Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
Assisted reproduction: Ethical and legal issues Laura Londra 1, Edward Wallach, Yulian Zhao* Department of Gynecology and Obstetrics at Johns Hopkins University School of Medicine, Division of Reproductive Endocrinology and Infertility, Lutherville, MD, USA
s u m m a r y Keywords: Assisted reproductive technologies Biomedical ethics In-vitro fertilization Legal aspects Reproductive medicine
Since inception, the use of assisted reproductive technologies (ART) has been accompanied by ethical, legal, and societal controversies. Guidelines have been developed to address many of these concerns; however, the rapid evolution of ART requires their frequent re-evaluation. We review the literature on ethical and legal aspects of ART, highlighting some of the most visible and challenging topics. Of specific interest are: reporting of ART procedures and outcomes; accessibility to ART procedures; issues related to fertility preservation, preimplantation genetic testing, gamete and embryo donation, and reproductive outcomes after embryo transfer. Improvements in ART reporting are needed nationally and worldwide. Reporting should include outcomes that enable patients to make informed decisions. Improving access to ART and optimizing long-term reproductive outcomes, while taking into account the legal and ethical consequences, are challenges that need to be addressed by the entire community of individuals involved in ART with the assistance of bioethicists, legal counselors, and members of society in general. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction The landscape of reproductive health was forever changed in 1978 after the birth of Louise Brown, ‘the world's first test tube baby’ [1]. The introduction of in-vitro fertilization (IVF) e with its ability to segment and modify what in the past had been a rather obscure biological process e brought as much social, ethical, and legal controversy as it did happiness and meaning to the lives of millions of individuals and couples. The basic bioethical principles of autonomy, beneficence, justice, and avoidance of maleficence are the pillars with which professional societies within the field of reproductive medicine have built recommendations guidelines [2]. These principles, although paramount for the protection of all parties involved, are often difficult to reconcile in the context of relentless scientific advancement, increasing social demands, and unique legal frameworks. In this review, we attempt to describe some of the most visible legal and ethical issues that have arisen in the dynamic field of assisted reproductive technologies (ART): (1) the way in which ART reporting systems provide information about the outcomes of ART procedures; (2) barriers to access to ART procedures; and (3) the ethical and legal implications of four specific areas of ART: fertility preservation, preimplantation genetic
* Corresponding author. Address: 10751 Falls Road, Suite 280, Lutherville, MD 21093, USA. Tel.: þ1 410 583 2762; fax: þ1 410 583 2767. E-mail address: [email protected] (Y. Zhao). 1 Edward E. Wallach Fellow in Reproductive Endocrinology and Infertility. http://dx.doi.org/10.1016/j.siny.2014.07.003 1744-165X/© 2014 Elsevier Ltd. All rights reserved.
testing, gamete and embryo donation, and reproductive outcomes after embryo transfer. 2. Legal and ethical aspects of ART reporting systems The monitoring of ART practices is essential to improving infertility care; this includes accurate and thorough reporting of the procedures and techniques used, as well as the documentation of reproductive outcomes that result from each type of procedure. This information constitutes the basis for improving practice guidelines and policies, and serves as an important resource for counseling patients. Worldwide, professional organizations have implemented reporting systems in order to generate more accurate estimates of measures of success and outcomes for ART procedures. The frequency and outcomes of techniques that are commonly reported through these systems include gamete donation, gamete cryopreservation, embryo cryopreservation, assisted hatching, and culture of embryos to the cleavage stage and to the blastocyst stage. Data on less common procedures such as surrogacy, multifetal reduction and in-vitro maturation of oocytes are less visible in the context of worldwide reporting systems. Since 1989, the International Committee for Monitoring Assisted Reproductive Technology (ICMART; originally known as International Working Group on Assisted Reproduction) has been reporting on the international availability, effectiveness and perinatal outcomes, as well as regional variations, of ART cycles [3]. In the USA, the Fertility Clinic
L. Londra et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 264e271
Success Rate and Certification Act was created in 1992 to standardize reporting of ART success rates across the country [4]. The Society for Assisted Reproductive Technology (SART) annually reports data on IVF cycles and birth outcomes for more than 90% of the ART clinics in the USA. Since 1996, the National Coalition for Oversight of Assisted Reproductive Technologies (NCOART) has connected various organizations involved in the practice of ART in the USA, including the American Society of Reproductive Medicine (ASRM), RESOLVE (the national infertility advocacy organization for consumers), the Centers for Disease Control (CDC), the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the American Association of Tissue Banks (AATB), the American Bar Association (ABA), the American Infertility Association (AIA), and the American Medical Association (AMA) [5]. Starting in 1996, the CDC initiated data collection on ART procedures performed in the USA, and since 2004 it has contracted with statistical survey research organizations to obtain data from IVF clinics through the web-based National ART Surveillance System (NASS). Relatively few clinics (~7%) do not report to the CDC and are listed as nonreporting programs in the Fertility Clinic Success Rates Report. Because these clinics tend to be smaller and conduct fewer procedures, NASS is estimated to contain information on more than 97% of all ART cycles performed in the USA [6,7]. Efforts have also been made to link IVF databases with registries for vital statistics in several states in the USA. Relevant data are routinely collected at the state level (birth certificate, infant deaths, hospital discharge, birth defects registries, and cancer registries), and are being used to conduct state-based surveillance of ART, infertility and related issues. The goal of this initiative, known as the SMART Collaborative, is to strengthen the capacity of states to evaluate perinatal outcomes and programs through state-based public health surveillance systems [8]. More recently, the Massachusetts Outcomes Study of Assisted Reproductive Technology (MOSART) database was developed as a similar model to assist in the understanding of the impact of each step of the IVF process on particular obstetric and birth outcomes [9]. The ASRM and the ESHRE regularly publish and update guidelines for the practice of ART, for techniques that are well established, such as IVF and embryo cryopreservation, as well as for experimental techniques, such as ovarian tissue cryopreservation [10]. These guidelines rely on the findings of worldwide and national reports of ART utilization and outcomes, and on scientific research. As an example, oocyte cryopreservation (OC) is the most recent technique to evolve from an experimental technique to a clinically accepted procedure within practice guidelines [11]. It is now considered reasonable to proceed with OC and banking of oocytes in women with a medical diagnosis of decreased ovarian reserve, recurrent fertilization failure, or recurrent failure of embryos to implant, as well as in women for whom embryo cryopreservation is not an option (e.g. no partner/sperm donor) [12]. Although the first reported birth after OC occurred in 1986 [13], technical challenges limited the use of the procedure until recently. Data from national and international reporting agencies are only now beginning to accumulate on the long-term outcomes of children born after using this technique. Reporting on the outcomes of IVF using this technique has not produced sufficient data to support recommendations for its use outside the setting of infertility, i.e. to ensure the possibility of future pregnancy in healthy women. 3. Legal and ethical issues regarding access to ART One question that arises frequently regarding infertility treatment access is whether prevention and/or treatment of infertility are a prudent use of resources [14]. The ‘right to procreate’ can be viewed as a ‘negative right’ or a ‘positive right’. In the first instance,
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the state does not interfere with one's ability to reproduce simply by not mandating sterilization and by not denying the use of infertility treatments. The case for the ‘positive right’, though, implies that the state should provide resources to help an otherwise infertile individual to procreate, expanding the concept of ‘access to the normal range of opportunities in society’ [15] to include the opportunity to parent a child. The ability to reproduce is considered the norm in most societies, but the complexity and nuances that surround the issue of accessibility to reproductive services is reflected in the significant policy differences seen worldwide and even within the USA, where laws and requisites differ from state to state with regard to access to and extent of insurance coverage for ART [16]. Recent data on the worldwide prevalence of involuntary childlessness indicate that more than 50 million couples would benefit from a medical intervention to achieve a pregnancy [17]. The consequences of undesired childlessness are particularly acute for women in developing countries, where unique sociocultural values are built around procreation, and childlessness often leads to stigmatization, isolation, ostracism, disinheritance and neglect by the entire family and community. In such settings, it is not uncommon for entire families to depend on children for economic survival, which extends the issue of procreation to one of social welfare and public health [18e20]. In 2004, the World Health Organization proposed ‘the provision of high-quality services for family-planning, including infertility services’ as part of its Global Strategy on Diet, Physical Activity and Health [21]. Yet, some of the most important international nonprofit organizations have continued to limit their focus to safe motherhood, the reduction of unsafe abortions and prevention of HIV. In 2006, ESHRE took steps toward providing infertility services to low-resource countries by forming a Special Task Force on ‘developing countries and infertility’. In 2007, it partnered with The Walking Egg Project, a non-profit organization that aims to make infertility care available and accessible through the development of low-cost ovarian stimulation protocols and simplified culture systems for IVF [22]. Contrary to common belief, most infertile women live in underdeveloped nations; The Walking Egg Project aims to stimulate research on social, cultural, ethical, and legal aspects of the problem of infertility in these economically disadvantaged populations [23,24].
4. Ethical and legal implications of ART procedures 4.1. Fertility preservation The introduction and continuous advances made in the field of cryopreservation catalyzed the development and application of fertility preservation techniques for those women, men, and children who have a disease or who are undergoing treatment that threatens their reproductive health. Fertility preservation for patients with cancer emerged in response to the increasing survival rates among reproductive-age patients. These patients could choose to preserve fertile gametes before undergoing gonadotoxic cancer treatments, with the intention of using them for IVF in the future [25]. In general, it is recommended that clinicians inform patients who are about to receive any treatment that could potentially harm their ultimate ability to conceive regarding the established methods for fertility preservation. Those methods include sperm cryopreservation in men and postpubertal boys and embryo and OC in women and postpubertal girls [26]. Currently, the cryopreservation of ovarian tissue can only be offered in the context of a research protocol with institutional review board oversight [12].
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Fertility preservation in patients with cancer raises numerous ethical concerns regarding the welfare of the offspring and the terms of the informed consent in cases where the individuals do not survive their cancer or are no longer able to make decisions. Informed consent in fertility preservation is generally similar to that used in other situations where gametes or embryos are cryopreserved; however, older children and adolescent patients may also provide assent to undergo fertility preservation procedures [27]. Following cancer treatment, additional questions require individual counseling, such as whether it is possible or safe to carry a pregnancy, which is highly dependent on the type of cancer and treatment. Fertility options should be reviewed with survivors in the context of their survivorship status, including trying to conceive spontaneously if there is remaining gonadal function, using their cryopreserved gametes or embryos, involving a gestational carrier, obtaining donated gametes or embryos, seeking adoption services, or deciding not to pursue pregnancy. Sperm cryopreservation has been available for decades, but the introduction of more effective techniques to cryopreserve oocytes, i.e. vitrification, has raised the possibility also of ‘banking’ oocytes. Parallels have been drawn between oocyte vitrification and the oral contraceptive pill in their ability to ‘level the playing field’ for women who need or want to postpone pregnancy [28]. In 2013, ASRM officially removed the label ‘experimental’ from OC and recommended that it be offered to women for fertility preservation [12]. OC is primarily directed to women or postpubertal girls who are unable or unwilling to produce embryos for cryopreservation; for example, young women without a partner or those who are unwilling to use banked sperm to produce embryos. Some infertile couples may have failed to obtain sperm on the day of oocyte retrieval; other patients may have personal or ethical reasons for not creating embryos at the time of oocyte retrieval. For prepubertal children, the only option for preserving fertility is cryopreservation of gonadal tissue. This procedure is still considered experimental although the number of live births reported after thawed tissue transplantation continues to increase [29,30]. Beyond its use in patients with cancer, OC is also a reasonable option for women with BRCA mutations who are advised to undergo salpingo-oophorectomy by age 35 years in order to reduce the likelihood of ovarian cancer later in life. Conditions associated with early ovarian failure, such as Turner syndrome and fragile X syndrome, are additional possible indications for OC. In men, the most common cause of anticipated loss of gonadal function in a non-cancer setting is Klinefelter syndrome, which affects one in 600 newborns. Since it is estimated that in 90% of cases these individuals are going to lose their ability to produce sperm by adulthood, a recommended strategy is to obtain and cryopreserve ejaculated sperm from adolescent or adult patients [31,32]. One ongoing ethical issue in the field of fertility preservation involves pressures to include otherwise healthy women for whom pregnancy is not possible or desired at the present time. It is interesting to note that, among IVF practices that offer oocyte banking, most procedures are not conducted in the context of infertility or fertility preservation; instead they are elective procedures designed to cryopreserve gametes for the purpose of postponing pregnancy for personal or professional reasons, also known as ‘delayed childbearing’ [33]. ASRM has cautioned practitioners about marketing OC to women, particularly to those in their late reproductive years for delayed childbearing, as it might offer false hope with success rates decreasing after age 38 years [34]. Pregnancy outcomes are also compromised in the older population, because older women are at increased risk for obstetric complications [35]. For these reasons, there seems to be insufficient evidence to recommend elective OC for deferred childbearing [11].
4.2. Preimplantation genetic testing 4.2.1. Preimplantation genetic screening There is an ongoing quest for methods that can determine embryo quality and enable the selection of embryos with the highest potential for a healthy pregnancy and normal baby. Chromosome aneuploidy is a major cause of IVF failure, pregnancy loss and, rarely, abnormal pregnancy or live birth. Currently, preimplantation genetic screening (PGS) enables analysis of the 23 pairs of chromosomes by comparative genomic hybridization (CGH), microarray-based CGH (array CGH), digital polymerase chain reaction (PCR), real-time quantitative PCR, single nucleotide polymorphism (SNP) microarray, and next generation sequencing technologies [36]. PGS therefore is currently used as an adjunct to IVF to increase pregnancy rates, decrease miscarriage rates and prevent abnormal pregnancy and live births. Indications for PGS include advanced maternal age (>35 years), previous aneuploid pregnancy, repeated IVF failure, repeated miscarriage and severe male infertility. Because the information provided by PGS will not change the quality of the embryo cohort, the most useful application is to identify aneuploid embryos. Consequently, PGS should reduce the ‘time to pregnancy’ by increasing the pregnancy rate per transfer if embryos with the highest implantation potential within the cohort are transferred first [37]. An additional technical issue with PGS involves the timing of embryo biopsy during development to retrieve cells that are representative of the true ploidy status of the future offspring. Improvements in implantation rates and decreases in miscarriage rates have been achieved based on biopsies of cells at the blastocyst stage of the embryo. Nevertheless, couples should always be informed about the risk of false-positive results, which could lead to the discarding of a normal embryo, or false-negative results, which could lead to the transfer of an abnormal embryo. Randomized studies that help to establish the magnitude of these risks for PGS at the blastocyst stage are very limited; a recent study estimated a clinical error rate of an aneuploidy designation at 4% [38]. The risks associated with embryo biopsy have thus far not been completely elucidated. Concern centers on damaging a healthy embryo as a result of the biopsy and on potential long-term effects in the offspring. Non-invasive methods to assess embryo development and quality are thus being developed. Most recently, the morphokinetic patterns of embryo development in culture, recorded in incubators fitted with time-lapse microscopy, have been correlated with karyotype results [39]. The effectiveness and accuracy of these technologies for screening embryos is still preliminary, but continue to be pursued because they avoid the potential risks associated with biopsy. The ability to analyze the genetic make-up of the embryo prior to transfer has triggered controversy over the ethical implications of embryo selection. Concerns exist regarding the consequences of having genetic information in advance, such as the potential for gender selection and discarding embryos affected with known genetic disorders. Gender selection is in itself considered highly questionable from both ethical and biological points of view. Some professional organizations have tempered their views when selection is done in the name of ‘family balancing’, i.e. when a family has only children of the same sex and would like to have a child of the opposite sex. In their practice guidelines, multiple professional societies have voiced concerns about the potential for inherent gender discrimination, inappropriate use of medical resources, psychological harm to sex-selected offspring (i.e. placing high expectations on the resulting children), marital conflict over sex selection decisions, and reinforcement of gender bias in society as a whole [40,41]. The consequences of technologies that enable sex selection are particularly serious in countries such as India and
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China, where a cultural bias favoring males has led to a severely altered sex ratio with significantly fewer females [42]. However, an altered sex ratio in these populations has not been related to the use of PGS but to the early termination of pregnancies once the sex of the fetus has been identified [43]. Preconception selection of gender based on sperm separation or other techniques is still considered experimental. The ASRM recommends that the use of ART techniques for ‘family balancing’ should be considered if the couples are fully informed of the risks of failure, affirm that they will fully accept children of the undesired sex if the gender selection technique fails, are counseled about having unrealistic expectations about the child of the preferred gender, and are offered the opportunity to participate in research to track and assess the safety, efficacy and demographics of preconception selection [41]. 4.2.2. Preimplantation genetic diagnosis Preimplantation genetic diagnosis (PGD) was initially developed to help selected couples prevent the birth of a child with a known single-gene abnormality or an adult-onset genetic condition. Couples who wish to have PGD may or may not be infertile; in certain cases, particularly where one of the parents is a balanced carrier of a structural chromosome abnormality, infertility or recurrent miscarriage may be a consequence of the genetic defect. PGD is considered ethically justifiable when the genetic condition is serious and there are no known safe, effective interventions to treat it [44]. The extent to which a condition is considered ‘serious’ is not clearly defined, but PGD is being used to identify embryos that carry genes for childhood-onset diseases such as hemophilia or cystic fibrosis, and, more recently, to identify embryos with singlegene diseases that do not develop until adulthood, such as Huntington disease, and with cancer predisposition genes such as BRCA [45]. The use of PGD reduces the chance that parents will be faced with the difficult decision to terminate a pregnancy if the genetic disorder is detected during the course of gestation. PGD has been widely accepted for this purpose, although it has also been suggested that PGD may have the effect of devaluing persons in the community with disabilities that could have been detected and selected against in the embryo stage [46]. On the other hand, it has been reported that, although infrequently, patients who carry certain genetic conditions such as deafness or dwarfism had requested PGD on their embryos with the intention of transferring only those embryos that test positive for the condition, which poses a very challenging ethical dilemma for the caregiver [47]. The fear that in the future, PGD technology may lead to the manipulation of genetic material within an embryo is a matter of concern. The potential for using preimplantational testing to create a ‘donor child’ who is immunologically compatible with an existing sick sibling in need of a tissue or organ transplant has raised concerns about the need to set limits for PGD and establish procedures to protect such children from exploitation until they are able to make autonomous decisions. In such situations, parents may not be the best proxy decision-makers, because they face a conflict of interest between their children [46]. Rigorous public and scientific oversight of these technologies is vital to ensure that scientific advances are tempered with the best interests of society. 4.3. Gamete and embryo donation Gamete and embryo donation have significantly expanded the options available to infertile couples. However, they each pose unique ethical and legal issues, some of which remain unresolved. Government and non-governmental agencies, academic institutions, the public and the media have debated the safety and well-being of the donors, the infertile couples and, increasingly, the offspring. Recommendations and guidelines for gamete and
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embryo donation vary worldwide, reflecting specific needs and views; the ability to use donor gametes and embryos varies from a total ban to a lack of specific statutes governing its use [48]. There are at least two aspects of the donation procedure that highlight the need for regulations, legal agreements, and informed consent. First, the ability to cryopreserve sperm and oocytes for later use extends the period of time between the acquisition of the donated gametes and the actual fertilization and embryo development. This temporal separation broadens the potential areas of ethical and legal contention. Informed consent and legal agreements about the use and storage of the gametes, as well as how medical records are kept over time, need to include provisions for periodic updates in the terms of the contract among donors, practices and recipients. Another aspect of gamete donation that carries ethical and legal implications is the fact that oocyte donors must undergo hormonal stimulation and oocyte retrieval procedures. In comparison to donation of male gametes, the donation of oocytes introduces a higher level of medical risk that includes ovarian hyperstimulation syndrome and surgical complications [49e51]. Although the reported frequency of complications in IVF cycles is relatively low [52], oocyte donors need to be fully informed of specific risks, and donation programs have an obligation to ensure that donors have appropriate health insurance coverage. Additionally, genetic testing performed in a candidate gamete donor may produce unexpected information. It is therefore important to have an agreement in place prior to testing that stipulates how the results and their disclosure will be managed. Furthermore, whereas donors are asked to be honest about their family and personal health histories before the gamete or embryo donation, it is less clear as to what extent donors should keep programs or recipients updated about relevant health issues following donation to protect the health of the offspring. Perhaps two of the most contentious issues surrounding gamete donation are the disclosure to the offspring and compensation for donors. Interests and views among involved parties e the donors, programs, parents and offspring e may vary regarding disclosure of the use of donor gametes or embryos. Voluntary disclosure is ultimately a choice of recipient couples, but, in recent years, the disclosure to the donor-conceived offspring has been encouraged in guideline recommendations [53,54]. These recommendations are supported by studies showing that disclosure may be less disruptive for the donor-conceived person than previously anticipated [55,56]. Yet, disclosure to the offspring about donor use raises an additional issue: the right to access information about the donor. The balancing of the rights of all parties involved requires the utmost sensitivity [57,58]. Though ASRM has identified different levels of donor information sharing [59], the most recent recommendations [53], coupled with the concerns voiced by ethics and legal experts about permitting either the donor or the offspring to break anonymity, will undoubtedly continue to fuel a lively debate on this issue worldwide [54,60,61]. In certain countries, such as the UK, the donor's anonymity can be legally lifted once the child reaches adulthood, based on the idea that the children were not part of the original donorerecipient contract and the decisionmaking process that motivated their existence. Therefore, the rights of the children are seen to override those of the adults who voluntarily participated in the original contract [62]. Furthermore, the amount of information and record-keeping obligations have increased, as reflected in recommendations from professional societies calling for permanent record maintenance [63]. Similar concerns regarding the management of anonymity issues apply to the case of embryo donation. Parties must be counseled that even if proper legal arrangements are in place at the time of the donation procedure, later changes in law may affect the enforcement of previous agreements. Another consideration regarding disclosure is
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the possibility that donors may have or plan to have their own children in the future, such that a donor-conceived child may have genetic siblings. As such, donors should also be advised that their present or future partner may have an interest in the consequences of the donation or its disclosure [58]. The ethical and legal aspects that surround the issue of compensation for gamete donors has been the subject of intense media coverage [64,65] and academic debate [60], which has overwhelmingly focused on the financial incentives for egg donors. The reason is apparent: compared to sperm donors, the financial compensation for egg donors is far higher, as are the risks and complexity involved in undergoing an IVF cycle to retrieve oocytes. The concept of turning human gametes into a commodity (‘commodification’), has raised ethical concerns and is given as the main argument against the idea of remunerating oocyte donors [50]. Regulations governing this practice are constantly evolving and differ substantially from country to country. In the USA, the ASRM has affirmed that ‘financial compensation of women donating oocytes for infertility therapy … is justified on ethical grounds’ [59,66]. ASRM guidelines state that ‘time, inconvenience, and discomfort’ associated with the donation process should be the guide for compensation, rather than particular human traits, or personal characteristics of the donors. However, a recent survey found that the content of 34e56% of agency and clinic websites does not reflect the ASRM recommendations [67] on this matter. Finally, couples undergoing IVF often reach their desired family size before transferring all of their generated embryos or using their cryopreserved gametes. The magnitude of the problem of unused cryopreserved embryos has been explored in US IVF practices, under the spotlight of intense media debate regarding embryo fate [68]. The findings have led to periodic updates on guidelines from the Ethics Committee of ASRM [69] on the multiple ways to deal with surplus cryopreserved embryos: thawing and discarding, donating the embryos to another couple for the purpose of a pregnancy attempt, donating embryos to an institution for the purpose of advancing research, and indefinite storage. Uterine transfer of the embryos at a time not favorable to implantation has been proposed as a sensible way of dealing with the fate of these embryos [70]. One area of recent debate has been the use of surplus embryos for stem cell research, which overlaps with the issue of donating oocytes for research [71e73]. Each of these strategies has encountered supporters and detractors [71,74,75], which ultimately reflects in the wide variations in laws and regulations in place worldwide. At present, US law does not give clear guidance on discarding abandoned embryos. The ASRM continuously provides updated guidelines on how best to manage these issues in a rapidly changing scientific and legal environment [69,71,76e79].
4.4. Reproductive outcomes after ART ART is associated with potential risks to both the mother and fetus. Because multiple embryos are transferred in the majority of ART procedures, ART has been associated with a substantial risk for multiple-gestation pregnancy and multiple births [6,80,81]. Multiple births are associated with greater health problems for mothers and infants, including higher rates of caesarean deliveries, prematurity, low birth weight, infant death, elevated risk of birth defects and disability [82,83]. The contribution of ART to adverse perinatal outcomes in recent years is mainly due to the persistently high
number of twin pregnancies. The transfer of a single embryo in patients with a favorable prognosis has been shown to be effective in keeping pregnancy rates and live birth rates high, but with a significant reduction in multiple births; however, the ethical forces at play in the absence of a mandatory policy or oversight regarding the number of embryos transferred have been difficult to reconcile in the USA [2]. In Europe, the Belgian model of practice with singleembryo transfer (SET) is an example of a successful intervention. From 1 July 2003, SET and elective SET have been established by Belgian law in first and second IVF cycles, respectively, for patients aged
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
Assisted reproduction: Ethical and legal issues Laura Londra 1, Edward Wallach, Yulian Zhao* Department of Gynecology and Obstetrics at Johns Hopkins University School of Medicine, Division of Reproductive Endocrinology and Infertility, Lutherville, MD, USA
s u m m a r y Keywords: Assisted reproductive technologies Biomedical ethics In-vitro fertilization Legal aspects Reproductive medicine
Since inception, the use of assisted reproductive technologies (ART) has been accompanied by ethical, legal, and societal controversies. Guidelines have been developed to address many of these concerns; however, the rapid evolution of ART requires their frequent re-evaluation. We review the literature on ethical and legal aspects of ART, highlighting some of the most visible and challenging topics. Of specific interest are: reporting of ART procedures and outcomes; accessibility to ART procedures; issues related to fertility preservation, preimplantation genetic testing, gamete and embryo donation, and reproductive outcomes after embryo transfer. Improvements in ART reporting are needed nationally and worldwide. Reporting should include outcomes that enable patients to make informed decisions. Improving access to ART and optimizing long-term reproductive outcomes, while taking into account the legal and ethical consequences, are challenges that need to be addressed by the entire community of individuals involved in ART with the assistance of bioethicists, legal counselors, and members of society in general. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction The landscape of reproductive health was forever changed in 1978 after the birth of Louise Brown, ‘the world's first test tube baby’ [1]. The introduction of in-vitro fertilization (IVF) e with its ability to segment and modify what in the past had been a rather obscure biological process e brought as much social, ethical, and legal controversy as it did happiness and meaning to the lives of millions of individuals and couples. The basic bioethical principles of autonomy, beneficence, justice, and avoidance of maleficence are the pillars with which professional societies within the field of reproductive medicine have built recommendations guidelines [2]. These principles, although paramount for the protection of all parties involved, are often difficult to reconcile in the context of relentless scientific advancement, increasing social demands, and unique legal frameworks. In this review, we attempt to describe some of the most visible legal and ethical issues that have arisen in the dynamic field of assisted reproductive technologies (ART): (1) the way in which ART reporting systems provide information about the outcomes of ART procedures; (2) barriers to access to ART procedures; and (3) the ethical and legal implications of four specific areas of ART: fertility preservation, preimplantation genetic
* Corresponding author. Address: 10751 Falls Road, Suite 280, Lutherville, MD 21093, USA. Tel.: þ1 410 583 2762; fax: þ1 410 583 2767. E-mail address: [email protected] (Y. Zhao). 1 Edward E. Wallach Fellow in Reproductive Endocrinology and Infertility. http://dx.doi.org/10.1016/j.siny.2014.07.003 1744-165X/© 2014 Elsevier Ltd. All rights reserved.
testing, gamete and embryo donation, and reproductive outcomes after embryo transfer. 2. Legal and ethical aspects of ART reporting systems The monitoring of ART practices is essential to improving infertility care; this includes accurate and thorough reporting of the procedures and techniques used, as well as the documentation of reproductive outcomes that result from each type of procedure. This information constitutes the basis for improving practice guidelines and policies, and serves as an important resource for counseling patients. Worldwide, professional organizations have implemented reporting systems in order to generate more accurate estimates of measures of success and outcomes for ART procedures. The frequency and outcomes of techniques that are commonly reported through these systems include gamete donation, gamete cryopreservation, embryo cryopreservation, assisted hatching, and culture of embryos to the cleavage stage and to the blastocyst stage. Data on less common procedures such as surrogacy, multifetal reduction and in-vitro maturation of oocytes are less visible in the context of worldwide reporting systems. Since 1989, the International Committee for Monitoring Assisted Reproductive Technology (ICMART; originally known as International Working Group on Assisted Reproduction) has been reporting on the international availability, effectiveness and perinatal outcomes, as well as regional variations, of ART cycles [3]. In the USA, the Fertility Clinic
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Success Rate and Certification Act was created in 1992 to standardize reporting of ART success rates across the country [4]. The Society for Assisted Reproductive Technology (SART) annually reports data on IVF cycles and birth outcomes for more than 90% of the ART clinics in the USA. Since 1996, the National Coalition for Oversight of Assisted Reproductive Technologies (NCOART) has connected various organizations involved in the practice of ART in the USA, including the American Society of Reproductive Medicine (ASRM), RESOLVE (the national infertility advocacy organization for consumers), the Centers for Disease Control (CDC), the Food and Drug Administration (FDA), the National Institutes of Health (NIH), the American Association of Tissue Banks (AATB), the American Bar Association (ABA), the American Infertility Association (AIA), and the American Medical Association (AMA) [5]. Starting in 1996, the CDC initiated data collection on ART procedures performed in the USA, and since 2004 it has contracted with statistical survey research organizations to obtain data from IVF clinics through the web-based National ART Surveillance System (NASS). Relatively few clinics (~7%) do not report to the CDC and are listed as nonreporting programs in the Fertility Clinic Success Rates Report. Because these clinics tend to be smaller and conduct fewer procedures, NASS is estimated to contain information on more than 97% of all ART cycles performed in the USA [6,7]. Efforts have also been made to link IVF databases with registries for vital statistics in several states in the USA. Relevant data are routinely collected at the state level (birth certificate, infant deaths, hospital discharge, birth defects registries, and cancer registries), and are being used to conduct state-based surveillance of ART, infertility and related issues. The goal of this initiative, known as the SMART Collaborative, is to strengthen the capacity of states to evaluate perinatal outcomes and programs through state-based public health surveillance systems [8]. More recently, the Massachusetts Outcomes Study of Assisted Reproductive Technology (MOSART) database was developed as a similar model to assist in the understanding of the impact of each step of the IVF process on particular obstetric and birth outcomes [9]. The ASRM and the ESHRE regularly publish and update guidelines for the practice of ART, for techniques that are well established, such as IVF and embryo cryopreservation, as well as for experimental techniques, such as ovarian tissue cryopreservation [10]. These guidelines rely on the findings of worldwide and national reports of ART utilization and outcomes, and on scientific research. As an example, oocyte cryopreservation (OC) is the most recent technique to evolve from an experimental technique to a clinically accepted procedure within practice guidelines [11]. It is now considered reasonable to proceed with OC and banking of oocytes in women with a medical diagnosis of decreased ovarian reserve, recurrent fertilization failure, or recurrent failure of embryos to implant, as well as in women for whom embryo cryopreservation is not an option (e.g. no partner/sperm donor) [12]. Although the first reported birth after OC occurred in 1986 [13], technical challenges limited the use of the procedure until recently. Data from national and international reporting agencies are only now beginning to accumulate on the long-term outcomes of children born after using this technique. Reporting on the outcomes of IVF using this technique has not produced sufficient data to support recommendations for its use outside the setting of infertility, i.e. to ensure the possibility of future pregnancy in healthy women. 3. Legal and ethical issues regarding access to ART One question that arises frequently regarding infertility treatment access is whether prevention and/or treatment of infertility are a prudent use of resources [14]. The ‘right to procreate’ can be viewed as a ‘negative right’ or a ‘positive right’. In the first instance,
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the state does not interfere with one's ability to reproduce simply by not mandating sterilization and by not denying the use of infertility treatments. The case for the ‘positive right’, though, implies that the state should provide resources to help an otherwise infertile individual to procreate, expanding the concept of ‘access to the normal range of opportunities in society’ [15] to include the opportunity to parent a child. The ability to reproduce is considered the norm in most societies, but the complexity and nuances that surround the issue of accessibility to reproductive services is reflected in the significant policy differences seen worldwide and even within the USA, where laws and requisites differ from state to state with regard to access to and extent of insurance coverage for ART [16]. Recent data on the worldwide prevalence of involuntary childlessness indicate that more than 50 million couples would benefit from a medical intervention to achieve a pregnancy [17]. The consequences of undesired childlessness are particularly acute for women in developing countries, where unique sociocultural values are built around procreation, and childlessness often leads to stigmatization, isolation, ostracism, disinheritance and neglect by the entire family and community. In such settings, it is not uncommon for entire families to depend on children for economic survival, which extends the issue of procreation to one of social welfare and public health [18e20]. In 2004, the World Health Organization proposed ‘the provision of high-quality services for family-planning, including infertility services’ as part of its Global Strategy on Diet, Physical Activity and Health [21]. Yet, some of the most important international nonprofit organizations have continued to limit their focus to safe motherhood, the reduction of unsafe abortions and prevention of HIV. In 2006, ESHRE took steps toward providing infertility services to low-resource countries by forming a Special Task Force on ‘developing countries and infertility’. In 2007, it partnered with The Walking Egg Project, a non-profit organization that aims to make infertility care available and accessible through the development of low-cost ovarian stimulation protocols and simplified culture systems for IVF [22]. Contrary to common belief, most infertile women live in underdeveloped nations; The Walking Egg Project aims to stimulate research on social, cultural, ethical, and legal aspects of the problem of infertility in these economically disadvantaged populations [23,24].
4. Ethical and legal implications of ART procedures 4.1. Fertility preservation The introduction and continuous advances made in the field of cryopreservation catalyzed the development and application of fertility preservation techniques for those women, men, and children who have a disease or who are undergoing treatment that threatens their reproductive health. Fertility preservation for patients with cancer emerged in response to the increasing survival rates among reproductive-age patients. These patients could choose to preserve fertile gametes before undergoing gonadotoxic cancer treatments, with the intention of using them for IVF in the future [25]. In general, it is recommended that clinicians inform patients who are about to receive any treatment that could potentially harm their ultimate ability to conceive regarding the established methods for fertility preservation. Those methods include sperm cryopreservation in men and postpubertal boys and embryo and OC in women and postpubertal girls [26]. Currently, the cryopreservation of ovarian tissue can only be offered in the context of a research protocol with institutional review board oversight [12].
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Fertility preservation in patients with cancer raises numerous ethical concerns regarding the welfare of the offspring and the terms of the informed consent in cases where the individuals do not survive their cancer or are no longer able to make decisions. Informed consent in fertility preservation is generally similar to that used in other situations where gametes or embryos are cryopreserved; however, older children and adolescent patients may also provide assent to undergo fertility preservation procedures [27]. Following cancer treatment, additional questions require individual counseling, such as whether it is possible or safe to carry a pregnancy, which is highly dependent on the type of cancer and treatment. Fertility options should be reviewed with survivors in the context of their survivorship status, including trying to conceive spontaneously if there is remaining gonadal function, using their cryopreserved gametes or embryos, involving a gestational carrier, obtaining donated gametes or embryos, seeking adoption services, or deciding not to pursue pregnancy. Sperm cryopreservation has been available for decades, but the introduction of more effective techniques to cryopreserve oocytes, i.e. vitrification, has raised the possibility also of ‘banking’ oocytes. Parallels have been drawn between oocyte vitrification and the oral contraceptive pill in their ability to ‘level the playing field’ for women who need or want to postpone pregnancy [28]. In 2013, ASRM officially removed the label ‘experimental’ from OC and recommended that it be offered to women for fertility preservation [12]. OC is primarily directed to women or postpubertal girls who are unable or unwilling to produce embryos for cryopreservation; for example, young women without a partner or those who are unwilling to use banked sperm to produce embryos. Some infertile couples may have failed to obtain sperm on the day of oocyte retrieval; other patients may have personal or ethical reasons for not creating embryos at the time of oocyte retrieval. For prepubertal children, the only option for preserving fertility is cryopreservation of gonadal tissue. This procedure is still considered experimental although the number of live births reported after thawed tissue transplantation continues to increase [29,30]. Beyond its use in patients with cancer, OC is also a reasonable option for women with BRCA mutations who are advised to undergo salpingo-oophorectomy by age 35 years in order to reduce the likelihood of ovarian cancer later in life. Conditions associated with early ovarian failure, such as Turner syndrome and fragile X syndrome, are additional possible indications for OC. In men, the most common cause of anticipated loss of gonadal function in a non-cancer setting is Klinefelter syndrome, which affects one in 600 newborns. Since it is estimated that in 90% of cases these individuals are going to lose their ability to produce sperm by adulthood, a recommended strategy is to obtain and cryopreserve ejaculated sperm from adolescent or adult patients [31,32]. One ongoing ethical issue in the field of fertility preservation involves pressures to include otherwise healthy women for whom pregnancy is not possible or desired at the present time. It is interesting to note that, among IVF practices that offer oocyte banking, most procedures are not conducted in the context of infertility or fertility preservation; instead they are elective procedures designed to cryopreserve gametes for the purpose of postponing pregnancy for personal or professional reasons, also known as ‘delayed childbearing’ [33]. ASRM has cautioned practitioners about marketing OC to women, particularly to those in their late reproductive years for delayed childbearing, as it might offer false hope with success rates decreasing after age 38 years [34]. Pregnancy outcomes are also compromised in the older population, because older women are at increased risk for obstetric complications [35]. For these reasons, there seems to be insufficient evidence to recommend elective OC for deferred childbearing [11].
4.2. Preimplantation genetic testing 4.2.1. Preimplantation genetic screening There is an ongoing quest for methods that can determine embryo quality and enable the selection of embryos with the highest potential for a healthy pregnancy and normal baby. Chromosome aneuploidy is a major cause of IVF failure, pregnancy loss and, rarely, abnormal pregnancy or live birth. Currently, preimplantation genetic screening (PGS) enables analysis of the 23 pairs of chromosomes by comparative genomic hybridization (CGH), microarray-based CGH (array CGH), digital polymerase chain reaction (PCR), real-time quantitative PCR, single nucleotide polymorphism (SNP) microarray, and next generation sequencing technologies [36]. PGS therefore is currently used as an adjunct to IVF to increase pregnancy rates, decrease miscarriage rates and prevent abnormal pregnancy and live births. Indications for PGS include advanced maternal age (>35 years), previous aneuploid pregnancy, repeated IVF failure, repeated miscarriage and severe male infertility. Because the information provided by PGS will not change the quality of the embryo cohort, the most useful application is to identify aneuploid embryos. Consequently, PGS should reduce the ‘time to pregnancy’ by increasing the pregnancy rate per transfer if embryos with the highest implantation potential within the cohort are transferred first [37]. An additional technical issue with PGS involves the timing of embryo biopsy during development to retrieve cells that are representative of the true ploidy status of the future offspring. Improvements in implantation rates and decreases in miscarriage rates have been achieved based on biopsies of cells at the blastocyst stage of the embryo. Nevertheless, couples should always be informed about the risk of false-positive results, which could lead to the discarding of a normal embryo, or false-negative results, which could lead to the transfer of an abnormal embryo. Randomized studies that help to establish the magnitude of these risks for PGS at the blastocyst stage are very limited; a recent study estimated a clinical error rate of an aneuploidy designation at 4% [38]. The risks associated with embryo biopsy have thus far not been completely elucidated. Concern centers on damaging a healthy embryo as a result of the biopsy and on potential long-term effects in the offspring. Non-invasive methods to assess embryo development and quality are thus being developed. Most recently, the morphokinetic patterns of embryo development in culture, recorded in incubators fitted with time-lapse microscopy, have been correlated with karyotype results [39]. The effectiveness and accuracy of these technologies for screening embryos is still preliminary, but continue to be pursued because they avoid the potential risks associated with biopsy. The ability to analyze the genetic make-up of the embryo prior to transfer has triggered controversy over the ethical implications of embryo selection. Concerns exist regarding the consequences of having genetic information in advance, such as the potential for gender selection and discarding embryos affected with known genetic disorders. Gender selection is in itself considered highly questionable from both ethical and biological points of view. Some professional organizations have tempered their views when selection is done in the name of ‘family balancing’, i.e. when a family has only children of the same sex and would like to have a child of the opposite sex. In their practice guidelines, multiple professional societies have voiced concerns about the potential for inherent gender discrimination, inappropriate use of medical resources, psychological harm to sex-selected offspring (i.e. placing high expectations on the resulting children), marital conflict over sex selection decisions, and reinforcement of gender bias in society as a whole [40,41]. The consequences of technologies that enable sex selection are particularly serious in countries such as India and
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China, where a cultural bias favoring males has led to a severely altered sex ratio with significantly fewer females [42]. However, an altered sex ratio in these populations has not been related to the use of PGS but to the early termination of pregnancies once the sex of the fetus has been identified [43]. Preconception selection of gender based on sperm separation or other techniques is still considered experimental. The ASRM recommends that the use of ART techniques for ‘family balancing’ should be considered if the couples are fully informed of the risks of failure, affirm that they will fully accept children of the undesired sex if the gender selection technique fails, are counseled about having unrealistic expectations about the child of the preferred gender, and are offered the opportunity to participate in research to track and assess the safety, efficacy and demographics of preconception selection [41]. 4.2.2. Preimplantation genetic diagnosis Preimplantation genetic diagnosis (PGD) was initially developed to help selected couples prevent the birth of a child with a known single-gene abnormality or an adult-onset genetic condition. Couples who wish to have PGD may or may not be infertile; in certain cases, particularly where one of the parents is a balanced carrier of a structural chromosome abnormality, infertility or recurrent miscarriage may be a consequence of the genetic defect. PGD is considered ethically justifiable when the genetic condition is serious and there are no known safe, effective interventions to treat it [44]. The extent to which a condition is considered ‘serious’ is not clearly defined, but PGD is being used to identify embryos that carry genes for childhood-onset diseases such as hemophilia or cystic fibrosis, and, more recently, to identify embryos with singlegene diseases that do not develop until adulthood, such as Huntington disease, and with cancer predisposition genes such as BRCA [45]. The use of PGD reduces the chance that parents will be faced with the difficult decision to terminate a pregnancy if the genetic disorder is detected during the course of gestation. PGD has been widely accepted for this purpose, although it has also been suggested that PGD may have the effect of devaluing persons in the community with disabilities that could have been detected and selected against in the embryo stage [46]. On the other hand, it has been reported that, although infrequently, patients who carry certain genetic conditions such as deafness or dwarfism had requested PGD on their embryos with the intention of transferring only those embryos that test positive for the condition, which poses a very challenging ethical dilemma for the caregiver [47]. The fear that in the future, PGD technology may lead to the manipulation of genetic material within an embryo is a matter of concern. The potential for using preimplantational testing to create a ‘donor child’ who is immunologically compatible with an existing sick sibling in need of a tissue or organ transplant has raised concerns about the need to set limits for PGD and establish procedures to protect such children from exploitation until they are able to make autonomous decisions. In such situations, parents may not be the best proxy decision-makers, because they face a conflict of interest between their children [46]. Rigorous public and scientific oversight of these technologies is vital to ensure that scientific advances are tempered with the best interests of society. 4.3. Gamete and embryo donation Gamete and embryo donation have significantly expanded the options available to infertile couples. However, they each pose unique ethical and legal issues, some of which remain unresolved. Government and non-governmental agencies, academic institutions, the public and the media have debated the safety and well-being of the donors, the infertile couples and, increasingly, the offspring. Recommendations and guidelines for gamete and
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embryo donation vary worldwide, reflecting specific needs and views; the ability to use donor gametes and embryos varies from a total ban to a lack of specific statutes governing its use [48]. There are at least two aspects of the donation procedure that highlight the need for regulations, legal agreements, and informed consent. First, the ability to cryopreserve sperm and oocytes for later use extends the period of time between the acquisition of the donated gametes and the actual fertilization and embryo development. This temporal separation broadens the potential areas of ethical and legal contention. Informed consent and legal agreements about the use and storage of the gametes, as well as how medical records are kept over time, need to include provisions for periodic updates in the terms of the contract among donors, practices and recipients. Another aspect of gamete donation that carries ethical and legal implications is the fact that oocyte donors must undergo hormonal stimulation and oocyte retrieval procedures. In comparison to donation of male gametes, the donation of oocytes introduces a higher level of medical risk that includes ovarian hyperstimulation syndrome and surgical complications [49e51]. Although the reported frequency of complications in IVF cycles is relatively low [52], oocyte donors need to be fully informed of specific risks, and donation programs have an obligation to ensure that donors have appropriate health insurance coverage. Additionally, genetic testing performed in a candidate gamete donor may produce unexpected information. It is therefore important to have an agreement in place prior to testing that stipulates how the results and their disclosure will be managed. Furthermore, whereas donors are asked to be honest about their family and personal health histories before the gamete or embryo donation, it is less clear as to what extent donors should keep programs or recipients updated about relevant health issues following donation to protect the health of the offspring. Perhaps two of the most contentious issues surrounding gamete donation are the disclosure to the offspring and compensation for donors. Interests and views among involved parties e the donors, programs, parents and offspring e may vary regarding disclosure of the use of donor gametes or embryos. Voluntary disclosure is ultimately a choice of recipient couples, but, in recent years, the disclosure to the donor-conceived offspring has been encouraged in guideline recommendations [53,54]. These recommendations are supported by studies showing that disclosure may be less disruptive for the donor-conceived person than previously anticipated [55,56]. Yet, disclosure to the offspring about donor use raises an additional issue: the right to access information about the donor. The balancing of the rights of all parties involved requires the utmost sensitivity [57,58]. Though ASRM has identified different levels of donor information sharing [59], the most recent recommendations [53], coupled with the concerns voiced by ethics and legal experts about permitting either the donor or the offspring to break anonymity, will undoubtedly continue to fuel a lively debate on this issue worldwide [54,60,61]. In certain countries, such as the UK, the donor's anonymity can be legally lifted once the child reaches adulthood, based on the idea that the children were not part of the original donorerecipient contract and the decisionmaking process that motivated their existence. Therefore, the rights of the children are seen to override those of the adults who voluntarily participated in the original contract [62]. Furthermore, the amount of information and record-keeping obligations have increased, as reflected in recommendations from professional societies calling for permanent record maintenance [63]. Similar concerns regarding the management of anonymity issues apply to the case of embryo donation. Parties must be counseled that even if proper legal arrangements are in place at the time of the donation procedure, later changes in law may affect the enforcement of previous agreements. Another consideration regarding disclosure is
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the possibility that donors may have or plan to have their own children in the future, such that a donor-conceived child may have genetic siblings. As such, donors should also be advised that their present or future partner may have an interest in the consequences of the donation or its disclosure [58]. The ethical and legal aspects that surround the issue of compensation for gamete donors has been the subject of intense media coverage [64,65] and academic debate [60], which has overwhelmingly focused on the financial incentives for egg donors. The reason is apparent: compared to sperm donors, the financial compensation for egg donors is far higher, as are the risks and complexity involved in undergoing an IVF cycle to retrieve oocytes. The concept of turning human gametes into a commodity (‘commodification’), has raised ethical concerns and is given as the main argument against the idea of remunerating oocyte donors [50]. Regulations governing this practice are constantly evolving and differ substantially from country to country. In the USA, the ASRM has affirmed that ‘financial compensation of women donating oocytes for infertility therapy … is justified on ethical grounds’ [59,66]. ASRM guidelines state that ‘time, inconvenience, and discomfort’ associated with the donation process should be the guide for compensation, rather than particular human traits, or personal characteristics of the donors. However, a recent survey found that the content of 34e56% of agency and clinic websites does not reflect the ASRM recommendations [67] on this matter. Finally, couples undergoing IVF often reach their desired family size before transferring all of their generated embryos or using their cryopreserved gametes. The magnitude of the problem of unused cryopreserved embryos has been explored in US IVF practices, under the spotlight of intense media debate regarding embryo fate [68]. The findings have led to periodic updates on guidelines from the Ethics Committee of ASRM [69] on the multiple ways to deal with surplus cryopreserved embryos: thawing and discarding, donating the embryos to another couple for the purpose of a pregnancy attempt, donating embryos to an institution for the purpose of advancing research, and indefinite storage. Uterine transfer of the embryos at a time not favorable to implantation has been proposed as a sensible way of dealing with the fate of these embryos [70]. One area of recent debate has been the use of surplus embryos for stem cell research, which overlaps with the issue of donating oocytes for research [71e73]. Each of these strategies has encountered supporters and detractors [71,74,75], which ultimately reflects in the wide variations in laws and regulations in place worldwide. At present, US law does not give clear guidance on discarding abandoned embryos. The ASRM continuously provides updated guidelines on how best to manage these issues in a rapidly changing scientific and legal environment [69,71,76e79].
4.4. Reproductive outcomes after ART ART is associated with potential risks to both the mother and fetus. Because multiple embryos are transferred in the majority of ART procedures, ART has been associated with a substantial risk for multiple-gestation pregnancy and multiple births [6,80,81]. Multiple births are associated with greater health problems for mothers and infants, including higher rates of caesarean deliveries, prematurity, low birth weight, infant death, elevated risk of birth defects and disability [82,83]. The contribution of ART to adverse perinatal outcomes in recent years is mainly due to the persistently high
number of twin pregnancies. The transfer of a single embryo in patients with a favorable prognosis has been shown to be effective in keeping pregnancy rates and live birth rates high, but with a significant reduction in multiple births; however, the ethical forces at play in the absence of a mandatory policy or oversight regarding the number of embryos transferred have been difficult to reconcile in the USA [2]. In Europe, the Belgian model of practice with singleembryo transfer (SET) is an example of a successful intervention. From 1 July 2003, SET and elective SET have been established by Belgian law in first and second IVF cycles, respectively, for patients aged
