DISCUSSION DOCUMENT

U.S. Public Policy and the Biotechnologies
That Touch the Beginnings of Human Life:
A Detailed Overview

CONTENTS

Introduction

I. Power to Initiate Human Life by Artificial Means

II. Power to Screen and Select for Genetic Conditions
and Traits

III. Power to Modify Traits and Characteristics

IV. Power to Observe and Manipulate Nascent Human
Life In Vitro for Purposes of Scientific Research

V. Commerce and Commodification

Summary and Conclusion

Footnotes

Endnotes

INTRODUCTION

It is by now commonplace that advances in biomedical science and technology are raising challenging and profound ethical issues—for individuals and families, for scientists and health care professionals, and for the broader society. Many important human goods are implicated, among them health and the relief of suffering, respect for life and the human person, human freedom, and human dignity. The flourishing field of modern bioethics, not yet forty years old, arose to explore these issues, and various bodies, including local research review boards, academic bioethics institutes, and several national commissions have been wrestling with them. Yet amid all this activity, it is far from clear whose business it is to monitor, oversee, and offer guidance where guidance is needed, in order to safeguard the myriad and often competing human goods at stake. Which institutions, public or private, are now responsible for which sort of oversight or regulatory activity, and in the name of what? We can readily name some—the Food and Drug Administration, for example—that are responsible for the efficacy and safety of new drugs or devices. But which permanent bodies, if any, are charged with effective authority to protect some of the other goods we care about? And how well are they doing their job?

At its very first meeting, the President’s Council on Bioethics signaled an interest in exploring how, if at all, the existing regulatory mechanisms in the United States address the ethical and moral issues that arise from advances in biomedical science and technology. Some members of the Council suggested that new regulatory institutions might need to be devised. Others were skeptical, especially before we knew how well the current arrangements worked or which principles should guide any such new institutions. In the Council’s 2002 report, Human Cloning and Human Dignity, a suggestion emerged for pursuing this interest regarding regulation in the context of a specific domain. Members observed that for the activities at the intersection of assisted reproduction, preimplantation genetic diagnosis, and human embryo research,

we lack comprehensive knowledge about what is being done, with what success, at what risk, under what ethical guidelines, respecting which moral boundaries, subject to what oversight and regulation, and with what sanctions for misconduct or abuse. If we are to have wise public policy regarding these scientifically and medically promising but morally challenging activities, we need careful study and sustained public moral discourse on this general subject, and not only on specific narrowly defined pieces of the field.¹

Three months following the release of the report, Council members agreed to undertake a thoroughgoing inquiry into the current regulation of those biotechnologies that touch the beginnings of human life. This discussion document is the first fruit of that inquiry. Its principal aim is to provide Council members with a detailed account of the institutions and authorities that presently govern the uses and applications of the biotechnologies and practices at the intersection of assisted reproduction, genetics, and human embryo research. The document explores precisely who currently provides oversight and guidance in this context, pursuant to what authority, according to what principles and values, and to what ultimate practical effect. It is strictly diagnostic and expository in nature. It is intentionally neutral regarding what changes, if any, might be necessary, desirable, or feasible if one should wish to improve upon the present arrangements.
The precise focus of this inquiry is the growing powers over the beginnings of human life, especially as exercised ex vivo, in the clinic and the laboratory. These powers emerge out of the confluence of work in reproductive biology, developmental biology, and genetics. The practices of assisted reproduction are today being augmented by techniques of genetic screening and selection of embryos; some day, the gametes or embryos employed may be modifiable by directed genetic manipulation. Our focus here is not assisted reproduction, as such, nor is it the human embryo or the evolving understanding of human genetics and the powers of genetic diagnosis and manipulation. Rather, we are concerned with the unique interactions among these elements, and the new possibilities they create for controlling and perhaps someday remaking the character of procreation and human life.

Our point of departure will be the practice of assisted reproduction. We are well aware that assisted reproduction is not new—indeed, it has become firmly established within the practice of medicine, and is thus subject to the usual formal and informal mechanisms that govern medical practice. Our purpose here is not to second-guess how this novel and profoundly important practice grew and came to be governed in the way it has. However, three reasons, taken together, recommend this point of departure. First, all the other new powers of interest—preimplantation genetic diagnosis, germ line genetic modification, human embryo research—presuppose the existence of nascent life in vitro. The power to evaluate and perhaps eventually to engineer genetic traits in vitro depend on the prior power to initiate and sustain embryonic life in the laboratory. Thus, in vitro fertilization and related techniques are the starting point for all the others, both in practice and, hence, in our inquiry. Second, as a consequence, any oversight or regulation of the use of genetic technologies in the beginnings of human life will necessarily depend on the systems of oversight and regulation of assisted reproduction itself, what they are and how well they work. Third, the coming additions of genetic technologies to those of assisted reproduction make it clear—if it has not been clear before—that we are dealing here with a most unusual branch of medicine. Regarded as an ordinary branch of medical practice, the activities of assisted reproduction now come under an unusual amount of professional self-scrutiny and guidance. But there is ample reason for this extra scrutiny: in no other area of medicine does the treatment of an ailment—in this case, infertility—call for the creation of another human being. Here, the therapeutic intervention, addressing the needs and desires of the procreating adults, aims at and consists in the production of a new human life, who, although patient to the manipulations, has of course no say in the matter. It is this deep concern for the safety and well-being of children born with the aid of these new biotechnologies that suggests to us the need for special attention—especially now that genetic screening and selection are being added to the practices of assisted reproduction.

All regulatory institutions and practices operate, either explicitly or tacitly, in order to promote or protect one or more important human goods. Identifying those goods and the challenges they face is indispensable for any analysis and evaluation of how—and how well—regulatory activities are conducted. It is therefore useful, at the start of this document, to identify the major goods, values, and ethical concerns that the Council finds pertinent to the subject area, and hence to our assessment. First among these, as already indicated, is the health and well-being of the human subjects directly affected by the biotechnologies, not only the couple seeking their use but also and especially all children who may be born with their aid. At stake are not only the bodily health and safety of children-to-be, but also the attitudes with which they will be regarded and the expectations under which they will live, in an age in which more and more aspects of their genetic make-up could be the result of technical intervention and deliberate human decision.

Other human goods of great interest include: (1) The joys of overcoming infertility and the blessings of having children, as well as (2) relief from the sorrows and burdens of being or caring for children with serious genetic disease, and (3) the desire for new knowledge of human development and genetic function and new treatments for diseases and disabilities—the main goals of the associated genetic and reproductive technologies under consideration. (4) The sanctity of human life and the respect owed to its nascent stages. (5) Various aspects of human freedom: the freedom of parents to make their own reproductive decisions or to refuse genetic screening, of scientists to do research, of children to be protected from despotic attempts to shape their lives through control of their genetic make-up and the expectations that accompany this activity. (6) Various aspects of justice and equality: equitable access to the use and benefits of the new technologies, equal respect and opportunity in a world that places increased emphasis on genetic distinctions, and the dangers of discrimination and contempt for genetic “defectiveness” or “inferiority.” (7) Privacy of genetic information and reproductive practice. (8) Various aspects of human dignity: the dignity of human sexuality and procreation, of the human body and its parts, of human responsibility and self-understanding.

Throughout our analysis we shall be mindful of how the various regulatory practices address a series of ethical concerns that are connected with those goods. Some concerns are raised by the practice of ART as such, others by the practices of genetic screening and selection or of genetic manipulation and engineering, and still others by research on human embryos. In addition, there are concerns raised by the commercialization of human reproductive services and the advent of commerce in eggs, sperm, and embryos. Beyond the obvious concerns with health and safety, a partial list of these broader ethical concerns includes the following: the import of making entrance into human life contingent on passing certain genetic tests; the consequences for the relations between parents and children of genetic selection; the boundary between disease-preventing and so-called “enhancement” uses of these technologies—how to define it and what to do about it; consequences of moving procreation more and more into the laboratory and turning it in the direction of manufacture; aggravation of current social inequalities or the creation of new grounds for inequality and discrimination; the use, cryopreservation, and destruction of nascent human life; the dangers of coercion in the advent of mandatory screening; the hazards of living with too much genetic knowledge; truthfulness in reporting technological successes and failures; consumer protection; the effects of commercialization on the dignity of human procreation; and the effects on human self-understanding and judgments of personal responsibility that arise from an account of human life that appears to teach the primacy of genetic causation. Not all of these concerns are equally susceptible to regulatory activity, and few of them are likely to be the subjects of anything so drastic as restrictive legislation. But most if not all of these concerns are sufficiently serious as to suggest the desirability of monitoring what is going on, with a view at the very least of informing patients and policy makers of how well we are handling any possible untoward consequences.

Before moving to the substantive analysis of the present regulatory landscape, it is worth briefly noticing some unique aspects of American law that create the backdrop against which the current regulatory mechanisms exist.

First, because practices touching reproduction and nascent human life raise questions closely linked to the central themes of the abortion debate, efforts at regulation are fraught with political difficulty. Any proposed regulatory efforts of assisted reproduction are viewed by many people through the prism of Roe v. Wade and its progeny, arousing suspicion and concern among individuals on both sides of the abortion conflict. Defenders of the right of privacy or reproductive freedom want no infringement of any of their prerogatives. Pro-life opponents of embryo destruction or in vitro fertilization oppose the public and official legitimization of these practices that a federal regulatory system might imply. This situation creates a powerful disincentive for any regulation of ART or related activities. More generally, there is deep disagreement in our society about the respect owed to in vitro embryonic human life and the weight it should carry in relation to other moral considerations, such as helping infertile couples to have children, helping couples to have healthy children, and advancing knowledge in the research context. This disagreement is one of the main reasons for the current relatively laissez-faire approach to regulation. While some observers complain that the standoff over the moral status of nascent human life has prevented meaningful and useful regulation of ART and related practices, others respond that resolution of this dispute is the sine qua non of any responsible approaches to regulation.

Second, the practice of medicine (now embracing ART) occupies a special place in the American legislative and legal system. The practice of medicine is principally regulated through state licensure and certification of physicians rather than by reference to specific legislative proscriptions or prescriptions of conduct. Legislatures defer to the profession not only because medicine is highly esteemed, but also because of lack of institutional competence. Most governmental authorities simply lack the expertise to provide meaningful oversight of professional activity, and medicine is a profession where crucial judgments must be made on a case-by-case basis by a practitioner familiar with the details and circumstances involved. The law tends to give physicians ample latitude to make such judgments.

Third, the U.S. Constitution has several features that bear on the present discussion. The American system of federalism has tended to vest principal authority for safeguarding the health, safety, and general welfare of citizens in their respective states. This broad mandate of the states creates a lack of uniformity across local jurisdictions, but also permits states to serve as “laboratories” for regulatory experimentation. Moreover, the enumeration of federal powers in the Constitution sets limits on what the national government may legislate. Only conduct that meets a specific jurisdictional threshold (for example, activities that implicate interstate commerce) is reachable by federal mechanisms of regulation. Additionally, the Constitution recognizes certain individual rights inhering in all citizens (or, depending on the right, in all persons), as well as liberties that may be vindicated against both state and federal governments. The assertion of such “fundamental” rights can be controversial if not clearly grounded in the constitutional text and especially when discerned first by judges rather than legislatures. One such controversial “fundamental” right is, of course, the right to privacy in intimate matters relating to procreation. The relevance of the right to privacy to the regulation of assisted reproduction is easily recognized, while its likely application in actual cases is difficult to predict.

A fourth principal concept in American law, directly relevant to the present inquiry, is that the public and private realms of conduct are legally and ethically distinct. The reach of law is in many ways driven by this distinction: public action may properly be regulated by the government, especially to protect public health, safety, and welfare, and to vindicate individual rights; by contrast, the realm of private conduct (that is, actions undertaken in private, affecting only the particular individuals involved) is the zone of maximal individual liberty. To be sure, this is an abstract notion, complicated in practice. Technologies and practices that touch the beginnings of human life implicate the most intimate and private activities: procreation, child rearing, human suffering, and moral reasoning. In such matters, there is a strong legal and cultural presumption in favor of personal liberty. This presumption is only overcome by an equally compelling governmental and societal interest, typically the protection of life and limb. The tension between these concepts—public and private, liberty and the public good—should be borne in mind when considering these technologies and practices.

A fifth concept, related but different, is the distinction often drawn between publicly funded and privately funded activities. Some activities the law chooses silently to tolerate while withholding its official sanction or endorsement through public support. This distinction is especially significant in some arenas touched on in this discussion. Scientific research involving human embryos, for instance, is not legally prohibited, though federal government funding of nearly all such activity is prohibited. This distinction has played an important role in the political controversies surrounding embryo research, and is held by many people on all sides of the question to be of great significance.

A sixth crucial principle is the special role of parents in American law. They are considered the principal protectors of the well being of their children, including their as yet unborn children. As such, they are granted wide latitude by the law to make decisions that directly affect their children’s well being, and this is especially true in the context of assisted reproduction.

A seventh theme extant in American law relevant to the present inquiry is the presumption in favor of commerce and free enterprise. The values of freedom to contract, to participate in the free market, and to profit from the fruits of one’s labors, are memorialized in the Constitution, statutes, and decisional authorities that comprise U.S. law. Any governmental efforts to regulate biotechnology and related activities are written against this backdrop. Similarly, unlike many other nations, our health care system is not run by the government, and physicians jealously guard their prerogative to control their own economic activity. The largely private funding of medical care also places additional obstacles in the way of attempts at government regulation.

An eighth element that informs the present inquiry is the absence of human dignity as an explicit concept in American law. Much of the legal discourse in this country employs operative terms such as liberty, equality, and justice. Unlike some of our European counterparts, however, “human dignity” is not in our legal lexicon. Thus, legislators and courts lack the language (and thus the explicit authority) to fashion responses and remedies to conduct that threatens the dignity of the person.

Ninth, it is necessary to bear in mind the range and variety of activities that may be properly deemed “regulation” for purposes of this inquiry. Regulation comes in myriad forms, from various sources, with widely differing results. Regulation can include a variety of mechanisms, ranging from legal prohibition and statutory obligations, to mere monitoring and data collection. Methods of enforcement range from criminal prosecution to mere hortatory suggestion. Moreover, the source of regulation can be governmental (with the coercive power of the state as the principal mechanism for implementation) or nongovernmental (where market forces and peer evaluation are the chief means of implementation).

The final unique aspect of regulation in the United States is the nation’s deeply ingrained commitment to pluralism. An ambition to regulate assisted reproduction runs up against American individualism and a powerful aversion to “legislating morals.” Americans expect their governments to give compelling reasons before restricting individual liberty. Many people also harbor suspicions that governmental regulations and the bureaucracies needed to manage them are harmful, ineffective, and threatening to salutary personal freedoms and economic progress.

All these considerations make thinking about regulating biotechnologies touching the beginnings of human life extremely complicated, in ways peculiar to the United States. Although the Council has heard presentations on regulatory schemes used in other countries, this document does not deal with them. We are eager, first of all, to disclose and assess what is going on in our own country. And we are frankly doubtful that, given the noted peculiarities of American law and political culture, foreign practices can serve directly as models for what we can and should do here.

I. POWER TO INITIATE HUMAN LIFE BY ARTIFICIAL MEANS

The first and fundamental power under consideration is the power to initiate human life by artificial means. Because this power is the basis of all others touching the beginnings of human life, we give it central consideration. This power is chiefly exercised within the human context of assisted reproduction—that is, the established clinical practice developed to treat infertility and culminating in the birth of a live-born child. Accordingly, the following discussion of the domain of assisted reproduction will serve as a point of departure for the entire inquiry. Although readers are no doubt familiar with the main features of this activity, we shall give a detailed account in order to make clear the various aspects that could give rise to a need for monitoring, oversight, or regulation.

Techniques and Practices

Most methods of assisted reproduction involve five discrete phases: (i) collection and preparation of gametes; (ii) fertilization; (iii) transfer of the embryo to a woman’s uterus; (iv) pregnancy; and (v) birth. Each phase will be discussed separately, followed by a brief discussion of the ethical concerns that arise as a result. Additional issues connected with solicitation and intake of gamete donors will be discussed extensively in Section V (on commerce and commodification), below.

Collection and Preparation of Gametes

The precursors of nascent human life are the gametes: sperm and ova. In the context of assisted reproduction parents seeking to conceive usually provide their own gametes. In the United States in the year 2000, 75.2 percent of the ART cycles undertaken involved never-frozen, self-provided ova or embryos and another 13.1 percent involved frozen self-provided ova or embryos. Only about ten percent involved donated ova or embryos: 7.7 percent never-frozen, 2.8 percent previously frozen. ²

Sperm is acquired directly from the male prospective parent by well known means. The minority of men who cannot ejaculate, or who have a blocked reproductive tube, may undergo assisted sperm retrieval (ASR). Alternatively, sperm precursor cells obtained by testicular biopsy may be used for purposes of insemination (though this yields a lower pregnancy rate).

Acquiring ova from women for use in artificial reproduction is significantly more onerous, painful, and risky than is acquiring sperm. In the normal course of ovulation, one mature oocyte is produced per menstrual cycle. However, in the context of assisted reproduction, in an effort to increase the probability of success, many more ova are required. Thus, the ova source (who is typically also the gestational mother) undergoes a process of drug-induced ovarian stimulation intended to cause ovaries to produce many more mature oocytes during that cycle. This procedure, commonly referred to as “superovulation,” requires the daily injection of a synthetic gonadatropin analog, accompanied by frequent monitoring using blood tests and ultrasound examinations. This treatment begins midway through the previous menstrual cycle and continues until just before ova retrieval. The synthetic gonadatropin analogs give the clinician greater control over ovarian stimulation and prevent premature release of the ova. These hormones are contraindicated in the presence of pregnancy.

A very small percentage of women in 2000 (fewer than 1 percent of assisted reproduction patients) ³ opted not to undergo ovarian stimulation prior to ova retrieval.⁴ In such “unstimulated” procedures, the clinician monitors the development of an ovarian follicle (via ultrasound) and uses daily blood sampling to predict the moment of ovulation. Only one follicle develops and the timing of maturation and release is not controlled. As a result, this process yields a lower success rate than does IVF following ovarian stimulation.⁵

When blood testing and ultrasound monitoring suggest that the ova are sufficiently mature, the clinician attempts to harvest the ova. This is typically achieved by one of two means: laparoscopy or ultrasound-guided transvaginal aspiration. In laparoscopy, three abdominal incisions are made and the ova are extracted with vacuum aspiration. This procedure typically requires the patient to undergo general anesthesia. The clinician inserts a needle into the patient’s abdomen and fills the abdominal cavity with gas. An incision is made through the wall of the abdomen, and a laparoscope is inserted to permit viewing of the reproductive organs. Two additional incisions are made through which instruments are inserted to grasp the ovary and aspirate the mature follicles. In ultrasound-guided transvaginal aspiration a needle guided by ultrasound is inserted through the vaginal wall and into the mature ovarian follicles. The needle is used to withdraw an ovum from each follicle, along with a certain amount of fluid. This is an outpatient procedure. Risks and complications can include accidental puncture of nearby organs such as the bowel, ureter, bladder, or blood vessels, as well as the typical risks accompanying outpatient surgery (for example, risks related to administration of anesthesia, infection, etc.).

Once sperm and ova have been collected, they are cultured and treated to maximize the probability of success. Ova are transferred into a culture medium containing the mother’s blood serum. With sperm, the seminal fluid is removed and replaced with an artificial medium. For infertile men, the clinician removes excess material and concentrates the motile sperm. ⁱ

Fertilization

Once the ova and sperm have been properly prepared, the clinician attempts to induce fertilization—the union of sperm and ovum culminating in the fusion of their separate pronuclei and the initiation of a new, integrated, self-directing organism. It is common practice to attempt to fertilize all available ova.ⁱⁱ Fertilization can be achieved through a number of means including (i) in vitro fertilization (IVF), (ii) gamete intrafallopian transfer (GIFT), (iii) intracytoplasmic sperm injection (ICSI), and (iv) various methods of zona pellucida manipulation.

IVF is the most common method of artificial fertilization. In 2000, it was used by 98 percent of ART patients.⁶ As noted previously, both sperm and ovum are cultured to maximize the probability of fertilization. The ova are examined and rated for maturity in an effort to calculate the optimal time for fertilization. They are usually placed in a tissue culture medium and left undisturbed for two to twenty-four hours. The sperm is prepared as described above. Once the gametes are adequately prepared, thousands of tiny droplets of sperm are placed in the culture medium containing the ova. This process is repeated for all of the available ova. After a day, each of the oocytes is examined to determine whether fertilization has occurred.

Attempts at fertilization via gamete intrafallopian transfer (GIFT) are rare. In 2000, they accounted for less than 1 percent of all attempts at fertilization used by ART patients.⁷ As the name suggests, fertilization using GIFT occurs within the woman’s body. It was introduced in 1984 as an alternative to IVF. Ovarian stimulation and retrieval are performed in the same manner as in IVF. In a single procedure, ova are retrieved, combined with the sperm, and transferred back into the fallopian tube. Typically, two or more ova are transferred. It requires only one functional fallopian tube to work. Because fertilization takes place inside the woman’s body, substantially less lab work is required and there is no need for embryo culturing. However, GIFT requires laparoscopy for ova retrieval or for ovum/sperm transfer and exposes the patient to the increased risk of a multiple gestation. Additionally, because fertilization occurs inside the woman’s body, one cannot determine the cause of failure, for example, whether the ovum was not fertilized or the embryo did not implant.

A new and increasingly widespread means of fertilization is intracytoplasmic sperm injection. As the name implies, ICSI is a procedure in which ovum-sperm fusion is accomplished not by chance, but by injecting a single sperm directly into an oocyte. In ICSI, the oocyte is treated with an enzyme that removes certain cells that surround it (“nurse cells”). The sperm are placed in a viscous solution that greatly slows their motility. A single sperm is selected and drawn into a thin injection pipette from which it is injected into the cytoplasm of the ovum cell.

ISCI is indicated in cases of severe male-factor infertility, with male patients having either malformed sperm or an abnormally low sperm count. ICSI is ideal for situations in which the patient’s sperm would not otherwise penetrate the exterior of the oocyte.ⁱⁱⁱ But its growing popularity has more to do with the wish to increase the success rates for fertilization. ICSI was used in 47 percent of all ART cycles in 2000⁸, but 39.9 percent of the ICSI cycles in 2000 were undertaken by couples without male factor infertility.⁹ ICSI was first introduced by Belgian researchers in 1992. Two years later, relying on a two-study review of safety and efficacy, the American Society for Reproductive Medicine declared ISCI to be a “clinical” rather than “experimental” procedure.^iv

Clinicians can also attempt to induce fertilization artificially through manipulation of the zona pellucida, the thick extra-cellular covering that surrounds the ovum. To assist the sperm’s penetration of the ovum, clinicians perforate the zona pellucida using an acidic solution (“zona drilling”), or a needle or pipette (“partial zona dissection”). Alternatively, clinicians inject sperm underneath the zona pellucida, but not directly into the ovum’s cytoplasm (“subzonal insemination”). Zona drilling results in few pregnancies and has been linked to inhibition of early embryo growth, perhaps due to the acidic solution entering the ovum itself.¹⁰ Few embryos conceived through partial zona dissection have a normal appearance, perhaps due to the introduction of toxins or microorganisms into the ovum in the perforation process.¹¹ Subzonal insemination can be effective in the hands of a skilled practitioner, but frequently results in unfertilized oocytes or fertilization by multiple sperm, rendering the embryo unusable.¹² The safety risks associated with these procedures is discussed below.

A recently developed adjunct to in vitro fertilization is ooplasm transfer. This procedure has been used for women whose fertilized ova do not develop normally owing to a deficiency in their mitochondria. To remedy this problem at the time of fertilization, the oocyte is injected with donor cytoplasm, containing healthy mitochondria. Because the new cytoplasm contains the donor’s DNA, the resulting child will have DNA from three individuals: the father, the mother, and mitochondrial DNA from the ooplasm donor. Moreover, the donor mitochondria could be passed on to future generations through the resulting child. To date, there have been thirty children born worldwide as a result of this procedure.^{v 13} However, for reasons discussed elsewhere in this document this technique is not currently approved for use in clinical practice in the United States.

Following IVF, the new embryos remain in the culture medium. Nutrients (such as human or calf fetal serum) are added to the medium. Some commercially produced preparations exist, but it is typical for ART clinics to make their own preparations on-site. Some ART clinics co-culture developing embryos. That is, they culture the embryos in a medium containing other cells that enhance the growth of the embryos and remove toxins. Various cells have been used for such co-culture, including cells extracted from the uterus or fallopian tubes of patients or donors, rat liver cells, monkey kidney cells, cow uterine cells, and even human ovarian cancer cells. The embryos remain in culture and are warmed in an incubator until they are either transferred into the recipient’s uterus or cryopreserved.

Because in many cases not all embryos are transferred in each cycle, cryopreservation of embryos has become an integral process of ART.^vi Indeed, ASRM has deemed cryopreservation “essential” and provides extensive guidance as to the maintenance of cryopreservation facilities. Cryopreservation is a complicated process that requires embryo preparation, sophisticated freezing technology, reliable storage, and meticulous record keeping. To guard against the formation of ice crystals that could destroy the embryo, the clinician introduces a cryoprotectant solution into the early-stage embryo’s interior. The prepared embryos are then placed in a straw-like structure that is gradually frozen. Once frozen, these structures are stored in canisters kept at very low temperature (typically around minus 196 degrees Centigrade) by liquid nitrogen. Some researchers suggest that it is possible to safely cryopreserve embryos for fifty years or longer.¹⁴ A recently reported study by the Society for Assisted Reproductive Technology and RAND estimates that 400,000 embryos are in cryostorage in the United States.¹⁵

Most ART patients do not transfer cryopreserved embryos. In 2000, only 13 percent of all ART cycles involved transfer of frozen embryos.¹⁶ The rate of live births for cycles using cryopreserved embryos is significantly lower than it is for never-frozen embryos (20.3 percent versus 31.6 percent).¹⁷ The Society for Reproductive Medicine estimates that only 65 percent of frozen embryos survive the thawing process. ¹⁸ There are, however, incentives for couples to use cryopreserved embryos, as doing so eliminates the cost and effort of undergoing further oocyte retrieval. Indeed, this can decrease the cost of a future cycle by $6,000.¹⁹ Transfer of cryopreserved embryos might be preferable in cases in which the recipient is suffering from ovulation hyperstimulation syndrome (discussed below). Because pregnancy aggravates this disorder, delayed transfer can be helpful, and cryopreservation allows such delay. The additional control over the timing of transfer conferred by cryopreservation is also helpful to women whose uterine lining is not yet fully prepared to receive an embryo at the time of its creation. The option of cryopreservation also reduces the pressure to implant all embryos at once, thus reducing the risk of high-order multiple pregnancies.

Transfer

Following initiation of nascent human life by fertilization, the next discrete phase in the assisted reproduction process is transfer of the embryo into the uterus of the mother (or gestational surrogate).^vii

Typically, the embryos are transferred on the second or third day after fertilization, at the four to eight cell stage. To maximize the probability of implantation, some clinicians cultivate the embryo until the blastocyst stage (five days after fertilization) before transferring them to the uterus.²⁰ Prior to transfer, the embryos are evaluated by the clinician according to shape and appearance. There is believed to be some correlation between the external appearance of an embryo and its likelihood of implantation and successful development, but appearances may be misleading. There are many cases in which unhealthy-looking embryos implant and develop into healthy fetuses and children, as well as examples of healthy-looking embryos failing to implant or experiencing developmental problems.²¹ Other methods of embryo evaluation include analysis of chemicals produced by the embryos in culture and pre-evaluation of the quality of sperm and ovum.

A more recently developed method of embryo analysis is preimplantation genetic diagnosis. In PGD, one or more cells are extracted from the embryo by means of biopsy. The clinician tests the sample for chromosomal or genetic characteristics, including the sex of the embryo, with special attention to any genetic disorder for which the relevant mutation has been identified in the parents or an earlier child. (PGD will be discussed further in Section II below.)

Prior to transfer, however, some clinicians attempt to facilitate implantation by means of a process called assisted hatching. Several days after fertilization, an embryo must break out of the zona pellucida so that it can implant into the uterine wall. In some instances, the zona pellucida proves to be too hard to break (possibly due to exposure to culture media, effects of the cryopreservation process, or the absence of exposure to chemicals that the embryo would have encountered had it traveled through the fallopian tube en route to the uterus), and implantation fails as a result. To aid in hatching, clinicians use various chemical, lasers, or mechanical manipulation of the zona pellucida.²²

Once the embryos have been selected and prepared, they are transferred into the uterus. The total number of embryos transferred per cycle varies, usually according to the age of the patient recipient. According to the CDC’s 2000 report, the average number of embryos transferred per procedure was 3.1 for never-frozen embryos and 3.0 for frozen embryos.²³ For women under the age of 35, the average number of never-frozen embryos transplanted per transfer procedure was 2.9. For women aged 35 to 37, 38 to 40, and 41 to 42, the average numbers of never-frozen embryos transplanted per transfer procedure were, respectively, 3.2, 3.5, and 3.7.²⁴ The CDC report notes that in 34 percent of ART cycles using never-frozen, self-provided ova or embryos in 2000, 4 or more embryos were transferred.²⁵

Typically embryos are transferred into the uterus using a catheter. With the patient lying on her back or face-down with knees drawn to her chest, the catheter is inserted through her cervix and the embryos are injected into her uterus (along with some amount of the culture fluid). This procedure does not require anesthesia. Following injection, the patient must lie still for at least one hour. While the transfer procedure is regarded as simple, different practitioners tend to achieve different outcomes. Statistics show that the likelihood of implantation decreases with each attempted transfer procedure.

An alternative method of embryo transfer is zygote intrafallopian transfer (ZIFT). In ZIFT, the embryo is placed (via laparoscopy) directly into the fallopian tube, rather than the uterus. In this way, it is similar to the transfer of gametes in GIFT. Some individuals opt for ZIFT on the theory that it enhances the likelihood of implantation, given that the embryo matures en route to the uterus, presumably as it would in natural conception and implantation. Additionally, many patients prefer ZIFT to GIFT because the process of fertilization and early development of the embryo may be monitored.²⁶ However, ZIFT remains a rare choice, accounting for approximately 1 percent of all ART cycles in 2000.²⁷ This may be because ZIFT requires laparoscopy.

Pregnancy

Successful implantation in the uterine lining marks the beginning of pregnancy. In 2000, 30.7 percent of the ART cycles undertaken resulted in clinical pregnancy.^viii This number varied according to patient age.²⁸ After the inception of pregnancy, patients are carefully monitored and treated by an obstetrician. Pregnancies resulting from assisted reproduction are often treated as high risk.²⁹ Clinicians recommend prenatal diagnosis and testing for all pregnancies resulting from assisted reproduction.

There are a number of medications and procedures that may be indicated during a pregnancy facilitated by assisted reproduction. It is typical for a patient to receive progesterone injections to support key functions necessary to pregnancy. Under certain circumstances, patients receive medications to treat immunological problems.

Among pregnancies facilitated by assisted reproductive technologies, multiple gestations are common. The rate of multiple-fetus pregnancies from ART cycles using never-frozen, self-provided ova or embryos in 2000 was 36.1 percent.^ix For the same time period, the multiple infant birth rate in the United States was 3 percent.³⁰ The extraordinarily high rate of multiple pregnancies resulting from assisted reproduction is attributable both to the transfer of multiple embryos per cycle and to a high rate of twinning of single embryos implanted.^x ART patients have a much higher rate of identical twins than the normal population. This is not a result of multiple embryos implanted in the uterus (these would result in non-identical twins), but rather splitting of single embryos during embryonic development. Some commentators suggest that the phenomenon of twinning may be the embryo’s reaction to an external trauma. In the context of ART, this trauma could be caused by the various exposures and manipulations experienced throughout the process of assisted reproduction.

In an effort to reduce the risks of multiple pregnancy, practitioners sometimes employ a procedure termed “fetal reduction,” the reduction in the number of fetuses in utero by selective destruction. Fetuses are selected for destruction according to size, position, and viability (based on the clinician’s judgment). Guided by ultrasound, the clinician inserts a needle through the mother’s abdomen (transabdominal multifetal reduction) or vagina (transvaginal multifetal reduction), through the uterine wall, and into the selected fetus. The clinician then administers a lethal injection to the fetus—typically potassium chloride. The dead fetus’s body decomposes and is resorbed. This process is repeated until the desired number of living fetuses remains. To be effective, transabdominal multifetal reduction must be performed at ten to twelve weeks gestation. Transvaginal multifetal reduction must be performed between six and eight weeks gestation (eight weeks is recommended).

Delivery

In 2000, for never-frozen self-provided ova or embryos, the overall rate of live births per cycle^xi was 25.4 percent (31.6 percent live births per transfer).^{xii 31} Among these pregnancies, 82.6 percent resulted in live births.³² Of these resulting 19,042 live births, 35 percent resulted in multiple infant births (30.7 percent twins and 4.3 percent triplets or more). ^{xiii 33} One 1993 Canadian study showed that nearly 25 percent of all births facilitated by ART end prematurely, and 30 percent of the resulting infants had low birthweight.^{xiv 34} While this low birthweight may be attributable to the high rate of multiple pregnancies, one 1987-89 French study reported that even for singleton births facilitated by ART, the rate of prematurity and low birthweight was twice that of children conceived by natural means.³⁵ Another study suggests that women using ART are more likely to induce labor and undergo elective caesarian section delivery.³⁶

Disposition of Unused Embryos

As mentioned above, in many, if not most, cases, there are in vitro embryos that remain untransferred following a successful ART cycle. There are five possible outcomes for such an embryo: (1) It may remain in cryostorage until transferred into the mother’s uterus in a future ART cycle. (2) It can be donated to another person or couple. (3) It can be donated for purposes of research. (4) It can remain in cryostorage indefinitely. (5) It can be thawed and destroyed.

Ethical Concerns

The new power to initiate human life by artificial means raises a variety of ethical issues. Some concern the well being of the participants in assisted reproduction: gamete donors, prospective parents, and resulting children. Other issues arise from the increased ability to exercise control over procreation. Still other issues concern the use and disposition of nascent human life that is incident to these new powers and techniques. While these do not exhaust the ethical concerns that attend the advent of the new powers to initiate human life, they will be the chief focus of the following discussion. Though different people assign different weight to the various ethical issues, all have merit and are deserving of some serious attention.

The Intersection of Vulnerability and Untested Technology

The human context in which assisted reproduction is practiced raises an initial ethical concern. Where the process is successful, the overcoming of infertility is a source of joy for tens of thousands of parents each year. But success is not the rule; especially for older patients, and even where there are successful outcomes, the submitting to the process is anything but joyous. Infertility can cause deep anguish and feelings of desperation for the individuals and families affected by it. It frustrates one of the most fundamental and basic of human desires—the desire to have offspring, to have a child of one’s own flesh. The infertile come to practitioners of assisted reproduction usually after prolonged periods of failure and dismay, in a state of vulnerability. This vulnerability may lead some individuals to take undue risks, or may render them potentially susceptible to exploitation by rogue clinicians.

Safety, especially regarding the child-to-be, is a major concern in this area. Many assisted reproductive technologies have been used in clinical practice without prior rigorous testing, study in primates, or studies of long term outcomes. IVF itself was performed on at least 1200 women³⁷ before it was ever performed on chimps³⁸ although it had previously been extensively investigated in mice. The same is true for ICSI. The oldest child conceived by ICSI is now around eleven years old (thus, the first successful procedure was circa 1992),³⁹ whereas the oldest non-human primate conceived by ICSI is about five years old (1997)⁴⁰ and the first successful ICSI procedure in mice was reported in 1995.⁴¹ Absent such studies, it is unclear to what extent minor alterations in the ART process affect development of the child-to-be.⁴²

In the discussion of specific ethical concerns that follows, it is helpful to keep in mind this intersection of patient vulnerability and novel (in some cases untested) technology.

Well Being of Child-to-Be. An invisible—yet the central figure—in the process of assisted reproduction, directly affected by every action taken but incapable of giving consent to such actions, is the child born with the aid of ART. Actions undertaken and choices made during gamete retrieval and preparation, fertilization, transfer, pregnancy, and of course birth, may directly affect the health and status of the resulting child.⁴³

The health of the child-to-be may be affected by actions taken as early as gamete retrieval and preparation. Some studies show that superovulation decreases embryo and fetal viability.⁴⁴ One study of embryos created during stimulated cycles revealed a high level of “developmental arrest, embryonic aneuploidy, mosaicism, apoptosis and failure of cytokinesis.”⁴⁵

Surprisingly, there have been very few comprehensive or long-term studies of the health and well-being of children born using ART, although over 170,000 children have been born in the United States with its aid.⁴⁶Some recent studies have associated various birth defects and developmental difficulties with the uses of various technologies and practices of assisted reproduction. None of these studies provide a causal link between ART and the dysfunctions observed, and some commentators have taken issue with some of the methodologies used. Nevertheless, these findings have alarmed many observers. One such study concluded that children conceived by assisted reproduction are twice as likely to suffer major birth defects.⁴⁷ Specifically, among the children in the study conceived by IVF, 9 percent were diagnosed with a major birth defect or defects by the age of one year. Among children conceived using ICSI, the rate was 8.6 percent. The incidence of such abnormalities among children in the study conceived by natural means was 4.2 percent. Another study undertaken around the same time period reached similar conclusions.⁴⁸ Other recent studies have associated the use of assisted reproduction technologies with diseases and malformations including Beckwith-Wiedemann syndrome^xv, rare urological defects, retinoblastoma,⁴⁹ neural tube defects,⁵⁰ Angelman syndrome⁵¹, and hermaphrodite chimerism⁵².

It bears noting that while many are concerned about the increased risk suggested by these studies, the overall incidence of such harms is low enough that infertile couples have not been deterred in their efforts to conceive using IVF or ICSI. Indeed, ART clinicians (and in some cases the authors of these studies)⁵³ advise their patients that such data should not dissuade them from pursuing infertility treatment.

ICSI has raised specific concerns among some observers largely for the same reasons that it has proven so successful as a means of fertilization. Because ICSI circumvents the ovum’s natural barrier against sperm otherwise incapable of insemination, some suspect that removing this barrier may permit a damaged sperm (for example, aneuploid or with damaged DNA) to fertilize an ovum, resulting in harm to the child-to-be. Some male ART patients have a gene mutation or a chromosomal deletion that renders them infertile. If a sperm can be retrieved from one of these patients, he may be able to conceive a child via ICSI. However, this could mean that the genetic abnormality would be passed on to the resulting child. For example, two thirds of men with congenital bilateral absence of the vas deferens (rendering them unable to ejaculate) carry certain cystic fibrosis gene mutations. ICSI may permit these men to overcome their infertility, but the resulting child will (in 50 percent of the cases) bear this gene mutation. Similarly, another form of male factor infertility characterized by a very low sperm count is associated with a particular Y-chromosome deletion. The use of ICSI in such cases risks the transfer of this chromosome deletion to the resulting child, rendering any male child infertile, and, according to some studies, at risk for sex-chromosome aneuploidy. Additional studies have associated the use of ICSI with an increased incidence in novel chromosomal abnormalities and mental developmental delays. ⁵⁴

Finally, it is a matter of concern that there have not been many longitudinal studies analyzing the long term effects of ICSI on the children born with its aid. The Belgian group that pioneered ICSI has collected a database that details neonatal outcome and congenital malformations in children conceived through ICSI.⁵⁵ There do not seem to be any ongoing or published studies of this kind investigating the effects of ICSI beyond the neonatal stage.

Many adjuncts to the fertilization and transfer process raise similar safety concerns for the children born as a result.^xvi The enormous variation in the success rates of among ART clinics—a most important but little-known fact—suggest that differences in culture media and gamete isolation and processing may play a role. Factors such as culture conditions and length of time in culture may also affect the development of the child-to-be.⁵⁶ Specifically, some authorities claim that differences in salt or amino acids in the culture media can affect gene expression. Other commentators have raised safety concerns about co-culturing embryos with ovarian cancer cells. Additionally, one researcher notes that the process of extended culture in mice (for example, permitting extended embryo development prior to transfer) can cause imprinting problems and yields a higher rate of identical twins. ⁵⁷

Other adjuncts to fertilization and transfer are probably not risk-free. Cryopreservation might affect gene expression or lead to other molecular effects such as “telomere shortening and replicative senescence, damage to plasma and nuclear membranes, and inappropriate chromatin condensation.”⁵⁸ Similarly, ooplasm transfer has been linked to an unusually high rate of Turner’s syndrome.⁵⁹ Finally, assisted hatching (or any technique that results in manipulation of the zona pellucida) has been associated with a higher incidence of monozygotic twinning and an increased risk of twins carried in the same amniotic sac, which can lead to malformation, disparities in growth, and pregnancy complications.⁶⁰

Multiple gestations, far more common in the context of assisted reproduction than in natural conception,⁶¹ have adverse impacts on the health of the child-to-be.⁶² Such pregnancies greatly increase the risk of prenatal death.⁶³ Multiple pregnancies are more likely to end prematurely, and prematurity is associated with myriad health problems including serious infection, respiratory distress syndrome, and heart defects.⁶⁴ One in ten children born following high order pregnancies dies before one year of age.⁶⁵ Children born following a multiple pregnancy are at greater risk for such disabilities as blindness, respiratory dysfunction, and brain damage.⁶⁶ Moreover, infants born following such a pregnancy tend to have an extremely low birthweight, which has been associated with a number of health problems, including some that manifest themselves only later in life, such as hypertension, cardiac disease, stroke, and osteoporosis in middle age.⁶⁷ Interestingly, the phenomenon of low birthweight is not limited to infants born from multiple pregnancies. Even singletons born with the aid of ART tend to have an abnormally high incidence of low birthweight.⁶⁸

So-called “fetal reduction” would be expected to reduce the problems associated with multiple pregnancy. But fetal reduction is itself associated with a number of adverse effects on the children who remain following the procedure. One study shows that following transabdominal multifetal reduction there is a miscarriage rate of 16.2 percent, and 16.5 percent of the remaining pregnancies end in premature birth.⁶⁹ The alternative method, transvaginal multifetal reduction, carries a higher risk of infection and has been associated with a higher risk of infant mortality than its counterpart.⁷⁰ It has been observed that children born following fetal reduction (by either method) tend to be premature, thus exposing them to the complications described above.⁷¹ One study has suggested that children born following fetal reduction are much more vulnerable to periventricular leukomalacia—characterized by brain dysfunction and developmental difficulties.⁷²

Well-Being of Women in the ART Process

Another concern is for the well-being of the women who participate directly in the process of assisted reproduction, namely, the ova donors and child bearers. As mentioned previously, these are frequently the same person, but because the risks are distinct, they will be treated separately.

Ova Donors. There are a number of ethical questions implicated by the process of ovarian stimulation, monitoring, and retrieval. A principle ethical concern is for the health of the woman subject to this process. Aside from the discomforts and burdens of ovarian stimulation and monitoring (such as frequent injections of hormones, blood work, and ultrasound), there are also risks incidental to hormonal stimulation. One such risk is “ovarian hyperstimulation syndrome,” characterized by dramatic enlargement of the ovaries and fluid imbalances that are potentially life threatening. Complications can include rupture of the ovaries, cysts, and cancer. The reported incidence of severe ovarian hyperstimulation syndrome is between 0.5 and 5.0 percent.⁷³ Additionally, adverse side effects of the hormones administered during superovulation have included memory loss, neurological dysfunction, cardiac disorders, and even sudden death.⁷⁴ There do not appear to be any studies on the incidence of such side effects.⁷⁵

Child Bearers (Gestational Mothers). Another source of ethical concern is the risk to the health of women who become pregnant as a result of ART. As noted above, many such pregnancies are treated as “high risk.” These pregnancies tend to experience a higher incidence of complications than natural pregnancies. Some commentators have suggested that this is due to the age of the patients (who tend to be older than most childbearing women) and the high rate of multiple pregnancies. ⁷⁶

As noted above, multiple pregnancies are far more common in the ART context, owing both to the practice of transferring multiple embryos and the high incidence of spontaneous twinning with any single embryo. Multiple pregnancies pose greater risks to the mother than do singleton pregnancies. A woman carrying multiple fetuses is more likely to suffer from pre-eclampsia, high blood pressure, or anemia.⁷⁷ Because multiple gestation pregnancies are generally more taxing on the mother’s body, there is greater potential to aggravate pre-existing medical conditions.⁷⁸ Moreover, such pregnancies expose the woman to higher risks of uterine rupture, placenta previa, or abruption. One commentator has noted that the added expense growing out of complications from high order pregnancies is one of the primary reasons that assisted reproduction is not covered by insurance.⁷⁹

Meaning of Enhanced Control Over Procreation

A different set of concerns relate to how these new powers may affect the understanding of human procreation, as well as the structure of the family.

Concerns about the meaning of parenthood are directly raised by cryopreservation, ooplasm transfer, and the possible use of fetal oocytes. For example, cryopreservation of sperm and embryos makes posthumous parentage possible. For instance, some American soldiers have been reported to store up sperm on the eve of shipping out to a battle zone. And instances have been reported in which women have requested that their newly deceased husband’s sperm be harvested via assisted sperm retrieval and used for artificial insemination. If techniques for cryopreservation of ova are ever perfected, or if ova can be derived from adult stem cells, new opportunities for posthumous conception involving deceased women will arise.

Ooplasm transfer raises slightly different issues of parenthood. Because the donated ooplasm contains mitochondrial DNA from the donor, the resulting child receives a genetic contribution from three different persons. Moreover, because mitochondrial DNA is maternally inherited, if the resulting child is female, she will pass on to her child the genetic contribution of both her mother and the female ooplasm donor.

A projected technique that combines the ethical concerns of posthumous conception and ooplasm transfer is the harvesting and use of fetal oocytes. Some researchers have posited that oocytes (or their precursors) might be harvested from aborted fetuses and used as donated ova (once they have matured in vitro) or for tissue transplantation to patients who have impaired ovarian function. In the first instance, the aborted fetus could fairly be considered the genetic mother of a child-to-be, and in the second instance it would contribute some genetic information to the resulting child. If recent studies in mice deriving oocytes from embryonic stem cells⁸⁰ can be repeated in humans, a five-day-old embryo (source of the stem cells) could become the genetic mother of new children.

Fetal reduction raises its own set of concerns. In this procedure, parents effectively make the choice that some unborn children (each of which was conceived in the hope that it would become a live-born child to term) will live and some will die. Regardless of one’s views on abortion in general or the precise moral status one assigns to the fetus, such selective and deadly invasion of a life-yielding pregnancy is disquieting.

Use and Destruction of Nascent Human Life

The new powers to initiate life by artificial means also entail the loss of embryonic life, especially where superovulation is used and many ova are fertilized at once. Large numbers of embryos die at all stages of the process of assisted reproduction (in vitro and in vivo).^xvii An unknown number of additional embryos are destroyed when it is determined that they are no longer needed or desired. Some of these embryos are destroyed at the clinics where they were created. Still others are donated to researchers, who use them in experiments that involve or lead to their destruction. Thousands of embryos are cryopreserved for indefinite periods of time. As previously noted, there were an estimated 400,000 embryos in cryostorage in the United States as of April 11, 2002.

To the extent that the early human embryo is entitled to moral respect, actions that result in the end of embryonic life are significant and require careful consideration.

Current Regulation

The following detailed discussion provides an overview of the current state of regulation of the biotechnologies and practices discussed above. The discussion will be broadly divided into sections treating the governmental and nongovernmental regulation of assisted reproduction, both direct and indirect. Each source of regulation will be described in terms of its aims, animating values, jurisdictional scope and requirements, mechanisms of regulation, and efficacy.

Direct Governmental Regulation of Assisted Reproduction

A. Federal Oversight.

1. Consumer Protection and Embryo Laboratory Standards. There is only one federal statute that aims at the regulation of assisted reproduction as such: The Fertility Clinic Success Rate and Certification Act of 1992 (“the Act”).⁸¹ The purposes of the statute and its related regulations are twofold: (i) to provide consumers with reliable and useful information about the efficacy of ART services provide by fertility clinics, and (ii) to provide states with a model certification process for embryo laboratories.

(a) Success Rates. Under the implementing regulations of the ACT, each ART program or clinic in the United States is required to report annually to the CDC data relating to its rates of success.⁸² The Act defines ART as “all treatments or procedures which include the handling of human oocytes or embryos, including in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, and such other specific technologies as the Secretary [of Health and Human Services] may include in this definition ...”⁸³ An “ART program or clinic” is defined as a legal entity practicing under state law, recognizable to the consumer, that provides ART services to couples who have experienced infertility or are undergoing ART for other reasons.⁸⁴ Each ART program is required to collect and report data for each cycle of treatment initiated. For these purposes, an “ART cycle” is initiated when a woman begins taking fertility drugs or starts ovarian monitoring with the intent of creating embryos for transfer. The data that must be collected includes: patient demographics; medical history and infertility diagnosis; clinical information pertaining to the ART cycle; and information on resulting pregnancies and births. Information is presented in terms of pregnancies per cycle, live births per cycle, and live births per transfer (including never-frozen and frozen embryos from both patients and donors). The statistics are also organized according to age (younger than 35, 35 to 39, and older than 39). Moreover, programs are required to report information on cancelled cycles, average embryos transferred per cycle, multiple birth rates per transfer, percentage of patients with particular diagnoses, and types and frequency of ARTs used (for example, the frequency with which ICSI is used).

The data, reported by the Society for Assisted Reproductive Technology (with whom CDC has contracted to implement the ACT) is subject to external validation through an auditing process.^xviii Specifically, SART’s Validation Committee performs its audits in conjunction with the CDC. This validation committee is composed of fourteen members assembled from both SART and non-SART member programs. Inspection teams of two Validation Committee members visit clinics (currently forty) randomly selected by CDC. All live births reported by the clinic are validated. Additionally, twenty other variables are validated from fifty randomly selected cycles. The data collected during the on-site inspections are compiled and jointly reviewed by the Validation Committee and CDC.

An ART program can satisfy these requirements by reporting its data to SART. Alternatively, an ART program is deemed to be in compliance if it is already a voluntary member of SART and participates in SART’s reporting program. If a clinic or program fails to comply with the requirements of the act, it is listed as “nonreporting” in the annual CDC publication that collects and analyzes the data reported. There are no other penalties for failure to report.

Have the reporting requirements of the Act been an effective means of informing and protecting consumers? Critics assert that because there are no stiff penalties for noncompliance, the law is merely hortatory. Supporters of the Act respond that the stigma of being listed as a “nonreporting” clinic creates sufficient market pressure to compel the vast majority of ART programs to report the required data. Indeed, in 2000, 383 of the nation’s 408 ART programs were deemed in compliance with the Act’s reporting requirements. Additional critics of the Act’s efficacy assert that the reporting requirements are incomplete. For example, there is no requirement that clinics provide the average cost per successful pregnancy. Moreover, focusing on success rates may create an incentive to transfer too many embryos per cycle, resulting in multiple pregnancies that can be extremely risky and costly. Emphasis on success rates may induce some clinicians to use ICSI, which adds costs and implicates the extra risks discussed above. Additionally, some point out that success rates are highly manipulable and thus not useful. For example, the Genetics and IVF Institute in Fairfax, Virginia, details on its website the ways in which clinics can manipulate success rates by such tactics as patient selection, reclassification of cycles, and transfer of high numbers of embryos. Finally, some critics go so far as to charge that the Act is little more than a fig leaf drafted and currently implemented by the ART industry as a shield against more meaningful regulation.

(b) Model Certification Program. The second function of the Act is to provide states with a model certification program for embryo laboratories. An “embryo laboratory” is defined as “a facility in which human oocytes are subject to assisted reproductive technology treatment or procedures based on manipulation of oocytes or embryos which are subject to implantation.”⁸⁵ Unlike the reporting system, adoption of the model program is entirely voluntary. The model certification program is intended to provide a resource for states that wish to develop their own programs, or professional organizations seeking to develop guidelines or standards for embryo labs. States can apply to the Secretary of Health and Human Services to adopt the program and qualifying states will be required to administer the program as provided by the regulations. To date, no state has done so.

The overarching purpose of the model program is to help states to assure consistent quality assurance and control, record keeping, performance of procedures, and quality of personnel. The specific standards applied were developed in conjunction with the College of American Pathologists and ASRM, borrowing generously from the guidelines used in the voluntary certification program (discussed further below).

The final version of the program, incorporating comments received by the CDC, was published in the Federal Register on July 21, 1999.⁸⁶ Under the program, embryo laboratories may apply to their respective states for certification. Those laboratories that choose to do so are inspected and certified by states or approved accreditation organizations. Certification is valid for a two-year period. The Secretary, through the CDC, has authority to inspect any laboratory that has been certified by a state to ensure compliance with the standards. The penalty for noncompliance under the model program is revocation of certification. A key limitation in the program is that neither the Secretary nor the states may establish “any regulation, standard or requirement which has the effect of exercising supervision or control over the practice of medicine in assisted reproductive technologies.”⁸⁷

Has this model program achieved the Act’s objective of helping states to assure quality and uniformity in embryo laboratory procedures and personnel? As previously noted, to date, no state has adopted the program. Some critics question the usefulness of the model program as a regulatory mechanism in any event. Even if a state were to adopt the program, there is no requirement that laboratories apply for certification; it is entirely voluntary.

B. State Oversight

There are a variety of state laws that bear directly on the clinical practice of assisted reproduction. The vast majority of state statutes directly concerned with assisted reproduction, however, focus mostly on the question of access to such services. These states have legislative directives as to whether and to what extent assisted reproduction services will be covered as insurance benefits. Other state statutes regarding assisted reproduction aim to prevent the malfeasance of rogue practitioners (for example, California criminalizes unauthorized use of sperm, ova, and embryos). Still others focus on the regulation of gamete and embryo donation (for example, California sets forth screening requirements for donated sperm). There are a host of states whose laws dictate parental rights and obligations in the context of assisted reproduction.⁸⁸ A few jurisdictions (such as New Hampshire and Pennsylvania) have statutes that provide for fairly comprehensive regulation of the practitioners and participants in ART. Many jurisdictions have statutes that bear generally on the treatment and disposition of embryos, but a subset of these jurisdictions explicitly speak to the treatment of embryos in the context of assisted reproduction (including Louisiana, New Mexico, and South Dakota). Some illustrative examples are provided below.

New Hampshire has an “In Vitro Fertilization and Pre-embryo Transfer” statutory scheme that provides that “IVF will be performed in accordance with the rules adopted by the [state] department of health and human services.”⁸⁹ The state additionally specifies who may receive IVF treatment, namely, a woman who is at least twenty-one years of age, who has been medically evaluated for her “acceptability” to undergo the treatment (it is unclear what this means), and who has undergone requisite counseling.⁹⁰ New Hampshire likewise extends the medical and counseling requirement to the woman’s husband.⁹¹

Pennsylvania also regulates ART as such, but focuses its efforts on record keeping and standards for maintenance of clinical facilities.⁹² All IVF practitioners are required to submit reports and be available for inspection. The reports must include the names of the practitioners, their locations, the number of ova fertilized, the number of embryos destroyed or discarded, and the number of women “implanted with a fertilized egg.”

New Mexico, Louisiana, and South Dakota all have embryo experimentation statutes that directly speak to the context of assisted reproduction.⁹³ The New Mexico statute prohibits any “clinical research activit[ies] involving fetuses, live-born infants or pregnant women.”⁹⁴ Clinical research “includes research involving human in vitro fertilization, but ... shall not include human in vitro fertilization performed to treat infertility; provided that this procedure shall include provisions to insure that each living fertilized ovum, zygote or embryo is implanted in a human female recipient ...”⁹⁵ There have been no court opinions interpreting this language, but some commentators suggest that this effectively proscribes the practice of IVF except in cases in which all embryos are transferred to the mother.⁹⁶

South Dakota, like New Mexico, prohibits “non-therapeutic research” on embryos. In contrast to New Mexico, however, it explicitly exempts from this definition “IVF and transfer, or diagnostic tests which may assist in the future care of a child subjected to this test.” Again, there are no cases interpreting this language, but it seems that this statute would not require the transfer to a uterus of all embryos created in the process of IVF.

Louisiana’s regulation of ART provides the highest level of protection to the embryo in any U.S. jurisdiction. It defines the embryo as a “juridical person” with nearly all of the attendant rights and protections of infants. It stipulates that the use of an in vitro embryo is solely for “the support and contribution of the complete development of human in utero implantation.” Embryo farming or culture for any other purpose is proscribed. The embryo is not the property of the clinician or gamete donors. If the in vitro patients identify themselves, they are deemed parents according to the Louisiana Civil Code. If the in vitro patients do not identify themselves, the “physician shall be deemed to be the temporary guardian ... until adoptive implantation can occur.” The physician who creates the embryo through IVF is directly responsible for its safekeeping. The gamete donors owe the embryo “a high duty of care and prudent administration.” They may, however, renounce their parental rights through a formal proceeding, after which the embryo shall be available for adoptive implantation. Donors may convey their parental rights to another married couple, but only if “the other couple is willing and able to receive” the embryo. Under Louisiana law, the judicial standard governing any disputes involving the embryo is “the best interests of the embryo.” This means, of course, there can be no intentional destruction of a viable embryo.

In addition to providing such a high level of protection to embryos in the context of ART, Louisiana has set standards for who and where IVF may be performed. It may only be practiced by a licensed physician in medical facilities that each meet “the standards of [ASRM] and the American College of Obstetricians and Gynecologists ..."

Some states have statutes that preclude “experimentation” on embryos. Given the experimental nature of certain ART procedures (such as preimplantation genetic diagnosis, or even arguably IVF itself), these statutes might be construed broadly to reach such practices. Individuals have challenged such statutes on constitutional grounds, arguing that the operative terms are so vague as to violate the Constitutional guarantee of due process. Practitioners have argued that they were not adequately on notice of which procedures could expose them to criminal liability. Courts in three jurisdictions have invalidated such statutes on these grounds.⁹⁷ One Court among these three struck the statute on the additional ground that it impermissibly infringed the plaintiff’s right to choose a particular means of reproduction, noting: “It takes no great leap of logic to see that within the cluster of constitutionally protected choices that includes access to contraceptives, there must be included within that cluster the right to submit to a medical procedure that may bring about, rather than prevent, pregnancy.”⁹⁸

Indirect Governmental Regulation of Assisted Reproduction

There are a number of state and federal governmental authorities that do not explicitly aim at the regulation of ART, but indirectly and incidentally provide some measure of oversight and direction.

A. Federal Oversight

1. Safety and Efficacy of Products and Public Health. The U.S. Food and Drug Administration (FDA) is the federal agency that regulates the articles used in assisted reproduction, but does not, as a general matter, oversee the practice of assisted reproduction.

FDA regulates drugs, devices, and biologics that are or will be marketed for use in the United States. Its principal purpose is to ensure the safety and efficacy of products according to their approved use.⁹⁹ The FDA is also broadly authorized to take measures to prevent the spread of communicable disease.¹⁰⁰ Additionally, it exercises regulatory authority over clinical trials of unapproved products subject to its regulations. The FDA does not, however, have the authority to regulate “the practice of medicine” (which is the province of the states). Thus, physicians may, in the course of administering medical treatment according to acceptable standards of care, employ approved articles in a manner that is outside the scope of their approved use. This is sometimes called “off-label” use.

The FDA’s jurisdiction is chiefly based on the interstate commerce clause of the United States Constitution. Specifically, FDA’s principal powers derive from the authority conferred by the Food, Drug, and Cosmetic Act (FDCA) and the Public Health Services Act (PHSA) to regulate the introduction of certain products (and their components) into interstate commerce. Given the Supreme Court’s historically expansive interpretation of what constitutes “interstate activity” for purposes of deciding cases involving the commerce clause, this has not proven to be a meaningful limitation on the FDA’s authority. Nevertheless, it is conceivable that one might mount a credible constitutional challenge to FDA regulation of any activity that is wholly intrastate.

FDA regulatory mechanisms are driven by the statutory definitions provided by the FDCA and PHSA. If FDA determines that a given article falls within the broad statutory definitions of “drug,” “device,” or “biologic,” it will exercise jurisdiction, provided the interstate nexus is satisfied. Thus, to describe the breadth and depth of FDA’s authority, particularly as it relates to assisted reproduction, it is necessary to explain in some detail these statutory definitions and related provisions.

“Drug” is defined by the FDCA in an extremely expansive way, encompassing any officially recognized article that is (i) intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man ... and (ii) (excepting foods) intended to affect the structure or any function of the body of man, and (iii) intended for use as a component of any of the foregoing articles.¹⁰¹ It is unlawful to introduce a “new drug”—which encompasses nearly every prescription and many non-prescription drugs—into interstate commerce without an FDA-approved New Drug Application.¹⁰² The NDA process is onerous and expensive, requiring the sponsor to provide large amounts of information to the FDA including details regarding the composition of the drug, “the chemistry of the formulation for delivering the active ingredient, methods of manufacture and packaging, proposed labeling, and, most critically, the results of clinical studies that will support a conclusion that the drug product is safe and effective.”¹⁰³ As Professor Richard Merrill points out, the FDA’s proscription on distribution of unapproved drugs, combined with its demand for clinical trials as a pre-requisite to new drug approval, seems to create a paradox.¹⁰⁴ For how can a “new drug” be tested for safety and efficacy if it cannot move in interstate commerce? FDA resolves this tension by creating a limited exemption for distribution of an “Investigational New Drug” (IND)¹⁰⁵—that is, a special approval for purposes of a clinical trial. Upon receipt of an IND application, FDA imposes a thirty-day waiting period during which it reviews the proposed protocols. FDA can withhold an IND (called a “clinical hold”) and effectively prevent clinical trials for a new drug if it finds that (i) human subjects would be exposed to unreasonable and significant risk of illness or injury or (ii) the IND does not contain sufficient information required ... to assess the risks to subjects of the proposed study.

Pursuant to Section 351 of the PHSA, the FDA has the authority to regulate “biological products,” defined as “any virus, therapeutic serum, toxin, anti-toxin, vaccine, blood, blood component or derivative, allergenic product or analogous product, applicable to the prevention, treatment or cure of diseases or injuries to humans.”¹⁰⁶ This is, on its face, a very broad definition, particularly in light of the somewhat ambiguous phrase “analogous product.” Under Section 351, it is unlawful to introduce any biological product into interstate commerce without an approved biologics license application (BLA).¹⁰⁷ The BLA process is much akin to the NDA process in that applicants are required to demonstrate that the biological product is “safe, pure, and potent,” and manufactured in a facility meeting certain specifications.¹⁰⁸ The data in support of the application must be developed through clinical and nonclinical studies. The same regulations governing preclinical testing and testing of new drugs in the IND context¹⁰⁹ govern these activities in the BLA process as well. Indeed, the definition of “biological product” falls within the statutory definition of “drug” in the FDCA. However, if a biologic is licensed under Section 351, it need not be approved under the parallel FDCA provisions.¹¹⁰

Pursuant to its authority to regulate biological products, FDA’s Center for Biologics Evaluation and Research (CBER) has also undertaken regulation of cellular and gene therapy products. Researchers developing gene therapy products must receive an IND before studying gene therapy products in humans and must meet FDA requirements for safety and efficacy before such products can be marketed. The regulation of such activities is discussed extensively in Section IV below.

Section 361 of the PHSA empowers the FDA to prevent the spread of communicable diseases.¹¹¹ Under this authority, CBER has issued regulations and proposed regulations for Human Cellular and Tissue-Based Products (HCT/Ps), which include a variety of medical products derived from the human body and used for the replacement, reproductive, or therapeutic purposes such as semen, ova, and embryos used for reproductive purposes.^{xix 112} Sperm, ova and embryos were originally exempted from this definition, but were later added out of concern for the transmission of disease. In 1997, FDA issued guidance documents on a proposed scheme for the comprehensive regulation of HCT/Ps. In 1998, the FDA published a proposed rule regulating these products.¹¹³ The scheme would require “minimally processed or manipulated” tissues transplanted from one person to another for their normal structural functions to be screened for infectious diseases and subject to FDA’s good tissue practices. These tissues would not, however, be subject to the onerous requirements of premarket approval. “Minimal manipulation” was defined as “processing that does not alter the relevant biological characteristics and, thus potentially, the function or integrity of the cells or tissues.”¹¹⁴“More than minimally manipulated” tissues and cells that are (i) combined with non-cellular or non-tissue components, (ii) labeled or promoted for purposes other than their normal function, or (iii) have systemic effect (except in cases of autologous use, transplantation into a first degree blood relative or reproductive use) would require FDA’s more stringent premarket review and approval described above.

The only portion of the proposed HCT/P scheme applicable to reproductive tissue that has been enacted as a final rule is the requirement that owners and operators of establishments or persons engaged in the recovery, screening, testing, processing, storage, or distribution of HCT/Ps, must register and list those human cells, tissues and cellular and tissue-based products with CBER.^xx However, there are several important exceptions to these registration requirements. Specifically, registration is not required if: (i) an establishment removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure; (ii) an establishment does not recover, screen, test, process, label, package, or distribute, but only receives or stores HCT/Ps solely for implantation, transplantation, infusion, or transfer within the facility; or (iii) an establishment that only recovers reproductive cells or tissue and immediately transfers them into a sexually intimate partner of the cell or tissue donor.¹¹⁵

Like the statutory terms discussed above, “device” is defined in a similarly expansive manner, covering any “instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar related article, including any component . . . that is” officially recognized, intended for the diagnosis, treatment, cure, mitigation, or prevention of disease in man, or intended to affect the structure and function of the body of man, “and which does not achieve its primary intended purpose through chemical action within or on the body of man ... and which is not dependent upon being metabolized for achievement of its primary intended purpose.”¹¹⁶ Devices are categorized according to the risk of harm associated with their use.¹¹⁷ Those devices (Class I or II) that present a low safety risk are subject to a simple approval process known as “premarket notification.”¹¹⁸ Devices that present the greatest risk (Class III), such as those used to sustain or support life, or are implanted in the human body, are subject to premarket approval akin to the NDA procedure, that demonstrates safety and efficacy for intended use.

FDA has a number of means at its disposal to enforce the foregoing regulations under the PHSA and FDCA. FDA has authority to conduct inspections to determine compliance with these requirements.¹¹⁹ Approved BLAs or NDAs can be suspended or revoked.¹²⁰ Although rarely exercised, FDA has the authority to recall previously approved products.¹²¹ If a manufacturer or sponsor is found to be in violation of any of the foregoing provisions, they may be subject to seizure of the offending articles, injunction, or even criminal prosecution.¹²²

In what ways do the above regulations of drugs, devices, and biologics impact the practice of assisted reproduction? First, to the extent that articles used in ART meet the statutory definition of drug, device, or biologic, they must be approved pursuant to the relevant procedures prior to marketing and use.^xxi This is, however, principally a regulatory mechanism applicable to the manufacturers of these articles—rather than the clinicians who use them following their approval. Once the given article is approved, the FDA loses much of its regulatory authority. Clinicians treating infertile patients are regarded as engaged in the practice of medicine, which is beyond the regulatory reach of the FDA. Consider the following:

The physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert, without informing or obtaining the approval of the Food and Drug Administration. ... [T]he Act does not require a physician to file an investigational new drug plan before prescribing an approved drug for unapproved use or submit ... data concerning the therapeutic results and adverse reactions.¹²³

Further, federal courts have held that a licensed physician can prescribe a lawful drug for a non-FDA approved purpose in treatment of a patient.¹²⁴ If the FDA wants to control (or influence) off-label use of approved products it would likely impose some new labeling requirement warning users of the dangers animating its concern. Again, this would regulate of the manufacturer more than the clinician administering these articles in the practice of medicine. Theoretically, if the FDA were concerned that the risks of widespread off-label use utterly outweighed the benefits of the approved use, it could withdraw its approval. But this is almost never done.

The FDA’s tissue regulations, if and when they go into effect, may have some impact on assisted reproduction. These regulations would require certain owners and operators of facilities that work with reproductive tissues to register and list such tissues with CBER. However, many fertility clinics would be exempt from these requirements pursuant to the broad exceptions described above.

In the main, FDA has abstained from regulating the field of assisted reproduction. This is understandable, given that assisted reproduction falls under the aegis of the practice of medicine. Additionally, because the subject matter is so intensely personal, regulation would be fraught with political difficulties. Given that FDA’s authority is largely driven by the definition of “articles” under its purview, extension of this authority to the context of assisted reproduction would require analytically dubious re-categorization of certain aspects of human procreation. For example, in order to acquire jurisdiction, it might be necessary for the FDA to construe an embryo as a “drug,” “biological product,” or “device.” What would safety and efficacy mean in such a context? Finally, the FDA may have been historically hesitant to assert jurisdiction over assisted reproduction because of the nature of the regulatory mechanisms themselves. The categorization and approval mechanisms through which FDA exercises much of its authority are not graduated or flexible. Thus, when FDA asserts jurisdiction over an article by defining it as a “new drug” subject to the relevant approval requirements, it becomes immediately unlawful to distribute it. FDA’s unwillingness to regulate assisted reproduction may be partly borne of a concern that to do so would effectively shut down the entire ART industry.

There are, however, some notable exceptions to FDA’s reluctance to step into the arena of assisted reproduction. Already mentioned is the regulation of sperm, ova, and embryos as reproduct