technologies, 1993).
Understanding that assisted reproduction is an ethically complex area of medicine, whether the clinician is a family physician, general gynecologist, fertility specialist, nurse, social worker, or psychologist, is essential in its practice. Family physicians and general gynecologists may become skilled in many aspects of infertility investigation, including history taking, physical examination, assessment of semen and ovulation characteristics, tubal patency, as well as parameters of general health. As referring physicians, these individuals should be aware of the infertility clinics that provide optimal care. Infertility specialists have the obligation to be educated in all currently clinically proven investigations and treatments. These specialists have an obligation to keep accurate records and report their findings in a manner in which the pregnancy and treatment-complication rates are clearly apparent to patients and referring physicians. All clinicians have the obligation to provide a free and comprehensive informed choice process.
Clinicians need to be mindful of the fact that that there may be both national and state/territorial/provincial legislation governing assisted human reproductive practices. Access to appropriate infertility treatment is problematic in countries such as Canada and the USA where, unlike Western European countries, Australia, and Israel, IVF is not covered under a publicly funded healthcare system, and advocacy for socioeconomically disadvantaged patients is required. Professional practice guidelines should be developed in order to have uniform reporting of data and to advise both fertility specialists and referring physicians as to the standards of care.
The ethical issues embedded in the case include the inability of some women/couples, because of their financial or social situation, to access assisted reproduction and the informed choice process, particularly considering clinical factors (e.g., age of the woman) that may allow for more risky treatment strategies and require different information in the informed choice process. The fact that Ms. F is 38 years of age may allow ethical practice to commence infertility investigation if after one year pregnancy does not occur (or slightly before because of irregular ovulation, as with Ms. F), as well as permitting the transfer of more than one or two embryos during the treatment cycle. This couple should be made aware in the informed choice process that their chance of having a child, biologically related to them, through assisted reproduction or otherwise is much lower than the overall statistics reported by infertility clinics. Further, the additional risk of multiple pregnancy, and the physical and cognitive risks to the child inherent in multiple births, need to be addressed, as the option of more than two embryos being transferred will likely be offered. Ms. F and Mr. G, as all women/couples in their age group (and indeed all women/couples), should be counseled about the possibility of adoption, and about the fact that in most “developed” countries, access to an infant through adoption is very limited, and access to international adoption is restricted to the financially well off.
An earlier version of this chapter has appeared: Shanner, L. and Nisker, J. (2001). Assisted reproductive technologies. CMAJ 164: 1589–1594.