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COPYRIGHT 2005 Health Law Institute
I. Introduction
Assisted reproductive technologies (ARTs) have become almost commonplace in the developed world. It is estimated that 1% of American children are now conceived using some form of assisted reproduction, (1) and that over a million children have been born as a result of the use of ARTs (2) In the past several years, however, scientists have begun to sound a cautionary note about the health outcomes of ARTs, as it appears that children conceived using ARTs may be at higher risk of birth defects and certain genetic anomalies than those conceived naturally.
As a result of these new findings, a consensus appears to be emerging that research into the safety of assisted reproductive technologies (ARTs) is required. Such research will require a longitudinal, prospective design in order to answer questions about short and long-term health outcomes for those conceived using ARTs. There are a number of scientific issues that require attention before ART outcomes research can be successfully conducted; these include: sample size limitations, the diversity of both types of ARTs and birth defects, and confounding variables such as maternal age and folic acid consumption. (3) But a substantial non-scientific impediment to the conduct of this research also demands consideration: legal and ethical constraints that have the potential to complicate the research enterprise. In particular, given the research context, law and policy relating to the research participation of pregnant women and children must be attended to. The question of whether and to what extent pregnant women and children may participate in health research has been a persistent concern in both legal and ethical circles. (4) On the one hand, current ethical guidelines exhort researchers to include these populations where possible; (5) on the other, the law seems to pose a barrier to their participation.
In this article, the intent of which is to raise issues requiring further consideration, I will examine legal and ethical standards relating to consent in the Canadian context, and highlight the legal and ethical concerns that arise at different stages of longitudinal prospective research studies in the ART context. In Part II, I explain the ART context and highlight the concerns that have led to calls for long-term follow-up of children conceived using ARTs. In Part III, I discuss consent to research participation along the continuum of participants in longitudinal ART outcomes research, and in Part IV, I move on to consider legal and ethical regulation of health research generally. I conclude by noting that the legal and ethical parameters around consent to longitudinal ART research must be clarified in order to permit rather than hinder the conduct of this important research.
II. The Context: Assisted Reproductive Technologies
In the almost 30 years since the birth of the first "test-tube baby," (6) the science around reproductive and genetic technologies has exploded, giving rise to new tests and technological breakthroughs on a routine basis. Preimplantation genetic diagnosis (PGD), for example, permits scientists to diagnose genetic conditions in an in vitro embryo, (7) prior to it being implanted in a woman's uterus through in vitro fertilization (IVF), a technology in which an ovum is fertilized with a sperm cell outside the woman's body. (8) And if IVF alone will not suffice to assist a couple to conceive, because of very low sperm count or immotile sperm, a procedure termed intra-cytoplasmic sperm injection (ICSI) might be appropriate--a single sperm cell can be injected directly into the ovum to ensure that fertilization takes place. (9) Other variations on the IVF theme include a procedure called in vitro maturation (or IVM), in which immature oocytes are matured in vitro for 24-48 hours, eliminating the need for risky hormonal stimulation of the ovaries prior to harvesting eggs, (10) and IVF with blastocyst embryo transfer, which involves waiting for five to six days post-fertilization to transfer the embryo(s) to the woman's uterus, which, it is hoped, will lead to a greater likelihood of implantation. (11) Reproductive cloning, perhaps the most 'high tech' of the new reproductive technologies (and certainly the most controversial), allegedly looms on the horizon as well. (12)
While the science continues to drive forward, concerns have begun to emerge that children born of ARTs are at higher risk of birth defects (13) and certain genetic anomalies than children conceived naturally. These concerns are exacerbated by the reality that comprehensive safety and efficacy studies were not conducted prior to the adoption of most reproductive technologies into clinical practice. (14)
Birth defects are more common in multiple gestation pregnancies, (15) and ARTs often lead to multiples, but recent studies have also found increased rates of birth defects in single gestation pregnancies as well. (16) There are a number of possible points on the ART-treatment continuum at which problems may arise, including ovarian stimulation, fertilization and early embryonic development (in the culture medium), and the embryo transfer process. In addition, it has been suggested that both fetal and placental development can be affected by ART procedures, and both of these possibilities have implications for health outcomes. (17) Finally, it remains uncertain whether the procedures themselves, or the underlying infertility, cause these developmental errors. (18)
Some of the reproductive technologies, such as ICSI (19) and assisted hatching (20) (a procedure that involves thinning or making a small hole in the protective layer that surrounds the embryo (21))involve invasive procedures. It has been suggested, for example, that ICSI might theoretically damage sperm cells and oocytes, and that further study is needed in order to allay concerns about its safety. (22) Although the available evidence points to no association between ARTs and "serious malformations," (23) there have been indications that ARTs may be associated with conditions caused by epigenetic changes and imprinting disorders, which play a role in congenital syndromes and which may contribute to an increased risk of cancer. (24) As a result of these suggested associations, as well as other concerns raised by specific technologies and potential developmental and psychosocial issues related to ART-caused multiple births, (25) a number of commentators have acknowledged the pressing need for further research. (26) In particular, there have been calls for longitudinal studies in ART-conceived children in order to determine whether these reported risks are "rare events without wider implications" or whether they represent the 'tip of the iceberg.' (27)
As a number of commentators have noted, the data to be acquired from ART outcomes research will have significant implications for ART practice, (28) as well as for legal and policy decisions around acceptable and appropriate uses of the technologies.
III. Consent to Participation in Research
Research into the long-term safety of ARTs is essential, but the suggestion that it should be carried out raises questions about the feasibility of such studies in light of relevant legal issues, which focus primarily on consent to participation in research, and related issues of risk and harm. The legal and ethical uncertainty surrounding research of the type contemplated here is compounded by a number of factors, including who the participants are, where the law is found, and the challenges posed by the nature of longitudinal research for legal rules around consent. (29) Legal regulation of health research in Canada is, to say the least, not well integrated. Quebec has explicitly enshrined a number of general principles relating to research participation in its Civil Code. (30) In the remainder of Canada, legal rules respecting consent vary slightly according to jurisdiction, and are found in both common law and legislation. Health research is also subject to ethical "regulation" and while this is more uniform across the country, jurisdictional (31) variations do exist. Canadian ethical guidelines arise out of the 1998 Tri-Council Policy Statement; (32) accordingly, the ethical principles and guidelines discussed herein will be based upon the Tri-Council Policy Statement.
Consent, or more particularly, informed consent, is a cornerstone of legal and ethical governance of health research. (33) In order to satisfy legal and ethical requirements, researchers must obtain the "free and informed consent" (34) of each participant. Legally and ethically valid consent to participation in research must be voluntary (given without undue influence, manipulation or coercion (35)), it must be given by a person competent to provide it, (36) and it must be "informed." In the clinical practice context, the law holds that an informed patient is one who has been apprised of all "material, special or unusual risks" related to the proposed therapeutic intervention. (37) In the health research context, particularly where the research is not of intended benefit to the participants, the courts have held researchers to a higher standard of disclosure, that of "full disclosure" of all risks: rare, remote or potential. (38) Canadian ethics policy also demands that the researcher provide prospective subjects (or authorized third parties) with "full and frank disclosure of all information relevant to free and informed consent." (39)
In the context of a longitudinal study of health outcomes for children conceived using ARTs, there are a number of points during the study at which consent issues will arise: during pregnancy, in early and late childhood, and adolescence. Each of these points will be considered in turn.
i. During pregnancy
Recruitment of research subjects to longitudinal studies related to ARTs will take place immediately prior to or during pregnancy. Thus, consent to participation will initially be sought from the pregnant (or prospectively pregnant) woman. This, in turn, introduces concerns about potential risks that might flow from research-related procedures, such as amniocentesis (40) and chorionic villus sampling, (41) aimed at gathering genetic or environmental information about the fetus, and raises questions about whether a pregnant woman can consent to research, particularly genetic research, being conducted on the fetus she carries.
Although I am not keen to engage the debate around the moral and legal status of the fetus, (42) the question of the adequacy and legitimacy of maternal consent for research on the fetus demands attention. (43) As I have argued elsewhere, law and society must be prepared to respect the autonomy of pregnant women who refuse medical treatment that is recommended in the "best interests" of their fetus. (44) The ability to reject unwanted medical treatment, however, does not necessarily translate into an ability to consent to potentially harmful interventions undertaken for research purposes. A woman's right to forego medical treatment can be defended on the basis of her interest in her bodily integrity and her right to self-determination, even if the decision might have negative consequences for the fetus. (45) But whether a woman can consent to an unnecessary procedure that poses some risks to the fetus remains an open question. (46)
It is uncontroversial that treatment can be given where it is both needed by the fetus and consented to by the pregnant woman. Similarly, research into treatment methods applied to the fetus may be consented to by the pregnant woman: (47) Article 9 of the Tri-Council Policy Statement states only that fetal research (including the use of fetal tissue (48)) requires the free and informed consent of the pregnant woman. It is unclear whether placental tissue, the umbilical cord and cord blood would be considered fetal tissue, body parts of the pregnant woman, or some combination thereof. (49) Article 9 does not contemplate the situation of non-therapeutic research involving a fetus, nor does any other section of the Tri-Council Policy Statement. And, where research is the sole reason for subjecting a fetus to a risky procedure such as chorionic villus sampling (small though...
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