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
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.
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 cyclexi
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
syndromexv, 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 reproductive tissue
through HCT/P registration requirements. A more controversial example
is the FDA’s recent pronouncements on cloning for reproduction—if
cloning for reproduction can fairly be characterized as a method
of assisted reproduction. Here, the FDA has invoked its authority
by asserting that the implantation of a cloned embryo into a woman’s
uterus is tantamount to the clinical study of an unapproved new
drug, requiring an IND.125
Because of safety concerns, FDA declared that a clinical hold would
be issued. To date, no IND has been submitted. It bears noting that
the animating principles of FDA’s regulation in this context
are, as usual, safety and efficacy. A former head of CBER, Katherine
Zoon, told a congressional committee that if concerns over safety
are properly addressed, FDA would likely approve an IND for cloning
for reproduction.126
Finally, the FDA has also ventured into the field of assisted reproduction
to halt the practice of ooplasm transfer. In 2001, FDA asserted
that clinicians at St. Barnabas Hospital in New Jersey were required
to submit an IND before performing further procedures involving
ooplasm transfer, on the grounds that it is a form of gene transfer
research, as the procedure results in the transfer of mitochondrial
DNA. This sent a shock wave through the ART community, and most
if not all practitioners halted the procedure altogether rather
than submit to the IND process.
These examples serve to illustrate the contours and limits of FDA’s
authority in the context of assisted reproduction. First, it is
clear that the FDA will act if it perceives a sufficiently grave
harm that can be formulated in terms of FDA’s mandate—safety
and efficacy. However, to assert jurisdiction, FDA must sometimes
engage in unsatisfying (or even offensive) definitional contortions.
By most lights, for example, human embryos are not drugs. Finally,
these examples demonstrate that the line between clinical experimentation
and the practice of medicine is not always easy to draw.
2. Quality Assurance and Control in Clinical Laboratories.
Another Federal authority that indirectly affects assisted reproduction
is