16 Assisted reproduction Roxanne Mykitiuk and Jeff Nisker Ms. F and Mr. G are trying to have a child. They have been Ovulation induction through clomiphene citrate having sexual intercourse approximately three times a has been practiced for over 30 years (Messinis, 2005). week for the past year, and daily around the time when This oral therapeutic strategy can assist 50–80% of Ms. F thinks she is ovulating. They are both 38 years old. women with ovulatory dysfunction become preg- Ms. F has had regular menstrual cycles up to the last three nant, depending on the etiology of their disorder months, in which she has had only two. They are worried (with the exception of premature ovarian failure) they have delayed starting a family too long and will not be (Messinis, 2005). Aromatase inhibitors are new oral able to afford the expensive fertility treatment they may ovulation induction agents (Casper and Mitwally, require at Ms. F’s age. They have questions regarding the success of in vitro fertilization and the possibility of having 2006; Holzer et al., 2006). When these are unsucces- twins or triplets. sful in inducing ovulation, menotropins (also refer- red to as gonadotropins) may be used (Messinis, 2005). This is a much riskier strategy, with side eff- What is assisted reproduction? ects including ovarian hyperstimulation syndrome (Budev et al., 2005) and the creation of high-order Assisted reproduction enables the deliberate multiple pregnancies (Barrett and Bocking, 2000a, b). manipulation of the processes and materials of Provision of sperm, by other than the woman’s human reproduction outside of sexual intercourse. partner, was one of the earliest forms of assisted In describing the practices that constitute assisted reproduction and has been encompassed in med- reproduction, it must be understood that all such ical practice for 50 years (Daniels et al., 2006). practices are embedded with ethical issues, whether Sperm donation is a common practice when a standard therapies such as ovulation induction woman’s partner has sperm of low count or quality (Messinis, 2005), insemination with donor sperm or carries a communicable disease, when she is in a (Daniels et al., 2006), and in vitro fertilization (IVF) lesbian relationship, or if she is single. Oocytes may (Steptoe and Edwards, 1978); emerging practices be provided to women who no longer have an such as pre-implantation genetic diagnosis (PGD) ‘‘ovarian reserve,’’ because of their advanced age (Handyside, 1990; Nisker and Gore-Langton, 1995); (Pastor et al., 2005) or having undergone cancer or practices prohibited under law in many coun- treatment (Byrne et al., 1999; Nisker et al., 2006). tries, such as the purchase or bartering of oocytes Menotropin ovarian stimulation create multiple (Gurmankin, 2001; Nisker, 1996, 1997, 2001). oocytes for IVF (Abramov et al., 1999). When the An earlier version of this chapter has appeared: Shanner, L. and Nisker, J. (2001). Assisted reproductive technologies. CMAJ 164: 1589–1594. 112 Assisted reproduction 113 oocytes reach approximately 2 cm in diameter, they the gestational carrier, sperm other than that of the are matured with human chorionic gonadotropin man for whom the embryo/fetus is being gestated, and approximately 36 hours later are removed or both (Rodgers et al., 1997). through transvaginal ultrasonographic-guided nee- A relatively new area relates to the genetic dles (Yuzpe et al., 1989). The oocytes are placed in scrutiny of embryos by PGD (Handyside et al., Petri dishes under strict sterile conditions, sperm is 1990; Nisker and Gore-Langton, 1995), or most added, and if fertilization occurs, the embryos are recently, preimplantation genetic haplotyping (PGH) microscopically observed for two days (up to four (Renwick et al., 2006). The embryos or polar bodies days if the plan is to transfer blastocysts) (Blake et al., (Verlinsky et al., 1990) are assessed genetically 2002). Embryos are then transferred to the uterus through polymerase chain reaction (Mullis and (Min et al., 2006) (one or two embryos preferred, but Faloona, 1987) or fluorescent in situ hybridization often more in older women), and the remaining (Delhanty et al., 1993). Genetic determinations of embryos are cryopreserved for transfer in non- an embryo through PGD may be used not only to treatment cycles (Trounson and Mohr, 1983). Cryo- implant embryos to avoid a specific genetic char- preserved embryos no longer required for repro- acteristic but also to implant embryos with par- ductive purposes are usually donated to research ticular characteristics, for example embryos of a (Nisker and White, 2005) or discarded. They may, specific histocompatibility in a savior sibling however, be donated to another couple, although scenario (Pennings et al., 2002), embryos that will this rarely occurs for a number of reasons, including result in a child who is deaf (Levy, 2002) or who has parental fear of allowing a child for another couple Duchene’s dwarfism (Nunes, 2006). 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 Why is assisted reproduction important? infertility etiology may be blocked Fallopian tubes, endometriosis, sperm problems (with intracyto- Assisted reproduction enables subfertile heterosex- plasmic sperm injection) (Van Steirteghem et al., ual couples, single women, and women in lesbian 1994) or unexplained. They become higher following relationships to have children. In addition, individ- the transfer of cryopreserved embryos (Alsalili et al., uals and couples who carry genetic conditions may 1995; Mishell, 2001). The risks of IVF are in both the wish to use assisted reproduction in order to avoid menotropin stimulation (Abramov et al.,1999; passing (or to deliberately pass) these conditions on Buckett et al., 2005) and the surgery (Alsalili et al., to their children. Thus, assisted reproduction is 1995). There are also risks to the child and family important for both medical and social indications. unit, such as those owing to multiple births (Barrett Assisted reproduction is increasingly important and Bocking, 2000a, b). as many women delay having a child until they Gestational agreements (Rodgers et al., 1997; Ber, have employment and financial security. Delay in 2000) are often used in conjunction with assisted becoming pregnant predisposes a woman not only reproduction practices (Mykitiuk and Wallrap, to deplete her ovarian reserve but also to develop 2002; Rivard and Hunter, 2005). Although the more other etiologies of infertility, such as endometriosis common type of gestational agreement occurs or tubal occlusion, as well as lengthening her when the gestational carrier is impregnated with exposure to environmental toxins (Younglai et al., the sperm of the partner of a woman who, because 2002), an under-researched area (Royal Commis- of medical problems, cannot gestate her own sion on New Reproductive Technologies, 1993). embryo/fetus, gestational agreements may also Assisted reproduction is also increasingly impor- include those in which the embryo’s genetic make- tant as more women are surviving cancer treat- up has resulted from an oocyte other than that of ment, including leukemias in girls and adolescents, 114 R. Mykitiuk and J. Nisker lymphomas, and breast cancer (Nisker et al., 2006). Informed choice Women who have received chemotherapy, for Free and informed choice requires that the patient example, may have a dramatic decrease in the must be informed about the benefits and risks of number of ovarian Follicles that remain, and thus treatment, alternative courses of action, and the the normal attrition rate frequently causes these consequences of not having the treatment women to develop ovarian failure in their thirties (Mykitiuk and Wallrap, 2002). This includes the (Sklar et al., 2006). provision of sufficient information for the patient to be able to both understand and appreciate the Ethics chances of having a child for that particular patient Commercialization in that particular infertility clinic, including clarifi- cation of the meaning of success rates (as to bio- Commercialization and commodification of gam- chemical pregnancy or live birth), and the specific etes, and commercial gestational agreements, risks of treatment inherent for that patient (in gen- offend a number of ethical precepts including eral and in that particular clinic). Patients should respect for human integrity and dignity through the also be informed about the potential for multiple non-commodification and non-commercialization births to have physical and cognitive consequences of the person, her or his bodily parts, tissues, sub- for children, as well as social consequences for stances and processes; protection of vulnerable them and their families and financial costs (Barrett persons from coercion or inducement; and respect and Bocking, 2000a,b; Elster, 2000; Mykitiuk and for the patient–physician relationship by avoiding a Wallrap, 2002; Adamson and Baker, 2004). conflict of interest between the two parties (Royal A free choice process is difficult to ensure for sisters Commission on New Reproductive Technologies, and close friends of infertile women who have been 1993; Nisker and White, 2005). asked to become oocyte ‘‘donors’’ or gestational ‘‘Donation’’ is an ethically charged term in that, carriers for them (Rodgers et al., 1997; Ber, 2000). until the 1990s, in most countries, ‘‘donors’’ of sperm These women have indicated that they would feel and oocytes have been paid in the range of $100 for that they were a bad sister or a bad friend if they did sperm and between $1500 and $5000 for oocyte not comply with the request. Further, even in the donation (Nisker, 1996, 1997, 2001; Gurmankin, best-case scenarios for altruistic oocyte donation or 2001). In addition, oocyte ‘‘donors’’ are almost gestational agreements, ethical problems remain. always economically disadvantaged women who Informed choice is particularly difficult for those either sell their eggs to support their family or pay who are soon to undergo cancer treatment (Nisker tuition, or who barter half of their oocytes in order to et al., 2006).